Medicine and science in the fight against doping in sport.

The fight against doping in sports commenced as a result of the death of a Danish cyclist during the Rome Olympic Games in 1960. The International Olympic Committee (IOC) established a Medical Commission (IOC-MC) which had the task of designing a strategy to combat the misuse of drugs in Olympic Sport. Some International Sport Federations (IF) and National Sports Federations followed suit, but progress was modest until the world's best male sprinter was found doped with anabolic steroids at the Olympic Games in Seoul in 1988. Further progress was made following the cessation of the cold war in 1989 and in 1999 public authorities around the world joined the Olympic Movement in a unique partnership by creating WADA--the 'World Anti-Doping Agency'. The troubled history of the anti-doping fight from the 1960s until today is reviewed. In particular, the development of detection methods for an ever increasing number of drugs that can be used to dope is described, as are the measures that have been taken to protect the health of the athletes, including those who may need banned substances for medical reasons.

Quantification of terbutaline in urine by enzyme-linked immunosorbent assay and capillary electrophoresis after oral and inhaled administrations.

The International Olympic Committee and World AntiDoping Agency restricts the use of beta2-agonists and only the inhaled administration of terbutaline, salbutamol, formoterol and salmeterol is permitted for therapeutic reasons. The aim of this study was to develop a test for the quantitation of terbutaline in urine and evaluate different parameters to distinguish between oral and inhaled administration of the drug. Urine samples were collected from asthmatic and non-asthmatic recreational swimmers who had received repeated doses of oral (3x2.5 mg plus 1x5 mg during 24 h) and inhaled (12x0.5 mg in 24 h with half of it being in the last 4 h) racemic terbutaline, and single oral (5 mg) or single inhaled doses (1 mg). Total terbutaline concentrations (free+conjugated) were determined by enzyme-linked immunosorbent assay. Results showed that after oral administrations urinary terbutaline concentrations were higher than those detected after inhalation. For confirmation purposes, a chiral capillary electrophoretic procedure was established and validated. A solid-phase extraction with Bond-Elut Certify cartridges was undertaken, separation performed using a 50 mM phosphate buffer (pH 2.5) containing 10 mM of (2-hydroxypropyl)-beta-cyclodextrin as running buffer and diode-array UV detection set at 204 nm. The proposed procedure is rapid, selective and sensitive allowing quantitation of free terbutaline enantiomers in urine. No statistical differences were found between total free terbutaline concentrations [S-(+)+R-(-)] in urine collected after oral and inhaled administrations of the drug. After oral doses enantiomeric [S-(+)]/[R-(-)] ratios lower than those obtained after inhalation were observed probably due to an enantioselective metabolism that take place in the intestine, but differences between both routes of administration were not statistically significant. Although different trends were observed after oral and inhaled doses in total terbutaline, total free terbutaline concentrations and in ratios between its enantiomers, differences observed were not sufficiently significant to establish cut-off values to clearly distinguish between both routes of administration.

Laboratory protocol for exercise asthma to evaluate salbutamol given by two devices.

PURPOSE: As new delivery devices and formulations are being introduced for drugs given by inhalation, there is a need to evaluate their equivalence with old preparations. One way to do this is to investigate their equivalence in protecting from exercise-induced asthma (EIA). METHODS: We used a protocol for EIA to compare the protective effect of salbutamol delivered by the pressurised metered dose inhaler (pMDI) and the new Diskus dry powder device. Twenty-seven asthmatic subjects with moderately severe EIA completed an exercise test on four separate days at two study centers. Exercise was performed by cycling for 8 min while inhaling dry air (0% RH, 20-24 degrees C). The target workload in W was predicted as (53.76 x predicted FEV1) - 11.07 and 95% of this target was achieved at 4 min of exercise. This target was chosen in order to achieve ventilation between 50 and 60% of predicted maximum in the last 4 min. RESULTS: There was no significant difference in the workload, ventilation, or heart rate achieved on the study days. The severity of EIA was measured as the % fall in FEV1. EIA severity was similar on the placebo and control day and the coefficient of variation was 19.4%. The mean +/- SD % fall on the control, placebo, salbutamol by Diskus, and pMDI were 42.0% +/- 15, 39.4% +/-17.6, 13.4% +/- 13.2, and 8.5% +/- 13.8, respectively. Salbutamol significantly inhibited the % fall in FEV1 after exercise, and there was no difference between the preparations. CONCLUSION: The protocol described here is suitable for evaluating equivalence of salbutamol preparations in protecting against EIA and could be used to evaluate the protective effect of other medications.

