METABOLISM RESISTANT FENFLURAMINE ANALOGS AND METHODS OF USING THE SAME

Metabolism-resistant fenfluramine analogs are provided. The subject fenfluramine analogs find use in the treatment of a variety of diseases. For example, methods of treating epilepsy by administering a fenfluramine analog to a subject in need thereof are provided. Also provided are methods of suppressing appetite in a subject in need thereof. Pharmaceutical compositions for use in practicing the subject methods are also provided. 8. The method of , wherein the compound is a compound according to one of -.9. The method of claim 7 , further comprising co-administering to the subject an antiepileptic agent.11. The method of claim 7 , wherein the compound is a compound according to one of -. Pursuant to 35 U.S.C. §119 (e), this application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 62/271,168, filed Dec. 22, 2015, the disclosure of which application is hereby incorporated by reference herein in its entirety.This invention relates generally to the field of compounds structurally related to the amphetamine drug fenfluramine and their use in the treatment of neurological related diseases.Fenfluramine is an amphetamine drug that was once widely prescribed as an appetite suppressant to treat obesity. Fenfluramine is devoid of the psychomotor stimulant and abuse potential of D-amphetamine and interacts with the 5-hydroxytryptamine (serotonin, 5-HT) transporters to release 5-HT from neurons. Fenfluramine has been investigated for anticonvulsive activity in the treatment of Dravet Syndrome, or severe myoclonic epilepsy in infancy, a rare and malignant epileptic syndrome. This type of epilepsy has an early onset in previously healthy children.Anorectic treatment with fenfluramine has been associated with the development of cardiac valvulopathy and pulmonary hypertension, including the condition cardiac fibrosis which led to the withdrawal of fenfluramine from world-wide markets. Interaction of fenfluramine's major metabolite norfenfluramine ...

PISTON CLOSURES FOR DRUG DELIVERY CAPSULES

A drug capsule and a method for making a drug capsule for a drug delivery device, such as an auto injector or needle-free injector, with improved stability and container closure integrity. The injector comprises a drug capsule sealed by a piston fabricated from PTFE modified by the inclusion of a co-polymer of PPVE, preferably in an amount less than 1% by weight, resulting in better performance while the device is stored and subjected to temperature cycling. 120.-. (canceled)21. A drug capsule for use in a drug delivery device , comprising:a syringe body comprising borosilicate glass;a piston comprising polytetrafluoroethylene (PTFE) contained within said syringe body;wherein the PTFE has been modified by the inclusion of perfluor(propyl vinyl ether) (PPVE),wherein the drug capsule is factory prefilled with a liquid formulation.22. The drug capsule of wherein the borosilicate glass is strengthened by ion exchange.23. The drug capsule of claim 21 , wherein the piston comprises less than 1% by weight of PPVE.24. The drug capsule of wherein the piston further comprises at least one circumferential rib of essentially triangular cross section with a triangle top where it contacts the syringe body removed.25. The drug capsule of claim 21 , wherein the drug capsule contains a drug formulation comprising a biologic drug further wherein the drug capsule does not contain a lubricant.26. The drug capsule of claim 21 , wherein the drug capsule is attached to an actuator to form a drug delivery system.27. The drug capsule of claim 26 , wherein the drug delivery system is an autoinjector with features comprising a characteristic selected from the group consisting of:a spool valve;a cap comprising a spin cap;a spool retaining cage; anda cap comprising two sets of threads.28. The drug capsule of claim 26 , wherein the drug delivery system comprises a characteristic selected from the group consisting of:portable;self-contained;single dose disposable;all mechanical,being an ...

VISCOUS FORMULATIONS AND THEIR USE IN NEEDLE-FREE INJECTION

Formulations are described that are viscous and will benefit from needle-free delivery at high driving pressures. Conventional delivery of these viscous formulations by hypodermic syringes is inconvenient as well as painful. Formulations include those which have a viscosity of about 5 cS or more at about 20° C. and which can have 0.5 ml or more administered by a needle-free injector in about 0.1 second±0.02 seconds. 123.-. (canceled)24. A needle free injector device , comprising:a container;a liquid formulation in the container, the formulation having a viscosity of 5 cS or more at 20° C.; anda nozzle leading from the container, the nozzle comprising a channel and an exit opening configured to have a ratio of channel length to exit opening diameter of less than 10.25. The injector of claim 24 , wherein the ratio of channel length to exit opening diameter is less than 7.26. The injector of claim 24 , wherein the viscosity of the liquid is more than 10 cS at 20° C.27. The injector of claim 24 , wherein the viscosity of the liquid is 20 cS or more at 20° C. and the ratio of channel length to exit opening diameter is less than 5.28. The injector of claim 24 , wherein the viscosity of the formulation is 100 cS or more at 20° C.29. The injector of claim 24 , wherein the ratio of length to exit diameter is 1.7±20%.30. The injector of claim 24 , wherein the viscosity of the formulation is 1000 cS or more at 20° C.31. The injector of claim 26 , wherein the formulation comprises a pharmaceutically acceptable carrier and a pharmaceutically active drug.32. The needle free injector of claim 31 , wherein the drug is a psychiatric drug.33. The injector of claim 32 , wherein the psychiatric drug is selected from the group consisting of chlorpromazine claim 32 , fluphenazine claim 32 , mesoridazine claim 32 , perphenazine claim 32 , prochlorperazine claim 32 , promazine claim 32 , thioridazine/sulforidazine claim 32 , trifluoperazine claim 32 , indoles claim 32 , butyrophenones ...

