Doping in sport

CORRESPONDENCE

Authors’ reply Sir—We welcome R H Davies’ suggestion of introducing seminars on stress management for medical students and doctors. Indeed the medical school at Newcastle University had introduced such a programme as part of the core curriculum for medical students. Pre-registration house officers are given information about stress management and some hospitals in the north east have stress management sessions that can be attended on a voluntary basis. Further effort is being made to improve such services. However, we feel such services should be available at all medical schools and hospitals. Benjamin Frankel and colleagues raise the point that the definition of current user of illicit drugs in our report was unclear. Current use was broken down with accompanying figures into weekly, monthly, and very occasionally for cannabis, the most commonly used illicit drug, but it is unlikely that responders would have classed themselves as current users if they took drugs only once a year. As detailed in our earlier report,1 the revised Department of Health (1995) safe levels of alcohol consumption have been criticised in that they apply mainly to men over age 40 and postmenopausal women; retention of the previous limits have been advocated by many experts on alcohol.2,3 Frankel et al also suggest that alcohol consumption in our study could have been overestimated since 21% of house officers initially contacted did not participate in our survey. We should point out that the alcohol consumption we reported was based on those who were drinkers. Although we accept that mean values for alcohol consumption may have been different if all those who were contacted had participated, it is erroneous to suggest that, for certain, alcohol consumption in those who did not participate were very different from the population as a whole. With respect to the comparison of lifestyles in junior doctors with those of the same cohort as second-year medical students, we did, in fact, state that alcohol consumption in junior doctors had increased compared with when they were second-year medical students. Finally, the study was designed to assess the extent of alcohol and illicit drug use in junior doctors. Evaluation of any effect of such substancces on their quality of work would require a separate study. J A Whitehead raised the question of compulsory random drug and alcohol testing for doctors, and we agree that

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this suggestion raises many difficult issues. However, since as many as one in 15 doctors may be suffering from some sort of dependence,4 it would be prudent to suggest that some form of intervention was now needed. *D Birch, H Ashton, F Kamali Wolfson Unit of Clinical Pharmacology, University of Newcastle, Newcastle upon Tyne, NE2 4HH, UK 1

2

3 4

Webb E, Ashton CH, Kelly P, Kamali F. Alcohol and drug use in UK university students. Lancet 1996; 348: 922–25. Royal College of Physicians. Alcohol and the heart in perspective: sensible limits reaffirmed. Summary of the report of a working group of the Royal Colleges of Physicians, Psychiatrists and General Practitioners. J R Coll Phys Lond 1995; 29: 266. Edwards G. Sensible drinking. BMJ 1996; 312: 1. British Medical Association. The misuse of alcohol and other drugs by doctors. London: BMA, 1998.

and suggest an array of side-effects including arterial hypertension, cerebral seizures, and graft thrombosis.4 Studies in Jehovah’s Witnesses before hip surgery discontinued EPO therapy once a packed-cell volume of 0·45 was reached.5 Thus the health risks of using EPO to increase packed-cell volume as high as 0·50 are unknown. Anecdotes abound relating EPO use to the sudden deaths of elite cyclists despite the UCI’s cut-off. It would be tragic if athletes were exposed to similar risk by the adoption of a policy whose sequelae are currently unknown. Gail Davey, *Richard Nerurkar 21 Springfield Road, Teddington, Middlesex TW11 9AP, UK 1

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Doping in sport 3

Sir—We are glad that investigators such as J J M Marx and P C J Vergouwen (Aug 8, p 451)1 are trying to clarify the scientific basis of rules governing doping in sport. However, certain important information was omitted from their research letter. Had the athletes under investigation resided or recently trained at altitude? “Participants in world championships and Olympic games” might include Kenyan or Ethiopian athletes normally resident at altitude or European athletes recently returned from altitude training. Living or training at altitude increases the packed-cell volume mechanisms.2,3 Did mean packed-cell volume differ significantly between athletes predominantly at sea level and those more usually resident at altitude? This information is needed before we formulate rules or cut-off points for track and field athletes similar to those enforced by the Union Cycliste Internationale (UCI). We acknowledge that administration of recombinant human erythropoietin (EPO) is impossible to detect but we do not feel that this is an argument for the International Olympic Committee to permit its use. Nor is the “correction” of physiological inequalities. The playing field of genetic endowment is never perfectly level, and this is one of many things that make sport exciting and competitive. More importantly for athletes themselves, little is known about the short or long-term effects of EPO administration in healthy people. Most studies have been done in patients with end-stage renal failure,

