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)

Patients with epilepsy on long term antiepileptic drug (AED) therapy deserve special consideration not only concerning seizure control but also the effect on anaesthetic metabolism and hepatorenal functions. In the present study, we examined the effects of sevoflurane anaesthesia on plasma inorganic fluoride (F-) level and hepatorenal function in patients with and without AED therapy. Twenty-two patients (12 with AEDs = AED group, and ten without AEDs = control group = C group), ASA I, who were free of hepatorenal disease, received approximately 2-3 h sevoflurane anaesthesia. Plasma F- analysis was performed at the stages of: 1) induction of anaesthesia, 2) conclusion of anaesthesia, 3) 15 h after the conclusion of anaesthesia, using an ion-selective electrode calibrated with a standard solution of sodium fluoride. Pre- and postoperative hepatic (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin) and renal (blood urea nitrogen, creatinine) function was tested. There were no significant differences between the two groups in the average age (AED group = 9.4 and control group = 10.1 y.o.), body weight, duration of anesthesia, and MAC hours (2.6 and 2.4). The mean peak F- levels were 15.5 and 13.6 microM, in AED and C groups (not significant), respectively. No patient exhibited F- values greater than 50 microM, the hypothetical nephrotoxic threshold. The patients showed no abnormal values either in hepatic or renal function tests postoperatively. These results suggest approximately 2-3 h sevoflurane anaesthesia to be safe in patients taking AEDs.
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PMID:Clinical characteristics and biotransformation of sevoflurane in paediatric patients during antiepileptic drug therapy. 888 Aug 18

Phenytoin is extensively used in Europe and the United States for the treatment of generalized tonic clonic seizures (grand mal). However, the efficacy is lowered by the erratic bioavailability after oral administration. The current study was conducted in order to investigate the physicochemical properties, the bioavailability, and the anticonvulsant activity of cyanoguanidinophenytoin (CNG-DPH), a structural analogue of phenytoin, which was obtained by the replacement of the urea moiety by a cyanoguanidine moiety. CNG-DPH was prepared under homogeneous Biltz conditions and under heterogeneous phase-transfer conditions. CNG-DPH is poorly water soluble and has a pKa of 5.3. At pH 7.4, log P was 1.16, from which a pH-independent log P of 3 can be calculated. Pharmacokinetic parameters were obtained after oral administration of CNG-DPH to rats and were compared to those of phenytoin after administration of an equimolar amount. AUC, tmax, and Cmax were significantly increased compared to those of phenytoin. The anticonvulsant profile was similar to the profile of phenytoin. CNG-DPH was active in the maximal electroshock seizure test, albeit 7-fold less active than phenytoin. The analogue did not protect animals against convulsions induced by chemicals such as pentylenetetrazole, picrotoxin, N-methyl-aspartate, strychnine, and bicuculline. It is concluded that while the bioisosteric exchange of the urea moiety of the molecule with the cyanoguanidine moiety dramatically changed the physicochemical and pharmacokinetic parameters compared to those of phenytoin, the concomitant change of the affinity toward molecular targets reduced the pharmacological activity and the therapeutic efficacy of the compound.
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PMID:Bioavailability and anticonvulsant activity of 2-cyanoguanidinophenytoin, a structural analogue of phenytoin. 889 74

The N-[(4-cycloheptylaminopyrid-3-yl)sulfonyl]-N'-cycloheptyl urea, a neuroprotective agent, and 10 chemically related sulfonyl(thio)ureas were evaluated in the maximal electroshock seizure test in mice. This sulfonylurea, BM 27, and two structurally related sulfonylthioureas, BM 11 and BM 34, emerged with a 50% effective dose (ED50) of 2.87, 1.72, and 1.19 mg/kg, respectively. Their anticonvulsant profiles were found to be similar to that of phenytoin: active in the maximal electroshock seizure (MES) test and inactive in chemically induced seizures (pentetrazole, strychnine, bicuculline, picrotoxine, N-methyl-D,L-aspartic acid). These compounds exhibited a higher protective index and potency than those of phenytoin. Additional work remains necessary, however, to determine whether BM 27 is of clinical interest.
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PMID:Anticonvulsant activity of pyrid-3-yl-sulfonyl ureas and thioureas. 907 May 96

A 3-year-old male German shepherd dog was presented with severe generalised seizures. The dog was protein-intolerant and showed severe hyperammonaemia on ammonia stimulation. The hyperammonaemic state was present for at least 6 weeks and then spontaneously resolved. No obvious cause (liver disease, portocaval shunts, urea cycle enzyme deficiencies, drug therapy or urinary tract obstruction) could be identified. It is possible that this dog had a variation of transient hyperammonaemic syndrome, described in man and recently in a juvenile Irish wolfhound, that extended into adulthood.
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PMID:Transient hyperammonaemia in an adult German shepherd dog. 929 Oct 77

