{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T07:13:50Z","timestamp":1791184430507,"version":"4.1.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[1999,8,24]]},"abstract":"<jats:p><jats:italic>Background<\/jats:italic>\u2014Coadministration 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.<\/jats:p><jats:p><jats:italic>Methods and Results<\/jats:italic>\u2014We 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.<\/jats:p><jats:p><jats:italic>Conclusions<\/jats:italic>\u2014We 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.<\/jats:p>","DOI":"10.1161\/01.cir.100.8.869","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:42:29Z","timestamp":1339461749000},"page":"869-875","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":187,"title":["Aminorex, Fenfluramine, and Chlorphentermine Are Serotonin Transporter Substrates"],"prefix":"10.1161","volume":"100","author":[{"given":"Richard B.","family":"Rothman","sequence":"first","affiliation":[{"name":"From the Clinical Psychopharmacology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario A.","family":"Ayestas","sequence":"additional","affiliation":[{"name":"From the Clinical Psychopharmacology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina M.","family":"Dersch","sequence":"additional","affiliation":[{"name":"From the Clinical Psychopharmacology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Baumann","sequence":"additional","affiliation":[{"name":"From the Clinical Psychopharmacology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_1_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1992.76"},{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1998.tb08222.x"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199608293350901"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199708283370901"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199701093360207"},{"key":"e_1_3_1_6_2","doi-asserted-by":"crossref","unstructured":"Gurtner HP. Aminorex pulmonary hypertension. In: Fishman AP ed. The Pulmonary Circulation: Normal and Abnormal. Philadelphia Pa: University of Pennsylvania Press; 1990:397\u2013411.","DOI":"10.9783\/9781512801736-031"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-72305-6_11"},{"key":"e_1_3_1_8_2","first-page":"1300","volume":"27","year":"1976","unstructured":"Schnabel KF, Schulz V, Busch S, Just H. Drug-induced primary vascular pulmonary hypertension. Med Welt. 1976;27:1300\u20131303.","journal-title":"Med Welt"},{"key":"e_1_3_1_9_2","first-page":"2096","volume":"22","year":"1972","unstructured":"Lullmann H, Parwaresch MR, Sattler M, Seiler KU, Siegfriedt A. The effects of anorectic agents on the pulmonary pressure and morphology of rat lungs after chronic administration. Arzneimittelforschung. 1972;22:2096\u20132099.","journal-title":"Arzneimittelforschung"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(99)80156-9"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.1986.tb03859.x"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(94)00663-6"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1992.tb08356.x"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.94.9.2216"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.6.2542"},{"key":"e_1_3_1_16_2","unstructured":"Gillis CN. Peripheral metabolism of serotonin. In: Vanhoutte PM ed. Serotonin and the Cardiovascular System. New York NY: Raven Press; 1985:27\u201336."},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(92)90023-W"},{"key":"e_1_3_1_18_2","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1016\/S0022-3565(25)24002-2","volume":"271","year":"1994","unstructured":"Baumann MH, Char GU, de Costa BR, Rice KC, Rothman RB. GBR12909 attenuates cocaine-induced activation of mesolimbic dopamine neurons in the rat. J Pharmacol Exp Ther. 1994;271:1216\u20131222.","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/syn.890140106"},{"key":"e_1_3_1_20_2","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/S0022-3565(25)22365-5","volume":"270","year":"1994","unstructured":"Rothman RB, Cadet JL, Akunne HC, Silverthorn ML, Baumann MH, Carroll FI, Rice KC, de Costa BR, Partilla JS, Wang JB, Uhl G, Glowa JR, Dersch CM. Studies of the biogenic amine transporters, IV: demonstration of a multiplicity of binding sites in rat caudate membranes for the cocaine analog [125I]RTI-55. J Pharmacol Exp Ther. 1994;270:296\u2013309.","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_1_21_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0022-3565(25)29169-8","volume":"181","year":"1972","unstructured":"Cox RH Jr, Maickel RP. Comparison of anorexigenic and behavioral potency of phenylethylamines. J Pharmacol Exp Ther. 1972;181:1\u20139.","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/0091-3057(92)90462-O"},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-03-00960.1997"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1998.70051941.x"},{"key":"e_1_3_1_25_2","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1016\/S0026-895X(25)13357-9","volume":"44","year":"1993","unstructured":"Schuldiner S, Steiner-Mordoch S, Yelin R, Wall SC, Rudnick G. Amphetamine derivatives interact with both plasma membrane and secretory vesicle biogenic amine transporters. Mol Pharmacol. 