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)

The finding that the development of lidocaine-kindled seizures is blocked by carbamazepine suggests an interaction of carbamazepine with local anesthetic mechanisms. To study the site of interaction, the effects of lidocaine, carbamazepine and another anticonvulsant drug, phenytoin on scorpion venom-enhanced specific binding of [3H]batrachotoxinin A 20-alpha-benzoate to the sodium channel gating complex were examined in vitro in a rat brain hippocampus preparation. Lidocaine shifted the concentration inhibition curve of carbamazepine to the right and vice versa. Carbamazepine shifted the concentration inhibition curve of phenytoin to the right and vice versa. The experimentally determined apparent dissociation constants were in a good agreement with the dissociation constants calculated for a one-site model, suggesting that the interaction occurs because lidocaine shares a common binding site with carbamazepine and phenytoin in the voltage-dependent sodium channels.
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PMID:Evidence for a common site of action of lidocaine and carbamazepine in voltage-dependent sodium channels. 255 44

Aromatic and heterocyclic esters of 1-methyl-4-piperidinol and 1,4-dimethyl-4-piperidinol and aromatic esters of (dialkylamino)alkanols were prepared and evaluated for antiepileptic activity by the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure threshold (scMet) assays and for minimal central neurotoxicity by the rotorod ataxia test. The most potent compound, namely the 2-phenylbenzoate (57) of 3-(diethylamino)propanol, was slightly more potent than diphenylhydantoin in the MES assay, while the 2-phenylbenzoate (24) of 1-methyl-4-piperidinol and the 2-phenylbenzoate (56) of (diethylamino)ethanol displayed activity comparable to that of diphenylhydantoin. The 2-phenethylbenzoate ester (6) of 1-methyl-4-piperidinol exhibited one-third the activity of diphenylhydantoin. The 2,4,5-trimethylbenzoate 40 and 2,4,6-trimethylbenzoate 41 of 1-methyl-4-pieridinol were even less potent, but did display activity in the phenobarbital-methsuximide range. Certain compounds interact with sites associated with the GABA receptor-chloride channel complex, but their potencies as anticonvulsant agents do not correlate with interaction at sites on the channel complex. Certain analogues antagonize binding of a batrachotoxin analogue to sodium channel sites, a property indicative of local anesthetic activity. There are structural similarities between 2-phenylbenzoates 57, 56, and 24 and diphenylhydantoin, and the latter anticonvulsant also antagonizes binding of the batrachotoxin analogue.
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PMID:Anticonvulsant activity of piperidinol and (dialkylamino)alkanol esters. 301 69

The inhibitory action of a number of clinically effective anticonvulsants on neurotoxin-activated sodium channels in cultured neuroblastoma cells and rat brain synaptosomes has been examined. Diphenylhydantoin (KI = 35 microM) and carbamazepine (KI = 41 microM) inhibited batrachotoxin-activated 22Na+ influx in N18 cells. Similarly, batrachotoxin-activated 22Na+ influx in rat brain synaptosomes was also inhibited by diphenylhydantoin (KI = 38 microM) and carbamazepine (KI = 22 microM). Comparison of KI values with mean brain levels of these drugs achieved during prevention of electroshock seizures indicates that diphenylhydantoin and carbamazepine occupy 35% and 50%, respectively, of their receptor sites associated with sodium channels at mean therapeutic concentrations. Diazepam (KI = 51 to 63 microM) and phenobarbital (KI = 1.2 to 1.3 mM) inhibited batrachotoxin-activated 22Na+ flux in N18 cells and synaptosomes at concentrations in excess of mean therapeutic central nervous system levels. Carbamazepine, like diphenylhydantoin, acts as a competitive inhibitor of sodium channel activation by the full agonist batrachotoxin, but produces mixed inhibition of veratridine-activated channels. This finding is consistent with the conclusion that both carbamazepine and diphenylhydantoin act as allosteric inhibitors of neurotoxin-activated sodium channels. The dose-response relationships for carbamazepine and diphenylhydantoin inhibition of 22Na+ flux in N18 cells are shifted 1.5-fold to higher concentrations when 22Na+ flux measurements are made in the presence of physiological concentrations of sodium and calcium ions. These results suggest that anticonvulsant inhibition of neurotoxin-activated 22Na+ flux in our standard ion flux media, containing low concentrations of Na+ and no Ca2+, is likely to reflect an effect of these agents expected in vivo. The results of this study provide further evidence to support the hypothesis that diphenylhydantoin and carbamazepine, both of which possess similar therapeutic profiles in the treatment of grand mal and partial seizures, may exert their pharmacological effects by occupancy of receptor sites associated with the activation of voltage-sensitive sodium channels in the central nervous system.
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PMID:Inhibition of voltage-sensitive sodium channels in neuroblastoma cells and synaptosomes by the anticonvulsant drugs diphenylhydantoin and carbamazepine. 632 45

