UMLS:C0036572 - FACTA Search

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Query: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:[Development of new antiepileptics. IV. Anticonvulsant activity of some derivatives of 1-(p-sulfamoyl-phenyl)-pyrrolidin-2-one (author's transl)]. 58 4

The generalized repetitive fast discharge (GRFD) is an ictal pattern representing the EEG counterpart of tonic seizures occurring mainly in Lennox-Gastaut syndrome (LGS) during slow-wave sleep. The history of terminology, electromorphology, correlations with sleep, ictal clinical correlations and associations with different epileptic syndromes as well as the clinical significance of the pattern is described reviewing the pertinent literature and our own experiences. The physiopathogenesis from both the electrophysiological and pharmacological aspects is discussed in the framework of a concept according to which GRFD is considered as a malignant derivative of an existing slow spike-wave mechanism, due to the permanent or momentary breakdown of the GABA-ergic inhibitory process. In observations performed on some patients we found a paradoxical GRFD-eliciting effect of BDZ drugs and hexobarbiturate after chronic treatment with BDZ agents and/or barbiturate, and a GRFD-blocking effect of Anexate (Flumazenil), a BDZ antagonist on the pattern, appearing either spontaneously in slow-wave sleep or elicited by diazepam or barbiturate. Our findings support the assumption that BDZ (Barbiturate) GABA-Chloride Ionophore Complex plays an important role, both in the development of and possibly in the therapeutic approach to, the GRFD phenomena. Some hypotheses about the role played by the complex based on these observations are put forward.
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PMID:Runs of rapid spikes in sleep: a characteristic EEG expression of generalized malignant epileptic encephalopathies. A conceptual review with new pharmacological data. 166 48

Adult male and female genetically seizure-prone rats were assessed for sound-induced seizures. Heterozygous control groups were compared with mild seizure (designated GEPR 3) and severe seizure animals (GEPR 9). Groups of animals were killed and crude synaptosome fractions (P2) prepared from freshly dissected cerebral cortices. Binding sites for gamma-aminobutyric acid (GABA) were assessed by [3H]-muscimol in the absence or presence of excess GABA and/or pentobarbital. Binding sites for benzodiazepines were assessed by [3H]-flunitrazepam in the presence or absence of clonazepam. Compared to controls, GEPR 3 animals had a modest increase and GEPR 9 animals a larger increase in Bmax for both high and low affinity GABA sites, with no change in Kd. Chloride-dependent, barbiturate-enhanced GABA binding (increased Bmax) was observed in all conditions and groups. Likewise benzodiazepine binding (Bmax) increased slightly in GEPR 9 animals. There were no observed changes in binding sites for a survey of biogenic amines. Seizure-prone animals appear to have compensatory denervation-like supersensitivity for their most prominent inhibitory receptor, which may or may not be linked to the seizure event.
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PMID:Cerebral cortical GABA and benzodiazepine binding sites in genetically seizure prone rats. 301 15

An arylaminopyridazine derivative of gamma-aminobutyric acid (GABA), SR 95103, has been shown to be a selective antagonist of GABA at the GABAA receptor site. Subsequent structure-activity studies showed that suppressing the methyl in the 4-position of the pyridazine ring, and substituting the phenyl ring at the para position with a chlorine (SR 42641) or a methoxy group (SR 95531) led to compounds which exhibited the highest affinities for the GABA receptor site in this series. In the present study we examined the biochemical interaction of these compounds with the GABA receptor as well as their biochemical selectivity for this receptor. SR 95531 and SR 42641 displaced [3H]GABA from rat brain membranes with apparent Ki values of 0.15 microM and 0.28 microM respectively and Hill numbers near 1.0. The two compounds antagonized the GABA-elicited enhancement of [3H]diazepam-binding in a concentration-dependent manner without affecting [3H]diazepam-binding per se. Scatchard and Lineweaver-Burk analysis of the interaction of the two compounds with the GABAA receptor sites, revealed that the compounds were competitive at the high affinity site, but non-competitive at the low affinity site. Neither compound interacted with other GABAergic processes or with a variety of central receptor sites. When administered intravenously, SR 95531 and SR 42641 elicited tonic-clonic seizures in mice. Based on these results, it is postulated that SR 95531 and SR 42641 are specific, potent and competitive GABAA antagonists.
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PMID:Biochemical characterization of the interaction of three pyridazinyl-GABA derivatives with the GABAA receptor site. 302 66

