Increase of extracellular brain calcium involved in interleukin-1 beta-induced pyresis in the rabbit: antagonism by dexamethasone.

1This study investigates the role of extracellular brain calcium in the hyperthermia induced by interleukin-1 beta (IL-1 beta). 2 Intracerebroventricular (i.c.v.) injection of IL-1 beta (12.5 ng kg(-1)) in rabbits caused a prompt and sustained rise in cerebrospinal fluid (CSF) Ca2+ concentration ([Ca2+]) followed by enhanced prostaglandin E(2) (PGE(2)) release and hyperthermia. 3 A linear and significant correlation was observed between the increase in [Ca2+] induced by IL-1 beta and the rise in body temperature. 4 Ventriculo-cisternal perfusion with artificial CSF containing the calcium chelator EGTA (1.3 mM) blocked the IL-1-induced PGE(2) release and countered the febrile response. 5 I.c.v. administration of dexamethasone (Dex) (2.4 and 24 mu g kg(-1)) 100 min prior to IL-1 beta, dose-dependently antagonized the cytokine-induced Ca2+ increase, the PGE(2) release and the febrile response. 6 These results suggest that changes in extracellular brain calcium are involved in the regulation of body temperature. In this light, the antipyretic action of Dex may be related to its effect on Ca2+ uptake

Pharmacokinetics of chlorimipramine, chlorpromazine and their N-dealkylated metabolites in plasma of healthy volunteers after a single oral dose of the parent compounds.

A single oral dose of 0.7 mg kg-1 chlorimipramine (n = 18) and chlorpromazine (n = 16) was given to each subject 45 days apart and plasma concentrations of parent drugs and their monodesmethyl and didesmethyl metabolites were measured by GC. Ingestion of chlorimipramine resulted in an area under the plasma concentration-time curve (AUC0-24) for parent drug plus metabolites 5-fold higher than that observed in the same subjects following chlorpromazine intake (600 +/- 87 and 124 +/- 14 ng mL-1, respectively). Plasma chlorimipramine levels reached a mean peak value of 43.8 ng mL-1, which occurred 2 h after administration. Desmethyl metabolite kinetics of chlorimipramine appeared to be elimination rate-limited and those of chlorpromazine appeared to be formation-rate-limited. The response to single doses of these two drugs in healthy subjects highlights the two distinct dispositional processes involved, thus offering pharmacokinetic explanation of the hitherto empirical discrepancy in dosage levels in chronic treatment

HPLC determination of inorganic cation levels in CSF and plasma of conscious rabbits.

An HPLC method is described using conductimetric detection for the quantitative determination of sodium, potassium, magnesium, and calcium in cerebrospinal fluid (CSF) and plasma of conscious rabbits. This method enabled the four cations to be estimated with rapidity, sensitivity, accuracy, and precision. The mean millimolar concentrations +/- SD found in CSF and (plasma) of 15 untreated animals were as follows: sodium, 146.96 +/- 17.84 (135.06 +/- 20.11); potassium, 3.32 +/- 0.56 (4.57 +/- 1.03); magnesium, 0.90 +/- 0.20 (0.72 +/- 0.13); and calcium, 1.47 +/- 0.19 (3.32 +/- 0.59)