Discrimination of prohibited oral use of salbutamol from authorized inhaled asthma treatment.

BACKGROUND: The administration of salbutamol is permitted only by inhalation by the International Olympic Committee (IOC) for the management of asthma and exercise-induced asthma in athletes. The establishment of criteria to distinguish between the (IOC) authorized use (inhaled) and the (IOC) prohibited use (oral) of salbutamol appeared possible using simultaneous evaluation of variables based on the concentration of nonconjugated enantiomers of salbutamol excreted in urine. METHODS: Urine was collected from asthmatic and nonasthmatic swimmers who had received various preexercise doses of oral (five doses of 4 mg) or inhaled (two doses of 100 microgram) salbutamol. Urine was also obtained from subjects who had received the maximum dosage of inhaled salbutamol advisable for competing athletes to provide protection from exercise-induced asthma and treatment of asthma (1600 microgram in 24 h, 800 microgram being in the last 4 h). All samples were analyzed to determine the total amount of unchanged salbutamol excreted in urine and the ratio between the S: and R: enantiomers. RESULTS: The discriminant function D = -3.776 + 1.46 x 10(-3) ([S:(+)] + [R:(-)]) + 1.012 ([S:(+)]/[R(-)]) can be used to classify data into two groups, inhaled and oral. The confirmatory criterion suggested (cutoff at D = 1.06, 4 SD from the mean D value of the inhaled distribution) has been verified in different sets of samples showing suspicious concentrations by conventional screening procedures in doping control. An 11.8% false-negative (oral classified as inhaled) rate is assumed with the confirmatory criterion proposed, but virtually no false positives (inhaled classified as oral) are obtained (<1 in 33 000). CONCLUSIONS: The overall procedure recommended is to screen all samples and to apply the confirmation criterion proposed to samples showing free racemic salbutamol concentrations >500 microgram/L by gas chromatography-mass spectrometry or free + conjugated racemic salbutamol concentrations >1400 microgram/L by ELISA.

Distinction of inhaled and oral salbutamol by urine analysis using conventional screening procedures for doping control.

Salbutamol administration in athletes is permitted only by inhalation, for the management of asthma. The authors discuss different criteria for suspecting oral use of salbutamol, taking into account the data obtained by application of two conventional screening procedures for doping control: gas chromatography/mass spectrometry (GC/MS) and enzyme-linked immunosorbent assay (ELISA). Urine samples obtained after administration of oral and inhaled salbutamol to asthmatic and nonasthmatic swimmers were analyzed using both analytical approaches. As expected, concentrations obtained by the ELISA test (detection of total salbutamol) were higher than those obtained using the GC/MS procedure (detection of nonsulfated salbutamol). After oral administration, the ELISA test detected significantly higher salbutamol concentrations than those detected after inhalation, reflecting the greater doses administered orally. Urine samples with total salbutamol greater than 1400 ng/mL were obtained after oral doses, but no sample reached this value after inhaled doses. Higher concentrations of nonsulfated salbutamol have also been detected after oral intake, although there is an overlap between the distributions of concentrations after oral and inhaled doses. A cut-off concentration of 500 ng/mL can be used for nonsulfated salbutamol to select suspicious samples, giving 11.8% false negative results and 4.3% false positive results. An additional criterion evaluated was the androsterone-salbutamol peak height ratio, which was lower after oral doses because of the higher concentrations of salbutamol in urine. This ratio was lower than 2 for all the samples collected after oral administration, although 6.8% false positive samples resulted because of low concentrations of androsterone in female urine. Several possibilities for detecting suspicious samples from athletes who have taken prohibited oral salbutamol are available with conventional screening procedures in doping control.

Is salmeterol ergogenic?

