EPSA Science! Monthly Doping in sport by EPSA

The Science of Doping in Sport August Edition 2021

Introduction Dear readers, In the light of the recent Olympic games in Tokyo, Japan, I am delighted to present to you the August edition of Science! Monthly on Doping in sport. Which techniques are used? What are the reasons for using doping and why we keep finding new cases? These are some of the questions that we are going to answer in this edition of EPSA Science! Monthly. Enjoy reading! This time, I am honored to present to you SAFF. Student’s Association of Faculty of Pharmacy (SAFF) was founded in 1999 and it is a local students association representing students of Faculty of Pharmacy, University of Sarajevo. The team of the Association consists of the Governing Board, which is the Executive, and six committees. We are proud that SAFF is behind a series of successful projects in the field of health, of which we can highlight the national project "Antibiotics – the last line of defense" supported by the World Health Organization, Pharmaceutical & Medical Knowledge Showdown which brought together students of pharmacy and medicine from the region, the Congress Food – Nutrition – Health, which is organized annually in cooperation with other partners and which brings together hundreds of students, and of course, the 17th EPSA Autumn Assembly 2020.

SAFF

Author: Merima Bukva EPSA – European Pharmaceutical Students’ Association

Faster, higher, stronger – at all costs? A brief introduction to the history, present and future of doping in sport Baron Pierre de Coubertin, who "revived" the Ancient Olympic Games, defined sport as "the search for physical beauty and health through a delicate balance of mind and body." However, the Olympic motto "faster, higher, stronger" is inseparable from a desire for better results and represents the very nature of sport – just as there is in human nature the desire to gain an advantage over an opponent, whenever there is a competition. How fast is fast enough and how strong is strong enough and what is allowed to achieve that goal? In ancient times there was no moral doubt about it and anything that could lead to an increase in the ability of competitors was widely accepted. It was recorded in the second century AD that Galen gave gladiators bull testicles to increase their physical fitness, the ephedra extract was used in China 5,000 years ago, while hallucinogenic mushrooms (probably fly agarics) were used at the Ancient Olympic Games.

Image 1. Number of positive tests per every olympic game from 1972 until 2012 (1) A similar attitude was maintained in the second half of the 19th century, when the methods of industrial production were significantly improved, which was accompanied by the tendency to increase the productivity of the working class through hygiene and health. In such environment, drugs and other stumulants are seen in good light: as the ability to improve performance, implement social reforms, and combat physical exhaustion. This is evidenced by the case of Thomas Hicks, who won the 1904 Olympic marathon using strychnine and brandy, and the case of Dorand Pietri, who is said to have used atropine and strychnine during the 1908 marathon at the London Olympics. (2) A similar attitude prevailed during World War II when both the Allies and the Nazis EPSA – European Pharmaceutical Students’ Association

used amphetamines to improve the ability of soldiers, especially pilots. This also had dramatic consequences for sport, especially in the post-war period when amphetamines were available everywhere, primarily from stockpiles left over from the war (3). Anabolic steroids appeared in sports as early as 1945, when the use of methyl testosterone was recorded among bodybuilders from the west coast of the United States, but the real epidemic of abuse began with the discovery of methandrostenolone and its introduction in therapy under the name Dianabol in 1954 (4). Anabolic steroids peaked during the second half of the 1970s and into the 1980s, but are still thought to account for almost half of all drugs abused in sports. Influenced by the public and certain sports circles, the issue of doping has been presented long ago as cheating and a matter of fair play, so the International Olympic Committee put the issue of drug abuse in sports back in 1938, resulting in the establishment of the Medical and Scientific Commission. Despite the fact that even today there are efforts among athletes and coaches to legalize doping (5), a real epidemic of abuse of various drugs and medical procedures (erythropoietin, insulin, growth hormone, autotransfusion) during the 1990s resulted in the founding World AntiDoping Agency (WADA) in 1999. Today it is quite clear that political and financial interests impose the aspiration to win, as well as the fact that even the youngest people are involved in professional sports. It is found easier to manipulate the young, which further emphasizes the role and importance of WADA in promoting health and fair play in sports. New trends, such as the possibility of genetic doping (6), impose additional ethical and health dilemmas, and point to the importance of continuous health promotion and the idea of fair competition in sport, both among amateur and professional competitors.

