US20090227686A1 - Methods of preventing, treating and diagnosing disorders of protein aggregation - Google Patents
Methods of preventing, treating and diagnosing disorders of protein aggregation Download PDFInfo
- Publication number
- US20090227686A1 US20090227686A1 US12/396,515 US39651509A US2009227686A1 US 20090227686 A1 US20090227686 A1 US 20090227686A1 US 39651509 A US39651509 A US 39651509A US 2009227686 A1 US2009227686 A1 US 2009227686A1
- Authority
- US
- United States
- Prior art keywords
- inositol
- scyllo
- amyloid
- mice
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 0 *C1([1*])C(*)([6*])[C@](*)([5*])[C@@](*)([4*])C(*)([3*])[C@]1(*)[2*] Chemical compound *C1([1*])C(*)([6*])[C@](*)([5*])[C@@](*)([4*])C(*)([3*])[C@]1(*)[2*] 0.000 description 6
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/60—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances involving radioactive labelled substances
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
Definitions
- the invention relates to methods for treating Alzheimer's Disease and other amyloidoses; more particularly, it relates to methods for inhibiting and reducing amyloid fibril formation in therapeutic intervention in Alzheimer's disease and other amyloidoses.
- Alzheimer's disease is characterized neuropathologically by amyloid deposits, neurofibrillary tangles, and selective neuronal loss.
- the major component of the amyloid deposits is amyloid- ⁇ (A ⁇ , a 39-43 residue peptide. Soluble forms of A ⁇ generated from cleavage of amyloid precursor protein are normal products of metabolism.
- residues 1-42 (A ⁇ 42) in Alzheimer's disease was highlighted in the discovery that mutations in codon 717 of the amyloid precursor protein gene, presenilin 1 and presenilin 2 genes result in an increased production of A ⁇ 42 over A ⁇ 1-40.
- a ⁇ can be neurotoxic or enhance the susceptibility of neurons to excitotoxic, metabolic, or oxidative insults. Initially it was thought that only the fibrillar form of A was toxic to neurons but more thorough characterization of A ⁇ structures demonstrated that dimers and small aggregates of A ⁇ are also neurotoxic. These data suggested that prevention of A ⁇ oligomerization would be a likely strategy to prevent AD-related neurodegeneration.
- Several studies have demonstrated that in vitro A ⁇ -induced neurotoxicity can be ablated by compounds that can increase neuronal resistance by targeting cellular pathways involved in apoptosis, block downstream pathways after A ⁇ induction of destructive routes, or block A ⁇ oligomerization and ultimately fibril formation. The site at which A ⁇ acts to induce neurotoxicity has yet to be elucidated but its toxic effects have been blocked by a variety of disparate agents.
- a ⁇ -fibrils may be an early and intervenable step during the progression of AD. Formation of amyloid plaques, as well as neurotoxicity and inflammation may be direct or indirect consequences of the interaction of A with molecules containing sugar moieties.
- a ⁇ interaction with glycosaminoglycans results in aggregation of A ⁇ possibly adding to their insolubility and plaque persistence.
- Glycosaminoglycans have also been implicated in neuronal toxicity and microglial activation.
- interaction with glycolipids such as gangliosides results in the stabilization and prevention of Ab fibril formation, as well as, the site of A ⁇ production.
- the family of phosphatidylinositols results in acceleration of fibril formation.
- the headgroup of phosphatidylinositol is myo-inositol, a naturally occurring simple sugar involved in lipid biosynthesis, signal transduction, and osmolarity control.
- amyloid deposition and usually involve systemic organs (i.e. organs or tissues lying outside the central nervous system), with the amyloid accumulation leading to organ dysfunction or failure.
- systemic organs i.e. organs or tissues lying outside the central nervous system
- amyloid accumulation leading to organ dysfunction or failure.
- Alzheimer's disease and “systemic” amyloid diseases there is currently no cure or effective treatment, and the patient usually dies within 3 to 10 years from disease onset.
- U.S. Pat. No. 4,847,082 discloses the use of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid for the treatment of Alzheimer's disease. It also discloses that isomers of phytic acid or phytate salt comprise the hexakisphosphate myo-inositol, hexakisphosphate scyllo-inositol, hexakisphosphate D-chiro-inositol, hexakisphosphate L-chiro-inositol, hexakisphosphate neo-inositol and hexakisphosphate muco-inositol conformations.
- Phytic acid is inositol-hexakisphosphate (IP6).
- U.S. Pat. No. 5,112,814 discloses the use of phytic acid and isomers thereof for the treatment of Parkinson's disease.
- the phytic acid isomers disclosed in this patent retain the six phosphate groups on the six-carbon inositol sugar.
