Page last updated: 2024-12-05

fenfluramine

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Description

Fenfluramine is a serotonin-releasing agent that was once used as an appetite suppressant. It was synthesized in the 1970s and gained popularity in the 1990s as a weight-loss drug. Fenfluramine was effective in promoting weight loss, but it was withdrawn from the market in 1997 after studies showed that it could cause serious heart valve problems. Fenfluramine is still studied today because it has potential as a treatment for obesity and other conditions, such as binge eating disorder. Researchers are investigating ways to modify the drug to reduce its side effects while preserving its therapeutic benefits.'

Fenfluramine: A centrally active drug that apparently both blocks serotonin uptake and provokes transport-mediated serotonin release. [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]

fenfluramine : A secondary amino compound that is 1-phenyl-propan-2-amine in which one of the meta-hydrogens is substituted by trifluoromethyl, and one of the hydrogens attached to the nitrogen is substituted by an ethyl group. It binds to the serotonin reuptake pump, causing inhbition of serotonin uptake and release of serotonin. The resulting increased levels of serotonin lead to greater serotonin receptor activation which in turn lead to enhancement of serotoninergic transmission in the centres of feeding behavior located in the hypothalamus. This suppresses the appetite for carbohydrates. Fenfluramine was used as the hydrochloride for treatment of diabetes and obesity. It was withdrawn worldwide after reports of heart valve disease and pulmonary hypertension. [Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

Cross-References

ID SourceID
PubMed CID3337
CHEMBL ID87493
CHEBI ID5000
SCHEMBL ID16215
MeSH IDM0008328

Synonyms (102)

Synonym
fintepla
AC-16024
z-008
obedrex
brabafen
ponderax pa
s-768
pesos
fenfluramin
CHEMBL87493
phenfluramine
zx008
acino
z008
j5.760f ,
zx-008
rotondin
phenethylamine, n-ethyl-.alpha.-methyl-m-(trifluoromethyl)-
benzeneethanamine, n-ethyl-.alpha.-methyl-3-(trifluoromethyl)-
KBIO1_000980
DIVK1C_000980
n-ethyl-1-[3-(trifluoromethyl)phenyl]propan-2-amine
dea no. 1670
n-ethyl-alpha-methyl-3-trifluoromethylphenethylamine
fenfluraminum [inn-latin]
s 768
pondimin
phenethylamine, n-ethyl-alpha-methyl-m-(trifluoromethyl)-
fenfluramina [dcit]
2-ethylamino-1-(3-trifluoromethylphenyl)propane
n-ethyl-alpha-methyl-m-(trifluoromethyl)phenethylamine
1-(meta-trifluoromethyl-phenyl)-2 ethylaminopropane
brn 4783711
3-(trifluoromethyl)-n-ethyl-alpha-methylphenethylamine
fenfluramine [inn:ban]
hsdb 3080
benzeneethanamine, n-ethyl-alpha-methyl-3-(trifluoromethyl)-
ponderax
(+-)-fenfluramine
n-ethyl-alpha-methyl-3-(trifluoromethyl)benzeneethanamine
einecs 207-276-3
PRESTWICK_868
C06996
fenfluramine
458-24-2
NCGC00159473-02
fenfluramina
DB00574
NINDS_000980
IDI1_000980
NCGC00159473-04
NCGC00159473-03
ethyl-[1-methyl-2-(3-trifluoromethyl-phenyl)-ethyl]-amine
1-(m-trifluoromethyl-phenyl)-2-ethylaminopropane
fenfluraminum
CHEBI:5000 ,
n-ethyl-1-(3-(trifluoromethyl)phenyl)propan-2-amine
L000742
ponderax (tn)
fenfluramine (inn)
D07945
NCGC00159473-05
2ds058h2cf ,
unii-2ds058h2cf
dl-fenfluramine
cas-458-24-2
dtxsid4023044 ,
tox21_111697
dtxcid103044
bdbm84738
nsc_3337
fenfluramine (-)
fenfluramine (+)
cas_16105-77-4
AKOS011892098
25990-46-9
n-ethyl-.alpha.-methyl-m-(trifluoromethyl)phenethylamine
fenfluramine [vandf]
n-ethyl-.alpha.-methyl-3-(trifluoromethyl)benzeneethanamine
fenfluramine [hsdb]
fenfluramine [who-dd]
fenfluramine [mi]
fenfluramine [inn]
gtpl4613
ethyl({1-[3-(trifluoromethyl)phenyl]propan-2-yl})amine
SCHEMBL16215
fenfluraminehydrochloride
ponderex (salt/mix)
fenfluramine hydrochloride (salt/mix)
pondimin (salt/mix)
n-ethyl-.alpha.-methyl-m-(trifluoromethyl)phenethylamine hydrochloride (salt/mix)
n-ethyl-1-[3-(trifluoromethyl)phenyl]-2-propanamine #
n-ethyl-.alpha.-methyl-3-trifluoromethylphenethylamine
adipomin (salt/mix)
3-(trifluoromethyl)-n-ethyl-.alpha.-methylphenethylamine
fenfluramine hydrochloride 100 microg/ml in acetonitrile
Q418928
FT-0770401
a08aa02
ethyl-(1-methyl-2-(3-trifluoromethyl-phenyl)-ethyl)-amine
fenfluraminum (inn-latin)
dexfenfluramine|fenfluramine

Research Excerpts

Overview

Fenfluramine is a new ASM for the treatment of seizures associated with DS as add-on therapy to other ASMs for patients aged 2 years and older. It is an effective antiepileptic drug for pediatric patients with Dravet syndrome, demonstrating clinically meaningful reduction in convulsive frequency.

ExcerptReferenceRelevance
"Fenfluramine is a new ASM for the treatment of seizures associated with DS as add-on therapy to other ASMs for patients aged 2 years and older."( The contribution of fenfluramine to the treatment of Dravet syndrome in Spain through Multi-Criteria Decision Analysis.
Abad-Sazatornil, MR; Aibar, JÁ; Aras, LM; Cardenal-Muñoz, E; Falip, M; Gil, A; Gil-Nagel, A; Poveda, JL; Sánchez, R; Sánchez-Carpintero, R; Sancho-López, A; Torrejón, M; Trillo-Mata, JL, 2022
)
1.77
"Fenfluramine is an effective antiepileptic drug for pediatric patients with Dravet syndrome, demonstrating clinically meaningful reduction in convulsive frequency, and generally could be well tolerated."( Efficacy and safety of fenfluramine in patients with Dravet syndrome: A meta-analysis.
Li, W; Wang, C; Zhang, L, 2021
)
2.37
"Fenfluramine appears to be a safe and efficacious antiseizure medication in patients with Dravet syndrome."( Efficacy and tolerability of fenfluramine in patients with Dravet syndrome: A systematic review and meta-analysis.
Dawman, L; Joshi, K; Kasinathan, A; Panda, P; Panda, PK; Sharawat, IK, 2021
)
2.36
"Fenfluramine is a drug that enhances serotonin release in the brain."( Fenfluramine, a serotonin-releasing drug, prevents seizure-induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP.
Faingold, CL; Tupal, S, 2019
)
2.68
"d-Fenfluramine is a 5-HT releasing drug, frequently used in the study of the responsivity of the 5-HT system in subjects with psychiatric disorders, including depression."( Acute challenge with d-fenfluramine decreases regional cerebral glucose utilization in Sham, but not in OBX, rats: an autoradiographic study.
Diksic, M; Sato, H; Skelin, I, 2010
)
1.23
"Fenfluramine is an amphetamine-like drug that has been used in the past as a part of antiobesity treatments."( Successful use of fenfluramine as an add-on treatment for Dravet syndrome.
Boel, M; Ceulemans, B; Jorens, PG; Lagae, L; Leyssens, K; Neels, P; Van Rossem, C, 2012
)
1.43
"Fenfluramine (FEN) is an amphetamine derivative with anorectic properties similar to amphetamine, but without the stimulatory or abuse potential. "( Administration of D,L-fenfluramine to rats produces learning deficits in the Cincinnati water maze but not the Morris water maze: relationship to adrenal cortical output.
McCrea, AE; Morford, LL; Vorhees, CV; Williams, MT; Wood, SL,
)
1.89
"Fenfluramine (FEN) is a substituted amphetamine known for its anorectic effects, without the stimulatory or abuse potential associated with other amphetamine derivatives. "( Metyrapone attenuates the sequential learning deficits but not monoamine depletions following d,l-fenfluramine administration to adult rats.
Blankenmeyer, TL; Brown-Strittholt, CA; Gudelsky, GA; Skelton, MR; Vorhees, CV; Williams, MT, 2004
)
1.98
"Fenfluramine is a valuable tool in neuroendocrinological studies, dealing with serotoninergic mechanisms."( Depending on the stimulus, central serotoninergic activation by fenfluramine blocks or does not alter growth hormone secretion in man.
Cabezas-Cerrato, J; Casanueva, FF; Peñalva, A; Villanueva, L, 1984
)
1.23
"d-Fenfluramine is a 5-HT agonist which decreases food intake and excessive carbohydrate intake in humans. "( A placebo-controlled trial of d-fenfluramine in bulimia nervosa.
Eisler, I; Fahy, TA; Russell, GF, 1993
)
1.29
"d-Fenfluramine is an appetite suppressant drug that acts by releasing serotonin from axon terminals and inhibiting its reuptake. "( d-fenfluramine in a rat model of dietary fat-induced obesity.
Bray, GA; Fisler, JS; Underberger, SJ; York, DA, 1993
)
1.73
"Fenfluramine is an anorectic drug widely used for the regulation of food intake that presents some adverse effects at the central and peripheral levels. "( Chronic fenfluramine treatment of rats with different ages: effects on brain oxidative stress-related parameters.
Azzalis, LA; Camarini, R; Carlini, EA; D'Almeida, V; Junqueira, VB, 1996
)
2.17
"D-Fenfluramine is a drug that acutely releases 5-HT into the synaptic cleft and blocks its reuptake."( Sensitive measurement of agonist-stimulated [3H]inositol monophosphate accumulation in rat cortical miniprisms.
Erfurth, A; Wurtman, RJ, 1997
)
0.86
"Fenfluramine (FE) is a halogenated amphetamine derivative used in the treatment of obesity and thought to induce serotonin (5-HT) release from nerve terminals and to reduce re-uptake. "( Interaction between the serotonergic, dopaminergic, and glutamatergic systems in fenfluramine-induced Fos expression in striatal neurons.
Guerra, MJ; Labandeira-Garcia, JL; Liste, I, 1998
)
1.97
"d-Fenfluramine-induced HTR, is a 5-HT2A receptor-mediated phenomenon and its induction frequency can be regarded as an indirect but in vivo measure of basal brain 5-HT concentration."( Deficits in D-fenfluramine-sensitive pool of brain 5-HT following withdrawal from chronic cocaine exposure.
Darmani, NA, 1997
)
1.22
"D-Fenfluramine is a serotonin (5-hydroxytryptamine, 5-HT) releaser and reuptake inhibitor. "( The 5-HT1A and 5-HT2A/2C receptor antagonists WAY-100635 and ritanserin do not attenuate D-fenfluramine-induced fos expression in the brain.
Gray, TS; Javed, A; Van de Kar, LD, 1998
)
1.24
"1. Fenfluramine is an optically active 5-hydroxytryptamine (5-HT) releaser and re-uptake inhibitor."( Pituitary-adrenal responses to combined oral D-fenfluramine and intravenous naloxone in humans.
Crosbie, GV; Grice, JE; Hockings, GI; Jackson, RV; Torpy, DJ; Walters, MM,
)
0.9
"Fenfluramine is an amphetamine analogue which has been widely used in the treatment of obesity. "( The appetite suppressant d-fenfluramine induces apoptosis in human serotonergic cells.
Bengel, D; Heils, A; Isaacs, KR; Lesch, KP; Murphy, DL, 1998
)
2.04
"Fenfluramine is an indirect agonist of 5-hydroxytryptamine (5-HT) receptors that acts by evoking 5-HT release and blocking 5-HT reuptake in neuronal cells. "( Antinociceptive properties of fenfluramine, a serotonin reuptake inhibitor, in a rat model of neuropathy.
Bowersox, SS; Gao, D; Pettus, M; Wang, YX, 1999
)
2.03
"Fenfluramine (FE) is a halogenated amphetamine derivative that has been used in the treatment of obesity. "( Fenfluramine-induced increase in preproenkephalin mRNA levels in the striatum: interaction between the serotonergic, glutamatergic, and dopaminergic systems.
Guerra, MJ; Labandeira-Garcia, JL; Liste, I; Muñoz, A, 2000
)
3.19
"D-Fenfluramine is a medication that induces neuronal release of serotonin."( Increased left posterior parietal-temporal cortex activation after D-fenfluramine in women with panic disorder.
Brown, GM; Houle, S; Kennedy, SH; Meyer, JH; Swinson, R, 2000
)
1.1
"Fenfluramine is a substituted phenylethylamine structurally related to amphetamine. "( Fenfluramine poisoning.
Temple, AR; Veltri, JC, 1975
)
3.14
"Fenfluramine is a recently introduced anorexigenic drug for the treatment of obesity. "( Fenfluramine-associated hypertension.
Mabadeje, AF, 1975
)
3.14
"D-Fenfluramine is a potent stimulator of thermogenesis in the rat, an action which may contribute to its effects on body weight. "( Thermogenesis, brown adipose tissue and dexfenfluramine in animal studies.
Le Feuvre, RA; Rothwell, NJ, 1992
)
1.27
"Fenfluramine is an amphetamine derivative which is used as a weight-reducing agent in the treatment of obesity. "( Role for brain corticotropin-releasing factor in the weight-reducing effects of chronic fenfluramine treatment in rats.
Appel, NM; Bissette, G; Contrera, JF; Culp, S; De Souza, EB; Nemeroff, CB; Owens, MJ; Zaczek, R, 1991
)
1.95
"Fenfluramine is a serotonin releaser and reuptake blocker which is marketed as an anorectic agent."( Fenfluramine augmentation of serotonin reuptake blockade antiobsessional treatment.
DeCaria, CM; Hollander, E; Klein, DF; Liebowitz, MR; Schneier, FR; Schneier, HA, 1990
)
2.44
"Fenfluramine is an amphetamine derivative that in humans is used primarily as an anorectic agent in the treatment of obesity. "( Effects of high-dose fenfluramine treatment on monoamine uptake sites in rat brain: assessment using quantitative autoradiography.
Appel, NM; Contrera, JF; De Souza, EB; Mitchell, WM, 1990
)
2.04
"Fenfluramine (FN) is a potent serotonin-releasing drug used primarily as an anorectic agent. "( A characterization of the acute cardiopulmonary toxicity of fenfluramine in the rat.
Hunsinger, RN; Wright, D,
)
1.82
"Fenfluramine is a widely prescribed anorectic drug as adjuvant therapy for obesity. "( Pulmonary hypertension and fenfluramine.
Cheriex, EC; Pouwels, HM; Smeets, JL; Wouters, EF, 1990
)
2.02
"Fenfluramine is an anorectic agent in clinical use that is believed to act by enhancing 5-hydroxytryptamine (5-HT) neurotransmission. "( Effect of depletion of brain serotonin by repeated fenfluramine on neurochemical and anorectic effects of acute fenfluramine.
Kleven, MS; Schuster, CR; Seiden, LS, 1988
)
1.97
"d-Fenfluramine is an anorectic drug believed to act by enhancement on serotonergic function in the brain. "( Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release.
Fuller, RW; Robertson, DW; Snoddy, HD, 1988
)
1.29
"Fenfluramine is an effective appetite suppressant that mediates its action via serotoninergic neurons. "( Failure of fenfluramine to affect basal and insulin-stimulated hexose transport in rat skeletal muscle.
Cerasi, E; Kunievsky, B; Nathan, C; Sasson, S, 1989
)
2.11
"Fenfluramine is an amphetamine derivative which is used primarily as an anorectic agent in the treatment of obesity. "( Fenfluramine selectively and differentially decreases the density of serotonergic nerve terminals in rat brain: evidence from immunocytochemical studies.
Appel, NM; Contrera, JF; De Souza, EB, 1989
)
3.16
"Dexfenfluramine is a good candidate for such a use; the demonstration of its long-term efficacy, i.e., maintenance of the initial weight loss with no escape with time, is in progress (ISIS study)."( Place of dexfenfluramine in the management of obesity.
Guy-Grand, BJ, 1988
)
1.17
"1. Fenfluramine is an anorexogenic agent used clinically because it is devoid of central stimulatory effects.2. "( Action of fenfluramine on monoamine stores of rat tissues.
Costa, E; Groppetti, A; Revuelta, A, 1971
)
1.27

Effects

Fenfluramine has a potent anticonvulsive effect in DS. It also has a lowering effect on brain serotonin, and peripheral effects on glucose and triglyceride metabolism.

Fenfluramine has been used for a number of years as a short-term adjunct to diet in the management of obesity. It produces decreases in daily energy intake varying between 13 and 25% depending on the time for which the drug has been administered. Fenfluramines also has an original effect on some food intake disorders.

