Therapy of Angina Pectoris with Low-Dose Perhexiline

Horgan, John; O'Callaghan, W G; Teo, K. K.

doi:10.1097/00005344-198105000-00015

Cited by 15 publications

(7 citation statements)

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“…In the late 1960s, perhexiline (2-[2,2-dicyclohexylethyl]piperidine) was first shown to reduce the symptoms of angina in coronary patients, which was subsequently confirmed in double-blind placebo-controlled trials when administered as monotherapy [56][57][58][59][60][61] or when administered in addition to conventional therapy (β-adrenergic receptor antagonists, nitrates and Ca 2+ antagonists) [62]. Perhexiline has no consistent effects on heart rate or arterial blood pressure [56][57][58][59][60][61][62] and has been shown to switch substrate selection from fatty acid toward carbohydrate and reduce lactate production during ischaemia in the isolated perfused rat heart [63,64].…”

Section: Perhexilinementioning

confidence: 99%

“…Perhexiline has no consistent effects on heart rate or arterial blood pressure [56][57][58][59][60][61][62] and has been shown to switch substrate selection from fatty acid toward carbohydrate and reduce lactate production during ischaemia in the isolated perfused rat heart [63,64]. In 1996, Kennedy and Horowitz demonstrated that perhexiline inhibits CPT-I activity with an IC 50 of 77 µM [65], which is greater than the clinical plasma levels generally observed (approximately 1 µM) [66][67] but similar to level shown to reduce lactate production in the ischaemic rat heart [64].…”

Section: Perhexilinementioning

confidence: 99%

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Partial fatty acid oxidation inhibitors for stable angina

Stanley

2002

Expert Opinion on Investigational Drugs

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Partial fatty acid oxidation inhibition is effective therapy for the treatment of chronic stable angina and is particularly useful in patients with persistent angina despite optimal traditional therapy. The heart derives most of its energy from the oxidation of fatty acids. Fatty acid oxidation strongly inhibits pyruvate oxidation in the mitochondria and the uptake and oxidation of glucose. The primary effect of demand-induced ischaemia is impaired aerobic formation of ATP in the mitochondria, resulting in activation of non-oxidative glycolysis and lactate production, despite a relatively high residual myocardial oxygen consumption and continued reliance on fatty acid oxidation. Traditional drugs for chronic stable angina act by reducing the use of ATP through suppression of heart rate and blood pressure or by increasing aerobic formation of ATP by increasing coronary blood flow. Partial inhibition of fatty acid oxidation increases glucose and pyruvate oxidation and decreases lactate production, resulting in higher pH and improved contractile function during ischaemia. These agents do not affect heart rate, coronary blood flow or arterial blood pressure. Clinical trials with ranolazine or trimetazidine, either alone or in combination with a Ca2+ channel antagonist or a beta-adrenergic receptor antagonist, have demonstrated reduced symptoms of exercise-induced angina.

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Section: Perhexilinementioning

confidence: 99%

Section: Perhexilinementioning

confidence: 99%

Partial fatty acid oxidation inhibitors for stable angina

Stanley

2002

Expert Opinion on Investigational Drugs

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“…Half of these 26 studies [5,7,8,10,13,16,18,[20][21][22][23]25,26] also had objective assessments of efficacy, such as exercise tolerance and workload-or exercise-induced ECG changes suggestive of ischemia.…”

Section: Perhexiline Versus Placebo As Monotherapymentioning

confidence: 99%

“…11 of the 13 trials which had objective outcome measures showed that patients derived significantly greater benefit with perhexiline than with placebo. [8,10,13,16,18,[20][21][22][23]25,26] The objective measures included maximal ST segment depression, pain-free exercise tolerance, work performance and energy expenditure equivalents.…”

Section: Perhexiline Versus Placebo As Monotherapymentioning

confidence: 99%

Systematic Review of the Efficacy and Safety of Perhexiline in the Treatment of Ischemic Heart Disease

Killalea

Krum

2001

American Journal of Cardiovascular Drugs

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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)

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“…Agents that inhibit CPT-I such as perhexiline, etoxomir, and oxfenicine may be relevant therapeutic tools in the treatment of angina. Perhexiline's efficacy as a treatment for stable angina was shown in a number of controlled clinical studies [23]. Unfortunately, perhexiline treatment is associated with the development of neuropathy and hepatotoxicity in a significant number of patients [24,25].…”

Section: Inhibitors Of Carnitine Palmitoylmentioning

confidence: 99%