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A Primate Model for Testing Anticonvulsant Drugs

A Primate Model for Testing Anticonvulsant Drugs Abstract Senegalese baboons (Papio papio), with a natural syndrome of photosensitive epilepsy, consistently show generalized myoclonic jerks if stimulated stroboscopically at hourly intervals, two to eight hours after the intravenous administration of allylglycine, 200 mg/kg. This provides a model for testing the acute antiepileptic effects of established or new drugs. The relationship between concentration of drug, antiepileptic action, and acute neurological toxic effects can be studied. Phenobarbital (15 mg/kg) and diazepam (0.5 to 1.5 mg/kg) were highly effective in the absence of signs of toxic reaction (plasma levels: phenobarbital sodium, 0.7 to 1.7 mg/100 ml; diazepam, μ 0.5 μg/ml). After administration of carbamazepine (30 to 40 mg/kg) and diphenylhydantoin sodium (40 to 50 mg/kg), antiepileptic action was seen, but was accompanied by severe toxic signs (nystagmus and ataxia). Sulthiame (20 to 125 mg/kg) and ethosuximide (50 to 100 mg/kg) had little antiepileptic activity and no acute toxic effects. This primate model may aid the identification of new drugs that are active against grand mal seizures and status epilepticus. References 1. Killam KF, Killam EK, Naquet R: An animal model of light sensitive epilepsy . Electroencephalogr Clin Neurophysiol 22:497-513, 1967.Crossref 2. Meldrum BS, Balzamo E: Epilepsy in the photosensitive baboon, Papio papio, and drugs acting on cerebral GABA and serotonin mechanisms, in Medical Primatology, Proceedings of the 3rd Conference of Experimental Medicine and Surgery in Primates, Lyon 1972. Basel, Switzerland, S Karger AG, 1972, pp 212-288. 3. Naquet R, Meldrum, BS: Photogenic seizures in baboons , in Purpura D, et al (eds): Experimental Models of Epilepsy . New York, Raven Press, 1972, pp 373-406. 4. Stark LG, Killam KF, Killam EK: The anticonvulsant effect of phenobarbital, diphenylhydantoin and two benzodiazepines in the baboon, Papio papio . J Pharmacol Exp Ther 173:125-132, 1970. 5. Wada JA, Terao A, Booker HE: Longitudinal correlative analysis of epileptic baboon, Papio papio . Neurology 22:1272-1285, 1972.Crossref 6. Meldrum BS, Balzano E, Gadea M, et al: Photic and drug-induced epilepsy in the baboon (Papio papio): The effects of isoniazid, thiosemicarbazide, pyridoxine and amino-oxyacetic acid . Electroencephalogr Clin Neurophysiol . 29:333-347, 1970.Crossref 7. Meldrum BS, Horton RW: Convulsive effects of 4-deoxypyridoxine and of bicuculline in photosensitive baboons (Papio papio) and in rhesus monkeys (Macaca mulatta) . Brain Res 35:419-436, 1971.Crossref 8. Horton RW, Meldrum BS: Seizures induced by allylglycine, 3-mercaptopropionic acid and 4-deoxypyridoxine in mice and photosensitive baboons and different modes of inhibition of cerebral glutamic acid decarboxylase . Br J Pharmacol 49:52-63, 1973.Crossref 9. Toseland PA, Grove J, Berry DJ: An isothermal GLC determination of the plasma levels of carbamazepine, diphenylhydantoin, phenobarbitone and primidone . Clin Chim Acta 38:321-328, 1972.Crossref 10. Olesen OV: Determination of sultiam (Ospolot) in serum and urine by thin-layer chromatography: Serum levels and urinary output in patients under long-term treatment . Acta Pharmacol Toxicol 26:22-28, 1968.Crossref 11. Berlin A, Siwers B, Agurell S, et al: Determination of bioavailability of diazepam in various formulations from steady state plasma concentration data . Clin Pharmacol Ther 13:733-744, 1972. 12. Lunde PKM, Rane A, Yaffe SJ, et al: Plasma protein binding of diphenylhydantoin in man: Interaction with other drugs and the effect of temperature and plasma dilution . Clin Pharmacol Ther 11:846-855, 1972. 13. Vajda F, et al: Brain, cerebrospinal fluid and plasma concentrations of diphenylhydantoin and phenobarbitone in man . Clin Pharmacol Ther , to be published. 14. Van Der Kleijn E, et al: Pharmacokinetics of diazepam in dogs, mice and humans . Acta Pharmacol Toxicol 29( (suppl 3) ): 109-127, 1971.Crossref 15. Garattini S, et al: Metabolic studies on benzodiazepines in various animal species , in Garattini S, Mussini E, Randall LO (eds): The Benzodiazepines . New York, Raven Press, 1973, pp 75-97. 16. Mattson RH: The benzodiazepines , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 497-516. 17. Buchthal F, Lennox-Buchthal MA: Relations of serum concentration to control of seizures , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 335-343. 18. Booker HE, Darcey B: Serum concentrations of free diphenylhydantoin and their relationship to clinical intoxication . Epilepsia 14:177-184, 1973.Crossref 19. Reynolds EH: Anticonvulsants, folic acid and epilepsy . Lancet 1:1376-1378, 1973.Crossref 20. Reynolds EH: Chronic antiepileptic toxicity . Epilepsia , to be published. 21. Sherwin AI, Robb JP: Relation of plasma levels to clinical control , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 443-448. 22. Penry JK, Porter RJ, Dreifuss FE: Relation of plasma levels to clinical control , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 431-441. 23. Houghton GW, Richens A: Inhibition of phenytoin metabolism by sulthiame in epileptic patients . Br J Clin Pharmacol 1:59-66, 1974.Crossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Neurology American Medical Association

