Method and composition for treating alzheimer-type dementia

Abstract

There is described a method for increasing the maximal tolerated dose and thus the efficacy of an acetylcholinesterase inhibitor (AChEI) in a patient suffering from an Alzheimer type dementia by decreasing concomitant adverse effects by administration of said AChEI in combination with a non-anticholinergic antiemetic agent, whereby an enhanced acetylcholinesterase inhibition in the CNS of said patient is achieved and alleviation of the symptoms of Alzheimer type dementia in said patient is thereby improved to a greater extent. The use of a non-anticholinergic antiemetic agent for the preparation of a pharmaceutical composition for the treatment of Alzheimer type dementia in combination with an acetylcholinesterase inhibitor (AChEI) and pharmaceutical compositions comprising (a) a 5HT 3 receptor antagonist, a dopamine antagonist, a H1-receptor antagonist, a cannabinoid agonist, aprepitant or casopitant as an antiemetic agent and (b) an acetylcholinesterase inhibitor are also described.

1 . A method for increasing the therapeutic effect of an acetylcholinesterase inhibitor (AChEI) in a patient suffering from an Alzheimer type dementia, which comprises administering to said patient said AChEI at a dose level which is higher than the recommended maximal dose level, in combination with a compound that reduces, including to the extent of eliminating, dose-limiting side effects of said AChEI dose level, said compound being a non-anticholinergic antiemetic agent. 
     
     
         2 . The method of  claim 1 , wherein said dose level is increased up to a factor of 4. 
     
     
         3 . The method of  claim 1 , wherein said AChEI is administered to said patient concurrently or sequentially with said non-anticholinergic antiemetic agent, whereby an enhanced acetylcholinesterase inhibition in the CNS of said patient is achieved and the symptoms of an Alzheimer type dementia in said patient are improved. 
     
     
         4 . The method of  claim 1 , wherein said AChEI is administered to said patient at a dose level which is from 1.5 to 3 times higher than the recommended dose in the treatment of Alzheimer type dementia. 
     
     
         5 . The method of  claim 1 , wherein the non-anticholinergic antiemetic agent is formulated in a pharmaceutical composition, in admixture with a pharmaceutical carrier, in an amount of from 50% to 300% of the dosage used for preventing vomiting. 
     
     
         6 . The method of  claim 1 , wherein said non-anticholinergic antiemetic agent is selected from the group consisting of 5-HT3 receptor antagonists, dopamine antagonists, H1 histamine receptor antagonists, NK1 receptor antagonists and cannabinoid agonists. 
     
     
         7 . The method of  claim 6 , wherein said non-anticholinergic antiemetic agent is a 5HT3-antagonist selected from the group consisting of ondansetron, the pharmaceutically acceptable salts and solvates of ondansetron, granisetron, the pharmaceutically acceptable salts and solvates of granisetron, tropisetron, the pharmaceutically acceptable salts and solvates of tropisetron, lerisetron, the pharmaceutically acceptable salts and solvates of lerisetron, ramosetron and the pharmaceutically acceptable salts and solvates of ramosetron. 
     
     
         8 . The method of  claim 6 , wherein said dopamine antagonist is selected from the group consisting of domperidone, the pharmaceutically acceptable salts of domperidone, metoclopramide, the pharmaceutically acceptable salts and solvates of metoclopramide, bromopride, the pharmaceutically acceptable salts of bromopride, clebopride, the pharmaceutically acceptable salts of clebopride, alizapride and the pharmaceutically acceptable salts of alizapride. 
     
     
         9 . The method of  claim 6 , wherein said H1 histamine receptor antagonist is meclizine or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         10 . The method of  claim 6 , wherein said cannabinoid agonist is dronabinol or nabilone. 
     
     
         11 . The method of  claim 6 , wherein said NK1 receptor antagonist is aprepitant or casopitant. 
     
     
         12 . The method of  claim 6 , wherein said AChEI is selected from the group consisting of 1,2,3,4-tetrahydro-9-acridinamine (tacrine); (1R,9S,13 E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.02,7]trideca-2 (7),3,10-trien-5-one (huperzine A); (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one (donepezil) and pharmaceutically acceptable salts thereof; (S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) and pharmaceutically acceptable salts thereof; and 4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol (galantamine) and its pharmaceutically acceptable salts thereof. 
     
