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Contents CPD | SUPPLEMENTATION

The challenge of Obesity in the psychiatric population The Benefits of supplementation in Pregnancy PAF in allergic rhinitis Post infection Cough in Covid-19 patients Distinguishing Vaginal Infections - Dr Trudy Smith Covid-19 In Rhinology and allergy Non surgical management of AK - Dr Sian Hartshorne Rupatadine Efficacy Trials: Fill the gap - Dr Inaki Izquierdo To complete the quiz and earn your 3 points, find this

article on www.medicalacademic.co.za. You will Amino Acids Immunity need to readand and complete the questions for the CPD found on page 4 as well, in order to earn all 3 points

The Role of Demulcents and secretolytics in treating coughs Immunity support all year around as well as of the conceptus.

Behavioural or psychiatric symptoms Painful throat• Infections

day in 1998 following publication of several studies supporting the periconceptional The following supplementation is use of this nutrient in the prevention of recommended during pregnancy. neural tube defects. This dose was deemed IRON to provide more folic acid than required to During pregnancy, iron requirement produce an optimal haemoglobin response in progressively increases until the third pregnant women. month, in parallel with the accumulation The most well-known use of folic acid in foetal tissues. The transfer from the is its role in preventing neural tube defects maternal compartment to the foetus is (NTD) during pregnancy. However folate, regulated by a complex mechanism of with its dynamic effects on red blood cell transport that include: release from maternal production and DNA methylation, affects liver—in which it is stored as ferritin—into numerous bodily functions and is beneficial circulation as Fe2+, uptake by the placenta, for much besides pregnancy. transfer to the foetus (by a specific protein), Folic acid is important for functioning of oxidation to Fe3+, storage (as ferritin) or the nervous system at all ages (Reynolds, transport into the foetal circulation (still 2002). Folic acid is a B vitamin essential for s recommended that women bound to transferrin). the integrity and function of DNA, relative 1000mg of calcium a day if CPD Inadequate intakes during pregnancy deficiency of which may occur in conditions sidering getting pregnant. Vaginal metronidazole 0.75% is such as pregnancy and hyper-proliferative or IONS associated with the increase of iron demand be obtained from natural daily forgreater 10 days, at be yogurt, done canned recommenced makes pregnant once mothers at even risk chronic inflammatory disorders (Gisondi h ascan low-fat gnesium, and future of iron deficiency, that may affect growth ines, rice and cheese. followed by twice-weekly application foret al 2006). Folate and the metabolically scopy and culture, should ideally be based on and development of the foetus and increase related B-vitamins, vitamin B12 and 2009) looked at the mmon methodologies for role four to six months. ucleic acid ups. Based on the survey the risk of preterm delivery, low birth riboflavin, haveof attracted much scientific ents in the periconceptional A study women with clear that very large sts, whiff tests weight and post-partum haemorrhages. andosteoporosis public health interest in recent years nutrientinsufficient deficiencies have consume Moreover, according to some recent studies, (McNulty and Scott 2006). ted with significantly high in Israel reported erals that are to support HOW DOES METRONIDAZOLE WORK? one in the tive estimates of their increased inadequate iron intakes during pregnancy risks, ranging from infertility Metronidazole is an antimicrobial agent. Itsignificantly s. bone mineral are associated with increased cardiovascular Neural uctural defects tube defects density magnesium, zinc and causes disruption of DNA and the inhibition amongst those women risk for the offspring in adulthood. seases. Neural tube defects (NTDs) are congenital were measured in osteoporosis who took supplement In fact,acid iron supplementation in domen thatwith fertility, conception, abnormalities ofathe brain and spinal column of nucleic synthesis. Susceptible enia (n = 28) as pregnancy is often recommended to improve thatthat oetal organogenesis causecontained serious mortality and morbidity the T-score ofBV the femur To complete the quiz earn your 3 points, and find this anaerobes takebirth up theand metronidazole ent with or and magnesium hy lifestyle atstages all stages of life. pregnancy outcomes. On the other re X-ray the critical et al 2016). Research has gy absorptiometry articleand www.medicalacademic.co.za. You will(Moussa need iton to a reduced intermediate, etric indices, dietary during the metabolise ema fissures hand, to anread excessively highthe ironquestions intake may ected byornutrition that folate levels are low in 75% and complete for the CPD indicated found opper, magnesium, zinc onthe pageto 34 as well, instress, tolipid earn all 3 points expose women oxidative nal period. Reactive of women of childbearing age (McDowell et kills bacteria byorder interacting candidiasis orof oxygen which ssessed. The results peroxidation, impaired calcium metabolism talintake homocysteine al 2008). In neonates, infants, children and that the mean dietary plasma and maintain adequate amounts in disorders havewith treatments but noIt cures. ry of nutrients DNA. is hypertension. activeglucose against Gardnerella changes suggest m, zinc and calcium in respective and gestational ors involved in the adolescents, inborn errors of folate transport blood. This leads to excess excretion in urine Owing to a lack of compelling evidence for women with vaginalis, Mycoplasma hoministoand anus or low membrane and crystallisation form kidney stones. the role ofiscalcium as a singleACID contributory nes the impact ofbone FOLIC The preconceptional period and metabolism are associated with a cantly lower thanthe Concern for excess calcium intake is element in relation to these diseases, th and compares portant since itaaffects both Bacteroides variety of overlapping syndromes, which are A prophylactic dose of directed 300µg (0.3mg) per evidence ary allowance. The species. There is tolittle ssure primarily those who are prone estimates of calcium requirement have required asfrom part ofmean cedations. (P = 0.001) and copper early stages of gestation. influenced by age of clinical presentation, throughout pregnancy was to milk alkalisuggested syndrome (the simultaneous made based bone health outcomes, of ofday resistance despite widespread clinical dermatosis or been ignificantly lower than presenceOrganization of hypercalcaemia, metabolic with and the goal of optimising bone mineral through dietary intake and include (Reynolds 2002): in 1968 by the World Health 40% of these participants density. Calcium is unique among nutrients, alkalosis and renal insufficiency). use(WHO). for the past three decades. Oral tablets usium affect the different phases • Developmental delay The supplemental dose was levels lower than the Although calcium can interact with iron, in that the body’s reserve is also functional: y calcium is found nd • Cognitive deterioration increased to 400µg (0.4mg) of folic per require a prescription theandacid gel can within be zinc,while magnesium phosphorus the increasing bone mass is linearly related to heredevelopment it functions as a of pregnancy

The US Public Health Service s that women of childbearing 00µg of folate or folic acid is B vitamin helps reduce a neural tube birth defects a bifida. If there is a family ural tube defects, it may be increase the daily intake. ay be obtained naturally y, dark green vegetables (ie us fruits, nuts, legumes, , and fortified bread and se foods can be supplemented tal vitamin which usually 0µg of folic acid.

osted a webinar for Medical Chronicle,

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ance n

nts

deficiency in body postt.ralThe remaining n with low bone density metabolism, serving minerals onprocesses, bone health, ysiological ith magnesium, traction, blood calcium, opper actionare andrecommended.

• Signs of/failure of demyelination • Seizures.

The Importance of nutrition and health supplements The molecular requirements for neural tube closure are complex (Moussa et al 2016).

Neural development occurs earlyskin cancers: Prof Eggert Stockfleth Treating non-melanoma in embryogenesis (by six weeks of gestation), when the majority of women are

not aware of their pregnancy (Moussa et al Anaemia in Covid-19: A potential risk factor 2016). In the foetus the relation between maternal folate status and the risk of

neuralnegative tube defects is well established: Controlling the aspects of pregnancy: A focus on heartburn clinical trials have shown that periconceptual preventive treatment with

mcg or higher of folic acidcommon significantly Distinguishing400 the most vaginal infection reduces the risks of such defects (Reynolds 2002).

A recent study determined that globally Treating paediatric chronic nasal inflammation Dr Corli Lodder as many as 230 000 children unnecessarily developed folic acid-preventable spinal

bifida (FAP SBA) in 2017, and that several Fight fatigue with optimal nutrition countries in Africa and Asia with a high number of FAP SBA-affected births do

not have mandatory fortification policies Montelukast and rupatadine: Potential agents for Covid-19 (Kancherla et al 2018).

Autism spectrum disorder Condyloma Acuminatum - Dr Jeremiah Olarogun Folic acid has also been hypothesised to play a beneficial role in autism

spectrum disorder (ASD) prevention in Treating obesity in patients with psychiatric disorders - Dr Eugene Allers the womb (Moussa et al 2016). Autism is a neurodevelopmental disorder that

potentially originates during the first The Misogynistic Mystery Reality of PCOS and Infertility Dr Razina Patel month of pregnancy, when folate isand known to be critical (Schmidt et al 2012).

In a study sample of 85 176 children, Overview of Chronic Kidney Disease Dr Heleen Bierman derived from the population-based,

intestine, thereby the mineral, absorption reduction fracture risk. As with anyreducing vitamin and it is Oneinstudy of postmenopausal women obtained OTC. It shows equivalent cure of these databalanced do not diet to To a either great extent, individuals are betterminerals, to focus available on a healthy, with osteoporosis or osteopaenia, mineralsofaremagnesium, depleted and protected excess of calcium meet that dailythese requirements which isfrom when bonesintakes are weaker than normal suggest rates to other recommended treatment py. Self-diagnosis humans consumeasdiets containing by aprior tightly regulated intestinal absorption to use supplements a backup. But the to developing osteoporosis, found that when calcium above recommended levels. the the action of including oral metronidazole and en used, leavingmechanism reality is thatthenot all of us will achieve over 40%through ofoptions the study participants had low Forrecommended example, even daily though highofintakes of 1.25-dihydroxyvitamin intake magnesium, magnesium levels. D, the hormonally clindamycin. ed. calcium can calcium. exert acute effects on iron active form of intravaginal vitamin D.ofWhen the amount sIUM of calcium have let alone Why are so many us lacking in ourth mostrisks abundant absorption, there is anosupplement evidence ofcontaining reduced of absorbed calcium is morediet thanrich what ncreased Not only can magnesium? A Western in the overall and is essential It has a 96% lower systemic absorption ironthese status iron stores withpeople long-term body needs, the excess is excreted by in the olithiasis (kidney keyorminerals assist who processed food and relatively poor k physical and mental calcium supplementation. kidney in most healthy people. patients ncer, hypertension are predisposed to osteoporosis, but micronutrients to be Ifone of the main andseems significantly improved GI tolerability vsa ONS tary intake may be Great heterogeneity exists in the can consume inadequate of calcium, rtery disease, insulin supplement containing magnesium reasons. By makingamounts better food choices, the body’s demands. formulation of dietary recommended the body starts dissolving bones to release y.tce, Most of these oralbetter metronidazole. possible side we can provide also assist those who suffer from intakes nutrition for our bone ncies are relatively muscle cramps. are an excellent ead to a range of co- health. Green vegetables Metronidazole little totono , and other Another aspect consider is the source of magnesium, as are nuts, seeds, shows g loss of energy, fatigue, evidence that adults on a Western diet unprocessed grains, and some legumes. and mineral antibacterial resistance compared to getabolic a regimen. develop a low-grade acidosis which is Supplementation can also play an

nesium supplementation

• Motor and gait abnormalities

prospective Norwegian Mother and Child Cohort Study (MoBa), it was determined that of children whose mothers took folic

urine. In the gut, calcium and magnesium may compete for intestinal absorption. If there is a small amount of calcium but an abundance of magnesium in the contents MEDICAL CHRONICLE | February 2021 19 of the intestine, the magnesium gets more actively absorbed. However, a high intake of calcium can reduce the absorption of both calcium and magnesium. The amount of calcium or magnesium absorbed depends on the dietary ratio of calcium to magnesium. Although clinical evidence is still fragmentary, beneficial effects of the supplementation of these minerals in a manner which supports calcium and magnesium homeostasis is documented. In an article entitled, Decreased magnesium

MEDICAL CHRONICLE 3

CPD| |Expires OBESITY CPD 31/01/2022

The challenge of obesity in the psychiatric population SA has the highest overweight and obesity rate in subSaharan Africa, with up to 70% of women and a third of men battling with serious weight problems. To complete the quiz and earn your 3 points, find this article on www.medicalacademic.co.za. You will need to read and complete the questions for the next CPD on page 9 as well, in order to earn all 3 points

CCORDING TO REPORTS from 2016, up to 70% of women and one third of men classified as overweight or obese. More astounding is the fact that 40% of women in South Africa are classified as obese, which means that their Body Mass Index (BMI) is greater than 301. A patient is defined as overweight if they have a BMI between 25 and 29.9 and are obese if their BMI is over 30.02. THE OBESITYMOOD DISORDER LINK Obesity is the most common chronic physical illness in modern society, and depression is the most prevalent psychological condition. Despite the high prevalence of these conditions, exploration of any association between them has been limited. The nature of the relationship between obesity and depressive illness remains unclear, with data more suggestive of a positive relationship rather than the ‘fat and jolly’ hypothesis. Many mechanisms exist through which depression and obesity may be linked or interact. Symptoms of depression correlate significantly with reported body image

dissatisfaction. According to Dixon et al (2003), the severely obese person certainly suffers stigmatisation, discrimination, and major psychosocial disturbance, which may cause or aggravate a depressive illness. In addition, repeated failed attempts to lose weight are the norm, and this failure may be accompanied by thoughts of guilt, hopelessness, and poor selfesteem. “Obesity is associated with a high prevalence of binge eating disorder, which is frequently accompanied by depression and seen more commonly in those attempting to lose weight,” the authors said. Serious health consequences and physical disability often accompany severe obesity, and these in turn may aggravate depression. Alternative hypotheses link the development of obesity to depression. Obesity may develop because of reduced interest and enjoyment of physical activity or, in susceptible subjects, increased appetite for energy-rich comfort foods. Dixon et al’s findings (2003) support the hypothesis that depression is a significant comorbidity of severe obesity. The authors found that most patients (53%) presented with Beck Depression

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Inventory (BDI) questionnaire scores of 16 or greater, indicating a high prevalence of characteristic attitudes and symptoms of depression. Although affecting severely obese subjects generally, younger subjects, women, and those with a poor body image experience the greatest burden, with these factors having an additive effect. These findings are consistent with the results of previous studies. “We have previously shown very poor measures of quality of life in severely obese subjects, with the impairment greatest in the physical rather than the mental component measures. Symptoms of depression in these obese subjects, indicated by high BDI scores, were strongly associated with poor qualityof-life scores for all eight SF-36 domain scores, especially those related to social functioning, emotional role, and mental health,” the authors stated. The co-occurrence of mood disorders and obesity may be associated with poorer physical and psychological health, as well as more frequent consultations with healthcare professionals, according to the review of cross-sectional study data published in the Journal of Affective Disorders.

9.16 kgs 3 months2

Investigators (Romain et al, 2018) collected data from the 2007-2008 Canadian Community Health Survey, which provides information on health status, healthcare utilisation, and health determinants of inhabitants of the Quebec province. For the present analyses, the response data included were from adults (aged >18 years) with obesity (body mass index [BMI] ≥30 kg/m2). The presence of mood disorder was defined as a past or current diagnosis by a healthcare professional of depression, bipolar disorder, mania or dysthymia. The prevalence of most physical comorbidities was significantly higher in the obesity and mood disorder group compared with the group of obese individuals without mood disorder, although no differences were observed for type 2 diabetes or heart disease. Specifically, odds ratios (ORs) ranged from 1.8 (95% CI, 1.1-2.8) for hypertension to 2.8 (95% CI, 1.3-6.0) for stomach ulcer. The total number of reported chronic diseases was also higher in the obesity and mood disorder group compared with the group of obese individuals without mood disorder (P <.0001).

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References: 1. Duromine® approved package insert, July 2000. 2. Munro JF, Maccuish A. C, Wilson EM, Duncan LJP. Comparison of Continuous and Intermittent Anorectic Therapy in Obesity. Brit Med J 1968;1;352-354. Scheduling status: S5 Proprietary name (and dosage form): Duromine 15 mg and 30 mg Capsules. Composition: Sustained action ion-exchange resinate granules, available as capsules containing phentermine 15 mg and 30 mg Pharmacological classification: A 11.3 Anorexigenics. Indications: Duromine is an anorectic agent used in the management of obesity. Reference number: 15 mg: B657; 30 mg: B658 [Act 101/1965]. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 15269L. IN4036/21.

February 2021 | MEDICAL CHRONICLE 414MEDICAL CHRONICLE

CPD31/01/2022 | OBESITY CPD | Expires Similarly, Mcelroy et al (2004) reviewed evidence regarding a possible relationship between mood disorders and obesity to better inform mental health professionals about their overlap. They performed a MEDLINE search of the English-language literature for the years 1966-2003. They evaluated studies of obesity (and related conditions) in persons with mood disorders and of mood disorders in persons with obesity. They also compared studies of obesity and mood disorders regarding phenomenology, comorbidity, family history, biology, and pharmacologic treatment response. The most rigorous clinical studies suggest that: • Children and adolescents with major depressive disorder may be at increased risk for developing overweight • Patients with bipolar disorder may have elevated rates of overweight, obesity and abdominal obesity. Obese persons seeking weight-loss treatment may have elevated rates of depressive and bipolar disorders. The most rigorous community studies suggest that depression with atypical symptoms in females is significantly more likely to be associated with overweight than depression with typical symptoms. Obesity is associated with major depressive disorder in females. Abdominal obesity may be associated with depressive symptoms but most overweight and obese persons in the community do not have mood disorders. Studies of phenomenology, comorbidity, family history, biology, and pharmacologic treatment response of mood disorders and obesity show that both conditions share many similarities along all of these indices. Although the overlap between mood disorders and obesity may be coincidental, it suggests the two conditions may be related. According to Mansure et al (2014), obesity and mood disorders are highly prevalent and co-morbid. Epidemiological studies have highlighted the public health relevance of this association, insofar as both conditions and its co-occurrence are associated with a staggering illnessassociated burden.

Accumulating evidence indicates that obesity and mood disorders are intrinsically linked and share a series of clinical, neurobiological, genetic and environmental factors. The relationship of these conditions has been described as convergent and bidirectional. Some authors have attempted to describe a specific subtype of mood disorders characterised by a higher incidence of obesity and metabolic problems. However, the nature of this association remains poorly understood. Overall, accumulating evidence indicates that there is a consistent association of multiple abnormalities in neuropsychological constructs, as well as correspondent brain abnormalities, with broad-based metabolic dysfunction, suggesting, therefore, that the existence of a ‘metabolic-mood syndrome’ is possible. Nonetheless, empirical evidence is necessary to support and develop this concept. Future research should focus on dimensional constructs and employ integrative, multidisciplinary and multimodal approaches. THE ANTIDEPRESSANT - OBESITY LINK Major depressive disorder (MDD) and obesity are both common heterogeneous disorders with complex aetiology, with a major impact on public health. Antidepressant prescribing has risen nearly 400% since 1988, according to data from the Centers for Disease Control and Prevention (CDC). In parallel, adult obesity rates have doubled since 1980, from 15% to 30%, while childhood obesity rates have more than tripled. Rising obesity rates have significant health consequences, contributing to increased rates of more than thirty serious diseases. Years after weight gain was recognised as a side effect of antidepressant therapy, researchers have presented evidence of its contribution to the increase in obesity. Despite the concomitant rise of antidepressant use and of the obesity rates in Western societies, the association between the two, as well as the mechanisms underlying antidepressantinduced weight gain, remain underexplored.

Lee et al (2016) highlighted the complex relationship between antidepressant use, MDD and weight gain. Clinical findings have suggested that obesity may increase the risk of developing MDD, and vice versa. Hypothalamic–pituitary–adrenal (HPA) axis activation occurs in the state of stress. Concurrently, the HPA axis is also dysregulated in obesity and metabolic syndrome, making it the most well-understood shared common pathophysiological pathway with MDD. Numerous studies have investigated the effects of different classes of antidepressants on body weight. Previous clinical studies suggest that the tricyclics amitriptyline, nortriptyline and imipramine, and the serotonin norepinephrine reuptake inhibitor mirtazapine are associated with weight gain. Despite the fact that selective serotonin reuptake inhibitor (SSRI) use has been associated with weight loss during acute treatment, a number of studies have shown that SSRIs may be associated with long-term risk of weight gain. However, because of high variability and multiple confounds in clinical studies, the long-term effect of SSRI treatment and SSRI exposure on body weight remains unclear. A recently developed animal paradigm shows that the combination of stress and antidepressants followed by long-term highfat diet results, long after discontinuation of antidepressant treatment, in markedly increased weight, in excess of what is caused by high-fat diet alone. On the basis of existing epidemiological, clinical and preclinical data, the authors have generated the testable hypothesis that escalating use of antidepressants, resulting in high rates of antidepressant exposure, might be a contributory factor to the obesity epidemic. Gafoor et al (2018), evaluated the longterm association between antidepressant prescribing and body weight. The main outcomes were antidepressant prescribing, incidence of ≥5% increase in body weight, and transition to overweight or obesity. Adjusted rate ratios were estimated from a Poisson model adjusting for age, sex, depression recording, comorbidity, co-prescribing of antiepileptics or

antipsychotics, deprivation, smoking, and advice on diet. In the year of study entry, 17 803 men and 35 307 (women with a mean age of 51.5 years were prescribed antidepressants. During 1 836 452 person years of followup, the incidence of new episodes of ≥5 weight gain in participants not prescribed antidepressants was 8.1 per 100 person years and in participants prescribed antidepressants was 11.2 per 100 person years (adjusted rate ratio 1.21, 95% confidence interval 1.19 to 1.22, P<0.001). The risk of weight gain remained increased during at least six years of follow-up. In the second year of treatment, the number of participants treated with antidepressants for one year for one additional episode of ≥5% weight gain was 27 (95% confidence interval 25 to 29). In people who were initially of normal weight, the adjusted rate ratio for transition to overweight or obesity was 1.29 (1.25 to 1.34). In people who were initially overweight, the adjusted rate ratio for transition to obesity was 1.29 (1.25 to 1.33). Weight gain as a side effect of antidepressant treatment was not confined to those who were overweight or obese at the start of their therapy, but included patients who were of normal weight prior to treatment. The authors conclude that the impact of antidepressant drugs contributing to the increase in obesity in the UK has been overlooked, and should be considered a major risk factor. Their assessment of the impact of antidepressant therapy on generating obesity can be applied to the US where, as in the UK, it has been almost entirely ignored as a risk factor. That antidepressants and related drugs used for bipolar disorder and other mental disorders cause weight gain is well known to patients and their mental health providers. The authors concluded that widespread utilisation of antidepressants may be contributing to long-term increased risk of weight gain at population level. The potential for weight gain should be considered when antidepressant treatment is indicated. PHENTERMINE USE IN THIS GROUP OF PATIENTS Pharmacological therapy and the use of appetite suppressants, particularly phentermine, is recommended in many cases in which bariatric surgery is judged to be too extreme an intervention or lifestyle changes alone won’t be sufficient. Pharmacological therapy has been proposed as a necessary adjunct to lifestyle changes to improve weight loss in people with obesity and overweight individuals with metabolic complications. Phentermine, the most often-prescribed weight loss drug in the US, is thought to cause weight loss through a reduction in hunger, which it achieves by stimulating the release of norepinephrine in the hypothalamus. One of the earliest studies on phentermine, the Munro study of 1968, showed significant weight loss (9.16kgs) in 12 weeks. One hundred and eight women aged from 21 to 60 were included in the trial. All were clinically obese and overweight. In another 12-week MEDICAL CHRONICLE | February 2021 5 15 MEDICAL CHRONICLE

CPD 31/01/2022 CPD| |Expires OBESITY

randomised, double-blind, placebocontrolled clinical trial, 77 adults with obesity received either phentermine or placebo and were enrolled in a weight-loss programme. The phentermine group lost 12% of baseline body weight compared with 8% in the placebo group. Cravings for all food groups decreased in both groups. However, there was a greater reduction in cravings for fats and sweets in the phentermine group compared with the placebo group. The study authors concluded that both phentermine combined with a meal replacement programme and meal replacements alone significantly reduced

body weight and food cravings. However, the addition of phentermine enhanced these effects. Treatment with phentermine, in addition to lifestyle interventions, has been shown to result in a statistically significant but modest increase in weight loss (Iughetti et al 2011). The authors of a long-term study into the efficacy of phentermine found that phentermine was somewhat more efficient at weight loss than both diet or amphetamine resinate, with very few side effects (lughetti et al 2011). In a recent study to evaluate the weight loss effectiveness of phentermine as an adjunctive treatment to standard of

care lifestyle modification therapy (SOC) among adolescents with obesity in the setting of a paediatric weight management clinic, phentermine added to SOC resulted in statistically significant weight loss at one-month, three-months, and six-months among adolescents with obesity (Ryder et al 2017).In a study aimed at investigating whether phentermine treatment induces phentermine abuse, psychological dependence (addiction) or phentermine drug craving in overweight, obese and weight loss maintenance patients and to investigate whether amphetamine-like withdrawal occurs after abrupt cessation of long-

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*Studies were conducted on the HCl formulation. Duromine is available as sustained action ion exchange resinate granules in capsules containing phentermine 15 mg or 30 mg. Duromine should be used in conjunction with an exercise, diet and behaviour modification program. Patients require medical review after a defined course of treatment, which ideally should not exceed 3 months. References: 1. Duromine® approved package insert, July 2000. 2. Wing RR, Hill JO, Lang W, et al. Benefits of Modest Weight Loss in Improving Cardiovascular Risk Factors in Overweight and Obese Individuals With Type 2 Diabetes. Diabetes Care 2011;34:1481–1486Australian Diabetes Society. 3. Haslam D, Sattar N, Lean M. ABC of obesity. Obesity-time to wake up. BMJ 2006;333:640-642. 4. Munro JF, Maccuish A. C, Wilson EM, Duncan LJP. Comparison of Continuous and Intermittent Anorectic Therapy in Obesity. Brit Med J 1968;1;352-354. 5. Impact Rx – November 2020. Scheduling status: S5 Proprietary name (and dosage form): Duromine 15 mg and 30 mg Capsules. Composition: Sustained action ion-exchange resinate granules, available as capsules containing phentermine 15 mg and 30 mg Pharmacological classification: A 11.3 Anorexigenics. Indications: Duromine is an anorectic agent used in the management of obesity. Reference number: 15 mg: B657; 30 mg: B658 [Act 101/1965]. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 15269L. IN4028/21.

616MEDICAL CHRONICLE February 2021 | MEDICAL CHRONICLE

term phentermine treatment, it was found that phentermine abuse or psychological dependence (addiction) does not occur in patients treated with phentermine for obesity (Hendricks et al 2014). Phentermine treatment does not induce phentermine drug craving, a hallmark sign of addiction (Hendricks et al 2014). Also, amphetaminelike withdrawal does not occur upon abrupt treatment cessation even at doses much higher than commonly recommended and after treatment durations of up to 21 years (Hendricks et al 2014).Phentermine is available as a monotherapy or in combination with topiramate in the US, where there is longer-term clinical data available. CONCLUSION Recognising the contribution of psychotropic drugs to the rising rate of obesity may lead to interventions to prevent or diminish weight gain. Ideally a patient should be advised on diet and exercise at the initiation of the drug therapy. Acknowledgment by practitioners of the real possibility of weight gain as a side effect of psychotropic drug treatment, and the availability of individual and/or group weight loss support must be part of the treatment plan. Obesity is not a benign side effect. It has well known health consequences, and may significantly affect the quality of life of the individual. Social isolation, employment discrimination, embarrassment at a body no longer recognisable are but a few of the consequences. Consideration of a patient’s weight status prior to treatment is also important. REFERENCES Romain AJ, Marleau J, Baillot A. Impact of obesity and mood disorders on physical comorbidities, psychological well-being, health behaviours and use of health services. J Affect Disord. 2018;225:381-388. Mcelroy, Susan & Kotwal, Renu & Malhotra, Shishuka & Nelson, Erik & Keck, Paul. Are Mood Disorders and Obesity Related? A Review for the Mental Health Professional. The Journal of clinical psychiatry. 2004;65:634-51, quiz 730. 10.4088/JCP.v65n0507. Dixon et al. Depression in Association with Severe Obesity. Arch Intern Med 2003;163:2058-2065. Mansur R et al. Is there a “metabolic-mood syndrome”? A review of the relationship between obesity and mood disorders. Neuroscience & Biobehavioural Reviews. 2015;52:89-104. Lee SH, Paz-Filho G, Mastronardi C, Licinio J, Wong ML. Is increased antidepressant exposure a contributory factor to the obesity pandemic? Transl Psychiatry. 2016;15;6:e759. doi: 10.1038/tp.2016.25. PMID: 26978741; PMCID: PMC4872449. Gafoor Rafael, Booth Helen P, Gulliford Martin C. Antidepressant utilisation and incidence of weight gain during 10 years’ follow-up: population based cohort study BMJ 2018; 361:k1951. Munro et al. Comparison of Continuous and Intermittent Anorectic Therapy in Obesity. BMJ 1968;1:352-354. Moldovan, CP, et al. Effects of a Meal Replacement System Alone or in Combination with Phentermine on Weight Loss and Food Cravings. Obesity 2016;24:2344–2350. Ryder et al. Effect of Phentermine on Weight Reduction in a Paediatric Weight Management Clinic. Int J Obes (Lond). 2017;41:90-93. doi:10.1038/ijo.2016.185. Hendricks https://image.shutterstock.com/imagephoto/beautiful-overweight-woman-runningpark-600w-1546074611.jpg. Addiction potential of phentermine prescribed during long-term treatment of obesity. International Journal of Obesity 2014;38:292298. Iughetti L, China M, Berri R, Predieri B. Pharmacological treatment of obesity in children and adolescents: present and future. J Obes. 2011:928165. doi:10.1155/2011/928165.

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MEDICAL CHRONICLE 7

CPD| |Expires SUPPLEMENTATION CPD 31/01/2022

The benefits of supplementation in pregnancy During pregnancy, the immune system changes so that it can protect both mother and baby from disease.

