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Serotonin Metabolism in Functional Somatic Illness
Published in Peter Manu, The Psychopathology of Functional Somatic Syndromes, 2020
The baseline prolactin levels were similar in the two groups and did not change significantly from the first to the second day of testing. The maximum net prolactin response measured after fenfluramine challenge was significantly lower in the premenstrual dysphoric disorder group (p < 0.02). For instance, three hours after the challenge, the net response averaged 20 ng/mL in the healthy control group, but only 7.5 ng/mL in the group with premenstrual dysphoric disorder. The magnitude of the difference persisted when the data were controlled for age, weight, and fenfluramine and norfenfluramine levels. The authors contended that the central serotonergic deficiency identified in premenstrual dysphoric disorder is specific for this condition and not a consequence of previous episodes of mood disorders. This view is supported by data demonstrating enhanced prolactin response to the fenfluramine challenge in patients with treated (O’Keane et al., 1992) and remitted depression (Shapira et al., 1993). However, data published after the completion of this study indicated that the prolactin response to fenfluramine remained abnormal at least one year after the last major depressive episode (Flory et al., 1998).
The Metabolism of Amphetamines and Related Stimulants in Animals and Man
Published in John Caldwell, S. Joseph Mulé, Amphetamines and Related Stimulants: Chemical, Biological, Clinical, and Sociological Aspects, 2019
β-Hydroxylation is a reaction apparently restricted to primary amines.2 Thus, the only β-hydroxylated metabolites found after the administration of methamphetamine are norephedrine and p-hydroxynorephedrine,12 and p-hydroxynorephedrine is the only β-hydroxylated metabolite of Pondinil.2 This metabolic route is prevented by the second α-methyl group in the side chain of the phentermines and by ring substituents, such as 3′-CF3 as in the case of norfenfluramine.2 However, smaller ring substituents, e.g., 4′-Cl and 4′-OH, permit β-hydroxylation to occur.2
The Cardiovascular System
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Calvert Louden, David Brott, Chidozie J. Amuzie, Bindu Bennet, Ronnie Chamanza
In humans, drug-induced valvulopathy has been reported with ergot alkaloids (such as methysergide and ergotamine), ergot-derived dopaminergic agonists (such as pergolide and cabergoline), appetite suppressants (such as phentermine and drugs metabolized into norfenfluramine such as fenfluramine, dexfenfluramine, and benfluorex), 3,4 methylendioxymetamphetamine (MDMA, ‘Ecstasy’), guanfacine, oxymetazoline, quinidine, xylometazoline, and fenoldapam can be associated with drug-induced valvular disease, characterized grossly by thickness, with a shiny glistening hue and/or an opaque to off-white color. The increased thickness of the valves can lead to valvular regurgitation, and has been associated with these appetite suppressants (Andrejak and Tribouilloy 2013; Connolly et al. 1997). Carcinoid heart disease is a neuroendocrine malignancy in humans, related to oncogenic enterochromaffin cells which produce abundant serotonin. The characteristic features include thickened, glistening, white valvular lesion, presence of abundant extracellular matrix of glycosaminoglycans and collagen, proliferation of myofibroblasts and SMC, with few calcifications. Inflammation is not prominent and there is no change in the structure of the valve. The pathophysiology of this condition is attributed to a sustained long-term increased secretion of vasoactive substances that includes serotonin. Long-term pergolide or serotonin administration in animal models can cause comparable morphological valve lesions, and a 5HT2B antagonist (cyproheptadine) can prevent the development of pergolide-induced valvular lesions (Droogmans et al. 2009; Raj et al. 2009). Furthermore, both phentermine and fenfluramine can cause an increase in circulating levels of serotonin (Zolkowska et al. 2006). Ergot-derived dopamine agonists, pergolide, and cabergoline used to treat Parkinson’s disease are potent agonists of serotonin 2B receptors and can produce similar valvular lesions (Pritchett et al. 2002). Because most of these drugs or their active metabolites have high affinity for the 5HT2B receptors (which are present abundantly in the aortic and mitral valve leaflets), the cardiac valvular lesions associated with dopamine agonists, appetite suppressants, MDMA, ergot alkaloids are thought to involve a similar mechanism and the 5-HT2B receptor is implicated as the culprit (Andrejak and Tribouilloy 2013; Newman-Tancredi et al. 2002). Specifically, the development of vavlular lesions is attributed to the stimulation of the 5HT2B receptors by these agonist drugs, leading to the upregulation of target genes involved in stimulation of glycosaminoglycan production and collagen synthesis, and proliferation of fibroblasts and SMC through different intracellular pathways (Andrejak and Tribouilloy 2013).
