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)

Alterations in the energy state and glucose metabolism of hippocampal slices exposed to high extracellular K+ ([K+]o) were monitored using 31P and 13C NMR spectroscopy. Slices were perfused (37 degrees C) continuously within the NMR spectrometer and tissue viability and metabolic activity were maintained for at least 18 h. 31P spectra showed that upon exposure to 40 mM [K+]o, there was a rapid compromise in tissue energetics where, by 15 min of exposure, the ratio of phosphocreatine and of nucleoside triphosphates to inorganic phosphate (extra- and intracellular) decreased 30-50% relative to pre-exposure values. This was accompanied by a pH decrease of approximately 0.3 units in both the intra and extracellular environments. A lower but stable energy state was reached at approximately 15 min of exposure and full recovery was observed by 30 min following the removal of high [K+]o. Utilizing 13C NMR in the presence of [1-13C]glucose, an immediate and dramatic acceleration in tissue glycolysis was observed when slices were exposed to 40 mM [K+]o: the rates of both [1-13C]glucose consumption and [3-13C] acetate synthesis increased by approximately 20 fold. By 60 min following the removal of high-[K+]o, pre-exposure rates of tissue glycolysis were restored. The results indicated that the rapid and dramatic induction of energy production via glycolysis probably accounts for the ability of hippocampal slices to maintain viability and recuperate from brief but intense depolarizing conditions which are reminiscent of seizure states in vivo.
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PMID:Energetics and glucose metabolism in hippocampal slices during depolarization: 31P and 13C NMR studies. 851 24

The contraceptive implant depot medroxyprogesterone acetate (DMPA) may offer advantages to women with medical problems which contraindicate the use of estrogen. In such women, the risks of pregnancy must be weighted against the risk posed by a contraceptive method. While young women with well-controlled hypertension can use DMPA or the combined oral contraceptive, patients with uncontrolled hypertension or other risk factors may be better managed with DMPA. DMPA is also an appropriate choice for many women with cardiac disorders which can be associated with an extremely high risk of adverse pregnancy outcomes. Because it is not associated with increased thrombotic risk, DMPA is also safe in women over 35 years old who smoke. The contraceptive is likewise indicated in women with a history of thromboembolic disease (despite package labeling which was based on trials of high doses of DMPA as a cancer treatment). DMPA also is safe in women with sickle cell disease and actually has been shown to reduce the incidence of sickle cell crisis. Evidence also suggests that DMPA injections in anticoagulated women do not increase the incidence of hematoma formation. DMPA will not protect women with underlying predisposing causes of thrombosis from experiencing a thrombotic event. Whereas the contraceptive efficacy of hormonal contraception may be reduced in epileptic women using hepatic enzyme induction agents, DMPA has been reported to reduce seizure frequency with few contraceptive failures in such women. In diabetic women with peripheral vascular disease and in women with systemic lupus erythematosus, DMPA, unlike contraceptives with estrogen, avoids the enhanced risk of thrombosis. Because the best pregnancy outcome in women with medical problems occurs when the pregnancy is planned, such women should use the most effective contraceptive methods available to them.
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PMID:Depot medroxyprogesterone acetate contraception in women with medical problems. 872 4

