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EFFECT OF PROPRANOLOL AND NIFEDIPINE ON MAXIMAL ELECTROSHOCK-INDUCED SEIZURES IN MICE: INDIVIDUALLY AND IN COMBINATION
Pharmacological Research, Vol. 38, No. 6, 1998 Article Number: fr980390
EFFECT OF PROPRANOLOL AND NIFEDIPINE ON MAXIMAL ELECTROSHOCK-INDUCED SEIZURES IN MICE: INDIVIDUALLY AND IN COMBINATION S.S. RAJU a,U , H.N. GOPALAKRISHNAb and N. VENKATADRI b a
Department of Pharmacology, School of Medical Sciences, Uni¨ ersiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia and bDepartment of Pharmacology, Kasturba Medical College, Mangalore 575001, India Accepted 5 August 1998
A comparative effect of propranolol and nifedipine administered individually and in combination at graded dose levels; and that of phenytoin at 30 mg kgy1 on maximal electroshock ŽMES.-induced seizure in mice was investigated. Propranolol in doses of 10 mg kgy1 and 20 mg kgy1 , and nifedipine in doses of 8 mg kgy1 and 16 mg kgy1 significantly modified MES activity. Propranolol Ž40 mg kgy1 ., and a combination of propranolol Ž20 mg kgy1 . and nifedipine Ž8 mg kgy1 ., produced antiMES activity, which was comparable to that of phenytoin Ž30 mg kgy1 .. In mice treated with propranolol and nifedipine combination, the tonic flexor and tonic extensor phase ratios ŽFrE ratio. were significantly higher than individual drug responses. Our findings suggest that a combination of propranolol and nifedipine has either synergistic or an additive effect in controlling MES-induced seizures in mice. Q 1998 The Italian Pharmacological Society KEY WORDS: propranolol and nifedipine combination, phenytoin, maximal electroshock induced seizures, flexor and tonic extensor phase ratio, anticonvulsant effect.
INTRODUCTION The combination of propranolol and nifedipine has an additive therapeutic effect in the treatment of cardiovascular disorders like hypertension and angina pectoris; and each one mutually reduces the occurrence of adverse effects of the other w1x. The pharmacological effects of propranolol w2x and nifedipine w1x suggest the following assumptions: Ži. the adverse effects of propranolol due to its cardiac depressant, bronchoconstrictor and vaso-constrictor effects Žbradycardia, heart block, precipitation of bronchospasm and peripheral vascular disorders. can be countered by nifedipine; and Žii. the adverse effects of nifedipine due to its profound arteriolar vasodilatation and reflex sympathetic activation Žheadache, flushing, tachycardia, palpitations and precipitation of angina pectoris. can be countered by propranolol. Both propranolol w3]7x and nifedipine w8]11x have established anticonvulsant action in several experimental models of grand mal epilepsy. There are reports available in the literature showing synergistic U
Corresponding author.
1043]6618r98r120449]04r$30.00r0
or additive anticonvulsant effect, when propranolol is combined with carbamazepine w12x or local anaesthetics w13x; and nifedipine is combined with regular antiepileptic drugs w14, 15x. However, there are no documentary reports in the literature, on the anticonvulsant effect of the combination of propranolol and nifedipine either in experimental models of epilepsy or in epilepsy patients. Hence the present study was undertaken to determine the antiepileptic effect of a combination of propranolol and nifedipine, as compared to an individual drug, and to the standard antiepileptic drug phenytoin.
