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PubMedDate not supplied

Anticonvulsant effects of phenobarbital and primidone during ontogenesis in rats.

The influence of phenobarbital (PHB, 10, 20, 40 or 80 mg/kg i.p.) and primidone (PRI, 40 or 80 mg/kg i.p.) on metrazol-induced motor seizures was studied in rats 7, 12, 15, 18, 25 and 90 days old. PHB blocked both types of seizures induced by metrazol-minimal (mMS) as well as generalized tonic-clonic (MMS)--in all age groups where they appeared under control conditions. The effect against major seizures was always better expressed than against mMS. Pretreatment with PHB led to the appearance of mMS in 7- and 12-day-old rat pups, where control animals did not exhibit this type of seizure. Combined administration of the 2 high doses of PHB and metrazol resulted in the appearance of behavioral automatisms in young rats. PRI abolished MMS in adult rats only, no changes were seen in 25-day-old animals and specific suppression of the tonic phase of MMS was observed in younger rats. mMS were influenced only in 7- and 12-day-old rats, where an increase in their incidence was recorded. Pretreatment with PRI never induced automatisms. The different actions of PHB and PRI speak in favor of an anticonvulsant action of PRI itself.

Animals↗
PubMed2005

Is primidone the drug of choice for epileptic patients with QT-prolongation? A comprehensive analysis of literature.

Sudden unexplained/unexpected death (SUDEP) in epilepsy is a major cause of death accounting for 7-17% of the mortality among epileptic patients. Prolongation of QT-interval has been issued as a major mechanism in SUDEP since it is associated with fatal cardiac arrhythmias. This condition may be further precipitated by anti-epileptic treatment. Despite thorough literature research, we did not find any reports suggesting that primidone is responsible for QT-prolongation. On the contrary, all the retrieved reports addressed that the drug shortened QT-interval and corrected signs and symptoms of the underlying disease.

Anticonvulsants↗
PubMed1975

Improved method for the simultaneous determination of phenobarbital, primidone and diphenylhydantoin in patient's serum by gas-liquid chromatography.

A quantitative gas-liquid chromatographic method for the simultaneous determination of phenobarbital, primidone and diphenylhydantoin in human serum is described. A double extraction is employed to improve the removal of interfering substances. The N,N-dimethyl derivatives of the compounds are prepared by "oncolumn" methylation with 50% Methelute. Decomposition of phenobarbital to N-methyl-a-phenylbutyramide was negligible if the contact time with Methelute was less than 10 min. The drugs were stable in serum for at least two weeks. This procedure provides a rapid, sensitive, selective and accurate method for the routine determination of serum concentrations of three of the most commonly prescribed anticonvulsant drugs.

Anticonvulsants↗
PubMed1978

Rapid micro-method for the measurement of phenobarbitone, primidone and phenytoin in blood plasma or serum by gas-liquid chromatography.

A rapid gas-liquid chromatographic method has been developed for the analysis of phenobarbitone, primidone and phenytoin in small (50 microliter) volumes of either blood plasma or serum. Neither solvent transfer nor evaporation are required in the extraction, which takes less than 3 min to complete, and a quantitative analysis may be performed, in duplicate, within 20 min. Sources of interference in the assay are minimal, and prior treatment of the column with gamma-glycidoxypropyltrimethoxysilane facilitates the measurement of as little as 10 ng of underivatized drug "on-column" using a flame-ionisation detector. The method has proved valuable when used for detection and measurement of these three compounds at concentrations of 2 mg/1 or greater.

Animals↗
PubMed1996

Developmental and behavioral effects of prenatal primidone exposure in the rat.

Pregnant Sprague-Dawley rats were administered primidone (PRM) by oral gavage on gestation days 8-17 in doses of 0.40, and 80 mg/kg. Although these doses of PRM did not produce significant differences in litter size, birth weight, mortality, date of attainment of developmental landmarks or measures of preweaning reflex and motor development, there were a number of significant differences that developed as the animals approached and entered adulthood. When tested as adults, the 80 mg/kg male rats showed a deficit in the performance of an eight-arm radial maze task. These same animals showed a significant reduction in open field activity when tested as adults. In addition, both male and female PRM-treated animals showed reduced body weights at different periods corresponding to onset of sexual maturation during development. These findings are consistent with the larger body of literature reporting on the neurobehavioral teratology of phenobarbital, including its ability to produce lesions in the hippocampus and endocrine dysfunction resulting in reproductive deficits. These results suggest that PRM produces its adverse effects as a result of its metabolism to phenobarbital, which in turn affects the limbic system.