METABOLISM RESISTANT FENFLURAMINE ANALOGS AND METHODS OF USING THE SAME

Metabolism-resistant fenfluramine analogs are provided. The subject fenfluramine analogs find use in the treatment of a variety of diseases. For example, methods of treating epilepsy by administering a fenfluramine analog to a subject in need thereof are provided. Also provided are methods of suppressing appetite in a subject in need thereof. Pharmaceutical compositions for use in practicing the subject methods are also provided. 8. The method of , wherein the compound is a compound according to one of -.9. The method of claim 7 , further comprising co-administering to the subject an antiepileptic agent.11. (canceled) Pursuant to 35 U.S.C. § 119 (e), this application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 62/271,168, filed Dec. 22, 2015, the disclosure of which application is hereby incorporated by reference herein in its entirety.This invention relates generally to the field of compounds structurally related to the amphetamine drug fenfluramine and their use in the treatment of neurological related diseases.Fenfluramine is an amphetamine drug that was once widely prescribed as an appetite suppressant to treat obesity. Fenfluramine is devoid of the psychomotor stimulant and abuse potential of D-amphetamine and interacts with the 5-hydroxytryptamine (serotonin, 5-HT) transporters to release 5-HT from neurons. Fenfluramine has been investigated for anticonvulsive activity in the treatment of Dravet Syndrome, or severe myoclonic epilepsy in infancy, a rare and malignant epileptic syndrome. This type of epilepsy has an early onset in previously healthy children.Anorectic treatment with fenfluramine has been associated with the development of cardiac valvulopathy and pulmonary hypertension, including the condition cardiac fibrosis which led to the withdrawal of fenfluramine from world-wide markets. Interaction of fenfluramine's major metabolite norfenfluramine with the 5-HT2B receptor is associated with heart valve hypertrophy. In ...

COMPOSITIONS AND METHODS FOR TREATING SEIZURE DISORDERS

Functional analogs of fenfluramine are provided. The subject fenfluramine functional analogs find use in the treatment of a variety of diseases. For example, methods of treating epilepsy by administering a fenfluramine analog to a subject in need thereof are provided. Also provided are methods of treating a neurodegenerative disease in a subject in need thereof. Pharmaceutical compositions for use in practicing the subject methods are also provided. 1. A method for treating a patient in need of treatment comprising the step of administering an effective dose of a therapeutic agent , wherein the therapeutic agent comprises a compound active at one or more targets selected from the group consisting of:(a) a 5-HT receptor protein selected from the group consisting of the 5-HT1A receptor, the 5-HT1D receptor, the 5-HT1E receptor, the 5-HT2A receptor, the 5-HT2C receptor, the 5-HT5A receptor, and the 5-HT7 receptor,(b) an adrenergic receptor protein selected from the beta-1 adrenergic receptor, and the beta-2 adrenergic receptor,(c) a muscarinic acetylcholine receptor protein selected from the group consisting of the M1 muscarinic acetylcholine receptor the M2 muscarinic acetylcholine receptor, the M3 muscarinic acetylcholine receptor, the M4 muscarinic acetylcholine receptor, and the M5 muscarinic acetylcholine receptor,(d) a chaperone protein selected from the group consisting of the sigma-1 receptor and the sigma-2 receptor,(e) a sodium channel subunit protein selected from the group consisting of the Nav 1.1 subunit, the Nav 1.2 subunit, the subunit, the Nav 1.3 subunit, the Nav 1.4 subunit, the Nav 1.5 subunit, the Nav 1.6 subunit, and the Nav 1.7 subunit, and(f) a neurotransmitter transport protein selected from the group consisting of a serotonin transporter (SET), a dopamine transporter (DAT), and a norepinephrine transporter (NET).2. The method of claim 1 , wherein the therapeutic agent is a compound of Appendix 1.3. The method of claim 1 , wherein the ...

Method of increasing time between convulsive seizures

A method of increasing an average time between seizures in a human patient diagnosed with Dravet syndrome, comprising administering to the patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base, acid or amine thereof, and repeating the administering over a period of days until the patient exhibits an increase from baseline in average time between convulsive seizures of 6 hours, days weeks or more.

METHOD OF REDUCING SEIZURE TYPE EXPERIENCED BY A DRAVET PATIENT

A method of reducing a particular type of seizure in a human patient diagnosed with Dravet syndrome, by administering to the patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base, acid or amine thereof, and repeating the administering over a period of days until the patient exhibits a reduction from baseline in seizures of a particular type. The reduction may be of one, two or three specific types of seizures. 1. A method of treating a patient diagnosed with Dravet syndrome , comprising:administering to the patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base or acid thereof; andrepeating the administering over a period of days until the patient exhibits a reduction from baseline in a seizure type experienced by the patient.2. The method as claimed in claim 1 , wherein the fenfluramine is the only active ingredient administered to the patient.3. The method of claim 1 , further comprising administering a co-therapeutic agent.4. The method as claimed in claim 1 , wherein two seizure types are reduced.5. The method as claimed in claim 1 , wherein three seizure types are reduced.6. The method as claimed in claim 1 , wherein the seizure type reduced is selected from the group consisting of non-convulsive seizures claim 1 , generalized seizures claim 1 , myoclonic seizures claim 1 , absence seizures claim 1 , and febrile seizures claim 1 , or any combination thereof.7. The method as claimed in claim 1 , further comprising:recording seizure types experienced daily by the patient in an electronic diary.8. The method of claim 3 , wherein the co-therapeutic agent is selected from the group consisting of claim 3 , carbamazepine claim 3 , ethosuximide claim 3 , fosphenytoin claim 3 , lamotrigine claim 3 , levetiracetam claim 3 , phenobarbital claim 3 , topiramate claim 3 , valproic acid claim 3 , valproate claim 3 , verapamil claim 3 , and benzodiazepines such as clobazam claim 3 , ...

