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

Seizures, often with fatal outcome, are a manifestation of pronounced theophylline toxicity. Prodromal symptoms are not always apparent, and the seizures are reported to be, in certain cases, refractory to treatment with anticonvulsant drugs. The purpose of this investigation was to examine, by an established animal model, which of the commonly used anticonvulsants can reduce the central nervous system sensitivity to theophylline neurotoxicity and what should be the preferred treatment in cases in which theophylline toxicity is anticipated. The anticonvulsant agents in doses that are found to be effective in other types of experimentally induced seizures in rats, clonazepam 5 mg/kg, diazepam 5 mg/kg, phenytoin 8 mg/kg, phenobarbital 100 mg/kg, valproic acid 150 mg/kg, and magnesium sulphate 300 mg/kg, or the vehicle (controls) were administered intravenously to Lewis female rats. Thirty minutes later, theophylline was infused at a constant rate of 1.3 mg/min until onset of maximal seizures. Theophylline concentrations in the cerebrospinal fluid, brain, and serum were assayed by a high-performance liquid chromatography method. It was found that pretreatment with either clonazepam, diazepam, phenobarbital, or valproic acid increased the central nervous system thresholds to the theophylline-induced seizures, whereas phenytoin and magnesium sulphate did not attenuate the sensitivity of the brain to the stimulatory action of this widely used bronchodilator. Therefore, whenever theophylline toxicity is suspected, treatment with either diazepam, clonazepam, phenobarbital, or valproic acid can reduce the hazard associated with theophylline-induced seizures.
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PMID:Effect of pretreatment with anticonvulsants on theophylline-induced seizures in the rat. 830 56

Theophylline has been a mainstay of asthma therapy despite its narrow therapeutic index, which makes toxicity a common problem. To study toxicity in children, we reviewed hospital laboratory records (1980 to 1988) and identified cases (n = 163) with theophylline concentrations of > 133 mumol/L (24 micrograms/ml). We reviewed these cases for symptoms of theophylline intoxication; we were interested in associating symptoms with serum drug concentrations and in understanding how intoxication occurred. The median patient age was 3.0 years; 40/163 were younger than one year. Males were 90/163 patients (55%). Patients were classified by pattern of ingestion: 20 patients had acute ingestions; 17 patients had an acute ingestion while on chronic medication; and 126 patients became toxic on chronic therapy. Symptoms were absent in 44/150 patients (29%) with theophylline concentrations of 139 to 278 mumol/L (25-50 micrograms/ml); concentrations of > 278 mumol/L (50 micrograms/ml) were always associated with symptoms. The most common clinical symptoms were tachycardia (47%) and vomiting (52%); both occurred more frequently with higher theophylline concentrations (P < 0.002 and P < 0.01). Nine patients had seizures, including five who were previously neurologically normal. Seizures developed with a theophylline concentration of < 278 mumol/L (50 micrograms/ml) in four of these five patients. There was no association between seizures and patient age or between seizures and a particular pattern of theophylline use. In 105/126 cases of intoxication associated with chronic use, the cause of the intoxication could not be determined. Appropriate management of theophylline toxicity can occur only if toxicity is recognized.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Theophylline toxicity in children: a retrospective review. 834 82

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

Two asthmatic children who developed status epilepticus during theophylline treatment followed by semi-coma were reported. They suffered from severe neurological sequelae. A two-year-old male received oral maintenance theophylline therapy and a four-year-old male received intravenous theophylline therapy at the time of seizures. Theophylline blood levels measured several hours after the onset of seizures were within or below the therapeutic level; 12.7 and 8.8 micrograms/ml. They had febrile convulsions prior to the onset of episode and one of them was mildly delayed in psychomotor development. Brain CT scans showed diffuse cortical low-density in the acute period. Follow up CT scans revealed progressive cortical low-density in the subacute period and subsequently reached to the peak in the 10th day and 19th day of illness respectively. We consider that the progressive and long-lasting severe cortical edema on brain CT scan is characteristic of theophylline-associated encephalopathy.
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PMID:[Two cases of theophylline-associated encephalopathy in childhood: clinical and CT findings]. 851 90

