Development of tolerance to the CNS effects of aminoglutethimide in mice.
Initially, there is a high incidence of CNS-depressant side-effects when the aromatase inhibitor, aminoglutethimide, is used in the treatment of patients with advanced breast cancer. Tolerance to these effects develops with continued dosing. This study examines the development of tolerance to various indices of CNS depression with the drug in mice. Single doses of aminoglutethimide induced a dose-dependent depression of spontaneous locomotor activity, rotarod performance, righting reflex and body temperature and a dose-related antileptazol activity. On repeated dosing with the drug, tolerance to these various activities occurred. The tolerance was found to be dose-dependent in the rotarod and righting reflex tests and time-dependent in the locomotor and body temperature tests. Although the results do not allow a determination of whether this clearly demonstrated phenomenon in the mouse is primarily functional or dispositional, the slow onset (14 days) for complete tolerance may be indicative of a functional mechanism.
Welsh School of Pharmacy, University of Wales College of Cardiff, U.K.
B
B
Ahmad
P J
PJ
Nicholls
D000616:Aminoglutethimide / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants; D001831:Body Temperature / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D012890:Sleep / Q000187:drug effects
D000927:Anticonvulsants; D002492:Central Nervous System Depressants; D000616:Aminoglutethimide; D010433:Pentylenetetrazole