IFFERENT PARTS OF the immune system are enhanced while others are suppressed. This creates a balance that can prevent infection in the baby without compromising the health of the mother. A healthy, balanced diet is strongly recommended before, during, and after pregnancy. Good nutrition and appropriate weight gain can improve pregnancy outcomes. More and more evidence shows that the types of food we eat have a worsening effect on our gut health and immune system, which play major roles in protecting our overall health. The Western diet is made up of food that’s loaded with saturated fats and refined sugars and contains little fibre and healthy fats (like omega-3 fatty acids). According to a study published in 2016 in BMJ Open, more than half of Americans’ calories come from

Preg

'ultra-processed' foods, which contain tons of sodium, synthetic trans fats, and artificial sweeteners to make them more flavourful and extend their shelf life. Supplementation and fortification are the most common strategies used to target micronutrient deficiencies, due to their relative ease of delivery and cost effectiveness. Maize and wheat flour are the staple foods in South Africa, and in 2003 the South African government introduced mandatory fortification of these foods with vitamin A, iron, zinc, folic acid, thiamine, riboflavin, niacin and vitamin B6. A study by Steyn et al 2008 evaluated the effects of fortification on selected nutrient intakes. Fortification was found to raise mean levels of thiamine, riboflavin, niacin, vitamin B6 and folate above the recommended nutrient intakes. Although

the fortifications positively increase the micronutrient profile of rural South Africans, some of the fortified micronutrients, including zinc and vitamin A, remain below adequate intake. Although, in the general population, a healthy balanced diet should largely obviate the need for vitamin and mineral supplementation, pregnancy, and lactation create extra nutritional demands that, for some individuals, may make supplementation advisable. General guidelines for supplementation in pregnancy are Vitamin A: recommended intake of 550µg, folate: 520µg, iron 22mg, calcium 1000mg. PRECONCEPTION NUTRITION Preconception nutrition research has shown that food and healthy nutrition are tied to

fertility health in both women and men. Additionally, there are substances that can hinder fertility. Oysters contain high levels of zinc – a nutrient that contributes to semen and testosterone production in men, and ovulation and fertility in women. There are several studies that indicate that deficiencies in zinc affect both male and female fertility. Maintaining the recommended dietary allowance of zinc (15mg a day) can help keep the reproductive system functioning well. Maintaining a diet composed of fruits, vegetables, whole grains, lean meats, and dairy products should provide the recommended dietary allowance of vitamins and minerals for proper reproductive functioning. Below is a list of suggestions for healthy nutrition prior to conception:

Omega

SA’s No.1 Prescribed Prenatal Supplement1

BEFORE, DURING AND AFTER PREGNANCY

Reference: 1. Impact Rx. Script data (Vitamins & Minerals / Constructed class). MAT Nov 2020. Proprietary name and dosage form: PregOmega® Plus Tablets and Soft Gel Capsules. Complementary Medicine: Health Supplement. This unregistered medicine has not been evaluated by SAHPRA for its quality, safety or intended use. Name and business address: iNova Pharmaceuticals (Pty) Ltd. Co. Reg. No. 1952/001640/07,15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information is available on request from iNova Pharmaceuticals. For more information, speak to your healthcare professional. IN1338/21

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February 2021 | MEDICAL CHRONICLE 818MEDICAL CHRONICLE

2021/02/04 15:23

CPD | Expires 31/01/2022 CPD | SUPPLEMENTATION

To complete the quiz and earn your 3 points, find this article on www.medicalacademic.co.za. You will need to read and complete the questions for the CPD found on page 4 as well, in order to earn all 3 points

• Folic acid: The US Public Health Service recommends that women of childbearing age obtain 400µg of folate or folic acid each day. This B vitamin helps reduce a baby’s risk of neural tube birth defects such as spina bifida. If there is a family history of neural tube defects, it may be necessary to increase the daily intake. Folic acid may be obtained naturally through leafy, dark green vegetables (ie spinach), citrus fruits, nuts, legumes, whole grains, and fortified bread and cereals. These foods can be supplemented with a prenatal vitamin which usually contains 800µg of folic acid. • Calcium: It is recommended that women get at least 1000mg of calcium a day if they are considering getting pregnant. Calcium may be obtained from natural sources such as low-fat yogurt, canned salmon, sardines, rice and cheese. Cetin et al (2009) looked at the role of micronutrients in the periconceptional period. Micronutrient deficiencies have been associated with significantly high reproductive risks, ranging from infertility to foetal structural defects and long-term diseases. They found that fertility, conception, implantation, foetal organogenesis and placentation are the critical stages potentially affected by nutrition during the periconceptional period. Reactive oxygen species and total homocysteine plasma levels are factors involved in the respective mechanisms. The preconceptional period is particularly important since it affects both fertility and the early stages of gestation. Micronutrients through dietary intake and maternal status affect the different phases of the onset and development of pregnancy

as well as of the conceptus. The following supplementation is recommended during pregnancy. IRON During pregnancy, iron requirement progressively increases until the third month, in parallel with the accumulation in foetal tissues. The transfer from the maternal compartment to the foetus is regulated by a complex mechanism of transport that include: release from maternal liver—in which it is stored as ferritin—into circulation as Fe2+, uptake by the placenta, transfer to the foetus (by a specific protein), oxidation to Fe3+, storage (as ferritin) or transport into the foetal circulation (still bound to transferrin). Inadequate intakes during pregnancy associated with the increase of iron demand makes pregnant mothers at even greater risk of iron deficiency, that may affect growth and development of the foetus and increase the risk of preterm delivery, low birth weight and post-partum haemorrhages. Moreover, according to some recent studies, inadequate iron intakes during pregnancy are associated with increased cardiovascular risk for the offspring in adulthood. In fact, iron supplementation in pregnancy is often recommended to improve pregnancy and birth outcomes. On the other hand, an excessively high iron intake may expose women to oxidative stress, lipid peroxidation, impaired glucose metabolism and gestational hypertension. FOLIC ACID A prophylactic dose of 300µg (0.3mg) per day throughout pregnancy was suggested in 1968 by the World Health Organization (WHO). The supplemental dose was increased to 400µg (0.4mg) of folic acid per

day in 1998 following publication of several studies supporting the periconceptional use of this nutrient in the prevention of neural tube defects. This dose was deemed to provide more folic acid than required to produce an optimal haemoglobin response in pregnant women. The most well-known use of folic acid is its role in preventing neural tube defects (NTD) during pregnancy. However folate, with its dynamic effects on red blood cell production and DNA methylation, affects numerous bodily functions and is beneficial for much besides pregnancy. Folic acid is important for functioning of the nervous system at all ages (Reynolds, 2002). Folic acid is a B vitamin essential for the integrity and function of DNA, relative deficiency of which may occur in conditions such as pregnancy and hyper-proliferative or chronic inflammatory disorders (Gisondi et al 2006). Folate and the metabolically related B-vitamins, vitamin B12 and riboflavin, have attracted much scientific and public health interest in recent years (McNulty and Scott 2006).

Neural tube defects Neural tube defects (NTDs) are congenital abnormalities of the brain and spinal column that cause serious mortality and morbidity (Moussa et al 2016). Research has indicated that folate levels are low in 75% of women of childbearing age (McDowell et al 2008). In neonates, infants, children and adolescents, inborn errors of folate transport and metabolism are associated with a variety of overlapping syndromes, which are influenced by age of clinical presentation, and include (Reynolds 2002): • Developmental delay • Cognitive deterioration

• Motor and gait abnormalities • Behavioural or psychiatric symptoms • Signs of/failure of demyelination • Seizures. The molecular requirements for neural tube closure are complex (Moussa et al 2016). Neural development occurs early in embryogenesis (by six weeks of gestation), when the majority of women are not aware of their pregnancy (Moussa et al 2016). In the foetus the relation between maternal folate status and the risk of neural tube defects is well established: clinical trials have shown that periconceptual preventive treatment with 400 mcg or higher of folic acid significantly reduces the risks of such defects (Reynolds 2002). A recent study determined that globally as many as 230 000 children unnecessarily developed folic acid-preventable spinal bifida (FAP SBA) in 2017, and that several countries in Africa and Asia with a high number of FAP SBA-affected births do not have mandatory fortification policies (Kancherla et al 2018).

Autism spectrum disorder Folic acid has also been hypothesised to play a beneficial role in autism spectrum disorder (ASD) prevention in the womb (Moussa et al 2016). Autism is a neurodevelopmental disorder that potentially originates during the first month of pregnancy, when folate is known to be critical (Schmidt et al 2012). In a study sample of 85 176 children, derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa), it was determined that of children whose mothers took folic MEDICAL CHRONICLE 9 MEDICAL CHRONICLE | February 2021 19

CPD 31/01/2022 CPD| |Expires SUPPLEMENTATION acid, 0.10% (64/61 042) had autistic disorder, compared with 0.21% (50/24 134) in those unexposed to folic acid (Suren et al 2013). Another survey, of families enrolled in the CHARGE (Childhood Autism Risks from Genetics and Environment) study, found that mean folic acid intake was significantly greater for mothers of typically developed children than for mothers of children with ASD in the first month of pregnancy (Schmidt et al 2012).

Preeclampsia There is an association between supplementation with multivitamins containing folic acid in the second trimester

Preg

and reduced risk of preeclampsia, possibly by optimising the homocysteine pathway in order to correct hyperhomocysteinemia (Moussa et al 2016). Homocysteine has been proposed to be an independent risk factor for developing gestational hypertension or preeclampsia (Moussa et al 2016).

Cleft lip and palate Craniofacial deformities such as cleft lip and palate are major human birth defects with a worldwide frequency of 1 in 700 and substantial clinical impact (Murray 2002). Intake of 400µg a day or more of folic acid in the periconceptional period

seems to reduce the risk of isolated cleft lip with or without cleft palate (Wilcox et al 2006). VITAMIN D Diet and intake of vitamin D and calcium in pregnancy can impact both the mother and her baby’s bone mass – and insufficient intake results in an increased risk of osteoporosis later in life. Dr Olufemi Owolabi, an obstetrician and gynaecologist at Mediclinic Ermelo, said diet and intake of Vitamin D and calcium in pregnancy can impact both the mother and her baby’s bone mass – and insufficient intake results in an increased risk of osteoporosis later in life.

Omega

SA’s No.1 Prescribed Prenatal Supplement1

BEFORE, DURING AND AFTER PREGNANCY Reference: 1. Impact Rx. Script data (Vitamins & Minerals / Constructed class). MAT Nov 2020. Proprietary name and dosage form: PregOmega® Plus Tablets and Soft Gel Capsules. Composition: Each fish oil soft gel capsule contains: 822 mg Pharmaceutical Grade Fish Oil (derived from tuna and deep marine fish oil) providing: 260 mg DHA, 91 mg EPA. Each calcium tablet contains: 500 mg calcium, 400 IU vitamin D3 and 125 mg magnesium. Each vitamin & mineral tablet contains: 2 666 IU Vitamin A, 3 mg Vitamin B1, 2 mg Vitamin B2, 10 mg Vitamin B3, 1 mg Vitamin B6, 2 μg Vitamin B12, 50 mg Vitamin C, 100 IU Vitamin D3, 230 mg Calcium, 0,15 mg Copper (AAC), 500 μg Folic Acid, 15 mg Iron (AAC), 0,5 mg Magnesium, 0,05 mg Manganese (AAC), 0,025 mg Molybdenum (AAC), 0,84 mg Potassium, 0,085 mg Zinc. Complementary Medicine: Health Supplement. This unregistered medicine has not been evaluated by SAHPRA for its quality, safety or intended use. Name and business address: iNova Pharmaceuticals (Pty) Ltd. Co. Reg. No. 1952/001640/07,15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information is available on request from iNova Pharmaceuticals. For more information, speak to your healthcare professional. IN1339/21

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A full-term baby accumulates 30g of calcium in bone mass, so the mother needs to ensure she gets an adequate amount to maintain her own bone strength and provide for the baby too,” said Dr Owolabi. “This is very important for a healthy pregnancy and delivery.” Vitamin D deficiency is thought to be common among pregnant women, particularly during the winter months, and has been found to be associated with an increased risk of pre-eclampsia, gestational diabetes mellitus, preterm birth, and other tissue specific conditions. The largest source of vitamin D in adults is synthesis from solar radiation; half an hour of sunlight delivers 50 000IU of vitamin D with white complexioned skin. Dietary intake of vitamin D makes a relatively small contribution to overall vitamin D status as there is little vitamin D that occurs naturally in the food supply. Melanin absorbs ultraviolet B (UVB) from sunlight and diminishes cholecalciferol production by at least 90%. Dietary vitamin D is absorbed from the intestine and circulates in plasma bound to a vitamin D binding protein. Pre-eclampsia and neonatal hypocalcaemia are the most prevalent complications of maternal hypocalcaemia and are clearly associated with substantial morbidity. A statistical association of glucose intolerance and hypovitaminosis D has been demonstrated. Maternal vitamin D is important to foetal bone development. Foetal lung development and neonatal immune conditions such as asthma may relate in part to maternal vitamin D levels. The largest source of vitamin D in adults is synthesis from solar radiation; half an hour of sunlight delivers 50 000IU of vitamin D with white complexioned skin. CALCIUM “Calcium is an essential nutrient,” said Dr Owolabi, explaining that 99% of the body’s calcium is found in the bones and teeth. “Calcium helps with the skeletal development of the foetus, and also plays a role in neuromuscular function and blood coagulation. During pregnancy, calcium supplementation can reduce the risk of high blood pressure and premature labour.” In a small proportion of women, inadequate calcium and Vitamin D intake may lead to a weakening of the bones during pregnancy. For women already diagnosed with low bone density or osteoporosis, optimising bone health during pregnancy through supplements is very important. Dr Owolabi said women who need to pay special attention to calcium intake during pregnancy include those who have any of these conditions: • Autoimmune disorders like rheumatoid arthritis or lupus • Surgical procedure, especially a gastrectomy (surgical removal of a part or whole of the stomach) • Endocrine problems like diabetes or hyperthyroidism • Malignancy • Stroke • AIDS.

CPD | SUPPLEMENTATION CPD | Expires 31/01/2022 outcome is assessed, the application of age-specific sensitive neurodevelopmental tools, and the functional domain evaluated. Maternal and neonatal concentrations of DHA and arachidonic acid are associated with improved outcomes in early infancy, and concentrations of DHA are associated with favourable neurodevelopmental outcome beyond early infancy.

“Bone density starts decreasing after 35 years of age,” adds Dr Owolabi, which makes adequate calcium and Vitamin D intake especially important for all women above this age. Thomas et al (2006) examined calcium supplementation during pregnancy and lactation. Studies indicate that calcium consumption should be encouraged, especially during pregnancy and lactation, to replace maternal skeletal calcium stores that are depleted during these periods. Because the foetus in utero and the neonate through breast-feeding are dependent on maternal sources for the total calcium load, adequate maternal calcium intake also can affect foetal bone health positively. Proper calcium consumption can be attained through the diet by the consumption of dairy products or leafy greens (such as kale), the consumption of fortified foods, or by supplementation with widely available calcium-containing supplement products. Because many women experience heartburn during pregnancy, calcium-based antacids are ideal for providing heartburn relief, and they offer a calcium supplement to ensure maternal and foetal bone health, without the danger of adverse effects on the neonate. OMEGA-3 FATTY ACIDS Omega-3 (n-3) fatty acids are essential to maintain satisfactory human health and need to be consumed in the diet. Western diets are often deficient in n-3 fatty acids because of an insufficient intake of cold water oily fish. The main n-3 fatty acids in fatty fish are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). To date, no formally accepted dietary reference intakes for EPA and DHA exist, while international intake recommendations differ widely. According to Opperman, 2013,

supplementation is an easy and convenient way of increasing dietary n-3 fatty acid intake, but very little information is available to health professionals when advising consumers on choosing a supplement to suit their lifestyle. Reliable nutrition information on product labels is vital since misleading information may lead to erroneous dosages with concomitant adverse effects. Since no formal regulatory structure for dietary supplements currently exists in South Africa, consumers depend on self-regulation within the industry for assurance of product quality, consistency, potency and purity of n-3 fatty acid supplements. Therefore, the aim of this article is to equip health professionals with proper knowledge with special reference to the bioavailability of fish oil supplements, reliability of labelling information, dietary intake recommendations, potential adverse effects and some general advice when purchasing n-3 fatty acid supplements. Hadders-Algra et al (2011) analysed prenatal and early postnatal supplementation with long-chain polyunsaturated fatty acids and the relevant neurodevelopmental considerations. It takes over 20 years before the human brain obtains its complex adult configuration. The most dramatic neurodevelopmental changes occur prenatally and early postnatally, including a major transformation in cortical organisation 3-4 months after term. The long-lasting changes have practical implications for studies evaluating the effect of prenatal and early postnatal supplementation with longchain polyunsaturated fatty acids (LCPUFAs). Whether studies of the effect of supplementation will reveal an effect not only depends on the dosage and duration of supplementation but also on the timing of supplementation, the age at which the

FIRST TRIMESTER SUPPLEMENTATION The following prenatal vitamins contain key nutrients to help support first trimester developmental milestones: • Folic acid – The US Food and Drug Administration recommends that pregnant women consume 800µg of folate daily during pregnancy. The development and closure of a baby’s neural tube (which eventually becomes the spine) occurs between day 14 and day 28 of pregnancy. Folic acid levels impact neural tube closure and because this development occurs so early in pregnancy, moms-to-be must be sure they are consuming adequate amounts of folic acid. • Iron – The U.S. Food and Drug Administration recommends that pregnant women get 18mg of iron daily. Sufficient iron helps a growing baby receive the amount of oxygen needed to develop a strong heart and lungs, and muscles. Iron also helps keep the mother’s muscles, heart, lungs, and other organs functioning healthfully while boosting her energy. • DHA – The National Institutes of Health recommend 300mg of DHA during the first trimester of pregnancy. DHA is essential for growth and functional development of an infant’s brain. During pregnancy, DHA also helps with the baby’s length of gestation and birth weight. • Vitamin B6 – The US Food and Drug Administration recommends that pregnant women consume 2.5mg of vitamin B6 daily during pregnancy. It is estimated that nearly 85% of pregnant women suffer from common morning sickness, which is most prevalent during the first trimester. The American Congress of Obstetricians and Gynaecologists recommends vitamin B6 to help ease nausea, one of the symptoms associated with common morning sickness. SECOND TRIMESTER SUPPLEMENTATION During the second trimester, it’s especially important for the patient to take a prenatal multivitamin to ensure they’re meeting all of their vitamin and mineral needs during pregnancy. It’s particularly beneficial for these patients to eat foods containing omega-3 fats, which are vital for the baby’s brain development. Many of the best sources of omega-3 fatty acids are in seafood. THIRD TRIMESTER SUPPLEMENTATION These prenatal vitamins contain key nutrients to help support third trimester developmental milestones:

• Iron – The US Food and Drug Administration (FDA) recommends that pregnant women get 18mg of iron daily. During the third trimester, the mother’s blood volume increases to meet the needs of her baby and the placenta. Sufficient iron consumption during the third trimester helps a growing baby receive the amount of oxygen needed to develop a strong heart and lungs, and muscles. Iron deficiency during pregnancy increases the risk of premature birth and low birthweight. • DHA – The National Institutes of Health recommend that women consume 300mg of DHA during the first trimester of pregnancy and continue throughout pregnancy. A baby’s brain develops dramatically during the third trimester, and DHA is essential for its growth and functional development.4 During pregnancy, DHA also helps with a baby’s length of gestation and birth weight. During the third trimester, when a baby’s body is dramatically developing, DHA aids in a healthy birth weight and the length of gestation. • Calcium – The FDA recommends that pregnant and lactating women get 1300mg of calcium daily. This is especially important in the third trimester as a baby’s bones develop. If a mother does not consume enough calcium, her baby will draw the mineral from her bones. Calcium works with vitamin D to develop and maintain bone strength and healthy teeth for mothers and babies. In babies, it also helps the heart, nerves, muscles and other body systems develop properly. And for mothers in their third trimester, adequate calcium intake may reduce systolic and diastolic blood pressure and the risk of preeclampsia. • Vitamin D – FDA recommends that pregnant and lactating women get 400IU of vitamin D daily. One of the primary benefits of vitamin D is in helping the body maintain and build bone mineralisation. Vitamin D helps the body absorb calcium, which is necessary in building a strong skeletal system. However, vitamin D does not only help build and maintain healthy bones. Ample vitamin D supplies also may help reduce a mother’s risk of developing preeclampsia and gestational diabetes, which occur more often in the third trimester. CONCLUSION The nutritional status of women when becoming pregnant and during pregnancy can have significant influence on foetal, infant and maternal health outcomes. Micronutrient deficiencies such as calcium, iron, vitamin A and iodine can lead to poor maternal health outcomes and pregnancy complications which put the mother and baby at risk. Poor maternal weight gain in pregnancy due to an inadequate diet increases the risk of premature delivery, low birthweight and birth defects.

References available on request. MEDICAL CHRONICLE | February 2021 11 21 MEDICAL CHRONICLE

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CPD | Expires 28/02/2022

PAF in allergic rhinitis Clinical and therapeutic implications

This is a summary of a CPD-accredited article available on www.medicalacademic.co.za

A possible cause for research on the effects of platelet-activating factor (PAF) in allergic rhinitis and its potential use as a treatment goal being less abundant than research on asthma, may be related to failed results obtained with new PAF-blocking drugs in asthma. Nevertheless, as evidenced by recent studies carried out in allergic rhinitis, antihistamines with a dual blocking effect–anti-H1 and anti-PAF–have a stronger therapeutic effect in allergic rhinitis.

AF IS A lipid mediator involved in allergic diseases. It is released from multiple cells in the immune system, such as eosinophils, neutrophils, mast cells, basophils, epithelial and endothelial cells, both during the immediate phase and the late phase of the allergic response. Normal PAF levels in plasma (54±40 pg/mL) are elevated in some conditions, such as liver cirrhosis, disseminated intravascular coagulation or anaphylaxis. PAF IN ALLERGIC RHINITIS In allergic rhinitis, the PAF is considered to be the strongest induction factor for vascular permeability, and it plays a key role in rhinorrhoea and nasal congestion. Patients present high levels of PAF and its precursor—lyso-PAF—in nasal secretions and serum, and nasal provocations with allergens induce a rapid increase of lyso-PAF and PAF-AH in nasal secretions. Furthermore, similarly to asthma, nasal provocation with PAF reproduces rhinitis symptoms, reduces the air volume of the nasal airway, increases eosinophil and neutrophil infiltration, and nasal hyperreactivity. Other than that, the PAF operates as a priming or enhancing factor for the inflammatory response to specific (allergens) and non-specific stimuli (histamine or bradykinin). From a clinical perspective, the symptom most strongly related to PAF is nasal congestion. It is also the worst-tolerated symptom by patients, with a limited effect from antihistamines, so that a treatment with nasal corticosteroids is required. This is why the development of new drugs targeted at blocking the effect of PAF would represent an excellent alternative to treat patients with allergic rhinitis.

Figure 1: Importance of platelet-activating factor (PAF) in the early and late phases of allergic response (from Munoz-Cano et al, 2019).

Late phase mast cell granulation

Early phase mast cell granulation

Proteases Histamine Allergens Chemotactic factors (LTs, PAF, IL-5) Mast Cells

Rupatadine is a second-generation antihistamine, effective and safe in the treatment of allergic rhinitis and urticaria. It blocks mast cell degranulation, eosinophil and neutrophil chemotaxis, and the production of IL-5, IL-8, GM-CSF, and TNF-ɑ cytokines. In nasal provocation studies with PAF, rupatadine has shown a higher therapeutic effect in the control of rhinitis symptoms than other antihistamines with no anti-PAF effect. In vitro studies have provided evidence of an inhibitory capacity vis-à-vis PAF-induced mast cell degranulation comparable to that of CV6209, a pure PAF-receptor antagonist, as well as the inhibitory effect of PAFinduced release of histamine and cytokines.

CysLTs Prostaglandins PAF Bradykinin Interleukins TNF-a GM-CSF In this way, drugs with an anti-PAF effect may contribute to a better management of nasal symptoms, such as nasal congestion or rhinorrhoea, when compared to other drugs with no anti-inflammatory properties, like antihistamines. PAF plays an important role in allergic rhinitis, and in contrast to the observation in asthma, blocking this mediator seems to improve rhinitis symptoms, and therefore may be considered a therapeutic target. However, PAF is only one of the several inflammatory mediators involved in allergic rhinitis. In our opinion, we propose that anti-PAF drugs may contribute to a better control of nasal symptoms, such as nasal congestion or rhinorrhoea, compared to the

Eosinophils LTs, GM-CSF TNF-a, IL-1, IL-3, PAF ECP, MBP Basophils Histamine, LTs TNF-a, IL-4, IL-5, IL-6 Monocytes LTs, TNF-a PAF, IL-1 Lymphocytes IL-4, IL-13, IL-5 IL-3, GM-CSF

use of antihistamines with no other antiinflammatory properties. PAF IN ASTHMA PAF plays a significant role in asthma. Bronchial provocation with PAF induces bronchoconstriction, an increased airway hyperreactivity, favours the production of mucus, increases pulmonary vascular permeability, and stimulates the production of cysteinyl leukotrienes. Moreover, as is the case with anaphylaxis, there is an inverse correlation between PAF-AH and the seriousness of asthma. A mutation of the PAF-AH gene has been described that would lead to the production of an inactive PAF-AH enzyme. A partial

HAVE YOU HEARD OF ANTI-HISTA-PAF ? #

BLOCKS BOTH HISTAMINE AND PAF* FOR MORE EFFECTIVE RELIEF OF ALLERGIC RHINITIS AND URTICARIA SYMPTOMS.2-8 antihistamine/anti-platelet activating factor. *platelet activating factor References: 1 Ridolo E, et al. Rupatadine for the treatment of allergic rhinitis and urticaria: a look at the clinical data. Clin Invest 2014;4(5):453-461. 2. Picado C. Rupatadine: pharmacological profile and its use in the treatment of allergic disorders. Exp Opin Pharmacother. 2006;7(14):1989-2001. 3. Fantin S, et al. A 12-week placebo-controlled study of rupatadine 10 mg once daily compared with cetirizine 10 mg once daily, in the treatment of persistent allergic rhinitis. Allergy. 2008;63:924-931. 4. Maiti R, et al. Rupatadine and levocetirizine for seasonal allergic rhinitis. Arch Otolaryngol Head Neck Surg. 2010; 136(8):796-800. 5. Saint-Martin F. A randomized, double-blind, parallel-group study, comparing the efficacy and safety of rupatadine (20 and 10 mg), a new PAF and H1 receptor-specific histamine antagonist, to loratadine 10 mg in the treatment of seasonal allergic rhinitis. J Invest Allergol Clin Immunol. 2004;14(1):34-40. 6. Dakhale GN, et al. Clinical effectiveness and safety of cetirizine versus rupatadine in chronic spontaneous urticaria: a randomized, double-blind, 6-week trial. Int J Dermatol. 2014;53:643-649. 7. Maiti R, et al. Rupatadine and levocetirizine in chronic idiopathic urticaria: a comparative study of efficacy and safety. J Drugs Dermatol. 2011;10(12):1444-1450. 8. Kolasani BP, et al. A comparative study of efficacy and safety of rupatadine versus desloratadine in patients with chronic idiopathic urticaria. Asian J Biomed Pharm Sci. 2013;3(21):42-47. Scheduling status: S2 Proprietary name (and dosage form): RUPANASE 10 Tablets. Composition: Each tablet contains 12.80 mg rupatadine fumarate equivalent to Rupatadine 10 mg base. Contains sugar: lactose monohydrate 61.1 mg per tablet. Pharmacological classification: A.5.7.1 Antihistaminics. Indications: RUPANASE 10 is indicated for the symptomatic treatment of Allergic Rhinitis and Urticaria in adults and adolescents (over 12 years of age). Registration number: 46/5.7.1/0119. Name and business address of applicant: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 16397L. IN4080/21.

PAF*

AWAY THEIR ALLERGIES. 1,2

12 March 2021 | MEDICAL CHRONICLE 12 MEDICAL CHRONICLE

ONLINE CPD CPD | Expires 28/02/2022 deficiency of PAF-AH is a risk factor for the development of asthma and asthma exacerbations, and total deficiency is a risk factor for serious asthma. Nevertheless, in spite of the significant pathophysiological implications of PAF in asthma, blocking it by means of new PAF-inhibitory drugs, using recombinant PAF-AH, or dual-antagonist antihistamines and anti-PAFs, such as azelastine, oxatomide, epinastine and ketotifen, has not achieved a significant effect on asthma symptoms, although they can be useful in mild to moderate asthma, as a supplementary treatment to other drugs. This exposes the intricate cell-signalling network and pathways involved in the pathogenesis of asthma, as well as the location of PAF as a mediator to lower-level signalling pathways. This is why corticosteroids with the ability to block high-level inflammatory signalling pathways and to act on many mediators in multiple cell types and tissues, continue to be the current treatment of choice for asthma. Despite the important role of PAF in asthma, the blockage of this mediator alone does not seem to have a significant effect on asthma symptoms. Considering the complex networks and signalling pathways involved in asthma pathogenesis, PAF seems to be just a downstream mediator. It may be, for this reason, that corticosteroids are still the first-line treatment, because of its capacity of blocking upstream signals, and therefore, creates the effect of multiple mediators on multiple cells types and tissues. PAF IN CHRONIC SPONTANEOUS URTICARIA AND FOOD ALLERGY The effects of PAF in chronic urticaria are associated to the increase of vascular permeability, mainly in skin capillaries, enhancing the effect of other mediators in the development of wheals. An interesting study by Ulambayar et al, published in 2019, shows that patients with chronic spontaneous urticaria present increased PAF levels and decreased PAF-AH levels, and that cases refractory to treatment with fourfold doses of antihistamines are the ones with the most extreme levels. There is also an inverse relationship between PAF-AH levels and the duration of urticaria, and a positive correlation between PAF-AH levels and triglycerides, total cholesterol and body mass index. PAF-AH circulates in active form as a complex with low-density lipoproteins (LDL), hence when LDL levels decrease in plasma, PAF-AH levels are also reduced and the half-life of PAF is elevated, which can lead to an increased risk of serious anaphylaxis, food allergy, and other allergic reactions. In children with urticaria with/without angioedema due to an allergy to peanuts, a strong correlation has been proven between PAF-AH and apoprotein B, as a good marker for LDL concentration. The authors suggested that therapeutic strategies like rupatadine, to inhibit PAF or to stimulate PAF-AH, might be beneficial for antihistamine refractory response in CSU patients.

threatening reaction, often mediated by allergic mechanisms in response to food, drug or insect allergy. Mast cells and basophils are the main cells involved in the development of anaphylactic reactions, and tryptase is the most widely used protease as a mast-cell activation and clonal expansion marker. However, PAF plays a more relevant role in the pathophysiology of anaphylaxis, probably because of its ability to amplify the allergic response from local to systemic. Research on animal models has shown that PAF blocking significantly reduces the magnitude and duration of anaphylaxis— something which is not achieved by

blocking histamine or leukotrienes. Moreover, combined therapies that block multiple mediators get a stronger beneficial effect. PAF and PAF-AH levels are correlated to the seriousness of anaphylaxis more accurately than tryptase or histamine. This is due to an increased vascular permeability driven by PAF, which means that cases with higher PAF levels and/or lower PAF-AH levels are associated to more serious anaphylaxis or fatal anaphylaxis related to low blood pressure, rather than cases with not so extreme levels, which usually present non-fatal anaphylaxis related to urticaria and/or angioedema.

CONCLUSION Antihistamines with a dual blocking effect– anti-H1 and anti-PAF–have a stronger therapeutic effect in allergic rhinitis. Therefore, it is worth noting that despite the fact that the ‘one airway, one disease' concept is still valid, some drugs can have a different impact on the higher and lower respiratory tract, and so they are useful for some diseases but not for others. Source: Muñoz-Cano RM, Casas-Saucedo R, Valero Santiago A, et al. Platelet-Activating Factor (PAF) in Allergic Rhinitis: Clinical and Therapeutic Implications. J Clin Med. 2019: 29;8:1338. doi: 10.3390/jcm8091338. PMID: 31470575; PMCID: PMC6780525.

PAF*

AWAY THEIR ALLERGIES. 1,2

HAVE YOU HEARD OF ANTI-HISTA-PAF ? #

RUPANASE BLOCKS BOTH HISTAMINE AND PAF* FOR MORE EFFECTIVE RELIEF OF ALLERGIC RHINITIS AND URTICARIA SYMPTOMS. 2-8

Starts to work from 15 minutes9 Relieves nasal congestion within 2 hours9 Relieves chronic idiopathic urticaria symptoms within 12 hours10 24-hour relief11 Non-drowsy11

*platelet activating factor antihistamine/anti-platelet activating factor References: 1 Ridolo E, et al. Rupatadine for the treatment of allergic rhinitis and urticaria: a look at the clinical data. Clin Invest 2014;4(5):453-461. 2. Picado C. Rupatadine: pharmacological profile and its use in the treatment of allergic disorders. Exp Opin Pharmacother. 2006;7(14):19892001. 3. Fantin S, et al. A 12-week placebo-controlled study of rupatadine 10 mg once daily compared with cetirizine 10 mg once daily, in the treatment of persistent allergic rhinitis. Allergy. 2008;63:924-931. 4. Maiti R, et al. Rupatadine and levocetirizine for seasonal allergic rhinitis. Arch Otolaryngol Head Neck Surg. 2010; 136(8):796-800. 5. Saint-Martin F. A randomized, double-blind, parallel-group study, comparing the efficacy and safety of rupatadine (20 and 10 mg), a new PAF and H1 receptor-specific histamine antagonist, to loratadine 10 mg in the treatment of seasonal allergic rhinitis. J Invest Allergol Clin Immunol. 2004;14(1):34-40. 6. Dakhale GN, et al. Clinical effectiveness and safety of cetirizine versus rupatadine in chronic spontaneous urticaria: a randomized, double-blind, 6-week trial. Int J Dermatol. 2014;53:643-649. 7. Maiti R, et al. Rupatadine and levocetirizine in chronic idiopathic urticaria: a comparative study of efficacy and safety. J Drugs Dermatol. 2011;10(12):1444-1450. 8. Kolasani BP, et al. A comparative study of efficacy and safety of rupatadine versus desloratadine in patients with chronic idiopathic urticaria. Asian J Biomed Pharm Sci. 2013;3(21):42-47. 9. Steubner P, et al. Effects of rupatadine vs placebo on allergen-induced symptoms in patients exposed to aeroallergens in the Vienna Challenge Chamber. Ann Allergy Asthma Immunol. 2006;96:37-44. 10. Gimemez-Arnau A, et al. Fast onset of action of rupatadine in the reduction of pruritus in patients suffering from chronic urticaria: a pooled analysis. Allergy. 2007; 62(83): 306. 11. RUPANASE package insert, 02 October 2014. #

Available in pack sizes of 10’s, 20’s & 30’s

Scheduling status: S2 Proprietary name (and dosage form): RUPANASE 10 Tablets. Composition: Each tablet contains 12.80 mg rupatadine fumarate equivalent to Rupatadine 10 mg base. Contains sugar: lactose monohydrate 61.1 mg per tablet. Pharmacological classification: A.5.7.1 Antihistaminics. Indications: RUPANASE 10 is indicated for the symptomatic treatment of Allergic Rhinitis and Urticaria in adults and adolescents (over 12 years of age). Registration number: 46/5.7.1/0119. Name and business address of applicant: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. IN3496/19

PAF IN ANAPHYLAXIS Anaphylaxis is a severe, immediate, lifeMEDICAL CHRONICLE | March 2021 13 13 MEDICAL CHRONICLE

CLINICAL | RESPIRATORY INOVA FOCUS

Post infection cough in Covid-19 patients

A cough is a common symptom in many people that develop Covid-19. Although we’re still learning more about Covid-19, some studies have found that a cough due to this respiratory illness tends to persist for an average of 19 days.

