Barrie Levitt

Reduction in Myocardial Ischemia with Nitroglycerin or Nitroglycerin plus Phenylephrine Administered during Acute Myocardial Infarction

Nitroglycerin reduces ischemic injury during acute myocardial infarction (AMI) in dogs--an effect that is potentiated when drug-induced hypotension and tachycardia are prevented with phenylephrine. To determine the effectiveness of nitroglycerin, alone or with phenylephrine, during AMI in man, 12 patients (five or whom had left heart failure) were evaluated by summing ST-segment abnormalities (sigmaST) from 35 precordial electrodes. The seven patients without heart failure did not benefit consistently from nitroglycerin alone; however, addition of phenylephrine to abolish nitroglycerin-induced arterial pressure reduction uniformly diminished sigmaST (4.9 to 3.2 mv; P less than 0.05). In patients with heart failure, nitroglycerin alone consistently reduced ischemia (5.8 to 4.4 mv, P less than 0.05); addition of phenylephrine often partially reversed this effect. Thus, administration of nitroglycerin, alone or with phenylephrine, can reduce myocardial ischemic injury during AMI in man; however, the response to phenylephrine depends on the presence or absence of left ventricular failure before treatment.

Dose-related hemodynamic and renal effects of dopamine in congestive heart failure.

Summary The hemodynamic effects of dopamine were studied in nine patients with congestive heart failure. A dose-related increase in cardiac output and stroke volume was observed with infusion rates up to 5 μg per kilogram per minute in all patients; more rapid infusions resulted in a diminished response in many individuals. Tachycardia was significant only at an infusion rate of 10 μg per kilogram per minute. Dose-related increments in aortic dp/dt, urine flow, sodium excretion, and creatinine clearance were also observed. A correlation of invasive and noninvasive techniques for evaluating the hemodynamic effects of dopamine is presented and the potential clinical usefulness of dopamine discussed.

The Cimetidine-Lidocaine Interaction

Lidocaine is a widely used antiarrhythmic agent whose plasma clearance varies with changes in hepatic blood flow. Cimetidine, an H2-receptor antagonist, has been shown to decrease hepatic blood flow. To ascertain whether cimetidine affected serum lidocaine concentration, we studied 21 patients receiving lidocaine infusions and divided them into two groups. Fifteen patients received cimetidine, 300 mg every 6 hours, in addition to lidocaine; six patients received only lidocaine. In 14 of the 15 patients receiving both lidocaine and cimetidine, a rise in serum lidocaine levels was seen, whereas no change was noted in the control group. Six of the 15 patients were found to have levels in the toxic range and two had symptoms. An additional three patients on lidocaine received diphenhydramine, an H1-receptor antagonist. No elevation in serum lidocaine levels was noted after administration of diphenhydramine. We conclude that there exists an interaction between lidocaine and cimetidine and that the rise in serum lidocaine levels may be mediated by cimetidines inhibition of the H2 receptor.

Role of the nervous system in the genesis of cardiac rhythm disorders

The search for effective prophylaxis of sudden cardiac death has led to a consideration of the basic pathogenic mechanisms underlying disorders of cardiac rhythm. Although the myocardmm is undeniably important m the genesis of these disorders, the nervous system may be equally important. Several independent lines of evidence lead to this conclusion Experimental evidence: Experimental procedures that alter central nervous system function have repeatedly been demonstrated to result in cardiac arrhythmias or electrocardiographic changes, or both. Nearly every arrhythmia observed clinically can be reproduced by stimulation of the dlencephalon and mesencephalon l Evans and Gill& have demonstrated that rhythm disorders produced by hypothalamic stimulation can be blocked by the use of antladrenergic and anticholinergic drugs. Simultaneous stimulation of sympathetic and parasympathetic nerve trunks can also produce disorders of rhythm 3 Randall and coworkers4v5 observed that stimulation of the sympathetic nerves could induce both atria1 and ventricular ectopic rhythms Similarly, Alessl, Moe et a1.6 and Ninomaya7 have demonstrated that parasympathetic stlmulatlon

The influence of heart rate on the refractory period of the atrium and A-V conducting system

Abstract The refractory periods of the atrium and A-V transmission system were studied in the cat and man using the interpolated extrasystole technique. Increasing heart rate by atrial pacing shortened the atrial refractory period, and the A-V functional refractory period. However, the A-V effective refractory period was prolonged by increased frequency of pacing. In the cat, bilateral section of the vagus nerve usually made the A-V effective refractory period impossible to measure.

Bifascicular block: a clinical and electrophysiologic study.