Prenatal methylazoxymethanol acetate (MAMac) injection disrupts cell migration in developing rats. We investigated the electrophysiological characteristics of hippocampal CA1 pyramidal neurons from young MAMac-treated animals (postnatal days 25-35). In vitro intracellular recordings from CA1 cells in MAMac-treated tissue revealed resting membrane potential (mean, -61.5 +/- 1.5 mV), action potential amplitude (mean, 69 +/- 3.1 mV), action potential duration (mean, 2.1 +/- 0.2 ms), input resistance (mean, 51.5 +/- 3.6 M omega) and time constant (mean, 33.2 +/- 1.2 ms) similar to those of CA1 cells from control tissue. However, MAMac-treated tissue could be distinguished as having a higher percentage of cells (62% vs. 10%) which fire a burst of action potentials in response to suprathreshold current injection. The synaptic responses of CA1 cells in MAMac-treated and control tissue were comparable. The CA1 field response to stimulation was also comparable at all stimulus intensities tested (50-1500 microA). Elevation of extracellular potassium concentration ([K+]o) from 3 mM to 6 mM resulted in epileptiform discharge activity in response to stratum radiatum stimulation in all MAMac-treated slices (10/10) but in only one-third of controls (3/9). Spontaneous epileptiform discharges were also observed in the majority (8/13) of MAMac-treated slices bathed in 6 mM KCl but in no controls. These data suggest that MAMac treatment during fetal development not only disrupts normal anatomical organization but also leads to alterations in electrophysiological features of the hippocampal CA1 pyramidal cell region. As such, the MAMac model may provide insights into early onset seizure syndromes associated with developmental abnormalities.
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PMID:Electrophysiology of CA1 pyramidal neurons in an animal model of neuronal migration disorders: prenatal methylazoxymethanol treatment. 877 1

US teenagers have had access to the injectable contraceptive depot medroxyprogesterone acetate (DMPA; Depo-Provera) since the US Food and Drug Administration approved it in 1992. DMPA suppresses follicle stimulating hormone and luteinizing hormone (LH) levels, which in turn prevents the LH surge and thus inhibits ovulation. It also causes a thick cervical mucus (reducing sperm penetration). Since DMPA also changes tubal mobility and creates shallow and atrophic endometrium, implantation is prevented. DMPA must be administered every 3 months to be effective. Its first-year failure rate is 0.3%, which is lower than that of oral contraceptives (3%). Advantages of DMPA are that it: allows for privacy; improves compliance (since action is required every 3 months rather than every day); has no estrogen-related complications (e.g., thrombophlebitis); is effective; is safe for breast feeding teenagers; reduces seizure frequency in teenagers with epilepsy; has a favorable effect on sickle cell disease or coagulopathy; reduces menstrual flow, thus preventing iron-deficiency anemia; reduces menstrual pain and pre-menstrual symptoms; and decreases risk of pelvic inflammatory disease. The leading disadvantages are menstrual irregularities and spotting. Some other possible disadvantages include weight gain (most common reason for discontinuation), delayed return of fertility, headaches, acne, and nervousness. Health providers must perform a complete history of teenagers requesting DMPA. They should determine the presence or absence of absolute and relative contraindications to DMPA. Absolute contraindications are known or suspected pregnancy, undiagnosed or abnormal vaginal bleeding, known or suspected history of breast cancer, acute liver disease or jaundice, thromboembolism, and sensitivity to DMPA. DMPA is administered intramuscularly at a concentration of 150 mg/ml. Health providers need to use a frank, nonjudgmental, empathic, and unhurried approach to facilitate a trusting relationship and rapport with teenagers. Advanced counseling on the pros and cons of DMPA, how DMPA works, and DMPA's inability to protect against sexually transmitted diseases is essential.
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PMID:Use of depo-provera in teens. 892 Mar 51

The convulsive, pro-convulsive and lethal effects of two theophylline-containing bronchodilating agents, aminophylline and acepifylline, have been evaluated in rats. Aminophylline (theophylline ethylenediamine) caused seizures and death in a dose-dependent manner; an intraperitoneal dose of 250 mg kg-1 caused seizures and death in all rats. Intraperitoneal doses of acepifylline (theophylline ethanoate of piperazine) up to 1000 mg kg-1, however, did not cause seizure or death. Further, pre-treatment of the rats by intraperitoneal administration of a subconvulsive dose (100 mg kg-1) of aminophylline caused a significant decrease in CD50 and LD50 values for pentylenetetrazole and a significant increase in the number of positive responders (i.e. rats with a pentylenetetrazole-induced seizure score of 3 or more on a seizure scale ranging from 0 to 6) and death rate compared with those obtained for rats pre-treated with an equivalent intraperitoneal dose (140 mg kg-1) of acepifylline ('equivalent dose' referred to here denotes the theophylline content of the two preparations). The study has established the neurosafety profile of acepifylline and documents a safer alternative to aminophylline for use in asthmatics suffering from concomitant epilepsy or other seizure-prone neurological defects.
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PMID:A comparative study of aminophylline- and acepifylline-induced seizures and death in the chemoconvulsion model in rats. 937 62

