Jeffrey E. Edwards

GF120918, a P-Glycoprotein Modulator, Increases the Concentration of Unbound Amprenavir in the Central Nervous System in Rats

ABSTRACT The goal of this study was to determine the distribution of unbound amprenavir in the central nervous system (CNS) of rats. The concentration of unbound amprenavir in the extracellular fluid of the brain and the blood was examined in the presence and absence of the MDR modulator GF120918 by microdialysis. The brain-to-blood ratio of amprenavir in the absence and presence of GF120918 was found to be significantly different (P < 0.003; 0.076 and 0.617, respectively). The use of the MDR modulator GF120918 could potentially increase the penetration of human immunodeficiency virus protease inhibitors into the CNS.

Hydromorphone transfer into breast milk after intranasal administration.

Study Objectives. To determine the distribution of hydromorphone into breast milk and the potential exposure of the suckling infant, and whether the distribution of hydromorphone into milk can be predicted accurately by a passive diffusion model.

Role of P-glycoprotein in distribution of nelfinavir across the blood-mammary tissue barrier and blood-brain barrier

ABSTRACT As a first approach in understanding the possible efficacy and toxicity of human immunodeficiency virus protease inhibitors during breast feeding, the milk-to-plasma ratio of nelfinavir was determined in lactating rats. The milk-to-plasma ratio of nelfinavir was determined to be 0.56 ± 0.10 (means ± standard deviations). Western blotting indicated that P-glycoprotein is expressed in rat mammary and brain tissue; however, the multidrug-resistant modulator GF120918 showed a significant effect only at the blood-brain barrier and not at the mammary-epithelial tissue barrier.

Design and evaluation of novel biphenyl sulfonamide derivatives with potent histamine H(3) receptor inverse agonist activity.

Antagonism of the histamine-H(3) receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were shown to be potent and selective antagonists of the H(3) receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-alpha-methyl histamine (RAMH) induced dipsogenia, and one compound (4e) provided an increase in wakefulness in rats as measured by polysomnographic methods. However, more detailed analysis of the PK/PD relationship suggested the presence of a common active metabolite which may preclude this series of compounds from further development.

APD791, 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide, a Novel 5-Hydroxytryptamine 2A Receptor Antagonist: Pharmacological Profile, Pharmacokinetics, Platelet Activity and Vascular Biology

We have evaluated the receptor pharmacology, antiplatelet activity, and vascular pharmacology of APD791 [3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide] a novel 5-hydroxytryptamine 2A (5-HT2A) receptor antagonist. APD791 displayed high-affinity binding to membranes (Ki = 4.9 nM) and functional inverse agonism of inositol phosphate accumulation (IC50 = 5.2 nM) in human embryonic kidney cells stably expressing the human 5-HT2A receptor. In competition binding assays, APD791 was greater than 2000-fold selective for the 5-HT2A receptor versus 5-HT2C and 5-HT2B receptors, and was inactive when tested against a wide panel of other G-protein-coupled receptors. APD791 inhibited 5-HT-mediated amplification of ADP-stimulated human and dog platelet aggregation (IC50 = 8.7 and 23.1 nM, respectively). Similar potency was observed for inhibition of 5-HT-stimulated DNA synthesis in rabbit aortic smooth muscle cells (IC50 = 13 nM) and 5-HT-mediated vasoconstriction in rabbit aortic rings. Oral administration of APD791 to dogs resulted in acute (1-h) and subchronic (10-day) inhibition of 5-HT-mediated amplification of collagen-stimulated platelet aggregation in whole blood. Two active metabolites, APD791-M1 and APD791-M2, were generated upon incubation of APD791 with human liver microsomes and were also indentified in dogs after oral administration of APD791. The affinity and selectivity profiles of both metabolites were similar to APD791. These results demonstrate that APD791 is an orally available, high-affinity 5-HT2A receptor antagonist with potent activity on platelets and vascular smooth muscle.