- McLaurin et al. disclosed that myo-inositol stabilizes a small micelle of A ⁇ 42 (J. Mol. Biol. 278, 183-194, 1998).
- McLaurin et al. disclose that epi- and scyllo- but not chiro-inositol were able to induce a structural transition from random to ⁇ -structure in A ⁇ 42 (J Biol Chem. Jun. 16; 275(24):18495-502, 2000; and J Struct Biol 130:259-270, 2000).
- none of the stereoisomers were able to induce a structural transition in A ⁇ 40.
- Electron microscopy showed that inositol stabilizes small aggregates of A ⁇ 42.
- Alzheimer's disease Much work in Alzheimer's disease has been accomplished, but little is conventionally known about compounds or agents for therapeutic regimes to arrest or reverse amyloid formation, deposition, accumulation and/or persistence that occurs in Alzheimer's disease and other amyloidoses.
- New compounds or agents for therapeutic regimes to arrest or reverse amyloid formation, deposition, accumulation and/or persistence that occurs in Alzheimer's disease and other amyloidoses are therefore urgent needed.
- the present invention provides a method of treating or preventing in a subject a condition of the central or peripheral nervous system or systemic organ associated with a disorder in protein folding or aggregation, or amyloid formation, deposition, accumulation, or persistence comprising administering to said subject a pharmaceutically effective amount of compound selected having the following structure:
- R 1 , R 1′ , R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , and R 6′ is independently selected from the group of:
- the present invention also provides a method of preventing abnormal protein folding, abnormal protein aggregation, amyloid formation, deposition, accumulation, or persistence, or amyloid lipid interactions in a subject comprising administering to said subject a pharmaceutically effective amount of a compound having the following structure:
- R 1 , R 1′ , R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , and R 6′ is independently selected from the group of:
- the present invention further provides a method of causing the dissociation of abnormally aggregated proteins and/or dissolving or disrupting pre-formed or pre-deposited amyloid fibril or amyloid in a subject comprising administering to said subject a pharmaceutically effective amount of a compound having the following structure:
- R 1 , R 1′ , R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , and R 6′ is independently selected from the group of:
- the present invention also provides a method of diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in a subject comprising: (a) administering to said subject a radioactive compound or compound tagged with a substance that emits a detectable signal in a quantity sufficient and under conditions to allow for the binding of said compound to the abnormally folded or aggregated protein and/or fibrils or amyloid, if present; and (b) detecting the radioactivity or the signal from the compound bound to the abnormally folded or aggregated protein and/or fibrils or amyloid, thus diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in said subject, wherein said compound has the following structure:
- R 1 , R 1′ , R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , and R 6′ is independently selected from the group of:
- the present invention further provides a method of diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in a subject comprising: (a) collecting a sample from said subject; (b) contacting said sample with a radioactive compound or compound tagged with a substance that emits a detectable signal under conditions to allow the binding of said compound to the abnormally folded or aggregated protein and/or amyloid fibril or amyloid if present; and (c) detecting the radioactivity or the signal from the compound bound to the abnormally folded or aggregated protein and/or fibrils or amyloid, thus diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in said subject, wherein said compound has the following structure:
- each of R 1 , R 1′ , R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , and R 6′ is independently selected from the group of;
- FIG. 1A shows the structure of myo-, epi- and scyllo-inositol while FIGS. 1B-1H show the spatial reference memory version of the Morris water maze test in TgCRND8 mice.
- Myo-inositol treatment did not alter cognitive function ( 1 B).
- FIGS. 2A-2I show at 6 months of age, the plaque burden and astrogliosis in TgCRND8 treated with epi- and scyllo-inositol treated mice.
- Control animals have a high plaque load and astrogliosis in the hippocampus ( 2 A) and cerebral cortex ( 2 B). Higher magnification demonstrates that astrocytic activation is not only associated with plaque load ( 2 C).
- Epi-inositol treatment has a modest effect on amyloid burden with a decrease in astrogliosis ( 2 D, 2 E and 2 F).
- Scyllo-inositol treatment significantly decreased amyloid burden and gliosis ( 2 G, 2 H, and 2 I).
- FIGS. 3A-3D show that the A ⁇ species, 1-42, 1-40 and 1-38, in control and treated TgCRND8 mice was indistinguishable ( 3 A) as was the extent of APP processing ( 3 B).
- Vascular amyloid burden was quantitated on serial sagittal sections in treated and untreated TgCRND8 mice.
- TgCRND8 mice have a significant vascular amyloid burden that is associated with small and medium sized vessels, the load is decreased in scyllo-inositol treated TgCRND8 mice ( 3 A). Scyllo-inositol treatment significantly decreased the total vascular load in comparison to untreated and epi-inositol treated TgCRND8 mice ( 3 C). Scyllo-inositol decreases plaque deposition as illustrated by the significant decrease in mean plaque size ( 3 D).