MATERIALS AND METHODS
Experimental animals Male albino mice Ž10]12 weeks old. of Wistar strain weighing between 25 and 30 g were used in this study. They were housed eight per cage, with free access to food and water. They were kept on a 12r12 h light]dark cycle, under controlled temperature Ž228C.. Each animal was tested only once. The animals were divided into 15 groups of eight in each. Drugs were administered i.p. 1 h before the maximal electroshock ŽMES. seizure test. Seizures were inQ1998 The Italian Pharmacological Society
Pharmacological Research, Vol. 38, No. 6, 1998
450
Table I Dosage of various drugs administered i.p. in mice Drugs administered
Dose (mg kgy 1)
Propranolol Propranolol Propranolol Nifedipine Nifedipine Nifedipine Propranolol q nifedipine Propranolol q nifedipine Propranolol q nifedipine Propranolol q nifedipine Propranolol q nifedipine Propranolol q nifedipine Normal saline 30% Polyethylene glycol Phenytoin sodium
10 20 40 4 8 16 10 q 4 10 q 8 10 q 16 20 q 4 20 q 8 40 q 4 0.5 ml micey1 0.5 ml micey1 30
Groups 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
duced by delivery of a 60-Hz current of 50 mA intensity for 0.2 s through ear-clip electrodes. The dosage of the various drugs Žin graded doses; individually and in combination. administered to these animals are shown in Table I. Nifedipine was dissolved in 30% polyethylene glycol ŽPEG. as it is not soluble in water. Then all the drugs were diluted with normal saline to obtain graded dose-concentration. Hence normal saline and PEG were administered to two groups for control purpose. Anticonvulsant action of the drugs was assessed by calculating: Ži. tonic flexion timertonic extension time ratio ŽFrE ratio., if both the phases were present; Žii. percentage of animals in which only the tonic extensor phase was abolished; and Žiii. percentage of animals in which both tonic flexor and tonic extensor phases were abolished. FrE ratio of each animal was calculated and expressed as mean " SE for the groups and were subjected to the Student’s t-test for statistical analysis. RESULTS Significant increase in FrE ratio was observed with
propranolol Ž10 mg kgy1 and 20 mg kgy1 .. On increasing its dose to 40 mg kgy1 , the tonic extensor phase was abolished in 40% of animals and both tonic flexor and tonic extensor phases were abolished in 30% of animals. Nifedipine did not alter the FrE ratio in lower doses Ž4 mg kgy1 .. However, a significant increase in the FrE ratio was seen at higher doses Ž8 mg kgy1 ; 16 mg kgy1 .. FrE ratios of various combinations of propranolol and nifedipine were, significantly greater than these drugs when used alone Ž P- 0.01.. Combination of propranolol Ž10 mg kgy1 . with nifedipine of increasing doses Ž4, 8 and 16 mg kgy1 . increased the FrE ratio significantly Ž P- 0.01.. ŽTable II. A combination of propranolol Ž20 mg kgy1 . and nifedipine Ž4 mg kgy1 . abolished the tonic extensor phase in 30% of animals and both tonic flexor and tonic extensor phases in 20% of animals. A combination of a high concentration of propranolol Ž40 mg kgy1 . with nifedipine Ž4 mg kgy1 ., and propranolol Ž20 mg kgy1 . with a high concentration of nifedipine Ž8 mg kgy1 . abolished the tonic extensor phase in 80% of animals; and both tonic flexor and tonic extensor phases in 40% of animals. ŽTable III. Phenytoin Ž30 mg kgy1 . alone was capable of abolishing the tonic extensor phase in 100% of animals, and both tonic flexor and tonic extensor phases in 70% of animals. This effect was comparable to the following combinations of propranolol and nifedipine: Ži. propranolol Ž20 mg kgy1 . and nifedipine Ž4 mg kgy1 .; Žii. propranolol Ž20 mg kgy1 . and nifedipine Ž8 mg kgy1 .; and Žiii. propranolol Ž40 mg kgy1 . and nifedipine Ž4 mg kgy1 ., and propranolol Ž40 mg kgy1 . alone.
DISCUSSION The findings in our study reveal that a combination of propranolol and nifedipine abolished the tonic extensor phase as well as both tonic flexor and tonic extensor phases in a majority of the animals. An-
Table II r E ratio Effect of propranolol, nifedipine and their combination on Fr Groups Normal saline 30% Polyethylene glycol Propranolol 10 mg kgy1 Propranolol 20 mg kgy1 Nifedipine 4 mg kgy1 Nifedipine 8 mg kgy1 Nifedipine 16 mg kgy1 Propranolol 10 mg kgy1 q nifedipine 4 mg kgy1 Propranolol 10 mg kgy1 q nifedipine 8 mg kgy1 Propranolol 10 mg kgy1 q nifedipine 16 mg kgy1 In comparison with control groups: U P- 0.01; †P- 0.001. In comparison with propranolol 10 mg kgy1 group: ‡ P- 0.01; §P - 0.001.
