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At least 19 recordsLinked to original sources
PubMed1979

Relationships between plasma concentrations of diphenylhydantoin, phenobarbital, carbamazepine, and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant or neurotoxic effects in experimental animals.

The relationships between plasma concentrations of diphenylhydantoin (DPH), phenobarbital (PB), carbamazepine (CBZ), and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant and neurotoxic effects were studied in various species of animals. Anticonvulsant activities of test drugs were examined by the maximal electroshock seizure (MES) test. Neurotoxicities were determined by the rotorod performance test in mice and rats and by behavioral observations in rabbits, dogs, and monkeys. It was demonstrated that both the anticonvulsant effects and the neurotoxic effects of the drugs tested were more closely correlated with their plasma concentrations than with the dosages administered. There was a critical plasma concentration for each drug to show an anticonvulsant effect or to cause a neurotoxic effect in an individual animal. The critical plasma concentrations for anticonvulsant and neurotoxic effects of each drug were relatively constant among different species, with the exception of DPH in rabbits, which had twice the value in other species. The therapeutic ranges of plasma concentrations of DPH, PB, and CBZ determined in various species of animals coincided well with those recommended clinically. AD-810 was found to be effective against MES without signs of neurological toxicity in the ranges of plasma concentrations of 9.8 to 74.0, 10.8 to 95.0, 9.6 to 117.0, and 12.6 to 96.2 microgram/ml in mice, rats, rabbits, and dogs, respectively. These results seem to suggest that AD-810 may be effective clinically at plasma concentrations above 10 microgram/ml, with a therapeutic range up to 70 microgram/ml, which is much wider than the therapeutic ranges of DPH (10--20 microgram/ml), PB (10--30 microgram/ml), and CBZ (4--10 microgram/ml).

Animals↗
PubMed1978

Therapeutic monitoring of anticonvulsant drugs in psychiatric patients: rapid, simultaneous gas-chromatographic determination of six commonly used anticonvulsants without interference from other drugs.

A simple, sensitive and precise gas-chromatographic method for simultaneous extraction, derivatization and determination of methsuximide, ethosuximide, diphenylhydantoin, carbamazepine, phenobarbital and primidone in the presence of other drugs has been described. The method is especially useful for drug monitoring in patients on multiple anticonvulsant therapy while also on combination therapy with psychotropic drugs. It overcomes the analytical interferences between mephenytoin and phenobarbital; methsuximide and primidone; kemadrin and primidone; cholesterol and primidone; prolixin, haldol and other drugs; encountered in other methods using underivatized, trimethylsilylated or methylated drugs. As little as 0.5 microgram/ml of a drug can be determined and if needed the method can be scaled down to 0.3 ml plasma. The method yielded recoveries of 97-103% with standard deviations of 0.7-1.8. For a constant check of the precision, an internal quality control using daily analysis of a sample from a frozen plasma pool supplemented with known concentrations of the anticonvulsants was used. The method is suitable for use in routine clinical laboratory.

Anticonvulsants↗
PubMed1979

[The frequency of adult anticonvulsant osteomalacia in relation to duration of therapy and dosage of anticonvulsants (author's transl)].

Of 837 epileptics over 16 years of age treated with mono- or combined hydantoin therapy 20.3% showed radiographic signs of anticonvulsant osteomalacia. With the exception of the patients with severe disturbances of the skeletal system no positive correlation was found with duration of therapy. The percentage of moderate bone changes was the highest in the patients treated for 1 to 2 years; the percentage of severe bone changes in the group treated over 10 years. The rate of osteomalacia correlated with the total dose of hydantoin, phenobarbital, or primidone; the correlation with the dose per year was even more evident. The risk of osteomalacia rose distinctly with doses over 3000 equivalent units/year. The patients with combined hydantoin-barbiturate treatment showed a higher risk than those treated with phenytoin alone. The rate of osteomalacia was the highest in the patients aged under 20 years and over 50 years. Males showed a relatively higher rate of osteomalacia than females, they were treated however with a higher dose per year. The chemical parameters blood alkaline phosphatase and 25-hydroxycholecalciferol corresponded to the radiographic signs, whereas calcium and anorganic phosphate showed no correlation. Early routine radiologic and chemical control especially of the epileptic patients with high risk of osteomalacia should be routinely performed in future.

Adult↗
PubMed1978

In vivo interaction of anticonvulsant drugs. The mathematical correlation of plasma levels of anticonvulsant drugs in epileptic patients.

