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PubMedDate not supplied

Efficacy of primidone for seizure control in neonates and young infants.

Primidone can be used for seizures refractory to standard antiepileptic drugs. We administered primidone, 25 mg/kg/day in 3 divided doses, to 10 patients and obtained serum levels of primidone, phenobarbital, and phenylethylmalonic acid at 1, 2, 4, 6, and 8 hours on day 1, alternate days until discharge, and after 6 weeks. Other antiepileptic drugs were discontinued in 8 of 10 patients with refractory seizures. Mean primidone levels were 10.6 +/- 4.4 micrograms/ml by day 3 and remained stable until discharge. Phenylethylmalonic acid was detected by 6 hours and increased to 11.1 +/- 4.0 micrograms/ml by day 7. Phenobarbital levels in 3 of 10 patients not previously treated with phenobarbital ranged from 0.6-3.4 micrograms/ml by day 5. The mean initial phenobarbital level was 30.1 +/- 10.5 micrograms/ml and had decreased to less than 15 micrograms/ml by day 7. Seizure control occurred within 5 days in 8 of 10 patients and was achieved by day 3 in 6 of 8 patients, coinciding with primidone levels greater than 10 micrograms/ml. No toxic effects of primidone were observed. All levels decreased during subsequent examinations suggesting auto-induction of metabolic systems. Our data indicate that seizure control is best correlated with primidone and phenylethylmalonic acid levels and unrelated to phenobarbital levels in this age group.

Dose-Response Relationship, Drug↗
PubMed1976

A comparison of the effectiveness of primidone versus carbamazepine in epileptic outpatients.

Prior to the release of carbamazepine for the treatment of patients with psychomotor and grand mal seizures, primidone was regarded as the drug of choice for these disorders, especially when combined with diphenylhydantoin (DPH). It was, therefore, of interest to compare the effectiveness of carbamazepine against primidone when added to a therapeutic dose of DPH. Forty-five patients completed a 6-month study with each patient serving as his own control. The patients were initially stabilized on therapeutic doses of DPH and one of the test compounds, while all other medications were withdrawn. After 3 months of treatment, they were transferred onto the other drug for a second 3-month period. Extensive laboratory testing, including anticonvulsant levels, electroencephalograms, and neuropsychological evaluations, was performed. For the most part, the patients remained on outpatient status, returning for reports of seizure frequency, side effects, and laboratory studies every 14 days. The study was conducted in a single blind fashion by the treating neurologists; double blind by the electroencephalographer and psychologists. The results indicated that the two drugs did not differ in their effectiveness on seizure control. There were somewhat more side effects--none serious--with carbamazepine than with primidone. The EEG showed increased fast activity with primidone and increased theta activity with carbamazepine. There was no difference in regard to decrease of electroencephalographic seizure discharges. The patients showed more impairment on a repeatable neuropsychological test battery with primidone than with carbamazepine, and they also showed an increase on the psychopathic deviate scale of the Minnesota Multiphasic Inventory. Depressive feelings, when present, lessened while under treatment with carbamazepine. The results suggest that patients with the seizure types under consideration and who do not respond to DPH alone or to a DPH-phenobarbital combination can be placed on either carbamazepine or primidone while phenobarbital is discontinued. A patient who is intellectually and emotionally intact with no past history of behavioral disturbances may do better on primidone than carbamazepine, because this drug gives fewer side effects. On the other hand, those patients who have a past history of emotional and/or intellectual disturbances may profit more from carbamazepine.

Adolescent↗
PubMed1979

Flow-dependent salivary primidone levels in epileptic children.