OST-ACUTE COVID-19 symptoms vary widely. Even so-called mild Covid-19 may be associated with longterm symptoms, most commonly cough, low grade fever, and fatigue, all of which may relapse and remit. Other reported symptoms include shortness of breath, chest pain, headaches, neurocognitive difficulties, muscle pains and weakness, gastrointestinal upset, rashes, metabolic disruption (such as poor control of diabetes), thromboembolic conditions, and depression and other mental health conditions. Many such patients recover spontaneously (if slowly) with holistic support, rest, symptomatic treatment, and gradual increase in activity. The World Health Organization (WHO) notes that people who’ve recovered from Covid-19 may experience a post-viral cough beyond the period in which they can spread the virus to others. Sore throat, cough and muscle pain are more common in people who test positive for the new UK variant of coronavirus, a study by the Office for National Statistics (ONS) suggests. The data, published 27 January, also show that people with the new variant are less likely to experience a loss of sense of smell or taste.

and neuropsychiatric sequelae have been described for other coronaviruses (SARS and MERS), and these have pathophysiological parallels with post-acute Covid-19. In the local context, according to Dr Marlin McKay of Goldman Medical Centre, Johannesburg, post-Covid-19 coughs are fairly common, seen in up to 30% of recovered patients in his practice. It is more common in patients who had severe disease but also in patients who had a mild course. Duration of cough is anywhere from a few weeks to a few months.

PREVALENCE In 2020 Latif et al conducted a study of 100 people. The majority of the patients were males and the cardinal symptoms of the disease were fever, cough, and shortness of breath as described earlier. Around 15% of the patients who had initially positive covid-19 PCR tests experienced cough after 14 days of isolation and treatment. The cough was either persistent or they developed a new cough. Some of the patients had a cough after being tested negative for Covid-19. One of the patients developed severe shortness of breath and cough even after testing negative for Covid-19 PCR twice. We have noticed that in considerable numbers of the patients who were treated and tested negative for PCR, experienced postinfectious cough that was either persistent or new-onset cough that lingers on for seven to 12 days. According to BMJ, approximately 10% of people experience prolonged illness after Covid-19. It is not known why some people’s recovery is prolonged. Persistent viraemia due to weak or absent antibody response, relapse or reinfection, inflammatory and other immune reactions, deconditioning, and mental factors such as post-traumatic stress may all contribute. Long term respiratory, musculoskeletal,

Initially, Covid-19 patients describe their symptoms as dry cough with shortness of breath but now research has shown that some patients get a wet and phlegmy cough. Dr McKay sees both the dry cough (more common) as well as phlegmy or productive cough.

24 March 2021 | MEDICAL CHRONICLE 14 MEDICAL CHRONICLE

TYPES OF COUGH Coughs come in a variety of forms. A productive cough is a cough that brings up mucus or phlegm, while a non-productive cough is dry. Additionally, coughs can be further defined by their duration: • Acute cough. An acute cough is a one that lasts less than three weeks. • Subacute cough. A cough is considered subacute when it lasts between three and eight weeks. • Chronic cough. A chronic cough is one that lasts more than eight weeks.

COMPLICATIONS A cough is usually a reflex action to clear dust, phlegm and other irritants from the lungs and windpipe. Recovering Covid-19 patients may continue to experience a dry cough for some time. Over time, this can develop into a cycle, where excessive coughing causes irritation and inflammation, which worsens the cough. A dry cough may have no obvious cause. A problematic cough can also cause mouth breathing, which means that lots of dry, fast-flowing air enters the lungs, affecting the delicate airway membranes and causing further coughing. A persistent cough can disrupt dayto-day life and also cause a variety of potential complications, such as exhaustion or fatigue, difficulty sleeping, headache, a hoarse voice, muscle aches and pains from coughing, dizziness, vomiting, loss of bladder control, bleeding in the eye and broken ribs.

TREATMENT According to Dr McKay, treatment is mainly supportive – similar to management of any patient with a post-viral cough. “We also need to exclude any conditions, which may be contributing to the cough, such as asthma, acid reflux and post nasal drip. We use over-the-counter (OTC) cough suppressants and sometimes inhaled or oral corticosteroids,” he said. Symptomatic treatment depends on the type of cough. Symptomatic treatment for a chesty, productive cough includes the use of mucolytics and bronchodilators if needed. Salbutamol, one of the frequently used SABAs for acute relief of bronchospasm in asthma, can provide relief for patients suffering from a tight chest and difficulty breathing. Salbutamol is a highly selective B2adrenergic bronchodilator that stimulates the B2 adrenergic receptors in the lungs to relax smooth muscles. It is used to rapidly treat asthma, bronchospasm and reversible airways obstruction by widening the airways of the lungs. Because a wet cough should not be suppressed, as the phlegm or mucous may cause breathing problems or infection, mucolytics such as bromhexine are useful, since they help to decrease mucous viscosity, making it easier for the patient to cough up mucus. Bromhexine directly loosens and thins bronchial secretions by reducing the surface tension and viscosity of mucous (Hanson, 2018). It is a widely prescribed mucoactive OTC drug used to treat a range of respiratory conditions, mainly conditions associated with mucous secretion disturbances. Various clinical studies have demonstrated that bromhexine influences cough, demonstrating that bromhexine treatment leads to a normalisation in expectoration, and reduces the severity and frequency of coughing. Treatment with bromhexine is associated with favourable improvements in mucous clearance and is indicated in various respiratory disorders with abnormal mucous secretion and impaired mucus transport. Furthermore, bromhexine is well tolerated

and studies showed low incidence of mild side effects. Symptomatic treatment for a dry cough includes the use of antitussive cough syrups containing either pholcodine, codeine or dextromethorphan. Among OTC cough medications for use in acute dry cough, pholcodine seems to have one of the better safety profiles, due to its lack of serious adverse effects. Unlike codeine, it does not metabolise into morphine and is thus far safer for everyday use. Pholcodine has also been proven to be just as effective at treating the symptoms of acute cough as dextromethorphan. Pholcodine suppresses the dry cough, reducing frequency as well as the intensity of the cough. Although codeine is the most widely used antitussive, there are serious concerns about its efficacy and safety profile, which family practitioners in particular need to be aware of. References available on request.

INOVA FOCUS

RELIEVING

COUGHS FOR OVER

HELP SWITCH

OFF

COUGHS 2-4

10 HOURS

UP TO 10 HOURS

DRY COUGH RELIEF2*

* Pholtex Forte 10 non-consecutive hours from 2 doses References: 1. iNova Pharmaceuticals Data on file. 2. Pholtex Forte approved package insert, February 1999. 3. Pholtex Junior approved package insert, February 2004. 4. Pholtex Plus approved package insert, July 2017. Scheduling status: S2 Proprietary name (and dosage form): PHOLTEX FORTE liquid. Composition: Each 5 mL liquid contains Pholcodine 15 mg. Registration number: 32/10.1/0116. Scheduling status: S2 Proprietary name (and dosage form): PHOLTEX JUNIOR syrup. Composition: Each 5 mL liquid contains Pholcodine 5 mg. Registration number: 29/10.1/0013. Scheduling status: S2 Proprietary name (and dosage form): PHOLTEX PLUS liquid. Composition: Each 5 mL contains: Pholcodine 5 mg; Phenylephrine hydrochloride 3,3 mg. Registration number: 46/16.5/0711. Name and business address of applicant: iNova Pharmaceuticals (Pty) Ltd. Co. Reg. No.1952/001640/07. 15e Riley Road, Bedfordview. Tel: 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 14254L. IN3966/21.

MEDICAL CHRONICLE 15

WEBINAR CPD | ExpiresREPORT 29/03/2022

Distinguishing vaginal infections

Dr Trudy Smith, gynaecologist based at Wits Donald Gordon Medical Centre recently hosted a webinar for Medical Chronicle, sponsored by iNova Pharmaceuticals. Here is a summary of her presentation. To request your CPD certificate from watching the replay, please email john.woodford@newmedia.co.za. Please allow us 6-8 weeks to process the CPD certificates, which are allocated based on your viewing time of the full presentation.

he vagina is rich in glycogen in oestrogenised women. Doderlein lactobacilli convert glucose from the glycogen into lactic acid. The pH of the vagina is normally acidic, below 4.5, which maintains the normal vaginal ecosystem. WHAT DO LACTOBACILLI DO Lactobacilli in vaginal microbiota of healthy women offer protection against different diseases including recurrent urinary tract infections, bacterial vaginosis and vaginal candidiasis. This protection is achieved through the production of different antimicrobial compounds such as hydrogen peroxide and lactic acid. They also offer protection through their capacity to adhere and compete for adhesion sites in the vaginal epithelium and the production of bacteriocins (antibacterial peptides/proteins that either kill or inhibit the growth of closely related bacteria). FACTORS THAT AFFECT THE ECOSYSTEM The following all play a role in the vaginal ecosystem: • Antibiotics • Hormones or lack of hormones • Contraceptive preparations • Douches • Vaginal medications • Sexual trauma • Stress • Diabetes mellitus • Decrease in host immunity. DYSBIOSIS Dysbiosis is a state in which there is an imbalance of microorganisms. When this occurs, the vagina becomes more alkaline, short-chain fatty acids create an alkaline environment and aerobic bacteria increase. There is a loss of the barrier integrity and amine production occurs, in the case of bacterial vaginosis. VAGINITIS Most women assume that all infections are Candida. However, bacterial vaginosis accounts for 40%-50% of cases, vaginal candidiasis 20%-25% and trichomoniasis accounts for 15%-20% of the cases.

UNTREATED BV IN REPRODUCTIVE WOMEN If left untreated, bacterial vaginosis (BV) increases HIV transmission by 2-4 fold, with 23% of antenatal seroconversion in 36 May 2021 | MEDICAL CHRONICLE 16 MEDICAL CHRONICLE

pregnant Malawian patients. It also results in an increased risk of pregnancy complications such as chorioamnionitis, spontaneous abortion, premature delivery and low birthweight. SYMPTOMS Presenting symptoms of BV include: • Change in the volume, colour, or odour of vaginal discharge • Pruritus • Burning • Irritation • Erythema • Dyspareunia • Spotting • Dysuria. DIAGNOSING BV In terms of the Amsel criteria for diagnosing BV, look for the following: • Vaginal pH >4.5 • Thin, homogeneous milky like discharge • Fishy odour with the addition of potassium hydroxide (Whiff test) but also ask if there is a fishy smell when the patient washes with soap • Look for clue cells on microscopy. A diagnosis may be based on a positive for three of the four criteria. TIMING OF SYMPTOMS Candida vulvovaginitis often occurs in the pre-menstrual phase, whereas trichomoniasis and BV occur during or after menses. If symptoms occur after a recent sexual encounter, this may be due to a sexually transmitted disease.

SPECIAL INVESTIGATIONS Special investigations that can be done include pH testing, microscopy and culture, rapid antigen tests, and nucleic acid amplification tests. pH tests, whiff tests and microscopy can be done in the doctor’s office. EXAMINATION A normal vulva is consistent with BV or leukorrhea. Erythema oedema or fissures suggest trichomoniasis, candidiasis or dermatitis. Architectural changes suggest lichen sclerosis, lichen planus or membrane pemphigus. Pain with pressure from a cotton swab indicates a dermatosis or provoked vulvodynia. BV TREATMENT Avoid empiric blind therapy. Self-diagnosis and OTC treatment is often used, leaving the patient partially treated. CDC RECOMMENDATIONS Consider patient preference, possible side effects, drug interactions, and other coinfections when selecting a regimen. Refrain from intercourse or use condoms consistently and correctly during the treatment regimen. Douching might increase the risk for relapse, and no data support the use of douching for treatment or relief of symptoms. RECURRENT BV This is very common, with 70% of patients experiencing recurrent infections over a nine-month period. Diagnosis confirmation should be done if recurrence occurs.

BV VS CANDIDIASIS Use the following criteria to distinguish the two conditions. Symptoms

Bacterial vaginosis

Candidiasis

Type of smell Increase in discharge Is there an itch or redness Stinging or burning while urinating

Fishy Musty Milky grey discharge No No

No smell White curd clumps Yes Yes

Treatment of male partners is not recommended for BV. Medication

Dose

Metronidazole Metronidazole gel 0.75%

500mg orally twice daily 7 days One intravaginal application 5 days daily One intravaginal application daily 7 days

Clindamycin cream 2%

Duration

Vaginal metronidazole 0.75% is recommenced once daily for 10 days, followed by twice-weekly application for four to six months. HOW DOES METRONIDAZOLE WORK? Metronidazole is an antimicrobial agent. It causes disruption of DNA and the inhibition of nucleic acid synthesis. Susceptible anaerobes take up the metronidazole and metabolise it to a reduced intermediate, which kills the bacteria by interacting with DNA. It is active against Gardnerella vaginalis, Mycoplasma hominis and Bacteroides species. There is little evidence of resistance despite widespread clinical use for the past three decades. Oral tablets require a prescription while the gel can be obtained OTC. It shows equivalent cure rates to other recommended treatment options including oral metronidazole and intravaginal clindamycin. It has a 96% lower systemic absorption and significantly improved GI tolerability vs oral metronidazole. Metronidazole shows little to no antibacterial resistance compared to intravaginal clindamycin. A review study showed 61% increase in vaginal lactobacilli one week after treatment with intravaginal metronidazole compared to 11% increase in intravaginal clindamycin. The water-based gel formulation of metronidazole that stays in the vagina has no mineral oil and does not weaken latex. It is unlikely to stain clothes and is fragrance-free.

BACTERIAL VAGINOSIS DO’S AND DON’TS Do • Wipe from front to back vagina

Do not Use perfumed products in and around the vagina • Do not stay in wet Over wash the underwear vagina • after working out Spend too long or swimming in a hot bath • Shower Wash underwear in strong detergent • Use water and Smoke not soap to wash • Ware loose fitting cotton underwear • and not G-strings Douche.

WEBINAR REPORT CPD | Expires 22/03/2022

Covid-19 in rhinology and allergy

Prof Joaquim Mullol, director of the Rhinology Unit & Smell Clinic, ENT Department, Hospital Clínic Barcelona, recently shared his extensive knowledge at a webinar held by Medical Chronicle and sponsored by iNova Pharmaceuticals. The following article is based on his presentation titled: Covid-19 in Rhinology and Allergy – impact on smell and type 2 inflammation.

HE LOSS OF smell and taste is common (60%-70% of cases) in SARS-CoV-2-infected patients. One in five patients with Covid-19, loss of smell and taste can present as sudden, severe, and isolated from other nasal or systemic symptoms. Loss of smell is more frequently diagnosed (70%-80%) when measured with smell tests than using questionnaires (45%-50%). For a proper and safe diagnosis, the use of individualised olfactory and gustatory tests or a visual analogue scale (VAS, 0-10cm horizontal line), in person or by telemedicine, is recommended in patients with Covid-19. A potential protective effect of developing Covid-19 is currently being hypothesised in patients with respiratory type 2 inflammation (allergic rhinitis, asthma, chronic rhinosinusitis with nasal polyps), potentially due to eosinophil tissue infiltration. During the outbreak of Covid-19, while awaiting immunisation by vaccination of the general population, the best treatment is prevention of infection: Frequent hand washing, use of facial masks, social distancing, and home isolation when required. In patients with sudden, severe and isolated loss of smell or taste, immediate home isolation is recommended when waiting for a SARS-CoV-2 diagnostic test. In the absence of effective drugs, olfactory training is a valid, effective, and recommended therapy to recover the sense of smell in Covid-19 patients that should be started as soon as possible. However, patients with respiratory type 2 diseases, the regular use of first-line therapeutic drugs (anti-H1, corticosteroids, allergen immunotherapy or biologicals) should not be discontinued. CRITICISM OF METHODOLOGY Most studies provide only qualitative (surveys and questionnaires) but no quantitative (smell test, VAS) data on the loss of smell or taste. There is also no distinction between flavour (smell + taste) and real taste. CRITICISM OF RESULTS There is a high variability in the frequency of loss of smell (from 5% to 85%) and high variability in the frequency of loss of taste (from 5% to 88%). Data on loss of smell and taste seems to confirm ‘flavour = taste’. FINAL CONCLUSIONS Most Covid-19 patients (>60%) present loss of smell and/or loss/ distortion of taste as additional symptoms in Covid-19. Some Covid-19 patients (15-20%) present a sudden-severe-isolated loss of smell/taste. Most patients (>90%) recover the sense of smell/taste within the first month. Olfactory training is recommended.

Recommendations in Covid-19 outbreak 1. More than 90% of patients improve within the first month 2. Intranasal corticosteroids can be recommended at regular doses in concomitant upper airway disease (allergic rhinitis, CRS, CRSwNP) but are not recommended in sudden, severe, and

To watch this webinar click here: https://event.webinarjam.com/ login/09k09ux1tozfz1hm6w9ap

isolated loss of smell 3. Olfactory training could be started after one month or immediately.

2. Receptor blockers 3. Vaccination (T-cells) 4. Mechanical filtration.

The trinity of Covid-19 is: Immunity – Inflammation – Intervention Prevention: 1. Vaccination (Ab)

To watch a replay of this presentation and earn a CPD point, go to: https://bit. ly/3dmumbA

FREE content for CPD Medical Chronicle readers

For more information, please contact us: Editor: Conrad.Strydom@newmedia.co.za Sales: kimeke.jooste@newmedia.co.za

IT’S AS EASY AS: • Visit www.medicalacademic.co.za • Click on CPD Portal • Fill out form

MEDICAL CHRONICLE | April 2021 33 MEDICAL CHRONICLE 17

CPD| |Expires DERMATOLOGY CPD 31/03/2022

Non-surgical management of

actinic keratoses and non-melanoma skin cancers Actinic keratoses, basal cell carcinoma (BCC), squamous cell carcinoma and malignant melanoma are all pre-malignant and malignant skin cancers caused by photodamage. There are other rare tumours included in this group, such as Merkel cell carcinoma. Basal cell carcinomas are worldwide the most common skin cancer and can in certain circumstances be difficult to treat. To earn your CPD points answer the quiz on www.medicalacademic.co.za

ON-SURGICAL TREATMENT of these premalignant and malignant skin cancers, especially for those in difficult areas and those with large tumour size, includes cryotherapy, topical imiquimod, topical 5 -fluorouracil and photodynamic therapy. This article will focus on AK and BCC. Actinic keratoses are small, scaly, sandpaper-like papules found on sunexposed areas of skin including the face, balding scalp, and arms. Histologically actinic keratoses are a proliferation of cytologic atypical keratinocytes in the epidermodermal junction zone. With a risk of evolving into squamous cell carcinoma these lesions are considered to be premalignant. Ultraviolet light, specifically UVA and UVB directly and indirectly cause of specific mutational damage changes to the DNA

in keratinocytes. Long-term UV radiation is known to produce local and systemic immunosuppression, mutations in the p53 tumour suppressor gene, and DNA pyrimidine covalent dimers, all of which are believed to contribute to the development of AK. General risk factors for the development of AK are numerous and well-established. RISK FACTORS One of the most prominent is the age of the patient, with patients older than 40 at increased risk and patients of an advanced age at a far greater risk than average. Having lighter skin and hair, especially red or blonde, indicates an increased risk, as does chronic sun-exposure. The progression from AK to squamous cell carcinoma has an incidence of anywhere

’s No. SA A’s No

1 1 PRESCRIBED PRESCRIBED S

SHEDDING SOME LIGHT ON TREATING AK*

BY BY DERMATOLOGISTS§1§1 DERMATOLOGISTS

between 0.025%-16%, differing according to various research. In widespread AK this carcinogenic risk therefore increases exponentially. It is therefore good preventative clinical practice to treat actinic keratoses. However extensive widespread AK presents a challenge to treat. Data has shown that the non-surgical treatment modalities most commonly used to treat AK are cryotherapy, topical imiquimod, topical 5-flourouracil and photodynamic therapy. Dr Sian Hartshorne is a practicing dermatologist and current president of the South African Society for Dermatologic Surgery and the scientific programme co-ordinator of the African Women’s Dermatologic Society, who has the following findings on the topics of AK and BCCs.

Dr Sian Hartshorne

CLINICAL PRESENTATION OF ACTINIC KERATOSES: • Papules and plaques (1mm – 2.5cm) • Flesh-coloured, slightly red-brown pigmented • Erythematous • Rough, hyperkeratotic surface • Light-exposed areas (mainly face, lower lips, bald areas on the head, neck, arms, hands)

Worldwide, more dermatological experts prefer imiquimod2**

Category D6B topical chemotherapeutic agents * Actinic Keratosis; ** Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis;

References: 1. Impact Rx - September 2020. 2. Werner RM. et al. Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version. JEADV 2015;29:2069-2079. Scheduling status: S4 Proprietary name and dosage form: ALDARA Cream. Composition: Each 2,0 g cream pump contains 5 % Imiquimod (100 mg). ALDARA Cream Sachet. Composition: Each 250 mg cream sachet contains 5 % Imiquimod (12,5 mg). Preservatives: Methyl hydroxybenzoate 0.2 % m/m, Propyl hydroxybenzoate 0.02 % m/m, Benzyl alcohol 2 % m/m. Pharmacological classification: A 34 Other. Indications: ALDARA Cream is indicated for the topical treatment of superficial basal cell carcinoma (sBCC), and of external genital/perianal warts (condyloma acuminata) and clinically typical, non hyperkeratotic, nonhypertrophic actinic keratosis (AKs) on the face or scalp in adult patients. Registration number: 32/34/0541. Name and business address of the holder of the certificate of registration: iNova Pharmaceuticals (Pty) Ltd. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 15200L. IN4059/21.

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Superficial basal cell carcinoma

• Often itchy • May cause thickening of skin in response to scratching therefore resulting in large hyperkeratotic nodules. NATURAL COURSE OF AK There are three possibilities in the clinical course of AK – persistence, spontaneous regression and progression to invasive SCC (0.025% to 16%). However, we have no ability to predict what will be the outcome of any AK. Risk of progression to SCC increases with the increase in number of actinic keratoses. The mortality rate of invasive SCC is approximately 1%. The risk of progression is minimised by effective treatment and all AKs should be treated. Prevention of widespread AK is through daily sunscreen use. This prevents development of new AK, SCC and has an additional moisturising benefit. With daily sunscreen use, there can be a decrease in the average number of existing AK of approximately 30% (if daily sunscreen is used over two year period). MANAGEMENT OF WIDESPREAD AK Moisturisers decrease the dryness and scaling and therefore help to ‘flatten’ keratoses and decrease itch. The combination of moisturising sun protection plus other preparations may help to decrease actinic keratoses. The following preparations can be used to decrease the scaling of actinic keratoses: • 10-20% Salicylic acid in UEA • 10% Lactic acid in UEA • Use at daily on arms and legs • Stop if skin becomes too irritated • Chemical peels – up to 70% glycolic acid peels NONSURGICAL MANAGEMENT OF AK Physical therapies include cryotherapy, surgical excision, radiation and laser. Topical therapies include imiquimod, 5-Fluorouracil, diclofenac, and ingenol mebutate. Photodynamic therapy is also an option.

CRYOTHERAPY Cryotherapy involves the application of liquid nitrogen for 20-40s, in a spray technique. Cotton wool wrapped onto a wooden orange stick or pus swab can be used for more focused areas, especially for facial areas. The roll technique of cryotherapy is a lighter technique over large areas decreasing pain and blistering, and leading to quicker healing, less scarring and hypopigmentation. IMIQUIMOD Imiquimod is a novel topically active positive immune response modifier that enhances the body’s immune response against dysplastic cells. It is a member of imidazoquinolines family. It has proven strong antiviral (HPV) and anti-tumour properties.

Imiquimod mode of action Imiquimod enhances non-specific and specific immune response, especially cellmediated pathways. It activates dendritic cells through Toll-like receptor 7. Activated dendritic cells migrate to local lymph nodes and initiate T-cell activity. It induces IFNa, IL6, IL12, TNFa. T-cells then travel via the bloodstream and selectively destroy dysplastic cells of the actinic keratoses. It also induces immunologic memory. Imiquimod induces cellular memory via the activation of effector T-cells, Langerhans cells, lymphocytes, and macrophages. These cells circulate lymphatically and activate the adaptive immune response. Imiquimod’s ability to induce immunologic memory results in a low incidence of recurrence. Imiquimod should be applied three times per week at night. For example, Monday, Wednesday and Friday for four weeks. Advantages of imiquimod It is highly selective and has a specific effect on dysplastic cells, with no effect on normal cells, and a treatment effect on subclinical actinic keratoses. Surface field treatment can be achieved (field cancerisation), for example on the scalp.

There is an excellent cosmetic outcome. It is cost effective and easy to use in elderly or those on many medications. In a comparative study (Krawtchenko, 2007) comparing imiquimod vs 5-FU and cryotherapy, imiquimod showed the highest sustained clearance rates at one year follow-up of both the lesions that were initially treated and of the treatment field.

Disadvantages of imiquimod Disadvantages include flu like symptoms if there is a very severe reaction: Myalgia, headache, fatigue. Local skin reactions such as redness, itching and burning can occur as with many of the topical treatments. There may be photosensitivity, so patients are advised to avoid sunlight as much as possible, wear sunblock and protective clothing. Use with caution in patients with autoimmune disorders or organ transplant/ immunosuppression. 5-FLOUROURACIL Similarly to Imiquimod 5-Fluorouracil can be used to treat extensive actinic keratoses. However the mode of action is a more direct chemotherapeutic effect via interference of DNA synthesis and RNA transcription. The cream is applied twice daily for 14-21 days and should elicit a very red reaction. Although very effective there are the disadvantages of burning and discomfort locally on the areas treated. Once treatment is completed these symptoms clear rapidly and there should be an excellent cosmetic outcome. PHOTODYNAMIC THERAPY Photodynamic therapy (PDT) is a treatment for AK, basal cell carcinoma and Bowen’s disease involving the topical application of a light-sensitive substance followed by its activation through illumination with a specific light source. An incidental benefit is photorejuvenation. For photodynamic therapy of widespread AK, one must prepare the skin

well by removing as much hyperkeratosis as possible and cover all treatment areas for three hours. For arms and legs with very thick hyperkeratotic plaques, prepare skin for two weeks prior to treatment with: 5-fluorouracil twice daily or 20% salicylic acid in UEA or cryotherapy or 70% glycolic acid peel. This produces an excellent recovery and cosmetic end result but it can be expensive. COMBINATION THERAPIES OF TREATMENT OF WIDESPREAD ACTINIC KERATOSES These include: • Glycolic acid peels, cryotherapy and micropore wraps • Glycolic acid peels, cryotherapy and PDT • 5-Fluorouracil and PDT • Microneedling and PDT • Fractionated CO2 laser and PDT. BASAL CELL CARCINOMA Basal cell carcinoma (BCC) are slowly growing, locally invasive tumours of the skin that arise from basal layer of epidermis and from hair follicles. They form 80% of non-melanoma skin cancers and are the most common form of skin cancer in fair skin colour patients (Fitzpatrick I/II). The incidence of BCC continues to rise by approximately 10% per year. BCC is the most common skin cancer, especially in fair-skinned populations. The incidence of BCC continues to rise by approximately 10% per year. Although nodular BCC is the most common subtype of BCC, superficial BCC (sBCC) accounts for 10%-17% of all BCCs and up to 38% of BCCs in certain locations, such as the neck. Squamous cell carcinoma (SCC) is the second most common cutaneous neoplasm, with in situ carcinoma accounting for approximately 12%. Collectively, sBCC and SCC in situ represent a substantial percentage of malignant cutaneous neoplasms. BCC, the most frequently occurring cutaneous malignancies, generally do not MEDICAL CHRONICLE | April 202119 15 MEDICAL CHRONICLE

CPD 31/03/2022 CPD| Expires | DERMATOLOGY

metastasize but can be locally invasive. The treatment aim is to completely cure the tumour, but the cosmetic outcome is also a reasonable concern for patients. BCC occur in mostly sun-exposed areas as a result of UV light damage. It is known that in rare genetic disorder Gorlin-Goltz syndrome patients have multitudes of BCC and that there is an aberrant activation of hedgehog (HH)/glioma-associated oncogene signalling pathway. BCC can be classified into different histological sub-types according to their growth pattern. The different histological

sub-types broadly distinguish between nodular, superficial and infiltrative, and other less frequently occurring types according to their growth patterns. Micro-nodular and infiltrative sub-types are recognised as high risk and should rarely be treated other than surgically. Apart from the histological appearance, other well-recognised factors that can influence the prognosis and outcomes for treated BCC are the size and site of the tumour, how clearly the margins are defined and failure of previous treatment.

CAUSES AND RISK FACTORS Basal cell carcinomas occur in mostly sun-exposed areas as a result of UV light damage. Exposure to ultraviolet radiation is therefore generally accepted as the major cause of basal-cell carcinoma. Whereas SCC appears to be strongly related to cumulative sun exposure, the relationship between exposure to ultraviolet radiation and the risk of BCC is more complex. The timing, pattern, and amount of exposure to ultraviolet radiation all appear to be important. The risk of this disease is significantly increased by recreational

CHANGING THE NATURE OF TREATMENT

Consider Aldara as a first choice for Actinic Keratosis (AK) and superficial Basal Cell Carcinoma (sBCC)

• • •

•

• •

Worldwide, more dermatologists prefer 5 % imiquimod to 5 % 5-FU for treatment of AK*1 Superior sustained clearance and cosmetic outcomes vs. 5-FU and cryotherapy2 Effective for multiple, multiform AKs3

5 % Imiquimod cream is superior to both MAL-PDT and 5 % 5-FU cream and considered a first choice by dermatologists for sBCC**4 Preferred by patients to surgery for treatment of low risk sBCC^5 Effective for multiple or large sBCCs6,7

5-FU: 5-fluorouracil; MAL-PDT: methyl aminolevulinate photodynamic therapy. *Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis – International League of Dermatological Societies in cooperation with the European Dermatology Forum: imiquimod had a higher agreement (≥ 75 %) than 5-FU (≥ 50 %) as suggested treatment for single or multiple AK lesions.1 **A 5-year follow-up study of 601 patients with sBCC concluded that imiquimod is considered first choice for non-invasive treatment of most primary sBCCs because it was superior to both Photodynamic therapy and 5-FU in terms of efficacy of sBCC.1 ^Analysis of the SINS trial evaluating long term success of excisional surgery vs. imiquimod for low risk sBCC, showed that patients preferred ALDARA to surgery, regardless of previous experience of BCC symptoms and treatment2 References: 1. Werner RM. et al. Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis – International League of Dermatological Societies in cooperation with the European Dermatology Forum – Short version. JEADV 2015;29:2069-2079. 2. Krawtchenko N. et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol 2007;157 (Suppl.2):34-40. 3. Stockfleth E. et al. Treatment of multiple, multiform actinic keratoses on the head with imiquimod 5% cream. Eur J Dermatol 2009;19(4):1-5. 4. Jansen M. et al: Five Year Results of a Randomized Controlled Trial Comparing Effectiveness of Photodynamic Therapy, Topical Imiquimod, and Topical 5-Fluorouracil in Patients with Superficial Basal Cell Carcinoma. J Invest Dermatol 2018;138:527-533. 5. Tinelli M. et al. What determines patient preferences for treating low risk basal cell carcinoma when comparing surgery vs imiquimod? A discrete choice experiment survey from the SINS trial. BMC Dermatol 2012;12:19. 6. Shumack S. et al. 5% Imiquimod Cream for the Treatment of Large Superficial Basal Cell Carcinoma. Arch Dermatol 2004;140:1286-1287. 7. Marks R. et al. Efficacy and Safety of 5% Imiquimod Cream in Treating Patients With Multiple Superficial Basal Cell Carcinomas. Arch Dermatol 2004;140:1284-1285. Scheduling status: S4 Proprietary name and dosage form: ALDARA Cream. Composition: Each 2,0 g cream pump contains 5 % Imiquimod (100 mg). ALDARA Cream Sachet. Composition: Each 250 mg cream sachet contains 5 % Imiquimod (12,5 mg). Preservatives: Methyl hydroxybenzoate 0.2 % m/m, Propyl hydroxybenzoate 0.02 % m/m, Benzyl alcohol 2 % m/m. Pharmacological classification: A 34 Other. Indications: ALDARA Cream is indicated for the topical treatment of superficial basal cell carcinoma (sBCC), and of external genital/perianal warts (condyloma acuminata) and clinically typical, non hyperkeratotic, nonhypertrophic actinic keratosis (AKs) on the face or scalp in adult patients. Registration number: 32/34/0541. Name and business address of the holder of the certificate of registration: iNova Pharmaceuticals (Pty) Ltd. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 16596L. IN3641/20.