The phenytoin plasma levels were measured in 45 epileptic patients whose only treatment was phenytoin. The plasma of 20 other patients receiving both phenytoin and phenobarbital was also tested for concentration of these two drugs and 18 patients treated with phenytoin, phenobarbital and primidone were investigated in the same way. The results were used to calculate the plasma levels of phenytoin in relation to dosage and to measure the effect of the simultaneous use of phenobarbital on the phenytoin plasma levels and of primidone together with phenobarbital on phenytoin concentration. The results led to the following conclusions: The population of epileptic patients can be divided into 2 groups. In the first group the patients reach equilibrium at the relatively high phenytoin plasma level for a given dose of phenytoin, and in the second group the phenytoin plasma level tends to be significantly lower for parallel dosages. Both groups, in their behavior, obey mathematically an exponential graph specific for each group. Phenobarbital tends to lower the plasma phenytoin level when the two drugs are used simultaneously. It is also possible, by the graphs produced, to calculate the expected phenytoin plasma levels when using the drugs together. Primidone and phenobarbital together decrease the phenytoin level much more than expected from the effect of phenobarbital alone.

Dose-Response Relationship, Drug↗
PubMed1977

Skeletal status in mentally retarded patients on anticonvulsive therapy.

X-ray densitometric measurement of radius mineral content and radiogrammetry of the cortical index of the second metacarpal were made on 644 institutionalized mentally retarded males and females, 224 of whom had received long-term anticonvulsant drug treatment. Analysis of variance of radius mineral content and metacarpal cortical index indicated that values for mentally retarded persons are not significantly different from the normal-for-age values. Radius density among anticonvulsant males, however, was significantly lower than that of non-anticonvulsant males in four out of five age groups. Among females the anticonvulsant patients were not significantly lower in radius density than the non-anticonvulsant females. Similar trends were evident in cortical indices of the second metacarpal: Two out of five age groups of anticonvulsant males were significantly lower than non-anticonvulsant males, while only one of five age groups of anticonvulsant females was significantly lower than non-anticonvulsant females. The effects of diphenylhydantoin and phenobarbital are similar in their adverse effects on bone growth and development.

Absorptiometry, Photon↗
PubMed1977

Studies on the contribution of active metabolites to the anticonvulsant effects of propranolol.

The anticonvulsant activity of propranolol and two selected metabolites, propranolol glycol and N-desisopropylpropranolol were compared in mice against 4 types of experimentally induced seizures: pentylenetetrazol, strychnine, low frequency and maximal electroshock. Both metabolites possessed significant anticonvulsant activity with propranolol glycol being 1/2 to 1/3 as potent and N-desisopropylpropranolol being 1/6 as potent as propranolol. The possible contribution of these two active metabolites to the acute anticonvulsant efficacy of propranolol was assessed in time course studies. Maximal anticonvulsant activity occurred between 2.5--10 min after propranolol (5-20 mg/kg, i.v.) and was significantly diminished after 30 min. Following propranolol, brain levels of both metabolites were extremely low ( less than 10 ng/g) at the onset of anticonvulsant action and reached peak levels between 15-30 min at which time anticonvulsant activity was already declining. In contrast, brain levels of propranolol were similar in time course to that observed for its anticonvulsant effect and there was significant positive correlation between these two parameters in 3 of the 4 seizure models. These data indicate that although these two metabolites are pharmacologically active, they do not contribute significantly to the acute anticonvulsant actions observed after propranolol administration.

Animals↗
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↗
PubMed1978

The anticonvulsant action of L-2,4-diaminobutyric acid.

The GABA uptake inhibitor, L-2,4-diaminobutyric acid (L-DABA) was examined for potential anticonvulsant activity in mice. Given intracerebroventricularly (i.c.v., 2 mumoles) L-DABA almost doubled the CD50 of picrotoxin and 3-mercaptopropionate (3-MP), a glutamate decarboxylase inhibitor--the convulsants being administered 15 min after the L-DABA. The anticonvulsant effect was not observed after 40 min. L-DABA given i.p (5 mmoles/kg) was also anticonvulsant against 3-MP but given i.p. or i.c.v. had no anticonvulsant action against strychnine. The D-isomer of DABA, less active as an inhibitor of GABA uptake, had no anticonvulsant activity against 3-MP and nor did three other inhibitors of GABA uptake, namely nipecotic acid, cis-1,3-aminocyclohexane carboxylic acid (ACHA) and beta-alanine. Possible mechanisms of the anticonvulsant action of L-DABA are discussed.

3-Mercaptopropionic Acid↗
PubMed1976

Plasma level monitoring of anticonvulsants.

