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)

Spiro[4.5]decane-2-carboxylic acid (12a), spiro[4.5]decane-2,2-dicarboxylic acid (11a), spiro[4.6]undecane-2-carboxylic acid (12b), spiro[4.6]undecane- 2,2-dicarboxylic acid (11b), and spiro[4.6]undecane-2-acetic acid (13) were synthesized by an improved method and evaluated for anticonvulsant activity. These analogues were synthesized to evaluate the role of the carboxylic acid group as an essential substituent in valproic acid (di-n-propylacetic acid, 1). Carbocyclic spiranes are known to resist metabolic alteration so that any activity elicited by these compounds would be due to the carboxylic acid function and not to any metabolic change. Spiro[4.6]undecane-2-carboxylic acid (12b) was the most active analogue tested and the pentylenetetrazol and picrotoxin evaluations of 12b compared favorably to 1. However, 12b failed to provide adequate protection against maximal electroshock seizures, bicuculline, or strychnine in mice. Possible reasons for these results are discussed.
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PMID:Spiro[4.5] and spiro[4.6] carboxylic acids: cyclic analogues of valproic acid. Synthesis and anticonvulsant evaluation. 392 Mar 94

The effects of suloctidil (MY103) on the central (CNS) and peripheral nervous systems were investigated with single and consecutive administration. The general behavior in mice, awareness and motor activity were slightly depressed with the dose above 300 mg/kg, p.o. of MY 103. Soft stool was also marked in the dose above 100 mg/kg, p.o. in beagles and 1000 mg/kg, p.o. in mice. In beagles, vomiting was another syndrome with 100 and 300 mg/kg, p.o. of MY 103. Spontaneous motor activity was significantly decreased after MY 103 by p.o. administration in the dose above 100 mg/kg in mice and 300 mg/kg in rats. In sleep anesthesia studies, MY 103 and iproniazid did not potentiate the effect of a subthreshold dose of barbital, but those two drugs significantly prolonged the sleeping time of pentobarbital as chlorpromazine did. No anticonvulsive effect was observed with MY 103 in chemo- and electroshock seizure tests. My 103 of 300 mg/kg, p.o. significantly decreased the acetic acid induced writhing number, but no analgesic activity was found in the Haffner's method in mice. In the rotarod test, MY 103 of 30-300 mg/kg, p.o. inhibited the motor coordination dose-dependently. MY 103 antagonized the m-amphetamine group toxicity. A cataleptogenic effect was observed following the relatively high dose of MY 103 by an i.p. route. This effect was antagonized by atropine. The spinal reflexes in the immobilized cat, and spontaneous rabbit EEG were not affected by MY 103. The conditioned avoidance response (CAR) was also not changed with MY 103 in rats. In the isolated phrenic-nerve diaphragm preparation, 10(-4)M MY 103 irreversively inhibited the muscle twitches elicited by nerve and muscle stimulation, but suloctidil at 300 micrograms/kg, i.v., did not suppress the tibialis muscle twitches in vivo. In the consecutive administration study, MY 103 suppressed the CAR in rats and prolonged the thiopental-sleeping time in an administration period-related manner. These changes disappeared rapidly after drug withdrawal. Taking these evidences together, it can be concluded that MY 103 has little effect on the CNS with single administration, but the tendency to depress the CNS was observed after the repeated administration of MY 103.
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PMID:[Effects of suloctidil on the central and peripheral nervous systems]. 631 48

Twelve new N-aminosuccinimides were synthesized by the condensation of hydrazines with succinic anhydrides in glacial acetic acid. The compounds were evaluated in the maximal electroshock seizure and subcutaneous pentylenetetrazol seizure threshold tests for anticonvulsant activity and in the rotorod test for neurotoxicity in mice. The lowest dose at which several of the compounds exhibited anticonvulsant activity was 300 mg/kg.
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PMID:Synthesis and anticonvulsant evaluation of N-aminosuccinimides. 671 53

It was found previously that 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (6-MeO-THbetaC) increased brain concentration of the neurotransmitter serotonin (5-HT) and decreased the concentration of its metabolite 5-hydroxyindole acetic acid (5-HIAA) at the same time the compound attenuated audiogenic seizures (AGS) in DBA/2J mice. In the present study we determined the time-course and dose-response effects of 6-MeO-THbetaC for blockade of AGS. Drugs sharing common effects with 6-MeO-THbetaC were also tested. At a dose of 100 mg/kg, 6-MeO-THbetaC blocked AGS between 10 min and 12 hr after injection, with maximal inhibition at 1 hr at which time a dose-related decrease in AGS was also demonstrated. All of the drugs tested which blocked AGS, including 6-MeO-THbetaC, THbetaC, 5-Hydroxytryptophan, chlorimipramine and pargyline, have biochemical similarities suggesting that facilitating serotonin function may be responsible for seizure-attenuating effects.
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PMID:Effects of 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (6-MeO-THbetaC) on audiogenic seizures in DBA/2J mice. 676 69

