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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this investigation was to determine whether the neurotoxicity of theophylline is altered in advanced pregnancy. Sprague-Dawley rats that were 20 days pregnant and nonpregnant rats of the same age and strain received infusions of aminophylline until onset of maximal seizures which occurred after 28 and 30 minutes respectively. Theophylline concentrations at this endpoint in serum (total) and CSF were similar but serum (free) and brain concentrations were slightly different in pregnant rats. Theophylline serum protein binding determined by equilibrium dialysis was lower in pregnant rats. Fetal serum concentrations at onset of seizures in the mother were similar to maternal brain and CSF concentrations and correlated significantly with the former. It is concluded that advanced pregnancy has a negligible effect on the neurotoxic response to theophylline in rats.
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PMID:Theophylline neurotoxicity in pregnant rats. 333 45

Seizures, often with fatal outcome, are a manifestation of pronounced theophylline intoxication. The purpose of this investigation was to characterize the relationship between theophylline concentrations and theophylline-induced convulsions and to develop an animal model suitable for exploring conditions that might predispose theophylline-treated individuals to seizures. Female Lewis rats (approximately 170 g) received an i.v. infusion of theophylline (as aminophylline) at one of three different rates (1.03-5.1 mg/min/rat) until the animals exhibited a maximal seizure (which occurred after 11 +/- 1 to 42 +/- 3 min of infusion). The total dose, the serum concentration (both total and unbound drug) and the brain concentration of theophylline at onset of seizures increased with increasing infusion rate. The theophylline concentration in cerebrospinal fluid at onset of seizures (mean +/- S.D., 232 +/- 17 mg/l, n = 41) was not affected by the infusion rate. The theophylline metabolites 1-methyluric acid and 1,3-dimethyluric acid were found in serum but at very much lower concentrations than those of theophylline. 1-Methylxanthine and caffeine were not detected in any serum sample, 3-methylxanthine was present in low concentrations in only some serum samples and 1-methyluric acid and 3-methylxanthine were found in the brain in low concentrations (less than 10 mg/kg). Theophylline metabolites were not detected in cerebrospinal fluid. Direct i.v. infusion of either 1-methyluric acid, 1,3-dimethyluric acid or 3-methylxanthine did not produce seizures despite high concentrations in serum. Ethylenediamine infusions also did not cause seizures.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kinetics of drug action in disease states. XVI. Pharmacodynamics of theophylline-induced seizures in rats. 348 96

There are pronounced interindividual differences in the neurotoxicity of theophylline in humans as reflected by the wide range of plasma theophylline concentrations associated with the occurrence of life-threatening, generalized seizures in patients treated with this widely used bronchodilator. The variability indicates that there may be a number of as yet unrecognized risk factors for theophylline neurotoxicity. After the development of an animal model of theophylline-induced seizures, renal failure was identified as one such risk factor. This investigation was designed to determine if experimental liver disease will alter the neurotoxic effect of theophylline. Studies were performed on rats with extrahepatic cholestasis produced by bile duct ligation and with hepatic necrosis induced by carbon tetrachloride administration and on respective controls. Theophylline was infused i.v. at 1.03 mg/min until the onset of maximal seizures. Theophylline and theophylline metabolite concentrations at that time were determined in serum (unbound and total drug), brain and cerebrospinal fluid. Extrahepatic cholestasis was associated with small increases in unbound theophylline concentration in serum, theophylline concentration in brain and serum free fraction in serum at onset of seizures. The concentrations of theophylline metabolites were negligible. There were no apparent effects of extrahepatic cholestasis or hepatic necrosis on theophylline concentrations at onset of seizures in cerebrospinal fluid, the fluid that was shown in a preceding study to be the best indicator of the theophylline concentration at the site of the neurotoxic effect. It is concluded that experimental liver disease had no apparent effect on the neurotoxicity of theophylline under the conditions of this investigation.
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PMID:Kinetics of drug action in disease states. XIX. Effect of experimental liver disease on the neurotoxicity of theophylline in rats. 349 38

