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)

The possibility of using polysorbate 80-coated polybutylcyanoacrylate nanoparticles to deliver low molecular polar hydrophilic drugs to the CNS has been studied. Tubocurarine (a quaternary ammonium salt) does not penetrate the normal intact blood-brain barrier. However, the injection of this drug directly into the cerebral ventricles of the brain provokes the development of epileptiform seizures as assessed by electroencephalogram (EEG). An in situ perfused rat brain technique was used as an experimental technique together with a simultaneous recording of the EEG. Nanoparticles were prepared by butylcyanoacrylate polymerization in an acidic medium. Fifteen minutes after the introduction of tubocurarine-loaded polysorbate 80-coated nanoparticles into the perfusate, epileptiform spikes in the EEG appeared. Intraventricular injection of tubocurarine caused the appearance of the EEG seizures 5 min after administration. Neither tubocurarine solution nor tubocurarine-loaded nanoparticles without polysorbate 80 or a mixture of polysorbate 80 and tubocurarine were able to influence the EEG. Thus only the loading of tubocurarine onto the polysorbate 80-coated nanoparticles appears to enable the transport of this quaternary ammonium compound through the blood-brain barrier.
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PMID:Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polybutylcyanoacrylate nanoparticles: an in situ brain perfusion study. 946 8

The Pi peak in a 31P NMR spectrum of the brain can be deconvoluted into six separate Lorentzian peaks with the same linewidth as that of the phosphocreatine peak in the spectrum. In an earlier communication we showed that the six Pi peaks in normal brain represent two extracellular and four intracellular compartments. In that report we have identified the first of the extracellular peaks by marking plasma with infused Pi, thereby substantially increasing the amplitude of the single peak at pH 7.35. 2-Deoxyglucose-6-phosphate (2-DG-6-P) was placed in the brain interstitial space by microdialysis. The resulting 2-DG-6-P peak was deconvoluted into three separate peaks. The chemical shift of the principle 2-DG-6-P peak gave a calculated pH of 7.24 +/- 0.02 for interstitial fluid pH, a value that agreed well with the pH of the second extracellular Pi peak at pH 7.25 +/- 0.01. We identified the intracellular compartments by selectively stressing cellular energy metabolism in three of the four intracellular spaces. A seizure-producing chemical, flurothyl, was used to activate the neuron, thereby causing a demand for energy that could not be completely met by oxidative phosphorylation alone. The resulting loss of high-energy phosphate reserves caused a significant increase in intracellular Pi only in those cells associated with the Pi peak at pH 6.95 +/- 0.01. This suggests that this compartment represents the neuron. Ammonia is detoxified in the astrocyte (glutamine synthetase) by incorporating it into glutamine, a process that requires large amounts of glucose and ATP. The intraarterial infusion of ammonium acetate into the brain stressed astrocyte energy metabolism resulting in an increase in the Pi of the cells at pH of 7.05 +/- 0.01 and 7.15 +/- 0.02. This finding, coupled with our observation that these same cells take up infused Pi probably via the astrocyte end-foot processes, lead us to conclude that these two compartments represent two different types of astrocytes, probably protoplasmic and fibrous, respectively. As a result of this study, we now believe the brain contains four extracellular and four intracellular compartments.
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PMID:NMR-based identification of intra- and extracellular compartments of the brain Pi peak. 983 54

A fast and simple method for separation of 16 seizure drug substances using capillary electrophoresis in a non-aqueous separation medium is described. The separation medium consists of a mixture of acetonitrile, methanol and glycerol with ammonium acetate/acetic acid as the electrolyte. The analytes are detected by UV detection at 214 nm. Injection from the detection end (8.5 cm to detector) combined with the usage of a short capillary (32.5 cm total length) makes it possible to separate all 16 amines within 2 min. The choice of solvents, electrolytes and viscosity increasing additives are discussed with special emphasis to their influence on the separation selectivity.
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PMID:Fast separation of 16 seizure drug substances using non-aqueous capillary electrophoresis. 1007 70

