Perhexiline: Old Drug, New Tricks? A Summary of Its Anti-Cancer Effects.

Cancer metabolic plasticity, including changes in fatty acid metabolism utilisation, is now widely appreciated as a key driver for cancer cell growth, survival and malignancy. Hence, cancer metabolic pathways have been the focus of much recent drug development. Perhexiline is a prophylactic antianginal drug known to act by inhibiting carnitine palmitoyltransferase 1 (CPT1) and 2 (CPT2), mitochondrial enzymes critical for fatty acid metabolism. In this review, we discuss the growing evidence that perhexiline has potent anti-cancer properties when tested as a monotherapy or in combination with traditional chemotherapeutics. We review the CPT1/2 dependent and independent mechanisms of its anti-cancer activities. Finally, we speculate on the clinical feasibility and utility of repurposing perhexiline as an anti-cancer agent, its limitations including known side effects and its potential added benefit of limiting cardiotoxicity induced by other chemotherapeutics.

Can Perhexiline Be Utilized Without Long-Term Toxicity? A Clinical Practice Audit.

BACKGROUND: Perhexiline, originally used as a first-line prophylactic antianginal agent, is now regarded primarily as a treatment for otherwise refractory myocardial ischemia. Recent studies have also demonstrated its short-term utility in heart failure, hypertrophic cardiomyopathy, and inoperable aortic stenosis. Its benefits on myocardial energetics state are potentially counter-balanced by risk of hepatotoxicity and peripheral neuropathy during long-term treatment if drug accumulation occurs. Since perhexiline exhibits complex pharmacokinetics with wide inter-individual variability, its long-term use requires regular plasma concentration monitoring. In this study, the risk of neuro- and hepato-toxicity during long-term perhexiline therapy in relation to the intensity of therapeutic drug monitoring was investigated. Furthermore, determinants of mortality during perhexiline treatment were evaluated. METHODS: In 170 patients treated with perhexiline for a median of 50 months (interquartile range: 31-94 months), outcomes and relationship to plasma drug concentrations were documented. RESULTS: Rationale for treatment with perhexiline included myocardial ischemia in 88% and severe systolic heart failure in 38%. Plasma concentrations were within the therapeutic range of 150-600 ng/mL on 65% of assay occasions and toxic levels accounted for 8.8% of measurements. No patient developed hepatotoxicity attributable to perhexiline while 3 developed peripheral neuropathy possibly induced by treatment. Actuarial 5-year survival rate was 83% overall, and 76.3% in patients with associated systolic heart failure. CONCLUSIONS: This first audit of a large population treated long-term perhexiline demonstrates the following: (1) Although the frequency of monitoring is less than ideal, therapeutic drug monitoring effectively limits occurrence of toxic drug concentrations and virtually eliminates long-term hepato- and neuro-toxicity and (2) Mortality rates during long-term therapy, notably for patients with concomitant heart failure, are surprisingly low.

Mechanistic review of drug-induced steatohepatitis.

Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents.

Interaction of terbinafine (anti-fungal agent) with perhexiline: a case report.

Perhexiline is a unique anti-anginal agent that is frequently used in the treatment of chronic refractory angina. Its utility has been limited because of its complex pharmacokinetics that were only appreciated following the development of a therapeutic perhexiline assay. Perhexiline is cleared primarily via formation of mono-hydroxy metabolites (OH-perhexiline) by cytochrome P450 2D6 (CYP2D6). Drugs that are inhibitors of CYP2D6 may therefore inhibit perhexiline metabolism, increase plasma perhexiline concentration and may consequently increase the risk of toxicity. We report a case of a rise in perhexiline plasma concentration to a toxic level following the introduction of terbinafine hydrochloride; a moderate CYP2D6 inhibiting drug.

A case series of concomitant treatment of perhexiline with amiodarone.