Epileptic patients given phenobarbital (3 mg/kg, n = 8) or finlepsin (20 mg/kg, n = 7) were found to have a statistically significant increase (p < 0.05) in the parameters of the lipid peroxidation end product malonic dialdehyde in the erythrocytes (3.34 +/- 1.13 mumol/liter) and blood plasma (0.099 +/- 0.04 mumol/liter) in comparison to the control group (n = 9; 1.58 +/- 0.96 mumol/liter and 0.045 +/- 0.02 mumol/liter, respectively). The urea level (6.7 +/- 1.28 mumol/liter) and the ammonia level (31.59 +/- 10.46 mumol/liter) increase were statistically insignificant as compared to the controls (5.76 +/- 0.66 mumol/liter and 26.41 +/- 5.96 mumol/liter, respectively). Bemitil (n = -7) in a dose of 20 mg/kg reduced in 10 days the amount of malonic dialdehyde in the erythrocytes (1.57 +/- 0.61 mumol/liter, p < 0.05) and plasma (0.043 +/- 0.02 mumol/liter, p < 0.05) as well as the amount of urea (3.76 +/- 0.96 mumol/liter,) and ammonia p < 0.05 and ammonia (18.17 +/- 2.02 mumol/liter, p < 0.05) in the blood. A favorable therapeutic effect (lesser frequency of seizures and lesser asthenia of the of the children) was observed at the same time. The frequency of paroxysms reduced to 50% in 4 patients (2 with complex-partial seizures, one with absence, and one with simple-partial seizures) and to 75-% in the fifth patient with complex-partial seizures. The therapeutic effect in the 6th and 7th patients could not be evaluated.
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PMID:[The effect of bemitil on the parameters of lipid peroxidation and nitrogen metabolism in epilepsy in children]. 932 90

Anticonvulsant activity, lethality and neurotoxicity of a valproic acid (VPA) analog, N-(2-propylpentanoyl) urea (VPU) in comparison to its parent compound were investigated in mice. Intraperitoneally administered VPU demonstrated a higher protection than VPA in both the maximal electroshock seizure (MES) and the pentylenetetrazole (PTZ) tests exhibiting a median effective dose (ED50) of 66 and 57 mg/kg, respectively. VPU weakly blocked the effect of bicuculline and was ineffective in strychnine test. Furthermore, VPU was also active orally demonstrating an ED50 approximately 6 times higher than its ED50 by the intraperitoneal route. Based on the relatively high median lethal dose (LD50), 1553 mg/kg, VPU possesses a greater margin of safety (LD50/ED50) than did VPA. Unwanted (side) effects in terms of impairment of motor activity and neurotoxicity were assessed by the rotorod test, locomotor activity test as well as potentiation of barbiturate sleeping time. The median neurotoxic dose (TD50) as measured by rotorod test were 625 mg/kg for intraperitoneally given VPU. This finding results in higher protective index (PI = TD50/ED50) of VPU (PI = 9.5) than that of VPA (PI = 1.1) implying that, in therapeutic dose, VPU may produce less neurological side effects than did VPA. Superiority of VPU in terms of higher potency in parallel with minimal neurological deficit as assessed by rotorod test was evident throughout the observation period of 12 hours. Similar results on locomotor activity as well as potentiation of barbiturate sleeping time were obtained with VPU and VPA. Thus, VPU is preferably expected to exert minor degree of CNS depression. Taken altogether, our findings demonstrate greater anticovulsant activity for VPU than for VPA. In addition, this compound is also orally active and seems to offer a greater safety margin in parallel with lower unwanted effects in relation to its parent compound. As indicated by the animal data obtained, VPU is an attractive anticonvulsant candidate for further investigation.
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PMID:Preliminary evaluation of the anticonvulsant activity of a valproic acid analog: N-(2-propylpentanoyl) urea. 934 28

Ornithine Transcarbamylase (OTC) is a key urea cycle enzyme. Congenital OTC deficiencies in humans result in hyperammonemia and a spectrum of neurological symptoms including hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals cerebral atrophy, ventricular enlargement and Alzheimer type II astrocytosis. Using an animal model of congenital OTC deficiency, the sparse fur (spf) mouse, recent studies have revealed significant alterations of cholinergic, serotoninergic and glutamatergic neurotransmitter systems. Possible pathophysiologic mechanisms responsible for neuronal cell loss in OTC deficiency include a deficit in cerebral energy metabolism, and glutamate excitotoxicity. Therapy continues to rely on alternative substrate administration including sodium benzoate and sodium phenylacetate. Experimental evidence suggests that acetyl-L-carnitine and glutamate (NMDA) receptor antagonists could be potentially useful therapeutic agents. Liver transplantation is effective in many patients and recent experimental studies using adenoviral vectors suggest that gene therapy may ultimately be useful in the treatment of congenital OTC deficiency.
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PMID:Ornithine transcarbamylase deficiency: pathogenesis of the cerebral disorder and new prospects for therapy. 934 66

