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in sport and exercise


									How to Treat            Pull-out section                                                                                
 EARN CPD POINTS Complete How to Treat quizzes online ( or in every issue – see page 30.

                                                                                                                                                                      Prescribing for
                                                                                                                                                                      the sports patient

                                                                                                                                                                      Drugs used to
                                                                                                                                                                      enhance sporting

                                                                                                                                                                      How drug abuse
                                                                                                                                                                      problems may

                                                                                                                                                                      Ethics of

                                                                                                                                                                      The future of
                                                                                                                                                                      drugs in sport

                                                                                                                                                                     The author

                                                                                                                                                                     DR MICHAEL KENNEDY,
                                                                                                                                                                     consultant physician and
                                                                                                                                                                     clinical pharmacologist in
                                                                                                                                                                     private practice; VMO at Manly

                                                                                                                                                                     Hospital and Mater Hospital,
                                                                                                                                                                     North Sydney; and research
                                                                                                                                                                     associate, department of clinical
                                                                                                                                                                     pharmacology and toxicology,
                                                                                                                                                                     St Vincent’s Hospital,
                                                                                                                                                                     Darlinghurst, NSW.

   in sport and exercise
MEDICAL practitioners may                                                                                                 mended, such as avoiding injecting into
become involved in the area of med-                Table 1: Clinically important drug exercise interactions               the site of working muscle by changing
ication in sport in various ways. As                                                                                      injection sites, lowering insulin dose
doctors we are often expected to         Drug                             Exercise effect                                 and ensuring adequate glucose is taken
know almost everything about drugs,      Insulin                          Increases absorption                            or available during exercise.
so a frequent question for the doctor
will be about the safety and efficacy    Lithium                          Increases plasma concentration                  Drug distribution
of medications used by athletes.         Transdermal nitrates             Increases absorption                            Alterations in drug distribution
  GPs may manage sports patients                                                                                          throughout the body as a result of
who present with symptoms that are       Warfarin                         Decreases INR                                   exercise have been studied in only a
potentially drug related, or they may    Theophylline                     Increases plasma concentration and extends      few drugs. An increase in distribution
be asked to advise patients about the                                     half-life                                       of digoxin results in highly significant
effects of a prescribed or comple-                                                                                        reductions in plasma concentrations
mentary therapy on sporting perfor-     oxygen used per kilogram of body         tion of transdermal nitrates and         because of increased binding to stri-
mance. Less frequently there may be     weight per minute exercising), gastric   insulin is increased during exercise.    ated muscle. However, the concentra-
a request to prescribe a drug to        emptying is slowed and at this level     In one study of the absorption rates     tions return to pre-exercise levels one
enhance performance.                    of intensity there will be delayed       of insulin from the arm, abdomen         hour after exercise.
                                        absorption of drugs.                     and leg in 11 subjects with type 1          The clinical significance of this is
Effect of exercise on                     Studies of a six-week exercise pro-    diabetes during and after four con-      uncertain and a 16-week exercise
pharmacokinetics                        gram have demonstrated increases in      secutive periods of cycling, there was   program was found to have no effect
Absorption                              small bowel transit time, so in some     increased absorption from the leg.1      on the kinetics of digoxin when con-
Low levels of exercise have little      cases, such as with slow-release for-    Such effects are clearly of clinical     centrations were studied in patients at
effect on gastric emptying but when     mulations, drug absorption may be        importance.                              rest.
exercise reaches 70% of maximum,        impaired.                                   Strategies to prevent hypoglycaemia      Although some small decreases in
that is, 70% VO2 max (the amount of       Cutaneous blood flow and absorp-       from these kinds of effects are recom-                          cont’d next page

                                                                                                                         14 January 2005 | Australian Doctor |      23
 How to treat - medication in sport and exercise

 from previous page                          Drug metabolism                      In a study of 21 patients receiv-       ance of diazepam was unaffected            studies on this.
 the volume of distribution, with                                               ing propranolol 80-320mg/day,             by exercise.1
 resulting rises in plasma concentra-
                                             occurs in many                     exercise resulted in the plasma             Renal blood flow falls from              Therapeutic index
 tions, have been found in the cases         organs but                         concentrations rising 13-41% but          1.1L/min at rest to 0.9L/min               Theophylline is a drug with a low
 of atropine, theophylline, salbuta-         principally through                falling to pre-exercise values on         during moderate exercise and               therapeutic index. With exercise
 mol, oxprenolol and verapamil,              the liver.                         recovery.1 Long-term exercise does        0.6L/min in extreme exercise.              its volume of distribution decreases
 these are not likely to be of clinical                                         not alter the kinetics of propra-           Atenolol, a beta blocker, is             but its half-life increases from 6.5
 importance.                                                                    nolol at rest.                            largely eliminated by renal mecha-         hours to up to 7.2 hours.
                                                                                  The pharmacokinetics of                 nisms. When 100mg atenolol was                This finding can be important
 Metabolism                                                                     carvedilol (Dilatrend, Kredex), a         administered to 12 healthy sub-            because changes in half-life may
 Drug metabolism occurs in many                                                 beta-blocking agent with high first-      jects, exercise was found to               increase the risk of toxicity.
 organs but principally through the                                             pass metabolism, were unaffected          decrease renal clearance by 8% in             Warfarin is widely used and has a
 liver. Hepatic blood flow falls                                                by exercise in one study of 11            one study, 1 and in another the            low therapeutic index. While there
 from a normal value of 1.35L/min                                               patients with hypertension.1              plasma concentrations rose 9%              have not been any pharmacokinetic
 to 0.6L/min during medium-level                                                  Hepatic drug metabolism is              after exercise.1                           studies carried out during exercise, a
 exercise and to 0.3L/min during                                                unaffected by short episodes of             Lithium, which is also elimi-            two-to-threefold increase in overall
 extreme exercise. It would thus be                                             exercise, but physical conditioning       nated by the kidneys, would also           walking distance has been shown to
 expected that drugs with high                                                  has been shown to increase the            be expected to have considerable           decrease INR values, hence the need
 hepatic extraction ratios would                                                clearance of phenazone, a marker          variations in its plasma concentra-        to carefully monitor such patients
 have decreased clearance during                                                of drug metabolism. In one of the         tions in endurance exercise,               when instituting an exercise pro-
 exercise.                                                                      few studies in this field, the clear-     although there are no specific             gram (see table 1, previous page).