F r E ratio 0.150" 0.0084 0.174" 0.0123 0.266" 0.0129U 0.601" 0.0448† 0.183" 0.0077 0.257" 0.07U 0.515" 0.0431† 0.359" 0.0311†‡ 0.452" 0.0473†§ 0.625" 0.0562†§
Pharmacological Research, Vol. 38, No. 6, 1998
451
Table III Effect of propranolol, nifedipine and their combination on tonic extensor and tonic flexor phases of MES induced seizures Groups
Percent (%) of mice only tonic extensor phase was abolished
Percent (%) of mice both tonic extensor and tonic flexor phases were abolished
60 30 80 80 100
30 20 40 40 70
Propranolol 40 mg kgy1 Propranolol 20 mg kgy1 q nifedipine 4 mg kgy1 Propranolol 20 mg kgy1 q nifedipine 8 mg kgy1 Propranolol 40 mg kgy1 q nifedipine 4 mg kgy1 Phenytoin 30 mg kgy1
other interesting finding was that the above drugs, when used individually, did not have similar effects. Therefore a combination of propranolol and nifedipine may play a role in the therapy of grand mal seizures. The additive or synergistic effect may be due to combination of b-adrenergic receptor blockade w5, 16, 17x or a direct membrane stabilising action of propranolol w4, 18x and the calcium channel blocking effect of nifedipine w10x. The observation of comparable anticonvulsant effect of propranolol and nifedipine combination to phenytoin Žas noted in the present study. has not been reported earlier. Renshaw et al. w12x have reported the beneficial effect of propranolol in controlling the carbamazepine resistant complex seizures in one patient. They postulated the possibility of its synergistic effect. Hence the authors feel that, it is worthwhile to undertake a clinical trail of propranolol and nifedipine combination or propranolol with another dihydropyridine group of calcium channel blockers in the treatment of grand mal epilepsy, especially when it is associated with cardiovascular disease. This two-drug combination controls both grand mal epilepsy and cardiovascular disorders like ischaemic heart disease and hypertension simultaneously; at the same time each drug can alleviate the adverse effects of the other. Further this combination has the advantage of high therapeutic index when compared to phenytoin’s low therapeutic index; and the possibility of lower dose requirement of phenytoin if needed. Further clinical studies are necessary to ascertain the requirements of phenytoin in epileptic patients associated with cardiovascular disease, where concomitant administration of propranolol and nifedipine with phenytoin is warranted.
2.
3.
4.
5.
6.
7. 8.
9.
10.
11.
12.
REFERENCES 13. 1. Murad F. Drugs used for treatment of angina: organic nitrates, calcium channel blockers, and badrenergic antagonists. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Gilman
14.
AG, Rall TW, Nies AS, Taylor P, eds. Pergamon press, 1990: pp. 765]83. Hoffman BB, Lefkowitz RJ. Adrenergic receptor antagonists. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Gilman AG, Rall TW, Nies AS, Taylor P, eds. Pergamon press 1990: pp. 221]43. Akkan AG, Yillar DO, Eskazan E, Akcasu A, Ozuner Z. The effect of propranolol on maximal electroshock seizures in mice. Int J Clin Pharmacol Ther Toxicol 1989; 27: 255]7. Khanna N, Ray A, Alkondan M, Sen P. Effect of beta-adrenoreceptor antagonists and some related drugs on maximal electroshock seizures in mice. Indian J Exp Biol 1989; 27: 128]30. Paul V, Krishnamoorthy MS. The effect of betaadrenoreceptor antagonists alone and in combination with a GABA-elevating agent on isoniazide induced convulsions in mice. Indian J Physiol Pharmacol 1989; 33: 175]8. Stringer JL, Lothman EW. Cholinergic and adrenergic agents modify the initiation and termination of epileptic discharge in the dentate gyrus. Neuropharmacology 1991; 30: 