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PubMed1984

[Simultaneous determination of 4 anticonvulsant drugs by high pressure liquid chromatography (HPLC)].

We describe a sensitive and precise method for the simultaneous high pressure liquid-chromatography determination of phenobarbital, diphenylhydantoin, primidone, and carbamazepine in serum. The drugs are extracted into chloroform, dried and dissolved in the mobile phase. The drugs are eluted from a reverse-phase column with methanol/water and detected by their absorption at 214 nm. Concentrations are estimated from their peak heights. The results, when compared with those by enzyme-immunoassay, gave correlation coefficients of 0.990 for phenobarbital, 0.993 for diphenylhydantoin, 0.992 for primidone and 0.994 for carbamazepine.

Carbamazepine↗
PubMed1976

Clinical pharmacokinetics of anticonvulsants.

Anticonvulsant therapy was among the first areas to benefit from clinical pharmacokinetic studies. The most important advantage is that the frequent interindividual variation in the plasma level/dose ratio for these drugs can be circumvented by plasma level monitoring. For several anticonvulsants the brain concentration is shown to parallel the plasma concentration. Phenytoin (diphenylhydantoin) is stil the most important anticonvulsant and the one for which kinetics have been thoroughly investigated in man. These investigations have revealed several reasons for the wellknown difficulties in using this drug clinically. The absorption rate and fraction are very much dependent on the pharmaceutical preparation, and changes of brand may alter the plasma level of phenytoin in spite of unaltered dose. The elimination capacity is saturable causing dose dependent kinetics, which again means disproportional changes in plasma level with changes in dose. Great individual variations exist in the rate of metabolism, and several pharmacokinetic drug interactions are known. As an optimum therapeutic plasma concentration range has been established monitoring plasma levels must be strongly advocated. Interpretation of plasma levels in uraemic patients must take into account decreased protein binding of the drug. Carbamazepine is probably as effective as phenytoin. The elimination is a first order process, but the rate of metabolism increases after a few weeks' treatment. An active metabolite (epoxide) may be the cause of some side-effects. Combined treatment with other anticonvulsant drugs decreases the half-life and more frequent dosing may be necessary. An optimum therapeutic concentration range has been suggested and plasma monitoring is advocated, along with that of the active metabolite, the epoxide. Phenobarbitone is still much used but its kinetics have been investigated to a lesser extent. The main problem is the variability in the rate of elimination. In children the half-life of phenobarbitone is only half of that in adults. An optimum therapeutic plasma range has been established and monitoring is recommended. Primidone may have an anticonvulsant activity in itself, but its main metabolite is phenobarbitone. The relatively rapid elimination of primidone is offset by the long half-life of phenobarbitone. An optimum therapeutic range has been suggested, but plasma level monitoring must include determination of phenobarbitone. Ethosuximide. The clinical pharmacokinetics of this important petit mal anticonvulsant is not well known. It has a relatively long half-life (in adults 2 to 3 days; in children shorter). An optimum therapeutic range has been suggested, and routine monitoring of plasma levels may be recommended. Diazepam exerts a repid anticonvulsant activity when the plasma concentration exceeds approximately 500ng/ml after intravenous injection. The kinetic pattern is complex in man. Clonazepam. The clinical pharmacokinetics are still not fully investigated but a therapeutic range has been suggested...

Administration, Oral↗
PubMed2000

Pharmacologic treatment of essential tremor.

Essential tremor (ET) is a common movement disorder that often causes functional disability, potentially leading to physical and emotional difficulties. The paucity of data available regarding the underlying pathophysiologic mechanism of ET hinders the development of innovative approaches to pharmacotherapeutic treatments. Options for drug therapy include the use of primidone, beta-adrenergic blockers, such as propranolol, alcohol, and other drugs, such as benzodiazepines, gabapentin, carbonic anhydrase inhibitors, clozapine, flunarizine, clonidine, and the methylxanthine derivative theophylline. Chemodenervation with botulinum toxin type A may be a therapeutic option for selected patients with ET. Each drug is classified as to the quality of evidence for efficacy and the suggested strength of therapeutic recommendation. In general clinical practice, primidone and propranolol have proven efficacy in ET.

