Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Perhexiline”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources
PubMed2006

Effect of the anti-anginal agent, perhexiline, on neutrophil, valvular and vascular superoxide formation.

The prophylactic anti-anginal agent, perhexiline, may also be effective in acute coronary syndromes and advanced aortic valvular stenosis, conditions associated with enhanced inflammation. Its potential effects on superoxide formation via NADPH oxidase were measured by lucigenin-mediated chemiluminescence. Perhexiline inhibited superoxide formation in intact neutrophils stimulated with formyl Met Leu Phe (fMLP) 4 muM or with phorbol myristate acetate (PMA) 162 nM - IC50 2.3 microM (1.5-3.6), n=4. Sub-unit assembly of NADPH oxidase by PMA was unaffected by pretreatment with perhexiline 2 microM, a concentration which reduced superoxide formation by 44+/-5% (n=4) in intact neutrophils. Perhexiline inhibited preassembled neutrophil NADPH oxidase and that in membranes of pig valve interstitial cells, human umbilical vein endothelial cells (HUVECs) and cardiac fibroblasts, but not that in rat aorta (rings or membrane preparations). These data imply that perhexiline inhibits the phagocytic NADPH oxidase directly, and that pig aortic valvular interstitial cells possess a similar enzyme, a conclusion supported by immunohistochemical localisation of the gp91phox subunit in these cells. However further study is required to clarify the effect of perhexiline on different NADPH oxidase isoforms particularly in the vasculature.

Angina Pectoris↗
PubMedDate not supplied

Therapy of angina pectoris with low-dose perhexiline.

We conducted a double-blind, crossover study into the effect of 100 mg of perhexiline maleate twice daily on the response to exercise of 15 patients with proven ischemic heart disease. Patients were evaluated by bicycle ergometry, on three occasions, before treatment and after 2 weeks of treatment with placebo or perhexiline. Patients were able to exercise for a longer period as shown by comparing perhexiline to pretreatment (mean change, 54.9%; p less than 0.001) and placebo values (38.9%; p less than 0.001). An increase in work performed while taking perhexiline was demonstrated when compared to pretreatment (mean change, 29.7%; p less than 0.001) and placebo (26.3%; p less than 0.001). An increase in heart rate at maximal exercise was observed when compared to pretreatment (mean change, 9.7%; p less than 0.01) and placebo (8.8%; p less than 0.01). A reduction in heart rate for a given workload was obtained when compared to pretreatment (mean change, 7.0%; p less than 0.005) and placebo (2.9%; p less than 0.01). An increase in resting systolic blood pressure while taking perhexiline was shown when compared to pretreatment (mean change, 12.8%; p less than 0.02) and placebo measurements (8.5%; p less than 0.05). Perhexiline in a dose of 200 mg daily is effective against angina pectoris and significantly increases exercise tolerance. The likelihood of side effects may be decreased by using this dosage regimen.

Adult↗
PubMed1990

Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent.

Despite large gains in the medical and surgical treatment of angina pectoris in the past two decades, many patients are refractory to conventional medical therapy and are unsuitable for a first or, more commonly, repeat coronary revascularization procedure. We evaluated the efficacy of perhexiline maleate, a drug with an antianginal mechanism of action in humans that is as yet unknown, by using a randomized double-blind placebo-controlled crossover design in 17 patients with refractory angina who continued to receive maximal antianginal therapy, typically including nitrates, a beta-blocker, and a calcium channel antagonist. In view of perhexiline's potential for hepatic and neurological toxicity, plasma drug levels were monitored and maintained in the 150-600 ng/ml range. Sixty-three percent of patients were judged perhexiline responders by objective exercise testing criteria, as compared with 18% of patients on placebo (p less than 0.05). By blinded review of subjective measures of anginal frequency and severity, 65% of patients noted an improvement while on perhexiline, whereas no patient identified the placebo phase with improvement. Side effects observed in 29% of patients were minor and related to transient elevations of blood levels of more than 600 ng/ml; no patient suffered hemodynamic or cardiac conduction abnormalities attributable to perhexiline. With attention to the pharmacokinetics of perhexiline's elimination in individual patients, this novel antianginal agent seems to be safe and effective and deserves further evaluation in patients already receiving maximal antianginal therapy who are not candidates for revascularization procedures.

Aged↗
PubMed1982

Effect of an antianginal drug, perhexiline, on myocardial oxygen consumption in anesthetized open-chest dogs compared with verapamil and glyceryl trinitrate.