     Prescribing for the sports patient
 IN the past, sporting activity was largely the domain of the                                                                           Diuretics                           Lipid-lowering agents
 young and fit. The situation is now very different, with almost all                                                                    Diuretics are used alone and        These are one of the best
 age groups taking part in exercise or sporting activity.                                                                               in combination formulations         examples of a medication
    Today exercise is recommended as part of the management of                                                                          for the management of hyper-        prescribed as a primary pre-
 various medical conditions and even athletes with severe dis-                                                                          tension and heart failure.          ventive agent and taken for
 abilities such as paraplegia may take part in endurance sports.                                                                        They are also often used to         many years by many people
    With the current emphasis on drug-related prevention and                                                                            ‘make weight’ in some sports        who are physiologically
 management of diseases, many patients participating in sport or                                                                        such as weightlifting and           normal.
 exercise will be taking medications such as lipid-lowering agents,                                                                     boxing, and can lead to severe         It is well recognised that
 antihypertensives, psychotropic agents or contraceptive med-                                                                           dehydration resulting in syn-       3-hydroxy-3-methylglutaryl
 ications. They may be taking one or more prescribed medications                                                                        cope.                               coenzyme A (HMG CoA)
 and possibly one or two complementary therapies.                                                                                          When used for the treat-         reductase inhibitors cause
    Despite the many medications consumed, there are surprisingly                                                                       ment of hypertension there is       myositis and even rhabdomy-
 few data about their effects on sporting performance. There are                                                                        an initial decrease in plasma       olysis in a small percentage
 several reasons for this. For example, pharmaceutical companies                                                                        volume, which usually returns       of patients. However, drug-
 usually do not see the need for such studies in ‘normal’ subjects                                                                      to normal. The therapeutic          related rhabdomyolysis as a
 and any adverse finding would have a negative effect on a prod-                                                                        effects are largely mediated by     result of exercise combined
 uct’s marketing profile. Such studies are also usually have a low                                                                      actions on the peripheral cir-      with use of HMG CoA
 priority for grant-allocating bodies.                                                                                                  culation.                           reductase inhibitors has not
                                                                                                                                           Studies in athletes show         been reported.
 Cardiovascular drugs                                                                                                                   frusemide 40mg has little              Exercise results in a rise in
 Nitrates                                                                                                                               effect on VO2 max, but higher       creatine kinase level, which
 All nitrates relax smooth muscle and hence decrease cardiac                                                                            doses have an adverse reac-         may be more prolonged in
 preload. In patients with ischaemic heart disease, nitrates increase                                                                   tion profile greater than           users of these agents. Such ele-
 treadmill time. There is also increased absorption of medication                                                                       would be expected from dehy-        vations, while infrequent, have
 from transdermal patches during exercise.                                                                                              dration alone.                      also been reported in associa-
    Patients using nitrates should be made aware of the possibility                                                                        The carbonic anhydrase           tion with the use of some of
 of adverse reactions such as dizziness or presyncope during                                                                            inhibitor acetazolamide is          the newer antipsychotic agents
 exercise. Patients with coronary disease undertaking exercise                                                                          used to prevent some of the         such as olanzapine and cloza-
 should also be advised about the possibility of syncope when                                                                           medical complications               pine (see next page).
 using sublingual or aerosol preparations, and also of the need to                                                                      associated with high alti-             At this time it is not possi-
 sit down when using a nitrate formulation to relieve angina.                                                                           tudes. It causes a decrease         ble to implicate any specific
                                                                                                                                        in exercise endurance, pos-         agents, so an association
 ACE inhibitors and angiotensin-II-receptor antagonists                                                                                 sibly because of mild acido-        should be considered in cases
 ACE inhibitors vary in their pharmacokinetic profiles and tissue                                                                       sis inhibiting muscle glycol-       in which any of these drugs is
 binding. While there are differing claims about the efficacy of                                                                        ysis.                               being administered and there
 individual agents, there is no doubt about their ability to improve    Most patients                  Most patients undertaking           Diuretics are sometimes          are clinical symptoms.
 exercise levels in patients with heart failure.                                                    exercise in cardiac rehabilita-     prescribed by doctors to               Clearly, elevations greater
    There are several exercise studies in both hypertensive and nor-    undertaking                 tion programs will find beta        avoid anabolic-steroid-             than three times the upper
 motensive subjects using treadmill and stationary exercise bike        exercise in cardiac         blockers do not hinder their        related oedema but more             limit of the reference range
 protocols. When compared with placebo there is no change in            rehabilitation              progress. Apart from those          often they are taken by             persisting for several days
 either VO2 max or lactate threshold on various exercise-related                                    who develop bronchospasm,           steroid users without medical       after exercise has stopped
                                                                        programs will               the most common adverse             advice. Diuretics of any type       need to be considered as drug
    There is a slight attenuation in the peak level of blood pres-      find beta blockers          reaction experienced is fatigue.    are banned in various sports,       rather than sport related.
 sure. Some reports of decreased endurance with one agent have          do not hinder                                                   because they are used as            There is no indication for
 yet to be confirmed with other similar studies.                        their progress.             Calcium-channel blockers            masking agents.                     routine testing unless there is
    Angiotensin-II-receptor antagonists have clinical profiles and                                  These fall into two broad cat-         Many steroid abusers are         a reasonable clinical indica-
 haemodynamic actions similar to those of ACE inhibitors.                                           egories — those decreasing          aware of potassium loss that        tion.
                                                                                                    AV conduction (verapamil,           occurs with diuretics and take         The bile-acid-binding resins
 Beta blockers                                                                                      diltiazem) and the dihydropy-       supplements. They sometimes         cholestyramine and colestid
 These agents can be classified by their lipid solubility, beta1                                    ridines (nifedipine, felodipine,    co-administer spironolactone,       are hydrophilic and cause
 selectivity, partial agonist activity or partial alpha-blocking                                    amlodipine, lercanidipine)          which can result in lethal          constipation. It is therefore
 actions. Extensive studies evaluating their effects on exercise                                    which have no effect on AV          hyperkalaemia.                      essential to ensure adequate
 performance have shown:                                                                            conduction.                                                             hydration in people who exer-
 ■ Attenuation of exercise-related tachycardia.                                                        All members of this group        Digoxin                             cise and take these medica-
 ■ Decreased negative effect on cardiac output with increasing                                      increase the threshold at which     Cardiac glycosides increase         tions.
   stroke volume.                                                                                   angina occurs. The maximum          cardiac output in patients with        The fibric-acid derivatives
 ■ Decreased VO2 max (greater effect in trained patients).                                          heart rate reached with exer-       cardiac failure. They do not        gemfibrozil, clofibrate and
 ■ Increased sense of fatigue.                                                                      cise will be attenuated by dilti-   improve sporting performance        fenofibrate are unlikely to
 ■ Raising of the workload at which angina occurs.                                                  azem and verapamil.                 in normal patients. In patients     have an effect on sporting
 ■ Apparent marginal advantages for ß1-selective agents if their                                       Two types of adverse reac-       with atrial fibrillation, digoxin   performance, but elevations
   doses remain low.                                                                                tion commonly occur: the            will not inhibit exercise-          of creatine kinase may occur
 ■ A lesser effect on isometric exercise.                                                           dihydropyridines often pro-         induced tachycardia. It can         and great care should be
 ■ Variable effects on heat regulation.                                                             duce peripheral oedema, while       alter the ST segment during         taken if they are combined
 ■ A risk of exercise-induced bronchospasm in susceptible                                           diltiazem and verapamil often       stress testing, causing a false-    with HMG CoA reductase
   patients.                                                                                        cause constipation.                 positive result.                    inhibitors.