METHOD OF REDUCTION MEDICATION IN TREATING DRAVET SYNDROME

A method of reducing dosing of a concomitant medication in a human patient diagnosed with Dravet syndrome, by administering to the patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base, acid or amine thereof, and repeating the administering over a period of days while reducing the dose of one or more concomitant anti-seizure or anti-epileptic drugs (AEDs) from baseline and thereby decreasing the amount of medication given to the patient while reducing adverse side effects. Pharmaceutical compositions and formulations for use in practicing the subject methods are also provided. 1. A method of treating a patient diagnosed with Dravet syndrome , comprising:administering to the patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base or acid thereof;administering to the patient over a period of days a concomitant anti-epileptic drug (AED); andcontinuing to administer the fenfluramine and the AED over a period of days while gradually reducing AED administered while maintaining efficacy of treatment.2. The method as claimed in claim 1 , wherein the concomitant AED is reduced in increments while monitoring efficacy of the treatment.3. The method of claim 2 , wherein the incremental reduction continues over a period of days.4. The method of claim 2 , wherein the incremental reduction continues over a period of weeks.5. The method of claim 2 , wherein the incremental reduction continues over a period of months.6. The method of claim 3 , wherein the reduction continues until the patient no longer receives a dose of the concomitant AED.7. The method of claim 1 , wherein the AED is selected from the group consisting of claim 1 , carbamazepine claim 1 , ethosuximide claim 1 , fosphenytoin claim 1 , lamotrigine claim 1 , levetiracetam claim 1 , phenobarbital claim 1 , topiramate claim 1 , valproic acid claim 1 , valproate claim 1 , verapamil claim 1 , and benzodiazepines such as clobazam ...

METHOD OF TREATING SELECTED PATIENT POPULATION EXPERIENCING DRAVET SYNDROME

Provided herein is a method of treating a selected patient population, wherein the patient population is selected based on a determination that the patients have previously been non-responsive when treated with cannabidiol. In some embodiments, the method comprises selecting the patient based on a previously failed treatment with cannabidiol, based on lack of efficacy or tolerability. Pharmaceutical compositions and formulations for use in practicing the subject methods are also provided. The method comprises identifying a population of patients diagnosed with Dravet syndrome who were found previously to have been non-responsive when treated with cannabidiol. The selected population of patients is then treated by administering, to each identified patient, a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base, acid or amine thereof, and repeating the administering over a period of a day or days, or over a period of weeks, months or years, until the patient exhibits a reduction from baseline in convulsive seizure frequency. 1. A method of treating a patient in a selected patient population diagnosed with Dravet syndrome , comprising:determining a patient has previously been non-responsive when treated with cannabidiol or the patient's response to cannabidiol diminished over time;identifying the patient so determined as being non-responsive;administering to the non-responsive patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base or acid thereof; andrepeating the administering over a period of days until the patient exhibits a reduction from baseline in convulsive seizure frequency.2. The method as claimed in claim 1 , wherein the fenfluramine is the only active ingredient administered to the patient.3. The method of claim 1 , further comprising:administering a co-therapeutic agent.4. The method of claim 3 , wherein the co-therapeutic agent is selected from the group consisting of ...

METHOD OF TREATING SELECTED PATIENT POPULATION EXPERIENCING DRAVET SYNDROME

Provided herein is a method of treating a selected patient population, wherein the patient population is selected based on a determination that the patients have previously been non-responsive when treated with stiripentol. In some embodiments, the method comprises selecting the patient based on a previously failed treatment with stiripentol, based on lack of efficacy or tolerability. Pharmaceutical compositions and formulations for use in practicing the subject methods are also provided. The method comprises identifying a population of patients diagnosed with Dravet syndrome who were found previously to have been non-responsive when treated with stiripentol. The selected population of patients is then treated by administering, to each identified patient, a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base, acid or amine thereof, and repeating the administering over a period of a day or days, or over a period of weeks, months or years, until the patient exhibits a reduction from baseline in convulsive seizure frequency. 1. A method of treating a patient in a selected patient population diagnosed with Dravet syndrome , comprising:determining a patient has previously been non-responsive when treated with stiripentol or the patient's response to stiripentol diminished over time;identifying the patient so determined as being non-responsive;administering to the non-responsive patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base or acid thereof; andrepeating the administering over a period of days until the patient exhibits a reduction from baseline in convulsive seizure frequency.2. The method as claimed in claim 1 , wherein the fenfluramine is the only active ingredient administered to the patient.3. The method of claim 1 , further comprising:administering a co-therapeutic agent.4. The method of claim 3 , wherein the co-therapeutic agent is selected from the group consisting of ...

Ketogenic diet compatible fenfluramine formulation

A method of treating symptoms of a subtype of epilepsy, e.g., Dravet syndrome, in a patient diagnosed with a subtype of epilepsy, by administering to the patient an effective dose of a fenfluramine formulation in combination with a ketogenic diet over a period of time sufficient to reduce or completely eliminate seizures in the patient. Also provided are compositions and kits finding use in practicing embodiments of the methods.

