Evidentia Sept Oct issue 2010

Volume 4 Issue 5 September/October 2010 ISSN 1753-464X

Conference reports from: Amsterdam, Glasgow, Manchester, New Orleans and Orlando

Bringing clinical evidence to practice in primary and secondary care

CONTENTS 4

Guest Editorial - New and emerging therapies in Type 2 diabetes

by Dr. G Tarigopula and Professor MJ Davies

6

COVER STORY

Impact of most common skin diseases on lifestyle choices Reporting from the British Association of Dermatologists meeting, Manchester,

11 Study shows cigarette smoking is a risk factor for Alzheimer's disease Smoking Cessation report

14 Pioglitazone plus exenatide brings more benefit to patients Reporting from the American Diabetes Association meeting, Orlando

16 Clear take-home messages from ECNP Reporting from the European College of Neuropsychopharmacology meeting, Amsterdam

20 IBD - Chemokine Inhibitor shows promise 25 Access to opioid-base

Part 2 of reports from Digestive Disease Week, New Orleans

pain relief is a human rights issue

23 EMA Highlights - Emerging uses of EMA approved drugs 24 European patient survey adds weight to expert call for greater clinical consensus on BTCP Reports from the European Association for Palliative Care meeting, Glasgow

28 The BIG FOUR - Reporting from some of the latest journal articles 30 World Health Matters - Medical news from around the world 25

32 FDA Highlights - Emerging uses of FDA-approved drugs 34 View from The Waiting Room - A load of hot air

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Guest Editorial Dr. G Tarigopula and Professor MJ Davies, University Hospitals of Leicester NHS Trust

New and emerging therapies in Type 2 diabetes

T

ype 2 diabetes (T2DM) is a chronic metabolic disease associated with microvascular and macrovascular complications. Intensive glucose control has been shown to limit and/or reduce the burden of microvascular and macrovascular complications of diabetes.1 It is widely accepted that current glucose lowering therapies including the use of insulin have failed to achieve optimal glycaemic control.2,3 Moreover these drugs are often limited by unacceptable side effects, hypoglycaemia and weight gain. Hence there is an urgent need to develop drugs which are well tolerated and demonstrate a sustained glucose lowering effect with a good safety profile.

Newer therapies have addressed these issues to some extent and some of the newer emerging therapies appear to be promising.

New licensed therapies Incretin based therapies make use of the antidiabetic properties of the endogenous GLP-1 hormone (so called incretin enhancers). They act either as mimetics increasing the supraphysiological levels of the GLP-1 or prevent the degradation of the DPP-4 enzyme thereby increasing the endogenous availability of GLP-1.

The GLP-1 agonist drugs act by enhancing glucose dependent secretion of insulin and also decrease glucagon production. Other beneficial effects include delay in gastric emptying and reduced appetite.4 A major advantage of the GLP-1 agonists are improvements in glycaemic control with sustained weight loss.5,6 The currently used GLP-1 agonists, exenatide and liraglutide and the DPP-4 inhibitors including sitagliptin, saxagliptin and vildagliptin are briefly discussed below.

Exenatide Exenatide is given as a subcutaneous injection and has to be injected twice daily in view of its short half life of 3 hours. Reductions in HbA1c of up to 1.0% were seen with Contributors: Thomas R. Collins, Steve Devrell, Professor Melanie Davies, Gary Finnegan, Peter Mas-Mollinedo, Bruce Sylvester, Dr. Giridhar Tarigopula, Samuel Peters.

monotherapy,7 whereas when added to oral hypoglycaemic agents, reductions of up to 1.5% have been demonstrated.8 In clinical studies, exenatide has been shown to induce significant weight loss of around 3.6kg.8 Other beneficial effects include reduction in blood pressure, improvements in lipid profile 8 and beta cell function.9 Side effects associated with exenatide are typically gastrointestinal related and include nausea and vomiting which is often transient. Pancreatitis is a very rare adverse effect that has been reported. Frequent dose adjustments are not required with exenatide.

However in combination with a sulphonylurea, the dose of sulphonylureas may be reduced to prevent the risk of hypoglycaemia.10

Liraglutide Liraglutide is a once daily GLP-1 agonist with a longer half life than exenatide. Using liraglutide as add-on therapy to oral hypoglycaemic agents, HbA1c reductions in the range of -1.0% to -1.5% were observed.11 liraglutide was associated with reductions in fasting and post prandial sugars, improvements in blood pressure and lipid profile and similar weight loss to exenatide.11,12 Clinical studies comparing the effects of liraglutide with twice daily exenatide, showed that liraglutide was better tolerated and with greater improvements in HbA1c of 0.32% compared to exenatide.13 liraglutide was better tolerated with fewer hypoglycaemic effects and lower rate of persistent nausea compared to exenatide.

DPP-4 inhibitors The DPP-4 inhibtors (sitagliptin, saxagliptin, vildagliptin) have also demonstrated modest improvement in glycaemic control. In clinical trials, HbA1c reductions of 0.7%-0.9% were seen with the gliptins when used either alone or in combination with oral agents such as metformin, sulphonylurea or a glitazone.14-16 These drugs are taken orally and are generally well tolerated. Importantly, they are weight neutral

Editorial / Advisory Board: Omar Ali Bsc MRPhamS, Y Callan MD MRCGP M Gray MRPharmS, M Gupta MD MRCP Tim Lewis MD FRCP, K O’Neill Bsc MRCGP Mr Ian Pearce, C Weston MD MRCP

and infrequently associated with hypoglycaemia except when used in combination with a sulphonylurea. Reported side effects include upper respiratory and urinary tract infections.

Treatment of Type 2 diabetes Long acting GLP-1 agonists/ analogues (once weekly) currently in phase III clinical trials include exenatide and taspoglutide.

Long acting release exenatide Studies using once weekly exenatide have been promising. At 30 weeks, there was a significant reduction in HbA1c compared to twice daily exenatide (-1.9% vs. -1.5%, respectively).

Improvements in weight and blood pressure were similar with both regimens. However, reduction in lipid profile was significantly more with once weekly exenatide.8 At one year follow-up, patients continued to show sustained reductions in HbA1c and weight loss.17 Gastrointestinal side effects like nausea were significantly less with once weekly exenatide.

Clinical trials with taspoglutide, a long acting GLP-1 analogue showed significant reductions in HbA1c (-1.0 to -1.2%) and weight (-2.8 kg) when added to Type 2 diabetes patients inadequately controlled on metformin18 and has been compared to sitagliptin and exenatide.18-20 Taspoglutide also showed improvements in glycaemic control, significant weight loss and less hypoglycaemia when compared to insulin glargine.21

Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors Sodium–glucose transporter proteins are found in the proximal convoluted tubule of kidneys and are mainly responsible for glucose reabsorption. SGLT-2 inhibitors are a new class of drugs which inhibit absorption of glucose in the proximal tubules promoting glycosuria and hence decreasing blood glucose levels with a mechanism of action which is independent of insulin secretion.

Publisher: Peter Mas-Mollinedo peter@icr-uk.com Editor: Karen O’Malley, MPSI karen@icr-uk.com

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ICR-UK Limited, PO Box 448, West Byfleet, Surrey KT14 9AU Tel: 0845 094 1699 Fax: 0845 094 1690 © ICR-UK Limited. The information contained in Evidentia is intended to be used with professional medical knowledge and in conjunction with other sources of clinical evidence and product literature.

ICR-UK & sister company IMI, publish a number of medical jour nals and electronic jour nals. For more information visit www.icr-uk.com ICR-UK are affiliate members of the ABPI ISSN: 1753-464X Designed by JAM Design 01483 426017 P r i n t e d b y S t e p h e n s & G e o r g e 0 1 6 8 5 3 8 8 8 8 8 D i s t r i b u t e d b y P r e c i s i o n D i r e c t M a r k e t i n g 0 1 2 8 4 7 1 8 9 0 0

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at

British Association of Dermatologists

< CONTINUED FROM PAGE 4

Dapagliflozin is one of this new class of oral selective SGLT-2 inhibitors. Others include canaglifloxin, remoglifloxin and serglifloxin.

Data from clinical trials involving 389 Type 2 diabetes patients after 12 weeks of dapagliflozin monotherapy, showed reductions in HbA1c ranging from 0.5-0.9% and a weight loss of 2.5-3.4kg independent of dosage .

There were improvements in both fasting blood glucose and post prandial hyperglycaemia.22,23 In a larger study involving 546 patients, incremental doses from 2.5 up to 10mg showed HbA1c reductions in the range of 0.67-0.84%.24 Statistically significant weight loss was also noted in this study. However, concerns of genital tract infections, polyuria and electrolyte abnormalities and long-term cardiovascular disease (CVD) status needs to be evaluated in larger trials.

Glucokinase activators Glucokinase is an enzyme that is the main ‘glucose sensor’ in the pancreas and liver.

Activation of glucokinase enhances insulin release and promotes liver glycogen synthesis and a reduction in hepatic glucose. Glucokinase activators have demonstrated potent antihyperglycaemic effects in animal experiments25 and clinical development of these drugs is in progress. The ability to influence dual sites in the glucose homeostatic pathway suggests that these drugs have the potential to become useful therapies in the treatment of Type 2 diabetes.

Glucagon-receptor antagonists An increase in hepatic glucose output and glycogen metabolism particularly in the fasting state due to hyperglucagonaemia occurs in people with Type 2 diabetes. Glucagon-receptor antagonists work on the premise that blocking the glucagon receptors results in reduced production of hepatic glucose and therefore contributes to overall metabolic control. Early studies in animal models have shown some promise,26 and has stimulated further interest in the search for the ideal novel compounds in this class of drugs for the treatment of Type 2 diabetes.

Conclusions A number of glucose lowering therapies have been recently developed and emerging therapies also look promising. While it is important to focus on glycaemic control with drug therapies, multifactorial interventions addressing CVD risk factors with patient education remain the gold standard of management in Type 2 diabetes. The ultimate challenge in improving cardiovascular outcomes in these high risk patients and CVD outcome trials with these recent classes of drugs are a top priority.

References are available on request

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EVIDENTIA •

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Reports from the BAD meeting, Manchester

Impact of most common skin diseases on lifestyle choices

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ew research into a range of common skin diseases affecting hundreds of thousands of Britons will reveal the true impact of the conditions on the lives of patients. A series of studies, presented at the British Association of Dermatologists’ conference in Manchester, shows the influence that diseases such as acne, eczema and psoriasis, can have on people’s relationships, work and everyday lives. In total, nine out of ten (90%) patients with a chronic skin condition said it had influenced a major life-changing decision - with one in five (22%) saying that their disease had even influenced their decision on whether or not to have children.

One study1 found: • Almost half (46%) said their skin disease had a bearing on their choice of clothing they wore.

• One in five said it influenced whether they wore make-up (22%).

• The same proportion said that their condition prevented them from socialising and a third (34%) had stopped swimming.

• Two thirds (66%) said their skin disease had influenced a major life-changing decision relating to their career, while decisions relating to education (44%) were also affected.

• One in five (20%) said their disease had a bearing on whether they took early retirement.

Another study2 found that skin conditions are the most frequent reason for people to consult their GP with a new problem, more so than respiratory problems, musculoskeletal disorders and mental illness.

A third study3, relating just to psoriasis, found that: • Two thirds of patients with severe symptoms said the disease has had a negative impact on their working life.

• Four out of ten (42%) said the disease had limited their income, or restricted their future employment or career choice.

• A third of such patients (32%) reported discrimination in the workplace on the basis of their condition, while one in five (19%) said that their disease had contributed to

S E P T E M B E R / O C TO B E R 2 0 1 0

them resigning or being dismissed from a job.

More than a third (37%) felt that, owing to their disease, they have not performed as well in education as they could have done.

Nine out of ten (87%) felt that their mood, mental health and general enjoyment of life suffers, with three-quarters (73%) saying they have reduced drive and 69% saying they have reduced aspirations because they have psoriasis.

Psoriasis was also found to influence patients’ personal relationships, with 67% saying that their disease has prevented them pursuing intimate relationships. Three out of ten (29%) have ended an intimate relationship because of their condition.

Most patients (87%) believed there to be a lack of understanding about psoriasis among the public.

•

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Chief Executive of The Psoriasis Association, Helen McAteer said: “This is the largest UK web-based survey to assess quality of life issues in psoriasis. Our findings illustrate that severe psoriasis has a significant and long-lasting impact on people’s lives in the UK - far greater than was previously appreciated.”

Nina Goad of the British Association of Dermatologists said: “I work with skin disease patients on a daily basis so I am aware of the profound effect that symptoms can have on people’s lives, but despite this I was still stopped in my tracks by some of the findings of this research.

“The fact that such a high number of people cite having a skin disease as a major consideration in the decision of whether to have children, or say that it has brought about the end of a relationship or caused them to stop socialising, is just so sad.

“Add to this the statistics about job losses and discrimination in the workplace, and a clear picture begins to emerge of what so many people in the UK are having to endure. Of course not all patients will be influenced to this degree, but it is worrying that so many are. And we are not talking about one rare disease here, which would be bad enough. Skin conditions are incredibly common.”

References are available on request.

by Peter Mas Mollinedo

UV-B treatment may improve psoriasis and vitamin D levels

T

reatment with narrow-band UV-B rays may increase serum levels of vitamin D in the wintertime while clearing psoriasis, according to a report in the Archives of Dermatology, one of the JAMA/Archives journals.

Psoriasis affects 1.5% to 3% of the population, according to background information in the article. Abnormalities in vitamin D metabolism may be partly responsible for the development and worsening of this skin condition. "Most vitamin D is obtained by skin production following exposure to solar UV-B, while less than 15% is obtained from dietary sources such as oily fish and fortified foods," the authors write. Narrowband UV-B treatment

‘

At the end of the study,

all patients in the treatment group were vitamin D sufficient, but 75% of the

control group had vitamin D insufficiency [serum 25(OH)D level of less than 20 nanograms

’

per mililitre].

has become the standard light therapy for psoriasis. Caitriona Ryan, M.B., B.Ch., B.A.O., then of St. Vincent's University Hospital, Dublin, and now of Baylor Research Institute, Dallas, and colleagues assessed 30 consecutive patients with psoriasis who were treated with narrowband UV-B three times per week until their psoriasis cleared between October 2008 and February 2009. Their serum vitamin D levels - measured before the study, after four weeks of treatment and after completing

treatment - were compared with those of 30 control patients who also had psoriasis but did not undergo UV-B therapy. Psoriasis severity and dermatology-related quality of life were also assessed before and after treatment.

Levels of serum 25-hydroxyvitamin D [25(OH)D] - the most accurate measurement of vitamin D levels in the body - increased significantly among individuals receiving UV-B therapy, from a median (midpoint) of 23 nanograms per mililitre to 59 nanograms per mililitre at the end of treatment. There was no change in the control group. "At the end of the study, all patients in the treatment group were vitamin D sufficient, but 75% of the control group had vitamin D insufficiency [serum 25(OH)D level of less than 20 nanograms per mililitre]," the authors write. In addition, psoriasis severity scores decreased in the UV-B group, from a median of 7.1 at the beginning of the study to 0.5 after treatment.

Median scores did not change in the control group.

Among those treated with UV-B, change in vitamin D level was associated with the number of exposures and the cumulative dose of UV-B, but not with whether psoriasis responded to the treatment. "In fact, those who required a greater number of exposures to clear had a significantly higher serum 25(OH)D level, most likely EVIDENTIA •

produced by more prolonged exposure to narrowband UV-B," the authors write. "We cannot conclude, therefore, that narrowband UV-B mediates its therapeutic effects by increasing vitamin D levels. This suggests that the improvement in both vitamin D status and psoriasis are contemporaneous, but unrelated, consequences of narrowband UV-B, or that there is another explanation for the causal relationship."

The results also highlight the significant rate of vitamin D insufficiency in Irish patients with psoriasis who are not being treated with UV-B, suggesting that additional supplements may be needed to prevent harmful effects of this deficiency, the authors note.

Reference: Arch Dermatol 2010; 146[8]: 836-842

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Gentle yet Strong

A soothing cream with the antimicrobial power to deal with Staph aureus associated with atopic eczema.

