Littérature scientifique sur le sujet « Fenfluramine hydrochloride »

We have analyzed the vibrational, structural, and thermal properties of a pure enantiomer of fenfluramine. At room temperature the samples, as-received or ground, are in the α-phase, in which hydrogen bonds are formed among adjacent molecules. Evidence of these H bonds is no longer found in samples which have been annealed above a critical temperature. Grain size, sample treatment, or defects influence the temperature range where the H bonds break down; this phenomenon is accompanied by thermal effects such as endothermic peaks or anomalies of heat capacity, and followed by a slow structural rearrangement into a γ-phase. No evidence of hydrogen bonds is found in the water recrystallized fenfluramine, which maintains up to the melting temperature a crystallographic form (β-form) distinct from both α - and γ-phases. It is suggested that “folded” and “extended” fenfluramine molecules are characteristic of the α- and β-phase, respectively.

Prolactin release in response to fenfluramine hydrochloride (60 mg orally) and placebo was evaluated in 18 medication-free patients with RDC major depressive disorder, endogenous subtype, before and after a series of bilateral treatments with ECT. Before ECT, fenfluramine induced a twofold increase in plasma prolactin levels. This response was significantly enhanced after the ECT series, while baseline prolactin levels and response to the placebo challenge were not altered. There was no significant difference in plasma fenfluramine and norfenfluramine levels during the pre- and post-ECT challenges. These findings suggest that ECT enhances central serotonergic responsivity and extend to depressed patients pre-clinical observations regarding the effect of electroconvulsive shock on serotonergic function.

Dravet Syndrome is a severe, drug-resistant, and rare epileptiform disorder that is typically presented in the first year of life in an otherwise healthy child. It is characterized by prolonged seizures that are often resistant to current anti-epileptic drug regimens, which made them poorly controlled, and almost 50% of patients experience at least four tonic-clonic seizures per month. There are three new medicines: stiripentol, cannabidiol, and fenfluramine, with documented efficacy and safety as adjunctive therapies in pharmacoresistant Dravet syndrome treatment. This study aimed to assess the efficacy and safety of fenfluramine in the treatment of Dravet syndrome. Our study material consisted of publications, which were found in PubMed, Google Scholar, and Embase databases. In order to find the proper publications, the search has been conducted with the use of a combination of keywords like: “fenfluramine”, “Dravet syndrome”, “epilepsy treatment”, “Dravet syndrome pediatric patients”. The first step was to find proper publications from the last 10 years. The second step was to carry out an overview of the found publications. Results of mentioned studies proved that in Dravet syndrome, fenfluramine provided a significantly greater reduction in convulsive seizure frequency compared with placebo. No patient developed valvular heart disease or pulmonary arterial hypertension, the side effects that occurred during its use were mild and the drug was generally well-tolerated. The bioequivalence and tolerability of single oral doses of fenfluramine hydrochloride oral solution in the fed and fasted states support drug administration without regard to meals. Fenfluramine may represent a new important treatment option for Dravet syndrome.

The purpose of this study was to examine the relationship between age-associated changes in central serotonergic function and abnormalities associated with major depression. Under randomized double-blind conditions, prolactin and cortisol responses to the serotonin-releasing agent d,l-fenfluramine hydrochloride (60 mg orally) and placebo were examined in 30 normal subjects (15 men, 15 women; age range 21–84 years) and 39 patients with major depressive disorder, endogenous subtype (14 men, 25 women; age range 29–72 years). In the normal subjects, a significant Age x Challenge x Time interaction was observed in the prolactin response (p = .03). This was primarily due to the elevated prolactin responses of the younger healthy women. Peak minus baseline (delta) prolactin responses were negatively correlated with age (women, p = .004; men, p = .06). In the depressed patients there was no age-related decline in prolactin response to fenfluramine. When depressed and healthy younger subjects were compared, delta prolactin responses to fenfluramine were significantly blunted in young patients with depression (p = .003) irrespective of the significant effect of gender (p = .01), but not in older depressed patients. Cortisol responses to fenfluramine did not reveal consistent effects of age, gender, or diagnosis. Age-related decline in central serotonergic function may make older individuals more vulnerable to depression and possibly render depressive episodes more frequent, more severe, and less amenable to treatment.

