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)

An experienced diver drowned after a generalised seizure caused by oxygen toxicity during a 19-minute "technical" dive to a depth of 47 m. He had used a 50% oxygen/nitrogen gas mixture inappropriately during the dive. This case attests the risk of oxygen toxicity from oxygen-enriched air during deep dives, the shortcomings of the diver's equipment, and the need to examine, with knowledge of diving physiology and practice, both the body and equipment.
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PMID:A diving fatality due to oxygen toxicity during a "technical" dive. 881 83

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

The expression of c-Fos, c-Jun and Hsp70 was examined in the hippocampus at 6, 12, 24, 48, 72 h, 4, 7 and 42 days following a combination of unilateral common carotid artery ligation and 60 min of systemic hypoxia (8% oxygen, 92% nitrogen) in 25-day-old male rats. While pyknotic cells were not visible in the hippocampus of control animals, pyknosis was evident in the ipsilateral, but not the contralateral hippocampus, of hypoxic-ischemic animals beginning at 24 h post-hypoxia. Immunohistochemical analysis revealed no c-Fos-, c-Jun- or Hsp70-immunoreactivity (IR) in any control animals. However, at 6 h post-hypoxia, Fos- and Jun-IR was evident throughout the injured ipsilateral hippocampus and later appeared throughout the contralateral hippocampus, which never showed signs of pyknosis. In contrast, Hsp70-IR was first observed at 24 h post-hypoxia and was restricted to the injured ipsilateral hippocampus. Hsp70-IR was not, however, limited to dying neurons. H-I/seizure animals did not express these proteins at any time point. These results suggest that, even in irreversibly injured neurons, Fos, Jun and Hsp70 appear to be involved in the aftermath of ischemia but probably do not play a pivotal role in the outcome of H-I compromised cells. Furthermore, compounded injury (H-I/seizure) appears to block the synthesis these proteins.
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PMID:The effects of hypoxia-ischemia on expression of c-Fos, c-Jun and Hsp70 in the young rat hippocampus. 937 54

We have explored the structure-activity relationship (SAR) surrounding the clinically efficacious antiepileptic drug topiramate (1), a unique sugar sulfamate anticonvulsant that was discovered in our laboratories. Systematic structural modification of the parent compound was directed to identifying potent anticonvulsants with a long duration of action and a favorable neurotoxicity index. In this context, we have probed the pharmacological importance of several molecular features: (1) the sulfamate group (6-8, 22-25, 27, 84), (2) the linker between the sulfamate group and the pyran ring (9, 10, 21a,b), (3) the substituents on the 2,3- (58-60, 85, 86) and 4, 5-fused (30-38, 43, 45-47, 52, 53) 1,3-dioxolane rings, (4) the constitution of the 4,5-fused 1,3-dioxolane ring (2, 54, 55, 63-68, 76, 77, 80, 83a-r, 84-87, 90a, 91a, 93a), (5) the ring oxygen atoms (95, 96, 100-102, 104, 105), and (6) the absolute stereochemistry (106 and 107). We established the C1 configuration as R for the predominant alcohol diastereomer from the highly selective addition of methylmagnesium bromide to aldehyde 15 (16:1 ratio) by single-crystal X-ray analysis of the major diastereomer of sulfamate 21a. Details for the stereoselective syntheses of the hydrindane carbocyclic analogues 95, 96, 100, and 104 are presented. We also report the synthesis of cyclic imidosulfites 90a and 93a, and imidosulfate 91a, which are rare examples in the class of such five-membered-ring sulfur species. Imidosulfite 93a required the preparation and use of the novel sulfur dichloride reagent, BocN=SCl2. Our SAR investigation led to the impressive 4,5-cyclic sulfate analogue 2 (RWJ-37947), which exhibits potent anticonvulsant activity in the maximal electroshock seizure (MES) test (ca. 8 times greater than 1 in mice at 4 h, ED50 = 6.3 mg/kg; ca. 15 times greater than 1 in rats at 8 h, ED50 = 1.0 mg/kg) with a long duration of action (>24 h in mice and rats, po) and very low neurotoxicity (TD50 value of >1000 mg/kg at 2 h, po in mice). Cyclic sulfate 2, like topiramate and phenytoin, did not interfere with seizures induced by pentylenetetrazole, bicucculine, picrotoxin, and strychnine; also, 2 was not active in diverse in vitro receptor binding and uptake assays. However, 2 turned out to be a potent inhibitor of carbonic anhydrase from different rat tissue sources (e. g., IC50 of 84 nM for the blood enzyme and 21 nM for the brain enzyme). An examination of several analogues of 2 (83a-r, 85-87, 90a, 91a, 93a) indicated that potent anticonvulsant activity is associated with relatively small alkyl substituents on nitrogen (Me/H, 83a; Me/Me, 83m; Et/H, 83b; allyl/H, 83e; c-Pr/H, 83j; c-Bu/H, 83k) and with limited changes in the cyclic sulfate group, such as 4,5-cyclic sulfite 87a/b. The potent anticonvulsants 83a and 83j had greatly diminished carbonic anhydrase inhibitory activity; thus, inhibition of this enzyme may not be a significant factor in the anticonvulsant activity. The alpha-L-sorbopyranoses 67, 68, and 80, which mainly possess a skew conformation (ref 29), were nearly twice as potent as topiramate (1). The L-fructose enantiomers of 1 (106) and 2 (107), synthesized from L-sorbose, were found to have moderate anticonvulsant activity, with eudysmic ratios (MES ED50 in mice at 4 h, po) of 1:106 = 1.5 and 2:107 = 3.5. The log P values for 1 and 2 were determined experimentally to be 0.53 and 0.42, respectively, which are less than the optimal 2.0 for CNS active agents. However, analogues with more favorable calculated log P (clogP) values, in conjunction with just minor steric perturbation according to the developed SAR profile, such as 47 (clogP = 2.09), 83m (1.93), and 86 (1.50), did not display improved potency: 47 is less potent than 1, 83m is equipotent with 2, and 86 is less potent than 2. Although the measured log P value for diethyl analogue 31 is 1.52, this did not translate into enhanced potency relative to 1. (ABSTRACT TRUNCATED)
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PMID:Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives. 954 21

