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PT-141, a cyclic heptapeptide melanocortin analog, was evaluated following intranasal administration in healthy male subjects and in Viagra-responsive erectile dysfunction (ED) patients. Erectile response was assessed by RigiScan™ in healthy subjects without visual sexual stimulation (VSS) and in Viagra ® -responsive ED patients with VSS. In healthy subjects, mean C max and AUC (0– t ) increased in a dose-dependent manner. Median T max was 0.50 h and mean t 1/2 ranged from 1.85 to 2.09 h. In both studies, an erectile response induced by PT-141 administration was statistically significant, compared to placebo, at doses greater than 7 mg, with the onset of the first erection occurring in approximately 30 min. PT-141 was safely administered and well tolerated in both studies. A maximum-tolerated dose was not identified. Flushing and nausea were the most common adverse events reported in both studies and no clinically significant changes in vital signs, laboratory tests, ECGs, or physical exams were observed. Based upon its erectogenic potential and tolerability profile, PT-141 is a promising candidate for further evaluation as a treatment for male ED.

PT-141, a cyclic heptapeptide melanocortin analog, was evaluated following subcutaneous administration to healthy male subjects and to patients with erectile dysfunction (ED) who report an inadequate response to Viagra ® . An inadequate response was defined for this study by patient report indicating that achievement of an erection suitable for vaginal penetration occurred ≤50% of the time while taking 100 mg Viagra ® . Erectile responses were assessed by RigiScan™ in healthy subjects in the absence of visual sexual stimulation (VSS) and in ED patients in the presence of VSS. Doses ranging from 0.3 to 10 mg were administered to healthy male subjects, resulting in a statistically significant erectile response at doses greater than 1.0 mg. ED patients were treated with placebo, 4 or 6 mg PT-141 in a crossover design in the presence of VSS. The erectile response induced by PT-141 was statistically significant at both doses. PT-141 was safe and well tolerated in both studies. The erectogenic potential of PT-141, its tolerability profile and its ability to cause significant erections in patients who do not have an adequate response to a PDE5 inhibitor suggest that PT-141 may provide an alternative treatment for ED with a potentially broad patient base.

During ischemic stroke, neurons at risk are exposed to pathologically high levels of intracellular calcium (Ca ++ ), initiating a fatal biochemical cascade. To protect these neurons, we have developed openers of large-conductance, Ca ++ -activated (maxi-K or BK) potassium channels, thereby augmenting an endogenous mechanism for regulating Ca ++ entry and membrane potential. The novel fluoro-oxindoles BMS-204352 and racemic compound 1 are potent, effective and uniquely Ca ++ -sensitive openers of maxi-K channels. In rat models of permanent large-vessel stroke, BMS-204352 provided significant levels of cortical neuroprotection when administered two hours after the onset of occlusion, but had no effects on blood pressure or cerebral blood flow. This novel approach may restrict Ca ++ entry in neurons at risk while having minimal side effects.

The response of rat liver adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] to catecholamines is enhanced after adrenalectomy. To investigate this phenomenon, we developed an in vitro assay for β -adrenergic receptors of plasma membranes derived from livers of control and adrenalectomized rats, using [125I]iodohydroxybenzylpindolol (IHYP), a potent β -adrenergic receptor antagonist. Binding of IHYP reached equilibrium within 30 min and dissociation occurred with a half-time of approximately 60 min. The l-isomers of isoproterenol and propranolol were at least 50 times more potent as inhibitors of IHYP binding than were the corresponding d-isomers. Adrenalectomy did not affect the rates of association or dissociation of IHYP or the dissociation constants of several ligands that are active at β -adrenergic receptors. The number of binding sites for IHYP was determined in homogenates and in purified membranes of livers from control and adrenalectomized rats. The number of sites increased 3- to 5-fold after adrenalectomy. A similar increase in hormone stimulation of adenylate cyclase was observed. These changes were reversed by the administration of cortisone. The increase in the number of binding sites for IHYP may be a compensatory response to the impairments in gluconeogenesis and glycogenolysis which occur after adrenalectomy.

The binding of [3H]domperidone and [3H]spiroperidol was examined in membranes prepared from rat striatum. Scatchard analysis of the binding of [3H]domperidone resulted in curvilinear plots consistent with the presence of multiple classes of binding sites. Nonlinear regression analysis of untransformed data showed that the curvature was best explained by the presence of two populations of binding sites. Scatchard plots of the binding of [3H]spiroperidol were linear, suggesting that this radioligand binds to a single class of receptors. However, results obtained in studies of the inhibition of [3H]spiroperidol binding by a number of competing ligands were not consistent with the interaction of these agents with a single class of binding sites. Computer-assisted analysis of the Hofstee plots of six competing ligands gave the same relative proportion for two classes of sites as determined by analysis of the binding of [3H]domperidone. The two classes of receptors labeled with [3H]spiroperidol had affinities for domperidone that were similar to those of the two populations of binding sites for [3H]domperidone. Furthermore, the number of binding sites for [3H]spiroperidol was equal to the total number of binding sites for [3H]domperidone. These findings suggest that the two radioligands bind to the same two classes of binding sites. It is unlikely that either of the two classes of striatal sites are receptors for serotonin. The approach described will make it possible to assess the effects of physiological or pharmacological manipulations on the densities or properties of subtypes of dopamine receptors.