BACKGROUND: Concomitant treatment with amiodarone and perhsexiline has been considered to be relatively contraindicated because of the hypothetical risk of potentiated adverse effects mediated by additive inhibition of carnitine palmitoyl transferase 1. AIM: To study the prevalence of adverse effects associated with the concomitant use of perhexiline and amiodarone. METHODS: A retrospective analysis of a single hospital database of patients receiving perhexiline and amiodarone between July 2009 and April 2011. Files were reviewed for short- and long-term adverse effects requiring drug cessation. Glucose concentration, gamma glutamyl transferase activity. and perhexiline blood concentrations were recorded. RESULTS: We identified 26 patients concomitantly treated with perhexiline and amiodarone, 20 on a long-term basis. In 6 cases, amiodarone was introduced on top of preceding perhexiline. In none of the cases were drugs stopped because of adverse effects. Although blood glucose concentrations fell significantly 48 hours postadmission to hospital, this seems to reflect the resolution of "admission hyperglycemia" rather than onset of hypoglycemia; the latter was rare (5 patients), mild, and clinically silent. In 4 patients, gamma glutamyl transferase approximately doubled. CONCLUSIONS: Traditionally, concomitant treatment with amiodarone and perhexiline has been considered to be relatively contraindicated on the basis of the theoretical potential for synergistic toxicity. This cohort of 26 patients received this concomitant treatment without any excess of major adverse reactions. Our findings suggest that concomitant treatment with perhexiline and amiodarone may be safe in the setting of (1) previous tolerance of either agent, and (2) titration of plasma perhexiline concentrations to guide therapy.

Effects of aging, renal dysfunction, left ventricular systolic impairment, and weight on steady state pharmacokinetics of perhexiline.

MATERIALS AND METHODS: Two hundred patients at steady-state on long-term perhexiline were identified retrospectively. The ratio of maintenance dose to steady-state plasma concentration (dose:[Px]) was correlated with the following putative determinants via simple and multiple linear regression analyses: age, weight, left ventricular ejection fraction (LVEF), and creatinine clearance (CrCl, Cockroft-Gault formula). A Mann-Whitney U test was performed to determine if severe left ventricular systolic impairment affected maintenance dose. RESULTS: Advanced age, left ventricular systolic impairment, and renal impairment were frequently encountered. Using simple linear regression, age was a negative correlate of dose:[P] (R = 0.23, P = 0.001), whereas weight (R = 0.27, P = 0.0001) and CrCl (R = 0.30, P < 0.0001) were positive correlates. Mann-Whitney U analysis showed no difference between dose: [Px] among patients with LVEF of less than 30% versus 30% or greater. Advancing age was strongly associated with decreasing weight (R = -0.45, P < 0.00001) and calculated CrCl varied directly with weight, as expected (R = 0.66, P < 0.0001). Stepwise multiple linear regression using age, LVEF, CrCl, and weight as potential predictors of dose:[P] yielded only weight as a significant determinant. DISCUSSION: Perhexiline has become a "last-line" agent for refractory angina as a result of complex pharmacokinetics and potential toxicity. Use has increased predictably in the aged and infirm who have exhausted standard medical and surgical therapeutic options. Beyond genotype, the effect of patient characteristics on maintenance dose has not been explored in detail. In this study, dose requirement declined with age in a frail and wasting population as a result of weight-related pharmacokinetic factors. LVEF had no apparent effect on maintenance dose and should not be considered a contraindication to use. CONCLUSION: A weight-adjusted starting dose may facilitate the safe and effective prescription of perhexiline and is calculated by 50 + 2 × weight (kg) mg/d, rounded to the closest 50 mg/day.

Optic neuropathy secondary to perhexiline and amiodarone.

Bilateral optic disc swelling is an important clinical sign for potentially life-threatening and sight-threatening conditions, with the most common being raised intracranial pressure and pseudopapillitis. Perhexiline-related and amiodarone-related optic disc swellings are diagnoses of exclusion. This report describes the diagnosis of a man with perhexiline-induced and amiodarone-induced optic neuropathy after extensive investigation consisting of full ophthalmic examination, biochemical screen, temporal artery biopsy, CT, MRI, positron emission tomography and lumbar puncture. There was partial to complete resolution of optic neuropathy following cessation of the causative medication. We postulate that the underlying mechanism of perhexiline toxicity could be mitochondrial dysfunction related. Our case demonstrates that patients treated with perhexiline and amiodarone should be monitored closely for ocular side effects.

Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment.