The plasma concentrations of anticonvulsant drugs, and of certain of their biologically active metabolites, tend to be proportionate to the antiepileptic effects of these drugs. Consequently, anticonvulsant drug levels in plasma are monitored to help guide the clinician in managing his patients' epilepsies. In making use of the measurements, the clinician needs to know the relation between plasma level and biological effect for the various drugs. He also needs to have some awareness of simple pharmacokinetic principles. These are important in deciding when plasma levels should be monitored in relation to the patients' clinical state, to the dosage interval, and to change in the dosage of anticonvulsant or other drug. The clinician also requires pharmacokinetic knowledge in altering anticonvulsant drug dosage in his patients, and in interpreting plasma anticonvulsant level data, particularly when the patient is concurrently suffering from non-neurological disease. The ability to monitor plasma anticonvulsant levels has appreciably improved the treatment of epilepsy, but to obtain maximum benefits from the method, both pharmacokinetic insight and clinical wisdom are required.

Adult↗
PubMed1978

Anticonvulsant action of cannabis in the rat: role of brain monoamines.

The role of brain monoamines in the anticonvulsant action of Cannabis indica resin (CI), against maximal electroshock-induced seizures in albino rats, was investigated by using pharmacologic agents that influence brain monoamine activity. Delta-9-tetrahydrocannabinol content of cannabis resin was estimated to be 17%. The anticonvulsant action of CI (200 mg/kg, i.p.) was significantly inhibited after pretreatment with drugs that reduce brain serotonin activity but not by drugs that reduce brain catecholamine activity. Similarly, the anticonvulsant action of a subanticonvulsant dose (50 mg/kg, i.p.) of CI was potentiated by serotonin precursors but not by catecholamine precursors. Potentiation of the anticonvulsant action of CI by nialamide or by imipramine was inhibited after pretreatment with 5,6-dihydroxytryptamine. The results suggest that the anticonvulsant action of CI in the rat is serotonin- and not catecholamine-mediated.

Animals↗
PubMed1979

Enhancement of GABA-mediated postsynaptic inhibition in cultured mammalian spinal cord neurons: a common mode of anticonvulsant action.

Murine spinal cord neurons grown in dissociated cell culture were used to study the effects of barbiturate (phenobarbital, mephobarbital) and benzodiazepine (diazepam, chlordiazepoxide( anticonvulsants on amino acid responses. Both types of anticonvulsant augmented GABA-mediated postsynaptic inhibition without augmenting beta-alanine or glycine-mediated postsynaptic inhibition. Barbiturates, but not benzodiazepines, antagonized glutamate-mediated postsynaptic excitation. Augmentation of GABA-mediated inhibition by the anticonvulsants should contribute to their anticonvulsant action; antagonism of glutamate-mediated excitation by barbiturates should also contribute to their anticonvulsant action and could be at least in part responsible for their sedative actions.

Animals↗
PubMed1979

Correlation between benzodiazepine receptor occupation and anticonvulsant effects of diazepam.

The benzodiazepines are potent anticonvulsants for a wide variety of experimental and clinical seizure disorders. The demonstration of saturable, high-affinity and stereospecific binding sites for the benzodiazepines in the mammalian central nervous system suggests the presence of pharmacological receptors mediating the anticonvulsant properties of these compounds. The good correlation between the anticonvulsant potencies of a series of benzodiazepines and their ability to inhibit 3H-diazepam binding in vitro further supports this hypothesis, but evidence for a direct interaction between benzodiazepines and their receptors, and a subsequent inhibition of seizure activity (or elevation of seizure threshold) is lacking. Recent reports from our laboratory and others have demonstrated the feasibility of labelling benzodiazepine receptors in vivo following parental administration of tritiated benzodiazepine. This technique permits one to study the relationship between the anticonvulsant activity of the benzodiazepines in vivo and the number of 'drug-occupied' receptors in vitro. We now report that there is an excellent correlation between benzodiazepine receptor occupancy by diazepam and protection against pentylenetetrazol-induced seizures. Furthermore, these results demonstrate that only a small fraction of benzodiazepine receptors need be occupied to produce a complete anticonvulsant effect.

Animals↗
PubMed1977

Anticonvulsant activity and selective inhibition of NAD-dependent oxidations by 1,4-disubstituted piperazines.

