Treatment of Cognitive Disorders with Certain Alpha-7 Nicotinic Acid Receptor Agonists in Combination with Acetylcholinesterase Inhibitors
A method for improving cognition comprising administering to a patient certain alpha-7 receptor agonists and an acetylcholinesterase inhibitor is described together with related compositions.
1 . A method for improving cognition comprising administering to a patient a compound selected from the group consisting of: (S)-1-(2-fluorophenyl)ethyl (S)-quinuclidin-3-ylcarbamate, N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (TC-5619), (S)—N-(quinuclidin-3-yl)-1H-indazole-3-carboxamide, and (R)-3-(6-(1H-indol-5-yl)pyridazin-3-yloxy)quinuclidine or a pharmaceutically acceptable salt thereof, and an acetylcholinesterase inhibitor.
2 . The method of claim 1 wherein the patient has been diagnosed with Alzheimer's disease or pre-Alzheimer's disease.
3 . The method of claim 1 wherein the patient has been diagnosed with mild to moderate Alzheimer's disease.
4 . The method of claim 1 wherein the patient has been diagnosed with moderate to severe Alzheimer's disease.
5 . The method of claim 1 , wherein the acetylcholinesterase inhibitor is selected from tacrine, donepezil, rivastigmine and galantamine.
6 . The method of claim 5 wherein the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine and galantamine.
7 . The method of claim 5 wherein the acetylcholinesterase inhibitor is selected from donepezil and rivastigmine.
8 . The method of claim 1 , wherein the patient has been administered an acetylcholinesterase inhibitor for a period of time prior to being administered a compound selected from the group consisting of: (S)-1-(2-fluorophenyl)ethyl (S)-quinuclidin-3-ylcarbamate, (2S, 3R)-N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide, (S)—N-(quinuclidin-3-yl)-1H-indazole-3-carboxamide, and (R)-3-(6-(1H-indol-5-yl)pyridazin-3-yloxy)quinuclidine or a pharmaceutically acceptable salt thereof.
9 . The method of claim 8 wherein the prior administration has been for at least one month.
10 . The method of claim 9 wherein the prior administration has been for at least three months.
11 . The method of claim 10 wherein the prior administration has been for at least six months.
12 . The method of claim 1 , wherein the method improves one or more of: learning, delayed memory, attention, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory or executive function.
13 . The method of claim 1 wherein one or both of the alpha-7 agonist and the acetylcholinesterase inhibitor is administered at a subclinical dose.
14 . The method of claim 13 wherein the alpha-7 receptor agonist is orally administered at less than 1.0 mg/day.
15 . The method of claim 13 wherein the alpha-7 receptor agonist is orally administered at less than 0.5 mg/day.
16 . The method of claim 13 wherein the alpha-7 receptor agonist is orally administered at less than 0.3 mg/day.
17 . The method of claim 13 wherein the alpha-7 receptor agonist is orally administered at less than 0.1 mg/day.
18 . The method of claim 13 wherein the acetylcholinesterase inhibitor is donepezil and is orally administered at less than 5 mg/day.
19 . The method of claim 13 wherein the acetylcholinesterase inhibitor is donepezil and is orally administered 4.5 mg/day or less.
20 . The method of claim 13 wherein the acetylcholinesterase inhibitor is donepezil and is orally administered at 4.0 mg/day or less.
21 . The method of claim 13 wherein the acetylcholinesterase inhibitor is donepezil and is orally administered at 2.5 mg/day or less.
22 . The method of claim 13 wherein the acetylcholinesterase inhibitor is donepezil and is orally administered at 1.5 mg/day or less.
23 . The method of claim 13 wherein the acetylcholinesterase inhibitor is donepezil and is orally administered at than 1.0 mg/day or less.
24 . The method of claim 1 wherein the acetylcholinesterase inhibitor is administered at a dose that achieves 10-65% steady state red blood cell acetylcholinesterase inhibition.