CONGNITIVE FUNCTION WITH FENFLURAMINE

Disclosed herein are methods of improving cognitive function in a patient as measured by, for example, improvement in score on a validated scale that measures cognitive function, such as the Behavior Rating Inventory of Executive Function (BRIEF), by administering the test to a patient and obtaining a pre-treatment test score, treating the patient with fenfluramine or its pharmaceutically acceptable salt, and after treatment, re-administering the test of cognitive function to the patient and obtaining a post-treatment score, to allow observation of an improvement in the test score. In some embodiments, the patient is also being treated for the symptoms of epilepsy. 1. A method of obtaining improvement in neurologic function as assessed by observing a statistically significant improvement in at least one ranking level in a patient using the BRIEF test , comprising:administering a BRIEF test to a patient and obtaining a set of BRIEF scores;treating the patient with fenfluramine, or a pharmaceutically acceptable salt thereof over a period of days; andcontinuing treatment with the fenfluramine, or the pharmaceutically acceptable salt thereof, until a re-administration of the BRIEF test to the patient shows improvement in the patient's neurological function.2. The method of claim 1 , wherein the patient has been diagnosed with a disease or condition selected from an epilepsy or epileptic encephalopathy (e.g. claim 1 , Dravet syndrome claim 1 , Doose syndrome claim 1 , infantile spasms claim 1 , Lennox-Gastaut syndrome); attentional disorders (e.g. claim 1 , attention deficit disorder (ADD) or attention deficit/hyperactivity disorder (ADHD)); developmental disorders claim 1 , such as autism spectrum disorders (ASDs) claim 1 , including autism claim 1 , Asperger syndrome claim 1 , pervasive developmental disorder (PDD) and pervasive developmental disorder not otherwise specified (PDD-NOS); oppositional defiant disorder (ODD); learning disabilities (e.g. dyslexia claim 1 , ...

NEEDLE-FREE INJECTORS AND DESIGN PARAMETERS THEREOF THAT OPTIMIZE INJECTION PERFORMANCE

A needle free injector system and a method for delivering a formulation using this system are disclosed. The method comprises actuating a needle free injector to pressurize a liquid formulation and force the formulation through an orifice in a skin puncture phase followed by injection of the formulation during a delivery phase. The skin puncture phase is defined by a pressure profile vs. time curve after actuation which has a main pressure peak with a maximum pressure. The delivery phase occurs at a lower pressure than the maximum pressure of the main peak pressure. The device may have one or more orifices and pressurizing the formulation during the puncture phase and delivery phase to extrude the formulation through each orifice is structured so as to improve characteristics of needle free delivery. 120.-. (canceled)21. A needle free injector wherein a liquid formulation is pressurized and extruded out of at least one orifice of the injector;wherein the injector is configured such that upon actuation the injector generates a pressure profile vs. time curve comprising a puncture phase including a main pressure peak with a maximum pressure, {'br': None, '17.4*MPP(MPa)−TotIT0.5(ms/0.5 ml)>=363.2'}, 'characterized by a delivery time per 0.5 mL of injectate per orifice, wherein the delivery time and the peak pressure are chosen to satisfy the relationshipwherein TotIT0.5 is measured in ms, and MPP is measured in MPa.22. The needle free injector of claim 21 , wherein the delivery time and the peak pressure are chosen to satisfy the relationship:{'br': None, '17.4*MPP(MPa)−TotIT0.5(ms/0.5 ml)>=505.4.'}23. The needle free injector of claim 21 , wherein the delivery time and the peak pressure are chosen to satisfy the relationship:{'br': None, '17.4*MPP(MPa)−TotIT0.5(ms/0.5 ml)>=530.2.'}24. The needle free injector of claim 22 , further comprising an energy source selected from:a mechanical spring;a compressed gas;a pyrotechnic charge.25. The needle free injector of claim ...

METHOD OF REDUCTION IN CONVULSIVE SEIZURE FREQUENCY

A method of reducing convulsive seizure frequency in a human patient diagnosed with Dravet syndrome, comprising administering to the patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base, acid or amine thereof, and repeating the administering over a period of days until the patient exhibits a significant reduction (e.g., 40% or greater) from baseline in convulsive seizure frequency. In some embodiments of the method, convulsive seizures are completely eliminated for 10 days or more, 20 days or more, 30 days or more, 50 days or more, 100 days or more. 1. A method of treating a patient diagnosed with Dravet syndrome , comprising:administering to the patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base or acid thereof; andrepeating the administering over a period of days until the patient exhibits a reduction from baseline in convulsive seizure frequency of 40% or more.2. The method as claimed in claim 1 , wherein the fenfluramine is the only active ingredient administered to the patient.3. The method of claim 1 , further comprising:administering a co-therapeutic agent.4. The method of claim 3 , wherein the co-therapeutic agent is selected from the group consisting of claim 3 , carbamazepine claim 3 , ethosuximide claim 3 , fosphenytoin claim 3 , lamotrigine claim 3 , levetiracetam claim 3 , phenobarbital claim 3 , topiramate claim 3 , valproic acid claim 3 , valproate claim 3 , verapamil claim 3 , and benzodiazepines such as clobazam claim 3 , clonazepam claim 3 , diazepam claim 3 , lorazepam claim 3 , and midazolam and a pharmaceutically acceptable salt or base thereof.5. The method of claim 4 , wherein the co-therapeutic agent is a combination of stiripentol claim 4 , valproate and clobazam.6. The method of claim 1 , wherein the co-therapeutic agent is cannabidiol.7. The method of claim 1 , wherein the administering is over a period of months claim 1 , and the co- ...

