Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Perhexiline”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed1988

Modulation of induced resistance to adriamycin in two human breast cancer cell lines with tamoxifen or perhexiline maleate.

The clinical utility of adriamycin in the treatment of patients with metastatic breast cancer is often-limited by the development of drug resistance. It has been recognized that in addition to the development of primary resistance against adriamycin, malignant cells can simultaneously develop cross-resistance to other agents. An adriamycin-resistant human breast cancer cell line (MCF 7Ad) was developed by exposing the parent line (MCF 7) to gradually increasing concentrations of adriamycin while the cells were being grown in monolayer. Using these lines in a clonogenic assay, the relative drug sensitivities to adriamycin, vinblastine, melphalan, 5-fluorouracil and methotrexate were studied. MCF 7Ad was 12.5-fold more resistant to adriamycin than MCF 7 and 500-fold cross-resistant to vinblastine. There was no cross-resistance to melphalan, 5-fluorouracil or methotrexate. The resistance of MCF 7Ad was decreased by simultaneous exposure to tamoxifen (by a factor of 3.33) or perhexiline maleate (by a factor of 7.50). This decreased resistance was evidenced by a shift to the left of the sensitivity curves. However, there was no consistent change in the sensitivity curves of MCF 7. At the selected concentration of tamoxifen and perhexiline maleate, the cloning efficiency of MCF 7 and MCF 7Ad was 80%-90% of control values in medium without tamoxifen, perhexiline maleate or cytotoxic drugs. The resistance of MCF 7Ad to adriamycin was associated with a lower accumulation of [14C]adriamycin than exhibited by the sensitive MCF 7 line. There was no consistent change in [14C]adriamycin accumulation in MCF 7 or MCF 7Ad when tamoxifen was added, but when perhexiline maleate was added the [14C] accumulation increased. These results suggest that the tamoxifen-induced change in MCF 7Ad adriamycin resistance was not due to an increase in the amount of cell-associated adriamycin, but rather to some other mechanism that increased the cytotoxicity of the adriamycin.

Breast Neoplasms↗
PubMed1988

The effects of perhexiline maleate on low density lipoprotein processing and cholesterol metabolism in cultured human fibroblasts.

The effects of perhexiline maleate (PM, Pexid) on low density lipoprotein (LDL) processing and cholesterol metabolism were investigated after a 24 h pretreatment with the drug. Perhexiline maleate increased LDL uptake in the range 10(-6) to 10(-5) M (180% of control for 10(-5) M), whereas LDL binding and degradation were not affected. Sterol synthesis from sodium acetate was enhanced by perhexiline maleate (X 2.2 for 10(-5) M), while cholesterol esterification with oleic acid was decreased (40% of control for 10(-5) M). These effects of perhexiline on cholesterol metabolism are specific, since the synthesis of triacylglycerols from sodium acetate is not affected and since the incorporation of oleic acid into triacylglycerols is much less impaired. The decreased cholesterol esterification is accompanied by a reduction of acylcoenzyme A-cholesterol-O-acyltransferase (ACAT) activity measured in vitro on cell extracts.

Cells, Cultured↗
PubMed1987

Studies on the metabolism of perhexiline in man.

We have studied the disposition of perhexiline and its two major metabolites, M1 and M3, in healthy volunteers and in patients with biliary T-tube drains after cholecystectomy. In healthy volunteers the genetic control for impaired hepatic oxidation is identical for debrisoquine, sparteine, and perhexiline. Poor metabolizers demonstrate markedly reduced production and excretion of the major metabolite, M1. Their production of M3 is also reduced, but to a lesser degree than for M1, confirming substrate stereoselectivity by hepatic oxidases. Biphasic urinary elimination of M1 and M3 is seen in intact extensive oxidizers, whereas only the first phase is apparent in patients with biliary T-tube drainage. This suggests the possibility of enterohepatic recycling of these compounds, which may account for their prolonged elimination. More than 90% of an ingested dose of perhexiline maleate remains unaccounted for at 24 h after ingestion, even in extensive metabolizers. A careful, radiolabelled tissue-distribution study is warranted to elucidate the complicated metabolic fate of perhexiline.

Adult↗
PubMed1980

Effects of perhexiline on contractile response of rabbit aorta to norepinephrine and potassium.

Perhexiline (3.2 X 10(-7)-6.4 X 10(-6) M) and verapamil (2 X 10(-8)-2 X 10(-7) M) inhibited the contraction of rabbit aorta induced with 40 mM K+ and with low concentrations (5.9 X 10(-9)-5.9 X 10(-8) M) of norepinephrine more effectively than the contraction induced by higher concentrations of norepinephrine. The tension induced by 1.2 X 10(-6) M norepinephrine was augmented with the above concentrations of perhexiline and verapamil. Higher concentrations (3.2 X 10(-5)-6.4 X 10(-5) M) of perhexiline significantly reduced the peak tension induced by norepinephrine. The results suggest that perhexiline is a Ca2+ antagonist and also has an unspecific spasmolytic action.