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exposure to the sun during childhood and adolescence. Intense intermittent exposure to the sun is associated with a higher risk of BCC than is a similar degree of continuous exposure. Physical factors, including fair complexion, red or blonde hair, and light eye colour, influence responsiveness to ultraviolet radiation but are also independent risk factors. Exposures to ionising radiation, arsenic and oral methoxsalen have also been linked to the development of BCC. It is also known that in rare genetic disorder Gorlin-Goltz syndrome (basal cell naevus syndrome) patients develop multitudes of BCC due to a mutation on the PTCH1 gene which results in an aberrant activation of the hedgehog (HH)/gliomaassociated oncogene signalling pathway. Immunosuppression predisposes patients to BCC. The 4:1 ratio of BCC to SCC seen in immunocompetent patients is reversed in organ-transplant recipients. Among Australian heart-transplant recipients, there were 21 times as many cases of BCC as among Australians who had not received a heart transplant, and 123 times as many cases as among Americans who had not received a heart transplant. Renaltransplant recipients have a risk of BCC that is 10 times that among a population of those who have not received renal transplants. In a meta-analysis of seven studies, Marcil and Stern showed that after an index case of BCC, the incidence of subsequent cases among such patients was increased by a factor of 10, as compared with that in the general population. Significant predictors of a greater number of BCC include an initial truncal occurrence, an age of more than 60 years at the first presentation, the presence of the superficial histologic subtype, and male sex. Susceptibility to a truncal location has been linked with genetic polymorphisms in glutathione S-transferase and cytochrome P-450. Risk factors for extensive subclinical spread include a tumour diameter greater than 2cm, location on the central part of the face or ears, long-standing duration, incomplete excision, an aggressive histologic pattern of growth, and perineural or perivascular involvement. Tumours with subclinical extension or indistinct borders are more frequently associated with residual positive margins after excision and have a higher recurrence rate than more limited or well-defined tumours. Metastasis of BCC is extremely rare occurring in rare genetic disorders such as Gorlin -Goltz syndrome. Metastases arise most commonly from primary tumours on the face and ear, with the median interval between the appearance of the tumour and metastasis estimated to be nine years. The prognosis for metastatic disease is poor, with mean survival ranging from 8 months to 3.6 years. CLINICAL PRESENTATION AND HISTOLOGIC APPEARANCE BCC characteristically arises in body areas

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Pigmented nodular basal call carcinoma

exposed to the sun and is most common on the head and neck (80%), followed by the trunk (15%) and arms and legs. BCCs have also been reported in unusual sites, including the axillae, breasts, perianal area, genitalia, palms, and soles. Nodular BCC is the classic form, which most often presents as a pearly papule or nodule with overlying telangiectases and a rolled border, at times exhibiting central crusting or ulceration. Occasionally, nodular BCC may resemble enlarged pores or pits on the sebaceous skin of the central portion of the face. Superficial BCC presents as a slowly growing scaly erythematous pink patch or plaque, which resembles eczema, psoriasis, or Bowen’s disease (intraepidermal carcinoma). Both nodular and superficial forms may contain melanin, imparting a brown, blue, or black colour to these lesions. The morpheaform type, also known as sclerosing, fibrosing, or infiltrative BCC, typically appears as an indurated, whitish, scar-like plaque with indistinct margins. Suspicious lesions occurring in highrisk areas, such as the central portion of the face, should undergo prompt biopsy to obtain a timely diagnosis and to expedite definitive treatment. Skin biopsy will also identify amelanotic (nonpigmented) or

minimally pigmented melanomas, which can sometimes mimic BCC. In a review of 1039 consecutive cases of BCC, Sexton et al found that the most common histologic subtypes are mixed (38%), nodular (21%), superficial (17%), and micronodular (14%). Uncommon variants, including basosquamous, keratotic, granular-cell, adamantinoid, clear-cell, and BCC with matrical differentiation, have also been described. TREATMENT Superficial BCC is confined to or contiguous with the epidermis, and SCC in situ by definition does not invade the underlying dermis. Because of the lack of deeper invasion, these skin cancers are usually treated with a variety of destructive modalities, such as cryotherapy or electrodesiccation and curettage, that may yield cure rates for BCC of greater than 90%. Hypopigmentation or atrophic scarring are common sequelae of these modes of treatment because of nonselective injury to surrounding healthy tissue. Other methods of treatment, such as surgery or radiotherapy, may also produce visible scarring. Chemical destruction with 5-fluorouracil may result in good

cosmetic outcomes but initially may produce significant inflammation, resulting in decreased patient compliance with treatment. IMIQUIMOD Imiquimod uses the body’s own immune system to fight certain skin diseases. It activates the immune cells in the body, leading to a localised increased immunity of the skin. This allows the skin to recognise and remove the diseased skin cells. The immune response modifier, imiquimod, acts through Toll-like receptor (TLR)-7 (and to a lesser extent, TLR-8) signalling and has been shown to induce interferon (IFN-a) production in human blood cell cultures and when administered orally in humans. IFN-a appears to act upon natural killer (NK) cells and conventional dendritic cells (DCs) to stimulate IFN-c, tumour necrosis factor (TNF)-a, monocyte chemoattractant proteins (MCPs) and other cytokines. Locally, imiquimod stimulates the production of various cytokines at the cellular level that increase immunity and afford anticancer activity. Overall, the cosmetic as well as clinical outcome of use of imiquimod is excellent. Treatment of sBCC lesions involves application at night onto the affected area.

Apply for five nights per week (therefore having no treatment for the following two nights) and continue to complete a treatment programme for six weeks. BCC is a hedgehog (HH)-driven malignancy with oncogenic gliomaassociated oncogene (GLI) signalling activated in a ligand-independent manner. Imiquimod can also directly repress HH signalling by negatively modulating GLI activity in BCC and medulloblastoma cells. Evidence suggests that the repressive effect of imiquimod on HH signalling is not dependent on TLR/MYD88 signalling. These results suggest a mechanism for imiquimod engaging adenosine receptors (ADORAs) to control GLI signalling. As explained by Gruber et al (2013), deregulated hedgehog (HH)/GLI signaling plays an aetiologic role in the initiation, progression and maintenance of many cancers. Small molecule targeting of HH signaling by inhibiting the essential pathway effector smoothened (SMO) has proven exceptionally efficient for the treatment of advanced and metastatic basal cell carcinoma. That said, severe side effects, limited response rates, SMO-independent GLI signaling and rapid development of drug resistance limit the therapeutic success of SMO antagonists, urgently calling for the identification of alternative and additional strategies repressing oncogenic HH signaling. The authors highlighted findings showing that the Toll-like receptor-7/8 (TLR7/8) agonist imiquimod (imiquimod), an immune modulator approved for the treatment of BCC, can also act as a potent cell autonomous inhibitor of oncogenic HH signaling. Surprisingly, imiquimod reduces HH signal strength independent of TLR signaling, via adenosine receptor (ADORA)/Adenylate cyclase (AC)/Protein kinase A (PKA) activation. They highlight the molecular mechanisms of imiquimodmediated repression of HH/GLI and discussed the possible benefits as well as challenges of using ADORA agonists for the treatment of HH-associated cancer. Pharmacological activation of ADORA with either an ADORA agonist or imiquimod resulted in a protein kinase A (PKA)mediated GLI phosphorylation and reduction in GLI activator levels. The activation of PKA and HH pathway target gene downregulation in response to imiquimod were abrogated by ADORA inhibition. Furthermore, activated Smoothened signalling, which positively signals to GLI transcription factors, could be effectively counteracted by imiquimod. These results reveal a previously unknown mode of action of imiquimod in the treatment of BCC and also suggest a role for ADORAs in the regulation of oncogenic HH signalling.

Histological clearance rate Geisse et al (2004) showed a histological clearance rate of 82% (95% CI: 76%-87%) and 79% (95% CI: 73%-85%) for the five times per week and seven times per week in MEDICAL CHRONICLE 21 MEDICAL CHRONICLE | April 2021 17

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a) Superficial basal cell carcinoma on upper back

week in the imiquimod groups, respectively. Two identical, multicentre, randomised, double-blind, vehicle-controlled, doseresponse studies were initiated at 55 centres in the US. All protocols and informed consent documents were submitted to and approved by each study centre’s institutional review board. Before study procedures were initiated, each subject voluntarily signed an informed consent form. Subjects applied study cream to a single target sBCC once daily according to their assigned treatment regimen for six weeks and applied a small drop of study cream (approximately 4-7mm in diameter) based on the size of their sBCC. Each dose of cream was to be applied at approximately the same time of day, just prior to bedtime, and was to be rubbed into the lesion and the area approximately 1cm surrounding the lesion until the cream vanished. The cream was to remain on the skin for at least eight hours without occlusion, and was then removed with mild soap and water. The study indicates that imiquimod achieved an 82% histological clearance of sBCCs 12 weeks post treatment, and 94 % of patients showed initial histological clearance. Imiquimod showed a 93% NPV, which indicates that sBCCs responded well to treatment.

Sustained clearance The immune response modifier directly represses HH signalling by negatively modulating GLI activity. Apply five times a week for six weeks. This produces a good cosmetic result. Do not use for morphoeic BCC or pigmented BCC. It also shouldn’t be used in cases with immunosuppression. A study by Jansen et al (2018), five-year results of a randomised controlled trial with 601 patients comparing effectiveness of 22 MEDICAL CHRONICLE 18 April 2021 | MEDICAL CHRONICLE

photodynamic therapy, topical imiquimod, and topical 5-fluorouracil in patients with sBCC, showed that 5% imiquimod cream is superior to both methyl aminolevulinate PDT and 5-fluorouracil cream in terms of efficacy. “We therefore consider 5% imiquimod cream as the first choice for noninvasive treatment in most primary superficial basal cell carcinomas,” the authors stated.

Multiple or large sBCCs There has been increasing interest in the use of 5% imiquimod cream in the treatment of patients with superficial basal cell carcinomas (sBCCs). To date, the reports of its efficacy apply to single tumours in individuals. However, in clinical practice it is common for patients to have more than one sBCC when they present for treatment. The aim of this study was to assess the safety and efficacy of two dosing regimens of 5% imiquimod cream for the treatment of patients with multiple sBCCs. In a study by Shumack et al (2004) 67 adults with a total of 208 histologically confirmed sBCCs on their trunk, limbs, or neck (2-6 tumours per person) applied 5% imiquimod cream seven times per week or five times per week for six weeks. Twelve weeks after treatment, the tumour sites were examined clinically and histologically for evidence of residual tumour. In this study, patients had 2-6 tumours, 90% had 2-4 target tumours. In 77% of patients with multiple sBCCs, these were histologically cleared 12 weeks after treatment. Cosmetic outcomes In Gollnick et al’s (2005) study, during the six-week treatment period, subjects or a caregiver applied imiquimod 5% cream five times per week (consecutive days),

b) Superficial basal cell carcinoma after 4 weeks of treatment with topical imiquimod

at approximately the same time of day by gently rubbing the cream on the tumour area and about 1cm around it until the cream disappeared. Safety evaluations consisted of physical examinations, vital sign measurements, clinical laboratory tests (haematology, blood chemistry, and urinalysis), pregnancy tests (where indicated for women of reproductive potential), and use of concomitant medications. Local skin reactions (LSRs) of erythema, oedema, induration, vesicles, erosion, ulceration, scaling/flaking, and scabbing/crusting were assessed by the investigator at the target tumour site and in the surrounding area at each clinic visit, beginning with the initiation visit, and using a rating scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe. In addition, skin quality assessments were made at the target treatment site and surrounding area in order to assess cosmetic outcome. Based on clinical evaluation, initial clearance rate for the ITT population was 89% at the 12-week posttreatment visit. The clinical clearance rates did not appear to be influenced by such factors as age, skin type, target tumour size, number of baseline non-target tumours, or geographical location. In general, clinical response rates increased as LSR severity increased – 73%86% response with no LSRs. Approximately 80%-100% responded with mild LSRs; and 90% to 100% response with moderate or severe LSRs. Assessments demonstrated that all LSRs returned to baseline and remained stable. It will be important for physicians to communicate to patients that these LSRs are a normal and expected part of the treatment process but that the treatment is well tolerated by most patients. These LSRs are commonly seen during treatment and may also prove to be useful in

predicting which patients will respond to imiquimod and achieve complete clearance of their sBCC. Only 1% of patients reported pain as a side effect, and as clearance rates increased so the LSRs decreased. It’s it essential for a good patient compliance and success of the treatment that patients are informed that erythema, erosion, scabbing/crusting will happen and that this is a sign that treatment is working. Patients should take a rest period if they experience discomfit or if the erythema becomes excessive.

References Caperton, C et al. Safety, efficacy, and patient acceptability of imiquimod for topical treatment of actinic keratoses Clinical, Cosmetic and Investigational Dermatology 2011:4 35–40. Wolff F et al. Imiquimod directly inhibits Hedgehog signalling by stimulating adenosine receptor/protein kinase A-mediated GLI phosphorylation Oncogene 2013:32, 5574–5581. Gruber, W et al. An old friend with new skills: Imiquimod as novel inhibitor of Hedgehog signalling in basal cell carcinoma. Oncoscience 2014;9:567-573. Jansen, M et al. Five-Year Results of a Randomized Controlled Trial Comparing Effectiveness of Photodynamic Therapy, Topical Imiquimod, and Topical 5-Fluorouracil in Patients with Superficial Basal Cell Carcinoma. Journal of Investigative Dermatology 2018: 138, 527e533; doi:10.1016/j.jid.2017.09.033. Ooi, T, et al. Imiquimod-induced regression of actinic keratosis is associated with infiltration by T lymphocytes and dendritic cells: a randomized controlled trial. Br J Dermatol 2006 Jan;154(1):72-8. Gollnick, H, et al. Recurrence rate of superficial basal cell carcinoma following treatment with imiquimod 5% cream: conclusion of a 5-year long-term followup study in Europe. Eur J Dermatol. 2008 NovDec;18(6):677-82. Krawtchenko, N, et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007 Dec;157 Suppl 2:34-40. Shumack S, et al. Efficacy of Topical 5% Imiquimod Cream for the Treatment of Nodular Basal Cell Carcinoma. Arch Dermatol 2002 trial.

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The equivalent of 8 sachets*4

Provides 32 actuations4

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*1 x sachet = 250 mg § Category D6B topical chemotherapeutic agents References: 1. Krawtchenko N. et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol 2007;157 (Suppl.2):34-40. 2. Gollnick H. et al. Recurrence rate of superficial basal cell carcinoma following successful treatment with imiquimod 5 % cream: interim 2-year results from an ongoing 5-year follow-up study in Europe. Eur J Dermatol 2005;15(5):374-381. 3. Impact Rx - March 2021. 4. Aldara™ approved package insert. August 2007. Scheduling status: S4 Proprietary name and dosage form: ALDARA Cream. Composition: Each 2,0 g cream pump contains 5 % Imiquimod (100 mg). ALDARA Cream Sachet. Composition: Each 250 mg cream sachet contains 5 % Imiquimod (12,5 mg). Preservatives: Methyl hydroxybenzoate 0.2 % m/m, Propyl hydroxybenzoate 0.02 % m/m, Benzyl alcohol 2 % m/m. Pharmacological classification: A 34 Other. Indications: ALDARA Cream is indicated for the topical treatment of superficial basal cell carcinoma (sBCC), and of external genital/perianal warts (condyloma acuminata) and clinically typical, non hyperkeratotic, nonhypertrophic actinic keratosis (AKs) on the face or scalp in adult patients. Registration number: 32/34/0541. Name and business address of the holder of the certificate of registration: iNova Pharmaceuticals (Pty) Ltd. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For MEDICAL full CHRONICLE 23 prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 17711L. IN4299/21.

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RUPANASE JUNIOR: FILLING THE GAP iNova recently lauched Rupanase Junior in partnership with Medical Chronicle. Dr Iñaki Izquierdo, based in Spain, gave a clinical trial review of the rupatadine efficacy trials.

t is noted that in second-generation antihistamines in paediatrics, the following is needed to improve clinical evidence: • More specific guidelines for the treatment of allergic diseases in children • Much more clinical efficacy demonstrated in paediatric populations. • Many paediatric doses are based on extrapolations from adults • Preferably, double-blind comparative trials instead of prospective studies (no controlled) to assess the safety profile. • More convenient oral paediatric doses with more accurate dosing devices.

- Chronic spontaneous urticaria: UK: - Thailand

0.1-0.3% 13%

Phase III study in chronic spontaneous urticaria:

Characteristics of first- and second-generation H1-antihistamines

PHASE III STUDY IN CHRONIC SPONTANEOUS URTICARIA: RESULTS (I) Rupatadine is effective in the relief of urticaria symptoms after 6 weeks (42 days) of treatment Rupatadine significantly reduces the number of wheals after 6 weeks (42 days) of treatment to a higher extent than desloratadine. Rupatadine significantly reduces the percentage change in pruritus compared to placebo after 6 weeks (42 days) of treatment. Rupatadine significantly reduces the symptoms of urticaria starting on week 1 and over the study period. Rupatadine significantly improves QoL in children with urticaria after 6 weeks of treatment.

International guidelines In terms of international guidelines, non-sedating antihistamines are first line treatments for both allergic rhinitis and chronic urticaria in children. Dosing and efficacy data in children has emerged mainly by extrapolation from adults. However, children are not mini adults, physiologically and socially, and extrapolation is not acceptable. Peculiarities in children include: • Immaturity/organism in growth • Gastric emptying time is increased • Increased intestinal motility, • Enzyme maturation, • Impaired renal function • Gastric pH reaches adult acidity (pH 2-3) by 20-30 months • Faster metabolic rate • Young children have a higher % extra cellular water and require higher doses of hydrophilic drugs (e.g. levocetirizine) • CYP3A4 reaches adult activity at 6 months and may exceed adult activity between 1-4 years. UNIQUE PROPERTIES OF RUPANASE JUNIOR IN CHILDREN Clinical evidence was gained in large trials with persistent allergic rhinitis in children 6-11 years. It was approved for allergic rhinitis (AR) in children 2-11 years and chronic spontaneous urticaria (CSU) in young children 2-11 years. It showed a very positive balance risk/benefit: • No CNS effects = placebo • No QTc prolongation • No interaction with foods KEY POINTS FOR RUPANASE JUNIOR IN AR CHILDREN • Efficacy • Nasal symptoms • Onset of action • Quality of life. PIVOTAL AR PHASE III STUDY: CONCLUSIONS • First clinical evidence from a large-scale study of an H1-receptor antagonist in children (aged 6-11 years) with persistent AR • Rupatadine oral solution (1mg/mL) is effective in improving significantl nasal and non-nasal symptoms at 4 and 6 weeks (overall and in children weighing ≥25kg) • Rupatadine oral solution (1mg/mL) has a rapid onset of action at 12 hours after the first dose • Rupatadine significantly improved the QoL (PRQLQ benefit), compared with placebo, at 4 and 6 weeks • Rupatadine provides significantly better scores for all QoL domains compared to placebo after 4 weeks of treatment in children ≥25kg. CHILDHOOD URTICARIA The prevalence of childhood urticaria: • UK • Germany • Denmark - Mostly acute

2 June 2021 CHRONICLE | MEDICAL CHRONICLE 24 MEDICAL

3.4% 4.4% 5.6% (<6 weeks)

PHASE III STUDY IN CHRONIC SPONTANEOUS URTICARIA: EFFICACY AND QOL CONCLUSIONS • Rupatadine is effective in the relief of urticaria symptoms with a sustained action • Rupatadine significantly reduces the percentage change in pruritus compared to placebo after 6 weeks (42 days) of treatment • Rupatadine significantly reduces the number of wheals after 6 weeks (42 days) of treatment to a higher extent than desloratadine • Rupatadine significantly improved the QoL (CDQLI), compared with placebo at 6 weeks • Efficacy results are in accordance with adolescents/adults results. SAFETY PROFILE IN CHILDREN AGED 2-11 YEARS Rupatadine is safe and well tolerated (similar to placebo) in 2-11 years old children • The incidence of adverse reactions in children aged 2-11 years treated with rupatadine paediatric oral solution is lower than that reported in adults • Rupatadine was well tolerated, similar to placebo • The most common adverse reaction was headache, but the incidence with rupatadine was similar to that found for placebo • No related serious adverse reactions were reported • No ECG concerns (QTc prolongation) were detected. THERAPEUTIC INDICATIONS Rupatadine 1mg/mL oral solution is indicated for the symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis) and urticaria in children aged 2-11 years. Dosage: In children weighing equal or more than 25kg: 5ml (5mg of rupatadine) of oral solution. In children weighing equal or more than 10 kg up to less than 25 kg:2.5 ml (2.5mg of rupatadine) of oral solution. Once a day, with or without food. RUPANASE JUNIOR ‘REAL’ ADVANTAGES IN CHILDREN Rupanase Junior is a new, safe and affective choice in allergic paediatric patients. Both pivotal trials were powered to assess efficacy in several subset of paediatric age (2-5 and 6-11 years old). Unique antiH1 second-generation compound in children 2-11 years old with clinical evidence according to latest guideline recommendations.

In case you missed the live webinar, here is the link to the replay video: https://bit.ly/3fUaDTg REFERENCES Bousquet et al. ARIA Guidelines 2008. Allergy, 2008; 63 (Suppl 86): 8-160 Zuberbier T et al. EAACI/GA2LEN/EDF/WAO Urticaria Guideline. Allergy, 2014; 69: 868-88 Powell RJ et al. BSACI Guidelines for the management of chronic urticaria and angioedema. Clin Exp Allergy, 2007; 37: 631-650 Izquierdo I, et al. Clin Trans Allergy. 2013; 3(suppl.2): P33. De Benedictis FM et al. Allergy 2008;63:1395–1404 Fitzsimons R, Arch Dis Child Edu 2014 Church et al. Pediatric Allergy & Immunol, 2011; 22: 1-8 Khakoo et al. Pediatric Allergy & Immunol, 2008; 19: 303-366 Tuchinda et al. Asia Pac J Allergy Immunol, 1986; 4: 41-5 Finlay A.Y., Khan G.K. Dermatology Life Quality Index (DLQI) A simple practical measure for routine clinical use. Clinical and Experimental Derm 1994; 19:210-16. Potter P. et al. Pediatr Allergy Immunol 2016:27:55-61 Nieto A, et al. Expert Opin Pharmacother. 2021 Mar;22(4):511-519. Potter P. et al. Allergy 2013; 68 (Suppl 97):275 Potter et al. Pediatr Allergy Immunol. 2013; 24(3) 144-50. Bousquet et al. ARIA Guidelines 2008. Allergy, 2008; 63 (Suppl 86): 8-160 Zuberbier T et al. EAACI/GA2LEN/EDF/WAO Urticaria Guideline. Allergy, 2009; 64: 1417-1426

INOVA FOCUS

NEW

PAF

AWAY THEIR ALLERGIES. 1,2

HAVE YOU HEARD OF ANTI-HISTA-PAF ? #

RUPANASE BLOCKS BOTH HISTAMINE AND PAF* FOR MORE EFFECTIVE RELIEF OF ALLERGIC RHINITIS AND URTICARIA SYMPTOMS.2-4 Once-daily 24-hour relief†5 Non-drowsy6 Relieves AR§ symptoms dose3 and chronic urticaria symptoms

IN EN! R D L I CH ONCE DAILY

BANANA FLAVOUR *platelet activating factor antihistamine/anti-platelet activating factor § Allergic Rhinitis † based on once a day dosing #

Syringe included

References: 1. Ridolo E, et al. Rupatadine for the treatment of allergic rhinitis and urticaria: a look at the clinical data. Clin Invest 2014;4(5):453-461. 2. 2006;7(14):1989-2001. 3. Potter P, et al. Rupatadine oral solution in children with persistent allergic rhinitis: A randomized, double-blind, placebo-controlled study. Pediatr Allergy Immunol. 2013;24(2):144-150. 4. spontaneous urticaria in children aged 2–11 years. Pediatr Allergy Immunol. 2016;27(1):55-61. 5. Valle M, et al. PD39 - Application of population pharmacokinetic modeling and simulation in the design of the optimal dose regime of rupatadine in children 2-5 year old children. Clin Transl Allergy 2014;4(Suppl 1):P39. 6. RUPANASE Junior approved package insert, June 2020. Scheduling status: S2 Proprietary name and dosage form: Rupanase Junior Oral Solution. Composition: Each mℓ of oral solution contains: 1,28 mg rupatadine fumarate equivalent to 1 mg rupatadine base. Pharmacological A.5.7.1 Antihistaminics. Registration number: 50/5.7.1/0569. Name and business address of applicant: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 14517L. IN4026/21

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Amino acids and immunity Amino acids, especially L- Arginine may improve immune response as they are involved T-Cell proliferation and the development of cell memory. L-arginine plays a key role in modulating host defences and cellular immunity. This is a summary of a CPD article available on www.medicalchronicle.co.za

O UNDERSTAND HOW vital amino acids are, we have to understand how essential proteins are to life. Next to water, protein makes up the greatest portion of our body weight. Almost 50% of the human body is composed of proteins. In our bodies, proteins make up cells, muscles, tissue and so much more. Immunoglobulins (antibodies) are proteins that fight antigens such as bacteria. Proteins require amino acids, which also enable vitamins and minerals to perform their jobs properly, even if the vitamin or mineral is absorbed into the body, they cannot be effective unless the necessary amino acids are present. Amino acids’ role in protein synthesis is well defined, but they contribute to a host of other intracellular metabolic pathways, including adenosine triphosphate (ATP) generation, nucleotide synthesis, and redox balance, to support cellular and organismal function. Immune cells critically depend

on such pathways to acquire energy and biomass as well as to reprogramme their metabolism upon activation to support growth, proliferation, and effector functions. Amino acid metabolism plays a key role in this metabolic rewiring, and it supports various immune cell functions beyond increased protein synthesis (Kelly et al, 2020). Although a balanced diet with high quality and sufficient quantity of nutrients is essential, there is growing evidence that some non-synthetic supplements can assist optimal nutrition. The use of nutritional supplements especially the provision of amino acids, has grown year-on-year. There are few articles in the literature to address the topic of nutritional supplementation and immune consequences, from a metabolic and molecular standpoint. The use of proteins and amino acids for supplementation deserves special attention, since these molecules are critical for anti-

oxidant and fuel provision, participating in the whole-body energy homeostasis, growth, development, recovery and immune responses (Cruzat et al, 2014). Most of the recent studies clearly demonstrate the importance of nutrients for trauma and surgical patients, as well as the frail elderly. So, strategies that include specific nutrients for enhanced immune function are frequently used in clinical nutrition therapy (such as for patients with burns, sepsis, cancer, HIV and post-surgical situations using enteral nutrition. However, the concept of 'immuno-nutrition' may be more widely applied, since the specific nutritional substrates for immune response can act on alternative targets, such as the gut mucosal barrier (Cruzat et al, 2014). L-GLUTAMINE L-Glutamine is known as an ‘immunonutrient’, which is fuel for many immune cells, such as lymphocytes

and macrophages. In cases of injury or inflammation, cells have a greater need for glutamine as it improves the neutrophils bactericidal function. Glutamine also results in restoration of cell function in normal cells and maintains the integrity of the cell. Taking oral lysine daily seems to reduce recurrences of herpes simplex labalis infections by blocking the replication of the HSV-1. Oral lysine also seems to reduce the severity and healing time of herpes simplex labalis infections. A specific combination product containing lysine and zinc oxide seems to decrease symptoms and duration of herpes lesions. L-glutamine is probably the most widely recognised immuno-nutrient since it can be used as an oxidisable fuel, a substrate for nucleotide synthesis, a modulator of intermediary metabolism of amino acids, heat shock proteins (HSP) expression and a component of glutathione (GSH)-

Support your immune system ENERGY

WELLBEING

IMMUNE DEFENCE

MENTAL VITALITY

5- in-1 supplement with Amino Acids - Antioxidants - B - Complex vitamins - Vitamins & Minerals This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Health Supplements do not replace a healthy diet and lifestyle. Proprietary name (and dosage form): StaminoGro®Tablets. Composition: Each tablet contains: 187,5 mg L-Arginine, 150 mg, L-Glutamine, 75 mg Glycine, 50 mg L-Lysine, 45 mg L-Ornithine, 450 _g Beta-carotene, 5 mg Lipoic Acid, 15 _g Selenium (AAC), 75 mg Vitamin C, 5 IU Vitamin E, 5,62 mg Zinc, 125 _g Folic Acid, 0,75 mg Vitamin B1, 1,25 mg Vitamin B2, 6 mg Vitamin B3, 6 mg Vitamin B5, 6 mg Vitamin B6, 6 _g Vitamin B12, 100 mg Calcium, 75 IU Vitamin D3, 20 _g Biotin, 4,1 mg Choline, 500 _g Copper (AAC), 60 mg Magnesium, 1 mg Manganese. Full product information refer to www.inovapharma.co.za or www.staminogro.com Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07,15E Riley Road, Bedfordview. Tel. No. 011 087 0000. IN1500/21

16 May 2021CHRONICLE | MEDICAL CHRONICLE 26 MEDICAL

ONLINE | CPD CPD | Expires 31/03/2022 mediated antioxidant defence, serving as a key substrate for cell survival, maintenance and proliferation. Several clinical nutritional studies in the 1990s found benefits in the dramatic decrease in plasma and tissues L-glutamine levels as well as immune cell function, including lymphocytes and neutrophils. Several important publications have described the importance of L-glutamine in clinical nutrition (Cruzat et al, 2014).

Effect of oral glutamine on whole body carbohydrate storage Glutamine is a glucogenic, nonessential amino acid that can be synthesised within the tissues of the body, with skeletal muscle and liver being the most quantitatively important producers. There is considerable evidence to suggest that the size of the intramuscular glutamine pool exerts a controlling influence over whole body protein balance. For example, during various catabolic conditions such as after surgery, the pool size is reduced and in the anabolic state it is increased. There is also some evidence to suggest that a relative immuno deficiency that is symptomatic of ‘overtraining syndrome’ may be one consequence of glutamine depletion, because glutamine is a favoured fuel and nitrogen source for macrophages and lymphocytes. It has also been reported that glutamine stimulates the activity of hepatic glycogen synthase, possibly through a cellswelling-mediated action. Glutamine is readily taken up into skeletal muscle via the high-capacity, sodium-dependent system Nm, resulting in an increased intramuscular glutamine concentration and thus promoting cell swelling. Meijer et al found that both hepatocyte swelling and a rise in glutamate concentration (both of which would result from an increased systemic glutamine concentration) stimulate glycogen synthase phosphatase and cause an activation of glycogen synthase through dephosphorylation. “Work from our laboratory suggests that, in vitro, myotube glycogen synthesis is also modulated by cell volume changes, independently of changes in glucose uptake. In recent studies, our laboratory also found the intravenous administration of glutamine to promote muscle glycogen resynthesis during recovery after exhaustive exercise, possibly because glutamine was acting as a glycogenic substrate and/or through an activation of glycogen synthase,” the authors stated. Provision of glutamine orally was successful in elevating plasma glutamine at the peak concentration by 46%, which suggests that a substantial proportion of the oral load escaped utilisation by the gut mucosal cells and uptake by the liver and kidneys. If the entire glutamine dose had been distributed within the blood and extracellular fluid compartments, then a 3-mM rise in blood glutamine concentration might have been expected, whereas plasma glutamine concentration was only observed to rise by 0.3mM. This might suggest that only 10% of the oral dose reached the extracellular fluid compartments.

Ingestion of glutamine alone appears to promote muscle glycogen resynthesis during recovery from exhaustive exercise, relative to that expected from studies in which no substrate was provided. The promotion of muscle glycogen synthesis by consumption of glucose polymer and of glutamine was not additive. However, the addition of glutamine to the glucose polymer drink resulted in a greater storage of carbohydrate in sites other than skeletal muscle, the most likely candidate being the liver. L-arginine – NO (Nitric Oxide) pathway According to Cruzat et al, 2014, nitric oxide (NO) plays an important role in many functions in the body regulating

vasodilatation and blood flow, inflammation and immune system activation, insulin secretion and sensitivity, mitochondrial function and neurotransmission. The amino acid L-arginine is the main precursor of NO via nitric oxide synthase (NOS) activity, so the availability of this amino acid may modulate NO production in conditions of competition for this amino acid. Dietary L-arginine and L-citrulline supplements may increase levels of NO metabolites. CONCLUSION The body is constantly recycling proteins and even though the body makes 80% of the amino acids we need, the other 20%

required from our diet is very important. Amino acids will feed into and impact on the regulation of key metabolic pathways in immune cells and the cellular oxidative stress response. At the anti-inflammatory molecular level, new findings have been reported such as enhancement of HSP levels, NO synthesis, and GSH/ oxidised glutathione regulation, all essential for optimal immune function. Supplementation is critical because if dietary protein is inadequate, body protein is broken down faster to replenish the amino acid pool ie muscle. References available on request.

