Biomedical subjects

A W Gomoll

Publications and source records attributed to A W Gomoll.

At least 19 recordsLinked to original sources

PubMed1997

Selectivity of BMS-180448 on myocardial versus brain blood flow in dogs and ferrets.

Openers of adenosine triphosphate (ATP)-sensitive potassium channels relax vascular smooth muscle and protect ischemic myocardium. Cromakalim and BMS-180448 are examples of this class of compounds. They are equipotent in their cardioprotective activity, but cromakalim and related compounds are extremely hypotensive, an activity that limits their use. The effects of cumulative i.v. doses of BMS-180448 or cromakalim on hemodynamics and regional blood flow (radiolabeled microspheres) were evaluated in pentobarbital-anesthetized dogs and ferrets. Both compounds significantly reduced mean arterial blood pressure, cromakalim after 0.03-0.04 mg/kg in both species, and BMS-180448 only after 10 mg/kg in dogs and 30 mg/kg in ferrets. Neither drug affected cardiac output. BMS-180448, like cromakalim, increased blood flow in the heart, with augmented regional left ventricular blood flow occurring more in the subepicardium than in the subendocardium. The effect of BMS-180448 on myocardial blood flow, in both the dog and ferret, occurred at doses that were less hypotensive than those of cromakalim. The most striking difference between the actions of these agents was seen in the brain where cromakalim, but not BMS-180448, increased blood flow in all regions. The results of these studies further demonstrate the myocardium-specific vasodilator activity of BMS-180448. Moreover, the cerebral vasodilator effect of K(ATP) openers, which has been thought responsible for the occurrence of headache in clinical trials, has been found lacking in BMS-180448; this difference may represent a clear advantage in the pharmacologic profile of the agent.

Adenosine Triphosphate↗

PubMed1997

Effect of timing of treatment of the glyburide-reversible cardioprotective activity of BMS-180448.

The effect of the timing of treatment with the ATP-regulated potassium channel agonist BMS-180448 was evaluated in isolated rat heart and ferret models of ischemia and reperfusion. In rat hearts, 10 microM BMS-180448, given before and after global ischemia as well as only during reflow, improved reperfusion contractile function and attenuated lactic dehydrogenase release, although reperfusion-only treatment was less effective. Cromakalim (10 microM) and bimakalim (10 microM) treatment before and after global ischemia afforded a degree of protection similar to that of BMS-180448, although they were not cardioprotective when given only during reperfusion. Pre- and post-treatment cardioprotection were abolished by glyburide. Ischemia/reperfusion significantly increased cytosolic calcium concentration ([Ca++]i) and BMS-180448 given only during reperfusion attenuated this change. In anesthetized ferrets, BMS-180448 (2 mg/kg) or vehicle was infused i.v. during a 40-min interval beginning 1) 10 min before coronary occlusion, 2) at the 45th min of ischemia or 3) at the 5th min of reperfusion. Preocclusion administration of BMS-180448 was associated with a 35% reduction in infarct damage from that recorded in vehicle-treated control ferrets. Drug administered at the midpoint of ischemia reduced infarct size approximately 44%, whereas delaying BMS-180448 infusion until the 5th min of reperfusion reduced, but still provided a significant (17%) level of salvage. The favorable effects of BMS-180448 in the ferret were not associated with changes in either collateral blood flow or peripheral hemodynamics. Thus BMS-180448 shows some protective effects when given only during reperfusion. Cromakalim and bimakalim did not exert similar actions and the difference may be secondary to the faster penetration of BMS-180448.

Animals↗

PubMed1995

Dose-related cardioprotection by ifetroban in relation to inhibition of thrombosis and ex vivo platelet function.