NEEDLE-FREE INJECTORS AND DESIGN PARAMETERS THEREOF THAT OPTIMIZE INJECTION PERFORMANCE

A needle free injector system and a method for delivering a formulation using this system are disclosed. The method comprises actuating a needle free injector to pressurize a liquid formulation and force the formulation through an orifice in a skin puncture phase followed by injection of the formulation during a delivery phase. The skin puncture phase is defined by a pressure profile vs. time curve after actuation which has a main pressure peak with a maximum pressure. The delivery phase occurs at a lower pressure than the maximum pressure of the main peak pressure. The device may have one or more orifices and pressurizing the formulation during the puncture phase and delivery phase to extrude the formulation through each orifice is structured so as to improve characteristics of needle free delivery. 120.-. (canceled)21. A needle free injector wherein a liquid formulation is pressurized and extruded out of at least one orifice of the injector;wherein the injector is configured such that upon actuation the injector generates a pressure profile vs. time curve comprising a puncture phase including a main pressure peak with a maximum pressure, {'br': None, 'i': *MPP', 'MPa', 'TotIT, '17.4()−0.5(ms/0.5 ml)>=363.2'}, 'characterized by a delivery time per 0.5 mL of injectate per orifice, wherein the delivery time and the peak pressure are chosen to satisfy the relationshipwherein TotIT0.5 is measured in ms, and MPP is measured in MPa.22. The needle free injector of claim 21 , wherein the delivery time and the peak pressure are chosen to satisfy the relationship:{'br': None, 'i': *MPP', 'MPa', 'TotIT, '17.4()−0.5(ms/0.5 ml)>=505.4.'}23. The needle free injector of claim 21 , wherein the delivery time and the peak pressure are chosen to satisfy the relationship:{'br': None, 'i': *MPP', 'MPa', 'TotIT, '17.4()−0.5(ms/0.5 ml)>=530.2.'}24. The needle free injector of claim 22 , further comprising an energy source selected from:a mechanical spring;a compressed gas;a pyrotechnic ...

METABOLISM RESISTANT FENFLURAMINE ANALOGS AND METHODS OF USING THE SAME

Metabolism-resistant fenfluramine analogs are provided. The subject fenfluramine analogs find use in the treatment of a variety of diseases. For example, methods of treating epilepsy by administering a fenfluramine analog to a subject in need thereof are provided. Also provided are methods of suppressing appetite in a subject in need thereof. Pharmaceutical compositions for use in practicing the subject methods are also provided. 211.-. (canceled)13. The method of claim 12 , further comprising:co-administering to the subject an antiepileptic agent.14. The method of wherein the antiepileptic agent is selected from the group consisting of Acetazolamide claim 13 , Carbamazepine claim 13 , Clobazam claim 13 , Clonazepam claim 13 , Eslicarbazepine acetate claim 13 , Ethosuximide claim 13 , Gabapentin claim 13 , Lacosamide claim 13 , Lamotrigine claim 13 , Levetiracetam claim 13 , Nitrazepam claim 13 , Oxcarbazepine claim 13 , Perampanel claim 13 , Piracetam claim 13 , Phenobarbital claim 13 , Phenytoin claim 13 , Pregabalin claim 13 , Primidone claim 13 , Retigabine claim 13 , Rufinamide claim 13 , Sodium valproate claim 13 , Stiripentol claim 13 , Tiagabine claim 13 , Topiramate claim 13 , Vigabatrin and Zonisamide. This invention relates generally to the field of compounds structurally related to the amphetamine drug fenfluramine and their use in the treatment of neurological related diseases.Fenfluramine is an amphetamine drug that was once widely prescribed as an appetite suppressant to treat obesity. Fenfluramine is devoid of the psychomotor stimulant and abuse potential of D-amphetamine and interacts with the 5-hydroxytryptamine (serotonin, 5-HT) transporters to release 5-HT from neurons. Fenfluramine has been investigated for anticonvulsive activity in the treatment of Dravet Syndrome, or severe myoclonic epilepsy in infancy, a rare and malignant epileptic syndrome. This type of epilepsy has an early onset in previously healthy children.Anorectic treatment with ...

METHOD OF REDUCTION IN CONVULSIVE SEIZURE FREQUENCY

A method of reducing convulsive seizure frequency in a human patient diagnosed with Dravet syndrome, comprising administering to the patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base, acid or amine thereof, and repeating the administering over a period of days until the patient exhibits a significant reduction (e.g., 40% or greater) from baseline in convulsive seizure frequency. In some embodiments of the method, convulsive seizures are completely eliminated for 10 days or more, 20 days or more, 30 days or more, 50 days or more, 100 days or more. 1. A method of treating a patient diagnosed with Dravet syndrome , comprising:identifying a patient who is ≤6 years old and experiencing severe seizures, treatment refractory seizures or both;administering to the patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, thereof; andrepeating the administering over a period of days until the patient exhibits a reduction from baseline in severity of seizures or convulsive seizure frequency of 60% or more.2. The method as claimed in claim 1 , wherein the fenfluramine is the only active ingredient administered to the patient.3. The method of claim 1 , further comprising:administering a co-therapeutic agent.4. The method of claim 3 , wherein the co-therapeutic agent is selected from the group consisting of claim 3 , carbamazepine claim 3 , ethosuximide claim 3 , fosphenytoin claim 3 , lamotrigine claim 3 , levetiracetam claim 3 , phenobarbital claim 3 , topiramate claim 3 , valproic acid claim 3 , valproate claim 3 , verapamil claim 3 , and benzodiazepines such as clobazam claim 3 , clonazepam claim 3 , diazepam claim 3 , lorazepam claim 3 , and midazolam and a pharmaceutically acceptable salt or base thereof.5. The method of claim 4 , wherein the co-therapeutic agent is a combination of one or more agents selected from stiripentol claim 4 , valproate and clobazam.6. The method of claim 1 , ...

