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)

Effects of calcium channel blockers were investigated on withdrawal signs in lorazepam dependent rats. Physical dependence was produced by giving lorazepam admixed with the food in the following dose schedule: 10 x 4, 20 x 4, 40 x 4, 80 x 4 and 120 x 7 (mg/kg daily x days). Parameters such as body weight, food intake, spontaneous locomotor activity (SLA), body temperature, reaction time to pain, foot shock-aggression (FSA) and audiogenic seizures were observed during the period of administration of lorazepam and after its withdrawal. Calcium channel blockers viz. verapamil, nifedipine and nimodipine in different doses were administered orally twice daily in separate groups during the withdrawal period. The withdrawal signs observed in control group (without calcium channel blockers) were hyperkinesia, hyperthermia, hyper-aggression and audiogenic seizures. The administration of verapamil (5-20 mg/kg), nifedipine (1.75-7 mg/kg) and nimodipine (5-20 mg/kg) during the withdrawal period of lorazepam showed dose dependent significant blockade of all the withdrawal signs. Audiogenic seizures were completely blocked by 20 mg/kg dose of verapamil and nimodipine while nifedipine was partially effective. It may be concluded that calcium channel blockers exert protective effects on benzodiazepine withdrawal syndrome.
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PMID:Effect of calcium channel blockers on withdrawal syndrome of lorazepam in rats. 870 72

Pentylenetetrazole (PTZ)-induced convulsions and the maximal electroshock (MES) seizure test were employed to study the anticonvulsant effects of nifedipine (2, 3.5 and 5 mg kg-1), flunarizine (10, 20 and 40 mg kg-1) and diltiazem (10, 15 and 30 mg kg-1). Nifedipine and flunarizine prolonged the latent period and reduced the mean duration of PTZ induced seizures. They also reduced the severity of convulsions and the number of deaths due to PTZ significantly. Nifedipine was more potent in this regard (P < 0.01). All these drugs prolonged the latent period and reduced the duration of tonic extensor phase of MES seizures in a significant manner. Flunarizine was most potent in this test. Complete protection from tonic extensor phase was observed in 10-50% animals pretreated with nifedipine and flunarizine in a dose dependent manner. The response of diltiazem was weak in both these tests. It is concluded that all three calcium channel blockers possess an important but different anticonvulsant effect and their significant clinical use can be made while keeping in view the characteristics of their pharmacological action.
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PMID:Comparative evaluation of anticonvulsant activity of calcium channel blockers in experimental animals. 871 76

This study investigated the behavioural and anticonvulsant effects of voltage-sensitive calcium channel blockers in DBA/2 mice. Omega-Conotoxin MVIIC (0.1, 0.3 micrograms ICV/mouse) and omega-agatoxin IVA (0.1, 0.3, 1 micrograms ICV), which act predominantly at P- and/or Q-type calcium channels, prevented clonic and tonic sound-induced seizures in this animal model of reflex epilepsy (ED50 values with 95% confidence limits for protection against clonic sound-induced seizures were 0.09 (0.04-0.36) micrograms ICV and 0.09 (0.05-0.15) micrograms ICV respectively and against tonic seizures 0.07 (0.03-0.16) micrograms ICV and 0.08 (0.04-0.13) micrograms ICV, respectively). The N-type calcium channel antagonists omega-conotoxin GVIA and omega-conotoxin MVIIA were also tested in this model. Omega-Conotoxin GVIA was anticonvulsant in DBA/2 mice, but only at high doses (3 micrograms ICV prevented tonic seizures in 60% of the animals; 10 micrograms ICV prevented clonic seizures in 60% and tonic seizures in 90% of the animals), whereas omega-conotoxin MVIIA did not inhibit sound-induced seizures in doses up to 10 micrograms ICV. Both omega-conotoxin GVIA and omega-conotoxin MVIIA induced an intense shaking syndrome in doses as low as 0.1 microgram ICV, whereas omega-conotoxin MVIIC and omega-agatoxin IVA did not produce shaking at any of the doses examined. Finally, omega-conotoxin GI (0.01-1 microgram ICV) and alpha-conotoxin SI (0.3-30 micrograms ICV), which both act at acetylcholine nicotinic receptors, were not anticonvulsant and did not induce shaking in DBA/2 mice. These results confirm that blockers of N- and P-/Q-type calcium channels produce different behavioural responses in animals. The anticonvulsant effects of omega-conotoxin MVIIC and omega-agatoxin IVA in DBA/2 mice are consistent with reports that P- and/or Q-type calcium channel blockers inhibit the release of excitatory amino acids and are worthy of further exploration.
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PMID:Behavioural and anticonvulsant effects of Ca2+ channel toxins in DBA/2 mice. 885 21