In 36 epileptic children treated with primidone alone or in combination with additional anticonvulsants, salivary drug levels were compared in resting (I) and in flow-stimulated (II) saliva and were related to the corresponding serum levels. Primidone levels in saliva I and saliva II were highly correlated (r = 0.97) but were significantly (p less than 0.001) lower in saliva II; the mean difference was -38%. Serum primidone levels were highly correlated to salivary primidone levels both in saliva I (r = 0.92) and in salvia II (r = 0.91). A significant negative correlation could be established between the salivary flow rate and the saliva/serum ratio of primidone, especially in saliva I (r = 0.61; p less than 0.001). The mean saliva I/serum ratio was 1.115, reflecting drug accumulation in resting saliva. The reason primidone accumulates remains unclear. When salivary flow was stimulated, the mean saliva/serum ratio decreased to 0.7, indicating the development of a drug concentration slope from blood to saliva. This is explained by the limited permeation of the drug through cellular membranes due to its rather low lipid solubility. From the data it can be concluded that saliva is suitable for monitoring primidone levels provided the conditions of sample collection are standardized.

Anticonvulsants↗
PubMed1982

Primidone but not phenylethylmalonamide, a major metabolite, increases nerve-evoked transmitter release at the frog neuromuscular junction.

The fundamental responses of primidone and phenylethylmalonamide (PEMA), a major metabolite, were investigated electrophysiologically at the frog (Rana pipiens) neuromuscular junction. Concentrations of 0.2 to 1.,0 mM of each drug were used. Primidone significantly increased nerve-evoked transmitter release in a dose-dependent manner up to 186% of control at 1.0 mM concentration, whereas PEMA had no significant effect. In a separate set of experiments in which the sciatic nerve was not stimulated, primidone significantly increased transmitter release in high external K+ (7.5 mM) (no Mg++), but had no significant effect in normal K+ (2.5 mM (no Mg++). The effect of primidone in high K+ diminished in the presence of Mg++ or of decreased Ca++; PEMA also increased the frequency of MEPPs in high K+, but this effect was not sustained and diminished slowly to control values over a period of 50 min. In addition to its predominant presynaptic action, primidone also decreased MEPP amplitude to 79% of control compatible with the relatively small postjunctional depressant action, whereas PEMA had no effect. Propylene glycol, the solvent used for primidone, did not alter the effects of the drug. In conclusion, primidone but not PEMA has a predominant presynaptic action resulting in a dose-dependent increase in nerve-stimulated transmitter release and EPP amplitude.

Animals↗
PubMed1993

The use of primidone in neonates with theophylline-resistant apnea.

OBJECTIVE: To determine whether primidone reduced the occurrence of apnea of prematurity in neonates with apnea resistant to theophylline. DESIGN: Retrospective review. SETTING: Neonatal intensive care unit. PARTICIPANTS: Sixteen premature infants (mean age, 27.8 weeks) in whom apnea and bradycardia recurred despite therapeutic levels of theophylline. Six of the patients were receiving assisted ventilation. INTERVENTION: Administration of primidone (10 to 15 mg/kg per day) orally or by nasogastric tube at a mean age of 35 days. RESULTS: Apnea and bradycardia decreased significantly 24 to 72 hours after initiation of primidone treatment (by 68% and 69%, respectively) compared with pretreatment events. We obtained similar results after a separate analysis of the 10 patients who had been weaned from assisted ventilation before treatment with primidone. No toxic reactions were observed. CONCLUSIONS: Primidone represents a possible adjuvant therapy in theophylline-resistant apnea of prematurity. Caution is advised, because of primidone's complex pharmacologic characteristics, until there are further controlled prospective studies.

Apnea↗
PubMedDate not supplied

An interpretation of 14C-urea and 14C-primidone extraction in isolated rabbit lungs.

We measured the venous concentration versus time curves of 14C-urea and 14C-primidone after rapid bolus injections of a vascular reference indicator, fluorescein isothiocyanate dextran, and one of the two 14C-labeled indicators in isolated rabbit lungs perfused with Krebs-Ringer bicarbonate solution containing 4.5% bovine serum albumin at flow rates (F) of 6.67, 3.33, 1.67, and 0.83 ml/sec and with nearly constant microvascular pressure and total lung vascular volume. When we calculated the permeability-surface area product, PS, from the 14C-urea and 14C-primidone outflow curves using the Crone model, the estimates of the PS product were directly proportional to F. However, the fractional change in the PS with flow was different for the two indicators. We also estimated the PS from the same 14C-urea and 14C-primidone data using an alternative model that includes perfusion heterogeneity, estimated in a previous study, and flow-limited and barrier-limited extravascular volumes accessible to both urea and primidone. This model was able to fit the outflow curves of either 14C-urea or 14C-primidone at all four flows studied with one flow-independent PS for each indicator. The ability of the new model to explain the 14C-urea and 14C-primidone data with no flow-dependent change in PS suggests that a change in PS with F estimated using other models such as the Crone model is not sufficient for capillary surface area recruitment.

