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At least 19 recordsLinked to original sources
PubMed1996

Relationship between plasma perhexiline concentration and symptomatic status during short-term perhexiline therapy.

We tested the hypothesis that resolution versus persistence of symptomatic ischaemia and/or development of nausea/dizziness on the third day of loading with perhexiline maleate (PM), is correlated with perhexiline plasma concentrations after the standard loading phase in patients with acute coronary syndromes. Forty consecutive patients with either unstable angina pectoris or non-Q-wave myocardial infarction with persistent angina pectoris, despite maximal pharmacological therapy (other than PM), were studied. All patients received PM 400 mg/day for 3 days and 200 mg/day thereafter. On days 2 and 3 observers blinded to the 72-96 h plasma perhexiline concentration assessed the patient regarding episodes of angina and/or nausea/dizziness. On the third day of loading with PM, 12 patients experienced angina and 11 patients had nausea and/or dizziness. Plasma perhexiline concentrations at 72-96 h varied widely: mean 0.46 +/- 0.26 (range 0.11-1.77) microgram/ml. There was a relationship of borderline statistical significance between resolution of anginal symptoms and plasma perhexiline concentration > 0.15 microgram/ml (p = 0.055). There was a close relationship between emergence of nausea/dizziness with plasma perhexiline concentration > 0.06 microgram/ml (p < 0.01). We conclude that this study (a) suggests that PM exerts incremental antianginal effects over those of other antiischaemic agents in patients with acute coronary syndromes and (b) establishes that the development of nausea and/or dizziness in such patients is strongly predictive of accumulation of perhexiline beyond the therapeutic range of the drug.

Aged↗
PubMed1984

Polymorphic hydroxylation of perhexiline maleate in man.

Long term perhexiline maleate therapy causes peripheral neuropathy and hepatic damage in certain subjects. An association between these adverse reactions and a genetically determined relative inability to hydroxylate debrisoquine has been described. This association could indicate either that the effects of perhexiline impair debrisoquine oxidation thus producing a phenocopy, or that perhexiline is polymorphically hydroxylated and that the polymorphism is controlled by the same alleles as control the debrisoquine polymorphism. To test the second possibility, a study investigating the hydroxylation status of a population of healthy volunteer subjects has been performed using perhexiline maleate. Hydroxylation phenotyping was performed on 50 normal volunteers. A standard oral dose was given and plasma and urinary perhexiline, 4-monohydroxyperhexiline (MI metabolite), and 4'monohydroxyperhexiline (MIII metabolite) was measured. The 24-hour plasma perhexiline concentration, the 24-hour plasma MI metabolite concentration, and 12 to 24-hour urinary MI metabolite excretion were clearly bimodal, suggesting the existence of a polymorphism for perhexiline hydroxylation. Poor metabolisers represent 6% of the population studied. Known poor metabolisers of debrisoquine are also poor metabolisers of perhexiline, while known extensive metabolisers of debrisoquine are also extensive metabolisers of perhexiline, indicating that in white British subjects the hydroxylation polymorphism is under identical genetic control for both compounds. The poor metaboliser sub-group exhibited the highest plasma perhexiline levels. Perhexiline phenotyping separates the poor and extensive metaboliser phenotypes much more clearly than other tests and defines a sub-group at risk from perhexiline toxicity. Pretreatment phenotyping using this test, followed by exclusion of poor metabolisers from perhexiline therapy, should substantially reduce the incidence of major adverse effects.

Adult↗
PubMed1986

Stereoselective pharmacokinetics of perhexiline.