24   | Australian Doctor | 14 January 2005                                 
Antidiabetic agents                                                                                                     two amphetamines, which             Anticonvulsants
Exercise results in numerous                                                                                            would result in a positive test     Anticonvulsants must be con-
changes in glucose homeosta-                                                                                            for a banned drug.                  tinued in all patients with
sis and is a recommended                                                                                                   Lithium poses several            epilepsy who participate in
part of the management of                                                                                               potential problems: it has a        sporting activities. Serious
most patients with diabetes.                                                                                            low therapeutic index and is        and sometimes fatal results
   Increases in cutaneous                                                                                               eliminated by the kidneys.          can occur if medication is
blood flow plus the effects of                                                                                          In sporting activity during         stopped or if people with
exercising muscle at the injec-                                                                                         hot weather, when there is          poorly controlled epilepsy
tion site result in increased                                                                                           often considerable fluid loss       undertake some sports, such
insulin absorption from a                                                                                               via sweat, decreased renal          as surfing.
subcutaneous site.                                                                                                      clearance may result in con-          It was thought that the
   This interaction and                                                                                                 siderable alterations in            ‘anxiolytic’ properties of bar-
increased uptake of insulin                                                                                             plasma concentrations. It is        biturates may be of some
into striated muscle and other                                                                                          very important in such cases        benefit in some sports but
metabolic changes necessitate                                                                                           to ensure adequate hydra-           they were found to decrease
careful adjustment of insulin                                                                                           tion.                               performance in all areas.
doses before any strenuous                                                                                                 Considerable exercise-
exercise.                                                                                                               related elevations in creatine      Antibiotics
   The physiological effects of                                                                                         kinase level have been              When an athlete is seeking
exercise last for many hours                                                                                            reported in association with        medical advice for a febrile
after exercise, so doses need                                                                                           some of the newer antipsy-          illness, their illness alone may
to be altered during, and for                                                                                           chotic agents such as olanza-       predispose them to a cardiac
the day after, exercise.                                                                                                pine (Zyprexa) and clozapine        arrhythmia or hyperthermia
Dosing will need to be indi-                                                                                            (Clopine, Clozapine Synthon,        during extreme exercise. The
vidualised to the duration                                                                                              Clozaril). The mechanism is         best prescription may be to
and intensity of exercise as                                                                                            unclear and some patients           avoid exercise until symp-
well as the stability of the                                                                                            have elevated levels indepen-       toms pass.
diabetes. Particular care is                                                                                            dent of exercise.                      While there are concerns
also needed in older people                                                                                                As yet there have been no        about antibiotics limiting per-
receiving oral agents so as to                                                                                          reported cases of exercise          formance, the limited avail-
avoid hypoglycaemia.                                                                                                    rhabdomyolysis in patients          able data have not shown
                                                                                                                        taking these medications, but       any decrease.
Vitamin supplements                                                                                                     it is advisable to change treat-       Quinolones should be pre-
Vitamins are taken in large                                                                                             ment when an elevated crea-         scribed with care because
quantities by athletes of all                                                                                           tine kinase level is found and      they have been reported to
ages but they are of no value                                                                                           the patient is undertaking          cause tendon rupture.
in enhancing performance.                                                                                               strenuous sporting activity.
Although they are usually                                                                                               There is no reason to rou-          Gastrointestinal drugs
considered to be of low toxi-     Sporting          ration and performance in         Probenecid remains on the         tinely measure the creatine         Antacids are used to enhance
city, unusual cases, such as                        those without asthma.             banned list as a masking          kinase level unless there is a      performance by inducing
hypervitaminosis A, have
                                  performance is      Clenbuterol is a long-acting    agent.                            clinical indication.                metabolic alkalosis. How-
been reported.                    not improved by   beta 2 agonist available in                                                                             ever, the doses required to do
                                  vitamin or        Europe and used by body           Oral contraceptives               Stimulants                          this will usually result in an
Iron and ‘athlete’s               mineral           builders as an anabolic agent.    A small number of studies         There are few legitimate rea-       increased osmotic load, with
anaemia’                                            Locally available long-acting     have shown a slight decrease      sons for the use of this group      resulting abdominal discom-
Although endurance athletes       supplements.      beta2 agonists such as efor-      in static muscle endurance in     of frequently abused drugs.         fort and increased gas pro-
increase their red cell mass                        moterol (Foradile, Oxis) and      women taking the oral con-        One of the reasons for intro-       duction.
and plasma volume, the                              salmeterol (Serevent) do not      traceptive pill. This would be    ducing drug control was                Antinauseants have central
plasma volume increase is                           appear to have been abused        of little relevance to any but    amphetamine-related deaths          sedating properties and may
usually greater and there is a                      by body builders.                 the elite athlete.                in sport.                           impair fine motor control,
subsequent fall in haemoglo-                                                                                                                                which can be important in
bin concentration. There is                         Xanthines                         Corticosteroids                   Psychostimulants                    activities such as gymnastics
also increased GI blood loss                        Caffeine has been shown to        These do not enhance perfor-      Methylphenydate, now                or diving.
in some athletes.                                   have a positive effect on per-    mance. Corticosteroid injec-      widely prescribed for atten-           Antidiarrhoeal agents are a
   When anaemia is first                            formance in some endurance        tions are often used for vari-    tion deficit disorder, can          heterogeneous group and,
detected in an athlete, there                       sports. However, high con-        ous sporting injuries. On         cause hypertension and pre-         while they have no significant
is absolutely no case for                           centrations can produce a         occasions, tendon rupture can     cipitate arrhythmias in the         effect on performance, any
immediate prescription of                           marked tachycardia and in         result from both injected and     sporting situation. To my           condition causing diarrhoea
iron supplements. At the ini-                       some people caffeine is pro-      systemic corticosteroid use.      knowledge, there have been          will predispose to dehydra-
tial consultation take a com-                       arrhythmogenic. While it is                                         no adverse cardiac events           tion.
plete medical, sporting and                         no longer banned in sporting      Psychotropics and                 reported in association with           Histamine H 1 -blocking
drug history, perform a thor-                       competition, a monitoring         antidepressants                   the use of methylphenidate          agents and proton-pump
ough physical examination                           program is being undertaken.      These comprise a large and        for ADD. Use of this agent          inhibitors would be unlikely
and order appropriate                                  Theophylline is dispensed      heterogenous group that           will result in a positive drug      to alter performance.
haematological and bio-                             in various formulations and       would not be expected to          test result (see author’s case
chemical investigations.                            still has a place in the man-     have any effects on perfor-       study, page 28).                    Complementary therapies
When clinical evaluation and                        agement of respiratory dis-       mance other than those asso-                                          Athletes consume a wide
investigation do not find a                         ease. In one well-conducted       ciated with their adverse reac-   Decongestants                       variety of complementary
pathological cause, the diag-                       study examining the effect of     tion profile. Most of these       Ephedrine and its steroiso-         medicines and dietary sup-
nosis of athletes anaemia can                       theophylline in athletes with-    agents have not been studied      mer pseudoephedrine have            plements. They are even pro-
be made.                                            out asthma, the drug had no       in exercise performance, but      often resulted in an athlete        moted by Olympians in
   In one study of elite net-                       effect on performance.3           tricyclic antidepressants have    returning an inadvertent            advertisements.
ballers with depressed ferritin                                                       been shown to decrease peak       positive drug test. Pseu-              There are large bodies of
levels, iron supplements were                       NSAIDs                            isokinetic (exercising at fixed   doephedrine is no longer on         data relating to many comple-
found to be without benefit                         The small body of available       workload) power.                  the ‘banned list’ but it is         mentary medicines, but most
on aerobic performance.2 In                         data shows NSAIDs have no            SSRIs have been thought to     subject to a monitoring             investigations have involved
any case of an athlete pre-                         adverse effect on sporting        have some advantage in            study.                              small numbers and are usu-
senting with a low haemo-                           performance, but care is nec-     enhancing performance             Neither drug will enhance           ally methodologically flawed.
globin level, NSAID use caus-                       essary to ensure there are no     because of a perceived anxi-      performance, but both have             Some supplements may
ing blood loss should always                        adverse effects on the stom-      olytic effect as well as some     the potential to cause tachy-       contain pharmacological
be excluded.                                        ach or small bowel, leading       data demonstrating increased      cardia, arrhythmias and             agents such as ephedrine, with
                                                    to anaemia.                       running time in a rat model.      hypertension.                       predictable adverse reactions.
Respiratory drugs                                                                     Subsequent human studies             When taken for relief of         The anabolic steroid nan-
Beta2 agonists                                      Hypouricaemics                    did not show any alterations,     symptoms, it should always          drolone has been found in
Beta2 agonists inhibit exer-                        Allopurinol has no effect on      positive or negative, in the      be borne in mind that a             some supplements, but this
cise-induced asthma and are                         performance. It is preferred      setting of high-intensity exer-   ‘mild’ respiratory or febrile       has not been considered a sat-
recommended for use before                          to the uricosurics, such as       cise.                             illness may be associated with      isfactory defence for positive
exercise by people with                             probencid (Probid), which            Selegiline (Eldepryl, Sel-     a subclinical myocarditis. A        drug tests.
asthma. They are now widely                         enhance urate deposition          gene) is an inhibitor of          febrile unwell athlete should          Sporting performance is
abused on the incorrect belief                      when a fall in urine output       monoamine oxidase type B.         not undertake strenuous             not improved by vitamin or
that they will improve respi-                       and pH occurs with exercise.      Its metabolic profile includes    exercise.                           mineral supplements.