Animals↗
PubMedDate not supplied

Blood and cerebrospinal fluid pharmacokinetics of primidone and its primary pharmacologically active metabolites, phenobarbital and phenylethylmalonamide in the rat.

Primidone is a clinically useful antiepileptic drug that is metabolised to two pharmacologically active metabolites phenobarbital and phenylethylmalonamide. As data on the inter-relationship between the systemic and central nervous system pharmacokinetics of primidone and its metabolites are sparse, we have investigated their temporal inter-relationship using a freely behaving rat model which allows repeated sampling of blood (100 microl) and cerebrospinal fluid (CSF; 20 microl). After administration, by intraperitoneal injection (50, 100 or 200 mg/kg), primidone rapidly appeared in both serum (Tmax mean range 1.5-2.5 h) and CSF (Tmax mean range 2.0-3.5 h), suggesting ready penetration of the blood-brain-barrier. This was also the case for phenylethylmalonamide and phenobarbital but peak concentration occurred later. Primidone, phenylethylmalonamide and phenobarbital concentrations rose linearly and dose-dependently in both serum and CSF. The mean free fraction (free/total concentration ratio) for primidone, phenylethylmalonamide and phenobarbital was 0.86, 0.97 and 0.88, respectively, and, as their respective mean CSF/serum ratio values were 0.73, 1.06 and 0.65, it would suggest that equilibration between the blood and CSF compartments is rapid. CSF mean t(1/2) values for primidone, phenylethylmalonamide and phenobarbital were similar to those of sera and essentially paralleled the pattern seen in sera.

Animals↗
PubMed1978

Epileptiform seizures in domestic fowl. VIII. Anticonvulsant activity of primidone and its metabolites, phenobarbital and phenylethylmalonamide.

Primidone is an effective anticonvulsant against seizures induced in epileptic fowl by exposure to intermittent photic stimulation. Epileptic fowl metabolize primidone to phenobarbital. Pretreatment of epileptic fowl with SKF 525A to prevent the metabolism of primidone to phenobarbital indicated that primidone itself had anticonvulsant activity. Phenylethylmalonamide, a second metabolite of primidone, did not have anticonvulsant activity when administered at the same dose as primidone.

Animals↗
PubMed1982

Interactions between primidone, carbamazepine, and nicotinamide.

The effect of nicotinamide on the conversion of primidone to phenobarbital was studied in mice and in three epileptic patients. In mice, 200 mg per kilogram of nicotinamide increased the half-life of primidone by 47.6%, and the conversion to phenobarbital and phenylethylmalonamide was decreased by 32.4% and 14.5%, respectively. Nicotinamide also decreased the conversion of primidone to phenobarbital in patients. The dose of nicotinamide correlated directly with the primidone-phenobarbital ratio (r = 0.861, p less than 0.01). Nicotinamide also increased carbamazepine levels in two patients treated with this drug. The data demonstrate that nicotinamide inhibits metabolism of primidone in mice and metabolism of primidone and carbamazepine in humans. This probably occurs by inhibition of cytochrome P-450 by nicotinamide.

Animals↗
PubMed2001

Effects of encapsulation of primidone on its oxidative metabolism in rats.

