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 potential of the investigational 5-hydroxytryptamine (5HT3) antagonist, LY277359, to alter cardiovascular, central nervous system (CNS), smooth muscle, and gastrointestinal functions at multiples of pharmacologically active doses, was examined to provide a profile of possible secondary pharmacological effects. In the anesthetized dog, significant cardiovascular effects were observed at doses 100-1000 and 4-15 times those found to be pharmacologically active at 5HT3 receptors in vivo in rats and dogs, respectively. These effects were limited to decreased heart rate (approximately 20%) at intravenous doses of 1.75 and 3.5 mg/kg and prolonged Q-Tc intervals (approximately 20 to 50%) at doses of 0.438 to 3.5 mg/kg. At an oral dose of 135 mg/kg (representing 1500-4500 times the pharmacologically active dose in rats), LY277359 induced hypoactive behavior and reduced body temperature in mice. Seizure activity was potentiated at high oral doses of LY277359 (45 and 135 mg/kg). A single oral dose of 135 mg/kg increased hexobarbital-induced sleep time. In smooth and cardiac muscle tissue studies in vitro, LY277359 was essentially inactive: it did not alter contractile activity or receptor function of the guinea pig ileum, rat vas deferens, rat uterus, or guinea pig atria at concentrations of 10(-5) to 10(-10) mol/l. At a concentration 50,000 times the 5HT3 antagonistic level in vitro (10(-4) mol/l), LY277359 inhibited the response of the ileum to field stimulation, acetylcholine and angiotensin I, and suppressed the rate of the spontaneously beating guinea pig atria in a noncompetitive manner.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:General pharmacology of a new potent 5-hydroxytryptamine antagonist. 186 53

A 46 years old male alcoholic was admitted with an assumed alcohol withdrawal syndrome accompanied by tonic-clonic seizures. Parenteral nutrition with fructose, sorbitol, xylitol, dextran, hydroxyethylstarch, electrolytes, vitamins and amino acids was undertaken. He died 20 d later due to renal insufficiency and bronchopneumonia. Calcium-oxalate-monohydrate (whewellite) was found in the central nervous system, the kidneys, the testes, the epididymis, the cardiac muscle cells and the lungs. The presence of urate crystals was suspected. The pathogenesis of secondary oxalosis is discussed.
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PMID:[Cerebrorenal oxalate formation--a metabolic abnormality following parenteral infusions of carbohydrate exchange substances]. 312 59

Electrical excitability of skeletal and cardiac muscle cells and neurons results from a balance of inhibitory and excitatory influences. Ionic concentration gradients established by adenosine 5'-triphosphate (ATP)-dependent pumps can be maintained because the lipid bilayer is an extremely good insulator. Once ionic concentrations are established, movement of one or more ions down their respective concentration gradients can establish voltage differences across a membrane. The Nernst equation allows prediction of membrane potentials based on the particular ion involved and the concentration gradient for that ion in the cell. A large number of voltage-gated ion channels, ligand-gated channels, and transporters are involved in maintaining this balance. The specific channels and transporters involved differ in various cell types. In any case, normal membrane excitability is tightly regulated by the balance of these opposing influences. It is not surprising that the disruption of the balance of excitability of various cells might lead to neurological phenotypes. However, large changes in excitability of muscle or nerve may well be lethal. Therefore, nature may select against such major changes. A growing body of evidence suggests that subtle changes in some ion channels can lead to a slight increase in membrane excitability that results in a neurological phenotype. Interestingly, these phenotypes are frequently episodic. That is, under many circumstances, the nerve or muscle may be functioning properly; however, under certain circumstances, a precipitating event can lead to abnormal excitability resulting in one of any number of phenotypes discussed below. In this chapter, discussion will be focused on a number of monogenic disorders of the nervous system where episodic phenotypes are known to result from specific mutations of ion channels. The similarities between a large group of seemingly disparate disorders will be emphasized. Finally, some energy will be directed at developing the hypothesis that more subtle variations in proteins regula ting membrane excitability-though not causing a Mendelian disorder-may yield a predisposition to certain episodic phenomenon such as seizures and migraine headache.
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PMID:Ion channel diseases: episodic disorders of the nervous system. 1071 59

