Amrinone: a new non-glycosidic, non-adrenergic cardiotonic agent effective in the treatment of intractable myocardial failure in man.

SUMMARYThe cardiotonic activity of a new, noncatechol, nonglycoside agent, amrinone, waa investigated in vitro and in anesthestized and unanesthetized dogs. Amrinone (3-1000 /ig/ml) caused a dose-dependent increase in papillary muscle developed tension and df/dt without significant changes in duration of the contractile cycle or time-to-peak tension. Amrinone induced slight increases in right atrial rate with no changes in electrophysiological properties of the cat papillary muscle or dog Purkinje fibers. In anesthetized dogs, intravenous bolus injections of amrinone at doses ranging from 1 to 10 mg/kg caused increases in cardiac contractile force and left ventricular dp/dt max with relatively small changes in heart rate and blood pressure. No significant changes in lead II ECG were observed. In unanesthetized dogs, intravenous infusion of amrinone (10-100 /ig/kg per min) caused increases in left ventricular dp/dt max and only small changes in heart rate and blood pressure. Amrinone, tested orally in this model at doses of 2-10 mg/kg, produced a positive inotropic effect with a rapid onset and long duration of action. The inotropic response to amrinone was not blocked by propranolol, dibenzyline, chlorisondamine, atropine, metiamide, or reserpine. Amrinone's inotropic response was not associated with significant alterations in cardiac norepinephrine, phosphodiesterase, cyclic AMP, or Na + ,K + -activated ATPase. Ore Res 45: 666-677, 1979 A LARGE number of agents have positive inotropic effects on the heart. However, of these, only two classes of compounds have been found to be useful in the treatment of heart failure in man. The cardiac glycosides have enjoyed a valued position for nearly 200 years in spite of the fact that they have a narrow therapeutic range, and digitalis intoxication is one of the most common drug-induced adverse reactions in this country (Mason et al., 1971;Beller et al., 1971;Doherty and Kane, 1975). The catecholamines have limitations in that they are arrhythmogenic, are chronotropic, have a short duration of action, and cannot be given orally (Goldberg, 1968). Dopamine (Goldberg, 1974;Beregovich et al., 1974) and the synthetic catecholamine, amine dobutamine (Tuttle and Mills, 1975;Goldberg et al, 1977), both of which have been introduced recently for clinical use, suffer from most of the same drawbacks as the older catecholamines. Other inotropic agents, such as glucagon (Farah and Tuttle, 1960;Glick et al., 1968) has proved of value in the management of congestive heart failure (Cohn and Franciosa, 1977;Mehta, 1977).The development of an orally active non-catechol and non-glycoside cardiotonic agent has been the goal of this laboratory for several years (Alousi and Farah, 1975;Alousi et al., 1978;Farah and Alousi, 1978). Amrinone (Win 40680), a 5-amino-3,4'-bipyridine-6(lH)-one, is a novel chemical entity with rather unique cardiac inotropic properties Farah and Alousi, 1978). In this report, the action of amrinone on the heart is studied in several models, and in light of these res...

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“…Preliminary results in patients (Benotti et al, 1978;Le Jemtel et al, 1979) have confirmed our findings in the dog.…”

Section: Discussionsupporting

confidence: 86%

Cardiotonic activity of amrinone--Win 40680 [5-amino-3,4'-bipyridine-6(1H)-one].

Alousi¹,

Farah²,

Lesher³

et al. 1979

Circulation Research

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219

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“…The inotropic effect of amrinone has already been widely reported (Alousi er al., 1978; Benotti er al., Endelson er al., 1981;Farah and Alousi, 1978;Lejmetel et al, 1979). In humans, these inotropic effects are characterized by an increase in the rate of left ventricular pressure development and cardiac output accompanied by a decrease in ventricular filling pressure (Benotti et al, 1978;Lejmetel et al, 1979).…”

Section: Discussionmentioning

confidence: 99%

Echocardiographic evaluation of cardiovascular effects of amrinone

Modena

Benassi

Mattioli

1984

Clinical Cardiology

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Amrinone, a new inotropic drug, was infused at a dosage of 2.5 mg/kg body weight in 14 patients affected by dilatative cardiomyopathy in New York Heart Association (NYHA) functional class III and IV. Cardiac index, mean arterial pressure, and some echocardiographic parameters were evaluated. Cardiac index (CI) increased from 2.03±0.24 to 2.82±0.43 1/min/m2 (p<0.001). Fractional shortening (FS) increased from 16.4 ± 5.2 to 21.5±5.3% (p<0.05). End‐diastolic and end‐systolic diameters showed a significant reduction. Mean arterial pressure decreased from 90.7±8.8 to 87.3±8.4 mmHg (p<0.001), the end‐systolic stress (ESS) decreased from 5.8±1 to 5.2±1 g/cm (p<0.001). Analyzing the relationship between FS and ESS, it was possible in some cases to suppose the presence of an important vasodilator effect of the drug. The afterload in 7 patients was therefore modified before and after infusion of the drug to analyze FS at the same levels of afterload. This was done to evaluate the vasodilator effect of amrinone. Examining the regression line of FS/ESS ratio it was possible to observe a predominant vasodilator effect in some patients, but in most, a sinergic action was noted. This may be useful for chronic treatment of congestive heart failure, reducing amrinone doses, and using it in association with other vasodilator drugs.

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“…Amrinone (Sterling-Winthrop), a new bipyridine analogue, has recently been reported to improve cardiac function in refractory congestive cardiac failure (Benotti et al, 1978;LeJemtel et al, 1979), possibly as the result of phosphodiesterase inhibition (Honerjager et al, 1981;Endoh et al, 1982). Platelet function alterations induced by amrinone have been evaluated in both in vitro studies and in an animal model (Rao et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

The effects of amrinone on platelet count, survival and function in patients with congestive cardiac failure.

Wilmshurst¹,

Al-Hasani²,

Semple³

et al. 1984

Brit J Clinical Pharma

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In a prospective trial, the immediate and long‐term haematological effects of amrinone were studied in sixteen patients with refractory cardiac failure. The platelet count was significantly and variably reduced in all patients and the reduction was related to log plasma amrinone concentration. Platelet survival was significantly reduced in those cases studied. No evidence of disseminated intravascular coagulation or intravascular platelet deposition was observed and the reduced platelet survival was not considered to be the result of an immunological process. Evidence of a marrow response to the reduced platelet count and survival was seen. Although no haemorrhagic symptoms were observed in the patients, the haematological side‐effects were considered to be of such severity as to limit the use of this drug in clinical practice.

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Amrinone: a new non-glycosidic, non-adrenergic cardiotonic agent effective in the treatment of intractable myocardial failure in man.

Cited by 219 publications

References 8 publications

Cardiotonic activity of amrinone--Win 40680 [5-amino-3,4'-bipyridine-6(1H)-one].

Cardiotonic activity of amrinone--Win 40680 [5-amino-3,4'-bipyridine-6(1H)-one].

Echocardiographic evaluation of cardiovascular effects of amrinone

The effects of amrinone on platelet count, survival and function in patients with congestive cardiac failure.

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