Effect of aminophylline upon the protective activity of common antiepileptic drugs and their plasma levels in mice

doi:10.1016/0168-0102(89)90009-6

Neuroscience Research

Volume 6, Issue 5, June 1989, Pages 470-474

https://doi.org/10.1016/0168-0102(89)90009-6 Get rights and content

Abstract

Aminophylline (50 mg/kg) decreased the protective efficacy of carbamazepine (20 mg/kg), diphenylhydantoin (8–12 mg/kg), phenobarbital (20 and 25 mg/kg), and valproate (250 and 300 mg/kg) against electroconvulsions in mice. On the other hand, aminophylline (5 mg/kg) was devoid of such activity. Plasma levels of antiepileptic drugs were measured with the help of the Abbott TDx analyzer and after administration of carbamazepine (20 mg/kg), diphenylhydantoin (10 mg/kg), phenobarbital (25 mg/kg), and valproate (250 mg/kg) were as follows: 8.61, 6.48, 24.3 and 329 μg/ml, respectively. Aminophylline (50 mg/kg) remained without any significant influence upon these plasma levels. This may lead to the conclusion that aminophylline-induced reversal of antiepileptic drug activity is not dependent upon a pharmacokinetic mechanism and probably occurs at the neuronal level.

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Cited by (34)

