RESUMO
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.
Assuntos
Fármacos Cardiovasculares , Neoplasias , Humanos , Perexilina/efeitos adversos , Fármacos Cardiovasculares/farmacologia , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/induzido quimicamente , Ácidos Graxos/metabolismoRESUMO
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.
Assuntos
Amiodarona/efeitos adversos , Doenças do Nervo Óptico/induzido quimicamente , Perexilina/efeitos adversos , Vasodilatadores/efeitos adversos , Idoso , Angiofluoresceinografia , Humanos , Masculino , Doenças do Nervo Óptico/diagnóstico por imagem , Recidiva , Tomografia de Coerência ÓpticaRESUMO
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.
Assuntos
Fármacos Cardiovasculares/administração & dosagem , Monitoramento de Medicamentos/métodos , Perexilina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/farmacocinética , Feminino , Seguimentos , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Insuficiência Cardíaca Sistólica/mortalidade , Humanos , Masculino , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/mortalidade , Perexilina/efeitos adversos , Perexilina/farmacocinética , Taxa de Sobrevida , Fatores de TempoRESUMO
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.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado Gorduroso/patologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Amiodarona/efeitos adversos , Animais , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Modelos Animais de Doenças , Fígado Gorduroso/induzido quimicamente , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Irinotecano , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metotrexato/efeitos adversos , Mitocôndrias Hepáticas/patologia , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Perexilina/efeitos adversos , Tamoxifeno/efeitos adversos , Tetraciclina/efeitos adversos , Ácido Valproico/efeitos adversosRESUMO
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.
Assuntos
Antifúngicos , Bloqueadores dos Canais de Cálcio , Naftalenos , Perexilina , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacocinética , Interações Medicamentosas , Humanos , Masculino , Pessoa de Meia-Idade , Naftalenos/administração & dosagem , Naftalenos/efeitos adversos , Naftalenos/farmacocinética , Perexilina/administração & dosagem , Perexilina/efeitos adversos , Perexilina/farmacocinética , TerbinafinaRESUMO
Nonalcoholic steatohepatitis (NASH) is defined histopathologically by the presence of macrovesicular steatosis, cellular ballooning, and inflammation. NASH represents a complex multifactorial disease that typically occurs within the context of the metabolic syndrome. NASH lacks homogeneity, and other forms of NASH can present atypically. Less than 50% of patients with NASH respond to pharmacologic treatment, which speaks to this heterogeneity. The authors discuss drugs, disease entities, and nutritional states that can cause or exacerbate underlying NASH indirectly through worsening insulin resistance or directly by interfering with lipid metabolism, promoting oxidative injury, or activating inflammatory pathways.
Assuntos
Fígado Gorduroso , Amiodarona/efeitos adversos , Antirretrovirais/efeitos adversos , Infecções Bacterianas/complicações , Cannabis/efeitos adversos , Dieta/efeitos adversos , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , Doenças Genéticas Inatas/complicações , Glucocorticoides/efeitos adversos , Humanos , Hipotireoidismo/complicações , Resistência à Insulina , Enteropatias/complicações , Enteropatias/microbiologia , Metabolismo dos Lipídeos , Síndrome Metabólica/complicações , Metotrexato/efeitos adversos , Hepatopatia Gordurosa não Alcoólica , Doenças Profissionais/induzido quimicamente , Perexilina/efeitos adversosRESUMO
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.
Assuntos
Amiodarona/efeitos adversos , Perexilina/análogos & derivados , Vasodilatadores/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiodarona/administração & dosagem , Amiodarona/uso terapêutico , Glicemia/efeitos dos fármacos , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Bases de Dados Factuais , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Perexilina/administração & dosagem , Perexilina/efeitos adversos , Perexilina/uso terapêutico , Prevalência , Estudos Retrospectivos , Vasodilatadores/administração & dosagem , Vasodilatadores/uso terapêutico , gama-Glutamiltransferase/efeitos dos fármacos , gama-Glutamiltransferase/metabolismoAssuntos
Hipoglicemia/induzido quimicamente , Infarto do Miocárdio/tratamento farmacológico , Perexilina/análogos & derivados , Idoso de 80 Anos ou mais , Glicemia/análise , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Eletrocardiografia , Seguimentos , Humanos , Hipoglicemia/fisiopatologia , Masculino , Infarto do Miocárdio/diagnóstico , Perexilina/efeitos adversos , Perexilina/uso terapêutico , Medição de Risco , Índice de Gravidade de DoençaRESUMO
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.
