Jump to content

Fenfluramine

From Wikipedia, the free encyclopedia
(Redirected from ZX008)

Fenfluramine
Ball-and-stick models of fenfluramine, showing the dextro isomer above and the levo isomer below
Clinical data
Trade namesSeizures: Fintepla
Weight loss: Pondimin, Ponderax, Ponderal, others
Other namesZX008; 3-Trifluoromethyl-N-ethylamphetamine
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa620045
License data
Pregnancy
category
  • AU: B2
Routes of
administration		By mouth
Drug classSerotonin–norepinephrine releasing agent; Serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonist; Anoretic; Anticonvulsant
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life13–30 hours[6]
Identifiers
  • (RS)-N-Ethyl- 1-[3-(trifluoromethyl)phenyl]propan-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.006.616 Edit this at Wikidata
Chemical and physical data
FormulaC12H16F3N
Molar mass231.262 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • CCNC(C)Cc1cccc(C(F)(F)F)c1
  • InChI=1S/C12H16F3N/c1-3-16-9(2)7-10-5-4-6-11(8-10)12(13,14)15/h4-6,8-9,16H,3,7H2,1-2H3 checkY
  • Key:DBGIVFWFUFKIQN-UHFFFAOYSA-N checkY
  (verify)

Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome.[3][7][4] It was formerly used as an appetite suppressant in the treatment of obesity, but was discontinued for this use due to cardiovascular toxicity before being repurposed for new indications.[8][9] Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.[8][10][11]

Side effects of fenfluramine in people treated for seizures include decreased appetite, somnolence, sedation, lethargy, diarrhea, constipation, abnormal echocardiogram, fatigue, malaise, asthenia, ataxia, balance disorder, gait disturbance, increased blood pressure, drooling, excessive salivation, fever, upper respiratory tract infection, vomiting, appetite loss, weight loss, falls, and status epilepticus.[3] Fenfluramine acts as a serotonin and norepinephrine releasing agent, agonist of the serotonin 5-HT2 receptors, and sigma σ1 receptor positive modulator.[12][13][14] Its mechanism of action in the treatment of seizures is unknown,[3] but may involve increased activation of certain serotonin receptors and the sigma σ1 receptor.[13][9][15] Chemically, fenfluramine is a phenethylamine and amphetamine.[12]

Fenfluramine was developed in the early 1960s and was first introduced for medical use as an appetite suppressant in France in 1963 followed by approval in the United States in 1973.[8] In the 1990s, fenfluramine came to be associated with cardiovascular toxicity, and because of this, was withdrawn from the United States market in 1997.[8][16] Subsequently, it was repurposed for the treatment of seizures and was reintroduced in the United States and the European Union in 2020.[7][4][9] Fenfluramine was previously a schedule IV controlled substance in the United States.[7] However, the substance has since no-longer been subject to control pursuant to rule-making issued on 23 December 2022.[17]

Medical uses

[edit]

Seizures

[edit]

Fenfluramine is indicated for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome in people age two and older.[3][7][4]

Dravet syndrome is a life-threatening, rare and chronic form of epilepsy.[7] It is often characterized by severe and unrelenting seizures despite medical treatment.[7]

Obesity

[edit]

Fenfluramine was formerly used as an appetite suppressant in the treatment of obesity, but was withdrawn for this use due to cardiovascular toxicity.[8]

Adverse effects

[edit]

The most common adverse reactions in people with seizures include decreased appetite; drowsiness, sedation and lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue or lack of energy; ataxia (lack of coordination), balance disorder, gait disturbance (trouble with walking); increased blood pressure; drooling, salivary hypersecretion (saliva overproduction); pyrexia (fever); upper respiratory tract infection; vomiting; decreased weight; risk of falls; and status epilepticus.[7]

The U.S. Food and Drug Administration (FDA) fenfluramine labeling includes a boxed warning stating the drug is associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH).[7] Because of the risks of VHD and PAH, fenfluramine is available only through a restricted drug distribution program, under a risk evaluation and mitigation strategy (REMS).[7] The fenfluramine REMS requires health care professionals who prescribe fenfluramine and pharmacies that dispense fenfluramine to be specially certified in the fenfluramine REMS and that patients be enrolled in the REMS.[7] As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive fenfluramine.[7]