Eczmol contains 1% chlorhexidine gluconate which is highly active against Gram positive bacteria, especially Staph aureus, a clinically significant trigger factor in the pathogenesis of atopic eczema. the gentle cream base spreads easily and evenly and is quickly absorbed into the skin.

Eczmol 1% w/w Cream: Abbreviated Prescribing Information Presentation: Please refer to the full Summary of Product Characteristics before prescribing. Indications: Eczmol 1% Cream is an antimicrobial emollient which can also be used as an alternative to soap in the management of dry and pruritic skin conditions including eczema and dermatitis. Dosage: For external use only. For adults, the elderly, infants and children. For application to the skin: Apply Eczmol to the affected areas as often as necessary. For use as a soap substitute: Eczmol may also be used as a cleanser in the bath or shower, or for other toiletry purposes, instead of ordinary soap or shower gel. Contraindications: Preparations containing chlorhexidine are contraindicated for patients who have previously shown a hypersensitivity reaction. However, such reactions are

uncommon. Do not use in cases of known sensitivity to any of the ingredients. Warnings and Precautions: For topical application only. Keep out of the eyes and ears and avoid contact with the brain and meninges. Hypersensitivity to some of the ingredients of Eczmol may be more common in patients with leg ulcer or stasis dermatitis. Eczmol should therefore be used in caution in these patients. Eczmol contains the ingredient cetostearyl alcohol which may cause local skin reactions (e.g. contact dermatitis). Adverse events (see SPC for full list): Irritative skin reactions can occasionally occur. Generalised allergic reactions to chlorhexidine have also been reported but are uncommon. Packaging size and price: 250ml HDPE bottle. ÂŁ3.70. MA Number: Eczmol 1% w/w Cream PL06831/0242. Date of preparation: January 2010. Further

1% chlorhexidine gluconate w/w cream

ANtIMICRoBIAL EMoLLIENt AND SoAP SUBStItUtE information available from the MA holder: Genus Pharmaceuticals Limited, Park View House, 65 London Road, Newbury, Berkshire, RG14 1JN. API.ECZ.V1

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Genus Pharmaceuticals on 01635 568400.

Date of preparation: March 2010 ECZ0110659

GENUS

Dermatology Report

Women who drink beer more likely to develop psoriasis

R

egular beer - but not light beer or other types of alcohol - appears to be associated with an increased risk of developing psoriasis, according to a report posted online in the Archives of Dermatology, one of the JAMA/Archives journals. "Psoriasis is a common immunemediated skin disease," the authors write as background information in the article.

‘

Non-light beer was the only alcoholic beverage that increased the risk for psoriasis, suggesting that certain non-alcoholic components of beer, which are not found in wine or liquor, may play an important role in new-onset psoriasis.

’

"The association between alcohol consumption and increased risk of psoriasis onset and psoriasis worsening has long been suspected. For example, individuals with psoriasis drink more alcohol than individuals without psoriasis, and alcohol intake may exacerbate psoriasis severity."

For other diseases, type of alcoholic beverage has been shown to influence risk - for instance, beer confers a larger risk for gout than wine or spirits. To evaluate the association between different types of alcohol and psoriasis risk, Abrar A. Qureshi, M.D., M.P.H., of Brigham and Women's Hospital and Harvard Medical School, Boston, assessed data from 82,869 women who were age 27 to 44 years in 1991. The women, participants in the Nurses' Health Study II, reported the amount and type of

alcohol they consumed on biennial questionnaires. They also reported whether they had received a diagnosis of psoriasis.

Through 2005, 1,150 cases of psoriasis developed, 1,069 of which were used for analysis. Compared with women who did not drink alcohol, the risk of psoriasis was 72% greater among women who had an average of 2.3 drinks per week or more. When beverages were assessed by type, there was an association between non-light beer drinking and psoriasis, such that women who drank five or more beers per week had a risk for the condition that was 1.8 times higher. Light beer, red wine, white wine and liquor were not associated with psoriasis risk.

When only confirmed psoriasis cases - those in which women provided more details about their condition on a seven-item selfassessment - were considered, the risk for psoriasis was 2.3 times higher for women who drank five or more beers per week than women who did not drink beer.

"Non-light beer was the only alcoholic beverage that increased the risk for psoriasis, suggesting that certain non-alcoholic components of beer, which are not found in wine or liquor, may play an important role in new-onset psoriasis," the authors write. "One of these components may be the starch source used in making beer. Beer is one of the few non-distilled alcoholic beverages that use a starch source for fermentation, which is commonly barley." Barley EVIDENTIA •

and other starches contain gluten, to which some individuals with psoriasis show a sensitivity. Lower amounts of grain are used to make light beer as compared with non-light beer, potentially explaining why light beer was not associated with psoriasis risk, they note.

"Women with a high risk of psoriasis may consider avoiding higher intake of non-light beer," the authors conclude. "We suggest conducting further investigations into the potential mechanisms of non-light beer inducing new-onset psoriasis."

Reference: Arch Dermatol Published online August 16, 2010. doi:10.1001/archdermatol.2010.204

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9

Hats off ® to Xamiol

Fast and effective relief from Scalp Psoriasis2 Abbreviated Prescribing Information for Xamiol® 50 microgram/g + 0.5 mg/g gel Indications: Topical treatment of scalp psoriasis.

Active ingredients: 50 µg/g calcipotriol (as monohydrate) and 0.5 mg/g betamethasone (as dipropionate).

Dosage and Administration: apply to affected areas of scalp once daily. recommended treatment period is 4 weeks. after this period repeated treatment can be initiated under medical supervision.

Usually between 1g and 4g/day is sufficient for treatment. When using calcipotriol containing products the maximum dose should not exceed 15g/day and 100g/week. Treated area should not exceed 30% of body surface. Not recommended for use in people under 18 years. Shake bottle before use. The hair should not be washed immediately after application as the gel should remain on the scalp during the night or day.

Contra-indications: hypersensitivity to any constituents. Patients with known calcium metabolism disorders. Viral skin lesions, fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis or syphilis, perioral dermatitis, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers and wounds. Guttate, erythrodermic, exfoliative or pustular psoriasis. Severe renal insufficiency or severe hepatic disorders.

Precautions and Warnings: avoid concurrent treatment with other steroids on the scalp. adrenocortical suppression or impact on the metabolic control of diabetes mellitus may occur. avoid application under occlusive dressings. Efficacy and safety on areas other than the scalp has not been established. avoid application on large areas of damaged skin or on mucous membranes or skin

Date of preparation: February 2010 2008/10151

folds. Skin of the face or genitals should be treated with weaker corticosteroids. avoid inadvertent transfer to face, mouth and eyes.

Wash hands after applying. There may be a risk of generalised pustular psoriasis. With long-term use there is an increased risk of undesirable local and systemic corticosteroid effects in which case treatment should be discontinued. There may be a risk of rebound when discontinuing treatment. No experience of concurrent use with other antipsoriatic products administered systemically or with phototherapy. Physicians are recommended to advise patients to limit or avoid excessive exposure to natural or artificial sunlight.

Use with UV radiation only if the physician and patient consider that the potential benefits outweigh the potential risks. Contains butylated hydroxytoluene which may cause local skin reactions or irritation to the eyes and mucous membranes.

Use in Pregnancy and Lactation: Only use in pregnancy when potential benefit justifies potential risks. Caution when prescribed for women who breast-feed.

Side Effects: Pruritus. additional undesirable effects observed for calcipotriol and betamethasone: Calcipotriol: application site reactions, skin irritation, burning and stinging sensation, dry skin, erythema, rash, dermatitis, eczema, psoriasis aggravated, photosensitivity and hypersensitivity reactions including very rare cases of angioedema and facial oedema. hypercalcaemia or hypercalciuria may appear very rarely. Betamethasone: local reactions, especially during prolonged application including skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, depigmentation, increase of intra-ocular pressure, cataract, colloid milia, generalised pustular psoriasis, infections. Systemic effects occur more frequently when

applied under occlusion, on skin folds, to large areas and long term treatment.

Legal Category: POm. Product Licence Number and Holder: 05293/0006.

LEO Pharmaceutical Products, Ballerup, Denmark.

Basic NHS Price: £36.50/60g.

Last revised: February 2009.

Further information can be found in the Summary of Product Characteristics or from: LEO Pharma, Longwick road, Princes risborough, Buckinghamshire, hP27 9rr. ® registered Trademark e-mail: Xamiol.UKenquiries@leo-pharma.com

adverse events should be reported. reporting forms and information can be found at www.yellowcard.gov.uk. adverse events should also be reported to Drug Safety at LEO Pharma by calling 01844 347333.

©LEO. LEO Pharma, UK, aLL LEO TraDEmarKS mENTIONED BELONG TO ThE LEO GrOUP

a convenient and easyto-use, cosmetically acceptable1, once daily gel formulation

References: 1. LEO Data on file mBL0503 acceptability data 2. Jemec GBE et al. J Am Acad Dermatol 2008; 59:455-63

LEO®

Smoking Cessation report

Study shows cigarette smoking is a risk factor for Alzheimer's disease

A

n analysis of published studies on the relationship between Alzheimer's disease and smoking indicates that smoking cigarettes is a significant risk factor for the disease. After controlling for study design, quality of the journals, time of publication, and tobacco industry affiliation of the authors, the UCSF research team also found an association between tobacco industry affiliation and the conclusions of individual studies.

Industry-affiliated studies indicated that smoking protects against the development of AD, while independent studies showed that smoking increased the risk of developing the disease.

Study findings were published online in the Journal of Alzheimer's Disease.

"For many years, published studies and popular media have perpetuated the myth that smoking is protective against the development of AD. The disease's impact on quality of life and health care costs continues to rise. It is therefore critical that we better understand its causes, in particular, the role of cigarette smoking," said Janine K. Cataldo, PhD, RN,

assistant professor in the UCSF School of Nursing and lead author of the study.

According to the Alzheimer's Association, 5.3 million Americans currently have the disease, and that number will escalate rapidly as

‘

For many years, published studies and popular media have perpetuated the myth that smoking is protective against the development of AD. The disease's impact on quality of life and health care costs continues to rise.

’

the baby boom generation ages. AD also triples health care costs for Americans aged 65 and older, the organisation states. The UCSF team reviewed 43 published studies from 1984 to

2007. Authors of one-fourth of the studies had an affiliation with the tobacco industry. The UCSF team determined that the average risk of a smoker developing AD, based on studies without tobacco industry affiliation, was estimated to be 1.72, meaning that smoking nearly doubled the risk of AD. In contrast, the team found that studies authored by individuals with tobacco industry affiliations, showed a risk factor of 0.86 (less than one), suggesting that smoking protects against AD. When all studies were considered together, the risk factor for developing AD from smoking was essentially neutral at a statistically insignificant 1.05.

Previous reviews of the association between smoking and AD have not controlled for study design and author affiliation with the tobacco industry, according to Cataldo. To determine if study authors had connections to the tobacco industry, the UCSF team analysed 877 previously secret tobacco industry documents.

The researchers used an inclusive definition of "tobacco industry affiliation" and examined authors' current or past funding, employment, paid consultation, and collaboration or coauthorship on a study with someone who had current or previous tobacco industry funding within 10 years of publication. "We know that industry-sponsored research is more likely to reach conclusions favorable to the sponsor," said Stanton A. Glantz, PhD, of the UCSF Department of Medicine and a study co-author.

"Our findings point to the ongoing corrosive nature of tobacco industry funding and point to the need for academic institutions to decline tobacco industry funding to protect the research process."

Disclosure: Judith J. Prochaska, PhD, MPH, of the UCSF Department of Psychiatry, also is a co-author. The team's research was supported by grants from the California Tobacco Related Disease Research Program, the National Cancer Institute, and the National Institute on Drug Abuse.

Reference: Journal of Alzheimer's Disease (January issue, 19:2)

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NEW DATA 91% of middle-aged smokers exhibit one or more symptoms of COPD2 Smoking cessation is the single most effective intervention to reduce risk of COPD development and progression3 50

Continuous abstinence rate weeks 9-12 (%)

CHAMPIX can help your mild to moderate COPD patients stop smoking1

42.3%

40

CHAMPIX vs. placebo OR = 8.4 (95% CI: 4.99-14.14), p<0.0001

30 20

8.8%

10 0

CHAMPIX 1 mg bd (n=248)

placebo (n=251)

In a 27 centre, double-blind, multinational study investigating patients with mild-moderate COPD who smoked an average of 24 cigarettes/day over the past month for an average of 41 years:1* CHAMPIX provided ~8x greater odds of stopping smoking after 12 weeks of treatment vs. placebo (OR = 8.40; 95% CI: 4.99-14.14, p<0.0001)1 After one year, 18.6% of patients treated with CHAMPIX remained smoke-free, vs. 5.6% treated with placebo (OR = 4.04; 95% CI: 2.13-7.67, p<0.0001)1 *Adapted from Tashkin D et al. Presented at CHEST, 2009. A 27 centre, double-blind, multinational study investigated CHAMPIX vs. placebo for smoking cessation in mild to moderate COPD patients (postbronchodilator FEV1/FEV <70% and FEV1% predicted normal value ≥50%). Subjects received either CHAMPIX 1 mg bd or placebo for 12 weeks, with a 40-week non-treatment follow-up. Primary endpoint was CO-confirmed continuous abstinence rate for weeks 9–12. Mean patient baseline characteristics (±SD): number cigs/day over past month 24 (±11); smoking duration 41 (±9) years.

CHAMPIX® Film-Coated Tablets (varenicline tartrate) ABBREVIATED PRESCRIBING INFORMATION – UK. (See Champix Summary of Product characteristics for full Prescribing Information). Please refer to the SmPC before prescribing Champix 0.5 mg and 1 mg. Presentation: White, capsular-shaped, biconvex tablets debossed with “Pfizer” on one side and “CHX 0.5” on the other side and light blue, capsular-shaped, biconvex tablets debossed with “Pfizer” on one side and “CHX 1.0” on the other side. Indications: Champix is indicated for smoking cessation in adults. Dosage: The recommended dose is 1 mg varenicline twice daily following a 1-week titration as follows: Days 1-3: 0.5 mg once daily, Days 4-7: 0.5 mg twice daily and Day 8-End of treatment: 1 mg twice daily. The patient should set a date to stop smoking. Dosing should start 1-2 weeks before this date. Patients who cannot tolerate adverse effects may have the dose lowered temporarily or permanently to 0.5 mg twice daily. Patients should be treated with Champix for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment at 1 mg twice daily may be considered. Following the end of treatment, dose tapering may be considered in patients with a high risk of relapse. Patients with renal insufficiency: Mild to moderate renal impairment: No dosage adjustment is necessary. Patients with moderate renal impairment who experience intolerable adverse events: Dosing may be reduced to 1 mg once daily. Severe renal impairment: 1 mg once daily is recommended. Dosing should begin at 0.5 mg once daily for the first 3 days then increased to 1 mg once daily. Patients with end stage renal disease: Treatment is not recommended. Patients with hepatic impairment and elderly patients: No dosage adjustment is necessary. Paediatric patients: Not recommended in patients below the age of 18 years. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and precautions: Effect of smoking cessation: Stopping smoking may alter the pharmacokinetics or pharmacodynamics of some medicinal products, for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin). Changes in behaviour or thinking, anxiety, psychosis, mood swings, aggressive behaviour, depression, suicidal ideation and behaviour and

Date of preparation: January 2010 CHA851b ©Pfizer 2009

suicide attempts have been reported in patients attempting to quit smoking with Champix in the post-marketing experience. Not all patients had stopped smoking at the time of onset of symptoms and not all patients had known pre-existing psychiatric illness. Champix should be discontinued immediately if agitation, depressed mood or changes in behaviour or thinking that are of concern for the doctor, the patient, family or caregivers are observed, or if the patient develops suicidal ideation or suicidal behaviour. In many post-marketing cases, resolution of symptoms after discontinuation of varenicline was reported, although in some cases the symptoms persisted; therefore, ongoing follow up should be provided until symptoms resolve. Depressed mood, rarely including suicidal ideation and suicide attempt, may be a symptom of nicotine withdrawal. In addition, smoking cessation, with or without pharmacotherapy, has been associated with the exacerbation of underlying psychiatric illness (e.g. depression). The safety and efficacy of Champix in patients with serious psychiatric illness has not been established. There is no clinical experience with Champix in patients with epilepsy. At the end of treatment, discontinuation of Champix was associated with an increase in irritability, urge to smoke, depression, and/or insomnia in up to 3% of patients, therefore dose tapering may be considered. There have been post-marketing reports of hypersensitivity reactions including angioedema and reports of rare but severe cutaneous reactions, including Stevens-Johnson Syndrome and Erythema Multiforme in patients using varenicline. Patients experiencing these symptoms should discontinue treatment with varenicline and contact a healthcare provider immediately. Pregnancy and lactation: Champix should not be used during pregnancy. It is unknown whether varenicline is excreted in human breast milk. Champix should only be prescribed to breast-feeding mothers when the benefit outweighs the risk. Driving and operating machinery: Champix may have minor or moderate influence on the ability to drive and use machines. Champix may cause dizziness and somnolence and therefore may influence the ability to drive and use machines. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medicinal product affects their

ability to perform these activities. Side-Effects: Adverse reactions during clinical trials were usually mild to moderate. Most commonly reported side-effects were abnormal dreams, insomnia, headache and nausea. Commonly reported side-effects were increased appetite, somnolence, dizziness, dysgeusia, vomiting, constipation, diarrhoea, abdominal distension, stomach discomfort, dyspepsia, flatulence, dry mouth and fatigue. See SmPC for other less commonly reported side effects. Overdose: Standard supportive measures to be adopted as required.

