No abstract

Dihydropyridine calcium antagonists are candidate anticonvulsants, but little is known of their penetration into brain. Nifedipine (NFD) and nimodipine (NMD) pharmacokinetics were compared in mouse blood and brain, and their activity against pentylenetetrazol (PTZ) was assessed. After intraperitoneal (i.p.) injection, both dihydropyridines achieved peak blood and brain concentrations in 5 min. Estimated blood and brain elimination half-lives (t1/2) of NMD (16.7 and 22.4 min) were slightly longer than those of NFD (11.2 and 14.7 min). Brain and blood concentrations correlated with both NFD (r = 0.701, p less than 0.001) and NMD (r = 0.572, p less than 0.001). Injection of the dihydropyridines as a suspension (Tween 80) did not alter brain penetration, although systemic absorption was more erratic. NFD (p less than 0.001), NMD (p less than 0.02), and carbamazepine (CBZ, p less than 0.001) i.p. inhibited PTZ-induced seizures. Brain concentrations of PTZ were not altered by NFD pretreatment. Combining NFD and CBZ was less effective than giving NFD alone (p less than 0.005). NFD (p less than 0.002) and NMD (p less than 0.001) inhibited PTZ seizures after 2-week oral dosing, but low dosing was more effective than high dosing (p less than 0.002). NFD and NMD cross the blood-brain barrier (BBB) in mice and inhibit PTZ seizures. A possible therapeutic window was identified, and NFD and CBZ were less effective in combination than singly. A pharmacodynamic interaction may exist, inhibiting effective use of dihydropyridines as adjunctive therapy in epileptic patients.

No abstract

1 The effect of cimetidine (CMT; 400 mg twice daily) and matching placebo on the enzyme-inducing properties of carbamazepine (CBZ; 200 mg at night for 15 days) was studied in seven healthy male volunteers. 2 CMT alone had no significant effect on antipyrine kinetics, urinary 6,-hydroxycortisol excretion or leucocyte 8-aminolaevulinic acid synthase (ALA.S) activity. 3 CBZ increased leucocyte ALA.S activity by 204% following 1 week's treatment (P < 0.001). Thereafter, ALA.S activity fell despite continued CBZ administration. Concomitant CMT did not influence this response. 4 Antipyrine clearance and urinary 6 ,3-hydroxycortisol excretion were both increased by CBZ after 2 weeks' treatment (P < 0.01). CMT blocked CBZ induction of antipyrine metabolism but the rise in urinary 6 P-hydroxycortisol excretion was unaffected.5 Plasma CBZ concentrations 10, 14 and 18 h following the 8th and 15th doses were higher when CMT was taken concurrently (P < 0.05). CBZ half-life fell by 36% and clearance rose by 29% (both P < 0.001) with placebo and by 10% and 7% (both NS) when CMT was taken concurrently. 6 CMT inhibits CBZ auto-and hetero-induction in man. 7 Epileptic patients receiving CBZ chronically may be at risk of toxicity if CMT is also prescribed.

Stanozolol is an anabolic steroid which is used in the treatment of aplastic anaemia and has been recently advocated for the prophylaxis of vascular thrombosis. Similar steroid substances stimulate the activity of delta-aminolaevulinic acid synthase (ALA S), the rate limiting enzyme of haem biosynthesis, in rat hepatocytes and chick embryo liver cell cultures and activate acute hepatic porphyria. In the present study stanozolol (10 mg daily for 14 days) has been shown to increase significantly leucocyte ALA S activity in 9 healthy male subjects. There was a concomitant rise in urinary ALA and total porphyrin excretion but no change in antipyrine kinetics or urinary 6 B hydroxycortisol excretion. In a complementary study in male Sprague Dawley rats, stanozolol administered intraperitoneally, produced a dose-dependent increase in hepatic ALA S activity without changing hepatic cytochrome P 450 content. Stanozolol has been clearly shown to elevate ALA S activity, probably directly, and thereby, porphyrin production without affecting hepatic monooxygenase activity. This porphyrinogenic effect may be relevant to the successful treatment of aplastic anaemia with anabolic steroids. Leucocyte ALA S activity may provide a human system for the study of drug porphyrinogenicity in vivo.