Agents for the treatment of heart failure

Bristol, James A.; Evans, Dale B.

doi:10.1002/med.2610030304

Cited by 18 publications

(16 citation statements)

References 145 publications

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“…The use of sympathomimetic agents such as dobutamine and dopamine is also limited because of their chronotropic liability and oral ineffectiveness.1,2) Thus, the absence of safe, orally effective-, positive inotropic agents for the treatment of CHF has stimulated the development of several new nonglycoside, nonsympathomimetic, cardiotonic agents such as amrinone, milrinone, sulmazole, and fenoximone. 3) In the course of our studies on new antiulcer agents, 2-phenylthiazolidine-3-thiocarboxamides (I), conformationally restricted analoguee4) of metiamide, have been synthesized. Unexpectedly, in the isolated guinea pig heart, these compounds were found to display positive inotropic activity which was not blocked by propranolol.…”

mentioning

confidence: 99%

Synthesis of 2-phenylthiazolidine derivatives as cardiotonic agents. I. 2-Phenylthiazolidine-3-thiocarboxamides.

Nate

Sekine

Honma

et al. 1987

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of novel 2-phenylthiazolidine-3-thiocarboxamides (II) was synthesized and tested for positive inotropic activity in the isolated guinea pig heart and in anesthetized dogs. Reaction of the benzaldehydes (VI, XI, XIV and XV) with cysteamine followed by treatment with isothiocyanates readily gave II. Structure-activity relationships were investigated by varying the structural parameters. N-Methyl-2 -phenylthiazolidine -3-thiocarboxamides having an ortho substituent such as a Me or OMe group exhibited significant positive inotropic action, which was not blocked by propranolol.Among the various ortho-alkoxyphenyl derivatives synthesized, the 2-(2-(3-(4-phenylpiperazino)propoxy)phenyl) derivative (I67) was found to exhibit more potent and longerlasting activity than amrinone without any significant effect on heart rate or blood pressure.Keywords 2 -phenylthiazolidine -3-thiocarboxamide ; positive inotropic activity; structureactivity relationship; cardiotonic agent Cardiac glycosides and sympathomimetic agents have been used for the treatment of congestive heart failure (CHF) for many years. Although cardiac glycosides such as digitoxin and digoxin have been the principal agents used for CHF, their use is limited by arrhythmogenic liability and very narrow therapeutic index. The use of sympathomimetic agents such as dobutamine and dopamine is also limited because of their chronotropic liability and oral ineffectiveness.1,2) Thus, the absence of safe, orally effective-, positive inotropic agents for the treatment of CHF has stimulated the development of several new nonglycoside, nonsympathomimetic, cardiotonic agents such as amrinone, milrinone, sulmazole, and fenoximone.3)In the course of our studies on new antiulcer agents, 2-phenylthiazolidine-3-thiocarboxamides (I), conformationally restricted analoguee4) of metiamide, have been synthesized. Unexpectedly, in the isolated guinea pig heart, these compounds were found to display positive inotropic activity which was not blocked by propranolol. In view of the structural novelty of this class of compounds as cardiotonic agents, we have synthesized a large number of derivatives by varying the structural parameters. In this paper, we report the synthesis and cardiotonic activity of a series of new 2-phenylthiazolidines represented by the general formula II and related compounds.Chart I

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mentioning

confidence: 99%

Synthesis of 2-phenylthiazolidine derivatives as cardiotonic agents. I. 2-Phenylthiazolidine-3-thiocarboxamides.

Nate

Sekine

Honma

et al. 1987

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…In the lambs, however, the hemodynamic responses to the infused drugs were quite uniform in the age range studied. The differences in chronotropic effects seen in humans and lambs could be related to species differences in adrenoceptor type, number, or sensitivity 20,21,24,25 In contrast to isoproterenol and dobutamine, dopamine had no effect on heart rate. This is in agreement LABORATORY INVESTIGATION-CONGENITAL HEART DISEASE in adult tissue.…”

Section: Discussionmentioning

confidence: 99%

Comparative circulatory effects of isoproterenol, dopamine, and dobutamine in conscious lambs with and without aortopulmonary left-to-right shunts.

Toorop¹,

Hardjowijono²,

Dalinghaus³

et al. 1987

Circulation

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We studied the effect on the circulation of the catecholamines isoproterenol, dopamine, and dobutamine in chronically instrumented lambs with aortopulmonary left-to-right shunts (ages 11 to 87 days) and without shunts (ages 8 to 97 days). Infusion of 0.1 ,ug/kg/min isoproterenol or 10 gvg/kg/min dobutamine markedly increased heart rate and systemic and pulmonary blood flows, while stroke volume and the left-to-right shunt flow did not change. Since 1222of myocardial performance: contractility, preload, and afterload.4 Moreover, isolated heart preparations have shown that the inotropic response to dopamine in perfused ventricles increased with advancing age in contrast to the response to isoproterenol, which was equal at all ages.5' ' Not only these age-related differences but also the different response of newborn and adult vessels to adrenergic stimuli7 suggest that different catecholamines should be used in children and adults. Therefore we infused dobutamine, dopamine, and isoproterenol into conscious lambs with and without aortopulmonary left-to-right shunts. Little is known about the hemodynamic effects of catecholamines in the presence of a left-to-right shunt lesion8 despite the fact that these lesions are the most common of all congenital heart diseases and often result in circulatory congestion, for which proper treatment should be instituted.The objectives of this study were to compare the hemodynamic changes caused by the infusion of dopamine, dobutamine, and isoproterenol into conscious lambs with and without aortopulmonary left-to-right shunts to establish differences in changes between the

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“…A hetereogeneous group of positive inotropic drugs were evaluated. Although these substances demonstrated improved hemodynamics and an improvement of symptoms in the short-term treatment of heart failure [59], [60], [61], [62], their use for longterm treatment has not been advocated due to a high incidence of adverse events and increased mortality that were observed in large clinical trials [63].…”

Section: Nonglycosidic Inotropic Agentsmentioning

confidence: 99%

“…They are used as selective bronchodilators (→ Antiasthmatic Agents), but they also enhance cardiac contractility. However, vasodilation rather than direct positive inotropic effects probably is the dominant mechanism of action [59], [60], [83].…”

Section: Trade Names (Hydrogen Fumarate): Corwin (Zeneca)mentioning

confidence: 99%