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)

Several thiourea and urea derivatives were prepared by the reaction of 4-aminopyrazoles with substituted isothiocyanates or isocyanates. The novel compounds were tested anticonvulsant activity using by pentylenetetrazole-induced seizure (PTZ) and maximal electroshock seizure (MES) tests. Among the tested compounds, thiourea derivatives of 4b were afforded 90 and 100% protection in PTZ and MES tests at 50mg/kg, respectively. Urea derivatives of 5a and 5b were afforded 82 and 100% protection both at 25 and 50mg/kg. Also synthesized compounds were screened for antituberculosis activity against Mycobacterium tuberculosis H37Rv at 6.25 microg/mL concentration but they were not found active at these concentration. In addition, some selected compounds were evaluated for in vitro anti-HIV activity and they were all negative.
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PMID:Synthesis and biological evaluation of new N-substituted-N'-(3,5-di/1,3,5-trimethylpyrazole-4-yl)thiourea/urea derivatives. 1599 Feb 84

Valproic acid has been widely used for the treatment of epilepsy. Although it is usually well tolerated, it has been associated with some side effects. A poor studied side effect is the hyperammonemia, which independs from the drug hepatotoxic action. The hyperammonemia may occurs just after the beginning or during the treatment and is characterized by vomiting, progressive impairment of consciousness, focal neurologic signs and increased seizure frequency. We report boy a 6 year-old boy who presented with hyperammonemia during the use of valproic acid within the therapeutic range. Complementary investigation was negative for aminoacidopathy, organic acidemia and urea cycle disorders. The hypothesis of secondary effect to the valproic acid was reinforced by the normalization of ammonia levels after drug withdrawal. The pathogenesis of valproate-induced hyperammonemia have been discussed. We conclude that routine monitoring of ammonia blood concentration are strongly recommended in patients under valproic acid treatment.
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PMID:[Hyperammonemia secondary to the use of valproic acid: case report]. 1610 Sep 94

The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (MIM 238970) is an autosomal recessive metabolic disorder caused by a deficiency of the mitochondrial ornithine transporter, one of the urea cycle components. Mutations in the SLC25A15 gene have been coupled to the HHH syndrome. We describe a Japanese female patient with the HHH syndrome due to a novel homozygous R275X SLC25A15 mutation and male sibling who presumably carried the same mutation. He exhibited slowly progressive deterioration with seizures, a gait disturbance due to polyneuropathy, episodic confusion, and died of acute encephalopathy at 34 years of age while the proband exhibited moderate mental retardation, seizures, mild spastic paraplegia, and deafness without neurological deterioration for more than 20 years. The clinical features of previously documented patients with the homozygous SLC25A15 mutation demonstrated that genotype did not simply correlate with clinical severity. The phenotypic variability might depend on other factors, such as dietary and other genetic ones.
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PMID:A novel R275X mutation of the SLC25A15 gene in a Japanese patient with the HHH syndrome. 1637 11

Hyperammonemic disorders such as acute liver failure (ALF) or urea cycle enzymopathies are associated with hyperexcitability, seizures, brain edema and increased extracellular brain glutamate. Mechanisms responsible for increased glutamate content in the extracellular space of the brain include decreased uptake by perineuronal astrocytes and/or increased release from neurons and/or astrocytes. Exposure of astrocytes to millimolar concentrations of ammonia results in cell swelling, loss of expression of the glutamate transporters excitatory amino acid transporter (EAAT-1) and EAAT-2 and increased release of glutamate. Three distinct mechanisms are theoretically possible to explain ammonia-induced glutamate release from astrocytes namely: release due to swelling; reversal of glutamate transporters and due to Ca2+-dependent vesicular release. Recent identification of vesicular docking and fusion proteins in astrocytes together with glutamate-release (due to intracellular alkanization and mobilization of intracellular Ca2+-stores) studies implies that vesicular release is a predominant mechanism responsible for ammonia-induced release of glutamate from astrocytes.
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PMID:Effect of ammonia on astrocytic glutamate uptake/release mechanisms. 1663 45