Emerging therapeutic targets for epilepsy: preclinical insights
Published in Expert Opinion on Therapeutic Targets, 2022
Krzysztof Łukawski, Stanisław J. Czuczwar
Fenfluramine, already approved for the treatment of DS [for review, 22,101], also deserves attention. Primarily used as an appetite suppressor (d-fenfluramine), it was withdrawn in 1997 due to cardiac vulvopathy caused mainly by d-norfenfluramine, a metabolite of d-fenfluramine. Interestingly, vulvopathy resulted from the stimulation of 5-HT2B receptors whilst its antiseizure activity is associated with its agonistic interaction with 5-HT1D, 5-HT2C receptors and possibly sigma-1 receptors. Its anticonvulsant efficacy was confirmed in a mutant zebrafish model of DS convulsions [22]. Clinical trials (double-blind and placebo-controlled) point to a good efficacy of fenfluramine (at daily doses up to 0.7 mg/kg) in controlling seizure activity associated with DS and also with Lennox-Gastaut syndrome [22,101]. The clinically effective dose-range was lower than that causing vulvopathy [22]. Anyway, the experimental data indicate that l-fenfluramine exerts clear cut anticonvulsant activity in the zebrafish model so a possibility exists that racemic-fenfluramine could be replaced by the l-enantiomer in the management of DS thus further reducing the risk of cardiotoxicity and loss of appetite [22]. So far, fenfluramine is recommended as an add-on therapy in patients with DS in combinations with first- or second-line AEDs [22,101].
Fenfluramine hydrochloride for the treatment of Dravet syndrome
Published in Expert Opinion on Orphan Drugs, 2020
Blandine Dozières-Puyravel, Stéphane Auvin
Fenfluramine (3‐trifluoromethyl‐N‐ethylamphetamine) was first developed and approved as an appetite suppressant, but this was withdrawn from the market in 1997 due to the identification of the risk of cardiac valvulopathy and development of pulmonary arterial hypertension (PAH) [1]. Fenfluramine is a potent 5-hydroxytryptamine (5-HT, serotonin) releaser. Norfenfluramine is an active metabolite of fenfluramine, which has a high affinity for 5-HT2B and 5-HT2C receptor subtypes [2]. The antiseizure properties of fenfluramine were initially reported in small observational studies of pediatric patients with photosensitive epilepsy, including self-induced behavior [1,3]. After the withdrawal, a Belgian royal decree (March 2002) for compassionate use allowed the prescription of fenfluramine in Dravet syndrome (DS), leading to the first real-life study as a first step for drug development [4]. This drug development initially based on clinical observation might represent one of the best examples of repurposing of a drug in the epilepsy field.
A critical evaluation of fenfluramine hydrochloride for the treatment of Dravet syndrome
Published in Expert Review of Neurotherapeutics, 2022
An-Sofie Schoonjans, Berten Ceulemans
Fenfluramine is composed of two stereoisomers, dexfenfluramine and levofenfluramine, which are N-de-ethylated in the liver to yield the active metabolites (+) and (-) norfenfluramine. Over 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6, with the possibility of additional metabolism by CYP2C9, CYP2C19, and CYP3A4. Norfenfluramine is then deaminated and oxidized to form inactive metabolites. Norfenfluramine is not a strong substrate of any CYP450 enzyme. In addition, fenfluramine and norfenfluramine do not inhibit or induce any of the CYP450 enzymes at clinically relevant concentration. Eventually, fenfluramine is primarily excreted through urine (>90%), less than 5% is found in feces.