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PubMed1987

Essential tremor variants: effect of treatment.

Essential tremor may not represent a single condition. Subclassifications include kinetic predominant tremor; combined resting-postural tremor; primary writing tremor; isolated voice, chin, or tongue tremor; and orthostatic truncal tremor. We report patients with these disorders. An association of these conditions with essential tremor is suggested by a high occurrence of a family history of essential tremor, frequent presence of a mild postural tremor, and tremor reduction with alcohol ingestion. Pharmacologic responsiveness is different for these disorders. Propranolol and primidone often have beneficial effects but clonazepam was the only drug effective in some cases of kinetic predominant tremor and in orthostatic truncal tremor. Combined resting-postural tremor and voice tremor were often unresponsive to treatment.

Adult↗

PubMedDate not supplied

Effects of anticonvulsive drugs on the activity of gammaglutamyltransferase and aminotransferases in serum.

A cross-sectional study was performed to define patients at risk of developing liver disease due to long-term treatment with anticonvulsive drugs. The activities of gamma-glutamyltransferase, aspartate aminotransferase, and alanine aminotransferase and the concentrations of primidone, phenobarbital, phenytoin, and valproic acid in serum were estimated. Epileptic children before therapy were used as controls. The results indicated enzyme induction due to phenobarbital and both enzyme induction and liver cell damage or plasma membrane leakage due to phenytoin. Gamma-glutamyltransferase may be an early indicator of liver disease due to valproic acid.

Adolescent↗

PubMed1985

Evaluation of an automated system (Optimate) for substrate-labeled fluorescent immunoassays.

Performance characteristics of substrate-labeled fluorescent immunoassays for the drugs phenytoin, phenobarbital, primidone, carbamazepine, theophylline, gentamicin, tobramycin, amikacin, and quinidine run on an Optimate automated fluorometric analyzer were compared with those of automated enzyme multiplied immunoassays (EMIT) for the same drugs performed on a Cobas centrifugal analyzer for patient samples and controls. For 100 patient samples assayed by both systems for each drug, excellent correlations were obtained, with correlation coefficients ranging from 0.96 to 0.99. Likewise, very good within-run (n = 10) and between-run (n = 30) precision was obtained by both methods. Values for controls and clinical specimens by the Optimate methods calculated using the same-day calibration curves were not significantly different from those calculated from calibration curves stored 14 days, indicating at least 14-day curve stability for all assays.

Anti-Bacterial Agents↗

PubMed2004

Levetiracetam in focal epilepsy and hepatic porphyria: a case report.

We report a patient with focal epilepsy and latent hereditary coproporphyria who had exacerbation of clinical symptoms of porphyria under treatment with valproate and primidone and was then treated with levetiracetam without exacerbation of clinically latent porphyria.

Acute Disease↗

PubMed2004

Anticonvulsant efficacy of the low-affinity partial benzodiazepine receptor agonist ELB 138 in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures.

PURPOSE: Ataxia, sedation, amnesia, ethanol and barbiturate potentiation, loss of efficacy (tolerance), development of dependence, and the potential for drug abuse limit the clinical use of benzodiazepines (BZDs) for long-term treatment of epilepsy or anxiety. BZD ligands that are in current use act as full allosteric modulators of gamma-aminobutyric acid (GABA)-gated chloride channels and, on long-term administration, trigger a functional uncoupling between the GABAA and BZD recognition sites. Partial allosteric modulators, which have a low intrinsic activity at the BZD recognition site of the GABAA receptor, might eventually overcome the limitations of full agonists such as diazepam (DZP). METHODS: In the present study, the new low-affinity partial BZD-receptor agonist ELB 138 [former name AWD 131-138; 1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one] was evaluated in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures. RESULTS: ELB 138 was shown to increase potently the pentylenetetrazole (PTZ) seizure threshold in dogs. Prolonged oral administration with twice-daily dosing of ELB 138 with either 5 or 40 mg/kg over a 5-week period was not associated with loss of anticonvulsant efficacy in the PTZ dog model. To study whether physical dependence developed during long-term treatment, the BZD antagonist flumazenil was injected after 5 weeks of treatment with ELB 138. Compared with prolonged treatment with DZP, only relatively mild abstinence symptoms were precipitated in dogs treated with ELB 138, particularly at the lower dosage (5 mg/kg, b.i.d.). In a prospective trial in dogs with newly diagnosed epilepsy, ELB 138 markedly reduced seizure frequency and severity without significant difference to standard treatments (phenobarbital or primidone) but was much better tolerated than the standard drugs. In dogs with chronic epilepsy, most dogs exhibited a reduction in seizure frequency and severity during add-on treatment with ELB 138. CONCLUSIONS: The data demonstrate that the partial BZD receptor agonist ELB 138 exerts significant anticonvulsant efficacy without tolerance in a dog seizure model as well as in epileptic dogs with spontaneously recurrent seizures. These data thus substantiate that partial agonism at the BZD site of GABAA receptors offers advantages versus full agonism and constitutes a valuable approach for treatment of seizures.