BACKGROUND: Chronic heart failure (CHF) is a major cause of morbidity and mortality that requires a novel approach to therapy. Perhexiline is an antianginal drug that augments glucose metabolism by blocking muscle mitochondrial free fatty acid uptake, thereby increasing metabolic efficiency. We assessed the effects of perhexiline treatment in CHF patients. METHODS AND RESULTS: In a double-blind fashion, we randomly assigned patients with optimally medicated CHF to either perhexiline (n=28) or placebo (n=28). The primary end point was peak exercise oxygen consumption (VO2max), an important prognostic marker. In addition, the effect of perhexiline on myocardial function and quality of life was assessed. Quantitative stress echocardiography with tissue Doppler measurements was used to assess regional myocardial function in patients with ischemic CHF. 31P magnetic resonance spectroscopy was used to assess the effect of perhexiline on skeletal muscle energetics in patients with nonischemic CHF. Treatment with perhexiline led to significant improvements in VO2max (16.1+/-0.6 to 18.8+/-1.1 mL . kg(-1) . min(-1); P<0.001), quality of life (Minnesota score reduction from 45+/-5 to 34+/-5; P=0.04), and left ventricular ejection fraction (24+/-1% to 34+/-2%; P<0.001). Perhexiline treatment also increased resting and peak dobutamine stress regional myocardial function (by 15% and 24%, respectively) and normalized skeletal muscle phosphocreatine recovery after exercise. There were no adverse effects during the treatment period. CONCLUSIONS: In patients with CHF, metabolic modulation with perhexiline improved VO2max, left ventricular ejection fraction, symptoms, resting and peak stress myocardial function, and skeletal muscle energetics. Perhexiline may therefore represent a novel treatment for CHF with a good safety profile, provided that the dosage is adjusted according to plasma levels.

Perhexiline maleate and peripheral neuropathy.

Peripheral neuropathy has been noted as a complication of therapy with perhexiline maleate, a drug widely used in France (and in clinical trials in the United States) for the prophylactic treatment of angina pectoris. In 24 patients with this complication, the marked slowing of motor nerve conduction velocity and the electromyographic changes imply mainly a demyelinating disorder. Improvement was noted with cessation of therapy. In a few cases the presence of active denervation signified a poor prognosis, with only slight improvement. The underlying mechanism causing the neuropathy is not yet fully known, although some evidence indicates that it may be a lipid storage process.

Drug-induced steatohepatitis.

Drugs rarely cause steatohepatitis, but amiodarone, perhexiline, and DH, have unequivocally been found to independently induce the histologic picture of alcoholic liver disease or NASH. All three agents have similar pathogenetic mechanisms of hepatotoxicity, targeting mitochondrial ATP production and fatty acid catabolism. Other drugs that occasionally cause steatohepatitis, most importantly steroid hormones, likely exacerbate the pathogenetic mechanisms leading to NASH. Similar to NASH, lipid peroxidation resulting from mitochondrial injury may account for all of the histologic findings in drug-induced steatohepatitis. Further research should determine the mechanisms by which drug-induced steatosis, a benign lesion, evolves to steatohepatitis and progressive fibrosis.

Perhexiline maleate as a cause of reversible parkinsonism and peripheral neuropathy.

In a 78-year-old woman receiving perhexiline maleate for intractable angina pectoris, a syndrome of parkinsonism and peripheral neuropathy developed. The neuropathy was confirmed by electromyographic and nerve conduction studies. The parkinsonism and peripheral neuropathy disappeared when perhexiline maleate was discontinued.

Liver damage due to perhexiline maleate.

Two middle-aged men, who had received perhexiline in recommended dosage, showed clinical and histological evidence of severe hepatic damage, and one of them died. Histological study of the livers showed a striking resemblance to alcoholic hepatitis.

Perhexiline maleate in the treatment of angina pectoris in patients awaiting coronary artery bypass surgery.

Twenty-five patients with angina pectoris due to coronary artery disease who had not responded to other medical therapy and on the waiting list for coronary bypass surgery were treated over a period of 4 weeks with perhexiline maleate (100 mg to 400 mg/day) in addition to their other therapy. There was an 80% reduction in the average number of both anginal attacks and nitroglycerin requirement when the pre-treatment week and the 4th week of perhexiline maleate therapy were compared (p less than 0.0001). Six of the patients had no anginal attacks at all and did not require sublingual nitro glycerin tablets during the 4th week of perhexiline maleate therapy.

Peripheral neuropathy due to perhexilene maleate.

Observations are presented on 3 patients, including one autopsy report, with peripheral neuropathy due to perhexilene maleate (Pexid). Clinically and biochemically perhexilene neuropathy presents features unusual for a drug-induced neuropathy. Patients liable to develop neuropathy can be recognised from clinical criteria or by the use of routine electrophysiological determinations of nerve conduction velocities. At this stage the neuropathy is readily reversible if perhexilene therapy is discontinued. We have sought to examine the problems entailed in the future safety of perhexilene and allied drugs.