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

Branched-chain amino acids, and mainly leucine act as nitrogen donors in the cerebral glutamate-glutamine cycle, thereby reducing brain excitability. Rats equipped with cortical electrodes received 300 mg/kg of leucine, isoleucine, valine or the ketoacid of leucine, alpha-ketoisocaproate at 2 h before the induction of seizures by 40 mg/kg pentylenetetrazol. Control groups received saline or a commercial mixture of amino acids, Vamine(R). Leucine and isoleucine increased the latency to absence-like and tonic-clonic seizures but did not influence the duration of the tonic-clonic seizure. Vamine(R), valine and alpha-ketoisocaproate had no effect. These data are consistent with the role of leucine in buffering brain glutamate concentration.
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PMID:Modulation of pentylenetetrazol-induced seizure activity by branched-chain amino acids and alpha-ketoisocaproate. 987 52

Six enzyme defects of the urea cycle have been described. Ornithine transcarbamylase deficiency is the most frequent of these diseases. The cumulative frequency is 1:8000. Most patients become symptomatic in childhood, but onset of symptoms may occur later in childhood or even adulthood. The patients present with recurrent episodes of an unspecific acute encephalopathy, seizures and clouding of consciousness to a variable degree. Focal neurological signs such as hemiparesis, aphasia or ataxia may also occur. These episodes may be triggered by infection, protein overload or drugs. Diagnostic are increased blood ammonia levels. Characteristic patterns of plasma amino acids and the determination of orotic acid in the urine mostly discriminate the individual disorders. Further diagnostic steps include the allopurinol challenge test, liver or skin biopsy for measurement of enzyme activity and molecular genetic studies. Treatment requires restriction of protein intake, supplementation of arginine and activation of alternative pathways of nitrogen excretion with benzoate or phenylbutyrate. Untreated, the acute episode may be lethal. Long-term treatment improves the clinical outcome considerably. Urea cycle defects should be included in the differential diagnosis of any encephalopathy or coma of unclear origin, and blood ammonia should be determined early in the evaluation of such patients.
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PMID:[Enzyme defects of the urea cycle in differential acute encephalopathy diagnosis in adulthood. Diagnosis and current therapy concepts]. 1009 45