Animals↗
PubMed1990

Metabolic studies with phenobarbitone, primidone and their N-alkyl derivatives: quantification of substrates and metabolites using chemical ionization gas chromatography-mass spectrometry.

Metabolic studies with phenobarbitone, primidone and some of their N-alkyl derivatives required the concurrent assay of any mixture of these substrates (twelve compounds) and their major metabolites (an additional twenty-two compounds) in urine. The method described in the present report met this requirement by incorporating two complementary derivatization techniques into a gas chromatographic-mass spectrometric (GC-MS) assay procedure. Following hydrolysis of conjugates with beta-glucuronidase, urine samples were extracted with ethyl acetate (3 X 5 ml). The combined extracts were dried over sodium sulphate, divided into two equal portions, and the solvent was removed. One residue was derivatized by propylation using 1-iodopropane with base catalysis. The other residue was silylated using methyl-N-(tert.-butyldimethylsilyl)trifluoroacetamide. The derivatives in each case were analysed by GC-MS, using temperature-programmed packed-column GC and chemical ionization MS. Mass spectra were acquired over an appropriate mass range, and peak areas for the compounds of interest were determined from specific mass chromatograms. Satisfactory precision, accuracy, specificity and sensitivity were obtained for all analytes. All compounds produced satisfactory derivatives by at least one procedure; twelve compounds could be analysed by both techniques. The method illustrates the utility of chemical ionization GC-MS for the simultaneous quantitative analysis of multiple related analytes in complex biological samples.

Administration, Oral↗
PubMed1999

Examples of successful crystal structure prediction: polymorphs of primidone and progesterone.

The field of crystal structure prediction and its potential value to the pharmaceutical industry is described. The process of structure prediction employed here is summarized and the results of its application to primidone and progesterone are reported. It is shown that the process successfully generates the known polymorphs of these molecules, starting from the molecular structure alone. Observations related to the application of the structure prediction process are reported.

Crystallization↗
PubMed1981

Phenobarbital, primidone and sodium valproate in the prophylaxis of febrile convulsions.

Of 196 children with febrile convulsions, 6.9 were placed on phenobarbital, 4-5 mg/kg/day b.i.d., and 32 on primidone, 15-20 mg/kg/day b.i.d. The remaining 95 children were given sodium valproate; the dosage was 20-25 mg/kg/day b.i.d. in 38 of them, 20-25 mg/kg/day t.i.d. in 24 of them, and 30 mg/kg/day b.i.d. in 33 patients. Recurrence rate of febrile convulsions during one year were not statistically different among these five groups. However, the dosage regimen of valproate of 20-25 mg/kg/day b.i.d. was relatively inferior to the other regimens of valproate in the prophylactic effect. This may be explained by the facts that when the same daily dosage of sodium valproate was given, the daily fluctuation of plasma levels was greater with the b.i.d.-regimen than with the t.i.d.-regimen, and that when the dosage interval was the same, the minimum plasma level of the day was lower with the smaller daily dosage regimen than with the larger one.

Child, Preschool↗
PubMedDate not supplied

Primidone-induced embryolethality and DRL deficits in surviving offspring.

Pregnant Sprague-Dawley rats were administered primidone (PRM) by oral gavage on gestation days 8-20 in doses of 0 or 120 mg/kg. This dose did not produce body weight differences in the dams during the dosing period nor were there differences in the birth weights of the offspring. PRM was embryolethal with only 43% of drug-treated dams maintaining their pregnancies, whereas 100% of the pregnant controls produced offspring. An analysis of resorption sites in PRM-treated dams that did not deliver showed a nearly identical number of implantation sites (12.6) compared to the litter size of controls (12.8) that delivered pups. There were no overall differences in exploratory activity levels between PRM-treated and control animals. However, in the PRM-treated females there was an absence of the sexually dimorphic increase in activity seen in control females when compared to control males. The PRM-treated males showed an impairment in the acquisition of a DRL-20 (differential reinforcement of low rates) operant schedule over a 9-week acquisition period. There were no differences in the total response rates between the groups, suggesting that this is a specific learning deficit and not a performance deficit. The results of these experiments provide evidence that prenatal PRM exposure can be embryolethal and also impair behavior in the surviving rat offspring.

Animals↗
PubMed1981

Primidone kinetics: effects of concurrent drugs and duration of therapy.