Varenicline has been shown to be dialyzed in patients with end stage renal disease, however, there is no experience in dialysis following overdose. Legal category: POM Basic NHS cost: Pack of 25 11 x 0.5 mg and 14 x 1 mg tablets Card (EU/1/06/360/003) £27.30. Pack of 28 1 mg tablets Card (EU/1/06/360/004) £27.30. Pack of 56 0.5 mg tablets HDPE Bottle (EU/1/06/360/001) £54.60. Pack of 56 1 mg tablets HDPE Bottle (EU/1/06/360/002) £54.60. Pack of 56 1 mg tablets Card (EU/1/06/360/005) £54.60. Not all pack sizes may be marketed / marketed at launch. Marketing Authorisation Holder: Pfizer Limited, Sandwich, Kent, CT13 9NJ, United Kingdom. Further information on request: Pfizer Limited, Walton Oaks, Dorking Road, Tadworth, Surrey, KT20 7NS. Last revised: 11/2009. Ref: CI7_0.

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Pfizer Medical Information on 01304 616161.

For further information, please contact Pfizer Medical Information on 01304 616161 or email medinfo.uk@pfizer.com References: 1. Tashkin D et al. Efficacy and safety of varenicline for smoking cessation in patients with mild to moderate Chronic Obstructive Pulmonary Disease (COPD). Poster Abstract Presented at CHEST, Oct 31st - Nov 5th, 2009, San Diego, California: Abstract 1054. 2. Calverley PMA. COPD: Early Detection and Intervention. Chest 2000; 117:365S-371S. 3. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Pocket guide to COPD diagnosis, management and prevention. A guide for healthcare professionals. Updated 2008.

Smoking Cessation report

Smoking cessation benefits MI patients with heart damage Smoking cessation markedly improved survival for patients with MI and residual left ventricular dysfunction.

W

hen smokers with left ventricular systolic dysfunction following MI had quit, six months later, they had a propensity scoreadjusted hazard ratio for all-cause death of 0.57 (95% CI 0.31 to 0.91) compared with similar patients who continued to smoke, according to Amil M. Shah, MD, of Brigham and Women's Hospital in Boston, and colleagues. Similar risk reductions were seen for composites of death and recurrent MI (adjusted HR 0.68, 95% CI 0.47 to 0.99) and death and heart failure hospitalisation (adjusted HR 0.65, 95% CI 0.46 to 0.92), the researchers reported online in the American Journal of Cardiology.

"The magnitude of risk decrease associated with smoking cessation after MI in this high-risk population was similar to that described in cohort studies of unselected subjects after MI," Shah and colleagues wrote. In fact, they suggested, smoking cessation may be the most effective way to reduce adverse outcomes in patients with post-MI left ventricular dysfunction. The roughly 40% decreases seen in the study were about double those previously documented for drug treatment with ACE inhibitors, beta blockers, or aldosterone antagonists. The findings came from the 20year-old Survival and Ventricular Enlargement (SAVE) trial, which studied the effects of the ACE inhibitor captopril in patients with left ventricular ejection fraction of 40% or less following MI. Of the study's 2,331 total participants, 731 were smokers at the time of their MI, survived for at least six months, and were therefore eligible for the current analysis.

These participants included 268 who were still smoking at six months post-MI and 463 who had stopped. They were followed for up to five years (median 42 months) with all-cause mortality, recurrent MI, heart failure hospitalisation, and stroke counted in each group. Shah and colleagues found the following unadjusted event rates:

• •

Death from all causes: 16.4% for persistent smokers, 8.9% for quitters Recurrent MI: 9.0% for persistent smokers, 8.9% for quitters Stroke: 4.5% for persistent smokers, 3.1% for quitters Heart failure hospitalisation: 13.8% for persistent smokers, 11.7% for quitters • •

These data suggested that the benefits seen in the composite measures of death combined with recurrent MI or heart failure hospitalisation were driven largely by the improved overall survival, rather than effects on specific

‘

Smoking cessation's benefits could have been muddied by patients' smoking habits beyond six months. Of those classified as having quit at six months, 22% eventually resumed intermittent smoking and 5% took up the habit at full force.

’

cardiovascular events. Smoking cessation's benefits could have been muddied by patients' smoking habits beyond six months. Of those classified as having quit at six months, 22% eventually resumed intermittent smoking and 5% took up the habit at full force. In those who were still smoking at six months, 33% later cut back to intermittent smoking and 3% quit entirely. But the duration of smoking cessation was tracked during follow-up, and similar reductions in event rates were seen in patients who stayed off tobacco for six, 12, or 24 EVIDENTIA •

months. A sensitivity analysis, modeling smoking cessation as a time-related variable with a two-year lag, showed that smoking cessation cut all-cause mortality risk in half (HR 0.50, 95% CI 0.31 to 0.79). Reductions in the composite outcomes combining death with recurrent MI or heart failure hospitalisation were in the same range (HR 0.53 and 0.60, respectively) and statistically significant. Shah and colleagues identified several limitations to the study. The most important was that participants self-selected to stop smoking or not, with those continuing to smoke having been heavier smokers in the past. Also, smoking status was reported by patients and not independently confirmed. Treatment assignments in the trial might have affected the outcomes, but Shah and colleagues found that the effects of smoking cessation were similar in patients assigned to captopril therapy versus placebo. Another limitation was that the treatment phase of the study occurred from 1987 to 1990, at which point standard post-MI therapies were different from today. Only 2% of participants were receiving cholesterollowering drugs, for example. Other potentially confounding factors may also have gone unmeasured, Shah and colleagues indicated.

Nevertheless, they concluded that smoking cessation is probably at least as beneficial to MI patients with substantial left ventricular dysfunction as it is to those with less severe aftereffects. "Our study highlights the critical nature of an aggressive and sustained effort to promote smoking cessation in subjects with LV dysfunction after MI," they wrote.

Disclosure: No external funding for the SAVE data analysis was reported. Shah had no financial disclosures.

Reference: Shah A, et al. Risk of all-cause mortality, recurrent myocardial infarction, and heart failure hospitalisation associated with smoking status following myocardial infarction with left ventricular dysfunction. Am J Cardiol 2010; DOI: 10.1016/j.amjcard.2010.05.021

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American Diabetes Association - by Thomas R. Collins Reporting from the ADA meeting, Orlando

Pioglitazone plus exenatide brings more benefit to patients

C

ombining pioglitazone treatment with exenatide treatment brings about an added improvement in glycaemic control than either drug brings about on its own, according to results from a small study presented here at the 70th Scientific Sessions of the American Diabetes Association.

It is the first study to look at the effects of combined treatment with the thiazolidinedione (TZD) pioglitazone with the glucagon-like protein 1 (GLP-1) exenatide, researchers said.

“TZD’s have a major action to improve peripheral insulin resistance - and this has been shown in many papers before,” said Alberto Chavez, MD, of the University of Texas Health Science Center. “They also improve beta cell function by indirect and direct effects on pancreatic beta cells. On the other hand, the GLP-1 analogues like exenatide enhance mealstimulated insulin secretion and suppress elevated glucagon secretion. So based upon these mechanisms it is reasonable to assume that if we combine both therapies, we’ll have a greater effect on beta cell function and

glycaemic control and have both benefits of the therapies.”

The trial was a randomised, open-label, 24week study, with 25 subjects randomised to receive either exenatide (10mcg bid); pioglitazone (45mg qd); or pioglitazone and exenatide.

At baseline, fasting plasma glucose (FPG) averaged 150 in the pioglitazone group, and fell to 116 after six months. FPG was 169 in the exenatide group, and fell to 142 after six months. It averaged 185 in the combined group at baseline, and fell to 126. Those were all significant differences compared to baseline, but the change in the combined group was more pronounced.

HbA1c levels were 8.3 in the pioglitazone group at baseline, and fell to 7.0 after six months. It averaged 7.9 in the exenatide group, and fell to 6.8 after six months of treatment.

And in the combined group, it averaged 8.6, and fell to 6.5. Again the changes compared to baseline were all significant, but the change in the combined group was the biggest.

The combined group did see an increase in body weight and in body fat, but the change

was not as pronounced as in the exenatide group, indicating that adding the exenatide helped with weight gain, a common problem with pioglitazone. Scores on the Matsuda Index for insulin sensitivity got significantly higher in both the pioglitazone group and the combined group, but it was more pronounced in the combined group. There was not a significant change in the exenatide group.

Insulin secretion also improved the most in the combination therapy group. “You can see here there’s a clear trend in the combination group to improve the insulin secretory capacity of the beta cells,” Dr. Chavez said. The results are promising for using the two treatments together, he said.

“Taking into consideration these results, we can conclude that a combination treatment with pioglitazone and exenatide causes a greater and additive improvement in glycaemic control than with either agent alone,” Dr. Chavez said. “exenatide attenuates weight gain caused by pioglitazone. pioglitazone and exenatide improve beta cell function more than with either pioglitazone alone or exenatide alone.”

Hopes grow for artificial pancreas

O

ptimism is on the rise for the artificial pancreas, a system intended to constantly monitor glucose levels and adjust insulin automatically - so much so that experts say that use of the technology is a matter of when, not if.

The latest results for the devices are encouraging, with the device found to significantly improve overnight glucose levels in adults with Type 1 diabetes.

The artificial pancreas is a fusion of the continuous glucose monitoring device and insulin pump with an algorithm that can determine how much insulin to deliver and when.

“It will significantly impact the lives of those with body Type 1 and Type 2 diabetes by

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providing exquisite control of blood sugars and will prevent the short-term complications of Type 1 diabetes - hypoglycaemia - and the longterm complications of the disease,” said Richard Insel, MD, Executive Vice President of Research at the Juvenile Diabetes Research Foundation.

The foundation launched its artificial pancreas project five years ago.

Aaron Kowalski, PhD, Research Director of the project, said the hope is that the system will improve the quality of life for patients while further research is done.

“There are going to be near-term solutions,” said Kowalski, who himself has suffered from Type 1 diabetes for 30 years. “These devices can control insulin pumps and automate some degree in the near-term. And then we have

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visions to become more and more automated.

And hopefully this will allow us, as scientists at JDRF and researchers, to keep people healthy while we drive toward a biological approach ultimately, which will take longer.”

Roman Havorka, PhD, Principal Research Associate at the University of Cambridge Metabolic Research Laboratories, led research, just released, showing that adults with Type 1 diabetes who used the system spent 23% more of their time overnight within target glucose range, compared to those not using the system.

Those using the system were within range 70% of the time overnight, compared to 47% of those not on the system. Patients also had lower incidence of hypoglycaemia.

Dr. Havorka found that the benefits

remained even after the patients ate a large meal and drank a glass of wine, showing that the system can work in real-life situations.

“It basically smoothes the edges of the highs and lows,” he said.

This latest work builds on previous research which showed that children and teenagers with Type 1 diabetes had better glucose control and lower incidence of hypoglycaemia while sleeping.

His research will now turn to use of the systems in the home.

In a related study, Marilyn Ritholz, PhD, Psychologist at the Joslin Diabetes Center and Assistant Professor at Harvard Medical School, found that those who had success with a continuous glucose monitoring system displayed some common characteristics.

A big factor was that they turned to problem-solving rather than having an emotional response.

“They insisted on trying to figure out how

to use the CGM,” Dr. Ritholz said. “On the other hand, the non-responders used what we call emotion-based coping. They easily became

‘

These devices can control

insulin pumps and automate some degree in the near-term.

And then we have visions to become

’

more and more automated.

overwhelmed and they just gave up, they just didn’t want to continue.”

Downloading glucose-monitoring data and analysing it, as well as having more encouragement from significant others, were

two other characteristics that separated the responders from the non-responders.

Dr. Ritholz also noted body-image concerns from the participants, who said they felt more aware of their diabetes and that the disease was “in their face” more often because of the device. This didn’t correspond to a response or a nonresponse, but Dr Ritholz said it is an important consideration as artificial pancreas research continues.

Dr. Kowalski stressed that the artificial pancreas has real potential to ease the burden of diabetes, describing how he spends all day thinking about what he’s eaten, what he’s doing, what he’s about to do, and the exercise he’s done or will do, and how that awareness might not be needed quite as much with the artificial pancreas.

“What this system will do is not only provide powerful mathematics,” he said, “but it will also provide a constant vigilance.”

Choose Actos, now!

e2 For Typ ients s pat diabete lled on o uncontr min metfor

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Takeda UK Ltd.

Please refer to the summary of product characteristics for details on the full side-effect profile of Actos.

Further information is available from Takeda UK Ltd, Takeda House, Mercury Park, Wycombe Lane, Wooburn Green, High Wycombe, Bucks HP10 0HH. Tel: 01628-537900 Legal category: POM Date of preparation: September 2010 Code: AC100862a

EVIDENTIA •

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actos

®

pioglitazone HCl

Thinking of tomorrow, today

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European College of Neuropsychopharmacology - by Samuel Peters Reporting from the ECNP meeting, Amsterdam

Clear take-home messages from ECNP

M

ore than 7,000 psychiatrists, neurologists, psychologists and neuroscience researchers from all over the world met at the 23rd Congress of the European College of Neuropsychopharmacology (ECNP) in Amsterdam.

As well as providing a platform for the discussion of the latest discoveries, insights and perspectives, the congress covered a wide variety of issues of critical public health concern, such as depression, schizophrenia, addiction, chronopsychiatry, and neurodegenerative disorders, including multiple sclerosis, Parkinson's and Alzheimer's disease. The programme specifically emphasised the translation of new knowledge on fundamental disease mechanisms into clinical practice and clear take-home messages, paving the way for improved pharmacological and non-drug treatments for

ABBREVIATED PRESCRIBING INFORMATION ARICEPT® (donepezil hydrochloride film-coated tablet) ARICEPT EVESS® (donepezil hydrochloride orodispersible tablet) Please refer to the SmPC before prescribing ARICEPT 5 mg, ARICEPT 10 mg, ARICEPT EVESS 5 mg or ARICEPT EVESS 10 mg. Indication: Symptomatic treatment of mild to moderately severe Alzheimer’s dementia. Dose and administration: Adults/elderly; 5 mg daily which may be increased to 10 mg once daily after at least one month. Aricept Evess orodispersible tablets should be placed on the tongue and allowed to disintegrate before swallowing with or without water. Aricept film-coated tablets are taken orally. Treatment with Aricept or Aricept Evess should be initiated and supervised by a physician with experience of Alzheimer’s dementia. A caregiver should be available to monitor compliance. Monitor regularly to ensure continued therapeutic benefit, consider discontinuation when evidence of a therapeutic effect ceases. No dose adjustment necessary for patients with renal impairment. Dose escalation, according to tolerability, should be performed in patients with mild to moderate hepatic impairment. Children; Not recommended. Contra-Indications: Hypersensitivity to donepezil, piperidine derivatives or any excipients used in Aricept or Aricept Evess. Pregnancy: Donepezil should not be used unless clearly necessary. Lactation: Excretion into human breast milk unknown. Women on donepezil should not breast feed. Warnings and Precautions: Exaggeration of succinylcholine-type muscle relaxation. Avoid concurrent use of anticholinesterases, cholinergic agonists, cholinergic antagonists. Possibility of vagotonic effect on the heart which may be particularly important with “sick sinus syndrome”, and supraventricular conduction conditions. There have been reports of syncope and seizures - in such patients the possibility of heart block or long sinusal pauses should be considered. Careful monitoring of patients at risk of ulcer disease including those receiving NSAIDs. Cholinomimetics may cause bladder outflow obstruction. Seizures occur in Alzheimer’s disease and cholinomimetics have the potential to cause seizures and they may also have the potential to exacerbate or induce extrapyramidal symptoms. Care in patients suffering from asthma and obstructive pulmonary disease. No data available for patients with severe hepatic impairment. In three 6-month clinical trials in individuals with vascular dementia (VaD), the combined mortality rate was numerically higher, in the donepezil group (1.7%) than in the placebo group (1.1%), but this difference was not statistically significant. In pooled Alzheimer’s disease studies (n=4146),

ARI2516j

ARI2018

the prevention and treatment of all mental disorders and disorders of the brain in general.

