Effective Amounts of (3aR)-1,3a,8-Trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b]indol-5-yl Phenylcarbamate and Methods of Treating or Preventing Neurodegeneration
The invention includes an amount of (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate for administering to a subject and also a method of preventing or treating neurotoxicity or neurodegenerative processes in a subject in need thereof using the amount thereof.
1 . An amount of (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate (Compound (1)) or a salt thereof, wherein administering said amount to a subject results in a peak plasma circulating level of Compound (1) ranging from about 10 ng/mL to about 160 ng/ml in said subject.
2 . The amount of claim 1 , wherein said peak plasma circulating level ranges from about 80 ng/mL to about 160 ng/ml in said subject.
3 . The amount of claim 1 , wherein said peak plasma circulating level is reached within about 6 hours after said administering.
4 . The amount of claim 3 , wherein said peak plasma circulating level is reached within about 3 hours after said administering.
5 . The amount of claim 1 , wherein the plasma circulating level of Compound (1) is equal to or greater than about 20 ng/mL for at least 12 hours after said administering.
6 . The amount of claim 5 , wherein the plasma circulating level of Compound (1) is equal to or greater than about 20 ng/mL for at least 9 hours after said administering.
7 . The amount of claim 1 , wherein said administering results in a peak plasma concentration of Compound (2) ranging from about 15% to about 30% of the peak plasma concentration of Compound (1) in said subject.
8 . The amount of claim 1 , wherein said administering results in a peak plasma concentration of Compound (3) ranging from about 15% to about 30% of the peak plasma concentration of Compound (1) in said subject.
9 . The amount of claim 1 , wherein said administering results in a peak plasma concentration of Compound (4) ranging from about 1% to about 9% of the peak plasma concentration of Compound (1) in said subject.
10 . The amount of claim 1 , wherein said administering results in a steady state plasma concentration of Compound (1) of at least about 100 ng/ml in said subject.
11 . The amount of claim 1 , wherein said administering results in a steady state plasma concentration of Compound (2) of at least about 10 ng/ml in said subject.
12 . The amount of claim 1 , wherein said administering results in a steady state plasma concentration of Compound (3) of at least about 10 ng/ml in said subject.
13 . The amount of claim 1 , wherein said administering results in a steady state plasma concentration of Compound (4) of at least about 3 ng/ml in said subject.
14 . The amount of claim 1 , wherein said administering results in a brain level of Compound (1) that ranges from about 4 to about 10 times the plasma level of Compound (1) in said subject.
15 . The amount of claim 14 , wherein the brain level of Compound (2) ranges from about 15% to about 150% of the brain level of Compound (1) in said subject.
16 . The amount of claim 14 , wherein the brain level of Compound (3) ranges from about 15% to about 150% of the brain level of Compound (1) in said subject.
17 . The amount of claim 14 , wherein the brain level of Compound (4) is lower than the brain level of Compound (2) or Compound (3) in said subject.
18 . The amount of claim 1 , wherein said subject is a human.
19 . A method of inhibiting production of a neurotoxic aggregating protein in a subject, said method comprising administering to said subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of Compound (1) or a salt thereof, wherein administering said composition to said subject results in a peak plasma circulating level of Compound (1) ranging from about 10 ng/ml to about 160 mg/ml in said subject, whereby production of said neurotoxic aggregating protein in said subject is inhibited.
20 . The method of claim 16 , wherein said neurotoxic aggregating protein is selected from the group consisting of APP, Aβ, SOD, Tau, alpha-synuclein (SNCA), NAC, TSE prion, and HTT.
21 . The method of claim 19 , wherein said peak plasma circulating level ranges from about 80 ng/mL to about 160 ng/ml in said subject.
22 . The method of claim 19 , wherein said peak plasma circulating level is reached within about 6 hours after said administering.
23 . The method of claim 22 , wherein said peak plasma circulating level is reached within about 3 hours after said administering.
24 . The method of claim 19 , wherein the plasma circulating level of Compound (1) is equal to or greater than about 20 ng/mL for at least 12 hours after said administering.
25 . The method of claim 24 , wherein the plasma circulating level of Compound (1) is equal to or greater than about 20 ng/mL for at least 9 hours after said administering.
26 . The method of claim 19 , wherein said administering results in a peak plasma concentration of Compound (2) ranging from about 15% to about 30% of the peak plasma concentration of Compound (1) in said subject.
27 . The method of claim 19 , wherein said administering results in a peak plasma concentration of Compound (3) ranging from about 15% to about 30% of the peak plasma concentration of Compound (1) in said subject.
28 . The method of claim 19 , wherein said administering results in a peak plasma concentration of Compound (4) ranging from about 1% to about 9% of the peak plasma concentration of Compound a) in said subject.
29 . The method of claim 19 , wherein said administering results in a steady state plasma concentration of Compound (1) of at least about 100 ng/ml in said subject.
