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Thomas Baum

Bio: Thomas Baum is an academic researcher from Schering-Plough. The author has contributed to research in topics: Angiotensin-converting enzyme & Labetalol. The author has an hindex of 18, co-authored 45 publications receiving 942 citations.

Papers
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Journal Article
TL;DR: It is concluded that SCH 19927 is a more potent beta adrenoceptor blocker and less potent alpha blocker than labetalol, and the separation of adrenergic blocker activities indicates that steric requirements for alpha and beta blockade differ in the labetAlol molecule.
Abstract: Labetalol is a mixture of four isomers. Its alpha and beta adrenergic blocking properties were compared to those of the R,R-isomer, SCH 19927. In anesthetized dogs, i.v. administration of both compounds produced competitive beta and alpha blockade as judged by inhibition of the tachycardia and vasopressor responses to i.v. injections of isoproterenol and phenylpherine, respectively. SCH 19927 was 3 to 4 times as potent as beta blocker, but only one-third as potent an alpha blocker as labetalol. Therefore, the separation of beta and alpha blocking activity of SCH 19927 clearly exceeded that of labetalol. SCH 19927 also demonstrated greater beta blocking potency than labetalol after oral administration to conscious dogs or rats that were subsequently pithed. SCH 19927 did not affect, whereas labetalol slightly reduced, pressor responses to sympathetic stimulation in the pithed rat. Both drugs were relatively devoid of intrinsic beta-1 sympathomimetic activity in the ganglion-blocked dog. It is concluded that SCH 19927 is a more potent beta adrenoceptor blocker and less potent alpha blocker than labetalol. The separation of adrenergic blocker activities indicates that steric requirements for alpha and beta blockade differ in the labetalol molecule.

80 citations

Journal ArticleDOI
TL;DR: The synthesis of a series of N-(mercaptoacyl)-4-substituted-(S)-prolines (2 and 3) is described, which were evaluated in vitro for inhibition of angiotensin-converting enzyme (ACE) and in vivo for ACE inhibition.
Abstract: The synthesis of a series of N-(mercaptoacyl)-4-substituted-(S)-prolines (2 and 3) is described. These compounds were evaluated in vitro for inhibition of angiotensin-converting enzyme (ACE), and selected compounds were evaluated in vivo for ACE inhibition. The most potent compounds in vitro are 108, 109, 111, 114, and 116, having relative potencies of 1.0, 1.0, 1.3, 1.1, and 2.6 as compared to the potency of captopril. The most potent compounds in vivo intravenously are 108, 111, 114, 116, 117, and 97.

74 citations

Journal ArticleDOI
TL;DR: The antihypertensive activity of labetalol can be ascribed to at least three identified complementary mechanisms, beta-adrenergic blockade, Beta- adrenergic mediated vasodilatation, and alpha-adrevation blockade, whereas the antihypermethine activity of 2a derives from the first two mechanisms only.
Abstract: A useful method for the separation of labetalol into its two racemic diastereomers, as well as a stereoselective synthesis of its four stereoisomers, is described. The absolute stereochemistry of each isomer was determined by analysis of the DC spectra and confirmed by X-ray analysis. The alpha- and beta 1-adrenergic blocking properties, as well as the relative antihypertensive activities, have been measured in rats. The R,R isomer, 2a (SCH 19927), possesses virtually all of the beta 1-blocking activity elicited by labetalol and displays little alpha-blocking activity. In contrast, the S,R isomer, 3a, has most of the alpha-blocking activity. Of the four isomers, only 2a has antihypertensive potency comparable to that of labetalol. These findings, coupled with published data showing that labetalol possesses beta-adrenergic mediated peripheral vasodilating activity deriving essentially from its R,R isomer, lead to the following conclusion: The antihypertensive activity of labetalol can be ascribed to at least three identified complementary mechanisms, beta-adrenergic blockade, beta-adrenergic mediated vasodilatation, and alpha-adrenergic blockade, whereas the antihypertensive activity of 2a derives from the first two mechanisms only.

73 citations

Journal Article
TL;DR: It is concluded that vasodilatation is largely responsible for the antihypertensive response to labetalol and particularly to SCH 19927, a potentially useful agent which would be expected to reduce pressure in humans by two complementary mechanisms, beta blockade and vasodILatation.
Abstract: SCH 19927, one of the four chiral forms of labetalol, is approximately 4 times as potent as a beta adrenergic receptor blocker as the parent racemate, but is only one-third as potent in blocking alpha receptors. The present report describes its antihypertensive and hemodynamic actions. SCH 19927 and labetalol lowered blood pressure in hypertensive rats and dogs. SCH 19927 was somewhat more effective at lower doses, but the two agents produced comparable responses at higher doses. Both reduced blood pressure and peripheral resistance and increased cardiac output in anesthetized dogs. Intraarterial injection in to the femoral vascular bed, either in the presence or absence of neurogenic vasoconstrictor tone, resulted in dose-related vasodilatation. In contrast, alpha blockers, e.g., phentolamine and prazosin, are essentially devoid of vasodilator activity in denervated beds. It is concluded that vasodilatation is largely responsible for the antihypertensive response to labetalol and particularly to SCH 19927. SCH 19927 is a potentially useful agent which would be expected to reduce pressure in humans by two complementary mechanisms, beta blockade and vasodilatation. It should possess less orthostatic potential than labetalol.