Ketogenic diet compatible fenfluramine formulation

A method of treating symptoms of a subtype of epilepsy, e.g., Dravet syndrome, in a patient diagnosed with a subtype of epilepsy, by administering to the patient an effective dose of a fenfluramine formulation in combination with a ketogenic diet over a period of time sufficient to reduce or completely eliminate seizures in the patient. Also provided are compositions and kits finding use in practicing embodiments of the methods.

METHOD OF TREATING SELECTED PATIENT POPULATION EXPERIENCING DRAVET SYNDROME

Provided herein is a method of treating a selected patient population, wherein the patient population is selected based on a determination that the patients have previously been non-responsive when treated with cannabidiol. In some embodiments, the method comprises selecting the patient based on a previously failed treatment with cannabidiol, based on lack of efficacy or tolerability. Pharmaceutical compositions and formulations for use in practicing the subject methods are also provided. The method comprises identifying a population of patients diagnosed with Dravet syndrome who were found previously to have been non-responsive when treated with cannabidiol. The selected population of patients is then treated by administering, to each identified patient, a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base, acid or amine thereof, and repeating the administering over a period of a day or days, or over a period of weeks, months or years, until the patient exhibits a reduction from baseline in convulsive seizure frequency. 1. A method of treating a patient in a selected patient population , comprising:diagnosing a patient as suffering from Dravet syndrome;determining the patient has previously been non-responsive when treated with cannabidiol or the patient's response to cannabidiol diminished over time;identifying the patient so determined as being non-responsive;administering to the non-responsive patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base or acid thereof in combination with a therapeutically effective dose of cannabidiol; andrepeating the administering over a period of days until the patient exhibits a reduction from baseline in convulsive seizure frequency.27-. (canceled)8. The method of claim 1 , further comprising:repeating the administering until the patient exhibits a ≥80% reduction from baseline in convulsive seizure frequency.9. The method of wherein the ...

COMPOSITIONS AND METHODS FOR TREATING SEIZURE DISORDERS

Functional analogs of fenfluramine are provided. The subject fenfluramine functional analogs find use in the treatment of a variety of diseases. For example, methods of treating epilepsy by administering a fenfluramine analog to a subject in need thereof are provided. Also provided are methods of treating a neurodegenerative disease in a subject in need thereof. Pharmaceutical compositions for use in practicing the subject methods are also provided. 1. A method for treating a patient diagnosed with a form of refractory epilepsy selected from the group consisting of Dravet syndrome , Lennox-Gastaut syndrome , Doose syndrome , West syndrome , comprising:administering an effective dose of a therapeutic agent, wherein the therapeutic agent comprises a compound active at one or more 5-HT receptor selected from the 5-HT1A receptor. the 5-HT1D receptor, the 5-HT2A receptor, and the 5-HT2C receptor.25.-. (canceled)6. The method of claim 1 , wherein the therapeutic agent is active at to two or more targets.7. The method of claim 6 , wherein the therapeutic agent is active at the 5-HT1A receptor and further is active at the sigma-1 receptor.8. (canceled)1018.-. (canceled)19. The method of claim 1 , further wherein the therapeutic agent is at least one of:(a) inactive at the 5-HT2B receptor;(b) a neutral agonist of the 5-HT2B receptor; and(c) an inverse agonist of the 5-HT2B receptor 5-HT2B receptor.20. (canceled)21. The method of claim 1 , wherein an effective dose of the therapeutic agent is administered in a pharmaceutically acceptable carrier.22. The method of claim 21 , wherein the pharmaceutical composition is a formulation adapted to a dosage forms selected from the group consisting of an oral dosage form claim 21 , an intravenous dosage form claim 21 , rectal dosage form claim 21 , subcutaneous dosage form claim 21 , and a transdermal dosage form.23. The method of claim 22 , wherein the oral dosage form selected from the group consisting of a liquid claim 22 , a ...

CHANGING COGNITIVE FUNCTION WITH FENFLURAMINE

Disclosed herein are methods of improving cognitive function in a patient as measured by, for example, improvement in score on a validated scale that measures cognitive function, such as the Behavior Rating Inventory of Executive Function (BRIEF), by administering the test to a patient and obtaining a pre-treatment test score, treating the patient with fenfluramine or its pharmaceutically acceptable salt, and after treatment, re-administering the test of cognitive function to the patient and obtaining a post-treatment score, to allow observation of an improvement in the test score. In some embodiments, the patient is also being treated for the symptoms of epilepsy. 1. A method of obtaining a statistically significant improvement in at least one ranking level in test results for a patient given a Behavior Rating Inventory of Executive Function (BRIEF) test , comprising:administering a BRIEF test to a patient and obtaining a first set of BRIEF scores;treating the patient with fenfluramine, or a pharmaceutically acceptable salt thereof over a period of time; andre-administering the BRIEF test to the patient to obtain a second set of BREIF scores after treating with fenfluramine, or a pharmaceutically acceptable salt thereof; andcomparing the first set of BRIEF scores to the second set of BRIEF scores and showing a statistically significant improvement in at least one ranking level between the first set of BRIEF scores and the second set of BRIEF scores.2. The method of claim 1 , wherein the patient has been diagnosed with a form of epilepsy.3. The method of claim 2 , wherein the form of epilepsy is Dravet syndrome.4. The method of claim 2 , wherein the the form of epilepsy is Lennox-Gastaut syndrome.5. The method of claim 1 , wherein the fenfluramine is formulated with a pharmaceutically acceptable carrier claim 1 , and administered in an effective dose selected from less than about 10.0 mg/kg/day claim 1 , less than 1.0 mg/kg/day claim 1 , about 0.8 mg/kg/day claim 1 ...