Among three calcium channel inhibitors, only nicardipine (10-40 mg/kg) significantly inhibited clonic seizures induced by pentylenetetrazol administered at its CD97 (convulsive dose 97%) of 81 mg/kg, subcutaneously. Nimodipine and flunarizine (both up to 80 mg/kg) did not suppress pentylenetetrazol-induced clonic seizures per se. Co-administration of nicardipine (5 mg/kg) resulted in a significant enhancement of the protective potency of either ethosuximide (50 mg/kg) or valproate (100 mg/kg) against clonic seizures in this test. Similar effects were noted in case of combined treatment of nimodipine (20-40 mg/kg) with these antiepileptics. On the contrary, flunarizine (up to 20 mg/kg) did not modify the anticonvulsive action of these antiepileptic drugs. Moreover, none of the studied calcium channel inhibitors influenced the protective activity of clonazepam (0.01 mg/kg). The antiepileptic drugs, administered alone in above doses, were ineffective against pentylenetetrazol-induced clonic convulsions. In case of ethosuximide and valproate, the motor performance in the chimney test was worsened by co-administration of nimodipine (40 mg/kg). We found no pharmacokinetic interactions (at least in relation to the plasma levels of ethosuximide and valproate) that could explain the observed results. Thus, we conclude that a combination of some calcium channel inhibitors and antiepileptic drugs may provide more efficient protection against experimental seizures which may bear a potential clinical significance.
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PMID:Influence of nicardipine, nimodipine and flunarizine on the anticonvulsant efficacy of antiepileptics against pentylenetetrazol in mice. 887 66

A case of moyamoya disease is presented. The patient is a 15-year-old white Spanish girl who had the onset of the neurological symptoms at 8 months of age with seizures, transient ischemic attacks and residual left hemiparesis. Cerebral arteriography performed at the age of 1 year revealed all the features of moyamoya disease in the territory of both carotids and in the vertebrobasilar arteries. The presence of an embryonic tentorial artery, the Bernasconi-Cassinari artery, originating from the right internal carotid artery, was disclosed at 1 year of age but did not appear in an arteriogram performed at 6 years of age and it was revisualized by magnetic resonance arteriography (MRA) performed at the age of 15 years. This finding seems to indicate a very early intrauterine onset of the disease in this case and demonstrates the superiority of MRA over conventional arteriography to discover anomalies of intracranial vessels. Administration of nicardipine, a calcium channel blocker, added to conventional antiepileptic drugs that the patient had previously taken, improved the epileptic and the neurological disease.
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PMID:Moyamoya disease with a marked collateral supply through the artery of Bernasconi-Cassinari. 890 48

3-(2-Hydroxyethyl) 5-methyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedi-carboxyla te (7) was prepared using a modified Hantzsch reaction, which was then elaborated to 3-[2-[[(1-methyl-1,4-dihydropyrid-3-yl)carbonyl]oxy]ethyl]5-methyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylat e [10, felodipine-chemical delivery system (CDS)]. The equipotent 3-(2-hydroxyethyl) 7 (IC50 = 3.04 x 10(-8) M) and felodipine-CDS (10, IC50 = 3.10 x 10(-8) M) were, respectively, 2- and 21-fold less potent calcium channel antagonists than the reference drugs nimodipine (IC50 = 1.49 x 10(-8) M) and felodipine (IC50 = 1.45 x 10(-9) M). Compounds 7, 10, nimodipine, and felodipine are highly lipophilic (Kp = 236, 366, 187, and 442, respectively). 3-(2-Hydroxyethyl) 7, felodipine-CDS (10), and felodipine provided protection against maximal electroshock-induced seizures in mice but were inactive in the subcutaneous metrazol anticonvulsant screen. In vitro incubation studies of felodipine with rat plasma and 20% brain homogenates showed felodipine was very stable in both biological media. Similar incubations of felodipine-CDS showed its rate of biotransformation followed psuedo-first-order kinetics with half-lives of 15.5 h in rat plasma and 1.3 h in 20% rat brain homgenates. In vivo biodistribution of felodipine and felodipine-CDS was studied. Uptake of felodipine in brain produced a peak brain concentration of 5 micrograms/g of brain tissue at 5 min, after which it rapidly egressed from brain resulting in undetectable levels at 60 min. Peak blood concentrations of 10 occurred at about 7 min followed by a rapid decline to a near undetectable concentration by 17 min. The pyridinium salt species 9, resulting from oxidation of 10, also reached peak concentrations at about 7 min but it slowly decreased to undetectable concentrations at 2 h. 3-(2-Hydroxyethyl) 7 remained at near undetectable concentrations throughout a 2 h time period. Localization of 10 in brain provided a peak concentration of 4.2 micrograms/g of brain tissue at 5 min and then decreased to negligible concentrations at 15 min. The concentration of oxidized pyridinium species 9 in brain remained high providing detectable concentrations up to 4 days. In contrast, the concentration of the 3-(2-hydroxyethyl) hydrolysis product 7 in brain remained at very low levels throughout the study. The slow hydrolysis rate of the pyridinium ester 9 to the 3-(2-hydroxyethyl) 7 and the rapid egression of felodipine-CDS from brain are believed to contribute to the moderate anticonvulsant activity exhibited hy the felodipine-CDS (10).
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PMID:Synthesis, biological evaluation, calcium channel antagonist activity, and anticonvulsant activity of felodipine coupled to a dihydropyridine-pyridinium salt redox chemical delivery system. 891 46