The programme was topped off with three press conferences highlighting advances in core research areas:

Developmental gene-environment interactions: a model for psychosis "Recent research findings in psychiatry indicate that genes are likely to influence disorder mostly indirectly via their impact upon physiological pathways," said Professor Jim van Os of the Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, the Netherlands. "Thus genes work by increasing the likelihood of developing a psychiatric disorder, rather than as direct causes of disorder per se."

Until recently, researchers found it difficult to unveil the causes of schizophrenia and

related psychotic disorders. 100 years after the modern definition of schizophrenia, research is beginning to understand the biological mechanisms underlying the symptoms of this most mysterious of mental disorders and the psychosocial factors that moderate their expression. Recent research findings in psychiatry indicate that genes are likely to influence disorder mostly indirectly, via their impact upon physiological pathways, and work by increasing the likelihood of developing a psychiatric disorder, rather than as direct causes of disorder per se (Van Os et al., 2008). A significant proportion of psychotic disorder may be understood as the rare poor outcome of a common developmental phenotype characterised by persistence of detectable subclinical psychotic experiences. The current model of geneenvironment interaction is nurturing

and in Alzheimer’s disease studies pooled with other dementia studies including vascular dementia studies (total n=6888), the mortality rate was numerically higher in the placebo group than in the donepezil group. Aricept film-coated tablets contain lactose and should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. Donepezil has minor or moderate influence on ability to drive/use machines so this should be routinely evaluated. Drug Interactions: Interaction possible with inhibitors or inducers of cytochrome P450; use such combinations with care. May interfere with anticholinergic agents. Possible synergistic activity with succinylcholine-type muscle relaxants, beta-blockers, cholinergic agents. Side effects: Most commonly diarrhoea, muscle cramps, fatigue, nausea, vomiting, and insomnia. Very common effects (*1/10): diarrhoea, nausea, headache. Common effects (*1/100, <1/10): common cold, anorexia, hallucinations, agitation, aggressive behaviour, syncope, dizziness, insomnia, vomiting, abdominal disturbance, rash, pruritis, muscle cramps, urinary incontinence, fatigue, pain, accident. Uncommon effects (*1/1,000, <1/100): seizure, bradycardia, gastrointestinal haemorrhage, gastric & duodenal ulcers, minor increases in serum creatine kinase.

Rare (*1/10,000, <1/1,000): extrapyramidal symptoms, sinoatrial block, atrioventricular block, liver dysfunction including hepatitis. Presentation and basic NHS cost: Blister packed in strips of 14. ARICEPT 5 mg; white, film coated tablets marked 5 and Aricept, packs of 28 £59.85 ARICEPT 10 mg; yellow, film coated tablets marked 10 and Aricept, packs of 28 £83.89 ARICEPT EVESS 5 mg; white, embossed, orodispersible tablets marked 5 and Aricept, packs of 28 £59.85. ARICEPT EVESS 10 mg; yellow, embossed, orodispersible tablets marked 10 and Aricept, packs of 28 £83.89. Marketing authorisation numbers: ARICEPT 5 mg; PL 10555/0006. ARICEPT 10 mg; PL 10555/0007. ARICEPT EVESS 5 mg; PL 10555/0019 ARICEPT EVESS 10 mg; PL 10555/0020. Marketing authorisation holder: Eisai Ltd. Further Information from: Eisai Ltd, EKC, Mosquito Way, Hatfield, Hertfordshire, AL10 9SN and Pfizer Limited, Walton Oaks, Dorking Road, Tadworth, Surrey KT20 7NS. Legal category: POM. Date of preparation: December 2009.

Adverse events should be reported.

Reporting forms and information can be found at www.yellowcard.gov.uk.

Adverse events should also be reported to Eisai Ltd on 0208 600 1400 or Lmedinfo@eisai.net Date of preparation: January 2010.

promising approaches to understand the symptoms of schizophrenia and related psychotic disorders and improve treatment.

Circadian rhythms: their role and dysfunction in affective disorders "Biological clocks play a major role in the pathophysiology of affective disorders," Professor Anna Wirz-Justice of the Psychiatric University Clinics in Basel, Switzerland, pointed out, noting that synchronising impaired circadian rhythms, improving sleep, or paradoxically staying awake most of the night can be extremely helpful in treating patients with depression and bipolar disorder. Circadian dysfunction can have drastic consequences on brain functions. Increasing evidence suggests that disrupted temporal organisation impairs behaviour, cognition, and affect (Benca et al., 2009). Disruption of circadian clock genes impairs sleep-wake cycle and behavioural rhythms, which may be implicated in mental disorders. Several different psychiatric disorders, including depression, bipolar disorder, seasonal affective disorder (SAD), schizophrenia, and borderline-related disorders

are commonly associated with abnormalities in circadian rhythms. In particular, biological clocks play a major role in the pathophysiology of affective disorders. Chronotherapeutic combinations of light and wake therapy achieve fast results and, by reducing residual symptoms, also minimise relapse over many months. In addition, chronotherapeutics seem to be a major facilitator of drug response, and, in combination with antidepressants, a promising method to stabilise patients over the long term. Researchers are working on extending our knowledge concerning pharmaceutical and non-pharmaceutical ways to alter circadian rhythms. Recent discoveries of molecular clocks responsible for the generation of circadian rhythms provide novel insights into temporal disruption, offering new therapeutic avenues for the treatment of affective disorders.

The neural basis of the depressive self In the general population, depression is still frequently associated with bad life style, impairment of volition and 'psychological weakness'. However, the results of brain

imaging studies clearly have confirmed that depression is a true brain disease associated with dysfunction of specific brain regions involved in cognitive control and emotional response, explained Professor Philippe Fossati from the University Pierre & Marie Curie in Paris, France. Depression needs to be defined at the neurobiological level in order to improve the efficiency of treatment and reduce the burden of depressive disorders. Neurobiological markers of depression may help psychiatrists to target specific neural processes and regions involved in affective regulation and to tailor antidepressant treatment according to the biological needs of the patients. This could improve patients chances to responding to specific treatment modalities.

Award Further highlights were the presentation of the ECNP Neuropsychopharmacology Award to Kaj Blennow, Sweden, for his pioneering research into Alzheimerâ&#x20AC;&#x2122;s disease. The ECNP Neuropsychopharmacology Award is presented

FA C E T H E F E A R THE E ARLIER YOU DIAGNOSE AL ZHEIMER â&#x20AC;&#x2122;S DISE A SE , THE SO ONER YOU C AN DO SO METHING ABOUT IT

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European College of Neuropsychopharmacology - by Samuel Peters Reporting from the ECNP meeting, Amsterdam

Clear take-home messages from ECNP < CONTINUED FROM PAGE 17

annually and recognises distinguished research in neuropsychopharmacology and closely related disciplines. The award is accompanied by a prize of €20,000. Kaj Blennow, Professor

Professor Kaj Blennow

‘

In the field of brain disorders, the development of good biomarkers can enhance the possibilities for early diagnostics and the measurement of treatment effects.

’

in Clinical Neurochemistry at the University of Gothenburg and Senior Consultant at the Neurochemical Laboratory of Sahlgrenska University Hospital, Gothenburg, Sweden, is one of the world's leading researchers in Alzheimer's disease. His work has focused on the development of laboratory measures for clinical diagnosis and therapy monitoring in Alzheimer's disease, with significant implications for both drug development and patient care. "In the field of brain disorders, the development of good biomarkers can enhance the possibilities for early diagnostics and the measurement of treatment effects," Blennow said at the Congress. "In the future this could enable clinicians to diagnose and treat Alzheimer's disease before the person experiences any symptoms." The scope of Blennow's research is extensive. In Alzheimer's

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disease, as well as biomarkers, it has embraced genetic mechanisms, neurochemical pathogenesis and neurotransmitter disturbances. He has also extended his neurochemical innovations into other fields of neuropsychopharmacology, such as schizophrenia and depression. "We clearly need new drug targets and innovative leads for novel therapies," Blennow commented on the recent closure of neuroscience labs of major pharmaceutical companies in Europe. "The basis for modern drug development, which has a strong tradition in Europe for more than 50 years improving the quality of life of people struck by brain disorders, has to be kept alive."

By 2040 the incidence of Alzheimer's disease is expected to double in Western Europe and triple in Eastern Europe, as Europe's population ages. Speaking on behalf of the ECNP 2010 Award Jury, Guy Goodwin of the University of Oxford, United Kingdom, said, "Kaj Blennow's contributions to addressing this growing public health challenge have been outstanding. We are delighted to be able to present him with this award."

The ECNP Lifetime Achievement Award was presented to Moussa B. H. Youdim, Israel, for his innovative and lasting contribution to the field of neurodegenerative diseases and neuropsychiatric drug development.

Moussa B. H. Youdim, born in 1940 in Teheran, is Finkelstein Professor of Life Sciences and at Rappaport Faculty of Medicine at the Technion-Israel Institute of Technology, Haifa, Israel. He is also founder and Director of the Eve Topf and U.S. National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Teaching, an independent extension of the Department of Pharmacology dedicated to advancing the understanding of neuropsychiatric disorders.

"With regard to current treatment standards based on symptom control, innovative neuroprotective therapies are needed in the common neurodegenerative disorders," he emphasised on the occasion of the 23rd ECNP Congress in Amsterdam, the Netherlands.

Moussa Youdim has gained a worldwide reputation for his work in addressing this need in Parkinson's disease and Alzheimer's disease over nearly 50 years of highly productive activity.

He is especially known for his key role in

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establishing the importance of the monoamine oxidase enzymes, which are central to the metabolism of neurotransmitters such as dopamine, noradrenaline and serotonin, and the connection between these enzymes and abnormal brain iron metabolism. He has also

Professor Moussa B. H. Youdim

‘

A current challenge for drug discovery designed for complex brain disorders such as Parkinson's or Alzheimer's disease is to look for multimodal drugs with a disease modifying effect.

’

pursued this research into the clinic, with the development of novel treatments for neurodegenerative diseases. "A current challenge for drug discovery designed for complex brain disorders such as Parkinson's or Alzheimer's disease is to look for multimodal drugs with a disease modifying effect," said Youdim.

Presenting the award at the 23rd ECNP Congress, the chairman of the ECNP Award Jury 2010, Tomas Hökfelt of the Karolinska Institute in Stockholm, highlighted Youdim's scientific discoveries and their public health implications. "Demographic changes in Europe are making Parkinson's and Alzheimer's an increasing public health concern. Moussa Youdim's contribution to our understanding and better treatment of these conditions has been lasting and significant. We congratulate him on this well-deserved award."

Catching multiple sclerosis before it strikes Tel Aviv University finds MS biomarkers almost a decade before symptoms appear.

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ultiple sclerosis (MS) is an equal opportunity destroyer. It attacks the central nervous system and eventually renders most patients disabled.

Among its high-profile victims are celebrated cellist Jacqueline du Pre, whose career was ended by MS, and Joan Didion, one of America's greatest writers - but they are far from alone.

The National MS Society estimates that there are currently about 400,000 cases in the U.S. and more that two million suffer from the disease over the world. Although there is currently no cure, a breakthrough finding from a Tel Aviv University scientist and physician may lead to earlier diagnosis, more effective intervention, and perhaps even a cure for the autoimmune disease.

Professor Anat Achiron of Tel Aviv University's Sackler Faculty of Medicine and vice-dean of research at Sheba Medical Center has uncovered a new way of detecting MS in the blood through her research at Sheba. The findings, just published in the journal Neurobiology of Disease, are expected to pave the way for a diagnosis of MS before symptoms can appear, allowing for earlier treatment.

"We are not yet able to treat people with MS to prevent the onset of the disease but knowledge is power," Professor Achiron says.

"Every time we meet a new patient exhibiting symptoms of MS, we must ask ourselves how long this has been going on. We can diagnose MS by brain MRI, but we've never been able to know how 'fresh' the disease is," she says.

Clues for early intervention If doctors can predict the onset of MS early enough, intervention therapies using immunomodulatory drugs such as Copaxone or beta-interferon drugs that stave off MS symptoms, might be used.

"We theorised that if we looked at the gene expression signature of blood cells in healthy people, we could look for possible biological markers that characterise those who subsequently developed MS," says Professor Achiron.

Examining blood samples of twenty 19-yearold Israelis who were inducted into the army as healthy soldiers, and the nine of them who later

developed MS, Professor Achiron and her team at Sheba were able to use a "high throughput analysis" using more than 12,000 gene transcripts expressions. The screening compared similarities and differences in the blood of those who developed MS and those who did not, eventually establishing biological markers.

"Those who will develop MS will show a different blood signature from those who will not,"

‘

Those who will develop

MS will show a different blood signature from

’

those who will not.

says Professor Achiron. "When we compared the gene expression signatures, we saw a similar pattern of the same working biological processes."

Seeing nine years into the future These early genetic markers may now be used to test for multiple sclerosis up to nine years before healthy young adults start developing symptoms. And because MS is thought to have a genetic component and a tendency to be found in siblings, Professor Achiron says the biomarkers can be used as a tool for brothers and sisters of patients.

Why test in advance of a cure?

"The idea is that we'll know more about the genetics of MS through this new discovery, with the hope that early EVIDENTIA •

intervention therapies may be more effective, and help advance medicine toward a cure," Professor Achiron says.

By the time a person notices symptoms, significant and irreversible nerve damage is already done. MS is classified as an autoimmune disease that afflicts the brain and spinal cord. Symptoms vary, because the location and severity of each attack can be different, and until now, there has been no way of knowing who it will strike. The disease causes the body's immune system's T cells to mistakenly regard the myelin sheath around our body's neurons as foreign, so the immune system starts attacking the sheath, causing neurons to short circuit. The disease is more prelevent in cold climates and attacks twice as many women as men.

This new insight into who will develop MS in the future is a first on the path of finding a cure to the disease.

Two of the most important drugs that shorten multiple sclerosis attacks were developed in Israel, and Tel Aviv University is considered a center of excellence in MS research. Other researchers in the study include David Magalashvili and Anna Feldman of Tel Aviv University, and Drs. Itamar Grotto and Ran Balicer of the Israel Defence Forces.

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Digestive Disease Week - by Bruce Sylvestor Part 2 of reports from DDW, New Orleans

IBD - Chemokine Inhibitor shows promise Data from a multinational clinical trial showed a first-in-class chemokine receptor antagonist maintained remission in Crohn's disease and permitted steroid tapering during 36 weeks of maintenance therapy.

A

mong patients in remission at the end of induction therapy, 64% of those randomised to CCX282-B (Traficet-EN) remained in remission compared with 47% of placebo-treated patients. Analysis of all patients showed that a significantly higher proportion of patients in the CCX282-B arm were in remission at the end of the maintenance phase.

Twice as many patients in the placebo arm initiated corticosteroid therapy or required an increase in dose compared with patients treated orally with CCX282-B, Satish Keshav, MD, PhD, reported at Digestive Disease Week.