Assuntos
Envelhecimento , Angina Pectoris/tratamento farmacológico , Fármacos Cardiovasculares/farmacocinética , Perexilina/farmacocinética , Insuficiência Renal/metabolismo , Disfunção Ventricular Esquerda , Idoso , Idoso de 80 Anos ou mais , Angina Pectoris/fisiopatologia , Peso Corporal/fisiologia , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/uso terapêutico , Creatinina/metabolismo , Humanos , Pessoa de Meia-Idade , Perexilina/efeitos adversos , Perexilina/sangue , Perexilina/uso terapêutico , Estudos RetrospectivosRESUMO
BACKGROUND: Perhexiline improves functional capacity in heart failure, but the mechanisms are undefined. We sought its effects on myocardial deformation in patients with viable myocardium. METHODS: Thirty-six medically-treated patients, stable at least 6 months post-infarction with LV dysfunction and myocardial viability shown by dobutamine echo (DbE) were randomised to receive perhexiline or matching placebo for 1 year. Cardiopulmonary exercise testing and DbE were performed at baseline and follow-up. Peak-systolic strain (S) and strain rate (SR) were measured offline in 111 dysfunctional segments in the placebo and 88 in the treatment group at rest, low-dose (LDD) and peak-dose dobutamine (PDD). RESULTS: The serum perhexiline level was 0.27+/-0.7 microg/l. There was no difference in the wall motion response to dobutamine at baseline and follow-up. Resting strain and SR were similar in the two groups at baseline and follow-up. However, SR at LDD and PDD increased in the placebo group and worsened during the same period in the perhexiline group. Patients on perhexiline and placebo had a similar rate-pressure product and exercise duration at baseline (7.9+/-2.7 vs 8.7+/-3.3 min, p=NS) and follow-up (9.6+/-4.6 vs 10.1+/-3.03 min, p=NS). CONCLUSION: Perhexiline does not improve the deformation of abnormal myocardial segments in patients with ischaemic LV dysfunction.
Assuntos
Fármacos Cardiovasculares/administração & dosagem , Isquemia Miocárdica/tratamento farmacológico , Perexilina/administração & dosagem , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Cardiotônicos , Fármacos Cardiovasculares/efeitos adversos , Dobutamina , Ecocardiografia , Teste de Esforço , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/fisiopatologia , Perexilina/efeitos adversos , Placebos , Falha de Tratamento , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/fisiologiaRESUMO
Perhexiline, 2-(2,2-dicyclohexylethyl)piperidine, was originally developed as an anti-anginal drug in the 1970s. Despite its success, its use diminished due to the occurrence of poorly understood side effects including neurotoxicity and hepatotoxicity in a small proportion of patients. Recently, perhexiline's mechanism of action and the molecular basis of its toxicity have been elucidated. Perhexiline reduces fatty acid metabolism through the inhibition of carnitine palmitoyltransferase, the enzyme responsible for mitochondrial uptake of long-chain fatty acids. The corresponding shift to greater carbohydrate utilization increases myocardial efficiency (work done per unit oxygen consumption) and this oxygen-sparing effect explains its antianginal efficacy. Perhexiline's side effects are attributable to high plasma concentrations occurring with standard doses in patients with impaired metabolism due to CYP2D6 mutations. Accordingly, dose modification in these poorly metabolizing patients identified through therapeutic plasma monitoring can eliminate any significant side effects. Herein we detail perhexiline's pharmacology with particular emphasis on its mechanism of action and its side effects. We discuss how therapeutic plasma monitoring has led to perhexiline's safe reintroduction into clinical practice and how recent clinical data attesting to its safety and remarkable efficacy led to a renaissance in its use in both refractory angina and chronic heart failure. Finally, we discuss the application of pharmacogenetics in combination with therapeutic plasma monitoring to potentially broaden perhexiline's use in heart failure, aortic stenosis, and other cardiac conditions.
Assuntos
Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacologia , Cardiopatias/tratamento farmacológico , Perexilina/efeitos adversos , Perexilina/farmacologia , Vasodilatadores/efeitos adversos , Vasodilatadores/farmacologia , Angina Pectoris/tratamento farmacológico , Animais , Estenose da Valva Aórtica/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Carnitina O-Palmitoiltransferase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Monitoramento de Medicamentos , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Estrutura Molecular , Mutação , Isquemia Miocárdica/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Perexilina/química , Perexilina/farmacocinética , Resultado do Tratamento , Vasodilatadores/química , Vasodilatadores/farmacocinéticaRESUMO
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.
Assuntos
Fármacos Cardiovasculares/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Perexilina/administração & dosagem , Idoso , Fármacos Cardiovasculares/efeitos adversos , Doença Crônica , Ecocardiografia sob Estresse , Ácidos Graxos/metabolismo , Feminino , Glucose/metabolismo , Insuficiência Cardíaca/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Perexilina/efeitos adversos , Qualidade de Vida , Volume Sistólico/efeitos dos fármacos , Resultado do TratamentoRESUMO
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.