OBJECTIVE: To assess the effects of 50 micrograms of inhaled salmeterol on pulmonary function, selected physical capacities, and fine motor control in 16 nonasthmatic male cyclists and triathletes, mean age of 23.2 (SD = 3.5) years. DESIGN: Randomized double-blind placebo-controlled crossover trial. SETTING: Human Physical Performance Laboratory, the University of Western Australia. SUBJECTS: Sixteen healthy male high-performance nonasthmatic athletes with a mean age of 23.2 years participated in the study. INTERVENTION: Subjects attended three experimental testing sessions at which salmeterol (50 micrograms), a placebo, or "no treatment" was administered in random order in a double-blind fashion, on separate occasions, prior to exercise. MAIN OUTCOME MEASURES: During each testing, session lung function was measured before and 10 min after the treatment. Tests of reaction time and hand steadiness and then two anaerobic cycle tests followed. The first, a 10-s all-out sprint was followed, after a 3-min rest, by a 30-s all-out sprint performed on a front access bicycle ergometer. After 10 min recovery, leg flexion-extension peak torque was measured on a Biodex isokinetic dynamometer at speeds of 120 and 180 degrees s-1. MAIN RESULTS: Lung function variables, reaction time, movement time, alactic anaerobic power, lactacid anaerobic power, and leg-flexion and leg-extension muscular strength were similar among the three treatment groups. CONCLUSIONS: The preexercise administration of 50 micrograms of inhaled salmeterol has no performance-enhancing effects in nonasthmatic athletes. We believe that athletes with asthma should be permitted to use salmeterol before competition.

Asthmatic drugs and competitive sport. An update.

Almost all asthmatics are prone to asthma triggered by moderate to severe exercise. Fortunately there are a number of pharmaceutical agents now available which can prevent and/or reverse exercise-induced asthma (EIA) and allow many asthmatics to participate in vigorous physical activities with minimum respiratory disadvantage. Regular exercise is an accepted part of the management of asthma and EIA can now be controlled so successfully that a number of elite sportspersons, in almost all types of sporting events, are asthmatic. This control of EIA, which is essential if asthmatics are to participate safely, requires that the patient and his/her doctor initiate a strategy to manage the disease during sport and other physical activities. In recent years the mortality and morbidity from asthma have been increasing and this has indicated the need to improve patient care. One of the most important innovations aiming to improve the control and treatment of asthma has been the recent development of the 6 point asthma management plan which is a strategy to simplify and optimise the long term management of asthma. It aims to improve the quality of life of most asthmatics and more importantly, prevent deaths due to asthma. Because antidoping controls operate in many high performance sports it is essential that the EIA management plan rely on those medications which are permitted. The list of allowable drugs is in continual flux as new ones are added and others are challenged on the grounds of possible ergogenicity. All aerosol beta 2-agonists except fenoterol, the khellin derivatives, theophylline, ipratropium bromide and the aerosol corticosteroids are currently permitted. Some nonasthmatic athletes who are aware of the improved performance of asthmatic athletes when using pre-exercise medication have been known to take antiasthma medication in the hope that it might improve their performance. Current evidence indicates, however, that the permitted medications are not ergogenic and do not give the asthmatic any advantage over the nonasthmatic athlete but merely removes the respiratory disadvantage under which he/she competes.

Effects of nedocromil sodium, cromolyn sodium, and a placebo in exercise-induced asthma.

The incidence and severity of exercise-induced asthma were determined in nineteen asthmatic patients who performed eight minutes of exercise following four treatments administered in a random order. The treatments were nedocromil sodium, cromolyn sodium, placebo, and no treatment. It was concluded that nedocromil sodium (8 mg) and cromolyn sodium (4 mg) provide equal protection against exercise-induced asthma.

Rimiterol and the prevention of exercise-induced asthma.

The potential for rimiterol to protect athletes from exercise-induced asthma (EIA) has not been fully established. Ten athletes with asthma (15 to 30 years of age) undertook 8 minutes of submaximal exercise (80% of anaerobic threshold) on the treadmill ergometer, once after inhaling rimiterol and once after inhaling a placebo. Treatment with all bronchodilator drugs was stopped for the 12 hours preceding each exercise test. Two puffs (400 micrograms) of rimiterol or placebo were administered in a double-blind crossover manner 2 minutes before each exercise test. Lung function measurements were made before exercise and immediately, 5, 10, 15, 20, 25, and 30 minutes after completion of exercise. The results of a two-way analysis of variance revealed significant (p less than 0.01) difference in the FEV1 scores obtained after rimiterol inhalation and placebo inhalation, 5, 10, 15, 20, 25, and 30 minutes after cessation of exercise. After inhalation of rimiterol, there were no significant changes in FEV1. After inhaling the placebo, significant reductions (p less than 0.01) in FEV1 occurred after cessation of exercise (5, 10, 15, and 20 minutes). All subjects exhibited EIA after placebo, and none after rimiterol. The mean maximum drop after exercise in FEV1 after inhalation of rimiterol (2.807 +/- 5.55) and placebo (24.54 +/- 8.4) was significantly different (t = 6.849). It was concluded that inhalation of rimiterol 2 minutes before exercise afforded significant protection from EIA in all subjects tested.