A sixty-six year old female was admitted to the hospital with an incomplete hemiparesis on the left side combined with a short episode of unconsciousness. According to her husband's account she had a seizure. Relevant laboratory measurements: plasma sodium concentration 113.9 mmol/l, plasma concentration of ADH 10.3 pg/ml, urine sodium concentration 44.4 mmol/l. The plasma concentrations of creatinine and urea were within normal limits. The working hypothesis was SIAD (syndrome of inappropriate antidiuresis) or Schwartz-Bartter-syndrome. The patient was treated immediately with water restriction (500-1000 ml/day), furosemide and i.v. replacement of urinary sodium losses by 3% NaCl. The analysis of cerebrospinal fluid showed pleocytosis and increased concentrations of immunoglobulins G and M. Serological diagnosis was positive for antigen of varicella-zoster virus. These observations were thought to be compatible with a diagnosis of SIAD in the setting of encephalitis. Under water restriction, infusion of 3% saline, treatment with loop diuretics and aciclovir (3 x 750 mg daily) the neurological function returned to normal within 2 days. A standard oral water load on the 14th hospital days showed a return to a normal water metabolism.
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PMID:[Sudden hyponatremia with unconsciousness. Case report and brief overview of the syndrome of inadequate antidiuresis (SIAD or Schwartz-Bartter syndrome]. 944 Oct 28

We conducted a prospective cohort study to detect any relationships between specific clinical features and laboratory indices at initiation of hemodialysis and long-term survival. One hundred and thirty-nine consecutive patients with chronic renal failure hospitalized to start maintenance hemodialysis between January 1990 and December 1994 were enrolled, and follow-up was completed through December 1995. At baseline, subjects were assigned to one of five groups based on their major indication for initiation of hemodialysis. The indications were: (a) nausea and vomiting; (b) severe weakness; (c) no major symptom (dialysis started because of 'high' serum creatinine and blood urea nitrogen concentrations); (d) volume overload, and (e) miscellaneous (angina, pericarditis, seizure, pruritus, and hyperkalemia). Blood urea nitrogen, serum creatinine and serum albumin concentrations were measured once before the first dialysis. The main outcome measure was death. The 139 study subjects included 77 women and 62 men comprising 116 Blacks (83%), 15 Hispanics (11%), and 8 Whites (6%) of mean age 54 +/- 15 years. Mean length of follow-up was 39 months. At baseline, mean blood urea nitrogen concentration was 121 +/- 38 mg/dl, mean serum creatinine concentration was 12.6 +/- 5.2 mg/dl, and mean serum albumin concentration was 3.5 +/- 0.62 g/dl. Forty-two subjects (30%) died during follow-up. Cox regression analysis showed that there was no significant association between mortality and any of the indicators evaluated (indication for initiation of dialysis (p = 0.2), serum creatinine concentration (< 10 vs. > or = 10 mg/dl) (p = 0.8), blood ure nitrogen concentration (< 100 vs. > or = 100 mg/dl) (p = 0.68) and serum albumin concentration (< 4 vs. > or = 4 g/dl) (p = 0.62). All analyses included adjustment for age and diabetes. We conclude that in patients with chronic renal failure, the clinical features and laboratory indices used as guidelines for initiation of renal replacement therapy do not correlate with survival. Objective parameters that will permit initiation of dialysis at a time that will maximize survival in patients with chronic renal failure are needed.
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PMID:Timing of initiation of uremia therapy and survival in patients with progressive renal disease. 962 34

Congenital ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea cycle enzymes in humans. A large percentage of survivors of neonatal OTC deficiency suffer severe developmental disorders, including seizures, mental retardation and cerebral palsy. Neuropathological studies reveal ventricular enlargement, cerebral atrophy and delayed myelination, as well as Alzheimer type II astrocytosis. Using the sparse-fur (spf) mouse model of congenital OTC deficiency, studies of central cholinergic integrity revealed a developmental delay in choline acetyltransferase activity and of high-affinity [3H]-choline uptake in several brain structures. Subsequent studies of muscarinic cholinergic binding site distribution showed a widespread loss of M1 sites, consistent with cholinergic cell loss. These alterations are similar to those reported in Alzheimer's disease, suggesting that the severe cognitive dysfunction in congenital OTC deficiency may at least partly result from a muscarinic cholinergic lesion. Possible mechanisms involved in the pathogenesis of cholinergic cell loss in congenital OTC deficiency include ammonia-induced inhibition of pyruvate and alpha-oxoglutarate oxidation, resulting in decreased synthesis of acetyl CoA and a cerebral energy deficit, as well as NMDA receptor-mediated excitotoxicity. Treatment of spf mice with acetyl-L-carnitine (ALCAR) results in partial recovery of the developmental choline acetyltransferase deficit, suggesting a potential therapeutic benefit of ALCAR in congenital OTC deficiency. Other therapies currently used include ammonia-lowering strategies (using sodium benzoate or sodium phenylacetate) and, in severe cases, liver transplantation.
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PMID:Evidence for a central cholinergic deficit in congenital ornithine transcarbamylase deficiency. 977 87


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