- FIG. 4 shows the effect of water on the cognitive function of TgCRND8 and non-Tg mice using the spatial reference memory version of the Morris Water Maze in a three day trial paradigm.
- FIG. 5 shows the effect of scyllo-inositol on the cognitive function of TgCRND8 and non-Tg mice using the spatial reference memory version of the Morris Water Maze in a three day trial paradigm.
- FIG. 6 shows the effect of epi-inositol on the cognitive function of TgCRND8 and non-Tg mice using the spatial reference memory version of the Morris Water Maze in a three day trial paradigm.
- FIG. 7 shows the effect of myo-inositol on the cognitive function of TgCRND8 and non-Tg mice using the spatial reference memory version of the Morris Water Maze in a three day trial paradigm.
- FIG. 8 shows the effect of scyllo-inositol, epi-inositol and myo-inositol on the cognitive function of TgCRND8 (learning phase and memory test) and compared with wild type mice using the spatial reference memory version of the Morris Water Maze in a three-day trial paradigm.
- FIG. 9 shows the percentage of brain area covered with plaques in untreated TgCRND8 mice versus mice treated with scyllo-inositol, epi-inositol or myo-inositol.
- FIGS. 10A and 10B show the survival rates of TgCRND8 mice treated with water versus epi-inositol or myo-inositol ( 10 A) or versus scyllo-inositol ( 10 B).
- FIGS. 12A and B show the results of a spatial reference memory test in the treatment studies when performed in a 3-day trial paradigm.
- FIGS. 13A and B show A ⁇ levels within the CNS after administration of various doses of scyllo-inositol were administered once daily for one month to five month old TgCRND8 mice. Soluble A ⁇ 42 levels were decreased at all doses and were significantly different from untreated controls (A). In contrast, insoluble A ⁇ 42 was not significantly different under all conditions (B). Vertical bars represent S.E.M.
- FIG. 14 TgCRND8 mice administered various doses of scyllo-inositol once daily for one month were analyzed for levels of brain A ⁇ 40. No difference was detected in soluble (A) and insoluble (B) levels of A ⁇ 40 of untreated and scyllo-inositol treated TgCRND8 mice at all doses examined.
- FIG. 15 shows the cognitive performance of 6-month old allo-inositol-treated TgCRND8 mice compared with that of their non-transgenic littermates.
- FIGS. 6A-D show that at 2 months of age, the plaque burden in TgPS1 ⁇ APP mice is decreased in scyllo-inositol treated mice.
- Control animals have a high plaque load in the hippocampus (A) and cerebral cortex (B). Scyllo-inositol treatment significantly decreased amyloid burden (C, D). Plaque burden identified using anti-A ⁇ antibody (brown). Scale Bar 300 ⁇ m.
- FIGS. 7A-C show the quantification of the plaque burden in TgPS1 ⁇ APP mice after scyllo-inositol treatment.
- the present invention discloses novel, unpredictable and unexpected properties of certain inositol stereoisomers in relation to the treatment of amyloid-related disorders such as Alzheimer's Disease.
- the present invention describes the unpredictable results that only certain inositol stereoisomers, in particular scyllo- and allo-inositols reduce amyloid plaque burden, improve cognition and increase lifespan in animal models of amyloid-related disorders, whereas others studied did not have such effects.
- inositol stereoisomers e.g. epi- and scyllo-inositols
- the present invention describes the unexpected results that scyllo-inositol inhibits already established cerebral amyloid deposition, and does so in the living brain. This is not implied by the previously published in vitro data which considered only certain neuronal cell types in culture, not the complex tissues of the living brain, and only suggested that inositols might inhibit de novo aggregation, thereby having no relevance to established disease.
- the compounds of the present invention are 1,2,3,4,5,6-cyclohexanehexyls, more preferably selected from the group of cis-, epi-, allo-, muco-, neo-, scyllo-, D-chiro- and L-chiro-inositols.
- these compounds are 1,2,3,4,5-cyclohexanepentols (quercitols), more preferably selected from the group of epi-, vibo-, scyllo-, allo-, talo-, gala-, cis-, muco-, neo-, proto-quercitols and enantiomers thereof.
- quercitols 1,2,3,4,5-cyclohexanepentols
- these compounds are selected from the group of a cyclohexanetetrol, a cyclohexanetriol, stereoisomer of cyclohexanetetrol, stereoisomer of cyclohexanetriol, enantiomer of cyclohexanetetrol, and enantiomer of cyclohexanetriol.
- These compounds may also be compound is pentahydxycyclohexanones or stereoisomers or enantiomers thereof.
- these compounds are inosose compounds selected from the group of scyllo-inosose, L-chiro-inosose-1 and L-epi-inosose.