Two xanthine derivatives, aminophylline and enprofylline, were tested on the protective activity of phenobarbital, 20 mg/kg i.p. (60 min before the test) against amygdala-kindled seizures in female rats. Enprofylline, 27.8 mg/kg i.p. (0.143 mmol/kg) 30 min, and aminophylline, 10 mg/kg i.p. (0.043 mmol/kg) 30 min, did not modify any kindling parameter. Aminophylline, 30 mg/kg (0.143 mmol of theophylline/kg), considerably increased seizure and afterdischarge durations. Aminophylline, 30 mg/kg, abolished the effect of phenobarbital (20 mg/kg) upon these seizure parameters. Both values reached the level observed in animals treated with aminophylline alone. Aminophylline, 10 mg/kg, only moderately increased afterdischarge duration in phenobarbital (20 mg/kg)-treated group. Enprofylline, 27.8 mg/kg, was devoid of any action upon the protection offered by phenobarbital in this model of epilepsy.
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PMID:Effects of aminophylline and enprofylline on the protective activity of phenobarbital against amygdala-kindled seizures in rats. 350 99

The recent marketing of slow release preparations of theophylline and new indications for the use of the drug have resulted in a marked increase in the sale of theophylline products. This phenomenon combined with the drug's highly variable pharmacokinetics has led to an increase in the number of theophylline intoxications. The morbidity and mortality rates associated with theophylline intoxication are significant. Therefore it is essential that clinicians are aware of the pathophysiology, clinical presentation and treatment of this poisoning. Theophylline intoxication mainly affects the gastrointestinal, cardiovascular and central nervous systems. Signs and symptoms range from mild gastrointestinal upset to serious central nervous system manifestations such as seizures, a symptom often associated with a bad prognosis. Theophylline serum concentrations are very useful for making decisions regarding treatment. However, their interpretation should take into account several factors such as the age of the patient and the type of intoxication (acute versus chronic). Prevention of gastrointestinal absorption should be the principal objective of treatment of an oral theophylline poisoning. The repetitive administration of activated charcoal not only prevents theophylline absorption but also increases its rate of Once absorbed, external methods such as haemodialysis and haemoperfusion can significantly accelerate the elimination of the drug from the body. Finally, the rapid suppression of seizures and cardiac arrhythmias are essential to prevent severe neurological sequelae and death. Since theophylline intoxication can be potentially life-threatening, its administration should be monitored with regular measurements of the serum theophylline concentration, especially in the very young and the very old.
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PMID:Theophylline poisoning. Pharmacological considerations and clinical management. 353 17

We tested the effects of the adenosine antagonist, theophylline, on electrically induced afterdischarges in the hippocampus of rats. Theophylline did not significantly alter the threshold for afterdischarge initiation or the duration of the initial afterdischarge. However, theophylline greatly prolonged the duration of secondary afterdischarges, and permitted generalization to motor seizures. Because theophylline antagonizes adenosine, and the hippocampus is a region rich in adenosine binding sites, we interpret these results to mean that endogenous adenosine has little action on focal seizure initiation, but a strong action to suppress secondary seizures and to inhibit seizure generalization.
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PMID:Proconvulsant effects of theophylline on hippocampal afterdischarges. 358 55

The pro-convulsant actions of theophylline and caffeine have been investigated using the hippocampal slice preparation and rats administered kainic acid or Metrazol. Both theophylline and caffeine induced the generation of epileptiform activity in the CA3 region of the hippocampal slice with convulsive dose50 (CD50) values of 3 microM respectively. Kainic acid-induced bursting in hippocampal slices was enhanced by theophylline (0.3-30 microM) and caffeine (1-100 microM). Theophylline induced burst firing in response to electrical stimulation in hippocampal area CA3 but not area CA1. Theophylline (50 mg/kg) strongly potentiated the effect of the limbic convulsant kainic acid in vivo whilst a dose of 200 mg/kg was necessary to significantly lower the threshold dose of Metrazol required to induce generalized convulsions. We conclude that alkylxanthines, probably by antagonizing the effect of endogenous adenosine, exert a pro-convulsant action in the hippocampus which preferentially promotes limbic seizures.
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PMID:Pro-convulsant actions of theophylline and caffeine in the hippocampus: implications for the management of temporal lobe epilepsy. 369 Mar 22