Acidophilia is one of the hallmarks of acute neuronal damage and death in brain ischemia, excitotoxic and traumatic lesions and epileptic seizures. We here describe a novel and simple method for visualizing acidophilic neurons on paraffin sections, using vanadium acid fuchsin (VAF) staining and toluidine blue or hematoxylin counterstaining. Paraffin sections of the brain fixed in ethanol-formalin-acetic acid mixture are stained in 0.1% acid fuchsin containing 0.125% of ammonium metavanadate and 1% of glacial acetic acid, differentiated if overstained in 0.01% of borax solution, and counterstained with 0.05-0.025% of toluidine blue in acetate buffer (pH 3.3) or Gill's II hematoxylin. The sections are dehydrated, cleared in xylene and mounted in Canada balsam or any synthetic mounting media for light microscopy. VAF combined with toluidine blue or hematoxylin results in highly selective and reproducible color contrast staining of acidophilic neurons as well as glial nuclei and hyperchromatic neurons. As a progressive method, acid fuchsin staining usually does not require differentiation. The red acidophilic neurons are clearly visible on the background of non-damaged cells, which significantly facilitates the identification, and localization of damaged neurons, even at low magnification under the light microscope.
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PMID:Improved selective, simple, and contrast staining of acidophilic neurons with vanadium acid fuchsin. 1077 32

Glutamatergic neurotransmission, particularly of the NMDA receptor type, has been implicated in the excitotoxic response to several external and internal stimuli. In the present investigation, we report that S-methyl-N,N-diethylthiocarbamate sulfoxide (DETC-MeSO) selectively and specifically blocks the NMDA receptor subtype of the glutamate receptors, and attenuates glutamate-induced neurotoxicity in rat-cultured primary neurons. Other major ionotropic glutamate receptor subtypes, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate, were insensitive to DETC-MeSO both in vitro and in vivo. Disulfiram, the parent compound of DETC-MeSO, also inhibits glutamate receptors partially in vivo; however, it fails to inhibit glutamate receptors in mice pretreated with N-butyl imidazole, a cytochrome P450 enzyme inhibitor, implicating the need for bioactivation of disulfiram to be an effective antagonist. We showed that glutamate-induced increase in (45)Ca2+ was attenuated in rat-cultured primary neurons following pretreatment with DETC-MeSO. The Ca2+ influx into primary neurons, studied by confocal microscopy of the fluorescent Ca2+ dye fura-2, demonstrated a complete attenuation of NMDA-induced Ca2+ influx. Similarly, DETC-MeSO attenuated NMDA-induced (45)Ca2+ uptake. Glutamate-induced (45)Ca2+ uptake and Ca2+ influx, however, were partially blocked by DETC-MeSO, and this is consistent with both in vitro and in vivo studies in which DETC-MeSO partially blocked mouse brain glutamate receptors. In addition, DETC-MeSO pretreatment effectively prevented seizures in mice induced either by NMDA, ammonium acetate, or ethanol-induced kindling seizures, all of which are believed to be mediated by NMDA receptors. These data demonstrate that DETC-MeSO produces the neuroprotective effect through antagonism of NMDA receptors in vivo.
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PMID:S-methyl-N,N-diethylthiocarbamate sulfoxide elicits neuroprotective effect against N-methyl-D-aspartate receptor-mediated neurotoxicity. 1117 83

Nitrogen based fertilizers represent an important element in the farm economy, but their storage and use are associated with major risks to livestock and humans. An accidental ammonia exposure occurred at a Midwest county fair in Illinois. Six deaths occurred in show livestock; a Holstein cow, 3 Holstein heifers, a goat, and a lamb. Mortality was associated with consumption of water inadvertently contaminated with a liquid fertilizer containing ammonium nitrate and urea commonly used for irrigating agricultural crop fields and brought onto the fairgrounds by a tanker truck previously used to transport liquid fertilizer. The show animals that drank the contaminated water immediately became ill, developed seizures and died within a few hours. Postmortem findings were unremarkable to nonspecific. Rumen contents from the lamb, Holstein cow, and Holstein heifer had ammonia-nitrogen concentrations of l,000, 1,150 and 1,440 ppm, respectively. Water from the heifer's water bucket, the cow's water bucket, and the tanker truck, had nitrate levels of 6,336, 6,116, and 6,248 ppm, respectively. The ammonia toxicosis was attributed to the contaminated water brought onto the fairgrounds by the tankertruck that previously transported liquid ammonium nitrateand urea. This accident underscores the importance of meticulous observation of safety guidelines and measured working practices in agriculture and animal husbandry.
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PMID:Accidental ammonia exposure to county fair show livestock due to contaminated drinking water. 1236 Nov 12

