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PubMed1977

Kinetics of primidone metabolism and excretion in children.

The metabolism and excretion of orally administered primidone was studied in 12 children, aged 7 to 14 yr during long-term dosing. Plasma concentrations of primidone (Pr) peaked at 4 to 6 hr and declined exponentially from 6 to 24 hr, with half-life (t1/2) values ranging from 4.5 to 11 hr. A mean of 92% (72% to 123%) of the administered dose was recovered within 24 hr from the urine as Pr and its metabolites. Of the total Pr daily dose, 42.3% (15.2% to 65.9%) was recovered as unchanged drug, 45.2% (16.3% to 65.3%) as phenylethylmalonamide (PEMA), and 4.9% (1.1% to 8.0%) as phenobarbital (Pb). The mean rate constant for conversion of Pr to PEMA (K1) was 0.0424 hr-1, for conversion of Pr to Pb (K2) was 0.0045 hr-1, and for excretion of unchanged Pr (K3) was 0.0389 hr-1. Of Pb excreted, 43% (13% to 100%) was unchanged, 15% (0% to 27%) was unconjugated p-OH Pb, 20% (0% to 44%) was conjugated p-OH Pb, and 22% (0% to 33%) was conjugated 3,4-OH Pb. KE appears to be important determinant of the steady-state plasma concentration of Pb, but interindividual differences in K2 have little influence on the overall rate constant for elimination of Pr.

Adolescent↗
PubMed1976

Preparation and properties of solid dispersion system containing citric acid and primidone.

Solid dispersions containing 1--32% (w/w) primidone were prepared by fusing the drug with citric acid and rapidly cooling the melt. The solidified dispersions were clear glasses which devitrified on aging or when stored at 60 degrees for up to 3 days. The phase diagram of the devitrified system indicated that the drug may exist as a solid solution at 1--3% (w/w) concentrations but that a eutectic mixture is formed at higher concentrations. The solubility of primidone increased in the presence of citric acid. Preliminary dissolution studies showed that the dissolution rate from the solid dispersion was greater than that of the pure drug or the physical mixture.

Chemical Phenomena↗
PubMed1981

Chromosomal investigations in epileptic children during long-term therapy with phenytoin or primidone.

In epileptic children the long-term therapy with anticonvulsant drugs is absolutely necessary. However, anticonvulsant drugs have been suspected to be mutagenic and teratogenic. To investigate this problem metaphase chromosome observations were performed using short-time culture of peripheral blood lymphocytes from twenty children. Ten of the children had been treated with phenytoin and the other ten with primidone on monotherapy. The long-term administration of anticonvulsant drugs was monitored by measurement of the serum concentrations of phenytoin and primidone, by seizure anamnesis, and by repeated EEG investigations. Analyzing 100 mitoses from each proband, we found no increase of structural or numerical aberrations in our patients compared with six controls. In adults, however, anticonvulsant drugs have been found to cause structural aberrations and chromosomal damage. The absence of these lesions in children may reflect the higher efficiency of DNA-repair in local DNA-damage.

Adolescent↗
PubMed1975

Brain concentrations of phenytoin, phenobarbitone and primidone in epileptic patients.

Plasma, brain, lumbar CSF, skeletal muscle, skin and bone concentrations of phenytoin, phenobarbitone and primidone have been measured in specimens from patients undergoing temporal lobectomy for chronic epilepsy. A good correlation was found between the plasma and brain concentrations of each drug. Similarly, a good correlation was found between the plasma and CSF concentrations of each drug. Assuming that CSF is an ultrafiltrate of plasma, the percentage of phenytoin, phenobarbitone and primidone which was unbound in plasma was 10-14%, 43% and 81% respectively. Skeletal muscle concentrations of phenytoin and phenobarbitone and the skin concentration of phenytoin, also correlated with the plasma concentrations, but the remaining tissues did not give significant correlations.

Adolescent↗
PubMed1978

A practical routine gas chromatographic determination of phenobarbital, primidone and diphenylhydantoin.

A gas chromatographic method for the routine determination of phenobarbital, primidone and diphenylhydantoin using alkaline extraction and on-column methylation has been developed. The procedure has been optimized for recovery of all three anticonvulsant drugs with particular attention to primidone. Correlation with photometric methods for phenobarbital and diphenylhydantoin show the technique offers significant advantages in both accuracy and precision over other methods.

