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)

Adenosine is an endogenous neuromodulator that suppresses excitatory neurotransmission. We postulated that adenosine-mediated mechanisms resist status epilepticus (SE) entry and limit SE severity. In the first experiment rats were given an adenosine agonist (2-chloroadenosine), an adenosine antagonist (aminophylline), or saline vehicle, prior to SE induction with pulsed-train current delivered to amygdala in successive 5-min current-on sessions. Saline-treated animals entered limbic SE, with predominantly exploratory behavior, after 6.0 +/- 0.9 current-on sessions. Aminophylline increased major convulsive activity during stimulation and resulted in entry into convulsive SE after only 2.1 +/- 0.1 sessions. 2-Chloroadenosine, in contrast, suppressed major convulsive activity during stimulation, and blocked (in 3/7) or delayed (4/7) SE entry, with successes requiring 12.8 +/- 0.9 stimulation sessions. In a second experiment, animals already in exploratory SE were administered a single injection of saline vehicle, aminophylline, or 2-chloroadenosine. Aminophylline converted exploratory SE into lethally severe convulsive SE. 2-Chloroadenosine suppressed SE behaviorally and electrographically, and protected recipients from the seizure-associated cerebral damage seen in saline-administered SE controls. These results support the hypothesis that endogenous adenosine mechanisms resist SE entry, modulate the severity of ongoing SE, and limit the anatomic spread of seizure activity.
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PMID:Effect of an adenosine antagonist and an adenosine agonist on status entry and severity in a model of limbic status epilepticus. 808 55

The protective efficacy of phenobarbital (PB, 120 min before testing) and valproate (VPA, 30 min before testing) alone or combined with aminophylline (a single dose of 50 mg/kg, 3-day or 14-day administration twice daily 50 mg/kg at 8.00 a.m. and 8.00 p.m.) was evaluated against maximal electroshock-induced seizures (MES) in male mice. All drugs were given intraperitoneally (i.p.), and the protection provided by PB and VPA was evaluated as the respective ED50 value (in mg/kg). Aminophylline in a single dose of 50 mg/kg (30 min before electroconvulsions) distinctly reduced the protective efficacy of both PB and VPA, reflected by the increase in the respective ED50 values from 22 to 31 mg/kg (p < 0.001) for PB and from 247 to 281 mg/kg (p < 0.001) for VPA. After administration of aminophylline for 3 days (electroshock was performed 30 min after the last aminophylline injection), the respective ED50 values for PB and VPA were 29.5 (p < 0.01) and 269 mg/kg (p < 0.01 vs. saline-treated animals). Chronic treatment with aminophylline (14 days) resulted in further impairment of the protective activity of PB and VPA. Specifically, the ED50 value of PB was 39 mg/kg (p < 0.05 vs. PB+single injection of aminophylline) and that of VPA was 318 mg/kg (p < 0.01 vs VPA+single injection of aminophylline). Plasma levels of both PB and VPA were not affected by chronic aminophylline; moreover, the plasma level of theophylline was even lower after chronic aminophylline as compared with single aminophylline administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of chronic aminophylline on the anticonvulsant efficacy of phenobarbital and valproate in mice. 845 47

Aminophylline reversed the protective action of both, D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (D-CPP-ene-a competitive NMDA antagonist) and valproate (used as a conventional antiepileptic drug for comparative purposes) against maximal electroshock-induced seizures. The respective ED50 values of aminophylline were 55.7 and 98.4 mg/kg i.p. However, aminophylline (up to 100 mg/kg i.p.) did not influence the protective efficacy of 1-(4-aminophenyl)-4-methyl-7,8-methyl- enedioxy-5H-2,3-benzodiazepine (GYKI 52466-a non-NMDA antagonist). Strychnine affected the protection provided by D-CPP-ene, GYKI 52466, and valproate against maximal electroshock-the ED50 values of strychnine for the reversal of the anticonvulsive effects of D-CPP-ene, GYKI 52466 or valproate were 0.082, 0.35 and 0.28 mg/kg s.c., respectively. An involvement of strychnine sensitive glycinergic receptor-mediated events in the mechanism of the anticonvulsive activity of excitatory amino acid antagonists and valproate may be postulated. The ineffectiveness of aminophylline to reduce the anticonvulsive effects of GYKI 52466 may distinguish a new class of antiepileptic drugs offering an advantage over conventional antiepileptics in patients with epilepsy, requiring aminophylline for pulmonary reasons.
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PMID:Influence of aminophylline and strychnine on the protective activity of excitatory amino acid antagonists against maximal electroshock-induced convulsions in mice. 873 42