Aged↗
PubMed1975

[Polarographic determination of some phenylsubstituted anticonvulsants].

A method is described to determine the anticonvulsive drugs phenobarbital, phenytoin, mephenytoin, methylphenobarbital and primidone. A serum extract is nitrated, separated by thin-layer chromatography, and the nitro compounds are determined by polarography. The rates of recovery are: phenobarbital 81%, phenytoin 79%, mephenytoin 80%, methylphenobarbital 86% and primidone 84%. The sensitivity limits range from 3.5 mug/ml plasma for phenytoin to 5.5 mug/ml for mephenytoin and methylphenobarbital. This method might be useful not only for determination of therapeutic blood levels but also for toxicology because it saves time and the expenditure of work is small. The mean deviation for mononitrated anticonvulsive drugs is +/- 2.8% (for 50 mug/ml) and +/- 11.6% (for 10 mug/ml). For phenytoin being dinitrated, the values are +/- 0.6% and +/- 7.5% for 50 mug and 5 mug, respectively). We determined blood levels of out-patients containing phenobarbital and phenytoin besides other substances. Having once established calibrating curvers internal or external standards are not required.

Anticonvulsants↗
PubMed1976

Rapid micromethod for measuring anticonvulsant drugs in serum by high-performance liquid chromatography.

We describe an assay system for measuring phenobarbital, diphenylhydantoin, primidone, ethosuximide, and carbamazepine in 25 mul of serum. The procedure involves precipitation of proteins with an acetonitrile solution containing cyheptamide as an internal standard, and reverse-phase chromatography on a 4 mm X 30 cm column containing "muBondapak C18." The anticonvulsants are eluted with an equivolume mixture of potassium phosphate buffer (10 mmol/liter, pH 8.0) and acetonitrile at a flow rate of 0.8 ml/min, detected by their absorbance at 200 nm, and quantitated by measuring peak areas. When measurement of primidone is not required, a 254-nm detector may be used. Each analysis requires 10 min. Optimum column temperature has been found to decrease with use. Analytical recoveries for the five drugs varied from 92% to 102% with good precision (coefficients of variation between 2.8% and 9.2% for therapeutic and toxic concentrations). The results obtained with this method compare favorably with results obtained by gas-liquid chromatography (correlation coefficients between 0.77 and 0.98). In over 1300 patients' samples analyzed to date, the only drugs known to have interfered with the assay are gentamicin, diazoxide, and mephobarbital.

Anticonvulsants↗
PubMed1976

Rapid gas-chromatographic measurement of anticonvulsant drugs in serum.

We describe a rapid method for precisely measuring concentrations of anticonvulsant drugs in serum. The simple procedure, adaptable to the clinical laboratory, can be used for the routine simultaneous measurement in sera of phenobarbital, primidone, dephenylhydantoin, and (or) ethosuximide. The extraction procedure requires no solvent evaporation and gives a good yield for primidone and quantitative extraction for the other drugs. The relatively small amount of "early phenobarbital" formed during on-column methylation permits a precise analysis of phenobarbital based on a single peak. Results can be made available directly, without manual measurements or calculations.

Anticonvulsants↗
PubMed1963

Treatment of epilepsy.

The main clinical types of epilepsy and their treatment are described. The treatment of choice in petit mal epilepsy is trimethadione (Trimedone) 0.3 g., three to six times a day, or acetazolamide (Diamox) 125-250 mg., three to four times a day. Phenobarbital is usually given as well to prevent grand mal seizures. Diphenylhydantoin sodium (Dilantin Sodium), 100 mg., and/or phenobarbital, 30-100 mg., three to four times a day, is recommended in patients with focal and grand mal epilepsy. Psychomotor automatisms are a form of focal seizure. Primidone (Mysoline), in doses of 125-250 mg. two to three times a day, is a very useful anticonvulsant in patients with myoclonic features, psychomotor automatisms and grand mal seizures. Primidone should be started in small doses. Drug reactions, especially cerebellar ataxia in the case of diphenylhydantoin and blood dyscrasias in the case of some drugs, should be recognized. Excessive drowsiness can be avoided by proper dosage and proper timing of drug administration. Patients should be seen regularly at least two to three times a year. The objective of treatment is to achieve optimum control of seizures by using the appropriate drug in adequate dosage. Social adaptation is good in the majority of patients, who should be encouraged to carry on their life independently, usually free to marry and have children. Attention to special occupational hazards has to be considered. Education of employers and employees is often necessary. Special work arrangements are occasionally indicated for selected patients. Patients should be seizure-free for two to three years before permission is given to drive an automobile.