The aim of this study was to evaluate the influence of primidone (PRM) nanoencapsulation on its metabolism. Suspensions of PRM powder and PRM-loaded poly-epsilon-caprolactone nanocapsules were administered orally in the same way to rats. Primidone-loaded poly-epsilon-caprolactone nanocapsules were prepared according to the interfacial deposition technique. Free PRM suspensions were obtained by addition of PRM powder to a suspension of 0.212% carboxymethylcellulose CMC 12H in water. The dose was 20 mg/kg, n = 6, for each experiment. Urinary and faecal levels of PRM and of its three major metabolites, phenylethylmalonamide (PEMA), phenobarbital (PB), and p-hydroxyphenobarbital (p-HO-PB), were determined. Concentrations were evaluated by high-performance liquid chromatography (HPLC) according to a validated analytical method. After PRM nanocapsule administration, non-metabolised PRM urinary levels were increased compared to those observed after administration of a suspension of primidone powder (43.7+/-8.8% after PRM-loaded nanocapsule and 37.7+/-8.1% after free PRM administration). For phenylethylmalonamide, no difference was observed in urinary excretion in the two cases. For two of the oxidised metabolites, PB and p-HO-PB, excretion was delayed and shortened. The amount of these oxidised metabolites was lowered from 0.95% after free PRM administration to 0.25% after PRM-loaded nanocapsule administration. No difference was noted in non-metabolised primidone excretion in faeces. These results suggest that primidone-loaded nanocapsules could be used as a vehicle for oral primidone administration in order to minimise the phenobarbital metabolic pathway.

Animals↗
PubMed1985

Effects of long-term primidone and phenytoin administration on canine hepatic function and morphology.

Primidone, phenytoin, or phenytoin and primidone in combination were given to healthy Beagle dogs for 6 months. Serum biochemical changes in dogs given primidone alone or phenytoin and primidone in combination for the entire 6-month test period included increased activities of alanine aminotransferase, alkaline phosphatase (AP), and gamma-glutamyltransferase, and decreased concentrations of albumin and cholesterol. Changes in dogs given phenytoin alone were limited to increased AP activity and decreased albumin concentration. Sulfobromophthalein excretion and conjugated bile acid concentration were within normal limits. All dogs given primidone alone or phenytoin alone remained clinically healthy throughout the treatment period. Three of 8 dogs given both drugs in combination became clinically ill after 9, 14, and 15 weeks of treatment, and were euthanatized. Two of the dogs developed clinical jaundice. In addition to the serum biochemical abnormalities observed in clinically healthy dogs, these dogs developed hyperbilirubinemia, delayed sulfobromophthalein excretion, and increased conjugated bile acid concentrations. Histologic examination of the liver showed intracanalicular casts of bile pigment typical of intrahepatic cholestasis in all 3 dogs. Histologic findings characteristic of treated dogs included hepatocellular hypertrophy attributable to hyperplasia of the smooth endoplasmic reticulum. Single-cell necrosis and multifocal lipidosis were observed in individuals of all treatment groups. Electron microscopy of the liver showed dilated bile canaliculi and damaged sinusoidal epithelium in dogs given both drugs. The elevated serum AP activity, associated with anticonvulsant drug therapy, was found to be exclusively the liver isoenzyme by cellulose acetate electrophoresis. The hepatic AP was localized to primarily the canalicular membranes by enzyme histochemistry. There was a statistically significant positive correlation between the AP activities of liver and serum. The results of this study indicate that long-term administration of anticonvulsant drugs to dogs is associated with clinical, serum biochemical, and histologic evidence of hepatic dysfunction. High drug dosage contributed most to abnormal serum biochemical test results, and combining phenytoin with primidone was responsible for more severe electron microscopic lesions of the liver of surviving dogs and for the death of 3 dogs.

Alanine Transaminase↗
PubMed1980

Serum concentrations of primidone and its metabolites, phenylethylmalonamide and phenobarbital, in the dog.

