Quantitative Positron Emission Tomography Studies of the Serotonin Transporter in Humans Previously Treated with the Appetite Suppressants Fenfluramine or Dexfenfluramine

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• 作者：Una D. McCann (1)
  Zsolt Szabo (2)
  Melin Vranesic (2)
  Esen Seckin (2)
  Gary Wand (1) (3)
  Anna DuVal (1)
  Robert F. Dannals (2)
  George A. Ricaurte (4)
  
• 关键词：Neurotoxicity ; Serotonin ; Amphetamines
• 刊名：Molecular Imaging and Biology
• 出版年：2007
• 出版时间：May 2007
• 年：2007
• 卷：9
• 期：3
• 页码：151-157
• 全文大小：164KB
• 参考文献：1. Colman E (2005) Anorectics on trial: a half-century of federal regulation of prescription appetite suppressants. Ann Intern Med 143:380-85
  2. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV (1997) Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 337:581-88. Erratum in: N Engl J Med 337:1783 (1997 Aug 28)
  3. Harvey J, McMaster S (1975) Fenfluramine: evidence for a neurotoxic action on midbrain and a long-term depletion of serotonin. Psychopharmacol Commun 1:217-28
  4. Sanders-Bush E, Bushing JA, Sulser F (1975) Long-term effects of p-chloroamphetamine and related drugs on central serotonergic mechanisms. J Pharmacol Exp Ther 192:33-1
  5. Harvey J, McMaster S, Fuller R (1977) Comparison between the neurotoxic and serotonin depleting effects of various halogenated derivatives of amphetamine in the rat. J Pharmacol Exp Ther 202:581-89
  6. Clineschmidt B, Zachel A, Totaro J, Pflueger A, McGuffin J (1978) Fenfluramine and brain serotonin. Ann NY Acad Sci 305:222-41 ss="external" href="http://dx.doi.org/10.1111/j.1749-6632.1978.tb31526.x">CrossRef
  7. Schuster CR, Lewis M, Seiden L (1986) Fenfluramine: neurotoxicity. Psychopharmacol Bull 22:148-51
  8. Kleven MS, Schuster CR, Seiden LS (1988) Effects of depletion of brain serotonin by repeated fenfluramine on neurochemical and anorectic effects of acute fenfluramine. J Pharmacol Exp Ther 246:822-28
  9. Kleven MS, Seiden LS (1989) D-,L-, DL-fenfluramine cause long lasting depletions of serotonin in rat brain. Brain Res 505:351-53 ss="external" href="http://dx.doi.org/10.1016/0006-8993(89)91467-4">CrossRef
  10. Appel NM, Contrera JF, De Souza EB (1990) Fenfluramine selectively and differentially decreases the density of serotonergic nerve terminals in rat brain: evidence from immunocytochemical studies. J Pharmacol Exp Ther 249:928-43
  11. Johnson MP, Nichols DE (1990) Comparative serotonin neurotoxicity of the stereoisomers of fenfluramine and norfenfluramine. Pharmacol Biochem Behav 36:105-09 ss="external" href="http://dx.doi.org/10.1016/0091-3057(90)90133-3">CrossRef
  12. Molliver DC, Molliver ME (1990) Anatomic evidence of a neurotoxic effect of (-) fenfluramine upon serotonergic projections in the rat. Brain Res 511:165-68 ss="external" href="http://dx.doi.org/10.1016/0006-8993(90)90237-6">CrossRef
  13. Zaczek R, Battaglia G, Culp S, Appel NM, Contrera JF, De Souza EB (1990) Effects of repeated fenfluramine administration on indexes of monoamine function in rat brain: pharmacokinetic, dose response, regional specificity and time-course data. J Pharmacol Exp Ther 253:104-12
  14. Caccia S, Aneli M, Ferrrese A, Fracaso C, Garattini S (1993) The role of d-norfenfluramine in the indole-depleting effect of fenfluramine. Eur J Pharmacol 233:71-7 ss="external" href="http://dx.doi.org/10.1016/0014-2999(93)90350-Q">CrossRef
  15. Westphalen R, Dodd P (1995) The nature of D-L-induced 5-HT re-uptake transporter loss in rats. Mol Neurobiol 11:165-75
  16. McCann U, Hatzidimitriou G, Ridenour A, Fischer C, Yuan J, Katz J, Ricaurte G (1994) Dexfenfluramine and serotonin neurotoxicity: further preclinical evidence that clinical caution is indicated. J Pharmacol Exp Ther 269:792-98
  17. McCann UD, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA (1998) Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy- on brain serotonin neurons in human beings. Lancet 352:1433-437 ss="external" href="http://dx.doi.org/10.1016/S0140-6736(98)04329-3">CrossRef
  18. McCann UD, Szabo Z, Seckin E, Rosenblatt P, Mathews WB, Ravert HT, Dannals RF, Ricaurte GA (2005) Quantitative PET studies of the serotonin transporter in MDMA users and controls using [<sup class="a-plus-plus">11sup>C]McN5652 and [<sup class="a-plus-plus">11sup>C]DASB. Neuropsychopharmacology 30:1741-750 ss="external" href="http://dx.doi.org/10.1038/sj.npp.1300736">CrossRef
  19. Buchert R, Thomasius R, Nebeling B, Petersen K, Obrocki J, Jenicke L, Wilke F, Wartberg L, Zapletalova P, Clausen M (2003) Long-term effects of “ecstasy-use on serotonin transporters of the brain investigated by PET. J Nucl Med 44:375-84
  20. Buchert R, Thomasius R, Wilke F, Petersen K, Nebeling B, Obrocki J, Schulze O, Schmidt U, Clausen M (2004) A voxel-based PET investigation of the long-term effects of “Ecstasy-consumption on brain serotonin transporters. Am J Psychiatry 161:1181-189 ss="external" href="http://dx.doi.org/10.1176/appi.ajp.161.7.1181">CrossRef