At higher therapeutic doses, headache, diarrhea, dizziness, dry mouth, erectile dysfunction, anxiety, insomnia, irritability, lethargy, and CNS stimulation have been reported with fenfluramine.[6]

There have been reports associating chronic fenfluramine treatment with emotional instability, cognitive deficits, depression, psychosis, exacerbation of pre-existing psychosis (schizophrenia), and sleep disturbances.[6][18] It has been suggested that some of these effects may be mediated by serotonergic neurotoxicity/depletion of serotonin with chronic administration and/or activation of serotonin 5-HT2A receptors.[18][19][20][21]

Heart valve disease

[edit]

The distinctive valvular abnormality seen with fenfluramine is a thickening of the leaflet and chordae tendineae. One mechanism used to explain this phenomenon involves heart valve serotonin receptors, which are thought to help regulate growth. Since fenfluramine and its active metabolite norfenfluramine stimulate serotonin receptors, this may have led to the valvular abnormalities found in patients using fenfluramine. In particular norfenfluramine is a potent inhibitor of the re-uptake of 5-HT into nerve terminals.[22] Fenfluramine and its active metabolite norfenfluramine affect the 5-HT2B receptors, which are plentiful in human cardiac valves. The suggested mechanism by which fenfluramine causes damage is through over or inappropriate stimulation of these receptors leading to inappropriate valve cell division. Supporting this idea is the fact that this valve abnormality has also occurred in patients using other drugs that act on 5-HT2B receptors.[23][24]

According to a study of 5,743 former users conducted by a plaintiff's expert cardiologist, damage to the heart valve continued long after stopping the medication.[25] Of the users tested, 20% of women, and 12% of men were affected. For all ex-users, there was a 7-fold increase of chances of needing surgery for faulty heart valves caused by the drug.[25]

Overdose

[edit]

In overdose, fenfluramine can cause serotonin syndrome and rapidly result in death.[8][26]

Pharmacology

[edit]

Pharmacodynamics

[edit]

Fenfluramine acts primarily as a serotonin releasing agent.[27][28] It increases the level of serotonin, a neurotransmitter that regulates mood, appetite and other functions.[27][28] Fenfluramine causes the release of serotonin by disrupting vesicular storage of the neurotransmitter, and reversing serotonin transporter function.[29] The drug also acts as a norepinephrine releasing agent to a lesser extent, particularly via its active metabolite norfenfluramine.[27][28] At high concentrations, norfenfluramine, though not fenfluramine, also acts as a dopamine releasing agent, and so fenfluramine may do this at very high doses as well.[27][28] In addition to monoamine release, while fenfluramine binds only very weakly to the serotonin 5-HT2 receptors, norfenfluramine binds to and activates the serotonin 5-HT2B and 5-HT2C receptors with high affinity and the serotonin 5-HT2A receptor with moderate affinity.[30][31] The result of the increased serotonergic and noradrenergic neurotransmission is a feeling of fullness and reduced appetite.

The combination of fenfluramine with phentermine, a norepinephrine–dopamine releasing agent acting primarily on norepinephrine, results in a well-balanced serotonin–norepinephrine releasing agent with weaker effects of dopamine release.[27][28]

Fenfluramine, phentermine, and monoamine release (EC50Tooltip Half-maximal effective concentration, nM)
Drug NETooltip Norepinephrine DATooltip Dopamine 5-HTTooltip Serotonin Type Ref
Fenfluramine 739 >10,000 79.3–108 SRATooltip Serotonin–norepinephrine releasing agent [32][27][28]
  D-Fenfluramine 302 >10,000 51.7 SNRATooltip Serotonin–norepinephrine releasing agent [32][27]
  L-Fenfluramine >10,000 >10,000 147 SRA [27][33]
Norfenfluramine 168–170 1,900–1,925 104 SNRA [27][28]
Phentermine 39.4 262 3,511 NDRATooltip Norepinephrine–dopamine releasing agent [32]

