Allen W. Gomoll

Pharmacology, pharmacodynamics and pharmacokinetics of sotalol.

Sotalol is a nonselective, water-soluble beta-adrenoceptor antagonist with no membrane-stabilizing activity or intrinsic sympathomimetic activity. Sotalol is, essentially, completely absorbed and is not metabolized. Consequently, bioavailability is close to 100%. Age and food have slight but unimportant effects on bioavailability. Cmax of sotalol is 2 to 3 hours with a t1/2 between 7 and 15 hours. Excretion of sotalol is primarily through the kidneys, with no metabolism by liver and no first-pass effect. Therefore, sotalol plasma levels and half-life are directly related to creatinine clearance and glomerular filtration rate. Appropriate dose adjustments must be made for patients with impaired renal function or increased renal blood flow, as in pregnancy. The beta-adrenoceptor antagonistic effects of sotalol are directly related to plasma levels, which, in turn, are directly related to dose. However, the beta-adrenoceptor antagonism t1/2 is longer than the sotalol plasma t1/2. As a consequence of its ability to prolong the action potential duration, sotalol also increases cardiac contractility in isolated ventricular, but not atrial, preparations by 20 to 40%. This positive inotropic effect is not blocked by beta or alpha blockade or reserpine pretreatment and seems to be related to sotalols effects on cardiac ionic currents. Like the effects of sotalol on action potential duration, the positive inotropic effects are inversely proportional to rate. The hemodynamics of sotalol indicate a relative lack of direct cardiac depressant activity in both animals and humans. The typical hemodynamic effects of sotalol in normotensive humans, even with depressed myocardial function, are a reduction in heart rate with little or no change in blood pressure, a reduction in cardiac output with no change in stroke volume, and little or no change in pulmonary wedge pressure and left ventricular end-diastolic pressure or volume, and little or no change in ejection fraction either at rest or during exercise.

Monoclonal leukocyte antibody does not decrease the injury of transient focal cerebral ischemia in cats.

We tested the hypothesis that inhibition of leukocyte function by administration of monoclonal antibody 60.3 (MoAb 60.3) improves electrophysiological recovery and decreases injury volume following transient focal cerebral ischemia in cats. Methods Halothane-anesthetized cats underwent 90 minutes of left middle cerebral artery and bilateral common carotid artery occlusion followed by 180 minutes of reperfusion. Cats were assigned to receive either 2 mg/kg MoAb 60.3 (n=8) directed at the CDw18 leukocyte antigen complex or an equal volume of diluent (sterile saline; n=10) at 45 minutes of ischemia in a blinded fashion. Results Blood flow to the left temporoparietal cortex decreased to <5 ml/min/100 g with ischemia, but was minimally affected on the right side. Postischemic hyperemia occurred in the left caudate nucleus, whereas blood flow in other brain regions returned to control. No region demonstrated delayed hypoperfusion, and there were no differences between groups. Somatosensory evoked potential recorded over the left cortex was ablated during ischemia and recovered to <10% of baseline amplitude at 180 minutes of reperfusion in both groups. Left hemispheric injury volume, as assessed by 2,3,5 -triphenyltetrazolium chloride staining, was not affected by drug treatment (mean±SE values: MoAb 60.3, 37±5%; placebo, 38±7% of hemisphere). Conclusions Inhibition of leukocyte function with MoAb 60.3 does not afford protection from severe focal ischemia and reperfusion in cats.

Comparative β-blocking activities and electrophysiologic actions of racemic sotalol and its optical isomers in anesthetized dogs

