Nonpeptide glycoprotein IIb/IIIa inhibitors. 8. Antiplatelet activity and oral antithrombotic efficacy of L-734,217.

The antiplatelet activity of L-734,217, a nonpeptide platelet GPIIb/IIIa antagonist, was evaluated in the rat, guinea pig and dog. IC50 for inhibition of in vitro platelet aggregation for these species (agonists: adenosine diphosphate, collagen) were rat, 838,000 and > 1,100,000 nM; guinea pig, 124 and 156 nM; dog, 42 and 50 nM. In an in vivo rat/in vitro dog platelet aggregation assay, effective antiaggregatory plasma concentrations of L-734,217 were achieved after 8.0 to 16.0 mg/kg p.o. vs. 0.3 to 1.0 mg/kg i.v. to rats. Delays in platelet-dependent hemostatic plug formation in severed mesenteric arteries were observed after 2.0 to 5.0 mg/kg p.o. vs. 0.1 to 0.2 mg/kg i.v. to guinea pigs. Dose-dependent inhibitions of ex vivo platelet aggregation after 0.3 to 3.0 mg/kg p.o. and 0.03 to 0.3 mg/kg i.v. L-734,217 to conscious dogs yielded estimates of 8 to 16% oral bioavailability. The antiplatelet activity of 3.0 mg/kg p.o. L-734,217 in dogs was unaffected by dosage form or food. In a conscious dog model of left circumflex coronary artery electrolytic lesion, 3.0 mg/kg p.o. L-734,217 q4 to 8 hr reduced thrombus mass, prevented occlusive coronary artery thrombosis and reduced or prevented myocardial infarction and ventricular ectopy. In anesthetized dogs, a dissociation between inhibition of ex vivo platelet aggregation and template bleeding time prolongation was observed with i.v. L-734,217. The results of the coadministration of heparin, aspirin and L-734,217 to anesthetized dogs suggested a synergistic effect on template bleeding time with no effect on plasma L-734,217 concentrations. These findings indicate L-734,217 to be an important lead structure for the development of therapeutically useful oral antiplatelet agents.

Differential efficacy of the class III agent MK-499 against programmed stimulation-induced and ischemic-induced ventricular arrhythmias in a canine model of previous myocardial infarction.

Class III activity has been proposed as a potential mechanism for the treatment of reentrant arrhythmias. The purpose of the present study was to assess the concordance in antiarrhythmic efficacy of MK-499, a selective blocker of IKr, the rapidly activating component of cardiac delayed rectifier K+ current, against programmed ventricular stimulation (PVS)-induced ventricular tachycardias and thrombotically induced lethal ischemic arrhythmias, and to characterize the electrophysiologic determinants of antiarrhythmic efficacy in the canine model of previous myocardial infarction. Single i.v. doses of 1.0, 3.0 and 10.0 micrograms/kg MK-499 were administered to anesthetized dogs with anterior myocardial infarctions. Protection (suppression + stabilization/slowing) vs. PVS-induced ventricular tachycardias occurred in 5/11 (45%) preparations at 1.0 microgram/kg, in 9/12 (75%) preparations at 3.0 micrograms/kg and in 10/11 (91%) preparations at 10.0 micrograms/kg i.v. MK-499. The incidences of lethal ventricular arrhythmias developing in response to thrombotically induced posterolateral myocardial ischemia were 34/40 (85%) in vehicle controls, 7/11 (64%) at 1.0 microgram/kg, 6/12 (50%, P < .05) at 3.0 micrograms/kg and 4/11 (36%, P < .01) at 10.0 micrograms/kg i.v. MK-499. Low-dose i.v. MK-499 prolonged ECG QT interval and increased noninfarct zone and infarct zone ventricular refractoriness. However, there was a poor concordance (56%) between response to PVS with MK-499 and response to thrombotically induced acute myocardial ischemia. Furthermore, different trends of association between site and magnitude of Class III effect and antiarrhythmic efficacy were observed for PVS- vs. ischemia-induced arrhythmias. Hence, although low-dose i.v. MK-499 provided significant protection against both electrically and ischemically triggered arrhythmias in the setting of previous myocardial infarction, protection against PVS-induced ventricular tachycardias was not highly predictive of protection against lethal ischemic arrhythmias in this preparation.

Cardiac electrophysiologic and antiarrhythmic actions of tedisamil.