Two amino-phenyl-pyridazine derivatives, SR 41378 and CM 40907, have been reported to antagonize seizures in mice, rats and Papio papio baboons with comparable potencies. Structurally, SR 41378 differs from CM 40907 by an additional chlorine in position 6 of the phenyl ring. In the present study the activity of these two compounds in the operant approach-avoidance conflict test in rats was examined and compared with that of diazepam, pentobarbital, meprobamate and valproate. SR 41378 increased punished responding, a measure of anticonflict activity (ED50 = 5.2 mg/kg), and decreased nonpunished responding, a measure of sedative activity, with a threshold active dose of 20 mg/kg i.p. The overall potency of SR 41378 was comparable to that of pentobarbital. CM 40907 (10-40 mg/kg i.p.) did not affect punished responding and decreased nonpunished responding at the dose of 40 mg/kg i.p. The duration of the anticonflict activity of SR 41378 increased with the dose and lasted over 4 h at the 20-mg/kg i.p. dose. At this dose, sedation lasted 1 h. An increase in anticonflict potency and tolerance to sedation were observed after a 5-day treatment with SR 41378 (20 mg/kg i.p.). The anticonflict and sedative activities of SR 41378 were not antagonized by Ro 15-1788 or CGS 8216. In vitro SR 41378 did not interact with benzodiazepine receptor sites. In conclusion, although CM 40907 and SR 41378 exhibit similar anticonvulsant activities, the present study reveals a major pharmacological difference between the two compounds because SR 41378 also possesses anticonflict properties.
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PMID:Evaluation of two anticonvulsant amino-pyridazine derivatives in the conflict test in rats. 309 40

In this paper we describe the synthesis of a series of alpha-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substitutent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity realized for the alpha-phenylethyl analogue 3, in this paper we explored the effects of substitution on the aromatic ring as a strategy to increase the affinity to these compounds for group II mGluRs. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold increases in affinity. Substitution with p-fluorine, as in 97 (IC50 = 0.022 +/- 0.002), was the exception. Here, a greater increase in affinity was realized than for either the ortho- or meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution of the aromatic. At best, only modest increases in affinity were realized for certain compounds bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and 104, were resolved into their four constituent isomers, and affinity and functional activity for group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1. With an IC50 = 2.9 +/- 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent compound from this SAR. Amino acid 168 demonstrated high plasma levels following intraperitoneal (i.p.) administration and readily penetrated into the brain. This compound, however, had only limited (approximately 5%) oral bioavailability. Systemic administration of 168 protected mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with an ED50 = 31 mg/kg (i.p., 60 min preinjection). Thus, 168 represents a valuable tool to study the role of group II mGluRs in disease.
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PMID:2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability. 946 67