We have investigated the effect of soman-induced seizures on rat brain levels of nitrogen oxides (NOx) and lipid peroxidation (LPO) 30 min and 24 h after intoxication. Following administration of soman (90 microg/kg s.c.), acetylcholinesterase activity was reduced to <10% of control after 30 min, whereas some de novo synthesis had occurred after 24 h. Significant increases in the LPO products malondialdehyde (MDA) and (E)-4-hydroxy-2-nonenal (4-HNE) were seen in the cortex, hippocampus, striatum, thalamus and medulla-pons 30 min after administration. A significant increase in the brain NOx levels, suggesting an increase in NO production, was seen in the cortex after 30 min and in the hippocampus and the striatum after 24 h. No significant changes were observed in cerebellum. These data suggest the possibility that free radical reactions may be a primary cause of neuronal degeneration after soman intoxication.
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PMID:Increased levels of nitrogen oxides and lipid peroxidation in the rat brain after soman-induced seizures. 1046 93

By bioisosteric transformations and successive optimization of known GABA uptake inhibitors, several series of novel GABA uptake inhibitors have been prepared by different synthetic approaches. These compounds are derivatives of nipecotic acid and guvacine, substituted at the nitrogen of these amino acids by various lipophilic moieties such as diarylaminoalkoxyalkyl or diarylalkoxyalkyl. The in vitro values for inhibition of [(3)H]GABA uptake in rat synaptosomes was determined for each compound, and it was found that the most potent compound from this series, (R)-1-(2-(3,3-diphenyl-1-propyloxy)ethyl)-3-piperidinecarboxyli c acid hydrochloride (29), is so far the most potent parent compound inhibiting GABA uptake into synaptosomes. Structure-activity results confirm our earlier observations, that an electronegative center in the chain connecting the amino acid and diaryl moiety is very critical in order to obtain high in vitro potency. Several of the novel compounds were also evaluated for their ability in vivo to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). Some of the compounds tested show a high in vivo potency comparable with that of the recently launched anticonvulsant product 6 ((R)-1-(4, 4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid).
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PMID:Synthesis of novel GABA uptake inhibitors. 4. Bioisosteric transformation and successive optimization of known GABA uptake inhibitors leading to a series of potent anticonvulsant drug candidates. 1054 72

Antagonists at the 1A/2B subtype of the NMDA receptor (NR1A/2B) are typically small molecules that consist of a 4-benzyl- or a 4-phenylpiperidine with an omega-phenylalkyl substituent on the heterocyclic nitrogen. Many of these antagonists, for example ifenprodil (1), incorporate a 4-hydroxy substituent on the omega-phenyl group. In this study, the position of this 4-hydroxy substituent was transferred from the omega-phenyl group to the benzyl or phenyl group located on the 4-position of the piperidine ring. Analogues incorporating pyrrolidine in lieu of piperidine were also prepared. Electrical recordings using cloned receptors expressed in Xenopus oocytes show that high-potency antagonists at the NR1A/2B subtype are obtained employing N-(omega-phenylalkyl)-substituted 4-(4-hydroxyphenyl)piperidine, 4-(4-hydroxybenzyl)piperidine, and (+/-)-3-(4-hydroxyphenyl)pyrrolidine as exemplified by 21 (IC(50) = 0.022 microM), 33 (IC(50) = 0.059 microM), and 40 (IC(50) = 0.017 microM), respectively. These high-potency antagonists are >1000 times more potent at the NR1A/2B subtype than at either the NR1A/2A or NR1A/2C subtypes. The binding affinities of 21 at alpha(1)-adrenergic receptors ([(3)H]prazosin, IC(50) = 0.54 microM) and dopamine D2 receptors ([(3)H]raclopride, IC(50) = 1.2 microM) are reduced by incorporating a hydroxy group onto the 4-position of the piperidine ring and the beta-carbon of the N-alkyl spacer to give (+/-)-27: IC(50) NR1A/2B, 0.026; alpha(1), 14; D2, 105 microM. The high-potency phenolic antagonist 21 and its low-potency O-methylated analogue 18 are both potent anticonvulsants in a mouse maximal electroshock-induced seizure (MES) study (ED(50) (iv) = 0.23 and 0.56 mg/kg, respectively). These data indicate that such compounds penetrate the blood-brain barrier but their MES activity may not be related to NMDA receptor antagonism.
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PMID:Synthesis of N-substituted 4-(4-hydroxyphenyl)piperidines, 4-(4-hydroxybenzyl)piperidines, and (+/-)-3-(4-hydroxyphenyl)pyrrolidines: selective antagonists at the 1A/2B NMDA receptor subtype. 1071 62


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