                                                                                                                 14 January 2005 | Australian Doctor |    25
 How to treat - medication in sport and exercise

      Drugs used to enhance sporting performance
     DRUGS have been used in                                                                         schools found 6.6% of 12th-         not the sporting arena.          in two well-designed studies
     attempts to enhance perfor-                                                                     grade students (aged 18 on        ■ Normal volunteers used in        to increase strength and
     mance since the classical                                                                       average) had or were using          investigations are physio-       lean body mass in men.
     Olympics and will continue                                                                      anabolic steroids and two-          logically different to ath-    ■ Erythropoietin       (EPO)
     to be used as long as there is                                                                  thirds had started use at 16        letes, and even medium-per-      increases VO2 max.
     competition in sport.                                                                           or younger.                         forming athletes are           ■ Caffeine increases perfor-

       Use of anabolic steroids in                                                                      Despite the almost reli-         different from the sporting      mance in some endurance
     power sports and body-                                                                          gious belief of their value         elite.                           sports, such as cross-coun-
     building is widespread. A                                                                       held by athletes, sports          ■ Any simulated competition        try skiing.
     National Household Survey                                                                       administrators, the public          has little relationship to a   ■ Beta blockers improve per-

     in the US found that more                                                                       and many doctors, the sci-          real event, let alone a          formance in some sports
     than 300,000 people had                                                                         entific facts are less convinc-     national or international        such as archery and shoot-
     used anabolic steroids in the                                                                   ing.                                event.                           ing.
     preceding year. Erythropoi-                                                                        When considering the effi-     ■ Few studies have measured      ■ Systemic alkalosis may

     etin and stimulants are                                                                         cacy of a drug in the unique        individual concentrations of     improve endurance.
     widely used in endurance                                                                        situation of sporting compe-        the drug under investiga-      ■ Amphetamines improve

     sports such as cycling.                                                                         tition, with all the associated     tion.                            performance in some, but
       Probably no sport is             steroid use is in middle-level   Use of anabolic             psychological ‘hype’ and tac-     ■ Studies often have been too      not all, sports people.
     exempt from drug abuse.            competitors who want to                                      tics, the doctor should             small to detect an effect.        For most other agents,
     However, use and abuse are         achieve personal bests or in
                                                                         steroids in power           remember the following               In terms of good scientific   data are lacking or at best
     not the exclusive domain of        people who simply want to        sports and                  points:                           data, the following facts are    controversial. One fact is
     the elite athlete or even the      improve their appearance.        bodybuilding is             ■ Most data relating to effi-     well accepted:                   certain — no drug will turn
     competition athlete. For              Age is not a factor. A        widespread.                   cacy come from the artifi-      ■ Intramuscular testosterone     a poor performer into a
     example, most anabolic             study conducted in US high                                     cial area of the laboratory,      enanthate has been shown       champion overnight.