Blood plasma and urine excretion pharmacokinetics of the (+) and (-) enantiomers of perhexiline have been determined in oral single-dose studies in eight human volunteers, and compared with the pharmacokinetics of the racemate drug in the same subjects. The (-) enantiomer is more rapidly metabolized and eliminated, and is stereoselectively hydroxylated to the cis-monohydroxy-perhexiline. The peak plasma concn of unchanged perhexiline is greater, while that of the cis-monohydroxy-perhexiline metabolite is lower, after administration of the (+) enantiomer than after the (-) enantiomer or the racemate. Similarly, the AUC values for unchanged perhexiline and for the trans-monohydroxy-perhexiline metabolite are greatest and the AUC value for the cis-monohydroxy-perhexiline metabolite is lowest for the (+) enantiomer. The three stereoisomeric forms of perhexiline all had the same times to peak plasma concn of the unchanged drug or of the cis-metabolite, and all three forms had a similar plasma elimination half-life for unchanged perhexiline. Metabolism of racemic perhexiline to the cis-monohydroxy metabolite is the major mechanism of elimination of the drug in man and has been shown to be polymorphic in human populations. The (-) enantiomer which shows stereoselective metabolism to the cis metabolite might therefore show a greater polymorphic effect. Studies with rat-liver microsomal preparations in vitro showed that, in contrast to the human studies in vivo, hydroxylation of perhexiline yields mostly the trans-monohydroxy metabolite. The DA strain of rats exhibited slower rates of hydroxylation in vitro than Wistar or Lewis strains of rats.

Adult↗
PubMed1996

Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone.

The mechanism of the anti-anginal effect of perhexiline is unclear but appears to involve a shift in cardiac metabolism from utilization of fatty acid to that of carbohydrate. We tested the hypothesis that perhexiline inhibits the enzyme carnitine palmitoyltransferase-1 (CPT-1), which controls access of long chain fatty acids to the mitochondrial site of beta-oxidation. Perhexiline produced a concentration-dependent inhibition of CPT-1 in rat cardiac and hepatic mitochondria in vitro, with half-maximal inhibition (IC50) at 77 and 148 mumol/L, respectively. Amiodarone, another drug with anti-anginal properties, also inhibited cardiac CPT-1 (IC50 = 228 mumol/L). The rank order of potency for inhibition was malonyl-CoA > 4-hydroxyphenylglyoxylate (HPG) = perhexiline > amiodarone = monohydroxy-perhexiline. Kinetic analysis revealed competitive inhibition of cardiac and hepatic CPT-1 by perhexiline with respect to palmitoyl-CoA but non-competitive inhibition with respect to carnitine. Curvilinear Dixon plots generated "apparent inhibitory constant (Ki)" values for perhexiline, which indicated a greater sensitivity of the cardiac than the hepatic enzyme to inhibition by perhexiline. Perhexiline inhibition of CPT-1, unlike that of malonyl-CoA and HPG, was unaffected by pretreatment with the protease nagarse. These data establish for the first time that two agents with proven anti-anginal effects inhibit cardiac CPT-1. This action is likely to contribute to the anti-ischaemic effects of both perhexiline and amiodarone.

Amiodarone↗
PubMed2000

Effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart.

Perhexiline is a potent prophylactic anti-anginal agent that has been shown to inhibit myocardial utilization of long-chain fatty acids and to inhibit the mitochondrial enzyme carnitine palmitoyltransferase (CPT)-1. We compared the hemodynamic and biochemical effects of perhexiline (0.5 and 2.0 microM) and of another CPT-1 inhibitor, oxfenicine (0.5 mM), in Langendorff-perfused rat hearts subjected to 60 min of low-flow ischemia (95% flow reduction) followed by 30 min of reperfusion. Both perhexiline (2 microM only) and oxfenicine attenuated (p < 0.003, p < 0.0002, respectively) increases in diastolic tension during ischemia, without significant effects on developed tension, or on cardiac function during reperfusion. Myocardial concentrations of long-chain acylcarnitines (LCAC), products of CPT-1 action, were decreased (p < 0.05) by oxfenicine, unaffected by 2 microM perhexiline, and increased slightly by 0.5 microM perhexiline. Perhexiline, but not the active metabolite of oxfenicine, also inhibited cardiac CPT-2 with similar IC50 and Emax, although lower Hill slope, compared with CPT-1. Oxfenicine, but not perhexiline, reduced concentrations of the endogenous CPT-1 inhibitor, malonyl-CoA. Perhexiline, but not oxfenicine, inhibited myocardial release of lactate during normal flow. We conclude that (a) perhexiline protects against diastolic dysfunction during ischemia in this model, independent of major changes in LCAC accumulation and (b) this may result from simultaneous effects of perhexiline on myocardial CPT-1 and CPT-2.