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 aim of this study was to determine the interaction potential of the new antiepileptic drug felbamate (2-phenyl-1,3-propanediol dicarbamate) with three Ca2+ channel blockers (nicardipine, nifedipine, and flunarizine), one Ca2+ channel activator (Bay K 8644; 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridi ne carboxylic acid), and two methylxanthines (caffeine and aminophylline (theophylline2 . ethylenediamine)) which are all known to markedly change protective effects of conventional antiepileptic drugs. To do so, the maximal electroshock seizure test in mice (an experimental model predicting drug efficacy in the treatment of human generalized tonic-clonic seizures) was employed to (1) quantify changes in the protective efficacy and potency of felbamate produced by adjunct drugs and (2) assess the ability of aminophylline and caffeine to affect protective efficacy afforded by a submaximal protective dose of felbamate against maximal electroshock-induced seizures. Doses of adjunct drugs were selected based on their effects on the threshold for electroconvulsions and on appropriate literature. Nicardipine (10-30 mg/kg), nifedipine (5-20 mg/kg), flunarizine (2.5-10 mg/kg), Bay K 8644 (2.5-5 mg/kg), and aminophylline (50-75 mg/kg) did not change the protective efficacy and potency of felbamate against maximal electroshock-induced tonic convulsions. Aminophylline in the dose of 100 mg/kg, however, diminished the protective potency of felbamate as evidenced by a statistically significant increase in the protective ED50 value of felbamate (a dose, in mg/kg, predicted to protect 50% of mice against convulsive stimulus) from 79.6 to 118 mg/kg; P < 0.05). Aminophylline and caffeine only at high doses (100 and 161.7 mg/kg, respectively) significantly diminished the protective efficacy of felbamate (110 mg/kg) from 96% to 27% and 40% (P < 0.05), respectively. In conclusion, felbamate shows low interaction potential with Ca2+ channel modulators and methylxanthines. Such low interaction potential clearly differentiates felbamate from conventional antiepileptic drugs where protective effects are readily altered by the compounds tested in the present study.
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PMID:Felbamate demonstrates low propensity for interaction with methylxanthines and Ca2+ channel modulators against experimental seizures in mice. 971 56

The study was designed to compare the proconvulsive activity of two theophylline-containing bronchodilating agents, aminophylline and acepifylline and their antagonistic effects to diazepam, phenytoin, MK-801 and carbamazepine in electroshock seizure model in rats. Graded intensity (30-150 mA for 0.2 s) of electroshock was applied to different groups of rats pretreated either with normal saline (0.5 ml, i.p.), graded doses (25-150 mgkg-1, i.p.) of aminophylline, graded doses (70-560 mgkg-1, i.p.) of acepifylline, graded doses of the antiseizure drugs or to rats pretreated with aminophylline (25 mgkg-1, i.p.) + antiseizure drugs or acepifylline (70 mgkg-1, i.p.) + antiseizure drugs. CI 50 +/- s.e.m. value was 88.41 +/- 2.14 mA in saline treated rats. In aminophylline pretreated rats the values were 84.14 +/- 2.03, 68.06 +/- 1.24, 54.28 +/- 1.96 and 39.58 +/- 2.31 mA at 25 mgkg-1 (0.06 mmolekg-1), 50 mgkg-1 (0.12 mmolekg-1), 100 mgkg-1 (0.24 mmolekg-1) and 150 mgkg-1 (0.36 mmolekg-1), i.p. doses respectively. The values were 85.73 +/- 1.09, 64.86 +/- 2.37, 61.58 +/- 1.37 and 60.62 +/- 2.41 mA at 70 mgkg-1 (0.125 mmolekg-1), 140 mgkg-1 (0.25 mmolekg-1), 280 mgkg-1 (0.50 mmolekg-1) and 560 mgkg-1 (1.0 mmolekg-1), i.p. doses respectively for the acepifylline pretreated groups of rats. Diazepam, MK-801, phenytoin and carbamazepine significantly antagonized electroshock-induced seizure in a dose-dependent manner. Subsensitizing dose of aminophylline (25 mgkg-1, i.p.) but not that of acepifylline (70 mgkg-1, i.p.) pretreatment significantly antagonized the efficacy of all the antiseizure drugs. The study highlighted that acepifylline might be safely used in epileptic patients well controlled on antiepileptic drugs. Aminophylline, on the other hand, should be avoided since it might produce breakthrough seizure attacks due to its greater proconvulsive and anti-antiseizure drug effects.
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PMID:A comparative study of aminophylline and acepifylline on reversal phenomenon of anticonvulsant drug efficacy in electroshock model of seizures in rats. 1121 35

The anticonvulsant action of chlormethiazole was evaluated with the use of subthreshold doses of convulsants affecting the purinergic, glycinergic and gamma-aminobutyric acid (GABA)-mediated transmission, i.e. aminophylline, strychnine, bicuculline and picrotoxin in the model of generalized tonic-clonic convulsions. Chlormethiazole protected mice against maximal electroshock-induced seizures with an ED50 of 130.8 mg/kg. Aminophylline (100 mg/kg) and strychnine (0.4 mg/kg) reversed the protective action of chlormethiazole against electroconvulsions raising the ED50 values of this drug to 218.6 and 208.6 mg/kg, respectively. In contrast, GABA antagonists, bicuculline and picrotoxin, neither affected the protection provided by chlormethiazole nor did they alter the protective activity of valproate, phenobarbital, diphenylhydantoin and carbamazepine against electroconvulsions. Our results indicate that (a) the anticonvulsant activity of chlormethiazole might be related to its interaction with strychnine-sensitive glycinergic as well as purinergic neurotransmission, (b) purinergic and strychnine-sensitive glycinergic events contribute more prominently than GABAergic ones to the anticonvulsant activity of the drugs providing protection against maximal electroshock-induced convulsions.
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PMID:Anticonvulsant action of chlormethiazole is prevented by subconvulsive amounts of strychnine and aminophylline but not by bicuculline and picrotoxin. 1134 82