30 . The method of claim 19 , wherein said administering results in a steady state plasma concentration of Compound (2) of at least about 10 ng/ml in said subject.
31 . The method of claim 19 , wherein said administering results in a steady state plasma concentration of Compound (3) of at least about 10 ng/ml in said subject.
32 . The method of claim 19 , wherein said administering results in a steady state plasma concentration of Compound (4) of at least about 3 ng/ml in said subject.
33 . The method of claim 19 , wherein said administering results in a brain level of Compound (1) that ranges from about 4 to about 10 times the plasma level of Compound (1) in said subject.
34 . The method of claim 33 , wherein the brain level of Compound (2) ranges from about 15% to about 150% of the brain level of Compound (1) in said subject.
35 . The method of claim 33 , wherein the brain level of Compound (3) ranges from about 15% to about 150% of the brain level of Compound (1) in said subject.
36 . The method of claim 33 wherein the brain level of Compound (4) is lower than the brain level of Compound (2) or Compound (3) in said subject.
37 . The amount of claim 19 , wherein said subject is a human.
38 . The method of claim 19 , wherein said administering results in a reduction equal to or greater than about 25% in a cerebrospinal fluid marker selected from the group consisting of sAPP α, sAPP β, Tau and pTau in said subject.
39 . The method of claim 38 , wherein said administering results in a reduction equal to or greater than about 30% in a cerebrospinal fluid marker selected from the group consisting of sAPP α, sAPP β, Tau and pTau in said subject.
40 . A method of treating dementia in a subject, said method comprising administering to said subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of Compound (1) or a salt thereof, wherein administering said composition to said subject results in a peak plasma circulating level of Compound (1) ranging from about 10 ng/mL to about 160 ng/ml in said subject, whereby said dementia in said subject is treated.
41 . The method of claim 40 , wherein said dementia is Alzheimer's disease.
42 . The method of claim 41 , wherein said dementia is selected from the group consisting of Parkinson's disease, Huntington's disease, Prion's disease, Amyloid Lateral Sclerosis and a tauopathy.
43 . The method of claim 40 , wherein said peak plasma circulating level ranges from about 80 ng/mL to about 160 ng/ml in said subject.
44 . The method of claim 40 , wherein said peak plasma circulating level is reached within about 6 hours after said administering.
45 . The method of claim 44 , wherein said peak plasma circulating level is reached within about 3 hours after said administering.
46 . The method of claim 40 , wherein the plasma circulating level of Compound (1) is equal to or greater than about 20 ng/mL for at least 12 hours after said administering.
47 . The method of claim 46 , wherein the plasma circulating level of Compound (1) is equal to or greater than about 20 ng/mL for at least 9 hours after said administering.
48 . The method of claim 40 , wherein said administering results in a peak plasma concentration of Compound (2) ranging from about 15% to about 30% of the peak plasma concentration of Compound (1) in said subject.
49 . The method of claim 40 , wherein said administering results in a peak plasma concentration of Compound (3) ranging from about 15% to about 30% of the peak plasma concentration of Compound (1) in said subject.
50 . The method of claim 40 , wherein said administering results in a peak plasma concentration of Compound (4) ranging from about 1% to about 9% of the peak plasma concentration of Compound (1) in said subject.
51 . The method of claim 40 , wherein said administering results in a steady state plasma concentration of Compound (1) of at least about 100 ng/ml in said subject.
52 . The method of claim 40 , wherein said administering results in a steady state plasma concentration of Compound (2) of at least about 10 ng/ml in said subject.
53 . The method of claim 40 , wherein said administering results in a steady state plasma concentration of Compound (3) of at least about 10 ng/ml in said subject.
54 . The method of claim 40 , wherein said administering results in a steady state plasma concentration of Compound (4) of at least about 3 ng/ml in said subject.
55 . The method of claim 40 , wherein said administering results in a brain level of Compound (1) that ranges from about 4 to about 10 times the plasma level of Compound (1) in said subject.
56 . The method of claim 55 , wherein the brain level of Compound (2) ranges from about 15% to about 150% of the brain level of Compound (1) in said subject.
57 . The method of claim 55 , wherein the brain level of Compound (3) ranges from about 15% to about 150% of the brain level of Compound (1) in said subject.
58 . The method of claim 55 wherein the brain level of Compound (4) is lower than the brain level of Compound (2) or Compound (3) in said subject.
59 . The amount of claim 40 , wherein said subject is a human.
60 . The method of claim 40 , wherein said administering results in a reduction equal to or greater than about 25% in a cerebrospinal fluid marker selected from the group consisting of sAPP α, sAPP β, Tau and pTau in said subject.
61 . The method of claim 60 , wherein said administering results in a reduction equal to or greater than about 30% in a cerebrospinal fluid marker selected from the group consisting of sAPP α, sAPP β, Tau and pTau in said subject.