Author: Magdalena Šober

EPSA – European Pharmaceutical Students’ Association

Anabolic steroids Anabolic steroids are used to increase physical ability and muscle mass. When taken for a long time, in large doses and without medical supervision, they can cause improper and unreasonable behavior and a wide range of side effects. Anabolic steroids are testosterone and all drugs that are chemically and pharmacologically related to it, which lead to an increase in muscle mass. Anabolic steroids have androgenic effects (e.g., changes in hair or libido, aggression) and anabolic effects (e.g., increased protein utilization, changes in muscle mass). Androgenic effects cannot be separated from anabolic ones, but some anabolic steroids with minimal androgenic effects have been synthesized. Estimates of the incidence of lifetime anabolic steroid abuse range from 0.5 to 5% of the population, but subpopulations vary significantly (eg, higher incidence in bodybuilders and competing athletes). Athletes can take steroids for a while, stop, and then start again several times a year (cyclic intake). Intermittent discontinuation of the drug is thought to allow the endogenous testosterone levels, sperm count, and hypothalamic – pituitary – gonadal axis to return to normal. Oral evidence suggests that cyclic administration may reduce adverse effects and the need to increase the amount of drug to achieve the desired effect. (7)

Image 2. Weightlifting Athletes often take multiple medications at the same time (called accumulation) and change the routes of administration (oral, IM, or transdermal). Increasing the dose during the cycle (pyramidal intake) can lead to doses that are 5 to 100 times higher than the EPSA – European Pharmaceutical Students’ Association

physiological one. The purpose of accumulation and pyramid uptake is to increase receptor binding and to reduce side effects, but these beneficial effects have not been proven. (8)

Benefits and side effects: The most characteristic sign is a rapid increase in muscle mass. The rate and severity of the increase were directly related to the doses taken. Patients taking physiological doses will show a slow and often inconspicuous increase, those taking mega doses can increase lean body (muscle) mass and a few kilograms per month. There is also an increase in energy levels and libido (in men), but they are harder to detect. Psychological effects (usually only at very high doses) are often observed by the family: strong and irregular mood swings, irrational behavior, increased aggression, irritability, increased libido and depression. Frequent complaints are increased acne and gynecomastia, as well as masculinizing effects in women. Some of these effects (e.g., alopecia, clitoral enlargement, hirsutism, deepening of the voice) may be irreversible. In addition, breast volume may be reduced; the vaginal mucosa may atrophy; menstruation may change or stop; libido may increase or, less frequently, decrease and aggression and appetite may increase. (9)

Author: Amar Alagić

EPSA – European Pharmaceutical Students’ Association

Blood doping You might have heard of doping in competitive sports by using performance–enhancing drugs, usually steroids and central nervous system stimulants, but have you ever come across the term ''blood doping''? The World Anti–Doping Agency (WADA) refers to it as “the misuse of certain techniques and/or substances to increase one’s red blood cell mass, which allows the body to transport more oxygen to muscles and therefore increase stamina and performance’’.

Image 3. Cycling Namely, the oxygen delivery to skeletal muscles, which is necessary for their activity, is directly connected to the oxygen carrying capacity of the blood. This is especially important in aerobic sports such as running, cycling or skiing. All the way back in 1972, it had been demonstrated that drawing and then re-infusing a person's blood increases red cells, therefore facilitates physical activity. In this study, 1200 mL of blood was taken from athletes and they continued to exercise in a low–blood–volume state. Next, their blood was re–infused prior to repeating the exercise. After the re–infusion, thanks to the hemoglobin from the taken blood, their exercise to exhaustion time increased by 25%. This way, through the augmentation of the oxygen–carrying capacity of the blood, athletic performance was improved. After a number of scandals at the 1972 Munich Olympic and 1984 Los Angeles Games, where athletes were found to be using foreign blood in addition to their own, International Olympic Committee Medical and Scientific Commission (IOC-MC) prohibited blood doping in 1986, with first homologous blood doping tests approved at the 1994 Winter Games in Lillehammer. This test, besides ABO EPSA – European Pharmaceutical Students’ Association