Animals↗

PubMed1984

A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients.

The antipyrine clearance and the urinary excretion of D-glucaric acid (D-GA) were determined in 122 patients receiving chronic anticonvulsant drug treatment and in 21 drug-free control subjects. Patients treated with carbamazepine (CBZ), phenytoin (DPH), primidone (PMD) and phenobarbitone (PB), either alone or in combination, showed higher values of antipyrine clearance and excreted larger amounts of D-GA as compared to controls. While antipyrine clearance values did not differ significantly from one drug group to another, D-GA excretion was significantly higher in patients treated with CBZ than in those treated with DPH. In patients treated with sodium valproate antipyrine clearance did not differ from control values. There was a trend for D-GA excretion to be higher in these patients but the difference was not statistically significant. Significant positive correlations were found between the dosage of CBZ, DPH, PMD and PB and both indices of enzyme induction. These data demonstrate a dose-dependent degree of enzyme induction in patients receiving therapeutic doses of these anticonvulsants. The relative potency at average dose levels for antipyrine clearance was PB (1), DPH (0.92), CBZ (0.84), PMD (0.82) and for log D-GA excretion was PB (1), CBZ (0.96), PMD (0.95), DPH (0.90).

Anticonvulsants↗

PubMed1978

Thyroid function tests in patients on long-term treatment with various anticonvulsant drugs.

Thyroid function tests were studied in patients undergoing long-term treatment with various anticonvulsant drugs. Previous reports that diphenylhydantoin induces a decrease in the serum concentrations of total and free thyroxine (T4) and triiodothyronine (T3) without a change in the TSH concentration were confirmed. Diphenylhydantoin had no effect on reverse T3. Carbamazepine was also found to decrease serum T4, the free T4 index and T3 but, with the exception of T3, the decrease was smaller than that induced by diphenylhydantoin. Dipropylacetic acid did not influence the serum thyroid hormone concentrations, and neither did primidone. This demonstrates that the interaction between anticonvulsant drugs of different chemical structure and thyroid hormone metabolism is diverse. None of the drugs tested altered serum TSH or the T3 uptake test for the estimation of unsaturated thyroid hormone binding-capacity in serum. These two tests are considered diagnostically more dependable than the measurement of thyroid hormones in serum when diphenylhydantoin and carbamazepine are administered.

Adolescent↗

PubMed1994

Comparison of community and institutional prescription of antiepileptic drugs for individuals with learning disabilities.

The use of antiepileptic agents for individuals with learning disabilities (mental handicap) resident both within National Health Service facilities and the community was surveyed in the UK. There was no difference in rates of polypharmacy, but there were significant differences in choice of antiepileptic agent. In particular, individuals resident in the community were more likely to be in receipt of phenytoin, primidone and phenobarbitone, which are particularly recognized as producing adverse effects on cognition and behaviour.

Adult↗

PubMed1981

A possible neurochemical basis of the central stimulatory effects of pp'DDT.

The striatal neurochemical changes induced by pp'DDT (600 mg/kg) in mice were: an increase in the concentration of free ammonia, a decrease in the level of GABA and a reduction in the level of acetylcholine. These changes were maximal 5 h after treatment with pp'DDT, when the animals developed 'severe' convulsions. The convulsions and striatal neurochemical changes were modified to different degrees by barbiturates. Phenobarbitone protected all the animals from pp'DDT-induced convulsions. The levels of striatal acetylcholine and GABA in these animals were within normal limits. Prominal reduced the severity of convulsions in pp'DDT-treated animals. The levels of striatal acetylcholine and GABA were significantly lower than control values in these animals. Primidone neither modified the convulsions nor the striatal neurochemical changes in pp'DDT-treated animals. The increase in the concentration of free ammonia, in pp'DDT-treated animals, was not modified by barbiturates. Aminooxyacetic acid raised the GABA level above normal and abolished the convulsions in pp'DDT-treated animals; the level of acetylcholine was within normal limits in these animals. Hydroxylamine produced a similar but less marked effect. Pyridoxine had no effect on convulsions or striatal neurochemical changes induced by pp'DDT. The increase in the concentration of free ammonia in pp'DDT-treated animals was not modified by these agents. It is likely that pp'DDT produced stimulatory effects by increasing the concentration of free ammonia which may be involved in reducing the level of GABA, while changes in the level of acetylcholine may be an effect of pp'DDT-induced convulsions.