The relative activities of d-, 1- and racemic-sotalol were studied in two series of anesthetized dogs. Estimates of relative beta-adrenergic blocking potency were based upon the ability of the compounds to antagonize isoproterenol-elicited increases in heart rate and decreases in diastolic blood pressure. On a molar basis, d-sotalol displayed 1/12-1/14th and 1-sotalol 1.6-3.2 X the potency of the racemic parent drug as beta-antagonists. His bundle electrogram (HBE) measurements, surface ECG recordings and the extra stimulus technique at a constant pacing cycle length were utilized to assess the comparative effects of sotalol and its optical isomers on cardiac conduction and refractoriness. At i.v. doses spanning equiactive beta-blocking levels, d- (1, 4, 16 mg X kg-1), 1- (0.25, 1, 4 mg X kg-1) or dl-sotalol (0.5, 2, 8 mg X kg-1) caused dose-dependent increases in ventricular and, to an even greater extent, atrial refractoriness. The mean plasma drug concentrations (Cp) attained with these doses were: d-sotalol 9.5, 44 and 267 nmol X l-1; 1-sotalol 9.6, 16 and 66 nmol X l-1; and dl-sotalol 5.4, 23 and 106 nmol X l-1. The relative mg potency from greatest to least was 1-sotalol greater than dl-sotalol greater than d-sotalol in prolonging the ventricular effective refractory period (V-ERP); the mean increases above control at the highest dose of each were 58 +/- 4, 47 +/- 6 and 38 +/- 3 ms, respectively. At those same dose levels, atrial refractoriness (A-ERP) was maximally elevated 49 +/- 11, 82 +/- 5 and 104 +/- 10 ms by 1-, dl- and d-sotalol, respectively. These increases in refractoriness occurred without alterations in atrial, His-Purkinje or ventricular conduction velocity; however, all three forms of sotalol significantly reduced AV nodal conduction. At the dose multiples studied, the effects on this variable (AH interval) were greatest following 1-sotalol (20-60 ms) or racemic sotalol (20-57 ms) and least following the d-isomer (7-43 ms). The profile of effects observed with d-sotalol is that of an agent with Class III electrophysiologic effects and weak beta-adrenergic blocking properties.

Pharmacologic basis of the antiarrhythmic and hemodynamic effects of sotalol

Sotalol is a competitive beta adrenoceptor antagonist devoid of membrane-stabilizing activity and intrinsic sympathomimetic activity that has no preferential actions on beta 1 or beta 2 responses. No other tested receptor systems are affected by sotalol. In addition to having class II (beta blockade) effects, sotalol also has class III antiarrhythmic activity. It increases the action potential duration (APD) and prolongs atrial and ventricular repolarization. The effect on APD is independent of beta blockade; the same effect is seen with similar concentrations of the d stereoisomer of sotalol, which does not have beta-blocking activity. Sotalol prolongs the rate-corrected QT interval and ventricular and atrial refractoriness without affecting atrial, His-Purkinje, or ventricular conduction velocity. Atrioventricular nodal conduction is decreased, largely because of beta blockade. Sotalol increases the fibrillation threshold and decreases the defibrillation threshold. Sotalol is an effective antiarrhythmic in various animal models of arrhythmia (e.g., chloroform, hydrocarbon-catecholamine, ouabain, and coronary ligation). In addition, it reduces the severity and frequency of arrhythmias induced by programmed electrical simulation. By comparison, metoprolol is ineffective and d-sotalol is as effective as the racemate in this model, indicating that this effect is independent of beta blockade. Sotalol causes concentration-dependent increases in the contractility of isolated ventricular tissue that is not blocked by previous beta or alpha blockade or catecholamine depletion. The positive inotropic effect may be related to inhibition of time-dependent K+ current responsible for the increase in APD. Like propranolol, sotalol decreases contractile force, heart rate, arterial blood pressure, left ventricular dP/dt, and cardiac output in intact animals due to blockade of circulating catecholamines. Sotalol consistently reduces the heart rate to a greater degree than propranolol and causes significantly less cardiac suppression than propranolol at a given heart rate.

Selected immunologic properties of tiprinast, a non-steroidal antiallergy agent

Tiprinast [(3,4-dihydro-5-methyl-6-(2-methylpropyl)-4-oxothieno[2,3-d]- pyrimidine-2-carboxylic acid] is a new antiallergy compound which shares many of the pharmacological actions of disodium cromoglycate (DSCG). Both compounds inhibit passive cutaneous anaphylaxis in the rat, histamine release from rat peritoneal mast cells and nasal constriction due to antigen in the rat. In all cases tiprinast is more potent than DSCG and also longer acting.