and Rh groups, used 8 additional blood group factors. In 2004, a new test which used flow cytometry to determine foreign erythrocytes was developed and used in Athens. In the late 80s, after the recombinant human erythropoietin (rHuEPO) was manufactured to assist people with renal failure, athletes, especially cyclists, took this compound as a superior alternative. Total hemoglobin mass is important for the determination of aerobic power and erythropoietin promotes the production of red cells, therefore their protein - hemoglobin. A research had been conducted in 1990 in which six week treatment with rHuEPO resulted in increase of the work time to exhaustion of 14 examinees by 15.7%, in comparison to blood infusion which increased it by 10.8%, whereas results for maximal oxygen uptake (VO2max) were 10.7% and 10.8%, respectively. Therefore, it has been proven that rHuEPO was as effective as a blood re–infusion, but it showed its effects more slowly. The first generation rHuEPO has a short half–life and therefore requires more frequent dosing. Second generation Darbepoetin alfa has a three times longer half–life and increased activity, but since it can be detected in a longer period of time, it is not as appealing to athletes. Even though IOC–MC prohibited erythropoietin immediately, first tests were not available until the 2000 Games in Sydney. Here, two tests were utilized – a urine test which was based on isoelectric focusing method, and an ONscore blood test which analyzed five blood parameters. In Beijing 2008, tests were based on the determination of continuous erythropoietin receptor activator (CERA). Probably the most famous case of blood–doping, which was widely covered in the media, is a Lance Armstrong case. As a former professional road racing cyclist, Armstrong was stripped of his seven Tour de France titles as a result of an investigation and finally a confession of using performance-enhancing drugs and blood transfusions, as well as the rHuEPO and its derivatives.

Author: Merima Bukva EPSA – European Pharmaceutical Students’ Association

Beta–blockers and alcohol Beta–blockers and doping The use of beta–blockers in endurance sports leads to a decrease in physical capacity since beta–blockers negatively affect hemodynamics and metabolism. However, when it comes to sports which require besides moderate endurance also high psychological readiness, they lead to an increase in physical capacity and a reduction in the stress caused by the competition itself. A significant decrease in heart rate, a moderate decrease in blood pressure, as well as a decrease in the number of extrasystoles that occur occasionally have been reported with the use of beta–blockers in sports. Studies comparing the effects of beta–blockers in the context of doping in different sports have shown that beta–blockers decrease stress and therefore increase performance, for example: bob runners and sport shooters. The effects were opposite in ski and parachute jumpers. (18, 19) So, should beta–blockers be considered “doping”? The answer is – yes. Since they are capable of increasing physical capacity, they should be considered doping. According to WADA, they are prohibited in the following sports: archery, automobile, billiards (all disciplines), darts, golf, shooting, skiing/snowboarding, and underwater sports. However, the use of beta–blockers should be regulated by Therapeutic Use Exemption Committees when it comes to the justified therapeutic use of beta–blockers in these sports, which often represents a challenge for the committees. (20)

Image 4. Archery EPSA – European Pharmaceutical Students’ Association

A methodological approach that has been shown to be effective in proving the presence of beta-blockers is the screening of urine samples using gas chromatography, both for beta–blockers and their metabolites. (21)

