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John D. Horowitz - One of the best experts on this subject based on the ideXlab platform.

  • can Perhexiline be utilized without long term toxicity a clinical practice audit
    Therapeutic Drug Monitoring, 2016
    Co-Authors: Helen Phuong, Cherrin Chong, Bo Y Choi, Betty Raman, John D. Horowitz
    Abstract:

    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.

  • stereoselective handling of Perhexiline implications regarding accumulation within the human myocardium
    European Journal of Clinical Pharmacology, 2015
    Co-Authors: Cherrin Chong, John D. Horowitz, Giovanni Licari, Nigel E Drury, Michael Frenneaux, Domenico Pagano, Benedetta C Sallustio
    Abstract:

    Purpose Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of Perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of Perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of Perhexiline within myocardium.

  • improvement in cardiac energetics by Perhexiline in heart failure due to dilated cardiomyopathy
    Jacc-Heart Failure, 2015
    Co-Authors: Roger Beadle, Khalid Abozguia, Zaheer Yousef, Lynne Williams, Michael Kuehl, Sarah Bowater, Francisco Leyva, Anton J M Wagenmakers, Frank Thies, John D. Horowitz
    Abstract:

    Objectives: The aim of this study was to determine whether short-term treatment with Perhexiline improves cardiac energetics, left ventricular function, and symptoms of heart failure by altering cardiac substrate utilization. Background: Perhexiline improves exercise capacity and left ventricular ejection fraction (LVEF) in patients with heart failure (HF). P cardiac magnetic resonance spectroscopy can be used to quantify the myocardial phosphocreatine/adenosine triphosphate ratio. Because improvement of HF syndrome can improve cardiac energetics secondarily, we investigated the effects of short-term Perhexiline therapy. Methods: Patients with systolic HF of nonischemic etiology (n= 50, 62 ± 1.8 years of age, New York Heart Association functional class II to IV, LVEF: 27.0 ± 1.44%) were randomized to receive Perhexiline 200 mg or placebo for 1 month in a double-blind fashion. Clinical assessment, echocardiography, and P cardiac magnetic resonance spectroscopy were performed at baseline and after 1 month. A substudy of 22 patients also underwent cross-heart blood sampling at completion of the study to quantify metabolite utilization. Results: Perhexiline therapy was associated with a 30% increase in the phosphocreatine/adenosine triphosphate ratio (from 1.16 ± 0.39 to 1.51 ± 0.51; p< 0.001) versus a 3% decrease with placebo (from 1.36 ± 0.31 to 1.34 ± 0.31; p=0.37). Perhexiline therapy also led to an improvement in New York Heart Association functional class compared with placebo (p= 0.036). Short-term Perhexiline therapy did not change LVEF. Cross-heart measures of cardiac substrate uptake and respiratory exchange ratio (which reflects the ratio of substrates used) did not differ between patients who received Perhexiline versus placebo. Conclusions: Perhexiline improves cardiac energetics and symptom status with no evidence of altered cardiac substrate utilization. No change in LVEF is seen at this early stage. (Metabolic Manipulation in Chronic Heart Failure; NCT00841139).

  • interaction of terbinafine anti fungal agent with Perhexiline a case report
    Heart Lung and Circulation, 2014
    Co-Authors: A Sheikh, John D. Horowitz, Benedetta C Sallustio, Ian S Westley, John F Beltrame
    Abstract:

    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.

  • relationship between plasma atrial and ventricular Perhexiline concentrations in humans insights into factors affecting myocardial uptake
    British Journal of Clinical Pharmacology, 2014
    Co-Authors: John D. Horowitz, Giovanni Licari, Cherrin Chong, Nigel E Drury, Michael Frenneaux, Domenico Pagano, Neil J Howell, Benedetta C Sallustio
    Abstract:

    Little is known regarding the steady-state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti-anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma Perhexiline concentrations and its uptake into the myocardium.

Benedetta C Sallustio - One of the best experts on this subject based on the ideXlab platform.