"These results suggest that blocking CCR9 with an oral medication may be an effective strategy for maintaining remission in Crohn's disease in the long term," said Keshav, of John Radcliffe Hospital in Oxford, England. CCX282-B targets chemokine receptor CCR9, which is expressed selectively on intestinal lymphocytes and dendritic cells. CCR9 mediates migration of immune cells to the intestine, and blockade of the receptor inhibits migration, said Keshav. In phase I-II clinical studies, more than 600 patients received CCX282-B at doses as high as 1,000mg BID without the emergence of adverse safety signals. Keshav reported findings from the maintenance phase of the Prospective Randomised Oral Therapy Evaluation in Crohn's Disease Trial-1 (PROTECT-1), the first-ever clinical trial of a chemokine receptor in patients with inflammatory bowel disease. Investigators in 17 countries enrolled 436 patients, who were treated for a total of 56 weeks. Eligibility criteria included a Crohn's Disease Activity Index (CDAI) score >250 and a C-reactive protein (CRP) level >7.5mg/L. At study entry, patients were randomised 1.5:1:1:1 to placebo or to one of three doses of CCX282-B for 12 weeks of induction therapy.

Upon completion of the induction phase, all patients received CCX282-B at a dose of 250mg BID for four weeks. The protocol defined response as a decline in CDAI score ≥70 points. Patients who achieved response after the four-week treatment period were randomised 1:1.5 to placebo or CCX282-B 250 mg BID for the 36-week maintenance phase,

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with corticosteroid tapering as feasible. Patients who did not meet the CDAI threshold for response discontinued. At the end of the maintenance phase, all patients stopped assigned therapy and were followed for an additional four weeks. Patients on stable treatment regimens for Crohn's disease prior to enrollment could continue to take the medication, including thiopurines, methotrexate, and as much as 20mg of prednisone or equivalent. The trial excluded patients who had received a tumor necrosis factor (TNF) inhibitor or four integrin antibody

‘

At the end of the maintenance phase, all patients stopped assigned therapy and were followed for an additional four weeks.

’

within the 12 weeks preceding randomisation.

By the end of the induction phase, 50% to 60% of patients treated with CCX282-B had achieved clinical response, as had about 50% of the placebo group. The maintenance phase included 95 placebo-treated patients and 145 in the CCX282-B arm. The study population had a mean age of 36 and a mean body mass index of 24, and 55% had never smoked.

Women accounted for about half of the total population. Median baseline CDAI was 129, and median CRP level was 13mg/L. During the maintenance phase, sustained response was defined as no increase in CDAI score >70 points and a CDAI score <250 at all times. Failure to meet either criterion at any point in time was considered loss of sustained response. The median CDAI score in the CCX282-B patients declined below that of the placebo group after 12 weeks and continued to decline for most of the 36-week maintenance period. Placebotreated patients' CDAI remained largely unchanged until the last eight weeks, when the score increased. Separate analyses of

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abdominal pain, diarrhea, and well-being all showed substantial advantages for the CCX282-B group. By intention-to-treat (ITT) analysis, 46% of CCX282-B patients had sustained response, compared with 42% of the placebo group. ITT analysis with last observation carried forward (LOCF) showed that 56% and 52% of CCX282-B and placebo patients, respectively, had sustained response.

Neither difference was statistically significant.

Significantly more patients in the CCX282-B arm attained remission (CDAI ≤150) at 36 weeks (47% versus 31%, P=0.01). Moreover, 64% of CCX282-B patients in remission at the start of maintenance remained in remission compared with 47% of the placebo group (P=0.06). Numerically more patients on active treatment achieved sustained remission (41% versus 30%). After 36 weeks, 21% of the placebo group and 11% of the CCX282-B patients had initiated steroid therapy or increased the dose of existing therapy (P=0.04).

Also at the end of maintenance therapy, median CRP values were 8.7mg/L in the CCX282-B group and 12.3 in the placebo group. Keshav reported that 19.4% of CCX282-B patients had CRP levels <3mg/L, versus 9.4% of placebo-treated patients (P=0.04). The two groups had similar rates of adverse events, gastrointestinal adverse events, serious adverse events, and adverse events leading to withdrawal. No patient in either group developed a serious infection. Originally developed by ChemoCentyx of Mountainview, California, the chemokine receptor antagonist will enter clinical development with GlaxoSmithKline under the name GSK1605786A, according to Keshav.

Disclosure: The study was supported by ChemoCentyx. Keshav disclosed relationships with ChemoCentyx, Abbott, Procter & Gamble, Schering-Plough, Ferring Pharmaceuticals, and GlaxoSmithKline.

Reference: Keshav S, et al. Chemokine receptor antagonist CCX282-B (Traficet-EN) maintains remission of Crohn's disease in PROTECT-1 study. DDW 2010; Abstract 647.

Sustained release Colpermin IBS Relief saves its peppermint power ‘til it’s needed

.....

W AIT

....TAKE COLPERMIN ....... .N

O

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Y . . . . . . ..

ET .... .

.

....

... .....

....

HOLD IT

. . . .. .

G ET READY.. ... !

.

.

.... . ..

EASE NOW REL

... . .

D R IP ... DRIP... DR IP . ....

....

.......

Colpermin IBS Relief is the only peppermint oil capsule available with both an enteric coating and a sustained-release formulation, designed to optimise delivery.1,2 So don’t forget to look for MR when prescribing.

Peppermint oil is a logical first-line therapy in IBS because in a meta-analysis of treatments for IBS3 the ‘Number Needed to Treat’ for a successful outcome was 2.5. It was 5 for other antispasmodics.4 Prescribing information can be found overleaf

.

RI DRIP D RIP D

P

Rx Peppermint Oil EC MR 100 0.2 ml

Digestive Disease Week Part 2 of reports from DDW, New Orleans

Modest result for new monoclonal antibody A novel monoclonal antibody had only modest efficacy in patients with moderate-to-severe ulcerative colitis.

G

enerally, patients taking MDX-1100 didn't appear to have significantly improved response, remission, or mucosal healing rates compared with those on placebo, according to Lloyd Mayer, MD, of Mount Sinai Hospital in New York City.

But those who had the highest blood levels of the antibody at the end of the eight-week trial had significantly better responses than those on placebo, Mayer and colleagues reported at a latebreaker session at Digestive Disease Week.

Mayer said the unique feature of the MDX-1100 monoclonal antibody is its target: IP-10, a CXC chemokine ligand that mediates T-cell migration via its receptor, CXCR-3. This chemokine is found in high concentration in the tissues of patients with Crohn's disease and ulcerative colitis. Mayer said that in mouse models, blocking this

‘

The primary endpoint was clinical

response at the end of the

Prescribing Information Colpermin IBS Relief Capsules Presentation: Sustained release capsules containing peppermint oil 0.2ml Uses: Relief of the symptoms of irritable bowel syndrome. Dosage: Adults and the elderly: One capsule three times a day. Two capsules three times a day in severe discomfort. Children: Not to be used under the age of 15 years. Contraindications: None. Precautions: Swallow capsule whole. Worsening of symptoms may occur in heart burn sufferers; discontinue treatment in these patients. Do not take if allergy to peanuts or soya. Consult a doctor before use in the following circumstances: first presentation of symptoms for confirmation of IBS, aged 40 years or over and some time since last attack, symptoms have changed, blood passed from the bowel, nausea or vomiting, loss of appetite or weight, paleness and tiredness, severe constipation, fever, recent foreign travel, pregnancy or planned pregnancy, abnormal vaginal bleeding or discharge, difficulty or pain in passing urine. If there are new symptoms or worsening of the condition, or failure to improve over two weeks, the patient should consult their doctor. Do not take immediately after food or with indigestion remedies. Pregnancy and lactation: Not recommended. Side effects: Heartburn, perianal irritation. Rarely, allergic reactions incl. rash, headache, bradycardia, muscle tremor and ataxia which may occur when taken with alcohol. NHS cost: 20s: £3.40; 100s: £12.05. Legal cat: GSL. PL holder: McNeil Products Ltd, Maidenhead, Berkshire, SL6 3UG. PL no: 15513/0141.

Date of prep: Feb 2010 References: 1. Colpermin SmPC. May 2008.McNeil Products Ltd. 2. White DA et al. Int J Pharm 1987; 40: 151-5.

3. NICE Clinical Practice Guideline. Irritable bowel syndrome in adults: Diagnosis and management of irritable bowel syndrome in primary care. Feb 2008.

4. Ford AC et al. BMJ 2008; 337: a2313.

’

eight-week period.

chemokine can improve the disease. So the researchers conducted a phase IIa placebo-controlled trial to evaluate the safety and efficacy of MDX-1100 in patients with moderate-to-severely active ulcerative colitis who had not responded adequately to medical therapy. It included 109 patients who were randomised to receive intravenously either placebo or 10mg/kg of the drug every two weeks, for a total of four doses. The primary endpoint was clinical response at the end of the eight-week period. In the entire study group, clinical response rates at the end of the study were greater in patients on the drug, but were not significantly different (53% vs. 35%).Neither were the remission and mucosal healing rates between drug and placebo (18% vs. 17% and 42% vs. 35%).

So the researchers assessed serum antibody concentrations. When they were highest, the effect of the drug was significant with rates of 88% for response, 44% for remission, and 69% for mucosal healing in the highest tertiles. The next stage would be to look at a higher dose of the drug and see if that has any impact on efficacy. Adverse events were generally comparable between two groups, but a higher proportion of those on the drug had infections and serious infections than those on placebo (12.7% vs. 5.8% and 5.5% vs.1.9%).

Disclosure:

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk Adverse events should also be reported to McNeil Products Limited on 01344 864 042.

The researchers reported no conflicts of interest.

Reference: Mayer L, et al. A randomised placebo-controlled trial of MDX-1100, an anti-IP-10

Date of preparation: June 2010

05773

antibody, for moderately-to-severely active ulcerative colitis. DDW 2010; Abstract 711a.

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EMA Highlights - by Gary Finnegan

Emerging Uses of EMA-Approved Drugs EU-US COLLABORATION ON CONFIDENTIALITY

PATIENT GROUPS RELYING ON INDUSTRY BACKING

M

T

edicines regulators on both sides of the Atlantic have permanently extended confidentiality arrangements which will allow continued information exchange on human and veterinary medicines.

Scientific advice, orphan drug designation, and paediatric medicine development, are just some of the areas where the EMA and US Food and Drug Administration (FDA) have shared information since 2003 under a temporary agreement.

The authorities are also cooperating on postmarketing surveillance and informing one another about planned inspections of good clinical practice (GCP) and good manufacturing practice (GMP).

In a separate development the EMA hosted an international workshop in London in September emphasising the need for cooperation on a global framework for clinical trials. The event was part of a consultation process on the Agency’s reflection paper on GCP and ethical aspects of clinical research in third countries.

Over the past five years, fewer than 40% of patients enrolled in major clinical trials examined by the EMA were treated at sites in Europe. This has led the European regulator to step up its efforts to raise standards of clinical research globally, particularly in the developing world.

“Wherever in the world we stand, the majority of clinical trials are being conducted somewhere else in the world, under a different regulatory framework and in different cultural settings. However, we all rely on the same trials to make decisions: as regulators, to allow or disallow marketing authorisations, and, as patients and healthcare providers, to use or not to use a medicine,” said Fergus Sweeney, Head of Inspections at the European Medicines Agency.

wo-thirds of the patient and consumer organisations working with the European Medicines Agency receive funding from the pharmaceutical sector, according to health campaigners.

Health Action International claim the regulator's efforts to involve independent patient groups could be undermined by the extent to which they rely on industry funds.

Based on new data on financial transparency, the group said fewer than half of the 23 organisations working with the EMA have complied with the Agency's financial reporting guidelines.

HAI is pointing the finger at the regulator for failing to rigorously enforce its own guidelines at a time when the Agency is working to improve transparency.

The annual average corporate contribution per sponsored organisation rose from €185,500 in 2006, to €282,090 in 2007, to €321,230 in 2008. These amounts correspond to 47%, 51% and 57% of organisational average annual revenue, respectively.

“It is to the credit of the regulatory process in the EU that the EMA has in recent years tried to involve patient and consumer groups in some aspects of drug policy and approval,” write Dr. Graham Dukes of the University of Oslo and Dr. Andrew Herxheimer of the Cochrane Collaboration in the HAI report.

“But the procedures have to be well defined and respected, and the consumer groups involved must be financially independent and truly impartial,” say the authors.

CHMP GIVE GREEN LIGHT TO NEW MEDICINES

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he EMA Committee for Medicinal Products for Human Use (CHMP) has recommended the granting of EVIDENTIA •

marketing authorisation for the following medicines: - Twynsta (telmisartan/amlodipine) from Boehringer Ingelheim International GmbH intended for the treatment of essential hypertension; - Clopidogrel Teva Pharma BV (clopidogrel, as hydrobromide) from Teva Pharma BV, for the prevention of atherothrombotic events; - Myclausen (mycophenolate mofetil) from Herbert J. Passauer GmbH & Co. KG, for the prophylaxis of acute transplant rejection in combination with ciclosporin and corticosteroids; The Committee also gave positive opinions for extensions of indications for a number of medicines already on the market: - Arixtra (fondaparinux sodium) from Glaxo Group Ltd, to include treatment of acute symptomatic spontaneous superficial vein thrombosis of the lower limbs without concomitant deep vein thrombosis; - M-M-RVAXPRO (measles, mumps and rubella vaccine live) from Sanofi Pasteur MSD, SNC, to include vaccination of healthy children from nine months of age under special circumstances, in accordance with official recommendations or when early protection is considered necessary; - Viread (tenofovir disoproxil) from Gilead Sciences International Ltd, to include treatment of chronic hepatitis B in adults with decompensated liver disease.

The CHMP has also recommended an extension of the therapeutic indications of Xalatan eye drops and associated names (latanoprost), from the Pfizer group of companies, to include the reduction of elevated intraocular pressure in the treatment of paediatric patients with elevated intraocular pressure and paediatric glaucoma. The Committee’s recommendation was made on the basis of data generated in accordance with an agreed paediatric investigation plan (PIP).

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European Association for Palliative Care - by Samuel Peters Reports from the EAPC meeting, Glasgow

European patient survey adds weight to expert call for greater clinical consensus on BTCP Experts concerned that inadequate treatment strategies make cancer patients suffer unnecessarily.

F

urther results from the European Survey of Breakthrough Cancer Pain1 were presented for the first time today at the 6th Research Congress of the European Association for Palliative Care (EAPC) in Glasgow.

The survey, which is the first international survey to look in detail at breakthrough cancer pain (BTCP) from a patient perspective, show that up to 45% of cancer patients experiencing breakthrough pain do not adhere to medication despite suffering from devastating episodes.

“The low adherence to drug therapy is a remarkable discovery and demonstrates that current treatments aren’t adequately meeting patients’ needs during these incapacitating episodes of pain,” explained Dr. Andrew Davies, Department of Palliative Medicine, Royal Marsden Hospital, UK and the principal investigator of this survey.

The survey, moreover, found that up to 50% of patients seek additional help from non-

Transplant.MED is a FREE quarterly e-journal delivered to you by email The editorial will be drawn from key conferences such as the British Transplantation Society annual meeting as well as major journals and symposia.

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pharmacological methods such as heat, positional changes and rest demonstrating the need for improved pain relief. When asked about the ideal BTCP medication, patients wanted (in order of ranking) • A medication that relieves the pain completely • A medication that relieves the pain quickly • A medication that causes few side effects • A medication that is easy to use • A medication that can be given by a relative/carer

Unfortunately, many patients are being treated with medications that are more suited to the management of persistent pain, and so are not receiving the most appropriate treatment for their breakthrough pain.

A systematic literature review conducted with the purpose of assessing and classifying cancer breakthrough pain on behalf of the European Palliative Care Research Collaborative (EPCRC) 6 likewise concludes that variations in cancer pain intensity are highly prevalent, yet the phenomenon is not well understood.

“There is no widely accepted definition, classification system or well-validated assessment tool for cancer-related breakthrough pain, but there is strong concurrence on most of its key attributes. An internationally agreed upon definition and classification system for cancer-related breakthrough pain, and a standard approach on how to measure it is required in order to improve patient care and support research in this poorprognosis cancer pain syndrome,” said coauthor, Professor Stein Kaasa, Chair of the European Association for Palliative Care Research Network (EAPC RN), principal investigator of the European Palliative Care Research Collaborative (EPCRC) and chair of the European Palliative Care Research Centre (PRC).

