John D. Horowitz

Perhexiline maleate treatment for severe angina pectoris — correlations with pharmacokinetics

Perhexiline maleate, which causes inhibition of myocardial fatty acid catabolism with a concomitant increase in glucose utilization, is particularly useful in the management of patients with severe angina pectoris. While perhexiline exerts no significant negative inotropic or dromotropic effects, its short- and long-term use has hitherto been restricted because of complex pharmacokinetics and the eventual development, in many patients, of hepatitis and peripheral neuropathy. Correlations between perhexiline dose, plasma drug concentrations, efficacy and development of toxicity were examined prospectively in 3 groups of patients. The first group (n = 29) were patients in whom perhexiline was added to previously prescribed anti-anginal medication for short-term (pre-surgical or post-myocardial infarction) control of angina pectoris. Over a mean treatment period of 18 +/- 2 (SEM) days, 13 patients experienced a marked reduction in frequency and severity of attacks. No adverse effects occurred. A second group of patients (n = 19) were treated chronically with 50-400 mg/day of perhexiline, dosage being adjusted to minimize symptoms. Over a mean treatment period of 8.8 +/- 1.7 months, 5 patients became asymptomatic, while 9 developed evidence of hepatitis or neurotoxicity, with concomitant plasma perhexiline concentrations of 720-2680 ng/ml. Subsequently, a further group of similar patients (n = 22) were treated for 12.4 +/- 2.6 months, perhexiline dosage being adjusted to maintain plasma perhexiline concentrations below 600 ng/ml. Nine patients became asymptomatic, while none developed adverse effects. It is concluded that perhexiline is useful both as a short-term adjunct to anti-anginal therapy and in the long-term management of patients unsuitable for coronary artery bypass grafting. The risk of long-term toxicity can be reduced markedly by maintenance of plasma drug concentrations below 600 ng/ml without significantly compromising anti-anginal efficacy.

S-nitrosothiols as vasodilators: implications regarding tolerance to nitric oxide-containing vasodilators

1 The formation of an S‐nitrosothiol compound, S‐nitroso‐N‐acetylcysteine (SNAC) has recently been proposed to mediate the augmentation of the anti‐aggregatory and haemodynamic effects of glyceryl trinitrate observed in the presence of N‐acetylcysteine. This study investigated the effects on an isolated coronary artery preparation of acute and prolonged exposure to S‐nitrosothiol compounds and nitric oxide (NO). 2 Single doses of NO and of the S‐nitrosothiol compounds, SNAC and S‐nitroso‐N‐acetylpenicillamine (SNAP), induced rapid, but transient, relaxations in U46619‐contracted bovine isolated coronary artery rings. Peak relaxation responses to SNAP and NO were attenuated in the presence of N‐acetylcysteine, cysteine, ascorbic acid and methylene blue. The duration of the relaxation responses to SNAC was two to three times longer than those to SNAP and NO. In the presence of N‐acetylcysteine (but not cysteine, ascorbic acid or methylene blue) the duration of the relaxation responses to SNAP and NO (but not to SNAC) was markedly increased. H.p.l.c. assay confirmed that, in the presence of N‐acetylcysteine, SNAP and, to a lesser degree, NO were converted to the relatively more stable and longer acting vasodilator, SNAC. 3 When compared to control rings, coronary artery rings superfused with glyceryl trinitrate were subsequently markedly less responsive to the vasodilator actions of glyceryl trinitrate, whereas responsiveness to SNAC or NO was only marginally reduced. On the other hand, coronary artery rings superfused with SNAC or NO were subsequently less responsive to glyceryl trinitrate, SNAC and NO. Thus prolonged vascular exposure to SNAC or NO induced a form of tolerance different from that induced with glyceryl trinitrate and which is possibly associated with impaired guanylate cyclase activity. 4 Coronary artery rings superfused with NO were markedly less responsive to glyceryl trinitrate and NO, whereas responses to the endothelium‐dependent vasodilator A23187 and to theophylline were not significantly attenuated. 5 It is concluded that formation of the more stable vasodilator SNAC occurs on incubation of N‐acetylcysteine with SNAP or NO. While coronary artery responsiveness to SNAC and NO is virtually unchanged in the presence of glyceryl trinitrate‐induced tolerance, after prolonged exposure to SNAC or NO tolerance may develop to these vasodilators with cross‐tolerance to glyceryl trinitrate but not A23187. Thus, formation or therapeutic utilization of SNAC may acutely circumvent the problem of glyceryl trinitrate‐induced tolerance but, during prolonged vascular exposure to SNAC, attenuation of vascular responsiveness may occur to a wide range of vasodilators.

