quazinone and Heart-Failure

There are now several new CT drugs undergoing clinical study for the treatment of CHF. While most of these new agents are like digitalis in that they possess significant inotropic activity, they differ from digitalis in that they tend to also have pronounced vasodilator properties. Such compounds, because they are not pure CT agents, should not be regarded as true digitalis replacements. Despite the increased understanding about the cAMP cascade and about cardiac muscle contraction in general, the long search for a specific digitalis replacement cannot be regarded as having been accomplished. It should also be noted that the initial clinical assessment for any of these new compounds will be complicated by the fact that they are tested in only the latter stages of CHF where prognosis is very poor and the possibility of showing significant improvement in mortality is extremely difficult. It will be unfortunate if the potential for positive inotropic agents (pure CT drugs) is compromised by clinical studies that employ mixed inotropic-vasodilator compounds in extremely sick patient populations. The continued use of the digitalis glycosides for such a long period of history implies that at least some subpopulation of CHF patients should derive benefit from therapy with an appropriately selective CT drug. Neither the appropriate drug nor the appropriate specific patient population, both of which are needed to properly address the eventual role of inotropic therapy in CHF, have, as yet, been identified.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Cardiotonic Agents; Cyclic AMP; Digitalis Glycosides; Heart Failure; Humans; Myocardial Contraction; Receptors, Adrenergic, beta; Structure-Activity Relationship

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Administration, Oral; Aminopyridines; Amrinone; Cardiotonic Agents; Coenzymes; Enoximone; Heart; Heart Failure; Hemodynamics; Humans; Imidazoles; Injections, Intravenous; Milrinone; Nifedipine; Oxyfedrine; Phosphodiesterase Inhibitors; Pyridazines; Pyridones; Quinazolines; Ubiquinone

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Aminopyridines; Amrinone; Cardiotonic Agents; Glucagon; Glucosides; Heart Failure; Histamine; Humans; Imidazoles; Inosine; Quinazolines; Xanthines

Topics: Aminopyridines; Amrinone; Cardiac Glycosides; Cardiotonic Agents; Glucagon; Heart Failure; Histamine; Humans; Imidazoles; Inosine; Phosphodiesterase Inhibitors; Quinazolines; Sympathomimetics

The dose-response for the new cardiotonic agent RO13-6438 was studied in 6 patients with grade III or IV congestive heart failure. Oral doses of 10, 20, or 30 mg of RO 13-6438 were administered on 3 consecutive days in accordance with a double-blind, randomized cross-over pattern. Hemodynamic changes, which were dose-dependent, included an increase in cardiac index combined with decreases in pulmonary capillary wedge pressure and systemic and pulmonary arterial pressures. Heart rate remained unchanged. The area under the plasma RO 13-6438 concentration time curve and the peak plasma concentration were dose-related. At each measurement, the log concentration of RO 13-6438 correlated with the percent changes in both cardiac index and capillary wedge pressure recorded at that time.

Topics: Administration, Oral; Aged; Aged, 80 and over; Cardiotonic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Tolerance; Female; Heart Failure; Hemodynamics; Humans; Lung; Male; Middle Aged; Quinazolines; Vascular Resistance

Hybridization of structural elements of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline ring system common to the cyclic AMP (cAMP) phosphodiesterase (PDE) inhibitors lixazinone (RS-82856, 1) and anagrelide (3) with complementary features of other PDE inhibitor cardiotonic agents prompted the design and synthesis of the title compounds 7a-d, 11, 12, and 13a,b. The necessary features of these compounds were determined within the framework of the proposed active-site models for the high affinity form of cAMP PDE inhibited by cGMP (type IV). Evaluation of these targets, both in vitro as inhibitors of platelet or cardiac type IV PDE or in vivo as inotropic agents in the pentobarbital-anesthetized dog model of congestive heart failure, showed that these structure possessed negligibly enhanced activities over the parent heterocyclic system, and remained significantly inferior to 1 in all respects. This difference is ascribed to the absence of the N-cyclohexyl-N-methylbutyramidyl-4-oxy side chain of 1. The proposal that the acidic lactam-type functionality, common to the type IV PDE inhibitor inotropic agents such as 4-6 and 8-10, mimics the polarizable cyclic phosphate moiety of cAMP suggested that the side chain of 1 may function as an effective surrogate for selected characteristics of the adenine portion of cAMP. However, the results of this study show that incorporation of adenine-like hydrogen-bonding functionalities common to other type IV PDE inhibitors into the 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline system did not enhance activity to the levels observed for 1 and analogues. These observations, coupled with the kinetic pattern of inhibition of type IV PDE observed for 1 and analogues, suggest that access to a secondary, lipophilic-tolerant binding site, possibly coincident with the adenine binding domain, and adjacent to the catalytic ribose-phosphate binding site of platelet and cardiac type IV PDE, is responsible for the increased potency of these compounds.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Blood Platelets; Cardiotonic Agents; Dogs; Drug Evaluation; Heart Failure; Humans; Myocardium; Platelet Aggregation; Quinazolines; Structure-Activity Relationship