Chloride fluxes play a crucial role in synaptic inhibition, cell pH regulation, as well as in cell volume control. In many neuropathological processes, cell swelling is a pivotal parameter, since cell volume changes and the dimension of the interstitial space critically modulate synchronized neuronal activity as well as the tissue's susceptibility to seizures or spreading depression. This study therefore focuses on the effects of different Cl(-) transport inhibitors and Cl(-) substitution on neuronal function and hypoxia-induced changes in rat hippocampal tissue slices. Orthodromically evoked focal excitatory postsynaptic potentials were depressed by furosemide (2mM), 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid (1mM) and Cl(-) substitution by methylsulfate, but were enhanced by 4,4'-dinitrostilbene-2,2'-disulfonic acid (1mM). All four treatments induced multiple population spike firing in response to single orthodromic volleys, suggesting reduced synaptic inhibition. Antidromic population spikes increased following Cl(-) withdrawal, were unaffected in the presence of furosemide and 4, 4'-dinitrostilbene-2,2'-disulfonic acid, but were abolished by 4, 4'-diisothiocyanatostilbene-2,2'-disulfonic acid. The amplitude of the hypoxic spreading-depression-like extracellular potential shift was reduced by furosemide, 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid and Cl(-) withdrawal, i.e. by the same treatments that depressed orthodromically evoked postsynaptic potentials. Furosemide prolonged the time to onset and the duration of the spreading-depression-like extracellular potential shift, while 4, 4'-dinitrostilbene-2,2'-disulfonic acid shortened the time to onset. Spreading-depression-related cell swelling was recorded as the shrinkage of relative interstitial space, which was measured as tetramethylammonium-chloride space. Neither the Cl(-) transport inhibitors nor Cl(-) withdrawal had any detectable effect on spreading-depression-related cell swelling. CA1 pyramidal neurons usually hyperpolarized during drug application and their input resistance decreased. Cl(-) withdrawal increased their input resistance and caused spontaneous burst firing. Hypoxia caused the expected spreading-depression-like rapid, near complete depolarization of single pyramidal neurons and drastically reduced their input resistance. The three Cl(-) transport inhibitors and Cl(-) withdrawal delayed the onset of the hypoxic depolarization. In low Cl(-) solutions, the apparent threshold potential at which spreading depression was triggered shifted to more positive membrane potentials. The final voltage of the hypoxic depolarization was, however, not affected. It appears from these results that the reduction in the hypoxic spreading-depression-like extracellular potential shifts by Cl(-) transport inhibitors is at least partially attributable to desynchronization of depolarization, not to decreased depolarization in individual cells. Other contributing factors could be changes in recording conditions, depression of swelling-induced amino acid release from glial cells and unspecific side-effects of the applied drugs. Desynchronization could also account for the delayed spreading-depression onset. It is concluded that Cl(-) fluxes play a role in the triggering of spreading depression, but the spreading-depression-like depolarization itself or its self-regenerative character is not mediated by Cl(-).
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PMID:Effects of chloride transport inhibition and chloride substitution on neuron function and on hypoxic spreading-depression-like depolarization in rat hippocampal slices. 1077 37

Outbreaks of Salmonella and Escherichia coli O157:H7 infections associated with alfalfa and other seed sprouts have occurred with increased frequency in recent years. This study was undertaken to determine the efficacy of a liquid prototype produce wash product (Fit), compared with water and chlorinated water, in killing Salmonella and E. coli O157:H7 inoculated onto alfalfa seeds. We investigated the efficacy of treatments as influenced by seeds from two different lots obtained from two seeds suppliers and by two methods of inoculation. The efficacy of treatments was influenced by differences in seed lots and amount of organic material in the inoculum. Significant (alpha = 0.05) reductions in Salmonella populations on seeds treated with 20,000 ppm of chlorine or Fit for 30 min ranged from 2.3 to 2.5 log10 CFU/g and 1.7 to 2.3 log10 CFU/g, respectively. Reductions (alpha = 0.05) in E. coli O157:H7 ranged from 2.0 to 2.1 log10 CFU/g and 1.7 to more than 5.4 log10 CFU/g of seeds treated, respectively, with 20,000 ppm of chlorine or Fit. Compared with treatment with 200 ppm of chlorine, treatment with either 20,000 ppm of chlorine or Fit resulted in significantly higher reductions in populations of Salmonella and E. coli O157:H7. None of the treatments eliminated these pathogens as evidenced by their detection on enrichment of treated seeds. Considering the human health and environmental hazards associated with the use of 20,000 ppm of chlorine, Fit provides an effective alternative to chlorine as a treatment to significantly reduce bacterial pathogens that have been associated with alfalfa seeds.
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PMID:Comparison of chlorine and a prototype produce wash product for effectiveness in killing Salmonella and Escherichia coli O157:H7 on alfalfa seeds. 1127 59