Primidone (PRM) kinetics was examined in two groups of adult seizure patients: (1) 10 newly diagnosed in whom only PRM was used, the monotherapy (MT) group, and (2) nine in whom PRM was added to other antiepileptics, the combination therapy (CT) group. Time-concentration data were obtained after an initial dose of 250 mg and during subsequent steady-state periods. PRM elimination was slower (p less than 0.05) after the initial dose in MT patients (half-life (t 1/2) = 15.2 hr, apparent clearance = 35 ml/hr/kg) than in CT patients (t 1/2 = 8.3 hr, clearance = 51 ml/hr/kg). PRM metabolites, phenobarbital and phenylethylmalonamide, appeared much earlier in CT patients. Continued PRM exposure in MT patients was accompanied by an increase in apparent clearance in three of seven patients, but no change in four of seven. In four CT patients in whom other antiepileptics were withdrawn there was a decrease in apparent clearance (61.4 to 29.9 ml/hr/kg) no rates in the range of MT patients. PRM kinetics is influenced by concurrent antiepileptic drugs and by duration of PRM therapy.

Adolescent↗
PubMed1980

Rapid centrifugal analyzer enzyme immunoassays for phenytoin, phenobarbital, and primidone.

The adaptation of the homogeneous enzyme immunoassays (EMIT) for phenytoin, phenobarbital, and primidone to a centrifugal analyzer is described. The sample volume required was 10 microliter, and the assay had the capacity to analyze sera from 28 patients within 180 sec. The assay temperature was 30 C, and absorbance was monitored at 340 nm. Coefficients of variation for within-day precision ranged from 2.1% to 3.7%, and analytic recovery was quantitative. The centrifugal analyzer EMIT assay results correlated well with those obtained using high-pressure liquid and gas-liquid chromatographic technics. A logit-log transformation of the absorbance rate versus concentration data was obtained using a modified Gauss-Newtonian nonlinear least-squares fit analysis. Severe hemolysis and lipemia caused interference.

Computers↗
PubMed1998

Accelerated recovery and disposition from rocuronium in an end-stage renal failure patient on chronic anticonvulsant therapy with sodium valproate and primidone.

An end-stage renal failure patient, receiving chronic treatment with the anticonvulsants, sodium valproate and primidone, showed accelerated recovery with enhanced elimination (T1/2(z) = 52 min) and clearance (Cl = 14.4 ml min-1 kg-1) of rocuronium. The pharmacokinetic and pharmacodynamic effects of rocuronium in this patient are compared with those published for healthy and renal failure patients. Increased hepatic binding of rocuronium rather than metabolism is suggested as the possible cause of this effect.

Adult↗
PubMed2002

Determination of lamotrigine simultaneously with carbamazepine, carbamazepine epoxide, phenytoin, phenobarbital, and primidone in human plasma by SPME-GC-TSD.

A simple and rapid analytical method is presented for the determination of lamotrigine simultaneously with primidone, carbamazepine, carbamazepine epoxide, phenobarbital, and phenytoin in human plasma using solid-phase microextraction (SPME) and gas chromatography with thermionic specific detection. The best conditions for the SPME procedure is established as following: direct extraction on a 65-microm Carbowax-divinylbenzene fiber; 1.0 mL of a sample plasma matrix modified with 15% NaCl and 3 mL of a potassium phosphate buffer (pH 7.0); extraction temperature at 30 degrees C; and stirring at a rate of 2500 rpm for 15 min. The method shows good linearity between 0.05 and 40.0 microg/mL with regression coefficients ranging between 0.9965 and 0.9995 and a coefficient of variation of the points of the calibration curve lower than 10%. The lowest limit of quantitation for the plasma-investigated drugs varies from 0.05 to 0.20 microg/mL, according to the drug. The proposed method is sensitive enough to work into subtherapeutic and therapeutic concentrations, being that it is applied in pharmacokinetic studies and patient routine therapeutic drug monitoring.

Anticonvulsants↗
PubMedDate not supplied

Simultaneous plasma lamotrigine analysis with carbamazepine, carbamazepine 10,11 epoxide, primidone, phenytoin, phenobarbital, and PEMA by micellar electrokinetic capillary chromatography (MECC).

The determination of lamotrigine (LTG) simultaneously with carbamazepine (CBZ), carbamazepine 10,11 epoxide (CBZ-E), primidone (PRM), phenytoin (PHT), phenobarbital (PB), and 2-phenyl-2-ethyl-malonamide (PEMA) in human plasma was developed using micellar electrokinetic capillary chromatography (MECC) with a diode-array detector. The reproducibility of both separation and quantitation with MECC analysis were appropriate for the intra- and interassay coefficients. The evaluated drugs concentration intervals of LTG, 0.5-10.0 micro g/mL; CBZ, 1.0-16.0 micro g/mL; PEMA, 1.0-20.0 micro g/mL; PB, 1.0-60.0 micro g/mL; PRM, 1.0-20.0 micro g/mL; PHT, 0.7-40.0 micro g/mL; and CBZ-E, 1.0-14.0 micro g/mL were linear with correlation coefficients higher than 0.987 and coefficients of the variation of the points of the calibration curve lower than 10%. The limit of quantitation of the investigated drugs in plasma varied from 0.5 to 1.0 micro g/mL, depending upon the drug. The MECC technique was sensitive enough to work with microsamples into the subtherapeutic, therapeutic, and toxic concentrations, as well as showed to be simple and efficient when applied to monitoring therapeutic drugs in patients treated with a combination of lamotrigine and other antiepileptic drugs such as hepatic enzyme-inducing agents.