The effects of theophylline on the physical performance and work capacity of well-trained athletes.

Theophylline, a pharmacologic agent presently permitted during international sporting competition, has come under scrutiny because of the suggestion that it may be ergogenic. This study examined the effects of serum theophylline levels of 10 to 20 mg/L and the administration of a placebo on selected measures of physical performance and work capacity to determine any ergogenic outcomes. Seven male and three female elite athletes from a variety of team sports and aged 18 to 30 years participated in the study. The variables measured were height, mass, maximal oxygen consumption, muscular endurance, muscular power, muscular strength, FVC, FEV1, and reaction time. When the scores obtained after ingestion of theophylline and a placebo with a double-blind, crossover technique were compared, no significant difference was found for any of these variables. A two-way analysis of variance of FEV1 scores obtained before and after maximal exercise revealed no significant "F" ratios. This indicated that none of these trained athletes demonstrated exercise-induced asthma and that there was no difference in airway resistance after maximal exercise while they were under the influence of theophylline or placebo. We conclude that no ergogenic effects were attributable to theophylline therapy which should therefore remain an acceptable means of management of athletes with asthma participating in international sporting events.

Operation for non-union of stress fracture of the tarsal navicular.

Stress fractures of the tarsal navicular do not heal predictably with conservative treatment, so we recommend operation if the fracture remains symptomatic, and radiographs show wide separation of a complete fracture, extension of an incomplete fracture, delayed healing, or a medullary cyst. An autologous bone graft is inserted after en-bloc resection of the fracture surfaces. It is important that the fracture is fully exposed to its distal limits before the graft is inserted. We have grafted 19 fractures in 18 patients. Six fractures were complete, 12 incomplete and one had a residual medullary cyst. Of the 15 patients with adequate follow-up, 12 had been able to return to a pre-injury level of activity by five to 12 months.

The effect of running training on exercise-induced asthma.

A running training program had no effect upon the severity of exercise-induced asthma, however, it appeared as if the children benefitted not only from a decrease in the frequency and duration of asthma in daily life, but also by improvement in self-confidence and ability to participate in group activities.

The use of anti-asthmatic drugs. Do they affect sports performance?

Recent major advances in pharmacological management have provided asthmatics with a satisfactory range of drugs to control asthma. These include sodium cromoglycate (cromolyn sodium), H1-antagonists, belladonna alkaloids, methyl xanthines, glucocorticoids and beta 2-adrenoceptor stimulants. Despite the tendency for most asthmatics to develop bronchoconstriction after exercise, sport and physical activity are now accepted as valuable in the overall management of patients with asthma. Thus, control of exercise-induced asthma (EIA) is essential, if asthmatics are to participate safely in physical activity and without respiratory disadvantage in competitive sport. Fortunately, inhibition or minimization of exercise-induced asthma may be achieved in most asthmatics by pre-exercise aerosol beta 2-agonists supplemented if necessary by sodium cromoglycate and/or theophylline. Regular medication as required to attain and maintain normal ventilatory function throughout each day is the objective in all patients with asthma and appears to be a prerequisiste to control exercise-induced asthma. The introduction of anti-doping controls into high performance sport has presented added difficulties for the asthmatic athlete. Although not always so, currently all of the classes of drugs previously noted are acceptable for the treatment of asthma and exercise-induced asthma. Anomalies may exist in the banning of 2 beta 2-adrenoceptor agonists, fenoterol and orciprenaline (metaproterenol). All sympathomimetic amines with alpha- or predominantly beta-stimulation are banned. The perpetuation of the need to report the use of beta 2-agonists prior to competition appears unnecessary. Although relatively little specific research has been undertaken, there is minimal evidence to suggest that asthmatics can derive any additional ergogenic advantage from medication to control asthma and exercise-induced asthma. beta 2-agonists, sodium cromoglycate and glucocorticoids administered by the aerosol route are not considered to be ergogenic. Some doubts have been raised concerning theophylline and its enhancement of both cardiac and respiratory muscle function. Investigations as to the validity of the suggestion that theophylline could augment physical performance appear warranted. It is reported that some athletes may be unnecessarily taking oral and perhaps parenteral glucocorticoids to obtain certain side effects. Any decision to ban these agents except for aerosol or local use could be supported.

