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Benedetta C Sallustio - One of the best experts on this subject based on the ideXlab platform.
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Enantioselectivity in the tissue distribution of Perhexiline contributes to different effects on hepatic histology and peripheral neural function in rats.
Pharmacology Research & Perspectives, 2018Co-Authors: Giovanni Licari, Andrew A. Somogyi, Robert W. Milne, Benedetta C SallustioAbstract:: 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
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comparison of cyp2d metabolism and hepatotoxicity of the myocardial metabolic agent Perhexiline in sprague dawley and dark agouti rats
Xenobiotica, 2015Co-Authors: Giovanni Licari, Andrew A. Somogyi, Robert W. Milne, Benedetta C SallustioAbstract:Abstract1. Perhexiline, a chiral anti-anginal agent, may be useful to develop new cardiovascular therapies, despite its potential hepatotoxicity.2. This study compared Dark Agouti (DA) and Sprague–Dawley (SD) rats, as models of Perhexiline’s metabolism and hepatotoxicity in humans. Rats (n = 4/group) received vehicle or 200 mg/kg/d of racemic Perhexiline Maleate for 8 weeks. Plasma and liver samples were collected to determine concentrations of Perhexiline and its metabolites, hepatic function and histology.3. Median (range) plasma and liver Perhexiline concentrations in SD rats were 0.09 (0.04–0.13) mg/L and 5.42 (0.92–8.22) ng/mg, respectively. In comparison, DA rats showed higher (p < 0.05) plasma 0.50 (0.16–1.13) mg/L and liver 24.5 (9.40–54.7) ng/mg Perhexiline concentrations, respectively, 2.5- and 3.7-fold higher cis-OH-Perhexiline concentrations, respectively (p < 0.05), and lower plasma metabolic ratio (0.89 versus 1.55, p < 0.05). In both strains, the (+):(−) enantiomer ratio was 2:1. Perhexilin...
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Comparison of CYP2D metabolism and hepatotoxicity of the myocardial metabolic agent Perhexiline in Sprague–Dawley and Dark Agouti rats
Xenobiotica, 2014Co-Authors: Giovanni Licari, Andrew A. Somogyi, Robert W. Milne, Benedetta C SallustioAbstract:Abstract1. Perhexiline, a chiral anti-anginal agent, may be useful to develop new cardiovascular therapies, despite its potential hepatotoxicity.2. This study compared Dark Agouti (DA) and Sprague–Dawley (SD) rats, as models of Perhexiline’s metabolism and hepatotoxicity in humans. Rats (n = 4/group) received vehicle or 200 mg/kg/d of racemic Perhexiline Maleate for 8 weeks. Plasma and liver samples were collected to determine concentrations of Perhexiline and its metabolites, hepatic function and histology.3. Median (range) plasma and liver Perhexiline concentrations in SD rats were 0.09 (0.04–0.13) mg/L and 5.42 (0.92–8.22) ng/mg, respectively. In comparison, DA rats showed higher (p
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Perhexiline Maleate in the treatment of fibrodysplasia ossificans progressiva an open labeled clinical trial
Orphanet Journal of Rare Diseases, 2013Co-Authors: Hiroshi Kitoh, Benedetta C Sallustio, John D Horowitz, Masataka Achiwa, Hiroshi Kaneko, Kenichi Mishima, Masaki Matsushita, Izumi Kadono, Kinji Ohno, Naoki IshiguroAbstract:Background Currently, there are no effective medical treatment options to prevent the formation of heterotopic bones in fibrodysplasia ossificans progressiva (FOP). By the drug repositioning strategy, we confirmed that Perhexiline Maleate (Pex) potentially ameliorates heterotopic ossification in model cells and mice. Here, we conducted a prospective study to assess the efficacy and safety of Pex in the treatment of FOP patients.
