Influence of Different Methylxanthines on the Anticonvulsant Action of Common Antiepileptic Drugs in Mice

Abstract

The protective activity of carbamazepine (CBZ, 60 min before testing), phenobarbital (PB, 120 min), phenytoin (PHT, 120 min), and valproate (VPA, 30 min) alone or concurrent with methylxanthine derivatives was evaluated against maximal electroshock-induced seizures (MES) in male mice. All drugs were administered intraperitoneally (i.p.), and the protection offered by antiepileptic drugs (AEDs) was expressed as ED50 in mg/kg. Caffeine sodium benzoate in doses of 0.0595-0.476 mmol/kg (11.55-92.4 mg/kg) distinctly reduced the anticonvulsant efficacy of PB, in the highest dose tested with an increase in ED50 value from 19.5 to 38 mg/kg. This methylxanthine derivative in the dose range of 0.119-0.476 mmol/kg (23.1-92.4 mg/kg) also efficiently inhibited the protective action of PHT. When combined with caffeine (0.238 and 0.476 mmol/kg), the ED50 of PHT was raised from 12 to 17 and 24 mg/kg, respectively. In doses of 0.238 and 0.476 mmol/kg, caffeine also diminished the efficacy of CBZ and VPA, and at the highest dose tested the methylxanthine elevated the respective ED50s from 13 to 20.5 mg/kg and from 270 to 420 mg/kg. Generally caffeine sodium benzoate (up to 0.476 mmol/kg) did not affect the plasma levels of studied AEDs, and only at 0.476 mmol/kg did it significantly decrease the level of PHT. Among the other methylxanthines, pentoxifylline (0.238-0.476 mmol/kg; 66.3-132.5 mg/kg) and diprophylline (0.952 mmol/kg; 242.1 mg/kg) inhibited the protective potential of PHT and the respective ED50s were raised from 12 to 16.5, 15.5, and 14 mg/kg. No significant alterations in PHT plasma levels were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Convulsant effects of some xanthine derivatives in genetically epilepsy-prone rats

“…Further studies in the field of experimental epilepsy have also provided evidence that theophylline, diprophylline and enprofylline exhibit different effects on the protective efficacy of common antiepileptic drugs against convulsions induced in animals (Czuczwar et al 1987a(Czuczwar et al , b, 1990). In addition, other experimental studies showed a clear difference in the ECoG recordings and behavioural effects in rats pretreated with theophylline or enprofylline when the behavioural excitation was induced by subconvulsive doses of pentylenetetrazole (Cutrufo et al 1992).…”

Mechanisms of Action of Antiepileptic Drugs

“…Apart from the pure drug-resistant epilepsy, some epileptic patients may face intractable seizures due to other than pharmacoresistance reasons. During the 90s of the XX century, a number of experimental papers clearly indicated that caffeine, administered in doses far below its convulsive potential, significantly reduced the anticonvulsant activity of conventional antiepileptic drugs against maximal electroshock-induced seizures in mice [124][125][126]. It is noteworthy, that this untoward effect of caffeine did not undergo any tolerance and actually, was increased upon chronic administration of the methylxanthine derivative [125,126].…”

“…+, at least 25% increase in the respective ED50 value; ++, at least 50% increase; +++, at least 90% increase; 0, no significant effect. Data were transformed from Czuczwar et al[124].…”

A prospective study of smoking, caffeine, and alcohol as risk factors for seizures or epilepsy in young adult women: Data from the Nurses’ Health Study II

“…At high doses, caffeine and related methylxanthines have acute convulsive effects. Caffeine causes seizures in genetically susceptible rats (De Sarro et al., 1997) and reduces seizure thresholds to certain convulsants (Chu, 1981; Czuczwar et al., 1990). The mechanism may involve the antagonism of adenosine (adenosine promotes seizure termination) (Whitcomb et al., 1990).…”