Comparability of the electrophysiologic responses and plasma and myocardial tissue concentrations of sotalol and its d stereoisomer in the dog

The relative plasma, myocardial, and skeletal muscle concentrations as well as activities of racemic and d-sotalol were assessed in both anesthetized and conscious dogs. In acute anesthetized experiments, the agents were infused i.v. over a 15-min interval at doses of 1 and 4 mg/kg. Arterial blood samples and punch biopsy specimens from the left ventricular myocardium and skeletal muscle (gastrocnemius) were taken at the completion of each infusion and at periodic intervals for the ensuing 3 h. The drugs were also administered over a 2-week dosing interval to conscious dogs at a dose of 5 mg/kg given twice daily. ECG alterations and venous blood samples were withdrawn on the 1st, 3rd, 7th, and 14th day of drug administration. Myocardial and skeletal muscle samples were taken at killing on day 14. In anesthetized dogs, both forms of sotalol decreased heart rate, lowered arterial pressure, prolonged ventricular refractoriness, and caused measurable increases in the PR, QT, and QTc intervals in the absence of any effect on QRS duration. Similar effects on heart rate and QTc and lack of influence on the PR and QRS interval were observed in conscious animals. Tissue drug concentrations were closely correlated with plasma drug levels. Comparable mean steady-state tissue/plasma ratios of 2.26–2.94 were attained immediately following acute i.v. drug infusions. These were larger than those observed following chronic oral drug administration for 14 days. The data, however, clearly demonstrated the equivalence of the plasma and myocardial drug levels obtained in dogs following i.v. infusion of 1 mg/kg or oral administration of 5 mg/kg of dl- or d-sotalol. In acute experiments, there were no differences between the distributive and washout phases of either drug under the short-term conditions of the experiments. No preferential uptake of either agent in atrial, ventricular, or septal areas of the myocardium was demonstrable.

Failure of aspirin to interfere with the cardioprotective effects of ifetroban

The thromboxane receptor antagonist ifetroban ([1S-(1 alpha,2 alpha,3 alpha, 4 alpha)]-2-[[3-[4-[(pentylamino)carbonyl]-2-oxazolyl]- 7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid) and aspirin were evaluated for direct and combined effects on myocardial infarct size in anesthetized ferrets subjected to coronary artery occlusion (90 min) and reperfusion (5 h). Aspirin (10 mg/kg) or vehicle was administered as an i.v. bolus dose at the 45th min of occlusion in an initial assessment of its cardioprotective potential in this species. In interaction studies, aspirin was injected i.v. 10 min prior to occlusion (10 mg/kg) and at the 45th min of ischemia (5 mg/kg) both with and without subsequent administration of ifetroban (0.3 mg/kg + 0.3 mg/kg per h) beginning at the 75th min of occlusion. Aspirin administration alone caused non-significant (P > 0.05) 5-7% reductions in tissue damage (19.8-21.8% of left ventricle) from that observed in vehicle-controls (20.4-22.9% of left ventricle). Ifetroban alone significantly (P < 0.05) reduced infarct size compared to vehicle treatment (13 +/- 1% vs. 23 +/- 2% of left ventricle), and this was not prevented by combination with aspirin (12 +/- 2% vs. 22 +/- 3% of left ventricle). In the absence and presence of aspirin, ifetroban reduced infarct size by 42% and 43%, respectively. Concurrently, thromboxane A2-generating capacity in blood (measured as thromboxane B2 in clotted serum) was decreased ca. 99% by aspirin treatment. Thus, virtually complete platelet cyclooxygenase inhibition by aspirin afforded no cardioprotective action in the ferret and, more importantly, this inhibition did not interfere with the myocardial salvage efficacy of ifetroban.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiology, hemodynamic and arrhythmia efficacy model studies on encainide.