Support your immune system

5- in-1 supplement with Amino Acids - Antioxidants - B - Complex vitamins - Vitamins & Minerals

ENERGY

WELLBEING

IMMUNE DEFENCE

MENTAL VITALITY

This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Health Supplements do not replace a healthy diet and lifestyle. Proprietary name (and dosage form): StaminoGro®Tablets. Composition: Each tablet contains: 187,5 mg L-Arginine, 150 mg, L-Glutamine, 75 mg Glycine, 50 mg L-Lysine, 45 mg L-Ornithine, 450 _g Beta-carotene, 5 mg Lipoic Acid, 15 _g Selenium (AAC), 75 mg Vitamin C, 5 IU Vitamin E, 5,62 mg Zinc, 125 _g Folic Acid, 0,75 mg Vitamin B1, 1,25 mg Vitamin B2, 6 mg Vitamin B3, 6 mg Vitamin B5, 6 mg Vitamin B6, 6 _g Vitamin B12, 100 mg Calcium, 75 IU Vitamin D3, 20 _g Biotin, 4,1 mg Choline, 500 _g Copper (AAC), 60 mg Magnesium, 1 mg Manganese. Full product information refer to www.inovapharma.co.za or www.staminogro.com Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07,15E Riley Road, Bedfordview. Tel. No. 011 087 0000. IN1500/21

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The role of demulcents and secretolytics

in treating coughs

There is a global trend in both consumers and healthcare practitioners to opt for natural medication and cough syrups before heading to chemical or medicinal treatment. This is a summary of a CPD article available on www.medicalchronicle.co.za

ATURAL INGREDIENTS SUCH as thyme, ivy and marshmallow root have been used for over 1000 years to relieve cough and have proven clinical efficacy and safety. Healthcare practitioners have noted that patient and parent compliance is better with a natural product vs a chemical product and there might be less side effects using natural products. According to Dr Peter Voitl, a specialist paediatrician and paediatric expert for the European Medicines Commission for Paediatrics with special focus on phytotherapy, one could make the argument that demulcents like Althaea officinalis, more commonly known as marshmallow root extract, could be used as a first-line treatment for cough.

MARSHMALLOW ROOT EXTRACT According to EMA and WHO monographs Althaea officinalis (marshmallow root extract) is a herbal demulcent traditionally used for symptomatic treatment of oral or pharyngeal irritation and associated dry cough. It has also been used as an emollient for wounds and dry skin. Herbal demulcents are rich in carbohydrate mucilage which creates a physical coating on the cough receptors located in the throat/epipharynx. This forms a protective barrier against irritants, relieves irritation and soothes inflamed tissues, such as mucous membranes. Marshmallow root extract coats the cough receptors to reduce receptor sensitivity and therefore the urge to cough.

According to Al-snafi (2013), the demulcent effects of marshmallow root are due to its high content of polysaccharide hydrocolloids, which form a protective coating on the oral and pharyngeal mucosa, soothing local irritation and inflammation. The authors explained that it significantly reduced the intensity and the number of cough episodes triggered from laryngopharyngeal and tracheobronchial areas, with statistically significant coughsuppressing activity that was noticeably higher than that of the other drugs used in clinical practice to treat coughing. Marshmallow root extract is comprised of long-stranded polysaccharides that are too large to be systemically absorbed and since it does not reach the larynx,

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18 May 2021CHRONICLE | MEDICAL CHRONICLE 28 MEDICAL

DRY2

1-3

TICKLY WET CHESTY2 MUCUS

1-3

ANY COUGH*

trachea and bronchi it does not impact the cough reflex within these areas and can be safely administered with expectorants. A combination of an expectorant and a demulcent can be beneficial during colds, when a cough can change from dry to wet and back to dry again. Considering that demulcents act locally and not centrally to reduce the urge to cough, the combination with an expectorant will facilitate the patient to cough up mucus. According to Sultana et al (2016), common symptoms associated with a cough include an itchy throat, chest pain and congestion. The repetition of coughing promotes inflammation and discomfort, which in turn result in more coughing. Ciuman (2012) found

Scheduling Status: Proprietary name (and dosage form): Pholtex Bronchostop® Cough Syrup. Composition: Each 5 ml syrup contains: 39 mg Thyme herb extract and 277 mg Marshmallow root dry extract. Pharmacological Classification: Complementary Medicine: Discipline Specific Traditional Claims D33.6 Western Herbal Medicine. Scheduling Status: Proprietary name (and dosage form): Pholtex Bronchostop® Cough Pastilles. Composition: Each pastille contains: 51.1 mg Thyme herb extract and 4.5 mg Marshmallow root dry extract. Pharmacological Classification: Complementary Medicine: Discipline Specific Traditional Claims D33.6 Western Herbal Medicine. Proprietary name (and dosage form): Pholtex Bronchostop® Children’s Cough Syrup. Composition: Each 5 ml syrup contains: 48 mg Marshmallow root dry extract and 250 mg Honey. These unregistered medicines have not been evaluated by the SAHPRA for their quality, safety or intended use. The claims made in this material is for medical information and educational purposes only. For full prescribing information, refer to the individual professional information or instructions for use. Further information is available on request from iNova Pharmaceuticals. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. 17015L. IN3979/21.

2021/05/05 10:46

CPD | Expires 30/04/2022 ONLINE | CPD that phytopharmaceuticals containing marshmallow leaf or root have an antitussive and abirritative effect as the polysaccharides within the substance swell with water and produce a mucous layer inhibiting the hyperactive ciliary activity. This makes it suitable for dry coughs. Dr Voitl stressed that the coating effect of marshmallow root extract is a key differentiator vs other natural ingredients and is a highly underestimated benefit for cough. In his opinion, it could be used as a first-line treatment for cough. The safety of use in defined conditions of marshmallow root products can be derived from the long-standing use and experience as well as from various clinical studies (EMA Monograph). One study cited in the EMA monographs examines the effect of Althaea Officinalis on cough associated with ACE inhibitors. In this study patients completed a questionnaire rating their cough after four weeks of treatment vs placebo. The outcome showed significant cough score reduction with no differences in the spirometry parameters (Rouhi and Ganji, 2007 - EMA). Dr Voitl however suggests that a change from the ACE inhibitor to a sartan pharmaceutical should be considered and that a stronger chemical central acting antitussives may be necessary to supress the cough. A retrospective observational study on 599 children documented by 53 physicians

assessed the efficacy and tolerability of Marshmallow root extract in the treatment of mucous membrane irritation in the mouth and pharynx and associated dry irritating cough and found that marshmallow root extract had an efficacy of >90% (Bassler, 2005 - EMA). https://www.karger.com/ Article/Abstract/489560

impaired in secretolytic action.” According to Goldman (2014), there is increasing evidence that a single dose of honey might reduce mucus secretion and reduce cough in children. It is important to note that honey shouldn’t be used in patients under one year due to the risk of botulism.

HONEY Honey is another demulcent commonly used to relieve cough in children over the age of one and is recommended by the World Health Organisation. Demulcents act quickly to coat the throat and relieve the cough. It both reduces the cough frequency and severity of cough. Honey also protects the pharyngeal mucosa against irritants. Demulcents are highly beneficial at night as it reduces cough, to allow for a peaceful night’s rest. According to Dr Voitl , demulcents are highly valuable in children for relief of cough, as cough in children is often characterised by painful irritation. Dr Voitl advises that “a wet cough in children does not necessarily require treatment because their cilia have better sectromotoric activity than in adults. The additional secretolytic action of a cough syrup is not always necessary for children and in some cases can be counterproductive. As children become older and become exposed to smoke, pollution, allergens, their cilia action may become

THYME Where secretolytic actions are necessary, Dr Voitl expressed his preference for thyme as an expectorant. According to the EMA monograph, thyme extract has been used orally to treat dyspepsia and other gastrointestinal disturbances, coughs due to colds, bronchitis and pertussis, and laryngitis and tonsillitis (as a gargle). Topical applications of thyme extract have been used in the treatment of minor wounds, the common cold, disorders of the oral cavity, and as an antibacterial agent in oral hygiene. Both the essential oil and thymol are ingredients of a number of proprietary drugs including antiseptic and healing ointments, syrups for the treatment of respiratory disorders, and preparations for inhalation. According to Capasso (2003), thyme is a direct acting expectorant that contains essential oils that stimulate the serous glandular cells and ciliated epithelium. The article suggests that post administration the essential oils are absorbed from the

gastro-intestinal tract into the blood and are partially eliminated through the lungs. As the exhaled molecules pass through the bronchial tree, they stimulate the bronchial gland function, suppress mucous glandular activity and reduce surface tension and improve mucociliary clearance. Various studies state that Thyme (Thymus Vulgaris) provides expectorant, mucolytic, and antispasmodic effects. Data also suggests that thyme has potential antibacterial, antifungal and antiviral activity (Assessment Report, 2013). CONCLUSION Dr Voitl concluded that marshmallow root extract, honey and thyme are natural ingredients that are a safe first-line therapy for cough. He affirmed that demulcents are important in treating cough and are highly beneficial from the age of one year to adulthood. Dr Voitl regards demulcents as a highly underestimated field in effectively treating coughs. He stressed the importance of taste when administrating products to children, stating “For a first-line treatment for children, you need something that the patient is willing to take in terms of taste, it should be proven to be safe, and effective for the different bronchial system of children.”

Reference available on request.

RELIEVES ANY COUGH*

1-3

Marshmallow root dry extract

DRY2

• Soothes dry, tickly coughs1-3,5-7

WET CHESTY2

• Creates protective coating that relieves irritation and inflammation1-3,5-7

MUCUS

• Reduces the urge to cough1-3,5-7

1-3

TICKLY

Thyme herb extract • Relieves wet, chesty coughs1-3,5 • Thins mucus, making it easier to cough up1-3,5

* Children’s Cough Syrup - Cough associated with colds ** Syrups only References: 1. Pholtex Bronchostop® Cough Syrup professional information, September 2019. 2. Pholtex Bronchostop® Children’s Cough Syrup instructions for Use, February 2019. 3. Pholtex Bronchostop® Cough Pastilles professional information, September 2019. 4. IMS. Data on file. 5. Capasso F. et al. Phytotherapy. Chapter 18 – Plants and the respiratory System. Springer Science & Business Media, 2003. 6. Al-Snafi AE. The Pharmaceutical Importance of Althaea officinalis and Althaea rosea: A Review. International Journal of PharmTech Research 2013;5(3):1378-1385. 7. WHO Herbal monographs Volume 2 [online]. Available from https://apps. who.int/medicinedocs/en/d/Js4927e/. Accessed 13 November 2019. Scheduling Status: Proprietary name (and dosage form): Pholtex Bronchostop® Cough Syrup. Composition: Each 5 ml syrup contains: 39 mg Thyme herb extract and 277 mg Marshmallow root dry extract. Pharmacological Classification: Complementary Medicine: Discipline Specific Traditional Claims D33.6 Western Herbal Medicine. Scheduling Status: Proprietary name (and dosage form): Pholtex Bronchostop® Cough Pastilles. Composition: Each pastille contains: 51.1 mg Thyme herb extract and 4.5 mg Marshmallow root dry extract. Pharmacological Classification: Complementary Medicine: Discipline Specific Traditional Claims D33.6 Western Herbal Medicine. Proprietary name (and dosage form): Pholtex Bronchostop® Children’s Cough Syrup. Composition: Each 5 ml syrup contains: 48 mg Marshmallow root dry extract and 250 mg Honey. These unregistered medicines have not been evaluated by the SAHPRA for their quality, safety or intended use. The claims made in this material is for medical information and educational purposes only. For full prescribing information, refer to the individual professional information or instructions for use. Further information is available on request from iNova Pharmaceuticals. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. 17015L. IN3979/21.

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ADVERTORIAL

INOVA FOCUS

Immunity support, all year round

A balanced immune system is key to protect the body from illness, all year round. The first line of defence involves a healthy lifestyle.

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BEFORE IT BEATS YOU

VITAMIN

BEAT THE FLU

PELARGONIUM SIDOIDES Many herbal medicines used in ethnomedicine are beneficial in the treatment of infectious conditions such as respiratory ailments, cold and flu. Locally, many such medicines are derived from the plant Pelargonium sidoides, also known as the African geranium. Interest in P. sidoides and its extract EPs 7630 has been heightened by reports of therapeutic benefits in infectious conditions of the respiratory tract such as TB and related diseases. Pelargonium sidoides has strong immunomodulatory effects that increase the

Even though our bodies need strong immune systems all year round, they may be more compromised or at risk at certain times of the year. Winter for instance is the time of year when cold or flu viruses are more prevalent. Viruses pose a considerable challenge to the body’s immune system because they hide inside cells. This makes it difficult for antibodies to reach them. Viruses attach themselves to different host cells in the body and inject their genetic material into it. The viral DNA or RNA incorporates itself into the host cell’s genetic material where the virus replicates. During release, the newly created viruses are released from the host cell, which causes the host cell to break apart. It is important to realise that a viral infection does not always lead to

speed of viral replication. The 4 key herbal ingredients contained in FLUGON® are: • Pelargonium • Quercetin • Echinacea • Elderberry

illness. The viral infection occurs when the virus begins to replicate and multiply. The illness or disease only occurs when many body cells are damaged by the infection, which is also when the symptoms appear. That is why a strong immune system plays such a vital role – if the immune system manages to fight off the virus that entered the cells and replicated (before the host cells are damaged), the patient will not get sick (develop symptoms). The body will, however, respond in different ways to fight these foreign bodies. The lifecycle of a virus can be divided into several major stages: attachment, entry, uncoating, replication, maturation, and release. FLUGON®’s herbal ingredients interfere with this viral life cycle. The herbal antivirals in Flugon help lessen the severity of symptoms and help shorten the duration of cold or flu while reducing the

• Selenium • Vitamin C

HER

everal components of a healthy lifestyle have been shown to play a key role in supporting the immune system. Evidence suggests that regular moderate activity is particularly beneficial for immune enhancement and reducing the risk of infection. Getting enough sleep, staying hydrated and managing stress are all components of a healthy lifestyle. Avoiding nutritional deficiencies seems the most pragmatic nutritional strategy. This can be achieved with a balanced diet which includes a variety of fruits and vegetables. Further benefit may be gained from some supplements which support a healthy diet, helping to prepare the body’s immune system to fight off unwanted infections. The FLUGON® range contains the following vitamins and minerals to help support the immune system: • Vitamin D3 • Zinc

VITAMIN D

These unregistered medicines have not been evaluated by the SAHPRA for its quality, safety or intended use. For full product information refer to the individual packs. For more information, speak to your healthcare provider. Legals visit www.flugon.co.za. Name and business address: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za IN Number: IN1410/21

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MEDICAL CHRONICLE | May 2021 21

ADVERTORIAL

INOVA FOCUS

The Flugon Colds, Flu and Allergy range contains ingredients such as Beta-carotene, citrus bioflavonoids, for their antioxidant properties

release of pro-inflammatory cytokines which are responsible for supporting an immune response. It has also been demonstrated to have an indirect antibacterial effect through inhibition of bacterial adhesion to human epithelial cells. It interferes with the virus so it cannot attach to the surface of epithelial cells, thereby lowering the potential replication of the virus. In numerous randomised controlled trials and systematic reviews such as those published by the Cochrane Collaboration, Pelargonium sidoides extract EPs 7630 was shown to be effective in acute respiratory tract infections (aRTI) in all investigated age-groups. Following the therapeutic use of EPs 7630 in modern phytomedicine for the treatment of upper respiratory tract infections, the demonstrated antiviral effects of this extract against a panel of viruses including seasonal influenza A virus strains (H1N1, H3N2), respiratory syncytial virus, human coronavirus, parainfluenza virus and coxsackie virus provided evidence of feasible beneficial effects in patients suffering from acute bronchitis and related infectious diseases. In a study of EPs 7630’s effectiveness versus acute bronchitis, as measured by reductions in Bronchitis Severity Score (BSS), it was found that, between day 0

22 May 2021 | MEDICAL CHRONICLE

and day 7, the mean BSS score decreased by 2.7±2.3 (mean±standard deviation) for placebo, 4.3±1.9 for a group treated with 30 mg EPs 7630, 6.1±2.1 for the 60 mg group and 6.3±2.0 points for the 90 mg group. In the same study, an evaluation of patients’ satisfaction with

Pelargonium sidoides has strong immunomodulatory effects that increase the release of proinflammatory cytokines which are responsible for supporting an immune response. treatment showed that patients were more often satisfied or very satisfied with EPs 7630 (55.9% for EPs 7630 30 mg, 86.2% for EPs 7630 60 mg, 84.0% for EPs 7630 90 mg) than with placebo (23.5%). In a study examining the effect of Eps 7630 on symptoms of the common cold, the

treatment outcome was assessed as better in the EPs 7630 group than in the placebo group by both the investigator and the patients on day five. From baseline to day five, common cold symptoms, assessed as symptom intensity differences (SSID) of the cold intensity score (CIS), improved by 14.6 points in EPs 7630 treated group compared with 7.6 points in the placebo group. Furthermore, after 10 days, 63.5% versus 11.8% in the EPs 7630 versus placebo group were clinically cured (CIS=0). In multiple studies, adverse events associated with P. sidoides were assessed as being non-serious, minor, or transitory, with the most frequent adverse events being mild gastrointestinal complaints. QUERCETIN Quercetin is the aglycone (noncarbohydrate portion) of rutin, quercetrin and other glycoside flavonoids. It is widely found in the plant kingdom, including in oak trees (Quercus spp.), onions (Allium cepa) and tea (Camellia sinensis). Quercetin is also found in red wine, grapefruit, onions, apples, black tea, and, in lesser amounts, in leafy green vegetables and beans. It has effects on many different enzymatic systems in the body, most of them via its interaction with the calcium-regulating enzyme calmodulin.

A bioflavonoid, quercetin has both antioxidant and anti-inflammatory activity. Quercetin is known for its antioxidant activity in radical scavenging and antiallergic properties characterised by stimulation of the immune system, antiviral activity, inhibition of histamine release, decrease in pro-inflammatory cytokines, leukotrienes creation, and suppression of interleukin IL-4 production. Its potent antioxidant effect is directly due to its ability to be converted into substances that protect against oxidative stress. It is also effective in the inhibition of enzymes such as lipoxygenase, eosinophil and peroxidase and the suppression of inflammatory mediators. All mentioned mechanisms of action contribute to the anti-inflammatory and immunomodulating properties of quercetin that can be effectively utilised in treatment of latephase, and late-late-phase bronchial asthma responses, allergic rhinitis and restricted peanut-induced anaphylactic reactions. Plant extract of quercetin is the main ingredient of many potential antiallergic drugs, supplements and enriched products. Quercetin is an effective eosinophilic inflammation suppressor for diseases like allergic rhinitis and asthma. A study found

MEDICAL CHRONICLE 31

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INOVA FOCUS

ADVERTORIAL that quercetin-loaded microemulsion had a powerful anti-inflammatory effect and inhibited, in a dose-dependent way, eosinophil recruitment to the bronchoalveolar lavage fluid, as well as reducing mucous production in the lungs. ECHINACEA Echinacea is a flowering plant that grows in the U.S. and Canada, also called coneflower. As a herbal medicine, it has been used for centuries, customarily as a treatment for the common cold, coughs, bronchitis, upper respiratory infections, and some inflammatory conditions.

ELDERBERRY EXTRACT Elderberry (Sambucus nigra L.) has a long history of being used in treating colds and influenza. This folk belief has been partly validated by the results of some studies, which show that elderberries do indeed have significant benefits against cold and influenza symptoms. Elderberry’s antiviral properties are a function of its proven ability to prevent viral replication by neutralising hemagglutinin spikes on the surface of viruses. This prevents viral replication by neutralising viral surface proteins. In a study of elderberry extract’s effects using Real Time Mass Spectrometry and a Direct Binding Assay, it was found that

pain and fever. Anthocyanins have received attention as important dietary constituents that may provide health benefits and contribute antioxidant capacity beyond that provided by essential micronutrients such as ascorbate, tocopherols, and selenium.

elderberry inhibited human influenza A (H1N1) infection in vitro. The Direct Binding Assay established that flavonoids from the elderberry extract bind to H1N1 virions and, when bound, block the ability of the viruses to infect host cells, and that this inhibition compares favourably to the known antiinfluenza activities of Oseltamivir and Amantadine. Elderberry is rich in phytonutrients (chemical compounds produced by plants) and natural nutrients, including anthocyanins, vitamins A, C, B6 and calcium. They are effective against cold and flu viruses thanks to anthocyanins that enhance immune function and have antiinflammatory action that may reduce aches,

IN CONCLUSION: Nature’s cycle will run its course and viruses will continue to be with us, especially during winter. A strong immune system plays a vital role in fighting infections. FLUGON® supports immunity and helps to shorten the duration of cold or flu symptoms. Furthermore, FLUGON® is non-drowsy and can be taken daily for immune support.

A study found that quercetin-loaded microemulsion had a powerful antiinflammatory effect and inhibited, in a dose-dependent way, eosinophil recruitment to the bronchoalveolar lavage fluid, as well as reducing mucous production in the lungs

HELP BUILD YOUR IMMUNITY TO

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Family offering*

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BEFORE IT BEATS YOU

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Echinacea has important immune support and anti-inflammatory properties, especially for the alleviation of cold symptoms. It interferes with the ability of the flu virus to attach to and enter epithelial cells and may prevent the replication of the virus within infected cells. These immune support and maintenance effects are caused by three mechanisms: Phagocytosis activation: Studies show that the plant and its active components affect the phagocytic immune system, but not the specifically acquired immune system. Enhancement of respiratory activity: Evidence from published trials suggests that echinacea may be beneficial for the early treatment of acute upper respiratory tract infections. Increased white blood cell mobility: Echinacea may invoke an immune response through altered expression of leukocyte hsp70 and increased white cell counts. Echinacea may also reverse inflammation caused by bacteria by reducing inflammatory cytokines. Rhinovirus, HSV-1, influenza A virus, adenovirus type 3 and 11, and respiratory syncytial virus stimulate the secretion of more than 30 different cytokines, including the pro-inflammatory cytokines. These are collectively involved in many of the symptoms common to colds and flu, such as sneezing, fever, sore throat, nasal discharges and inflammation in various respiratory tissues. Echinacea was able to completely or partly reverse this stimulation.

VITAMIN D

* Flugon offers a range of products from the age of 1 year . # Not in all Flugon products. These unregistered medicines have not been evaluated by the SAHPRA for its quality, safety or intended use. For full product information refer to the individual packs. For more information, speak to your healthcare provider. Legals visit www.flugon.co.za. Name and business address: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za IN Number: IN1409/21

MEDICAL CHRONICLE | May 2021 23

CPD| Expires 31/05/2022 CPD

Painful throat infections and treatment with benzydamine & chlorhexidine combinations

To complete the quiz and earn your 3 points, find this article on www.medicalacademic.co.za. You will need to read and complete the questions for the CPD found on page 36 as well, in order to earn all 3 points

The sore throat is one of the most common conditions encountered in a general practice. Pharyngitis is inflammation of the mucous membranes that line the back of the throat, or pharynx. This inflammation can cause discomfort, dryness and difficulty swallowing.

NFLAMMATION OF THE throat is a common medical issue, and it can result from a variety of causes, including: • Laryngitis • Tonsillitis • Throat ulcers. The main symptom of pharyngitis is a sore, dry, or itchy throat. Additional symptoms may appear depending on the type of infection, such as cold or flu symptoms. Acute pharyngitis is characterised by the rapid onset of sore throat and pharyngeal inflammation (with or without exudate). Absence of cough, nasal congestion and nasal discharge suggests a bacterial, rather than viral aetiology. Acute pharyngitis can be caused by a variety of viral and bacterial pathogens, including group A Streptococcus (GAS), as well as fungal pathogens (Candida). Bacterial pharyngitis is more common in winter (or early spring),

while enteroviral infection is more common in the summer and fall. Acute pharyngitis is generally a self-limited condition with resolution within two weeks. Quality of life in patients with acute pharyngitis or tonsillitis is significantly lower than in healthy persons, and it should be taken into account when efficacy of new therapeutic options is investigated. Benzydamine hydrochloride is a nonsteroidal anti-inflammatory molecule with local anaesthetic and analgesic activity, that delivers targeted relief from inflammatory conditions in the mouth and throat. Its unique chemical nature and mechanism of action makes benzydamine unique. CHEMICAL NATURE OF BENZYDAMINE VS OTHER NSAIDs Unlike other NSAIDs, which are aspirin-like and therefore acidic chemical molecules, benzydamine is a base. This explains its tendency to preferentially concentrate in inflamed tissues. Once at the site of

inflammation, benzydamine acts on a number of inflammatory mechanisms to relieve pain, redness and swelling. BENZYDAMINE’S MECHANISMS OF ACTION Cytokines are cell-signalling proteins that have a specific effect on the interactions and communications between cells and immune responses, and stimulate the movement of cells towards sites of inflammation. Benzydamine’s main anti-inflammatory activity results from its inhibition of the production of proinflammatory cytokines, mainly tumour necrosis factor alpha (TNF-α) and Interleukin-1 beta (IL-1α), a major driver of inflammation, and monocyte chemotactic protein-1 (MCP1). These are common pro-inflammatory cytokines. So although it is classified as a NSAID, it works as a CSAID (cytokine-suppressive antiinflammatory drug). Benzydamine acts as a modulator of cytokines, ensuring it does not inhibit antiinflammatory cytokines: Interleukin-10 (IL-10) Interleukin-1ra (IL-1ra). Benzydamine also elicits supportive anti-inflammatory activity, through cell membrane stabilisation, reducing both capillary vasodilation and the release of proinflammatory substances. Benzydamine’s local anaesthetic effect may be related to its capability for inhibiting the release of inflammatory mediators such as substance P, which causes the release of histamine from mast cells. The prevention of substance P release further contributes to an anti-inflammatory effect. BENZYDAMINE’S SAFETY PROFILE Benzydamine’s chemical structure makes

SORE THROAT?

it highly lipid soluble, with low plasma protein binding capacity. This promotes its absorption and selective binding into inflamed tissues, where it accumulates, reducing the possibility of systemic side effects. Benzydamine’s targeted activity makes it ideal for topical application and it has no known drug interactions. Benzydamine is only a weak inhibitor of prostaglandin synthesis, even following oral application, meaning it is an efficacious, more gastro-friendly anti-inflammatory choice. It is a well-established molecule with over 50 years of clinical experience. Its unique triple action provides antiinflammatory, analgesic and local anaesthetic relief for your patients with inflammatory conditions of the mouth and throat. Effects of chlorhexidine/benzydamine mouth spray on pain and quality of life in acute viral pharyngitis. Cingi et al conducted a prospective, randomised, double-blind, placebocontrolled, multicentre study to assess the efficacy of chlorhexidine gluconate/ benzydamine hydrochloride mouth spray for reducing pain and improving quality of life in patients with acute viral pharyngitis. Chlorhexidine belongs to the antimicrobial class of drugs. It works by decreasing the amount of bacteria in the mouth, providing a broad spectrum antiseptic activity, killing or inhibiting the growth of bacteria, viruses and fungi. Prior to treatment, patients rated the intensity of their pain on a visual analogue scale and evaluated their quality of life on the 36-Item, Short-Form Health Survey. Patients were then randomised to receive either paracetamol plus chlorhexidine/ benzydamine or paracetamol plus placebo

Fast, effective relief of a painful sore throat:1,2,3

References: 1. Andolex®-C Oral Rinse approved package insert. February 2017. 2. Almazan NA. Benzydamine HCl 0.15 % for Oropharyngeal Diseases and Surgeries: A Review of Clinical Trials. Philippine Scientific J. 2009;42(1):38-42. 3. Simard-Savoie S, Forest D. TOPICAL ANAESTHETIC ACTIVITY OF BENZYDAMINE. Cur Ther Res. 1978;23(6):734-745. 4. Impact Rx, December 2020. 5. IMS Total Private Market Value MAT, December 2020. Scheduling status: S1 Proprietary name (and dosage form): ANDOLEX®-C ORAL RINSE. Composition: Each 15 ml contains: Benzydamine HCI 22.5 mg, Chlorhexidine gluconate 18 mg, Alcohol 9 % v/v. Pharmacological classification: A. 16.4 Nasopharyngeal and bucco-pharyngeal antiseptics. Indications: For the relief of minor infections and painful inflammatory conditions of the mouth and throat. Chlorhexidine in Andolex®-C Oral Rinse helps to reduce the development of plaque. Registration number: 31/16.4/0143. Name and business address: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). IN4234/21.

14 June 2021 | MEDICAL CHRONICLE 34 MEDICAL CHRONICLE

CPD | Expires 31/05/2022 CPD for seven days. On days three and seven of treatment, the participants again rated the intensity of their pain, and on day seven, they again rated their quality of life. A total of 164 patients were evaluable at study's end-80 in the chlorhexidine/benzydamine group and 84 in the control group. A comparison of self-evaluations revealed that the active treatment group reported less pain on both day three (p <0.001) and day seven (p = 0.002). Likewise, the chlorhexidine/benzydamine group reported a significantly better quality of life on day seven (p < 0.001). Chlorhexidine/ benzydamine was well tolerated, and no serious adverse events were observed. The same study author assessed the effect of chlorhexidine gluconate and benzydamine hydrochloride mouth spray, used in conjunction with antibiotic treatment, on the intensity of clinical signs and quality of life of patients with group A streptococcal tonsillopharyngitis. Methods: Patients (n = 147) with streptococcal tonsillopharyngitis were recruited and randomly allocated to either the treatment group (penicillin plus chlorhexidine and benzydamine; n = 72) or control group (penicillin plus placebo; n = 75). Blinded assessments were conducted before and after 10 days' treatment, using an intensity rating scale for clinical sign severity, a visual analogue scale for subjective health state, the Short Form 36 Health Questionnaire for quality of life, and a customised questionnaire for side effects. Results: The treatment group showed a statistically significant reduction in the intensity of clinical signs, compared with the control group. On treatment day seven, there was no significant difference in quality of life between the treatment and control groups. The treatment drugs were well tolerated, and no serious adverse events were observed.

persistent sore throat. Consider non-infectious causes of sore throat (eg gastro-oesophageal reflux disease, chronic irritation from cigarette smoke, alcohol or hay fever). CONCLUSION Clinical studies show that benzydamine/chlorhexidine sprays significantly reduce the pain of a viral sore throat without causing any serious side effects, while in Strep throat the combination has shown to alleviate the intensity of clinical signs when used alongside a standard antibiotic treatment.

REFERENCES Claassen J. The sore throat. Continuing Medical Education, [S.l.], v. 30, n. 9, p. 306-313, sep. 2012. ISSN 2078-5143. Available at: <http://www.cmej.org. za/index.php/cmej/article/view/2447/2535>. Date accessed: 26 May 2021. Cingi C, Songu M, Ural A, Erdogmus N et al. Effect of chlorhexidine gluconate and benzydamine hydrochloride mouth spray on clinical signs and quality of life of patients with streptococcal tonsillopharyngitis: multicentre, prospective, randomised, double-blinded, placebo-controlled study. J Laryngol Otol. 2011 Jun;125(6):620-5. doi: 10.1017/S0022215111000065. Epub 2011 Feb 11. PMID: 21310101. Cingi C, Songu M, Ural A et al. Effects of chlorhexidine/benzydamine mouth spray on pain and quality of life in acute viral pharyngitis: a prospective, randomized, double-blind, placebocontrolled, multicentre study. Ear Nose Throat J. 2010 Nov;89(11):546-9. PMID: 21086279. IMS Total Private Market Value MAT. December 2020.

Impact Rx, December 2020. Almazan NA. Benzydamine HCl 0.15% for Oropharyngeal Diseases and Surgeries: A Review of Clinical Trials. Philippine Scientific J 2009;42(1): 38-42. Andolex®-C Oral Rinse approved package insert. February 2017. Turnbull RS. Benzydamine Hydrochloride (Tantum) In the Management Of Oral Inflammatory Conditions. J Can Den Assoc 1995;61(2):127-134. Sironi M, Massimiliano L, Transidico P, et al. Differential effect of benzydamine on proversus anti-inflammatory cytokine production: lack of inhibition on interleukin-10 and interleukin-1 receptor antagonist. Int J Clin Lab Res 2000;30:17-19. Mathivanan S, De La Torre Martinez R, Wolf C, et al. effect of econazole and benzydamine on sensory neurons in culture. J Phys and Pharm 2016;67(6)851-858. Benzydamine. Available from: https://www.drugbank.ca. Accessed date: 26 May 2021.

SORE THROAT?1

Conclusion: Chlorhexidine gluconate and benzydamine hydrochloride combination mouth spray, added to standard antibiotic treatment, significantly alleviate the intensity of clinical signs in patients with streptococcal pharyngitis. Further research is needed using larger sample sizes or alternative control groups. PERSISTENT SORE THROAT In cases of persistent sore throat, it is important to reconsider the initial diagnosis. Consider an alternative diagnosis or further investigation if the individual has not responded to a course of antibiotics. Consider a neoplasm if the sore throat is persistent, especially if there is a neck mass. Indications for urgent referral include: • An unexplained persistent sore or painful throat −‘persistent’ refers to a time frame of three-four weeks • Red, or red and white patches, or ulceration or swelling of the oral/ pharyngeal mucosa for more than three weeks • Odynophagia or dysphagia for more than three weeks • Unexplained hoarseness accompanied by

Fast, effective relief of a painful sore throat:1,2,3 Targeted pain relief in just 5 minutes2,3

Reduces swelling to enable easy swallowing1,2

Numbs the throat3

Kills bacteria1

References: 1. Andolex®-C Oral Rinse approved package insert. February 2017. 2. Almazan NA. Benzydamine HCl 0.15% for Oropharyngeal Diseases and Surgeries: A Review of Clinical Trials. Philippine Scientific J. 2009;42(1):38-42. 3. Simard-Savoie S, Forest D. TOPICAL ANAESTHETIC ACTIVITY OF BENZYDAMINE. Curr Ther Res. 1978;23(6):734-745. 4. Impact Rx, December 2020. 5. IMS Total Private Market Value MAT, December 2020. Scheduling status: S1 Proprietary name (and dosage form): ANDOLEX®-C ORAL RINSE. Composition: Each 15 ml contains: Benzydamine HCI 22.5 mg, Chlorhexidine gluconate 18 mg, Alcohol 9 % v/v. Pharmacological classification: A. 16.4 Nasopharyngeal and bucco-pharyngeal antiseptics. Indications: For the relief of minor infections and painful inflammatory conditions of the mouth and throat. Chlorhexidine in Andolex®-C Oral Rinse helps to reduce the development of plaque. Registration number: 31/16.4/0143. Name and business address: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). IN4233/21.