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effect of cyp2d6 metabolizer status on the disposition of the and enantiomers of Perhexiline in patients with myocardial ischaemia
Pharmacogenetics and Genomics, 2007Co-Authors: Sally C Inglis, Megan K Herbert, Andrew A. Somogyi, Janet K. Coller, Heather M. James, Robert W. Milne, John D Horowitz, Raymond G Morris, Benjamin J Davies, Benedetta C SallustioAbstract: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
Elliott M Antman - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Perhexiline Maleate in refractory angina a double blind placebo controlled clinical trial of a novel antianginal agent
Circulation, 1990Co-Authors: Patricia Cole, Andrew D Beamer, Noreen Mcgowan, Catherine Cantillon, K Benfell, Ralph A Kelly, L H Hartley, Thomas W Smith, Elliott M AntmanAbstract:Despite large gains in the medical and surgical treatment of angina pectoris in the past two decades, many patients are refractory to conventional medical therapy and are unsuitable for a first or, more commonly, repeat coronary revascularization procedure. We evaluated the efficacy of Perhexiline Maleate, a drug with an antianginal mechanism of action in humans that is as yet unknown, by using a randomized double-blind placebo-controlled crossover design in 17 patients with refractory angina who continued to receive maximal antianginal therapy, typically including nitrates, a beta-blocker, and a calcium channel antagonist. In view of Perhexiline's potential for hepatic and neurological toxicity, plasma drug levels were monitored and maintained in the 150-600 ng/ml range. Sixty-three percent of patients were judged Perhexiline responders by objective exercise testing criteria, as compared with 18% of patients on placebo (p less than 0.05). By blinded review of subjective measures of anginal frequency and ...
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Efficacy and safety of Perhexiline Maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent.
Circulation, 1990Co-Authors: Patricia Cole, Andrew D Beamer, Noreen Mcgowan, Catherine Cantillon, K Benfell, Ralph A Kelly, Thomas W Smith, Louise Hartley, Elliott M AntmanAbstract:Despite large gains in the medical and surgical treatment of angina pectoris in the past two decades, many patients are refractory to conventional medical therapy and are unsuitable for a first or, more commonly, repeat coronary revascularization procedure. We evaluated the efficacy of Perhexiline Maleate, a drug with an antianginal mechanism of action in humans that is as yet unknown, by using a randomized double-blind placebo-controlled crossover design in 17 patients with refractory angina who continued to receive maximal antianginal therapy, typically including nitrates, a beta-blocker, and a calcium channel antagonist. In view of Perhexiline's potential for hepatic and neurological toxicity, plasma drug levels were monitored and maintained in the 150-600 ng/ml range. Sixty-three percent of patients were judged Perhexiline responders by objective exercise testing criteria, as compared with 18% of patients on placebo (p less than 0.05). By blinded review of subjective measures of anginal frequency and severity, 65% of patients noted an improvement while on Perhexiline, whereas no patient identified the placebo phase with improvement. Side effects observed in 29% of patients were minor and related to transient elevations of blood levels of more than 600 ng/ml; no patient suffered hemodynamic or cardiac conduction abnormalities attributable to Perhexiline. With attention to the pharmacokinetics of Perhexiline's elimination in individual patients, this novel antianginal agent seems to be safe and effective and deserves further evaluation in patients already receiving maximal antianginal therapy who are not candidates for revascularization procedures.
Patricia Cole - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Perhexiline Maleate in refractory angina a double blind placebo controlled clinical trial of a novel antianginal agent
Circulation, 1990Co-Authors: Patricia Cole, Andrew D Beamer, Noreen Mcgowan, Catherine Cantillon, K Benfell, Ralph A Kelly, L H Hartley, Thomas W Smith, Elliott M AntmanAbstract:Despite large gains in the medical and surgical treatment of angina pectoris in the past two decades, many patients are refractory to conventional medical therapy and are unsuitable for a first or, more commonly, repeat coronary revascularization procedure. We evaluated the efficacy of Perhexiline Maleate, a drug with an antianginal mechanism of action in humans that is as yet unknown, by using a randomized double-blind placebo-controlled crossover design in 17 patients with refractory angina who continued to receive maximal antianginal therapy, typically including nitrates, a beta-blocker, and a calcium channel antagonist. In view of Perhexiline's potential for hepatic and neurological toxicity, plasma drug levels were monitored and maintained in the 150-600 ng/ml range. Sixty-three percent of patients were judged Perhexiline responders by objective exercise testing criteria, as compared with 18% of patients on placebo (p less than 0.05). By blinded review of subjective measures of anginal frequency and ...