      How drug abuse problems may present
     THE most important task for the                                                                                                                              hepatitis B and C and HIV have
     doctor is to take a full history and                                                                                                                         been transmitted by needle-sharing
     find out what the patient does with                                                                                                                          steroid users.
     the rest of their lives. Often an ath-
     lete, in particular an older patient,                                                                                                                        Psychological presentations
     will not mention their sporting                                                                                                                              Steroid-induced aggression, para-
     activity or associated medications.                                                                                                                          noia and a dependency state are
        A user of anabolic steroids will                                                                                                                          well documented and should be
     probably not look like Arnold                                                                                                                                considered in an athlete presenting
     Schwarzenegger and it is unusual                                                                                                                             with relevant symptoms.
     for a user of illicit drugs initially                                                                                                                          In the US, a syndrome of unusual
     to volunteer a history of drug use.                                                                                                                          post-game paranoia with ampheta-
     Also, many adverse drug reactions                                                                                                                            mine use has been documented.
     will be difficult to distinguish from                                                                                                                          The drug gamma-hydroxybu-
     the multitude of symptoms that an                                                                                                                            tyrate (GHB) stimulates growth-
     athlete may have as a result of their                                                                                                                        hormone release and is often
     sporting activity alone.                                                                                                                                     abused in sport. It may induce
                                                                                                                                                                  coma and cause other problems
     Cardiovascular presentations                                                                                                                                 such as withdrawal and paranoia.
     Most competitors in sporting
     events will not be elite athletes but                                                                                                                        Dermatological presentations
     there will be a lot of serious starters                                                                                                                      Many well-recognised skin prob-
     wanting to do a personal best and                                                                                                                            lems can arise from steroid use. For
     many may be taking prescribed                                                                                                                                example, men may lose hair and
     drugs, illicit drugs or something                                                                                                                            women may become hirsute.
     else to improve their performance.                                                                                                                           Abdominal striae, acne and periph-
        Consider the basic cardiovascu-                                                                                                                           eral oedema can occur in both
     lar physiology in sport. At the start                                                                                                                        sexes.
     of a run there is a combination of                                                                                                                             Skin abscesses may occur at
     decreased parasympathetic and                                                                                                                                injection sites, and careful exami-
     increased sympathetic activity asso-                                                                                                                         nation may find small subcuta-
     ciated with a host of local regula-                                                                                                                          neous lumps where agents such as
     tory mechanisms. The sum of this                                                                                                                             the steroid stanozol have been
     is a rise in pulse rate, a rise in sys-    Steroid-induced                 has been normotensive develops            ing sessions when the drug has          injected.
     tolic, but not diastolic, blood pres-                                      elevated blood pressure. Peripheral       been absorbed and inadequate glu-
     sure, and redistribution of blood
                                                aggression, paranoia            vascular occlusions and pulmonary         cose taken to compensate.               Endocrine presentations
     from the gut, liver and kidney to          and a dependency                emboli have also been reported                                                    Anabolic steroids produce pre-
     the active skeletal muscle.                state are well                  with anabolic steroid use.                Gastrointestinal effects                dictable endocrine effects, includ-
        The most extreme of all presen-         documented and                     Diuretics may be used to ‘make         Up to 50% of endurance athletes         ing decreased testis size and gynae-
     tations in exercise or sport is                                            weight’, increase muscle definition,      complain of upper- or lower-GI          comastia in men, and clitoral
     sudden death. Deaths also have             should be considered            remove steroid-related oedema or          symptoms. Often athletes under-         hypertrophy and decreased breast
     been associated with use of                in an athlete                   mask agents in drug testing.              taking lesser levels of activity also   size in women.
     amphetamines, ephedrine, the ille-         presenting with                                                           complain of abdominal pain or              Short-term infertility is common
     gal long-acting beta2 agonist clen-                                        Cerebral effects                          oesophageal reflux, probably a          in men and a small number of ath-
     buterol, and anabolic steroids. Ery-
                                                relevant symptoms.              Cerebral haemorrhage can occur in         result of disturbances in motility.     letes may develop persistent
     thropoietin increases peripheral                                           extreme isometric exercise such as          When an athlete presents with         hypogonadotrophic hypogonadism.
     resistance, thus elevating blood                                           inclined leg presses. The risk will       anaemia, NSAID use rather than a
     pressure, and has been linked to                                           be greatly increased by the use of        physiological ‘athletes anaemia’        Locomotor presentations
     sudden death in cyclists.                                                  stimulants, caffeine or anabolic          should be suspected. However, the       Almost all sports are associated
        If an athlete presents with palpi-                                      steroids and there are reports of         anaemia should always be fully          with some form of overuse syn-
     tations or a resting tachycardia, use                                      stroke, haemorrhage and transient         investigated.                           drome or muscle strain. HMG
     of ephedrine, pseudoephedrine,                                             cerebral ischaemia occurring with           Bicarbonate ingestion may             CoA reductase inhibitors are well
     beta2 agonists, anabolic steroids or                                       these agents.                             improve aerobic performance but         recognised as causing myositis and
     caffeine should be suspected.                                                 Insulin has been used by body          the amount required will result in      even rhabdomyolysis in a small
        Persisting hypertension occurs                                          builders and weightlifters because        an osmotic load and increased gas       percentage of patients.
     with use of stimulants or high-dose                                        of its anabolic properties. Hypo-         production.                               Although drug-related rhab-
     anabolic steroids and should be                                            glycaemic coma has been reported            Cholestatic jaundice may result       domyolysis as a result of exercise
     considered when an athlete who                                             in the gymnasium and after train-         from anabolic steroid use, and                                cont’d page 28