The Class III electrophysiologic and antiarrhythmic actions of the bradycardic agent tedisamil were assessed in vitro and in vivo. In ferret isolated right ventricular papillary muscles, tedisamil increased effective refractory period (ERP) in a concentration-dependent manner, with a 25% ERP increase achieved with 3.0 microM tedisamil, and a 133.4% +/- 28.8% increase in ERP achieved at the high 100 microM concentration tested. In anesthetized dogs, the cumulative i.v. administration of tedisamil significantly increased ventricular relative refractory period (VRRP) and ventricular effective refractory period (VERP) as well as electrocardiographic QTc intervals (100-1000 micrograms/kg i.v.). A 20msec increase in VRRP was achieved with 45.0 micrograms/kg i.v. tedisamil, and a 56.1 +/- 9.8 msec (40.1% +/- 8.1%) increase in VRRP was achieved at the highest dose tested (1000 micrograms/kg i.v.). In the same dosage range in anesthetized dogs, tedisamil produced significant hemodynamic effects, including reduction in HR (100-1000 micrograms/kg i.v.) and elevations in mean arterial pressure (1000 micrograms/kg i.v.), left ventricular developed pressure (1000 micrograms/kg i.v.) and the maximum rate of LV pressure development (100-1000 micrograms/kg i.v.). In anesthetized dogs studied chronically (8.2 +/- 0.6 days) after anterior myocardial infarction, tedisamil suppressed programmed stimulation-induced ventricular tachyarrhythmias (8/10, 80% suppression at 100-1000 micrograms/kg i.v.) and reduced the incidence of lethal ischemic arrhythmias developing in response to acute posterolateral myocardial ischemia (arrhythmic mortality 5/10, 50% tedisamil vs. 34/40, 85% vehicle control cohort; P = .027). The latter findings suggest that tedisamil might be useful in the prevention of malignant ventricular arrhythmias in the setting of myocardial ischemic injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac electrophysiologic and antiarrhythmic actions of 3,4-dihydro-1'-[2-(benzofurazan-5-yl) ethyl]-6-methanesulfonamidospiro [(2H)-1-benzopyran-2,4'-piperidin]-4-one HCl (L-691,121), a novel class III agent.

The cardiac electrophysiologic and antiarrhythmic actions of 3,4-dihydro-1'-[2-(benzofurazan-5-yl)ethyl]-6-methyl-sulfonamid ospiro [(2H)-1-benzopyran-2,4'-piperidin]-4-one HCl (L-691,121), a novel spirobenzopyran piperidine class III agent, were assessed in vitro and in vivo. In ferret isolated papillary muscles, L-691,121 significantly prolonged effective refractory period (EC25 = 13 nM) and elicited a modest positive inotropic effect. In guinea pig isolated ventricular myocytes, L-691,121 prolonged action potential duration by selectively blocking (IC50 = 4.4 nM) a rapidly activating and rectifying component of the delayed rectifier K+ current, Ikr. The class III activity of L-691,121 in isolated papillary muscles was reverse frequency-dependent, and reversed by hypoxic perfusion. L-691,121 modestly depressed spontaneous beating rate (-14%) in guinea pig isolated right atria at concentrations up to 3 microM. In anesthetized dogs, the i.v. administration of 10 to 100 micrograms/kg of L-691,121 significantly increased atrial and ventricular refractoriness and prolonged the electrocardiographic Q-T interval, but did not alter atrioventricular nodal, His-Purkinje, atrial or ventricular conduction. In conscious dogs with spontaneous premature ventricular complexes at 48 hr after myocardial infarction, 10 to 1000 micrograms/kg i.v. of L-691, 121 failed to reduce premature ventricular complex frequency. However, in anesthetized dogs studied chronically (7.9 +/- 0.3 days) after infarction, 10 and 100 micrograms/kg i.v. of L-691,121 suppressed the induction of ventricular tachyarrhythmia by programmed stimulation in 8/14 (57%) and 11/14 (79%) dogs tested, respectively, and reduced the incidence of lethal ventricular arrhythmias triggered by a secondary myocardial ischemic event from 14/15 (93%) in vehicle controls to 5/14 (36%; P < .01) in L-691,121-treated (100 micrograms/kg i.v.) animals. The latter findings suggest the potential for L-691,121 to prevent the development of malignant ventricular arrhythmias in the setting of previous myocardial infarction.

Demonstration of proarrhythmic activity with the class IC antiarrhythmic agent encainide in a canine model of previous myocardial infarction.

The antiarrhythmic efficacy and proarrhythmic potential of the class IC antiarrhythmic agent encainide were assessed in subacute and chronic postinfarction canine models, respectively. In conscious dogs with spontaneous premature ventricular complexes (PVCs) at 48 h after anterior myocardial infarction (MI), cumulative intravenous (i.v.) administration of 1.0 and 3 mg/kg encainide significantly reduced PVC frequency. However, in anesthetized dogs studied more chronically after anterior MI (range 8-44 days), i.v. administration of 0.3-3 mg/kg encainide resulted in induction of new ventricular tachyarrhythmias by programmed ventricular stimulation in 6 of 10 dogs with no inducible arrhythmias prior to encainide. Newly induced arrhythmias after encainide administration included unimorphic and polymorphic ventricular tachycardia (VT) as well as VT degenerating rapidly into ventricular fibrillation (VF). The incidences of new arrhythmia induction after cumulative i.v. administration of encainide were 3 of 9 after 0.3 mg/kg i.v. encainide, 4 of 9 after 1.0 mg/kg i.v. encainide, and 5 of 10 after 3.0 mg/kg i.v. encainide. Time elapsed between MI and electrophysiologic testing tended to predict proarrhythmic response to encainide, with the six preparations with newly induced arrhythmias tested earlier than the four preparations that remained nonresponsive to postencainide programmed stimulation (13.2 +/- 3.1 vs. 26.5 +/- 6.5 days postinfarction, respectively, p = 0.07). There was also a trend toward larger underlying anterior MIs in the six preparations with newly induced arrhythmias as compared with the four preparations that remained nonresponsive to postencainide programmed stimulation (13.2 +/- 2.9 vs. 7.5 +/- 2.1% of left ventricle, respectively, p = 0.19).(ABSTRACT TRUNCATED AT 250 WORDS)