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.
The effects of indoramin, a new hypotensive drug with competitive a-adrenergic receptor blocking properties, were studied in a double-blind investigation in healthy human subiects. Indoramin (20 mg.) London and Taplow, England Division of Clinical Pharmacology and Cardiac Department, St. Bartholomew's Hospital, London, and Medical Department, John Wyeth & Brother, Ltd., Taplow Indoramin ( 3-[ 2-( 4-benzamidopiperid-1-yl) ethyl] indole) (Formula 1) has been observed in animal experiments to combine competitive a-adrenergic receptor blocking properties with cardioinhibitory, local anesthetic, antihistamine, and anti-S-hydroxytryptamine activity.
380doramin was a more potent hypotensive agent than was guanethidine. Chronic administration to animals both orally and intravenously did not show toxic effects or tolerance.The use of a-blocking agents in the treatment of hypertension has, with the exception of their use in certain limited situations, proved clinically unsatisfactory. This is largely due to the fact that most of these drugs also possess undesirable pharmacologic properties. With phenoxybenzamine, an alkylating agent, the slow onset and long duration of action combined with accumulation of the drug on repeated dosage makes control of blood pressure difficult. It potentiates the ,8-action of norepineph-
We have performed single-dose pharmacokinetic studies on perhexiline in eight young volunteers, each given 300 mg of Pexid orally, using an h.p.l.c. method for the separation and quantification of the drug and its monohydroxy metabolites in plasma and urine. The plasma concentration of the cis-monohydroxyperhexiline (peak of 473 +/- 43 ng/ml at 7.5 +/- 2.0 h) was always higher than for unchanged perhexiline (peak of 112 +/- 20 ng/ml at 6.5 +/- 2.0 h) whereas the concentration of the transmetabolite was either low or undetectable in plasma. These findings indicate the occurrence of stereospecific pre-systemic metabolism of perhexiline which reduces the bioavailability of the parent drug. The plasma elimination half-life of perhexiline was 12.4 +/- 6.1 h (range 7-23 h) while that for cis-monohydroxyperhexiline was 19.9 +/- 7.7 h (range 10-29 h). Not more than 0.3% of unchanged perhexiline was excreted in the urine over five days in eight subjects. Between 3 and 23% of the orally administered drug was excreted as the cis- or trans-monohydroxy metabolites, the ratio of trans to cis metabolites being 0.52 +/- 0.20.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.