beta 1- and beta 2-adrenergic receptors coexist in atria of humans and a variety of other species. The significance of these receptors and the quantitative extent to which beta 2-adrenergic receptors contribute to the electrophysiologic effects of catecholamines acting at beta-adrenergic receptors have not been determined. In the present study, the beta 1-selective antagonist ICI 89,406 and the beta 2-selective antagonist ICI 118,551 were used to determine the relative densities of beta 1- and beta 2-adrenergic receptors on membranes prepared from dog atria and the contribution that each subtype makes to isoproterenol-induced shortening of action potential duration measured at 75% repolarization (APD75). Computer-aided nonlinear regression analysis of the inhibition of the specific binding of [125I]iodopindolol and the inhibition of isoproterenol-stimulated APD75 shortening by these antagonists showed that a two-site model fits the data better than a one-site model (P less than 0.0001). The affinity constants for each selective antagonist determined by inhibition of APD75 shortening were similar to those determined in studies of the inhibition of the specific binding of [125I]iodopindolol to beta 1- and beta 2-adrenergic receptors. beta 2-Adrenergic receptors made up approximately equal to 25% of the total number of beta-adrenergic receptors but mediated approximately equal to 50% of the electrophysiologic effect of isoproterenol. The inhibition of the binding of [125I]iodopindolol and of the APD75 shortening by propranolol, a nonselective antagonist, was best fit by a one-site model. In other experiments, dogs were treated with reserpine and atropine to eliminate complications caused by the presence of endogenous norepinephrine and acetylcholine. Results obtained with atria from these animals were similar to those obtained in studies with control atria. These data suggest that beta 2-adrenergic receptors as well as beta 1-adrenergic receptors are involved in mediating the electrophysiologic effects of catecholamines in dog atrial muscle and that both beta 1- and beta 2-adrenergic receptors are present on atrial muscle cells.

The development of a sensitive and specific enzymatic assay for dopamine-β -hydroxylase has enabled us to measure the activity of this enzyme in several tissues where it has not previously been measured. The administration of reserpine leads to an increase in dopamine-β -hydroxylase activity in the rat adrenal, heart, salivary gland, and in sympathetic ganglia. The increase in the heart is preceded by a small but significant fall. We have confirmed the increase in tyrosine hydroxylase which follows the administration of reserpine and have found that the activity of phenylethanolamine-N-methyltransferase also increases after administration of this drug. The activities of two enzymes not involved in the synthesis of catecholamines, monoamine oxidase and lactate dehydrogenase, are not affected by reserpine treatment. The rise of dopamine-β -hydroxylase activity in the sympathetic ganglia is blocked by surgical decentralization.

β1- and β2-adrenergic receptors coexist in atria of humans and a variety of other species. The significance of these receptors and the quantitative extent to which β2-adrenergic receptors contribute to the electrophysiologic effects of catecholamines acting at β -adrenergic receptors have not been determined. In the present study, the β1-selective antagonist ICI 89,406 and the β2-selective antagonist ICI 118,551 were used to determine the relative densities of β1- and β2-adrenergic receptors on membranes prepared from dog atria and the contribution that each subtype makes to isoproterenol-induced shortening of action potential duration measured at 75% repolarization (APD75). Computer-aided nonlinear regression analysis of the inhibition of the specific binding of [125I]iodopindolol and the inhibition of isoproterenol-stimulated APD75shortening by these antagonists showed that a two-site model fits the data better than a one-site model (P < 0.0001). The affinity constants for each selective antagonist determined by inhibition of APD75shortening were similar to those determined in studies of the inhibition of the specific binding of [125I]iodopindolol to β1- and β2-adrenergic receptors. β2-Adrenergic receptors made up ≈ 25% of the total number of β -adrenergic receptors but mediated ≈ 50% of the electrophysiologic effect of isoproterenol. The inhibition of the binding of [125I]iodopindolol and of the APD75shortening by propranolol, a nonselective antagonist, was best fit by a one-site model. In other experiments, dogs were treated with reserpine and atropine to eliminate complications caused by the presence of endogenous norepinephrine and acetylcholine. Results obtained with atria from these animals were similar to those obtained in studies with control atria. These data suggest that β2-adrenergic receptors as well as β1-adrenergic receptors are involved in mediating the electrophysiologic effects of catecholamines in dog atrial muscle and that both β1- and β2-adrenergic receptors are present on atrial muscle cells.

The intraventricular administration of 6-hydroxydopamine, a procedure which destroys noradrenergic nerve terminals in the central nervous system, caused an increase in the density of β-adrenergic receptors in rat cerebral cortex, without affecting their affinity for isoproterenol. The results suggest that changes in the density of adrenergic receptors are involved in 6-hydroxydopamine-induced supersensitivity at central noradrenergic synapses.