The efficacy levels of different physical and chemical washing treatments in the reduction of viral and bacterial pathogens from inoculated strawberries were evaluated. Escherichia coli O157:H7, Salmonella Montevideo, poliovirus 1, and the bacteriophages PRD1, phiX174, and MS2 were used as model and surrogate organisms. Chemicals readily available to producers and/or consumers were evaluated as antimicrobial additives for the production of washes. The gentle agitation of contaminated strawberries in water for 2 min led to reductions in microbial populations ranging from 41 to 79% and from 62 to 90% at water temperatures of 22 and 43 degrees C, respectively. Significant reductions (> 98%) in numbers of bacteria and viruses were obtained with sodium hypochlorite (50 to 300 ppm of free chlorine), Oxine or Carnebon (200 ppm of product generating "stabilized chlorine dioxide"), Tsunami (100 ppm of peroxyacetic acid), and Alcide (100 or 200 ppm of acidified sodium chlorite) washes. Overall, 200 ppm of acidified sodium chlorite produced the greatest reductions of microorganisms. Hydrogen peroxide (0.5%) was slightly less effective than free chlorine in a strawberry wash and caused slight fruit discoloration. Cetylpyridinium chloride (0.1%) was effective in the reduction of bacterial species, while trisodium phosphate (1%) was effective against viruses. The consumer-oriented produce wash Fit was very effective (> 99%) in reducing the numbers of bacteria but not in reducing the numbers of viruses. Another wash, Healthy Harvest, was significantly less effective than Fit in reducing bacterial pathogens but more effective for viruses. The performance of automatic dishwashing detergent was similar to that of Healthy Harvest and significantly better than that of liquid dishwashing detergent. Solutions containing table salt (2% NaCl) or vinegar (10%) reduced the numbers of bacteria by about 90%, whereas only the vinegar wash reduced the numbers of viruses significantly (ca. 95%).
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PMID:Reduction of poliovirus 1, bacteriophages, Salmonella montevideo, and Escherichia coli O157:H7 on strawberries by physical and disinfectant washes. 1259 75

Strychnine-sensitive glycine receptors (GlyRs) inhibit neurotransmission in the spinal cord and brainstem. To better define the function of this receptor in vivo, we constructed a point mutation that impairs receptor function in the alpha1-subunit and compared these knock-in mice to oscillator (spdot) mice lacking functional GlyR alpha1-subunits. Mutation of the serine residue at amino acid 267 to glutamine (alpha1S267Q) results in a GlyR with normal glycine potency but decreased maximal currents, as shown by electrophysiological recordings using Xenopus oocytes. In addition, single-channel recordings using human embryonic kidney 293 cells indicated profoundly altered properties of the mutated GlyR. We produced knock-in mice bearing the GlyR alpha1 S267Q mutation to assess the in vivo consequences of selectively decreasing GlyR efficacy. Chloride uptake into brain synaptoneurosomes from knock-in mice revealed decreased responses to maximally effective glycine concentrations, although wild-type levels of GlyR expression were observed using 3H-strychnine binding and immunoblotting. A profound increase in the acoustic startle response was observed in knock-in mice as well as a "limb clenching" phenotype. In contrast, no changes in coordination or pain perception were observed using the rotarod or hot-plate tests, and there was no change in GABA(A)-receptor-mediated chloride uptake. Homozygous S267Q knock-in mice, like homozygous spdot mice, exhibited seizures and died within 3 weeks of birth. In heterozygous spdot mice, both decreased 3H-strychnine binding and chloride flux were observed; however, neither enhanced acoustic startle responses nor limb clenching were seen. These data demonstrate that a dominant-negative point mutation in GlyR disrupting normal function can produce a more dramatic phenotype than the corresponding recessive null mutation, and provides a new animal model to evaluate GlyR function in vivo.
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PMID:Glycine receptor knock-in mice and hyperekplexia-like phenotypes: comparisons with the null mutant. 1295 67

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