Acetazolamide↗
PubMed1989

Barbiturate-related connective tissue disorders.

Development of Dupuytren's contractures, frozen shoulder, Ledderhose's syndrome, Peyronie's disease, fibromas, and general joint pain has been linked in retrospective studies and case reports to the use of antiepileptic drugs. We undertook a prospective survey of the incidence of connective tissue disorders in 622 patients newly treated with carbamazepine, phenobarbital, phenytoin sodium, or primidone. Ten of the 406 patients who were treated for 6 months or more developed connective tissue disorders. All affected patients were taking a barbiturate (primidone, 4 patients; phenobarbital, 6 patients). Seven of the 10 problems occurred during the first year of treatment. These data are prospective evidence of a statistically significant relationship between barbiturate use and the development of connective tissue disorders, and timing of appearance.

Adult↗
PubMed1988

Withdrawal of barbiturate anticonvulsant drugs: prospective controlled study.

A barbiturate (phenobarbital or primidone) was withdrawn over a period of 3 months from 25 institutionalized residents, all of whom had had three seizures or less in the past 6 months and were maintained on a nonsedating drug (phenytoin, carbamazepine, or valproic acid). Results were compared with a matched comparison group maintained on both drugs. Subjects withdrawn from primidone, but not those withdrawn from phenobarbital, had increased seizure frequency, probably due to withdrawal. After 14 months, seizure-free subjects withdrawn from barbiturates were no more likely to have had seizures than were comparison subjects. Barbiturates appear to be unnecessary and may be withdrawn.

Adolescent↗
PubMed1977

[Laboratory controls in long-term treatment with anticonvulsive drugs (author's transl)].

In the treatment of epilepsy often several substances with anticonvulsive effect are combined. Possible drug interactions in these cases can change the desired effect of treatment. Simultaneous administration of clonazepam or dipropylacetate (the latter in a short term combination) with diphenylhydantoin can cause a significant increase of diphenylhydantoin serum concentrations and intoxications. The combination of carbamazepin with diphenylhydantoin can cause a decrease of diphenylhydantoin serum concentrations. The simultaneous administration of diphenylhydantoin and phenobarbital can produce a significant increase of phenobarbital levels in the statistical average and in the case of a combination of primidon and diphenylhydantoin an intoxication by the primidon metabolite phenobarbital. These possible interactions which are not obvious at the beginning of therapy are supplemented by other factors as intercurrent diseases or erratic drug intake. With routine measurements of serum concentrations of anticonvulsive drugs some of these interfering factors can be eliminated by realizing them in time. Treatment becomes more effective and side effects are reduced. The development of a new check list for the treatment of epileptic patients should also improve the control and give better informations about the course of the disease.

Anticonvulsants↗
PubMed1985

Influence of anticonvulsant drugs on thyroid hormones in epileptic children.

Thyroid function tests were studied in epileptic children undergoing long-term anticonvulsive therapy with phenytoin, primidone or mephenytoin. Serum T4 was decreased in all three treated groups, serum T3 was diminished only in those treated with phenytoin or primidone. FT4 was also significantly decreased while serum TSH and TBG were not affected in the treated patients. The effect of anticonvulsant drugs on thyroid hormone catabolism and peripheral conversion of T4 seems to be important in these alterations.

Anticonvulsants↗
PubMed1984

The simultaneous determination of five anti-epileptic drugs in plasma by high performance liquid chromatography.