Interaction of famotidine, an H<inf>2</inf> histamine receptor antagonist, with conventional antiepileptic drugs in mice
2014, Pharmacological Reports
Citation Excerpt :
Retention was expressed as the medians with the 25th and 75th percentiles. Plasma levels of AEDs were measured according to Czuczwar et al. [21]. The animals were given either one of the studied AEDs and saline (control group) or combinations of the H2 receptor antagonist with AEDs.
H₂ histamine receptors are localized postsynaptically in the CNS. The aim of this study was to evaluate the effects of acute (1 day) and prolonged (7 day) administration of the H₂ histamine receptor antagonist, famotidine, on the anticonvulsant activity of conventional antiepileptic drugs (AEDs; valproate, carbamazepine, diphenylhydantoin and phenobarbital) against maximal electroshock (MES)-induced seizures in mice. In addition, the effects of these drugs alone or in combination with famotidine were studied on motor performance and long-term memory. The influence of H₂ receptor antagonist on brain concentrations and free plasma levels of the antiepileptic drugs was also evaluated. After acute or prolonged administration of famotidine (at dose of 10 mg/kg) the drug raised the threshold for electroconvulsions. No effect was observed on this parameter at lower doses. Famotidine (5 mg/kg), given acutely, significantly enhanced the anticonvulsant activity of valproate, which was expressed by a decrease in ED₅₀. After the 7-day treatment, famotidine (5 mg/kg) increased the anticonvulsant activity of diphenylhydantoin against MES. Famotidine (5 mg/kg), after acute and prolonged administration, combined with valproate, phenobarbital, diphenylhydantoin and carbamazepine did not alter their free plasma levels. In contrast, brain concentrations of valproate were elevated for 1-day treatment with famotidine (5 mg/kg). Moreover, famotidine co-applied with AEDs, given prolonged, worsened motor coordination in mice treated with carbamazepine or diphenylhydantoin. In contrast this histamine antagonist, did not impair the performance of mice evaluated in the long-term memory task. The results of this study indicate that famotidine modifies the anticonvulsant activity of some antiepileptic drugs.
Pharmacokinetic and pharmacodynamic interactions of aminophylline and topiramate in the mouse maximal electroshock-induced seizure model
2007, European Journal of Pharmacology
The aim of this study was to determine the influence of acute (single) and chronic (twice daily for 14 consecutive days) treatments with aminophylline (theophylline₂·ethylenediamine) on the anticonvulsant potential of topiramate (a broad-spectrum antiepileptic drug) in the mouse maximal electroshock-induced seizure model. Additionally, the effects of acute and chronic administration of aminophylline on the adverse effect potential of topiramate were assessed in the chimney test (motor performance). To evaluate pharmacokinetic characteristics of interaction between topiramate and aminophylline, total brain concentrations of topiramate and theophylline were estimated with fluorescence polarization immunoassay technique. Results indicate that aminophylline in non-convulsive doses of 50 and 100 mg/kg (i.p.), both in acute and chronic experiments, markedly attenuated the anticonvulsant potential of topiramate by raising its ED₅₀ value against maximal electroconvulsions. Aminophylline at a lower dose of 25 mg/kg did not affect significantly the ED₅₀ value of topiramate in the acute experiment, but the drug markedly increased the ED₅₀ value of topiramate during the chronic treatment in mice. Only, aminophylline at 12.5 mg/kg, in both acute and chronic experiments, did not affect the antielectroshock action of topiramate in mice. Moreover, aminophylline at a dose of 100 mg/kg had no impact on the adverse effect potential of topiramate in the chimney test. Pharmacokinetic evaluation of total brain concentrations of topiramate and theophylline revealed that topiramate significantly increased total brain theophylline concentrations following both acute and chronic applications of aminophylline. Conversely, aminophylline did not alter total brain concentrations of topiramate in mice. Based on this preclinical study, one can conclude that aminophylline attenuated the antiseizure action of topiramate in the mouse maximal electroshock-induced seizure model and the observed interaction between drugs was both pharmacokinetic and pharmacodynamic in nature.
Scopolamine-induced convulsions in fasted mice after food intake: Effects of glucose intake, antimuscarinic activity and anticonvulsant drugs
2005, Neuropharmacology
The present study was performed to further evaluate the contribution of antimuscarinic activity and hypoglycaemia to the development of scopolamine-induced convulsions in fasted mice after food intake. The effects of anticonvulsant drugs on convulsions were also evaluated. Antimuscarinic drugs atropine (3 mg/kg) and biperiden (10 mg/kg) were given intraperitoneally (i.p) to animals fasted for 48 h. Like scopolamine, both drugs induced convulsions after animals were allowed to eat ad libitum. Another group of animals was given glucose (5%) in drinking water during fasting. These animals, although they had normoglycaemic blood levels after fasting, also developed convulsions after treated with scopolamine i.p. (3 mg/kg), atropine (3 mg/kg) or biperiden (10 mg/kg) and allowed to eat ad libitum. Among the drugs studied, only valproate (340 mg/kg), gabapentin (50 mg/kg) and diazepam (2.5 and 5 mg/kg) markedly reduced the incidence of scopolamine-induced convulsions. The present results indicate that antimuscarinic activity, but not hypoglycaemia, underlies these convulsions which do not respond to most of the conventional anticonvulsant drugs.
Influence of antazoline and ketotifen on the anticonvulsant activity of conventional antiepileptics against maximal electroshock in mice
2004, European Neuropsychopharmacology
Experimental studies have indicated that the central histaminergic system plays an important role in the inhibition of seizures through the stimulation of histamine H₁ receptors. H₁ receptor antagonists, including classical antiallergic drugs, occasionally may induce convulsions in healthy children and patients with epilepsy. The purpose of this study was to investigate the effects of antazoline and ketotifen (two H₁ receptor antagonists) on the anticonvulsant activity of antiepileptic drugs against maximal electroshock (MES)-induced convulsions in mice. The following antiepileptic drugs were used: valproate, carbamazepine, diphenylhydantoin and phenobarbital. In addition, the effects of antiepileptic drugs alone or in combination with antazoline or ketotifen were studied on long-term memory (tested in the passive avoidance task) and motor performance (evaluated in the chimney test), acutely and after 7-day treatment with these H₁ receptor antagonists. The influence of antazoline and ketotifen on the free plasma and brain levels of the antiepileptics was also evaluated.