  • enantioselectivity in the tissue distribution of Perhexiline contributes to different effects on hepatic histology and peripheral neural function in rats
    Pharmacology Research & Perspectives, 2018
    Co-Authors: Giovanni Licari, Andrew A Somogyi, Robert W Milne, Benedetta C Sallustio
    Abstract:

    : Perhexiline, a chiral drug, is a potent antiischemic agent whose clinical utility is limited by hepatic and neural toxicities. It inhibits mitochondrial carnitine palmitoyltransferase-1, however, excessive inhibition predisposes toward tissue steatosis. This pilot study investigated the distribution of the two enantiomers and their toxicological potential. Dark Agouti rats (n = 4 per group) were administered vehicle or 200 mg/kg daily of racemic, (+)- or (-)-Perhexiline maleate orally for 8 weeks. Plasma biochemical liver function tests and Von Frey assessments of peripheral neural function were performed. Hepatic and neuronal histology, including lipid and glycogen content, was assessed using electron microscopy. Concentrations of the Perhexiline enantiomers and metabolites were quantified in plasma, liver and heart. Plasma Perhexiline concentrations following administration of racemate, (+)- or (-)-enantiomer were within the mid-upper clinical therapeutic range. There was extensive uptake of both enantiomers into liver and heart, with 2.5- to 4.5-fold greater net uptake of (+)- compared to (-)-Perhexiline (P < .05) when administered as pure enantiomers, but not when administered as racemate. There was no biochemical or gross histological evidence of hepatotoxicity. However, livers of animals administered (+)-Perhexiline had higher lipid (P < .01) and lower glycogen (P < .05) content, compared to those administered (-)-Perhexiline. Animals administered racemic Perhexiline had reduced peripheral neural function (P < .05) compared to controls or animals administered (-)-Perhexiline. For the same plasma concentrations, differences in tissue distribution may contribute to disparities in the effects of (+)- and (-)-Perhexiline on hepatic histology and neural function.

  • Enantioselectivity in the tissue distribution of Perhexiline contributes to different effects on hepatic histology and peripheral neural function in rats.
    Pharmacology Research & Perspectives, 2018
    Co-Authors: Giovanni Licari, Andrew A Somogyi, Robert W Milne, Benedetta C Sallustio
    Abstract:

    : Perhexiline, a chiral drug, is a potent antiischemic agent whose clinical utility is limited by hepatic and neural toxicities. It inhibits mitochondrial carnitine palmitoyltransferase-1, however, excessive inhibition predisposes toward tissue steatosis. This pilot study investigated the distribution of the two enantiomers and their toxicological potential. Dark Agouti rats (n = 4 per group) were administered vehicle or 200 mg/kg daily of racemic, (+)- or (-)-Perhexiline maleate orally for 8 weeks. Plasma biochemical liver function tests and Von Frey assessments of peripheral neural function were performed. Hepatic and neuronal histology, including lipid and glycogen content, was assessed using electron microscopy. Concentrations of the Perhexiline enantiomers and metabolites were quantified in plasma, liver and heart. Plasma Perhexiline concentrations following administration of racemate, (+)- or (-)-enantiomer were within the mid-upper clinical therapeutic range. There was extensive uptake of both enantiomers into liver and heart, with 2.5- to 4.5-fold greater net uptake of (+)- compared to (-)-Perhexiline (P 

  • Validation of a High-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Perhexiline and Cis-Hydroxy-Perhexiline Plasma Concentrations.
    Therapeutic Drug Monitoring, 2015
    Co-Authors: Ian S Westley, Giovanni Licari, Benedetta C Sallustio
    Abstract:

    BACKGROUND: The polymorphic nature of cytochrome P450 2D6 has made therapeutic drug monitoring of the anti-anginal agent Perhexiline a compulsory step in reducing adverse events associated with plasma concentrations above the therapeutic range (0.15-0.60 mg/L). The aim of this study was to develop a high-performance liquid chromatography-mass spectrometry/mass spectrometry method for the determination of plasma Perhexiline concentrations and its major metabolite cis-hydroxy-Perhexiline to reduce sample extraction procedures and improve sample turnaround times. METHODS: The method was validated by determining the precision and accuracy of calibrators and quality control material, comparing quality assurance program samples and patient samples measured by a previously reported liquid-liquid extraction fluorescence (FL) detection high-performance liquid chromatography method and performing matrix effects investigations. RESULTS: Replicates of calibrators at concentrations of 3.00 and 0.05 mg/L demonstrated imprecision of