A reinterpretation of the effect of temperature and water content of the inspired air in exercise-induced asthma.

To compare the importance of water loss with heat loss in the mechanism of exercise-induced asthma (EIA), we conditioned the air inspired during exercise to the same water content (Wi) while changing its temperature (Ti), and vice versa. We calculated separately the amount of heat and water required to bring the inspired air to alveolar conditions. Ten asthmatics ran for 8 min on 4 occasions in an environmental chamber. The air was conditioned to a Ti of 9 to 10 degrees C or 35 degrees C, with a Wi of 9 to 10 mg H2OL-1. The airway response to exercise was not significantly different when Ti varied by 25 degrees C, but the amount of water required to saturate the inspired air remained the same. However, the amount of heat required was significantly greater with cooler air (p less than 0.005). We conclude that it is the osmotic and not the cooling effects induced by the vaporization of water that is the more important factor determining EIA.

Stress fractures of the lower limbs in runners.

Stress fractures are a common sports injury and running can cause fractures in most bones from the metatarsals to the pubic rami. Pain after an increase in or modification to a running programme is the initial symptom; there will be point tenderness over bone. Rest from running for six to 10 weeks is necessary but alternative exercise must be prescribed for those 'addicted' to running.

Management of allergic Olympic athletes.

Twenty percent of the recent Australian Olympic athletes have had an allergic disorder. Because of the ban on all sympathomimetic drugs except some beta 2-agonists. Olympic team physicians have a major responsibility to ensure that no competitor is disqualified for infringing on the antidoping rules of the Medical Commission of the International Olympic Committee. Inadvertent contravention of these regulations may occur because numerous banned sympathomimetics are available to athletes and their coaches without medical prescription and are frequently contained in combination preparations. The unbroken 24 yr in which asthmatics have won Olympic medals have been both before and after the introduction of drug tests. Currently a comprehensive range of preventive and therapeutic medications are available for asthmatics to compete with minimal respiratory disadvantage. It was, however, during a period of unnecessary restriction that an American swimmer forfeited his gold medal because of prerace ingestion of a banned sympathomimetic agent. Should adverse air quality be encountered during the Los Angeles Olympics, allergic competitors will be among the most inconvenienced . Athletes with allergic rhinitis and sinusitis will be the most disadvantaged because sympathomimetic vasoconstrictors remain banned. It is strongly recommended that the Medical Commission of the International Olympic Committee meet with an appropriate body of experts (i.e., the American Academy of Allergy and Immunology) to review this ban on vasoconstrictor agents.

Duration of exercise in the provocation of exercise-induced asthma.

With running speed held constant, exercise durations of between two and 32 minutes all provoke significant asthma. However, the severity and length of the bronchoconstriction is less following exercise of two minutes duration. Exercise durations ranging from eight to 32 minutes show no difference in either incidence or severity of EIA.

Drug Tests for Athletes-Pro and Con.

Concerns about the costs and effectiveness of drug testing in reducing drug use and abuse among athletes has sparked a debate about whether testing should be continued, expanded in scope, or discontinued. THE PHYSICIAN AND SPORTSMEDICINE has asked physicians Daniel F. Hartley, Herman Adlercreutz. K. D. Fitch, and E. C. Percy for their views on the subject. Their comments are preceded by an introduction by Allan J. Ryan. MD.

Continuous and intermittent running in the provocation of asthma.

With total work constant, continuous running has been found to provoke more severe asthma than any of four different intermittent running regimes. This constitutes the first definite support for the clinical impression that exercise is better tolerated by asthmatics when broken into brief periods separated by intervals of recovery.