Acetylcholine↗

PubMed1986

Low levels of gamma-aminobutyric acid in cerebrospinal fluid of dogs with epilepsy.

gamma-Aminobutyric acid (GABA) levels were determined in cisternal cerebrospinal fluid (CSF) of 19 epileptic dogs with generalized tonic-clonic (grand mal) seizures using a radioreceptor assay. Thirty-four healthy age-matched dogs served as controls. The average CSF GABA level in epileptic dogs (40 pmol/ml) was significantly lower than that determined in controls (66 pmol/ml). Treatment with phenobarbital or primidone seemed not to affect CSF GABA levels.

Animals↗

PubMed1975

Prevention of febrile convulsions with dipropylacetate (Depakine).

In 47 children followed for 1 year after the first "simple" febrile convulsion, dipropylacetate (Depakine, 20 mg/kg) was as effective in preventing new febrile convulsions (a single recurrence in 4% of 47 children) as was phenobarbital (5 mg/kg) or primidone (25 mg/kg) (a single recurrence in 4% of 47 children), and there were no side effects. Of 47 untreated children followed for 1 year, 55% had 1 to 4 new febrile convulsions. All medications were given in divided doses morning and evening.

Anticonvulsants↗

PubMed1975

Anticonvulsant level in saliva, serum, and cerebrospinal fluid.

Levels of four anticonvulsant drugs were measured simultaneously in saliva, spinal fluid, and dialyzed serum, i.e., free drug in serum. The level of diphenylhydantoin and possibly of carbamazepine was the same in the three body fluids. The leves of phenobarbital was the same in spinal fluid and dialyzed serum, but was lower in saliva. The level of primidone was different in each body fluid. The technique is simple (flow of saliva stimulated when the subject chews candle was or Teflon) and will be useful to determine the level of free diphenylhydantoin and carbamazepine, which is more closely related to intoxication or drug failure than is the total level of drug.

Carbamazepine↗

PubMed1977

Gas chromatographic on-column methylation technique for the simulataneous determination of antiepileptic drugs in blood.

An on-column methylation technique (OCMT) is described for the simultaneous, gas chromatographic determination in blood of ethosuximide (ES), phenobarbital (PB), primidone (PD), phenytoin (DPH), and 5-ethyl-5-phenylhydantoin (EPH). Multiple internal standards are employed in the OCMT, in order to eliminate or to minimize greatly error sources common to the technology of gas chromatography and to compensate for the different chemical dispositions of the antiepileptic drugs in an OCMT. The internal standards used in the OCMT were as follows: alpha,alpha,beta-trimethylsuccinimide (TMS) was used for the determination of ES; 5-ethyl-5-para-tolylbarbituric acid (MPB), for PB; 5-ethyl-5-(para-tolyl) hexahydropyrimidine-4,6-dione (MPD), for PD; and 5-(para-tolyl)-5-phenylhydantoin (MPPH), for EPH and DPH. The use of ether, the buffering of the plasma sample at pH 7.6, and the use of dilute (0.30-0.35 M) trimethyl-phenylammonium hydroxide (TMPAH) contributed to the specificity of the extraction scheme of the OCMT. The precision and accuracy of the OCMT was attributed to the use of appropriate, multiple internal standards. A method is described for the preparation of standard solutions of drugs in blank plasma (biological matrix) and for the use of the standards in calibration and daily intra-laboratory control of the OCMT.

Anticonvulsants↗

PubMed1979

Pharmacological interactions of mesuximide with phenobarbital and phenytoin in hospitalized epileptic patients.

In order to study the pharmacological interactions of the anticonvulsant drugs mesuximide (MSM), phenobarbital (PB), and phenytoin (PHT), serum concentrations of N-desmethyl-mesuximide (N-DESM-MSM, the main metabolite of MSM), PB, and PHT were determined in 94 hospitalized patients suffering from petit mal epilepsy. When MSM was administered to patients on stable PB or primidone therapy, the mean concentrations of PB increased by statistically significant amounts of 38 and 40%, respectively. Similarly, the additional administration of MSM caused the mean concentration of PHT to rise by 78%. The data also indicate that patients with PB and/or PHT comedication have higher N-DESM-MSM serum concentrations than patients without comedication. The pharmacological reasons for these interactions are discussed. These studies demonstrate that the disturbing side effects of MSM are often due to the co-medication. A carefully planned therapeutical dose procedure with regular serum level determinations is proposed to avoid or at least reduce the adverse effects of MSM.

