Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension. (1/6)

BACKGROUND: Coadministration of phentermine and fenfluramine (phen/fen) effectively treats obesity and possibly addictive disorders. The association of fenfluramine and certain other anorexic agents with serious side effects, such as cardiac valvulopathy and primary pulmonary hypertension (PPH), limits the clinical utility of these drugs. Development of new medications that produce neurochemical effects like phen/fen without causing unwanted side effects would be a significant therapeutic breakthrough. METHODS AND RESULTS: We tested the hypothesis that fenfluramine (and other anorexic agents) might increase the risk of PPH through interactions with serotonin (5-HT) transporters. Because 5-HT transporter proteins in the lung and brain are identical, we examined, in rat brain, the effects of selected drugs on 5-HT efflux in vivo and monoamine transporters in vitro as a generalized index of transporter function. Our data show that drugs known or suspected to increase the risk of PPH (eg, aminorex, fenfluramine, and chlorphentermine) are 5-HT transporter substrates, whereas drugs that have not been shown to increase the risk of PPH are less potent in this regard. CONCLUSIONS: We speculate that medications that are 5-HT transporter substrates get translocated into pulmonary cells where, depending on the degree of drug retention, their intrinsic drug toxicity, and individual susceptibility, PPH could develop as a response to high levels of these drugs or metabolites. Emerging evidence suggests that it is possible to develop transporter substrates devoid of adverse side effects. Such medications could have therapeutic application in the management of obesity, drug dependence, depression, and other disorders.  (+info)

The metabolism, distribution and elimination of chlorphentermine in man. (2/6)

1 A gas-liquid chromatography procedure for the determination of chlorphentermine (I), N-hydroxychlorphentermine (II) and alpha,alpha-dimethyl-alpha-nitro-beta-(4-chlorophenyl)ethane (IV) in urine has been developed. Also methods are reported to determine conjugated II and the total N-oxidized metabolites of I, i.e. II, conjugated II, alpha,alpha-dimethyl-alpha-nitroso-beta-(4-chlorophenyl)ethane (III) and IV in urine. 2 The synthesis of alpha,alpha-dimethyl-alpha-nitroso-beta-(4-chlorophenyl)ethane (III) and its properties are reported. 3 The kinetics of urinary excretion of I and its metabolic products after the oral administration of I to a human subject on separate occasions have been studied. Under normal conditions of urinary pH, metabolism by N-oxidation was the main elimination route of I; acidifying the urine increased the urinary excretion of unchanged I at the expense of the N-oxidized products. 4 The importance of the N-oxidation metabolic route in the distribution of chlorphentermine (I) in man is discussed.  (+info)

N-[11C-Methyl]chlorphentermine and N,N-[11C-dimethyl]chlorphentermine as brain blood-flow agents for positron emission tomography. (3/6)

N-[11C-methyl]chlorphentermine ([11C]NMCP) and N,N-[11C-dimethyl]chlorphentermine ([11C]NDMCP) were prepared from chlorphentermine and 11CH3I in DMF and evaluated in rats as brain blood-flow agents for positron emission tomography (PET). Tissue distribution of [11C]NMCP showed that brain uptake was 2.70 +/- 0.40% of injected dose per organ at 5 min with no change in radioactivity concentration up to 30 min after i.v. injection. Approximately 80% of the initial brain uptake remained at 60 min. On the other hand, initial brain uptake of [11C] NDMCP (3.66 +/- 0.31 and 3.63 +/- 0.88% injected dose per organ at 5 and 15 min, respectively) was greater than that of [11C]NMCP. The brain activity however, rapidly decreased to 2.38 +/- 0.17 and 1.82 +/- 0.32% at 30 and 60 min, respectively. Because of its longer retention in the brain compared with [11C]NDMCP, [11C]NMCP would be a potential brain blood-flow agent for quantitative PET studies.  (+info)

Fluorescence studies of the binding of amphiphilic amines with phospholipids. (4/6)

The binding characteristics of several amine drugs with dispersed phospholipids (phosphatidylcholine, phosphatidylserine, and phosphatidylglycerol) have been studied using the fluorometric method and 1-anilino-8-naphthalene sulfonate and 1,6 diphenyl-1,3,5-hexatriene as fluorescence probes. The results show that amphiphilic amines, such as chlorphentermine, interact with phospholipids via both ionic and hydrophobic forces. The ionic interaction, which occurs between the protonated amine group of the drug and the phosphate oxygen of the lipid, changes the amphiphilic characteristics of the lipid by reducing the number of negative charges on the lipid vesicles, and inhibits the Ca2+-dependent lipid hydrolysis by blocking the Ca2+ binding sites on the lipid vesicles. The hydrophobic interaction, which involves the nonpolar moieties of the drug and the lipid, is of primary importance to the overall drug-lipid binding stability. Drugs without a strong hydrophobic moiety, such as dopamine, do not interact with phospholipids.  (+info)

Comparative potencies of amphetamine, fenfluramine and related compounds in taste aversion experiments in rats. (5/6)

1 Rats failed to drink a flavoured solution when its consumption had been followed by injection of amphetamine (conditioned taste aversion).2 There was very little difference between the potencies of (+)- and (-)-amphetamine.3p-Chloromethamphetamine was a more potent aversive agent than methamphetamine.4 Strong taste aversions were also conditioned with other congeners of amphetamine. The rank order of potency was: fenfluramine > chlorphentermine >p-hydroxyamphetamine.5 Cocaine induced only moderate taste aversions, even at high doses.6 Aversive potency did not appear to be correlated with known neurochemical actions of the drugs or with behavioural stimulation, but appeared to be a central action which may have been linked to anorexigenic potency or time course of action.  (+info)

Effect of chlorphentermine on the lipids of rat lungs. (6/6)

Chronic administration of chlorphentermine to rats resulted in a reduction of body weight compared to a normal control group. The weight of the heart, liver, kidney, and spleen was less in the treated group while the weight of the lungs was increased significantly. There was no change in the ratio of right ventricular to left ventricular weight in the rats treated with chlorphentermine, supporting the views that this drug does not cause pulmonary hypertension. Biochemical analysis showed that the increase in the weight of the lungs was due to the accumulation of phospholipid. All classes of phospholipid were affected, but particularly phosphatidyl choline, the tissue concentration of which increased nine times. Chlorphentermine also increased the proportion of palmitate present in pulmonary phosphatidyl choline. Histological examination of the lung after treatment with chlorphentermine showed evidence of this drug-induced lipidosis. No conclusion can as yet be reached as to the mechanism involved in the accumulation of phospholipid in the lung after chlorphentermine.  (+info)