No abstract

OBJECTIVE AND DESIGN:It has been proposed that the anti-obesity agent, phentermine, may act in part via inhibition of monoamine oxidase (MAO). The ability of phentermine to inhibit both MAO A and MAO B in vitro has been examined along with that of the fenfluramine isomers, a range of selective serotonin reuptake inhibitors and sibutramine and its active metabolites. RESULTS: In rat brain, harmaline and lazabemide showed potent and selective inhibition of MAO A and MAO B , their respective target enzymes, with IC 50 values of 2.3 and 18 nM. In contrast, all other drugs examined were only weak inhibitors of MAO A and MAO B with IC 50 values for each enzyme in the moderate to high micromolar range. For MAO A , the IC 50 for phentermine was estimated to be 143 mM, that for S( þ )-fenfluramine, 265 mM and that for sertraline, 31 mM. For MAO B , example IC 50 s were as follows: phentermine (285 mM), S( þ )-fenfluramine (800 mM) and paroxetine (16 mM). Sibutramine was unable to inhibit either enzyme, even at its limit of solubility. CONCLUSION: We therefore suggest that MAO inhibition is unlikely to play a role in the pharmacodynamic properties of any of the tested drugs, including phentermine. Instead, the lack of potency of these drugs as MAO inhibitors is contrasted with their powerful ability either to inhibit the uptake of one or more monoamines (fluoxetine, paroxetine, sertraline, sibutramine's active metabolites) or to evoke the release of one or more monoamines (S( þ )-fenfluramine, S( þ )-norfenfluramine, phentermine). These differences in mode of action may be linked to the adverse cardiovascular events experienced with some of the releasing agents.

OBJECTIVE AND DESIGN:This study examined the effects of the anti-obesity agents, phentermine and dexfenfluramine given alone or in combination, on in vitro and in vivo 5HT release from rat brain tissue. RESULTS: In vitro, phentermine was without effect on basal [ 3 H]5HT efflux from hypothalamic slices whereas dexfenfluramine (10 mM) evoked a 131% increase in [ 3 H]5HT release. In combination, the two drugs did not alter [ 3 H]5HT release beyond that caused by dexfenfluramine alone. At pharmacologically equivalent doses, phentermine (5.7 mg=kg, i.p.) caused a rapid, modest elevation, and dexfenfluramine (3 mg=kg, i.p.) a larger but equally rapid elevation of extracellular 5HT in the microdialysates from the rat anterior hypothalamus. In combination, the increase in extracellular 5HT evoked by these drugs was not significantly greater than the sum of their individual effects. CONCLUSIONS: This study provides evidence that phentermine's actions are not restricted to catecholamine systems and indicates that combining phentermine with dexfenfluramine results in an additive increase in neuronal 5HT release.