Dexfenfluramine and serotonin neurotoxicity: further preclinical evidence that clinical caution is indicated.
Dexfenfluramine, a drug used as an appetite suppressant in Europe, is currently under evaluation for approval in the United States. Studies in animals indicate that dexfenfluramine damages brain serotonin neurons, but have been challenged by some because of questions regarding their relevance to humans. The present studies were designed to address the three most salient questions regarding the applicability of preclinical dexfenfluramine neurotoxicity data to humans. Specifically, the present studies sought to determine: 1) whether dexfenfluramine's effects on brain serotonin neurons are transient and related to its therapeutic actions; 2) whether the p.o. route of administration affords protection against dexfenfluramine neurotoxicity; and 3) whether the mouse, an animal thought to best approximate the human with regard to dexfenfluramine metabolism, is sensitive to dexfenfluramine's neurotoxic action. Results from the present study indicate that monkeys continue to show large serotonergic deficits as long as 12 to 17 months after dexfenfluramine treatment, suggesting that dexfenfluramine's effects in nonhuman primates are persistent and unlikely to be related to its therapeutic actions. Furthermore, the present results indicate that the p.o. route of administration affords little or no protection against dexfenfluramine neurotoxicity. Finally, mice, like all other animals tested to date, were found to be susceptible to dexfenfluramine neurotoxicity. Taken together, these findings indicate that concern over possible dexfenfluramine neurotoxicity in humans is warranted, and that physicians and patients alike need to be aware of dexfenfluramine's toxic potential toward brain serotonin neurons.
McCann
U
U
Section on Anxiety and Affective Disorders, National Institute of Mental Health, Bethesda, Maryland.
Hatzidimitriou
G
G
Ridenour
A
A
Fischer
C
C
Yuan
J
J
Katz
J
J
Ricaurte
G
G
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005277:Fenfluramine / Q000633:toxicity*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012453:Saimiri; D012701:Serotonin / Q000378:metabolism*; D013045:Species Specificity
D005277:Fenfluramine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid