Norfenfluramine

Bromothymol blue (6.0...7.6) acid lipids, cholesterol glucuronides and gangliosides [241] aryloxybutanolamine derivatives [242] norfenfluramine derivatives [243] ethylamphetamines [244] in volatile mineral oil hydrocarbons [245] phospholipids [91]... 

Nitrous fiunes reagent 225, 226 Nondestructive detection 42 ff -with fluorescent reagents 44 -with iodine 46 -with pH-indicator 45 Noradrenaline 76, 240, 393 — 396 Norephedrine 76 Norfenefnne 76 Norfenfluramine derivatives 45 1 l-Nor-d -THC-9-carboxy lie acid 289,292 Novonal 339 Nucleosides 364... 

Finally, the actions of the so-called 5-HT releasing agent , if-fenfluramine, which is well known for its anorectic effects, should be mentioned here. This compound inhibits 5-HT uptake but its metabolite, if-norfenfluramine, increases 5-HT release as do high doses of (i-amphetamine. It is important to realise that this 5-HT release is independent of nerve impulses and the action of such compounds rests on their effects on the 5-HT transporters on the storage vesicles and terminal membrane. Once these drugs have been taken up into 5-HT neurons by the transporter, they cause 5-HT to leak out of its storage vesicles and, ultimately, to be extruded from the neuron by retrotransport (see below and Chapter 4 for further details). 

My second question is this You mentioned ferrfluramine. I presume you used the racemic mixture, which would mean that in the brain you would have both R and S fenfluramine and R and S norfenfluramine present. And since these differ widely in their effects on dopamine versus serotonin neuronal systems, have you studied individual enantiomers of either fenfluramine or norfenfluramine ... 

Further evidence implicating 5-HT2b receptors in drug-associated VHD came in the years following our predictions. In 2003, we used primary cultures of human heart valve interstitial cells (hVICs) to assess whether fenfluramine and/or norfenfluramine induced cell proliferation - an in vitro approximation of the proliferative lesions found in the valves of VHD patients - in a 5-HT2b receptor-dependent manner [11], Treatment of primary hVIC cultures with either fenfluramine or norfenfluramine increased biochemical indices of cell proliferation, an effect that was blocked by cotreatment with a 5-HT2b receptor-selective antagonist [11]. 

In addition to the pathways described above, nitrones can derive from condensation of a primary hydroxylamine with an aldehyde or ketone140. Under simulated biological conditions, Beckett and coworkers were able to demonstrate that primary hydroxylamines metabolically formed from amphetamine, mexiletine or norfenfluramine readily combined with ketones produced by metabolic deamination of the primary amines141. Reactions can be formulated according to equation 13, where R1 = aryl, alkyl or aralkyl, and R2 = alkyl or H. 

Key Words 3,4-Methylenedioxyamphetamine (MDA) 3,4-methylenedioxymethamphetamine (MDMA) 5-HT2B ergotamine fenfluramine methyserdige norfenfluramine pergolide pulmonary hypertension (PH) valvular heart disease (VHD). 

Setola V, Dukat M, Glennon RA, Roth BL. Molecular determinants for the interaction of the valvulopathic anorexigen norfenfluramine with the 5-HT2B receptor. Mol Pharmacol 2005 68(l) 20-33. 

Gas Chromatography. System GA—fenfluramine RI 1222, norfenfluramine RI 1133 system GB—fenfluramine RI 1158, norfenfluramine RI 1066 system GC—fenfluramine RI 1621, norfenfluramine RI 1470. 

High Pressure Liquid Chromatography. System HA—fenfluramine k 1.3, norfenfluramine k 1.0 system HC—k 0.88. 

Quantification. Gas Chromatography. In plasma or urine fenfluramine and norfenfluramine, detection limits fenfluramine 5 ng/ml and norfenfluramine lOOpg/ml in plasma, ECD— K. K. Midha era/.. Can. J.pharm. ScL, 1979,14,18-21. 

Disposition in the Body. Readily absorbed after oral administration and accumulates in the tissues. The major metabolite in the blood is the A-desethyl derivative, norfenfluramine, which is active. It is also metabolised by oxidation to m-trifluoromethyl-benzoic acid which is conjugated with glycine to form m-trifluoromethylhippuric acid. The rate of elimination is influenced by urinary pH and urinary flow. In acidic urine about 23% of a dose is excreted unchanged, and about 17% as norfenfluramine in 48 hours the remainder consists of m-trifluoromethylhippuric acid in alkaline urine about 2% is excreted as unchanged drug and norfenfluramine when the urinary pH is not controlled, 3 to 10% may be excreted as unchanged drug and 3 to 14% as norfenfluramine. Up to 5% of a dose is eliminated in the faeces as fenfluramine and norfenfluramine. 

A single oral dose of 60 mg administered to 5 subjects, resulted in a mean plasma concentration of 0.06 ig/ml of fenfluramine in 2 to 4 hours and 0.016 ig/ml of norfenfluramine in 4 to 6 hours. Steady-state plasma concentrations of 0.04 to 0.12 ig/m of fenfluramine were attained in 3 to 4 days after daily administration of 60 mg, in divided doses, to 6 subjects concentrations of norfenfluramine were similar (D. B. Campbell, Br. J. Pharmac., 1971,42, 465P-466P). 

Christensen J. D., Babb, S. M., Cohen, B. M. and Renshaw, P. F. (1998) Quantitation of dexfen-fluramine/d-norfenfluramine concentration in primate brain using 19F NMR spectroscopy. Magnetic Resonance in Medicine, 39, 149-154. 

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