Neurochemical mechanisms of phentermine and fenfluramine: Therapeutic and adverse effects

Rothman, Richard B.; Baumann, Michael H.

doi:10.1002/1098-2299(200010)51:2<52::aid-ddr2>3.0.co;2-h

Cited by 22 publications

(22 citation statements)

References 117 publications

(135 reference statements)

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“…We have recently shown that aminorex, and other amphetamine‐type drugs known to increase the risk for developing primary pulmonary hypertension (fenfluramines, chlorphentermine) share the common feature of being SERT substrates 50. On the other hand, not all SERT substrates are associated with primary pulmonary hypertension, and we have argued that it will be possible to develop 5‐HT releasing agents devoid of significant pulmonary toxicity 56. Taken together, the in vitro and in vivo findings show that amphetamine‐type appetite suppressants have a wide range of activities at monoamine transporters, with each drug exhibiting its own unique profile of actions.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, both food consumption and drug self‐administration are homeostatic deficit‐driven processes. When stimulant addiction is viewed as dysregulated appetitive behavior, it seems reasonable to theorize that medications used to combat obesity (i.e., excessive food consumption) could also treat drug addiction (i.e., excessive drug intake) 37,56. Thus, we speculated that amphetamine‐type appetite suppressants might be effective in the treatment of substance‐abuse disorders.…”

Section: Introductionmentioning

confidence: 99%

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Appetite Suppressants as Agonist Substitution Therapies for Stimulant Dependence

Rothman

Blough

Baumann

2002

Annals of the New York Academy of Sciences

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Several lines of evidence support a dual‐deficit model of stimulant withdrawal in which decreases in synaptic dopamine (DA) and serotonin (5‐HT) contribute to withdrawal symptoms, drug craving, and relapse. According to the dual‐deficit model, DA dysfunction during withdrawal underlies anhedonia and psychomotor disturbances, whereas 5‐HT dysfunction gives rise to depressed mood, obsessive thoughts, and lack of impulse control. The model suggests that medications capable of normalizing stimulant‐induced DA and 5‐HT deficits should be effective treatment adjuncts. Furthermore, the model may explain why medications targeting only one neurotransmitter system (i.e., DA) have failed to treat cocaine dependence. Amphetamine‐type appetite suppressants are logical choices for neurochemical normalization therapy of stimulant dependence, yet few clinical studies have tested anorectics in this regard. The chief purpose of the present work is to profile the activity of various anorectic agents at DA, 5‐HT, and NE transporters, in order to identify possible medications for stimulant dependence. Compounds were tested in vitro for their ability to stimulate release and inhibit uptake of [3H]DA, [3H]NE, and [3H]5‐HT. Selected compounds were tested in vivo for their ability to elevate extracellular levels of DA and 5‐HT in rat nucleus accumbens. The results show that clinically available appetite suppressants display a wide range of activities at monoamine transporters. However, no single medication possesses equal potency at DA and 5‐HT transporters, suggesting that none of the anorectics is ideally suited for treatment of stimulant addictions. Future efforts should focus on developing new medications that possess the desired therapeutic activity but lack the adverse effects associated with older amphetamine‐type anorectics.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Appetite Suppressants as Agonist Substitution Therapies for Stimulant Dependence

Rothman

Blough

Baumann

2002

Annals of the New York Academy of Sciences

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“…Phentermine (Adipex-P; Teva Pharmaceuticals, Philadelphia, PA) was initially approved by the FDA in 1959. It is a sympathomimetic amine pharmacologically related to amphetamine, 22 which acts centrally as an appetite suppressant and is the most commonly prescribed medication for the management of obesity in the United States. 23 As it is a sympathomimetic, it could theoretically result in acute angle closure due to pupil block in susceptible individuals with anatomically narrow angles.…”

Section: Discussionmentioning

confidence: 99%

Bilateral Angle Closure Following Use of a Weight Loss Combination Agent Containing Topiramate

Grewal

Goldstein

Khatana

et al. 2015

Journal of Glaucoma

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“…Part of our initial rationale for the development of dual DA/5‐HT releasers was based on the knowledge that selective 5‐HT releasing agents, such as fenfluramine, lack stimulant properties and are not self‐administered 34 . Additionally, fenfluramine antagonizes locomotor and rewarding actions of DA releasers 19,30,35 . Studies using co‐administered phentermine and fenfluramine show that drug treatments producing simultaneous elevations in extracellular DA and 5‐HT produce minimal motor activity, 30 are not rewarding, 36 and are not reinforcing 37 .…”

Section: Discussionmentioning

confidence: 99%

Balance between Dopamine and Serotonin Release Modulates Behavioral Effects of Amphetamine‐Type Drugs

Rothman¹,

Baumann²

2006

Annals of the New York Academy of Sciences

112

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The abuse of illicit stimulants is a worldwide crisis, yet few medicines are available for treating stimulant addiction. We have advocated the idea of "agonist therapy" for cocaine dependence. This strategy involves administration of stimulant-like medications (e.g., monoamine releasers) to alleviate cocaine withdrawal symptoms and prevent relapse. A chief limitation of this strategy is that many candidate medicines possess high abuse liability due to activation of mesolimbic dopamine (DA) neurons in reward pathways. Evidence suggests that serotonin (5-HT) neurons can provide an inhibitory influence over mesolimbic DA neurons. Thus, it might be predicted that the balance between DA and 5-HT transmission is a critical variable when developing medications with reduced stimulant side effects. In this article, we review recent studies from our laboratory that examined neurochemical and behavioral effects of a series of monoamine releasers which displayed different potencies at DA and 5-HT transporters. The data show that increasing 5-HT release can attenuate stimulant effects mediated by DA release, such as motor stimulation and drug self-administration. Our findings support the work of others and indicate that elevated synaptic 5-HT can dampen certain behavioral effects of DA-releasing agents. Moreover, the relationship between DA and 5-HT releasing potency is an important determinant in developing new agonist medications with reduced stimulant properties.

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Neurochemical mechanisms of phentermine and fenfluramine: Therapeutic and adverse effects

Cited by 22 publications

References 117 publications

Appetite Suppressants as Agonist Substitution Therapies for Stimulant Dependence

Appetite Suppressants as Agonist Substitution Therapies for Stimulant Dependence

Bilateral Angle Closure Following Use of a Weight Loss Combination Agent Containing Topiramate

Balance between Dopamine and Serotonin Release Modulates Behavioral Effects of Amphetamine‐Type Drugs

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