Alcohol and doping The harmful effects of alcohol on human physiology have been well studied and relate to neural function, metabolism, cardiovascular physiology, thermoregulation, and skeletal and muscular myopathy. Nevertheless, opinions on the impact of alcohol on exercise and sports performance remain contradictory. Although it reduces performance, alcohol can lead to a reduction of pain and anxiety. Therefore alcohol affects performance depending on the type and dose of alcohol, whether it is acute or chronic use, as well as the degree of elimination of alcohol from the body and the type of exercise/sport. Alcohol can also be a source of energy. (22, 23) It has a low impact on strength. At high doses, it negatively affects the functions of the central nervous system, reducing cognitive and motor functions, and changes in behavior can have effects on the performance itself. The effects can last for hours after intoxication. (24) In 2017, WADA removed alcohol from the list of prohibited substances, but a new rule from January 2021 prohibits drinking alcohol before doping tests again. The main reason for this is that alcohol can interfere with analytical procedures and thus lead to erroneous results in doping analyzes (25, 26). One study from the 1980s, conducted by World Archery implies that performance in some sports can be increased by the use of alcohol. Given this research, WADA believes that there is not enough evidence to confirm or disprove it (27, 28). Although WADA didn't prohibit alcohol between 2018 and January 2021, when it comes to professional archery, it was banned all the time (28).

Author: Amina Hrnčić EPSA – European Pharmaceutical Students’ Association

Insulin There is only vague information about the use of insulin by professional athletes, and most of it is anecdotal. The first suggestions of insulin as an anabolic agent were published in two bodybuilding magazines in 1996. After concerns raised by the medical officer at the Nagano Olympic Games, the International Olympic Committee immediately banned its use in those without diabetes. One case reports that three units of the fast-acting insulin lispro were injected immediately after the workout sessions together with a glucose and protein drink with the purpose of replenishing glycogen and adenosine triphosphate (ATP) quickly and promoting protein synthesis and muscle growth. It is alleged that short–acting insulin is being used in a haphazard way to increase muscle bulk in body builders, weight lifters and power lifters. Insulin is a 51 amino acid peptide hormone comprising two polypeptide chains linked by disulphide bridges, which is synthesized and secreted in a coordinated pulsatile fashion from the beta–cells of the islets of Langerhans into the portal vein. Glucose is the principal stimulus for insulin secretion, although other macronutrients, hormonal and neuronal factors also may alter this response. Although it is known that insulin’s main role is regulating blood levels of glucose, it also affects protein and fat metabolism, which makes it a pivotal hormone regulating cellular energy supply and macronutrient balance. The major insulin-sensitive tissues are the liver, skeletal muscle, and adipose tissue. Insulin inhibits gluconeogenesis and promotes glycogen storage. In muscle cells, it enables glycogen to be synthesized and stored, and carbohydrates to be utilized as the immediate available energy source for muscle contraction. The use of insulin after an exercise may replenish glycogen and ATP stores more quickly. Insulin promotes the storage of lipids and suppresses adipose tissue fat breakdown. It increases the rate of lipogenesis in adipose tissue and the liver and controls the formation and storage of triglyceride. While insulin stimulates the uptake of amino acid into cells and promotes protein synthesis, the major action of insulin is to inhibit the breakdown of proteins, which occurs at lower insulin concentrations. The adverse effects of insulin are well documented from experience in treating people with diabetes. The most commonly experienced adverse effect is hypoglycemia. Weight gain is also a problem in people with diabetes, but this is probably less of an issue for athletes whose diet and training program are strictly controlled. Although there are commercially available insulin assays, which cannot differentiate between endogenous and exogenous insulin. Insulin is an unstable substance, and the results may also be negatively affected by hemolysis or the presence of circulating antiinsulin antibodies. Although no test is available to detect human insulin, there are mass spectrometry methods for both blood and urine that can detect insulin analogs, which have been designed to alter their pharmacokinetics by genetic modification of human insulin, thus can be used to differentiate them from endogenous insulin.

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One of the famous scandals that occurred is related to Conte, who personally provided some athletes, including Marion Jones with insulin and other peptide hormones (EPO and GH). The other big scandal comes from Spain, in which 200 high–profile athletes, including Tyler Hamilton and Alberto Contador were using insulin, provided by dr. Fuentes, which suggests that most doping regimens were carefully designed. The trial has been ongoing since May 2006, and as doping is not a criminal offense in Spain, it is unlikely that the case will result in a prosecution.