Seven related Quarter Horse foals that died by 7 weeks of age were examined for glycogen branching enzyme (GBE) deficiency. Clinical signs varied from stillbirth, transient flexural limb deformities, seizures, and respiratory or cardiac failure to persistent recumbency. Leukopenia (5 of 5 foals) as well as high serum creatine kinase (CK; 5 of 5), aspartate transaminase (AST; 4 of 4), and gamma glutamyl transferase (GGT; 5 of 5) activities were present in most foals, and intermittent hypoglycemia was present in 2 foals. Gross postmortem lesions were minor, except for pulmonary edema in 2 foals. Muscle, heart, or liver samples from the foals contained abnormal periodic acid Schiff's (PAS)-positive globular or crystalline intracellular inclusions in amounts proportional to the foal's age at death. Accumulation of an unbranched polysaccharide in tissues was suggested by a shift in the iodine absorption spectra of polysaccharide isolated from the liver and muscle of affected foals. Skeletal muscle total polysaccharide concentrations were reduced by 30%, but liver and cardiac muscle glycogen concentrations were normal. Several glycolytic enzyme activities were normal, whereas GBE activity was virtually absent in cardiac and skeletal muscle, as well as in liver and peripheral blood cells of affected foals. GBE activities in peripheral blood cells of dams of affected foals and several of their half-siblings or full siblings were approximately 50% of controls. GBE protein in liver determined by Western blot was markedly reduced to absent in affected foals, and in a half-sibling of an affected foal, it was approximately one-half the amount of normal controls. Pedigree analysis also supported an autosomal recessive mode of inheritance. The affected foals have at least 2,600 half-siblings. Consequently, GBE deficiency may be a common cause of neonatal mortality in Quarter Horses that is obscured by the variety of clinical signs that resemble other equine neonatal diseases.
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PMID:Glycogen branching enzyme deficiency in quarter horse foals. 1181 63

A 14-year-old female Yorkshire terrier was presented with the complaint of cardiac murmur and convulsive seizure. Thickened mitral valve, left atrial enlargement, excess motions of the left ventricular (LV) free wall and the ventricular septum, and tricuspid, mitral and aortic valve regurgitations were recognized on echocardiography. Follow-up echocardiography revealed the progression of concentric LV hypertrophy and LV outflow obstruction. Clinical symptoms associated with cardiac failure did not develop during the observation period. The pathological examination of the heart revealed that the dog had the morphological hallmarks of hypertrophic cardiomyopathy: massive ventricular hypertrophy, disorganization of cardiac muscle cells, interstitial myocardial fibrosis, and abnormal intramural coronary arteries.
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PMID:Hypertrophic cardiomyopathy in an aged dog. 1286 41

mu-Conotoxins are peptides that block sodium channels. Molecular cloning was used to identify four novel mu-conotoxins: CnIIIA, CnIIIB, CIIIA, and MIIIA from Conus consors, C. catus and C. magus. A comparison of their sequences with those of previously characterized mu-conotoxins suggested that the new mu-conotoxins were likely to target tetrodotoxin-resistant (TTX-r) sodium channels. The four peptides were chemically synthesized, and their biological activities were characterized. The new conotoxins all blocked, albeit with varying potencies, TTX-r sodium currents in frog dorsal-root-ganglion (DRG) neurons. The more potent of the four new mu-conotoxins, CnIIIA and CIIIA, exhibited a strikingly different selectivity profile in blocking TTX-r versus TTX-sensitive channels, as determined by their ability to block extracellularly recorded action potentials in three preparations from frog: skeletal muscle, cardiac muscle and TTX-treated C-fibers. CnIIIA was highly specific for TTX-r sodium channels, whereas CIIIA was nonselective. Both peptides appeared significantly less potent in blocking TTX-r sodium currents in rat and mouse DRG neurons. When CnIIIA and CIIIA were injected intracranially into mice, both induced seizures, but only CIIIA caused paralysis. This is the most comprehensive characterization to date of the structural and functional diversities of an emerging group of mu-conotoxins targeting TTX-r sodium channels.
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PMID:Structural and functional diversities among mu-conotoxins targeting TTX-resistant sodium channels. 1653 55

Refractory status epilepticus (SE) is a condition of continuous seizure activity in which there is a regular, rapid, succession of spike discharges in the brain. It is incompatible with normal consciousness and is associated with an extremely high morbidity and mortality. Prior to 1990, prevailing opinion held that a brief period of anesthesia (up to two weeks) was to be recommended, but that if SE persisted this was a sign of irreversible brain damage. Therefore support of the patient in SE was not recommended beyond two weeks. On the basis of the theoretical constructs of chaos theory we hypothesized that, for selected cases, anesthesia should be continued indefinitely until the SE resolved. This became the standard of care at the University of Washington and at other institutions. After several years, the accumulating evidence lends support for this hypothesis and we are now able to propose which patients will benefit from such therapy. It is hypothesized that only those patients for whom there is no underlying brain disease, beyond epilepsy, are likely to benefit. Secondly, chaos theory suggests that a strong perturbation will cause a rapid transition from the stable attractor of SE to the stable attractor representing normal consciousness. In certain ways, SE is analogous to ventricular tachycardia, where the cardiac muscle has an abnormally fast rhythm incompatible with proper cardiac function. Therefore the second hypothesis is that a brain perturbation, analogous to defibrillation, may be even more useful than anesthesia in refractory SE.
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PMID:Chaos theory and the treatment of refractory status epilepticus: Who benefits from prolonged anesthesia, and is there a better way? 1699 98