Chromatography, Gas↗
PubMed1998

Simultaneous determination of primidone and its three major metabolites in rat urine by high-performance liquid chromatography using solid-phase extraction.

A new high-performance liquid chromatographic method for simultaneous determination of primidone (PRM) and of its three major metabolites, phenobarbital (PB), p-hydroxyphenobarbital (p-HO-PB) and phenylethylmalonamide (PEMA), in rat urine, was developed. After acid hydrolysis, these compounds were extracted from urine by means of a Bond Elut Certify LRC column with good clean-up. The extracts were chromatographed on a C18 reversed-phase column using isocratic elution at 40 degrees C, with UV detection at 227 nm. The limit of detection was 0.5 mg/ml for the four compounds. Good linearity (r2>0.99) was observed within the calibration ranges studied: 37.4-299.3 microg/ml for PRM, 26.4-211.2 microg/ml for PB, 12.5-100.2 microg/ml for p-HO-PB and 12.1-97.0 microg/ml for PEMA. Repeatability was in the range 3.1-6.8%. This method constitutes a useful tool for studies on the influence of various parameters on primidone metabolism.

Animals↗
PubMed1999

Primidone-loaded poly-epsilon-caprolactone nanocapsules: incorporation efficiency and in vitro release profiles.

This paper describes the preparation of primidone-loaded poly-epsilon-caprolactone nanocapsules according to the interfacial deposition technique. The colloidal suspension obtained showed a monomodal size distribution with a mean diameter ranging from 308 to 352 nm. By adjusting the process parameters, the encapsulation efficiency was about 74% with good reproducibility. Primidone release from the nanocapsules was found to be slower as compared to the oily control solution despite an important burst-effect. The release profile was not influenced by the pH of the release medium.

Caproates↗
PubMed1999

Spectrodensitometric determination of clorazepate dipotassium, primidone and chlorzoxazone each in presence of its degradation product.

The present work describes a quantitative thin layer procedure for estimating primidone, clorazepate dipotassium and chlorzoxazone in bulk powders and in dosage forms, each in the presence of its degradation product. The method consists of dissolving the drug in ethanol (for primidone), or methanol (for clorazepate dipotassium and chlorzoxazone) and then spotting this solution on a thin layer of silica gel G254. Quantitation is achieved by comparing the areas under the peaks obtained from scanning the thin layer chromatographic plates in a spectrodensitometer.

Anticonvulsants↗
PubMed1983

Simultaneous liquid chromatographic determination of chloramphenicol and antiepileptic drugs (phenobarbital, phenytoin, carbamazepine, and primidone) in plasma.

A method for the simultaneous analysis of chloramphenicol and four antiepileptic drugs (phenobarbital, phenytoin, carbamazepine, and primidone) in plasma by high-performance liquid chromatography (HPLC) is described. The method involves a preliminary extraction of 0.1 ml of plasma with diethyl ether containing phenacetin as an internal standard, chromatography with a reversed-phase column with a methanol-water mobile phase, and detection by measuring ultraviolet absorbance at 210 nm. The method demonstrated sufficient precision, sensitivity, and specificity: the recoveries of the drugs were greater than 95% with the exclusion of primidone (80.3%); the maximum within-day and day-to-day coefficients of variation for all drugs were less than 5%; the lower detection limits were 0.5 microgram/ml or less for all drugs analyzed; and six other antibiotics, phenylethylmalondiamide, carbamazepine-10,11-epoxide, and chloramphenicol esters did not interfere with the analysis. The HPLC method was tested for clinical applicability by analyzing plasma samples from a volunteer who received concurrent single doses of chloramphenicol, phenobarbital, and phenytoin. This method can be used for studying drug interactions between chloramphenicol and antiepileptic drugs and for monitoring the concentrations of these drugs in plasma when administered concurrently, to prevent concentration-related side effect(s) of each drug.

Adult↗
PubMed1983

Adaptation of microvolume EMIT assays for theophylline, phenobarbital, phenytoin, carbamazepine, primidone, ethosuximide, and gentamicin to a CentrifiChem chemistry analyzer.