Fenfluramine was identified as a potent positive modulator of the σ1 receptor in 2020 and this action may be involved in its therapeutic benefits in the treatment of seizures.[13][14]

In spite of acting as a serotonin 5-HT2A receptor agonist, fenfluramine has been described as non-hallucinogenic.[34] However, hallucinations have occasionally been reported when large doses of fenfluramine are taken.[34]

Pharmacokinetics

[edit]

The elimination half-life of fenfluramine has been reported as ranging from 13 to 30 hours.[6] The mean elimination half-lives of its enantiomers have been found to be 19 hours for dexfenfluramine and 25 hours for levfenfluramine.[8] Norfenfluramine, the major active metabolite of fenfluramine, has an elimination half-life that is about 1.5 to 2 times as long as that of fenfluramine, with mean values of 34 hours for dexnorfenfluramine and 50 hours for levnorfenfluramine.[8]

Chemistry

[edit]

Fenfluramine is a substituted amphetamine and is also known as 3-trifluoromethyl-N-ethylamphetamine.[8] It is a racemic mixture of two enantiomers, dexfenfluramine and levofenfluramine.[8] Some analogues of fenfluramine include norfenfluramine, benfluorex, flucetorex, and fludorex.

History

[edit]

Fenfluramine was developed in the early 1960s and was introduced in France in 1963.[8] Approximately 50 million Europeans were treated with fenfluramine for appetite suppression between 1963 and 1996.[8] Fenfluramine was approved in the United States in 1973.[8] The combination of fenfluramine and phentermine was proposed in 1984.[8] Approximately 5 million people in the United States were given fenfluramine or dexfenfluramine with or without phentermine between 1996 and 1998.[8]

In the early 1990s, French researchers reported an association of fenfluramine with primary pulmonary hypertension and dyspnea in a small sample of patients.[8] Fenfluramine was withdrawn from the U.S. market in 1997 after reports of heart valve disease[35][16] and continued findings of pulmonary hypertension, including a condition known as cardiac fibrosis.[36] It was subsequently withdrawn from other markets around the world. It was banned in India in 1998.[37]

Fenfluramine was an appetite suppressant which was used to treat obesity.[8] It was used both on its own and, in combination with phentermine, as part of the anti-obesity medication Fen-Phen.[8]

In June 2020, fenfluramine was approved for medical use in the United States with an indication to treat Dravet syndrome.[7][38]

The effectiveness of fenfluramine for the treatment of seizures associated with Dravet syndrome was demonstrated in two clinical studies in 202 subjects between ages two and eighteen.[7] The studies measured the change from baseline in the frequency of convulsive seizures.[7] In both studies, subjects treated with fenfluramine had significantly greater reductions in the frequency of convulsive seizures during the trials than subjects who received placebo (inactive treatment).[7] These reductions were seen within 3–4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.[7]

The U.S. Food and Drug Administration (FDA) granted the application for fenfluramine priority review and orphan drug designations.[7][39][40] The FDA granted approval of Fintepla to Zogenix, Inc.[7]

On 15 October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Fintepla, intended for the treatment of seizures associated with Dravet syndrome.[41] Fenfluramine was approved for medical use in the European Union in December 2020.[4]

Society and culture

[edit]
[edit]

Fenfluramine is a prescription medication in the US. Fenfluramine was removed from Schedule IV of the Controlled Substances Act in December 2022.[42]

Recreational use

[edit]

Unlike various other amphetamine derivatives, fenfluramine is reported to be dysphoric, "unpleasantly lethargic", and non-addictive at therapeutic doses.[43] However, it has been reported to be used recreationally at high doses ranging between 80 and 400 mg, which have been described as producing euphoria, amphetamine-like effects, sedation, and hallucinogenic effects, along with anxiety, nausea, diarrhea, and sometimes panic attacks, as well as depressive symptoms once the drug had worn off.[43][44][45] At very high doses (e.g., 240 mg, or between 200 and 600 mg), fenfluramine induces a psychedelic state resembling that produced by lysergic acid diethylamide (LSD).[45][46]

Research

[edit]

Social deficits

[edit]