4

5

Marx JJM, Vergouwen PCJ. Packed-cell volume in elite athletes. Lancet 1998; 352: 451. Khraisha S, Awidi A. Comparative study of serum ferritin and its correlation with different blood parameters of students at Amman and Dead Sea levels. Aviat Space Environ Med 1987; 58: 987–97. Ruiz-Arquelles GJ, Sanchez-Medal L, Loria A, Piedras J, Cordova MS. Red cell indices in normal adults residing at altitude from sea level to 2670 m. Am J Hematol 1980; 8: 265–71. Singbartl G. Adverse events of erythropoietin in long-term and in acute or short-term treatment. Clin Invest 1994; 72: 536–43. Sparling EA, Nelson CL, Lavender R, Smith J. The use of erythropoietin in the management of Jehovah’s Witnesses who have revision total hip arthroplasty. J Bone Joint Surg 1996; 78: 1548–52.

Authors’ reply Sir—A Lancet research letter format did not permit many details of the athletes we studied. Six of the 18 men and one of the 28 women lived at high altitude but they trained and competed periodically at low altitude. The packed-cell volume (PCV) in men was 0·44 (SD 0·02) in the lowlanders and 0·46 (0·05) in highlanders (not significant). The female highlander had a PCV of 0·45; the mean of the lowlanders was 0·40. Some lowlanders had resided and trained at altitude for one or two periods of 3–5 weeks per season—namely, five of 12 men and seven of 28 women. We measured PCV before and after such periods. Only in one man athlete did the PCV increase after altitude training. In a much longer study, including more high-altitude native athletes, we found a significantly higher PCV in highlanders. In men athletes a PCV above 0·50 was found in only 0·8% of blood samples of lowlanders but in 20·5% samples of native highlanders (unpublished). It is clear from many reports in the lay press that several athletes in a variety of sports have used

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erythropoietin (EPO), titrating PCV close to 0·50, a limit indicated by the Union Cycliste Internationale. A higher PCV is thought to be harmful. As Gail Davey and Richard Nerurkar point out, little is known about the risks of longterm use of EPO in athletes and of an artificial increase of PCV to 0·50 or more. It is not realistic to extrapolate the risk of thrombotic and other vascular events from patients with atherosclerotic lesions (eg, those with terminal renal insufficiency), to healthy people and certainly not to elite athletes, who are constantly challenging the limits of physiology. A group at risk may be native highlanders, having a physiologically increased PCV. The high PCV is certainly useful at high altitude, but what happens if those athletes train and compete at sea level? And what about altitude training by lowlanders? Fortunately, the effects on PCV of short periods at high altitude were not unimpressive. The often emotional discussion about the manipulation of PCV in athletes is dominated by concern about health risks and fairness in competition. It would be good to stimulate and finance solid scientific investigations on short and long-term hazards of an increased PCV in healthy people and athletes who live at altitude or sea-level. *J J M Marx, P C J Vergouwen *Departments of Internal Medicine and Topsport Medicine, University Medical Centre, PO Box 85500, 3508 GA Utrecht, Netherlands 1

Marx JJM, Vergouwen PCJ. Packed-cell volume in elite athletes. Lancet 1998; 352: 451.

Lipid lowering therapy in patients with HIV infection Sir—Keith Henry and colleagues (Sept 26, p 1031)1 draw many inferences about the value of treatment of hyperlipidaemia in patients with established HIV infection on the basis of only 133 patients and minimum trial data. Although individual cases of accelerated atheroma have been reported2 there are no data on the prevalence of coronary or peripheral arterial disease in this population or its severity. The data for the differences between protease inhibitors are interesting but small scale. The hyperlipidaemias described are mostly mild and the data given insufficient for detailed analysis because HDL or LDL results and the triglyceride range are not provided. National Cholesterol Education Program (NCEP) guidelines were applied to decide treatment but the number of patients that met the different NCEP treatment target criteria are not shown and the

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Drug

Elimination Liver Cytochrome half-life metabolism metabolism (h) (%) Major Minor

Atorvastatin 15–58 Cerivastatin 2–3 Fluvastatin 0·8–1·5 Lovastatin 3 Provastatin 1·3–2·6 Simvastatin 8 Bezafibrate 2 Ciprofibrate 38–86 Fenofibrate 20 Gemfibrozil 6–8

95 70 95 82 50 87 100 100 100 100

3A4 2C8 2C9 3A4 none 3A4 3A4 3A4 3A4 3A4

3A6 3A4 3A4 .. ? various 3A5 .. .. .. ..

