Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.
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PMID:Valproate monotherapy in the management of generalized and partial seizures. 312 Dec 91

In a prospective open study of 20 male epileptic residents of a mental handicap institution, polytherapy was gradually reduced to valproate monotherapy in 18 subjects. In terms of seizure frequency this was significantly disadvantageous but when carbamazepine was added or substituted, seizure control improved significantly. Drugs with documented adverse effects on cognitive function such as phenobarbitone and phenytoin were phased out. In the 18 subjects who achieved valproate monotherapy, no association between serum levels and seizure control could be demonstrated. Adverse effects of valproate were pancreatitis and thrombocytopenia; in one subject thrombocytopenia appeared to be associated with levels in the toxic range but in six other subjects 'toxic' levels of valproate did not give rise to any clinically detectable toxic signs. There was no instance of tremor or weight gain. It was concluded that, in the population studied (institutionalized patients with chronically uncontrolled seizures) valproate monotherapy was inappropriate but carbamazepine with or without valproate was a better option. Phasing out phenytoin and phenobarbitone was successful. Valproate serum levels did not contribute significantly to the conduct of the study; no general relationship between valproate serum levels and either seizure control or toxicity could be demonstrated.
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PMID:Is valproate monotherapy a practical possibility in chronically uncontrolled epilepsy? 312 41

Valproic acid and several structurally related carboxylic acids and tetrazole analogues have been shown to antagonize seizures induced by pentylenetetrazole in mice. To investigate the influence of the alkyl substituents on the anticonvulsant activity, the octanol-water partition coefficients and relative pKa values were determined. Within the series of active carboxylic acids, there was a good correlation between the anticonvulsant activity and the partition coefficient (r = 0.86). The influence of pKa on the anticonvulsant activity was small but of statistical significance. When the most active compound, 5-heptyltetrazole was added to the carboxylic acid series, a low correlation between the anticonvulsant activity and a linear combination of lipophilicity and pKa resulted. The effect of the polar moieties in alkyl-substituted anticonvulsant compounds was assessed by comparison of the regression equations with either an added pKa or dipole moment term to the term for lipophilicity. It appears that other factors, such as the nature of the alkyl substituent, influence the anticonvulsant activity. The inactivity of the cyclohexylmethyl-substituted compounds, cyclohexylacetic acid and 5-cyclohexylmethyltetrazole may be due to subtle steric effects at a critical step, either involving oxidative metabolism or an interaction at an active site.
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PMID:Quantitative structure-anticonvulsant activity relationships of valproic acid, related carboxylic acids and tetrazoles. 313 93

The anticonvulsive effectiveness of VPA syrup is evaluated in an international open phase III clinical trial. The study includes 96 childhood epilepsies and encompasses a rather heterogeneous test population regarding type of epilepsy and/or seizures. Clinical results stress the good therapeutic outcome in single drug treatment, regardless of the underlying epileptic syndrome, seizure type or serum concentration. Therapeutic failure is more often associated with combined drug treatment, symptomatic generalized epilepsies and serum levels below the therapeutic range. The anticonvulsive spectrum, tolerance and dose/level ratio are comparable with the characteristics of the drug's other galenic forms.
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PMID:VPA syrup in childhood epilepsy. Results of an international clinical multicentre trial. 314 May 68

The antiepileptic action of ethosuximide and valproate was studied in immature rats in the pentetrazole (PTZ) model. Valproate antagonized the effect of PTZ in rats of all ages, while ethosuximide was effective only in rats of 25 or more days of age: in 18 day old rats it modified the PTZ seizure pattern and was ineffective in younger animals or only slightly affected the PTZ seizure pattern. Similarly, the ECoG studies have shown that valproate antagonizes PTZ action at all ages, while ethosuximide only in mature rats.
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PMID:Comparison of antiepileptic action of valproate and ethosuximide in adult and immature rats. 314 56

A 5 years old girl with status epilepticus refractory to treatment with Diphenylhydantoin at a dose of 30 mg/kg/day and Thiopental in continuous IV perfusion at a dose of 4 mg/kg/h is presented. Control of status was achieved by continuous IV perfusion of Chlormethiazole at a dose of 10 mg/kg/h which also caused respiratory depression. Seizure activity reappeared after IV perfusion of Chlormethiazole was retired, and could be controlled only with Sodium Valproate. Mechanisms of action of Chlormethiazole and its effectiveness in treatment of refractory status epilepticus are revised.
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PMID:[Treatment of refractory status convulsivus with chlormethiazole]. 314 89