Image 5. Swimming

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Growth hormone Growth hormone (GH), also known as somatotropin, is a protein-type hormone that is responsible for numerous physiologic processes, such as skeletal and organ growth, calcium homeostasis, lipolysis, and the regulation of lean body mass. Its external effects on muscular mass and other systems have made it a target of abuse in the sporting world. The outcomes of GH supplementation in athletes are visible in four of the most common measures of physical performance: strength, power, endurance, and sprint capacity. While long-term replacement of GH normalizes muscle strength in adults with GH deficiency who have reduced isometric and isokinetic muscle strength, there was no significant effect of GH on muscle strength in healthy individuals. The finding of higher lactate concentrations in people undergoing evaluation of physical capacity after GH treatment provides evidence that the anaerobic energy system is stimulated by GH. GH treatment significantly improves sprint capacity without affecting muscle strength or aerobic capacity. While some previous studies report that GH treatment did not improve muscle strength or endurance, the collective evidence indicates that GH exerts a selective ergogenic effect on sprint capacity. Overall, external GH leads to increased lean body mass and bone density (although bone density may be reduced in the beginning) and decreases total body fat. It also improves maximal oxygen uptake, ventilatory threshold, and maximal power output. HGH abuse is a known problem within the sporting world, even at the pediatric level. 5% of high school athletes and 24% of community gym members report abusing HGH, while 12% of male weightlifters abuse HGH or IGF–1. In sports, especially baseball, this hormone is also abused, as investigation into PED use in Major League Baseball in 2007 showed numerous professional baseball players linked to HGH. Excessive use of GH may lead to acromegaly, which is basically bony overgrowth. Initial symptoms are vision changes or headache, abnormal bone growth in the face, macroglossia, or sleep apnea due to airway soft tissue hypertrophy. Water retention and resulting tissue edema may lead to neurological disorders. It also may lead to diabetes mellitus and lipid disorders. Heart disorders are also common. Acromegaly also increases the risk of colon and thyroid cancers. Detecting GH abuse is not easy because: 1. External GH has a structure identical to native GH. 2. GH has a short half–life (approximately 4 hours after subcutaneous injection and 22 minutes after intravenous injection). 3. GH is secreted in a pulsatile fashion. 4. Exercise and stress are potent stimulators of GH secretion, which can lead to false positive results.

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Most testing protocols use the “isoform” blood testing strategy, which revolts around the fact that external GH, although structurally identical to 22–kDa endogenous GH, suppresses pituitary secretion of other isoforms, leading to increase of the ratio of the 22–kDa isoform to other size isoforms. Alternative method is biomarker strategy, which does not measure GH, but other substances that are affected by GH, which are IGF–1 and procollagen type III amino–terminal propeptide (P–III–NP). The upside of this method is that IGF–1 and P–III–NP have longer serum half–lives, which means you can detect them even after 7 days. Vitamin D binding protein is suppressed by GH and remains intact during the washout phase and may prove to be of value. Novel biomarkers include Diacorin (a myokine), FN gene, FN protein, RAB gene and RAB protein. However, it is still to be tested if these biomarkers show better results than IGF–1 and P–III–NP.

Author: Faruk Šehić

EPSA – European Pharmaceutical Students’ Association

What are diuretics? Diuretics are substances used to excrete water from our body through the urinary tract. They help release sodium from our kidneys into our urine, that way decreasing the level of water in your bloodstream. They are most often used in the treatment of high blood pressure. Their use reduces the level of water in the blood vessels and thus reduces blood pressure. In addition to that, they can also be used to treat other conditions such as edema, congestive heart failure, etc. Diuretics have been on the IOC's (International Olympic Committee) list of banned substances since 1985 when a large number of athletes were punished for abusing them. According to official WADA data, in the period from 2003 to 2012, diuretics were present in a large number of cases as doping. The most used one was furosemide, followed by hydrochlorothiazide.