A high performance liquid chromatographic (HPLC) method is described for the simultaneous determination in plasma of carbamazepine, ethosuximide, phenobarbitone, phenytoin and primidone. The procedure involved the preliminary extraction of the drugs and the internal standard (hexobarbitone) into a mixture of organic solvents at pH 2. The dried extract was dissolved in methanol and 25 microliter of the concentrate was injected into a liquid chromatograph linked to a reverse-phase column. The drugs and internal standard were eluted from the column by a mixture of methanol and water, as the mobile phase, and detected with a UV spectrophotometer at 204 nm. This HPLC assay, which required 0.5 ml of plasma, was used to determine anti-epileptic drugs levels in 136 mentally-handicapped children suffering from epilepsy. Comparison between different batches of assays showed that recovery of the drugs from plasma varied from 60 to 98% and with a coefficient of variance between 3.8 to 9.8%. Detection limit of the method ranged from 2 micrograms ml-1 for primidone, to 1 microgram ml-1 for the remainder of the anti-epileptic drugs.

Anticonvulsants↗
PubMedDate not supplied

Permeation of lipophilic drugs through synthetic elastomers.

Permeability studies were carried out with three lipophilic drugs, namely, phenytoin and primidone (both widely used in the treatment of epilepsies and convulsive disorders), and dapsone (a sulfone antimicrobial agent used in the treatment of leprosy and to a lesser extent in dermatitis herpetiformis) through silica-filled poly(dimethyl siloxane) (Silastic) membranes, and anisotropic membranes of poly(ether-urethane)/poly(dimethyl siloxane) block copolymer (Avcothane, Cardiothane). These polymers are used in medical implants and in various cardiovascular devices. While both polymers were permeable to the drugs, the transport properties differed significantly. In the case of the poly(dimethyl siloxane) there was an initial large burst effect, followed by an exponential decrease in the rate of drugs released through the polymer films, although with dapsone the release rate became essentially constant between 100-180 h at 37 degrees C. In the case of the anisotropic films of the poly(ether-urethane)/poly(dimethyl siloxane) block copolymer, the permeabilities were much higher. Significantly, phenytoin exhibited essentially constant rate (zero-order) kinetics between 25-150 h, showing only a moderate burst effect that is probably not significant therapeutically. Importantly, dapsone showed neither a burst effect nor any significant time lag, and the release followed constant rate (zero-order) kinetics between 12-80 h, followed by only a moderate decrease in drug concentration up to 140 h (the experimental end-point). The diffusion coefficients calculated from initial desorption data at 37 degrees C for the poly(ether-urethane)/poly(dimethyl siloxane) block copolymer are as follows: phenytoin = 8.6 X 10(-9) cm2/s, primidone = 2.8 X 10(-9) cm2/s, and dapsone = 2.4 X 10(-8) cm2/s.(ABSTRACT TRUNCATED AT 250 WORDS)

Dapsone↗
PubMed1980

Measurement of anticonvulsants in serum by reversed-phase ion-pair liquid chromatography.

We describe a method for the simultaneous liquid-chromatographic determination of ethosuximide, ethylphenacemide, primidone, phenobarbital, carbamazepine, and phenytoin in serum. The drugs, together with an internal standard, are extracted into ethyl acetate at pH 7.0. The extract is analyzed isocratically at ambient temperature on a reversed-phase column of "SAS Hypersil" with a mobile phase of acetonitrile/tetrabutyl ammonium phosphate solution (2/8 by volume). The eluted drugs are detected by their absorption at 200 nm, and quantitated from their peak heights as compared with those of extracted standards. The day-to-day CV of the method varied between 5.1 and 9.6% for concentrations ranging from less than therapeutic to toxic. The results, when compared with those by gas chromatography, gave correlation coefficients of 0.936 for phenytoin, 0.977 for phenobarbital, and 0.939 for primidone. No drug interference was found except that amobarbital and ethylphenacemide co-chromatographed.

Anticonvulsants↗
PubMed1979

Carbamazepine levels in pregnancy and lactation.

An epileptic patient whose seizures were controlled with carbamazepine and primidone was followed throughout pregnancy and lactation. Blood levels of primidone decreased during pregnancy and rose postpartum requiring dosage adjustments. Pharmacologically insignificant amounts of the drug were detected in breast milk. A review of the literature revealed 94 infants exposed to carbamazepine in utero and no evidence to date that this drug carries a teratogenic risk.