Animals↗
PubMed1986

Simultaneous determination of perhexiline and its monohydroxy metabolites in biological fluids by gas chromatography-electron-capture detection.

A rapid and sensitive method for the simultaneous determination of perhexiline and its cis-4-axial and trans-4-equatorial monohydroxy metabolites (M1 and M3, respectively) in human plasma, urine and bile is described. The assay utilises a single diethyl ether extraction, heptafluorobutyric acid anhydride derivatisation and separation and detection by gas chromatography-electron-capture detection. The limits of detection are 0.1 microgram/ml for perhexiline and 0.025 microgram/ml for the M1 and M3 metabolites. This method has been used in a five-day kinetic study of three healthy adult males who ingested a single 300-mg dose of perhexiline maleate. One of these volunteer subjects exhibited elevated plasma perhexiline and markedly reduced plasma and urinary M1 concentrations together with profoundly prolonged plasma and urinary M1 elimination times when compared with the other two subjects. These differences are thought to be of genetic origin. There were also obvious differences in urinary M3 concentrations which were discussed.

Adult↗
PubMed1997

Method for the analysis of perhexiline and its hydroxy metabolite in plasma using high-performance liquid chromatography with precolumn derivatization.

A high-performance liquid chromatographic method for the analysis of perhexiline and its monohydroxy metabolite in plasma has been developed. After a simple extraction procedure, the analytes are derivatized over a 30-min period with trans-4-nitrocinnamoyl chloride. The derivatized products are monitored at 340 nm following separation on a 5-micron phenyl reversed-phase column under isocratic conditions. The limits of detection for perhexiline and its hydroxy metabolite are 0.03 and 0.02 mg/l, respectively. The between-day and within-day assay coefficients of variation for perhexiline and its hydroxy metabolite at concentrations of 0.2 and 1.0 mg/I were less than 10%. The method has proved robust and suitable for the routine monitoring of perhexiline and hydroxyperhexiline.

Cardiovascular Agents↗
PubMed2001

Population pharmacokinetics of perhexiline from very sparse, routine monitoring data.

Using NONMEM, the population pharmacokinetics of perhexiline were studied in 88 patients (34 F, 54 M) who were being treated for refractory angina. Their mean +/- SD (range) age was 75 +/- 9.9 years (46-92), and the length of perhexiline treatment was 56 +/- 77 weeks (0.3-416). The sampling time after a dose was 14.1 +/- 21.4 hours (0.5-200), and the perhexiline plasma concentrations were 0.39 +/- 0.32 mg/L (0.03-1.56). A one-compartment model with first-order absorption was fitted to the data using the first-order (FO) approximation. The best model contained 2 subpopulations (obtained via the $MIXTURE subroutine) of 77 subjects (subgroup A) and 11 subjects (subgroup B) that had typical values for clearance (CL/F) of 21.8 L/h and 2.06 L/h, respectively. The volumes of distribution (V/F) were 1470 L and 260 L, respectively, which suggested a reduction in presystemic metabolism in subgroup B. The interindividual variability (CV%) was modeled logarithmically and for CL/F ranged from 69.1% (subgroup A) to 86.3% (subgroup B). The interindividual variability in V/F was 111%. The residual variability unexplained by the population model was 28.2%. These results confirm and extend the existing pharmacokinetic data on perhexiline, especially the bimodal distribution of CL/F manifested via an inherited deficiency in hepatic and extrahepatic CYP2D6 activity.

Aged↗
PubMed1982

Impaired oxidation of debrisoquine in patients with perhexiline neuropathy.

The use of perhexiline maleate as an antianginal agent is occasionally associated with side effects, particularly neuropathy and liver damage. The reason why some individuals develop these toxic reactions is not clear, though some evidence suggests that they may result from impaired oxidative metabolism, due to genetic or hepatic factors, and consequential accumulation of the drug in toxic concentrations. Drug oxidation was measured with an oxidation phenotyping procedure in 34 patients treated with perhexiline, 20 of whom had developed neuropathy and 14 of whom had not. Most of the 20 patients with neuropathy, but not the unaffected patients, showed an impaired ability to effect metabolic drug oxidation. This impairment was independent of hepatic function, concurrent drug therapy, or tobacco or alcohol consumption. The fact that the ability to oxidise several drugs is genetically controlled points to a genetic susceptibility to developing neuropathy in response to perhexiline. Routine determination of the drug oxidation phenotype might lead to safer use of perhexiline by predicting patients who may be more at risk of developing a neuropathic reaction associated with its long-term use.

Adult↗
PubMed1978

Supression of ventricular extrasystoles by perhexiline.