Fenfluramine has been reported to improve social deficits in children with autism.[47][48] In addition, it has been found to produce prosocial behavior similarly to the entactogen MDMA in animals.[49][47] However, fenfluramine has shown limited effectiveness in treating the symptoms of autism generally.[50] Moreover, the cardiovascular toxicity and neurotoxicity of fenfluramine[51][52][53][54] make it unsuitable for clinical use in the treatment of social deficits.[47]

References

[edit]
  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ^ Anvisa (24 July 2023). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 25 July 2023). Archived from the original on 27 August 2023. Retrieved 27 August 2023.
  3. ^ a b c d e "FINTEPLA- fenfluramine solution". DailyMed. 14 December 2023. Retrieved 10 November 2024.
  4. ^ a b c d e "Fintepla EPAR". European Medicines Agency (EMA). 13 October 2020. Retrieved 8 January 2021.
  5. ^ "Fintepla Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  6. ^ a b c d Dart RC (2004). Medical Toxicology. Lippincott Williams & Wilkins. pp. 874–. ISBN 978-0-7817-2845-4. Archived from the original on 9 May 2018.
  7. ^ a b c d e f g h i j k l m n o p q r "FDA Approves New Therapy for Dravet Syndrome". U.S. Food and Drug Administration (FDA) (Press release). 25 June 2020. Retrieved 25 June 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  8. ^ a b c d e f g h i j k l m n o p q r Barceloux DG (3 February 2012). Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. John Wiley & Sons. pp. 255–262. ISBN 978-1-118-10605-1. Archived from the original on 9 May 2018.
  9. ^ a b c Odi R, Invernizzi RW, Gallily T, Bialer M, Perucca E (October 2021). "Fenfluramine repurposing from weight loss to epilepsy: What we do and do not know". Pharmacol Ther. 226: 107866. doi:10.1016/j.pharmthera.2021.107866. PMID 33895186.
  10. ^ Swiss Pharmaceutical Society (2000). Swiss Pharmaceutical Society (ed.). Index Nominum 2000: International Drug Directory. Taylor & Francis. pp. 431–432. ISBN 978-3-88763-075-1.
  11. ^ Kolata G (23 September 1997). "How Fen-Phen, A Diet 'Miracle,' Rose and Fell". New York Times. NY, NY, USA.
  12. ^ a b Rothman RB, Baumann MH (2000). "Neurochemical mechanisms of phentermine and fenfluramine: Therapeutic and adverse effects". Drug Development Research. 51 (2): 52–65. doi:10.1002/1098-2299(200010)51:2<52::AID-DDR2>3.0.CO;2-H. eISSN 1098-2299. ISSN 0272-4391. S2CID 84029575.
  13. ^ a b c Martin P, Reeder T, Sourbron J, de Witte PA, Gammaitoni AR, Galer BS (August 2021). "An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies". Int J Mol Sci. 22 (16): 8416. doi:10.3390/ijms22168416. PMC 8395113. PMID 34445144.
  14. ^ a b Martin P, de Witte PA, Maurice T, Gammaitoni A, Farfel G, Galer B (April 2020). "Fenfluramine acts as a positive modulator of sigma-1 receptors". Epilepsy Behav. 105: 106989. doi:10.1016/j.yebeh.2020.106989. PMID 32169824. S2CID 212643918.
  15. ^ Polster T (February 2019). "Individualized treatment approaches: Fenfluramine, a novel antiepileptic medication for the treatment of seizures in Dravet syndrome". Epilepsy Behav. 91: 99–102. doi:10.1016/j.yebeh.2018.08.021. PMID 30269941. S2CID 52889559.
  16. ^ a b Weissman NJ (April 2001). "Appetite suppressants and valvular heart disease". The American Journal of the Medical Sciences. 321 (4): 285–291. doi:10.1097/00000441-200104000-00008. PMID 11307869. S2CID 46466276.
  17. ^ "Schedules of Controlled Substances: Removal of Fenfluramine From Control". U.S. Federal Register. 23 December 2022.
  18. ^ a b O'Donnell J, Ahuja G (2005). Drug Injury: Liability, Analysis, and Prevention. Lawyers & Judges Publishing Company. pp. 276–. ISBN 978-0-913875-27-8.
  19. ^ Integrating the Neurobiology of Schizophrenia. Academic Press. 27 February 2007. pp. 142–. ISBN 978-0-08-047508-0.