ExcerptReferenceRelevance
"Fenfluramine has a potent anticonvulsive effect in DS. "( A critical evaluation of fenfluramine hydrochloride for the treatment of Dravet syndrome.
Ceulemans, B; Schoonjans, AS, 2022
)
2.47
"Fenfluramine has a lowering effect on brain serotonin, and peripheral effects on glucose and triglyceride metabolism."( Congenital generalized lipodystrophy and experimental lipoatrophic diabetes in rabbits treated successfully with fenfluramine.
Foss, I; Trygstad, O, 1977
)
1.19
"Dexfenfluramine also has an original effect on some food intake disorders."( [Dexfenfluramine and feeding behavior. Clinical and pharmacoclinical studies].
Fantino, M, 1989
)
1.35
"Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome."( Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial.
Agarwal, A; Ceulemans, B; Cross, JH; Devinsky, O; Farfel, G; Galer, BS; Gammaitoni, A; Guerrini, R; Knupp, K; Lagae, L; Lai, WW; Laux, L; Lock, M; Miller, I; Mistry, A; Morrison, G; Nikanorova, M; Polster, T; Sullivan, J; Talwar, D, 2019
)
2.68
"Fenfluramine has been used in association with both first- and second-line medications, while its use in monotherapy still needs to be assessed."( Fenfluramine for the Treatment of Dravet Syndrome and Lennox-Gastaut Syndrome.
Balagura, G; Cacciatore, M; Grasso, EA; Striano, P; Verrotti, A, 2020
)
2.72
"Fenfluramine has been shown to provide clinically meaningful and statistically significant reductions in convulsive seizure frequency in children and adolescents (aged 2-18 years) with Dravet syndrome in two randomized, placebo-controlled clinical trials. "( Fenfluramine HCl (Fintepla
Agarwal, A; Farfel, G; Galer, B; Gammaitoni, A; Lagae, L; Lock, M; Morrison, G; Nabbout, R; Polster, T; Pringsheim, M; Scheffer, IE; Sullivan, J; Talwar, D, 2020
)
3.44
"Fenfluramine has been recently approved by the FDA and EMA and is marketed as Fintepla®."( A critical evaluation of fenfluramine hydrochloride for the treatment of Dravet syndrome.
Ceulemans, B; Schoonjans, AS, 2022
)
1.75
"Fenfluramine has a potent anticonvulsive effect in DS. "( A critical evaluation of fenfluramine hydrochloride for the treatment of Dravet syndrome.
Ceulemans, B; Schoonjans, AS, 2022
)
2.47
"Fenfluramine hydrochloride has classically been described as acting pharmacologically through a serotonergic mechanism. "( Fenfluramine as antiseizure medication for epilepsy.
Cross, JH; Gogou, M, 2021
)
3.51
"Fenfluramine (Fintepla) has demonstrated profound reduction in convulsive seizure frequency in DS and was recently approved for use in DS in the US and EU."( Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth.
Agarwal, A; Ceulemans, B; Cortes, RM; Davis, R; Devinsky, O; Farfel, G; Galer, BS; Gammaiton, AR; Gil-Nagel, A; Knupp, KG; Lock, M; Nabbout, R; Polster, T; Scott Perry, M; Sullivan, J; Wirrell, E, 2021
)
1.7
"Fenfluramine has been reported to have a long-term clinically meaningful anticonvulsive effect in patients with DS."( Low-dose fenfluramine significantly reduces seizure frequency in Dravet syndrome: a prospective study of a new cohort of patients.
Ceulemans, B; Galer, BS; Gammaitoni, A; Gunning, B; Lagae, L; Marchau, F; Paelinck, BP; Schoonjans, A, 2017
)
1.59
"Fenfluramine has been associated with an increased risk of pulmonary hypertension and valvular disease. "( Mitral and aortic valvular disease associated with benfluorex use.
Castellant, P; Etienne, Y; Fatemi, M; Frachon, I; Jobic, Y; Quintin-Roué, I, 2011
)
1.81
"(+)-Fenfluramine has been found in Chinese and Korean slimming pills."( The fenfluramine metabolite (+)-norfenfluramine is vasoactive.
Fink, GD; Li, MW; Ni, W; Thakali, K; Watts, SW, 2004
)
1.36
"Dexfenfluramine, which has previously been reported to cause pulmonary hypertension, is an amphetamine-like anorexic agent, a pharmacological group known to predispose to this type of side effect."( [Severe pulmonary hypertension complicating a long treatment with dexfenfluramine].
Baudouy, M; Drai, E; Ferrari, E; Jourdan, J; Morand, P; Sanchez, B, 1994
)
1.04
"Dexfenfluramine has been shown to lower blood glucose concentrations independently of its effects in reducing food intake and body weight, in human and animal syndromes of non-insulin dependent diabetes. "( Acute dexfenfluramine administration normalizes glucose tolerance in rats with insulin-deficient diabetes.
Arora, R; Dryden, S; McKibbin, PE; Williams, G, 1994
)
1.33
"Fenfluramine has been classified as a neurotoxin because animals treated with this anorectic lose 5-HT uptake sites located on serotonergic nerve terminals. "( New evidence for a loss of serotonergic nerve terminals in rats treated with d,l-fenfluramine.
Dodd, PR; Westphalen, RI,
)
1.8
"d-Fenfluramine (d-Fen) has been demonstrated to alter body temperature (BT), decrease 5-hydroxytryptamine (5-HT) and decrease 5-HT plasma membrane transporters (PMT) in rats. "( Elevated environmental temperatures can induce hyperthermia during d-fenfluramine exposure and enhance 5-hydroxytryptamine (5-HT) depletion in the brain.
Bowyer, JF; Slikker, W; Stewart, CW, 1997
)
1.25
"Dexfenfluramine has been shown to reduce body weight and lower blood pressure in obese individuals. "( Blood pressure and plasma norepinephrine responses to dexfenfluramine in obese postmenopausal women.
Adler, G; Ditschuneit, HH; Flechtner-Mors, M; Yip, I, 1998
)
1.17
"D-fenfluramine has been identified as a highly selective serotonin (5-HT) releaser and re-uptake inhibitor. "( Prolactin response to D-fenfluramine challenge test as a predictor of treatment response to haloperidol in acute schizophrenia.
Czobor, P; Horácek, J; Libiger, J; Mohr, P; Motlová, L, 1998
)
1.33
"Fenfluramine (d-FEN) has been used as a serotonin challenge agent to assess central serotonin availability. "( Oral d-fenfluramine test in treatment-refractory depression. Plasma prolactin response compared in patients with and without suicide attempts and in a healthy reference group.
Agren, H; Prochazka, H; Sjögren, M,
)
2.03
"Fenfluramine has been considered to deplete neuronal 5-hydroxytryptamine (5-HT). "( Effect of fenfluramine administration on synaptosomal uptake of some neurotransmitters and on synaptosomal enzymes which metabolise GABA.
Belin, MF; Gonnard, P; Kouyoumdjiian, JC, 1979
)
2.1
"That fenfluramine has dose-related cerebral effects should be remembered in patients with a history of mental illness."( Dreaming, fenfluramine, and vitamin C.
Mullen, A; Wilson, BP; Wilson, CW, 1977
)
1.11
"Fenfluramine has a lowering effect on brain serotonin, and peripheral effects on glucose and triglyceride metabolism."( Congenital generalized lipodystrophy and experimental lipoatrophic diabetes in rabbits treated successfully with fenfluramine.
Foss, I; Trygstad, O, 1977
)
1.19
"Fenfluramine has been used for a number of years as a short-term adjunct to diet in the management of obesity. "( Fenfluramine: a review of its pharmacological properties and therapeutic efficacy in obesity.
Avery, GS; Brogden, RN; Pinder, RM; Sawyer, PR; Speight, TM, 1975
)
3.14
"Dexfenfluramine has been demonstrated to produce decreases in daily energy intake varying between 13 and 25% depending on the time for which the drug has been administered. "( Dexfenfluramine and appetite in humans.
Blundell, JE; Hill, AJ, 1992
)
1.53
"Dexfenfluramine has not been directly compared with nonpharmacological measures of weight control such as behaviour modification or exercise programmes."( Dexfenfluramine. A review of its pharmacological properties and therapeutic potential in obesity.
Heel, RC; McTavish, D, 1992
)
1.42
"Dexfenfluramine has been shown to promote weight loss in overweight people. "( The effects of dexfenfluramine on blood glucose control in patients with type 2 diabetes.
Molyneaux, LM; Overland, JE; Willey, KA; Yue, DK, 1992
)
1.24
"Fenfluramine has the potential to be of therapeutic value in patients with bulimia."( The role of pharmacotherapy in anorexia nervosa and bulimia.
Tolstoi, LG, 1989
)
1
"Dexfenfluramine also has an original effect on some food intake disorders."( [Dexfenfluramine and feeding behavior. Clinical and pharmacoclinical studies].
Fantino, M, 1989
)
1.35
"Fenfluramine therapy has been reported to improve behavior in infantile autism and has been associated with a decrease in abnormally increased blood serotonin content. "( Reduction of elevated CSF beta-endorphin by fenfluramine in infantile autism.
Hitzemann, R; Klykylo, WM; Ross, DL,
)
1.84

Actions

Fenfluramine may produce fewer problems of human abuse than do amphetamine-type agents. Fenfluramines cause dose-related, long-lasting reductions in serotonin axonal markers in all the animal species tested.

ExcerptReferenceRelevance
"Fenfluramine results in lower other medical costs in comparison with stiripentol and clobazam."( The contribution of fenfluramine to the treatment of Dravet syndrome in Spain through Multi-Criteria Decision Analysis.
Abad-Sazatornil, MR; Aibar, JÁ; Aras, LM; Cardenal-Muñoz, E; Falip, M; Gil, A; Gil-Nagel, A; Poveda, JL; Sánchez, R; Sánchez-Carpintero, R; Sancho-López, A; Torrejón, M; Trillo-Mata, JL, 2022
)
1.77
"Fenfluramine, which promotes 5-HT release, also reduced TI duration."( The effects of tryptophan and manipulations of serotonergic receptors on tonic immobility in chickens.
Bordash, GD; Corso, P; Wallnau, LB, 1981
)
0.98
"The fenfluramine-induced increase in acetylcholine release was significantly attenuated by pretreatment with the selective serotonin uptake inhibitor fluoxetine (10 mg/kg, i.p.)."( Serotonergic regulation of acetylcholine release in rat frontal cortex.
Day, J; Fibiger, HC; Hirano, H, 1995
)
0.77
"Fenfluramines cause dose-related, long-lasting reductions in serotonin axonal markers in all the animal species tested and with all the routes of drug administration used. "( Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. A systematic review of the evidence.
McCann, UD; Ricaurte, GA; Rubin, LJ; Seiden, LS, 1997
)
1.97
"Dexfenfluramine can cause the anorexigen-induced form of PPH that is clinically and histologically indistinguishable from PPH."( A role for potassium channels in smooth muscle cells and platelets in the etiology of primary pulmonary hypertension.
Archer, SL; Johnson, G; Michelakis, ED; Nelson, DP; Reeve, HL; Weir, EK, 1998
)
0.81
"The fenfluramine's ability to increase ACh release was potentiated by E(2) replacement with a 0.5 mg-pellet."( Effects of estrogen on acetylcholine release in frontal cortex of female rats: involvement of serotonergic neuronal systems.
Hirano, H; Matsuda, Y; Watanabe, Y, 2002
)
0.8
"Fenfluramine did not produce a thermogenic effect in the fasting animal, but significantly potentiated the thermogenic effect of the meal."( Modulation of the thermic effect of food by fenfluramine.
Levitsky, DA; Schuster, JA; Stallone, D; Strupp, BJ, 1986
)
1.25
"Fenfluramine, because of its distinctive properties, may produce fewer problems of human abuse than do amphetamine-type agents."( Fenfluramine: amphetamine congener that fails to maintain drug-taking behavior in the rhesus monkey.
Tessel, RE; Woods, JH, 1974
)
2.42
"Fenfluramine causes an increase in the turnover rate of tel-diencephalic 5-HT but such an acceleration could not be detected in the 5-HT stores of the brainstem.4."( Action of fenfluramine on monoamine stores of rat tissues.
Costa, E; Groppetti, A; Revuelta, A, 1971
)
1.37

Treatment

Fenfluramine may reduce monthly convulsive seizure frequency in patients with Dravet syndrome. Treatment resulted in a 30-fold increase in extracellular 5-HT levels in the ventral hippocampus and induced a significant reduction of [18F]MPPF binding in frontal cortex, hypothalamus, amygdala, and hippocampus.

ExcerptReferenceRelevance
"Fenfluramine treatment in DS reduced convulsive seizure frequency by 56% over placebo at the highest dose, with 8% of patients free of convulsive seizures, and 25% with only one convulsive seizure over 14 weeks."( Failure to use new breakthrough treatments for epilepsy.
Devinsky, O; Klein, P; Krauss, GL; Sperling, MR; Steinhoff, BJ, 2023
)
1.63
"Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens."( Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial.
Agarwal, A; Auvin, S; Chiron, C; Farfel, G; Galer, BS; Gil-Nagel, A; Knupp, K; Laux, L; Lock, M; Mistry, A; Morrison, G; Nabbout, R; Sanchez-Carpintero, R; Stephani, U; Villeneuve, N; Wirrell, E; Zuberi, S, 2020
)
3.44
"Fenfluramine treatment resulted in a 30-fold increase in extracellular 5-HT levels in the ventral hippocampus and induced a significant reduction of [18F]MPPF binding in the frontal cortex, hypothalamus, amygdala, and hippocampus."( Effect of increased serotonin levels on [18F]MPPF binding in rat brain: fenfluramine vs the combination of citalopram and ketanserin.
Bosker, FJ; Cremers, TI; den Boer, JA; Postema, F; Tiemersma-Wegman, TD; Udo de Haes, JI, 2005
)
1.28
"Fenfluramine-treated participants reported lower hunger ratings and greater fullness in the target supper-to-bedtime period than participants receiving placebo."( Extended-release fenfluramine: patient acceptance and efficacy of evening dosing.
Dorn, M; Sriwatanakul, K; Sundaresan, PR; Weintraub, M; Weis, OF, 1983
)
1.33
"D-Fenfluramine treatment restored the response to ADP."( Effect of aging and drug-induced weight reduction on rat vascular reactivity.
Boulanger, M; Duhault, J; Feletou, M; Moreau, N, 1993
)
0.84
"Fenfluramine-treated and control animals were submitted to strenuous swimming at days -2, 1, 4, and 7 relative to the onset of FFL treatment at day 0."( Dexfenfluramine treatment influences plasma catecholamines and energy substrate metabolism in rats.
Benthem, B; Leuvenink, H; Scheurink, AJ; Steffens, AB, 1993
)
1.63
"Dexfenfluramine treatment decreased the density of 5-HT uptake sites in the cortex, labelled with [3H]-citalopram, but this partially recovered towards control values at 60 days."( Repeated administration of escalating high doses of dexfenfluramine does not produce morphological evidence for neurotoxicity in the cortex of rats.
Collins, P; Hindmarsh, JG; Hunt, S; Jenner, P; Rose, S, 1996
)
1.06
"Dexfenfluramine treatment augments weight and fat loss on a reduced-fat, ad libitum diet, with some evidence for preferential loss of waist fat compared with hip fat. "( Dexfenfluramine as an adjunct to a reduced-fat, ad libitum diet: effects on body composition, nutrient intake and cardiovascular risk factors.
Carmichael, HE; Swinburn, BA; Wilson, MR, 1996
)
1.54
"Dexfenfluramine treatment was not associated with greater loss of weight. "( Evaluation of dexfenfluramine in a weight loss program for obese infertile women.
Clark, A; Galletly, C; Tomlinson, L, 1996
)
1.25
"D-fenfluramine treatment markedly improved the maximum relaxant response of aortic rings to acetylcholine, indicating improvement of the defective endothelium-derived relaxation factor system."( Improvement of insulin sensitivity and cardiovascular outcomes in the JCR:LA-cp rat by D-fenfluramine.
Amy, RM; Brindley, DN; Dolphin, PJ; Graham, SE; Russell, JC, 1998
)
1.08
"Fenfluramine treatment alone had no effect."( Cotreatment with racemic fenfluramine inhibits the development of tolerance to morphine analgesia in rats.
Arends, RH; Hayashi, TG; Luger, TJ; Shen, DD, 1998
)
1.32
"Fenfluramine treatment (10 mg/kg i.p.) resulted in a approximately 5-fold increase in extracellular 5-HT in medial prefrontal cortex and a approximately 15-fold increase in lateral hippocampus, maximal at approximately 40 min after injection."( Effect of 5-HT on binding of [(11)C] WAY 100635 to 5-HT(IA) receptors in rat brain, assessed using in vivo microdialysis nd PET after fenfluramine.
Grasby, P; Hirani, E; Hume, S; Myers, R; Opacka-Juffry, J; Pike, V; Townsend, C, 2001
)
1.24
"Dexfenfluramine- and placebo-treated patients achieved a similar weight loss (greater than 10% of initial weight, by 39.5 and 30.0%, greater than 20% of initial overweight by 42.1% and 32.5% and greater than 10 kg by 41.4 and 33.3%, respectively, of the initial cohorts)."( Dexfenfluramine in the treatment of severe obesity: a placebo-controlled investigation of the effects on weight loss, cardiovascular risk factors, food intake and eating behaviour.
Kok, AM; Mathus-Vliegen, EM; Res, AM; van de Voorde, K, 1992
)
1.42
"Dexfenfluramine treatment was associated with a significant reduction in weight (98.7 +/- 5.0 (+/- SE) vs 94.9 +/- 5.2 kg; p less than 0.001), BMI (35.0 +/- 1.2 vs 33.6 +/- 1.9 kg m-2; p less than 0.001), HbA1c (7.5 +/- 0.3 vs 6.3 +/- 0.2%; p less than 0.001), fructosamine (313.9 +/- 17.6 vs 274.3 +/- 10.4 mumol l-1; p less than 0.01), systolic (137 +/- 5 vs 128 +/- 6 mmHg; p less than 0.05), and diastolic blood pressure (85 +/- 2 vs 73 +/- 3 mmHg; p less than 0.001)."( The effects of dexfenfluramine on blood glucose control in patients with type 2 diabetes.
Molyneaux, LM; Overland, JE; Willey, KA; Yue, DK, 1992
)
1.13
"fenfluramine pretreatment, respectively) and, to a lesser extent, at 8 weeks (ED50 = 2.99 vs."( Effect of depletion of brain serotonin by repeated fenfluramine on neurochemical and anorectic effects of acute fenfluramine.
Kleven, MS; Schuster, CR; Seiden, LS, 1988
)
1.25
"Fenfluramine-treated rats had lower body weights in both chronic experiments even after food intake returned to normal."( Lateral hypothalamic lesions and fenfluramine increase thermogenesis in brown adipose tissue.
Bray, GA; Groos, E; Kemnitz, JW; Lupien, JR; Tokunaga, K, 1986
)
1.27
"Pretreatment with fenfluramine (5 and 10 mg/kg, ip) in doses which induced head twitches was found to antagonize apomorphine-induced cage climbing behaviour and methamphetamine stereotypy in mice. "( Antagonism of apomorphine-induced cage climbing behaviour and methamphetamine stereotypy by fenfluramine in mice.
Balsara, JJ; Chandorkar, AG; Gada, VP; Joshi, VV,
)
0.69
"Treatment with fenfluramine and fluoxetine caused a significant decrease in the number of 3H-5HT binding sites (Bmax)."( Manipulations of synaptic serotonin: discrepancy of effects on serotonin S1 and S2 sites.
Dumbrille-Ross, A; Tang, SW, 1983
)
0.61
"Treatment with fenfluramine or fluoxetine increased post-fasting anorexia, abolished the preference for carbohydrates and decreased lipid intake."( Effect of activation of the serotoninergic system during prolonged starvation on subsequent caloric intake and macronutrient selection in the Zucker rat.
Duhault, J; Espinal, J; Lacour, F; Rolland, Y, 1993
)
0.63
"Treatment with fenfluramine was associated with significant weight loss, improvement in food related behaviour, and a decrease in aggressive behaviour directed towards others."( Fenfluramine in Prader-Willi syndrome: a double blind, placebo controlled trial.
Pendergast, A; Selikowitz, M; Sunman, J; Wright, S, 1990
)
2.06

Toxicity

Fenfluramine was found to be less toxic than N-nitrosofen fluramine. A significant adverse effect of fen Fluramine on psychopathology was detected.