Previous in vitro and in vivo studies have provided evidence implicating cocaine block of cardiac sodium channels as a putative mechanism for cocaine-induced arrhythmias and sudden death. Cocaine also has been shown to cause seizures which can result in respiratory and/or metabolic acidosis. In this study we investigated how changes in both internal pH (pHi) and external pH (pHo) over the range of 6.6 to 9.2 modify the sodium channel blocking properties of cocaine in isolated guinea pig ventricular myocytes by using the whole-cell variant of the patch clamp technique. Use-dependent block produced by a train of 1-sec pulses to -20 mV was not affected by changes in pHi, but both the amplitude and time constant for approaching steady-state block were significantly affected by changes in pHo. Characterization of the time course of cocaine binding during a depolarizing pulse indicated that the kinetics of drug interaction with inactivated channels were independent of pHi, but were significantly affected by changes in pHo. The rate of recovery from channel block at a holding potential of -140 mV also was independent of pHi, but strongly dependent on pHo, with the unblocking time constant decreasing exponentially as pHo was increased. The results of this study indicate that cocaine's effect on cardiac sodium channels can be modulated significantly by changes in pHo, and provide further support for previously poorly tested assumptions of the modulated receptor hypothesis.
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PMID:The pH dependence of cocaine interaction with cardiac sodium channels. 756 93

Intracellular recordings were obtained from pyramidal neurons in the rat hippocampal CA1 area in order to investigate membrane mechanisms involved in veratridine-induced epileptiform activity. Veratridine (0.03-0.2 microM) caused no changes in the passive membrane parameters including the resting potential, input resistance, and time constant. In the presence of small doses (0.03-0.1 microM) of veratridine, a single stimulus caused a relatively slow, large, synaptic-independent potential called the slow depolarizing after-potential (SDAP). When the hippocampal slice was treated with higher doses of veratridine (over 0.1 microM), bursting, or seizure-like activity (SLA) occurred in response to a brief super threshold intracellular stimulation. The duration of SLA bursting could be as long as ten seconds depending on the amplitude of SDAP, and was independent of the stimulus strength or duration. The frequency and configuration of SLA were sensitive to changes in membrane potential caused by applied DC current. At 0.3 microM or higher, veratridine induced spontaneous rhythmic bursting that was also sensitive to membrane potential changes. The evoked or spontaneous bursting is characterized by being: (1) independent of synaptic transmission in that it persisted after complete blockade of evoked synaptic potential with kynurenic acid (0.5 mM), (2) sensitive to selective inhibition by low doses of the specific sodium channel blockers tetrodotoxin (TTX) or cocaine with no apparent influence on the evoked action potential. These results indicate that endogenous SLA bursting can be induced in hippocampal CA1 pyramidal neurons when certain properties of sodium channels are altered by veratridine.
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PMID:Endogenous bursting due to altered sodium channel function in rat hippocampal CA1 neurons. 766 74

Lamotrigine is an anticonvulsant chemically related to the antifolate compound pyrimidine. In the maximal electroshock test in rodents it is more potent and has a longer duration of action than other anticonvulsants, and it exhibits little acute neurotoxicity. Lamotrigine suppresses sustained repetitive firing by prolonging inactivation of the sodium channel in the neuronal membrane. It blocks the pathological, but not the normal, release of glutamate and aspartate. Lamotrigine is also cerebroprotective in rodent models of stroke or focal ischaemia. This effect correlates with the suppression of glutamate release and is probably due principally to the action on sodium channels. Lamotrigine has a favourable pharmacokinetic profile. It is rapidly and completely absorbed and has linear pharmacokinetics. Protein binding is moderate and, as lamotrigine does not induce liver enzymes, it does not alter the pharmacokinetics of other anticonvulsants. The half-life and clearance of lamotrigine are altered by concomitant antiepileptic therapy. In the presence of the enzyme inhibitor sodium valproate the half-life is doubled and this interaction is clinically significant.
Seizure 1994 Dec
PMID:Lamotrigine--a novel approach. 789 51

We previously demonstrated that metaphit (a phencyclidine analogue with an acylating isothiocyanate group) induces occurrence of audiogenic seizures in mice exposed to audio stimulation 24 h after metaphit administration. We have studied various receptor systems associated with excitatory and inhibitory networks: sites for competitive and noncompetitive antagonists of the N-methyl D-aspartic acid (NMDA) receptor complex, for [3H]muscimol on the gamma-aminobutyric acid (GABA) receptor complex, and for [3H]batrachotoxinin A20-alpha-benzoate on the voltage-dependent sodium channel. Mice were examined for neurochemical changes at 24 h after pretreatment with metaphit, when susceptibility to audiogenic seizures is greatest. Ex vivo receptor binding studies detected no changes; in vivo labeling of the phencyclidine site in the NMDA receptor complex was reduced by 20% in cortical and midbrain regions. A separate group of experiments was aimed at measuring brain levels of metaphit. One minute after retroorbital administration of [3H]metaphit at a dose sufficient to produce susceptibility to audiogenic seizures 24 h later, the brain level of [3H]metaphit (determined by high-performance liquid chromatography, HPLC) was 49 pmol/mg tissue; at 1, 4, and 24 h, the level was 12, 6, and 1.4 pmol/mg tissue or microM if metaphit was evenly distributed throughout the brain. Although the observed metaphit concentrations during the first 4 h are high enough to acylate receptors, no firm evidence for acylation was found for most of the examined receptors. Finally, the time course of the brain level of metaphit showing a continuous decrease is entirely different from that of development of the seizure susceptibility, which peaks at 18-24 h.
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PMID:Metaphit-induced audiogenic seizures in mice: II. Studies on N-methyl-D-aspartic acid, GABA, and sodium channel receptors and on the disposition of metaphit in the brain. 838 7