  20. ^ The Pharmacology of Corticotropin-releasing Factor (CRF). Effects on Sensorimotor Gating in the Rat. 2006. pp. 12–. ISBN 978-0-549-53661-1.[permanent dead link‍]
  21. ^ Muller CP, Jacobs B (30 December 2009). Handbook of the Behavioral Neurobiology of Serotonin. Academic Press. pp. 630–. ISBN 978-0-08-087817-1.
  22. ^ Vickers SP, Dourish CT, Kennett GA (2001). "Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors". Neuropharmacology. 41 (2): 200–9. doi:10.1016/s0028-3908(01)00063-6. PMID 11489456. S2CID 23374227.
  23. ^ Roth BL (January 2007). "Drugs and valvular heart disease". The New England Journal of Medicine. 356 (1): 6–9. doi:10.1056/NEJMp068265. PMID 17202450.
  24. ^ Rothman RB, Baumann MH (May 2009). "Serotonergic drugs and valvular heart disease". Expert Opinion on Drug Safety. 8 (3): 317–329. doi:10.1517/14740330902931524. PMC 2695569. PMID 19505264.
  25. ^ a b Dahl CF, Allen MR, Urie PM, Hopkins PN (November 2008). "Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals". BMC Medicine. 6: 34. doi:10.1186/1741-7015-6-34. PMC 2585088. PMID 18990200.
  26. ^ Mann SC, Caroff SN, Keck PE, Lazarus A (20 May 2008). Neuroleptic Malignant Syndrome and Related Conditions. American Psychiatric Pub. pp. 111–. ISBN 978-1-58562-744-8.
  27. ^ a b c d e f g h i Rothman RB, Clark RD, Partilla JS, Baumann MH (2003). "(+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters". J. Pharmacol. Exp. Ther. 305 (3): 1191–9. doi:10.1124/jpet.103.049684. PMID 12649307. S2CID 21164342.
  28. ^ a b c d e f g Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, et al. (2003). "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Mol. Pharmacol. 63 (6): 1223–9. doi:10.1124/mol.63.6.1223. PMID 12761331. S2CID 839426.
  29. ^ Nestler EJ (2001). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. McGraw-Hill.
  30. ^ Rothman RB, Blough BE, Baumann MH (2008). "Dopamine/serotonin releasers as medications for stimulant addictions". In Di Giovanni G, Di Matteo V, Esposito E (eds.). Serotonin-dopamine Interaction: Experimental Evidence and Therapeutic Relevance. Elsevier. pp. 393–. ISBN 978-0-444-53235-0.
  31. ^ Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, et al. (2000). "Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine". Mol. Pharmacol. 57 (1): 75–81. PMID 10617681.
  32. ^ a b c Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. S2CID 15573624.
  33. ^ Rothman RB, Baumann MH (2002). "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacol. Ther. 95 (1): 73–88. doi:10.1016/s0163-7258(02)00234-6. PMID 12163129.
  34. ^ a b Gumpper RH, Roth BL (January 2024). "Psychedelics: preclinical insights provide directions for future research". Neuropsychopharmacology. 49 (1): 119–127. doi:10.1038/s41386-023-01567-7. PMC 10700551. PMID 36932180.
  35. ^ Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, et al. (August 1997). "Valvular heart disease associated with fenfluramine-phentermine". The New England Journal of Medicine. 337 (9): 581–588. doi:10.1056/NEJM199708283370901. PMID 9271479.
  36. ^ "FDA Announces Withdrawal Fenfluramine and Dexfenfluramine (Fen-Phen)". U.S. Food and Drug Administration. 15 September 1997. Archived from the original on 19 July 2013.
  37. ^ "Drugs banned in India". Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India. Archived from the original on 21 February 2015. Retrieved 17 September 2013.
  38. ^ "FDA Approves FINTEPLA (fenfluramine) for the Treatment of Seizures Associated with Dravet Syndrome" (Press release). Zogenix Inc. 25 June 2020. Retrieved 25 June 2020 – via GlobeNewswire.
  39. ^ "Fenfluramine Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 25 June 2020.
  40. ^ "Fenfluramine Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 25 June 2020.