ExcerptReferenceRelevance
"Dexfenfluramine, a drug prescribed for appetite suppression, was evaluated in non-human primates for its potential to produce toxic effects on brain serotonin (5-HT) neurons."( Dexfenfluramine neurotoxicity in brains of non-human primates.
Katz, JL; Martello, AL; Martello, MB; Molliver, ME; Ricaurte, GA; Wilson, MA, 1991
)
1.52
" In other trials, prior treatment with diethylcarbamazine (DEC) was found to potentiate the lethality of FN, while cyproheptadine (CHP) pretreatment attenuated FN's toxic effects."( A characterization of the acute cardiopulmonary toxicity of fenfluramine in the rat.
Hunsinger, RN; Wright, D,
)
0.37
" A significant adverse effect of fenfluramine on psychopathology was detected through nurses' ratings, target symptom scales, the Brief Psychiatric Rating Scale, and time-sampled behavioral observations."( Adverse effects of fenfluramine in treatment refractory schizophrenia.
Banzett, L; Bowen, LL; Glynn, SM; Hubbard, JW; Liberman, RP; Marshall, BD; Midha, KK; Mintz, J, 1989
)
0.89
" In conclusion, dextrafenfluramine was proved to be in short term trials an effective and safe tool in overweight control in obese patients."( Efficacy and safety of dexfenfluramine in obese patients: a multicenter study.
Baggio, B; Bruni, R; Crepaldi, G; Enzi, G; Inelmen, EM, 1988
)
0.89
" Taken together, these findings indicate that concern over possible dexfenfluramine neurotoxicity in humans is warranted, and that physicians and patients alike need to be aware of dexfenfluramine's toxic potential toward brain serotonin neurons."( Dexfenfluramine and serotonin neurotoxicity: further preclinical evidence that clinical caution is indicated.
Fischer, C; Hatzidimitriou, G; Katz, J; McCann, U; Ricaurte, G; Ridenour, A; Yuan, J, 1994
)
1.14
"Data extracted from each report included key study characteristics, clinical information, co-interventions, and outcomes, including dropouts due to either adverse drug effects or perceived lack of effect."( An overview of the efficacy and safety of fenfluramine and mazindol in the treatment of obesity.
Imperiale, TF; Stahl, KA, 1993
)
0.55
" Dropouts due to adverse drug effects were more common in the treatment group (7% vs 2%; P < ."( An overview of the efficacy and safety of fenfluramine and mazindol in the treatment of obesity.
Imperiale, TF; Stahl, KA, 1993
)
0.55
"The apparent short-term efficacy of these appetite-suppressant drugs and the lack of severe adverse drug effects or addiction suggest that they may be useful in the treatment of obesity."( An overview of the efficacy and safety of fenfluramine and mazindol in the treatment of obesity.
Imperiale, TF; Stahl, KA, 1993
)
0.55
" Adverse events were usually moderate and transient, occurring at the beginning of treatment."( [A multicenter open study of dexfenfluramine in Italy. The efficacy and safety of using dexfenfluramine in treating patients with simple or complicated obesity. The DIMOS Group].
Enzi, G, 1997
)
0.58
" However, animal and human studies have demonstrated toxic effects of fenfluramines that clinicians should be aware of when considering prescribing the drugs."( Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. A systematic review of the evidence.
McCann, UD; Ricaurte, GA; Rubin, LJ; Seiden, LS, 1997
)
0.76
" PHEN also significantly enhanced FEN's long-term toxic effects on 5-HT axons."( Neurotoxic effects of +/-fenfluramine and phenteramine, alone and in combination, on monoamine neurons in the mouse brain.
McCann, UD; Ricaurte, GA; Yuan, J, 1998
)
0.6
"The removal of 5 pharmaceuticals from the market in a 12-month period because of unexpected adverse events raised concerns about the adequacy of the drug review process at the US Food and Drug Administration (FDA)."( The safety of newly approved medicines: do recent market removals mean there is a problem?
Friedman, MA; Hass, AE; Lumpkin, MM; Shuren, JE; Thompson, LJ; Woodcock, J, 1999
)
0.3
"This review summarizes the neurochemical, therapeutic and adverse effects of serotonin (5-HT) releasing agents."( Serotonin releasing agents. Neurochemical, therapeutic and adverse effects.
Baumann, MH; Rothman, RB, 2002
)
0.31
" In comparative effects based on cell viability and rhodamine 123 retention, an index of mitochondrial membrane potential, fenfluramine was less toxic than N-nitrosofenfluramine."( N-Nitrosofenfluramine induces cytotoxicity via mitochondrial dysfunction and oxidative stress in isolated rat hepatocytes.
Kamimura, H; Nagai, F; Nakagawa, Y; Suzuki, T, 2005
)
0.95
"5 million adverse drug reaction (ADR) reports for 8620 drugs/biologics that are listed for 1191 Coding Symbols for Thesaurus of Adverse Reaction (COSTAR) terms of adverse effects."( Assessment of the health effects of chemicals in humans: II. Construction of an adverse effects database for QSAR modeling.
Benz, RD; Contrera, JF; Kruhlak, NL; Matthews, EJ; Weaver, JL, 2004
)
0.32
" Receptorome screening has implicated N-deethylation of fenfluramine and serotonin 5-hydroxy-t-ryptamine 2B receptors in the adverse effects of the drug; subsequent studies corroborated this finding."( Screening the receptorome reveals molecular targets responsible for drug-induced side effects: focus on 'fen-phen'.
Roth, BL; Setola, V, 2005
)
0.57
"6mM, a low toxic dose."( ATP-generating glycolytic substrates prevent N-nitrosofenfluramine-induced cytotoxicity in isolated rat hepatocytes.
Ishii, H; Nakagawa, Y; Ogata, A; Suzuki, T; Tayama, S, 2006
)
0.58
" Further studies should be conducted to determine the subsequent course of benfluorex-induced VHD and PAH, and to identify genetic, biological and clinical factors that determine individual susceptibility to developing such adverse effects."( Adverse effects of benfluorex on heart valves and pulmonary circulation.
Andréjak, M; Maréchaux, S; Peltier, M; Szymanski, C; Tribouilloy, C, 2014
)
0.4
" In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS."( Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.
Battaglia, D; Cossu, A; Dalla Bernardina, B; Darra, F; Doccini, V; Granata, T; Guerrini, R; Luigia Gambardella, M; Mei, D; Pietrafusa, N; Quintiliani, M; Ragona, F; Rosati, A; Specchio, N; Spolverato, S; Trivisano, M; Vigevano, F, 2020
)
1.12
" Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months."( Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.
Battaglia, D; Cossu, A; Dalla Bernardina, B; Darra, F; Doccini, V; Granata, T; Guerrini, R; Luigia Gambardella, M; Mei, D; Pietrafusa, N; Quintiliani, M; Ragona, F; Rosati, A; Specchio, N; Spolverato, S; Trivisano, M; Vigevano, F, 2020
)
0.87
" The most common adverse event was decreased appetite (n = 7, 13."( Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.
Battaglia, D; Cossu, A; Dalla Bernardina, B; Darra, F; Doccini, V; Granata, T; Guerrini, R; Luigia Gambardella, M; Mei, D; Pietrafusa, N; Quintiliani, M; Ragona, F; Rosati, A; Specchio, N; Spolverato, S; Trivisano, M; Vigevano, F, 2020
)
0.87
" We calculated the risk ratio (RR) of ≥50% and 100% reduction seizure frequency from baseline, along with the treatment-related withdrawals and serious adverse events, using the fixed-effect model."( Efficacy and safety of fenfluramine in patients with Dravet syndrome: A meta-analysis.
Li, W; Wang, C; Zhang, L, 2021
)
0.93
" There were no significant differences in withdrawals and serious adverse events between the two treatment groups."( Efficacy and safety of fenfluramine in patients with Dravet syndrome: A meta-analysis.
Li, W; Wang, C; Zhang, L, 2021
)
0.93
" The primary efficacy outcome was ≥50% reduction in convulsive seizure frequency from baseline while the safety outcome was treatment-emergent adverse events (TEAEs)."( Comparative short-term efficacy and safety of add-on anti-seizure medications in Dravet syndrome: An indirect treatment comparison.
Asrar, MM; Bansal, D; Devi, N; Madaan, P; Sahu, JK, 2021
)
0.62
"0] and for occurrence of any treatment emergent adverse events (TEAEs) [OR:53."( Comparative short-term efficacy and safety of add-on anti-seizure medications in Dravet syndrome: An indirect treatment comparison.
Asrar, MM; Bansal, D; Devi, N; Madaan, P; Sahu, JK, 2021
)
0.62
" Most common treatment-emergent adverse events included decreased appetite (59 [22%]), somnolence (33 [13%]), and fatigue (33 [13%])."( Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated With Lennox-Gastaut Syndrome: A Randomized Clinical Trial.
Agarwal, A; Ceulemans, B; Davis, R; Farfel, GM; Galer, BS; Gammaitoni, AR; Gil-Nagel, A; Guerrini, R; Knupp, KG; Lagae, L; Lock, M; Nabbout, R; Nickels, KC; Riney, K; Scheffer, IE; Shore, S; Sullivan, JE; Zuberi, SM, 2022
)
1.03
" Seizure incidence was recorded in a written diary, and adverse events (AEs) were reported at each patient visit."( An examination of the efficacy and safety of fenfluramine in adults, children, and adolescents with Dravet syndrome in a real-world practice setting: A report from the Fenfluramine European Early Access Program.
Aledo-Serrano, Á; Darra, F; Gammaitoni, A; Gil-Nagel, A; Guerrini, R; Lothe, A; Mayer, T; Polster, T; Pringsheim, M; Specchio, N; Strzelczyk, A; Zuberi, SM, 2022
)
0.98
" The mainstay of treatment is with multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated with psychobehavioural adverse events, and effects (negative or positive) on cognition and sleep."( Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies.
Schubert-Bast, S; Strzelczyk, A, 2022
)
0.72

Pharmacokinetics

ExcerptReferenceRelevance
"6 l h-1) and the terminal half-life tended to be longer (17."( The pharmacokinetics of dexfenfluramine in obese and non-obese subjects.
Cheymol, G; Gellee, C; Poirier, JM; Weissenburger, J, 1995
)
0.59
" The method coupled with microdialysis was applied for a pharmacokinetic drug-drug interaction study of Phen and Fen following individual and combined intraperitoneal administration to rats."( Liquid chromatography studies on the pharmacokinetics of phentermine and fenfluramine in brain and blood microdialysates after intraperitoneal administration to rats.
Kaddoumi, A; Maki, T; Matsumura, Y; Nakamura, J; Nakashima, K; Nakashima, MN, 2003
)
0.55
" Results revealed that as the increase of urinary pH, the mean elimination half-life (t(1/2)), the mean residence time (MRT) and the area under the plasma concentration-time curve (AUC) of PPA, PSE, and FEN were greatly raised, while the total plasma clearance (CL/F) decreased considerably."( Influences of urinary pH on the pharmacokinetics of three amphetamine-type stimulants using a new high-performance liquid chromatographic method.
Feng, F; Wang, L; Wang, XQ; Zhu, L, 2009
)
0.35
"This study was undertaken to determine the plasma concentration and pharmacokinetic variability of fenfluramine (FFA) and its main active metabolite norfenfluramine (norFFA) in relation to the prevalence of adverse effects in patients with refractory epilepsy treated with FFA."( Therapeutic drug monitoring of fenfluramine in clinical practice: Pharmacokinetic variability and impact of concomitant antiseizure medications.
Ceulemans, B; Dewals, W; Paelinck, BP; Roosens, L; Schoonjans, AS, 2022
)
1.22

Compound-Compound Interactions

Chlordiazepoxide was generally additive with those of either d-amphetamine or fenfluramine when given in combination with one of the anorectic drugs. ZX008 is under development for adjunctive treatment of Dravet and Lennox-Gastaut syndrome.

ExcerptReferenceRelevance
" The effects of chlordiazepoxide on feeding parameters were generally additive with those of either d-amphetamine or fenfluramine, whenever chlordiazepoxide was given in combination with one of the anorectic drugs."( Feeding parameters with two food textures after chlordiazepoxide administration, alone or in combination with d-amphetamine or fenfluramine.
Cooper, SJ; Francis, RL, 1979
)
0.67
"Phase I, open-label, randomized, single-dose, 3-period crossover study assessing pharmacokinetics (PK) and safety of ZX008, a liquid oral formulation of fenfluramine (FFA) under development for adjunctive treatment of Dravet syndrome and Lennox-Gastaut syndrome, administered with and without a combined antiepileptic drug (AED) regimen of stiripentol (STP), valproate (VPA), and clobazam (CLB) (STP regimen)."( A phase I, randomized, open-label, single-dose, 3-period crossover study to evaluate the drug-drug interaction between ZX008 (fenfluramine HCl oral solution) and a regimen of stiripentol, clobazam, and valproate in healthy subjects
.
Boyd, B; Farfel, GM; Galer, BS; Gammaitoni, A; Smith, S, 2019
)
0.92

Bioavailability

ExcerptReferenceRelevance
" The apparently complex influence of weight loss on prolactin response to serotonergic challenge remains to be clarified as well as the role played by the bioavailability of the challenge drug and its metabolite."( Hormone responses to fenfluramine and placebo challenge in endogenous depression.
Cooper, TB; Gillon, D; Kindler, S; Lerer, B; Lichtenberg, P; Newman, ME; Shapira, B, 1992
)
0.6
" Bioavailability of the drug was about 20%."( Disposition of (-)-fenfluramine and its active metabolite, (-)-norfenfluramine in rat: a single dose-proportionality study.
Caccia, S; Fracasso, C; Garattini, S; Guiso, G; Spinelli, R, 1988
)
0.6
"14C-Tiflorex given either orally or intravenously to male rats (10 mg/kg; 250 microCi) was well absorbed orally; greater than 70% of the dose was excreted in the urine in the first 48 hr after dosing by either route of administration."( The metabolism and kinetics of tiflorex in the rat.
André, J; Dring, LG; Gillet, G; Gomeni, R; Mas-Chamberlin, C; Morselli, PL,
)
0.13
" The hypothesis is proposed that this treatment is successful because of the dual and balanced increase in the bioavailability of the neurotransmitters, dopamine and serotonin, in the nucleus accumbens."( Combined dopamine and serotonin agonists: a synergistic approach to alcoholism and other addictive behaviors.
Hitzig, P, 1993
)
0.29
" Systemic bioavailability is about 68%, and the drug is metabolized in the liver."( Dexfenfluramine hydrochloride: an anorexigenic agent.
Bever, KA; Perry, PJ, 1997
)
0.92
" Although some volunteer studies have shown substantial decreases in the bioavailability of ingested drugs, no controlled clinical trials have been performed and there is no conclusive evidence that WBI improves the outcome of the poisoned patient."( Position statement: whole bowel irrigation. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists.
Tenenbein, M, 1997
)
0.3
"The quantitative structure-bioavailability relationship of 232 structurally diverse drugs was studied to evaluate the feasibility of constructing a predictive model for the human oral bioavailability of prospective new medicinal agents."( QSAR model for drug human oral bioavailability.
Topliss, JG; Yoshida, F, 2000
)
0.31
"The ATP-binding cassette transporter P-glycoprotein (P-gp) is known to limit both brain penetration and oral bioavailability of many chemotherapy drugs."( A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein.
Ambudkar, SV; Brimacombe, KR; Chen, L; Gottesman, MM; Guha, R; Hall, MD; Klumpp-Thomas, C; Lee, OW; Lee, TD; Lusvarghi, S; Robey, RW; Shen, M; Tebase, BG, 2019
)
0.51

Dosage Studied

There was a strong correlation between drug dosage and plasma levels of fenfluramine. When given in combination with d,l-5-HTP, there was a potentiation of the down-regulation capabilities of fensil. There was a significant dose-response effect on Prl but not on GH levels.