METABOLISM RESISTANT FENFLURAMINE ANALOGS AND METHODS OF USING THE SAME

Metabolism-resistant fenfluramine analogs are provided. The subject fenfluramine analogs find use in the treatment of a variety of diseases. For example, methods of treating epilepsy by administering a fenfluramine analog to a subject in need thereof are provided. Also provided are methods of suppressing appetite in a subject in need thereof. Pharmaceutical compositions for use in practicing the subject methods are also provided. 111.-. (canceled)14. The method of claim 12 , wherein the method further comprises co-administering to the patient an antiepileptic agent. This invention relates generally to the field of compounds structurally related to the amphetamine drug fenfluramine and their use in the treatment of neurological related diseases.Fenfluramine is an amphetamine drug that was once widely prescribed as an appetite suppressant to treat obesity. Fenfluramine is devoid of the psychomotor stimulant and abuse potential of D-amphetamine and interacts with the 5-hydroxytryptamine (serotonin, 5-HT) transporters to release 5-HT from neurons. Fenfluramine has been investigated for anticonvulsive activity in the treatment of Dravet Syndrome, or severe myoclonic epilepsy in infancy, a rare and malignant epileptic syndrome. This type of epilepsy has an early onset in previously healthy children.Anorectic treatment with fenfluramine has been associated with the development of cardiac valvulopathy and pulmonary hypertension, including the condition cardiac fibrosis which led to the withdrawal of fenfluramine from world-wide markets. Interaction of fenfluramine's major metabolite norfenfluramine with the 5-HT2B receptor is associated with heart valve hypertrophy. In the treatment of epilepsy, the known cardiovascular risks of fenfluramine are weighed against beneficial anticonvulsive activity.Metabolism-resistant fenfluramine analogs are provided. The subject fenfluramine analogs find use in the treatment of a variety of diseases. For example, methods of treating ...

Method for delivery of viscous preparation with needle-free injection

【課題】皮下シリンジによる粘性製剤の、痛みを伴わない無針送達装置を提供する。 【解決手段】無針注射器、薬学的に活性な薬物を含む液体製剤容器、および容器からノズル出口開口へ導くチャネルを含み、該チャネルの長さ／前記ノズル出口開口の比が10未満である長さを有し、薬学的に活性な薬物が、精神薬であり、製剤は、約20℃で約5cS以上の粘度を有し、無針注射器により約0.1秒で0.5ml以上を投与することができるものを含むことを特徴とする。 【選択図】図３

Metabolism resistant fenfluramine analogs and methods of using the same

Metabolism-resistant fenfluramine analogs are provided. The subject fenfluramine analogs find use in the treatment of a variety of diseases. For example, methods of treating epilepsy by administering a fenfluramine analog to a subject in need thereof are provided. Also provided are methods of suppressing appetite in a subject in need thereof. Pharmaceutical compositions for use in practicing the subject methods are also provided.

Ketogenic diet compatible fenfluramine formulation

A method of treating symptoms of a subtype of epilepsy, e.g., Dravet syndrome, in a patient diagnosed with a subtype of epilepsy, by administering to the patient an effective dose of a fenfluramine formulation in combination with a ketogenic diet over a period of time sufficient to reduce or completely eliminate seizures in the patient. Also provided are compositions and kits finding use in practicing embodiments of the methods.

Delivery of viscous formulations by needle-free injection

Formulations are described that are viscous and will benefit from needle-free delivery at high driving pressures. Conventional delivery of these viscous formulations by hypodermic syringes is inconvenient as well as painful. Formulations include those which have a viscosity of about 5 cS or more at about 20~C and which can have 0.5 ml or more administered by a needleless injector in about 0.1 second.

Metabolism resistant fenfluramine analogs and methods of using the same

Metabolism-resistant fenfluramine analogs are provided. The subject fenfluramine analogs find use in the treatment of a variety of diseases. For example, methods of treating epilepsy by administering a fenfluramine analog to a subject in need thereof are provided. Also provided are methods of suppressing appetite in a subject in need thereof. Pharmaceutical compositions for use in practicing the subject methods are also provided.

Kits for drug delivery site preparation

Apparatuses and methods for preparing an injection site on a target organ for enhanced delivery are described. In one embodiment, a drug delivery device, such as an injector, is supplied in a kit with an applicator for topically applied drugs, including anesthetics, vasodilators, and/or absorption enhancers. The applicator may be combined with another function, such as a needle or orifice cap. In another embodiment, the delivery system is supplied with an alignment ring, gripper, or vacuum cup to ensure the delivery device is in contact with and at the desired angle relative to the target organ, and ensures that the delivery device does not move relative to the delivery site during delivery. Also disclosed are topical applicators and topical formulations.

Delivery of viscous formulations by needle-free injection

Viscous formulations and their use in needle-free injection

Formulations are described that are viscous and will benefit from needle-free delivery at high driving pressures. Conventional delivery of these viscous formulations by hypodermic syringes is inconvenient as well as painful. Formulations include those which have a viscosity of about 5 cS or more at about 20° C. and which can have 0.5 ml or more administered by a needle-free injector in about 0.1 second ±0.02 seconds.

