Jules Heuberger

Erythropoietin doping in cycling: lack of evidence for efficacy and a negative risk–benefit

Imagine a medicine that is expected to have very limited effects based upon knowledge of its pharmacology and (patho)physiology and that is studied in the wrong population, with low‐quality studies that use a surrogate end‐point that relates to the clinical end‐point in a partial manner at most. Such a medicine would surely not be recommended. The use of recombinant human erythropoietin (rHuEPO) to enhance performance in cycling is very common. A qualitative systematic review of the available literature was performed to examine the evidence for the ergogenic properties of this drug, which is normally used to treat anaemia in chronic renal failure patients. The results of this literature search show that there is no scientific basis from which to conclude that rHuEPO has performance‐enhancing properties in elite cyclists. The reported studies have many shortcomings regarding translation of the results to professional cycling endurance performance. Additionally, the possibly harmful side‐effects have not been adequately researched for this population but appear to be worrying, at least. The use of rHuEPO in cycling is rife but scientifically unsupported by evidence, and its use in sports is medical malpractice. What its use would have been, if the involved team physicians had been trained in clinical pharmacology and had investigated this properly, remains a matter of speculation. A single well‐controlled trial in athletes in real‐life circumstances would give a better indication of the real advantages and risk factors of rHuEPO use, but it would be an oversimplification to suggest that this would eradicate its use.

Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial

BACKGROUND Substances that potentially enhance performance (eg, recombinant human erythropoietin [rHuEPO]) are considered doping and are therefore forbidden in sports; however, the scientific evidence behind doping is frequently weak. We aimed to determine the effects of rHuEPO treatment in well trained cyclists on maximal, submaximal, and race performance and on safety, and to present a model clinical study for doping research on other substances. METHODS We did this double-blind, randomised, placebo-controlled trial at the Centre for Human Drug Research in Leiden (Netherlands). We enrolled healthy, well trained but non-professional male cyclists aged 18-50 years and randomly allocated (1:1) them to receive abdominal subcutaneous injections of rHuEPO (epoetin β; mean dose 6000 IU per week) or placebo (0·9% NaCl) for 8 weeks. Randomisation was stratified by age groups (18-34 years and 35-50 years), with a code generated by a statistician who was not masked to the study. The primary outcome was exercise performance, measured as maximal power output (Pmax), maximal oxygen consumption VO2 max, and gross efficiency in maximal exercise tests with 25 W increments per 5 min, as lactate threshold and ventilatory threshold 1 (VT1) and 2 (VT2) at submaximal levels during the maximal exercise test, and as mean power, VO2, and heart rate in the submaximal exercise tests at the highest mean power output for 45 min in a laboratory setting and in a race to the Mont Ventoux (France) summit, using intention-to-treat analyses. The trial is registered with the Dutch Trial Registry (Nederlands Trial Register), number NTR5643. FINDINGS Between March 7, 2016, and April 13, 2016, we randomly assigned 48 participants to the rHuEPO group (n=24) or the placebo group (n=24). Mean haemoglobin concentration (9·6 mmol/L vs 9·0 mmol/L [estimated difference 0·6, 95% CI 0·4 to 0·8]) and maximal power output (351·55 W vs 341·23 W [10·32, 3·47 to 17·17]), and VO2 max (60·121 mL/min per kg vs 57·415 mL/min per kg [2·707, 0·911 to 4·503]) in a maximal exercise test were higher in the rHuEPO group compared with the placebo group. Submaximal exercise test parameters mean power output (283·18 W vs 277·28 W [5·90, -0·87 to 12·67]) and VO2 (50·288 mL/min per kg vs 49·642 mL/min per kg [0·646, -1·307 to 2·600]) at day 46, and Mont Ventoux race times (1 h 40 min 32 s vs 1 h 40 min 15 s [0·3%, -8·3 to 9·6]) did not differ between groups. All adverse events were grade 1-2 and were similar between both groups. No events of grade 3 or worse were observed. INTERPRETATION Although rHuEPO treatment improved a laboratory test of maximal exercise, the more clinically relevant submaximal exercise test performance and road race performance were not affected. This study shows that clinical studies with doping substances can be done adequately and safely and are relevant in determining effects of alleged performance-enhancing drugs. FUNDING Centre for Human Drug Research, Leiden.

Indanes--Properties, Preparation, and Presence in Ligands for G Protein Coupled Receptors.

The indane (2,3‐dihydro‐1H‐indene) ring system is an attractive scaffold for biologically active compounds due to the combination of aromatic and aliphatic properties fused together in one rigid system. This bicyclic structure provides a wide range of possibilities to incorporate specific substituents in different directionalities, thus being an attractive scaffold for medicinal chemists. Notably, many indane‐based compounds are being used in the clinic to treat various diseases, such as indinavir, an HIV‐1 protease inhibitor; indantadol, a potent Monoamine Oxidase (MAO)‐inhibitor; the amine uptake inhibitor indatraline; and the ultra‐long‐acting β‐adrenoceptor agonist indacaterol. Given the diversity of targets these drugs act on, one could argue that the indane ring system is a privileged substructure. In the present review, the synthetic and medicinal chemistry of the indane ring system is described. In more detail, it contains a comprehensive overview of compounds bearing the indane substructure with G protein coupled receptor (GPCR) activity, with particular emphasis on their structure–activity relationships (SAR).

Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis

PURPOSE The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS). METHODS This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-controlled treatment phase. Twenty-four patients with progressive MS and moderate spasticity were enrolled. During the treatment phase, biomarkers for efficacy and secondary pharmacodynamic effects were measured at baseline and after 2 and 4 weeks of treatment. Serum samples were collected to determine pharmacokinetic properties and perform population modeling. Safety and tolerability profiles were assessed based on adverse events and safety measurements. FINDINGS Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo. Implications This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of Δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.

Accelerated Development of the Dual Orexin Receptor Antagonist ACT‐541468: Integration of a Microtracer in a First‐in‐Human Study

The orexin system regulates sleep and arousal and is targeted by ACT‐541468, a new dual orexin receptor antagonist (DORA). Healthy male subjects received a single oral dose of 5–200 mg to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), mass balance, metabolism, and absolute bioavailability utilizing a 14C‐labeled, orally and intravenously (i.v.) administered microtracer. The drug was safe and well tolerated; the PK profile was characterized by quick absorption and elimination, with median time to reach maximum concentration (tmax) of 0.8–2.8 h and geometric mean terminal half‐life (t1/2) of 5.9–8.8 h. Clear dose‐related effects on the central nervous system were observed at ≥25 mg, indicating a suitable PK‐PD profile for a sleep‐promoting drug, allowing for rapid onset and duration of action limited to the intended use. This comprehensive first‐in‐human study created a wealth of data, while saving resources in drug development.

Futility of current urine salbutamol doping control

Salbutamol is used in the management of obstructive bronchospasm, including that of some elite athletes. It is claimed that high salbutamol (oral) doses may also have an anabolic effect. Therefore, inhalation of salbutamol is restricted by the World Anti‐Doping Agency (WADA) to a maximal daily dose. Urine is tested for violations, but recent cases have resulted in a debate regarding the validity of this approach. It was our aim to determine whether current approaches are sufficiently able to differentiate approved usage from violations.

Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double‐Blind, Placebo‐Controlled, Crossover Trial

Increased excitability of motor neurons in patients with amyotrophic lateral sclerosis (ALS) may be a relevant factor leading to motor neuron damage. This randomized, double‐blind, three‐way crossover, placebo‐controlled study evaluated peripheral motor nerve excitability testing as a biomarker of hyperexcitability and assessed the effects of riluzole and retigabine in 18 patients with ALS. We performed excitability testing at baseline, and twice after participants had received a single dose of either 100 mg riluzole, 300 mg retigabine, or placebo. Between‐ and within‐day repeatability was at least acceptable for 14 out of 18 recorded excitability variables. No effects of riluzole on excitability testing were observed, but retigabine significantly decreased strength‐duration time‐constant (9.2%) and refractoriness at 2 ms (10.2) compared to placebo. Excitability testing was shown to be a reliable biomarker in patients with ALS, and the acute reversal of previously abnormal variables by retigabine justifies long‐term studies evaluating the impact on disease progression and survival.

World‐class cyclists on erythropoietin

In response to the Letter to the Editors by van Breda et al. 1 ‘Little soldiers in their cardboard cells’, we would like to acknowledge the point that the authors make regarding medical malpractice. Indeed, because of the ‘omerta’ (code of silence) in the cycling culture, the possible harm or injury caused by use of erythropoietin (EPO) in cyclists rarely sees daylight, and medical malpractice cannot be proved. Interestingly, Dr Eufemiano Fuentes was recently found guilty in Operacion Puerto of endangering public health through his doping practices. This verdict was possible partly because of the testimony by Jesus Manzano about his injury in the Tour de France of 2003, mentioned by van Breda et al. The case report in our paper 2 underlines the dangers into which these physicians put the athletes, and we hope to show the negative risk–benefit in EPO use and to encourage them to make a stand against these physicians who are practising negligence at least. Regarding the second point the authors make, it is true that a gain in maximal oxygen uptake is seen in the published studies. However, these studies are performed with trained cyclists at best, which are incomparable to world-class cyclists, as we showed in the original paper. The effects of EPO on performance parameters in elite cyclists are therefore unknown, making any further conclusions about the benefits of EPO use in this population unjustified. Additionally, it remains unclear even in trained cyclists whether EPO has an effect on submaximal exercise parameters, including power output at submaximal exercise, which is indeed the best predictor of cycling performances such as time trials 3–5. An increase of maximal oxygen uptake or maximal power output does not necessarily indicate a positive effect on submaximal parameters and therefore performance. Thus, on the basis of the evidence available in the literature, we conclude that it is not proved that EPO has a performance-enhancing effect in elite cyclists.