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

We sought to determine whether the clinically effective anticonvulsant drug valproate exhibited antiepileptogenic properties in the kindling model (we use the term anticonvulsant to mean suppression of seizure, and antiepileptogenic to mean suppression of development of epilepsy). We compared and contrasted valproate with two other anticonvulsant drugs, phenobarbital and carbamazepine. We investigated the effects of these drugs on the development of kindling, that is, the number of stimulation-induced afterdischarges required to induce enhanced seizure susceptibility in rats. Valproate exhibited powerful antiepileptogenic effects as evident in a dose-dependent increase in the number of afterdischarges required to induce kindling. These effects were not due to retained valproate or an active metabolite merely masking the expression of kindled seizures. By contrast, carbamazepine was devoid of any antiepieptogenic effects despite exhibiting marked anticonvulsant effects. Like valproate, phenobarbital exhibited both antiepileptogenic and anticonvulsant properties, but its antiepileptogenic properties were significantly less pronounced. The antiepileptogenic effects of valproate and phenobarbital strengthen the candidacy of these agents for the clinical studies needed to investigate pharmacological prevention of the development of epilepsy in high-risk groups.
 ...
PMID:Antiepileptogenic effects of conventional anticonvulsants in the kindling model of epilespy. 192 6

The heterogenous psychoses in epilepsies, caused by well known conditions, are not rare but associated with regularly a few of seizure-types not with the nature and development of attacks. Polar transitional ranks and converging courses of schizophrenic (accentuated) syndromes in epilepsies and idiopathic schizophrenias are rather frequent. Also (sub-)acute schizophrenic psychoses are corresponding to the complete palette of first and second rank symptoms (K. Schneider) of idiopathic schizophrenias. After manifestations of epilepsy these syndromes can appear at any time. It is given a profile of risks. Progressive avoidance of a. phenylaceturea, b. mixtures of antiepileptics did not put an end to psychotic syndromes: Long-term therapies with 1. Polytherapy, 2. Primidone and Phenytoin (dosedependant) as well as 3. Ethosuximide (-monotherapy) cause a disorder of feed back mechanisms, especially a disturbed regulation of vigilance and sleeping-waking-cycle and their psychological correlates. Carbamazepine and Sodium Valproate are, plasma-level-controlled of preventive antipsychotic effect. Selected neuroleptics of rather slight epileptogenic potency are of going down importance. Benzodiazepines are required mostly in prepsychotic syndromes, Lithium compounds in selected cases. There is no more alternative seizures or psychosis.
 ...
PMID:[Psychoses in epilepsy]. 198 Oct 95

The E-isomer of 2-unsaturated valproate (E-delta 2-VPA) is a pharmacologically active metabolite of VPA that is less teratogenic and hepatotoxic than its saturated precursor. To assess potential use of E-delta 2-VPA as an alternate to VPA, a dose-response study comparing the anticonvulsant activity and neurotoxicity of E-delta 2-VPA and VPA was conducted in rats using the intravenous (i.v.) pentylenetetrazol (PTZ)-infusion threshold seizure model. Assay of drug in whole brain and plasma allowed comparison of the drug concentration-effect relationships and the brain distribution characteristics of the two compounds. E-delta 2-VPA was two to three times more potent than VPA in elevating the clonic seizure threshold of PTZ, in reference to either plasma or whole-brain drug concentrations. Furthermore, much steeper response curves were observed with E-delta 2-VPA as compared with VPA. Within the pharmacologic concentration range (defined as EC25 to EC75), E-delta 2-VPA was less neurotoxic than VPA as assessed by behavioral tests. Therefore, E-delta 2-VPA has a much more favorable protective index than VPA. At low doses, the concentration ratios of brain to plasma for both E-delta 2-VPA and VPA increased markedly with increasing plasma drug concentration. E-delta 2-VPA and VPA were previously shown to exhibit saturable binding to rat plasma proteins. If we assume that uptake of drug into the CNS is limited to the equilibrium plasma free fraction in the brain microvasculature, much of the nonlinear brain distribution features of VPA could be accounted for by saturable drug plasma protein binding. On the other hand, more complex kinetics involving simultaneous saturation of plasma protein binding and blood-to-brain transport are proposed to explain the brain distribution of the unsaturated compound. In addition, the brain-to-free drug concentration ratios for both E-delta 2-VPA and VPA were below unity at high drug-concentration range, consistent with the presence of an efficient efflux mechanism of these compounds from brain.
 ...
PMID:Comparative pharmacodynamics and brain distribution of E-delta 2-valproate and valproate in rats. 200 28