Analysis of the major lipid classes in human peripheral nerve biopsies. Age group differences and abnormalities of ganglioside level in perhexiline maleate therapy.

We report here the results of a simple and reproducible technique which can be used in semi-routine analysis of peripheral nerve biopsy specimens, so as to have a quantitative analysis of the major lipid classes, i.e. cholesterol, cerebrosides, ethanolamine phospholipids, phosphatidyl-choline, phosphatidyl-serine + phosphatidylinositol, sphingomyelin and gangliosides. Glycolipid hexoses, cholesterol and total phospholipids have been compared in different age groups. Although all lipid classes increased from the younger to the older age group, the molar ratio of cholesterol to phospholipid differed less than the glycolipid to phospholipid ratio. Both increased significantly, even between age group 10--16 and older patients (36, 54, 61, 68, 72 and 73 years old). Although individual variations in lipid content are noteworthy, it must be emphasized that evolution with age of the lipid composition must be taken into account. Furthermore, this study confirms and extends earlier findings of increased ganglioside levels in some cases of peripheral neuropathies observed during perhexiline maleate therapy where characteristic lipid-like polymorphous inclusions have been demonstrated.

Systematic review of the efficacy and safety of perhexiline in the treatment of ischemic heart disease.

Perhexiline was introduced about 30 years ago and rapidly gained a reputation for efficacy in the management of angina pectoris. However, hepatic and neurological adverse effects associated with perhexiline administration led to a marked decline in its use. The drug was originally classified as a coronary vasodilator, and later as a calcium channel antagonist, but recent data suggests that it acts as a cardiac metabolic agent, through inhibition of the enzyme, carnitine palmitoyltransferase-1 (CPT-1). Given the drug's unique anti-ischemic action and favorable hemodynamic profile, together with an improved understanding of the mechanisms underlying the adverse effects of the drug and the clear clinical need for additional therapies in refractory patients, perhexiline is currently being re-appraised as a potentially useful agent in the management of severe myocardial ischemia. Perhexiline is being considered for registration or re-registration in a number of countries and is being evaluated in a large-scale clinical trial in elderly patients with aortic stenosis and myocardial ischemia. This systematic review examines the evidence from available published literature in relation to the efficacy and tolerability of perhexiline in the treatment of cardiac disease. While there is a lack of well designed controlled trials using objective end-points to determine efficacy (almost all trials used a crossover design, included small numbers of patients and had limited statistical analysis of results), there is consistency in the data available that perhexiline is considerably more effective than placebo when used as monotherapy. Furthermore, it affords additional symptom relief in those already receiving maximal conventional anti-anginal therapy. However, there is a paucity of trials demonstrating the efficacy of low dosages of perhexiline (100 to 200 mg/day) in patients with refractory angina pectoris. Available evidence also suggests that the incidence of adverse events can be minimised, and the efficacy maintained, by keeping plasma perhexiline concentrations within a therapeutic range (150 to 600 micro g/L)

Severe ocular side effects of perhexilene maleate: case report.

We report a case of perhexilene maleate (PEXID) toxicity in which the presenting feature was loss of vision secondary to chronic papilloedema. Vortex keratopathy similar to that seen in amiodarone keratopathy was present, and corneal and conjunctival biopsy findings are presented. To our knowledge this is the first case report of a keratopathy occurring in perhexilene toxicity. After withdrawal of the drug the papilloedema and keratopathy subsided, but some visual deficit remains. The properties of perhexilene maleate and other amphiphilic drugs are described, and the possible aetiology of vortex keratopathy is discussed.

Perhexiline maleate induced cirrhosis.

Perhexiline maleate is a potent anti-anginal drug which may cause alcoholic-type hepatitis and cirrhosis. We report a case of a patient who developed cirrhosis on a relatively low dose within 16 mth.

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.

Perhexiline maleate-induced hepatitis.

We report on a case of perhexiline maleate-induced hepatitis secondary to a long-term administration of recommended daily dosages of 300 mg. The patient had a spectacular weight loss of 29 kg. He developed hepatitis, which subsided after drug withdrawal. Our electron-microscopic findings with the typical inclusion bodies and impaired hydroxylation capacity point to an underlying metabolic disorder as the pathogenetic mechanism.