59]65. Lathers CM, Jim KF, Spivey WH. A comparison of intraosseous and intravenous routes of administration for antiseizure agents. Epilepsia 1989; 30: 472]9. Jagiello-Wojtowicz E, Czuczwar SJ, Chodkowska A, Szponar J, Kleinrok Z. Influence of calcium channel blockers on pentylene tetrazole electroshockinduced convulsions in mice. Pol J Pharmacol Pharm 1991; 43: 95]101. Desai CK, Dikshit RK, Mansuri SM, Shah UH. Comparative evaluation of anticonvulsant activity of calcium channel blockers in experimental animals. Indian J Exp Biol 1995; 33: 931]4. De Sarro G, De Sarro A, Federico F, Meldrum BS. Anticonvulsant properties of some calcium antagonists on sound-induced seizures in genetically epilepsy prone rats. Gen Pharmacol 1990; 20: 769]78. Vezzani A, Wu HQ, Stasi MA, Angelico P, Samanin R. Effect of various calcium channel blockers on three different models of limbic seizures in rats. Neuropharmacology 1988; 27: 451]8. Renshaw PF, Ford HE, Brotman AW. Possible synergistic anticonvulsant effect of propranolol and carbamazepine. Am J Psychiatry 1990; 147: 1687]8. Muller M, Schramek J. Combined application of propranolol and local anesthetics: enhanced anticonvulsant action. Biomed Biochim Acta 1988; 48: 333]6. Czuczwar SJ, Malek U, Kleinrok Z. Influence of calcium channel inhibitors upon the anticonvulsant
452
efficacy of common antiepileptics against pentylene tetrazole-induced convulsions in mice. Neuropharmacology 1990; 29: 943]8. 15. Czuczwar SJ, Chodkowska A, Kleinrok Z, Malek U, Jagiello-Wojtowicz E. Effects of calcium channel inhibitors upon the efficacy of common antiepileptic drugs. Eur J Pharmacol 1990; 176: 75]83. 16. Noebels JL, Rutecki PA. Altered hippocampal network excitability in the hyperadrenergic mutant mouse tottering. Brain Res 1990; 524: 225]30.
Pharmacological Research, Vol. 38, No. 6, 1998
17. Lints CE, Nyquist-Battie C. A possible role of betaadrenergic receptor in the expression of audiogenic seizures. Pharmacol Biochem Beha¨ 1985; 22: 711]6. 18. Fischer W, Muller M. Pharmacological modulation of central monoaminergic systems and influence on the anticonvulsant effectiveness in maximal electroshock seizure. Biomed Biochim Acta 1988; 47: 631]5.
EFFECT OF PROPRANOLOL AND NIFEDIPINE ON MAXIMAL ELECTROSHOCK-INDUCED SEIZURES IN MICE: INDIVIDUALLY AND IN COMBINATION S.S. RAJU a,U , H.N. GOPALAKRISHNAb and N. VENKATADRI b a
Department of Pharmacology, School of Medical Sciences, Uni¨ ersiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia and bDepartment of Pharmacology, Kasturba Medical College, Mangalore 575001, India Accepted 5 August 1998
A comparative effect of propranolol and nifedipine administered individually and in combination at graded dose levels; and that of phenytoin at 30 mg kgy1 on maximal electroshock ŽMES.-induced seizure in mice was investigated. Propranolol in doses of 10 mg kgy1 and 20 mg kgy1 , and nifedipine in doses of 8 mg kgy1 and 16 mg kgy1 significantly modified MES activity. Propranolol Ž40 mg kgy1 ., and a combination of propranolol Ž20 mg kgy1 . and nifedipine Ž8 mg kgy1 ., produced antiMES activity, which was comparable to that of phenytoin Ž30 mg kgy1 .. In mice treated with propranolol and nifedipine combination, the tonic flexor and tonic extensor phase ratios ŽFrE ratio. were significantly higher than individual drug responses. Our findings suggest that a combination of propranolol and nifedipine has either synergistic or an additive effect in controlling MES-induced seizures in mice. Q 1998 The Italian Pharmacological Society KEY WORDS: propranolol and nifedipine combination, phenytoin, maximal electroshock induced seizures, flexor and tonic extensor phase ratio, anticonvulsant effect.
