Quantitative estimation of diphenylhydantoin, primidone and phenobarbital in plasma by gas-liquid chromatography.
TL;DR: A gas-liquid Chromatographic method for the simultaneous determination of phenobarbital, primidone and diphenylhydantoin in human plasma following therapeutic doses has been developed and has the advantages of specificity, sensitivity and simple derivative formation.
About: This article is published in Clinica Chimica Acta.The article was published on 1970-08-01. It has received 219 citations till now.
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TL;DR: Monitoring the blood levels of anti-epileptic drugs has increased the efficiency and safety of drug therapy in epilepsy, and facilitates individualization of dosage regimen, reveals irregular drug intake, and identifies the responsible agent in intoxicated patients on multiple drug therapy.
Abstract: Monitoring the blood levels of anti-epileptic drugs has increased the efficiency and safety of drug therapy in epilepsy. It facilitates individualization of dosage regimen, reveals irregular drug intake, and identifies the responsible agent In intoxicated patients on multiple drug therapy. Blood levels should not be adjusted arbitrarily, however, but used as information in formulating the clinical judgment for each patient. Effective and toxic blood level ranges, as well as the range of levels expected with a given dose (applicable to the majority of patients), are given for the major antiepileptic drugs. These include diphenylhydantoin, phenobarbital, primidone, ethosuximide, and carbamazepine. Indications for ordering blood level determinations are outlined.
187 citations
TL;DR: DPH, but not other anticonvulsants, may cause orofacial dyskinesias, limb chorea, and dystonia in intoxicated patients, which are similar to those caused by neuroleptic drugs and may be related to dopamine antagonistic properties possessed by DPH.
Abstract: Anticonvulsants cause dyskinesias more commonly than has been appreciated. Diphenylhydantoin (DPH), carbamazepine, primidone, and phenobarbitone may cause asterixis. DPH, but not other anticonvulsants, may cause orofacial dyskinesias, limb chorea, and dystonia in intoxicated patients. These dyskinesias are similar to those caused by neuroleptic drugs and may be related to dopamine antagonistic properties possessed by DPH.
150 citations
TL;DR: It is concluded that phenytoin has no role in the treatment of diabetic symmetrical polyneuropathy, and the incidence of undesirable side effects was increased.
Abstract: The efficacy of phenytoin in the treatment of the symptoms of diabetic symmetrical polyneuropathy has been tested in a double-blind, crossover study. Symptoms were evaluated daily by linear analogue self-assessment, while control of blood glucose and plasma phenytoin level were monitored on a weekly basis. There was no significant improvement in symptoms on phenytoin, whether analyzed in aggregate, as pain alone, or on the last 3 days of each treatment week. Blood glucose, however, was elevated in diabetic patients taking phenytoin, and the incidence of undesirable side effects was increased. It is concluded that phenytoin has no role in the treatment of diabetic symmetrical polyneuropathy.
135 citations
TL;DR: Thirty-one, previously untreated, adult outpatients with idiopathic or focal grand-mal and/or focal minor seizures were treated initially with phenytoin, suggesting that many epileptic patients could be satisfactorily treated with one drug instead of the polypharmacy which they usually receive.
112 citations
TL;DR: Drug levels in plasma can serve as an indicator of their concentration in brain and a significant correlation was found between brain and plasma phenobarbital levels during neurosurgical therapy of focal epilepsy.
Abstract: Phenobarbital and diphenylhydantoin were measured concurrently in cerebral tissue and plasma during neurosurgical therapy of focal epilepsy. A significant correlation was found between brain and plasma phenobarbital levels. The mean brain: plasma phenobarbital ratio in ten patients was 0.91 ± 0.08 (SEM). The frequency of cortical spike discharges following drug withdrawal was independent of the brain phenobarbital concentration. A single patient taking diphenylhydantoin alone had a ratio of 1.5 which agreed with the value of 1.3 observed in a nonsurgical patient studied post mortem. White matter contained approximately twice as much diphenylhydantoin as gray matter. A significant correlation was also observed between brain and plasma levels of these drugs in the rat. Hence, drug levels in plasma can serve as an indicator of their concentration in brain.
100 citations
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TL;DR: The correlation is described between the serum level of diphenylhydantoin and the anticonvulsant effect of the drug, the incidence of paroxysmal abnormalities in the electroencephalogram, and the occurrence of toxic side-effects.