  • validation of a high performance liquid chromatography tandem mass spectrometry method for the determination of Perhexiline and cis hydroxy Perhexiline plasma concentrations
    Therapeutic Drug Monitoring, 2015
    Co-Authors: Ian S Westley, Giovanni Licari, Benedetta C Sallustio
    Abstract:

    BACKGROUND: The polymorphic nature of cytochrome P450 2D6 has made therapeutic drug monitoring of the anti-anginal agent Perhexiline a compulsory step in reducing adverse events associated with plasma concentrations above the therapeutic range (0.15-0.60 mg/L). The aim of this study was to develop a high-performance liquid chromatography-mass spectrometry/mass spectrometry method for the determination of plasma Perhexiline concentrations and its major metabolite cis-hydroxy-Perhexiline to reduce sample extraction procedures and improve sample turnaround times. METHODS: The method was validated by determining the precision and accuracy of calibrators and quality control material, comparing quality assurance program samples and patient samples measured by a previously reported liquid-liquid extraction fluorescence (FL) detection high-performance liquid chromatography method and performing matrix effects investigations. RESULTS: Replicates of calibrators at concentrations of 3.00 and 0.05 mg/L demonstrated imprecision of <10.8% and inaccuracy of <8.2% for Perhexiline and <10.1% and <4.5% for cis-hydroxy-Perhexiline, respectively. All samples measured by the 2 methods (n = 102) demonstrated Deming regression of Perhexiline = 1.20 FL + 0.00 (Sy.x = 0.08, 1/slope = 0.67); cis-hydroxy-Perhexiline = 1.48 FL - 0.20 (Sy.x = 0.40, 1/slope = 0.67). CONCLUSIONS: The assay performance was deemed acceptable and integrated into the routine therapeutic drug monitoring program of the department.

  • stereoselective handling of Perhexiline implications regarding accumulation within the human myocardium
    European Journal of Clinical Pharmacology, 2015
    Co-Authors: Cherrin Chong, John D. Horowitz, Giovanni Licari, Nigel E Drury, Michael Frenneaux, Domenico Pagano, Benedetta C Sallustio
    Abstract:

    Purpose Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of Perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of Perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of Perhexiline within myocardium.

Raymond G Morris - One of the best experts on this subject based on the ideXlab platform.

  • effect of cyp2d6 metabolizer status on the disposition of the and enantiomers of Perhexiline in patients with myocardial ischaemia
    Pharmacogenetics and Genomics, 2007
    Co-Authors: Sally C Inglis, John D. Horowitz, Andrew A Somogyi, Robert W Milne, Raymond G Morris, Benjamin J Davies, Janet K Coller, Heather M James, Megan K Herbert, Benedetta C Sallustio
    Abstract:

    AimsThis study investigated the effects of increasing doses of rac-Perhexiline maleate and CYP2D6 phenotype and genotype on the pharmacokinetics of (+) and (−)-Perhexiline.MethodsIn a prospective study, steady-state plasma concentrations of (+) and (−)-Perhexiline were quantified in 10 CYP2D6 genoty

  • Effect of CYP2D6 metabolizer status on the disposition of the (+) and (-) enantiomers of Perhexiline in patients with myocardial ischaemia.
    Pharmacogenetics and Genomics, 2007
    Co-Authors: Sally C Inglis, John D. Horowitz, Andrew A Somogyi, Robert W Milne, Raymond G Morris, Benjamin J Davies, Janet K Coller, Heather M James, Megan K Herbert, Benedetta C Sallustio
    Abstract:

