Differential plasma duration of antiplatelet-activating factor and antihistamine activities of oral Sch 37370 in humans.

Abstract

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.

• Authors: M M Billah, H G Gilchrest, S P Eckel, C A Granzow, P J Lawton, E Radwanski, M D Brannan, M B Affrime, J D Christopher, W Richards
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 52 Issue 2 Pg. 151-9 (Aug 1992) ISSN: 0009-9236 [Print] United States
• PMID: 1505150 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial)

Chemical References

• Histamine Antagonists
• Piperidines
• Platelet Activating Factor
• Loratadine
• N-acetyldesloratadine

Topics

• Administration, Oral
• Adult
• Double-Blind Method
• Electrocardiography (drug effects)
• Histamine Antagonists (blood, pharmacokinetics, pharmacology)
• Humans
• Loratadine (analogs & derivatives)
• Male
• Piperidines (blood, pharmacokinetics, pharmacology)
• Platelet Activating Factor (antagonists & inhibitors)