Survival after myocardial revascularization for ischemic cardiomyopathy: a prospective ten-year follow-up study.

Abstract Objective The aim was to prospectively analyze all-cause mortality, predictors of survival, and late functional results after myocardial revascularization for ischemic cardiomyopathy over a 10-year follow-up. Methods We prospectively studied 57 patients with stable coronary artery disease and poor left ventricular ejection function ( Results Operative mortality was 1.7% (1/57). The mean left ventricular ejection fraction (0.30) at 15 months postoperatively did not change from before operation (0.28, P = .09). There were 8 deaths at 1 year and 42 deaths over the course of the study, producing a survival of 82.5% at 1 year, 55.7% at 5 years, and 23.9% at 10 years (95% confidence interval: 14.6%-39.1%). Symptom-free survival was 77.2% at 1 year and 20.3% at 10 years. The leading cause of death was heart failure in 29% (12/42). Multivariate analysis showed that large reversible defects on stress thallium were associated with improved left ventricular ejection fraction at 1 year ( P = .01) but only male sex was associated with improved long-term survival ( P = .036). Conclusions Myocardial revascularization for ischemic cardiomyopathy is associated with good functional relief from the symptoms of angina initially and, to a lesser extent, heart failure. Revascularization may have the advantage of preserving the remaining left ventricular function. However, the long-term mortality remains high.

Prediction of outcome after revascularization in patients with poor left ventricular function

BACKGROUND In patients with poor left ventricular function, the determinants of outcome after revascularization are unknown. METHODS We studied prospectively 57 patients with stable coronary artery disease and poor left ventricular function (left ventricular ejection fraction, 0.28 +/- 0.04) who underwent coronary artery bypass grafting. Clinical variables were assessed as predictors of outcome in all patients, and preoperative stress thallium-201 scintigraphic data were analysed in 37 patients. RESULTS The operative mortality was 1.7%. At 12 months after operation, 46 of the 49 survivors were angina-free and 35 had fewer heart failure symptoms, but postoperative left ventricular ejection fraction (0.30 +/- 0.09) did not change significantly. Eighteen survivors had left ventricular ejection fraction improved by 0.05 or more (0.30 +/- 0.03 preoperatively, 0.40 +/- 0.05 postoperatively; p = 0.0001). The adjusted odds ratio of large reversible thallium-201 defects in predicting such outcome was 15 (95% confidence interval, 1.6 to 140), whereas other clinical variables had no predictive value. The transplantation-free 5-year survival was 73%. CONCLUSIONS In patients with poor left ventricular function, surgical revascularization can be performed safely, with good symptomatic relief and long-term survival. One-year survival and improvement in left ventricular function is better in patients with large reversible defects on preoperative stress thallium-201 scintigraphy.

Short-term myocardial uptake of lidocaine and mexiletine in patients with ischemic heart disease.

Determination of short-term myocardial drug uptake and subsequent redistribution was performed in 27 patients with ischemic heart disease for the antiarrhythmic agents lidocaine and mexiletine, using frequent simultaneous measurements of drug concentration in aortic and coronary sinus blood, combined with measurement of coronary sinus blood flow after intravenous bolus injection of the drug. Maximal myocardial drug content per unit resting coronary sinus blood flow (MDC:F) was significantly greater in patients in whom coronary sinus pacing at 100 beat/min was performed during the initial period of drug uptake. Maximal myocardial drug content occurred after 2.4 +/- 0.2 (SEM) for lidocaine and after 5.5 +/- 0.6 min for mexiletine (p less than .001), and pacing did not affect time to maximum myocardial drug content. In nonpaced, but not paced, patients maximal MDC:F was greater in the lidocaine group than that in the mexiletine group. The subsequent efflux of lidocaine from the myocardium was more rapid that that of mexiletine in both paced and nonpaced groups.