    AimsThis study investigated the effects of increasing doses of rac-Perhexiline maleate and CYP2D6 phenotype and genotype on the pharmacokinetics of (+) and (−)-Perhexiline.MethodsIn a prospective study, steady-state plasma concentrations of (+) and (−)-Perhexiline were quantified in 10 CYP2D6 genoty

  • development of a regimen for rapid initiation of Perhexiline therapy in acute coronary syndromes
    Internal Medicine Journal, 2004
    Co-Authors: A Philpott, Raymond G Morris, S Chandy, John D. Horowitz
    Abstract:

    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 over­dosage 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. (Intern Med J 2004; 34: 361−363)

  • clinical inhibition of cyp2d6 catalysed metabolism by the antianginal agent Perhexiline
    British Journal of Clinical Pharmacology, 2004
    Co-Authors: Benjamin J Davies, John D. Horowitz, Andrew A Somogyi, Raymond G Morris, Janet K Coller, Heather M James, David Gillis, Benedetta C Sallustio
    Abstract:

    Aims Perhexiline is an antianginal agent that displays both saturable and polymorphic metabolism via CYP2D6. The aim of this study was to determine whether Perhexiline produces clinically significant inhibition of CYP2D6-catalysed metabolism in angina patients. Methods The effects of Perhexiline on CYP2D6-catalysed metabolism were investigated by comparing urinary total dextrorphan/dextromethorphan metabolic ratios following a single dose of dextromethorphan (16.4 mg) in eight matched control patients not taking Perhexiline and 24 patients taking Perhexiline. All of the patients taking Perhexiline had blood drawn for CYP2D6 genotyping as well as to measure plasma Perhexiline and cis-OH-Perhexiline concentrations. Results Median (range) dextrorphan/dextromethorphan metabolic ratios were significantly higher (P < 0.0001) in control patients, 271.1 (40.3–686.1), compared with Perhexiline-treated patients, 5.0 (0.3–107.9). In the Perhexiline-treated group 10/24 patients had metabolic ratios consistent with poor metabolizer phenotypes; however, none was a genotypic poor metabolizer. Interestingly, 89% of patients who had phenocopied to poor metabolizers had only one functional CYP2D6 gene. There was a significant negative linear correlation between the log of the dextrorphan/dextromethorphan metabolic ratio and plasma Perhexiline concentrations (r2 = 0.69, P < 0.0001). Compared with patients with at least two functional CYP2D6 genes, those with one functional gene were on similar Perhexiline dosage regimens but had significantly higher plasma Perhexiline concentrations, 0.73 (0.21–1.00) vs. 0.36 (0.04–0.69) mg l−1 (P = 0.04), lower cis-OH-Perhexiline/Perhexiline ratios, 2.85 (0.35–6.10) vs. 6.51 (1.84–11.67) (P = 0.03), and lower dextrorphan/dextromethorphan metabolic ratios, 2.51 (0.33–39.56) vs. 11.80 (2.90–36.93) (P = 0.005). Conclusions Perhexiline significantly inhibits CYP2D6-catalysed metabolism in angina patients. The plasma cis-OH-Perhexiline/Perhexiline ratio may help to both phenotype patients and predict those in whom Perhexiline may be most likely to cause clinically significant metabolic inhibition.

  • Clinical inhibition of CYP2D6-catalysed metabolism by the antianginal agent Perhexiline.
    British Journal of Clinical Pharmacology, 2004
    Co-Authors: Benjamin J Davies, John D. Horowitz, Andrew A Somogyi, Raymond G Morris, Janet K Coller, Heather M James, David Gillis, Benedetta C Sallustio
    Abstract:

    Aims Perhexiline is an antianginal agent that displays both saturable and polymorphic metabolism via CYP2D6. The aim of this study was to determine whether Perhexiline produces clinically significant inhibition of CYP2D6-catalysed metabolism in angina patients. Methods The effects of Perhexiline on CYP2D6-catalysed metabolism were investigated by comparing urinary total dextrorphan/dextromethorphan metabolic ratios following a single dose of dextromethorphan (16.4 mg) in eight matched control patients not taking Perhexiline and 24 patients taking Perhexiline. All of the patients taking Perhexiline had blood drawn for CYP2D6 genotyping as well as to measure plasma Perhexiline and cis-OH-Perhexiline concentrations. Results Median (range) dextrorphan/dextromethorphan metabolic ratios were significantly higher (P 

Michael Frenneaux - One of the best experts on this subject based on the ideXlab platform.