Mutations at the mouse tottering (tg) locus cause a delayed-onset, recessive neurological disorder resulting in ataxia, motor seizures, and behavioral absence seizures resembling petit mal epilepsy in humans. A more severe allele, leaner (tg(la)), also shows a slow, selective degeneration of cerebellar neurons. By positional cloning, we have identified an alpha1A voltage-sensitive calcium channel gene that is mutated in tg and tg(la) mice. The alpha1A gene is widely expressed in the central nervous system with prominent, uniform expression in the cerebellum. alpha1A expression does not mirror the localized pattern of cerebellar degeneration observed in tg(la) mice, providing evidence for regional differences in biological function of alpha1A channels. These studies define the first mutations in a mammalian central nervous system-specific voltage-sensitive calcium channel and identify the first gene involved in absence epilepsy.
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PMID:Absence epilepsy in tottering mutant mice is associated with calcium channel defects. 892 30

Gingival overgrowth is a known side effect of several seizure, immunosuppressant and calcium channel-blocker medications. Gingival overgrowth is not a reported side-effect of phenobarbital. This case report describes two patients with marked gingival overgrowth who had been medicated with phenobarbital exclusively since the initiation of seizure disorders. The clinical findings, surgical management, bleeding complications, and recommendations in management are discussed.
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PMID:Phenobarbital-induced gingival overgrowth? Report of two cases and complications in management. 901 73

Tottering and leaner, two mutations of the mouse tottering locus, have been studied extensively as models for human epilepsy. Here we describe the isolation, mapping, and expression analysis of Cacnl1a4, a gene encoding the alpha subunit of a proposed P-type calcium channel, and also report the physical mapping and expression patterns of the orthologous human gene. DNA sequencing and gene expression data demonstrate that Cacnl1a4 mutations are the primary cause of seizures and ataxia in tottering and leaner mutant mice, and suggest that tottering locus mutations and human diseases, episodic ataxia 2 and familial hemiplegic migraine, represent mutations in mouse and human versions of the same channel-encoding gene.
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PMID:Mutations in the Cacnl1a4 calcium channel gene are associated with seizures, cerebellar degeneration, and ataxia in tottering and leaner mutant mice. 906 Apr 10

A group of 3-alkyl 5-isopropyl 4-aryl-1,4-dihydro-2,6-dimethyl- 3,5-pyridinedicarboxylates 10-20 containing an amine, quaternary ammonium, aryl (heteroaryl)alkenyl, 4-(4-fluorophenyl)- piperazin-1-yl or methoxy moiety in the C-3 alkyl ester R-substituent in combination with a C-4 phenyl ring bearing a 2,3-Cl2, 3-NO2, 3-NMe2, 4-NMe2 or 3,4,5-(OMe)3 X-substituent were prepared using the Hantzsch 1,4-dihydropyridine reaction. In vitro calcium channel antagonist activity (CCA) was determined using a guinea pig ileum longitudinal smooth muscle assay. In the C-4 3-nitrophenyl series of compounds, the C-3 ester R-substituent was a determinant of CCA activity where the relative potency order was -CH2CH2CH=C-(2-methylphenyl)2 > or = -CH2CH2NMe2.HCI> -CH2CH2CH=C-(3-methyl-2-thienyl)2 > -CH2CH2+NMe3I -. The position and nature of the C-4 phenyl X-substituent, were also determinants of CCA activity where the relative activity order was 3-NMe2 > 4-NMe2 > 3,4.5-(OMe)3. Anticonvulsant activities were determined in mice using the subcutaneous metrazol (scMet) and maximal electroshock (MES) screens. The compounds investigated were generally not effective for protecting against scMet induced seizures, except for 10 (X = 2,3-Cl2, R = 2-[4-(4- fluorophenyl)piperazin-l-yl]ethyl] and 14a (X = 3-NMe2.HCl, R = CH2CH2OMe), which exhibited modest activity. Compound 11a (X = 3-NO2, R = -CH2CH2NMe2.HCl) was the most effective agent in the MES screen. All of the compounds investigated, except for 11b (X = 3-NO2, R = -CH2CH2+NMe3 I-, Kp = 0.15), are lipophilic with n-octanol/aqueous phosphate buffer (pH = 7.4) partition coefficients (Kp) in the 121-424 range relative to the reference drug nimodipine (Kp = 187). The structure-activity relationships acquired reinforce the concept that calcium is only one of several factors that are involved in seizure generation.
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PMID:Syntheses, calcium channel antagonist and anticonvulsant activities of substituted 1,4-dihydro-3,5-pyridinedicarboxylates containing various 3-alkyl ester substituents. 911 13


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