A pharmacological study on myocardial oxygen consumption was carried out in open-chest dogs using an arterio-venous oxygen difference analyzer. The continuous monitoring of the oxygen difference showed that the peak changes in coronary blood flow did not coincide with the greatest change in myocardial oxygen consumption. Perhexiline, 0.3-3 mg/kg intravenously, increased coronary blood flow and decreased myocardial oxygen consumption, dose-dependently. Perhexiline decreased aortic and systemic blood pressures and left ventricular work except for lower doses of perhexiline which slightly increased cardiac output and ventricular work. Over-all mechanical efficiency of the left ventricle was increased with perhexiline, while the efficiency was decreased around the peak effect of larger doses of the drug on systemic blood pressure and coronary artery. Verapamil, 0.03-0.3 mg/kg, showed essentially the same effects as perhexiline with ten-fold potency superior to perhexiline. Glyceryl trinitrate showed inconsistent effects on coronary flow and myocardial oxygen consumption, and it decreased cardiac work and mechanical efficiency of the left ventricle.

Animals↗
PubMed1990

Enhancement of ricin A chain immunotoxin activity by perhexiline on established and fresh leukemic cells.

In the perspective of increasing the clinical potential of ricin A chain immunotoxins (RTA-ITs), perhexiline (Pex) and four structural analogues (Pex 2, Pex 3, Pex 7, and Pex 11) were evaluated for their ability to enhance RTA-IT activity in vitro. Only perhexiline significantly enhanced the cytotoxic activity of anti-CD5 RTA-ITs, T101 and T101-F(ab')2, on CEM III cell line (30- to 2000-fold), and of anti-HLA-DR RTA-IT, HNC-241, on both RAJI cell line (greater than 100-fold) and two immortalized cell lines originating from patients suffering from B-cell chronic lymphocytic leukemia, EHEB and FS2 D5 (10-fold). On 16 consecutive fresh B-cell chronic lymphocytic leukemia cell samples, significant T101-F(ab')2 RTA-IT and HNC-241 RTA-IT enhancement was observed with perhexiline which was comparable to that of NH4Cl and monensin. Perhexiline almost completely blocked RTA-IT intracellular degradation and profoundly modified its routing. These observations were linked to perhexiline-induced lipidosis via inhibition of sphingomyelinase activity. In conclusion, since the concentrations used are relevant with the pharmacokinetics of this agent, perhexiline appears to be a promising agent for in vivo enhancement of ricin A chain immunotoxins.

Ammonium Chloride↗
PubMed1979

The effects of perhexiline on the sympathetic nervous system.

The effects of perhexiline on sympathetic nervous system function were studied in vitro and in vivo. Perhexiline decreased the field stimulation-induced contractile response of the isolated vas deferens and significantly decreased the quantity of norepinephrine released during stimulation of this preparation. In vivo studies in dogs showed that perhexiline reduced the heart rate response to cardiac accelerator nerve stimulation, an effect not associated with an increase in cholinergic tone or beta adrenergic blockade. Measurements of norepinephrine released from the heart during cardiac nerve stimulation showed that perhexiline (3 mg/kg) decreased norepinephrine release by approximately 35%. These results suggest that a presynatpic effect of perhexiline, which results in a decrease in norepinephrine release, contributes significantly to the attenuated heart rate response which occurs after administration of this drug. A decrease in transmitter release during sympathetic stimulation could play an important role in the mechanism for the protective effects of perhexiline in myocardial ischemic damage.

Animals↗
PubMed1981

Effect of Ca2+-antagonistic vasodilators, diltiazem, nifedipine, perhexiline and verapamil, on platelet aggregation in vitro.

Ca2+-Antagonistic vasodilators, diltiazem, nifedipine, perhexiline and verapamil, showed inhibitory activity on platelet aggregation in human platelet-rich plasma (PRP) induced with ADP, adrenaline and collagen. Preincubation of PRP with one of the drugs effectively prevented the aggregation induced by ADP, ID50s being 2.1 x 10(-4), 3.5 x 10(-5), 3.4 x 10(-5) and 2.3 x 10(-4) g/ml for diltiazem, nifedipine, perhexiline and verapamil, respectively. Nifedipine and perhexiline were equipotent and about 10 times as potent as diltiazem and verapamil. In addition, PRP maximally aggregated with 9.1 mumol/l ADP was disaggregated by administration of any of these drugs. The mechanism of action was considered to be Ca2+-antagonism because, with the exception of perhexiline, the potency ratio of the anti-aggregating activity had a close resemblance to that of the vasodilator activity of these drugs previously reported in the literature. Perhexiline showed the most potent anti-aggregating activity but has been reported to be the least potent vasodilator among the Ca2+-antagonists studied. This further studies are necessary to elucidate the mechanism of perhexiline's inhibition of platelet aggregation.

