Academic Journal
Fenfluramine repurposing from weight loss to epilepsy: What we do and do not know
| العنوان: | Fenfluramine repurposing from weight loss to epilepsy: What we do and do not know |
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| المؤلفون: | Odi R., Invernizzi R. W., Gallily T., Bialer M., Perucca E. |
| المساهمون: | Odi, R., Invernizzi, R. W., Gallily, T., Bialer, M., Perucca, E. |
| سنة النشر: | 2021 |
| المجموعة: | IRIS UNIPV (Università degli studi di Pavia) |
| مصطلحات موضوعية: | Adverse effect, Appetite suppression, Chiral switch, Dexfenfluramine, Epilepsy, Fenfluramine, Pharmacodynamic, Pharmacokinetic, Seizure, Stereoselectivity |
| الوصف: | In 2020, racemic-fenfluramine was approved in the U.S. and Europe for the treatment of seizures associated with Dravet syndrome, through a restricted/controlled access program aimed at minimizing safety risks. Fenfluramine had been used extensively in the past as an appetite suppressant, but it was withdrawn from the market in 1997 when it was found to cause cardiac valvulopathy. Available evidence indicates that appetite suppression and cardiac valvulopathy are mediated by different serotonergic mechanisms. In particular, appetite suppression can be ascribed mainly to the enantiomers d-fenfluramine and d-norfenfluramine, the primary metabolite of d-fenfluramine, whereas cardiac valvulopathy can be ascribed mainly to d-norfenfluramine. Because of early observations of markedly improved seizure control in some forms of epilepsy, fenfluramine remained available in Belgium through a Royal Decree after 1997 for use in a clinical trial in patients with Dravet syndrome at average dosages lower than those generally prescribed for appetite suppression. More recently, double-blind placebo-controlled trials established its efficacy in the treatment of convulsive seizures associated with Dravet syndrome and of drop seizures associated with Lennox-Gastaut syndrome, at doses up to 0.7 mg/kg/day (maximum 26 mg/day). Although no cardiovascular toxicity has been associated with the use of fenfluramine in epilepsy, the number of patients exposed to date has been limited and only few patients had duration of exposure longer than 3 years. This article analyzes available evidence on the mechanisms involved in fenfluramine-induced appetite suppression, antiseizure effects and cardiovascular toxicity. Despite evidence that stimulation of 5-HT2B receptors (the main mechanism leading to cardiac valvulopathy) is not required for antiseizure activity, there are many critical gaps in understanding fenfluramine's properties which are relevant to its use in epilepsy. Particular emphasis is placed on the remarkable lack of publicly ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | STAMPA |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/33895186; info:eu-repo/semantics/altIdentifier/wos/WOS:000670887200010; volume:226; firstpage:107866; journal:PHARMACOLOGY & THERAPEUTICS; http://hdl.handle.net/11571/1439712; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85110306318 |
| DOI: | 10.1016/j.pharmthera.2021.107866 |
| الاتاحة: | http://hdl.handle.net/11571/1439712 https://doi.org/10.1016/j.pharmthera.2021.107866 |
| رقم الانضمام: | edsbas.EAB07B8D |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.pharmthera.2021.107866 |
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