  21. Scheffel U, Szabo Z, Mathews WB, Finley PA, Dannals RF, Ravert HT, Szabo K, Yuan J, Ricaurte GA (1998) In vivo detection of short-and long-term MDMA neurotoxicity-a positron emission tomography study in the living baboon brain. Synapse 29(2):183-92 ss="external" href="http://dx.doi.org/10.1002/(SICI)1098-2396(199806)29:2<183::AID-SYN9>3.0.CO;2-3">CrossRef
  22. Szabo Z, McCann UD, Wilson AA, Scheffel U, Owonikoko T, Mathews WB, Ravert HT, Hilton J, Dannals RF, Ricaurte GA (2002) Comparison of (+)-(11)C-McN5652 and (11)C-DASB as serotonin transporter radioligands under various experimental conditions. J Nucl Med 43:678-92
  23. Scheffel U, Szabo Z, Mathews WB, Finley PA, Yuan J, Callahan B, Hatzidimitriou G, Dannals RF, Ravert HT, Ricaurte GA (1996) Fenfluramine-induced loss of serotonin transporters in baboon brain visualized with PET. Synapse 24(4):395-98 ss="external" href="http://dx.doi.org/10.1002/(SICI)1098-2396(199612)24:4<395::AID-SYN6>3.0.CO;2-8">CrossRef
  24. Szabo Z, Scheffel U, Mathews WB, Ravert HT, Szabo K, Kraut M, Palmon S, Ricaurte GA, Dannals RF (1999) Kinetic analysis of [<sup class="a-plus-plus">11sup>C]McN5652: a serotonin transporter radioligand. J Cereb Blood Flow Metab 19:967-81 ss="external" href="http://dx.doi.org/10.1097/00004647-199909000-00004">CrossRef
  25. Wilson AA, Ginovart N, Schmidt M, Meyer JH, Threlkeld PG, Houle S (2000) Novel radiotracers for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and / in vitro and / ex vivo evaluation of (11)C-labeled 2(phenylthio)araalkylamines. J Med Chem 43:310-11
  26. Hilton J, Yokoi F, Dannals RF, Ravert HT, Szabo Z, Wong DF (2000) Column-switching HPLC for the analysis of plasma in PET imaging studies. Nucl Med Biol 27:627-30 ss="external" href="http://dx.doi.org/10.1016/S0969-8051(00)00125-6">CrossRef
  27. Szabo Z, Owonikoko T, Peyrot M, Varga J, Mathews WB, Ravert HT, Dannals RF, Wand G (2004) Positron emission tomography imaging of the serotonin transporter in subjects with a history of alcoholism. Biol Psychiatry 55:766-71 ss="external" href="http://dx.doi.org/10.1016/j.biopsych.2003.11.023">CrossRef
  28. Varga J, Szabo Z (2002) A modified regression model for the Logan plot. J Cereb Blood Flow Metab 22:240-44 ss="external" href="http://dx.doi.org/10.1097/00004647-200202000-00012">CrossRef
  29. Frankle WG, Huang Y, Hwang DR, Talbot PS, Slifstein M, Van Heertum R, Abi-Dargham A, Laruelle M (2004) Comparative evaluation of serotonin transporter radioligands 11C-DASB and 11C-McN 5652 in healthy humans. J Nucl Med 45:682-94
  30. Murphy DL, Andrews AM, Wichems CH, Li O, Tohda M, Greenberg B (1998) Brain serotonin neurotransmission: an overview and update with an emphasis on serotonin subsystem heterogeneity, multiple receptors, interactions with other neurotransmitter systems, and consequent implications for understanding the actions of serotonergic drugs. J Clin Psychiatry 59:4-2, Review
  31. Arango V, Underwood MD, Mann JJ (2002) Serotonin brain circuits involved in major depression and suicide. Prog Brain Res 136:443-53, Review ss="external" href="http://dx.doi.org/10.1016/S0079-6123(02)36037-0">CrossRef
  32. Hornung JP (2003) The human raphe nuclei and the serotonergic system. J Chem Neuroanat 26:331-43, Review ss="external" href="http://dx.doi.org/10.1016/j.jchemneu.2003.10.002">CrossRef
  33. Golding D (1970) Unusual effect of fenfluramine. Br Med J 1:238
  34. Oswald I, Lewis SA, Dunleavy DLF, Brezinova V, Briggs M (1970) Drugs of dependence though not of abuse. Br Med J 3:70-3 ss="external" href="http://dx.doi.org/10.1136/bmj.3.5766.70">CrossRef
  35. Harding T (1971) Fenfluramine dependence. Br Med J 2:305
  36. Harding T (1972) Depression following fenfluramine withdrawal. Br J Psychiatry 121:338-39
  37. Toornvliet AC, Pijl H, Meinders AE (1994) Major depression during dexfenfluramine treatment. Int J Obesity 18:650
  38. Raison CL, Klein HM (1997) Psychotic mania associated with fenfluramine and phentermine use. Am J Psychiatry 154:711
  39. Preval H, Palyurek AM (1997) Psychotic episode associated with dexfentluramine. Am J Psychiatry 154:1624-625
  40. Verbaten MN (2003) Specific memory deficits in ecstasy users. The results of a meta-analysis. Hum Psychopharmacol 18:281-90 ss="external" href="http://dx.doi.org/10.1002/hup.482">CrossRef
  41. Staley JK, Krishnan-Sarin S, Zoghbi S, Tamagnan G, Fujita M, Seibyl JP, Maciejewski PK, O’Malley S, Innis RB (2001) Sex differences in [123I]beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers. Synapse 41:275-84 ss="external" href="http://dx.doi.org/10.1002/syn.1084">CrossRef
  42. Staley JK, Sanacora G, Tamagnan G, Maciejewski PK, Malison RT, Berman RM, Vythilingam M, Kugaya A, Baldwin RM, Seibyl JP, Charney D, Innis RB (2006) Sex differences in diencephalon serotonin transporter availability in major depression. Biol Psychiatry 59:40-7 ss="external" href="http://dx.doi.org/10.1016/j.biopsych.2005.06.012">CrossRef
  