     
         13 . The method of  claim 5 , wherein said pharmaceutical composition containing the non-anticholinergic antiemetic agent is in a unit form also containing an AChEI. 
     
     
         14 . A pharmaceutical unit form which comprises
 (a) a non-anticholinergic antiemetic agent selected from the group consisting of 5-HT3 receptor antagonists, dopamine antagonists, H1 histamine receptor antagonists, cannabinoid agonists, aprepitant and casopitant; and   (b) an AChEI;   in admixture with a pharmaceutical carrier.   
     
     
         15 . The unit form of  claim 14  wherein said non-anticholinergic antiemetic agent is selected from the group consisting of ondansetron and pharmaceutically acceptable salt thereof, in an amount (in ondansetron) of from 2 mg to 24 mg; granisetron and pharmaceutically acceptable salt thereof, in an amount (in granisetron) of from 0.5 mg to 3 mg; domperidone and pharmaceutically acceptable salts thereof, in an amount (in domperidone) of from 5 mg to 30 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in an amount (in metoclopramide) of from 5 mg to 30 mg; dronabinol, in an amount of from 1.25 mg to 30 mg; nabilone, in an amount of from 0.25 mg to 3 mg; aprepitant, in an amount of from 20 mg to 375 mg; and casopitant, in an amount of from 25 mg to 150 mg. 
     
     
         16 . The unit form of  claim 14 , wherein said AChEI is selected from the group consisting of phenserine and pharmaceutically acceptable salts thereof, in an amount (in phenserine) of from 15 to 45 mg; tacrine, in an amount of from 10 mg to 120 mg; huperzine A, in an amount of from 50 μg to 400 μg; donepezil and pharmaceutically acceptable salts thereof, in an amount (in donepezil) of from 5 mg to 30 mg; rivastigmine and pharmaceutically acceptable salts thereof, in an amount (in rivastigmine) of from 1.5 mg to 18 mg; galantamine and pharmaceutically acceptable salts thereof, in an amount (in galantamine) of from 4 mg to 36 mg. 
     
     
         17 . The unit form of  claim 14 , wherein said AChEI is selected from the group consisting of donepezil and pharmaceutically acceptable salts thereof, in an amount (in donepezil) of from 15 mg to 30 mg; rivastigmine and pharmaceutically acceptable salts thereof, in an amount (in rivastigmine) of from 9 mg to 18 mg; and galantamine and pharmaceutically acceptable salts thereof, in an amount (in galantamine) of from 16 mg to 36 mg. 
     
     
         18 . The unit form of  claim 14 , wherein said AChEI is selected from the group consisting of rivastigmine and pharmaceutically acceptable salts thereof, in an amount (in rivastigmine) of from 10 mg to 24 mg; and galantamine and pharmaceutically acceptable salts thereof, in an amount (in galantamine), of from 24 mg to 72 mg; said unit form being formulated for ER administration. 
     
     
         19 . The unit form of  claim 14 , wherein
 (a) the non-anticholinergic antiemetic agent is selected form the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in ondansetron) of from 2 mg to 16 mg; granisetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in granisetron) of from 0.5 mg to 2 mg; domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount (in domperidone) of from 5 mg to 20 mg; metoclopramide and pharmaceutically acceptable salts and solvates thereof, in an amount (in metoclopramide) of from 5 mg to 20 mg; dronabinol, in an amount of from 1.25 mg to 20 mg; nabilone, in an amount of from 0.25 mg to 2 mg; aprepitant, in an amount of from 20 mg to 250 mg; and casopitant, in an amount of from 25 mg to 100 mg; and   (b) the AChEI is selected from the group consisting of donepezil and pharmaceutically acceptable salts thereof, in an amount (in donepezil) of from 15 mg to 30 mg; rivastigmine and pharmaceutically acceptable salts thereof, in an amount (in rivastigmine) of from 9 mg to 18 mg; and galantamine and pharmaceutically acceptable salts thereof, in an amount (in galantamine) of from 16 mg to 36 mg;   said unit form being formulated as IR oral composition.