1993;44:1227\u20131231.","journal-title":"Mol Pharmacol"},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0701325"},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm9606599"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00968412"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1987.tb05752.x"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.16.7782"},{"key":"e_1_3_1_31_2","first-page":"64","volume":"355","year":"1997","unstructured":"Xu C, Coffey LL, Reith ME. Binding domains for blockers and substrates on the dopamine transporter in rat striatal membranes studied by protection against N-ethylmaleimide-induced reduction of [3H]WIN 35,428 binding. Naunyn Schmiedebergs Arch Pharmacol. 1997;355:64\u201373.","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"e_1_3_1_32_2","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/S0026-895X(25)08574-8","volume":"47","year":"1995","unstructured":"Wall SC, Gu H, Rudnick G. Biogenic amine flux mediated by cloned transporters stably expressed in cultured cell lines: amphetamine specificity for inhibition and efflux. Mol Pharmacol. 1995;47:544\u2013550.","journal-title":"Mol Pharmacol"},{"key":"e_1_3_1_33_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1997.03550080076043"},{"key":"e_1_3_1_34_2","first-page":"L46","volume":"266","year":"1994","unstructured":"Lee SL, Wang WW, Lanzillo JJ, Fanburg BL. Serotonin produces both hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cells in culture. Am J Physiol. 1994;266:L46\u2013L52.","journal-title":"Am J Physiol"},{"key":"e_1_3_1_35_2","first-page":"2586","volume":"43","year":"1984","unstructured":"Mehendale HM. Pulmonary disposition and effects of drugs on pulmonary removal of endogenous substances. Fed Proc. 1984;43:2586\u20132591.","journal-title":"Fed Proc"},{"key":"e_1_3_1_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00499026"},{"key":"e_1_3_1_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0397-277"},{"key":"e_1_3_1_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0091-3057(97)00557-1"},{"key":"e_1_3_1_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(93)90034-Z"},{"key":"e_1_3_1_40_2","first-page":"1028","volume":"24","year":"1994","unstructured":"Baumann MH, Ayestas MA, Rothman RB. Effects of d-fenfluramine and m-chlorophenylpiperazine on acute 5-HT release and long-term 5-HT depletion in rat brain. Soc Neurosci Abstr. 1994;24:1028. Abstract.","journal-title":"Soc Neurosci Abstr"},{"key":"e_1_3_1_41_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02245142"},{"key":"e_1_3_1_42_2","first-page":"PL267","volume":"53","year":"1993","unstructured":"Rothman RB, Becketts KM, Radesca LR, de Costa BR, Rice KC, Carroll FI, Dersch CM. Studies of the biogenic amine transporters. II. A brief study on the use of [3H]DA-uptake-inhibition to transporter-binding-inhibition ratios for the in vitro evaluation of putative cocaine antagonists. Life Sci. 1993;53:PL267\u2013PL272.","journal-title":"Life Sci"},{"key":"e_1_3_1_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(89)90067-8"},{"key":"e_1_3_1_44_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-199612200-00002"},{"key":"e_1_3_1_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s002130050296"},{"key":"e_1_3_1_46_2","first-page":"482","volume":"340","year":"1999","unstructured":"Abenhaim L, Rich S, Benichou J, Begaud B. Primary pulmonary hypertension and anorectic drugs. N Engl J Med.. 1999;340:482\u2013483.","journal-title":"N Engl J Med."}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/01.CIR.100.8.869","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T21:10:56Z","timestamp":1743369056000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/01.CIR.100.8.869"}},"subtitle":["Implications for Primary Pulmonary Hypertension"],"short-title":[],"issued":{"date-parts":[[1999,8,24]]},"references-count":46,"journal-issue":{"issue":"8","published-print":{"date-parts":[[1999,8,24]]}},"alternative-id":["10.1161\/01.CIR.100.8.869"],"URL":"https:\/\/doi.org\/10.1161\/01.cir.100.8.869","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[1999,8,24]]},"assertion":[{"value":"1998-10-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"1999-04-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"1999-08-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}