The dose-related cardioprotective efficacy of the thromboxane A2/prostaglandin endoperoxide (TP) receptor antagonist, ifetroban (BMS-180291), was investigated in an anesthetized ferret model of myocardial ischemia (90 min) followed by reperfusion (5 h). Treatment was begun at either the 75th minute of ischemia or 5 min after initiating reperfusion. The magnitude of TP receptor blockade was evaluated by ex vivo platelet function. Additional experiments in ferrets tested the antithrombotic potency of ifetroban as an inhibitor of thrombotic cyclic flow reduction (CFR) in the stenosed abdominal aorta (Folts model). Continuous ifetroban infusions of 0.03, 0.1 and 0.3 mg/kg/h reduced myocardial infarct size from 22% of the left ventricle in vehicle-control ferrets to 20, 12 and 9%, respectively. These represented reductions in infarct size of 8, 43 and 56%. Delaying initiation of treatment with high-dose ifetroban until 5 min into reperfusion also significantly reduced infarct size by 45%. High-dose ifetroban treatment did not prevent neutrophil (PMNL) accumulation measured as tissue myeloperoxidase activity in infarcted tissue. At the end of the 5-hour reperfusion period, the low, medium and high doses produced 90, 98 and 98% blockade of platelet TP receptors, respectively, measured as inhibition of ex vivo platelet shape change responses to U-46,619. Ifetroban inhibited thrombotic CFR at a threshold dose of 0.03 +/- 0.004 mg/kg, which antagonized 92% of ferret platelet TP receptors. Thus, ifetroban exhibited cardioprotective and antithrombotic activities and was effective at doses producing > 90% TP receptor blockade. Cardioprotective activity was not associated with any reductions of PMNL accumulation in infarcted tissue and was demonstrable even when treatment was delayed until 5 min after initiation of reperfusion.

Animals↗

PubMed1994

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)

Animals↗

PubMed1994

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.

Animals↗

PubMed1993

Myocardial salvage efficacy of a thromboxane receptor antagonist, SQ, 30,741, in relation to inhibition ex vivo of platelet function in the ferret.

The myocardial salvage efficacy of a thromboxane A2/prostaglandin endoperoxide (TP) receptor antagonist has not been previously determined in a ferret model of ischemia and reperfusion. Assessments of the reproducibility of infarct size resulting from a 90 min period of occlusion followed by 5 hr of reperfusion of the left anterior descending coronary artery in saline-treated control ferrets revealed a consistent mean level of tissue damage representing 23.1 +/- 1.4% of the left ventricle. In subsequent studies, ferrets were given the thromboxane receptor antagonist SQ 30,741 (1 mg/kg bolus and 1 mg/kg/hr infusion, i.v.) or vehicle. At this dose, SQ 30,741 significantly reduced infarct size from that measured in control ferrets by 44%. Concurrently, the drug produced a 97% inhibition of platelet TP receptors as measured by inhibition of the ex vivo platelet shape change response to U-46,619. Drug administration was not associated with measurable alterations in mean blood pressure, heart rate or the rate-pressure-product. The importance of this finding to clinical utility and the mechanism of the observed cardioprotective action, however, remain unclear. These data indicate that the ferret represents a useful model for the assessment of the myocardial salvage efficacy of TP receptor antagonists and are consistent with attenuation of ischemic myocardial damage by doses of these agents which produce > 96% TP receptor blockade.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1992

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

BACKGROUND AND PURPOSE: 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 less than 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 less than 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.

Animals↗

PubMed1991

Efficacy of a monoclonal antibody (MoAb 60.3) in reducing myocardial injury resulting from ischemia/reperfusion in the ferret.

The myocardial salvage efficacy of a monoclonal antibody (MoAb 60.3) directed at the CDw 18 membrane antigen complex essential for normal neutrophil function was evaluated in a ferret occlusion/reperfusion model. When infused i.v. over a 10-min interval beginning at the 45th minute of a 90-min occlusion at a fixed dose of 2 mg/kg, the antibody afforded 33 and 45% reductions in infarct size following reperfusion intervals of 6 and 24 h, respectively. Administration of that same dose via the left atrium over 1 h beginning at the 75th minute of occlusion and continuing until the 45th minute of reflow resulted in only a 14% reduction in infarct size. If MoAb 60.3 administration was withheld until the 5th-15th minute of reperfusion, the mean levels of salvage were 19 and 8%, respectively, following 6- and 24-h periods of reflow. Time-course hemodynamic data indicated that the monoclonal antibody caused no alterations in oxygen utilization that might be responsible for the levels of salvage observed.

