No abstract

We investigated whether the combination of chlormadinone acetate (CMA) and a luteinizing hormone releasing hormone (LH-RH) agonist, leuprorelin acetate (leuprorelin), more markedly decreased ventral prostate and seminal vesicle weights and plasma sex hormone levels in male rats. Four weeks after administration of 0.28, 0.84 or 2.8 mg/kg of leuprorelin, ventral prostate weights significantly decreased (53.8, 54.4 and 64.1%) and the plasma testosterone levels significantly lowered, but not dose-dependently. After repetitive administrations of 3 and 30 mg/kg/day of CMA, the rates of ventral prostatic atrophy were 37.1 and 65.9%, respectively. Although there was no change in the plasma testosterone level at 3 mg/kg, 30 mg/kg of CMA significantly decreased the level. A combination of leuprorelin (0.28 mg/kg) and CMA (3 or 30 mg/kg) more potently induced ventral prostatic and seminal vesicle atrophy than leuprorelin alone. Furthermore, a combination of leuprorelin and CMA (30 mg/kg) more markedly decreased the plasma testosterone level. According to the pharmacokinetic data for CMA in male rats, the doses of CMA correspond to the clinical dose. These findings suggest that combination therapy with an LH-RH agonist and CMA is more useful than therapy with the agonist alone in the treatment of prostate cancer.

Abstract-Cardiacand coronary vasodilator effects of gentamicin (GM) were investigated in isolated, blood-perfused papillary muscle, sino-atrial (SA) node and atrioventricular (AV) node preparations of dogs. GM (0.3-100 "mol) was injected intraarterially.GM produced an increase in coronary blood flow in all preparations. In paced papillary muscle preparations, GM reduced the force of contraction.In spontaneously beating papillary muscle preparations, GM decreased the rate of automaticity and the force of contraction.In SA node preparations, GM decreased the sinus rate. In AV node preparations, GM injected into the posterior septal artery (which supplies the AV node) increased AV conduction time and in large doses, produced third-degree AV block. In the same preparations, GM in large doses injected into the anterior septal artery (which supplies the His-Purkinje ventricular system) prolonged AV conduction time (i.e., intraventricular conduction time) and reduced the amplitude of ventricular bipolar electrograms.

Hormonally induced prostate growth produced bladder obstruction, in terms of pressure/flow characteristics, that are analogous to BPH. It is suggested that this type of hormonal treatment can be used to create a model for the study of the effects of controlled increased in prostate growth and the development of BPH on micturition.

The cardiohemodynamic effects of the potassium-channel openers, cromakalim and pinacidil, were studied by the use of the closed-loop method (for both drugs) and the cardiopulmonary bypass technique (for cromakalim only) in anesthetized, open-chest dogs. In closed-loop preparations, both drugs (cromakalim, 3 to 100 micrograms/kg; pinacidil, 10 to 300 micrograms/kg) administered intravenously decreased systemic blood pressure and increased venous return (sum of the flow through the inferior and the superior vena cava) and cardiac output (CO). With the highest doses of both drugs, venous return and CO decreased in some preparations in which right atrial pressure rose, and the maximum rate of rise of left ventricular pressure (LV dP/dt max) diminished. Except such preparations, right atrial pressure, heart rate, and atrioventricular conduction time remained virtually unchanged. The fall in systemic blood pressure produced by intermediate doses of pinacidil was greater in the preparations in which baroceptor reflexes were eliminated (denervated preparations) than in those with the reflexes left intact (nerve-intact preparations). The increases in venous return and CO, however, were not different when comparing the nerve-intact and the denervated preparations. In cardiopulmonary-bypass preparations, higher doses of cromakalim increased venous return while producing a fall in systemic blood pressure, suggesting that the decreased venous return and CO seen with higher doses of the potassium-channel openers in the closed-loop preparations were secondary to the decreased cardiac contractility. The potassium-channel openers should be characterized as vasodilators, which preferentially reduce afterload and increase venous return.

Profile of AN-132, a New Diamine Derivative Antiarrhythmic Agent, Revealed in the Isolated, BloodPerfused Dog Heart. Tohoku J. exp. Med., 1988, 156 (1), 65-78 -The cardiac and coronary effects of AN-132, a new antiarrhythmic agent, were investigated in isolated, blood-perfused atrioventricular (AV) node, sinoatrial (SA) node and papillary muscle preparations of dogs. AN-132 was administered intraarterially. In AV node preparations, whether injected into the anterior septal artery (ASA ; supplying the His-Purkinje-ventricular system) or the posterior septal artery (PSA ; supplying the AV node), AN-132 prolonged AV conduction time and produced second-or third-degree AV block at large doses in some preparations. Moreover, only when injected into the ASA AN-132 produced a broadening and diminution of amplitude of bipolar electrograms obtained from the right bundle branch and the ventricular septum. In SA node preparations, AN-132 decreased sinus rate and produced atrial standstill at large doses in some preparations. In paced papillary muscle preparations, AN-132 reduced the force of contraction. In spontaneously beating papillary muscle preparations, AN-132 decreased the rate of automaticity and the force of contraction. In all preparations, AN-132 produced a transient increase in blood flow only at large doses. The order of potencies of AN-132 based on the doses that produced 15% suppressions of the above cardiovas cular variables was as follows : cardiac muscle contraction>ventricular automaticity?intraventricular conduction>AV nodal conduction coronary blood flow> SA nodal automaticity. -AN-132 ; antiarrhythmic agent ; AV nodal conduction ; intraventricular conduction ; negative inotropy AN-132 (Fig. 1), a newly synthesized antiarrhythmic agent, has been reported to be effective in several animal models of cardiac arrhythmias, whether given

A series of novel pyridazinone derivatives (II) having a phenoxypropanolamine moiety was synthesized. Their hypotensive and beta-blocking activities were evaluated after intravenous administration of the compounds to anesthetized rats. Among them, the 5-chloro-2-cyanophenoxy derivative (29) showed the promising dual activities and was selected for further studies.

1. TZC-5665 is a novel pyridazinone derivative with vasodilatory and beta-adrenergic blocking activities and type III phosphodiesterase inhibitory action. 2. In healthy volunteers, TZC-5665 was rapidly absorbed and immediately metabolized. Its main metabolite, M-2, remained at a higher concentration in plasma. Orally administered TZC-5665 reduced end-diastolic left ventricular volume (20.16 ml) and exhibited a tendency to increase ejection fraction (0.04). 3. In dogs, M-2 dose-dependently increased cardiac contractility and reduced both preload and afterload. These effects appeared more potent in the failed heart than in the normal heart. At the same dose (30 micrograms/kg), the effects of M-2 seem to be more potent than those of milrinone. 4. We concluded that TZC-5665 is a useful medication for treating patients with chronic congestive heart failure (CHF) because of the positive inotropic and vasodilating effects due to its active metabolite in addition to its own beta-adrenergic blocking actions.