Sustained hemodynamic and clinical effects of a new cardiotonic agent, WIN 47203, in patients with severe congestive heart failure.

Abstract

produced substantial symptomatic improvement and increased maximal oxygen uptake at 1 week. Patients were further improved after 4 weeks of WIN 47203, and maximal oxygen uptake increased from 9.0 ± 1.9 to 11.6 ± 2.5 ml/kg/min (p < 0.01 vs control). No overt clinical or laboratory manifestations of toxicity were observed. Withdrawal of WIN 47203 in two patients in whom clinical benefit was not sustained resulted in clinical and hemodynamic deterioration, which was reversed by reinstitution of the drug. Therefore, this study demonstrates the acute and sustained cardiotonic efficacy of WIN 47203 in man. If long-term administration remains well tolerated and without side effects, this drug appears to be very promising for treatment of chronic severe congestive heart failure.PATIENTS with congestive heart failure become increasingly symptomatic as the severity of the disease progresses. In the advanced stage of the disease, patients are severely incapacitated despite optimal therapy with diuretics, digitalis and vasodilators.'-3 Amrinone, a nonglycosidic, nonadrenergic cardiotonic agent, improves ventricular performance and reduces symptoms at rest and during exertion.7 However, amrinone therapy is complicated by various side effects, e.g., thrombocytopenia, gastrointestinal intolerance, hepatotoxicity and fever. congestive heart failure. Methods SubjectsTherapy with WIN 47203 was offered to 11 patients with chronic congestive heart failure who were severely incapacitated despite treatment with diuretics, digitalis and nitrates. Eight of the patients had not benefited from therapy with arteriolar vasodilators, which were therefore discontinued. The severity of the functional impairment was confirmed by a maximal oxygen uptake below 12 ml/kg/min in every patient (average 9.0 ml/kg/min, range 6-11.2 ml/kg/min). The nature, benefits and risks of the study were fully explained and all patients gave informed consent. The protocol was approved by the Committee on Clinical

Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside.

“…Milrinone causes a marked increase in myocardial contractile force in vitro (1, 2), and consequently, it has been assumed that an increase in inotropic state is responsible, at least in part, for the marked beneficial hemodynamic effects of this agent in patients with severe congestive heart failure (3,4). However, milrinone (5, 6), like amrinone (14,15), is also a potent direct vascular smooth muscle relaxing agent in vitro.…”

“…Milrinone, a potent new bipyridine analogue of amrinone, exerts a positive inotropic action in vitro (1,2), and causes marked beneficial changes in hemodynamic function in patients with severe congestive heart failure, with decreases in right and left heart-filling pressures and increases in stroke volume and work (3,4). However, milrinone also possesses potent direct vascular smooth muscle-relaxing properties in vitro (5,6), and causes a reduction in mean arterial pressure in patients with heart failure (3,4), indicating that some, if not all, of the agent's overall hemodynamic effects are due to a reduction in left ventricular afterload.…”

“…However, milrinone also possesses potent direct vascular smooth muscle-relaxing properties in vitro (5,6), and causes a reduction in mean arterial pressure in patients with heart failure (3,4), indicating that some, if not all, of the agent's overall hemodynamic effects are due to a reduction in left ventricular afterload.…”

In vivo and in vitro Effects of Amrinone and Milrinone on Hepatic Xenobiotic Metabolism in Rats

“…Amrinone and milrinone are nonglyco side, noncatecholamine inotropic agents shown to relieve congestive heart failure in experimental animals and in humans [1][2][3][4], Manzione et al [5] found in a group of patients with congestive heart failure that the aminopyrine breath test was depressed 62% after amrinone treatment and increased 38% after milrinone treatment although the mean cardiac index in both groups increased significantly. This test is based on the fact that orally administered l4C-labeled amino pyrine is demethylated by the cytochrome P-450 system and the l4C02 formed excreted into the expired air [6,7], It thus reflects the activity of the hepatic mixed-function oxi dase system and has been used in humans to assess liver function.…”

Is inotropic therapy appropriate for patients with chronic congestive heart failure? Or is the digitalis leaf withering?

“…The digitalis compounds may produce, at least acutely, regional vasoconstriction (Mason, 1974) and the experimental inotropic agents amrinone (Ross et al, 1981;van Breeman et al, 1980), milrinone (Alousi et al, 1983) and MDL 17,043 (Uretsky et al, 1983) Multiple clinical studies have justified this assumption (Table II). Dobutamine (Leier et al, 1977), dopamine (Beregovich et al, 1974;Loeb et al, 1971;Holzer et al, 1-973), amrinone (Benotti et al, 1978;LeJemtel et al, 1979;Maskin et al, 1982), milrinone (Sinoway et al, 1983;Maskin et al, 1983a;Baim et al, 1983), MDL 17,043 (Uretsky et al, 1983), MDL 19,205 (Petain et al, 1984) and ARL-1 15-BS (Renard et al, 1983;Thormann et al, 1982), among others have been shown to improve haemodynamics acutely in patients with chronic severe (New York Heart Association Class III-IV) heart failure. Such improvement may occur even with drugs that act by a beta-adrenergic mechanism which may already have been endogenously stimulated (Figure 2).…”