Sandra A.G. Visser(1), Susanna Pozarek(1), Tomas Forsberg(2), Johan Gabrielsson(1).
AstraZeneca R&D Södertälje, DMPK & Bioanalytical Chemistry (1) and General Pharmacology (2), SE-15185 Södertälje, Sweden
Objectives: Clomethiazole (CMZ) enhances g-aminobutyric acid (GABAA) receptor activity and is used as a sedative, hypnotic and anticonvulsant drug. In several animal stroke models, CMZ is also effective as a neuroprotectant, reducing ischemia- induced cerebral damage and behavioral abnormalities in rodents and primates. CMZ has been shown to induce dose-dependent hypothermia in rats and the difference between doses producing neuroprotection and doses causing hypothermia was established as part of the safety evaluation of the compound. In the present investigation, the onset, intensity, and duration of hypothermia, and the rebound hyperthermic effects of CMZ were studied in rats.
Methods: The hypothermic effects of CMZ were studied in male Sprague Dawley rats after subcutaneous (sc) bolus administration of 0, 15, 150 and 600 µmol/kg and 24h continuous administration of 20 and 40 µmol/kg/h using osmotic pumps. Temperature was recorded using radiotelemetric transmitters between 4 days before dosing and 4 days after dosing. Plasma exposure to CMZ was obtained in different groups of (catheterized) rats with simultaneous temperature recording.
Results: All animals displayed asymmetric circadian variation of 1°C in their baseline body temperature. A dose-dependent decrease in temperature was observed upon bolus sc dosing followed by a rebound hyperthermic effect upon returning to predose baseline. In the 24h sc infusion groups, a decrease in temperature was observed for the first 6-10 hour. The effect then returned to baseline in spite of continuous exposure to CMZ, indicating tolerance. A rebound hyperthermic effect was observed, which lasted for several days during daytime but not nighttime.
Conclusions: The PK analysis showed that CMZ displays Michaelis-Menten kinetics. PD analysis showed a rapid lowering (onset) of body temperature that reached about 3°C reduction (intensity), and tolerance development (duration) of response in spite of the fact of continuous exposure to CMZ. A rebound hyperthermic effect was observed during daytime but not nighttime.
Reference: PAGE 12 () Abstr 436 [www.page-meeting.org/?abstract=436]
Poster: poster