Callahan B T, Yuan J, Ricaurte G A
Department of Neurology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21224, USA.
Synapse. 2000 Dec 15;38(4):471-6. doi: 10.1002/1098-2396(20001215)38:4<471::AID-SYN12>3.0.CO;2-6.
The anorectic drug phentermine produces dose-related toxic effects on brain dopamine (DA) neurons in animals. Until recently, phentermine was widely used in combination with fenfluramine for purposes of appetite suppression and weight loss. With the recent withdrawal of fenfluramine from the market, many people have begun combining phentermine with fluoxetine, a serotonin reuptake inhibitor which also produces mild anorectic effects. Fluoxetine, in addition to inhibiting serotonin reuptake, inhibits hepatic mixed function oxidase, which plays an important role in the metabolic degradation of amphetamines. The purpose of the present study was to assess the effects of fluoxetine on the anorectic and DA neurotoxic effects of phentermine in mice. Phentermine, in combination with fluoxetine, produced greater reductions in food intake and body weight than phentermine alone. The phentermine/fluoxetine combination also produced greater long-term reductions in brain DA levels than phentermine alone, likely reflecting greater DA neurotoxicity of the drug combination. Brain concentrations of phentermine were also found to be higher in animals pretreated with fluoxetine. These findings indicate that fluoxetine potentiates both the anorectic and DA neurotoxic effects of phentermine, probably by increasing phentermine brain levels. The clinical significance of these findings remains to be ascertained.
食欲抑制剂苯丁胺对动物脑内多巴胺（DA）神经元产生剂量相关的毒性作用。直到最近，苯丁胺还广泛与芬氟拉明联合使用以抑制食欲和减轻体重。随着芬氟拉明近期退出市场，许多人开始将苯丁胺与氟西汀联合使用，氟西汀是一种血清素再摄取抑制剂，也有轻微的抑制食欲作用。氟西汀除了抑制血清素再摄取外，还抑制肝脏混合功能氧化酶，该酶在苯丙胺类药物的代谢降解中起重要作用。本研究的目的是评估氟西汀对小鼠中苯丁胺的抑制食欲和DA神经毒性作用的影响。苯丁胺与氟西汀联合使用时，比单独使用苯丁胺能更有效地减少食物摄入量和体重。苯丁胺/氟西汀组合还比单独使用苯丁胺能更长期地降低脑内DA水平，这可能反映了该药物组合具有更大的DA神经毒性。还发现，预先用氟西汀处理的动物脑内苯丁胺浓度更高。这些发现表明，氟西汀可能通过提高苯丁胺在脑内的水平，增强了苯丁胺的抑制食欲和DA神经毒性作用。这些发现的临床意义尚待确定。
