Differential plasma duration of antiplatelet-activating factor and antihistamine activities of oral Sch 37370 in humans.
Preclinical studies have established that Sch 37370 (1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta [1,2-b]pyridin-11-ylidene)piperidine) is an orally active antagonist of platelet-activating factor (PAF) and histamine H1-receptors with potential therapeutic use in the treatment of asthma. To evaluate the efficacy and duration of anti-PAF and antihistamine actions of oral Sch 37370 in humans, a single dose (5 mg/kg) of Sch 37370 was given orally to each of 10 male subjects in a placebo-controlled, double-blind crossover study. Blood samples were drawn before and at various times (2 to 48 hours) after Sch 37370 or placebo. Plasma samples were analyzed for Sch 37370 by a gas chromatographic method, for the anti-PAF activity by measuring the aggregation of platelets stimulated with PAF, and for the antihistamine activity by measuring displacement of [3H]pyrilamine from rat brain membrane binding sites. The plasma anti-PAF activity declined from high levels at 2 hours to barely detectable levels at 24 hours; however, significant activity was still present at 12 hours. The plasma levels of Sch 37370 closely paralleled the anti-PAF profile. The plasma antihistamine activity reached a maximum within 2 to 8 hours and declined thereafter. However, 48 hours after Sch 37370, the antihistamine activity was still present at a significant level in most subjects. It is concluded that, in humans, oral Sch 37370 antagonizes both PAF and histamine with plasma antihistamine activity lasting longer than plasma anti-PAF activity.
Billah
M M
MM
Schering-Plough Research Institute, Bloomfield, NJ 07003.
Gilchrest
H G
HG
Eckel
S P
SP
Granzow
C A
CA
Lawton
P J
PJ
Radwanski
E
E
Brannan
M D
MD
Affrime
M B
MB
Christopher
J D
JD
Richards
W
W
D000284:Administration, Oral; D000328:Adult; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D006633:Histamine Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D017336:Loratadine / Q000031:analogs & derivatives; D008297:Male; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*
D006633:Histamine Antagonists; D010880:Piperidines; D010972:Platelet Activating Factor; D017336:Loratadine; C063524:N-acetyldesloratadine