We have developed microvolume EMIT procedures for theophylline, phenobarbital, phenytoin, carbamazepine, primidone, ethosuximide, and gentamicin using a centrifugal analyzer (CentrifiChem and Pipettor 1000) to reduce the manufacturer's recommended manual reagent consumption by one-sixth. In addition to developing the EMIT procedure, the performance of the analyzer and pipettor were verified. The analyzer and pipettor are capable of producing within-run precision at a 3-microliters sample volume and 210-microliters analyzer cuvette volume equal to or less than 1.5%. The performance of the EMIT procedures on the analyzer yielded spike drug recoveries of 90.8 to 106.1% for drug concentrations throughout the calibration concentration range of each assay. The percent error on standard reference material of the National Bureau of Standards ranged from a +12.0% to a -0.6% for ethosuximide, phenobarbital, phenytoin, and primidone. Patient comparison data yielded slopes from 0.930 to 1.110 for all assays. The other important feature of the adapted EMIT assay is its simplicity for use on a routine basis.

Anticonvulsants↗
PubMed1986

Phenylethylmalonamide serum levels in patients treated with primidone and the effects of other antiepileptic drugs.

Data are presented for the serum levels of 2-ethyl-2-phenylmalonamide (PEMA) in patients receiving anticonvulsant medication. Statistical analysis of these data indicates that the serum level of PEMA, which is a metabolite of primidone, is affected not only by the dose of primidone but also by the serum levels of other prescribed anticonvulsant drugs. In particular, phenobarbitone is shown to be a major perturbation upon the PEMA serum level.

Anticonvulsants↗
PubMed1993

Determination of phenobarbital, ethosuximide, and primidone in human serum by micellar electrokinetic capillary chromatography with direct sample injection.

The determination of antiepileptic drugs in human serum by micellar electrokinetic capillary chromatography (MECC) with direct sample injection is discussed. Nanoliter quantities of patient sera are applied to the beginning of a fused silica capillary filled with a phosphate/borate buffer (pH 9.2) containing 75 mM sodium dodecylsulfate. Upon application of an electric field along the capillary, endogenous and drug substances are transported toward the cathode and separate into distinct zones which are detected by on-column UV absorption. Phenobarbital, ethosuximide, and primidone are shown to elute in front of the solubilized proteins, thus permitting quantitation of these drugs without any sample pretreatment. For phenobarbital and ethosuximide, MECC data obtained using the external standard method and peak areas as the basis for quantitation are shown to be in excellent agreement with those of nonisotopic immunoassays and, for ethosuximide, also with those of high-performance liquid chromatography. The correlation coefficients (n = 50) are between 0.972 and 0.986. Intraday and interday reproducibility data are 2.0-4.5% and 4.5-8.0%, respectively. For primidone, insufficient samples have been available for a comprehensive comparison of MECC data with those of other analytic techniques.

Anticonvulsants↗
PubMed1987

Results of a nationwide Veterans Administration Cooperative Study comparing the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin, and primidone.

In 1985 a 5-year multicenter Veterans Administration Cooperative Study was completed that compared the efficacy and toxicity of phenobarbital, carbamazepine, phenytoin, and primidone in a double-blind prospective study design. A total of 622 patients, either previously untreated or undertreated, were entered into the study. Strict exclusion criteria limited confounding factors such as drug or alcohol abuse. Results showed that each of the four drugs used as monotherapy were similarly effective in the treatment of generalized tonic clonic seizures, but carbamazepine was significantly more effective in the treatment of complex partial seizures as measured by 100% control. When the results for all four drugs were combined, the data showed that approximately 80% of the patients were adequately managed on monotherapy. Differences in toxicity were the most significant factor that discriminated between these four drugs. Both carbamazepine and phenytoin were associated with significantly lower incidences of intolerable side effects than were primidone or phenobarbital. A behavioral toxicity battery was performed whenever possible prior to administration of any antiepileptic drug and at 1, 3, 6, and 12 months after initiation of monotherapy. Significant differences in performance on all subtests of the battery were found between patients with epilepsy and a control group matched by age, sex, and education. When the differential effects of all four drugs on behavioral toxicity were compared, few statistically significant differences emerged. However, carbamazepine consistently produced fewer adverse effects on tests of attention/concentration and motor performance than did the other three antiepileptic drugs.

Adult↗
PubMed1991

Loss of therapeutic control in congenital adrenal hyperplasia due to interaction between dexamethasone and primidone.

A 14-year-old girl with congenital adrenal hyperplasia showed rapid conversion from undertreatment to overtreatment when primidone, used to treat coexistent epilepsy, was withdrawn while on a constant steroid dose. In addition to signs of hypercortisolism and a decrease in random measurements of plasma testosterone and 170H-progesterone concentrations, the deterioration in control was also illustrated by changes in the pattern of blood spot steroid profiles. Adequate control was achieved only after a 3-fold reduction in steroid dose. The decrease in dose requirement was probably the result of a reversal of liver enzyme induction consequent upon the withdrawal of primidone.