Animals↗
PubMed1986

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.

Adult↗
PubMed1988

Inhibitory effects of some cyclohexylaralkylamines related to perhexiline on sodium influx, binding of [3H]batrachotoxinin A 20-alpha-benzoate and [3H]nitrendipine and on guinea pig left atria contractions.

The antagonist activities of some cyclohexylaralkylamines derived from perhexiline on the fast Na+ channel and slow Ca2+ channel in rat brain and rat heart were examined and compared to the antagonist activities of nifedipine, verapamil, prenylamine and perhexiline. Prenylamine, perhexiline and the cyclohexylaralkylamine derivatives inhibited the [3H]batrachotoxinin A 20-alpha-benzoate binding more than the [3H]nitrendipine binding in rat brain. The nature of the interaction of the cyclohexylaralkylamines with the binding of [3H]batrachotoxinin and [3H]nitrendipine was non-competitive. The synaptosomal 22Na uptake induced by protoveratrine B, a Na+ channel agonist, was also inhibited. Prenylamine, perhexiline and perhexiline derivatives were more potent on the fast Na+ channel than on the Ca2+ channel in contrast to nifedipine and verapamil. The inhibition of Na+ and Ca2+ channels was also shown in guinea pig left atria. Perhexiline, prenylamine and the perhexiline derivatives inhibited the protoveratrine B-induced contraction more than they inhibited that induced by CaCl2, in contrast with nifedipine and verapamil. Our results showed that prenylamine, perhexiline and its related cyclohexylaralkylamines inhibited the fast Na+ channel far more than the slow Ca2+ channel in rat brain, rat heart and guinea pig atria.

Animals↗
PubMed1999

Assessment of interlaboratory performance in the provision of perhexiline therapeutic drug monitoring services in Australia.

Perhexiline is a prophylactic antianginal agent particularly useful in patients whose angina is poorly controlled or refractory to conventional drug regimens. Although perhexiline can cause serious hepatic and neurological toxicity, maintaining trough plasma concentrations between 0.15-0.60 mg/L minimizes the risk of toxicity while providing relief of angina symptoms in a majority of patients. All pathology laboratories are required to participate in interlaboratory proficiency testing (PT) programs. The authors therefore initiated a monthly PT program to assess the performance of Australian laboratories measuring perhexiline (n = 8). PT specimens included perhexiline-spiked drug-free human plasma and pooled plasma from patients administered perhexiline. The performance of 8 Australian laboratories participating in the program was examined over a 30-month period. The mean relative standard deviation of the group was 18.2%. All centers performed well with respect to accuracy, achieving mean percentage bias within +/-8% of target perhexiline concentrations. The usefulness of the PT program was highlighted by the identification of two laboratories with an unacceptable degree of variability (up to 30% of results varied more than +/-55% from the target concentration), and the identification of potential analytical problems with the use of perhexiline metabolite concentrations for determining patients' hydroxylator status. Continued and improved use of PT by pathology laboratories is essential to ensuring the safe and effective clinical use of perhexiline.

Angina Pectoris↗
PubMed1997

Perhexiline improves symptomatic status in elderly patients with severe aortic stenosis.

BACKGROUND: The prognosis of severe symptomatic aortic stenosis is poor without aortic valve replacement, with no previous reports of beneficial effects of any medical treatment on either symptoms or outcome. However, this condition is increasingly a disease of the elderly and cardiothoracic surgery is associated with significant mortality and morbidity in this group. AIMS: We postulated that perhexiline, a novel anti-ischaemic agent with an oxygen-sparing metabolic effect in the myocardium (via inhibition of carnitine palmitoyltransferase-1) and no adverse haemodynamic effects, may improve symptomatic status in elderly patients with severe aortic stenosis. We report here our initial experience with perhexiline treatment in such patients. METHODS: Elderly patients with symptomatic severe aortic stenosis, who were deemed unsuitable for aortic valve replacement, were treated with perhexiline, the drug dosage titrated according to steady state plasma perhexiline concentrations. NYHA functional class was determined prior to and three months following commencement of perhexiline, and changes were analysed using McNemar's test. RESULTS: Fifteen patients, age range 73-87, were followed for up to 30 months (median 18 months). Symptomatic status improved in 13 of the 15 patients over the first three months of perhexiline therapy (p < 0.01), five patients becoming asymptomatic. Twelve month actuarial survival was 80% (95% CI = 57, 100). Perhexiline was well tolerated, with no withdrawals due to toxicity or deteriorating clinical status. CONCLUSION: Therapy with perhexiline was associated with a marked improvement in clinical status in this group of elderly patients with severe aortic stenosis.