The effects of GABA-modulating drugs were assessed in a pharmacological study of amygdala-kindled seizures in the rat. Fully-kindled subjects were tested with a randomized dose regimen, including drug vehicle, for each of seven drugs. Afterdischarge duration, motor seizure latency, motor seizure duration and motor seizure stage were scored. The GABA synthesis inhibitor, 3-mercaptopropionic acid, the GABA antagonist, bicuculline, and the chloride ionophore blocker, picrotoxin, all decreased motor seizure latency, but did not otherwise alter the kindled seizure duration or seizure stage. The inhibitor of GABA metabolism, gamma-vinyl-GABA, and pentobarbital, which competes for the picrotoxin binding site, both antagonized kindled seizures. Gamma-vinyl-GABA, however, did not appear to antagonize kindled seizures by a specific effect on GABA neurotransmission. The GABA agonists, imidazole acetic acid and [alpha-(chloro-4'phenyl)fluoro-5-hydroxy-2-benzylidene-amino]-4-butyramide (SL 76-002), did not alter the kindled seizures. The results of these experiments are not consistent with the hypothesis that kindled seizures result from a loss of GABA-mediated inhibition; however, GABA may have a role in the modulation of kindled seizure activity.
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PMID:Pharmacological investigation of gamma-aminobutyric acid (GABA) and fully-developed generalized seizures in the amygdala-kindled rat. 706 9

An experimental and clinical study was undertaken to determine whether Zenker's solution without glacial acetic acid (modified Zenker's solution) applied to the external surface of the dura mater can penetrate to injure the underlying cortex. Adult cats and dogs, the dura of which had an average thickness of 0.2 and 0.25 mm, respectively, were given intravenous Evans blue dye as an indicator of blood-brain barrier breakdown. This was followed by the application of modified Zenker's solution to the dura in a manner identical to the clinical practice. When the animals were killed 1 or 2 hours later, the cortex beneath the dura painted with modified Zenker's solution was stained massively. The thickness of human dura was measured; it varied from 0.22 to 0.28 mm in infants of 3 months or less, 0.27 to 0.42mm in infants 4 months to 12 months of age, and 0.32 to 0.45 mm in children to 1 to 18 years of age. Modified Zenker's solution applied to fresh dura for 3 minutes at autopsy gave visual evidence 1 hour later of penetration to the cortex beneath. In operative procedures for craniosynostosis, 69 patients were treated with modified Zenker's solution; of these, 7 developed seizures in the immediate postoperative period. No seizures occurred among the 39 patients on whom modified Zenker's solution was not used. It is concluded that modified Zenker's solution applied to the dura can damage the cortex beneath.
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PMID:Cortical damage from Zenker's solution applied to the dura mater. 720 76

Zenker's solution is a tissue fixative containing mercuric chloride, potassium bichromate, sodium sulfate, and glacial acetic acid. In 1956, Anderson and Johnson reported its use in clinical neurosurgery. They applied the solution to the exposed dura after craniectomy. Delayed bone formation was thought to be due to the suppression of the osteoblastic activity of the outer layer of the dura. The fixative has since become a well-accepted adjuvant to the treatment of craniosynostosis. In 1972, Pawl and Sugar reported postoperative seizures in 6 of 34 patients treated with this solution. They assumed that the fixative penetrated the dura and irritated or damaged the cortex. To clarify the effect of Zenker's solution on the underlying brain, we performed bilateral parasagittal craniectomies in a group of kittens and adult cats. Zenker's solution was applied to one side and the other side served as a control. The animals were killed after periods varying from 24 hours to 2 months. We then examined the cortex under the craniectomies. There was immediate breakdown of the blood-brain barrier, as evidenced by the penetration of intravenous Evans blue. In the postoperative period investigated, an inflammatory response in the underlying brain with thickening of the arachnoid occurred. The results and implications of these experiments are presented. (Neurosurgery, 6: 45--48, 1980)
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PMID:Effect of the dural application of Zenker's solution on the feline brain. 735

Intracerebroventricular administration to mice of 5,7-dihydroxytryptamine at a dose of 300 micrograms resulted in convulsive behaviour and death (latency 7.6 +/- 1.7 min.). Pretreatment with dizocilpine or chlormethiazole resulted in a dose dependent inhibition of the convulsive behaviour. A dose of dizocilpine of 0.12 mumol/kg or chlormethiazole at a dose of 150 mumol/kg prevented seizures for 30 min. Injection of 5,7-dihydroxytryptamine (75 micrograms, intracerebroventricularly) produced an approximate 50% neurotoxic loss of cerebral 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) 8 days later. This loss was not prevented by administration of either dizocilpine (4.5 mumol/kg intraperitoneally) or chlormethiazole (300 mumol/kg intraperitoneally) given 5 min. before and 55 min. after the 5,7-dihydroxytryptamine injection. It is proposed that chlormethiazole and dizocilpine may protect against 5,7-dihydroxytryptamine-induced seizures because of their anticonvulsant activity, but that they do not prevent the neurotoxic effects of the compound. The data also suggest that the neurotoxic effects of substituted amphetamines such as 3,4-methylene dioxymethamphetamine (MDMA or Ecstasy) do not result from the formation of a 5,7-dihydroxytryptamine like compound.
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PMID:Chlormethiazole and dizocilpine block the behavioural, but not the neurotoxic effects of 5,7-dihydroxytryptamine in mice. 751 15