Urea Cycle Disorders (UCD) is an inborn error of urea synthesis in which ammonium and other nitrogenous precursors of urea accumulate leading to episodic coma and a high mortality rate. Therapy with peritoneal dialysis, essential amino acids or their nitrogen-free analogues has increased survival. The authors report 5 cases of urea cycle disorders, all of whom developed and were rescued from hyperammonemic coma. However, the eventual outcome was quite variable. Argininosuccinate lyase deficiency (ALD) Case 1. A 2 month old male infant, a product of a consanguineous marriage (Suphanburi province); developed poor feeding on day 7, lethargy, convulsion, hepatomegaly and respiratory alkalosis leading to respiratory failure and coma. Hyperammonemia, elevation of glutamic acid and argininosuccinic acid and its anhydrides confirmed the diagnosis of ALD. He is now 9 years old and severely retarded. Case 2. A male infant with history of lethargy, poor feeding on day 3, treated as sepsis and required respiratory support for 6 days; subsequently readmitted at age 2 weeks with vomitting, lethargy, seizure activity and hyperammonemia, and was treated by a local pediatrician in Songkhla province. There was a history of parental consanguinity and he was referred to Siriraj Hospital on day 64 with severe essential amino acid deficiency and acrodermatitis enteropathica with markedly elevated plasma citrulline level. In spite of aggressive treatment; the patient developed sepsis and he expired on day 78. Ornithine transcarbamylase deficiency (OTC) Case 3. An eleven-month-old male infant, the product of a non-consanguineous marriage, developed neonatal onset of hyperammonemia on day 5 after poor feeding, lethargy, hypothermia, seizure, apnea and coma. He was rescued from neonatal hyperammonemic coma on day 9 after aggressive treatment, but expired at eleven months of age after overwhelming sepsis. Case 4. A male infant, sibling of case 3 was referred to Siriraj Hospital on day 8 with hyperammonemia and coma. In spite of intensive genetic counseling given after the birth of their first child with OTC, the couple chose to have another baby without informing any physician. The baby developed vomiting and lethargy on day 2; subsequently hyperammonemia was noted. In spite of aggressive treatment given; hepatic dysfunction, renal failure and disseminated intravascular coagulation defects occurred on day 15. He expired on day 18 after parental permission for discontinuation of all treatment. Argininosuccinate synthetase deficiency (ASS) or Citrullinemia. Case 5. A seven week old female infant, the product of a consanguineous marriage and of Pakistani ethnic origin; developed intermittent vomiting from day 6. Initial diagnoses included ruminations, sepsis and pyloric stenosis for which she was operated on (day 30); however, vomiting continued; subsequently seizures, hyperammonemic coma developed and she was rescued from hyperammonemic coma within 30 hours. Significant elevations of citrulline and L-glutamine were demonstrated. She was discharged in excellent condition to her home in Dubai, the United Arab Emirates.
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PMID:Urea cycle disorders in Thai infants: a report of 5 cases. 1240 52

We report 4 clinical cases of hyperammonemic encephalopathy (HE) associated with valproate acid (VPA) and review the literature on its pathophysiology. In all four cases, hepatic function was normal and valproic levels were within the therapeutic range. Elevated ammonium levels were found as the only biochemical abnormality. Patients showed decreased level of consciousness, confusion, ataxia and seizures. In 1 case the EEG showed diffused triphasic waves with frontal predominance. After suppression of treatment with VPA there was remission of clinical manifestations, and ammonium levels returned to normal. In order to obtain the correct diagnosis of HE, in all patients treated with either VPA mono or polytherapy, ammonium levels should be considered.
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PMID:[Hyperammonemic encephalopathy associated with valproate acid]. 1283 56

