Formulation for inhibiting formation of 5-ht2b agonists and methods of using same

Abstract

Drug combinations and their use are disclosed. A first drug is administered in combination with a second drug. The first drug such as fenfluramine is characterized by the formation of a metabolite including 5-HT 2B agonists such as norfenfluramine with known adverse side effects. The second drug is in the form of a CYP inhibitor such as cannabidiol which modulates the formation of metabolite down thereby making the first drug safer.

That which is claimed is: 
     
         1 . A method of inhibiting the metabolism of a first drug, which first drug is characterized by formation of a metabolite with adverse effects, the method comprising:
 co-administering the first drug with a second drug in the form of a CYP450 enzyme inhibitor,   whereby the CYP450 enzyme inhibitor modulates down formation of the metabolite of the first drug.   
     
     
         2 . A method of treating a patient, comprising:
 administering a first drug, which first drug is characterized by acting on a 5-HT receptor, and further by formation of a metabolite with known adverse effects acting on a 5-HT2B receptor; and   administering a second drug in the form of a CYP450 enzyme inhibitor,   
       whereby the CYP inhibitor modulates down formation of the metabolite of the first drug. 
     
     
         3 . A method of preventing, reducing or ameliorating seizures in a patient diagnosed with a neurological disease, comprising:
 administering a first drug, which first drug is characterized by acting on a 5-HT receptor, and formation of a metabolite with known adverse effects acting on a 5-HT2B receptor; and   administering a second drug in the form of a CYP inhibitor,   
       whereby the CYP inhibitor modulates down formation of the metabolite of the first drug. 
     
     
         4 . The method of  claim 3 , wherein the patient is diagnosed with a form of refractory epilepsy. 
     
     
         5 . The method of  claim 4 , wherein the form of refractory epilepsy is selected from the group consisting of Dravet syndrome, Lennox-Gastaut syndrome, Doose syndrome, and West syndrome. 
     
     
         6 . A method of suppressing appetite in a subject, comprising:
 administering a first drug, which first drug is characterized by acting on a 5-HT receptor, and formation of a metabolite with known adverse effects acting on a 5-HT2B receptor; and   administering a second drug in the form of a CYP inhibitor,   whereby the CYP inhibitor modulates down formation of the metabolite of the first drug.   
     
     
         7 . The method of  claim 3 , wherein the first drug is fenfluramine and the harmful metabolite is norfenfluramine. 
     
     
         8 . The method of  claim 3 , wherein the one or more metabolic inhibitors is a CYP450 inhibitor. 
     
     
         9 . The method of  claim 8 , wherein the CYP450 inhibitor is selected from the group consisting of a CYP1A2 inhibitor, a CYP2B6 inhibitor a CYP2C9 inhibitor, a CYP2C19 inhibitor, a CYP2D6 inhibitor, and a CYP3A4 inhibitor. 
     
     
         10 . The method of  claim 3 , wherein the CYP inhibitor is selected from the group consisting of stiripentol, clobazam and cannabidiol. 
     
     
         11 . The method of  claim 3 , wherein CYP inhibitor is cannabidiol. 
     
     
         12 . The method of  claim 3 , further comprising co-administering to the subject an effective amount of a co-therapeutic agent selected from the group consisting of acetazolamide, barbexaclone, beclamide, brivaracetam, buproprion, cinacalet, clobazam, clonazepam, clorazepate, diazepam, divaloprex, eslicarbazepine acetate, ethadione, ethotoin, felbamate, gabapentin, lacosamide, lorazepam, mephenytoin, methazolamide, methsuximide, methylphenobarbitol, midazolam, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, perampanel, piracetam, phenacemide, pheneturide, phensuximide, phenytoin, potassium bromide, pregabalin, primidone, retigabine, rufinamide, selectracetam, sodium valproate, stiripentol, sultiame, temazepam, tiagabine, topiramate, trimethadione, valnoctamide, valpromide, vigabatrin, zonisamide, and pharmaceutically acceptable salts thereof. 
     
     
         13 . A method of inhibiting the metabolism of fenfluramine, which is characterized by formation of norfenfluramine, the method comprising:
 co-administering fenfluramine with a CYP450 enzyme inhibitor,   whereby the CYP450 enzyme inhibitor modulates down formation of norfenfluramine.   
     
     
         14 . The method of  claim 13 , wherein the co-administering is to a patient diagnosed with a form of refractory epilepsy. 
     
     
         15 . The method of  claim 14 , wherein the form of refractory epilepsy is selected from the group consisting of Dravet syndrome, Lennox-Gastaut syndrome, Doose syndrome, and West syndrome. 
     
     
         16 . A method of suppressing appetite in a subject, comprising:
 administering to a patient a therapeutically effective amount of fenfluramine; and   administering a CYP inhibitor to the patient;   whereby the CYP inhibitor modulates down formation of norfenfluramine.   
     
     
         17 . The method of  claim 16 , wherein the CYP inhibitor is a CYP450 inhibitor. 
     
     
         18 . The method of  claim 17 , wherein the CYP450 inhibitor is selected from the group consisting of a CYP1A2 inhibitor, a CYP2B6 inhibitor a CYP2C9 inhibitor, a CYP2C19 inhibitor, a CYP2D6 inhibitor, and a CYP3A4 inhibitor. 
     
     
         19 . The method of  claim 16 , wherein the inhibitor is selected from the group consisting of stiripentol, clobazam and cannabidiol. 
     
     
         20 . The method of  claim 16 , further comprising co-administering to the subject an effective amount of an additional agent selected from the group consisting of acetazolamide, barbexaclone, beclamide, brivaracetam, buproprion, cinacalet, clobazam, clonazepam, clorazepate, diazepam, divaloprex, eslicarbazepine acetate, ethadione, ethotoin, felbamate, gabapentin, lacosamide, lorazepam, mephenytoin, methazolamide, methsuximide, methylphenobarbitol, midazolam, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, perampanel, piracetam, phenacemide, pheneturide, phensuximide, phenytoin, potassium bromide, pregabalin, primidone, retigabine, rufinamide, selectracetam, sodium valproate, stiripentol, sultiame, temazepam, tiagabine, topiramate, trimethadione, valnoctamide, valpromide, vigabatrin, zonisamide, and pharmaceutically acceptable salts thereof.