Adenosine Diphosphate↗
PubMed1994

Inhibition by perhexiline of oxidative phosphorylation and the beta-oxidation of fatty acids: possible role in pseudoalcoholic liver lesions.

In an attempt to better understand the mechanisms for pseudoalcoholic liver lesions in human beings, we determined the effects of perhexiline on mitochondrial functions in mice and rats. A first series of studies suggested that protonated perhexiline entered mouse mitochondria along the mitochondrial membrane potential. Release of a proton in the mitochondrial matrix led to uncoupling of oxidative phosphorylation, and accumulation of perhexiline inhibited complexes I and II of the respiratory chain, decreased ATP formation in vitro and decreased the mitochondrial beta-oxidation of long-, medium- and short-chain fatty acids in vitro and in vivo in mice. In cultured rat hepatocytes, exposure for 24 hr to 25 mumol/L perhexiline markedly decreased hepatocellular ATP and cell viability. Exposure to 5 mumol/L perhexiline did not modify ATP and viability but decreased the beta-oxidation of palmitic acid uniformly labeled with carbon 14 by 38%, increased hepatocyte triglyceride levels by 98% and produced microvesicular steatosis after 72 hr of culture. We conclude that perhexiline is concentrated inside mitochondria, where it inhibits both oxidative phosphorylation and the mitochondrial beta-oxidation of fatty acids. These effects may contribute to the development of necrosis, steatosis and possibly certain other pseudoalcoholic liver lesions in human beings.

Adenosine Triphosphate↗
PubMed1975

Electrophysiologic properties of perhexiline.

Perhexiline maleate (Pexid), a promising clinical antiarrhythmic and antianginal drug, was evaluated for its electrophysiologic effects on the entire conduction system of the intact canine heart throughout a wide range of therapeutic and potentially toxic doses. Intracardiac conduction times were measured by bipolar intramyocardial and transvenous endocardial electrodes before and following the intravenous administration of each dose of perhexiline maleate, 3 mg/kg every 30 min for a total of 4 doses in 7 open-chest anesthetized dogs. Eight animals served as controls in which similar operative technique and electrophysiologic variables were recorded after infusion of the maleate diluent. In addition, the effects of perhexiline on atrial and ventricular thresholds to electrical stimulation were recorded, as well as the QRS and QT intervals, sinus rate, and rhythm disorders. It was observed that perhexiline did not significantly (p greater than .05) alter sinus rate, QT interval, QRS duration, PR interval, intra-atrial conduction time, atrioventricular nodal conduction time, and His-Purkinje conduction velocity. The drug did not affect the cardiac threshold to electrical stimulation of less than 0.1 ma. No ectopic atrial or ventricular activity emerged during the accumulated influence of the agent. From this study, it is concluded that perhexiline does not exert deleterious actions on the conduction system of the intact canine heart. In view of the negligible toxic effects and its efficacy in treating ventricular tachyarrhythmias in patients, the drug deserves further clinical evaluation.

Animals↗
PubMed1988

Impairment of sulfobromophthalein biliary excretion and inhibition of glutathione S-transferase activity induced by perhexiline maleate in rats.

The effect of the antianginal agent perhexiline maleate (160 mg/kg i.g., daily for 4 days) on the biliary excretion of sulfobromophthalein (BSP) and BSP-glutathione and the hepatic activity of glutathione S-transferases was investigated in Wistar rats. Perhexiline maleate caused a significant reduction in the maximal biliary excretion of BSP (-28%). The decrease corresponded to a lowered excretion of the conjugated dye whereas the excretion of the parent compound did not change significantly. Administration of the drug caused no effect on the maximal biliary excretion of infused BSP-glutathione. Liver glutathione concentrations were similar in control and treated rats. Perhexiline maleate significantly reduced liver glutathione S-transferase activities toward BSP (-25%), 3,4-dichloronitrobenzene (DCNB) (-21%) and 1-chloro-3,4-dinitrobenzene (DNCB) (-27%). Kinetic studies of the enzyme in liver cytosol showed that perhexiline maleate induced an uncompetitive inhibition for the BSP substrate with a reduced Vmax and Km. The results indicate that the reduction in glutathione S-transferase activity plays an important role as a factor determining the impairment in the hepatobiliary transport of BSP caused by perhexiline maleate.