The antiarrhythmic effects of perhexiline were investigated in 13 of 20 patients with frequent and long standing ventricular extrasystoles in a double blind crossover trial using 24-hour electrocardiograph tape recordings, routine electrocardiograms, and treadmill exercise testing. With a dose of 300 to 400 mg per day, there was a significant decrease (mean 41%) in the number of ventricular extrasystoles per 24 hours. There were large differences in the individual responses to perhexiline, which were significantly related to the diurnal variations of ventricular extrasystoles: those patients whose ventricular extrasystoles disappeared spontaneously during sleep were less likely to respond to perhexiline than those whose ventricular extrasystoles persisted throughout the night. Suppression of ventricular extrasystoles was also apparent from the routine electrocardiogram and the exercise tests. Side effects (dizziness and unsteadiness) were troublesome in 5 of 20 patients. It is concluded that in selected patients perhexiline is an effective antiarrhythmic drug, and is likely to be most useful in patients with coexisting angina and ventricular extrasystoles. Because of its potential toxicity, it should not be used as a drug of first choice.

Cardiac Complexes, Premature↗
PubMed1988

The enterohepatic circulation of perhexiline metabolites in the male Wistar rat.

1. The biliary excretion of some perhexiline metabolites has been assessed in male Wistar rats with biliary cannulation. 2. After intragastric administration of perhexiline maleate (2 mg/kg body weight) multiple perhexiline metabolites were detected in bile. 3. When aliquots of this metabolite-laden bile were administered intraduoduodenally to further 'recipient' rats with biliary cannulation, similar metabolites were detected in the bile of these rats, but at reduced concentrations equivalent to 30-35% of those present in the bile of 'donor' rats. 4. These findings indicate that in the male Wistar rat, there may be substantial enterohepatic circulation of some perhexiline metabolites.

Animals↗
PubMed1979

Perhexiline maleate in the treatment of severe angina pectoris.

Perhexiline maleate was used as a prophylactic agent in 26 patients suffering from severe angina pectoris. The mean duration of treatment was 8.9 months, with a maximum of 28 months. Fifteen patients experienced a reduction in frequency of attacks to less than one-third of their previous level; six experienced a reduction to two-thirds of their previous level; no patient showed an increase in attack rates. During the period of study, there was one death. Frequently observed side effects included dizziness, gastrointestinal irritation and malaise. One patient developed clinically apparent hepatic dysfunction which resolved on withdrawal of perhexiline maleate, but recurred after rechallenge with a lower dose of the drug; the results of liver function tests in five others showed mild abnormalities. One patient developed peripheral neuropathy after taking perhexiline maleate for 18 months, but this resolved in two months after cessation of therapy. Good responses to perhexiline maleate were observed in patients who were concurrently treated with beta-adrenoreceptor blocking drugs.

Alprenolol↗
PubMed1979

Perhexiline maleate-induced cirrhosis.

The authors report the cases of 2 patients who died from cirrhosis after receiving perhexiline maleate, a drug widely used in Europe for the treatment of angina pectoris. Perhexiline maleate had been ingested for 24 and 28 mo, respectively. Manifestations of cirrhosis included jaundice, hepatic encephalopathy, ascites, and portal hypertension. Associated manifestations of intolerance to perhexiline maleate included peripheral neuropathy in 1 patient and marked weight loss in both. Histologic lesions resembled those observed in patients with alcoholic liver disease. Ultrastructural lesions included numerous enlarged lysosomes containing myeloid figures. Histochemical stains demonstrated increased phospholipid content of the hepatocytes. These findings are consistent with the view that prolonged administration of perhexiline maleate may induce both histologic lesions resembling those of alcoholic liver disease and ultrastructural and histochemical lesions resembling those of phospholipidosis.

Aged↗
PubMed1989

Effects of perhexiline maleate on asialo-orosomucoid receptor endocytosis and recycling in HTC cells.

Perhexiline is a lysosomotropic agent which has proved to be very valuable to certain patients suffering from angina pectoris. However long-term administration of the drug may induce hepato- and neuro-toxicity. Using HTC cells (a rat hepatoma-derived cell line) whose plasma membranes were labeled with NaB[3H]4 after oxidation by NaIO4, endocytosis and recycling of labeled asialo-orosomucoid (ASOR) receptors were investigated in the presence of 50 mumols/l perhexiline maleate. The results demonstrate that the drug induces a significant decrease of the rate of both the internalization and the recycling of ASOR receptors. The mechanisms responsible for these effects have not yet been elucidated. However, the current findings may be related to the previously observed inhibitory effect of perhexiline on cellular (Na+, K+)-ATPase and Mg++-ATPase activities. Our findings would then reflect insufficient cellular energy production, resulting from depressed ATP hydrolysis in the presence of perhexiline.