ExcerptRelevanceReference
" Dose-response relationships and time course of this effect for the various drugs were determined."( Effects of mazindol, fenfluramine and chlorimipramine on the 5-hydroxytryptamine uptake and storage mechanisms in rat brain: similarities and differences.
Carruba, MO; Mantegazza, P; Picotti, GB; Zambotti, F, 1977
)
0.58
" The starting dosage in obesity of 40mg daily should be increased gradually over 2 to 4 weeks to 60 to 120mg."( Fenfluramine: a review of its pharmacological properties and therapeutic efficacy in obesity.
Avery, GS; Brogden, RN; Pinder, RM; Sawyer, PR; Speight, TM, 1975
)
1.7
" These results suggest that endogenous serotonin causes a biphasic dose-response effect on T-cell activity with serotonin being required for optimal T-cell function, low doses being immune stimulatory and higher doses being suppressive."( Regulation of murine T-lymphocyte function by spleen cell-derived and exogenous serotonin.
Crayton, JW; Kut, JL; Wright, MA; Young, ME; Young, MR, 1992
)
0.28
" Dosing changes were based on an algorithm that aimed to achieve 120% of ideal body weight (IBW) while minimizing adverse effects."( Long-term weight control study. III (weeks 104 to 156). An open-label study of dose adjustment of fenfluramine and phentermine.
Moscucci, M; Schuster, B; Stein, EC; Sundaresan, PR; Weintraub, M, 1992
)
0.5
" The degree of clastogenicity was directly proportional to the dosage used and inversely related with the duration of treatment."( Clastogenic effect of fenfluramine in mice bone marrow cells in vivo.
Agarwal, K; Bhardwaj, KR; Mukherjee, A; Sen, S; Sharma, A; Sharma, R, 1992
)
0.6
" Consequently at high doses exposure of rat to the drug, as measured by the sum of area under the plasma concentration-time curve (AUC) of d-F and d-NF considerably exceeded that expected from simple dosage considerations, particularly with repeated administration of d-F."( Single- and multiple-dose kinetics of d-fenfluramine in rats given anorectic and toxic doses.
Anelli, M; Caccia, S; Ferrarese, A; Fracasso, C; Garattini, S, 1992
)
0.55
" These results suggest that, at comparable dosage levels relative to their ED50s, fluoxetine and D-fenfluramine cause comparable reversible effects on brain serotonin release."( Effects of fluoxetine or D-fenfluramine on serotonin release from, and levels in, rat frontal cortex.
Gleason, R; Morse, AN; Sarkissian, CF; Wurtman, RJ, 1990
)
0.79
" Results of these dose-response experiments indicated that there was no significant effect upon fenfluramine discrimination after multiple saline injections or after 10 days without training."( Functional consequences of fenfluramine neurotoxicity.
Schechter, MD, 1990
)
0.79
" In diabetic patients treated with sulphonylureas and phenformin at low dosage (glibenclamide 5 mg and phenformin 50 mg) it was possible to maintain good glycometabolic control using only the sulphonylurea gliclazide (160 mg/die)."( [Efficacy of sulfonylurea and sulfonylurea-benfluorex therapy in patients with type 2 diabetes treated with commercial sulfonylurea-biguanide combinations].
Benzi, L; Cecchetti, P; Ciccarone, AM; Di Cianni, G; Giannarelli, R; Navalesi, R; Penno, G,
)
0.13
" Three hours after dosing on day 3 they ate either a high carbohydrate (63 percent of total energy) or high protein (54 percent) lunchtime meal (the caloric load)."( Sensitivity of the appetite control system in obese subjects to nutritional and serotoninergic challenges.
Blundell, JE; Hill, AJ, 1990
)
0.28
" Complete dose-response functions for amphetamine and fenfluramine were determined before, during and after a period of repeated administration of each drug."( Differential development of tolerance to the effects of d-amphetamine and fenfluramine on food intake in baboons.
Foltin, RW, 1990
)
0.76
" Several 5-HT agonists were administered, in a dose-response fashion, to conscious rats and the effect on the levels of prolactin in plasma was measured."( Effect of selective serotonin (5-HT) agonists and 5-HT2 antagonist on prolactin secretion.
Bethea, CL; Lorens, SA; Urban, JH; Van de Kar, LD, 1989
)
0.28
" Once trained, these animals were given several doses of drugs used in training and dose-response relationships and ED50 values were generated."( Discriminative profile of MDMA.
Schechter, MD, 1986
)
0.27
" The appearance of flushing was also dependent on dietary TRP intake and the dosage of FA."( Fenfluramine-induced behavior changes in rats prefed serotonin-altering amounts of tryptophan and pyridoxine.
Fisher, H; Lee, NS; Trout, JR; Wagner, GC, 1988
)
1.72
" The results obtained by dosage of d-amphetamine, fenfluramine or mazindol, on days 5 and 8 after tumor implantation, failed to demonstrate conclusively any predominant modification of a dopaminergic, noradrenergic, or serotonergic system in the anorectic effects of these agents."( Effects of anorectic agents in rats bearing the Walker-256 tumor.
Johnson, K; Kinney, DR; Maickel, RP, 1987
)
0.53
" When given in combination with d,l-5-HTP, there was a potentiation of the down-regulation capabilities of fenfluramine at several different dosage levels; however, maximal down-regulation was also limited to 40%."( Down-regulation of [3H]5-hydroxytryptamine binding sites in chick embryo brain by monoamine oxidase inhibitors or fenfluramine and potentiation by d,l-5-hydroxytryptophan.
DuMontier, G; Jeng, I; Soblosky, JS, 1985
)
0.69
" A dose-response effect was shown between 40 and 80 mg in control subjects (n = 7); in 4 hyperprolactinemics the higher dose also failed to increase PRL levels."( Effect of fenfluramine oral administration on serum prolactin levels in healthy and hyperprolactinemic women.
Adelasco, P; Brambilla, G; Cavioni, V; Ferrari, C; Mattei, AM; Scarduelli, C; Zavaglia, C, 1985
)
0.67
" There was a significant dose-response effect of fenfluramine on Prl but not on GH levels."( Serotonergic regulation of prolactin and growth hormone secretion in man.
Lewis, DA; Sherman, BM, 1985
)
0.52
" In a dose-response study there was no significant increase with doses of 2 or 6 mg/kg but there was a significant increase at 20 mg/kg."( Effect of fenfluramine on GDP-binding to brown adipose tissue mitochondria.
Bray, GA; Lupien, JR, 1985
)
0.67
"14C-Tiflorex given either orally or intravenously to male rats (10 mg/kg; 250 microCi) was well absorbed orally; greater than 70% of the dose was excreted in the urine in the first 48 hr after dosing by either route of administration."( The metabolism and kinetics of tiflorex in the rat.
André, J; Dring, LG; Gillet, G; Gomeni, R; Mas-Chamberlin, C; Morselli, PL,
)
0.13
" Zotepine, chlorpromazine, propericiazine, and cyproheptadine inhibited hyperthermia induced by dosing with fenfluramine in rats in a warm environment (26-28 degrees C)."( The central anti-serotonin activity of zotepine, a new neuroleptic, in rats.
Hirai, O; Katsuki, S; Mori, J; Motoyama, Y; Ono, T; Satoh, H; Shimomura, K; Terai, T; Tomoi, M, 1982
)
0.48
" Participants viewed the study and the dosing regimen positively but had negative ideas about anorexiants in general."( Extended-release fenfluramine: patient acceptance and efficacy of evening dosing.
Dorn, M; Sriwatanakul, K; Sundaresan, PR; Weintraub, M; Weis, OF, 1983
)
0.61
" However, there was one notable exception; presenting was dramatically increased following dosing with methylphenidate and diethylpropion."( The effects of several anorexigenics on monkey social behavior.
Bedford, JA; Marquis, DK; Wilson, MC, 1984
)
0.27
" The dose-response curve for this discrimination was orderly with an ED50 of about one-half of the training dose (0."( A neuropharmacological analysis of the discriminative stimulus properties of fenfluramine.
Appel, JB; White, FJ, 1981
)
0.49
"Two schedules of imipramine (IM) administration were compared, a single intraperitoneal dose (10 mg/kg) (I) and chronic oral dosage (10 mg/kg twice a day for 14 days) (II)."( Different pharmacokinetic and pharmacological effects following acute and chronic treatment with imipramine.
Daniel, W; Maj, J; Melzacka, M; Mogilnicka, E, 1982
)
0.26
" There was a strong correlation between drug dosage and plasma levels of fenfluramine."( Plasma fenfluramine levels, weight loss and side effects: a failure to find a relationship.
Brownell, K; Campbell, DB; Pietrusko, R; Stunkard, A, 1982
)
0.95
" When graphically represented, the dose-response curves were shown to be parallel suggesting a common site and/or mechanism of action."( Effect of fenfluramine and nicotine upon a stimulant-depressant continuum.
Schechter, MD, 1981
)
0.67
" Mice were dosed daily (25 mg/kg po) for 28 days after which time carcass composition was determined."( The contribution of increased thermogenesis to the effect of anorectic drugs on body composition in mice.
Arch, JR, 1981
)
0.26
" Statistical analysis of the results from 22 patients showed that there was no significant difference between prothrombin times and anticoagulant dosage in the period when patients were receiving benfluorex and the values recorded during the baseline and follow-up periods."( Co-administration of benfluorex with oral anticoagulant therapy.
Brems, HM; De Witte, P, 1980
)
0.26
"0 kg m-2, who were poorly controlled on insulin (mean dosage 58."( Obese patients with type 2 diabetes poorly controlled by insulin and metformin: effects of adjunctive dexfenfluramine therapy on glycaemic control.
Molyneaux, LM; Willey, KA; Yue, DK,
)
0.35
") 2 h after Fen application, a strong synergism could be seen in the late treatment period as shown by the dose-response curves and by statistical analysis using the principle of least squares."( Potentiation by caffeine of the frequencies of chromosomal aberrations induced by chronic exposure to fenfluramine in mice.
Agarwal, K; Mukherjee, A; Sen, S; Sharma, A, 1994
)
0.5
" Comparative repeat dose simulation in monkey and man indicated that the dosage in primates would need to be increased 10-fold to achieve comparable dexfenfluramine steady-state plasma Cmax, producing nor-metabolite levels several times those in man, whilst for comparable metabolite Cmax, those of the parent drug would be correspondingly too low."( Oral kinetics of dexfenfluramine and dexnorfenfluramine in non-human primates.
Bergami, A; Caccia, S; Campbell, B; Fracasso, C; Garattini, S, 1995
)
0.81
"The acute appetite suppressant effect of dexfenfluramine (DF) in rats, which may depend upon its action to release serotonin (5-HT) in the brain, often declines with repeated dosing (tolerance)."( Effect of chronic dexfenfluramine on Fos in rat brain.
Li, BH; Rowland, NE, 1996
)
0.87
") induced penile erection in rats, with bell-shaped dose-response curves."( Brain somatostatin depletion by cysteamine attenuates the penile erection induced by serotonergic and dopaminergic, but not by cholinergic, activation in rats.
Maeda, N; Matsuoka, N; Yamaguchi, I; Yamazaki, M, 1996
)
0.29
" Neither d-fenfluramine, paroxetine, or ipsapirone following acute dosage had a statistically significant effect on nocturnal melatonin synthesis."( Nocturnal plasma melatonin concentrations in healthy volunteers: effect of single doses of d-fenfluramine, paroxetine, and ipsapirone.
Burrows, GD; Nathan, PJ; Norman, TR, 1996
)
0.9
" The threshold dose was two to three times higher in CD rats than in their intact controls, but the dynamic range of the dose-response curves of the two groups were overlapping with similar slopes of decline and with comparable maximal intake suppression."( Contribution of caudal brainstem to d-fenfluramine anorexia.
Donahey, JC; Grill, HJ; Kaplan, JM; King, L, 1997
)
0.57
" The dose-response curve for the three drugs was biphasic, suggesting that other mechanisms are operative at higher doses."( Pharmacological evaluation of IQM-95,333, a highly selective CCKA receptor antagonist with anxiolytic-like activity in animal models.
Ballaz, S; Barber, A; Del Río, J; Fortuño, A; García-López, MT; Gómez-Monterrey, I; González-Muñiz, R; Herranz, R; Martin-Martínez, M, 1997
)
0.3
" The recommended dosage is 15 mg twice daily."( Dexfenfluramine hydrochloride: an anorexigenic agent.
Bever, KA; Perry, PJ, 1997
)
0.92
" Experiments were conducted to determine 1) the dose-response of d-Fen on BT in a 28 degrees C environment, 2) the acute effect of d-Fen on long-term depletion of 5-HT and 5-HT PMT in a 4 degrees C, 22 degrees C or 28 degrees C environment and 3) the effect of a 22 degrees C environment vs."( Elevated environmental temperatures can induce hyperthermia during d-fenfluramine exposure and enhance 5-hydroxytryptamine (5-HT) depletion in the brain.
Bowyer, JF; Slikker, W; Stewart, CW, 1997
)
0.53
" The duration of the trial varied from 3 to 20 weeks, with the dexfenfluramine dosage being 15 mg twice daily."( Dexfenfluramine for weight gain secondary to psychotropics.
Gupta, S; Masand, PS, 1997
)
1.16
" The repeated FEN dosing regimen dramatically reduced (> 50%) postmortem 5-HT levels in the mediobasal hypothalamus, basolateral amygdala, and hippocampus, while the lateral hypothalamus was unaffected."( In vivo correlates of central serotonin function after high-dose fenfluramine administration.
Ayestas, MA; Baumann, MH; Rothman, RB, 1998
)
0.54
" At 1 and 2 weeks after the 4 d dosing regimen, acute FEN (1."( Functional consequences of central serotonin depletion produced by repeated fenfluramine administration in rats.
Ayestas, MA; Baumann, MH; Rothman, RB, 1998
)
0.53
" Because many obese patients skip breakfast and eat more in the afternoon and evening, medication was dosed in order to cover these high-risk eating periods."( Lower dosages of phentermine-fenfluramine given in the afternoon: five cases with significant weight loss.
Katz, DA; Maloney, MJ; McConville, BJ; Sutkamp, JC, 1999
)
0.59
"To determine whether the severity of valvulopathy was associated with the dosage of fenfluramine taken by fenfluramine-phentermine users with valvulopathy."( Dose-effect of fenfluramine use on the severity of valvular heart disease among fen-phen patients with valvulopathy.
Bowman, BA; Graham, DJ; Green, L; Li, R; Serdula, MK; Williamson, DF, 1999
)
0.88
"The proportion with severe valvulopathy increased from 20-66% with increasing fenfluramine dosage from /=60 mg/d."( Dose-effect of fenfluramine use on the severity of valvular heart disease among fen-phen patients with valvulopathy.
Bowman, BA; Graham, DJ; Green, L; Li, R; Serdula, MK; Williamson, DF, 1999
)
0.88
" Doppler echocardiographic examination should be performed after prolonged exposure (> 3 months) or a high dosage of these drugs, in circumstances such as the presence of cardiovascular symptoms, a cardiac murmur, or an uncertain cardiac examination because of weight of patients."( [Appetite suppressants and heart valve disorders].
Adams, C; Cohen, A, 1999
)
0.3
"2 times the equivalent human daily dosage according to body surface area."( Impact of antenatal exposure of mice to fenfluramine on cardiac development and long-term growth of the offspring.
Christensen, HD; Gonzalez, CL; Kupiec, TC; Paulsen, AL; Rayburn, WF; Sienko, AE; Stewart, JD, 2000
)
0.57
" Drugs were subsequently tested for potential long-lasting effects on brain tissue 5-HT after repeated dosing (2."( Serotonin transporters, serotonin release, and the mechanism of fenfluramine neurotoxicity.
Ayestas, MA; Baumann, MH; Dersch, CM; Partilla, JS; Rothman, RB, 2000
)
0.55
" Furthermore, using a dosing regimen adapted from studies on methamphetamine (e."( Elevations in plasmatic titers of corticosterone and aldosterone, in the absence of changes in ACTH, testosterone, or glial fibrillary acidic protein, 72 h following D,L-fenfluramine or D-fenfluramine administration to rats.
Inman-Wood, SL; McCrea, AE; Morford, LL; Vorhees, CV; Williams, MT,
)
0.33
"Establishing functional deficits as a result of neurotoxic dosing regimens of MDMA has been difficult."( Effects of fenfluramine, m-CPP and triazolam on repeated-acquisition in squirrel monkeys before and after neurotoxic MDMA administration.
Delatte, MS; McCann, UD; Moerschbaecher, JM; Ricaurte, GA; Stevenson, MW; Winsauer, PJ; Yuan, J, 2002
)
0.7
" The dose-response relationship between the cumulative dose of drugs and the presence of aortic regurgitation was significant for fenfluramine only (chi-square=5."( High prevalence of fenfluramine-related aortic regurgitation in women with end-stage renal disease secondary to Chinese herb nephropathy.
Muniz Martinez, MC; Nortier, J; Plein, D; Unger, P; Vandenbossche, JL; Vanherweghem, JL; Vereerstraeten, P, 2003
)
0.85
" There were 80% reductions in the plasma membrane-associated 5-HT transporters 6 months after either the FEN or MDMA dosing regimen indicating that both treatments produced long-term serotonergic effects."( Plasma levels of parent compound and metabolites after doses of either d-fenfluramine or d-3,4-methylenedioxymethamphetamine (MDMA) that produce long-term serotonergic alterations.
Ali, SF; Bowyer, JF; Frederick, DL; Itzak, Y; Mayorga, AJ; Newport, GD; Paule, MG; Slikker, W; Young, JF, 2003
)
0.55
" In the present study, we determined the effect of high-dose D-FEN or PCA, administered according to a "neurotoxic" dosing regimen, on the density of SERT sites using ligand binding methods and on SERT protein levels using Western blots."( High-dose fenfluramine administration decreases serotonin transporter binding, but not serotonin transporter protein levels, in rat forebrain.
Baumann, MH; Cadet, JL; Dersch, CM; Jayanthi, S; Prisinzano, T; Rice, KC; Rothman, RB; Wang, X, 2003
)
0.72
" dosing for measurement of obesity-related parameters."( Antiobesity effects of A-331440, a novel non-imidazole histamine H3 receptor antagonist.
Bennani, YL; Bush, EN; Esbenshade, TA; Faghih, R; Fox, GB; Hancock, AA; Jacobson, P; Knourek-Segel, V; Krueger, KM; Nuss, ME; Pan, JB; Shapiro, R; Witte, DG; Yao, BB, 2004
)
0.32
" This dosing regimen also produces deficits in sequential learning as measured in the Cincinnati water maze (CWM)."( Metyrapone attenuates the sequential learning deficits but not monoamine depletions following d,l-fenfluramine administration to adult rats.
Blankenmeyer, TL; Brown-Strittholt, CA; Gudelsky, GA; Skelton, MR; Vorhees, CV; Williams, MT, 2004
)
0.54
"The present study sought to perform a dose-response analysis of the effects of acute central leptin administration on meal patterning using a validated, objective meal definition and to compare these results to those obtained with a previously used, subjective meal definition."( Leptin and post-prandial satiety: acute central leptin more potently reduces meal frequency than meal size in the rat.
Inoue, K; Koob, GF; Tabarin, A; Valdez, GR; Zorrilla, EP, 2005
)
0.33
" For this purpose, neuronal activity was measured in rats with rivastigmine-induced elevated ACh levels after a 95% 5-HT depletion obtained by dosing p-chlorophenylalanine followed by D,L-fenfluramine."( Serotonin depletion results in a decrease of the neuronal activation caused by rivastigmine in the rat hippocampus.
Aznar, S; Knudsen, GM; Kornum, BR; Moller, A; Ronn, LC; Weikop, P, 2006
)
0.52
"1 mg/kg/injection) functioned as a positive reinforcer with sigmoidal or biphasic dose-response functions."( Self-administration of mixtures of fenfluramine and amphetamine by rhesus monkeys.
Wee, S; Woolverton, WL, 2006
)
0.61
" Depending on the intended indication and dosing regimen, PPL can delay or stop development of a compound in the drug discovery process."( Evaluation of a published in silico model and construction of a novel Bayesian model for predicting phospholipidosis inducing potential.
Gehlhaar, D; Greene, N; Johnson, TO; Pelletier, DJ; Tilloy-Ellul, A,
)
0.13
" Rhesus macaques self-administering cocaine underwent a 6-week dosing regimen with fluoxetine designed to approximate serum concentrations observed in humans."( Neurobiological changes mediating the effects of chronic fluoxetine on cocaine use.
Goodman, MM; Howell, LL; Kimmel, HL; Mun, J; Nye, JA; Rice, KC; Sawyer, EK; Stehouwer, JS; Voll, RJ, 2012
)
0.38
" From the ongoing clinical trial data, it is evident that fenfluramine is proving to be a promising antiepileptic drug with very favorable pharmacokinetics and with a good overall safety profile when used at a lower dosage (0."( Fenfluramine for the Treatment of Dravet Syndrome and Lennox-Gastaut Syndrome.
Balagura, G; Cacciatore, M; Grasso, EA; Striano, P; Verrotti, A, 2020
)
2.25
" This practical guide provides an overview of these main ASMs including their indications/contraindications, mechanism of action, efficacy, safety and tolerability profile, dosage requirements, and laboratory and clinical parameters to be evaluated."( A Practical Guide to the Treatment of Dravet Syndrome with Anti-Seizure Medication.
Schubert-Bast, S; Strzelczyk, A, 2022
)
0.72
" This continuing education article summarizes available efficacy and safety data involving cannabidiol, stiripentol, and fenfluramine and provides a practical review of dosing strategies, pharmacokinetics, and monitoring interventions relevant to their use."( Treatment-Refractory Dravet Syndrome: Considerations for Novel Medications.
Blackmer, AB; Lopez, JC; Orth, LE; Pare, JR,
)
0.34
[information is derived through text-mining from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Roles (3)