Adolescent↗

PubMed1980

Hepatotoxicity of sodium valproate and other anticonvulsants in rat hepatocyte cultures.

Valproic acid has recently been shown to be associated with liver disease in man. Rat hepatocyte cultures were used to test the hepatotoxicity of valproic acid and several other anticonvulsants. Dose-related hepatotoxicity was demonstrated for valproic acid at concentrations ranging from 10 to 320 micrograms/ml, therapeutic concentrations being 50-100 micrograms/ml. Hepatotoxicity could not be demonstrated for phenobarbital, phenytoin, primidone, and clonazepam. It is concluded that valproic acid is a dose-related hepatotoxin.

Animals↗

PubMed1981

Ictal effects of anticonvulsant medication withdrawal in epileptic patients.

Medication withdrawal is used in selected instances to precipitate seizures during evaluation of epileptic patients. Whether such medication manipulation can alter electrical seizure onset or clinical seizure type is not known. Information regarding the effects of anticonvulsant withdrawal on depth EEG onset and clinical manifestations of seizures was reviewed in 25 patients with partial complex seizures in whom intracranial electrodes were implanted. For the purposes of this study, the withdrawal period was defined as the time after abrupt cessation of medication between one and five half-lives of the drug and the base-line state as all other times. Ten patients were withdrawn from carbamazepine, 6 from phenobarbital, 2 from phenytoin, and 3 from primidone. Overall effects of anticonvulsant withdrawal in 18 patients and 21 instances of withdrawal with a total of 89 withdrawal and 71 base-line seizures were notable. Focal electrical onset and typical clinical seizure type during withdrawal were entirely consistent with electrical and/or clinical characteristics of seizures occurring during the base-line state in 13 instances. "New" clinical and/or electrical seizure types occurred during withdrawal only in a number of patients in whom bilateral or multifocal seizure onset was confirmed electrographically outside of the withdrawal period. In only 1 patient did withdrawal produce atypical clinical and electrical seizures when the base-line state showed a clinically typical seizure of clear-cut localized onset. After surgery this patient was shown to have unequivocal multifocal seizure onset. Thus, for purposes of localizing single epileptic foci, information obtained during the anticonvulsant withdrawal period provided no misleading information in this group of patients, while condensing the time needed for evaluation.

Adolescent↗

PubMed1982

Pharmacokinetics of phenylethylmalonamide (PEMA) in normal subjects and in patients treated with antiepileptic drugs.

The pharmacokinetics of phenylethylmalonamide (PEMA), a major metabolite of primidone, were investigated following administration of single oral doses (400 mg) to six normal subjects and six patients receiving chronic treatment with antiepileptic drugs. Peak serum PEMA levels were usually attained with 2-4 h after intake. The oral bioavailability estimated on the basis of the recovery of unchanged drug in the urine of normal subjects was at least 80%. Half-life values ranged from 17 to 25 h in normal subjects and from 10 to 23 h in the patients. No statistically significant difference in any of the calculated kinetic parameters could be found between the two groups. The data indicate that PEMA is readily absorbed from the gastrointestinal tract and that it is eliminated predominantly unchanged in the urine of man.

Adult↗

PubMed1984

Interactions between anticonvulsants and other commonly prescribed drugs.

Many drug interactions can be demonstrated, but only a few are so clinically significant that they necessitate adjusting drug dosages. The same drug combination may produce changes of variable extent or direction in different individuals. The reasons for this variability include genetic control of the rate and inducibility of drug metabolism, and environmental factors such as contact with chemicals. Among antimicrobial agents, chloramphenicol may cause accumulation of phenytoin (PHT) and phenobarbital (PB), and isoniazid may cause PHT, carbamazepine (CBZ), and primidone (PRM) to accumulate. Erythromycin may cause accumulation of CBZ. Among anti-ulcer agents, antacids may reduce PHT concentration while cimetidine may cause accumulation of PHT, CBZ, and diazepam (DZP). Salicylates displace strongly binding drugs such as PHT, DZP, or valproate (VPA) from the binding sites in plasma proteins, which may lead to some decline of the total plasma level with an increase in the unbound drug percentage. Conversely, anticonvulsants may influence the dosage requirements of oral anticoagulants by inducing their metabolism. Failures of oral contraceptives have been attributed to anticonvulsants in some patients. Probably the most predictable interaction that necessitates dosage adjustment is accumulation of PB caused by VPA. Intentional inhibition of PRM metabolism by nicotinamide serves as an example of attempts to utilize an interaction for improved therapeutic effect.

Analgesics↗