Theophylline-induced seizures have significant morbidity and mortality and are difficult to treat. Theophylline therapy for asthma has been observed to depress plasma pyridoxal 5'-phosphate (PLP) levels which may decrease gamma-aminobutyric acid (GABA) synthesis and thereby contribute to seizures. We hypothesized that treatment with pyridoxine might prove beneficial in theophylline-induced seizures. One hundred thirty-nine mice were injected with 250 mg theophylline/kg ip and 89 mice were injected with 250-750 mg pyridoxine/kg ip as treatment. Decreased rates of seizure (42 vs 70%, p < 0.002) and death (29 vs 56%, p < 0.002) were observed. Six New Zealand White rabbits were given 115 mg theophylline/kg iv over 50 min followed by treatment with an iv bolus of 115 mg pyridoxine/kg, with subsequent continuous drip infusion of 230 mg/kg over 50 min. Serum theophylline levels and plasma PLP levels showed significant negative correlation prior to pyridoxine infusion with a mean peak theophylline level of 182 micrograms/ml and a mean low PLP level of 64 nM/L. Electroencephalogram (EEG) tracings were obtained before infusions, during theophylline infusion and during pyridoxine infusion. All 6 rabbits developed abnormal EEGs during theophylline infusion and all 6 rabbit EEG patterns returned to baseline during treatment with pyridoxine. These findings suggest that pyridoxine may partially reverse theophylline-induced central nervous system toxicity.
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PMID:Pyridoxine as therapy in theophylline-induced seizures. 854 Feb 25

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

This study was undertaken to investigate the effect of sustained-release theophylline preparations on circulating vitamin B6 concentrations in children with asthma. Twenty-six children with asthma were treated with sustained-release theophylline preparations. Serum concentrations of theophylline and vitamin B6 [pyridoxal (PL) and pyridoxal-5'-phosphate (PLP)] were evaluated. The results obtained from this study were as follows: 1) The serum PL was significantly correlated with the duration of theophylline administration (r = -0.42). 2) The serum PL and PLP concentrations were significantly correlated with serum theophylline concentrations (r = -0.47, r = -0.59, respectively). 3) Serum PL and PLP concentrations in children treated for more than 5 weeks were significantly lower than those treated for less than 4 weeks (p < 0.01, p < 0.05, respectively). 4) Serum PL and PLP concentrations in children within theophylline therapeutic ranges (5-15 micrograms/ ml) were significantly lower than those with less than 5 micrograms/ml (p < 0.01, p < 0.01, respectively). These findings suggest that long-term theophylline therapy or serum theophylline concentration within the therapeutic ranges (5-15 micrograms/ml) can depress serum vitamin B6 concentration in children with asthma. Theophylline-induced seizure may be caused by decrease in gamma-aminobutyric acid concentration in the brain result from decrease in vitamin B6 concentration, even if the serum theophylline concentration is within the therapeutic ranges.
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PMID:[Serum concentrations of the pyridoxal and pyridoxal-5'-phosphate in children during sustained-release theophylline therapy]. 895 56

1. The effects of adenosine, the adenosine analogue, 2-chloroadenosine (2-CADO), the specific adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA) and A2 receptor agonist 5'-(N-cyclopropyl) carboxamidoadenosine (CPCA), were examined against seizures induced by acute administration of pentylenetetrazole (PTZ), 60 mg kg-1, and PTZ kindled seizures, in rats. 2. Adenosine 1000 mg kg-1, i.p., 5 min pretreatment and CPA 10 mg kg-1 i.p., 60 min pretreatment, showed significant protection against acute PTZ-induced seizures while, CPCA up to 10 mg kg-1 was ineffective. The adenosine analogue 2-CADO in a dose of 5 mg kg-1 was only partially protective and on increasing the dose to 10 mg kg-1, this protection was lost. 3. Theophylline, a non specific adenosine receptor antagonist at 50 mg kg-1 and the specific adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), at 1 mg kg-1, if administered before the maximally protective doses of adenosine and CPA, completely reversed the protection afforded by them against PTZ seizures. While, pretreatment with the adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), failed to reverse the protection. 4. Adenosine and the adenosine A1 receptor agonist in doses that protected against seizures after acute PTZ administration, offered only incomplete protection when tested against PTZ kindled seizures. 5. The effects of adenosine and adenosine receptor agonists on mean arterial pressure, heart rate and rectal temperature were studied, to rule out the possibility of their systemic effects mediating the protection of PTZ seizures. All these agents produced a fall in mean arterial pressure, heart rate and hypothermia in the doses exhibiting an anticonvulsant response. While the effect on blood pressure and heart rate was immediate i.e. seen within 5 min and, maintained throughout the observation period, the development of hypothermia lagged behind the onset of hypotension and bradycardia. However, there was no correlation between haemodynamic and hypothermic response and the anticonvulsant effect. 6. The results indicate that the adenosine mediated anticonvulsant effect is via stimulation of A1 receptors. Hypotension and hypothermia do not appear to contribute to the protection observed with adenosine and the adenosine A1 receptor agonists.
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PMID:Effect of adenosine receptor modulation on pentylenetetrazole-induced seizures in rats. 911 21

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


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