Aged↗
PubMed1984

Impaired oxidation of debrisoquine in patients with perhexiline liver injury.

Perhexiline maleate is an antianginal agent which depends on hepatic oxidation for its elimination. Its use may be complicated by the development of peripheral neuropathy and liver damage. The majority of patients with perhexiline neuropathy have an impaired ability to effect metabolic drug oxidation which is genetically determined. Information has not been available on drug oxidation capacity in patients with perhexiline liver injury. Drug oxidation was measured using an oxidation phenotyping procedure in four patients with perhexiline liver injury and in 70 patients with chronic liver disease serving as a control group. All four patients with perhexiline liver damage showed a substantial metabolic defect; three of the four patients (75%) showed a genetically determined impairment of oxidation capacity. The incidence of severely impaired oxidation capacity in the perhexiline group was significantly greater than in the patients with chronic liver disease (6/70; 8.6%) and in the healthy population (9%) (F = 0.0048). A clear association exists between perhexiline liver injury and diminished drug metabolic activity, suggesting that the propensity to develop perhexiline liver injury is, at least in part, genetically determined.

Adolescent↗
PubMed1995

Voltage- and time-dependent block by perhexiline of K+ currents in human atrium and in cells expressing a Kv1.5-type cloned channel.

Perhexiline maleate is an antianginal drug that has been shown to have antiarrhythmic effects in humans. To examine whether some of these clinical observations could be caused by block of cardiac K+ channels, we examined the effects of perhexiline on a rapidly activating delayed rectifier K+ channel (Kv1.5) cloned from human heart and stably expressed in human embryonic kidney cells as well as a corresponding K+ current (the ultra-rapid delayed rectifier, IKur) in human atrial myocytes. With the use of inside-out macropatches, we found that perhexiline inhibited Kv1.5 current in a time- and voltage-dependent manner with an IC50 value of 1.5 x 10(-6) M at +50 mV. Perhexiline reduced Kv1.5 tail current amplitude and slowed its decay relative to control. These data are consistent with blockade of open channels, probably from the intracellular surface. Perhexiline (3 microM) also blocked IKur in human atrial myocytes. The block that was observed was both time- and voltage-dependent in qualitatively similar ways to block of Kv1.5 channels. However, the time-dependent block of IKur by perhexiline was somewhat slower and its voltage-dependence steeper relative to its effects on Kv1.5. These data indicate that perhexiline blocks both cloned and native human cardiac K+ channels. Blockade of one or more types of voltage-dependent K+ channels may explain some of the electrophysiological effects of perhexiline observed in humans.

Atrial Function↗
PubMed1981

High-performance liquid chromatographic assay of perhexiline maleate in plasma.

A sensitive assay is described for the calcium antagonist perhexiline maleate. Alkalinized plasma was extracted with nb-hexane, the organic phase was evaporated, and the residue was dansylated prior to analysis by reversed-phase high-performance liquid chromatography using a fluorescence detector. Perhexiline was resolved from its mono- and dihydroxylated metabolites, and the limit of sensitivity was 5 ng of perhexiline/ml. This limit represents approximately 100 times the sensitivity of the previously described GLC assay. Single-dose pharmacokinetic studies were performed with 150- and 300-mg oral doses of perhexiline maleate in five patients with severe angina pectoris and impaired left ventricular function. Peak plasma perhexiline levels occurred 3-6 hr after drug ingestion in four patients and after 12-18 hr in the fifth patient. The mean elimination half-life, measured 24 hr after drug ingestion, varied with plasma perhexiline concentration. It was 11.2 +/- 2.1 hr after the 150-mg dose and 19.1 +/- 2.8 hr after the 300-mg dose. The mean ratio of areas under the concentration-time curve for the 300-versus 150-mg doses ws 5.3:1, suggesting that hepatic metabolism of perhexiline may be saturable and that the bioavailability of perhexiline is dose dependent.

