The effect of previous d-amphetamine treatment on the disposition and lethality of fenfluramine in the rat

Hunsinger, Ronald N.; Kibbe, Arthur H.; Wilson, Marvin C.

doi:10.1016/0041-008x(85)90345-x

Cited by 7 publications

(3 citation statements)

References 17 publications

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“…The mechanism underlying this apparent synergistic effect is not clear. One distinct possibility is that chronic treatment with PHEN/FEN decreases the body fat of rats [Roth and Rowland, 1999], and this effect could act to increase plasma levels of FEN [Hunsinger et al, 1985]. Rada and Hoebel [2000] administered dFEN alone and in combination with PHEN and measured extracellular levels of DA and acetylcholine in rat nucleus accumbens.…”

Section: Recent In Vivo Findingsmentioning

confidence: 99%

Neurochemical mechanisms of phentermine and fenfluramine: Therapeutic and adverse effects

Rothman

Baumann

2000

Drug Dev. Res.

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Section: Recent In Vivo Findingsmentioning

confidence: 99%

Neurochemical mechanisms of phentermine and fenfluramine: Therapeutic and adverse effects

Rothman

Baumann

2000

Drug Dev. Res.

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“…There are data available as to whether exposure to anorexic agents similar in structure to phentermine alters fen¯uramine bioactivity. Hunsinger et al 53 reported that rats given a series of daily injections of 4.0 mgakgaday amphetamine exhibited a greater sensitivity to the toxic actions of fen relative to rats given daily injections of vehicle. Speci®cally, amphetamine preexposure lowered the Fen¯uramine ± Phentermine synergism PJ Wellman and TJ Maher LD 50 value for fen from 97 mgakg to 68 mgakg (53).…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Hunsinger et al 53 reported that rats given a series of daily injections of 4.0 mgakgaday amphetamine exhibited a greater sensitivity to the toxic actions of fen relative to rats given daily injections of vehicle. Speci®cally, amphetamine preexposure lowered the Fen¯uramine ± Phentermine synergism PJ Wellman and TJ Maher LD 50 value for fen from 97 mgakg to 68 mgakg (53). Moreover, amphetamine preexposure increased the brain levels of fen relative to that evident in rats given vehicle pretreatment.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Synergistic interactions between Fenfluramine and Phentermine

Wellman

Maher

1999

Int J Obes

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Fen-phen' refers to the off-label combination of the appetite suppressants fen¯uramine and phentermine. The rationale for the fen-phen combination was that the two drugs exerted independent actions on brain satiety mechanisms so that it was possible to use lower doses of each drug and yet retain a common action on suppressing appetite while minimizing adverse drug effects. The focus of the present review is to consider whether fen¯uramine and phentermine exert actions that are additive in nature or whether these two drugs exhibit drug-drug synergism. The fen-phen combination results in synergism for the suppression of appetite and body weight, the reduction of brain serotonin levels, pulmonary vasoconstriction and valve disease. Fen-phen synergism may re¯ect changes in the pharmacokinetics of drug distribution, common actions on membrane ion currents, or interactions between neuronal release and reuptake mechanisms with MAO-mediated transmitter degradation. The synergism between fen¯uramine and phentermine highlights the need to more completely understand the pharmacology and neurochemistry of appetite suppressants prior to use in combination pharmacotherapy for the treatment of obesity.

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The use of toxicokinetics for the safety assessment of drugs acting in the brain

Campbell

1995

Mol Neurobiol

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Pharmacological and toxicological studies undertaken on drugs that affect the brain are frequently performed in disparate species under various experimental conditions, at doses often greatly in excess of those expected to be administered to humans, and the findings are extrapolated implicitly or explicitly with scant regard to differences in the biodisposition of the drugs. Such considerations are necessary since: 1. Species; 2. Strain; 3. Gender; 4. Route; 5. Dose; 6. Frequency and time of administration; 7. Temperature; 8. Coadministration of drugs; and 9. Surgical manipulation are but some of the factors that have been shown to influence the kinetics and metabolism of drugs. This article, using MDMA and other phenylethylamines as examples, provides evidence for the need to measure the exposure of the drugs and their active metabolites in blood and brain (toxicokinetics) in order that conclusions based only on dynamic, biochemical, or histological evidence are more pertinent. Further, the combined use of toxicokinetic-dynamic modeling can lead to a better appreciation of the mechanisms involved and a more useful approach to the calculation of safety margins.

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The effect of previous d-amphetamine treatment on the disposition and lethality of fenfluramine in the rat

Cited by 7 publications

References 17 publications

Neurochemical mechanisms of phentermine and fenfluramine: Therapeutic and adverse effects

Neurochemical mechanisms of phentermine and fenfluramine: Therapeutic and adverse effects

Synergistic interactions between Fenfluramine and Phentermine

The use of toxicokinetics for the safety assessment of drugs acting in the brain

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