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

A series of esters of the major metabolite of oxcarbazepine (2), 10, 11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)-12 were the most active of the series against MES-induced seizures with oral ED(50) values at t(max) of 10.9 +/- 2.3 and 4.7 +/- 0.9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b, f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1 produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6, (R)-7, and racemic alcohol 8, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to differ in the MES or rotarod tests; the ED(50) value for (S)-6 against MES-induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage-sensitive sodium channels was studied by investigating [(3)H]batrachotoxinin A 20-alpha-benzoate ([(3)H]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and 2 at inhibiting the binding of [(3)H]BTX to sodium channels and the influx of (22)Na(+) into rat brain synaptosomes. It is concluded that acetates (R)-11 and (S)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.
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PMID:Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives. 1041 78

In the present study metabolite concentrations were determined by proton magnetic resonance spectroscopy (MRS) in biopsies obtained from patients suffering intractable epilepsy from several different causes. Seven patients had gliosis, four had mild cortical dysplasia, three had tuberous sclerosis, two had astrocytomas, and one had a cavernous angioma. No significant differences were found in gliotic tissue in comparison with controls except for an increase in lactate. However, in the subgroup with tuberous sclerosis an increase was found in GABA and a dramatic decrease in N-acetyl aspartate (NAA). The most marked changes were found in the group with mild cortical dysplasia. There was a considerable decrease in NAA as well as large increases in GABA, alanine, tyrosine, acetate, inositol, glucose and lactate. The GABA content did not appear to correlate with antiepileptic therapy. Moreover, since all these patients required surgery, an elevated GABA level does not necessarily provide protection from seizures. The results indicate that use of proton MRS could become a useful presurgical predictor of underlying pathology.
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PMID:Proton magnetic resonance spectroscopy of brain biopsies from patients with intractable epilepsy. 1041 16

A novel computational technology derived from gene structure has been developed for screening, selecting, and designing pharmaceutical candidates. Pharmacophores, or three-dimensional molecular blueprints, were created by docking known active structures into specific sites in partially unwound DNA. The pharmacophores are composites of the van der Waals surfaces and hydrogen bonding functional groups of active molecules. Once created, molecules can be inserted into the pharmacophores and degree of fit quantitated by the volume of the molecule that fits within the composite surface and the magnitude of electrostatic interactions with charged atoms on the pharmacophore. Here, we describe endocrine pharmacophores and in particular the estrogen pharmacophore derived by docking active ligands into partially unwound DNA. Fit of candidate structures into the estrogen pharmacophore correlated with estrogenic (uterotropic) activity. For example, the super active estrogens moxestrol and 11beta-acetoxyestradiol fit better within the site than estradiol. Bisphenol A, a putative endocrine disrupter with suspected estrogenic activity, was a poor fit in the pharmacophore. Consistent with this prediction, bisphenol A was recently shown to lack uterotropic activity. The capacity of the endocrine pharmacophores to predict certain nontarget activities was demonstrated by using the antiandrogen cyproterone acetate that did not fit the estrogen or thyroid pharmacophores but fit partially into the progestin and glucocorticoid pharmacophores. Cyproterone acetate has been reported to have weak progestational and glucocorticoid activities. The pharmacophores provide for the first time a multidimensional computational method that can simultaneously predict multiple activities of diverse molecular structures.
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PMID:Multidimensional screening and design of pharmaceuticals by using endocrine pharmacophores. 1050 11


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