64 citations

Journal Article
TL;DR: The data suggest that AGEPC produces direct myocardial depression and distinct effects on the coronary and femoral vasculature, and some coronary effects may be mediated through metabolites of arachidonic acid.
Abstract: Acetyl glyceryl ether phosphoryl choline (AGEPC) is a potent vasodilator, platelet activator and inflammatory agent. The cardiac and peripheral vascular effects of AGEPC were assessed in anesthetized dogs in order to gain additional insight into the mechanism of action of this lipid. Injection of AGEPC (0.1-3.2 micrograms) directly into the femoral vasculature produced a dose-related vasodilation in the innervated and sympathetically denervated hindlimb. Vasodilator responses in the denervated limb were at least as great as those in the innervated limb, which indicates that the response is not due to inhibition of sympathetic vasoconstrictor tone. Vasodilator responses to AGEPC (1 microgram) were not significantly affected by theophylline (5 mg/kg), indomethacin (5 mg/kg) or BW755C (10 mg/kg), which implies that the effect is independent of purinergic P1 receptors, cyclooxygenase products and lipoxygenase products. Intracoronary injection of AGEPC (0.032-3.2 micrograms) reduced blood pressure, myocardial contractile force and coronary blood flow in a dose-related manner. Coronary vascular resistance was unchanged. In contrast, intracoronary injection of another activator of platelets, ADP (10 micrograms), increased blood flow. Responses of blood pressure, heart rate, contractile force and coronary flow to AGEPC were not affected by bilateral vagotomy or hexamethonium, which indicates that they are independent of reflexive mechanisms. Indomethacin attenuated the hypotension and coronary flow reductions to AGEPC. BW755C reduced the hypotensive response. Mechanical reduction of coronary flow by 30 to 40% did not affect blood pressure, heart rate or contractile force, which suggests that AGEPC-induced changes are not secondary to flow reduction. The data suggest that AGEPC produces direct myocardial depression and distinct effects on the coronary and femoral vasculature. The peripheral vascular effects are independent of the autonomic nervous system, purinergic mechanisms and arachidonic acid metabolites, whereas some coronary effects may be mediated through metabolites of arachidonic acid.

64 citations


Cited by
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TL;DR: It is emphasized how in clinical pharmacology, and particularly in pharmacokinetics, neglect of stereoselectivity in action leads to the performance of expensive “highly sophisticated scientific nonsense”.
Abstract: The significance of stereochemistry in therapeutic action is outlined and elucidated. Often only one isomer is therapeutically active, but this does not mean that the other is really inactive. It may very well contribute to the side-effects. The therapeutically non-active isomer in a racemate should be regarded as an impurity (50% or more). It is emphasized how in clinical pharmacology, and particularly in pharmacokinetics, neglect of stereoselectivity in action leads to the performance of expensive "highly sophisticated scientific nonsense". This also holds true in the development and marketing of new drugs as exemplified by various "pseudo-hybrid" drugs now reaching the clinic.

555 citations

Journal ArticleDOI
TL;DR: A review providing a comprehensive, rather than exhaustive, appraisal of enantioselective drug action and pharmacokinetic mechanism of action.

416 citations

Journal ArticleDOI
TL;DR: The goals of the present article are to provide a critical review of the literature on cocaine-associated chest pain and myocardial infarction and to give guidance for diagnostic and therapeutic interventions.
Abstract: The goals of the present article are to provide a critical review of the literature on cocaine-associated chest pain and myocardial infarction (MI) and to give guidance for diagnostic and therapeutic interventions. Classification of recommendations and levels of evidence are expressed in the American College of Cardiology/American Heart Association (ACC/AHA) format as follows: The Writing Committee conducted a comprehensive search of the medical literature concerning cocaine-associated chest pain and MI. The literature search included English-language publications on humans and animals from 1960 to 2007. In addition to broad-based searching concerning cocaine, specific targeted searches were performed on cocaine and the following topics: MI, chest pain, emergency department (ED), aspirin, nitroglycerin, calcium channel blocker, benzodiazepine, thrombolytics, phentolamine, heparin, primary angioplasty, ECG, and stress testing. Literature citations were generally limited to published articles listed in Index Medicus. The article was reviewed by 4 outside reviewers nominated by the AHA. Cocaine is the second most commonly used illicit drug in the United States, with only marijuana …

369 citations

Journal ArticleDOI
TL;DR: The finding that human heart can produce PAF, expresses PAF receptor, and is sensitive to the negative inotropic action of PAF suggests that this mediator may have a role also in human cardiovascular pathophysiology.
Abstract: Platelet-activating factor (PAF) is a phospholipid mediator that belongs to a family of biologically active, structurally related alkyl phosphoglycerides. PAF acts via a specific receptor that is coupled with a G protein, which activates a phosphatidylinositol-specific phospholipase C. In this review we focus on the aspects that are more relevant for the cell biology of the cardiovascular system. The in vitro studies provided evidence for a role of PAF both as intercellular and intracellular messenger involved in cell-to-cell communication. In the cardiovascular system, PAF may have a role in embryogenesis because it stimulates endothelial cell migration and angiogenesis and may affect cardiac function because it exhibits mechanical and electrophysiological actions on cardiomyocytes. Moreover, PAF may contribute to modulation of blood pressure mainly by affecting the renal vascular circulation. In pathological conditions, PAF has been involved in the hypotension and cardiac dysfunctions occurring in various cardiovascular stress situations such as cardiac anaphylaxis and hemorrhagic, traumatic, and septic shock syndromes. In addition, experimental studies indicate that PAF has a critical role in the development of myocardial ischemia-reperfusion injury. Indeed, PAF cooperates in the recruitment of leukocytes in inflamed tissue by promoting adhesion to the endothelium and extravascular transmigration of leukocytes. The finding that human heart can produce PAF, expresses PAF receptor, and is sensitive to the negative inotropic action of PAF suggests that this mediator may have a role also in human cardiovascular pathophysiology.

366 citations