Adult↗
PubMedDate not supplied

[The application of evoked potentials to the evolutive control of continuous spike/wave epilepsy during slow wave sleep].

We studied 4 patients (14-21 years old) with continuous spike/wave epilepsy during slow wave sleep with visual evoked potentials (VEP) and somatosensory evoked potentials (SEP). All the patients presented the same focality and received the same medication (primidone plus sodium valproate). No case had another pathology not related with epilepsy which could alter the evoked potential findings. The results obtained in the initial evoked potentials were compared with those achieved after 5 years of treatment. In the initial study interhemispheric asymmetry in the latency of the early component (L.N1) of the SEP was observed with a mean of 10%. Five years later normal SEP were obtained with the asymmetry having disappeared thus leading to the deduction that the physiopathologic improvement found in these patients was due to the treatment of sodium valproate together with primidone.

Adolescent↗
PubMed1976

Simultaneous high-pressure liquid-chromatographic determination of some anticonvulsants in serum.

We describe procedures for simultaneously determining some anticonvulsants (phenobarbital, diphenylhydantoin, primidone, ethosuximide, methsuximide, carbamazepine) in serum by high-pressure liquid chromatography. The drugs, together with an internal standard, phenacetin, are adsorbed from serum onto charcoal and eluted from it with organic solvent. The eluate is analyzed isocratically on a reverse-phase column with a mobile phase consisting of acetonitrile/water (17/83 by volume). The eluted drugs are detected by their absorption at 195 nm, and quantities estimated from their peak areas as compared with those of extracted standards. Results are reproducible to about 6%. Sensitivities, for 0.5-ml serum samples, of 0.1 mg/liter for all the drugs analyzed except ethosuximide (0.5 mg/liter) are attained routinely. Correlation of results with gas chromatography was 0.912 for phenobarbital, 0.982 for diphenylhydantoin, 0.886 for primidone, and 0.966 for ethosuximide. Amobarbital and secobarbital interfere with the analysis; chlordiazepoxide, methaqualone, salicylate, diazepam, and oxazepam do not. Including extraction, analysis time for a single sample is 20 min.

Anticonvulsants↗
PubMed1998

Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants: 122 cases (1992-1996).

OBJECTIVE: To determine therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide. DESIGN: Retrospective study. ANIMALS: 122 dogs with major motor epilepsy. PROCEDURE: Medical histories were collected for epileptic dogs treated with potassium bromide with or without phenobarbital sodium or primidone, from which serum was submitted for bromide analysis from May 1992 to May 1996 to the Therapeutic Drug Monitoring Program at Cornell University's College of Veterinary Medicine. A therapeutic response (improved seizure control) was defined as a > or = 50% reduction in seizure frequency following initiation of bromide treatment. Serum bromide and phenobarbital concentrations and therapeutic outcome were determined for all dogs. RESULTS: 72% of epileptic dogs had a > or = 50% reduction in seizure frequency following initiation of treatment with potassium bromide. Discontinuation of barbiturate treatment was possible in 19% of those dogs originally treated with phenobarbital or primidone. Of those dogs continued on bromide and phenobarbital, 45% maintained seizure control with serum phenobarbital concentrations < 20 micrograms/ml. Significantly higher serum bromide concentrations were required when dogs were initially or eventually treated with bromide alone (mean bromide concentration, 1,906 micrograms/ml) compared with dogs treated with potassium bromide along with a barbiturate (mean bromide concentration, 1,621 micrograms/ml). CLINICAL IMPLICATIONS: When dogs are treated with bromide and phenobarbital, a reasonable therapeutic range for serum bromide concentrations is 810 to 2,400 micrograms/ml, and for bromide treatment alone, the range is 880 to 3,000 micrograms/ml. When phenobarbital is used in combination with bromide, a reasonable therapeutic range for serum phenobarbital concentrations is 9 to 36 micrograms/ml, although in some dogs treated with bromide, phenobarbital can eventually be discontinued.

Animals↗