  • development of fluorinated analogues of Perhexiline with improved pharmacokinetic properties and retained efficacy
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Chihchung Tseng, Michael Frenneaux, Hannah Noordali, Monica Sani, Melanie Madhani, Denis M Grant, Matteo Zanda, Iain R Greig
    Abstract:

    We designed and synthesized Perhexiline analogues that have the same therapeutic profile as the parent cardiovascular drug but lacking its metabolic liability associated with CYP2D6 metabolism. Cycloalkyl Perhexiline analogues 6a–j were found to be unsuitable for further development, as they retained a pharmacokinetic profile very similar to that shown by the parent compound. Multistep synthesis of Perhexiline analogues incorporating fluorine atoms onto the cyclohexyl ring(s) provided a range of different fluoroPerhexiline analogues. Of these, analogues 50 (4,4-gem-difluoro) and 62 (4,4,4′,4′-tetrafluoro) were highly stable and showed greatly reduced susceptibility to CYP2D6-mediated metabolism. In vitro efficacy studies demonstrated that a number of derivatives retained acceptable potency against CPT-1. Having the best balance of properties, 50 was selected for further evaluation. Like Perhexiline, it was shown to be selectively concentrated in the myocardium and, using the Langendorff model, to be effec...

  • stereoselective handling of Perhexiline implications regarding accumulation within the human myocardium
    European Journal of Clinical Pharmacology, 2015
    Co-Authors: Cherrin Chong, John D. Horowitz, Giovanni Licari, Nigel E Drury, Michael Frenneaux, Domenico Pagano, Benedetta C Sallustio
    Abstract:

    Purpose Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of Perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of Perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of Perhexiline within myocardium.

  • relationship between plasma atrial and ventricular Perhexiline concentrations in humans insights into factors affecting myocardial uptake
    British Journal of Clinical Pharmacology, 2014
    Co-Authors: John D. Horowitz, Giovanni Licari, Cherrin Chong, Nigel E Drury, Michael Frenneaux, Domenico Pagano, Neil J Howell, Benedetta C Sallustio
    Abstract:

    Little is known regarding the steady-state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti-anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma Perhexiline concentrations and its uptake into the myocardium.

  • the effect of Perhexiline on myocardial protection during coronary artery surgery a two centre randomized double blind placebo controlled trial
    European Journal of Cardio-Thoracic Surgery, 2013
    Co-Authors: Nigel E Drury, Michael Frenneaux, Neil J Howell, Ralf J M Weber, Melanie Calvert, Michael E Lewis, Mark R Viant, Nick Freemantle, Domenico Pagano
    Abstract:

    OBJECTIVES: Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative Perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome. METHODS: In a prospective, randomized, double-blind, placebo-controlled trial, patients at two centres were randomized to receive either oral Perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided α-value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometrybased metabolomics. RESULTS: Over a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the Perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56–1.50, P=0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07–0.31, P=0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34–0.89, P=0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups on metabolomics analysis. CONCLUSIONS: Preoperative Perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry-visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery. ClinicalTrials.Gov ID: NCT00845364.