Assuntos
Antiarrítmicos/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Fígado Gorduroso/induzido quimicamente , Amiodarona/efeitos adversos , Animais , Hexestrol/efeitos adversos , Humanos , Perexilina/efeitos adversosAssuntos
Aminoquinolinas/efeitos adversos , Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Antimaláricos/efeitos adversos , Cloroquina/efeitos adversos , Hidroxicloroquina/efeitos adversos , Doenças Musculares/induzido quimicamente , Perexilina/análogos & derivados , Perexilina/efeitos adversos , Animais , Autofagia , Cátions , Diagnóstico Diferencial , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/patologia , Músculo Esquelético/citologia , Doenças Musculares/patologia , Prognóstico , Vacúolos/patologiaRESUMO
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)
Assuntos
Angina Pectoris/tratamento farmacológico , Fármacos Cardiovasculares/uso terapêutico , Perexilina/uso terapêutico , Fármacos Cardiovasculares/efeitos adversos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Humanos , Perexilina/efeitos adversos , Vigilância de Produtos Comercializados , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVE: To report two cases of perhexiline toxicity associated with selective serotonin re-uptake inhibitor (SSRI) treatment. CLINICAL PICTURE: Serum perhexiline concentrations progressively increased after a 69-year-old man was concurrently prescribed paroxetine for the treatment of depression. An 84-year-old woman was admitted to hospital with severe, symptomatic perhexiline toxicity associated with fluoxetine treatment. TREATMENT: In both cases, perhexiline therapy was suspended and treatment with SSRIs was withdrawn. OUTCOME: Serum perhexiline concentrations declined following the withdrawal of paroxetine in one case, but in the case of the second patient perhexiline concentrations were extremely slow to decrease, resulting in referral to a rehabilitative care unit for convalescence. CONCLUSIONS: Serum perhexiline concentrations may be elevated during concurrent treatment with SSRIs, potentially resulting in severe toxicity.
Assuntos
Transtorno Depressivo/tratamento farmacológico , Fluoxetina/efeitos adversos , Paroxetina/efeitos adversos , Perexilina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Vasodilatadores/efeitos adversos , Idoso , Inibidores do Citocromo P-450 CYP2D6 , Transtorno Depressivo/sangue , Transtorno Depressivo/psicologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Fluoxetina/uso terapêutico , Humanos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Paroxetina/uso terapêutico , Perexilina/farmacocinética , Perexilina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Vasodilatadores/farmacocinética , Vasodilatadores/uso terapêuticoRESUMO
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.
Assuntos
Angina Instável/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/sangue , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/sangue , Perexilina/efeitos adversos , Perexilina/sangue , Vasodilatadores/efeitos adversos , Vasodilatadores/sangue , Idoso , Idoso de 80 Anos ou mais , Angina Instável/sangue , Tontura/induzido quimicamente , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamenteRESUMO
AIMS: To review spontaneous reports of drug-associated adverse hepatic reactions. METHODS: Reports of drug-associated adverse hepatic reactions received by the New Zealand Centre for Adverse Reactions Monitoring over the 21 year period January 1974 to December 1994 were reviewed. Subdivision into three 7 year periods was undertaken to compare patterns. RESULTS: Of a total of 22,455 adverse medicine reaction (AMR) reports there were 943 reports of liver injury (4.2%). Two hundred and five drugs were associated with hepatic reactions. The top 20 drugs accounted for 57% of all liver reactions. Fifty-seven percent were reported in females. Hepatotoxicity was most commonly reported among patients 50-80 years old. Liver reactions were associated with a 3.3% mortality, but were responsible for 7.4% of all fatal occurrences. There was a steady increase in the number of reports over the 21 years. Although the largest number of reports of liver injury were received between 1988 and 1994, mortality was lowest during this period. There were substantial differences in the medicines associated with hepatic reactions during each of the three periods, although erythromycin was the commonest cause throughout. Erythromycin was associated with two deaths. Halothane and perhexilene were the most frequent cause of death and were two of the most important causes of liver injury during the first and second periods. Diclofenac, Augmentin and flucloxacillin were important causes of hepatotoxicity during period 3 but were not associated with a fatal outcome. CONCLUSION: Hepatic reactions accounted for 4.2% of all adverse medicine reactions and 7.4% of all fatal occurrences. The top 20 drugs were responsible for 57% of all liver reactions. Despite a steady increase in the number of reports during the 21 years, mortality was lowest during the last 7 years. Differences in the medicines causing liver injury during the three periods influenced the number of fatalities. Erythromycin was the most commonly reported cause of hepatic reactions but was usually associated with a favourable outcome. There were no reported deaths with diclofenac, Augmentin or flucloxacillin.