The Kv7 potassium channel family encompasses five members (from Kv7.1 to Kv7.5) having distinct expression pattern and functional role. Although Kv7.1 is prevalently expressed in the cardiac muscle, Kv7.2, Kv7.3, Kv7.4, and Kv7.5 are expressed in neural tissue. Mutations in Kv7.2 and/or Kv7.3 genes are responsible for an autosomal-dominant epilepsy of the newborn defined as benign familial neonatal seizures (BFNS), whereas defects in the Kv7.4 gene have been found in families affected by a rare form of nonsyndromic autosomal-dominant hearing loss (DFNA2). Compounds acting as direct activators of neuronal channels formed by Kv7 subunits have been approved for clinical use as analgesics or are in advanced stages of clinical evaluation as anticonvulsants; in addition to these indications, solid preclinical studies reveal their potential usefulness in other diseases characterized by neuronal hyperexcitability. In the present work, we will summarize the available evidence providing proof-of-principles that neuronal Kv7 channels are highly attractive pharmacological targets, review the molecular basis of their peculiar pharmacological sensitivity, introduce some newly synthesized I(KM) openers showing improved pharmacokinetic or pharmacodynamic properties compared to older congeners, and discuss the potential novel therapeutic application of neuronal Kv7 channels in diseases additional to epilepsy.
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PMID:Molecular pharmacology and therapeutic potential of neuronal Kv7-modulating drugs. 1806 39

Chloride intracellular channel 2 (CLIC2) protein is a member of the glutathione transferase class of proteins. Its' only known function is the regulation of ryanodine receptor (RyR) intracellular Ca(2+) release channels. These RyR proteins play a major role in the regulation of Ca(2+) signaling in many cells. Utilizing exome capture and deep sequencing of genes on the X-chromosome, we have identified a mutation in CLIC2 (c.303C>G, p.H101Q) which is associated with X-linked intellectual disability (ID), atrial fibrillation, cardiomegaly, congestive heart failure (CHF), some somatic features and seizures. Functional studies of the H101Q variant indicated that it stimulated rather than inhibited the action of RyR channels, with channels remaining open for longer times and potentially amplifying Ca(2+) signals dependent on RyR channel activity. The overly active RyRs in cardiac and skeletal muscle cells and neuronal cells would result in abnormal cardiac function and trigger post-synaptic pathways and neurotransmitter release. The presence of both cardiomegaly and CHF in the two affected males and atrial fibrillation in one are consistent with abnormal RyR2 channel function. Since the dysfunction of RyR2 channels in the brain via 'leaky mutations' can result in mild developmental delay and seizures, our data also suggest a vital role for the CLIC2 protein in maintaining normal cognitive function via its interaction with RyRs in the brain. Therefore, our patients appear to suffer from a new channelopathy comprised of ID, seizures and cardiac problems because of enhanced Ca(2+) release through RyRs in neuronal cells and cardiac muscle cells.
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PMID:An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity. 2281 92

Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. Patients with DS have a high risk of sudden unexplained death in epilepsy (SUDEP), widely believed to be due to cardiac mechanisms. Here we show that patients with DS commonly have peri-ictal respiratory dysfunction. One patient had severe and prolonged postictal hypoventilation during video EEG monitoring and died later of SUDEP. Mice with an Scn1aR1407X/+ loss-of-function mutation were monitored and died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures were induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea, bradycardia, and death were prevented by the same drugs given at doses high enough to cross the blood-brain barrier. When given via intracerebroventricular infusion at a very low dose, a muscarinic receptor antagonist prevented apnea, bradycardia, and death. We conclude that SUDEP in patients with DS can result from primary central apnea, which can cause bradycardia, presumably via a direct effect of hypoxemia on cardiac muscle.
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PMID:Severe peri-ictal respiratory dysfunction is common in Dravet syndrome. 2932 11


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