Animals↗
PubMed1983

Antianginal efficacy of perhexiline maleate in patients refractory to beta-adrenoreceptor blockade.

We performed a double-blind controlled crossover trial of perhexiline maleate versus identical placebo in daily doses of 100-400 mg in 20 male patients who were severely limited with angina pectoris despite therapy with beta-adrenoreceptor blockers. All patients had documented coronary artery disease and were awaiting coronary artery bypass grafting. Beta-blocker therapy was continued unchanged. A significant response compared to placebo was evident after 100 mg of perhexiline, and incremental therapeutic effects were evident up to 400 mg. The mean weekly angina rate fell from 18.2 +/- 2.8 basal to 6.2 +/- 1.5 on 200 mg (P less than 0.05) to 2.8 +/- 0.9 on 400 mg perhexiline (P less than 0.05). Nitroglycerin consumption fell in parallel. The mean exercise duration increased from 261 +/- 57 sec to 384 +/- 75 sec (P less than 0.05). Five patients became asymptomatic on perhexiline, and the number of pain-free days increased 100% (P less than 0.01) compared to placebo. No patient experienced hypotension or heart failure. This study shows that the addition of perhexiline to beta-adrenoreceptor antagonists in patients with severe angina pectoris is effective and represents an alternative therapy.

Adrenergic beta-Antagonists↗
PubMed2004

Development of a regimen for rapid initiation of perhexiline therapy in acute coronary syndromes.

Perhexiline is a prophylactic anti-anginal agent that ameliorates the metabolic basis for myocardial ischaemia and is increasingly used in the management of acute coronary syndromes. No intravenous preparation is available and usual oral loading regimens require 2-3 days to achieve therapeutic drug levels. Two patients presenting to hospital with single-dose over-dosage of perhexiline (6500 mg and 1000 mg, respectively) provided a basis for examining the safety of large single dosage of perhexiline and associated time-course of drug levels. Neither patient had previously taken perhexiline. Peak plasma perhexiline concentrations occurred within 12 h of ingestion and were 2.58 and 0.50 mg/L, respectively (therapeutic range 0.15-0.60 mg/L). The first patient developed transient nausea and vomiting; the second patient had no adverse effects. Subsequently, a series of 10 patients with acute coronary syndromes received an 800-mg loading dose. Peak concentrations occurred within 12 h postdose; the mean levels achieved were 0.40 +/- 0.16 mg/L (standard error of the mean). No serious adverse effects were seen. Two patients reported transient nausea or vomiting within 24 h of the loading dose. The utility of this rapid loading regimen for incremental suppression of myocardial ischaemia remains to be assessed.

Adult↗
PubMed1978

Comparative trial of perhexiline maleate and oxprenolol in patients with angina pectoris.

A random single-blind study of oxprenolol against perhexiline has been undertaken in angina pectoris. Both drugs were effective in treatment (P less than 0.01) but perhexiline was better than oxprenolol (P less than 0.05), 12 of the 14 patients preferring perhexiline. Offset against this was the greater incidence of side effects with perhexiline, including one patient who later developed peripheral neuropathy. Despite the greater efficacy of perhexiline, it is suggested that side effects should preclude its routine prescription as a drug of first choice in angina pectoris. It should remain of value in the special situations of resistant angina and angina with heart failure or bronchospasm, when its use should be carefully monitored for these side effects.

Adult↗
PubMed1981

Effects of perhexiline on myocardial phosphorylase activity, myocardial catecholamine content and heart rate.

A study was conducted on the effects of perhexiline on myocardial phosphorylase activity, myocardial catecholamine content and heart rate. Phosphorylase a activity and heart rate were investigated as an indicator of sympathetic nerve tone in order to clarify the characteristic of perhexiline with regard to the effects on myocardial metabolism in hyperthyroid rats and catecholamine deficient rats. Myocardial catecholamine and phosphorylase a activity were measured by von Euler's method and Cori's method respectively. Conclusion of this study are summarized as follows: 1) Perhexiline reduces the heart rate, and its effect is not always dependent upon the changes in myocardial norepinephrine content. 2) Perhexiline reduces myocardial phosphorylase a activity. It cannot be always said that the reduction is dependent upon the changes in myocardial norepinephrine. 3) Though slightly different from propranolol and dichloroisoproterenol, perhexiline possesses cardiac effects resembling beta-blockers.