26     | Australian Doctor | 10 December 2004                               
 How to treat - medication in sport and exercise

 from page 26                                                                           Disturbance in heat regulation               relationship between anabolic agents
 combined with use of HMG CoA                                                           When exercising, about 80% of the            and malignant disease in athletes.
 reductase inhibitors use has not been                                                  energy expended goes into heat pro-          The link to malignant hepatomas is
 reported, an association should be                                                     duction; hence the potential for hyper-      tenuous.
 considered in a symptomatic patient                                                    thermia to develop.                            There are only single case reports
 when any of these drugs have been                                                         Pseudoephedrine, antinauseants,           of a Wilms tumour in an adult, ade-
 used.                                                                                  anti-inflammatory agents, diuretics and      nocarcinoma of the colon and
    Tendon rupture is common in                                                         psychotropics have all been associated       prostate malignancy in athletes
 sport, but is well recognised in rela-                                                 with severe hyperthermia. These agents       taking anabolic steroids. However,
 tion to corticosteroid injection, ana-                                                 should be considered in any patient          the link between the vascular tumour
 bolic steroid use and quinolone use                                                    developing hyperthermia after exercise.      peliosis hepatitis and anabolic steroids
 in older patients. Bilateral necrosis                                                     It is also important to exclude an        has been well established.
 of the femoral heads has occurred                                                      infective episode because hyperthermia
 with the use of anabolic steroids.                                                     is also more likely to occur when an         Urological presentations
    There is no evidence to recom-                                                      athlete has a febrile illness.               Decreased urinary stream occurs with
 mend the use of anabolic steroids as                                                                                                anabolic steroids. There is a case report
 a means of increasing the healing                                                      Malignancy                                   of priapism occurring with the testos-
 rate of tendon or muscle damage.                                                       Much is said in the media about the          terone precursor androstenedione.

     Ethics of prescribing
 THERE is no doubt many                                                                                   The athlete autonomy                others. A further pressure is to
 doctors prescribe steroids to                                                                            argument                            be asked to receive team-
 athletes, and others will be                                                                             This argument is based on the       doctor-administered injections,
 approached to do so. While                                                                               patient’s right to self-determi-    such as vitamin B12.
 medical boards and learned                                                                               nation. The athletes are con-          Non-compliance with such

 colleges universally condemn                                                                             sidered to be aware of the          a regimen may be viewed
 the prescription of drugs to                                                                             positive and negative effects       unfavourably and result in
 enhance sporting perfor-                                                                                 of the drugs and are willing        non-selection. This is a seri-
 mance, it is nevertheless                                                                                to take the risks: all that is      ous violation of an athlete’s
 important to consider the                                                                                needed is the patient’s consent.    autonomy. It must be resisted
 arguments for and against                                                                                   The argument against this        by doctors when they are
 prescribing these medica-                                                                                is that there is no obligation,     made aware of, or asked to
 tions to athletes.                                                                                       moral or otherwise, to              participate in, this practice.
                                                                                                          simply do what a patient               The most extreme case
 Harm minimisation                                                                                        asks. As doctors we are             occurred in the former
 Simply put, this means ath-                                                                              expected to prescribe with          German Democratic Repub-
 letes will acquire and take                                                                              the aim of producing a clini-       lic, where athletes, many years
 the drugs with or without a         analogous to the case for          many athletes.                    cal benefit to the patient.         later, successfully lodged legal
 prescription. In the latter         prescribed use of heroin.            A further dilemma occurs           One important issue in the       proceedings against some of
 case they will receive illegal        Against this argument is         when some adverse effects         area of ethics is the pressure      the doctors involved in the
 supplies that are not sub-          the fact that little is known      occur and the user then           imposed on athletes by coaches      administration of steroids.
 jected to quality control and       about the pharmacology of          requests yet another drug,        and others to consume various          In summary, when asked
 may not even contain the            the multiple doses of ana-         such as tamoxifen to reverse      supplements. Such supple-           to prescribe, a doctor must
 drug listed on the label.           bolic steroids that would be       gynaecomastia.                    ments are often stated to be        be non-judgmental, treat any
 Whereas, if supervised, the         requested. Also, it has been         Finally, what is the pre-       ‘natural’ compounds such as         medical problems and                References
 supplies would be monitored         found that well-meaning            scriber to do when insulin,       kelp, various minerals, carni-      always decline the request to       1. Lenz TL, et al. Potential
 and any adverse effects             prescribers can be used as         erythropoietin or ampheta-        tine, bovine colostrum, coen-       prescribe inappropriate or          interactions between exer-
 detected and treated. This is       one source of supply by            mines are also requested?         zyme Q, ginseng and many            illegal medications.                cise and drug therapy.
                                                                                                                                                                                  Sports Medicine 2004;
                                                                                                                                                                                  2. Blee T, et al. The effects
     The future of drugs in sport                                                                           Author’s case study                                                   of intramuscular iron injec-
                                                                                                                                                                                  tions on serum feritin levels
                                                                                                                                                                                  and physical performance in
 DRUGS have been used to enhance performance for millen-                                                  Question
                                                                                                                                                                                  elite netballers. Journal of
 nia, and the practice continues to evolve with technological                                             A 16-YEAR-old netball player
                                                                                                                                                                                  Science and Medicine in
 advances.                                                                                                is receiving methylphenidate
                                                                                                                                                                                  Sport 1999; 2(4):311-21.
   The recent Bay Area Co-Operative Laboratory (BALCO)                                                    for attention deficit disorder.
                                                                                                                                                                                  3. Morton AR, et al. The
 scandal involving the use of an anabolic steroid, tetrahydro-                                            She is in a team that has
                                                                                                                                                                                  effects of theophylline on the
 gestrinone, demonstrates the availability of chemists to design                                          reached a level at which she is
                                                                                                                                                                                  physical performance and
 drugs that are difficult to detect.                                                                      subject to random drug testing.
                                                                                                                                                                                  work capacity of well trained
   The possibility of gene doping, using viral agents as vectors                                          What advice should be given?
                                                                                                                                                                                  athletes. Journal of Allergy
 to deliver growth-promoting genes into muscle, has been
                                                                                                                                                                                  and Clinical Immunology
 foreseen in the World Anti-Doping Code.                                                                  Answer
                                                                                                                                                                                  1989; 83(1):55-61.
   The pharmaceutical industry is developing agents for use in                                            Use of this agent will result in a positive drug test result.
 myo- and neurodegenerative disorders that will inhibit the                                               The sporting body’s medical officer needs to be made aware
 natural protein growth inhibitor myostatin. Such a drug                                                                                                                          Online resources
                                                                                                          of the situation. Application should also be made to the Aus-
                                                                                                                                                                                  Australian Sports Drug
 would be almost a Holy Grail for body builders.                                                          tralian Sports Drug Medical Advisory Committee (ASDMAC)
   Fortunately, there are many pharmacologists working on                                                 (phone (02) 6206 0262; e-mail
 means of detection. With rigorous out-of-competition testing                                                This committee can review an individual case and is recog-           World Anti-Doping Agency:
 and blood sampling, it is hoped this will maintain a level                                               nised under the World Anti-Doping Code as being able to       
 playing field in elite sport.                                                                            grant a therapeutic exemption.