Abstract The effect of surgery, antiarrhythmic drugs, and atrial pacing on the atrioventricular conducting system was studied in 39 patients with bifascicular block. Twenty-nine patients underwent 38 operations, 23 of which were major. A temporary cardiac pacemaker was inserted prior to surgery in 13 cases. The remaining 25 operations were performed without prophylactic pacemakers. In no patient did heart block develop either during surgery or in the first postoperative week. Twelve patients with bifascicular block received digoxin and either quinidine or procainamide in the usual doses. In none was exacerbation of the atrioventricular conduction defect observed. Ten patients had His bundle recordings during atrial pacing performed at gradually increasing rates until second degree heart block developed. Only two patients developed atrioventricular block at pacing rates below normal, one proximal and one distal to the His bundle.

Who Needs Individual Bioequivalence Studies for Narrow Therapeutic Index Drugs? A Case for Warfarin

Warfarin is, among drugs, considered to have a narrow therapeutic index for which individual bioequivalence has been suggested. To establish the propriety of “switching,” an individual bioequivalence study involving a replicate‐design study and three “switchings” in healthy subjects was undertaken using the U.S.‐brand warfarin sodium tablet and a generic product. A randomized, single‐center, open‐label, single‐dose, four‐way crossover replicate bioequivalence study was performed in 24 healthy male volunteers in which each subject received the same 5 mg warfarin test and reference tablets twice on different occasions under fasting conditions. Concentrations of warfarin in plasma were measured by a validated specific HPLC method. The individual pharmacokinetic parameters obtained with test and reference products were compared using pooled data and Lius method. Bioequivalence was shown with both average and individual bioequivalence methods. The individual bioequivalence assessment did not show a subject‐by‐formulation interaction, nor did it add value to the bioequivalence assessment of warfarin.

Neural basis for the genesis and control of digitalis arrhythmias.

The pharmacokinetics of ouabain associated with toxicity were studied in the cat and the guinea pig both in vivo and in vitro using ouabain-H3. After spinal cord transection a higher dose of ouabain was required to reach the lethal endpoint. This intervention also increased the myocardial and serum levels associated with toxicity were studied in the cat and the guinea pig both in vivo and in vitro using ouabain-H3. After spinal cord transection a higher dose of ouabain was required to reach the lethal endpoint. This intervention also increased the myocardial and serum levels associated with death. These findings were corroborated in experiments using digitoxin H3. In vitro, substantially higher ouabain tissue contents were associated with a lethal event. In addition, in cats and guinea pigs, the lethal myocardial ouabain content did not change when the infusion rate of ouabain was varied in vivo or the perfusate ouabain concentration was changed in vitro. In vivo, propranolol increases the myocardial ouabain content associated with death to in vitro levels. In vitro, the drugs prolongs the time to death by retarding the myocardial uptake of ouabain. These data suggest that the toxic effects of ouabain in the whole animal are largely neural and in the isolated heart, substantially myocardial.

A multiple‐dose safety and bioequivalence study of a narrow therapeutic index drug: A case for carbamazepine

Carbamazepine is among those drugs that have been considered to have a narrow therapeutic plasma concentration range, that is, a narrow therapeutic index. Although the US Food and Drug Administration has approved new generic products based on standard single‐dose bioequivalence studies, several state formularies, including the New Jersey Drug Utilization Review Council, have recently established additional criteria for acceptance of bioequivalence of narrow therapeutic index drugs, limiting the use of some approved generic drugs in specific states. To further validate the adequacy of single‐dose studies for the determination of bioequivalence of narrow therapeutic index drugs, a multiple‐dose study was conducted that more closely reflected therapeutic use.

The influence of heart rate on ouabain cardiotoxicity in cats with spinal cord transection.

The dose, serum level and ventricular content of ouabain needed to produce cardiotoxicity were examined in control cats, cats with transected spinal cords and cats with transected spinal cords whose heart rates were restored to control values by artificial pacing. The lethal dose of ouabain was higher in cats with transected spinal cords and not paced than it was in the control group. However, the lethal dose of ouabain in spinal-sectioned cats with ventricular pacing was no different from that in controls. However, in both groups of spinal-sectioned cats, death was associated with higher ventricular and serum levels of ouabain than in controls. The ventricular ouabain content of paced animals with transected spinal cords was higher than that of controls and lower than that of unpaced spinal cats. Thus, restoration of heart rate to control levels in spinal animals appeared to accelerate myocardial ouabain uptake. The lower myocardial ouabain content in the spinal-sectioned animals which were paced suggests that pacing sensitizes the heart to cardiotoxicity. Spinal section itself appears to decrease the sensitivity to ouabain partly through a decrease in cardiac rate and partly through a loss of neurogenic influence.