Several 1-(1-aryl-3-ethylthiocarbamido)-4-(arylaminothiocarbonyl)piperazines were synthesized, characterized by their sharp melting points and elemental analyses and evaluated for anticonvulsant activity. All disubstituted piperazines at a dose of 100 mg/kg i.p. provided 10-90% protection against pentylenetetrazol-induced convulsions in mice. These disubstituted piperazines selectively inhibited the in vitro oxidation of nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, alpha-ketoglutarate, beta-hydroxybutyrate and NADH by rat brain homogenates. The NAD-independent oxidation of succinate remained unaltered. The anticonvulsant activity possessed by disubstituted piperazines was unrelated with their ability to selectively inhibit respiratory activity of rat brain homogenates. Amongst 1-(substituted benzyl)-4-(substituted benzoyl)piperazines exhibiting central nervous system (1, 2) depressant activity it was found that 1-(2-chlorobenzyl)-4-(2-chlorobenzoyl)piperazine possessed maximum activity (2). The ability of piperazine carbamides (3) and piperazinothiocarbamides to possess anticonvulsant activity (4) prompted synthesis of 1-(1-aryl-3-ethylthiocarbamido)-4-(arylaminothiocarbonyl)piperazines and evaluation of their anticonvulsant activity. The effects of these disubstituted piperazines were also investigated on the in vitro respiratory activity of rat brain homogenates in an attempt to elucidate the biochemical mechanism of action for their anticonvulsant activity.

Animals↗
PubMed1976

Measurement of anticonvulsant activity in the Papio papio model of epilepsy.

The status of Papio papio as a model of clinical epilepsy has been reviewed. The anticonvulsant effects of single doses of various classic and experimental agents have been compared against seizures induced in the P. papio by intermittent light stimulation. Long-acting but not short-acting barbiturates have been shown fully to control seizures with minor sedative effects. Diphenylhydantoin (in chronic doses only) and trimethadione are often effective but not consistently so. Diazepam and clonazepam block seizures at very low doses both acutely and chronically. However, an initial dose well above threshold seems essential if anticonvulsant effects are to be maintained under chronic administration of these compounds. Carbamazepine and SC 13504 (1-benzhydryl-4(6 methyl-2-pyridylmethyleneimino)piperazine), as well as two nonstimulant analogues of amphetamine, were shown to be promising anticonvulsants in this model. A biphasic action of tetrahydrocannabinol, anticonvulsant at a few micrograms per kilogram but not at higher doses, was also demonstrated. Finally, the anticonvulsant action of intraventricular epinephrine and norepinephrine was reported.

Animals↗
PubMed1979

Inhibitory effects of anticonvulsant drugs on cyclic nucleotide accumulation in brain.

Veratridine causes deplorization of excitable cells and produces marked elevation of adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP) levels in incubated slices of mouse cerebral cortex. Phenytoin, carbamazepine, phenobarbital, primidone, phensuximide, methsuximide, alpha-methyl-alpha-phenylsuccinimide, and high concentrations of clonazepam are anticonvulsant drugs that preferentially prevent maximal electroshock seizures (MES) and generalized tonic-clonic convulsions; all these agents inhibit veratridine-induced accumulation of both cyclic AMP and cyclic GMP. In contrast, ethosuximide, trimethadione, valproic acid, and low concentrations of clonazepam are anticonvulsant drugs that act predominantly against Metrazol and absence seizures; these agents are ineffective or inhibit accumulation of only cyclic GMP. The results suggest that inhibition of cyclic AMP and cyclic GMP accumulation in depolarized brain tissue is a molecular neuropharmacological action characteristic of anticonvulsant drugs that have direct effects on cellular membrane function and prevent MES. Anticonvulsant drugs that do not inhibit accumulation of both cyclic AMP and cyclic GMP in depolarized brain tissue preferentially prevent Metrazol and absence seizures and probably exert their effects by altering neurotransmission mechanisms.

Animals↗
PubMed1978

[Development of new antiepileptics. IV. Anticonvulsant activity of some derivatives of 1-(p-sulfamoyl-phenyl)-pyrrolidin-2-one (author's transl)].

A series of derivatives of 1-(p-sulfamoyl-phenyl)-pyrrolidin-2-one were tested for anticonvulsant properties in rats and mice. The substance 1-(o-chloro-p-sulfamoyl-phenyl)-4-phenyl-pyrrolidin-2-one (1725) was found to have potent anticonvulsant activities in rats and mice against seizures induced by electroshock or pentylenetetrazol. The unsubstituted phenyl ring has to be in position 4, otherwise the activity of the product is weakened. The ortho position of the halogen atom on the N-phenyl is also important for the anticonvulsant effect; chlorine acts better than fluorine. The anticonvulsants tested also potentiate the sleeping time induced by pentobarbitone and attenuate the motor activity of mice. 1-(o-Chloro-p-sulfamoyl-phenyl)-4-phenyl-pyrrolidin-2-one (1725) has a LD50 of 1000 mg/kg p.o.; the lesser active substances generally have a LD50 greater than 5000 mg/kg p.o. Toxic effects of large doses were manifested by sedation and diarrhoea.

Animals↗