Survival in severe left ventricular failure is poor but has not been widely assessed since the introduction of several new nonglycosidic, nonsympathomimetic oral inotropic agents for long-term therapy. We examined retrospectively the survival of 82 patients with severe left heart failure during long-term treatment with oral milrinone (17 patients), posicor (12 patients), enoximone (47 patients), and piroximone (6 patients). Sixty-five patients were in New York Heart Association (NYHA) functional class 4, 15 patients were in class 3, and two patients were in class 2. There were 57 patients with ischemic and 25 patients were in class 2. There were 57 patients with ischemic and 25 patients with nonischemic etiology of left heart failure. Most patients were referred for inotropic therapy after failing to respond to conventional agents, including vasodilators. However, in almost all patients, marked hemodynamic and clinical improvement occurred initially. Overall survival was 36 percent at six months, the majority of deaths occurring during the first three months. Survival in relation to etiology of heart failure showed a trend toward increased mortality in patients associated with ischemic heart disease vs non-ischemic dilated cardiomyopathy. Sudden death mortality was also higher in the ischemic group (28 percent at six months vs 5 percent at six months; p less than 0.05). There was a trend toward reduced sudden death mortality in patients on antiarrhythmic agents during inotropic therapy (p = 0.06). We conclude that overall survival in symptomatic patients with severe left ventricular failure remains very low during long-term therapy with several new oral inotropic agents. Sudden death appears higher in patients with an ischemic etiology during therapy with these agents.

Topics: Administration, Oral; Aged; Anti-Arrhythmia Agents; Cardiotonic Agents; Death, Sudden; Drug Evaluation; Enoximone; Female; Heart Failure; Humans; Imidazoles; Male; Middle Aged; Milrinone; Pyridones; Quinazolines; Retrospective Studies; Time Factors

Systemic and coronary hemodynamics and transmyocardial norepinephrine release were determined before and after oral administration of RO13-6438, a new inotrope-vasodilator agent, in 12 patients with severe chronic heart failure unresponsive to conventional and vasodilator therapy. Improvement in left ventricular (LV) function was evident from a marked increase in cardiac index (from 2.09 +/- 0.45 to 3.30 +/- 0.73 liters/min/m2, p less than 0.01), stroke volume index (from 23 +/- 7 to 36 +/- 11 ml/m2, p less than 0.01), and stroke work index (from 23 +/- 11 to 36 +/- 14 g-m/m2, p less than 0.01), and concomitant fall in pulmonary capillary wedge pressure (from 26 +/- 7 to 16 +/- 8 mm Hg, p less than 0.01). Myocardial oxygen consumption did not change significantly (from 15.3 +/- 6.8 to 14.9 +/- 6.8 ml/min), but the ratio of minute work/myocardial oxygen consumption, an index of LV efficiency, increased significantly (p less than 0.05). Although average coronary sinus flow did not change, coronary sinus oxygen increased (from 3.2 +/- 0.8 to 4.2 +/- 1.5 vol%, p less than 0.05), and arterial-coronary sinus oxygen difference decreased (from 11.8 +/- 2.1 to 10.4 +/- 1.9 vol%, p less than 0.05), suggesting a primary vasodilating effect of RO13-6438 on the coronary vascular bed. Net transmyocardial norepinephrine release did not change despite the marked hemodynamic improvement. These findings suggest that RO13-6438 has the potential to cause marked improvement in LV function and LV efficiency in patients with severe, refractory congestive heart failure.

Topics: Adult; Aged; Blood Pressure; Cardiotonic Agents; Coronary Circulation; Female; Heart Failure; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Myocardium; Norepinephrine; Oxygen Consumption; Quinazolines; Vasodilator Agents