Among new researches bearing on cerebral palsy are the growth of brain cells in tissue cultures for experimentation; the use of polysaccharides to prevent the formation of a glial barrier to nerve growth after injury; observation of changes in reactions of neurons at various stages of development; the finding of hypernatremia and hyperchloremia in lesions of the frontal lobe and the thalamus; stimulation of cerebral blood flow by injection of sodium bicarbonate and retardation with ammonium chloride; and studies of serial sections of brains of palsied children who died. Study of development in the early months of life has made possible the detection of significant abnormalities in behavior early in life. Loss of hearing may be tested in very young children by measuring minute variations in electrical resistance of the skin upon auditory stimulation of the sympathetic nervous system. Conditions which have been described as having been confused with cerebral palsy are dislocation of a cervical vertebra, hereditary spastic paraplegia, transverse myelopathy, injury to the spinal cord or cauda equina by anomalous growths of the spine, and also encephalitis and meningitis. Sedation has proved a valuable adjunct to electroencephalographic study of cerebral palsy. Better criteria for abnormality in the young child should be determined and the application of them more clearly standardized. Simple exercises are useful for early training of palsied children to stimulate development. "Crossed laterality"-the dominant eye being contralateral to the preferred hand-has been counteracted by special training with great success in eliminating emotional and behavior problems and accelerating development.Recent studies indicate that only 50 per cent of cerebral palsy patients have normal or better intelligence. Subluxation of the hip joint, a common deformity associated with cerebral palsy, can sometimes be corrected by operation if detected at an early stage. Radical ablation of epileptogenic foci in the cortex is also being done in young patients if drug control of seizures fails. Frontal topectomy, cingulate gyrectomy or prefrontal labotomy may be advisable in cases in which proper response to drug therapy is not obtained. Improvement in behavior as well as control of seizures may follow the use of Benzedrine,(R) Dexedrine,(R) Dilantin(R) sodium, Mebaral(R) and phenobarbital. Alcohol, paraldehyde and chloral hydrate have been effective as relaxants.
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PMID:What's new in cerebral palsy. 1310 11

Glutamine has been shown to influence endothelial-dependent relaxation and nitric oxide production in vitro, possibly by limiting arginine availability, but its effects in vivo have not been well studied. Hyperammonemia is a pathophysiological condition in which glutamine is elevated and contributes to depressed CO(2) reactivity of cerebral arterioles. We tested the hypothesis that acute hyperammonemia decreases pial arteriolar dilation to acetylcholine in vivo and that this decrease could be prevented by inhibiting glutamine synthetase with L-methionine-S-sulfoximine (MSO) or by intravenous infusion of L-arginine. Pial arteriolar diameter responses to topical superfusion of acetylcholine were measured in anesthetized rats before and at 6 h of infusion of either sodium or ammonium acetate. Ammonium acetate infusion increased plasma ammonia concentration from approximately 30 to approximately 600 microM and increased cerebral glutamine concentration fourfold. Arteriolar dilation to acetylcholine was intact after infusion of sodium acetate in groups pretreated with vehicle or with MSO plus methionine, which was coadministered to prevent MSO-induced seizures. In contrast, dilation in response to acetylcholine was completely blocked in hyperammonemic groups pretreated with vehicle or methionine alone. However, MSO plus methionine administration before hyperammonemia, which maintained cerebral glutamine concentration at control values, preserved acetylcholine dilation. Intravenous infusion of L-arginine during the last 2 h of the ammonium acetate infusion partially restored dilation to acetylcholine without reducing cerebral glutamine accumulation. Superfusion of 1 or 2 mM L-glutamine through the cranial window for 1 h in the absence of hyperammonemia attenuated acetylcholine dilation but had no effect on endothelial-independent dilation to nitroprusside. We conclude that 1) hyperammonemia reduces acetylcholine-evoked dilation in cerebral arterioles, 2) this reduction depends on increased glutamine rather than ammonium ions, and 3) increasing arginine partially overcomes the inhibitory effect of glutamine.
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PMID:Glutamine-dependent inhibition of pial arteriolar dilation to acetylcholine with and without hyperammonemia in the rat. 1570 2


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