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PubMed2002

Primidone-induced hyperammonemic encephalopathy in a patient with cerebral astrocytoma.

A case of a patient with astrocytoma who showed somnolence and asterixis one month after tumour resection is presented. Although primidone had been prescribed preoperatively for five years and the same dose was maintained after the operation, the serum concentration of the primidone metabolite phenobarbital was elevated and she demonstrated hyperammonemic encephalopathy, which disappeared on withdrawal of the drug. A description of this seldom reported phenomenon during primidone therapy is given, with reference to valproate cases.

Anticonvulsants↗
PubMed1977

Drug interactions during anticonvulsant therapy in childhood: diphenylhydantoin, primidone, phenobarbitone, clonazepam, nitrazepam, carbamazepin and dipropylacetate.

It is well known that the concomitant use of different drugs may alter the reactions of the body towards the individual components. This is particularly important in long-term anticonvulsant therapy which is frequently a combined therapy. By carrying out statistical analysis of more than 6000 assays of the serum levels of antiepileptic drugs an attempt was made to gain insight into the possible drug interactions. The following results were obtained: 1. There was an increase in serum levels of diphenylhydantoin when either clonazepam or dipropylacetate (short-term therapy) was given concomitantly. 2. There was a decrease in serum levels of diphenylhydantoin when carbamazepine, primidone or dipropylacetate (long-term therapy) were administered concomitantly. 3. There was an increase in the serum level of phenobarbitone when it was administered together with diphenylhydantoin. 4. There was an increase in the serum level of primidone when it was administered together with clonazepam. 5. There was a decrease in the serum level of primidone if it was administered concomitantly with either carbamazepine or dipropylacetate (long-term therapy).

Adolescent↗
PubMed1976

Simultaneous quantitative gas-chromatographic analysis of ethosuximide, phenobarbitone, primidone and diphenylhydantoin.

1 Therapeutic serum concentrations of ethosuximide, phenobarbitone, primidone, and dipheylhydantoin were assayed from 1 ml of human serum. The extraction procedure was common to all four drugs and three internal standards. 2 Subsequent isothermal gas chromatographic analysis of serum extracts produced well resolved peaks for the underivatized quantitation of ethosuximide and phenobarbitone. Primidone and diphenylhydantoin were determined as methylated derivatives. 3 Mean coefficients of variation for the assay of each drug were less 7% on a newly packed and conditioned column and less than 10% after the technique had been in continuous use for 3 months. 4 The advantage of quantitation relative to peak area ratios rather than peak height ratios was minimal for the determination of ethosuximide, primidone and diphenylhydantoin but appeared significant for the assay of phenobarbitone.

Chromatography, Gas↗
PubMed1977

Teratogenic activity and metabolism of primidone in the mouse.

Primidone, 25, 50, 100, and 150 mg/kg, was administered orally to mice of the I.C.I. strain from days 6-16 of pregnancy. The fetuses were removed by caesarian section on day 19 and examined by dissection and alizarin staining for gross structural and skeletal defects. The most common abnormalities found were palatal defects with full-length or submucosal clefts. In the controls--25, 50, 100, and 150 mg/kg groups--the incidence of palatal defects was 0/85, 16/84, 18/117, 19/102, and 17/92 fetuses, respectively. Essentially no other major or minor drug-related abnormalities were found. The metabolism of primidone in the pregnant and nonpregnant mouse was also studied and shown to be similar to that previously reported in the rat. Peak blood levels of primidone were obtained after 1 hr; they fell to very low levels by 6 hr. and were completely cleared by 24 hr. The metabolites produced, PEMA and phenobarbital, are similar to those produced in other species including man. Blood levels following single oral doses of 5 to 150 mg/kg were dose-related so that no explanation for the lack of dose-related teratogenic effect was found.

Animals↗
PubMed1981

Benign familial tremor treated with primidone.