With obesity-related diabetes, it is possible to use biguanides, which have a slight anorectic effect. The presence of side effects in biguanides often complicates their long-term use, especially in elderly patients who have a history of chronic diseases of the lungs, heart, kidneys, and liver. In such cases, it is advisable to prescribe anorectic drugs that simultaneously affect carbohydrate metabolism.One of these drugs is p-ethyl-a-methyl-3-fluoromethylphenethylamine hydrochloride (minifage, ponderal), which has a stimulating effect on the central nervous system. Fenfluramine reduces the supply and synthesis of monoamines (5-hydroxytryptamine) in the diencephalic regions of the brain, due to which there is a decrease in food requirements and a decrease in body weight.A number of researchers have shown that the hypoglycemic effect of the drug occurs due to peripheral action. Fenfluramine affects the extraneuronal oxidation of monoamins and reduces the level of tryptophan in the blood. T. Pssquire in experiments on rats confirmed that this effect of the drug is achieved by improving the sensitivity of peripheral tissues to insulin, especially muscles.Some researchers observed a decrease in plasma fatty acids and cholesterol levels during treatment with ferfluramine.However, the issue of the effect of the drug on the residual secretion of the C-peptide of b-cells of the pancreas during treatment with fenfluramine is not covered in the literature available to us.In our study, 26 patients with obesity (the control group consisted of 18 healthy subjects who had previously impaired glucose tolerance) showed that fenfluramine restores phase I of insulin secretion on the background of an intravenous load with glucagon or glucose, and compensation for diabetes mellitus during treatment fenfluramine is apparently associated not only with a direct stimulating effect on the -cells of the islets of Langerhans but also with its peripheral effect.

A survey of approximately 4,000 questionnaires completed by parents of autistic children provided ratings on a variety of treatments and interventions. Among the biomedical treatments, the use of high-dosage vitamin B6 and magnesium (n = 318) received the highest ratings, with 8.5 parents reporting behavioral improvement to every one reporting behavioral worsening. Deanol (n = 121) was next most highly rated, with 1.8 parents reporting improvement to each one reporting worsening. Fenfluramine (n = 104) was third, with a ratio of 1.5:1. Thioridazine hydrochloride (Mellaril), by far the most often used drug on the list (n = 724), was fourth with a helped-worsened ratio of 1.4:1. The research literature on the use of vitamin B6-magnesium is briefly reviewed, and mention is made of recent findings regarding high-dosage folic acid in autism and biotin in Rett syndrome. (J Child Neurol 1988;3(Suppl):S68-S72).