Long QT syndrome (LQT) is an inherited cardiac disorder that causes syncope, seizures and sudden death from ventricular tachyarrhythmias. We used single-strand conformation polymorphism (SSCP) and DNA sequence analyses to identify mutations in the cardiac sodium channel gene, SCN5A, in affected members of four LQT families. These mutations include two identical intragenic deletions and two missense mutations. These data suggest that SCN5A mutations cause LQT. The location and character of these mutations suggest that this form of LQT results from a delay in cardiac sodium channel fast inactivation or altered voltage-dependence of inactivation.
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PMID:Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. 854 46

Lamotrigine (LTG) inhibits repetitive high frequency firing in depolarised neurones by selectively prolonging slow inactivation of the sodium channel, thereby suppressing the release of excitatory amino acids. It has been shown to be effective in 11 pivotal double-blind add-on trials in patients with refractory partial seizures with or without secondary generalisation. Subsequent anecdotal data support its efficacy for typical and atypical absences, myoclonic jerks, tonic or clonic seizures, Lennox-Gastaut syndrome and infantile spasms. Most recently LTG has been compared with carbamazepine and phenytoin in double-blind trials in patients with newly diagnosed partial and primary and secondary generalised tonic-clonic seizures. At the doses used, its efficacy was similar to the older agents for all seizure types, but LTG was better tolerated than both of the older agents. The commonest side-effects with LTG include headache, nausea, diplopia, dizziness, ataxia and tremor. Rash occurs in fewer than 5% patients. Its incidence can be reduced by starting treatment with a low dose, particularly in patients receiving concomitant sodium valproate which inhibits LTG metabolism. Enzyme inducers, such as carbamazepine, phenytoin and phenobarbital, accelerate its elimination, but LTG itself has no effect on hepatic metabolic processes. A pharmacodynamic interaction with carbamazepine necessitates a dosage reduction in some patients when LTG is introduced. LTG is a new antiepileptic agent with a long elimination half-life, a broad spectrum of activity, and a wide therapeutic ratio.
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PMID:Lamotrigine--an update. 895 Dec 13

A recently-developed method of gene mapping is reviewed. Several responses to EtOH were studied with the purpose of identifying genes with modest effects (Quantitative Trait Loci, or QTLs). As an example, results from a study of acute ethanol withdrawal severity are discussed. Mice from inbred strains C57BL/6J and DBA/2J, and 19 of their Recombinant Inbred (BXD RI) strains, were given 4 g/kg EtOH and their acute withdrawal severity assessed with the handling-induced convulsion (HIC). HIC scores varied markedly among strains. Comparison of the pattern of strain means for withdrawal with a database comprising genotype of each BXD RI strain for almost 800 mapped polymorphic genetic markers revealed associations with several potential QTLs appearing on several mouse chromosomes. To verify the presence of a gene affecting withdrawal, we then withdrawal-tested individual F2 mice bred from the F1 cross of the parental C57 and DBA strains. These mice were then genotyped for several polymorphic markers close to a putative QTL on chromosome 2. Possession of the DBA allele in severely withdrawing F2 animals was significantly associated with one such marker, D2Mit9, confirming the presence of a gene nearby affecting withdrawal. As a further test, mice of the replicated Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) lines, selected for severity of EtOH withdrawal HIC, were also genotyped. Alleles at the D2Mit9 locus assorted disproportionately (and consistently) between the two pairs of WSP and WSR lines, while alleles at other loci did not. Thus, three tests consistently suggest the influence of a gene, tentatively termed Aw1, 37 cM from the centromere on chromosome 2, that appears to control as much as 40% of the genetic variance in withdrawal. The provisional locus is located very near to two candidate genes. Gad1 codes for the synthesis of glutamic acid decarboxylase, the rate-limiting enzyme for synthesis of GABA. A cluster of genes (Scn1, Scn2, Scn3) code for voltage-sensitive sodium channel proteins. These genes are plausible candidates for affecting withdrawal HIC.
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PMID:Use of recombinant inbred strains for studying genetic determinants of responses to alcohol. 897 18


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