Encainide is a class IC agent possessing a broad spectrum of antiarrhythmic actions in a variety of animal models. It increases the ventricular fibrillation threshold of the perfused rabbit heart and in situ dog myocardium. Encainide suppresses atrial fibrillation resulting from topical application of aconitine in the anesthetized dog and ventricular fibrillation induced by chloroform asphyxiation in the mouse. In these latter 2 models, encainide is approximately 7 to 11 and 16 to 18 times more potent, respectively, on a milligram basis than quinidine. In anesthetized dogs encainide converts ouabain-induced tachyarrhythmias to normal sinus rhythm at a mean intravenous dose of 0.67 mg/kg. Single doses of 0.5 mg/kg intravenously or 1 mg/kg orally significantly reduced ventricular ectopy in conscious dogs 18 to 22 hours after 2-stage ligation of the left coronary artery. At doses and plasma concentrations exceeding efficacious therapeutic levels, encainide has no major negative inotropic effects and does not compromise cardiac function or hemodynamics. It is devoid of peripheral autonomic or mediator-evoked responses and, in particular, lacks anticholinergic actions. Encainide is rapidly absorbed by all routes of administration and extensively metabolized by the liver. The major metabolites, O-demethyl encainide and 3-methoxy-O-demethyl encainide, have been shown to have quantitatively different, but qualitatively similar, profiles of pharmacodynamic effects. Subacute and chronic administration of encainide at doses representing 11 times an effective oral human dose have produced no distinct or consistent toxicologic findings. Carcinogenicity and mutagenicity studies were negative.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of the ferret for a myocardial ischemia/salvage model

Exploratory work was undertaken in the anesthetized ferret to determine if it is an applicable species for use as an in vivo ischemic model and suitable for recovery surgical procedures. Experimental protocols utilizing varying combinations of left anterior descending (LAD) coronary artery occlusion (30, 60, 90 min) and reperfusion (4, 6, 18-24 hr) were evaluated. The results indicated that a 90-min/6-hr combination led to the production of an infarct equivalent, or slightly greater, in size to that observed following coronary artery occlusion either with and without reflow during an 18-24-hr recovery period prior to sacrifice. A combination of 90 min occlusion/4 hr reperfusion yielded an infarct area ca. 50% of that associated with 6 hr interval of reflow. An occlusive interval of 60 min or less combined with any reperfusion interval lack reproducibility. The administration of saline in varying volumes by different routes (IV versus left atrial) had no influence on either the absolute or, more especially, the relative (i.e., as a percent of left ventricle) tissue damage provoked by a 90-min/6-hr occlusion/reperfusion maneuver of the LAD coronary artery. When evaluated as a reference standard, superoxide dismutase (SOD) infused via the left atrium at a dose of 5 mg/kg afforded a 36% reduction in the area of ischemic damage in this model. These studies demonstrated that the ferret represents a useful species for initial, rapid, and economic--both in terms of cost and drug substance utilization--in vivo myocardial salvage screening assessments. The model permits an interpretation of potential test agent efficacy, dosage requirements, and hemodynamic actions, and it is suitable for basing a go/no-go decision that continued experimental development in more labor intense preparations is warranted.

Myocardial salvage efficacy of the thromboxane receptor antagonist ifetroban in ferrets and dogs

The effects of the thromboxane A2 (TXA2)/prostaglandin endoperoxide (TP) receptor antagonist ifetroban (BMS-180291) on infarct size (IS) resulting from coronary occlusion/reperfusion was determined in anesthetized dogs and ferrets. In dogs, ifetroban (1 + 1 mg/kg/h, intravenously, i.v.) or vehicle administration was initiated 10 min before left circumflex coronary artery (LCX) occlusion. In ferrets, the left anterior descending coronary artery (LAD) was occluded; after 75 min, a continuous infusion of ifetroban (0.3 + 0.3 mg/kg/h i.v.) or vehicle was started. After 90-min ischemia in both species, the LCX or LAD occlusion was released; reperfusion was continued for 5 h, at which time IS was determined. Regional myocardial blood flow (RMBF) before and during occlusion and during reperfusion were measured with radioactive microspheres. Ifetroban significantly decreased the extent of infarction to 39 +/- 5% of the area at risk (AAR) from 64 +/- 5% in dogs and to 15 +/- 2% of the left ventricle as compared with a control of 22 +/- 2% in ferrets. The protective effect of ifetroban in both species occurred with no increase in collateral BF or treatment-related alterations in peripheral hemodynamic status. Ifetroban, at the doses that reduced IS in ferrets, inhibited 99% of platelet TP receptors throughout the experiment, as measured by inhibition of the ex vivo platelet shape change response to U-46,619, a TP receptor agonist. Thus, doses of ifetroban causing profound TP receptor blockade also salvaged jeopardized myocardium in dogs and ferrets without changing collateral BF or peripheral hemodynamics.