Citrullinemia is an inborn error of the urea cycle caused by deficient argininosuccinate synthetase, which leads to accumulation of L-citrulline and ammonia in tissues and body fluids. The main symptoms include convulsions, tremor, seizures, coma, and brain edema. The pathophysiology of the neurological signs of citrullinemia remains unclear. In this context, we investigated the in vitro effects of L-citrulline and ammonia in cerebral cortex from 30-day-old rats on oxidative stress parameters, namely thiobarbituric acid-reactive substances (TBA-RS), chemiluminescence, mitochondrial membrane protein thiol content, intracellular content of hydrogen peroxide, total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR) as well as on the activities of the antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase). L-Citrulline significantly diminished TRAP (26%) and TAR (37%), while ammonia decreased TAR (30%). Ammonia increased SOD activity (65%) and L-citrulline did not affect the activities of any antioxidant enzymes. We also observed that L-citrulline and ammonia did not alter lipid peroxidation parameters, levels of hydrogen peroxide, and mitochondrial membrane protein thiol content. Taken together, these results may indicate that L-citrulline and ammonia decreased the antioxidant capacity of the brain, which may reflect a possible involvement of oxidative stress in the neuropathology of citrullinemia.
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PMID:Citrulline and ammonia accumulating in citrullinemia reduces antioxidant capacity of rat brain in vitro. 1677 71

Valproate-induced hyperammonemic encephalopathy (VHE) is an unusual complication characterized by a decreasing level of consciousness, focal neurological deficits, cognitive slowing, vomiting, drowsiness, and lethargy. We have thoroughly reviewed the predisposing factors and their screening, the biochemical and physiopathological mechanisms involved, the different treatments described, and those that are being investigated. Etiopathogenesis is not completely understood, although hyperammonemia has been postulated as the main cause of the clinical syndrome. The increase in serum ammonium level is due to several mechanisms, the most important one appearing to be the inhibition of carbamoylphosphate synthetase-I, the enzyme that begins the urea cycle. Polytherapy with several drugs, such as phenobarbital and topiramate, seems to contribute to hyperammonemia. Hyperammonemia leads to an increase in the glutamine level in the brain, which produces astrocyte swelling and cerebral edema. There are several studies that suggest that treatment with supplements of carnitine can lead to an early favorable clinical response due to the probable carnitine deficiency induced by a valproate (VPA) treatment. Development of the progressive confusional syndrome, associated with an increase in seizure frequency after VPA treatment onset, obliges us to rule out VHE by screening for blood ammonium levels and the existence of urea cycle enzyme deficiency, such as ornithine carbamoyltransferase deficiency. Electroencephalography (EEG) is characterized by signs of severe encephalopathy with continuous generalized slowing, a predominance of theta and delta activity, occasional bursts of frontal intermittent rhythmic delta activity, and triphasic waves. These EEG findings, as well as clinical manifestations and hyperammonemia, tend to normalize after VPA withdrawal.
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PMID:Valproate-induced hyperammonemic encephalopathy. 1677 19

We report the case of a young woman who had transient encephalopathy with nausea, cognitive impairment, 2 generalized seizures accompanied by visual impairment, and stenotic alterations of cerebral vessels lasting for weeks until complete resolution. These findings were associated with an elevated antideoxyribonuclease B level and biopsy-proven poststreptococcal glomerulonephritis. At the time of the encephalopathy, the patient had no electrolyte level disturbances, an only mildly elevated urea level, and moderate arterial hypertension and was on methylprednisolone therapy. For a couple of days, cranial magnetic resonance imaging showed multiple disseminated asymmetric hyperintensities on T(2)-weighted and fluid-attenuated inversion recovery, suggesting vasogenic edema. However, Doppler ultrasound examinations showed stenoses of extracerebral and multiple intracerebral arteries that persisted for several weeks, lasting considerably longer than the cerebral edema. This finding does not fit the context of hypertensive or steroid-induced encephalopathy, but is consistent with diagnosis of an accompanying vasculitis. Treatment with methylprednisolone for several weeks was associated with resolution of arterial stenoses and neurological symptoms, complete reversibility of Doppler sonographic findings, and significant improvement in renal function.
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PMID:Transient encephalopathy complicating poststreptococcal glomerulonephritis in an adult with diagnostic findings consistent with cerebral vasculitis. 1693 Dec 24

KYNA, an antagonist of ionotropic glutamate receptors and alpha7 nicotinic receptors, has been found as well in the brain as in the periphery. The altered metabolism of KYNA, especially its deficiency, can lead to the enhanced glutamate-mediated excitotoxicity, and was suggested to be a factor contributing to the development of neurodegeneration and seizures. Elevated serum concentration of homocysteine is considered to be an independent risk factor of atherosclerosis and is an emerging risk factor of cognitive dysfunction and stroke. In the present study, serum level of KYNA, homocysteine and other biochemical parameters were assessed in patients at early (up to 24 h after infarct) stage of stroke. Serum KYNA and homocysteine levels were similar in control (N = 26) and stroke (N = 24) groups. KYNA level correlated positively with the level of homocysteine in control and in stroke group, with p = 0.018; r = 0.462 and p = 0.027; r = 0.451, respectively. In control group, KYNA correlated positively also with age (p = 0.007; r = 0.514) and with creatinine level (p = 0.002; r = 0.581). In stroke group, serum KYNA correlated positively with creatinine (p = 0.001; r = 0.644) and with urea level (p < 0.001; r = 0.716). Homocysteine level correlated inversely with folate level in control (p = 0.01; r = -0.499) but not in stroke group (p = 0.13; r = -0.317). Serum homocysteine in stroke group correlated positively also with age (p = 0.001; r = 0.6401), and with urea level (p = 0.017; r = 0.4813). Clinical significance of the association between serum KYNA and homocysteine levels requires further investigation.
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PMID:Serum kynurenic acid positively correlates with cardiovascular disease risk factor, homocysteine: a study in stroke patients. 1696 96