  • metabolic alteration in hypertrophic cardiomyopathy metal hcm study randomised double blinded placebo controlled trial of Perhexiline therapy in patient with hypertrophic cardiomyopathy
    Heart, 2010
    Co-Authors: Khalid Abozguia, Thanh Trung Phan, Ibrar Ahmed, Houman Ashrafian, Perry M Elliott, William J Mckenna, Ganesh Nallurshivu, Abdul R Maher, Hugh Watkins, Michael Frenneaux
    Abstract:

    Background Patients with hypertrophic cardiomyopathy (HCM) exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathogenesis of HCM remains unproven. We hypothesised that the metabolic modulator, Perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. Methods Forty-six consecutive patients with symptomatic exercise limitation (peak oxygen consumption – peak VO2 Results Perhexiline improved myocardial PCr/ATP ratios (from 1.27±0.02 to 1.73±0.02; p=0.003) and normalised the abnormal prolongation of nTTPF between rest and exercise (δ nTTPF: +0.11±0.008 s vs −0.01±0.005; p=0.03). These changes were accompanied by improvement in peak VO2 (22.2±0.2 to 24.29±0.2 ml/kg/min; p=0.003) and symptoms (NYHA class by 0.8 units p Conclusion In symptomatic HCM, Perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathogenesis and provides a rationale for further consideration of metabolic therapies in HCM.

Nigel E Drury - One of the best experts on this subject based on the ideXlab platform.

  • stereoselective handling of Perhexiline implications regarding accumulation within the human myocardium
    European Journal of Clinical Pharmacology, 2015
    Co-Authors: Cherrin Chong, John D. Horowitz, Giovanni Licari, Nigel E Drury, Michael Frenneaux, Domenico Pagano, Benedetta C Sallustio
    Abstract:

    Purpose Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of Perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of Perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of Perhexiline within myocardium.

  • relationship between plasma atrial and ventricular Perhexiline concentrations in humans insights into factors affecting myocardial uptake
    British Journal of Clinical Pharmacology, 2014
    Co-Authors: John D. Horowitz, Giovanni Licari, Cherrin Chong, Nigel E Drury, Michael Frenneaux, Domenico Pagano, Neil J Howell, Benedetta C Sallustio
    Abstract:

    Little is known regarding the steady-state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti-anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma Perhexiline concentrations and its uptake into the myocardium.

  • the effect of Perhexiline on myocardial protection during coronary artery surgery a two centre randomized double blind placebo controlled trial
    European Journal of Cardio-Thoracic Surgery, 2013
    Co-Authors: Nigel E Drury, Michael Frenneaux, Neil J Howell, Ralf J M Weber, Melanie Calvert, Michael E Lewis, Mark R Viant, Nick Freemantle, Domenico Pagano
    Abstract:

    OBJECTIVES: Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative Perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome. METHODS: In a prospective, randomized, double-blind, placebo-controlled trial, patients at two centres were randomized to receive either oral Perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided α-value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometrybased metabolomics. RESULTS: Over a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the Perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56–1.50, P=0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07–0.31, P=0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34–0.89, P=0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups on metabolomics analysis. CONCLUSIONS: Preoperative Perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry-visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery. ClinicalTrials.Gov ID: NCT00845364.

  • On Perhexiline and its application to myocardial protection during cardiac surgery
    2012
    Co-Authors: Nigel E Drury
    Abstract:

    Perhexiline is an anti-anginal drug that is thought to shift myocardial metabolism from \(\beta\)-oxidation of fatty acids to glucose utilisation. An associated improvement in energy efficiency may be beneficial in ischaemia-reperfusion as an adjunct to established techniques for myocardial protection during cardiac surgery. In this thesis, I conduct a prospective double-blind randomised placebo-controlled trial of oral Perhexiline in patients undergoing coronary artery surgery, obtaining samples of serum, right atrium and left ventricle. I measure the concentration of Perhexiline using high performance liquid chromatography and find that although highly concentrated in the heart, it may not have reached steady-state in the ventricular myocardium. I perform enzymatic colourimetry and ultra-high resolution mass spectrometry to detect changes in carbohydrate and lipid metabolism; however, the myocardial metabolic profiles of patients on Perhexiline are indistinguishable from controls. On analysing the results of the clinical trial, I find no improvement in the primary endpoint, the incidence of a low cardiac output episode, or any secondary outcomes. I conclude that preoperative oral Perhexiline does not improve clinical markers of myocardial protection and despite significant accumulation in the myocardium, it has no significant effect on the measurable metabolic profile of the heart at the time of surgery.