Needle-free injectors and design parameters thereof that optimize injection performance

A needle free injector system and a method for delivering a formulation using this system are disclosed. The method comprises actuating a needle free injector to pressurize a liquid formulation and force the formulation through an orifice in a skin puncture phase followed by injection of the formulation during a delivery phase. The skin puncture phase is defined by a pressure profile vs. time curve after actuation which has a main pressure peak with a maximum pressure. The delivery phase occurs at a lower pressure than the maximum pressure of the main peak pressure. The device may have one or more orifices and pressurizing the formulation during the puncture phase and delivery phase to extrude the formulation through each orifice is structured so as to improve characteristics of needle free delivery.

Delivery of viscous formulations by needle-free injection

Formulations are described that are viscous and will benefit from needle-free delivery at high driving pressures. Conventional delivery of these viscous formulations by hypodermic syringes is inconvenient as well as painful. Formulations include those which have a viscosity of about 5 cS or more at about 20°C and which can have 0.5 ml or more administered by a needleless injector in about 0.1 second.

Delivery of viscous formulations by needle-free injection

Formulations are described that are viscous and will benefit from needle-free delivery at high driving pressures. Conventional delivery of these viscous formulations by hypodermic syringes is inconvenient as well as painful. Formulations include those which have a viscosity of about 5 cS or more at about 20~C and which can have 0.5 ml or more administered by a needleless injector in about 0.1 second.

Metabolism resistant fenfluramine analogs and methods of using the same

Metabolism-resistant fenfluramine analogs are provided. The subject fenfluramine analogs find use in the treatment of a variety of diseases. For example, methods of treating epilepsy by administering a fenfluramine analog to a subject in need thereof are provided. Also provided are methods of suppressing appetite in a subject in need thereof. Pharmaceutical compositions for use in practicing the subject methods are also provided.

Use of fenfluramine formulation in reducing number and frequencies of convulsive seizures in patient populations

A method of reducing convulsive seizure frequency in a human patient diagnosed with Dravet syndrome, comprising administering to the patient a therapeutically effective dose of fenfluramine or a pharmaceutically acceptable salt, base, acid or amine thereof, and repeating the administering over a period of days until the patient exhibits a significant reduction (e.g., 40% or greater) from baseline in convulsive seizure frequency. In some embodiments of the method, convulsive seizures are completely eliminated for 10 days or more, 20 days or more, 30 days or more, 50 days or more, 100 days or more.

Use of fenfluramine formulation in reducing number and frequencies of convulsive seizures in patient populations

Improvement in cognitive function with fenfluramine

Disclosed herein are methods of improving cognitive function in a patient as measured by, for example, improvement in score on a validated scale that measures cognitive function, such as the Behavior Rating Inventory of Executive Function (BRIEF), by administering the test to a patient and obtaining a pre-treatment test score, treating the patient with fenfluramine or its pharmaceutically acceptable salt, and after treatment, re-administering the test of cognitive function to the patient and obtaining a post-treatment score, to allow observation of an improvement in the test score. In some embodiments, the patient is also being treated for the symptoms of epilepsy.

フェンフルラミンによる認知機能の改善方法

【課題】神経機能の改善における使用のための製剤であって、該製剤が、フェンフルラミンまたはその薬学的に許容される塩を含む製剤を提供する。【解決手段】本明細書において、患者に検査を施行して処置前検査スコアを得る工程、フェンフルラミンまたはその薬学的に許容される塩で患者を処置する工程、および、処置後に認知機能の検査を患者に再施行して処置後スコアを得て、試験スコアの改善の観察を可能にする工程によって、例えば、実行機能の行動評価尺度（BRIEF）などの認知機能を測定する有効な尺度に対するスコアの改善によって測定される、患者における認知機能を改善する方法が開示される。いくつかの態様において、患者はてんかんの症状についても処置されている。【選択図】図７

Improvement in cognitive function with fenfluramine

Disclosed herein are methods of improving cognitive function in a patient as measured by, for example, improvement in score on a validated scale that measures cognitive function, such as the Behavior Rating Inventory of Executive Function (BRIEF), by administering the test to a patient and obtaining a pre-treatment test score, treating the patient with fenfluramine or its pharmaceutically acceptable salt, and after treatment, re-administering the test of cognitive function to the patient and obtaining a post-treatment score, to allow observation of an improvement in the test score. In some embodiments, the patient is also being treated for the symptoms of epilepsy.

Compositions and methods for treating seizure disorders

Functional analogs of fenfluramine are provided. The subject fenfluramine functional analogs find use in the treatment of a variety of diseases. For example, methods of treating epilepsy by administering a fenfluramine analog to a subject in need thereof are provided. Also provided are methods of treating a neurodegenerative disease in a subject in need thereof. Pharmaceutical compositions for use in practicing the subject methods are also provided.

Improvement in cognitive function with fenfluramine

Disclosed herein are methods of improving cognitive function in a patient as measured by, for example, improvement in score on a validated scale that measures cognitive function, such as the Behavior Rating Inventory of Executive Function (BRIEF), by administering the test to a patient and obtaining a pre-treatment test score, treating the patient with fenfluramine or its pharmaceutically acceptable salt, and after treatment, re-administering the test of cognitive function to the patient and obtaining a post-treatment score, to allow observation of an improvement in the test score. In some embodiments, the patient is also being treated for the symptoms of epilepsy.