Animals↗
PubMed1989

Perhexiline increases calcium-activated force in skinned psoas fibres by raising calcium affinity of troponin-C.

We investigated the influence of the calcium-/calmodulin antagonist perhexiline on the calcium sensitivity of skinned muscle fibres from rabbit psoas muscle suspended in MgATP salt solution (pH 7.0; 20 degrees C). Perhexiline strongly sensitized the skinned fibres for calcium; thus the relationship between isometric force development and calcium ion concentration was shifted to the left in the presence of perhexiline. Similar results have been achieved with skinned fibres from pig cardiac (ventricular) muscle fibres. In skinned psoas we also determined the binding of Ca2+ to troponin-C by using the method developed by Güth and Potter (1987). Troponin-C labelled with DANZ (5-dimethyl-aminonaphthalene-2-sulfonyl aziridine) was incorporated into skinned fibres after previous extraction of troponin-C. The fluorescence signal (at 460 nm) as well as force increased when the calcium ion concentration rose to pCa 5.7. Addition of perhexiline increased this force and the fluorescence signal indicating that the increase in calcium responsiveness of the contractile apparatus was, at least partly, due to an increase in calcium occupancy of troponin-C.

Animals↗
PubMed1988

Inhibition of (Na+,K+)-ATPase and Mg++-ATPase by a lysosomotropic drug: perhexiline maleate.

Human clinical observations and in vivo studies have shown that the amphiphilic drug perhexiline maleate is responsible for lipidosis storage disorders. When the drug was incubated in vivo with rat brain homogenates, the ouabain-sensitive (Na+,K+)-ATPase and the Mg++-ATPase activities were inhibited. 50% inhibition occurred at the drug concentrations 5.10(-5) M for (Na+,K+)-ATPase and at 10(-4) M for Mg++-ATPase, respectively. Kinetic studies performed on rat brain homogenates showed a mixed type inhibition of these enzymes by perhexiline maleate. The effect of other lysosomotropic drugs (imipramine, chlorpromazine, thioridazine and tamoxifen) on (Na+,K+)-ATPase and on Mg++-ATPase activities was found to be similar to that induced by perhexiline maleate. These results indicate that the inhibitory effect of perhexiline maleate on (Na+,K+)-ATPase and Mg++-ATPase may be a common feature shared by the lysosomotropic drugs.

Animals↗
PubMed1988

Soft drug derivatives related to perhexiline. Part II: In vivo studies.

A series of cyclohexylaralkylamines derived from perhexiline and synthesized according to the "soft drug" concept were evaluated for haemodynamic effects and myocardial oxygen consumption in vivo. In anaesthetized rabbits, the most active compounds, 2, 5, and 11 decreased arterial blood pressure, to a greater extent dp/dtmax and, to a lesser extent heart rate. The decrease in cardiac work and the decrease in cardiac output varied concomitantly. The cardiac effort index decreased in all cases to a greater degree than with perhexiline. In anaesthetized open-chest dogs, the potential antianginal properties of compounds 2, 5 and 11 were due to a decrease in cardiac work via a decrease in cardiac output and myocardial oxygen consumption. None of these compounds reduced arterial blood pressure. Compounds 2 and 5 decreased myocardial oxygen consumption more than perhexiline. Compound 5 was the most promising molecule of this series both as regards cardiac work and myocardial oxygen consumption, being active at a lower dose than perhexiline and having a long active span. These studies suggest that compounds 2, 5 and 11 might be beneficial to patients with angina pectoris.

Animals↗
PubMed1978

Perhexiline maleate in the treatment of angina pectoris. Five years of personal clinical experience.

A five-year personal experience of the use of perhexiline maleate (Pexid) in the treatment of severe angina pectoris is presented. Ninety-four patients, all severely incapacitated by cardiac pain, received perhexiline maleate for an average period of 12.2 months. Perhexiline maleate was used either alone or, more commonly, in conjuction with other antianginal therapy, such as beta-adrenergic receptor blocking agents. The results demonstrate that perhexiline maleate is a very effective agent which appears to be safe for long-term usage. Side effects have been frequent, and occasionally bothersome, but all have been transient and dose-dependent. The possibility that the regimens of treatment may materially improve long-term prognosis is raised.

Adrenergic beta-Antagonists↗
PubMed1979

The effects of perhexiline maleate (Pexid) and alcohol on rat liver.

Perhexiline maleate is an anti-anginal drug believed to cause liver damage. The possibility that this effect could be potentiated by alcohol has been investigated. Rats fed both the drug and alcohol did not show more severe liver damage than those fed alcohol alone. Livers from rats fed perhexiline alone did not differ from controls. There is no evidence from this study that alcohol potentiates the effect of perhexiline in rat liver. These results may have a bearing in perhexiline-induced liver damage in humans, but clinical studies are required.

Animals↗