The influence of antiepileptic drugs on the wet dog shakes (WDS) induced by intracerebroventricular injections of carbachol (30 micrograms icv) was investigated in rats. Diphenylhydantoin (DPH, 8 and 4 mg/kg), diazepam (0.4, 0.2 and 0.1 mg/kg), phenobarbital (12.5, 6.25 and 3.12 mg/kg), sodium valproate (Depakine, 200, 100 and 50 mg/kg) and trimethadione (200, 100 and 50 mg/kg) given ip inhibited the WDS in a dose-dependent manner. These drugs at the same doses did not change the intensity of shaking behavior induced by lithium chloride or 5-hydroxytryptamine. As the antiepileptic drugs tested in these experiments did not have anticholinergic activity and at used doses were not able to prevent electrical convulsions or pentetrazol-induced seizures, it appears that carbachol-induced WDS could be connected with convulsive activity and could be the initial stage of seizures.
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PMID:Inhibition by antiepileptics of carbachol but not lithium- or 5-methoxytryptamine-induced wet dog shakes in rats. 314 10

This article reviews the current literature describing the use of rectally administered antiepileptic drugs. Individual antiepileptic drugs are discussed in regard to efficacy, toxicity, and rate of absorption. Absorption occurs through passive diffusion; therefore, solutions are absorbed most quickly. Paraldehyde, diazepam, secobarbital, and valproic acid are used when rapid effect for termination of prolonged or serial seizures is desired. Valproic acid, lorazepam, carbamazepine, and phenytoin all can be used for maintenance therapy.
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PMID:Rectal administration of antiepileptic drugs in children. 333 21

Urinary valproate metabolite and endogenous organic acid profiles in a 6-yr-old girl with Reye's syndrome were investigated by means of gas chromatography-mass spectrometry. 2-n-Propyl-3-oxovaleric acid, normally the major metabolite of valproate in man, was undetectable, while 2-n-propylglutaric acid, the end product via omega-oxidation was markedly increased. Polyunsaturated valproate was not found. Valproate-glucuronide was still found as the major metabolite. The clinical findings coupled with a greatly increased excretion of lactate and adipate was compatible with Reye's syndrome. Ketone bodies were not detectable. This case study shows that Reye's syndrome causes altered valproate metabolism, consistent with the defective mitochondrial beta-oxidation of medium chain fatty acids, and suggests that valproic acid should not be used in the treatment of seizures in patients with this syndrome.
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PMID:Altered metabolic profiles of valproic acid in a patient with Reye's syndrome. 391 13

A newly developed synaptosomal model was used to evaluate the in vivo effects of the GABA-elevating drugs aminooxyacetic acid (AOAA, 30 mg/kg i.p.) and valproic acid (VPA, 200 mg/kg i.p.) on GABA levels in nerve endings of 11 brain regions in rats as a function of time after administration. The data obtained were compared with the magnitude and time course of the effects of both drugs in rats on body temperature, pain response and against seizures induced by electroshock, pentylenetetrazol and 3-mercaptopropionic acid. Following AOAA, maximum increases in synaptosomal GABA levels of brain regions were observed 6 hr after administration. At this time, GABA was significantly elevated up to 300% over control values in synaptosomal fractions from all 11 regions. However, the hypothermic and antinociceptive effects of the drug as well as its anticonvulsant action against electroshock and pentylenetetrazol induced seizures were maximal 1 hr after injection and had vanished after 6 hr, i.e. at the time of maximum GABA increases in synaptosomes. The only pharmacological effect of AOAA which paralleled the time course of the synaptosomal GABA elevation was the attenuation of seizures induced by 3-mercaptopropionic acid. Following VPA, the effect on synaptosomal GABA levels was much more rapid in onset and significant increases were already determined 5 to 30 min after administration. Significant increases of up to 80% over control values were found in synaptosomal fractions from olfactory bulb, frontal cortex, hippocampus, hypothalamus, tectum, substantia nigra and cerebellum. In contrast to AOAA, the time course of the synaptosomal GABA increases, at least in some regions, was similar to the time course of VPA's antinociceptice effects and its anticonvulsant effects in the three seizure models studied. The data may suggest that AOAA and VPA increase different pools of GABA within nerve terminals, only one of which is involved in GABA-mediated neurotransmission.
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PMID:In vivo effects of aminooxyacetic acid and valproic acid on nerve terminal (synaptosomal) GABA levels in discrete brain areas of the rat. Correlation to pharmacological activities. 392 47


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