Types of diuretics There are 3 main groups of Diuretics: 1. Thiazide diuretics – are used for managing primary hypertension, adjunctive therapy in edema that is associated with chronic heart failure (CHF), and estrogen therapy. 2. Loop diuretics – used to treat and manage heart failure, nephrotic syndrome or cirrhosis, and hypertension in addition to edema. 3. Potassium–sparing diuretics – diuretic effects, without losing potassium from your body. They are generally considered weak diuretics and are often combined with other drugs.

Doping in sports Diuretics are used as a doping substance for two main reasons: 1. To quickly reduce the weight of athletes in sports with weight categories, such as wrestling sports, weightlifting, bodybuilding, jockeys, etc. To achieve this effect, most widely used are drugs such as furosemide, bumetanide, spironolactone, and ethacrynic acid. Health problems can occur if large amounts are taken in a very short time. 2. To speed up the excretion of some other substances from the body (usually banned, mostly anabolic steroids). By increasing the volume of urine, diuretics lead to dilution of urine, i.e. a decrease in the concentration of prohibited substances and their metabolites, which makes it difficult to determine them by conventional methods.z EPSA – European Pharmaceutical Students’ Association

There is a link between the use of diuretics and increased physical activity. Diuretics have different effects on the physiology of exercises, such as metabolism (thermoregulation, potassium homeostasis), CVD, and the respiratory system. Most of the effects are due to the reduction of the volume of blood and other fluids in the body, as well as the reduction and imbalance of the electrolyte balance. Abuse of diuretics with increased physical exertion can lead to exhaustion, heart rhythm disorders, heart attack, and even death due to dehydration and hyperthermia. Hypokalemia, except with the use of potassium–sparing diuretics, can lead to muscle cramps and cardiac arrhythmias. Most diuretics also affect the metabolism of uric acid, which can lead to gout.

Image 6. Running

Side effects Side effects of diuretic abuse are: • • • • • • •

Hyponatremia; Hypo or hyperkalemia; Acid–base status disorder; Disorder of calcium and magnesium metabolism; Metabolic disorders (insulin resistance, dyslipidemia, hyperuricemia, androgenic effects); Ototoxicity; Allergic interstitial nephritis etc.

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Most famous doping scandals involving diuretics: Veronica Campbell–Brown – Jamaican athlete Anderson Luiz de Sousa (Deco) – Portuguese football player Ivan Ivanov – Bulgarian weightlifter Shane Warne – Australian cricket player Ben Johnson – Canadian sprinter

Author: Emina Gutošić

EPSA – European Pharmaceutical Students’ Association

Conclusion Although stimulants for improving performance in sports are now banned in almost all parts of the world, their use was once not only allowed, but also desirable. What led to the ban on their use? Doping is performed with substances of different origin and complexity, starting from simple examples such as ethanol, to complex steroid and hormone molecules and it doesn't stop there. In the past few years’ considerable progress regarding the knowledge of the human genome map has been achieved. As a result, attempts to use gene therapy in patient’s management are more and more often undertaken. In vitro studies improve the production of human recombinant proteins, such as insulin (INS), growth hormone (GH), insulin-like growth factor-1 (IGF-1) and erythropoietin (EPO), which could have therapeutic application, but are being progressively used in competitive sports to increase muscle mass, strength, endurance, mental fitness, aerobic strength, rapid weight loss etc. (41) Since the possibility of eradicating such doping is almost zero, mainly because gene therapy is advancing rapidly, this type of doping is almost guaranteed to be used in the near and distant future. (42) When we look at things this way, we think that the use of such stimulants is actually very useful and productive. However, the problem arises when side effects begin to occur. Some of them are transient and unconcerning, but some can also be very frightening. Thus, for example, abuse of growth hormone can lead to macroglossia (enlargement of the tongue), enlargement of facial bones or diabetes mellitus, and abuse of diuretics can lead to heart rhythm disorders, heart attacks or even death. Shocking, isn't it? There are rapid analytical tests for most doping – substances that detect them in samples in a relatively short period of time, but for some of them, such as insulin, it is still a big challenge. When we talk about it, it is clear that pharmacists are performing on the stage! Possessing a wide range of knowledge in chemistry and medicine, they can and do make an outstanding contribution to doping control. The Japanese Ministry of Education, Culture, Sports, Science and Technology formulated anti-doping guidelines in Japan in 2007, stating that doctors and pharmacists should be proactive in anti-doping activities, believing that pharmacists can provide support by giving drug information, counseling, database development and also by regulating the exemption for therapeutic use! (43) In order to enable even greater implementation of pharmacists in these streams, it is necessary to improve their education on this topic, which includes education on performance-enhancing substances and testing technologies, preparation and holding of presentations to athletes and the public, conducting research on literature on drugs and supplements, diets used to improve athletic performance, writing monographs on these substances, and participating in doping control programs. (44)