INTRODUCTION The combination of propranolol and nifedipine has an additive therapeutic effect in the treatment of cardiovascular disorders like hypertension and angina pectoris; and each one mutually reduces the occurrence of adverse effects of the other w1x. The pharmacological effects of propranolol w2x and nifedipine w1x suggest the following assumptions: Ži. the adverse effects of propranolol due to its cardiac depressant, bronchoconstrictor and vaso-constrictor effects Žbradycardia, heart block, precipitation of bronchospasm and peripheral vascular disorders. can be countered by nifedipine; and Žii. the adverse effects of nifedipine due to its profound arteriolar vasodilatation and reflex sympathetic activation Žheadache, flushing, tachycardia, palpitations and precipitation of angina pectoris. can be countered by propranolol. Both propranolol w3]7x and nifedipine w8]11x have established anticonvulsant action in several experimental models of grand mal epilepsy. There are reports available in the literature showing synergistic U
Corresponding author.
1043]6618r98r120449]04r$30.00r0
or additive anticonvulsant effect, when propranolol is combined with carbamazepine w12x or local anaesthetics w13x; and nifedipine is combined with regular antiepileptic drugs w14, 15x. However, there are no documentary reports in the literature, on the anticonvulsant effect of the combination of propranolol and nifedipine either in experimental models of epilepsy or in epilepsy patients. Hence the present study was undertaken to determine the antiepileptic effect of a combination of propranolol and nifedipine, as compared to an individual drug, and to the standard antiepileptic drug phenytoin.
MATERIALS AND METHODS
Experimental animals Male albino mice Ž10]12 weeks old. of Wistar strain weighing between 25 and 30 g were used in this study. They were housed eight per cage, with free access to food and water. They were kept on a 12r12 h light]dark cycle, under controlled temperature Ž228C.. Each animal was tested only once. The animals were divided into 15 groups of eight in each. Drugs were administered i.p. 1 h before the maximal electroshock ŽMES. seizure test. Seizures were inQ1998 The Italian Pharmacological Society
Pharmacological Research, Vol. 38, No. 6, 1998
450
Table I Dosage of various drugs administered i.p. in mice Drugs administered
Dose (mg kgy 1)
Propranolol Propranolol Propranolol Nifedipine Nifedipine Nifedipine Propranolol q nifedipine Propranolol q nifedipine Propranolol q nifedipine Propranolol q nifedipine Propranolol q nifedipine Propranolol q nifedipine Normal saline 30% Polyethylene glycol Phenytoin sodium
10 20 40 4 8 16 10 q 4 10 q 8 10 q 16 20 q 4 20 q 8 40 q 4 0.5 ml micey1 0.5 ml micey1 30
Groups 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
duced by delivery of a 60-Hz current of 50 mA intensity for 0.2 s through ear-clip electrodes. The dosage of the various drugs Žin graded doses; individually and in combination. administered to these animals are shown in Table I. Nifedipine was dissolved in 30% polyethylene glycol ŽPEG. as it is not soluble in water. Then all the drugs were diluted with normal saline to obtain graded dose-concentration. Hence normal saline and PEG were administered to two groups for control purpose. Anticonvulsant action of the drugs was assessed by calculating: Ži. tonic flexion timertonic extension time ratio ŽFrE ratio., if both the phases were present; Žii. percentage of animals in which only the tonic extensor phase was abolished; and Žiii. percentage of animals in which both tonic flexor and tonic extensor phases were abolished. FrE ratio of each animal was calculated and expressed as mean " SE for the groups and were subjected to the Student’s t-test for statistical analysis. RESULTS Significant increase in FrE ratio was observed with
propranolol Ž10 mg kgy1 and 20 mg kgy1 .. On increasing its dose to 40 mg kgy1 , the tonic extensor phase was abolished in 40% of animals and both tonic flexor and tonic extensor phases were abolished in 30% of animals. Nifedipine did not alter the FrE ratio in lower doses Ž4 mg kgy1 .. However, a significant increase in the FrE ratio was seen at higher doses Ž8 mg kgy1 ; 16 mg kgy1 .. FrE ratios of various combinations of propranolol and nifedipine were, significantly greater than these drugs when used alone Ž P- 0.01.. Combination of propranolol Ž10 mg kgy1 . with nifedipine of increasing doses Ž4, 8 and 16 mg kgy1 . increased the FrE ratio significantly Ž P- 0.01.. ŽTable II. A combination of propranolol Ž20 mg kgy1 . and nifedipine Ž4 mg kgy1 . abolished the tonic extensor phase in 30% of animals and both tonic flexor and tonic extensor phases in 20% of animals. A combination of a high concentration of propranolol Ž40 mg kgy1 . with nifedipine Ž4 mg kgy1 ., and propranolol Ž20 mg kgy1 . with a high concentration of nifedipine Ž8 mg kgy1 . abolished the tonic extensor phase in 80% of animals; and both tonic flexor and tonic extensor phases in 40% of animals. ŽTable III. Phenytoin Ž30 mg kgy1 . alone was capable of abolishing the tonic extensor phase in 100% of animals, and both tonic flexor and tonic extensor phases in 70% of animals. This effect was comparable to the following combinations of propranolol and nifedipine: Ži. propranolol Ž20 mg kgy1 . and nifedipine Ž4 mg kgy1 .; Žii. propranolol Ž20 mg kgy1 . and nifedipine Ž8 mg kgy1 .; and Žiii. propranolol Ž40 mg kgy1 . and nifedipine Ž4 mg kgy1 ., and propranolol Ž40 mg kgy1 . alone.