Primidone given to a patient for epilepsy produced an unexpected reduction in benign familial tremor. Over the next eight years the drug was therefore tried in a prospective study of 20 other patients with benign familial tremor alone. Of these, six could not tolerate the drug because of vertigo and nausea but 12 obtained a good response, which in some cases was dramatic. Investigations in two patients suggested that the effect was mediated predominantly by derived phenylethylmalonamide, though primidone had some effect, since tremor recurred slightly on withdrawing the drug despite a constant or rising blood phenylethylmalonamide concentration. Primidone is highly effective in benign familial tremor. More patients with the condition are intolerant of the drug than are usually found with epilepsy.

Adolescent↗
PubMed1983

Direct determination of primidone in serum or plasma by a magnetisable solid-phase fluoroimmunoassay.

A solid-phase separation fluoroimmunoassay for primidone in plasma or serum was developed using antibodies coupled to magnetisable cellulose/iron oxide particles and a fluorescein-labelled primidone derivative as tracer. Endogenous fluorophores and other potentially interfering components in serum samples were reliably and completely removed at the time the antibody-bound and free fractions were being separated. The separation and wash steps were greatly facilitated by use of magnetic sedimentation. The assay reached equilibrium within 30 minutes; all normal reliability criteria were satisfied; and the results correlated closely with those of an established enzymoimmunoassay method. The assay is specific for primidone, and no detectable interference by all other commonly employed anticonvulsants was found at serum levels of 1 g/l.

Animals↗
PubMedDate not supplied

Primidone-induced catatonic schizophrenia.

The authors report the case of a severely retarded, 19-year-old female (treated with primidone 250 mg tid since age 12) who was admitted with visual and auditory hallucinations. After four days of continuing hallucinations, she went into classic catatonic schizophrenia. Upon examination, her primidone serum level was found to be well above the normal therapeutic range. The primidone dosage was decreased, and symptoms subsided as serum levels returned to normal.

Adult↗
PubMed1988

Double-blind comparison of primidone and phenobarbital in essential tremor.

In a double-blind cross-over trial, primidone was superior to both placebo and phenobarbital in reducing essential tremor in 13 patients. Phenobarbital, at a dosage yielding serum barbiturate levels greater than those seen with primidone, was not better than placebo. Thus, primidone has an effect in essential tremor independent from that of its metabolite phenobarbital.

Clinical Trials as Topic↗
PubMed1995

Clinical pharmacokinetics of antiepileptic drugs in paediatric patients. Part I: Phenobarbital, primidone, valproic acid, ethosuximide and mesuximide.

This article reviews 119 papers published since 1964 on the pharmacokinetics of phenobarbital, primidone, valproic acid, ethosuximide and mesuximide (methsuximide) in paediatric patients. Particular attention has been paid to the role of age in determining the variability of pharmacokinetic parameters, but the effect of other factors, such as different formulations and routes of administration, concomitant treatments, gender and pathological conditions other than epilepsy, have also been considered. Mean phenobarbital terminal half-life (t1/2z) is very long in neonates (45 to 409 hours) and decreases with age. Therefore, a low dose per kilogram (dose/kg) is recommended during the neonatal period. The dose requirement decreases with increasing age, especially in children also taking valproic acid, which inhibits phenobarbital metabolism. Primidone is metabolised to phenobarbital and phenylethylmalonilamide; the metabolic conversion rate is increased by enzyme-inducing drugs and inversely correlated with age, being virtually absent in neonates. Valproic acid is extensively bound to plasma proteins, but there is a high interindividual and intraindividual diurnal variability in the binding, which depends on the concentration of binding proteins (i.e. albumin) and binding modulators (e.g. free fatty acids) but not on age (at least in those patients aged between 3 months and 65 years). The clearance (CL/F) of valproic acid positively correlates with the unbound concentrations and is strongly age-dependent, being low in neonates and high at the end of the first postnatal month, and progressively decreasing from 2 months to 14 years. The combination of these factors leads to a very poor correlation between plasma concentrations and dose/kg (C/D) and between plasma concentrations of total valproic acid and efficacy. Children also taking enzyme-inducing antiepileptic drugs require a larger valproic acid dose/kg, whereas the coadministration of aspirin (acetylsalicylic acid) may decrease the clearance of unbound drug (CLu/F), and thus require a decrease in the daily dose of valproic acid. Ethosuximide is well absorbed, minimally protein bound and slowly eliminated. Lower C/D ratios are reported in children younger than 10 years old than in older children and in individuals also taking enzyme-inducing drugs (i.e. primidone). According to the only available paper on mesuximide in paediatric patients, the C/D ratio is less sensitive to both age and associated therapy.