However, the results of the survey show that patients are not given a medication that matches these needs. 90% of patients were receiving oral opioids to manage their breakthrough pain. Studies have shown that the median interval from onset to peak intensity of the typical BTCP episode is only three minutes 2 and that the average episode lasts between 30-60 minutes.3, 4 The time to peak analgesic effect of oral opioids is documented to be approximately 60-90 minutes 5, long after a majority of the episodes have ended.

“Breakthrough pain is a distinct problem, and requires specific interventions including rescue medications that have an appropriately fast onset of action. Unfortunately, many patients are being treated with medications that are more suited to the management of persistent pain, and so are not receiving the most appropriate treatment for their breakthrough pain,” said Dr. Andrew Davies.

References: 1. Davies A et al. The Impact of Living with Breakthrough Cancer Pain – Results of a European Survey of Oncology Patients. Data presented at EAPC 2010 2. Portenoy RK et al. Breakthrough pain characteristics and impact in patients with cancer pain. Pain. 1999; 81: 129-34 3. Gómez-Batiste X et al. Breakthrough cancer pain: prevalence and characteristics in patients in Catalonia, Spain. J Pain Symptom Manage. 2002; 24: 45-52 4. Davies A et al. European survey of oncology patients’ experience of breakthrough cancer pain: UK, SE and DK results. Poster presented at EFIC 2009 5. Davies A et al. The management of cancer-related breakthrough pain: Recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland.

European Journal of Pain 2009; 13: 331-338 6. Haugen et al. Assessment and classification of cancer breakthrough pain: A systematic literature review.

Pain. 2010;149(3): 476-482 7. Ferrell BR et al. Use of routine and breakthrough analgesia in home care. Oncology Nursing Forum 1999; 26: 1655-61 8. Davies A et al. The management of cancer-related breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland.

European Journal of Pain 2009; 13(4): 331-8

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Inadequate access to opioid-based pain relief is a human rights issue for cancer patients

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any cancer patients in Europe are being denied access to adequate pain relief because of overzealous regulations restricting the availability and accessibility of opioidbased drugs such as morphine.

Authors of the Europe-wide study say that restricting access to pain-killing drugs in this way is a breach of patients' human rights, and they conclude that "there is an ethical and public health imperative to address these issues vigorously and urgently."

The study, which is published online in the cancer journal, Annals of Oncology is a joint report on the availability and accessibility of

‘

There is an ethical

and public health

imperative to address these issues vigorously

’

and urgently.

opioids for the relief of cancer pain by the European Society for Medical Oncology and the European Association for Palliative Care.

The authors collected data from 21 Eastern European countries and 20 Western European countries.

They evaluated the lists of allowed opioid drugs for the management of strong pain (opioid analgesics) for each country, the cost of opioid medication to patients and the regulatory barriers that can make it more difficult, if not impossible, for cancer patients and their doctors to get access to these medications in a timely manner.

They found that in some countries, particularly in Western Europe, access and availability was good (the UK was an example of a country that performed well in this respect), but in other countries, particularly in

prescribing and which contravene WHO and Eastern Europe, it was much more restricted. In INCB recommendations include: requiring countries, such as Lithuania, Tajikistan, Belarus, special patient permits, limiting the authority of Albania, Georgia and Ukraine, some essential physicians to prescribe opioids even for cancer opioid medicines were completely unavailable. patients with strong pain, imposing arbitrary The authors say that in many countries the dose limits that limit the ability to adjust the balance between enabling cancer patients to dose to individual patient needs, imposing receive the pain relief that they need, while, at severe limits on the duration of the prescription the same time, preventing prescription drugs (e.g. less than seven days' supply per being diverted for substance abuse in illicit prescription), restricting opioid dispensing so drug markets, is weighted too much in favour that it's harder for patients to access the of the latter. medication, increasing bureaucratic burdens They write: "Preventing drug abuse is through the use of complex or poorly accessible important, but it should not hinder patients' prescription forms or complex reporting ability to receive the care they need and deserve. This is the approach of the WHO [World Health Organisation] and the INCB CONTINUED ON PAGE 26 > [International Narcotics Control Board] . . .Both recommend that opioids should be available for cancer patients at hospital and community levels and that physicians should be able to prescribe opioids according to the individual needs of each patient.

"While most governments allow physicians to prescribe opioids for patients, regulations vary among nations and in many countries, regulations to reduce substance abuse and to restrict the diversion of medicinal opioids into illicit markets unduly interfere with medical availability for the relief of pain."

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European Association for Palliative Care - by Samuel Peters Reports from the EAPC meeting, Glasgow

Inadequate access to opioid-based pain relief is a human rights issue for cancer patients < CONTINUED FROM PAGE 25

requirements, and intimidating health care providers and pharmacists with intimidatory legal sanctions.

"As problematic as each of these violations are alone, when they are sequential in the process of prescribing and dispensing, their affects are multiplied, and the impact on patient care is profound," write the authors.

In addition, the authors say that few countries have adequate provisions for efficient emergency prescribing and dispensing of opioids in out-of-hours situations.

Availability and accessibility One of the authors, Dr. Nathan Cherny, of the Cancer Pain and Palliative Medicine Service at the Shaare Zedek Medical Center, Jerusalem, Israel, said: "In most of Western Europe, the issues of availability and accessibility appear to be fairly good. In some Eastern European countries, the situation is catastrophic. Many countries are in flagrant disregard of the regulatory guidelines of the International Narcotics Control Board, and we have highlighted the specific regulations and issues that need to be addressed to bring countries into compliance with the WHO and

INCB guidelines.

"This is an issue of cancer patients' human rights, and it's not only a legal imperative, but a moral imperative for the WHO and individual European countries to address the findings of

‘

This is an issue of cancer patients' human rights, and it's not only a legal imperative, but a moral imperative for the WHO and individual European countries to address the findings of our report.

Dr. Nathan Cherny

’

our report. At present, cancer patients in a number of countries are suffering unnecessarily as a result of the undertreatment of their pain."

The authors make a number of recommendations to improve the availability and accessibility of opioids: the WHO essential medicines list should be the minimum standard

Full reports from the European Society for Medical Oncology Congress can be found in

Oncology.med

for lists of allowed opioid drugs, with the more extensive list of the International Association for Hospice and Palliative Care being a long-term aim for all countries; governments should ensure access to immediate release morphine as soon as possible; governments should review and repeal over-vigilant and excessive restrictions that impede good clinical care of cancer pain; and regulatory provisions should be made for emergency prescribing and for allowing pharmacists to correct technical errors in prescriptions in discussion with the prescribing pharmacist.

To coincide with the paper's publication in Annals of Oncology, an editorial was recently published in the journal Palliative Medicine.2 The authors, led by James Cleary, associate professor of medicine at the Pain and Policy Study Group, WHO Collaborating Center for Policy and Communication in Cancer Care, University of Wisconsin Carbone Cancer Center, USA, write that the study is an important contribution to the discussion of opioid use in Europe. However, they point out that reform of national policies should be preceded by review of the actual laws and regulations, and that, following any reforms, implementation of the reforms was vital.

"Implementation may be the hardest step as it would be false to state that the inadequate treatment of cancer pain is due entirely to regulatory restrictions. We know from experience that policy change alone does not bring about increased access. We need to address the low priority of pain with health care, inadequate education, exaggerated fear of opioids and addiction, and problems in the supply chain for medications," they write. To do this, appropriate resources as well as leadership is required, they conclude.

References : 1. Formulary availability and regulatory barriers to

a request-only electronic journal.

accessibility of opioids for cancer pain in Europe: a report from the ESMO/EAPC Opioid Policy Initiative.

Annals of Oncology, Vol. 21: pp 615-626, 2010.

Please email: subscriptions@icr-uk.com and mark your email ʻOncology.MEDʼ

doi:10.1093/annonc/mdp581 2. Access to therapeutic opioid medications in Europe by 2011? Fifty years on from the Single Convention on Narcotic Drugs. Palliative Medicine Vol. 24: pp109-110. doi: 10.1177/0269216309360103

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www.nejm.org

ICATIBANT SHOWS PROMISE FOR TREATING HEREDITARY ANGIOEDEMA

R Reporting from some of the latest articles in

Journal Reviews by Bruce Sylvester

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esults from from two clinical trials suggest that icatibant, a new drug that blocks the action of an inflammatory protein known as bradykinin, is safe and effective in treating acute attacks of hereditary angioedema, a potentially life-threatening condition. The findings from both studies were published in the recent edition of the NEJM. "We have not had many options for treating painful, debilitating and potentially lifethreatenting attacks of hereditary angioedema, and these studies showed that icatibant improves symptoms and is not associated with any concerning side effects," said co-author Aleena Banerji, MD, of the Massachusetts General Hospital (MGH) Rheumatology, Allergy and Immunology Division, and assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

Hereditary angioedema (HAE) is caused by low levels or poor function of a protein called C1 esterase inhibitor. Patients face episodes of swelling caused by fluid leaking from blood vessels, potentially involving the face, extremities, gastrointestinal tract and the throat or, notably, the larynx, where it can cause lifethreatening airway blockage.

Icatibant blocks the receptor for bradykinin, a protein that dilates and increases the permeability of blood vessels and produces many symptoms of inflammation. Bradykinin is believed to mediate many symptom of HAE. Icatibant has received approval in the European Union, and is marketed under the brand name Firazyr. The NEJM study reports on two phase 3 trials - one based in the U.S. the other in Europe - conducted as part of the new-drug application to the U.S. Food and Drug Administration.

The studies were randomized, double-blind, prospective trials . The U.S.-based trial, called FAST-1, compared icatibant with a placebo for treatment of acute attacks. The European trial, FAST-2, used trenaxminic acid, an oral medication available in Europe, as the comparison drug.

Trial subjects, 56 in FAST-1 and 74 in FAST-2, received treatment within six hours of onset of a moderate to severe HAE attack. Response was primarily evaluated the time required for relief of the most severe symptom and secondarily

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evaluated for relief of all symptoms.

While icatibant produced faster symptom relief than the comparison drug in both studies, the difference was much greater in the FAST-2 trial, in which trenaxminic acid was the comparator drug. The authors hypothesised that the less significant results seen in FAST-1 might be the result of study design, particularly that treatment success was measured by relief of the most serious symptom only. And they noted that the limited size of the study groups might have affected the outcomes.

Also, more FAST-1 participants received C1 esterase inhibitor injections as rescue treatment, which might have hidden some icatibantassociated symptom improvement.

The investigators reported no serious treatment-related adverse events in either trial.

"These data do show that HAE patients receiving icatibant improve, and the drug seems to be very safe," said Dr. Banerji. "A larger, worldwide phase 3 trial of icatibant is currently in process and should help us clarify the picture further."

Journal of the American Medical Association www.jama.ama-assn.org

ROSIGLITAZONETREATMENT SHOWSINCREASEINCV RISKSANDDEATH

F

indings published online recently by JAMA indicate that Type-2 diabetes patients age 65 years and older who use rosiglitazone have an increased risk of stroke, heart failure, and all-cause mortality compared with pioglitazone users of the same age group.

"Rosiglitazone and pioglitazone are the only thiazolidinediones currently marketed in the United States," the authors provide as background information. "Studies have suggested that the use of rosiglitazone may be associated with an increased risk of serious cardiovascular events compared with other treatments for type 2 diabetes."

David J. Graham, M.D., M.P.H., from the Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, MD and colleagues, evaluated data from 227,571 Medicare beneficiaries (average age, 74.4 years) who were treated with rosiglitazone or pioglitazone through a Medicare Part D prescription drug plan from July 2006 through

June 2009. They evaluated follow-up data for up to three years after the initiation of the treatment.

"During follow-up, there were 1,746 acute myocardial infarctions (21.7% fatal), 1,052 strokes (7.3% fatal), 3,307 hospitalisations for heart failure (2.6% fatal), and 2,562 deaths for all causes among cohort members," the authors reported. While their analysis showed no differences in the risk for heart attack between rosiglitazone and pioglitazone, "…our study found that rosiglitazone was associated with a 1.25-fold increase in risk of heart failure compared with pioglitazone," and "…these data suggest that rosiglitazone was associated with a 1.27-fold increased risk of stroke and a 1.14-fold increased risk of death compared with pioglitazone," they said.

In conclusion, the authors wrote, "…in a population of more than 227,000 patients 65 years or older who initiated treatment with a thiazolidinedione, we found that, compared with pioglitazone, rosiglitazone was associated with an increased risk of stroke, heart failure, and death and the composite of AMI (heart attack), stroke, heart failure or death."

HEV 239 or placebo (hepatitis B vaccine) given intramuscularly at zero, one, and six months.

They were followed up for 19 months. The primary endpoint of the study was prevention of hepatitis E during 12 months from the 31st day after the third dose.

All subjects were randomised to vaccine (n=56,302) or placebo (n=56,302); 48 693 (86%) subjects in the vaccine cohort and 48,663 subjects (86%) in the placebo group received three vaccine doses and were included in the primary efficacy analysis.

During the 12 months after 30 days from receipt of the third dose 15 per-protocol participants in the placebo group developed hepatitis E compared with 0 in the vaccine group.

Vaccine efficacy after three doses was 100%.

Vaccine-related adverse events were few and mild, with no serious adverse events recorded.

The authors conclude: “In our trial, we found the vaccine well tolerated and efficacious for a general adult population. Further studies are needed to assess the safety and to support the benefits of the vaccine for pregnant women and for people younger than 15 years or older than 65 years.”

www.thelancet.com

BMJ

STUDY SHOWS PROMISE FOR HEPATITIS-E VACCINE

S

cientists estimate that up to one-third of the world’s population is infected with the hepatitis E virus. And even though most cases are in developing countries, hepatitis E is also the most common type of acute viral hepatitis in industrialised countries.

In a study published recently on Online First in The Lancet, researchers evaluated the efficacy and safety of the HEV239, a hepatitis E vaccine. The lead author was by Dr Ning-Shao Xia, Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, China.

Hepititis E tends to be self-limiting and usually does not become chronic. Severity of illness increases with age, with an overall case fatality ratio of 1–3%. Hepatitis E has a poor prognosis in pregnant women, with a mortality rate of 5–25%; survivors have high rates of spontaneous abortion and stillbirth. For patients with chronic liver disease, superinfection with hepatitis E virus often leads to a poor outcome.

In this randomised phase 3 trial, healthy adults of both sexes aged 16–65 years in Jiangsu Province, China were randomly assigned in a 1:1 ratio to receive three doses of

British Medical Journal www.bmj.org

SUPPORT PROGRAMMES HELP PREVENT WEIGHT GAIN IN WOMEN

A

ustralian researchers report that intervention based on simple health messages, small changes to behavior, and delivered conveniently in a community setting can be effective in preventing excess weight gain commonly experienced by young mothers. The research was published online recently in the British Medical Journal.

The authors noted that 60% of adults in Australia are either overweight or obese, and young women in Australia are now gaining weight at a faster rate than women in any other age, increasing risks of weight-related illnesses.

The study, organised by the Jean Hailes Foundation for Women's Health, investigated whether women who attended the HeLP-her Community Lifestyle Programme gained more or less weight than women who attended a single thirty minute group lecture about the benefits of following population dietary and physical activity guidelines. The study was led

by Dr. Catherine Lombard with Professor Helena Teede from the Jean Hailes Foundation EVIDENTIA •

for Women's Health in collaboration with Monash University in Melbourne, Australia The investigators enrolled 250 women, 25 to 49 years-old. Women within the healthy weight range were included as well as overweight and obese women.

The study subjects attended four interactive sessions at the local primary school where they discussed methods of behavioral change.

"We did not give the women a diet to follow or an exercise plan as we wanted the women to decide themselves what was important and possible to change at that time in their lives," said Dr. Lombard. "Women don't want to feel pressured to reduce weight. In this programme they decided what their needs were, and we supported them. We looked at what stops them from adopting healthy eating or engaging in more activity how could they overcome that," she said.

The women in the intervention group also received monthly SMS text messages encouraging healthy eating and lifestyle throughout the twelve months of the research project.

Women under 40 in the intervention group lost around 0.27kg. Women in the control group gained an average of 830 grams - just under a kilo - during the 12-month study and overall there was a 1kg difference between the groups. Subjects in the control group under 40 years-old and within a healthy weight range gained the most weight (1.72kg).