Animals↗
PubMed1986

Further studies on the pharmacokinetics of perhexiline maleate in humans.

We have performed single-dose pharmacokinetic studies on perhexiline in eight young volunteers, each given 300 mg of Pexid orally, using an h.p.l.c. method for the separation and quantification of the drug and its monohydroxy metabolites in plasma and urine. The plasma concentration of the cis-monohydroxyperhexiline (peak of 473 +/- 43 ng/ml at 7.5 +/- 2.0 h) was always higher than for unchanged perhexiline (peak of 112 +/- 20 ng/ml at 6.5 +/- 2.0 h) whereas the concentration of the transmetabolite was either low or undetectable in plasma. These findings indicate the occurrence of stereospecific pre-systemic metabolism of perhexiline which reduces the bioavailability of the parent drug. The plasma elimination half-life of perhexiline was 12.4 +/- 6.1 h (range 7-23 h) while that for cis-monohydroxyperhexiline was 19.9 +/- 7.7 h (range 10-29 h). Not more than 0.3% of unchanged perhexiline was excreted in the urine over five days in eight subjects. Between 3 and 23% of the orally administered drug was excreted as the cis- or trans-monohydroxy metabolites, the ratio of trans to cis metabolites being 0.52 +/- 0.20.

Adult↗
PubMed1988

Soft drug derivatives related to perhexiline. Part I: In vitro studies.

A series of cyclohexylaralkylamines derived from perhexiline was synthesized according to the "soft drug" concept. An amide function was introduced as a labile centre to give non-toxic moieties in vivo after the "soft drugs" had attained their therapeutic aims. Compounds were evaluated for their alpha-adrenolytic, calcium antagonist and vasodilator activities in vitro. Some of them, 2, 3, 7 and 15 on rat aorta had alpha-adrenolytic effects comparable to that of perhexiline. Most of them were about 10 times more active calcium antagonists on depolarized pig coronary artery than perhexiline. All derivatives produced concentration-related coronary dilation in the perfused guinea pig heart. Compound 2 was equipotent to perhexiline. The decrease in coronary resistance might, at least partly, be attributable to the alpha-blocking properties of the molecules. In conclusion, the introduction of an amide function into the perhexiline skeleton does not markedly alter the in vitro pharmacological properties.

Adrenergic alpha-Antagonists↗
PubMed1981

[Comparative hepatic toxicity of perhexiline maleate and griseofulvin in mice].

Hepatic toxicity was observed in mice which had received Griseofulvin or Perhexilin Maleate over a period of several months. Treatment of griseofulvin alone gave rise to hepatitis with the presence of Mallory bodies (MB) whereas the same length of treatment with Perhexilin Maleate was associated with steatonecrosis with an absence of MB. When treatment was followed by a one month rest period hepatic lesions disappeared with no trace of sequelae. Cross-treatment studies showed that one week of Perhexiline Maleate was sufficient to induce MB in mice pretreated with Griseofulvin. Similarly, Griseofulvin administered to mice pretreated with Perhexilin Maleate gave rise to MB formation after one week as opposed to the usual two months incubation time (DENK et al.). The histological nature and mode of formation of these MB was identical to that encountered in acute alcoholic hepatitis. On addition, combined drug therapy employing Perhexilin Maleate suggests a particular hepatic toxicity in man in cases where the liver has become predisposed due to other therapeutic.

Animals↗
PubMedDate not supplied

[Experimental anti-arrhythmic action of perhexiline].

The antiarrhythmic action of Perhexiline phosphate, in doses of 3 and 6 mg/kg on various experimental cardiac arrhytmias and on the physiological properties of the atrial myocardium has been studied in the anesthetized dog. Its action in concentrations of 3 and 6 mcg/ml on the transmembrane action potentials in isolated Purkinje fibers has also been analyzed. The activity of perhexiline is comparatively greater in the circus movement atrial flutter and in the arrhythmias caused by ouabain and by barium chloride intoxication than in the atrial tachysystolia caused by the local application of aconitine. Perhexiline prolongs the wave length (refractory period times conduction velocity) of the atrial impulse and depresses atrial excitability. These effects may explain its action on experimental atrial flutter. In isolated Purkinje fibers, perhexiline reduces the maximum velocity of depolarization, the overshoot, the amplitude of the action potential and its duration, measured at 50% of its repolarization phase. The relation of these electrophysiological effects of perhexiline to the genesis of each type of arrhythmia may explain its different type of activity in the experimental models studied.

Animals↗