     GP’s contribution
                                     Case study                                 steroids or testosterone.                   cled, had slight acne but was other-         gynaecomastia. I also explained the
                                     SD, 22, is an enrolled nurse. He first        I told him I would be happy to talk      wise well.                                   possible negative effects on fertility
                                     presented to our practice six months       with him and provide information               I went on to explain that side effects    and coronary heart disease.
                                     ago requesting a “Sustanon script”         about the effects and side effects of       of steroids are common and can be              I suggested he read the booklet from
                                     (testosterone) and asking if it was pos-   anabolic steroids and testosterone, but     serious (eg, mood swings). I told him        Sports Medicine Australia, think about
                                     sible to have this drug regularly          explained to him that I could not ethi-     that I have had female patients com-         our consultation and return in couple
                                     injected by our practice nurse.            cally or legally prescribe for purposes     plain that they had been physically          of weeks.
                                        He looked like, and admitted to         that were not medically indicated.          abused or feared being abused by their         On return he had read the booklet
     DR MARTINE WALKER               being, a body builder and openly              I gave him an information booklet        steroid-using boyfriends.                    and admitted to using steroids for
          Mosman, NSW                told me that the Sustanon was for          from Sports Medicine Australia and             We also discussed the less common         about the past six months. He said he
                                     bodybuilding purposes. I suspected         performed a physical examination,           but perhaps more worrying side               wanted to continue and hoped to do it
                                     he was already using anabolic              which revealed that he was well mus-        effects of testicular atrophy and                                    cont’d page 30

28   | Australian Doctor | 14 January 2005                                       
 How to treat - medication in sport and exercise

 from page 28                                enough to treat) and his liver                                                          When a doctor’s actions are                   Often in the past, football              illnesses can also predispose
 in a “medically safe” way.                  function is normal. His acne                                                            brought to the attention of the               players appeared in the media,           patients to malignant hyper-
    We discussed why he used                 has worsened and we are treat-                                                          relevant medical board on the                 having had marijuana use                 thermia. The best advice is: “If
 steroids and he admitted                    ing this with minomycin. He                                                             matter of prescribing or sup-                 detected on drug screens. Is             sick, don’t compete.”
 having poor self-esteem. He                 had also started taking                                                                 plying anabolic steroids, it                  tetrahydrocannabinol per-
 said he lived a “healthy” life              Nolvadex (tamoxifen) obtained                                                           may result in a decision that                 formance enhancing? If not,              You discuss the risk of tendon
 — he did not smoke or drink,                through the gym to counter                                                              the doctor is guilty of unsatis-              why the concern?                         rupture in association with oral
 but said using steroids helped              gynaecomastia.                                                                          factory professional conduct,                   Cannabinoids impair aero-              corticosteroid use. Is this a risk
 in his part-time work in secu-                                                                                                      and in some cases even pro-                   bic performance. The reason              we should be discussing with
 rity at nightclubs.                         Questions for the author                                                                fessional misconduct.                         for bans will depend on the              patients taking short-term oral
    I reiterated that I could not            Is there any evidence about                                                                                                           sport, but are usually in keep-          steroids such as for asthma,
 prescribe them and discour-                 the cardiovascular risk of                                                              General questions for the                     ing with the philosophy of a             croup or severe sinusitis?
 aged him from using steroids                long-term high-dose steroid or                                                          author                                        drug free sport and society.                No.
 from the gym (he was not sure               androgen use?                                                                           At what levels of competition
 what he was taking, but knew                   There have been several                                                              does drug testing begin?                      In what types of acute illness           Serious female runners often
 it included Stanazolol).                    case reports in Australia and                                                             Any sporting body can                       should we counsel athletes               become amenorrhoeic but are
    I suggested he continue to               overseas of AMIs and car-                                                               request the Australian Sports                 such as runners not to com-              reluctant to use pharmaceuti-
 come for monitoring of blood                diomyopathies being caused                                                              Drug Agency to conduct                        pete? What are the risks?                cals such as the oral contra-
 pressure, liver function and                by steroids. The risk must be                                                           drug testing on a fee-for-ser-                  In any serious cardiac or sys-         ceptive pill. What arguments
 lipids every three months. I                small when you consider their                                                           vice basis. Testing is almost                 temic illnesses, such activity is        can we use in discussion with
 suggested a referral for fur-               widespread use. Steroids                                                                universal at a national level                 an absolute contraindication.            our patients for and against
 ther counselling, but he                    decrease HDL-cholesterol and                What are the penalties for                  and is sometimes present at                   In the case of less severe ill-          the use of the pill in this situa-
 declined.                                   increase LDL-cholesterol                    doctors for prescribing ana-                state levels of competition.                  nesses advice should be given            tion?
    Since that time he has                   levels, which, combined with                bolic steroids or androgens for             Often a world record can                      that a ‘mild’ febrile illness may           Sporting performance is
 returned occasionally. His                  an increase in blood pressure,              non-medical uses?                           only be recorded if there is                  be associated with a subclinical         unaffected by the use of the
 blood pressure is normal, lipids            increases the risk of vascular                 All Australian states adopt              documentation of drug-free                    myocarditis with the potential           pill but the risk of pregnancy
 slightly raised (but not high               events.                                     a similar position on this issue.           status.                                       for serious arrhythmias. Such            is not.