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Bone health is crucial for a healthy life –

The importance of nutrition and health supplements Help prevent osteoporosis by leading a bone healthy lifestyle at all stages of life.

ONE IS LIVING tissue that is constantly being broken down and replaced and for this reason, an adequate supply of nutrient substrate is needed to support the formation phase of bone remodelling. Osteoporosis occurs when the ratio of bone synthesis to resorption is shifted towards resorption. In people with osteoporosis, the bones become porous and weaker, increasing the risk of fractures, especially in the hip, spinal vertebrae, and some peripheral joints, such as the wrists. The hormones oestrogen and androgen protect bones from increased mineral loss. With menopause, however, women's oestrogen level decreases – making older women especially more prone to osteoporosis, contrary to men of the same age. One of the risk factors for bone loss, and thus the development of osteoporosis,

PRESCRIBE A FIVE STAR CALCIUM SUPPLEMENT

is an inadequate dietary intake of nutrients important to bones. This review examines the impact of nutrition on bone health and compares the level of nutrient intake required as part of the dietary recommendations. CALCIUM Over 99% of total body calcium is found in bones and teeth, where it functions as a key structural element. The remaining body calcium functions in metabolism, serving as a signal for vital physiological processes, including vascular contraction, blood clotting, muscle contraction and nerve transmission. Inadequate intakes of calcium have been associated with increased risks of osteoporosis, nephrolithiasis (kidney stones), colorectal cancer, hypertension and stroke, coronary artery disease, insulin resistance and obesity. Most of these

To complete the quiz and earn your 3 points, find this article on www.medicalacademic.co.za. You will need to read and complete the questions for the CPD found on page 34 as well, in order to earn all 3 points

disorders have treatments but no cures. Owing to a lack of compelling evidence for the role of calcium as a single contributory element in relation to these diseases, estimates of calcium requirement have been made based of bone health outcomes, with the goal of optimising bone mineral density. Calcium is unique among nutrients, in that the body’s reserve is also functional: increasing bone mass is linearly related to reduction in fracture risk. To a great extent, individuals are protected from excess intakes of calcium by a tightly regulated intestinal absorption mechanism through the action of 1.25-dihydroxyvitamin D, the hormonally active form of vitamin D. When the amount of absorbed calcium is more than what the body needs, the excess is excreted by the kidney in most healthy people. If patients consume inadequate amounts of calcium, the body starts dissolving bones to release

calcium and maintain adequate amounts in blood. This leads to excess excretion in urine and crystallisation to form kidney stones. Concern for excess calcium intake is directed primarily to those who are prone to milk alkali syndrome (the simultaneous presence of hypercalcaemia, metabolic alkalosis and renal insufficiency). Although calcium can interact with iron, zinc, magnesium and phosphorus within the intestine, thereby reducing the absorption of these minerals, available data do not suggest that these minerals are depleted when humans consume diets containing calcium above the recommended levels. For example, even though high intakes of calcium can exert acute effects on iron absorption, there is no evidence of reduced iron status or iron stores with long-term calcium supplementation. Great heterogeneity exists in the formulation of dietary recommended intakes

Calcium

Magnesium

Vitamin C

Vitamin D3

Vitamin K2

500 mg

100 mg

60 mg

1000 IU

45 µg

Take 1 tablet daily with a meal. With Clinically Proven

BROUGHT TO YOU BY SA’S NO.1 PRESCRIBED CALCIUM RANGE1 References: 1. Impact Rx. MAT April 2021. Proprietary name (and dosage form): B-Cal®-K2 Tablets. Composition: Each tablet contains: 500 mg Calcium, 100 mg Magnesium, 60 mg Vitamin C, 1000 IU Vitamin D3, 45 µg Vitamin K2. Complementary medicine: Health Supplement. This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. IN1443/21

k2 med chron mini ad.indd 1

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CPD | Expires 31/05/2022 CPD for calcium and magnesium, and future recommendations should ideally be based on established and common methodologies for respective age groups. Based on the survey data available, it is clear that very large numbers of people consume insufficient levels of these minerals that are to support the most conservative estimates of their physiological needs. In fact, copper, magnesium, zinc and calcium status were measured in postmenopausal women with osteoporosis (n =23) and osteopenia (n = 28) as classified based on the T-score of the femur neck and dual energy X-ray absorptiometry results. Anthropometric indices, dietary intake and serum copper, magnesium, zinc and calcium were assessed. The results of this study showed that the mean dietary intake of magnesium, zinc and calcium in post-menopausal women with low bone density were significantly lower than recommended dietary allowance. The mean serum levels of zinc (P = 0.001) and copper (P = 0.000) were significantly lower than normal range and 40% of these participants had serum magnesium levels lower than the normal range. Due to the mineral deficiency in postmenopausal women with low bone density and the key role of minerals on bone health, supplementation with magnesium, calcium, zinc and perhaps copper are recommended. MAGIC MAGNESIUM Magnesium is the fourth most abundant mineral in the body overall and is essential for maintaining peak physical and mental functioning, yet dietary intake may be insufficient to meet the body’s demands. Magnesium deficiencies are relatively common and may lead to a range of symptoms including loss of energy, fatigue, muscle cramps, metabolic and mineral disturbances. Magnesium supplementation may be required to restore magnesium balance and consequently to improve overall health. Magnesium is vital for the absorption and metabolism of calcium. In simple terms, magnesium converts vitamin D into its active form so that it can help calcium absorption. Magnesium deficiency impacts on the bone also indirectly by affecting the homeostasis of the two master regulator hormones of calcium homeostasis, ie, parathyroid hormone (PTH) concentrations and 1.25(OH)2-vitamin D3 thus leading to hypocalcaemia. Magnesium also stimulates a particular hormone, calcitonin, which helps to preserve bone structure and draws calcium out of the blood and soft tissues back into the bones, preventing osteoporosis, some forms of arthritis and kidney stones. Over 60% of the body’s total magnesium supply is stored in our bones. Several studies have found a direct link between low magnesium levels and osteoporosis. However, low magnesium is not only about weakening bones or an issue for older women. Deficiency of this key mineral has also been linked to neuromuscular disorders, hypertension, cardiac arrhythmias, insulin resistance and eclampsia, mitral valve prolapse, atherogenesis and disordered bone metabolism.

A study of women with osteoporosis in Israel reported significantly increased bone mineral density amongst those women who took a supplement that contained magnesium

One study of postmenopausal women with either osteoporosis or osteopaenia, which is when bones are weaker than normal prior to developing osteoporosis, found that over 40% of the study participants had low magnesium levels. Why are so many of us lacking in magnesium? A Western diet rich in processed food and relatively poor in micronutrients seems to be one of the main reasons. By making better food choices, we can provide better nutrition for our bone health. Green vegetables are an excellent source of magnesium, as are nuts, seeds, unprocessed grains, and some legumes. Supplementation can also play an important role in improving the health of our bones. A study of women with osteoporosis in Israel reported significantly increased bone mineral density amongst those women who took a supplement that contained magnesium. Due to the apparent widespread deficiency of magnesium, and the ongoing recognition of the key role that certain minerals play with regards to bone health, supplementation with magnesium as well as calcium and even Vitamin D is often recommended. If the two biofactors vitamin D and magnesium, that are essential for bone synthesis, are not available, the course of osteoporosis can intensify. According to recent findings, magnesium is also credited with stabilising functions in bone building. If there is no stabilising magnesium during bone synthesis, this also decreases bone density. However, a healthy magnesium and calcium rich diet and supplementation should not only start after menopause. Studies have shown that sufficient magnesium intake in childhood positively relates to bone mass density as you grow older. The bottom line is that building healthy bones throughout your life is the best strategy to prevent osteoporosis later in life.

As with any vitamin and mineral, it is better to focus on a healthy, balanced diet to meet daily requirements of magnesium, and to use supplements as a backup. But the reality is that not all of us will achieve the recommended daily intake of magnesium, let alone calcium. Not only can a supplement containing these key minerals assist people who are predisposed to osteoporosis, but a supplement containing magnesium can also assist those who suffer from muscle cramps. Another aspect to consider is the evidence that adults on a Western diet develop a low-grade acidosis which is intensified by ageing. Recently, the acid load imposed by this diet has been suggested to play a role in the pathophysiology of osteoporosis. Indeed, metabolic acidosis has been shown to lead to calcium loss from bone, to inhibit osteoblast function and stimulate osteoclast activity, and to impair bone mineralisation. Accordingly, a neutralising diet improves bone microarchitecture and bone mineral density. It is therefore feasible that part of the effects of magnesium on the skeleton is due to its capability to act as a buffer for the acid produced by the typical Western diet.

The calcium/magnesium bond It is known that calcium can directly or indirectly compete with magnesium for (re)absorption inthe intestine and kidney. Ionized magnesium (Mg2+) and calcium (Ca2+) also antagonise each other in many physiological activities. Studies have shown the importance of the balance between magnesium and calcium in relation to physiological functions of these micronutrients. The same cell receptor that regulates calcium also senses magnesium. In the kidney, this calcium receptor can inhibit the re-absorption of magnesium such that excess magnesium can be passed into the

urine. In the gut, calcium and magnesium may compete for intestinal absorption. If there is a small amount of calcium but an abundance of magnesium in the contents of the intestine, the magnesium gets more actively absorbed. However, a high intake of calcium can reduce the absorption of both calcium and magnesium. The amount of calcium or magnesium absorbed depends on the dietary ratio of calcium to magnesium. Although clinical evidence is still fragmentary, beneficial effects of the supplementation of these minerals in a manner which supports calcium and magnesium homeostasis is documented. In an article entitled, Decreased magnesium status may mediate the increased cardiovascular risk associated with calcium supplementation (DiNicolantonio, 2017), the following is noted: In a series of magnesium balance studies conducted by Seelig about 50 years ago, she found that, in men with recommended dietary allowance (RDA)-level magnesium intakes (6 mg/kg/day or above), increasing dietary calcium to high levels did not impair magnesium balance — consistent with more recent reports. However, in men with relatively low (magnesium) intakes, a high calcium intake did indeed decrease magnesium balance. Somewhat paradoxically, a low calcium intake also impaired magnesium availability in this group. If these observations are confirmed in women, they imply that a high supplemental intake of calcium might impair magnesium balance in the rather high proportion of the population who have relatively low magnesium intakes, reflecting high intakes of ‘empty calorie’ foods. However, an increased intake of calcium-rich natural foods would not necessarily have a negative impact on magnesium balance because these foods also would supply magnesium. High calcium intakes in humans can indeed impair magnesium balance when magnesium intakes are low, MEDICAL CHRONICLE 37 MEDICAL CHRONICLE | June 2021 17

CPD| Expires 31/05/2022 CPD the clear implication is that calcium, when supplemented, should be given in conjunction with a balanced dose of magnesium. Especially if existing calcium is high. The conclusion includes that, “In the meantime, people (especially those consuming a relatively refined diet) who wish to supplement with calcium might be well advised to take a supplement that also includes highly bioavailable magnesium,” and “the concept of ‘balancing’ calcium and magnesium in supplements has, in fact, been the accepted wisdom in ‘health food’ circles for decades, owing to Seelig’s research and its promulgation by popular health food pundits," It should also be noted that the absorption and bioavailability of minerals can be affected by various factors such as age, sex, smoking status, alcohol use, physical activity, use of other vitamins and mineral supplements, etc and should be taken into consideration during patient assessment.

important nutrients. Also beneficial is taking vitamin D-rich medications with the respective indication of preventing or alleviating osteoporosis. Vitamin D is one of the few vitamins that humans can synthesize themselves. Vitamin D is activated through sunlight – to be more precise, UV-B radiation – on the skin. Vitamin D3 is synthesized from dehydrocholesterol. From the blood, it reaches the liver, where it is converted to its storage form. A healthy Central European adult who walks daily for approximately 20-30 minutes in the sun can fully satisfy his vitamin D need. After about 30 minutes, approximately 250 micrograms of vitamin D have been synthesized on a summer’s day. The body then virtually stops the synthesis to rule out an overdose caused by excessive sunlight. Unneeded vitamin D can be stored in fatty tissue, to be retrieved and activated in the winter months when the sun cannot send us enough UV-B radiation to synthesize more.

THE ROLE OF VITAMIN D For calcium to reach the bones in the first place, vitamin D is indispensable. Both vitamin D and magnesium are responsible for calcium's absorption and its incorporation into our bones. If they are not available, the locomotor system cannot function well. For optimal calcium supply as well as healthy bones and joints, calcium should always be purposefully taken, combined with magnesium and vitamin D. One of the main tasks of vitamin D lies in regulating calcium in our body – cholecalciferol (vitamin D3). It controls the absorption and utilisation of calcium from the diet. If there is too little vitamin D available, not enough calcium reaches the blood through the intestinal walls and the calcium level decreases – regardless of the calcium quantity supplied with the food. Although calcium in high doses can also reach the blood passively (ie without the help of vitamin D), this occurs only to a negligible extent. With babies and toddlers, this can become critical because they must incorporate a lot of calcium into their growing bones. Therefore, vitamin D is often administered to them as a preventive measure against rickets. In this disease – also called ‘bone softening’ – bones need the essential calcium, as the consequence is their impaired mineralisation, which leads to shortened and crooked limbs. However, vitamin D deficiency can also intensify diseases of old age such as osteoporosis. Vitamin D contributes to the principal factors that maintain calcium homeostasis. 1.25(OH)2-vitamin D, the hormonally active form of vitamin D, is the major controlling hormone of intestinal calcium absorption. Calcium homeostasis is also regulated by parathyroid hormone and ionized calcium. Increasing evidence indicates that the reason for disturbed calcium balance with age is inadequate vitamin D levels in the elderly. Thus, a diet that includes foods containing vitamin D and magnesium helps to counteract deficiency of these

WHAT IS VITAMIN K? Most people have never heard of vitamin K2. This vitamin is rare in the Western diet and hasn’t received much mainstream attention. However, this powerful nutrient plays an essential role in many aspects of health. In fact, vitamin K2 may be the missing link between diet and several chronic diseases. Vitamin K was discovered in 1929 as an essential nutrient for blood coagulation. The initial discovery was reported in a German scientific journal, where it was called ‘Koagulationsvitamin’ – which is where the ‘K’ comes from. It was also discovered by the dentist Weston Price, who travelled the world in the early 20th century studying the relationship between diet and disease in different populations. He found that the non-industrial diets were high in some unidentified nutrient, which seemed to provide protection against tooth decay and chronic disease. He referred to this mystery nutrient as ‘activator X’, which is now believed to have been vitamin K2. Vitamin K is a cofactor of α-carboxylase, an enzyme necessary for the α-carboxylation of glutamic acid residues in proteins, including osteocalcin, the principal noncollagenous protein of bone. Vitamin K deficiency increases under-carboxylated osteocalcin, a less fully functional form, and detected in osteoporotic patients. Population studies have also shown an association between low vitamin K intake and lower BMD or higher fracture risk. Conversely, vitamin K supplementation reduces under-caboxylated fractions of osteocalcin, urinary calcium excretion, and bone resorption and increases bone formation. There are two main forms of vitamin K: • Vitamin K1 (phylloquinone): Found in plant foods like leafy greens • Vitamin K2 (menaquinone): Found in animal foods and fermented foods.

18 June 2021 | MEDICAL CHRONICLE 38 MEDICAL CHRONICLE

Some scientists have suggested that the roles of vitamins K1 and K2 are quite different, and many feel that they should be

classified as separate nutrients altogether. Controlled studies observe that vitamin K2 supplements generally improve bone and heart health and plays a central role in the metabolism of calcium. Vitamin K2 can be further divided into several different subtypes, the most important ones being MK-4 and MK-7. Vitamin K2 occurs in nature in several forms. Each form is designated by the length of the side chain (the number of isoprenoid units) of this fat-soluble molecule. MK-4, a relatively short-chain menaquinone, is found in foods of animal origin, such as butter and egg yolks. Longer-chain menaquinones such as MK-7 is found in fermented foods, such as cheese, yogurt, in the Japanese fermented soy food natto. MK-7 is superior to MK-4 in terms of biological activity and half-life. It remains biologically active in the body for longer and allows for better distribution and activation of extra-hepatic K2-dependent proteins such as osteocalcin and matrix gla-protein. MK-7 reaches bones and vessel walls easier than MK-4. Osteoblasts and osteoclasts are the two types of bone cells that break down and build up bone in the bone remodelling process. Osteoclasts are the bone disassembly cells, osteoblasts are the bone

building cells. Osteoblasts secrete a protein called osteocalcin into the blood. Vitamin K2 activates the calcium-binding actions of two proteins – matrix GLA protein and osteocalcin. When osteocalcin is in an activated state (activated by vitamin K2 MK-7), osteocalcin binds to calcium and transports it from the blood and into the bone. Osteoblasts then integrate this calcium into the bone matrix, thereby increasing the bone‘s mineral density and strength. As part of the remodelling cycle, osteoclasts remove old or damaged bone, so that it can be replaced with new bone. Vitamin K also activates proteins that play a role in blood clotting, calcium metabolism and heart health. One of its most important functions is to regulate calcium deposition, promoting the calcification of bones and preventing the calcification of blood vessels and kidneys. In support of the above, there is also substantial evidence from controlled studies that K2 may provide major benefits for bone health. A three-year study in 244 postmenopausal women found that those taking vitamin K2 supplements had much slower decreases in age-related bone mineral density. Long-term studies in Japanese women have observed similar

CPD | Expires 31/05/2022 CPD benefits. Seven of these trials, which took fractures into consideration, found that vitamin K2 reduced spinal fractures by 60%, hip fractures by 77% and all nonspinal fractures by 81%. In line with these findings, vitamin K supplements are officially recommended for preventing and treating osteoporosis in Japan. In summary, Vitamin D3 aids absorption of calcium from the intestine and into the bloodstream. Vitamin K2 MK 7 activates osteocalcin proteins which binds to the calcium and transports it from the blood and into the bone where it incorporates calcium into the bone matrix instead of being deposited in the arteries in the form of plaque (a risk for heart disease). This vitamin plays a vital role in bone health by regulating the transport and distribution of calcium in the body. The missing ingredient has long been vitamin K2 MK 7. VITAMIN C Vitamin C is a cofactor in the hydroxylation of lysine and proline (these are amino acids, building blocks of protein). They are essentially required for collagen synthesis: prolyl hydroxylase (to stabilise the collagen molecule) and lysyl hydroxylase (to give structural strength cross-linking) and is required in the cross-linking of collagen fibrils in bone. Collagen is a hard, insoluble, and fibrous protein that makes up onethird of the protein in the human body, responsible for maintaining the structural integrity of bones. Vitamin C also stimulates alkaline phosphatase activity, a marker for osteoblast formation. Several studies have reported a beneficial effect of vitamin C intake on BMD in children, early post-menopausal women consuming at least 500mg of calcium, and in postmenopausal women. The RDA for vitamin C was recently increased to 75mg/d in women and 90mg/d in men. It is still based primarily on the prevention of deficiency, rather than the prevention of chronic disease and the promotion of optimum health. However, intakes higher than the RDAs have been related to better bone health. In postmenopausal women greater BMD was reported as vitamin C intake from supplements increased to 1000mg/d. Vitamin C is also an important antioxidant and cofactor which is involved in the regulation of development, function, and maintenance of several cell types in the body. Deficiencies in vitamin C can lead to conditions such as scurvy, which, among other ailments, causes gingivia, bone pain and impaired wound healing. CONCLUSION Our bones support us and allow us to move. They protect our brain, heart, and other organs from injury. The health of bones is increasingly important as we age. Older adults often have bone loss, which leads to an increased risk of fractures and debilitating effects of quality of life. It’s never too early to start thinking about bone health, as maximising bone health during younger years helps to lower fracture risk later in life.

REFERENCES Dai Q, Shu X, Deng X, et al. Modifying effect of calcium/magnesium intake ratio and mortality: a population-based cohort study. BMJ Open 2013;3:e002111. doi: 10.1136/bmjopen-2012-00211. McGrane K. Can Supplements Help Manage or Prevent Osteoporosis? Healthline 2012. Accessed 25 May 2021: www.healthline.com/nutrition/osteoporosissupplements#vitamin-d Castiglioni S, Cazzaniga A, Albisetti W, Maier JA. Magnesium and osteoporosis: current state of knowledge and future research directions. Nutrients. 2013;5(8):3022-3033. Published 2013 Jul 31. doi:10.3390/nu5083022. Kunutsor SK, Whitehouse MR, Blom AW, Laukkanen JA. Low serum magnesium levels are associated with increased risk of fractures: a long-term prospective cohort study. Eur J Epidemiol 2017;32(7):593-603. doi: 10.1007/s10654-017-0242-2. Epub 2017 Apr 12. PMID: 28405867; PMCID: PMC5570773. Outhoff K. Magnesium: effects on physical and mental performance. South African Family Practice

2018:60;32-34. 0.4102/safp.v60i4.4902. Mahdavi-Roshan M, Ebrahimi M, Ebrahimi A. Copper, magnesium, zinc and calcium status in osteopenic and osteoporotic post-menopausal women. Clin Cases Miner Bone Metab 2015;12:18-21. doi: 10.11138/ ccmbm/2015.12.1.018. PMID: 26136790; PMCID: PMC4469220. Castiglioni S, Cazzaniga A, Albisetti W, Maier JA. Magnesium and osteoporosis: current state of knowledge and future research directions. Nutrients. 2013;5(8):3022-3033. Published 2013 Jul 31. doi:10.3390/nu5083022. Orchard TS, Larson JC, Alghothani N, et al. Magnesium intake, bone mineral density, and fractures: results from the Women's Health Initiative Observational Study. Am J Clin Nutr 2014;99(4):92633. doi: 10.3945/ajcn.113.067488. Epub 2014 Feb 5. PMID: 24500155; PMCID: PMC3953885. Ware M. Why do we need magnesium? Medical News Today. 202. Accessed 25 May 2021. www. medicalnewstoday.com/articles/286839 DiNicolantonio JJ, McCarty MF, O'Keefe JH.

Decreased magnesium status may mediate the increased cardiovascular risk associated with calcium supplementation. Open Heart 2017;4(1):e000617. Published 2017 May 22. doi:10.1136/ openhrt-2017-000617. Price, CT et al. Essential Nutrients for Bone Health and a Review of their Availability in the Average North American Diet. The Open Orthopaedics Journal, 2012, 6, 143-149. Web MD. What Is Osteopenia?(2019) at www.webmd. com/osteoporosis/guide/osteopenia-early-signs-ofbone-loss#1 (website accessed on 24 May 2021) Othoinfo. Exercise and Bone Health (2012) at https:// orthoinfo.aaos.org/en/staying-healthy/exercise-andbone-health/ (website accessed on 24 May 2021) Tao M, Dai Q, Millen AE, Nie J, Edge SB, Trevisan M, Shields PG, Freudenheim JL. Associations of intakes of magnesium and calcium and survival among women with breast cancer: results from Western New York Exposures and Breast Cancer (WEB) Study. Am J Cancer Res 2016;6(1):105-113. www.ajcr.us / ISSN:2156-6976/ajcr0008684

BONE HEALTH in the SPOTLIGHT

PRESCRIBE A FIVE STAR CALCIUM SUPPLEMENT

With Clinically Proven Calcium

Magnesium

Vitamin C

Vitamin D3

Vitamin K2

The B-CAL -K2 formulation works synergistically to: Promote collagen formation for bone strength and flexibility Enhance calcium absorption & muscle functioning Contribute to bone cell & tissue formation Activate protein for bone strength Promote bone health and help prevent Osteoporosis ®

k2 med chron ad_21.indd 1

2021/06/01 17:24

MEDICAL CHRONICLE 39 MEDICAL CHRONICLE | June 2021 19

CPD | Expires 07/06/2022

WEBINAR REPORT

Treating non-melanoma skin cancers University Professor Eggert Stockfleth, who is the chair and director of the Department of Dermatology, Venerology and Allergology at University of Bochum and head of the European Skin Cancer Foundation (ESCF) recently presented on treating non-melanoma skin cancers. If you would like to watch the webinar, you can access it here: https://bit.ly/3yI1tjQ

To request your CPD certificate from watching the replay, please email john.woodford@newmedia.co.za

E BEGAN HIS medical training at the University of Hamburg and has also worked as visiting professor at German Cancer Center Heidelberg (DKFZ), Loyola University Chicago (USA), MayoClinic Rochester, NY (USA), the University of Melbourne (Australia), University Department of Dermatology in Kiel and Berlin (Charité, Germany). He is a member of several organisations including the European Academy of Dermatology and Oncology, European Dermatology Forum, Federal Association of Organ Transplant Patients, and both the European and American Academies of Dermatology. Prof Stockfleth has been involved in some of the original imiquimod studies and shared some valuable insights based on his many years of extensive experience. The key takeaways from his evidencebased presentation are: Non-melanoma skin cancers (NMSC) include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC is the most common form of skin cancer in South Africa and SCC is the second most common. One in six light-skinned individuals will develop at least one AK lesion. Treatment of non-melanoma skin cancers is important, because actinic keratosis (AK) can lead to squamous cell carcinoma, and it is not clear which types can progress. Topical therapies provide a noninvasive approach, which potentially reduces incidence of pain, risk for infection, and scarring. They cater for the clinical need to treat lesions in cosmetically sensitive or difficult-to-treat locations. This allows adjunctive therapy with office-based procedures. Field treatment is important in terms of diagnosis and treatment of sub-

clinical disease. Non-ablative treatment options include 5-Fluorouracil (antimetabolite), imiquimod 5% cream (immune response modifier, innate and cell-mediated immunity enhancement), and diclofenac 3% gel (cyclooxygenase inhibition). A FOCUS ON IMIQUIMOD Imiquimod activates the innate immune response including dendritic cells and cytokines and causes an upregulation of cell-mediated response. Imiquimod locally induces cytokines and chemokines through Toll-like receptor-7 (TLR7) on dendritic cells, macrophages, and monocytes in vitro (IFN-a, IL-12). It activates dendritic cells and increases migration to draining lymph nodes, stimulating T cell activity. Innate immunity and cell-mediated immunity are enhanced, with less chance of recurrence due to cellular memory. Data suggest that imiquimod may also directly induce tumour apoptosis. “For a tumour to progress it needs a tolerant immune system. This is the case for AK and BCC,” said Prof Stockfleth. An immune response modifier can break this tolerance. Prof Stockfleth noted that imiquimod will not do anything to healthy skin unlike 5-FU, a reaction only occurs where the immune system identifies abnormal cells. Imiquimod can be used anywhere on the body, including the genital area, except for the eye area. Large areas of s kin can be treated with imiquimod as has been done in multiple trials. Due to the mode of action, imiquimod treats clinically visible as well as sub-clinical lesions. In terms of treating patients who have had a Covid-19 vaccine, there is no clinical

Imiquimod (n=26)

5-FU (n=24)

Cryosurgery (n=25)

Clinical clearance

85%

96%

68%

Histological clearance

73%

67%

32%

Sustained clearance of cleared lesions

73%

54%

28%

Sustained field clearance

73%

33%

Cosmetic outcome

81%

data on the use of any of the treatments available with the vaccine and so the recommendation is to allow a four-week interval before using imiquimod. Imiquimod can be used in immune-compromised patients, including HIV-positive patients, except in patients with lupus. A randomised study of topical 5% imiquimod vs topical 5-fluorouracil vs cryosurgery in patients with AK had the following results in terms of clinical and histological outcomes including a one-year follow-up:

BCC and sBCC Imiquimod’s BCC Phase III data show complete response at 12 weeks posttreatment, clinical and histologic clearance, or clinical suspicion but histologic evidence of no sBCC. In sBCC, >80% of patients treated with topical imiquimod five times/week experienced histologic clearance, indicating that this dosing frequency is highly effective. Histologic complete response rate for five times/week dosing regimen was 82% (ITT population). Clinical and histologic complete response rate for the five times/week dosing regimen was 75% (ITT population).

Overall, stringent histologic assessment showed that imiquimod therapy was highly effective in the treatment of sBCC tumours. Clinical observations were supported by histologic clearance of target tumours. PDT VS IMIQUIMOD VS 5-FU FOR TREATING SBCC Five years after treatment results of this trial show that 5% imiquimod cream is superior to both methyl amino levulinate photodynamic therapy and 5-fluorouracil cream in terms of efficacy for superficial basal cell carcinoma. Five per cent Imiquimod cream was considered as the first choice for non-invasive treatment in most primary sBCC.

New mode of action It was found that imiquimod directly inhibits hedgehog signalling by stimulating adenosine receptor/ protein kinase A-mediated glioma-associated oncogene phosphorylation. These results reveal a previously unknown mode of action of imiquimod in the treatment of BCC and also suggest a role for adenosine receptors in the regulation of oncogenic hedgehog signalling.

Actinic Keratoses should be treated, as it is impossible to predict which lesions may become invasive1

For superior sustained clearance and cosmetic outcomes1

SA’s No.

PRESCRIBED BY DERMATOLOGISTS*3

43 %

less chance of recurrence with imiquimod vs. 5-FU2

References: 1. Krawtchenko N. et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol 2007;157 (Suppl.2):34-40. 2. De Berker D. et al. British Association of Dermatologists’ guidelines for the care of patients with actinic keratosis 2017. Br J Dermatol 2017;176:20–3. 3. Impact Rx - March 2021. Name and business address of the holder of the certificate of registration: iNova Pharmaceuticals (Pty) Ltd. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 17530L. IN4273/21.

40 MEDICAL CHRONICLE

MEDICAL CHRONICLE | July 2021 37

ONLINE CPD CPD | Expires 30/06/2022

Anaemia in Covid-19:

A potential risk factor Iron is an essential element for almost all living organisms as it is actively involved in a wide variety of metabolic processes.

A POSSIBLE RISK FACTOR IN COVID-19 Patients with Covid-19 typically present with lower airway disease and although data are limited, a few authors have investigated the significance of anaemia in Covid-19. Interestingly, a link between severe Covid-19 infection and anaemia has been speculated: • In 99 patients with Covid-19, 51% of patients showed a decreasing tendency in

These observations suggest a potential relationship between low haemoglobin levels and poor progression and prognosis of Covid-19. Tao et al, conducted a retrospective, single centre, observational study to evaluate the impact of anaemia on the clinical course of Covid-19 in 222 patients (with Covid-19 pneumonia). The results showed that Covid‐19 patients with anaemia were predisposed to more severe inflammatory responses, coagulation disorders and organ injuries. Routine blood work including white blood cell count (WBC), lymphocyte, neutrophils, eosinophils, red blood cell count (RBC), haematocrit, and platelet count were prominently lower in the anaemic group compared to the non-anaemic group (all P< 0.05). DIFFERENCES BETWEEN PATIENTS WITH ANAEMIA IN VARIOUS SEVERITY Among the 222 patients in this study, 46 patients were classified as having mild anaemia, 29 and four patients were classified as having moderate and severe

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anaemia, respectively. The corresponding haemoglobin levels of the three groups were 116, 103, and 72 g/L, respectively. Patients with moderate to severe anaemia were more likely to have dyspnoea than those with mild anaemia (24.2% versus 6.5%, P=0.025) and had lower levels of PaO2 and SaO2 (P<0.05). The severity of anaemia was positively associated with inflammatory responses and coagulation disorders, whereas no significant relationship with organ injuries was observed. The prevalence of CRP, PCT beyond the normal range, and elevated levels of

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erythrocyte sedimentation rate (ESR) and D-dimer, were prominently higher in patients moderate to severe anaemia compared to patients with mild anaemia. ASSOCIATIONS BETWEEN ANAEMIA AND SEVERE ILLNESS OF COVID‐19 The multivariable analysis indicated that anaemia was significant as an independent risk factor for patients with severe Covid‐19 disease, even after adjusting for baseline data (odd ratio [OR]: 3.47; 95% confidence interval [CI]: 1.02‐11.75; P=0.046) and laboratory indices (OR: 3.77; 95% CI: 1.33‐10.71; P=0.013). However, anaemia

FOR MZANSI

FORDABLE

ANAEMIA AND IRON DEFICIENCY Iron deficiency is known as the most common form of malnutrition worldwide and thought to be accountable for at least 50% of all anaemia cases. Iron deficiency anaemia occurs when iron stores are exhausted and the supply of iron to the tissues in the body is compromised. As a result of the lack of iron, there is an inadequate amount of red blood cells. Iron deficiency anaemia (IDA) is a severe stage of iron deficiency in which haemoglobin (or haematocrit) falls below acceptable limits. IDA is most prevalent and severe in young children (between six and 24 months of age) and in women of child-bearing age, but may also affect older children, adolescents, men and the elderly.

haemoglobin levels • In another study among 1099 patients with Covid-19, it was shown that patients with severe disease had significantly lower haemoglobin levels than those diagnosed with non-severe cases. The decline in haemoglobin was a striking feature in patients who were admitted to intensive care units, needed mechanical ventilation or had passed on.