"While not a huge amount of weight the key issue is that this simple programme stopped women putting on weight," said Jean Hailes Director of Research and Monash University Chair of Women's Health, Professor Helena Teede.

The authors noted that, in another decade or two, these women could be 15-20kg heavier, putting themselves at greater risk of chronic disease.

"We need to acknowledge the struggle this is for many women and their families on a daily basis. We know women are trying hard to lose weight, or to maintain a steady weight, but whatever they are currently doing isn't working. They need more support," said Professor Teede.

"Our research found that you can't just give women a few brochures about diet and exercise and expect them to do it themselves.

Excitingly, our research suggests that it only takes small, simple changes, together with a bit of support, for ordinary women to successfully control their weight," she says.

Sources: Massachusetts General Hospital , JAMA and Archives Journals, The Lancet, The Jean Hailes Foundation for Women's Health

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Medical news from around the world - by Gary Finnegan

World Health Matters

SWEDEN PRIVATISING ALCOHOL SALES ‘WILL SPARK VIOLENCE’ A study published in the journal Addiction has argued that privatising Sweden’s controversial government monopoly on alcohol sales will significantly increase alcoholrelated violence.

Sweden’s system of government-controlled off licenses is unpopular with the drinks industry and business groups but some public health experts see it as a model for getting a handle of alcohol-fuelled social problems.

However, the lobby to privatise the sale of alcohol has been dealt a blow by researchers who forecast that total alcohol consumption in Sweden would rise by between 17% and 37% depending on the nature of the privatisation policy. Thousands of alcohol-related deaths, assaults, and drink-driving offences would follow, along with up to 11 million more days sick leave.

Systembolaget, the Swedish Alcohol Retail Monopoly, currently controls the off-license sale of all beverages over 3.5% alcohol by volume.

The legality of the monopoly has been under scrutiny since Sweden entered the EU in 1995.

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Experts from seven alcohol research centres in Sweden, Finland, Norway, Canada, and the United States considered the effects of two models of privatisation that might one day replace Sweden's monopoly.

In the first scenario, Systembolaget's 400 stores would be replaced by about 800 governmentlicensed alcohol shops, doubling the number of retail outlets. Compared with Systembolaget's stores, private shops are likely to stay open longer, sell discounted alcohol, sell alcohol to underage drinkers, and use advertising to boost sales, all of which have been shown to increase alcohol consumption, the experts predict. This will result to in a 17% rise in drinking per person, 770 more deaths, 8,500 assaults and 4.5 million days of sick leave.

Allowing supermarkets to sell alcohol of any strength could lead to as many as 2,000 alcohol-related deaths, the group claims, adding that longer opening hours and lower prices can be directly linked to harm. Under this scenario, consumption could jump by as much as 37% while the number of assaults would rise by 20,000, along with a 6,600 increase in driving offences.

The research group warn that these figures are merely projections of what might happen rather than representing exact forecasts.

Addiction researchers in other nations are watching the situation in Sweden with great interest. According to Professor Thomas Babor at the University of Connecticut in the USA, the findings have profound implications for all countries where governments have attempted to control the sale of alcohol.

“With increasing pressure from the alcohol industry to dismantle or weaken alcohol monopolies in the USA and other countries, it is important to remember the public health benefits of maintaining reasonable controls over the distribution and marketing of alcoholic beverages, and the tremendous risks of removing them,” he said.

Reference: Addiction. 2010 Sep 1, Epub ahead of print

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AUSTRALIA FUNCTION FOUND FOR ALZHEIMER'S PROTEIN Researchers in Melbourne believe they have finally figured out the function for the protein that builds up in the brains of people with Alzheimer’s disease.

It has long been known that amyloid precursor protein (APP) forms plaques in Alzheimer’s patients leading to brain cell death and, ultimately, dementia. However, scientists have struggled to understand whether APP has any positive role to play in cell biology.

A team at the University of Melbourne believes APP is an iron oxidase - a protein whose job it is to convert iron from an unsafe form to a safe one for transport or storage. When APP fails to function

‘

It has long been known

that amyloid precursor protein (APP) forms plaques in

Alzheimer’s patients leading to brain cell death and,

’

ultimately, dementia.

properly, as it does in Alzheimer's disease, iron levels inside neurons mount to toxic levels.

“This opens a big window on Alzheimer's disease and iron metabolism,” said Ashley Bush of the Mental Health Research Institute, University of Melbourne.

“Although people have attributed several important physiological roles to APP,” added Jack Rogers of Harvard Medical School, “this now gives us an idea of what this critical protein does to underpin its role in iron metabolism.”

Previous studies had hinted at this discovery. It was previously reported that the RNA template for the APP protein includes an iron-responsive element. When iron levels rise, cells ramp up their APP production.

But amyloid in and of itself doesn’t really explain what goes wrong in the Alzheimer’s brain. “There has been a lot of attention on

amyloid, but it seems it is not a simple matter of amyloid as the sole culprit,” Bush said. For one thing, trials of drugs designed to target and clear amyloid plaques haven’t worked as intended.

In fact, the disease is also complicated by high concentrations of metals, including iron that builds up inside neurons and zinc that accumulates within the amyloid plaques outside of those brain cells. And studies have also linked the loss of other iron oxidases to pathological iron accumulation and neurodegenerative diseases characterised by dementia. “If iron is left unbridled in its soluble form, it can cause nerve death and damage,” Rogers said.

After 10 years of work, it appears Bush's and Roger's teams have connected the dots from the abnormal exchange of zinc to amyloid pathology and iron accumulation in Alzheimer's disease.

“It's a sequence of dominoes falling onto each other,” Bush said.

Based on the new evidence, the researchers propose that elevated iron in the Alzheimer's brain summons further APP production. But that APP - generated for the purpose of exporting iron - gets disabled by high levels of zinc that dissociate from the amlyoid plaques.

The findings suggest that zinc may be an ideal target in the fight against Alzheimer's disease, the researchers say. In fact, studies in animals and early, short-term clinical trials of zinc-ionophore drugs including clioquinol and PBT2 in people with Alzheimer's disease have so far produced promising results. PBT2 is slated for further testing.

"Our findings authenticate zinc as a target," Bush said. "It really makes it look like an attractive place to hit."

Reference: Cell, September 2010. Epub ahead of print

FRANCE RESEARCH LINKS HUNTINGTIN TO NEUROGENESIS New research from France has revealed that a protein which is often mutated in Huntington's disease (HD) plays an unexpected role in the process of neurogenesis. The research, published in the journal Neuron, provides new insight into HD pathology and has even broader implications for human health and disease, according to scientists.

Previous research has demonstrated that abnormal huntingtin protein (htt) is associated with HD pathology which leads to uncontrolled

movements, emotional disturbances, and severe mental deterioration.

“Given the predominant neurological signs and striking neuronal death in HD, most studies on htt function have focused on adult neurons,” explains senior study author, Dr. Sandrine Humbert from the Institut Curie in Orsay, France.

“However, although htt is not restricted to differentiated neurons and is found at high levels

‘

Given the predominant

neurological signs and striking neuronal death in HD, most

studies on htt function have

’

focused on adult neurons.

in dividing cells, no studies have investigated a possible role for htt during cell division.”

Cell division, known as mitosis, is the process where a single cell divides into two new but identical daughter cells. It is a complex and highly regulated sequence of events that occurs in a series of well-defined stages. One key step of mitosis involves the assembly and orientation of a structure called the “mitotic spindle”.

During mitosis, the proteins dynein and dynactin must interact with the spindle.

Because htt is known to facilitate dynein/dynactin activity, Dr. Humbert's group investigated whether htt played a functional role during mitosis.

The researchers discovered that htt was specifically localised to the mitotic spindle during mitosis in mouse neurons and that htt was required for recruitment of dynein/dynactin to the spindle. Importantly, interference with htt led to misorientation of the spindle in both mice and flies.

The French group went on to show that htt was critical for both mitosis and cell fate determination.

“Our findings demonstrate a previously unknown function for htt protein and open new lines of investigation for elucidating the pathogenic mechanisms in HD,” concludes Dr. Humbert. “This work also identifies htt as a crucial part of spindle orientation and neurogenesis.”

ITALY HEART ATTACKS JUMP IN YOUNG ITALIAN WOMEN The incidence of acute myocardial infarction in Italy sharply increased, particularly among young women, between the years 2001 and 2005, according to a comprehensive study funded by the Human Health Foundation (HHF), a nonprofit Italian charity for biomedical research and health education in Spoleto, Italy.

The results published in the journal Aging Clinical Experimental Research, shows that the total number of acute myocardial infarctions were over 118,000 (of which 75,000 were men and 43,000 women) in the year 2005 against 96,000 in 2001.

While men continue to suffer more heart attacks than women, the rate of increase in women is rising quickly. “The increase was 17.2% in men and 29.2% in women,” says lead author Dr. Prisco Piscitelli, an epidemiologist at the Euro Mediterranean Biomedical and Scientific Institute in Brindisi, Italy. “The greatest number of hospitalisations for heart failure was recorded in men aged 45 to 64 years (29,900 cases in 2005) and in women over 75 years of age (26,500 cases). In the later age group women overtook men, who had 24,000 admissions in 2005,” he said.

‘ ’ The increase was

17.2% in men and

29.2% in women.

Across the board, the increase in the number of hospitalisations for heart failure from 2001 to 2005 was found to be higher in women in all age groups examined, reaching peaks of 36% in women over seventy five years but with an increase of 22% found in younger women aged between 45 and 64 years.

“The study suggests that more information on measures to reduce risk factors for heart failure should be directed towards young women,” says Dr Antonio Giordano, President and Founder of the Sbarro Health Research Organisation for Biotechnology and Founder and Director of the Scientific Advisory Committee for the HHF.

Reference:

Reference:

Neuron 2010 Aug 12; 67(3): 392-406

Aging Clin Exp Res. 2010, Jul 21

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FDA Highlights - by Bruce Sylvester

Emerging Uses of FDA-Approved Drugs STATIN THERAPY RELATED TO REDUCTION IN CANCER RECURRENCE FOLLOWING PROSTATECTOMY

(SEARCH) database. They reported that 18% of the men (236) were taking a statin at the time of surgery.

They tracked post-surgical data on the subjects to evaluate recurrence rates, which en treated with a statin to lower were measured by increases in prostate-specific cholesterol achieved a 30% antigen (PSA) levels after surgery. reduction in prostate cancer The investigators reported that 304 men had recurrence after surgery compared with a rising PSA, including 37 (16%) of the statin men who do not take a statin, according to users and 267 (25%) of the non-users. a study published recently in Cancer.

Adjusting the data for different clinical and The authors also reported that higher pathological features between the user/non-user statin dosing was associated with lower risk subgroups, they found that statin use associated of recurrence. with a 30% reduction in recurrence risk.

"The findings add another layer of evidence Notably, men taking simvastatin 20mg/day suggesting that statins may have an important achieved a risk reduction of 43%, and among role in slowing the growth and progression of men taking more than simvastatin 20mg/day, prostate cancer," said senior author Stephen the risk reduction was 50%. Subjects taking Freedland, MD, Duke Prostate Center, Durham <20mg/day saw no recurrence-related benefit.

Veterans Affairs Medical Center, Durham, Statin users tended to be white, older, and North Carolina. "Previous studies have shown heavier than the non-users. They had lower that statins have anti-cancer properties, but it's clinical stages of disease at diagnosis, but they not entirely clear when it's best to use them - or had higher Gleason scores. even how they work."

"These findings are intriguing, but we do The investigators evaluated data on 1,319 need to approach them with some caution," men who had undergone radical said Robert Hamilton, MD, University of prostatectomy and who were included in the Toronto, Ontario, Canada. "For example, we Shared Equal Access Regional Cancer Hospital don't know the diet, exercise or smoking habits of these men. So it's not entirely clear if the lower risk we detected is related to the statins alone; it could be due to other factors we were not able to measure."

"We do feel, however, that based on these findings and those from other studies, the time is ripe to perform a wellcontrolled randomised trial to test whether statins do indeed slow prostate cancer progression," Statin users tended to be white, older, and heavier than Dr. Hamilton added. the non-users

M

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UNAPPROVED USE OF QUININE SULFATE GETS FDA WARNING

I

n July, the US Food and Drug Administration (FDA) issued a warning that off-label use of the malaria drug quinine sulfate to treat night time leg cramps causes serious side effects.

FDA scientists reviewed reports submitted to the Adverse Event Reporting System (AERS) between April 2005 and October 1, 2008. They found 38 cases within the US of serious side effects associated with the use of quinine.

They reported that off-label quinine use resulted in serious and life-threatening reactions in 24 cases, including thrombocytopenia and haemolytic uremic syndrome/thrombotic thrombocytopenic purpura.

They noted that the adverse side effects resulted in permanent kidney impairment and hospitalisation in some patients, and two patients died from drug-related reactions. Most of the subjects reporting serious side effects were treated with the drug off-label to prevent or treat leg cramps or restless leg syndrome.

The risk management plan developed by the manufacturer, a Risk Evaluation and Mitigation Strategy (REMS), requires that patients be given a Medication Guide explaining the conditions for which quinine treatment is and is not approved, and the potential side effects of the drug. The company will also issue a Dear Health Care Provider letter warning of the potential risk of serious and life-threatening haematologic reactions.

NALTREXONE AND BUPROPION FOR LOWERING BODYWEIGHT

C

ombination naltrexone and bupropion, plus diet and exercise, has helped reduce bodyweight by a mean of 5% or more over a year, depending on the dosage. Researchers reported this finding in the Contrave

Obesity Research 1 (COR-1) study, published as a Lancet Online first item.

Lead investigator Frank L. Greenway, MD, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA and colleagues studied men and women aged 18 to 65 years with a body-mass index (BMI) of 30 to 45kg/m2 and uncomplicated obesity, or BMI 27 to 45kg/m2 with abnormal blood fats or high blood pressure. They enrolled subjects from 34 sites in the United States.

The subjects received a diet of moderately reduced calories and exercise, plus one of three treatment regimens: sustained release (SR) naltrexone 32mg per day plus SR bupropion 360mg per day combined in fixeddose tablets (NB32 group), SR naltrexone 16mg per day plus SR bupropion 360mg per day combined in fixed-dose tablets (NB16 group), or matching placebo.

The three study groups received treatment twice daily for 56 weeks.

While 1,742 patients were randomised, only 50% of them completed all 56 weeks of treatment (NB32 [n = 296]; NB16 [n = 284]; placebo [n = 290]). Of the original 1,742 enrolled, 1,453 (83%) were included in the final analysis (NB32 [n = 471]; NB16 [n = 471]; placebo [n = 511]).

Mean body weight was about 100kg (220 lbs) before the study. Mean weight loss at 56 weeks was 1.4kg (3.1 lbs) in the placebo group, 4.9kg (10.8 lbs) in the NB16 group and 6.1kg (13.5 lbs) in the NB32 group.

Proportions of subjects achieving a 5% or more weight loss varied between groups.

Almost half of the subjects (48%) in the NB32 group achieved this goal, compared with 39% in the NB16 group and 16% in the placebo group. And more patients in the NB32 group (25%) and NB16 group (20%) lost greater than 10% of their bodyweight compared with the placebo group (7%).

Most drug-related adverse events were mild to moderate in severity and easily treated.

While the study did included men, 85% of each group was female, mostly middle-aged and white.

The exact effect of the exercise part of the regimen remains unknown since data for were not recorded. The authors also noted that this combination therapy needs to be studied headto-head against other therapies, for efficacy.

The authors concluded, "Although lifestyle

modification is first-line therapy for obesity, adherence to this intervention is poor. The combination of naltrexone plus bupropion could be a useful addition to the current range of medications that facilitate adherence to lifestyle modification and produce clinically meaningful weight loss for treatment of obesity and obesity-related disorders."

KETAMINE IN QUICK RELIEF OF DEPRESSION IN TREATMENT-RESISTANT BIPOLAR DISORDER

A

mong patients with bipolar disorder who have not responded to other treatments, a single intravenous dose of the anaesthetic agent ketamine appears to reduce symptoms of depression within 40 minutes. The findings were reported in the August issue of Archives of General Psychiatry.