Adolescent↗
PubMed1986

A comparison of primidone, propranolol, and placebo in essential tremor, using quantitative analysis.

The effects of placebo, propranolol and primidone were compared in 14 patients with essential tremor in a double blind, randomised, crossover study. Objective measures of tremor were obtained using an accelerometer with subsequent spectral analysis. Both propranolol (p less than 0.01) and primidone (p less than 0.01) gave significant improvement in tremor, but there was no significant difference in improvement between these drugs. Patients with higher dominant frequencies of tremor tended to respond to both drugs, while those with lower frequencies improved on one or other. There was no differential effect between the drugs with the frequency of tremor.

Clinical Trials as Topic↗
PubMed1983

Primidone, phenobarbital, and PEMA: I. Seizure protection, neurotoxicity, and therapeutic index of individual compounds in mice.

Neurotoxicity and protection against maximal electroshock and Metrazol seizures from primidone (PRM), phenobarbital (PB), and phenylethylmalonamide (PEMA) were determined in mice for each drug separately and expressed in terms of brain concentrations. Compared with PB, PEMA was 16 times less potent against electroshock and Metrazol seizures but only 8 times less toxic. Primidone was markedly less neurotoxic than PB and equally potent against electroshock, but PRM had no effect against Metrazol or bicuculline. PRM is a relatively nontoxic anticonvulsant with a different action than PB, and PEMA is both a weak and a relatively toxic anticonvulsant.

Animals↗
PubMed1992

Urinary metabolites of phenobarbitone, primidone, and their N-methyl and N-ethyl derivatives in humans.

1. Phenobarbitone (1) and three of its N-alkyl derivatives, and primidone (10) and four of its N-alkyl derivatives, were orally administered separately to two human volunteers. Total urine was collected for approximately 2 weeks following each dose, and the drugs and their metabolites were assayed by g.l.c.-mass spectrometry. 2. Recoveries in the phenobarbitone series increased from approximately 40% to approximately 50% as alkylation of (1) increased. There was a linear relationship between the extent of p-hydroxylation and the lipophilicity (log P) of the substrates. The increased total recovery was largely attributable to increased p-hydroxylation. 3. Urinary recoveries in the primidone series decreased from approximately 80% for (10) to approximately 30% for its diakyl derivatives, despite a slight increase in p-hydroxylation with increasing alkylation (and increasing lipophilicity). The decreased recovery was mainly the result of decreased urinary excretion of the drug.

Adult↗
PubMedDate not supplied

Carbamazepine replacement of phenytoin, phenobarbital and primidone in a rehabilitation setting: effects on seizure control.

Most patients who receive anticonvulsants after traumatic brain injury are treated with the sedative anticonvulsants phenytoin and/or phenobarbital, or perhaps primidone. However, there is considerable evidence demonstrating that these medications have a deleterious effect on cognitive function. Thus, in a rehabilitation setting, alternatives should be sought. Carbamazepine has been found to be relatively free of such effects, and would be an optimum alternative if seizure control were comparable. We have studied the effects of withdrawing phenytoin, phenobarbital and primidone, and using carbamazepine as the primary anticonvulsant in 27 patients at the Greenery Rehabilitation and Skilled Nursing Center for whom ongoing anticonvulsant treatment was considered to be necessary due to previous seizures or a high risk of the occurrence of seizure. We compared a 3 month baseline period (just prior to carbamazepine introduction or sedative anticonvulsant tapering), to a 3 month post-withdrawal period immediately following sedative anticonvulsant withdrawal, when carbamazepine was the sole anticonvulsant. In 20 out of 21 patients in whom carbamazepine replaced sedative anticonvulsants seizure control was essentially similar or somewhat improved. In only one patient did the substitution with carbamazepine result in a loss of seizure control. Six patients were initially receiving carbamazepine in combination with phenytoin and/or phenobarbital. The removal of phenytoin and phenobarbital, leaving carbamazepine as sole therapy, resulted in improved seizure control in three patients and no change in the other three. In the light of carbamazepine's reportedly less detrimental effects on cognitive function and behaviour in other patient populations, it should perhaps be considered as a first line anticonvulsant, especially for patients in rehabilitation settings.

Adult↗