RoleDescription
serotonin uptake inhibitorA compound that specifically inhibits the reuptake of serotonin in the brain. This increases the serotonin concentration in the synaptic cleft which then activates serotonin receptors to a greater extent.
serotonergic agonistAn agent that has an affinity for serotonin receptors and is able to mimic the effects of serotonin by stimulating the physiologic activity at the cell receptors. Serotonin agonists are used as antidepressants, anxiolytics, and in the treatment of migraine disorders.
appetite depressantAgent that is used to decrease appetite.
[role information is derived from Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

Drug Classes (2)

ClassDescription
secondary amino compoundA compound formally derived from ammonia by replacing two hydrogen atoms by organyl groups.
(trifluoromethyl)benzenesAn organofluorine compound that is (trifluoromethyl)benzene and derivatives arising from substitution of one or more of the phenyl hydrogens.
[compound class information is derived from Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

Protein Targets (13)

Potency Measurements

ProteinTaxonomyMeasurementAverage (µ)Min (ref.)Avg (ref.)Max (ref.)Bioassay(s)
Microtubule-associated protein tauHomo sapiens (human)Potency0.12590.180013.557439.8107AID1468
cytochrome P450 family 3 subfamily A polypeptide 4Homo sapiens (human)Potency23.91850.01237.983543.2770AID1645841
glucocorticoid receptor [Homo sapiens]Homo sapiens (human)Potency6.74000.000214.376460.0339AID720691
GVesicular stomatitis virusPotency37.90830.01238.964839.8107AID1645842
cytochrome P450 2D6Homo sapiens (human)Potency3.79080.00108.379861.1304AID1645840
euchromatic histone-lysine N-methyltransferase 2Homo sapiens (human)Potency7.07950.035520.977089.1251AID504332
potassium voltage-gated channel subfamily H member 2 isoform dHomo sapiens (human)Potency11.22020.01789.637444.6684AID588834
lamin isoform A-delta10Homo sapiens (human)Potency19.95260.891312.067628.1838AID1487
Interferon betaHomo sapiens (human)Potency37.90830.00339.158239.8107AID1645842
HLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)Potency37.90830.01238.964839.8107AID1645842
Inositol hexakisphosphate kinase 1Homo sapiens (human)Potency37.90830.01238.964839.8107AID1645842
cytochrome P450 2C9, partialHomo sapiens (human)Potency37.90830.01238.964839.8107AID1645842
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Activation Measurements

ProteinTaxonomyMeasurementAverageMin (ref.)Avg (ref.)Max (ref.)Bioassay(s)
Sodium-dependent serotonin transporterRattus norvegicus (Norway rat)EC50 (µMol)0.10800.00070.42361.7650AID1442369
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Biological Processes (45)

Processvia Protein(s)Taxonomy
cell surface receptor signaling pathway via JAK-STATInterferon betaHomo sapiens (human)
response to exogenous dsRNAInterferon betaHomo sapiens (human)
B cell activation involved in immune responseInterferon betaHomo sapiens (human)
cell surface receptor signaling pathwayInterferon betaHomo sapiens (human)
cell surface receptor signaling pathway via JAK-STATInterferon betaHomo sapiens (human)
response to virusInterferon betaHomo sapiens (human)
positive regulation of autophagyInterferon betaHomo sapiens (human)
cytokine-mediated signaling pathwayInterferon betaHomo sapiens (human)
natural killer cell activationInterferon betaHomo sapiens (human)
positive regulation of peptidyl-serine phosphorylation of STAT proteinInterferon betaHomo sapiens (human)
cellular response to interferon-betaInterferon betaHomo sapiens (human)
B cell proliferationInterferon betaHomo sapiens (human)
negative regulation of viral genome replicationInterferon betaHomo sapiens (human)
innate immune responseInterferon betaHomo sapiens (human)
positive regulation of innate immune responseInterferon betaHomo sapiens (human)
regulation of MHC class I biosynthetic processInterferon betaHomo sapiens (human)
negative regulation of T cell differentiationInterferon betaHomo sapiens (human)
positive regulation of transcription by RNA polymerase IIInterferon betaHomo sapiens (human)
defense response to virusInterferon betaHomo sapiens (human)
type I interferon-mediated signaling pathwayInterferon betaHomo sapiens (human)
neuron cellular homeostasisInterferon betaHomo sapiens (human)
cellular response to exogenous dsRNAInterferon betaHomo sapiens (human)
cellular response to virusInterferon betaHomo sapiens (human)
negative regulation of Lewy body formationInterferon betaHomo sapiens (human)
negative regulation of T-helper 2 cell cytokine productionInterferon betaHomo sapiens (human)
positive regulation of apoptotic signaling pathwayInterferon betaHomo sapiens (human)
response to exogenous dsRNAInterferon betaHomo sapiens (human)
B cell differentiationInterferon betaHomo sapiens (human)
natural killer cell activation involved in immune responseInterferon betaHomo sapiens (human)
adaptive immune responseInterferon betaHomo sapiens (human)
T cell activation involved in immune responseInterferon betaHomo sapiens (human)
humoral immune responseInterferon betaHomo sapiens (human)
positive regulation of T cell mediated cytotoxicityHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
adaptive immune responseHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independentHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
regulation of T cell anergyHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
defense responseHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
immune responseHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
detection of bacteriumHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
regulation of interleukin-12 productionHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
regulation of interleukin-6 productionHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
protection from natural killer cell mediated cytotoxicityHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
innate immune responseHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
regulation of dendritic cell differentiationHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
antigen processing and presentation of endogenous peptide antigen via MHC class IbHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
inositol phosphate metabolic processInositol hexakisphosphate kinase 1Homo sapiens (human)
phosphatidylinositol phosphate biosynthetic processInositol hexakisphosphate kinase 1Homo sapiens (human)
negative regulation of cold-induced thermogenesisInositol hexakisphosphate kinase 1Homo sapiens (human)
inositol phosphate biosynthetic processInositol hexakisphosphate kinase 1Homo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Molecular Functions (18)

Processvia Protein(s)Taxonomy
cytokine activityInterferon betaHomo sapiens (human)
cytokine receptor bindingInterferon betaHomo sapiens (human)
type I interferon receptor bindingInterferon betaHomo sapiens (human)
protein bindingInterferon betaHomo sapiens (human)
chloramphenicol O-acetyltransferase activityInterferon betaHomo sapiens (human)
TAP bindingHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
signaling receptor bindingHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
protein bindingHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
peptide antigen bindingHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
TAP bindingHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
protein-folding chaperone bindingHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
inositol-1,3,4,5,6-pentakisphosphate kinase activityInositol hexakisphosphate kinase 1Homo sapiens (human)
inositol hexakisphosphate kinase activityInositol hexakisphosphate kinase 1Homo sapiens (human)
inositol heptakisphosphate kinase activityInositol hexakisphosphate kinase 1Homo sapiens (human)
inositol hexakisphosphate 5-kinase activityInositol hexakisphosphate kinase 1Homo sapiens (human)
protein bindingInositol hexakisphosphate kinase 1Homo sapiens (human)
ATP bindingInositol hexakisphosphate kinase 1Homo sapiens (human)
inositol hexakisphosphate 1-kinase activityInositol hexakisphosphate kinase 1Homo sapiens (human)
inositol hexakisphosphate 3-kinase activityInositol hexakisphosphate kinase 1Homo sapiens (human)
inositol 5-diphosphate pentakisphosphate 5-kinase activityInositol hexakisphosphate kinase 1Homo sapiens (human)
inositol diphosphate tetrakisphosphate kinase activityInositol hexakisphosphate kinase 1Homo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Ceullar Components (22)

Processvia Protein(s)Taxonomy
extracellular spaceInterferon betaHomo sapiens (human)
extracellular regionInterferon betaHomo sapiens (human)
Golgi membraneHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
endoplasmic reticulumHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
Golgi apparatusHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
plasma membraneHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
cell surfaceHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
ER to Golgi transport vesicle membraneHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
membraneHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
secretory granule membraneHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
phagocytic vesicle membraneHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
early endosome membraneHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
recycling endosome membraneHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
extracellular exosomeHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
lumenal side of endoplasmic reticulum membraneHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
MHC class I protein complexHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
extracellular spaceHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
external side of plasma membraneHLA class I histocompatibility antigen, B alpha chain Homo sapiens (human)
fibrillar centerInositol hexakisphosphate kinase 1Homo sapiens (human)
nucleoplasmInositol hexakisphosphate kinase 1Homo sapiens (human)
cytosolInositol hexakisphosphate kinase 1Homo sapiens (human)
nucleusInositol hexakisphosphate kinase 1Homo sapiens (human)
cytoplasmInositol hexakisphosphate kinase 1Homo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Bioassays (28)

Assay IDTitleYearJournalArticle
AID1296008Cytotoxic Profiling of Annotated Libraries Using Quantitative High-Throughput Screening2020SLAS discovery : advancing life sciences R & D, 01, Volume: 25, Issue:1
Cytotoxic Profiling of Annotated and Diverse Chemical Libraries Using Quantitative High-Throughput Screening.
AID1346987P-glycoprotein substrates identified in KB-8-5-11 adenocarcinoma cell line, qHTS therapeutic library screen2019Molecular pharmacology, 11, Volume: 96, Issue:5
A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein.
AID1346986P-glycoprotein substrates identified in KB-3-1 adenocarcinoma cell line, qHTS therapeutic library screen2019Molecular pharmacology, 11, Volume: 96, Issue:5
A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein.
AID588219FDA HLAED, gamma-glutamyl transferase (GGT) increase2004Current drug discovery technologies, Dec, Volume: 1, Issue:4
Assessment of the health effects of chemicals in humans: II. Construction of an adverse effects database for QSAR modeling.
AID1442369Activity at SERT in rat synaptosomes assessed as release of [3H]HT after 5 mins by liquid scintillation counting method2017Journal of medicinal chemistry, 04-13, Volume: 60, Issue:7
The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse.
AID588217FDA HLAED, serum glutamic pyruvic transaminase (SGPT) increase2004Current drug discovery technologies, Dec, Volume: 1, Issue:4
Assessment of the health effects of chemicals in humans: II. Construction of an adverse effects database for QSAR modeling.
AID588214FDA HLAED, liver enzyme composite activity2004Current drug discovery technologies, Dec, Volume: 1, Issue:4
Assessment of the health effects of chemicals in humans: II. Construction of an adverse effects database for QSAR modeling.
AID540244Phospholipidosis-positive literature compound observed in guinea pig
AID588218FDA HLAED, lactate dehydrogenase (LDH) increase2004Current drug discovery technologies, Dec, Volume: 1, Issue:4
Assessment of the health effects of chemicals in humans: II. Construction of an adverse effects database for QSAR modeling.
AID588216FDA HLAED, serum glutamic oxaloacetic transaminase (SGOT) increase2004Current drug discovery technologies, Dec, Volume: 1, Issue:4
Assessment of the health effects of chemicals in humans: II. Construction of an adverse effects database for QSAR modeling.
AID588215FDA HLAED, alkaline phosphatase increase2004Current drug discovery technologies, Dec, Volume: 1, Issue:4
Assessment of the health effects of chemicals in humans: II. Construction of an adverse effects database for QSAR modeling.
AID588220Literature-mined public compounds from Kruhlak et al phospholipidosis modelling dataset2008Toxicology mechanisms and methods, , Volume: 18, Issue:2-3
Development of a phospholipidosis database and predictive quantitative structure-activity relationship (QSAR) models.
AID1132098Toxicity in Beagle dog assessed as emesis up to 10 mg/kg administered through gelatin capsule for every week for 6 weeks1978Journal of medicinal chemistry, Feb, Volume: 21, Issue:2
Linked Aryl Aryloxypropanolamines as a new class of lipid catabolis agents.
AID29811Oral bioavailability in human2000Journal of medicinal chemistry, Jun-29, Volume: 43, Issue:13
QSAR model for drug human oral bioavailability.
AID540237Phospholipidosis-positive literature compound observed in rat
AID696957Antiobesity activity in DIO Sprague-Dawley rat assessed as reduction of body weight at 3 mg/kg, po administered bid for 12 days2012ACS medicinal chemistry letters, Mar-08, Volume: 3, Issue:3
Discovery of MK-7725, A Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity.
AID319946Suppression of food intake in ip dosed DIO rat after 24 hrs relative to control2008Bioorganic & medicinal chemistry letters, Jan-01, Volume: 18, Issue:1
Identification and characterization of pyrrolidine diastereoisomers as potent functional agonists and antagonists of the human melanocortin-4 receptor.
AID302840Decrease in cumulative food intake in high-fat diet fed CD rat at 5 mg/kg, ip after 1 to 6 hrs2007Bioorganic & medicinal chemistry letters, Dec-01, Volume: 17, Issue:23
Synthesis and characterization of pyrrolidine derivatives as potent agonists of the human melanocortin-4 receptor.
AID26304Partition coefficient (logD6.5)2000Journal of medicinal chemistry, Jun-29, Volume: 43, Issue:13
QSAR model for drug human oral bioavailability.
AID1132072Antiobesity activity in mouse assessed as reduction in utero fat at 0.04% administered every day through diet for 10 days measured after day 10 relative to control1978Journal of medicinal chemistry, Feb, Volume: 21, Issue:2
Linked Aryl Aryloxypropanolamines as a new class of lipid catabolis agents.
AID1132077Antiobesity activity in mouse assessed as reduction in utero fat at 0.08% administered every day through diet for 10 days measured after day 10 relative to control1978Journal of medicinal chemistry, Feb, Volume: 21, Issue:2
Linked Aryl Aryloxypropanolamines as a new class of lipid catabolis agents.
AID29359Ionization constant (pKa)2000Journal of medicinal chemistry, Jun-29, Volume: 43, Issue:13
QSAR model for drug human oral bioavailability.
AID588208Literature-mined public compounds from Lowe et al phospholipidosis modelling dataset2010Molecular pharmaceutics, Oct-04, Volume: 7, Issue:5
Predicting phospholipidosis using machine learning.
AID319949Reduction of body weight in po dosed DIO rat2008Bioorganic & medicinal chemistry letters, Jan-01, Volume: 18, Issue:1
Identification and characterization of pyrrolidine diastereoisomers as potent functional agonists and antagonists of the human melanocortin-4 receptor.
AID1442371Activity at NET in rat synaptosomes assessed as release of [3H]NE after 30 mins by liquid scintillation counting method2017Journal of medicinal chemistry, 04-13, Volume: 60, Issue:7
The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse.
AID540239Phospholipidosis-positive literature compound observed in dog
AID22293Delta logD (logD6.5 - logD7.4)2000Journal of medicinal chemistry, Jun-29, Volume: 43, Issue:13
QSAR model for drug human oral bioavailability.
AID504749qHTS profiling for inhibitors of Plasmodium falciparum proliferation2011Science (New York, N.Y.), Aug-05, Volume: 333, Issue:6043
Chemical genomic profiling for antimalarial therapies, response signatures, and molecular targets.
[information is prepared from bioassay data collected from National Library of Medicine (NLM), extracted Dec-2023]

Research

Studies (2,963)

TimeframeStudies, This Drug (%)All Drugs %
pre-19901229 (41.48)18.7374
1990's1067 (36.01)18.2507
2000's415 (14.01)29.6817
2010's182 (6.14)24.3611
2020's70 (2.36)2.80
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Market Indicators

Research Demand Index: 56.91

According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be very strong demand-to-supply ratio for research on this compound.