The elimination of primidone, phenylethylmalonamide, and phenobarbital (administered IV) was studied in dogs. The elimination half-lives were primidone, 1.85 +/- 0.3 (SEM) hours; phenylethylmalonamide, 7.1 +/- 1.45 hours; and phenobarbital, 40.9 +/- 4.96 hours. Dogs given repeated oral doses of primidone for 14 or 21 days had smaller primidone serum concentrations after each dosing. Dogs given 1.0 g of primidone orally (59.2 decreasing to 50.5 mg/kg of body weight) for 21 days accumulated the phenobarbital metabolite with apparent steady-state concentrations of 10 to 20 micrograms/ml and phenylethylmalonamide in concentrations of 2 to 5 micrograms/ml. Serum primidone concentrations decreased after repeated dosing and were measurable in only 1 dog 24 hours after the 21st dose and peak concentrations of 4 to 7 micrograms/ml were measured at 4 hours after the 22nd dose.

Animals↗
PubMed1998

Physiologically based pharmacokinetics model of primidone and its metabolites phenobarbital and phenylethylmalonamide in humans, rats, and mice.

Physiologically based pharmacokinetic modeling of the parent chemical primidone and its two metabolites phenobarbital and phenylethylmalonamide (PEMA) was applied to investigate the differences of primidone metabolism among humans, rats, and mice. The model simulated previously published pharmacokinetic data of the parent chemical and its metabolites in plasma and brain tissues from separate studies of the three species. Metabolism of primidone and its metabolites varied widely among a sample of three human subjects from two separate studies. Estimated primidone metabolism, as expressed by the maximal velocity Vmax, ranged from 0 to 0.24 mg. min-1.kg-1 for the production of phenobarbital and from 0.003 to 0. 02 mg.min-1.kg-1 for the production of PEMA among three human subjects. Further model simulations indicated that rats were more efficient at producing and clearing phenobarbital and PEMA than mice. However, the overall metabolism profile of primidone and its metabolites in mice indicated that mice were at higher risk of toxicity owing to higher residence of phenobarbital in their tissues and owing to the carcinogenic potential of phenobarbital as illustrated in long-term bioassays. This result was in agreement with a recently finished National Toxicology Program (NTP) carcinogenicity study of primidone in rats and mice.

Animals↗
PubMedDate not supplied

Acute phenytoin and primidone intoxication: a pharmacokinetic analysis.

Serial plasma levels of phenytoin, primidone, and phenobarbital were determined in a patient following massive overdose of phenytoin and primidone. The patient's neurologic status improved slowly over a period of 10 days and correlated best with the rise and fall of phenytoin plasma concentrations. The pharmacokinetics of all three agents were characterized by nonlinear regression analysis of their respective plasma concentration-time profiles during the elimination phase, followed by analog computer simulations of their entire plasma concentration-time profile closely resembled the observed values. Average values of Km and Vmax obtained from patients undergoing chronic therapy were used in the simulation and appear to adequately describe phenytoin elimination in this overdose situation. The elimination half-lives of primidone and phenobarbital of 6.2 and 83.5 hours, respectively, were within the "normal range" for patients on chronic therapy. Two distinct absorption phases for primidone and three for phenytoin were noted. The marked decrease in the estimated absorption rate constant between phases 1 and 2 for each drug may have been due to slow dissolution of a large congealed mass of phenytoin and primidone in the gut. The analysis of serial plasma samples following a massive overdose is recommended to provide a reliable data base for therapeutic decisions.

Adult↗
PubMed1982

Pharmacokinetics of primidone elimination by uremic patients.

The hemodialyzability of primidone was investigated in four patients on long-term hemodialysis. Primidone, 500 or 250 mg, was given orally 2 hours before hemodialysis. Blood and dialyzate samples were collected periodically during the 4-hour dialysis and measured by gas-liquid chromatography and high-performance liquid chromatography for primidone. Dialysis clearance calculated by the instantaneous dialyzate method averaged 97.7 ml/min, which is considerably greater than the metabolic clearance of 30 ml/min for the drug. The extraction efficiency of the hollow-fiber dialyzers averaged 40.2 pr cent for plasma samples. A mean of 31.7 per cent of the administered dose of primidone was removed during hemodialysis. The half-life was 5.1 hours in our patients during hemodialysis, a nearly two-thirds reduction of the 13.9-hour half-life calculated in uremic patients. Because of the reduction in elimination half-life, greater dialysis clearance than metabolic clearance, high extraction efficiency, and significant drug removal during dialysis, we conclude that primidone is dialyzable.