The possible synergistic effect of valproic acid and ethosuximide in combination on pentylenetetrazole-induced epilepsy was investigated in rats. Valproic acid and ethosuximide administered intraperitoneally both showed dose-dependent anti-epileptic activity towards pentylenetetrazole-induced myoclonias and tonic-clonic seizures. The valproic acid-ethosuximide combination had a synergistic pharmacological effect. Against myoclonias combined valproic acid-ethosuximide produced a non-significant decrease in the effective dose of both drugs compared with treatment with either drug alone. In the case of tonic-clonic seizures the protective effect against the seizures was significantly increased by combined treatment compared with treatment with either drug alone. Neither plasma concentrations nor any other pharmacokinetic parameters were significantly changed when the same doses of valproic acid and ethosuximide were given, singly or in combination.
 ...
PMID:Synergistic anticonvulsant effect of valproic acid and ethosuximide on pentylenetetrazole-induced epileptic phenomena in rats. 201 16

Problems with anticonvulsants in women of child-bearing potential include potential adverse effects on appearance, contraception and pregnancy. These effects must be weighed against the overwhelming benefits of anticonvulsant treatment in the majority of women with epilepsy. Coarsened features, hirsutism and acne may occur in both men and women, particularly if they are exposed to phenytoin. Valproic acid may cause weight gain and hair loss, while carbamazepine treatment carries a significant risk of skin rashes. Anticonvulsants which are liver enzyme inducers (phenytoin, phenobarbital, primidone and carbamazepine) reduce the efficacy of the oral contraceptive pill. No 'pill failure' has been reported with valproic acid. There is a risk of increased seizure frequency in pregnancy irrespective of whether anticonvulsant treatment is taken. Individual seizures carry little risk to the mother or the fetus but status epilepticus has a significant maternal and fetal mortality. The risk of status epilepticus must be taken into account when deciding whether to stop anticonvulsant treatment before pregnancy. There is a 2 to 3 times increased malformation rate in the offspring of epileptic women on treatment. This is primarily due to the drug treatment, but epilepsy itself may also increase the malformation rate. Most malformations are mild and include facial clefts, congenital heart disease and skeletal abnormalities. Valproic acid, however, carries a 1% risk of causing neural tube defects: women receiving this drug who become pregnant should have an ultrasound and alpha-fetoprotein estimation at 16 to 18 weeks of pregnancy. If any abnormality is detected then amniocentesis should be carried out. Women with epilepsy should be counselled before conception and during pregnancy. Before achieving pregnancy a women should be on optimum treatment, preferably on one anticonvulsant. Consideration should be given to withdrawal of anticonvulsant drugs in any woman who has been seizure free for 2 years or who has only mild and infrequent seizures. Folate supplementation should be started prior to conception and should continue during pregnancy. There is a tendency for anticonvulsant drug concentrations to fall during pregnancy, and the dose may need to be increased if clinically indicated. Over 90% of epileptic women who become pregnant will have uneventful pregnancies and will produce healthy infants.
 ...
PMID:Risk-benefit assessment of anticonvulsants in women of child-bearing potential. 202 55

(1) Valproic acid is an anticonvulsant agent widely used in the management of various forms of epilepsy, including absence, myoclonic and tonic-clonic seizures. (2) It also has anticonvulsant potency in a wide variety of animal models of epilepsy. (3) This action is generally thought to be exerted through modulation of the activity of the endogenous inhibitory neurotransmitter, gamma-aminobutyric acid. (4) Evidence that valproic acid interacts with the gamma-aminobutyric acid system is presented. (5) Interactions of valproic acid with other neurotransmitters, i.e. aspartate, glutamate, taurine, serotonin, as well as with cyclic nucleotides and hormones are also considered. (6) Direct effects of valproic acid on excitable membranes and its relationships with analgesia are outlined.
 ...
PMID:Neurophysiological and biochemical changes evoked by valproic acid in the central nervous system. 211 Mar 71