Animals↗

PubMed1990

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.

Animals↗

PubMed1990

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Encainide.

Encainide is a class IC antiarrhythmic agent having little or no effect on action-potential duration or maximum diastolic potential but decreasing the maximum rate of phase O depolarization as well as increasing atrial and ventricular effective refractory periods. In intact animals or humans, encainide increases the AH, PR, QRS, and H-V intervals while not affecting the sinus node cycle length or JT interval. QT interval increases only by the concomitant increase in the QRS interval. Encainide is metabolized to O-demethyl encainide (ODE) and 3-methoxy-ODE (MODE), both of which are also antiarrhythmics with similar pharmacology to encainide. Encainide and its metabolites have little negative inotropic activity and ancillary pharmacology. Consequently, encainide has little or no effect on hemodynamic variables in patients with either normal or compromised cardiac function. The drug is well tolerated, with side effects being mainly those associated with its local anesthetic activity such as blurred vision and dizziness. Encainide is particularly effective in patients with excessive premature ventricular complexes (PVCs) and less so in patients with sustained ventricular tachycardia (VT). Like all antiarrhythmics, encainide may aggravate or precipitate new arrhythmias (proarrhythmia). The overall incidence of proarrhythmia is about 10%, with less occurring in patients with PVCs and more in those with sustained VT; also, the incidence of proarrhythmia is higher in patients with underlying heart disease. Encainide is also effective for the treatment of supra-ventricular arrhythmias, including atrial fibrillation, PSVT (both PAF as well as reentry of the nodal or W-P-W type), and ectopic atrial tachycardia. Its dosage and role in antiarrhythmic therapy are discussed.

Anilides↗

PubMed1987

Assessment of drug effects on spontaneous and induced ventricular arrhythmias in a 24-h canine infarction model.

The antiarrhythmic efficacy of encainide, sotalol, flecainide and disopyramide was evaluated in anesthetized dogs subjected to 2-stage total occlusion of the left anterior descending coronary artery. Utilization of this canine model, while anesthetized, permitted the assessment of drug effects not only on uni- and/or multi-focal ectopic ventricular arrhythmias, but also on dysrhythmias associated with aberrant conduction or reentrant excitation pathways. The former was assessed by quantification of ectopic-to-total beat ratios while the later was determined by subjecting the animal to provocative stimuli which produced repetitive ventricular responses. At the cumulative i.v. doses studied, encainide (0.5-4 mg/kg), flecainide (1-8 mg/kg) and disopyramide (0.3-10 mg/kg), but not sotalol (2-8 mg/kg), effectively suppressed ventricular ectopic activity in a dose-related manner. In contrast, sotalol was highly effective in preventing the induction of reentrant ventricular tachyarrhythmias. Disopyramide was only modestly active, while flecainide and encainide had the least favorable profiles of effect in suppressing re-entry arrhythmias in this model. Based on these observations, the anesthetized Harris dog appears to represent a useful two-faceted in vivo model for use in the evaluation of potential antiarrhythmic agents.

Anilides↗

PubMed1986

Comparative beta-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.

Action Potentials↗

PubMed1986

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)

Administration, Oral↗

PubMed1986

Comparative antiarrhythmic actions of encainide and its major metabolites.