Adolescent↗
PubMed1977

The metabolism of primidone in non-pregnant and 14-day pregnant mice.

1. Non-pregnant and day-14 pregnant mice treated with a single dose of primidone (5 to 150 mg/kg) by gastric intubation were bled at 1 and 4 h after dosage, and the plasma analysed for primidone, phenobarbitone and phenylethylmalondiamide (PEMA) by g.l.c. 2. Marked differences in the rate of metabolism were observed between the non-pregnant and day-14 pregnant mouse. Plasma levels of primidone and PEMA, but not phenobarbitone, were much lower in the day-14 pregnant mouse than in the non-pregnant animal.

Animals↗
PubMed1975

Plasma level studies on different brands of sodium diphenylhydantoin (DPH) and primidone.

Comparative plasma level studies on different brands of sodium diphenylhydantoin (DPH) and primidone are described. Steady state plasma levels of both drugs were measured in epileptic patients who were chronically maintained on this medication. Simultaneous measurements of phenobarbital, primidone and diphenylhydantoin were carried out by gas chromatography. Drug product equivalence and clinical significance of plasma levels of DPH and primidone are discussed.

Biological Availability↗
PubMed1976

Simultaneous measurement of phenobarbital, diphenylhydantoin, and primidone in blood by high-pressure liquid chromatography.

We describe a sensitive, precise high-pressure liquid chromatographic method in which 5-(p-methylphenyl)-5-phenylhydantoin is used as the internal standard for simultaneous determination of diphenylhydantoin, phenobarbital, and primidone in whole blood and plasma. These anticonvulsant drugs are well separated from each other and from normal blood constituents in less than 10 min. The lower limit of detection for each drug is 100 ng for primidone, 200 ng for dilantin, and 300 ng for phenobarbital. The eluted drugs were detected by their absorption at 254 nm, and evaluated from their peak heights as compared to internal standard. The method was successfully adapted for pediatric samples (100 to 500 mul of whole blood or plasma). Fifty specimens were analyzed for phenobarbital and diphenylhydantoin and 25 specimens for primidone by a standard gas-chromatographic method and by our liquid-chromatographic method; the resulting correlation coefficient was greater than 0.98.

Chromatography, Gas↗
PubMed1989

Acute primidone intoxication: report of a case.

A case of acute primidone intoxication, due to overdose, was evaluated at National Taiwan University Hospital. Serial assessment of the clinical manifestations, electroencephalograms and serum levels of primidone and phenobarbital were made. From these data, we conclude that the toxic effects, such as depression of the central nervous system and dysequilibrium, are due mostly to primidone itself, rather than its metabolite, phenobarbital.

Adult↗
PubMed1987

Dermatitis associated with the use of primidone in a dog.

A 9-year-old female dog with progressive pruritic dermatitis was examined 9 months after primidone treatment had been initiated. Alopecia, scaling, ulceration, pigmentation, and fissuring were evident over the dorsal trunk, head, perineum, caudal aspect of the thighs, hocks, elbows, and paws. Hydropic degeneration of epidermal basal cells, mononuclear lichenoid infiltrate in the superficial dermis, and marked parakeratotic hyperkeratosis were evident on biopsy. Antinuclear antibody in the serum was not detected and specific patterns of immunoglobulin deposition in the epidermis or basement membrane zone were lacking. Primidone-induced dermatitis was presumptively diagnosed. Successful treatment involved withdrawal of the primidone and administration of corticosteroids and antibiotics to relieve the pruritus and to eliminate the secondary pyoderma.