Theophylline, the widely used antiasthmatic drug, can cause life-threatening, generalized seizures when administered in excessive doses. The plasma concentrations of theophylline associated with these seizures vary widely among patients, thereby complicating efforts to prevent seizures by timely initiation of appropriate treatment. Some investigators suspect that chronic administration increases the neurotoxicity of theophylline but others have suggested the opposite. We have studied this problem in an animal model of theophylline-induced seizures. Osmotic pumps containing theophylline solution or drug-free solvent (for the surgical control group) were implanted in adult female Lewis rats, yielding almost constant serum theophylline concentrations of about 14 mg/liter for 7 days in the treated group. On the seventh day, theophylline was administered by much more rapid iv infusion to the two groups of animals and to one nonimplanted (nonsurgical) control group until onset of maximal seizures. There were no statistically significant differences between the three groups with respect to the concentrations of theophylline in serum, serum water, brain, and cerebrospinal fluid at onset of seizures. The concentrations of theophylline metabolites were either very low or undetectable. Under the experimental conditions, preexposure of rats for 7 days to theophylline in the human therapeutic concentration range had no apparent effect on the acute neurotoxicity of the drug.
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PMID:Chronic theophylline administration has no apparent effect on theophylline concentrations required to produce seizures in rats. 370 70

To determine the effect of phenobarbital sodium therapy and subependymal intraventricular hemorrhage (SEp-IVH) on the theophylline requirement of premature infants suffering with apnea and seizure activity, we compared three groups of patients as follows: group 1, those with apnea of prematurity (ten patients); group 2, those with apnea and SEp-IVH (ten patients); and group 3, those with apnea, SEp-IVH, and seizure activity for which they were receiving phenobarbital therapy (nine patients). Patients in groups 1 and 2 required lower dosages and blood levels of theophylline to control their apnea than did those in group 3, who required higher dosages and blood levels of methylxanthines. Theophylline dosages and blood levels did not significantly differ between groups 1 and 2. In group 3, the theophylline requirement for control of apnea was significantly increased after initiation of phenobarbital therapy. There seems to be a direct correlation between the increased requirement for theophylline and concomitant phenobarbital administration. The data suggest that phenobarbital increases theophylline requirement when treating neonatal apnea.
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PMID:Phenobarbital increases the theophylline requirement of premature infants being treated for apnea. 378 91

Theophylline, the bronchodilating agent, can cause life-threatening, generalized seizures when plasma concentrations exceed the usual therapeutic concentration range. However, the plasma concentrations of theophylline associated with this neurotoxic effect vary widely between patients. To determine the reasons for the wide variation, and thereby to facilitate prevention or early treatment of theophylline-induced neurotoxicity, an animal model of theophylline-induced seizures was developed and has now been used to determine the effect of experimental renal failure on the concentrations of theophylline that cause convulsions. Adult female rats were subjected to bilateral ureteral ligation or injected with uranyl nitrate to produce renal failure or dysfunction. Sham-operated and saline-injected rats, respectively, served as controls. Theophylline was infused i.v. at either 1.03 or 2.06 mg/min until the onset of maximal seizures. Renal failure due to ureter ligation was associated with a substantial reduction of the dose of drug required to produce seizures, the concentrations of total and free (unbound) theophylline in serum and the concentrations of theophylline in the brain and cerebrospinal fluid at onset of seizures. The concentrations of theophylline metabolites were very low and did not account for the enhanced neurotoxicity. No apparent change in the neurotoxicity of theophylline was observed in rats with uranyl nitrate-induced renal dysfunction. The results of the investigation on ureter-ligated rats are consistent with recent clinical findings of a higher incidence of theophylline-induced neurotoxicity in azotemic patients. The experimental methodology may therefore be suitable for the prospective identification of other potential clinical risk factors for theophylline neurotoxicity.
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PMID:Kinetics of drug action in disease states. XVIII. Effect of experimental renal failure on the pharmacodynamics of theophylline-induced seizures in rats. 380 13


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