PPROXIMATELY TWO-THIRDS of iron in the body is found in haemoglobin present in circulating erythrocytes, 25% is contained in a readily available iron store, and the remaining 15% is bound to myoglobin in muscle tissue and in enzymes involved in the oxidative metabolism and many other cell functions.

This is a summary of a CPD article available on www.medicalchronicle.co.za

ITY vs. ferric iron UALbioavailability QHigh

Optimal oxidative state absorption 3 times greater than that of iron in its ferric state2

TY side-effects UALIgastrointestinal QFewer

With added Vitamin C, Vitamin B12 and Folic acid for healthy red blood cells *Manufactured in SAHPRA good manufacturing practices (GMP) approved facility. References: 1. National Institute of Health [Internet]: Iron: Dietary Supplements Fact Sheet for Health Professionals c2016 [updated 2016 Feb 11; cited 2020 Apr 08]. Available from: https://ods. od.nih.gov/factsheets/Iron-HealthProfessional/. 2. Mahan, L.K. et al. Krause’s Food and the Nutrition Care Process (13th edition). United States of America. Saunders, animprint of Elsevier Inc, 2012; p.105, 106, 108, 342, 726, 727, 728, 730, 732, 739. Proprietary name (and dosage form): Ferrous Forte® Tablets. Composition: Each tablet contains: 20 mg elemental iron, 350 mcg folic acid, 15 mcg vitamin B12 and 60 mg vitamin C. Proprietary name (and dosage form): Ferrous Forte® Syrup. Composition: Each 5 ml contains: 24 mg elemental iron, 397 mcg folic acid, 18 mcg vitamin B12. Proprietary name (and dosage form): Ferrous Forte® Kids fizzy. Composition: Each tablet contains: 24 mg elemental iron, 199 mcg folic acid, 7.5 mcg vitamin B12 and 60 mg vitamin C. This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. For full prescribing information, refer to the package inserts. Further information is available on request from iNova Pharmaceuticals. Name and business address: iNova Pharmaceuticals (Pty) Ltd Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. IN1465/21.

MEDICAL CHRONICLE July 2021 21 MEDICAL| CHRONICLE 41

ONLINE CPD CPD | Expires 30/06/2022 have reported varied results. The direct correlation between the physiological mechanisms of anaemia in Covid-19 is not yet understood, however data from studies have revealed that anaemic patients had poorer lung function than non-anaemic patients. Anaemia and low haemoglobin are associated with low oxygen delivery, therefore a plausible speculation would be that Covid-19 patients with anaemia may be more susceptible to severe illness due to worsened pulmonary function and poor tissue oxygenation. As reported by Tao et al, symptoms of dyspnoea were higher and PaO2/SaO2 levels were lower in patients with moderate to severe anaemia, compared to those with mild anaemia.

Autopsy reports of Covid-19 patients revealed the presence of macrophages, neutrophils and lymphocytes in alveolar cavities. Patients with anaemia demonstrate an increased degree of neutrophilic infiltration, therefore an increased neutrophilic count might be indicative of serious pulmonary infiltration of inflammation, which may further worsen lung function. Iron requirements are essential to sustain haemoglobin synthesis, and these requirements are mostly satisfied by the iron recycling of senescent erythrocytes by macrophages. Angiotensin‐converting enzyme 2, the receptor of SARS‐CoV‐2, was confirmed to be expressed in macrophages.

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IRON DEFICIENCY ANAEMIA AND VACCINE EFFICACY Studies have linked anaemia to impair the response to some vaccines, however, the exact role of iron in the immune response to vaccination is not fully understood. Observations from animal studies suggest the importance of serum iron in regulating lymphocyte function during infection and vaccination. Since iron is essential for mitochondrial function in T-cells during immunity, which consequently is required for effector and memory responses, iron supplementation in populations who are iron deficient should, in theory, boost vaccine efficacy. On February 12, 2021 the European Haematology Association released the following recommendation: individuals with iron deficiency anaemia should correct the deficiency prior to vaccination against Covid-19. This recommendation was based on: • Recent reports about possible correlations between systemic iron status and disease severity • Results of a prospective study that indicated that when children with iron deficiency were vaccinated against various pathogens, a significantly improved immune-humoral response was seen with improved iron status ie following iron supplementation • The scientific rationale for improved FORDABLE AF immune responsiveness to vaccination from studies in animal models.

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High bioavailability vs. ferric iron3 Optimal oxidative state absorption 3 times greater than that of iron in its ferric state4 Fewer gastrointestinal side-effects#3 With added Vitamin C, Vitamin B12 and Folic acid for healthy red blood cells *Manufactured in SAHPRA good manufacturing practices (GMP) approved facility; #than ferric salts. References: 1. Ware M. Everything you need to know about iron. 23 February 2018. Available from https://www.medicalnewstoday.com/articles/287228.php#risks. Accessed 2020/01/31. 2. Mielgo-Ayuso J, Zourdos MC, Calleja-Gonzalez J, et al. Iron supplementation prevents a decline in iron stores and enhances strength performance in elite female volleyball players during the competitive season. Appl. Physiol. Nutr. Metab. 2015;40:1–8. 3. National Institute of Health [Internet]: Iron: Dietary Supplements Fact Sheet for Health Professionals c2016 [updated 2016 Feb 11; cited 2020 Apr 08]. Available from: https://ods. od.nih.gov/factsheets/IronHealthProfessional/. 4. Mahan, L.K. et al. Krause’s Food and the Nutrition Care Process (13th edition). United States of America. Saunders, animprint of Elsevier Inc, 2012; p.105, 106, 108, 342, 726, 727, 728, 730, 732, 739. Proprietary name (and dosage form): Ferrous Forte® Tablets. Composition: Each tablet contains: 20 mg elemental iron, 350 mcg folic acid, 15 mcg vitamin B12 and 60 mg vitamin C. Proprietary name (and dosage form): Ferrous Forte® Syrup. Composition: Each 5 ml contains: 24 mg elemental iron, 397 mcg folic acid, 18 mcg vitamin B12. Proprietary name (and dosage form): Ferrous Forte® Kids fizzy. Composition: Each tablet contains: 24 mg elemental iron, 199 mcg folic acid, 7.5 mcg vitamin B12 and 60 mg vitamin C. This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. For full prescribing information, refer to the package inserts. Further information is available on request from iNova Pharmaceuticals. Name and business address: iNova Pharmaceuticals (Pty) Ltd Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. IN1465/21.

22 MEDICAL July 2021 | MEDICAL CHRONICLE 42 CHRONICLE

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SARS‐CoV‐2 triggers macrophages to produce interleukin (IL)‐6 which drives the ‘cytokine storm’. At the same time, IL‐6 increases hepcidin levels, causing iron‐restricted erythropoiesis and anaemia of inflammation. Studies have identified a strong correlation between IL-6 levels and Covid-19 severity. Tao et al, observed a significantly higher number of patients in the severe anaemia group with elevated inflammation-related indicators (PCT, CRP). From this, it may be rational to hypothesise that more severe inflammatory responses may explain why patients with anaemia were more susceptible to a severe disease course in Covid‐19.

was not found to be a significant risk factor for overall mortality (P=0.996), possibly due to the limited mortality rate in this cohort. Observations from Tao et al, suggest that Covid-19 patients with anaemia may be more inclined to develop severe illness. In their cohort, patients with anaemia had more comorbidities, were older and had a higher risk of severe inflammatory responses and organ injuries. Additionally, the severity of anaemia correlated with more serious inflammatory responses. In summary, these observations suggest anaemia as an independent risk factor for severe Covid-19 illness. The accurate prevalence of anaemia in Covid-19 patients remains unclear as the limited available literature

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CONCLUSION Iron isTan LI Y essential micronutrient Q UA involved in numerous cellular processes. Iron deficiency is one of the most widespread LITY deficiencies and the leading A QUnutritional cause of anaemia. Anaemia has been an independent risk factor for adverse outcomes in many disease settings, including stroke, heart failure, pneumonia and influenza A. Despite study limitations, the prognostic significance of anaemia in Covid-19 from recent observations should not be overlooked and the question of whether the deterioration of Covid-19 is associated with severe anaemia is deserving of further study. Furthermore, since iron deficiency has been linked to impaired humoral immunity to vaccines, this may be of important relevance in vaccinating against Covid-19 and the fight against a pandemic that poses an ongoing threat to the human race.

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CPD| Expires ONLINE CPD CPD 31/07/2022

This is a summary of a CPD article on www.medicalchronicle.co.za. Complete the quiz to earn a CPD point.

Controlling the negative aspects of pregnancy:

A focus on heartburn

By the third trimester of pregnancy, three quarters of women will suffer from heartburn. It can occur in up to 85% of pregnant women and tend to worsen as pregnancy progresses.

OMMON SIDE EFFECTS of pregnancy include nausea, vomiting, swelling, varicose veins, backaches, haemorrhoids, heartburn, fatigue, constipation and sleep loss. HEARTBURN AND ACID Both heartburn and acid reflux tend to worsen as pregnancy progresses, for two reasons: 1. Hormone levels, especially the levels of progesterone, cause the muscle sphincter at the entrance of the stomach to relax,

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allowing stomach acids to travel back up the oesophagus, causing heartburn and indigestion. 2. During the later stages of pregnancy, as the baby grows, heartburn can also be caused by the baby physically putting pressure on the digestive tract. This is especially the case in a multiple pregnancy. Heartburn during pregnancy is not harmful to the foetus, but is extremely uncomfortable for the mother. It can affect

the patient’s sleep, diet and nutritional and emotional well-being. Lifestyle modifications include: 1. Eat smaller meals 2. Try to avoid food that causes heartburn, such as fatty, spicy foods, chocolates and caffeine, which can cause the valve to relax more 3. Wear loose-fitting clothing during pregnancy 4. Avoid lying down within two hours after eating a meal and elevate the head when

lying down to alleviate heartburn. However, if the above measures don’t help, patients will need an antacid or an alginate, available over the counter. Once swallowed, these medications form a strong, protective barrier on the contents of the stomach, preventing reflux of acid and food. They are non-teratogenic, which means it causes no harm to the baby. WHAT IS HEARTBURN? Heartburn or pyrosis is a burning or painful sensation in the upper part of the digestive

CPD | Expires 31/07/2022 ONLINE CPD tract including the throat. It is one of the most common gastrointestinal symptoms in pregnant women. The symptoms of heartburn in pregnancy may be frequent, severe and distressing, but serious complications are rare. The worldwide incidence of heartburn in pregnancy is 17% to 80% and it can occur in all trimesters of pregnancy. The pathogenesis of heartburn in pregnancy involves decreasing lower oesophageal sphincter pressure. The increased circulating progesterone during pregnancy causes lower oesophageal sphincter relaxation. In addition, the enlarging uterus causes increased intraabdominal pressure. The normal response of the lower oesophageal sphincter to accommodate this change is impaired during pregnancy. Abnormal gastric emptying or delayed small bowel transit might also contribute to heartburn in pregnancy. Diagnosis is usually made on symptoms alone, women with more severe illness may undergo diagnostic tests such as upper gastrointestinal endoscopy. The condition usually resolves after delivery.

ANTACIDS Antacids have no teratogenic effect in animal studies and therefore considered safe to use in pregnancy. Antacids are fast and effective at relieving the symptoms of heartburn and are preferred by patients as a result of the immediate symptom relief provided. About 30%-50% of women will only require antacids to ease their heartburn of pregnancy. Only limited data exist concerning the effects of antacids on the foetus with no controlled trials of efficacy. A recent European consensus conference recommended calcium/ magnesium-based antacids for pregnant women because of their safety profile. These experts found that calcium-based

antacids had the added benefit of increasing calcium supplementation to prevent the hypertension and pre-eclampsia associated with pregnancy. In addition, a large, randomised placebo-controlled trial found that magnesium sulphate supplementation reduces the risk of eclampsia by 50% compared with placebo, and may also reduce the risk of maternal death, with no serious short-term side effects. CONCLUSION Heartburn is a normal consequence of pregnancy, occurring in nearly two-thirds of women. The predominant cause is a decrease in lower oesophageal sphincter pressure caused by female sex hormones,

especially progesterone. Serious reflux complications (oesophagitis) during pregnancy are uncommon, so upper endoscopy and other diagnostic tests are usually not needed. Symptomatic GERD during pregnancy should be managed beginning with lifestyle modifications and dietary changes. Antacids or sucralfate are considered the first-line medical therapy. If symptoms persist, any of the H2RAs can be used. Proton-pump inhibitors are reserved for women with intractable symptoms or complicated reflux disease.

References available on request.

TREATMENT OPTIONS Many interventions have been used for the treatment of heartburn in pregnancy. These interventions include changes in diet, lifestyle modification and medications. Common drugs used for the treatment of heartburn in pregnancy include antacids, sucralfate, histamine 2-receptor antagonists, promotility drugs, proton pump inhibitors, and a raft-forming alginate reflux suppressant. Although there has been no evidence-based recommendation for the treatment of heartburn in pregnancy, antacids are considered as the first-line medication.

Alginate-based reflux suppressants Alginate-based reflux suppressants are licensed for use in pregnant women to combat the frequent symptoms of heartburn and regurgitation. It is equal to or significantly better than traditional antacids for relieving heartburn symptoms. Alginatebased reflux suppressants are designed to provide symptom relief by forming a physical barrier on top of the stomach contents in the form of a neutral floating gel or raft. The advantage of alginate-based reflux suppressants over antacids alone is that they provide rapid and longer lasting symptom relief. Due to the physical mode of action and long-term experience, these products are shown to be safe to use in pregnancy. There has been one multicentre, prospective, open-label, and baselinecontrolled study of liquid alginate-based reflux suppressants in the treatment of heartburn in pregnant women. The efficacy of the study medication was rated by the investigator (primary endpoint) and patient. Treatment was deemed to be a success in 91% of patients as judged by the investigator and 90% when assessed by the patient themselves. Alginates form a strong, non-systemic barrier in the stomach, preventing reflux of acid and food into the oesophagus. They are usually combined with antacids. MEDICAL CHRONICLE 45 MEDICAL CHRONICLE | August 2021 19

ONLINE CPD CPD | Expires 31/07/2022

Distinguishing the most

common vaginal infection Vaginal infections can have a substantial negative impact on a woman's quality of life. Stress associated with living with the infection can potentially place a strain on romantic relationships and self-image. It can also have a negative impact on social and physical activities, which can impact productivity at work and/or school.

ANY WOMEN SELF-DIAGNOSE and self-treat episodes of vaginal infection with over the counter treatments and may subsequently present with a history of 'recurrent thrush,' never having had this diagnosis confirmed by microbiological tests. It is important to confirm the diagnosis and to ensure a full sexual health screen has been done to exclude concurrent infection. Management of vaginal discharge requires an empathic approach with reassurance and psychological support as necessary. Most female patients have never heard of it yet Bacterial Vaginosis (BV) is the leading vaginal disorder in women of childbearing age, with an estimated prevalence of up to 50% of the cause of vaginal symptoms in women. Prevalence rates range from 5%-12% in women in the US and UK respectively to as high as 50% in some African countries.

According to Dr Corné Brink, gynaecologist and obstetrician from Fourways Life Hospital in Johannesburg, BV is the most common vaginal infection in women ages 15-44. WHAT’S THE DIFFERENCE BETWEEN BV AND THRUSH? BV is an imbalance in vaginal flora characterised by an increase in pH levels of the vagina (4.5 resulting the environment becoming more alkaline), low levels of lactobacilli and an increased frequency of facultatively anaerobic bacteria. The protective hydrogen peroxide producing lactobacillus species is replaced with Gardnerella vaginalis, obligatory anaerobic Gram-negative rods, Mobilincus species, and Mycoplasma hominis. More recently, novel bacteria associated with BV such as Atopobium vaginae have been discovered by utilising modern molecular biology

Reviewed by Dr Trudy Smith, Obstetrician and Gynaecologist, Wits Donald Gordon Medical Centre

This is a summary of a CPD-accredited article available on www.medicalchronicle.co.za

techniques, writes Machado et al. The bacteria responsible for BV do not persist in the male partner, and concurrent treatment of the male partner does not affect the rate of relapse. Condom use with male sexual partners may help reduce the risk of recurrence of BV due to the fact that semen may alter the pH of the vagina. Use of hormonal contraception does not increase the incidence of bacterial vaginosis but women with an intrauterine contraceptive device or system in situ have an increased risk of bacterial vaginosis. BV is the most common cause of unusual vaginal discharge, which develops when the normal environment, more specifically the pH level, of the vagina changes and becomes more alkaline. One in three women will get it at some stage. A vaginal yeast infection, thrush, is caused by candida albicans. It is not a sexually transmitted infection but can

sometimes develop after sexual intercourse or may be as a result of antibiotic use. It can develop in the vagina and on the male and female genitals. It is a very common cause of unusual vaginal discharge – three out of four women will have thrush at some point in their lives. According to Dr Brink, BV is a bacterial infection, or even more precisely a shift in the normal balance of bacteria in the vagina. Thrush is a yeast infection that most often comes from the gut. SYMPTOMS Symptomatic BV is characterised by an offensive and homogenous vaginal discharge. The odour is often described as fishy and associated with significant embarrassment and it is frustrating to both patient and clinician due to the lack of curative therapy. However, approximately half of microbiologically diagnosed BV

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RESTORE THE BALANCE FOR OPTIMAL VAGINAL HEALTH.1,2

Bacterial Vaginosis (BV) is the MOST COMMON vaginal infection, affecting 50 % of women#5,6

RIPT RE QUIR

In sub-Saharan African women and African American women4 References: 1. CDC: Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR / June 5, 2015 / Vol. 64 / No. 3. 2. Muzny CA, Schwebke JR. Pathogenesis of Bacterial Vaginosis: Discussion of Current Hypotheses. J Infect Dis 2016;214(S1):S1-5. 3. Impact Rx - October 2020. Data on file. 4. Metrogel Approved package insert December 2019. 5. Kingsburgh D, Strydom K-A. The aetiology, diagnosis and management of the vaginal discharge syndrome. Ampath Chat 2020 (Feb); Edition 66: 1-4. 6. Pirotta M, Fethers KA, Bradshaw CS. Bacterial vaginosis. More questions than answers. Australian Family Physician 2009; 38(6); 394-397. Scheduling status: S2 Proprietary name (and dosage form): MetroGel V Vaginal Gel. Composition: Metronidazole 37.5 mg/5 g. Preservatives: Methyl hydroxybenzoate 0.08 %, Propyl hydroxybenzoate 0.02 %. Pharmacological classification: A 20.2.6 Antimicrobial: medicines against protozoa. Indications: MetroGel V is indicated for the treatment of bacterial vaginosis. Registration number: 33/20.2.6/0243. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 17531B. IN4274/21.

17531B Metrogel Medchron Print ad Qtr pg branded R.indd 1

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COMPARING EFFICACY Two randomised controlled studies directly compared the efficacy of vaginal (0.75% metronidazole vaginal gel 5g, twice daily for five days) versus oral regimens (500mg twice daily for seven days). The efficacy of vaginal and oral regimens was similar when evaluated two weeks and five weeks after treatment. However,

the vaginal regimen was associated with less gastrointestinal complaints (33% vs 52%). Only one study has evaluated the use of oral clindamycin versus intravaginal administration. According to this study, oral administration of 450mg clindamycin three times daily and 2% clindamycin in vaginal cream 5g once daily, for seven days had similar cure rates. However, there is greater risk of recurrence of BV as clindamycin is a broad-spectrum antimicrobial which also targets lactobacilli which have a protective effect in the vagina. Clinical studies showed a 61% in growth of vaginal

lactobacilli one week after treatment with intravaginal metronidazole, in comparison with treatment with clindamycin which only showed 11 % growth of lactobacilli. Another consideration is that clindamycin is associated with evidence of antimicrobial resistance among vaginal anaerobic bacteria which may have implications for the future treatment of pelvic infections. Clindamycin cream and ovules are oil-based and might interfere with the safety of latex condoms and diaphragms. References available on request.

RESTORE THE BALANCE

FOR OPTIMAL VAGINAL HEALTH.1,2

Bacterial Vaginosis (BV) is the MOST COMMON vaginal infection, affecting 50 % of women#3,4

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TREATMENT Treatment is based on the culture and sensitivity of the bacteria, but options can include gels, creams and oral treatments. The two most common prescription medications used for the treatment of BV are metronidazole and clindamycin. Both medications need to be used for multiple days and can be taken in pill form by mouth, or with a gel or cream that is inserted inside the vagina. The CDC recommends metronidazole as a first line treatment for BV and recurrent BV. Oral formulations of metronidazole may be more convenient but may cause more side gastrointestinal side effects which can impact treatment adherence, such as a metallic taste in the mouth, nausea, and vomiting, and may result in a candida infection. Poor treatment adherence or treatment failure may result in incomplete cure, increased risk of recurrence or the possibility of developing resistance to metronidazole. A single-dose formulation of oral metronidazole is available, however, it is often more expensive and evidence suggests that the efficacy of the seven-day regime is superior to the single dose with cure rates after completion of treatment of 82% and 62% respectively. With this in mind, the intra-vaginal metronidazole is an alternative treatment option. Vaginally administered metronidazole has low systemic absorption resulting in better tolerability with fewer side effects than the oral formulation. Unlike oral metronidazole, intravaginal metronidazole was not significantly associated with candidiasis. Recurrence rates are high. Up to 80% of women will experience recurrence of BV within one year of treatment. For intravaginal metronidazole (0.75%), the CDC recommends that after the initial course of treatment which is once daily for five days,

the treatment be repeated for a further five days. In the even that further recurrence occurs, 0.75% metronidazole gel should be used twice weekly for four-six months.

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patients are asymptomatic. According to the International Journal of Obstetrics and Gynecology, of the estimated 21 million women infected with BV in the US every year, only about four million will seek treatment, and 50% of women treated will experience a recurrence of symptoms within a year, a consequence of low awareness of this condition. According to Dr Brink, 50%-75% of women with BV will be asymptomatic. “Those with symptoms will usually notice an off-white thin homogenous discharge that has a bit of a fishy odour. This fishy smell is often more pronounced after sexual intercourse,” she said. Women may report psychosexual symptoms with lack of libido and anxiety about infection as a consequence of recurrent episodes of BV and associated malodour. “There are different criteria for diagnosis of BV, but most commonly we will see a change in the pH of the vagina, with the discharge and a fishy odour when the discharge is mixed with a 10% potassium hydroxide solution. I diagnose it based on Pap smear results or vaginal swabs,” said Dr Brink.

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Recommended by the CDC* for treating BV, including recurrent BV1

Shows little to no resistance7

Targets anaerobic bacteria8-10 Preserves protective Lactobacilli9

Reduces systemic exposure by 96 % and improves tolerability11

In sub-Saharan African women and African American women4 * CDC = Centre for Disease Control and Prevention #

References: 1. CDC: Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR / June 5, 2015 / Vol. 64 / No. 3. 2. Muzny CA, Schwebke JR. Pathogenesis of Bacterial Vaginosis: Discussion of Current Hypotheses. J Infect Dis 2016;214(S1):S1-5. 3. Kingsburgh D, Strydom K-A. The aetiology, diagnosis and management of the vaginal discharge syndrome. Ampath Chat 2020 (Feb); Edition 66: 1-4. 4. Pirotta M, Fethers KA, Bradshaw CS. Bacterial vaginosis. More questions than answers. Australian Family Physician 2009; 38(6); 394-397. 5. Impact Rx - October 2020. Data on file. 6. Metrogel Approved package insert October 2000. 7. Beigi R, Austin M, Meyn L, et al. Antimicrobial resistance associated with the treatment of bacterial vaginosis. Am J Obstet Gynecol 2004;191:1124-1129. 8. Austin M, Beigi,R, Meyn L. Microbiologic Response to Treatment of Bacterial Vaginosis with Topical Clindamycin or Metronidazole. Journal of Clinical Microbiology, Sept. 2005, p. 4492-4497. 9. Agnew K, Hillier S. The Effect of Treatment Regimens for Vaginitis and Cervicitis on Vaginal Colonization by Lactobacilli. Sex Transm Dis 1995;22(5): 269-273. 10. Weir CB. Le JK. Metronidazole [online] May 2019 [cited 10 January 2020]; Available from URL: https://www.ncbi.nlm.nih.gov/books/NBK539728/. 11. Wain A. Metronidazole Vaginal Gel 0.75% (MetroGeI-Vaginal®) A Brief Review. Infect Dis Obstet Gynecol1998;6:3-7. Scheduling status: S2 Proprietary name (and dosage form): MetroGel V Vaginal Gel. Composition: Metronidazole 37.5 mg/5 g. Preservatives: Methyl hydroxybenzoate 0.08 %, Propyl hydroxybenzoate 0.02 %. Pharmacological classification: A 20.2.6 Antimicrobial: medicines against protozoa. Indications: MetroGel V is indicated for the treatment of bacterial vaginosis. Registration number: 33/20.2.6/0243. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 17531B. IN4274/21.

17531B Metrogel Medchron Print ad A4 branded R.indd 1

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WEBINAR REPORT

CPD | Expires 23/08/2022

Let’s simplify Covid confusion – Treating paediatric chronic nasal inflammation Dr Corli Lodder, a GP with a special interest in allergic diseases and a member of the Allergy Society of SA, recently presented a webinar on simplifying Covid confusion – treating paediatric chronic nasal inflammation.

To request your CPD certificate from watching the replay, please email john.woodford@newmedia.co.za

HIS WEBINAR WAS hosted by Medical Chronicle and sponsored by iNova Pharmaceuticals. The following is based on her presentation.Are we dealing with an allergy or is this a viral infection? DEFINITION OF ALLERGIC RHINITIS Allergic rhinitis (AR) manifests as inflammation of the lining of the nose and is accompanied by nasal symptoms, including rhinorrhea, sneezing, nasal congestion, and/or itching, often associated with ocular symptoms. AR is clinically defined as a symptomatic disorder of the nose induced after allergen exposure by IgE-mediated inflammation. COVID-19 – THIRD WAVE The predominant features to bear in mind are: • Children are affected • Flares with changing seasons • Day care centres are operational and this plays a role in the spread of the virus • Rhinovirus infections are commonly detected • Covid-19 can present as: – Acute sinusitis – Acute exacerbation of AR.

If you would like to watch the webinar, you can access it here: https://bit.ly/3a1b5vg

WHAT PATIENTS OR PARENTS THINK • My child always has a stuffy nose • My child always has a wet nose • It is just sinus again – it will pass soon • Hay fever is not serious • All antihistamines are the same • Children do not get Covid. Confirm the diagnosis before blindly suggesting treatment. FACTS ABOUT AR There are over 600 million suffers of AR worldwide. It leads to poor quality of life. According to guidelines, intranasal corticosteroids should be first-line of treatment in persistent AR. Antihistamines widely used to self-medicate.

AR in Children AR is the most common chronic condition in children. It is associated with chronic inflammation and can lead to complications. Treat this as a chronic disease – safely. Atypical presentation includes chronic cough, migraine, impaired hearing, recurrent otitis media with effusion, recurrent episodes of sinusitis, nasal polyposis, and poorly controlled asthma. Keratoconus is now considered as an

inflammatory condition. There is increased choroidal thickness in atopic individuals, which is worsened with eye rubbing. ATYPICAL COVID-19 SYMPTOMS These include: • Vomiting • Headache • Fever • Diarrhoea • Coagulopathy • Most common – asymptomatic.

What to do: • Diagnose AR aggressively • Treat according to guidelines • Treat with options with proof. First-generation antihistamines do not have proof • Control chronic inflammation actively • Target more than one cytokine if possible. TREATMENT IN 2021 Non-sedating antihistamines (oral, intranasal, ocular) leukotriene antagonist, intranasal chromones are recommended, as are intranasal corticosteroids (INCS). One can use INCS and intranasal azelastine/ olopatadine, oral corticosteroids. In extreme cases, referral to an allergist is an option.

Next-generation ARIA In terms of recommendations from Allergic Rhinitis and its Impact on Asthma initiative, the following are important factors: • Patient preference • Symptom severity • Safety/efficacy of treatment • Speed of onset • Current treatment • History of response to treatment • Effect on sleep and work productivity • Self-management strategies. WHAT BENEFIT WOULD RUPATADINE SUSPENSION OFFER? The combination of second-generation antihistamine plus platelet-activating factor inhibitor targets the blocked nose of persistent AR and protects against complications. Its safety has been proven in clinical trials. STOP THE CONFUSION Identify AR, confirm diagnosis and treat the nose. Treat as AR as chronic inflammation. If controlled and there are exacerbations, test for Covid-19.

Interested in sponsoring a

medical webinar? Medical Chronicle has hosted many successful webinars over the past year. From product launches to CPD-accredited talks, we’ve done it. To be part of these popular events, hosted on a platform that requires no downloading, contact:

Anel du Plooy  Anel.duPlooy@newmedia.co.za  082 786 9517

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Bacterial Vaginosis (BV) is the MOST COMMON vaginal infection, affecting 50 % of women#3,4

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Recommended by the CDC* for treating BV, including recurrent BV1

Shows little to no resistance7

Targets anaerobic bacteria8-10 Preserves protective Lactobacilli9

Reduces systemic exposure by 96 % and improves tolerability11

In sub-Saharan African women and African American women4 * CDC = Centre for Disease Control and Prevention #

ONLINE CPD CPD | Expires 30/08/2022

Fight fatigue with optimal nutrition

Dr Ilhaam Mohamed

Fatigue can be described as a lack of energy or a feeling of tiredness, exhaustion and low vitality.1a It is a subjective perception and negatively impacts work performance, family life and social relationships.2a This CPD article is available on www.medicalchronicle.co.za

IREDNESS AND FATIGUE are common symptoms in the primary health care system – approximately one fifth of patients present with fatigue, and one third of adolescent’s report having fatigue at least four days per week.2b The clinical presentation of fatigue may vary between individuals. Men often describe fatigue as tiredness whereas women are more likely to describe feeling anxious or depressed.2c These symptoms are often initiated by inadequate rest, physical effort, or mental strain unrelated to an underlying medical condition (physiological fatigue) and may be quickly relieved by rest or life-style changes. On the other hand, fatigue may be associated with an underlying medical condition (pathological fatigue) and is often persistent, lasting longer than four months and not ameliorated by rest.2d 3a In a French study of 24 healthy men and women, poor sleep followed by family and professional worries was the main reason for a feeling of fatigue, reported as a lack of motivation in 75% of subjects and a lack of vitality in 50% of patients.1b,c Medical conditions associated with fatigue include physical and/or chronic

ailments such as HIV infection and other viral illnesses (infectious mononucleosis and post Covid-19 infection), autoimmune disorders, chronic heart, liver or kidney disease, cancer, endocrine diseases (hypothyroidism, Addison’s Disease), neurological diseases (multiple sclerosis) and mental illness such as depression and anxiety. Medications used to treat disorders may also cause fatigue.2e,f Muscle fatigue is a commonly experienced phenomenon that limits athletic performance and other strenuous or prolonged activity. It is also increases and restricts daily life under various pathological conditions, including neurological muscular and cardiovascular disorders, as well as aging and frailty.3b Physical examination and laboratory investigations may identify underlying medical conditions which explain fatigue. Tiredness cannot generally be completely explained as a consequence of a single disease or pathological mechanism.4a No aetiology is found in approximately one third of patients who present with fatigue.2g Research exploring mechanisms of fatigue in different disease states is limited. To date, cancer research has

proposed biological mechanisms of fatigue. Inflammation, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, and activation of the autonomic nervous system may be involved in the development of fatigue in disease.5a Recently, studies have explored the notion that certain biological compounds involved in energy homeostasis, may play a role in physical and mental fatigue. Inadequate nutritional intake (low protein diet, vitamin and mineral deficiencies), underlying inflammatory mechanisms and immune system activation, may contribute to the feeling of tiredness through disturbances in energy production, production of cytokines and oxidative stress.1,6,9 Researchers propose that lowgrade inflammation induces a metabolic switch from energy-efficient oxidative phosphorylation to fast-acting, but less efficient, aerobic glycolytic energy and increases reactive oxygen species. These effects result in reduced glucose availability and, therefore, reduced cellular energy. Inflammation can also affect circadian rhythms and sleep (and vice versa), which can further exacerbate the effects on energy

availability and expenditure.7a,b Fatigue is, interestingly, one of the first and most common symptoms associated with an activated immune system. Activation of the immune system produces pro- and anti-inflammatory cytokines. The cytokine signal reaches the brain via several immune-to-brain pathways and induce modifications in neurotransmitter and neuroendocrine systems, along with modifications in brain functions, which lead to behavioural changes. During cancer treatment, the increase in circulating concentrations of inflammatory markers, such as C-reactive protein (CRP) and interleukin (IL-6), was related to the development of an overall feeling of fatigue.8a,b,c,d Subclinical or inadequate intake of vitamins and minerals can lead to a significant proportion of the population not meeting their optimum delivery needs in emerging and developed countries. These insufficiencies may subsequently result in a higher risk of pathologies. The majority of Americans consume sufficient amounts of most nutrients to offset clinical symptoms, but in many individuals, intake falls below adequate Intake levels.