Animals↗
PubMedDate not supplied

On P-chlorphenylalanine interference with phenobarbital formation from primidone.

Premedication with PCPA antagonized in rats the anticonvulsant activity of Primidone and of other drugs against seizures evoked by electroshock. Only in the case of Primidone, however, the anticonvulsant activity could not be re-established by increasing the dosage. Our investigations have shown that PCPA caused a strong inhibition of the conversion of Primidone to phenobarbital, both in vivo and in vitro.

Animals↗
PubMed1981

Anticonvulsant drugs in alcohol withdrawal: use of phenytoin, primidone, carbamazepine, valproic acid, and the sedative anticonvulsants.

The evidence for the efficacy of anticonvulsant drugs in the control of seizures during alcohol withdrawal is examined. The literature on the use of anticonvulsants to control anxiety, irritability, tension, and other symptoms of abstinence syndrome is reviewed. The data on benzodiazepines, phenobarbital, hydroxyzine, and neuroleptics are discussed briefly. There is no evidence to support the routine use of phenytoin for seizure prophylaxis in detoxication. However, phenytoin may be valuable in patients at a high risk for seizures, such as skid-row alcoholics. Only one retrospective study has been done on primidone; it claimed primidone was an efficacious adjuvant. Carbamazepine and valproic acid may be useful in the treatment of anxiety, dysphoric mood, somatization, and other symptoms of abstinence syndrome, as well as for seizure prophylaxis. The benzodiazepines, diazepam and chlordiazepoxide, are recognized as primary therapeutic agents in the detoxication of alcoholic patients. The major difficulty with the use of phenobarbital is that it cannot be used over as wide a range as the benzodiazepines. Hydroxyzine has been shown to be inferior to chlorazepate dipotassium. Most neuroleptics appear to be inappropriate for detoxication because they lower the seizure threshold; however, haloperidol has been found efficacious in acutely abstinent alcoholics. Carbamazepine, valproic acid, primidone, and phenobarbital should be tested against standard drugs such as chlordiazepoxide and diazepam in the detoxication of alcoholic patients.

Alcoholism↗
PubMed1976

Monitoring drug concentrations in a case of combined overdosage with primidone and methsuximide.

We describe a case of fatal overdosage with primidone and methsuximide. During the early phase of the patient's hospital course we found concentrations of methsuximide, N-desmethylmethsuximide, and primidone in serum that far exceeded the usual therapeutic concentrations, as determined by gas-liquid chromatography. Determination of N-desmethylmethsuximide in peritoneal fluid demonstrated concentrations comparable to those in serum. This led to the therapeutic decision to manage the patient by dialysis. Subsequently, serum samples collected during the course of hospitalization were analyzed quantitatively by gas-liquid chromatography for methsuximide, N-desmethylmethsuximide, primidone, phenobarbital, and diphenylhydantoin. Selected serum specimens were also analyzed by gas chromatography-mass spectrometry, and N-methyl-2-hydroxymethyl-2-phenylsuccinimide, a metabolite of methsuximide not previously described in human serum, was identified by analysis of its mass spectrum.

Adult↗
PubMed1979

Single-dose pharmacokinetics and anticonvulsant efficacy of primidone in mice.

The pharmacokinetics and efficacy of the anticonvulsant primidone (PRM) and its active metabolites, phenobarbital (PB) and phenylethylmalonamide (PEMA), were studied after single-dose administration in mice. The half-life of PB is twice that of PRM and PEMA. The plasma/brain ratios provide evidence of poor penetration of PRM into brain. The results support our findings of negligible or absent PRM concentrations in the brains of patients on primidone therapy who were undergoing surgery for intractable epilepsy. The anticonvulsant properties of PRM, PB, and PEMA against maximal electroshock in mice were also studied with the use of the metabolic inhibitor SKF 525A. The half-life, potency, peak anticonvulsant effect, and effective dose curves of these compounds indicate that the anticonvulsant effect of short-term oral PRM administration in mice is from derived PB.

Animals↗