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Fun fact: At the Faculty of Pharmacy in Sarajevo in 1983 the Doping Control Laboratory was established, which during the XIV Winter Olympic Games, but also at other international competitions after that, carried out the control of drug abuse by athletes. In 1984, the Laboratory at the Faculty of Pharmacy of the University of Sarajevo was the tenth of its kind in the world to be accredited by the International Olympic Committee and the International Amateur Athletics Federation (IAAF). This is certainly one of the extremely valuable examples of implementation in local, but also global doping control flows! Don't you agree? ☺

Author: Berina Bajrić

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Image 7: Prof. dr. Arnold Beckett, member of the IOC Medical Committee with members of the doping laboratory

Image 8: Olimpic Doping control laboratory at Faculty of Pharmacy in Sarajevo

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Image 9: Olympic Doping control laboratory at Faculty of Pharmacy in Sarajevo

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f. Ekblom B, Berglund B. Effect of erythropoietin administration on mammal aerobic power. Scand J Med Sci Sport 1991;1:88-93. g. Jelkmann W, Lundby C. Blood doping and its detection. Blood. 2011;118(9):2395-404. h. Macur J. Cycle of Lies: The Fall of Lance Armstrong. HarperCollins, US. 2014. 4. Beta–blockers and alcohol a. Schmid P. Der Einsatz von Beta-Rezeptoren-blockern im Leistungssport [Use of beta receptor blockers in performance sports]. Wien Med Wochenschr. 1990;140(6-7):184-8. German. b. Tesch PA. Exercise performance and beta-blockade. Sports Med. 1985;2(6):389-412. c. TUE Physician Guidelines Medical Information to Support the Decisions of TUECs, CARDIOVASCULAR CONDITIONS: THE THERAPEUTIC USE OF BETABLOCKERS IN ATHLETES, WADA- World Anti-Doping Program 15 Version 1.1, 2015 (https://www.wada-ama.org/sites/default/files/resources/files/wada-tpgcardiovascular_conditions-1.1.pdf). d. Hemmersbach P, de la Torre R. Stimulants, narcotics and beta-blockers: 25 years of development in analytical techniques for doping control. J Chromatogr B Biomed Appl. 1996;687(1):221-38. e. Shirreffs SM, Maughan RJ. The effect of alcohol on athletic performance. Curr Sports Med Rep. 2006;5(4):192-6. f. Suter PM, Schutz Y. The effect of exercise, alcohol or both combined on health and physical performance. Int J Obes (Lond). 2008;32 Suppl 6:S48-52. g. Vella LD, Cameron-Smith D. Alcohol, athletic performance and recovery. Nutrients. 2010;2(8):781-9. h. Prohibited List. The World Anti-Doping Code. International Standard. [Online]. Available at: https://www.antidoping.sk/data/files/234_prohibited_list_2018_en.pdf. i. 2021 World Anti-Doping Code and International Standard Framework. World Anti-Doping Agency. [Online]. Available at: Development and Implementation Guide for Stakeholders https://www.wadaama.org/sites/default/files/resources/files/worldconferencebackgrounder_0.pdf. j. Reilly T, Halliday F. Influence of alcohol ingestion on tasks related to archery. J Hum Ergol (Tokyo). 1985;14(2):99-104. k. Official interpretation clarifies in-competition alcohol ban for athletes . World Archery. [Online]. Available at: https://worldarchery.sport/news/167414/officialinterpretation-clarifies-competition-alcohol-ban-athletes. 5. Insulin a. Anderson LJ, Tamayose JM, Garcia JM. Use of growth hormone, IGF-I, and insulin for anabolic purpose: Pharmacological basis, methods of detection, and adverse effects. Mol Cell Endocrinol. 2018;464:65-74. b. Erotokritou-Mulligan I, Holt RI. Insulin-like growth factor I and insulin and their abuse in sport. Endocrinol Metab Clin North Am. 2010;39(1):33-43. c. Holt RI, Sönksen PH. Growth hormone, IGF-I and insulin and their abuse in sport. Br J Pharmacol. 2008;154(3):542-56. EPSA – European Pharmaceutical Students’ Association