Abstract: In a previous study 2 a method was described for determining diphenylhydantoin (5,5-diphenylhydantoin; phenytoin; Dilantin) concentrations in the serum when the drug was given in therapeutic amounts. With this method were determined the rate of rise of diphenylhydantoin in the serum after oral and after intravenous administration, the hourly and daily fluctuations, the ratio of dosage to serum level, and the rate of fall of serum diphenylhydantoin after withdrawal of the drug. In the study presented in this report the correlation is described between the serum level of diphenylhydantoin and the anticonvulsant effect of the drug, the incidence of paroxysmal abnormalities in the electroencephalogram, and the occurrence of toxic side-effects. Patients and Methods Patients. —1. Twelve patients, 19 to 58 years of age—six men and six women, hospitalized in the neuromedical, neurosurgical, or psychiatric department of the University Hospital. They had not taken diphenylhydantoin before admission to the hospital and
280 citations
Journal Article•
TL;DR: In the rat, highest concentrations were found in the liver and fat, followed in order of decreasing concentration by the heart, spleen, kidney, lung and skeletal muscle, and red blood cells were found to contain Dilantin in approximately the same concentration as plasma.
Abstract: A colorimetric procedure is described for the determination of Dilantin by nitration of the phenyl group, reduction to an aromatic amine, followed by diazotization and coupling with the Bratton-Marshall reagent. A double extraction procedure is used to separate Dilantin from biological specimens, and a 2-plate countercurrent extraction procedure is described for separating Dilantin from phenobarbital prior to colorimetric analysis. The colorimetric procedure has been applied to the determination of Dilantin concentrations in blood plasma and tissues following the administration of Dilantin. In the rat, highest concentrations were found in the liver and fat, followed in order of decreasing concentration by the heart, spleen, kidney, lung and skeletal muscle. Red blood cells were found to contain Dilantin in approximately the same concentration as plasma. Maximum blood levels were found in the rat in 6 to 8 hours after oral dosage (100 mgm./kgm.). A dog receiving 25 mgm./kgm. showed maximum blood levels in about 4 hours, with return to zero levels after 24 hours. Human subjects receiving a single 400 mgm. oral dose of sodium Dilantin showed maximum plasma levels of 2 to 5 microgm./ml. in about 8 hours, with a slow drop occurring thereafter at the rate of 50 per cent per 18 to 24 hours. Acid Dilantin crystals were found to be more slowly absorbed over a longer time period, resulting in lower but more prolonged blood levels. Epileptic patients receiving daily doses of Dilantin and phenobarbital over a period of years showed plasma levels of 0.9 to 10.5 microgm. per ml. These levels were fairly constant for each individual, but varied considerably between different individuals. Peroral administration of Dilantin to rats resulted in about 10 per cent of the dose being excreted in the feces. Only small amounts of Dilantin (∼1 per cent) were recovered in the urine by the assay procedure, and it is not certain that this represents unchanged Dilantin. Similar results were obtained on urinary excretion following parenteral administration of Dilantin. Small amounts of Dilantin were found in the bile of rats, and some degree of absorption was found in all parts of the gastro-intestinal tract. Unchanged Dilantin was recovered from rat liver and human plasma, and identified by comparison with a known sample of Dilantin through its Craig countercurrent distribution characteristics. Dilantin was also recovered from dog liver, and identified by comparison of its infra-red absorption spectrum with an authentic sample of Dilantin.
236 citations
TL;DR: Saturation, autoinduction, or product inhibition, singly or in combination, of the drug‐metabolizing enzyme system are possible mechanisms involved in the dose dependency and nonexponential decline of plasma diphenylhydantoin concentration.
Abstract: The rate of disappearance of diphenylhydantoin from plasma was studied in 70 healthy volunteers by giving them 100 mg. orally 3 times daily for 3 days and measuring the plasma diphenylhydantoin concentration for 4 consecutive days after the last dose of the drug. The mean plasma half‐life was 22.0 ± 9.0 hours and the difference between that of Negro and Caucasian males, 26.5 and 18.5 hours, respectively, was Significant. Dose dependency of the half‐life was demonstrated in 10 subjects studied. The decline in plasma diphenylhydantoin concentration in many subfects was not exponential and the disappearance of the drug from plasma was not always a first‐order process. The diphenylhydantoin half‐life in some subjects was shorter after long‐term administration than after short‐term administration of the drug. Saturation, autoinduction, or product inhibition, singly or in combination, of the drug‐metabolizing enzyme system are possible mechanisms involved in the dose dependency and nonexponential decline of plasma diphenylhydantoin concentration.
232 citations
TL;DR: Injection of methanol solutions of trimethylanilinium salts of barbiturates, phenolic alkaloids, and dimethylxanthines produced thermal decomposition in the injection port to give methyl derivatives suitable for quantitative gas chromatography.
177 citations
Journal Article•
114 citations