  41. ^ "Fintepla: Pending EC decision". European Medicines Agency (EMA). 16 October 2020. Archived from the original on 21 October 2020. Retrieved 16 October 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  42. ^ "Schedules of Controlled Substances: Removal of Fenfluramine from Control". Federal Register. DEA. 23 December 2022. Retrieved 14 July 2023.
  43. ^ a b Brust JC (2004). Neurological Aspects of Substance Abuse. Butterworth-Heinemann. pp. 117–. ISBN 978-0-7506-7313-6.
  44. ^ Competitive problems in the drug industry: hearings before Subcommittee on Monopoly and Anticompetitive Activities of the Select Committee on Small Business, United States Senate, Ninetieth Congress, first session. U.S. Government Printing Office. 1976. pp. 2–.
  45. ^ a b Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence. Springer Science & Business Media. 27 November 2013. pp. 258–. ISBN 978-3-642-66709-1.
  46. ^ Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence. Springer Science & Business Media. 27 November 2013. pp. 249–. ISBN 978-3-642-66709-1.
  47. ^ a b c Heifets BD, Salgado JS, Taylor MD, Hoerbelt P, Cardozo Pinto DF, Steinberg EE, et al. (December 2019). "Distinct neural mechanisms for the prosocial and rewarding properties of MDMA". Sci Transl Med. 11 (522). doi:10.1126/scitranslmed.aaw6435. PMC 7123941. PMID 31826983. FEN has been reported to improve social deficits in children with autism (34). However, like MDMA, long-term and/or heavy use of FEN is associated with cardiovascular and neurological toxicity (1, 7, 35).
  48. ^ Aman MG, Kern RA (July 1989). "Review of fenfluramine in the treatment of the developmental disabilities". J Am Acad Child Adolesc Psychiatry. 28 (4): 549–565. doi:10.1097/00004583-198907000-00014. PMID 2670881.
  49. ^ Behera HK, Joga R, Yerram S, Karnati P, Mergu T, Gandhi K, et al. (September 2024). "Exploring the regulatory framework of psychedelics in the US & Europe". Asian J Psychiatr. 102: 104242. doi:10.1016/j.ajp.2024.104242. PMID 39305768.
  50. ^ Markopoulos A, Inserra A, De Gregorio D, Gobbi G (2021). "Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder". Front Pharmacol. 12: 749068. doi:10.3389/fphar.2021.749068. PMC 8846292. PMID 35177979. Fenfluramine, a serotonin-releasing agent, enhances serotonin signaling in the brain. While few small-sample, placebo-controlled studies found moderate efficacy in fenfluramine's ability to increase IQ in individuals with ASD (Geller et al., 1982; Ritvo et al., 1984), far more have found that this treatment is only effective in mildy reducing some of the motor and attentional atypicalities in people with ASD. This data suggests that increasing brain serotonin levels (and consequently serotonin signaling) is generally ineffective in improving the behavioural condition of individuals with ASD.
  51. ^ Kostrzewa RM (2022). "Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons". Handbook of Neurotoxicity. Cham: Springer International Publishing. pp. 159–198. doi:10.1007/978-3-031-15080-7_53. ISBN 978-3-031-15079-1.
  52. ^ McCann UD, Seiden LS, Rubin LJ, Ricaurte GA (August 1997). "Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. A systematic review of the evidence". JAMA. 278 (8): 666–672. doi:10.1001/jama.1997.03550080076043. PMID 9272900.
  53. ^ Rothman RB, Baumann MH (April 2002). "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects". Pharmacol Biochem Behav. 71 (4): 825–836. doi:10.1016/s0091-3057(01)00669-4. PMID 11888573.
  54. ^ Johnson MP, Nichols DE (May 1990). "Comparative serotonin neurotoxicity of the stereoisomers of fenfluramine and norfenfluramine". Pharmacol Biochem Behav. 36 (1): 105–109. doi:10.1016/0091-3057(90)90133-3. PMID 2140899.

Further reading

[edit]
[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=Fenfluramine&oldid=1258309393"