6. Growth hormone a. Holt RIG, Ho KKY. The Use and Abuse of Growth Hormone in Sports. Endocr Rev. 2019;40(4):1163-1185. b. Siebert DM, Rao AL. The Use and Abuse of Human Growth Hormone in Sports. Sports Health. 2018;10(5):419-426. 7. What are diuretics? a. Zimmerman HJ. Diuretic drugs. Drugs used in cardiovascular disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott. 1999;662-4. b. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Online]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases;2012–. c. Akbari P, Khorasani-Zadeh A. Thiazide Diuretics. 2021 Jul 13. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;2021. d. Huxel C, Raja A, Ollivierre-Lawrence MD. Loop Diuretics. 2021 May 25. In: StatPearls [Online]. Treasure Island (FL): StatPearls Publishing;2021. e. Cadwallader AB, de la Torre X, Tieri A; The abuse of diuretics as performanceenhancing drugs and masking agents in sport doping: pharmacology, toxicology and analysis; Br J Pharmacol., 2010;161(1):1-16. f. Diuretics and masking agents. World Anti-Doping Agency. [Online]. Available at: https://www.wada-ama.org/en/content/what-is-prohibited/prohibited-at-alltimes/diuretics-and-masking-agents. g. Fight against doping Prohibited substances. Diuretics - “Furosemide. FEDERATION INTERNATIONALE DE GYMNASTIQUE. [Online]. Available at: https://www.gymnastics.sport/site/pages/medical/Medical-doc-lutte_antidopage_diuretiques-furosemide-e.pdf. 8. Conclusion a. Brzeziańska E, Domańska D, Jegier A. Gene doping in sport - perspectives and risks. Biol Sport. 2014;31(4):251-9. b. Cantelmo RA, da Silva AP, Mendes-Junior CT, Dorta DJ. Gene doping: Present and future. Eur J Sport Sci. 2020;20(8):1093-1101. c. Kasashi K. [Anti-doping reference for pharmacists]. Yakugaku Zasshi. 2009;129(12):1475-81. Japanese. d. Ambrose PJ. Educational opportunities and anti-doping roles and responsibilities for pharmacists. Yakugaku Zasshi. 2011;131(12):1761-4.

Images: a. Image 1: http://gsnider.blogspot.com/2015/11/doping-athletics-andolympics.html b. Image 2: https://www.freepik.com/free-photo/man-training-withweightlifting_9196950.htm#page=1&query=weightlifting&position=28 c. Image 3: https://www.freepik.com/free-photo/cyclist-byciclerace_11343802.htm#page=1&query=cycling%20competition&position=9 d. Image 4: https://www.freepik.com/photos/arrow EPSA – European Pharmaceutical Students’ Association

e. Image 5: https://www.pexels.com/photo/water-swimming-competition-pool73760/ f. Image 6: https://www.pexels.com/photo/photo-of-people-in-a-marathon2654902/ g. Image 7, 8, 9: Original images from the Faculty of Pharmacy, University of Sarajevo. Marjanović A., Omeragić E., Đeđibegović J., Šober M. History of Olimpic Doping control laboratory at Faculty of Pharmacy in Sarajevo, Faculty of Pharmacy, University of Sarajevo.

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