ABSTRACT INTRODUCTION. Epilepsy is one of the most common chronic neurological disorders characterized by the presence of spontaneous and recurrent seizures and it affects 1% of the population worldwide. Up to 30% of patients continue to have seizures despite an adequate and well-tolerated treatment with antiepileptic drugs (ASMs), used singularly or in combination. These individuals are regarded as having refractory or drug- resistant epilepsy. In 2010, an Internationally accepted definition of refractory epilepsy was proposed by a Task Force of International League Against Epilepsy (ILAE) as “failure of adequate trials of two tolerated, appropriately chosen and used ASM schedules to achieve sustained seizure freedom”. Regardless of the advances in the field of epilepsy and the acquisition of new antiepileptic drugs, the proportion of drug-resistant patients remain unchanged. Dravet syndrome (DS) is a rare, drug-resistant, developmental epileptic encephalopathy with onset in infancy characterized by multiple types of frequent, disabling epileptic seizures, developmental delay/cognitive impairment and an increased risk of sudden unexpected death in epilepsy (SUDEP). In more than 80% of patients, a sodium voltage-gated channel alpha subunit 1 gene (SCN1A) genetic variant can be demonstrated, although diagnosis is based on clinical criteria. Idiopathic generalized epilepsies (IGEs) are the most common group of epilepsies in children and adolescents and include four well-characterized epilepsy syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and IGE with generalized tonic–clonic seizures only. Distinctive features of IGE syndromes are typical age of onset, specific generalized seizures type, normal background EEG activity and interictal generalized spike-and-wave (GSW) discharges in the absence of any brain lesion and with normal developmental skills. Lacosamide (LCM) is a third generation ASM approved by European Medicines Agency (EMA) and US Food and Drug Administration (FDA) as both monotherapy and adjunctive therapy in treatment of focal seizures, with or without bilateral tonic-clonic seizures, in patient older than 16 (EMA) or 17 (FDA) years old. Stiripentol (STP) is a third generation ASM indicated as adjunctive therapy in Dravet syndrome, whose seizures are not adequately controlled with clobazam and valproate. Fenfluramine (FFA) Hydrochloride is fourth generation ASMs, recently noticed as effective for the treatment of convulsive seizures and non-convulsive SE in DS. In the 2019, Zogenix supported an EAP of FFA in patients with a clinical diagnosis of DS, without echocardiographic signs of cardiac valve disfunction and pulmonary arterial hypertension and in June 2020 FDA approved FFA for the treatment of seizures in DS. Levetiracetam (LEV) is one of the most widely used ASMs for both adults and children. It is approved by EMA and FDA as adjunctive therapy in IGEs with myoclonic or tonic-clonic seizures in patients >12 years, as monotherapy in focal seizures in patients >16 years and as add-on therapy in focal or focal to bilateral tonic- clonic seizures in children and adults. AIM OF THE STUDY. To evaluate efficacy, long-term efficacy and tolerability of LCM, STP, FFA, or LEV in a cohort of children, adolescents and young adults with different types of refractory epilepsies, including focal and generalized forms and epileptic encephalopathies such as DS. METHODS. Patients treated with Study Drugs as therapy for different, refractory, types of epilepsy and seen at the Neuroscience Center of Excellence-Meyer Children Hospital in different period time were included in our studies. Data were retrospectively reviewed. Responder rate, relapse free survival and retention rate were calculated. Tolerability was assessed by reporting adverse events. RESULTS. Lacosamide: A total of 88 individuals (41 female) aged 4 months to 18 years (median 10.5 years; mean ± SD 10.6 ± 4.8 years) received add-on LCM treatment for refractory epilepsy. Thirty-four patients (38.6%) were responders with a median time to relapse of 48 months. Nine (26.4%) of the 34 responders were seizure-free. For all 88 patients, the probability of remaining on LCM without additional therapy was 74.4% at 6 months, 47.7% at 12 months, 27.9% at 24 months, 18.0% at 48 months, and 8.2% at 72 months of follow-up. No statistically significant differences in relapse and retention time were observed with regard to epilepsy and seizure types, duration and course of epilepsy, number and type of antiepileptic drugs (AEDs; sodium channel blockers vs others) used in add-on. The most frequent adverse events were dermatological (4/11) and behavioral (3/11). Stiripentol first study: A total of 132 individuals aged from 5 months to 43 years received add-on STP, including 30 patients with DS. The median follow-up was 14.8 months (range=4 months-18 years, interquartile range=25.72). Twenty-nine individuals (22%) received more than two ASMs. Benzodiazepines, mainly clobazam, were the most commonly used add-on drugs. Sixty-six patients (50%) were responders, and 13 of them (9.8%) were seizure-free. Responder rate was higher in the genetic etiology group (57%), especially in DS (18/30; 60%), and in patients with refractory focal onset epilepsy without bilateral tonic-clonic seizures (5/15; 33%). The median relapse-free survival was 27 months in the 66 responders. The median time to STP failure was 24.6 months in all 132 individuals. Stiripentol second study: We expanded our analysis to a larger cohort of 196 patients with long-term follow-up. We observed a responder rate of 53% including seizure freedom in 9%. Etiology was associated with sustained response over time, with DS being the etiology with the highest responder rate (64%) at 48 months compared with syndromes with other genetic causes (13%) or unknown etiology (38%). A higher responder rate over time was also observed in patients with generalized (44%) and combined focal and generalized epilepsies (28%) than in patients with focal epilepsies (20%). The highest relapse free-survival was observed when STP was initiated at the youngest age (0-4 years) or in adulthood. Fenfluramine: Levetiracetam: A total of 88 patients with IGEs aged from 3.4 to 33.8 years, started LEV as monotherapy or add-on therapy. The median follow-up was 7.3 months (range=0.5-106 months). Thirty-four individuals (46.6%) received more than two ASMs. Thirty-five patients (39.8%) were responders, and 26 of them (29.5%) were seizure-free. The median time to LEV failure was 42 months and the median retention time was 10 months in all 88 individuals. A higher retention time was observed in patient older than 14 years. Fifty- Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. seven patients changed their therapy regimen by replacing LEV with another ASMs. Fourty-two (73.4%) remained responders at the last evaluation. About patients that replaced LEV with VPA or ETS, 23/27 (85.2%) or 9/12 (75%) were responders, respectively (p=0.19). neurological/psychiatric (17/18). CONCLUSIONS. Lacosamide: This study documents a real-world progressive and significant loss Stiripentol: suggest that STP is an effective and well-tolerated therapeutic option not only in DS but also in other epilepsy syndromes with or without an established genetic etiology, with sustained response over time. Fenfluramine: Levetiracetam: This study suggests that LEV did not result in a satisfactory clinical response in IGEs, considering their known good prognosis The most frequent adverse events were of LCM efficacy over time in a pediatric population. Further prospective studies on larger populations are required to confirm the remarkable loss of LCM efficacy over time. These studies In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated. Further confirmations based on prospectively or controlled designed studies with larger population are required to confirm our data.