"Bipolar disorder is one of the most severe psychiatric disorders and ranks in the top ten causes of medical disability worldwide," the authors wrote as background information in

‘

While several treatments for bipolar depression

are currently FDA-approved, some patients do

’

not respond.

the article. Approximately 4% of Americans will develop bipolar disorder at some point in their lives, and depressive symptoms dominate for most of the course of the illness.

While several treatments for bipolar depression are currently FDA-approved, some patients do not respond. Also, existing treatments have a lag of onset, most patients not responding during the first week of therapy, resulting in considerable illness and increased suicide risk.

Nancy Diazgranados, MD, MS, National Institute of Mental Health, Bethesda, Maryland, and colleagues assessed the effectiveness for bipolar depression of one modulator of the EVIDENTIA •

glutamatergic system, ketamine hydrochloride.

From October 2006 through June 2009, 18 subjects with bipolar depression who had failed to respond to the medications lithium or valproate received an intravenous infusion of either ketamine or a placebo on two test days two weeks apart. The order of the infusions was randomly assigned.

The investigators assessed the subjects before each injection using a depression rating scale, and then 40, 80, 120, and 230 minutes and 1, 2, 3, 7, 10, and 14 days afterward.

They found that within 40 minutes, those who received ketamine experienced a significant improvement in depressive symptoms compared with those who took placebo, an improvement that was largest at day two and remained significant through day three. At some point during the course of the trial, 71% of participants responded to ketamine and 6% responded to placebo.

"These findings are particularly noteworthy because a substantial proportion of study participants had been prescribed complex polypharmacy regimens in the past with substantial treatment failures," the authors wrote. "The mean number of past antidepressant trials was seven, and more than 55% of participants failed to respond to electroconvulsive therapy. The toll of this protracted and refractory illness on the subjects was evident, in that two-thirds of participants were on psychiatric disability and nearly all were unemployed."

The investigators reported no serious adverse side-effects during the study.

They concluded that these results support the hypothesis that the glutamatergic system is implicated in the development of bipolar disorder, and that targeting it may lead to improved therapies. "Future research will need to address whether differences in kinetics associated with intravenous administration - which allows for faster absorption and avoids hepatic metabolism are important or necessary for rapid antidepressant effects to occur," the authors wrote. In addition, "future studies should examine strategies for long-term maintenance of ketamine's rapid antidepressant response."

Sources: Duke University Medical Center, US Food and Drug Administration The Lancet and Archives of General Psychiatry

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by Steve Devrell

A load of hot air

A

View from The Waiting Room

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s I look out of my window, the skies are unseasonably dark, the ground unseasonably damp, the air unseasonably cool. Or is it so unseasonable? I mean, can you remember the last time we had long sunny periods in this country rather than short sunny intervals? Well, I suppose those of you who can remember 1976 will recall such a summer. It was the only summer in my life that I was living in a flat. Then there was 2003, the summer when people were dropping dead all over Northern Europe whilst I was on holiday in Southern California enduring three weeks of stubborn sea fog. This Easter I was in Barbados during the week that the drought ended there and did it end! In short don’t follow me around if you want a sun tan!

The winters have become milder I grant you, except of course for this year when we had a 1962 type winter (again nostalgia for the wrinklies.) So what is this climate change we are being warned about? I have noticed no real appreciable difference apart from generally milder winters, although we are being bombarded with all sorts of records like the warmest month since .... the wettest month since.... and the most frightening statistics of all which end with ‘since records began’ and there have been a few of those recently as well.

Well, the experts will tell you that we won’t notice any difference because we are dealing with long-term trends rather than short-term changes. But the truth is that our planet relies on such a delicate climatic balance that even a small change in temperature (four degrees centigrade) could be disastrous for the planet six degrees would be catastrophic.

The NHS admits that climate change is a health issue threatening billions of people and doctors are warning us that climate change is the biggest global health threat in the 21st century. The Lancet and University College London’s Institute for Global Health have recently produced a report on managing health effects of climate change. It highlights food shortages and an increased threat from tropical

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diseases including malaria, which could affect the UK by the end of this century.

The team that produced the report concentrated on six areas: patterns of disease and mortality, food security, water and sanitation, shelter and human settlements, extreme events and population migration. The lead author Professor Anthony Costello was at pains to point out that climate change is not just about deforestation or polar bears, it is about people.

The report goes on to say that climate change has the greatest change on the poorest people of the world, the very people who have contributed least to its causes.

The United Nations have also been active in working towards minimising the effects of climate change with reports from an intergovernmental panel containing advice and support from the World Health Organisation.

There is little doubt that the poor and vulnerable are at more risk from climate change than the richer more developed countries, and these people should be the major concern to reduce the risk of an immense ongoing humanitarian disaster. But there are likely to be health issues locally that will result from climate change.

In a recent BBC report from their ‘In Health’ section, it warned that climate change could cause thousands of deaths each year, although the reduced number of deaths from milder winter conditions would more than compensate for the increases. The warmer conditions could cut the number of elderly people who die during the winter months by around 20,000 each year.

The number of hospital patient days per year that are due to the cold could fall from 8.2 million to 6.1 million.

Instances of skin cancer were likely to rise by an estimated 5,000 per year and cases of cataracts were also likely to increase by an estimated 2,000. This, as a result of the increase in the regularity of summers like the one in 1976. Currently these summers are likely to occur every 350 years; by 2050 they could happen every 5 years. There could also be an extra 10,000 cases of food poisoning each year caused by the added difficulties of keeping

PRESCRIBING INFORMATION – UK AND ROI

food fresh in a warmer climate.

It is agreed that this country may be less adversely affected than many other parts of the world. The report however predicts that by 2080, much of the south of the UK would be vulnerable to the milder form of malaria plasmodium vivax for up to four months of the year. Mosquitoes will thrive in the higher temperatures and predicted increases in winter rainfall. These conditions would provide ideal breeding conditions. Areas with salt-marshes like south-east Kent would be most at risk.

Tourist destinations, especially in the Eastern Mediterranean could have higher instances of a more serious form of malaria and it predicted that by the end of this century, parts of Spain including the Costa del Sol will become an extension of the

‘

health and social services can cope with the predicted increased frequency of extreme events. However it is also widely acknowledged that the health impacts of climate change can be minimised by building climate change considerations into the UK’s health and social care infrastructure. Targeting improvements in health and social services for the most at risk groups - for example by improving social services for the elderly living on their own, or reviewing the design and facilities of residential care homes - may also help to reduce the potential health impacts of climate change. The Parliamentary Office of Science and Technology believes such initiatives could form part of a more holistic risk management approach to climate change issues.

Tourist destinations, especially in the

Eastern Mediterranean could have higher instances

’

of a more serious form of malaria...

Sahara Desert.

It is the frequency of weather patterns that determine climate change. It is predicted that cold winters will become much rarer, although winter rainfall will increase, threatening the risk of flooding to many low lying areas. Heatwaves will be more frequent in summer and this has prompted a plan for a ‘heatwave watch’ in the UK between 1st June and the 15th September. The threshold temperatures will vary from region to region, but warnings will generally be issued if the daytime temperatures exceed 30 degrees centigrade for more than two days running and the night temperature exceeds 15 degrees.

These are fairly manageable temperatures for us Mediterranean loving holidaymakers, but we enjoy air conditioning as pretty well standard these days and most of us are neither old nor frail. In the heatwave of August 2003, it is estimated that 15,000 extra deaths in Northern France and 2,000 extra in the UK were caused by the weather conditions.

Climate change and its impact on health may put additional strain on the UK health system. There is thus a need to ensure that

The UK national assessment of the likely health impacts of climate change identified a wide range of areas where more research was needed.

• The vulnerability of individuals and groups and into connecting disease prevention and social care to community monitoring.

• The effectiveness of education campaigns such as ‘Sun Safe’ in changing people’s attitudes and behaviour.

• Refinement of the methodology to quantify health impacts due to climate change.

• Better research into how best to communicate remaining uncertainties to policy makers and the public.

Although the UK has started to respond to such challenges, such initiatives require close co-ordination across a wide range of bodies. Consideration of health impacts is a fairly recent development in the climate change debate. It is clear therefore that further research is needed across a wide range of areas to reduce uncertainties in the predicted impacts. Will the money be made available for this? Well, time will tell.

REBIF ® 8.8 MICROGRAMS AND 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE REBIF ® 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE REBIF ® 44 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE REBIF ® 8.8 MICROGRAMS AND 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED PEN REBIF ® 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED PEN REBIF ® 44 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED PEN REBIF ® 8.8 MICROGRAMS/0.1ML AND REBIF ® 22 MICROGRAMS/0.25ML SOLUTION FOR INJECTION IN CARTRIDGE REBIF ® 22 MICROGRAMS/0.5ML SOLUTION FOR INJECTION IN CARTRIDGE REBIF ® 44 MICROGRAMS/0.5ML SOLUTION FOR INJECTION IN CARTRIDGE Interferon beta-1a Presentation Rebif 8.8μg and 22μg: Pre-filled glass syringe containing 8.8μg or 22μg of Interferon beta-1a in respectively 0.2 or 0.5ml.

Rebif 22μg or 44μg: Pre-filled glass syringe containing 22μg or 44μg Interferon beta-1a in 0.5ml. Rebif 8.8μg and 22μg: Disposable pre-filled pen injector (RebiDose) containing 8.8μg or 22μg of Interferon beta1a in respectively 0.2 or 0.5ml. Rebif 22μg or 44μg: Disposable pre-filled pen injector (RebiDose) containing 22μg or 44μg Interferon beta-1a in 0.5ml. Rebif 8.8μg/0.1ml and Rebif 22μg/0.25ml: Pre-filled glass cartridge containing 132μg of Interferon beta-1a in 1.5ml. Rebif 22μg/0.5ml or Rebif 44μg/0.5ml: Pre-filled glass cartridge containing 66μg or 132μg of Interferon beta-1a in 1.5ml. Indication Treatment of relapsing multiple sclerosis. Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without ongoing relapse activity. Dosage and administration Initiate under supervision of a physician experienced in the treatment of multiple sclerosis. Administer by subcutaneous injection. Recommended dose: Weeks 1 and 2: 8.8μg three times per week (TIW); weeks 3 and 4: 22μg TIW; week 5 onwards: 44μg TIW (22μg TIW if patients cannot tolerate higher dose). RebiDose pre-filled pen is for single use and should only be used following adequate training of the patient and/or carer. Follow the instructions provided in the package leaflet. Rebif solution for injection in cartridge is for multidose use and should only be used with the RebiSmart autoinjector device following adequate training of the patient and/or carer. Follow the instructions provided with the RebiSmart device. Limited published data suggest that the safety profile in adolescents aged 12–16 years receiving Rebif 22μg TIW is similar to that in adults. Do not use in patients under 12 years of age. Prior to injection and for 24h afterwards, an antipyretic analgesic is advised to decrease flu-like symptoms. Evaluate patients at least every second year of the treatment period.

Contraindications History of hypersensitivity to natural or recombinant interferon beta, or to any of the excipients; treatment initiation in pregnancy; current severe depression and/or suicidal ideation. Precautions Inform patients of most common adverse reactions. Use with caution in patients with previous or current depressive disorders and those with antecedents of suicidal ideation. Advise patients to report immediately any symptoms of depression and/or suicidal ideation. Closely monitor patients exhibiting depression and treat appropriately. Consider cessation of therapy.

Administer with caution in patients with a history of seizures and those receiving anti-epileptics, particularly if epilepsy is not adequately controlled. Closely monitor patients with cardiac disease for worsening of their condition during initiation of therapy. Patients should use an aseptic injection technique and rotate injection sites to minimise risk of injection site necrosis. If breaks in skin occur, patients should consult their doctor before continuing injections. If multiple lesions occur, discontinue Rebif until healed. Use with caution in patients with history of significant liver disease, active liver disease, alcohol abuse or increased serum ALT. Monitor serum ALT prior to the start of therapy, at months 1, 3 and 6 and periodically thereafter. Stop treatment if icterus or symptoms of liver dysfunction appear.

Treatment has potential to cause severe liver injury including acute hepatic failure.

Full haematological monitoring is recommended at months 1, 3 and 6 and periodically thereafter. All monitoring should be more frequent when initiating Rebif 44μg. New or worsening thyroid abnormalities may occur. Thyroid function testing is recommended at baseline and if abnormal every 6–12 months. Use with caution in, and closely monitor patients with, severe renal and hepatic failure or severe myelosuppression.

Serum neutralising antibodies may develop and are associated with reduced efficacy.

If a patient responds poorly and has neutralising antibodies, reassess treatment.

Use with caution in patients receiving medicines with a narrow therapeutic index cleared by cytochrome P450. Women of childbearing potential should use effective contraception. Limited data suggest a possible increased risk of spontaneous abortion. During lactation, either discontinue Rebif or nursing. If overdose occurs, hospitalise patient and give supportive treatment. Side effects In the case of severe or persistent undesirable effects, consider temporarily lowering or interrupting dose.

Very common: flu-like symptoms, injection site inflammation/reaction, headache, asymptomatic transaminase increase, neutropenia, lymphopenia, leucopenia, thrombocytopenia, anaemia. Common: injection site pain, myalgia, arthralgia, fatigue, rigors, fever, pruritus, rash, erythematous/maculo-papular rash, diarrhoea, vomiting, nausea, depression, insomnia, severe elevations of transaminase.

Serious side effects include: injection site necrosis, hepatic failure, hepatitis with or without icterus, severe liver injury, anaphylactic reactions, angioedema, erythema multiforme, erythema multiforme-like skin reactions, seizures, thromboembolic events, thrombotic thrombocytopenic purpura/haemolytic uremic syndrome, suicide attempt, Stevens–Johnson syndrome, dyspnoea, retinal vascular disorders.

Consult the Summary of Product Characteristics for more information relating to side effects. Legal category POM. Price Rebif 8.8μg and 22μg: 6 (0.2ml) + 6 (0.5ml) syringes – £552.19. Rebif 22μg: 12 syringes (0.5ml) – £624.77.

Rebif 44μg: 12 syringes (0.5ml) – £813.21. Rebif 8.8μg and 22μg: 6 (0.2ml) + 6 (0.5ml) pens – £552.19. Rebif 22μg: 12 pens (0.5ml) – £624.77. Rebif 44μg: 12 pens (0.5ml) – £813.21. Rebif 8.8μg/0.1ml and 22μg/0.25ml: 2 cartridges – £406.61. Rebif 22μg/0.5ml: 4 cartridges – £624.77. Rebif 44μg/0.5ml: 4 cartridges – £813.21. For prices in Ireland, consult distributors Allphar Services Ltd. Marketing Authorisation Holder and Numbers Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/98/063/007; 003; 006; 017; 013; 016; 010; 008; 009. For further information contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX. Tel: 020 8818 7373. Republic of Ireland: Merck Serono, 4045 Kingswood Road, Citywest Business Campus, Dublin 24. Tel: 01 4687590.

Date of Preparation July 2010.

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. In the Republic of Ireland information can be found at www.imb.ie.

Adverse events should also be reported to Merck Serono Limited Tel: +44(0)20 8818 7373 or email: medinfo.uk@merckserono.net.

References: 1. PRISMS Study Group. Lancet 1998;352:1498–1504.

2. Kappos L et al. Neurology 2006;67:944–953.

3. Steinberg SC et al. Clin Drug Investig 2010;30(2):89–100.

Date of Preparation: August 2010

REB10–0231

Rebif®: established, effective treatment for people with RRMS1,2 Delivered through innovation to help address adherence Rebif® is available in multidose cartridges for use with the RebiSmart™ electronic autoinjector device Up to 70% of RRMS patients treated with DMDs are non-adherent with therapy*3 RebiSmart™ is the only device in MS which allows adherence to be reviewed

*Retrospective analysis of 1606 RRMS patients treated with interferon-ß-1a (44µg sc tiw or 30µg im qw) or interferon-ß-1b; adherence was defined as a medication possession ratio of ≥85% over a period of 360 days.

RRMS: relapsing–remitting multiple sclerosis. DMD: disease-modifying drug. sc: subcutaneous. tiw: three times weekly. im: intramuscular. qw: once weekly.

Prescribing information can be found overleaf.

Merck Serono is a division of Merck