Adult↗
PubMed1985

Effect of nonionic surfactants on aqueous primidone suspensions.

The following interactions between the soluble surfactant, octoxynol 9, and the very slightly soluble, finely powdered drug, primidone, in aqueous suspension were investigated: adsorption/desorption of the surfactant, micellar solubilization of the drug, and deflocculation of its particles. The last effect, measured by the sedimentation volume of the suspensions, was also investigated for other octoxynols. The adsorption of octoxynol 9 on solid primidone was proportional to the equilibrium surfactant concentration up to the critical micelle concentration. It leveled off at higher concentrations, reaching saturation at completion of a close-packed surfactant monolayer. The adsorption was essentially completely reversible. The solubility of primidone in water was very slight; its micellar solubilization was even less extensive. The sedimentation volume of primidone suspensions decreased with increasing equilibrium concentration of octoxynol 9 and began to level off at the critical micelle concentration of 0.018%. At about twice that concentration, the sedimentation volume became almost constant, but reached its lowest value only at less than or equal to 0.5%. Slow rotation of suspensions prior to sedimentation promoted flocculation and higher sedimentation volumes between 0.01 and 0.03% octoxynol 9. Octoxynols with higher hydrophilic-lipophilic balance than octoxynol 9 produced considerably larger sedimentation volumes at comparable concentrations, due to a lower surface activity and a lesser tendency to adsorb on primidone.

Micelles↗
PubMed1984

Studies on the intracerebral metabolism of anticonvulsant drugs--I. Perfusion of primidone through the isolated brain of the rat.

Primidone and phenobarbital (each 85 nmoles/ml were separately perfused through the isolated brain of the rat. After 5 min of perfusion similar amounts of primidone and phenobarbital were taken up into the brain; for both drugs the concentration ratio between brain and perfusion medium was about 0.2. However, after 2 hr of perfusion the mean concentration ratio for primidone was about 0.55; for phenobarbital it was about 0.9 thus indicating a better uptake of phenobarbital. In two regions (hypophysis, mesencephalon) the concentration of phenobarbital was significantly higher than in perfusion medium. During 2 hr of perfusion of primidone, substantial quantities of phenobarbital and PEMA were formed amounting to 1400 pmoles for each metabolite. The highest concentration of the metabolites was found in septum, hypothalamus, hypophysis and mesencephalon. The in situ metabolism of primidone in the intact brain was demonstrated for the first time.

Animals↗
PubMed1980

Microassay for primidone and its metabolites phenylethylmalondiamide, phenobarbital and p-hydroxyphenobarbital in human serum, saliva, breast milk and tissues by gas chromatography--mass spectrometry using selected ion monitoring.

A method for the quantitative determination of primidone and its metabolites phenobarbital, phenylethylmalondiamide (PEMA) and hydroxyphenobarbital (free and conjugated) in serum, urine, saliva, breast milk and tissue has been developed. Following the addition of the methyl analogues of primidone, phenobarbital and PEMA as internal standards and of saturated ammonium sulphate, the samples (5--100 microliter) were extracted twice with ethyl acetate--benzene (20:80). The extracts were divided into two equal portions; one portion was ethylated by Greeley's method for the analysis of primidone, phenobarbital and hydroxy-phenobarbital, while the other was trimethylsilylated for the analysis of primidone and PEMA. A gas chromatographic--mass spectrometric system was used for the analysis of the derivatized extracts. Linear calibration curves were obtained in the concentration range studied (between 100 ng/ml and 30 microgram/ml). The recoveries of the drugs were between 80 and 93%. The relative standard deviations were between 3.2 and 5.9% (100-microliter serum samples containing 1 microgram/ml of the drugs). The lower detection limits were found to be between 1.4 and 3.7 ng/ml using serum samples of 100 microliter. These methods have been applied to the study of the placental transfer and neonatal disposition of primidone and its metabolites in the human.

Female↗