Additive effects on rat brain 5HT release of combining phentermine with dexfenfluramine

Prow, M. R.; Lancashire, Bill; Aspley, Sue; Heal, DJ; Kilpatrick, I.C.

doi:10.1038/sj.ijo.0801717

Cited by 11 publications

(6 citation statements)

References 21 publications

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“…In clinical studies, coadministration of serotonergic and noradrenergic drugs has led to additive weight loss . However, phentermine may be associated with increased serotonergic activity . Lorcaserin is a serotonergic agent; therefore, coadministration with phentermine could theoretically result in serotonergic events, adversely impacting safety.…”

Section: Introductioncontrasting

confidence: 40%

Coadministration of lorcaserin and phentermine for weight management: A 12‐week, randomized, pilot safety study

Smith

Garvey

Greenway

et al. 2017

Obesity

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ObjectiveTo assess the short‐term tolerability of lorcaserin alone or with two dose regimens of phentermine.MethodsThis was a 12‐week, randomized, double‐blind, pilot safety study of N = 238 nondiabetic patients with obesity or overweight with ≥1 comorbidity randomized to lorcaserin 10 mg twice daily (BID; LOR BID) alone or with phentermine 15 mg once daily (QD; LOR BID+PHEN QD) or 15 mg twice daily (LOR BID+PHEN BID). Patients reporting ≥ 1 of 9 potentially serotonergic adverse events (AEs), mean weight loss (WL), and ≥5% WL are reported.Results N = 238 were randomized, and N = 235 were treated. N = 94 reported potentially serotonergic AEs: 37.2% LOR BID, 42.3% LOR BID+PHEN QD, and 40.5% LOR BID+PHEN BID. AEs leading to discontinuation were reported approximately twice as often in the LOR BID+PHEN BID group versus the LOR BID group. Mean WL was 3.5 kg/3.3%, 7.0 kg/6.7%, and 7.6 kg/7.2% for LOR BID, LOR BID+PHEN QD, and LOR BID+PHEN BID, respectively. At least 5% WL was achieved by 28.2% LOR BID, 59.0% LOR BID+PHEN QD (P = 0.0002 vs. LOR BID), and 70.9% LOR BID+PHEN BID (P < 0.0001 vs. LOR BID) patients.ConclusionsPhentermine added to lorcaserin enhanced short‐term weight loss but did not increase incidence of potentially serotonergic AEs; however, phentermine twice daily increased discontinuation compared to both lorcaserin alone and lorcaserin plus phentermine once daily.

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Section: Introductioncontrasting

confidence: 40%

Coadministration of lorcaserin and phentermine for weight management: A 12‐week, randomized, pilot safety study

Smith

Garvey

Greenway

et al. 2017

Obesity

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“…5-HTP is not considered a serotonergic releasing agent. Phentermine acts as a weak 5-HT releaser (Prow et al, 2001;Rothman and Baumann, 2002a), and therefore may act to facilitate release of newly decarboxylated 5-HT stores following 5-HTP administration. These results indicate that this compound does not induce a similar neurotoxic profile as the previously used serotonergic anorectic drug, fenfluramine.…”

Section: Discussionmentioning

confidence: 99%

Alterations in alcohol consumption, withdrawal seizures, and monoamine transmission in rats treated with phentermine and 5-hydroxy-L-tryptophan

Halladay

Wagner

Sekowski

et al. 2006

Synapse

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We have previously shown that coadministration of the dopamine (DA) agonist phentermine plus the serotonergic agonist fenfluramine suppresses alcohol intake and withdrawal seizures in rats. In the present study, phentermine and the serotonin (5-HT) precursor, 5-hydroxy-L-tryptophan (5-HTP), were administered alone, or in combination, to rats fed on a 6% alcohol-containing diet or an isocaloric control diet. Following a 9-h withdrawal period from the alcohol-containing diet, phentermine enhanced the effects of 5-HTP on both reduction of alcohol withdrawal seizures as well as changes in striatal serotonin. Food intake was monitored for 24 h after drug treatment, and neurochemical measures were examined at various time points. Phentermine alone reduced food intake in all diet conditions, but this anorectic effect was followed by hyperphagia in control rats. Phentermine plus 5-HTP reduced the consumption of the alcohol-containing diet, while its effects on consumption of control diets were mixed. In vivo microdialysis in rat nucleus accumbens revealed that phentermine increased extracellular DA, whereas 5-HTP caused marked elevations in extracellular 5-HT. Coadministration of phentermine and 5-HTP evoked simultaneous elevations in extracellular DA and 5-HT that mirrored the effects of each drug alone. Collectively, these findings show that coadministered phentermine plus 5-HTP is effective in reducing alcohol intake and suppressing alcohol withdrawal seizures. These therapeutic actions may be related to elevations in synaptic DA and 5-HT in critical brain regions.

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“…A fixed-dose combination containing phentermine and topirimate (Qnexa) is being developed by Vivus. Phentermine, the nonselective releaser of noradrenaline, dopamine and 5-HT, 71,72,79 has been used as a short-term appetite suppressant since the 1960s. Topirimate is a marketed anticonvulsant drug and following anecdotal reports of weight loss occurring in epileptic patients, it was evaluated as a potential antiobesity drug in clinical trials.…”

Section: New Cns Approachesmentioning

confidence: 99%

A review of late-stage CNS drug candidates for the treatment of obesity

2012

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Obesity is an important causative factor in morbidity, disability and premature death. Increasing levels of obesity will impose enormous health, financial and social burdens on worldwide society unless effective interventions are implemented. For many obese individuals, diet and behavioural modification need to be supplemented by pharmacotherapy. Preclinical research has revealed a greater understanding of the complex nature of the hypothalamic regulation of food intake and has generated a wide range of new molecular targets for the development of drug candidates for obesity treatment. As shown by the clinical results that have been obtained with this next generation of therapies, some approaches, for example, fixed-dose drug combinations, have already demonstrated an ability to deliver levels of efficacy that are not achievable with the current antiobesity drug therapies. The regulatory and marketing landscape for development, registration and commercialisation of novel centrally acting drugs for treatment of obesity and related metabolic disorders has changed substantially in recent years. Now a much greater emphasis is placed on tolerability and safety, as well as efficacy. In this review we briefly describe the therapeutic approaches to tackle obesity that are in late-stage clinical development. We then discuss drugs in late-stage development for the treatment of obesity and also future directions.

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Additive effects on rat brain 5HT release of combining phentermine with dexfenfluramine

Cited by 11 publications

References 21 publications

Coadministration of lorcaserin and phentermine for weight management: A 12‐week, randomized, pilot safety study

Coadministration of lorcaserin and phentermine for weight management: A 12‐week, randomized, pilot safety study

Alterations in alcohol consumption, withdrawal seizures, and monoamine transmission in rats treated with phentermine and 5-hydroxy-L-tryptophan

A review of late-stage CNS drug candidates for the treatment of obesity

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