25 . A pharmaceutical composition comprising a compound selected from the group consisting of: (S)-1-(2-fluorophenyl)ethyl (S)-quinuclidin-3-ylcarbamate, N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (TC-5619), (S)—N-(quinuclidin-3-yl)-1H-indazole-3-carboxamide, and (R)-3-(6-(1H-indol-5-yl)pyridazin-3-yloxy)quinuclidine or a pharmaceutically acceptable salt thereof, an acetylcholinesterase inhibitor, and a pharmaceutically acceptable carrier.
26 . The pharmaceutical composition of claim 25 wherein the acetylcholinesterase inhibitor is selected from tacrine, donepezil, rivastigmine and galantamine.
27 . The pharmaceutical composition of claim 25 wherein the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine and galantamine.
28 . The pharmaceutical composition of claim 25 wherein the acetylcholinesterase inhibitor is selected from donepezil and rivastigmine.
29 . The pharmaceutical composition of claim 25 wherein the acetylcholinesterase inhibitor is donepezil.
30 . A daily unit dosage pharmaceutical composition comprising no more than 1.0 mg of a compound selected from the group consisting of: (S)-1-(2-fluorophenyl)ethyl (S)-quinuclidin-3-ylcarbamate, N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (TC-5619), (S)—N-(quinuclidin-3-yl)-1H-indazole-3-carboxamide, and (R)-3-(6-(1H-indol-5-yl)pyridazin-3-yloxy)quinuclidine or a pharmaceutically acceptable salt thereof, an acetylcholinesterase inhibitor and a pharmaceutically acceptable carrier.
31 . The daily unit dosage pharmaceutical composition of claim 30 comprising no more than 0.5 mg of (a compound selected from the group consisting of: (S)-1-(2-fluorophenyl)ethyl (S)-quinuclidin-3-ylcarbamate, N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (TC-5619), (S)—N-(quinuclidin-3-yl)-1H-indazole-3-carboxamide, and (R)-3-(6-(1H-indol-5-yl)pyridazin-3-yloxy)quinuclidine or a pharmaceutically acceptable salt thereof.
32 . The daily unit dosage pharmaceutical composition of claim 31 comprising no more than 0.3 mg a compound selected from the group consisting of: (S)-1-(2-fluorophenyl)ethyl (S)-quinuclidin-3-ylcarbamate, N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (TC-5619), (S)—N-(quinuclidin-3-yl)-1H-indazole-3-carboxamide, and (R)-3-(6-(1H-indol-5-yl)pyridazin-3-yloxy)quinuclidine or a pharmaceutically acceptable salt thereof.
33 . The daily unit dosage pharmaceutical composition of claim 31 comprising no more than 0.1 mg a compound selected from the group consisting of: (S)-1-(2-fluorophenyl)ethyl (S)-quinuclidin-3-ylcarbamate, N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (TC-5619), (S)—N-(quinuclidin-3-yl)-1H-indazole-3-carboxamide, and (R)-3-(6-(1H-indol-5-yl)pyridazin-3-yloxy)quinuclidine or a pharmaceutically acceptable salt thereof.
34 . The daily unit dosage pharmaceutical composition of claim 31 comprising no more than 5 mg of donepezil.
35 . The daily unit dosage pharmaceutical composition of claim 31 comprising no more than 4 mg of donepezil.
36 . The daily unit dosage pharmaceutical composition of claim 31 comprising no more than 2.5 mg of donepezil.
37 . The daily unit dosage pharmaceutical composition of claim 31 comprising no more than 1 mg of donepezil.
38 . Packaged pharmaceuticals comprising a package containing a first unit dosage pharmaceutical composition comprising a compound selected from the group consisting of: (S)-1-(2-fluorophenyl)ethyl (S)-quinuclidin-3-ylcarbamate, N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (TC-5619), (S)—N-(quinuclidin-3-yl)-1H-indazole-3-carboxamide, and (R)-3-(6-(1 H-indol-5-yl)pyridazin-3-yloxy)quinuclidine or a pharmaceutically acceptable salt thereof, and a second unit dosage pharmaceutical composition comprising an acetylcholinesterase inhibitor.