MetricThis Compound (vs All)
Research Demand Index56.91 (24.57)
Research Supply Index8.19 (2.92)
Research Growth Index4.34 (4.65)
Search Engine Demand Index101.77 (26.88)
Search Engine Supply Index2.03 (0.95)

This Compound (56.91)

All Compounds (24.57)

Study Types

Publication TypeThis drug (%)All Drugs (%)
Trials478 (15.36%)5.53%
Reviews265 (8.52%)6.00%
Case Studies156 (5.01%)4.05%
Observational6 (0.19%)0.25%
Other2,207 (70.92%)84.16%
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Clinical Trials (19)

Trial Overview

TrialPhaseEnrollmentStudy TypeStart DateStatus
"Investigation of Serotonin Neurotransmission in Ecstasy Users Employing Combined Dexfenfluramine Challenge and Positron Emission Tomography: a Functional Probe to Assess MDMA Neurotoxicity" [NCT01296802]50 participants (Actual)Interventional2006-04-30Completed
Fenfluramine for the Treatment of Refractory Epilepsy in Adult Dravet Patients [NCT05560282]Phase 315 participants (Anticipated)Interventional2022-12-10Not yet recruiting
Treatment of Dravet Syndrome With Fenfluramine (Expanded Access Protocol) [NCT04437004]0 participants Expanded AccessAvailable
Open-Label, Single-Arm, Phase 3 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Fenfluramine (Hydrochloride) in Infants 1 Year to Less Than 2 Years of Age With Dravet Syndrome [NCT06118255]Phase 320 participants (Anticipated)Interventional2023-12-31Recruiting
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome [NCT02682927]Phase 3262 participants (Actual)Interventional2016-01-15Completed
A Phase II Study of Fenfluramine for Treatment of Refractory Infantile Spasms [NCT04289467]Phase 210 participants (Anticipated)Interventional2023-09-01Not yet recruiting
ZX008 Expanded Access Protocol - Dravet Syndrome Treatment Plan [NCT03780127]0 participants Expanded AccessApproved for marketing
An Exploratory, Pilot Study to Assess the Usability of the Embrace Seizure Detection Watch in Children and Young Adults With Dravet Syndrome: A Sub-study to the ZX008-1503 Open-Label Extension Trial [NCT03299842]Phase 35 participants (Actual)Interventional2017-07-12Terminated(stopped due to The study was stopped due to low enrollment.)
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Fixed-Dose, Multicenter Study To Examine The Efficacy And Safety Of ZX008 In Subjects With CDKL5 Deficiency Disorder Followed By An Open-Label Extension [NCT05064878]Phase 3100 participants (Anticipated)Interventional2022-03-08Recruiting
Fenfluramine for the Treatment of Different Types of Developmental and Epileptic Encephalopathies: a Pilot Trial Exploring Epileptic and Non-epileptic Outcomes [NCT05232630]Phase 420 participants (Anticipated)Interventional2022-10-20Recruiting
Add-on Therapy With Low Dose Fenfluramine in Lennox Gastaut Epilepsy [NCT02655198]Phase 213 participants (Actual)Interventional2016-01-31Active, not recruiting
A Multicenter, 2-Cohort Trial to First Assess the Pharmacokinetic and Safety Profile of a Single Dose of ZX008 (Fenfluramine Hydrochloride) Oral Solution When Added to Standard of Care (Cohort 1), Followed by a Randomized, Double-blind, Placebo-controlled [NCT02926898]Phase 387 participants (Actual)Interventional2017-01-27Completed
An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy for Seizures in Patients With Rare Seizure Disorders Such as Epileptic Encephalopathies Including Dravet Syndrome and [NCT03936777]Phase 3412 participants (Actual)Interventional2019-04-22Active, not recruiting
The Effect of Seven Day Fenfluramine Administration on Cognition in Healthy Volunteers [NCT05026398]Phase 456 participants (Actual)Interventional2021-04-12Completed
Fenfluramine in CKDL5 Deficiency Disorder (CDD) [NCT03861871]Phase 27 participants (Actual)Interventional2019-10-29Completed
[NCT00000506]Phase 20 participants Interventional1983-05-31Completed
An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride HCl) Oral Solution as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome [NCT02823145]Phase 3375 participants (Actual)Interventional2016-06-08Completed
Predictive Values of Serotonergic Alterations for Outcome [NCT00000313]Phase 10 participants InterventionalTerminated
An Open-Label Treatment of ZX008 (Fenfluramine Hydrochloride) in Pediatric and Adult Epilepsy Patients (Ages 4-25) With Sunflower Syndrome. [NCT03790137]Phase 320 participants (Actual)Interventional2019-05-31Active, not recruiting
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

Trial Outcomes

TrialOutcome
NCT02682927 (25) [back to overview]Area Under the Concentration Time Curve of ZX008 From Time Zero to Time 24 Hours [AUC0-24hours] at Steady State
NCT02682927 (25) [back to overview]Change From Baseline in Convulsive + Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo
NCT02682927 (25) [back to overview]Change From Baseline in Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo
NCT02682927 (25) [back to overview]Change From Baseline in the Mean Convulsive Seizures Frequency (MCSF) to the Combined Titration and Maintenance Periods (T+M) in Participants Receiving ZX008 0.8 mg/kg/Day Compared to Placebo
NCT02682927 (25) [back to overview]Change From Baseline in the Mean Convulsive Seizures Frequency to the Combined Titration and Maintenance Period (T+M) in Participants Receiving ZX008 0.2 mg/kg/Day Compared to Placebo
NCT02682927 (25) [back to overview]Change From Baseline to Day 99 in the Overall Quality of Life Score From the Pediatric Quality of Life Inventory™ (PedsQL) Score in Each ZX008 Treatment Arm Compared to Placebo
NCT02682927 (25) [back to overview]Change From Baseline to Day 99 in the Quality of Life in Childhood Epilepsy (QOLCE) Score to Measure Quality of Life in Each ZX008 Treatment Arm Compared to Placebo
NCT02682927 (25) [back to overview]Change From Baseline to Day 99 in the Total Score From PedsQL Family Impact Module Score in Each ZX008 Treatment Arm Compared to Placebo
NCT02682927 (25) [back to overview]Elimination Half-life [t1/2 Beta] of ZX008 at Steady State
NCT02682927 (25) [back to overview]Longest Convulsive Seizure-free Interval in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
NCT02682927 (25) [back to overview]Maximum Observed Concentration of ZX008 Determined Directly From the Concentration Time Profile [Cmax] at Steady State
NCT02682927 (25) [back to overview]Number of Convulsive Seizure-free Days in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
NCT02682927 (25) [back to overview]Percentage of Participants Who Achieved a ≥50% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period
NCT02682927 (25) [back to overview]Percentage of Participants Who Achieved a ≥75% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period
NCT02682927 (25) [back to overview]Percentage of Participants Who Achieved a 100% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period
NCT02682927 (25) [back to overview]Percentage of Participants Who Achieved Greater Than or Equal to 25% (≥25%) Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period
NCT02682927 (25) [back to overview]Percentage of Participants With Hospitalization and Healthcare Resource Utilization to Treat Seizures in Each ZX008 Treatment Arm Compared to Placebo During Study
NCT02682927 (25) [back to overview]Percentage of Participants With Rescue Medication Usage in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
NCT02682927 (25) [back to overview]Percentage of Participants With Status Epilepticus (SE) in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
NCT02682927 (25) [back to overview]Time to Maximum Concentration [Tmax] of ZX008 at Steady State
NCT02682927 (25) [back to overview]Change From Baseline to Day 99 in Affective Symptoms of the Parent/Caregiver Using the Hospital Anxiety and Depression Scale (HADS) in Each ZX008 Treatment Arm Compared to Placebo
NCT02682927 (25) [back to overview]Distribution of Duration of Convulsive Seizures (in Percentage) in Each ZX008 Treatment Arm Compared to Placebo at Baseline and During the Titration and Maintenance Period
NCT02682927 (25) [back to overview]Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Rating Score, as Assessed by the Principal Investigator in Each ZX008 Treatment Arm Compared to Placebo
NCT02682927 (25) [back to overview]Percentage of Participants With Clinical Global Impression - Improvement Rating Score, as Assessed by the Parent/Caregiver in Each ZX008 Treatment Arm Compared to Placebo
NCT02682927 (25) [back to overview]Quality of Life (QoL) of the Parent/Caregiver Using the EQ- 5D-5L Scale in Each ZX008 Treatment Arm Compared to Placebo at Baseline and Day 99
NCT02823145 (8) [back to overview]Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36)
NCT02823145 (8) [back to overview]Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period
NCT02823145 (8) [back to overview]Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Day 1 to End of Study (EOS) Visit (Month 42) in the OLE Treatment Period
NCT02823145 (8) [back to overview]Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Month 2 to EOS (Month 42) in the OLE Treatment Period
NCT02823145 (8) [back to overview]Percentage of Participants With Serious Treatment-emergent Adverse Events (TEAEs) During the OLE Treatment Period
NCT02823145 (8) [back to overview]Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Open-label Extension (OLE) Treatment Period
NCT02823145 (8) [back to overview]Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Leading to Withdrawal From Investigational Medicinal Product (IMP) During the OLE Treatment Period
NCT02823145 (8) [back to overview]Convulsive Seizure Frequency (CSF) by Mean Daily Dose During the Overall OLE Treatment Period
NCT02926898 (3) [back to overview]Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period
NCT02926898 (3) [back to overview]Longest Convulsive Seizure-Free Interval (Days)
NCT02926898 (3) [back to overview]Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period
NCT03790137 (13) [back to overview]% Change in Frequency of Handwaving Episodes
NCT03790137 (13) [back to overview]Change in Frequency of Generalized Tonic-clonic Seizures
NCT03790137 (13) [back to overview]Change in Spike Frequency on EEG
NCT03790137 (13) [back to overview]Changes in Anger Determined by the Beck Self Report Inventory
NCT03790137 (13) [back to overview]Changes in Anxiety Determined by the Beck Self Report Inventory
NCT03790137 (13) [back to overview]Changes in Cognitive Functioning Determined by the Weschler Abbreviated Scale of Intelligence (WASI-II Subtests)
NCT03790137 (13) [back to overview]Changes in Cognitive Functioning Determined by the Weschler Intelligence Scale for Children (WISC-V) -Processing Speed Subtests.
NCT03790137 (13) [back to overview]Changes in Depression Determined by the Beck Self Report Inventory
NCT03790137 (13) [back to overview]Changes in Disruptive Behavior Determined by the Beck Self Report Inventory
NCT03790137 (13) [back to overview]Changes in Executive Functioning Determined by The Behavioral Rating Inventory of Executive Function (BRIEF) Questionnaire.
NCT03790137 (13) [back to overview]Changes in Quality of Life Determined by the Quality of Life in Childhood Epilepsy Questionnaire(QOLCE-16)
NCT03790137 (13) [back to overview]Changes in Self-Concept Determined by The Beck Self Report Inventory.
NCT03790137 (13) [back to overview]Number of Patients That Experienced a Photoparoxysmal Response on EEG
NCT03861871 (5) [back to overview]Change in Caregiver Global Impression of Change (CGIC) Score
NCT03861871 (5) [back to overview]Change in Investigator Global Impression of Change (IGIC) Score
NCT03861871 (5) [back to overview]Change in Pediatric Quality Of Life (PEDS-QL) Epilepsy Module Raw Score
NCT03861871 (5) [back to overview]Change in Quality of Life in Childhood Epilepsy (QOLCE) Score
NCT03861871 (5) [back to overview]Change From Baseline in Median Monthly Convulsive Seizure Frequency

Area Under the Concentration Time Curve of ZX008 From Time Zero to Time 24 Hours [AUC0-24hours] at Steady State

AUC0-24 is the area under the concentration time curve from time zero to 24 hours. (NCT02682927)
Timeframe: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

Interventionnanogram*hour per milliliter (ng*h/mL) (Geometric Mean)
Study 1: ZX008 0.2 mg/kg/Day356
Study 1: ZX008 0.8 mg/kg/Day1390
Study 3: ZX008 0.2 mg/kg/Day348
Study 3: ZX008 0.8 mg/kg/Day1290

[back to top]

Change From Baseline in Convulsive + Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo

Total seizure frequency were defined as the combination of convulsive and non-convulsive seizures. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). Non-convulsive seizures included focal without clear observable motor signs, absence or atypical absence, myoclonic and atonic. The seizure frequency was based on electronic diary data obtained for each participant. The number of all seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day convulsive or non-convulsive seizure frequency. (NCT02682927)
Timeframe: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Interventionseizure frequency per 28 days (Median)
Study 1: Placebo-4.45
Study 1: ZX008 0.2 mg/kg/Day-7.40
Study 1: ZX008 0.8 mg/kg/Day-22.95
Study 3: Placebo-1.09
Study 3: ZX008 0.2 mg/kg/Day-6.54
Study 3: ZX008 0.8 mg/kg/Day-11.39

[back to top]

Change From Baseline in Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo

Non-convulsive seizures included focal without clear observable motor signs, absence or atypical absence, myoclonic and atonic. The number of non-convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day non-convulsive seizure frequency. (NCT02682927)
Timeframe: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Interventionseizure frequency per 28 days (Median)
Study 1: Placebo-9.38
Study 1: ZX008 0.2 mg/kg/Day-4.85
Study 1: ZX008 0.8 mg/kg/Day-20.06
Study 3: Placebo-0.68
Study 3: ZX008 0.2 mg/kg/Day-0.67
Study 3: ZX008 0.8 mg/kg/Day-4.35

[back to top]

Change From Baseline in the Mean Convulsive Seizures Frequency (MCSF) to the Combined Titration and Maintenance Periods (T+M) in Participants Receiving ZX008 0.8 mg/kg/Day Compared to Placebo

Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF. (NCT02682927)
Timeframe: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Interventionseizure frequency per 28 days (Mean)
Study 1: Placebo-6.71
Study 1: ZX008 0.8 mg/kg/Day-13.11
Study 3: Placebo1.54
Study 3: ZX008 0.8 mg/kg/Day-3.54

[back to top]

Change From Baseline in the Mean Convulsive Seizures Frequency to the Combined Titration and Maintenance Period (T+M) in Participants Receiving ZX008 0.2 mg/kg/Day Compared to Placebo

Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF. (NCT02682927)
Timeframe: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Interventionseizure frequency per 28 days (Mean)
Study 1: Placebo-6.71
Study 1: ZX008 0.2 mg/kg/Day-18.81
Study 3: Placebo1.54
Study 3: ZX008 0.2 mg/kg/Day-5.89

[back to top]

Change From Baseline to Day 99 in the Overall Quality of Life Score From the Pediatric Quality of Life Inventory™ (PedsQL) Score in Each ZX008 Treatment Arm Compared to Placebo

The Pediatric Quality of Life Inventory (PedsQL) is a pediatric modular measure of health related quality of life (QoL) completed by the parent/caregiver on behalf of the participant. It consisted of 23 items across 4 core scales that measure physical (8 items), emotional, social, and school functioning (5 items each). Each of the responses to the 23 items is initially scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always). Scores are linearly transformed to a scale of 0 to 100, where 0=100, 1=75, 2=50, 3=25 and 4=0, and higher scores correspond to better health-related QoL. The Overall Quality of Life is the average of all the items over the number of items answered on all the Scales. (NCT02682927)
Timeframe: From Baseline to Day 99

Interventionscore on a scale (Mean)
Study 1: Placebo-1.6
Study 1: ZX008 0.2 mg/kg/Day6.8
Study 1: ZX008 0.8 mg/kg/Day5.9
Study 3: Placebo1.9
Study 3: ZX008 0.2 mg/kg/Day4.2
Study 3: ZX008 0.8 mg/kg/Day2.1

[back to top]

Change From Baseline to Day 99 in the Quality of Life in Childhood Epilepsy (QOLCE) Score to Measure Quality of Life in Each ZX008 Treatment Arm Compared to Placebo

QOLCE is a low-burden parent/caregiver completed assessment that evaluates how epilepsy affects day-to day functioning of the participant in various life areas, including physical activities, well being, cognition, social activities, behavior, and general health. QOLCE scores items on 16 subscales with possible 5-point response for each, where scores of 5 was best possible response and 1 was worst possible response. Item scores were then transformed to a 0-100 scale as follows: 1-0, 2-25, 3-50, 4-75, 5-100. A score for each participant for each subscale was calculated by averaging that participant's responses to each item in the subscale. Subscale scores per participant were averaged to obtain an overall QoL score for each participant. Higher the subscale and overall QoL scores, better the response. (NCT02682927)
Timeframe: From Baseline to Day 99

Interventionscore on a scale (Mean)
Study 1: Placebo1.5
Study 1: ZX008 0.2 mg/kg/Day0.8
Study 1: ZX008 0.8 mg/kg/Day5.8
Study 3: Placebo1.2
Study 3: ZX008 0.2 mg/kg/Day6.1
Study 3: ZX008 0.8 mg/kg/Day5.5

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Change From Baseline to Day 99 in the Total Score From PedsQL Family Impact Module Score in Each ZX008 Treatment Arm Compared to Placebo

