Administration and dosage of diaminophenothiazines
The invention provides novel regimens for treatment of neurodegenerative disorders utilising methylthioninium (MT)-containing compounds. The regimens are based on novel findings in relation to the dosage of MT compounds, and their interaction with symptomatic treatments based on modulation of acetylcholinesterase levels.
1. A method of therapeutic treatment of a neurodegenerative disorder of protein aggregation in a subject,
which method comprises orally administering two or more times per day to said subject a methylthioninium (MT)-containing compound,
wherein said administration provides a total daily dose of between 0.5 and 20 mg of MT to the subject per day,
wherein the MT-containing compound is a compound of the following formula (“LMTX”):
wherein each of H n A and H n B (where present) are protic acids which may be the same or different,
and wherein p=1 or 2; q=0 or 1; n=1 or 2; (p+q)×n=2,
and wherein said neurodegenerative disorder is selected from the group consisting of: Alzheimer's disease, Pick's disease, progressive supranuclear palsy, frontotemporal dementia (FTD), FTD with parkinsonism linked to chromosome 17, frontotemporal lobar degeneration syndromes, disinhibition-dementia-parkinsonism-amyotrophy complex, pallido-ponto-nigral degeneration, Guam-ALS syndrome, pallido-nigro-luysian degeneration, cortico-basal degeneration, dementia with argyrophilic grains, dementia pugilistica, chronic traumatic encephalopathy, Down's syndrome, subacute sclerosing panencephalitis, Niemann-Pick disease type C, Sanfilippo syndrome type B, a myotonic dystrophy DM1 or DM2, Huntington's disease, spinal bulbar muscular atrophy, dentatorubropallidoluysian atrophy, spinocerebellar ataxias, a TDP-43 proteinopathy which is FTLD-TDP, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, hereditary cerebral angiopathy, amyotrophic lateral sclerosis, and familial encephalopathy with neuronal inclusion bodies.
2. The method as claimed in claim 1 , wherein the total daily dose of MT is 2 to 15 mg.
3. The method as claimed in claim 1 , wherein;
(a) the compound has the following formula, wherein HA and HB are different mono-protic acids:
or
(b) compound has the following formula, wherein each of H n X is a protic acid:
or
(c) the compound has the following formula, wherein H 2 A is a di-protic acid:
4. The method as claimed in claim 1 , wherein the compound has the following formula and is a bis-monoprotic acid salt:
5. The method as claimed in claim 1 , wherein the or each protic acid is an inorganic acid.
6. The method as claimed in claim 1 , wherein the or each protic acid is an organic acid.
7. The method as claimed in claim 6 , wherein the or each protic acid is selected from the group consisting of H 2 CO 3 , CH 3 COOH, methanesulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, and p-toluenesulfonic acid.
8. The method as claimed in claim 7 , wherein the compound is LMTM:
9. The method as claimed in claim 8 , wherein said therapeutic treatment with the MT-containing compound comprises a total daily dose of LMTM of 0.8 to 33 mg/day.
10. The method as claimed in claim 9 , wherein said therapeutic treatment with the MT-containing compound comprises a dose of LMTM of 9 mg/day.
11. The method as claimed in claim 1 , wherein the compound is selected from the group consisting of:
12. A method of prophylactic treatment of a neurodegenerative disorder of protein aggregation in a subject,
which method comprises orally administering two or more times per day to said subject a methylthioninium (MT)-containing compound,
wherein said administration provides a total daily dose of between 0.5 and 20 mg of MT to the subject per day,
wherein the MT-containing compound is a compound of the following formula (“LMTX”):
wherein each of H n A and H n B (where present) are protic acids which may be the same or different,
and wherein p=1 or 2; q=0 or 1; n=1 or 2; (p+q)×n=2,
and wherein said neurodegenerative disorder is selected from the list consisting of:
Alzheimer's disease, Pick's disease, progressive supranuclear palsy, frontotemporal dementia (FTD), FTD with parkinsonism linked to chromosome 17, frontotemporal lobar degeneration syndromes, disinhibition-dementia-parkinsonism-amyotrophy complex, pallido-ponto-nigral degeneration, Guam-ALS syndrome, pallido-nigro luysian degeneration, cortico-basal degeneration, dementia with argyrophilic grains, dementia pugilistica, chronic traumatic encephalopathy, Down's syndrome, subacute sclerosing panencephalitis, Niemann-Pick disease, type C, Sanfilippo syndrome type B, a myotonic dystrophy DM1 or DM2, Huntington's disease, spinal bulbar muscular atrophy, dentatorubropallidoluysian atrophy, spinocerebellar ataxias, a TDP-43 proteinopathy which is FTLD-TDP, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, hereditary cerebral angiopathy, amyotrophic lateral sclerosis, and familial encephalopathy with neuronal inclusion bodies.
13. The method as claimed in claim 1 , wherein the subject has not historically received treatment with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist.
14. The method as claimed in claim 1 , wherein the subject has historically received treatment with an acetylcholinesterase inhibitor and/or an N-methyl-D-aspartate receptor antagonist, but ceased that medication at least week prior to treatment with the MT-containing compound.
15. The method as claimed in claim 1 , wherein the subject is selected as one who is receiving treatment with an acetylcholinesterase inhibitor and/or an N-methyl-D-aspartate receptor antagonist,
wherein said treatment with the acetylcholinesterase inhibitor and/or an N-methyl-D-aspartate receptor antagonist is discontinued prior to treatment with the MT-containing compound.
16. The method as claimed in claim 2 , wherein the total daily dose of MT is 3 to 10 mg.
17. The method as claimed in claim 9 , wherein the total daily dose of LMTM is 6 to 12 mg/day.
18. The method as claimed in claim 14 , wherein the subject has historically received treatment with an acetylcholinesterase inhibitor and/or an N-methyl-D-aspartate receptor antagonist, but ceased that medication at least 2 weeks prior to treatment with the MT-containing compound.
19. The method as claimed in claim 14 , wherein the subject has historically received treatment with an acetylcholinesterase inhibitor and/or an N-methyl-D-aspartate receptor antagonist, but ceased that medication at least 3 weeks prior to treatment with the MT-containing compound.
20. The method as claimed in claim 14 , wherein the subject has historically received treatment with an acetylcholinesterase inhibitor and/or an N-methyl-D-aspartate receptor antagonist, but ceased that medication at least 4 weeks prior to treatment with the MT-containing compound.