Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This investigation was designed to determine the effect of fever on the neurotoxicity of theophylline as reflected by the concentrations of this drug that cause convulsions in experimental animals. Fever was produced in male, inbred, adult Lewis rats (approximately 180 g) by sc injection of brewer's yeast; an elevation of body temperature of 1.2 +/- 0.4 degrees C (mean +/- SD) was achieved at the time of the pharmacodynamic measurements. Theophylline was infused iv at a rate of 1.03 mg/min until the onset of maximal seizures. Drug concentrations in serum, serum water, brain, and cerebrospinal fluid (CSF) at that time were determined by high-performance liquid chromatography. Compared with the control group, the group of febrile rats had statically significantly lower serum protein concentrations, decreased serum protein binding of theophylline, and slightly increased theophylline concentrations in the CSF at the onset of seizures. Inasmuch as theophylline concentrations in the CSF reflect the concentrations of this drug in the biophase, the results of this study show that fever does not increase the sensitivity of the central nervous system to the neurotoxic effects of theophylline in rats. In fact, a statistically significant positive correlation between theophylline concentrations in the CSF and body temperature was found in this investigation, suggesting a decreased sensitivity of the animals to the neurotoxic effects of theophylline at higher body temperature.
 ...
PMID:Kinetics of drug action in disease states. XXVI: Effect of fever on the pharmacodynamics of theophylline-induced seizures in rats. 317 43

We evaluated the efficacy of pretreatment with phenytoin and phenobarbital to prevent seizures in mice given convulsive doses of theophylline. The control LD50 for theophylline was determined in 48 mice by intraperitoneal injections of increasing doses without anticonvulsant treatment. Anticonvulsant effects were determined in 105 additional mice pretreated with either phenytoin 30 mg/kg (n = 35), phenobarbital 35 mg/kg (n = 30), or phenobarbital 60 mg/kg (n = 40) one hour before theophylline administration. The theophylline LD50 (95% confidence interval) was 239 mg/kg (range, 229 to 248 mg/kg) for controls, 204 mg/kg (range, 194 to 214 mg/kg) for phenytoin, 305 mg/kg (range, 288 to 323 mg/kg) for low-dose phenobarbital, and 319 mg/kg (range, 307 to 331 mg/kg) for high-dose phenobarbital. Each LD50 differed significantly from control (P less than .05). The phenobarbital groups were significantly different from phenytoin (P less than .05) but not from each other. Theophylline serum concentrations were not significantly different among groups after adjustment for different doses. The mean +/- SEM time to seizure in minutes after adjustment for theophylline dose was 23.5 +/- 4.0 minutes for controls, 5.7 +/- 7.5 minutes for phenytoin, 44.1 +/- 7.1 minutes for low-dose phenobarbital, and 63.7 +/- 6.5 minutes for high-dose phenobarbital.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Relative efficacy of phenytoin and phenobarbital for the prevention of theophylline-induced seizures in mice. 317 89

Theophylline can cause life-threatening seizures when administered in excessive doses. The plasma concentrations associated with this neurotoxic effect vary widely among patients. To determine the reasons for the wide variation, an animal model of theophylline-induced seizures was developed and has now been used to determine the effect of pre-exposure to caffeine on theophylline-induced neurotoxicity. Male adult rats received an iv infusion of either caffeine citrate or sodium citrate solution for 15 min. Theophylline was then infused at a relatively rapid rate until onset of maximum seizures. A third group of rats received a rapid infusion of caffeine only until onset of seizures. Samples of blood, brain, and cerebrospinal fluid were obtained at that time for determination of caffeine and theophylline concentrations by HPLC. Prior exposure to caffeine was associated with a statistically significant reduction in the total amount of theophylline required to produce seizures and caused theophylline concentrations at all sampling sites to be significantly lower than in controls. Caffeine alone required a larger total dose and higher concentrations than theophylline alone to produce seizures. It is concluded that acute exposure to caffeine can increase the risk of theophylline-induced neurotoxicity.
 ...
PMID:Caffeine as a potential risk factor for theophylline neurotoxicity. 322 66

Theophylline, with its narrow therapeutic margin, is a common cause of iatrogenic and deliberate overdose. Most cases of self-poisoning are with sustained release preparations, with peak concentrations occurring up to 12 or more hours after overdose. Toxic symptoms are often seen at concentrations above 15 mg/L. Theophylline is metabolised within the cytochrome P-450 system, with an average total body clearance of 50 to 60 ml/min. Clearance is, however, affected by many factors such as other drugs or disease, and in overdose zero order kinetics may result in prolonged half-lives. Toxicity is characterised by agitation, tremor, nausea, vomiting, abdominal pains, seizures, and tachyarrhythmias. Hypokalaemia and metabolic acidosis are more profound in acute toxicity, and hypercalcaemia is usually present. Seizures occur at lower concentrations after chronic over-medication than after acute overdose. Gastric lavage should be performed in all patients presenting early, and an oral multiple dose charcoal regimen started with 50 to 100g charcoal, repeating with 50g doses and checking theophylline concentrations at 2- to 4-hour intervals. Multiple dose charcoal can be expected to double the clearance of theophylline, being as effective as a haemodialysis. Of the invasive techniques available, charcoal haemoperfusion is the most effective, increasing clearance 4- to 6-fold. Supportive care is particularly important. The aggressive supplementation of potassium, treatment of emesis with droperidol and ranitidine, and treatment of tachyarrhythmias and hypotension (possibly with propranolol), together with oral multiple dose charcoal may obviate the need for haemoperfusion. Seizures suggest increased morbidity and mortality. Charcoal haemoperfusion should be considered if plasma concentrations are greater than 100 mg/L in an acute intoxication or greater than 60 mg/L in a chronic intoxication. The decision to haemoperfuse should not be based on plasma concentrations alone, but an overall evaluation of the patient's laboratory and clinical status.
 ...
PMID:Role of extracorporeal drug removal in acute theophylline poisoning. A review. 330 69

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.
 ...
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)
 ...
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.
 ...
PMID:Kinetics of drug action in disease states. XIX. Effect of experimental liver disease on the neurotoxicity of theophylline in rats. 349 38

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.
 ...
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.
 ...
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.
 ...
PMID:Pro-convulsant actions of theophylline and caffeine in the hippocampus: implications for the management of temporal lobe epilepsy. 369 Mar 22


<< Previous 1 2 3 4 5 Next >>