Thomas Shaughnessy

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A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4,(More)
Nicotinic acetylcholine receptors (nAChRs) function as ligand-gated ion channels activated by the neurotransmitter acetylcholine. Gene knockout and antisense studies coupled with pharmacological studies with nAChR agonists have documented a role of α4β2 nAChR activation in analgesia. ABT-594, for the first time, provided clinical validation to the nAChR(More)
This study was designed to compare the initial tremor response to 4.0 mg albuterol and 5.0 mg terbutaline orally administered and to study the question of tachyphylaxis by rechallenge after 3 wk of maintenance dosing. Twenty fasting patients with severe COPD in whom orally administered sympathomimetics were withheld for 2 wk were challenged with single(More)
Agents that activate the dopamine D2-like family of receptors elicit emesis in humans and other species with a vomiting/emetic reflex; however, the lack of dopamine receptor subtype selective agonists has hampered an understanding of which dopamine D2-like receptor subtype(s) contributes to the emetic response. In this study, stable cell lines expressing(More)
Our primary goal has been to discover leukotriene biosynthesis inhibitors with characteristics that are appropriate for use as clinical agents. The success of the use of zileuton in the treatment of asthma led us to explore further the use of the N-hydroxyurea class of 5-lipoxygenase inhibitors as longer-acting compounds with good lung penetration. A(More)
Leukotrienes are biologically active lipid mediators capable of producing airway inflammation, hyperresponsiveness and bronchoconstriction. The first enzyme in the metabolic pathway of arachidonic acid leading to the leukotrienes is 5-lipoxygenase (5-LO). A selective and potent 5-LO inhibitor, zileuton (N-1(1-benzo[b]thien-2-ylethyl)-N-hydroxyurea, A-64077)(More)
The functional antagonism between isoproterenol and methacholine, histamine and serotonin, as described in vitro in respiratory smooth muscle was explored in vivo in a canine model. Infusions of isoproterenol were administered during brief peaks of bronchospasm produced by aerosolized methacholine and histamine, or during sustained bronchospasm produced by(More)
INTRODUCTION Conscious rodent models are commonly used to assess the effects of new chemical entities on propulsion (transit) time in the gastrointestinal system. This study was designed to compare three compounds clinically known to cause constipative (morphine sulfate and propantheline bromide) and laxative (metoclopramide hydrochloride) effects on(More)
Evidence of a candidate drug's efficacy and safety is mandatory for successful drug registration by regulatory authorities. However, a third property, tolerability, often determines a drug's acceptance by the patient population. Gastrointestinal events often determine the maximum tolerated dose in Phase I clinical trials. If the plasma concentrations(More)