                          Australian Doctor
      How To Treat CPD
       Instructions                                                                                                                  may compete. Which antibiotic would you be                      d) Caffeine . . . . . . . . . . . . . . . . . . . . . . . .❏
                                                                                                                                     unlikely to use in this situation (choose
       Earn 2 CPD points by completing this quiz online or on the attached card. Mark your
                                                                                                                                     ONE)?                                                           8. Nigel’s haemoglobin is 120g/L. Which
       answers on the card and drop in the post (no stamp required) or fax to (02) 9422 2844.
       For immediate feedback click the ‘Earn CPD pts’ link at
                                                                                                                                     a) Cephalexin . . . . . . . . . . . . . . . . . . . . . .❏      ONE statement is incorrect regarding
       Note that some questions have more than one correct answer. The mark required for CPD
                                                                                                                                     b) Amoxicillin-clavulanate . . . . . . . . . . . . .❏           anaemia in this situation?
       points is 80%. Your CPD activity will be updated on your RACGP records every January,
                                                                                                                                     c) Trimethoprim . . . . . . . . . . . . . . . . . . . .❏        a) The anaemia may be
       April, July and October.
                                                                                                                                     d) Ciprofloxacin . . . . . . . . . . . . . . . . . . . .❏       physiological . . . . . . . . . . . . . . . . . . . . . . .❏
                                                                                                                                                                                                     b) Iron should be given immediately . . . . .❏
                                                                                                                                     5. Which ONE substance is not on the                            c) The anaemia should be
                                                                                                                                     ‘banned list’ for athletes?                                     investigated . . . . . . . . . . . . . . . . . . . . . . .❏
     1. Peta, 54, has diabetes and competes in                    b) The dose of oral hypoglycaemics                                 a) Probenecid . . . . . . . . . . . . . . . . . . . . . .❏      d) Blood loss should be considered . . . . .❏
     cross-country running. She takes a statin for                should remain unaltered . . . . . . . . . . . . . .❏               b) Pseudoephedrine . . . . . . . . . . . . . . . . .❏
     hypercholesterolaemia. Her routine tests                     c) Insulin should be injected into the                             c) Tetrahydrogestrinone . . . . . . . . . . . . . .❏            9. Paul, 36, a competitive cyclist, attends
     show a creatine phosphokinase (CPK) of 850                   thigh . . . . . . . . . . . . . . . . . . . . . . . . . . . . .❏   d) Amphetamines . . . . . . . . . . . . . . . . . . .❏          your surgery with a laceration. Blood
     U/L. She was in a competition 24 hours                       d) Ensure an adequate amount of glucose                                                                                            pressure is 150/100mmHg, compared with
     before her test. What TWO actions would                      is used or available during exercise . . . . .❏                    6. The clinical effects of which TWO drugs                      125/80mmHg four months ago. Which
     you advise?                                                                                                                     may be significantly affected by endurance                      THREE drugs would you consider as
     a) The statin should be stopped                              3. Peta asks for advice about enhancing her                        exercise?                                                       possible causes?
     immediately . . . . . . . . . . . . . . . . . . . . . . .❏   performance. Which ONE statement is                                a) Propanolol . . . . . . . . . . . . . . . . . . . . . .❏      a) High-dose anabolic steroids . . . . . . . . .❏
     b) Repeat CPK in several days . . . . . . . . .❏             correct?                                                           b) Warfarin . . . . . . . . . . . . . . . . . . . . . . . .❏    b) Ephedrine . . . . . . . . . . . . . . . . . . . . . . .❏
     c) The troponin level should be                              a) Iron supplements may be beneficial . . .❏                       c) Verapamil . . . . . . . . . . . . . . . . . . . . . . .❏     c) Erythropoietin . . . . . . . . . . . . . . . . . . . .❏
     checked and an ECG recorded . . . . . . . .❏                 b) Erythropoeitin may be beneficial . . . . .❏                     d) Lithium . . . . . . . . . . . . . . . . . . . . . . . . .❏   d) Citalopram . . . . . . . . . . . . . . . . . . . . . .❏
     d) Repeat CPK the following day . . . . . . .❏               c) Mega-doses of vitamins should be
                                                                  used routinely . . . . . . . . . . . . . . . . . . . . . .❏        7. Nigel, 28, swims long distances                              10. Paul tells you he uses antacids to
     2. Secondary therapy with oral                               d) Oral corticosteroids may be                                     competitively. He is seen in casualty with                      improve his performance, but no other
     hypoglycaemics fails, and insulin is added.                  beneficial . . . . . . . . . . . . . . . . . . . . . . . . .❏      supraventricular tachycardia. Which drug is                     drugs. Which TWO side effects might he
     What advice are you most likely to give Peta                                                                                    least likely to induce arrhythmias in a                         experience from high doses of antacids?
     about adjusting her medications when                         4. One month later, clinically Peta has mild                       sporting situation (choose ONE)?                                a) Chest pain . . . . . . . . . . . . . . . . . . . . . .❏
     training and competing (choose ONE)?                         pyelonephritis 48 hours before a                                   a) Metoprolol . . . . . . . . . . . . . . . . . . . . . .❏      b) Abdominal pain . . . . . . . . . . . . . . . . . .❏
     a) Decrease the insulin dose only on the                     competition. You advise her to withdraw                            b) Pseudoephedrine . . . . . . . . . . . . . . . . .❏           c) Headache . . . . . . . . . . . . . . . . . . . . . . .❏
     day of training or competing . . . . . . . . . .❏            from the competition, but she indicates she                        c) Methylphenidate . . . . . . . . . . . . . . . . . .❏         d) Increased gas production . . . . . . . . . . .❏

     HOW TO TREAT                            NEXT WEEK
     Editor: Dr Lynn Buglar                  The next How to Treat looks at the management of chronic pelvic pain in women. The authors are Dr David Knight, senior staff specialist in obstetrics and
     Co-ordinator: Julian McAllan            gynaecology, The Canberra Hospital, and clinical lecturer in obstetrics and gynaecology, Australian National University, Canberra; and Dr Steve Robson,
     Quiz: Dr Marg Tait                      director, department of obstetrics and gynaecology, The Canberra Hospital, and senior lecturer in obstetrics and gynaecology, Australian National University.

      That’s How to Treat. Now for the ‘How to’ guide to your practice.                                                                                                                                                                   • Legal
                                                                                                                                                                                                                                          • Ethical

             In Practice                                                                                                                                                                                                                  • Business
                                                                                                                                                                                                                                          • Finance

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