• 作者单位：Una D. McCann (1)
  Zsolt Szabo (2)
  Melin Vranesic (2)
  Esen Seckin (2)
  Gary Wand (1) (3)
  Anna DuVal (1)
  Robert F. Dannals (2)
  George A. Ricaurte (4)
  
  1. Department of Psychiatry and Behavioral Sciences, The Johns Hopkins School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD, 21224, USA
  2. Department of Radiology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
  3. Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA
  4. Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
  

文摘

Purpose The appetite suppressants fenfluramine and dexfenfluramine were widely prescribed before being withdrawn from the market in 1997. Both drugs are known to have the potential to damage brain serotonin (5-HT) axons and axon terminals in animals, including nonhuman primates. This study used quantitative positron emission tomography (PET) with [11C] McN5652, a serotonin transporter (SERT) ligand to determine whether humans previously exposed to fenfluramines showed reductions in SERT binding parameters. Procedures Subjects previously treated with fenfluramines for weight loss (N--5) and age-matched controls (N--7) underwent PET studies with [11C] McN5652. Global and regional distribution volumes (DVs) of [11C] McN5652 were compared in the two subject groups using parametric statistical analyses. Results Compared to controls, subjects previously exposed to fenfluramines had significant reductions in [11C]McN5652 binding in 14 of 15 regions of interest, more than four years after drug discontinuation. Conclusions These results are the first to provide direct evidence for fenfluramine-induced 5-HT neurotoxicity in humans.