1

2

3

4

Fibrates are metabolised in liver, but 70–80% are renally excreted.

Henry K, Melroe H, Huebesch J, Hermundson J, Simpson J, Atorvastatin and gemfibrozil for protease-inhibitor-related lipid abnormalities. Lancet 1998; 352: 1031–32. SoRelle R. Vascular and lipid syndromes in selected HIV-infected patients. Circulation 1998; 9: 829–30. Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of HMG-coA reductase inhibitors. Clin Pharmacokinet 1997; 32: 403–25. Shepherd J. Fibrates and statins in the treatment of hyperlipidaemia: an appraisal of their efficacy and safety. Eur Heart J 1995; 16: 5–13. Rossen RD. HMG-CoA reductase inhibitors: a new class of anti-inflammatory drugs? J Am Coll Cardiol 1997; 30: 1218–19.

Liver half-lives and cytochrome degradation mechanism for lipid lowering drugs

5

applicability of these criteria is dubious in the absence of epidemiological data. The use of fibrates or statins to treat hyperlipidaemia in HIV patients needs to take into account the high prevalence of abnormal liver function tests and possible drug interactions with the multiplicity of medications used in this group. The choice of lipid-lowering drug needs to take into account both drug metabolism and liver metabolism (table) because of possible interactions with the disease and other drugs.3 Most protease inhibitors are metabolised through cytochrome 3A4. Atorvastatin has a long elimination half-life, has active metabolites, and is metabolised through cytochrome 3A4, though interactions seem rare. Provastatin has the least metabolism through cytochromes and has principal renal excretion. Treatment with gemfibrozil has accounted for 90% of the cases of severe myalgia in studies of fibratestatin combination therapy.4 Far more data exist on the use of bezafibrate and fenofibrate in this type of treatment. The consensus amongst lipid specialists favours the use of short half-life statins and fibrates in combination therapy, given at different times, to reduce the possibility of drug interactions. Statins may have unexpected effects in this infection. All statins are antiinflammatory5 and can reduce lymphocyte proliferation or affect macrophage differentiation. Thus they have the potential to increase virus loads or the number of infective relapses in this group of patients. The safety and efficacy of statin or fibrate therapy should be assessed before lipidlowering drugs can be considered for routine primary prevention of coronary heart disease in HIV.

Sir—Keith Henry and co-workers1 highlight the increased risks of coronary atherosclerosis secondary to hyperlipidaemia associated with protease inhibitors. They report that patients receiving ritonavir and saquinavir are most likely to develop this complication. Of more immediate concern, is the risk of pancreatitis secondary to these lipid abnormalities. We describe a case of pancreatitis and pseudocyst formation in a patient receiving ritonavir and saquinavir. A 48-year-old man, found to be HIV seropositive in 1994 after an episode of acute pneumocystis pneumonia (PCP), was started on zidovudine, didanosine, and secondary PCP prophylaxis. In 1995, disseminated Mycobacterium avium-intracellulare infection was diagnosed. He was treated with rifabutin, stavudine, and indinavir. Because of peripheral neuropathy, his nucleoside reverse-transcriptase inhibitors were stopped and he was started on saquinavir 600 mg and ritonavir 600 mg twice daily. 4 months later, he was admitted with a 3-day history of severe upper abdominal pain and nausea. There was no history of alcohol intake or gallstones. On examination, there was upper abdominal tenderness and guarding. His amylase was raised (246 ␮mol/L), and liver enzymes were high (alkaline phosphatase 345 IU/L, aspartate aminotransferase 102 IU/L, ␥-glutamyl transferase 485 IU/L). An ultrasound and computed tomography (CT) scan showed a well-demarcated low attenuation cyst within the head of the pancreas (2⫻3 cm). There was no pancreatic calcification, gallstones or focal hepatic parenchymal changes. There was no evidence of hepatic-duct dilation or sclerosing cholangitis on endoscopic retrograde cholangiopancreatography. Protease inhibitors were discontinued and he was managed with analgesia and parenteral nutrition. A follow-up CT scan 3 weeks later showed complete involution of the cyst.

*Anthony S Wierzbicki, Timothy M Reynolds, Martin A Crook, Joanna Tatler, Barry S Peters Departments of *Chemical Pathology, Genitourinary Medicine, and Pharmacy, St Thomas’ Hospital, London SE1 7EH, UK; Burton Hospitals, Burton-on-Trent, Staffordshire

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