The anticonvulsant gabapentin (1-(aminomethyl)cyclohexane acetic acid) has been found to be effective for treatment of partial seizures, but the mechanism of action is unknown. Recent evidence from the rat optic nerve suggests that gabapentin may enhance promoted release of GABA, which is thought to be due to reverse operation of the GABA transporter. We have used whole-cell patch clamp recordings from CA1 pyramidal neurons in hippocampal slices to directly measure currents induced by nipecotic acid (NPA) during exposure to gabapentin. Under control conditions, pressure microejection of NPA increased whole-cell conductance with a reversal potential equal to the chloride equilibrium potential. This response was mimicked by GABA application, and blocked by bicuculline. The response to NPA was also present after blockade of synaptic transmission in the presence of calcium-free solution. These results are consistent with NPA promoting nonvesicular release of GABA from neighboring neurons or glia via reverse operation of the GABA uptake system, which then activated GABAA receptors on the recorded neurons. In control solution, the response to NPA slowly decreased over 45 min to approximately 50% of the initial response, consistent with GABAA receptor 'rundown'. However, in the presence of gabapentin there was a slow increase in the response, reaching approximately 170% of the control level after 45 min of gabapentin exposure. These results demonstrate that gabapentin enhances the promoted release of GABA by more than three-fold. The potentiation of the NPA response may be due to gabapentin increasing cytosolic GABA in neighboring cells via a delayed metabolic effect, and would have the functional effect of increasing neuronal inhibition during periods of hyperexcitability.
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PMID:Gabapentin potentiates the conductance increase induced by nipecotic acid in CA1 pyramidal neurons in vitro. 779 91

The general pharmacological properties of a novel cognition-enhancing agent, nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM-9384, CAS 77191-36-7) were investigated, and the following results were obtained. 1. Central nervous system: Nefiracetam showed depressant activities (such as ataxia) on general behavior (mice), and inhibited spontaneous locomotor activity, rota-rod and traction performances (mice) and polysynaptic potential of the spinal reflex (rats), and potentiated pentobarbital anesthesia (mice). The drug inhibited electroshock-induced seizure at relatively low doses, but did not affect chemoshock-induced seizure (mice). Nefiracetam failed to show analgesic activity in the tail pinch test, but inhibited the acetic acid-induced writhing syndrome (mice). An inhibitory pattern in the electroencephalogram was observed (cats). Nefiracetam had little or no effect on body temperature (rats). 2. Respiratory and cardiovascular systems: Nefiracetam induced transient decreases in blood pressure, left ventricular pressure and LV dp/dt max at higher doses (dogs). 3. Autonomic nervous system: Nefiracetam had no influence on pupil size (rabbits). The drug induced no significant effect on the pressor response to norepinephrine or depressor response to acetylcholine, but inhibited the contractile response of the nictitating membrane to preganglionic cervical sympathetic nerve stimulation at the highest dose (dogs). 4. Gastrointestinal system: Nefiracetam inhibited gastrointestinal propulsion (mice), gastric emptying rate and gastric secretion (rats) at higher doses. Nefiracetam produced no apparent damage in the gastric mucosa, and had no effect on bile secretion (rats). 5. Isolated smooth muscle: Nefiracetam had no effect on the resting tonus of isolated ileum, whereas it inhibited the contractile response to acetylcholine, histamine, serotonin, nicotine and BaCl2 at higher concentrations (guinea pigs). Nefiracetam had no effect on the resting tonus or the serotonin-induced contraction of stomach fundus (rats). The drug had no effect on the resting tonus or the norepinephrine-induced contraction of vas deferens, but tended to inhibit the contraction induced by nerve stimulation (guinea pigs). Nefiracetam had little or no effect on the resting tonus or oxytocin-induced contraction of virgin uterus, or on spontaneous contraction of pregnant uterus (rats). Nefiracetam did not affect the resting tonus of trachea, whereas it inhibited isoproterenol-induced relaxation at the highest concentration (guinea pigs). Nefiracetam had no chronotropic effect in isolated atria, but showed a slight negative inotropic effect at the highest concentration (guinea pigs). 6. Miscellaneous: Nefiracetam slightly decreased urinary volume, whereas it did not affect urinary electrolyte excretion (rats).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:General pharmacological profile of the new cognition-enhancing agent nefiracetam. 801 90


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