The PedsQL Family Impact measured the impact of pediatric chronic health conditions on parents and the family by measuring parent self-reported physical, emotional, social, and cognitive functioning, communication, worry, and family daily activities and relationships. There are a total of 36 items in the PedsQL: 6 items for Physical Functioning, 5 items each for Emotional Functioning, Cognitive Functioning and Worry, 4 for Social Functioning, 3 for Communication, 3 questions for Daily Activities, and 5 for Family Relationships. Each of the responses are initially scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always) and then linearly transformed to a scale of 0 to 100, where 0=100, 1=75, 2=50, 3=25 and 4=0, and higher scores mean better health-related QoL. (NCT02682927)
Timeframe: From Baseline to Day 99

Interventionscore on a scale (Mean)
Study 1: Placebo-4.4
Study 1: ZX008 0.2 mg/kg/Day3.9
Study 1: ZX008 0.8 mg/kg/Day5.4
Study 3: Placebo1.3
Study 3: ZX008 0.2 mg/kg/Day0.7
Study 3: ZX008 0.8 mg/kg/Day6.3

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Elimination Half-life [t1/2 Beta] of ZX008 at Steady State

t1/2 beta is the elimination half-life. (NCT02682927)
Timeframe: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

Interventionhours (h) (Geometric Mean)
Study 1: ZX008 0.2 mg/kg/Day18.4
Study 1: ZX008 0.8 mg/kg/Day21.1
Study 3: ZX008 0.2 mg/kg/Day18.1
Study 3: ZX008 0.8 mg/kg/Day18.6

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Longest Convulsive Seizure-free Interval in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period

The longest interval between convulsive seizures was calculated over the entire Titration and Maintenance Period and was derived as the maximum of the number of days between consecutive convulsive seizures. (NCT02682927)
Timeframe: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)

Interventiondays (Median)
Study 1: Placebo9.50
Study 1: ZX008 0.2 mg/kg/Day15.00
Study 1: ZX008 0.8 mg/kg/Day25.00
Study 3: Placebo10
Study 3: ZX008 0.2 mg/kg/Day18.5
Study 3: ZX008 0.8 mg/kg/Day30

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Maximum Observed Concentration of ZX008 Determined Directly From the Concentration Time Profile [Cmax] at Steady State

Cmax is the maximum observed concentration determined directly from the concentration-time profile. (NCT02682927)
Timeframe: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

Interventionnanograms per milliliter (ng/mL) (Geometric Mean)
Study 1: ZX008 0.2 mg/kg/Day17.7
Study 1: ZX008 0.8 mg/kg/Day67.9
Study 3: ZX008 0.2 mg/kg/Day17.4
Study 3: ZX008 0.8 mg/kg/Day64.5

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Number of Convulsive Seizure-free Days in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period

A convulsive seizure free day was defined as a day for which diary data are available and no convulsive seizures were reported. Convulsive seizure free days were taken from the electronic diary data. (NCT02682927)
Timeframe: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)

Interventionseizure free days (Median)
Study 1: Placebo15.14
Study 1: ZX008 0.2 mg/kg/Day20.86
Study 1: ZX008 0.8 mg/kg/Day24.43
Study 3: Placebo20.20
Study 3: ZX008 0.2 mg/kg/Day23.36
Study 3: ZX008 0.8 mg/kg/Day25.33

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Percentage of Participants Who Achieved a ≥50% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 50% or greater reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period. (NCT02682927)
Timeframe: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Interventionpercentage of participants (Number)
Study 1: Placebo12.5
Study 1: ZX008 0.2 mg/kg/Day38.5
Study 1: ZX008 0.8 mg/kg/Day67.5
Study 3: Placebo6.3
Study 3: ZX008 0.2 mg/kg/Day45.7
Study 3: ZX008 0.8 mg/kg/Day72.9

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Percentage of Participants Who Achieved a ≥75% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 75% or greater reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period. (NCT02682927)
Timeframe: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Interventionpercentage of participants (Number)
Study 1: Placebo2.5
Study 1: ZX008 0.2 mg/kg/Day23.1
Study 1: ZX008 0.8 mg/kg/Day50.0
Study 3: Placebo4.2
Study 3: ZX008 0.2 mg/kg/Day28.3
Study 3: ZX008 0.8 mg/kg/Day47.9

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Percentage of Participants Who Achieved a 100% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 100% reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period. (NCT02682927)
Timeframe: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Interventionpercentage of participants (Number)
Study 1: Placebo0
Study 1: ZX008 0.2 mg/kg/Day7.7
Study 1: ZX008 0.8 mg/kg/Day7.5
Study 3: Placebo0
Study 3: ZX008 0.2 mg/kg/Day0
Study 3: ZX008 0.8 mg/kg/Day12.5

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Percentage of Participants Who Achieved Greater Than or Equal to 25% (≥25%) Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 25% or greater reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period. (NCT02682927)
Timeframe: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Interventionpercentage of participants (Number)
Study 1: Placebo35.0
Study 1: ZX008 0.2 mg/kg/Day66.7
Study 1: ZX008 0.8 mg/kg/Day90.0
Study 3: Placebo27.1
Study 3: ZX008 0.2 mg/kg/Day71.7
Study 3: ZX008 0.8 mg/kg/Day83.3

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Percentage of Participants With Hospitalization and Healthcare Resource Utilization to Treat Seizures in Each ZX008 Treatment Arm Compared to Placebo During Study

Participants who utilized medical center care to treat a seizure during the study were reported. (NCT02682927)
Timeframe: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)

Interventionpercentage of participants (Number)
Study 1: Placebo22.5
Study 1: ZX008 0.2 mg/kg/Day17.9
Study 1: ZX008 0.8 mg/kg/Day15.0
Study 3: Placebo12.5
Study 3: ZX008 0.2 mg/kg/Day19.6
Study 3: ZX008 0.8 mg/kg/Day14.6

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Percentage of Participants With Rescue Medication Usage in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period

Rescue medication was administered according to each participant's usual or prescribed regimen consisting of 1 or more medications. The usage of rescue medication (number of days and number of medications used per seizure episode) was based on electronic diary data obtained for each participant. The number of days rescue medication was taken (normalized to 28 days) was calculated for each participant. Multiple medications taken on the same day were counted once for that day. (NCT02682927)
Timeframe: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Interventionpercentage of participants (Number)
Study 1: Placebo77.5
Study 1: ZX008 0.2 mg/kg/Day59.0
Study 1: ZX008 0.8 mg/kg/Day45.0
Study 3: Placebo60.4
Study 3: ZX008 0.2 mg/kg/Day65.2
Study 3: ZX008 0.8 mg/kg/Day47.9

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Percentage of Participants With Status Epilepticus (SE) in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period

The participants who either had SE episode recorded as an adverse event (AE) during treatment or a seizure greater than 10 minutes were reported for each treatment group. Additionally, a single participant who may had more than one episode of SE, and an episode of SE recorded as both an AE and as a seizure longer than 10 minutes was counted as a single event. (NCT02682927)
Timeframe: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)

Interventionpercentage of participants (Number)
Study 1: Placebo27.5
Study 1: ZX008 0.2 mg/kg/Day28.2
Study 1: ZX008 0.8 mg/kg/Day35.0
Study 3: Placebo16.7
Study 3: ZX008 0.2 mg/kg/Day19.6
Study 3: ZX008 0.8 mg/kg/Day25.0

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Time to Maximum Concentration [Tmax] of ZX008 at Steady State

Tmax is the time to maximum concentration at steady state. (NCT02682927)
Timeframe: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

Interventionhours (h) (Median)
Study 1: ZX008 0.2 mg/kg/Day2.90
Study 1: ZX008 0.8 mg/kg/Day3.00
Study 3: ZX008 0.2 mg/kg/Day2.90
Study 3: ZX008 0.8 mg/kg/Day2.90

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Change From Baseline to Day 99 in Affective Symptoms of the Parent/Caregiver Using the Hospital Anxiety and Depression Scale (HADS) in Each ZX008 Treatment Arm Compared to Placebo

The HADS is a tool that was validated to assess presence of anxiety or depression in an outpatient non-psychiatric population. The HADS a 14-item scale that generates ordinal data for 2 dimensions: 1) Anxiety (7 items), and 2) Depression (7 items). Each item has 4 possible answers rated 0 to 3, of which 0 = No distress and 3 = worst distress. All answers to the items for a dimension with their respective rating are added resulting in a range for each dimension from 0-21, out of which of 0-7 = normal; 8-10=borderline abnormal; 11-21=abnormal. Scores for the entire scale (emotional distress) range from 0 to 42, with higher scores indicating more distress. (NCT02682927)
Timeframe: From Baseline to Day 99

,,,,,
Interventionscore on a scale (Mean)
AnxietyDepressionTotal emotional distress
Study 1: Placebo-0.40.80.4
Study 1: ZX008 0.2 mg/kg/Day-0.80.2-0.6
Study 1: ZX008 0.8 mg/kg/Day-0.80.1-0.7
Study 3: Placebo-0.6-0.7-1.2
Study 3: ZX008 0.2 mg/kg/Day0.22.02.2
Study 3: ZX008 0.8 mg/kg/Day-0.7-0.8-1.5

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Distribution of Duration of Convulsive Seizures (in Percentage) in Each ZX008 Treatment Arm Compared to Placebo at Baseline and During the Titration and Maintenance Period

Duration of single convulsive seizures during the Baseline and the duration over the Titration and Maintenance Period were reported by treatment group using categories as <2 minutes, 2 to 10 minutes and > 10 minutes as collected in the seizure diary. (NCT02682927)
Timeframe: At Baseline and 14 weeks of Titration (2 weeks) and Maintenance Period (12 weeks)

,,,,,
Interventionpercentage of seizures (Number)
<2 min (Baseline)2-10 min (Baseline)>10 min (Baseline)<2 min (Titration + Maintenance Period)2-10 min (Titration + Maintenance Period)>10 min (Titration + Maintenance Period)
Study 1: Placebo69.2826.863.8671.3126.312.38
Study 1: ZX008 0.2 mg/kg/Day64.1334.950.9371.5925.612.79
Study 1: ZX008 0.8 mg/kg/Day71.6124.224.1772.2722.914.82
Study 3: Placebo64.2134.830.9665.8433.740.43
Study 3: ZX008 0.2 mg/kg/Day63.9033.662.4563.4531.345.22
Study 3: ZX008 0.8 mg/kg/Day74.1122.783.1084.6713.711.62

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Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Rating Score, as Assessed by the Principal Investigator in Each ZX008 Treatment Arm Compared to Placebo

CGI-I scale measures improvement in the participant's clinical status from Baseline. The severity of a participant's condition was rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), as follows: 1-very much improved,2-much improved, 3-minimally improved, 4- no change, 5-minimally worse, 6-much worse and 7-very much worse. The Principal Investigator rated their global impression of the participant's condition during the study. (NCT02682927)
Timeframe: At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)

,,,,,
Interventionpercentage of participants (Number)
1 = Very much improved (Visit 6)2 = Much improved (Visit 6)3 = Minimally improved (Visit 6)4 = No change (Visit 6)5 = Minimally worse (Visit 6)6 = Much worse (Visit 6)7 = Very much worse (Visit 6)1 = Very much improved (Visit 8)2 = Much improved (Visit 8)3 = Minimally improved (Visit 8)4 = No change (Visit 8)5 = Minimally worse (Visit 8)6 = Much worse (Visit 8)7 = Very much worse (Visit 8)1 = Very much improved (Visit 10)2 = Much improved (Visit 10)3 = Minimally improved (Visit 10)4 = No change (Visit 10)5 = Minimally worse (Visit 10)6 = Much worse (Visit 10)7 = Very much worse (Visit 10)1 = Very much improved (Visit 12)2 = Much improved (Visit 12)3 = Minimally improved (Visit 12)4 = No change (Visit 12)5 = Minimally worse (Visit 12)6 = Much worse (Visit 12)7 = Very much worse (Visit 12)
Study 1: Placebo5.012.520.040.05.000012.530.030.05.02.502.57.530.035.010.0002.57.530.047.52.52.50
Study 1: ZX008 0.2 mg/kg/Day23.112.820.525.67.7005.130.820.517.95.15.1017.917.925.628.27.72.6012.828.217.928.210.32.60
Study 1: ZX008 0.8 mg/kg/Day17.525.020.017.55.02.5017.537.510.010.002.52.520.047.55.07.500027.535.015.012.5002.5
Study 3: Placebo4.22.127.154.24.2004.26.316.750.04.22.104.210.412.560.40004.24.216.758.36.300
Study 3: ZX008 0.2 mg/kg/Day21.721.717.426.12.20017.410.926.134.800015.219.626.128.30008.728.321.728.310.900
Study 3: ZX008 0.8 mg/kg/Day16.727.127.112.52.14.2029.231.314.68.34.20035.418.816.74.202.1033.331.310.416.76.300

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Percentage of Participants With Clinical Global Impression - Improvement Rating Score, as Assessed by the Parent/Caregiver in Each ZX008 Treatment Arm Compared to Placebo

CGI-I scale measures improvement in the participant's clinical status from Baseline. The severity of a participant's condition was rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), as follows: 1-very much improved,2-much improved, 3-minimally improved, 4- no change, 5-minimally worse, 6-much worse and 7-very much worse. The Parent/Caregiver rated their global impression of the participant's condition during the study. (NCT02682927)
Timeframe: At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)

,,,,,
Interventionpercentage of participants (Number)
1 = Very much improved (Visit 6)2 = Much improved (Visit 6)3 = Minimally improved (Visit 6)4 = No change (Visit 6)5 = Minimally worse (Visit 6)6 = Much worse (Visit 6)7 = Very much worse (Visit 6)1 = Very much improved (Visit 8)2 = Much improved (Visit 8)3 = Minimally improved (Visit 8)4 = No change (Visit 8)5 = Minimally worse (Visit 8)6 = Much worse (Visit 8)7 = Very much worse (Visit 8)1 = Very much improved (Visit 10)2 = Much improved (Visit 10)3 = Minimally improved (Visit 10)4 = No change (Visit 10)5 = Minimally worse (Visit 10)6 = Much worse (Visit 10)7 = Very much worse (Visit 10)1 = Very much improved (Visit 12)2 = Much improved (Visit 12)3 = Minimally improved (Visit 12)4 = No change (Visit 12)5 = Minimally worse (Visit 12)6 = Much worse (Visit 12)7 = Very much worse (Visit 12)
Study 1: Placebo2.522.512.545.02.55.00015.025.020.015.02.502.512.522.532.512.52.52.52.57.520.035.017.57.50
Study 1: ZX008 0.2 mg/kg/Day17.920.528.212.87.72.6015.425.625.612.810.35.1020.517.920.525.67.77.7020.520.515.420.515.47.70
Study 1: ZX008 0.8 mg/kg/Day15.027.522.520.02.57.52.520.037.515.05.02.55.02.535.030.07.510.0002.527.527.510.015.05.05.02.5
Study 3: Placebo6.32.125.045.810.42.104.28.320.847.96.34.24.22.16.325.045.86.3002.16.318.850.010.42.10
Study 3: ZX008 0.2 mg/kg/Day13.023.926.119.62.22.206.530.428.317.46.52.208.728.326.126.104.306.528.330.413.08.74.32.2
Study 3: ZX008 0.8 mg/kg/Day16.731.331.32.16.32.12.139.629.214.66.302.1041.722.98.36.34.20033.329.220.84.24.22.12.1

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Quality of Life (QoL) of the Parent/Caregiver Using the EQ- 5D-5L Scale in Each ZX008 Treatment Arm Compared to Placebo at Baseline and Day 99

"The EuroQOL-5 Dimensions-5 Levels scale produced by European QOL Group (EQ-5D-5L) health questionnaire is a health-related QOL instrument with 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The 5 dimensions of EQ-5D-5L health questionnaire were assessed on a Likert scale with 5 possible levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The categories slight problems, moderate problems, severe problems and extreme problems are collapsed into one response category problems. The QOL of the parent/caregiver was assessed and percentage of participants was reported for each item." (NCT02682927)
Timeframe: At Baseline and Day 99

,,,,,
Interventionpercentage of participants (Number)
Mobility- No problems (Baseline)Mobility- Problems (Baseline)Mobility- No problems (Day 99)Mobility- Problems (Day 99)Self-care - No problems (Baseline)Self-care - Problems (Baseline)Self-care - No problems (Day 99)Self-care - Problems (Day 99)Usual activities- No problems (Baseline)Usual activities- Problems (Baseline)Usual activities- No problems (Day 99)Usual activities- Problems (Day 99)Pain/discomfort- No problems (Baseline)Pain/discomfort- Problems (Baseline)Pain/discomfort- No problems (Day 99)Pain/discomfort- Problems (Day 99)Anxiety/depression- No problems (Baseline)Anxiety/depression- Problems (Baseline)Anxiety/depression- No problems (Day 99)Anxiety/depression- Problems (Day 99)
Study 1: Placebo33.3366.6740.0060.0025.6474.3628.5771.4323.0876.9225.7174.2948.7251.2848.5751.4374.3625.6465.7134.29
Study 1: ZX008 0.2 mg/kg/Day52.9447.0645.9554.0541.1858.8243.2456.7641.1858.8232.4367.5741.1858.8251.3548.6561.7638.2467.5732.43
Study 1: ZX008 0.8 mg/kg/Day46.1553.8551.3548.6538.4661.5448.6551.3535.9064.1048.6551.3546.1553.8564.8635.1456.4143.5967.5732.43
Study 3: Placebo40.0060.0052.3847.6222.5077.5030.9569.0525.0075.0030.9569.0545.0055.0076.1945.2460.0040.0069.0530.95
Study 3: ZX008 0.2 mg/kg/Day54.5545.4551.1648.8436.3663.6434.8865.1239.3960.6125.5874.4251.5248.4846.5153.4963.6436.3667.4432.56
Study 3: ZX008 0.8 mg/kg/Day28.5771.4346.6753.3322.8677.1435.5664.4420.0080.0035.5664.4451.4348.5764.4435.5674.2925.7173.3326.67