DISCUSSION The findings in our study reveal that a combination of propranolol and nifedipine abolished the tonic extensor phase as well as both tonic flexor and tonic extensor phases in a majority of the animals. An-
Table II r E ratio Effect of propranolol, nifedipine and their combination on Fr Groups Normal saline 30% Polyethylene glycol Propranolol 10 mg kgy1 Propranolol 20 mg kgy1 Nifedipine 4 mg kgy1 Nifedipine 8 mg kgy1 Nifedipine 16 mg kgy1 Propranolol 10 mg kgy1 q nifedipine 4 mg kgy1 Propranolol 10 mg kgy1 q nifedipine 8 mg kgy1 Propranolol 10 mg kgy1 q nifedipine 16 mg kgy1 In comparison with control groups: U P- 0.01; †P- 0.001. In comparison with propranolol 10 mg kgy1 group: ‡ P- 0.01; §P - 0.001.
F r E ratio 0.150" 0.0084 0.174" 0.0123 0.266" 0.0129U 0.601" 0.0448† 0.183" 0.0077 0.257" 0.07U 0.515" 0.0431† 0.359" 0.0311†‡ 0.452" 0.0473†§ 0.625" 0.0562†§
Pharmacological Research, Vol. 38, No. 6, 1998
451
Table III Effect of propranolol, nifedipine and their combination on tonic extensor and tonic flexor phases of MES induced seizures Groups
Percent (%) of mice only tonic extensor phase was abolished
Percent (%) of mice both tonic extensor and tonic flexor phases were abolished
60 30 80 80 100
30 20 40 40 70
Propranolol 40 mg kgy1 Propranolol 20 mg kgy1 q nifedipine 4 mg kgy1 Propranolol 20 mg kgy1 q nifedipine 8 mg kgy1 Propranolol 40 mg kgy1 q nifedipine 4 mg kgy1 Phenytoin 30 mg kgy1
other interesting finding was that the above drugs, when used individually, did not have similar effects. Therefore a combination of propranolol and nifedipine may play a role in the therapy of grand mal seizures. The additive or synergistic effect may be due to combination of b-adrenergic receptor blockade w5, 16, 17x or a direct membrane stabilising action of propranolol w4, 18x and the calcium channel blocking effect of nifedipine w10x. The observation of comparable anticonvulsant effect of propranolol and nifedipine combination to phenytoin Žas noted in the present study. has not been reported earlier. Renshaw et al. w12x have reported the beneficial effect of propranolol in controlling the carbamazepine resistant complex seizures in one patient. They postulated the possibility of its synergistic effect. Hence the authors feel that, it is worthwhile to undertake a clinical trail of propranolol and nifedipine combination or propranolol with another dihydropyridine group of calcium channel blockers in the treatment of grand mal epilepsy, especially when it is associated with cardiovascular disease. This two-drug combination controls both grand mal epilepsy and cardiovascular disorders like ischaemic heart disease and hypertension simultaneously; at the same time each drug can alleviate the adverse effects of the other. Further this combination has the advantage of high therapeutic index when compared to phenytoin’s low therapeutic index; and the possibility of lower dose requirement of phenytoin if needed. Further clinical studies are necessary to ascertain the requirements of phenytoin in epileptic patients associated with cardiovascular disease, where concomitant administration of propranolol and nifedipine with phenytoin is warranted.
