Method and composition for treating alzheimer-type dementia

Abstract

There is described a method for increasing the maximal tolerated close and thus the efficacy of an acetyl choline esterase 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 acetyl choline esterase 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 acetyl choline esterase inhibitor (AChEl) and pharmaceutical compositions comprising (a) a 5HT3 receptor antagonist, a dopamine antagonist, a Hi-receptor antagonist, a cannabinoid agonist, aprepitant or casopitant as an antiemetic agent and (b) an acetylcholine esterase inhibitor are also described.

1 . A non-anticholinergic antiemetic agent for use for the treatment of Alzheimer type dementia in combination with an acetyl choline esterase inhibitor (AChEI), thereby allowing the maximal tolerated dose of said AChEI to be safe and tolerably increased, a higher acetyl choline esterase inhibition in the CNS to be achieved and relief of the symptoms of Alzheimer type dementia to be improved, by concomitantly decreasing concurrent adverse effects. 
     
     
         2 . The non-anticholinergic antiemetic agent for use as claimed in  claim 1 , wherein said AChEI is administered to said patient at a dose level which is higher than the maximal tolerated dose or the recommended maximal dose level. 
     
     
         3 . The non-anticholinergic antiemetic agent for use as claimed in  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. 
     
     
         4 . The non-anticholinergic antiemetic agent for use as claimed in  claim 1 , which 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. 
     
     
         5 . The non-anticholinergic antiemetic agent for use as claimed in  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. 
     
     
         6 . The non-anticholinergic antiemetic agent for use as claimed in  claim 5 , wherein said 5HT3-antagonist is selected from 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. 
     
     
         7 . The non-anticholinergic antiemetic agent for use as claimed in  claim 5 , wherein said dopamine antagonist is selected from 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. 
     
     
         8 . The non-anticholinergic antiemetic agent for use as claimed in  claim 5 , wherein said H1 histamine receptor antagonist is meclizine or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         9 . The non-anticholinergic antiemetic agent for use as claimed in  claim 5 , wherein said cannabinoid agonists is dronabinol or nabilone. 
     
     
         10 . The non-anticholinergic antiemetic agent for use as claimed in  claim 5 , wherein said NK1 receptor antagonist is aprepitant or casopitant. 
     
     
         11 . The non-anticholinergic antiemetic agent for use as claimed in  claim 1  wherein said AChEI is selected from the group consisting of 1,2,3,4-tetrahydro-9-acridinamine (tacrine); (1R,9S,13E)-1-amino-13-ethylidene-11-methyi-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. 
     
     
         12 . The non-anticholinergic antiemetic agent for use as claimed in  claim 4 , wherein said pharmaceutical composition containing the non-anticholinergic antiemetic agent is in a unit form also containing an AChEI. 
     
     
         13 . 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.   
     
     
         14 . The unit form of  claim 13  wherein said non-anticholinergic antiemetic agent is selected from 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. 
     
     
         15 . The unit form of  claim 13 , wherein said AChEI is selected from the group consisting of phenserine and pharmaceutically acceptable salts thereof, in an amount (in phenserine) of from 15 mg 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. 
     
     
         16 . The unit form of  claim 13 , 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. 
     
     
         17 . The unit form of  claim 13 , 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. 
     
     
         18 . The unit form of  claim 13 , wherein
 (a) the non-anticholinergic antiemetic agent is selected from 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.   
     
     
         19 . A pharmaceutical composition comprising, as an active ingredient, a non-anticholinergic antiemetic agent, for increasing the maximal recommended daily dose of an acetyl choline esterase inhibitor (AChEI), said AChEI being concomitantly administered with said composition to a patient suffering from Alzheimer type dementia. 
     
     
         20 . A pharmaceutical composition for inducing a higher acetyl choline esterase inhibition in the Central Nervous System of a patient suffering from Alzheimer type dementia, said patient taking a dose of acetyl choline esterase inhibitor (AChEI) higher than the maximal tolerated dose attainable when given alone, comprising, as an active ingredient, a non-anticholinergie antiemetic agent. 
     
     
         21 . A pharmaceutical composition comprising, as an active ingredient, a non-anticholinergic antiemetic agent, for increasing up to a factor of 4 the therapeutic dose of an acetyl choline esterase inhibitor (AChEI), said AChEI being concurrently or sequentially administered with said composition to a patient suffering from Alzheimer type dementia. 
     
     
         22 . The composition of  claim 21  wherein said AChEI dose is from 1.5 to 3 times higher than the recommended dose of said AChEI. 
     
     
         23 . A non-anticholinergic antiemetic agent for use for the treatment of Alzheimer type dementia in combination with an acetyl choline esterase inhibitor (AChEI), thereby allowing the maximal tolerated dose of said AChEI to be safe and tolerably increased, a higher acetyl choline esterase inhibition in the CNS to be achieved and relief of the symptoms of Alzheimer type dementia to be improved, by concomitantly decreasing concurrent adverse effects.