Anticonvulsants↗
PubMed1982

Comparison of fluorescent immunoassay and EMIT for assay of serum primidone concentration.

A fluorescent immunoassay procedure (FIA) for the assay of serum of plasma primidone concentrations that was developed by Ames Laboratories is compared to the established enzyme-multiplied immunoassay technique (EMIT) developed by Syva. The FIA compares favorably with the established EMIT system for accuracy, and the FIA is eight times more sensitive but requires a greater turnover time.

Fluorescent Antibody Technique↗
PubMed1983

Plasma levels of primidone and its metabolite phenobarbital: effect of age and associated therapy.

The effects of age and associated therapy on plasma primidone (PRM) and derived phenobarbital (PB) concentrations, and on plasma concentrations-to-PRM dose ratios (L/D ratio) were evaluated retrospectively from 408 consecutive PRM and derived PB determinations in 238 chronically treated epileptic patients (153 children and adolescents between 5 months and 15 years of age and 85 adults between 16 and 55 years of age). The correlation between PRM administered and both plasma PRM and derived PB levels was significant; the correlation between PRM and PB plasma levels was also significant, but the scatter of values for the linear regressions was such that the relationship had no predictive value. Significant differences in mean plasma PRM and PB L/D ratios were found between patients aged 0-3 years, 4-9 years, 10-15 years, and adults (16-55 years), with higher values in the older groups. The PB/PRM concentration ratios were significantly lower in children than in adolescents and adults. Concomitant treatment with carbamazepine affected PRM disposition and led to increased L/D ratios for PB and decreased L/D ratios for PRM, whereas phenytoin increased the L/D ratios for PB without any significant change in the L/D ratios for PRM. The variability in the results indicates the need for routine monitoring of PRM and derived PB plasma levels, particularly in pediatric populations, in order to tailor the dose to each patient.

Adolescent↗
PubMed1984

Development of tolerance to the side effects of primidone.

Side effects and antiepileptic drug levels were measured during initiation of and chronic treatment with primidone (PRM). A significant change in the toxicity/serum level ratio was observed 6 h after the initial PRM dose. The amount of toxicity manifested by patients receiving PRM as their initial antiepileptic drug was not different from that of those patients previously treated with phenytoin (PHT) or carbamazepine (CBZ). These findings indicate rapid development of functional tolerance to side effects of PRM, which is not altered by previous exposure to PHT or CBZ. Phenobarbital pretreatment appears to produce cross-tolerance to the effects of PRM.

Adult↗
PubMed1994

Simultaneous determination of felbamate, primidone, phenobarbital, carbamazepine, two carbamazepine metabolites, phenytoin, and one phenytoin metabolite in human plasma by high-performance liquid chromatography.

An isocratic liquid-chromatographic method employing one extraction step has been developed for the quantitation of five drugs and three metabolites in human plasma. The method uses 0.100-ml aliquots of human plasma and two internal standards. Chromatographic conditions include a 4.6 mm x 150 mm Spherisorb ODS2, 3 microns a high-performance liquid chromatography, (HPLC) column, a phosphate buffer-acetonitrile-methanol (700:160:140) mobile phase, and ultraviolet (UV) absorbance detection at 210 nm. Analytes and linear quantitation ranges (microgram/ml) were felbamate (FBM) 0.391-200; primidone (PRIM), 0.098-100; phenobarbital (PHENO), 0.195-100; carbamazepine (CBZ), 0.195-100; phenytoin (PHT), 0.195-200. For CBZ-transdiol (CBZ-TR) CBZ-epoxide (CBZ-EP), and the PHT metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH), the range was 0.049-25.0 micrograms/ml. Ethosuximide, methsuximide, 2-methyl-2-phenyl-succinimide (methsuximide metabolite), 2-ethyl-2-phenyl malonamide (PRIM metabolite, 5-ethyl-5-(4-hydroxyphenyl)-barbituric acid (PHENO metabolite), and mephenytoin do not interfere with quantitation of the above compounds.

Anticonvulsants↗