Aged↗
PubMed1999

The effects of perhexiline on the rat coronary vasculature.

The predominant site and mechanism(s) of perhexiline-induced coronary vasodilatation were investigated in the rat heart. Perhexiline was more potent in the Langendorff perfused heart than in the left anterior descending coronary artery (EC50; 0.27 microM, confidence limits 0.19-0.39: 2.7 microM, 2.0-3.4, respectively). Selective endothelial inactivation with Triton X-100 in the perfused heart, reduced the response to perhexiline 1 microM (76+8% to 30+3% of control). 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) 3 microM, Nomega-nitro-L-arginine 100 microM, or a combination of the latter with indomethacin 10 microM, had no significant effect on responses to perhexiline in the perfused heart. Unlike bradykinin-induced vasodilatation, responses to perhexiline were not inhibited by tetrabutylammonium 1 mM, or charybdotoxin 20 nM. SKF525A 5 microM inhibited both perhexiline and bradykinin responses, while apamin 1 microM and glibenclamide 3 microM inhibited neither. Perhexiline exerts partially endothelium-dependent coronary vasodilator effects in the rat, predominantly on small coronary arteries, which appear to be independent of nitric oxide (NO), prostacyclin and the endothelium-derived hyperpolarising factor (EDHF) released by bradykinin.

Animals↗
PubMed1984

Single-dose pharmacokinetics of perhexiline administered orally to humans.

A high-performance liquid chromatographic method for the simultaneous determination of perhexiline and its major metabolites, the cis- and trans-monohydroxyperhexilines M1 and M3, respectively, in human plasma or urine has been developed. Perhexiline and its metabolites are extracted from plasma or urine and derivatized with 1-fluoro-2,4-dinitrobenzene. The extracted dinitrophenyl derivatives of drug and metabolites are separated on a Spherisorb S5 ODS column by gradient elution. The limits of detection for perhexiline and its monohydroxy metabolites were 15 and 3 ng/ml, respectively. The inter-assay coefficients of variation for 100 ng/ml perhexiline, 100 ng/ml M1 and 400 ng/ml M3 were 10.5, 7.6 and 5.6%, respectively (n = 9). The method has been employed in a limited kinetic study with five healthy adult male volunteers who received 150-mg and 300-mg Pexid tablets at an interval of one week. In four subjects perhexiline exhibited marked first pass effects, with plasma M1 levels higher than unchanged perhexiline; in the urine M1 was the predominant metabolite except in one subject who had higher M3 than M1 in the 300-mg Pexid study. The fifth subject exhibited a defective capacity to hydroxylate perhexiline; M1 and M3 were not detectable in plasma, and the urinary excretion of the monohydroxyperhexilines was relatively less, with M3 present in higher amounts than M1.

Administration, Oral↗
PubMedDate not supplied

Vasodilating effects of perhexiline, glyceryl trinitrate, and verapamil on the coronary, femoral, renal, and mesenteric vasculature of the dog.

We compared the vasodilator effects of perhexiline on canine coronary, femoral, renal, and mesenteric arteries with those of glyceryl trinitrate and verapamil. Intravenous perhexiline produced vasodilation of all four vascular beds and decreased peripheral vascular resistance. High doses of perhexiline sometimes increased peripheral vascular resistance and reduced peripheral blood flow. This increase in resistance was abolished by hexamethonium. Intra-arterial perhexiline caused dose-dependent dilation in all four vascular beds without selectivity for the coronary circulation. Neither the autonomic nervous system nor inhibition of adenosine deaminase was involved in the vasodilator action of perhexiline. Perhexiline abolished renal blood flow autoregulation, an effect which was reversed by simultaneous administration of CaCl2. These results suggest that the vasodilator effect of perhexiline is mediated by its Ca2+-antagonistic activity. However, some differences in its effects from those of other Ca2+-antagonists remain to be clarified.

Animals↗