The local anesthetic, antiarrhythmic, and acute toxicologic properties of the O-demethyl (ODE), 3-methoxy-O-demethyl (MODE) and N-demethyl (NDE) analogs of encainide (E) were compared with those of parent drug in several models. In the mouse chloroform-induced fibrillation model, the order of antiarrhythmic potency was ODE greater than E greater than MODE greater than NDE. The acute LD50 values for ODE, E, MODE and NDE in mice were 22.6, 38.1, 43.6 and 81.1 mg/kg, i.p. Based upon the toxic/therapeutic ratio in mice, ODE appeared to have the greatest margin of safety and MODE the least; E and NDE were intermediate. In dogs with ouabain-induced tachyarrhythmias, the converting doses of encainide, ODE, MODE and NDE were 0.67, 0.15, 0.39 and 1.1 mg/kg, i.v., respectively. The ODE and MODE metabolites thus appear to be more potent on a mg basis, but both have shorter durations of action than the parent compound. Antiarrhythmic activity in this model was best reflected by plasma drug level (Cp) rather than dose of drug administered. Antiarrhythmic onset Cp associated with encainide (244 ng/ml), ODE (77 ng/ml), MODE (164 ng/ml) and NDE (851 ng/ml) have been identified in this anesthetized dog model. In conscious dogs previously subjected to Harris two-stage coronary artery ligation, the minimal effective doses of encainide were 0.5 mg/kg i.v. and 1 mg/kg orally. For ODE and MODE the minimal effective doses were 0.25 and 0.19 mg/kg injected i.v., respectively, and 0.5 and 0.38 mg/kg given orally. By both routes, encainide had the shortest onset, longest duration and most consistent profile of sustained antiarrhythmic effects. Antiarrhythmic activity did not correlate with local anesthetic potency of either encainide or its metabolites. The data are consistent with the hypothesis that the metabolites of encainide may contribute to and/or be responsible, at least in part, for the persistent antiarrhythmic actions observed clinically following chronic administration of the parent drug in patients.

Anesthetics, Local↗

PubMed1985

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.

Airway Resistance↗

PubMed1982

The antiarrhythmic action of encainide versus ventricular arrhythmias in the conscious dog following coronary artery ligation.

Encainide (MJ 9067) was given intravenously at 1, 2, or 5 mg/kg and orally at 1, 2.5, 5, or 10 mg/kg to conscious dogs 18--23 h after two-stage ligation of the left anterior descending coronary artery. Heart rate and ventricular ectopic rate were lowered in a dose-related manner by 40--70 and 55--158 beats/min, respectively, following drug administration. Ventricular arrhythmia was frequently abolished with doses of 2 mg/kg and above. The onset of antiarrhythmic activity was 1--2 min after intravenous injection and 15--30 min after oral ingestion. The duration of effect was 6--7 h or longer following either route of drug administration. Emesis occurred in 1 of 10 and 1 of 6 dogs, respectively, at the 2 and 5 mg/kg intravenous dose levels. Brief ataxia was also observed in one dog given the latter dose.

Administration, Oral↗

PubMed1982

Acute and chronic diuretic-induced alterations in urinary sodium and calcium excretion in the conscious rat.

The acute and chronic (5-day) effects of three low-ceiling diuretics (hydrochlorothiazide, indapamide or xipamide) and two high-ceiling diuretics (furosemide or muzolimine) on urinary volume and electrolyte excretion were examined in the saline-loaded conscious rat. The three low-ceiling agents produced qualitatively similar alterations in both acute and chronic volume and electrolyte excretion patterns. Each of these agents produced an acute disassociation between urinary sodium and calcium excretion and hypocalciuria after chronic administration. It is suggested that indapamide and xipamide, like hydrochlorothiazide, inhibit sodium but not calcium reabsorption in the distal nephron. Acute as well as chronic treatment with either furosemide or muzolimine produced dose-dependent increases in urinary volume and electrolyte excretion. A generally parallel response was observed on sodium and calcium excretion with these agents. It is suggested that muzolimine, like furosemide, inhibits both sodium and calcium reabsorption in the ascending limb of Henle's loop.

Animals↗