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Conclusion
Published in Jay A. Goldstein, Chronic Fatigue Syndromes, 2020
Ondansetron, a 5HT3 receptor antagonist, blocks the pyrogenic effects of IL-1 beta. Since IL-1 can also cause gastric stasis as a central effect, 22 it may also produce nausea by a similar mechanism. Pre- and post-treatment cortisols in CFS patients with intractable nausea who have received ondansetron do not change. As previously noted, fenfluramine, a 5HT agonist, has not benefitted my patients.
Serotonin Metabolism in Functional Somatic Illness
Published in Peter Manu, The Psychopathology of Functional Somatic Syndromes, 2020
A similar assessment of the serotonin function in chronic fatigue syndrome was published the same year by Canadian investigators from Dalhousie University, Halifax, Nova Scotia (Yatham et al., 1995). The sample comprised 11 patients and 11 age- and gender-matched healthy control subjects. Nine of the 11 chronic fatigue patients had a current or past psychiatric diagnosis. The experimental procedure required the oral administration of 60 mg of dl-fenfluramine. Blood samples for prolactin and cortisol were obtained at baseline and hourly for five hours after the ingestion of fenfluramine.
Obesity
Published in Geoffrey P. Webb, Nutrition, 2019
Up until 1997, fenfluramine and dexfenfluramine were the most widely used anti-obesity drugs in the UK and Europe. They act to increase the activity of the nerve transmitter serotonin or 5HT (5-hydroxytryptamine) in the brain. They block the re-uptake of serotonin which is the normal mechanism for inactivation of this transmitter after its release. When serotonin (5HT) is injected into the brains of animals, it also decreases feeding. These drugs mimic the actions of serotonin but do not have the addictive dopamine-like effects of the amphetamines. They act not by reducing the desire to eat but by causing the patient to feel full or satiated earlier. Fenfluramine was in use for about 30 years and tens of millions of Europeans took these drugs over that period (over 60,000 Britons in 1996 alone). In 1996, they were finally approved by the FDA for use in the USA. Long-term studies of over a year have reported significantly greater weight loss in people treated with drug and diet as compared to diet and placebo. Rare but potentially fatal side effects of these drugs had been known for some time (pulmonary hypertension), and there were suggestions from animal experiments that they may damage serotonin-producing brain cells. However, in 1997 new evidence was produced in the USA suggesting that they might cause damage to heart valves. This led to both drugs being withdrawn from the market in both Europe and the USA.
Current and future pharmacotherapy options for drug-resistant epilepsy
Published in Expert Opinion on Pharmacotherapy, 2022
Fenfluramine (3-trifluoromethyl-N-ethylamphetamine) was initially launched as an appetite suppressant in the 1970s but it was subsequently withdrawn from the market because of the increased risk of valvular heart disease as a side effect [57]. Orphan designation was granted by the EMA for fenfluramine for the treatment of Dravet syndrome in 2013. Currently, fenfluramine is only indicated for Dravet syndrome but studies are currently ongoing for LGS. It is a serotonin-releasing agent with its major active metabolite (norfenfluramine) binding to and activating 5-hydroxytryptamine receptors 2B and 2C with high affinity and 2A with moderate affinity [58]. Evidence from two RCTs in patients with Dravet Syndrome has demonstrated that adjunctive fenfluramine decreased convulsive motor seizures relative to placebo and was generally well tolerated [59,60]. Fenfluramine was also found to improve quality of life in children taking it compared to placebo [60]. As already alluded to, fenfluramine has been trialed in children with LGS in a pilot study, demonstrating more than a 50% reduction in convulsive seizures in most patients [61]. The most common serious adverse event was status epilepticus resulting in hospital admission [59–61] but most adverse events were otherwise minor and included reduced appetite, somnolence, weight loss and fatigue. Large multicenter international studies of fenfluramine in LGS are pending.
A critical evaluation of fenfluramine hydrochloride for the treatment of Dravet syndrome
Published in Expert Review of Neurotherapeutics, 2022
An-Sofie Schoonjans, Berten Ceulemans
More recently, in June 2020, the FDA approved fenfluramine for the treatment of seizures in patients with DS. Marketing approval from EMA followed in December 2020. Fenfluramine was identified in the mid-1960s as an anorectic drug and was approved globally for the treatment of obesity in 1973 [27]. It was often used in combination with phentermine (Phen-Fen). However, due to reports of cardiac valvulopathy and pulmonary hypertension, it was withdrawn from the market in 1997, since the possible risk outweighed the benefit in the treatment of obesity [28,29]. A Belgian Royal Decree permitted the continuation of low dose fenfluramine treatment in a trial for DS patients with refractory epilepsy. The investigator-initiated trials showed a remarkable efficacy and safety in this drug-resistant DS, results that have now been replicated in well-designed phase III studies.
Fenfluramine hydrochloride for the treatment of Dravet syndrome
Published in Expert Opinion on Orphan Drugs, 2020
Blandine Dozières-Puyravel, Stéphane Auvin
In 2016, the long-term use of fenfluramine in the same group of patients was reported. Ten of twelve patients continued to receive fenfluramine. Then, they were prospectively followed (2010–2014) [19]. The mean total treatment duration was 16.1 years (range, 6–27 years) (age, 7–40 years). The mean daily dose of fenfluramine was 0.27 mg/kg/day (range, 0.13–0.46 mg/kg/day with a maximum dose of 20 mg). The concomitant treatments were valproate in all patients, topiramate in five patients, benzodiazepines in four patients, and lamotrigine in two patients. Among this cohort, three patients were seizure-free for at least 5 years, and four patients were seizure-free for at least 2 years. Nine of ten patients had a mean seizure frequency <1 per month over the entire long-term observational study. Anorexia was reported in two patients. Two patients had behavioral problems that were not related to the use of fenfluramine according to the authors. During the 5-year observation period, a slight thickening of one or more cardiac valves was reported in six patients, but this valve thickening was inconsistent over time in four patients. Finally, only two patients showed slight valve thickening that remained stable over the study period without any valve dysfunction or any sign of PAH [19].