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Efficacy and safety of Perhexiline Maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent.
Circulation, 1990Co-Authors: Patricia Cole, Andrew D Beamer, Noreen Mcgowan, Catherine Cantillon, K Benfell, Ralph A Kelly, Thomas W Smith, Louise Hartley, Elliott M AntmanAbstract:Despite large gains in the medical and surgical treatment of angina pectoris in the past two decades, many patients are refractory to conventional medical therapy and are unsuitable for a first or, more commonly, repeat coronary revascularization procedure. We evaluated the efficacy of Perhexiline Maleate, a drug with an antianginal mechanism of action in humans that is as yet unknown, by using a randomized double-blind placebo-controlled crossover design in 17 patients with refractory angina who continued to receive maximal antianginal therapy, typically including nitrates, a beta-blocker, and a calcium channel antagonist. In view of Perhexiline's potential for hepatic and neurological toxicity, plasma drug levels were monitored and maintained in the 150-600 ng/ml range. Sixty-three percent of patients were judged Perhexiline responders by objective exercise testing criteria, as compared with 18% of patients on placebo (p less than 0.05). By blinded review of subjective measures of anginal frequency and severity, 65% of patients noted an improvement while on Perhexiline, whereas no patient identified the placebo phase with improvement. Side effects observed in 29% of patients were minor and related to transient elevations of blood levels of more than 600 ng/ml; no patient suffered hemodynamic or cardiac conduction abnormalities attributable to Perhexiline. With attention to the pharmacokinetics of Perhexiline's elimination in individual patients, this novel antianginal agent seems to be safe and effective and deserves further evaluation in patients already receiving maximal antianginal therapy who are not candidates for revascularization procedures.
John D Horowitz - One of the best experts on this subject based on the ideXlab platform.
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Perhexiline Maleate in the treatment of fibrodysplasia ossificans progressiva an open labeled clinical trial
Orphanet Journal of Rare Diseases, 2013Co-Authors: Hiroshi Kitoh, Benedetta C Sallustio, John D Horowitz, Masataka Achiwa, Hiroshi Kaneko, Kenichi Mishima, Masaki Matsushita, Izumi Kadono, Kinji Ohno, Naoki IshiguroAbstract:Background Currently, there are no effective medical treatment options to prevent the formation of heterotopic bones in fibrodysplasia ossificans progressiva (FOP). By the drug repositioning strategy, we confirmed that Perhexiline Maleate (Pex) potentially ameliorates heterotopic ossification in model cells and mice. Here, we conducted a prospective study to assess the efficacy and safety of Pex in the treatment of FOP patients.
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effect of cyp2d6 metabolizer status on the disposition of the and enantiomers of Perhexiline in patients with myocardial ischaemia
Pharmacogenetics and Genomics, 2007Co-Authors: Sally C Inglis, Megan K Herbert, Andrew A. Somogyi, Janet K. Coller, Heather M. James, Robert W. Milne, John D Horowitz, Raymond G Morris, Benjamin J Davies, Benedetta C SallustioAbstract: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
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Effect of CYP2D6 metabolizer status on the disposition of the (+) and (-) enantiomers of Perhexiline in patients with myocardial ischaemia.
Pharmacogenetics and Genomics, 2007Co-Authors: Sally C Inglis, Megan K Herbert, Andrew A. Somogyi, Janet K. Coller, Heather M. James, Robert W. Milne, John D Horowitz, Raymond G Morris, Benjamin J Davies, Benedetta C SallustioAbstract: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
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relationship between plasma Perhexiline concentration and symptomatic status during short term Perhexiline therapy
Therapeutic Drug Monitoring, 1996Co-Authors: Simon Stewart, David W Voss, Dianne L Northey, John D HorowitzAbstract:SummaryWe 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 c
Sandra Gemma - One of the best experts on this subject based on the ideXlab platform.