A Primate Model for Testing Anticonvulsant Drugs

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Publisher
American Medical Association
Copyright
Copyright © 1975 American Medical Association. All Rights Reserved.
ISSN
0003-9942
eISSN
1538-3687
DOI
10.1001/archneur.1975.00490470033003
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Abstract

Abstract Senegalese baboons (Papio papio), with a natural syndrome of photosensitive epilepsy, consistently show generalized myoclonic jerks if stimulated stroboscopically at hourly intervals, two to eight hours after the intravenous administration of allylglycine, 200 mg/kg. This provides a model for testing the acute antiepileptic effects of established or new drugs. The relationship between concentration of drug, antiepileptic action, and acute neurological toxic effects can be studied. Phenobarbital (15 mg/kg) and diazepam (0.5 to 1.5 mg/kg) were highly effective in the absence of signs of toxic reaction (plasma levels: phenobarbital sodium, 0.7 to 1.7 mg/100 ml; diazepam, μ 0.5 μg/ml). After administration of carbamazepine (30 to 40 mg/kg) and diphenylhydantoin sodium (40 to 50 mg/kg), antiepileptic action was seen, but was accompanied by severe toxic signs (nystagmus and ataxia). Sulthiame (20 to 125 mg/kg) and ethosuximide (50 to 100 mg/kg) had little antiepileptic activity and no acute toxic effects. This primate model may aid the identification of new drugs that are active against grand mal seizures and status epilepticus. References 1. Killam KF, Killam EK, Naquet R: An animal model of light sensitive epilepsy . Electroencephalogr Clin Neurophysiol 22:497-513, 1967.Crossref 2. Meldrum BS, Balzamo E: Epilepsy in the photosensitive baboon, Papio papio, and drugs acting on cerebral GABA and serotonin mechanisms, in Medical Primatology, Proceedings of the 3rd Conference of Experimental Medicine and Surgery in Primates, Lyon 1972. Basel, Switzerland, S Karger AG, 1972, pp 212-288. 3. Naquet R, Meldrum, BS: Photogenic seizures in baboons , in Purpura D, et al (eds): Experimental Models of Epilepsy . New York, Raven Press, 1972, pp 373-406. 4. Stark LG, Killam KF, Killam EK: The anticonvulsant effect of phenobarbital, diphenylhydantoin and two benzodiazepines in the baboon, Papio papio . J Pharmacol Exp Ther 173:125-132, 1970. 5. Wada JA, Terao A, Booker HE: Longitudinal correlative analysis of epileptic baboon, Papio papio . Neurology 22:1272-1285, 1972.Crossref 6. Meldrum BS, Balzano E, Gadea M, et al: Photic and drug-induced epilepsy in the baboon (Papio papio): The effects of isoniazid, thiosemicarbazide, pyridoxine and amino-oxyacetic acid . Electroencephalogr Clin Neurophysiol . 