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Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36)

Monthly (28 day) CSF was based on electronic diary data obtained for each participant. The total number of convulsive seizures in the ith interval (CSF in OLE, where, i=1, 2, 3, … , 14 ) was divided by the total number of days in the ith interval with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF of OLE. (NCT02823145)
Timeframe: At Month 1, Month 2, Month 3, Month 4-6, Month 7-9, Month 10-12, Month 13-15, Month 16-18, Month 19-21, Month 22-24, Month 25-27, Month 28-30, Month 31-33, and Month 34-36

Interventionseizure frequency per 28 days (Median)
Month 1Month 2Month 3Month 4-6Month 7-9Month 10-12Month 13-15Month 16-18Month 19-21Month 22-24Month 25-27Month 28-30Month 31-33Month 34-36
Any ZX008 Open Label Dose6.534.674.674.363.824.043.113.423.422.802.802.803.212.74

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Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period

Participants in the study were required to be on stable background therapy for the first 6 months of treatment, after which background AEDs could be reduced or withdrawn so long as one background AED remained. The percentage of participants who had changes in dose or type of concomitant AED medications during the first, second, third, fourth, fifth, and sixth months were analyzed and reported. (NCT02823145)
Timeframe: At Month 1, 2, 3, 4 , 5, and 6 of OLE Treatment Period

Interventionpercentage of participants (Number)
OLE Month 1OLE Month 2OLE Month 3OLE Month 4OLE Month 5OLE Month 6
Any ZX008 Open Label Dose5.27.17.48.36.89.6

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Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Day 1 to End of Study (EOS) Visit (Month 42) in the OLE Treatment Period

Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies (ZX008-1501/ZX008-1502, and ZX008-1504 Cohort 2). Participants in 1504- Cohort 1 and de novo participants (who entered 1503 without having been in any of the core studies) did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Day 1 to EOS was divided by the total number of days from Day 1 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day convulsive seizure frequency (CSF). The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant. (NCT02823145)
Timeframe: From Day 1 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core)

Interventionseizure frequency per 28 days (Median)
Any ZX008 Open Label Dose-6.67

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Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Month 2 to EOS (Month 42) in the OLE Treatment Period

Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies. Participants in 1504-Cohort 1 and de novo participants did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Month 2 to EOS was divided by the total number of days from Month 2 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF. The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant. (NCT02823145)
Timeframe: From Month 2 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core)

Interventionseizure frequency per 28 days (Median)
Any ZX008 Open Label Dose-7.04

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Percentage of Participants With Serious Treatment-emergent Adverse Events (TEAEs) During the OLE Treatment Period

Serious Adverse event (SAE) was defined as any untoward medical occurrence that at any dose: • results in death, • is life-threatening threatening, • results in initial inpatient hospitalization or prolongation of hospitalization, •results in persistent or significant disability or incapacity, • results in a congenital anomaly/birth defect, • results in any medically significant event that did not meet any of the other 5 SAE criteria, but which was judged by a physician to potentially jeopardize the participant or require medical or surgical intervention to prevent one of the above outcomes listed as an SAE criterion. (NCT02823145)
Timeframe: From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42)

Interventionpercentage of participants (Number)
Any ZX008 Open Label Dose26.5

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Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Open-label Extension (OLE) Treatment Period

Treatment-emergent adverse events (TEAE) were defined as any AEs that based on start date information occurs after the first intake of study treatment. (NCT02823145)
Timeframe: From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42)

Interventionpercentage of participants (Number)
Any ZX008 Open Label Dose98.1

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Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Leading to Withdrawal From Investigational Medicinal Product (IMP) During the OLE Treatment Period

A TEAE was defined as any AE that based on start date information occurs after the first intake of study treatment. Percentage of participants with TEAEs leading to withdrawal from IMP during OLE Treatment Period were reported. (NCT02823145)
Timeframe: From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42)

Interventionpercentage of participants (Number)
Any ZX008 Open Label Dose3.5

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Convulsive Seizure Frequency (CSF) by Mean Daily Dose During the Overall OLE Treatment Period

Convulsive seizure frequency over time, reported as per 28 days was analyzed by the actual dose administered. Participants were grouped into low (0.2 to <0.4 mg/kg), medium (0.4 to <0.6 mg/kg), and high dose (>0.6 mg/kg) groups depending on their mean daily doses of ZX008 during the OLE Treatment period. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28. The convulsive seizure frequency was calculated from all available data collected. (NCT02823145)
Timeframe: From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42)

Interventionseizure frequency per 28 days (Median)
ZX008 Low Dose (0 - <0.4 mg/kg/day)ZX008 Medium Dose (0.4 - <0.6 mg/kg/day)ZX008 High Dose (>=0.6 mg/kg/day)
Any ZX008 Open Label Dose3.944.806.00

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Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period

Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF. (NCT02926898)
Timeframe: 15 weeks (combined Titration + Maintenance Period)

InterventionConvulsive seizures per 28 days (Mean)
Cohort 2: ZX008 0.5 mg/kg/Day-3.18
Cohort 2: Matching Placebo-0.65

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Longest Convulsive Seizure-Free Interval (Days)

Comparison of the duration of the longest convulsive seizure-free interval (days) during the combined Titration + Maintenance Periods for the ZX008 0.5 mg/kg/day and placebo groups. (NCT02926898)
Timeframe: 15 weeks (combined Titration + Maintenance Period)

InterventionDays (Median)
Cohort 2: ZX008 0.5 mg/kg/Day22.0
Cohort 2: Matching Placebo13.0

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Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period

Percentage of participants who achieved ≥ a 50% reduction in convulsive seizure frequency from Baseline compared to the combined Titration + Maintenance Periods in the ZX008 0.5 mg/kg/day vs placebo groups. (NCT02926898)
Timeframe: 15 weeks (combined Titration + Maintenance Period)

InterventionPercentage of participants (Number)
Cohort 2: ZX008 0.5 mg/kg/Day53.5
Cohort 2: Matching Placebo4.5

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% Change in Frequency of Handwaving Episodes

"The number of handwaving episodes (seizures) per day were recorded on a seizure diary by either the subject or the parent of the subject. One handwaving episode was defined as the period starting from when the hand first came up toward the face, until there was a brief pause in waving. Subjects and their caregivers were instructed to record the total number of handwaving episodes each day during a one month baseline, and during the 3 month treatment period.~The baseline seizure frequency was calculated as an average of the reported handwaving episodes per day during the baseline period. This number was compared to the average episodes per day for the final month of the study (month 3 of treatment with fenfluramine) for each patient. The median percent change in frequency of handwaving episodes across all patients is reported below." (NCT03790137)
Timeframe: Month 3

Intervention% change in hand waving episodes (Median)
Treatment Group-66.2

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Change in Frequency of Generalized Tonic-clonic Seizures

Daily seizure logs will be maintained by either the subject or the parent of the subject and used to calculate seizure frequency. Frequency of Generalized Tonic-clonic seizures was recorded as an average number of seizures/day. The average number of tonic-clonic seizures per day during the baseline period was compared to the average number of tonic-clonic seizures per day during the final month (month 3) for each patient that had experienced at least one tonic-clonic seizure in their lifetime. (NCT03790137)
Timeframe: Month 3

Interventiontonic-clonic seizures/day (Mean)
Treatment Group0

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Change in Spike Frequency on EEG

The investigators will read and interpret pre-drug (baseline) and post-drug EEGs (month 3 of core study) for the first 9 patients. The average number of spikes/hour across these patients will be reported for both pre- and post-treatment EEGs. (NCT03790137)
Timeframe: Month 3

Interventionspikes/hour (Mean)
Pre-TreatmentPost-Treatment
Treatment Group73.950.4

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Changes in Anger Determined by the Beck Self Report Inventory

"The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.~The raw scores for subscales are calculated in the following manner:~Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.~Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.~Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.~Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.~Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.~Raw scores will be translated into T-scores.~T-scores for BYI are as follows:~55 or less = average~55-59 = mildly elevated~60-69 = moderately elevated~70+ = extremely elevated" (NCT03790137)
Timeframe: Month 3

InterventionT score (Mean)
Baseline ScoreMonth 3 Score
Treatment Group45.0041.75

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Changes in Anxiety Determined by the Beck Self Report Inventory

"The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.~The raw scores for subscales are calculated in the following manner:~Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.~Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.~Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.~Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.~Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.~Raw scores will be translated into T-scores.~T-scores for BYI are as follows:~55 or less = average~55-59 = mildly elevated~60-69 = moderately elevated~70+ = extremely elevated" (NCT03790137)
Timeframe: Month 3

InterventionT score (Mean)
Baseline ScoreMonth 3 Score
Treatment Group47.2945.13

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Changes in Cognitive Functioning Determined by the Weschler Abbreviated Scale of Intelligence (WASI-II Subtests)

"The Weschler Abbreviated Scale of Intelligence (WASI-II subtests) will be administered to the first 10 patients at baseline and 84 days after the start of the first dose of study drug. Results of these cognitive tests will be compared between baseline and 84 days post initial dose.~The WASI-II measures cognitive functioning through 2 subtests, vocabulary and matrix reasoning. The raw scores on these subtests are combined to give a composite full-scale IQ (FSIQ) that is scaled to an average of 100 and standard deviation of 15.~Maximum raw scores for the subtests are as follows (higher values are considered better and minimum score on each is 0).~Vocabulary:~ages 7-11: 47 ages 12-14: 53 ages 15-25: 59~Matrix Reasoning:~ages 6-8: 24 ages 9-25: 30" (NCT03790137)
Timeframe: Month 3 (~84 days after the first dose of fenfluramine.)

Interventionscore on a scale (Mean)
BaselineMonth 3
Treatment Group97.89106.22

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Changes in Cognitive Functioning Determined by the Weschler Intelligence Scale for Children (WISC-V) -Processing Speed Subtests.

"The Weschler Intelligence Scale for Children (WISC-V) -Processing Speed subtests will be administered at baseline and 84 days after the start of the first dose of study drug (Month 3; visit 5). Results of these cognitive tests will be compared between baseline and 84 days post initial dose.~Raw scores for the coding and symbol search subtests will be used to evaluate processing speed. The maximum raw scores are as follows (the minimum score is 0 and higher scores are considered better).~Coding:~ages 6-7: 65 ages 8-16: 119~Symbol search:~ages 6-7: 45 ages 8-16: 60" (NCT03790137)
Timeframe: Month 3 (approximately 84 days after the first dose of fenfluramine)

Interventionscore on a scale (Mean)
BaselineMonth 3
Treatment Group89.6392.14

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Changes in Depression Determined by the Beck Self Report Inventory

"The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.~The raw scores for subscales are calculated in the following manner:~Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.~Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.~Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.~Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.~Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.~Raw scores will be translated into T-scores.~T-scores for BYI are as follows:~55 or less = average~55-59 = mildly elevated~60-69 = moderately elevated~70+ = extremely elevated" (NCT03790137)
Timeframe: Month 3

InterventionT score (Mean)
Baseline ScoreMonth 3 Score
Treatment Group49.2947.13

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Changes in Disruptive Behavior Determined by the Beck Self Report Inventory

"The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.~The raw scores for subscales are calculated in the following manner:~Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.~Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.~Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.~Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.~Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.~Raw scores will be translated into T-scores.~T-scores for BYI are as follows:~55 or less = average~55-59 = mildly elevated~60-69 = moderately elevated~70+ = extremely elevated" (NCT03790137)
Timeframe: Month 3

InterventionT score (Mean)
Baseline ScoreMonth 3 Score
Treatment Group44.1443.50

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Changes in Executive Functioning Determined by The Behavioral Rating Inventory of Executive Function (BRIEF) Questionnaire.

"The Behavioral Rating Inventory of Executive Function (BRIEF) questionnaire will be administered at baseline, and 84 days after the first dose of fenfluramine (Month 3; Visit 5). This questionnaire assesses executive function across 8 clinical scales:~Inhibit~Shift~Emotional Control~Initiate~Working Memory~Plan/Organize~Organization of Materials~Monitor~Item level scores are rated on a 3 point Likert Scale from 1-3:~Never~Sometimes~Often~The Global Executive Composite (GEC) score is the total score of all 8 clinical subscales. The item scores are summed for each scale and raw scores are converted to Tscores. The mean of the GEC score will be reported.~T scores from 60 to 64 are considered mildly elevated. T scores from 65 to 69 are considered potentially clinically elevated. T scores at or above 70 are considered clinically elevated." (NCT03790137)
Timeframe: Month 3 (approximately 84 days after the first dose of fenfluramine)

InterventionT Score (Mean)
Baseline ScoreMonth 3 Score
Treatment Group61.2958.50

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Changes in Quality of Life Determined by the Quality of Life in Childhood Epilepsy Questionnaire(QOLCE-16)

"The Quality of Life in Childhood Epilepsy Questionnaire will be administered at baseline, and 84 days after the first dose (Month 3; visit 5). This questionnaire assesses mood, social relationships, and behaviors. Results will be compared.~The QOLCE assesses quality of life across 4 domains of functioning: cognitive, emotional, social and physical. Scores range from 0-100. Composite scores are calculated as a mean across all measures." (NCT03790137)
Timeframe: Month 3 (approximately 84 days after first dose of fenfluramine)

Interventionscore on a scale (Mean)
BaselineMonth 3
Treatment Group60.4160.76

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Changes in Self-Concept Determined by The Beck Self Report Inventory.

"The Beck Self Report Inventory will be administered at baseline, and 84 days after the first dose (Month 3; Visit 5). This questionnaire assesses self-concept, depression, anxiety, anger and disruptive behavior through a 100-item self-report.~The raw scores for subscales are calculated in the following manner:~Add scores from Items 1-20 for the total Beck Self Concept Inventory for Youth (BSCI-Y) score.~Add scores from Items 21-40 for the total Beck Anxiety Inventory for Youth (BAI-Y) score.~Add scores from Items 41-60 for the total Beck Depression Inventory for Youth (BDI-Y) score.~Add scores from Items 61-80 for the total Beck Anger Inventory for Youth (BANI-Y) score.~Add scores from Items 81-100 for the total Beck Disruptive Inventory for Youth (BDBI-Y) score.~Raw scores will be translated into T-scores.~T-scores for BYI are as follows:~55 or less = average~55-59 = mildly elevated~60-69 = moderately elevated~70+ = extremely elevated" (NCT03790137)
Timeframe: Month 3 (approximately 84 days after first dose of fenfluramine)

InterventionT-Score (Mean)
Baseline ScoreMonth 3 Score
Treatment Group44.4352.88

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Number of Patients That Experienced a Photoparoxysmal Response on EEG

The investigators will read and interpret pre- (baseline) and post-treatment (month 3) EEGs. The number of patients that experienced a photoparoxysmal response during the EEGs will be reported. (NCT03790137)
Timeframe: Month 3

InterventionParticipants (Count of Participants)
Baseline EEG (pre-treatment)Month 3 EEG (post-treatment)
Treatment Group53

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Change in Caregiver Global Impression of Change (CGIC) Score

The CGIC is a 1-item, parent/caregiver-completed assessment used determine how much their child/care-recipient has improved with treatment. The instrument asks parents/caregivers to rate their child's/care-recipient's improvement as: 1) very much improved; 2) much improved; 3) minimally improved; 4) unchanged; 5) a little worse; 6) much worse; 7) very much worse; the total score correspondingly ranges from 1-7. (NCT03861871)
Timeframe: Baseline, Week 14

Interventionscore on a scale (Mean)
Fenfluramine Hydrochloride-2.429

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Change in Investigator Global Impression of Change (IGIC) Score

The IGIC is a 1-item, investigator-completed assessment used determine how much a patient has improved with treatment. The instrument asks the investigator to rate patients' improvement as: 1) very much improved; 2) much improved; 3) minimally improved; 4) unchanged; 5) a little worse; 6) much worse; 7) very much worse; the total score correspondingly ranges from 1-7. (NCT03861871)
Timeframe: Baseline, Week 14

Interventionscore on a scale (Mean)
Fenfluramine Hydrochloride1.571

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Change in Pediatric Quality Of Life (PEDS-QL) Epilepsy Module Raw Score

The PedsQL Epilepsy Module is a 29-item measure with five scales: Impact, Cognitive, Sleep, Executive Function, and Mood/Behavior. The Impact scale (nine items) assesses how epilepsy interferes with daily activities, interacting with peers, independence, and increased disease burden due to treatment. The Cognitive Scale (six items) assesses memory, ability to learn new materials, school-related difficulties, and reading difficulties. The Sleep Scale (three items) assesses fatigue and sleep difficulties. The Executive Function Scale (six items) assesses organization, task initiation, impulsivity, and inattention. The Mood/Behavior Scale (five items) assesses feelings of anger, sadness, worries, and frustration tolerance. Scores range from 0-100 for each subscale, with higher scores representing better quality of life. The raw score is the sum of each subscale score and ranges from 0-500. (NCT03861871)
Timeframe: Baseline, Week 14

Interventionscore on a scale (Mean)
Fenfluramine Hydrochloride-103.571

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Change in Quality of Life in Childhood Epilepsy (QOLCE) Score

Parent/caregiver-completed assessment assessing how epilepsy affects day-to-day functioning of their child/care-recipient in various life areas. Each item is ranked on a 5-point Likert scale from 1 (response correlated with the lowest possible quality of life) to 5 (response correlated with the highest possible quality of life). Item scores are then transformed to a 0-100 scale as follows: 1 = 0, 2 = 25, 3 = 50, 4=75, and 5=100. The total score is the average of all item scores and ranges from 0-100. Higher scores indicate greater quality of life; an increase in scores indicates quality of life increased during the observational period. (NCT03861871)
Timeframe: Baseline, Week 14

Interventionscore on a scale (Mean)
Fenfluramine Hydrochloride-0.429

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Change From Baseline in Median Monthly Convulsive Seizure Frequency

Change between baseline and Week 14 in the median number of monthly convulsive seizures. (NCT03861871)
Timeframe: Baseline, Week 14

InterventionNumber of monthly seizures (Median)
Fenfluramine Hydrochloride88.429

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