Clopidogrel requires CYP450-mediated hepatic metabolism to form its active metabolite (clopi-H4). This randomized, placebo-controlled, crossover study was designed to characterize the effect of a high-fat or standard breakfast on adenosine diphosphate (ADP)-induced platelet aggregation and exposure to unchanged clopidogrel and clopi-H4 following clopidogrel (300-mg loading dose, 75 mg/d for 4 days) in 72 healthy men. At day 5 and as assessed by liquid chromatography-tandem mass spectrometry, unchanged clopidogrel area under the concentration- time curve from 0 to 24 hours (AUC(0-24)) increased 3.32-fold (90% confidence interval [CI], 2.88-3.84), and clopi-H4 AUC(0-24) decreased nonsignificantly by 12% (90% CI, 0.82-0.94) upon administration of clopidogrel with a standard breakfast. The estimated treatment difference in maximum platelet aggregation (MPA) induced by ADP 5 µM and assessed by light transmission aggregometry was 4.7%, with the 90% CI (0.9%-8.5%) contained within the prespecified equipotency range of ±15%. The mean ± standard deviation of day 5 inhibition of platelet aggregation was 49.7% ± 17.2% and 54.0% ± 13.3% in the fed and fasted states, respectively. Despite increased unchanged clopidogrel and slightly decreased clopi-H4 exposure following clopidogrel administration, the numerical increase in MPA in the fed versus fasted state was small and within the prespecified limit of equipotency. These findings confirm that clopidogrel can be taken with or without food.

The present study was designed to examine the effects of administration of a GABAergic agonist (Baclofen) on run-time to exhaustion in trained and untrained rats, and on some indicators of fatigue. Run-time to exhaustion on a treadmill set at a speed of 25 m.min-1 was significantly increased in both untrained (p < 0.01) and trained rats (p < 0.005) administered with baclofen one hour before the exercise. The animals who had run the longest time displayed the lowest concentrations of liver and muscle glycogen, and a decrease in plasma glucose concentrations (p < 0.05). The results of this investigation suggest that fatigue during prolonged exercise can be influenced by pharmacological administration of a GABAergic agonist. Indicators of fatigue such as glycemia, liver and muscular glycogen are not the limiting factors of performance and central mechanisms play a key role at exhaustion.

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involvement of a gamma-hydroxybutyric acid receptor in startle disease. Acta Paediatr 1994;83:678-80. Stockholm. ISSN 0803-5253 Startle disease or hyperexplexia is an autosomal dominant neurological disorder, with a neonatal onset, characterized by muscular hypertonia and myoclonic jerks, exaggerated by the slightest stimulus. Low concentrations of free gamma-aminobutyric acid (GABA) have been found in the cerebrospinal fluid of two affected infants. The involvement of GABA or its receptors has been raised and the use of GABA-agonist drugs has been suggested. We report a newborn with startle disease who also had a low concentration of GABA in the cercbrospinal fluid. No clinical improvement was observed with progabide, a GABA agonist. Furthermore, a high dose (100 mg/kg) of gammahydroxybutyrate (GHB) did not improve muscular stiffness and failed to induce gcncral anaesthesia. GHB, currently used as an effective general anaesthetic, is a structural analogue of GABA. It is present naturally at low concentrations in the brain and is regarded as an inhibitory neurotransmitter. Two specific GHB receptors, distinct from the GABA receptors, have been identified in rat brain. Failure to induce general anaesthesia with a high dose of GHB suggests that one of thcsc receptors could be involved in startle disease. a Gamma-hydroxyhutyric acid, neurotransmitter, startle disease