Antazoline (at 0.5 mg/kg), given acutely and after 7-day treatment, significantly diminished the electroconvulsive threshold. Similarly, ketotifen, after acute and chronic doses of 8 mg/kg markedly reduced the threshold for electroconvulsions. In both cases, antazoline and ketotifen were without effect upon this parameter at lower doses. Antazoline (0.25 mg/kg) significantly raised the ED₅₀ value of carbamazepine against MES (both, acutely and after 7-day treatment). Furthermore antazoline (0.25 mg/kg) also reduced the anticonvulsant activity of diphenylhydantoin, but only after repeated administration, without modifying the brain and free plasma level of this drug. Moreover, valproate and phenobarbital did not change their protective activity when combined with antazoline. Ketotifen (4 mg/kg) possessed a biphasic action, acutely it enhanced the anticonvulsant action of carbamazepine and phenobarbital while, following 7-day treatment, reduced the antiseizure activity of carbamazepine. Ketotifen did not affect the free plasma or brain levels of antiepileptics tested. Only acute antazoline (0.25 mg/kg) applied with valproate impaired the performance of mice evaluated in the chimney test. Ketotifen (4 mg/kg) co-administered with conventional antiepileptic drugs impaired motor coordination in mice treated with valproate, phenobarbital or diphenylhydantoin. Acute and chronic antazoline (0.25 mg/kg) alone or in combination with antiepileptic drugs did not disturb long-term memory, tested in the passive avoidance task. Similarly, ketotifen (4 mg/kg) did not impair long-term memory, acutely and after 7-day treatment. However, valproate alone or in combination with chronic ketotifen (4 mg/kg) worsened long-term memory. The results of this study indicate that H₁ receptor antagonists, crossing the blood brain barrier, should be used with caution in epileptic patients. This is because antazoline reduced the protective potential of diphenylhydantoin and carbamazepine. Also, ketotifen reduced the protection offered by carbamazepine and elevated the adverse activity of diphenylhydantoin, phenobarbital and valproate.
Interaction of astemizole, an H<inf>1</inf> receptor antagonist, with conventional antiepileptic drugs in mice
2003, Pharmacology Biochemistry and Behavior
Histamine is one of the aminergic neurotransmitters, playing an important role in the regulation of a number of physiological processes. There are several subtypes of histamine receptors—H₁, H₂, H₃ and the recently discovered H₄. H₁ receptors exist on mast cells, basophils, enterochromaffin cells and in the central nervous system, being located postsynaptically. H₁ receptor antagonists, including classical antiallergy drugs, occasionally have been expected to induce convulsions in children and epileptics. The aim of this study was to evaluate the effects of astemizole-given intraperitoneally, singly or for 7 days on the anticonvulsant activity of antiepileptic drugs (AEDs) against maximal electroshock (MES)-induced convulsions in mice. The following AEDs were administered intraperitoneally: valproate magnesium, carbamazepine, diphenylhydantoin and phenobarbital. Adverse effects were evaluated in the chimney test (motor performance) and passive avoidance task (long-term memory). Brain and plasma levels of AEDs were measured by immunofluorescence. Astemizole (a single dose and following a 7-day treatment at 2–6 mg/kg) reduced the threshold for electroconvulsions, being without effect upon this parameter at lower doses. Astemizole (1 mg/kg) did not significantly alter the protective effect of AEDs against MES (after acute and 7-day administration). Also, acute astemizole (2 mg/kg) remained ineffective in this respect. Astemizole (2 mg/kg), following chronic administration, significantly reduced the protective efficacy of phenobarbital and diphenylhydantoin, reflected by an increase in their ED₅₀ values (50% effective dose necessary to protect 50% of animals tested against MES) from 21.1 to 34.0 mg/kg and from 10.4 to 19.2 mg/kg, respectively. Astemizole (2 mg/kg) did not alter the protective activity of the remaining AEDs. Moreover, astemizole (2 mg/kg) did not influence the free plasma levels and brain concentration of the studied AEDs. Also, this H₁ receptor antagonist did not impair long-term memory or motor coordination when given acutely. However, 7-day treatment with astemizole (2 mg/kg) significantly decreased TD₅₀ (50% toxic dose required to induce motor impairment in 50% of animals) value of phenobarbital, being without effect on carbamazepine, valproate and diphenylhydantoin in this respect. Similarly, phenobarbital and diphenylhydantoin, administered alone at their ED₅₀s against MES, or combined with astemizole, disturbed long-term memory in mice. The results of this study indicate that astemizole may need to be used with caution in epileptic patients.
Influence of sex hormone antagonists on the anticonvulsant action of conventional antiepileptic drugs against amygdala-kindled seizures in male and female rats
2003, European Neuropsychopharmacology
The effects of three gonadal steroid antihormones, tamoxifen (TXF, an estrogen antagonist), cyproterone acetate (CYP, an antiandrogen) and mifepristone (MIF, a progesterone antagonist) alone or combined with conventional antiepileptics were evaluated in amygdala-kindled seizures in male and female rats. None of the three antihormones used in this study affected any seizure parameter. TXF (50 mg/kg) and CYP (50 mg/kg), when combined with carbamazepine, or phenobarbital applied at their subprotective doses of 15 mg/kg, resulted in significant reductions of the seizure and afterdischarge durations, both in male and female rats. Additionally, the combination of carbamazepine and CYP markedly increased the afterdischarge threshold in fully-kindled rats of both genders. The interaction between antihormones and carbamazepine, or phenobarbital, was not reversed by respective sex steroid hormones (estradiol, testosterone). However, the TXF- and CYP-induced anticonvulsant effects in combinations with carbamazepine were attenuated by bicuculline, N-methyl-d-aspartate (NMDA) and aminophylline. Kainic acid and strychnine remained ineffective in this respect. The effect of a combination of TXF with phenobarbital was reversed by bicuculline and NMDA and that of CYP with phenobarbital—by bicuculline and aminophylline. Neither TXF nor CYP altered the free plasma concentrations of carbamazepine or phenobarbital, so a pharmacokinetic interaction is not probable. The combined treatment of the two antihormones with antiepileptic drugs did not affect motor performance, and did not result in significant long-term memory deficits. Our data confirm the hypothesis that sex hormone antagonist-mediated events may play some role in seizure processes in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs against kindled seizures.

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Short communicationEffect of aminophylline upon the protective activity of common antiepileptic drugs and their plasma levels in mice

Abstract

Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Epilepsy Res.

Brain Res.

Caffeine and aminophylline-induced seizures

Epilepsia

Effect of aminophylline on the protective action of common antiepileptic drugs against electroconvulsions in mice

Epilepsia

Effect of aminophylline and enprofylline on the protective efficacy of common antiepileptic drugs against electroconvulsions in mice

Epilepsia

Aminophylline and CGS 8216 reverse the protective action of diazepam against electroconvulsions in mice

Epilepsia

Short communication
Effect of aminophylline upon the protective activity of common antiepileptic drugs and their plasma levels in mice