2.
3.
4.
5.
6.
7. 8.
9.
10.
11.
12.
REFERENCES 13. 1. Murad F. Drugs used for treatment of angina: organic nitrates, calcium channel blockers, and badrenergic antagonists. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Gilman
14.
AG, Rall TW, Nies AS, Taylor P, eds. Pergamon press, 1990: pp. 765]83. Hoffman BB, Lefkowitz RJ. Adrenergic receptor antagonists. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Gilman AG, Rall TW, Nies AS, Taylor P, eds. Pergamon press 1990: pp. 221]43. Akkan AG, Yillar DO, Eskazan E, Akcasu A, Ozuner Z. The effect of propranolol on maximal electroshock seizures in mice. Int J Clin Pharmacol Ther Toxicol 1989; 27: 255]7. Khanna N, Ray A, Alkondan M, Sen P. Effect of beta-adrenoreceptor antagonists and some related drugs on maximal electroshock seizures in mice. Indian J Exp Biol 1989; 27: 128]30. Paul V, Krishnamoorthy MS. The effect of betaadrenoreceptor antagonists alone and in combination with a GABA-elevating agent on isoniazide induced convulsions in mice. Indian J Physiol Pharmacol 1989; 33: 175]8. Stringer JL, Lothman EW. Cholinergic and adrenergic agents modify the initiation and termination of epileptic discharge in the dentate gyrus. Neuropharmacology 1991; 30: 59]65. Lathers CM, Jim KF, Spivey WH. A comparison of intraosseous and intravenous routes of administration for antiseizure agents. Epilepsia 1989; 30: 472]9. Jagiello-Wojtowicz E, Czuczwar SJ, Chodkowska A, Szponar J, Kleinrok Z. Influence of calcium channel blockers on pentylene tetrazole electroshockinduced convulsions in mice. Pol J Pharmacol Pharm 1991; 43: 95]101. Desai CK, Dikshit RK, Mansuri SM, Shah UH. Comparative evaluation of anticonvulsant activity of calcium channel blockers in experimental animals. Indian J Exp Biol 1995; 33: 931]4. De Sarro G, De Sarro A, Federico F, Meldrum BS. Anticonvulsant properties of some calcium antagonists on sound-induced seizures in genetically epilepsy prone rats. Gen Pharmacol 1990; 20: 769]78. Vezzani A, Wu HQ, Stasi MA, Angelico P, Samanin R. Effect of various calcium channel blockers on three different models of limbic seizures in rats. Neuropharmacology 1988; 27: 451]8. Renshaw PF, Ford HE, Brotman AW. Possible synergistic anticonvulsant effect of propranolol and carbamazepine. Am J Psychiatry 1990; 147: 1687]8. Muller M, Schramek J. Combined application of propranolol and local anesthetics: enhanced anticonvulsant action. Biomed Biochim Acta 1988; 48: 333]6. Czuczwar SJ, Malek U, Kleinrok Z. Influence of calcium channel inhibitors upon the anticonvulsant
452
efficacy of common antiepileptics against pentylene tetrazole-induced convulsions in mice. Neuropharmacology 1990; 29: 943]8. 15. Czuczwar SJ, Chodkowska A, Kleinrok Z, Malek U, Jagiello-Wojtowicz E. Effects of calcium channel inhibitors upon the efficacy of common antiepileptic drugs. Eur J Pharmacol 1990; 176: 75]83. 16. Noebels JL, Rutecki PA. Altered hippocampal network excitability in the hyperadrenergic mutant mouse tottering. Brain Res 1990; 524: 225]30.
Pharmacological Research, Vol. 38, No. 6, 1998
17. Lints CE, Nyquist-Battie C. A possible role of betaadrenergic receptor in the expression of audiogenic seizures. Pharmacol Biochem Beha¨ 1985; 22: 711]6. 18. Fischer W, Muller M. Pharmacological modulation of central monoaminergic systems and influence on the anticonvulsant effectiveness in maximal electroshock seizure. Biomed Biochim Acta 1988; 47: 631]5.