We reported a case of early infantile epileptic encephalopathy (EIEE) due to perinatal hypoxic-ischemic brain damage. This infant had frequent brief tonic seizures in series accompanied by apnea and bradycardia since two days after birth. Her EEG showed a typical suppression burst pattern. We administered PB. VPA and CZP, but could not control her seizures at all. Then, a thyrotropin releasing hormone (TRH) analog, in addition to PB and VPA, was administered intravenously (0.5 mg/day) to her. Three weeks after the administration of this TRH analog, her seizures ceased completely. We suggest that TRH analog therapy should be considered as one of therapeutics for EIEE whose prognosis is expected to be poor.
 ...
PMID:[Effectiveness of TRH analog in a case of early infantile epileptic encephalopathy]. 212 Nov 73

Twenty consecutive patients with chronic partial seizures with onset before twenty years of age were investigated by means of 0.5 T MRI (20) and HM-PAO (19) in order to identify focal alterations amenable to surgical therapy. MRI evidentiated parenchymal lesions in 7 patients. Findings consistent with unilateral medial temporal sclerosis and cortico-subcortical parietal scars were found in two patients each. Small solid nodular lesions in the temporal lobe were observed in two patients. These and one additional patient with nodular partially cystic lesions in temporal lobe were administered a paramagnetic contrast agent (Gadolinium DPA) intravenously. In one case a contrast enhancement was observed. Histologic examination post surgery revealed a low grade glioma in one patient. HM-PAO SPECT examination showed area of abnormal captation in 9 of 19 patients. Aspects of EEG correlation with the MRI and SPECT findings are discussed. Our data supported the usefulness of magnetic resonance and SPECT imaging in the completion of pre-surgical assessment in this kind of patients.
 ...
PMID:[MRI and HM-PAO SPECT in 20 patients with drug-resistant partial epilepsy]. 212 12

Valproic acid (VPA) is an antiepileptic drug used in the treatment of a wide variety of human seizures including generalized absence (GA) (petit mal) seizures. The mechanism of action of VPA in controlling GA seizures is not known. We tested the effects of VPA on the Ca2+ current components of acutely dissociated rat nodose ganglion neurons. VPA reduced the low-threshold (T) Ca2+ current at clinically relevant concentrations but had no effect on the high-threshold (N and L) current components. The effect on T current was concentration-dependent and most apparent at peak current. There was little effect seen on late current. VPA did not affect the rate or voltage-dependency of T current activation. The selective reduction of T current may be a means by which VPA is effective in controlling GA seizures.
 ...
PMID:Valproic acid selectively reduces the low-threshold (T) calcium current in rat nodose neurons. 217 4

The influence of the anti-epileptic drug, valproate, on K conductance (gK) was investigated in voltage-clamped Ranvier nodes of Xenopus laevis. A double pulse method was used in order to eliminate the effect of accumulation of potassium ions in the perinodal space, thus enabling the determination of the 'true' magnitude of gK. Valproate (2.4 mM) had a voltage-dependent action on the magnitude of gK. With small step depolarizations more negative than about -50 mV, valproate increased gK (20 ms after the step) to approximately 12% of the maximal gK, an increase which disappeared due to a relatively rapid (less than 200 ms) inactivation process. However, with step depolarizations more positive than about -50 mV, valproate markedly reduced gK (20 ms after the step) at greater depolarizations, with a maximum of about 40% of the maximal gK. Moreover, at these voltages gK was inactivated completely (less than or equal to 10 s), whereas under control conditions the inactivation was only partial. Both the temporary increase and the steady state decrease of gK could contribute to an anti-epileptic effect by increasing the action potential threshold and by preventing excessive depolarizations of the nerve during epileptic seizures, respectively.
 ...
PMID:Voltage-dependent action of valproate on potassium channels in frog node of Ranvier. 220 10


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>