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.