Forty five (24 male & 21 female) moderate to severe degree of predialysis CRF patients were prospectively studied over a period of 6 months (July- December, 2004) to see the effect of Recombinant Human Erythropoietin (rHuEpo/EPO) therapy on renal anaemia, progression of renal excretory function & quality of life at 3 and 6 months intervals from the starting of EPO therapy. Mean +/- SD age of the patients was 56 +/- 12 (30-77 yrs) and causes of CRF were Diabetic Nephropathy (DN)=15 (33%), Chronic Glomerulonephritis (CGN) =14(31%), Hypertension (HTN)=11(21%), Chronic Pyelonephritis (CPN)=03 (6.5%) and Obstructive Uropathy (OU)=02 (4.5%). Doses of rHuEpo was 80-100 IU/k week subcutaneously (SC) until the target Hb 11gm% & Hct 30% were achieved; there after the dose was titrated as appropriate. Serum Iron & Ferritin levels were also kept within normal reference level by iron therapy during the study period. Mean +/- SD base line (before starting EPO therapy) level of haemoblobin were 8.4 +/- 0.81(gm%), Hct 27.86 +/- 1.6 (%), blood urea 21.72 +/- 10.5 (mmol/L), S. creatinine 431.93 +/- 228.79 (mmol/L) & Ccr. 21.25 +/- 10 mum respectively. The results showed that significant improvement of haemoglobin level occurred (gm%) from 8.4 +/- 0.81 (gm%) to 9.51 +/- 1.02 (p<0.001) at 3 months and 8.4 +/- 0.81 to 11.10 +/- 1.4, (p<0.001) at 6 months interval. Haematocrit (Hct%) value also significantly increased from 27.86 +/- 1.5 to 30.57 +/- 3.62, (p<0.001) at 3 months and 27.86 +/- 1.5 to 32.81 +/- 3.92 (p<0.001) at 6 months of EPO therapy. Mean blood urea and S. creatinine levels decreased from base line level during the study period but did not show any statistical significance. There was no significant side-effects like uncontrolled hypertension, seizure or hyperviscosity syndrome in any of the study population. The quality of life in terms of improvement of physical ability and sense of well being were also improved in all the study patients. In conclusion, this study showed that the effect of rHuEpo therapy is beneficial for the correction of renal anaemia, can delay the progression of renal failure and improvement of overall quality of life in predialysis CRF patients.
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PMID:Effect rHuEpo on predialysis CRF patients: study of 45 cases. 1696 14

Late-onset urea cycle disorder in a 20-month-old boy is unusually associated with Klinefelter syndrome with a 47XXY karyotype. We record the typical clinical and biochemical findings of ornithine transcarbamylase (OTC) deficiency in a young boy with a short history of recurrent vomiting, self mutilating behaviour, lethargy, ataxia and seizures. Laboratory studies showed hyperammonaemia and orotic aciduria, with normal citrulline and other urea cycle amino acids. Unfortunately, a liver biopsy for OTC activity measurement was refused by the parents. A rapid reversal of phenotype was seen on the introduction of a low-protein diet with accompanying benzoate and phenylbutyrate administration. Linkage studies suggested the inheritance of two X chromosomes, which was confirmed by karyotype analysis. Sequencing of all exons and immediate splice site regions revealed no sequence alterations in these sections of the OTC gene. A search for skewing of X-inactivation in the liver was not possible but we did show a random pattern of X-inactivation in leukocytes. The possibility of maternal X chromosome iso-disomy in our patient was discounted by microsatellite analysis, which revealed the inheritance of two independent X chromosomes. Mutation analysis in the OTC gene has shown that approximately 20% of patients with liver biopsy confirmed OTC deficiency do not have mutations in the coding or immediate splice-site sequences of this gene. Their classification as OTC phenocopies remains speculative, awaiting clarification of the underlying DNA alteration. We report on the novel association of OTC deficiency and Klinefelter syndrome with the additional interest of a probable unusual genetic defect underlying the OTC abnormality.
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PMID:An OTC deficiency 'phenocopy' in association with Klinefelter syndrome. 1718 14


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