Myocardial Uptake of Drugs and Clinical Effects

SummaryThe process of uptake of cardioactive drugs into the myocardium is a major determinant of the efficacy and potential toxicity of such agents. Evaluation of responses to anti-arrhythmic and positive inotropic agents is best performed with reference to their concentration in the myocardium, and the potential toxicity of drugs such as tricyclic antidepressants and anthracycline antineoplastics is likely to be related to peak myocardial drug concentrations.Although it has been appreciated for many years that even during long term drug administration the myocardial drug content may not be readily predictable on the basis of estimation of plasma drug concentrations, methodology for direct assessment of myocardial drug content has remained limited. The results of in vitro experiments, utilising tissue culture preparations of myocardial cells or isolated atria, have shed some light on the role of local factors as determinants of myocardial drug uptake. For many agents, attainment of maximal cardiac drug content in vitro is a very slow process (taking up to 3 hours), although maximal inotropic and electrophysiological effects may occur more rapidly. The prolonged time course of drug washout from these preparations also reflects their extensive and slow intracellular accumulation. Mechanical activity of the myocardium appears to accelerate drug uptake, particularly for otherwise slowly equilibrating agents, but the major determinant of the extent of drug uptake into isolated myocardial preparations is lipophilicity, perhaps reflecting the passage of drugs through the sarcolemma.In intact animals, assessment of myocardial drug content after acute drug administration has been performed utilising serial myocardial biopsy or sacrifice of animals. Studies in open-chested dogs suggest that acute accumulation of agents may be most closely predicted from the second compartment of a 3-compartment pharmacokinetic model, and that there is a variable correlation between changes in plasma and myocardial drug concentrations. For example, bretylium concentrations within the myocardium continue to increase for up to 6 hours after drug administration.Factors which may influence drug uptake into the myocardium in intact animals include ischaemia, which usually results in a delay in both drug uptake and subsequent clearance. This change can also be inferred from the time course of onset of antiarrhythmic drug effects in some models of myocardial ischaemia. Anoxia may also inhibit myocardial drug uptake. On the other hand, shock states, circulatory volume overload and tachycardia all increase myocardial drug uptake, largely because of increased myocardial mechanical activity, and to a lesser extent, redistribution of total cardiac output towards the coronary circulation.Studies of myocardial drug concentration in human subjects have until recently been restricted because of methodological limitations to perioperative biopsy samples of myocardium. We have recently utilised the technique of coronary sinus catheterisation to study acute drug uptake in patients with ischaemic heart disease. Comparison of the antiarrhythmic agents lignocaine (lidocaine) and mexiletine using this methodology indicated that lignocaine uptake into the myocardium is more rapid, but that mexiletine is subsequently retained within the myocardium to a greater extent. Coronary sinus pacing induced an increase in both lignocaine and mexiletine uptake. This technique offers a potential means of comparing myocardial drug content with acute effects for most cardioactive agents. Its application may permit optimisation of acute administration of such drugs.

Perhexilene: effects on hepatic lysosomal function in rats

1. Perhexilene, a long‐acting anti‐anginal drug, can induce adverse effects on the liver which may be dose‐dependent. At high concentrations, perhexilene causes marked morphological change in hepatocyte lysosomes. The current study examined the effect of ‘therapeutic’ doses of perhexilene on hepatic lysosomal function, particularly the biliary release of lysosomal enzymes, using an isolated perfused rat liver (IPRL) model.

HAEMODYNAMIC EFFECTS OF A SINGLE LOW DOSE OF PRAZOSIN IN PATIENTS WITH CHRONIC CONGESTIVE CARDIAC FAILURE CORRELATIONS WITH PHARMACOKINETICS

1. The haemodynamic effects and pharmacokinetics of a single orally administered dose of 0.5 mg of prazosin have been compared in six patients with stable severe congestive cardiac failure. Administration of prazosin induced significant decreases in mean pulmonary capillary wedge pressure (from 27.5, s.e.m.=4.5 to 19.4, s.e.m.=5.1 mmHg; P<0.001), mean arterial blood pressure (from 94.5, s.e.m.=6.0 to 85.4, s.e.m.=5.0 mmHg; P<0.01), and systemic vascular resistance (from 1690, s.e.m.=360 to 1420, s.e.m.=200 dyn. s/cm5; P<0.05) and a rise in cardiac index from 1.98 (s.e.m.=0.07) to 2.28 (s.e.m.=0.16) litres/min per m2 (P<0.05). There was a non‐significant fall in heart rate.

RELATIONSHIP BETWEEN SYSTEMIC AND CORONARY VASCULAR RESPONSES TO DIGOXIN AND CONCURRENT DRUG THERAPY WITH VERAPAMIL/β‐ADRENOCEPTOR ANTAGONISTS IN HUMANS

1. In 24 patients who were undergoing coronary arteriography for the assessment of ischaemic heart disease, the relationship between the systemic and coronary vascular responses to acute intravenous digoxin administration (500 μg) and concurrent drug therapy with the calcium antagonist verapamil (group I) or a β‐adrenoceptor antagonist (group II) or neither of these agents (group III) was examined.