Influences of Epileptogenesis on Drug Adverse Effects
It is not known with certainty whether epileptogenesis alters a patient's responsiveness to antiepileptic agents. The discouraging experience with the competitive NMDA antagonist SDZ EAA-494 (d-CPP-ene)33 has brought our attention to the fact that drugs that are well tolerated by normal (healthy) volunteers can be unac-ceptably neurotoxic to epileptic patients. Some parallels can be drawn between laboratory and clinical evaluation of side effects of antiepileptic drugs. At both levels of drug development, toxicity and tolerance trials are performed in normal laboratory animals and healthy volunteers, respectively. At the laboratory level, however, it would be more appropriate (and possible!) to use epileptic animals, ideally with the type of seizures against which the drug is expected to be effective. Indeed, it has been shown that amygdala-kindled rats are more prone to show distinct neuropsy-chological abnormalities in response to administration of NMDA antagonists than age-matched nonkindled rats.18 Thus, the selective population toxicity could have been correctly predicted in the laboratory,18,34 and then confirmed during the subsequent clinical trial,33 that epileptogenesis, as mimicked by the kindling process, can lower the threshold for precipitation of some drug-induced neurological side effects.34
Further, it has been shown that some of the new prototype anticonvulsant drugs may also induce more pronounced adverse effects in kindled than in normal rats.17 This suggests that such studies may be more predictive of potential neurotoxicity. Another typical example of differences induced by epileptogenesis is that HA-966, a low-efficacy partial agonist at the glycine-insensitive site at the NMDA receptor (glycineB receptor), was devoid of significant electroencephalographic activity in normal rats,35 whereas kindled rats injected with this substance showed pronounced paroxysmal EEG activation,36 pointing to functional differences between normal and epileptic brains.
In related recent experiments we have demonstrated that neurotoxicity from NMDA antagonists in stroke patients could also be predicted using simple observational procedures in animals with middle cerebral artery (MCA) occlusion.45 MCA occluded rats showed more adverse effects (hyperlocomotion, stereotyped behavior) than age-matched, sham-lesioned animals, again demonstrating that chronic brain dysfunction may increase drug adverse effect potential and that side effects and tolerance studies on novel drugs should also be conducted in relevant animal models.
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