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CPD | Expires 30/08/2022 ONLINE CPD In these situations, supplementation may be of value. An improvement in cognition and psychological function, a reduction in mental and physical fatigue and a general feeling of well-being are commonly reported motivations for taking supplements.1d,e,f,g,m AMINO ACIDS AND FATIGUE In the human body, cells and organs require energy to maintain life. Amino acids are the building blocks for tissue proteins and essential substrates for important physiological functions. These are functionally classified as essential and non-essential amino acids. Essential amino acids are dependent on dietary intake whereas non-essential amino acids are synthesised within cells and therefore referred to as nutritionally nonessential. In certain conditions (pregnancy, lactation, injury, burns and disease), the rate of amino acid utilisation in the body is greater than the supply of nutrients from the diet. Under these conditions, certain amino may become ‘conditionally essential’.6a,b,c Therefore, in certain pathophysiological states, accompanied by decreased protein supply from dietary sources, the overall result is a loss of muscle mass, impaired immunity, and improper functioning of organs with subsequent fatigue. There is increasing evidence that regular essential amino acid intake as part of an oral diet is effective in reversing muscle catabolism, promoting muscle anabolism, and restoring immunological function. Therefore, the use of amino acids as supplements to diet would be expanding into the near future.9a MEASURING PROTEIN INTAKE Protein intake is measured by measuring nitrogen balance. Nitrogen balance is measured by collection of nitrogen losses in urine, faeces, skin, and miscellaneous losses (sweat, secretions, etc) and subtracting these losses from measured nitrogen content of protein intake. The amount of protein required to maintain nitrogen balance is dependent on amino acids, which further supports the claim that supplementation may be useful in maintaining energy homeostasis in persons with a protein deficient diet.10 Evidence for specific amino acids and their benefits in fighting fatigue: • L-lycine and L-arginine normalise hormonal stress response in humans with high trait anxiety11 • Novel administration of glycine improves sleep quality in humans who have repeated complaints of sleep12 • The anti-fatigue role of glutamine has also been described in athletes to delay the onset of fatigue and improve athletic performance. Glutamine supplementation also improves fatigue markers such as increased glycogen synthesis and reduces ammonia accumulation during physical exercise13a • The combination of L-glutamine and L-arginine as ‘immuno-nutrients’ provide support duration exercise and improve muscle fatigue14 • L-ornithine supplements have been shown to relieve stress and improve sleep quality related to fatigue.15

VITAMINS AND MINERALS CAN IMPROVE PHYSICAL AND MENTAL FATIGUE Enzymes breakdown ingested carbohydrates into monomeric sugars, lipids into fatty acids and proteins into amino acids. Acetyl CoA that is derived from glucose, fatty acids and amino acids, enter the Citric Acid Cycle in the mitochondria of cells. Through oxidative phosphorylation, there are billions of molecules of adenosine triphosphate (ATP) produced, the cell’s energy source. Macronutrients, vitamins and minerals are necessary to drive this highly efficient system. All the B vitamins, except for folate, are involved in at least

one, or several steps in the energy production system.1h CONCLUSION The incomplete knowledge of pathophysiological mechanisms of fatigue and the lack of a gold standard tool for its assessment contribute to the poor appreciation of fatigue in clinical practice.4b Dietary support with enhanced nutritional therapies have been tested in various patient populations with fatigue, although studies are of inconsistent quality. In vulnerable individuals with subclinical deficiencies or inadequate dietary intake, a nutrient supplement which addresses

energy demands and maintains nitrogen homeostasis needs, with added antiinflammatory and immunomodulatory effects, may assist in treating fatigue. This may be particularly relevant in patients who have had a severe Covid-19 infection. Supplementation may benefit patients who are likely to struggle to consume adequate amounts of protein-rich foods and also in older patients, those with chronic conditions and patients who have been discharged from intensive care who are likely to have muscle wasting or feel weak.22 References available on request.

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Montelukast and rupatadine

Potential agents for Covid-19 Recent articles have reported elevated markers of coagulation, endothelial injury, and microthromboses in lungs from deceased patients with Covid-19. Platelets are critical in the formation of thrombi, and their most potent trigger is platelet activating factor (PAF). This a summary of a CPD-accredited article available on www.medicalchronicle.co.za

AF IS PRODUCED by cells involved in host defense, and its biological actions bear similarities with Covid-19 disease manifestations, including pulmonary microthromboses and inflammation, possibly via activation of mast cells. The histamine-1 receptor antagonist rupatadine was developed to have anti PAF activity and inhibits activation of human mast cells in response to PAF. Rupatadine could be repurposed for Covid-19 prophylaxis. Similarly, with the lack of effective therapy, focusing on the immediate repurposing of existing drugs gives hope of curbing the pandemic. Interestingly, a recent exploration identified montelukast (MK), from the Leukasts family (LKs; ie cysteinyl leukotriene receptors antagonists), among the top-scoring clinically oriented drugs likely to inhibit SARS-CoV-2 main protease (Huynh et al 2020). One retrospective study consistently found that older asthmatic outpatients receiving MK had fewer episodes of confirmed Covid-19 than those not using MK (Bozek and Winterstein, 2020).

support other recent publications from different centres reporting the presence of elevated coagulation markers and microthromboses in the lung and other organs of patients with Covid-19. Most recently, platelet activation and aggregation have been reported in patients with severe Covid-19, but the triggers of these processes were not discussed. The most potent trigger of platelet aggregation is platelet-activating factor (PAF), first discovered by Benvesiste in

1971. Demopoulos et al elucidated its structure as a glyceryl-ether lipid (1-O-alkyl2-acetyl-snglycero-3-phosphocholine) and described its semisynthetic preparation in 1979. PAF is produced by cells involved in host defense, and its biological actions bear similarities with Covid-19 disease manifestations. It was recently reported that platelets, via release of PAF, trigger perivascular mast cell activation, leading to inflammation. Moreover, mast cell degranulation associated with interstitial edema and immunothrombosis was recently reported in alveolar septa of deceased patients with Covid-19. Mast cells are a rich

source of PAF and are plentiful in the lungs, where they may contribute to Covid-19. It was previously reported that levels of PAF were increased in allergic rhinitis and chronic urticaria, both of which involve activation of mast cells. Moreover, PAF appears to play a central role in inflammation. In this context, innate immunity to Covid-19 appears to involve activated T cells and specific antibodies. In addition, lung pathologic findings seen in severe acute respiratory syndrome (SARS) associated with Covid-19 are caused by a release of a storm of proinflammatory cytokines.

PROPERTIES OF MK RELATED TO COVID-19 SERIOUS OUTCOMES

Rupatadine’s role in the cytokine storm The cytokine storm, corresponding to an unopposed generation of both pro-inflammatory and anti-inflammatory cytokines by the innate immune system, is responsible for most of the serious pulmonary complications of Covid-19 (Russell et al 2020). The antagonist action of ZK on CystLT1 receptor protects the endothelium from inflammatory lesions induced by TNF-a (Zhou X. et al 2019). By increasing IFN-g production and inhibiting the expression of cytokines such as IL-1b, IL-6, and IL-8, the inflammatory chain-reaction could be better controlled (Han et al 2010). Clinically, MK is used to reduce drug-related cytokine reactions induced by daratumumab (Chari et al 2018) and rituximab (Kotchetkov et al 2020). In this indication, MK is associated with a marked decrease in frequency and intensity of cytokine reactions and this action seems to be strengthened by the addition of an H1-antihistamine, namely rupatadine (Kotchetkov et al 2020).

RUPATADINE’S ROLE Ackermann et al recently reported the presence of severe endothelial injury and widespread pulmonary microthromboses accompanied with increased angiogenesis in lungs from deceased patients with coronavirus 2019 (Covid-19). These results

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*platelet activating factor. †based on once a day dosing. §Allergic Rhinitis References: 1. Ridolo E, et al. Rupatadine for the treatment of allergic rhinitis and urticaria: a look at the clinical data. Clin Invest 2014;4(5):453-461. 2. Picado C. Rupatadine: pharmacological profile and its use in the treatment of allergic disorders. Exp Opin Pharmacother. 2006;7(14):1989-2001. 3. Potter P, et al. Rupatadine oral solution in children with persistent allergic rhinitis: A randomized, double-blind, placebo-controlled study. Pediatr Allergy Immunol. 2013;24(2):144-150. 4. Potter P, et al. Rupatadine is effective in the treatment of chronic spontaneous urticaria in children aged 2–11 years. Pediatr Allergy Immunol. 2016;27(1):55-61. 5. Valle M, et al. PD39 - Application of population pharmacokinetic modeling and simulation in the design of the optimal dose regime of rupatadine in children 2-5 year old children. Clin Transl Allergy 2014;4(Suppl 1):P39. 6. RUPANASE Junior approved package insert, June 2020. S2 Proprietary name and dosage form: RUPANASE® Junior Oral Solution. Composition: Each mℓ of oral solution contains: 1 mg rupatadine (as fumarate). Registration number: 50/5.7.1/0569. Name and business address of applicant: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. 17464L. IN4266/21.

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Mast cells are one of the richest sources of such cytokines, especially interleukin 6, which has been implicated in Covid-19. Because mast cells are involved in lung diseases, it makes sense that such patients would be even more susceptible to pulmonary complications of Covid-19. Given these findings, it would make sense to try to inhibit the action of PAF. A number of PAF inhibitors have been synthesised but are not available for clinical use, except for the histamine-1 receptor antagonist rupatadine, which was developed to specifically exhibit anti-PAF activity. The study authors reported that rupatadine also inhibits activation of human mast cells in response to PAF. Rupatadine could, therefore, be repurposed for at least Covid-19 prophylaxis. Interestingly, certain natural flavonoids also have anti-PAF activity, in addition to their having antiinflammatory actions and the ability to block Covid binding to target cells. MONTELUKAST Barre´et al published a review of evidence in 2020 advocating that montelukast should be further tested to prevent and treat Covid-19 outcomes. With the lack of effective therapy, focusing on the immediate repurposing of existing drugs gives hope of curbing the pandemic. Interestingly, montelukast, a drug usually used in asthma, may be proposed as a potential adjuvant therapy in Covid-19. The aim of the Barre´et al (2020) was to review the properties of montelukast that could be beneficial in Covid-19. Ten experimentally supported properties were retrieved, either related to SARSCoV-2 (antiviral properties, prevention of endotheliitis and of neurological disorders linked to SARS-CoV-2), and/or related to the host (improvement of atherogenic vascular inflammation, limitation of the ischaemia/reperfusion phenomenon, improvement of respiratory symptoms), and/or related to serious Covid-19 outcomes (limitation of the cytokine storm, mitigation of acute respiratory distress syndrome), and/or related to tissue sequelae (antioxidant properties, anti-fibrosis effects). Based on gathered theoretical evidence, the study authors argued that montelukast should be further tested to prevent and treat Covid-19 outcomes. MK works as a cysteinyl leukotriene (cysLT) receptor antagonist. Leukotrienes are inflammatory mediators produced by the immune system. They promote bronchoconstriction, inflammation, microvascular permeability, and mucus secretion in asthma and chronic obstructive pulmonary disease. Consequently, use of high-dose MK as an anti-inflammatory agent is effective in acute asthma (Wu et al 2003). MK is mainly used as a complementary therapy in adults in addition to inhaled corticosteroids. The use of MK is also known to decrease the frequency and severity of wheezing after an upper respiratory tract infection caused by

adenovirus, influenza, metapneumovirus or coronavirus (Brodlie et al 2015). Common side effects include diarrhoea, nausea, vomiting, mild rashes, asymptomatic elevations in liver enzymes and fever. In 2019 and 2020, concerns for neuropsychiatric reactions were added to the label in the UK and US where the most frequently suspected symptoms were nightmares, depression, insomnia, aggression, anxiety and abnormal behaviour (Glockler-Lauf et al 2019). Apart from MK, LKs also include zafirlukast (ZK) and pranlukast (PK). These

three compounds may have properties of potential interest to treat Covid-19. CONCLUSIONS Rupatadine inhibits activation of human mast cells in response to PAF. Rupatadine could, therefore, be repurposed for at least Covid-19 prophylaxis. Although quantity is not quality, the 10 effects of MK may constitute as many synergistic and potentiating therapeutic possibilities in Covid-19. MK is a commonly used drug that does not require any prior cardiological or biological examination; it can be prescribed

for pregnant women and frail older adults, and it shows a ‘comfortable’ therapeutic range. Moreover, it could be all the more effective for patients with comorbidities such as diabetes, sleep apnoea, smoking, obesity, or symptomatic atherosclerotic lesions. “We support the conduct of clinical trials testing the effect of MK in Covid-19 patients from a variety of populations, while keeping in mind its adverse effects,” the study authors stated. They emphasised however, that a potential massive use of MK in Covid-19 would risk depriving asthma patients of their treatment.

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Identifying and treating

genital warts Obstetrician/Gynaecologist Dr Femi Olarogun of the HART Fertility Clinic and Groote Schuur Hospital, Cape Town presented on diagnosing and treating genital warts. The following article is based on his presentation and was sponsored by iNova Pharmaceuticals.

Dr Jeremiah Olarogun MBBS, Dip Obs SA, MMED, FCOG (SA)

To watch the replay, go to https://bit.ly/3mSTqNm

NOGENITAL WARTS (AGW) are epidermal growth lesions caused by the different genotypes of human papilloma virus (HPV). HPV is usually sexually transmitted. AGW represent a failure of immune recognition, this is not linked to cervical cancer. PREVALENCE AND AETIOLOGY HPV is so common that nearly all sexually active men and women get the virus at some point in their lives. In the US, one in 100 sexually active adults has genital warts. In SA, 66.7% of women have HPV. Low risk HPV, types 6 and 11 are responsible for 90% of genital warts, which are rarely associated with pre-cancer and cancer. SCALE OF THE PROBLEM Transmission does not require lesions to be present. They create a massive cosmetic problem and is a source of substantial psychological issues for the patient, including shame, embarrassment, anger, depression and guilt. AGW and existing treatment modalities can also cause physical issues like pain, burning, irritation and itching. They also cause a strain on the budget of healthcare systems. For instance, the direct cost of treatment of AGW in 2012 (UK) was R1183.44m. DIAGNOSIS The challenge is to ensure that warts are correctly identified and other lesions are not missed. Initial diagnosis is often made or suspected by the patient. This must then be confirmed on clinical inspection. They appear as papillomatous plaques or flat lesions that could be single or multiple. Lesions can be flesh coloured, white, pink or brown. They typically manifest in areas in close contact during sex – vulva, penis, groin, perineum and peri-anal skin. They sometimes also arise in the oral cavity. Diagnosis of typical AGW does not require histological diagnosis. TYPES OF LESIONS THAT CAN BE CONFUSED WITH WARTS There are a number of physiological and pathological lesions that could be confused with AGW. These include vestibular papillae, sebacceous cysts, syphilis on mucosal plates, molluscum contagiosum, lichen planus, psoriasis and Condylomata lata. This also includes benign or malignant neoplastic lesions, papillomatosis, nevi, verrucous carcinoma, grade 2-3 vulval

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system to clear the lesions. Imiquimod is used by the patient three nights a week for up to 16 weeks. Sinecatechins is made from green tea polyphenols with anti-inflammatory, anti-proliferative, proapoptotic and anti-viral properties. It’s mode of action is not fully known. It is applied three times a day for up to 16 weeks. It has complete clearance rates of 40%-81%. It is similar to imiquimod but has higher recurrence rates.

intraepithelial neoplasia, Bowen’s disease and lymphangioma. WHEN TO BIOPSY Experience in this regard is paramount. Refer to a vulval specialist if it doesn’t look like obvious warts. Biopsy is usually indicated in flat warts, pigmented areas, older age group, immunosuppression and heavy smoking. TREATMENT CONSIDERATIONS Treatment should be individualised. Patients often want immediate resolution but consideration should be given to size, number, morphology, location and keratinisation. It is important to note if these are new or recurrent lesions. The wart area should be considered, as smaller surface area often require treatment for a shorter period. TREATMENT OPTIONS Ablative therapy Ablative therapy is used daily by practitioners to remove warts. It’s often awkward and painful for the patients. There is a high rate of recurrence and need for repeat therapy. There is also a high risk of bleeding, tissue destruction and scarring. Cryotherapy, freeing with liquid nitrogen, may cause hypopigmentation. Laser – carbon dioxide and Nd: YAG. Requires specialised and costly equipment and training. In electrocautery, fumes may contain contagious particles. In terms of surgery, scissors or scalpel are needed, especially in large obstructive lesions.Trichloroacetic acid requires a skilled professional and may cause local burning/ ulceration.

Immunotherapies This stimulates the body’s own immune

Other topical agents Podophyllotoxin 0.15% or 0.5% solution stops division of infected cells leading to tissue necrosis. It is applied twice daily for three consecutive days separated by fourday intervals, repeated for up to four weeks. It needs to be applied carefully to the lesions avoiding normal skin. It has a clearance rate of 45%-94%. Nitric-zinc complex contains nitric acid, zinc, copper and organic acids. It is applied 1-4 x daily at two-weekly intervals. It has clearance rates in initial small studies of 90%-99%. IMIQUIMOD This is a novel topically active positive immune response modifier. It enhances the body’s immune response against dysplastic cells and is a member of imidazoquinolines family. It has proven strong antiviral (HPV) and anti-tumour properties, enhancing non-specific and specific immune response, especially in cell-mediated pathways. MODES OF ACTION It activates dendritic cells through Toll-like receptor7. Activated dendritic cells migrate to local lymph nodes and initiate T-cell activity. It induces IFNa, IL6, IL12 and TNFa. T-cells travel via the bloodstream and selectively destroy tumour cells, other dysplastic cells and instigate resolution of actinic keratosis and superficial basal cell carcinomas. It stimulates natural killer cells, macrophages and B lymphocytes, and induces immunologic memory. Imiquimod induces cellular memory via the activation of effector T-cells, Langerhans cells, lymphocytes, and macrophages. These cells circulate lymphatically and activate the adaptive immune response. Imiquimod’s ability to induce immunologic memory results in a low incidence of recurrence and lowers viral load. Patients wash the area with mild soap and then dryand apply a small amount of cream

onto the lesions for three nights per week for up to 16 weeks. Approximately 40% of patients may experience complete clearance at four weeks.

Advantages It is highly selective with a specific effect on dysplastic cells and no effect on normal cells, but a treatment effect on subclinical actinic keratoses. Surface field treatment can be achieved. It lowers HPV viral load and treats clinically visible and sub-clinical lesions, with excellent cosmetic outcome. It is less invasive than some of the other treatments discussed and can be applied at home. It is available in pump or sachets, is also on state formulary. Disadvantages Local skin reactions include redness, itching and burning. Flu-like symptoms are rare and only in a very severe reaction, including myalgia, headache and fatigue. Treatment can take a few weeks. PREVENTION OF RECURRENCE Recurrence rates with conventional ablative therapies is relatively high, as these methods remove visible lesions without treating the underlying HPV infection. Immunotherapies described above have a lower recurrence rate as they stimulate host immune response to clear the warts. Studies have shown that combination of ablative techniques followed by immunotherapy may lead to even lower recurrence rates. The use of imiquimod prior to or after ablative therapy reduces the recurrence rate. SUMMARY AGW warts are common and by the time the patients present they have probably had the lesions for a while. There are various treatments available and these should be offered to patients depending on factors such as size, number, type, recurrence and surface area. Biopsy is indicated if diagnosis is uncertain. Ablative therapy may be associated with unwanted side effects. Imiquimod is an effective treatment that is well tolerated and can be used on its own or in conjunction with other forms of treatment. If you would like to earn a CPD certificate by watching the replay, email John.woodford@newmedia.co.za to let him know that you have watched the webinar.

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Handling obesity Identifying and treating skinpatients lesions duewith to sun psychiatric damage in different skin types in disorders EugeneMpofu, Allers, psychiatrist in female privatedermatologist practice, presented a webinar for Medical Chronicle on handling Dr Pholile the first black in South Africa, recently presented onrecently the important topic obesity in patients with psychiatric disorders. of sun damage. This webinar was made possible by Viatris. The following is based on her presentation.

Dr Eugene Allers, Psychiatrist in private practice

To watch the replay ofinthis andpopulation). still earn a CPD point, go topro-opio-melanocortin the replay: thewebinar psychiatric neurons. https://bit.ly/3bDu9R0 5-HT2C Agonists include fenfluramine, Metformin suppresses excessive hepatic Dr Pholile Mpofu

This webinar was made possible by iNova Pharmaceuticals. ToCANCER watch the click here: https://bit.ly/3lHyUyd. KIN ISreplay the most If you watch replay and Itwould like a CPD certificate, common cancerthe in Caucasians. does occur inemail peopleJohn.woodford@newmedia.co.za of colour, although ACTINIC KERATOSES the relative risk is low. Skin cancer in skin This is proliferation of cytologic atypical of colour is associated with increased involves lifestyle changes and medication. R ALLERS EXPLORED: keratinocytes in the dermal-epidermal morbidity and mortality due to late Standard changes are to notSCC • Psychiatric medication promoting junction zone.lifestyle Risk of progression presentation, atypical presentation, late described,with and the psychosocial weight increases increase ininterventions number treatment, and gain refusal of treatment (for areAKs. recommended, but it’s unclear what •example Appetite vs hunger of amputation). this includes or means. The role of exercise • Regulation of food intake Prevention and increased surveillance is is to maintain of weight rather than •essential Various in treatment options including Management widespread AK to lose this group, by means of regular Dietetics, psychotherapy and lifestyle •weight. Destructive therapies: Cryotherapy, skin exam modifications. by clinicians, self-examination, cognitive behavioural therapy have a role surgery, dermabrasion, laser public education, and screening to play. Anti-obesity pharmacotherapy Obesity is defined as a body mass index • Topical therapies: 5-Fluorouracil, programmes. agents are centrally acting, impairing of >30. It does not distinguish fatattention from imiquimod, diclofenac Patients should seek medical intake, peripherally acting, impairing muscle and does not us where body •dietary Chemical peels for a non-healing ulcertell(three weeks), new absorption, and increasing energy fat is stored. It ismoles, also defined by waist •dietary Photodynamic therapy. moles, changing and changing expenditure. The management of obesity in circumference (with BMI of 26-34), in men: lesions (oozing, bleeding, crusting). psychiatry is a multi-professional approach. >102cm, and women: cm. are increased ALBINISM Risk factors for skin>88 cancer medication This is lack of pigment or pigment dilution sunPsychiatric exposure, especially to promoting fair-skinned CENTRALLY weight gainskin includes antipsychotics, due to a defectACTING in the synthesis of melanin individuals, conditions that result in ANTI-OBESITY DRUGS antidepressants, sleep medication and leading to a congenital absence of pigment scarring or chronic inflammation, burn scars SNRIs include which is anxiolytics. Appetite is the psychological in the skin and sibutramine, eyes. and post-radiation therapy. mediated β1-adrenergic and driveUltraviolet to eat while hunger is the biological Cancervia riskα1isand 23.4% in this group, (UV) chronic exposure is a 5-HT2B/2C receptor mechanisms, while drive to eat. Psychiatric disorders are increasing with age, due to cumulative risk factor for nonmelanoma skin cancer its thermogenic effects are thought metabolic disorders, and, in many cases, exposure to UV radiation and inabilityto be (basal cell carcinoma [BCC], squamous mediated byisstimulating β3 adrenoceptors patients have food addiction and keratosis gut to tan. SCC more common than cell carcinoma [SCC] and actinic in brown tissue (this is problematic microbiome abnormalities. Treatment BCC hereadipose and occurs more commonly [AK]), melanoma and photoaging.

andthe lorcaserin, stimulation anorexigenic on head. Melanoma is rare. proopio- melanocortin (POMC) neurons in the hypothalamus. XERODERMA PIGMENTOSUM reuptake ThisNorepinephrine–dopamine is a rare inherited disease that inhibitors includesensitivity bupropion.toEnhanced causes extreme the sun’s UV dopamine neurotransmission rays. Without sun protection, stimulates the skin and POMC the arcuate nucleus of eyes areneurons severelyindamaged. These patients the hypothalamus acutely develop freckles atand an early ageincreases and the sun activity of POMC cells.onset Serotonin– damage leads to early of cancer of the norepinephrine–dopamine reuptake skin and eye. inhibitors include tesofensine. Dopamine and noradrenaline SCC reuptake inhibitors releasers include This cancer is moreand common in people phentermine, an amphetamine derivative. of colour, and is not always on It stimulates the hypothalamic release sun-exposed areas. It is more common of lower norepinephrine and reduces hunger in legs, the anogenital region, and sensation. It causes the release of head and neck. epinephrine or adrenaline outside(discoid of the Risk factors include scarring brain, erythematosus, resulting in breakdown storednonfat. lupus leprosy,ofburns), Topiramate is aradiation channel blocker blocks healing ulcers, therapy,that organ voltage-dependent sodium andand calcium transplant recipients, albinism, patients channels, inhibits the excitatory with xeroderma pigmentosum. glutamate pathway while enhancing the inhibitory effect of GABAIMMUNITY and it inhibits carbonic WEAKENED anhydrasewith activity. In terms of nonselective Patients depressed immunity, such as μ-opioid receptor antagonists, naltrexone organ transplant patients or those with HIV blocks B-endorphin action sarcoma, at the U-opioid are at risk for SCC, Kaposi BCC, receptor, thus preventing autoinhibition of and melanoma

The misogynistic mystery and

reality of PCOS

glucose production, through a reduction BCC in gluconeogenesis. is an than increase This condition is lessThere prevalent in glucose uptake in insulin signalling, SCC. Exposure to and UV light is a major with a decrease in fatty acid andfactors triglyceride aetiological factor. Predisposing synthesis increase in fatty acid include fairand skinanand albinism, xeroderma β-oxidation. In clinical trials, metformin pigmentosum, trauma and long-term showed a weight decrease ofarsenic -3.27kg (95% ulceration, radiation therapy, CI, -4.49 to -2.06), while topiramate ingestion, nevus sebaceous, basal cellhad -5.33kg (95% CI,and -7.20 to -3.46). nevus syndrome, immunosuppression. Liraglutide is a glucagon-like It is more common in femalespeptide-1 over 50, on (GLP-1) agonist. is a lipase the lowerreceptor legs. The skin in Orlistat these patients is inhibitor.pigmented. Sodium-glucose co-transporter usually 2 (SCLT2) inhibitors include dapagliflozin. Weight loss was butCOLOUR the medication MELANOMA INminimal SKIN OF had a beneficial on atherosclerotic Melanoma is theeffect third most common cardiovascular disease, and type of skin cancer in allheart racialfailure groups, renalthe disease. Recommendations for weight and most deadly. It is 5-18 times less control ininpsychiatric patients common Caucasians. Treataetiology the weight gain as a chronic The is undetermined in disorder, in a multi-disciplinary team. skin of colour. Areas of involvement Lifestylehands recommendations diet, include and feet (acralinclude lentiginous) exercise, and psychotherapy in the form of including under the nails (misdiagnosed as cognitive behavioural therapy. warts or fungal infection), and Medication is the second paradigm shift, mucous membranes. especially form of chronic medication. There isinathe good chance of survival if Be cautious in patients with bipolar detected early. Decreased survival isdisorder due to and schizophrenia thepresentation developmentand of aggressive disease,for late psychosis or mania. wrong diagnosis.

WEBINAR | Expires 19/09/2022

Dr Razina Patel, who dedicates her expertise to facilitating pregnancies at the Sandton Fertility Centre, presented on the reality of living with polycystic ovarian syndrome (PCOS). This webinar was made possible by iNova Pharmaceuticals. Watch the replay video here: https://bit.ly/2YacsFs

COS IS A DAILY reality for many South Africa women. It is the most common endocrine problem in women in their reproductive age. Worldwide, it affects 5%-12% of women of childbearing age. A CLINICAL APPROACH TO DIAGNOSIS The following steps are recommended in diagnosing PCOS: 1. Assess ovulatory dysfunction 2. Asses clinical hyperandrogenism 3. Assess biochemical hyperandrogenism 4. Assess polycystic ovarian morphology (PCOM) 5. Differentiate PCOS from other androgen excess and ovulatory disorders. METABOLIC CONSEQUENCES OF PCOS Metabolic consequences of PCOS include:

• Obesity • Insulin resistance • Impaired glucose tolerance • Diabetes • Sleep apnoea • Cardiovascular risk • Endometrial cancer • Depression and anxiety • Psychosexual function • Infertility • Obstetric complications. TREATMENT OF PCOS Treatment of the condition includes the following: • Lifestyle modification. • Manage metabolic risks • Manage clinical hyperandrogenism: - OCP - Antiandrogens - Cosmetic measure

- insulin sensitisers • Manage menstrual dysfunction • Manage fertility and subsequent pregnancy. CONCLUSION PCOS Is common and complex. The approach to managing it involves addressing the patient’s dominant symptom a well as the metabolic consequences of the disease. Lifestyle changes have benefits that are synergistic with pharmacological therapies. Standard therapies like metformin may not be evidence-based but have almost become routine while inositol and D-chiroinositol are showing great promise. These therapies are being used to improve hyperandrogenism and improve insulin sensitivity, thus assisting in ovulation, menstrual regularity, increasing fertility and preventing potential adverse

metabolic and cardiovascular consequences out of and in pregnancy - where, if left unchecked, it facilitates the same cycle of ill health in the unborn child. To earn a CPD point watch the replay and email john.woodford@newmedia.co.za to let him know.

Dr Razina Patel Gynaecologist and Fertility Specialist, MBBCH (Wits), FCOG (SA), Masters in Embrology - Univ Valencia

MEDICAL CHRONICLE | November 2021 33 MEDICAL CHRONICLE 55

WEBINAR | Expires 02/11/2022

Overview of chronic kidney disease webinar

A replay is now available for the ‘Overview of chronic kidney disease’ webinar held on 3 November 2021. The webinar was sponsored by iNova Pharmaceuticals and presented by Dr Heleen Bierman.

HRONIC KIDNEY DISEASE (CKD) is commonly associated with disorders of mineral and bone metabolism, manifested by either one or a combination of extra-skeletal calcification; abnormalities in bone turnover, mineralisation or strength; or abnormalities of calcium, phosphorus, PTH and vitamin D metabolism. Chronic kidney disease mineral and bone disorder (CKD-MBD) has a very early onset, commonly occurring during early CKD when kidney disease causes a decrease in bone formation. It is unfortunately associated with high mortality rates, primarily from cardiovascular complications. Several treatment modalities for CKD-MBD have presented themselves over the years. One is the modulation of the Klotho gene. Klotho is a gene which regulates

aging in mammals and has been implicated directly in the pathogenesis of CKD. Klotho levels decrease early in CKD and klotho deficiency could in turn cause vascular calcification culminating in atherosclerosis, osteoporosis, ectopic calcification, premature aging, apoptosis and CKD progression. It has been determined that the FGF23 gene decreases calcitriol levels and inhibits transcription if the klotho gene. Elevated FGF23 genes are associated with inflammatory markers in CKD. The

This webinar was made possible by iNova Pharmaceuticals. To watch the replay click here: https://bit.ly/3y5hzEr. If you watch the replay and would like a CPD certificate, email John.woodford@newmedia.co.za

Dr Heleen Bierman

importance of FGF23 and klotho to the pathogenesis of CKD-MBD underscores how silly it is to focus solely on vitamin D and calcium. Bone mineral disorder can be prevented by paying attention to phosphate levels. For every 1mg/dL increase in phosphate, a person’s risk of mortality from CKD increases 10%-62%. Higher phosphate levels lead to a faster decline in renal function. Dietary management is the primary way of managing this risk. Phosphorus binders should also be taken. It is also prudent to screen patients for vitamin D deficiency. The PRIMO and OPERA studies failed to demonstrate improvements in clinically relevant outcomes but did demonstrate increased risk of hypercalcaemia. Accordingly, routine use of calcitriol and its analogues in CKD 3a-5 is no longer recommended.

High resolution (300dpi), print ready CMYK PDF file with crop marks 1/4 Page (Hor) x 2 sets - 1 Generic Trim - 215mm(w) x 76mm(h) Type -205mm(w) x 66mm(h)

WEBINAR: Overview of Chronic Kidney Disease Mineral Bone Disorder (CKD-MBD) Calcium carbonate supplementation provides phosphate binding potential for individuals with kidney impairment1

PROUDLY SPONSORED BY SOUTH AFRICA’S NO. 1 PRESCRIBED CALCIUM RANGE2

References: 1. Slatopolsky E, Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing dialysis, 1986 JUL 17;315(3):157-61. 2. Impact Rx. Script data (Vitamins & Minerals / Constructed class) MAT March 2019. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert. Further information is available on request from iNova Pharmaceuticals. 17985L.

56 MEDICAL CHRONICLE

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