Altered drug disposition of the platelet activating factor antagonist apafant in mdr1a knockout mice.

The aim of the present study was to determine a potential impact of P-glycoprotein (P-gp) on the tissue distribution and disposition of apafant (WEB 2086, CAS 105219-56-5), a selective platelet-activating factor antagonist, and on digoxin in mdr1a(-/-) and wildtype mice. Transport experiments in Caco-2 monolayers at low concentrations (<10 microM) showed that the secretory flux of [(14)C]apafant and [(3)H]digoxin exceeded the absorptive flux nine times. This efflux was concentration dependent and subject to inhibition by the P-gp substrates verapamil and cyclosporin A.

Memory-related task performance by aged rhesus monkeys administered the muscarinic M(1)-preferring agonist, talsaclidine.

Rationale: Muscarinic-acetylcholine receptor agonists are yet to be used clinically for the treatment of Alzheimer's disease (AD) even though laboratory evidence continues to support the potential for such an approach.

Objectives: The purpose of this study was to evaluate the M(1)-preferring agonist talsaclidine in aged monkeys for effects on working memory.

Methods: Three doses (0.