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r and s Perhexiline Maleate enantioselective synthesis and functional studies on schistosoma mansoni larval and adult stages
Bioorganic Chemistry, 2020Co-Authors: Alessandra Guidi, Prasanth A Saraswati, Nicola Relitti, Roberto Gimmelli, Fulvio Saccoccia, Carmina Sirignano, Orazio Taglialatelascafati, Giuseppe Campiani, Giovina Ruberti, Sandra GemmaAbstract:Abstract Schistosomiasis is a neglected tropical disease mainly affecting the poorest tropical and subtropical areas of the world with the impressive number of roughly 200 million infections per year. Schistosomes are blood trematode flukes of the genus Schistosoma causing symptoms in humans and animals. Organ morbidity is caused by the accumulation of parasite eggs and subsequent development of fibrosis. If left untreated, schistosomiasis can result in substantial morbidity and even mortality. Praziquantel (PZQ) is the most effective and widely used compound for the treatment of the disease and in prevention control programs in the last 30 years. Unfortunately, it has no effect on juvenile immature schistosomes and cannot prevent re-infection or interfere with the schistosome life cycle; moreover drug-resistance represents a serious threat. The search for an alternative or complementary treatment is urgent and drug repurposing could accelerate a solution. The anti-anginal drug Perhexiline Maleate (PHX) has been previously shown to be effective on larval, juvenile, and adult stages of S. mansoni and to impact egg production in vitro. Since PHX is a racemic mixture of R-(+)- and S-(-)-enantiomers, we designed and realized a stereoselective synthesis of both PHX enantiomers and developed an analytical procedure for the direct quantification of the enantiomeric excess also suitable for semipreparative separation of PHX enantiomers. We next investigated the impact of each enantiomer on viability of newly transformed schistosomula (NTS) and worm pairs of S. mansoni as well as on egg production and vitellarium morphology by in vitro studies. Our results indicate that the R-(+)-PHX is mainly driving the anti-schistosomal activity but that also the S-(-)-PHX possesses a significant activity towards S. mansoni in vitro.
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(+)-(R)- and (-)-(S)-Perhexiline Maleate: Enantioselective synthesis and functional studies on Schistosoma mansoni larval and adult stages.
Bioorganic Chemistry, 2020Co-Authors: Alessandra Guidi, Nicola Relitti, Roberto Gimmelli, Fulvio Saccoccia, Carmina Sirignano, Giuseppe Campiani, Giovina Ruberti, A. Prasanth Saraswati, Orazio Taglialatela-scafati, Sandra GemmaAbstract:Abstract Schistosomiasis is a neglected tropical disease mainly affecting the poorest tropical and subtropical areas of the world with the impressive number of roughly 200 million infections per year. Schistosomes are blood trematode flukes of the genus Schistosoma causing symptoms in humans and animals. Organ morbidity is caused by the accumulation of parasite eggs and subsequent development of fibrosis. If left untreated, schistosomiasis can result in substantial morbidity and even mortality. Praziquantel (PZQ) is the most effective and widely used compound for the treatment of the disease, in prevention and control programs in the last 30 years. Unfortunately, it has no effect on juvenile immature schistosomes and cannot prevent reinfection or interfere with the schistosome life cycle; moreover drug-resistance represents a serious threat. The search for an alternative or complementary treatment is urgent and drug repurposing could accelerate a solution. The anti-anginal drug Perhexiline Maleate (PHX) has been previously shown to be effective on larval, juvenile, and adult stages of S. mansoni and to impact egg production in vitro. Since PHX is a racemic mixture of R-(+)- and S-(−)-enantiomers, we designed and realized a stereoselective synthesis of both PHX enantiomers and developed an analytical procedure for the direct quantification of the enantiomeric excess also suitable for semipreparative separation of PHX enantiomers. We next investigated the impact of each enantiomer on viability of newly transformed schistosomula (NTS) and worm pairs of S. mansoni as well as on egg production and vitellarium morphology by in vitro studies. Our results indicate that the R-(+)-PHX is mainly driving the anti-schistosomal activity but that also the S-(−)-PHX possesses a significant activity towards S. mansoni in vitro.