Contribution of cytochrome P-4502D6 phenotype to the neuromodulatory effects of dextromethorphan.

Dextromethorphan (DEM)-mediated N-methyl-D-aspartate receptor blockade may result from an action of unchanged DEM or its active metabolite, dextrorphan (DOR). In humans, DEM is metabolized into DOR by the polymorphic enzyme CYP2D6. We therefore investigated the impact of quinidine (Qd), a selective inhibitor of CYP2D6, on DEM disposition and the contribution of CYP2D6 phenotype on DEM antinociceptive and neuromodulatory effects. Using a randomized, double-blind, crossover, placebo-controlled design, healthy volunteers (n = 7) received Qd (50 mg Qd sulfate orally) or a placebo and, 12 h later, either DEM (50 mg DEM hydrobromide orally) or a placebo. DEM and DOR pharmacodynamics were assessed for their antinociceptive and neuromodulatory effects. Antinociceptive effects were assessed over 4 h by subjective pain threshold and RIII nociceptive reflex (RIII) monitoring. Neuromodulatory effects were studied using the primary and secondary hyperalgesia induced by the topical application of capsaicin. Two of seven subjects were genotypic CYP2D6 PM. Pretreatment of EM by Qd suppressed DOR formation and increased the plasma level of DEM to the levels of poor metabolizers. In poor metabolizers, DEM induced a significant increase in objective (+45%) and subjective (+35%) pain thresholds. In extensive metabolizers, only a slight and short-lasting increase in the subjective threshold was observed, whereas no effect was seen on the objective threshold. DEM modulates secondary hyperalgesia compared with DOR. The CYP2D6 phenotype affects the disposition of DEM and the production of the active metabolite DOR. The impact of the CYP2D6 phenotype is of major importance for the spinal antinociceptive and neuromodulatory effects of DEM.

[Retrospective study of drug-induced agranulocytosis in hospitalized patients in Geneva and comparison with cases reported to IOCM]. / Etude rétrospective des cas d'agranulocytose médicamenteuse hospitalisés à Genève et comparaison avec les cas notifiés à l'OICM.

In a retrospective study, 19 cases classified as idiosyncratic drug-induced agranulocytosis were found among 162 files of patients hospitalized in internal medicine clinics of the university hospital where this diagnosis had been coded. This would give an estimated incidence of 2.6 cases per million inhabitants per year for the Geneva area. In most cases several drugs were implicated in causation of the episodes. Suspected drugs were those commonly reported in the literature, but also some drugs which might already have been taken to treat infectious complications of agranulocytosis. A comparison of the Geneva cases with those notified to the Swiss Intercantonal Office for the Control of Medicines reveals a similar profile of involved drugs.

[Genetic and environmental effects on neuromodulation and the antinociceptive effect of dextromethorphan]. / Influences génétiques et environnementales sur la neuromodulation et l'effet antinociceptif du dextromethorphan.

Administration of NMDA antagonists leads to attenuation or disappearance of some symptoms of central sensitization, such as secondary hyperalgesia. However, the side effects of NMDA antagonists to a large extent counterbalance the expected benefits, thus preventing wide or prolonged use. Dextromethorphan and its metabolite dextrophan, on the other hand, are established and safe drugs. Experimentally they both antagonize the NMDA receptor. This study evaluates the effects of dextromethorphan and its metabolite in pain models using electrical stimulation for testing the antinociceptive effect and capsaicin-induced hyperalgesia. Dextromethorphan shows clear antinociceptive as well as neuromodulary effects, both depending heavily on the cytochrome P450 2D6 phenotype (CYP2D6).

[Drug-induced hepatic involvement, something to consider!]. / Atteintes hépatiques médicamenteuses, il faut y penser!

A retrospective study over the last 5 years on drug-induced liver injury was performed in the Internal Medicine Department of the University Hospital of Geneva. According to WHO and Council for International Organizations of Medical Sciences (CIOMS) criteria for drug-induced liver adverse events, 142 cases were identified, with 255 drugs fulfilling causality criteria of certain, probable or possible. 63 patients (44%) suffered severe consequences of liver injury, including 9 deaths. Drugs reported belonged to the therapeutic classes of antibiotics (43%), cardiovascular (20%), analgesics (10%), gastrointestinal (9%), psychotropic (7%), and others (11%). Despite bias inherent to the retrospective methodology, only 10% of the side effects were spontaneously reported to the pharmaco-vigilance board. This is in accordance with the known reporting rate. It can be concluded that spontaneous reports are to be regarded only as signals.