Aminoglutethimide (AGLD, an inhibitor of adrenal steroid synthesis) up to 5 mg/kg and spironolactone (SPIR, a mineralocorticosteroid antagonist and a weak antiandrogen) up to 50 mg/kg did not affect any seizure parameter in amygdala-kindled rats. AGLD (10 mg/kg) significantly reduced seizure activity in rats of both gender. The combination of AGLD (5 mg/kg) with phenobarbital (PB, applied at its subeffective dose of 15 mg/kg) significantly shortened motor seizure and afterdischarge duration in amygdala-kindled seizures. The combined treatment of AGLD (5 mg/kg) and clonazepam (CLO) at its subeffective dose of 0.01 mg/kg caused significant reduction of the seizure severity, seizure duration and afterdischarge duration. Finally, AGLD (5 mg/kg) proved ineffective upon the action of valproate (VPA) in this model of epilepsy. In contrast to AGLD, SPIR (50 mg/kg) did not affect the action of PB, CLO or VPA against kindled seizures in rats. AGLD did not alter the free plasma levels and brain concentration of PB or CLO, so a pharmacokinetic interaction does not seem probable. Among a variety of chemoconvulsants, bicuculline and N-methyl-D-aspartic acid reversed the effects of AGLD/PB and AGLD/CLO combinations. Aminophylline, kainic acid, strychnine and the glucocorticosteroid (hydrocortisone) were ineffective in this respect. Our data confirm the hypothesis that AGLD-mediated events may play a role in seizure activity and can affect the anticonvulsant activity of some conventional antiepileptic drugs against kindled seizures. Moreover, extrapolation of obtained results to clinical practice may indicate that patients with complex partial seizures may be safely co-medicated with AGLD or SPIR without the risk of worsening of seizure control.
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PMID:Aminoglutethimide but not spironolactone enhances the anticonvulsant effect of some antiepileptics against amygdala-kindled seizures in rats. 1552 39

The role of adenosine A1 receptors in the activity of drugs and substances protecting against seizures evoked by mitochondrial toxin, 3-nitropropionic acid (3-NPA) was studied in mice. Non-selective A1/A2 adenosine receptor antagonist, aminophylline and selective A1 adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) diminished the anticonvulsive effects of diazepam, phenobarbital, valproate and gabapentin. In contrast, A1/A2 adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline (8pSPT) not penetrating via blood-brain barrier was ineffective. Aminophylline and DPCPX but not 8pSPT also reversed the protective action of A1/A2 adenosine receptor agonist, 2-chloroadenosine (2-CADO) and selective A1 adenosine receptor agonist, R-N6-phenylisopropyloadenosine (R-PIA), against 3-NPA-evoked convulsions. Obtained results suggest that the central adenosine A1 receptor stimulation may play a role in the anticonvulsive potential of diazepam, phenobarbital, valproate and gabapentin in a novel model of 3-NPA-evoked seizures. Moreover, concomitant application of aminophylline with these drugs may reduce their clinical antiepileptic efficacy, especially among patients suffering from seizures related to the disturbances of mitochondrial respiratory chain.
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PMID:Adenosine A1 receptors and the anticonvulsant potential of drugs effective in the model of 3-nitropropionic acid-induced seizures in mice. 1557 77

Theophylline is a methylxanthine bronchodilator with a narrow therapeutic index and is prone to induce seizures, the mechanisms for which are not clearly defined. Free radicals have considerable neurotoxic potential and the present study evaluated the possible involvement of these bioactive moieties in aminophylline-induced seizures in mice. Aminophylline (50-250 mg/kg) induced convulsions and mortality in mice in a dose-dependent manner. The anti-oxidants, melatonin (25-100 mg/kg) and N-actylcysteine (100 and 200 mg/kg) attenuated aminophylline seizures and mortality. Similar antagonism of aminophylline seizures was also observed after pretreatments with nitric oxide (NO) synthase inhibitors, L-NAME (3 and 10 mg/kg) and 7-nitroindazole (10 and 30 mg/kg). Further, combined treatment with otherwise sub-effective doses of melatonin and L-NAME or 7-nitroindazole produced marked protective effects against these seizures. Aminophylline-induced seizures enhanced malondialdehyde (MDA) concentrations and NO metabolite (NOx) levels in the brain homogenates of mice, and these were attenuated by melatonin and L-NAME pretreatments. The results are suggestive of the possible involvement of free radicals (reactive oxygen and reactive nitrogen species) in the convulsiogenic effects of aminophylline.
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PMID:Possible role of free radicals in theophylline-induced seizures in mice. 1618 59


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