29:333-347, 1970.Crossref 7. Meldrum BS, Horton RW: Convulsive effects of 4-deoxypyridoxine and of bicuculline in photosensitive baboons (Papio papio) and in rhesus monkeys (Macaca mulatta) . Brain Res 35:419-436, 1971.Crossref 8. Horton RW, Meldrum BS: Seizures induced by allylglycine, 3-mercaptopropionic acid and 4-deoxypyridoxine in mice and photosensitive baboons and different modes of inhibition of cerebral glutamic acid decarboxylase . Br J Pharmacol 49:52-63, 1973.Crossref 9. Toseland PA, Grove J, Berry DJ: An isothermal GLC determination of the plasma levels of carbamazepine, diphenylhydantoin, phenobarbitone and primidone . Clin Chim Acta 38:321-328, 1972.Crossref 10. Olesen OV: Determination of sultiam (Ospolot) in serum and urine by thin-layer chromatography: Serum levels and urinary output in patients under long-term treatment . Acta Pharmacol Toxicol 26:22-28, 1968.Crossref 11. Berlin A, Siwers B, Agurell S, et al: Determination of bioavailability of diazepam in various formulations from steady state plasma concentration data . Clin Pharmacol Ther 13:733-744, 1972. 12. Lunde PKM, Rane A, Yaffe SJ, et al: Plasma protein binding of diphenylhydantoin in man: Interaction with other drugs and the effect of temperature and plasma dilution . Clin Pharmacol Ther 11:846-855, 1972. 13. Vajda F, et al: Brain, cerebrospinal fluid and plasma concentrations of diphenylhydantoin and phenobarbitone in man . Clin Pharmacol Ther , to be published. 14. Van Der Kleijn E, et al: Pharmacokinetics of diazepam in dogs, mice and humans . Acta Pharmacol Toxicol 29( (suppl 3) ): 109-127, 1971.Crossref 15. Garattini S, et al: Metabolic studies on benzodiazepines in various animal species , in Garattini S, Mussini E, Randall LO (eds): The Benzodiazepines . New York, Raven Press, 1973, pp 75-97. 16. Mattson RH: The benzodiazepines , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 497-516. 17. Buchthal F, Lennox-Buchthal MA: Relations of serum concentration to control of seizures , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 335-343. 18. Booker HE, Darcey B: Serum concentrations of free diphenylhydantoin and their relationship to clinical intoxication . Epilepsia 14:177-184, 1973.Crossref 19. Reynolds EH: Anticonvulsants, folic acid and epilepsy . Lancet 1:1376-1378, 1973.Crossref 20. Reynolds EH: Chronic antiepileptic toxicity . Epilepsia , to be published. 21. Sherwin AI, Robb JP: Relation of plasma levels to clinical control , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 443-448. 22. Penry JK, Porter RJ, Dreifuss FE: Relation of plasma levels to clinical control , in Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs . New York, Raven Press, 1972, pp 431-441. 23. Houghton GW, Richens A: Inhibition of phenytoin metabolism by sulthiame in epileptic patients . Br J Clin Pharmacol 1:59-66, 1974.Crossref

Journal

Archives of NeurologyAmerican Medical Association

Published: May 1, 1975

References