- these compounds are trihydroxyxcyclohexanones, or stereoisomers or enantiomers thereof. More preferably, ( ⁇ )-1-deoxy-scyllo-inosose.
- these compounds are pentahydxycyclohexanones (inosose), or stereoisomers or enantiomers thereof, more preferably selected from the group of scyllo-inosose, L-chiro-inosose-1 and L-epi-inosose.
- these compounds are trihydroxyxcyclohexanones or stereoisomers or enantiomers thereof such as ( ⁇ )-1-deoxy-scyllo-inosose.
- these compounds are O-monomethyl-cyclohexanehexyls or stereoisomers or enantiomers thereof, more preferably selected from the group of D-pinitol, L-quebrachitol and D-bornesitol.
- these compounds may be selected from the group of monoaminocyclohexanepentols (inosamines), diaminocyclohexanetetrols (inosadiamines), diaminocyclohexanetriols, stereoisomers thereof, and enantiomers thereof, and pharmaceutically acceptable salts thereof such as L-neo-inosamine, D,L-epi-inosamine-2, streptamine and deoxystreptamine.
- these compounds are monomercapto-cyclohexanepentols or stereoisomers or enantiomers thereof, more preferably 1L-1-deoxy-1-mercapto-8-O-methyl-chiro-inositol.
- the most preferred compounds of the present invention are allo-inositol and scyllo-inositol, with scyllo-inositol being the most preferred.
- the inositol stereoisomers of the present invention exclude myo-inositol and may also exclude epi-inositol.
- these compounds are found to be useful in treating or preventing in a subject a condition of the central or peripheral nervous system or systemic organ associated with a disorder in protein folding or aggregation, or amyloid formation, deposition, accumulation, or persistence.
- These compounds are also found to be useful in preventing abnormal protein folding, abnormal protein aggregation, amyloid formation, deposition, accumulation, or persistence, or amyloid lipid interactions as well as causing the dissociation of abnormally aggregated proteins and/or dissolving or disrupting pre-formed or pre-deposited amyloid fibril or amyloid in a subject.
- the condition of the central or peripheral nervous system or systemic organ results in the deposition of proteins, protein fragments and peptides in beta-pleated sheats and/or fibrils and/or aggregates. More preferably, the condition of the central or peripheral nervous system or systemic organ is selected from the group of: Alzheimer's disease, presenile and senile forms; amyloid angiopathy; mild cognitive impairment; Alzheimer's disease-related dementia; tauopathy; ⁇ -synucleinopathy; Parkinson's disease; Amyotrophic Lateral Sclerosis; motor neuron Disease; Spastic paraplagia; Huntington's Disease, spinocerebellar ataxia, Freidrich's Ataxia; neurodegenerative diseases associated with intracellular and/or intraneuronal aggregates of proteins with polyglutamine, polyalanine or other repeats arising from pathological expansions of tri- or tetra-nucleotide elements within corresponding genes; cerebrovascular diseases; Down's syndrome; head trauma with post-traumatic accumulation
- the Alzheimer's disease-related dementias are vascular or Alzheimer dementia and tauopathy selected from the group of argyrophilic grain dementia, corticobasal degeneration, dementia pugilistica, diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism, Prion-related disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian Motor Neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and tangle only dementia.
- the ⁇ -synucleinopathy is selected from the group of dementia with Lewy bodies, multiple system atrophy with glial cytoplasmic inclusions, Shy-Drager syndrome, striatonigral degeneration, olivopontocerebellar atrophy, neurodegeneration with brain iron accumulation type I, olfactory dysfunction, and amyotrophic lateral sclerosis.
- the Motor Neuron Disease is associated with filaments and aggregates of neurofilament and/or superoxide dismutase proteins
- the Spastic paraplegia is associated with defective function of chaperones and/or triple A proteins
- the spinocerebellar ataxia is DRPLA or Machado-Joseph Disease.
- the Prion related disease is selected from the group of Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, and variant Creutzfeldt-Jakob disease and the Amyloid Polyneuropathy is Senile amyloid polyneuropathy or Systemic Amyloidosis.
- the condition of the central or peripheral nervous system or systemic organ is Parkinson's disease including familial and non-familial types. Most preferably, said condition of the central or peripheral nervous system or systemic organ is Alzheimer's disease.
- the compound is administered to the subject at a dose of about 1 mg to about 1 g per kg, preferably 1 mg to about 200 mg per kg, more preferably about 10 mg to about 100 mg per kg and most preferably about 30 mg to 70 mg per kg of the weight of said subject.
- the administration can be accomplished by a variety of ways such as orally (oral pill, oral liquid or suspension), intravenously, intramuscularly, intraperitoneally, intradermally, transcutaneously, subcutaneously, intranasally, sublingually, by rectal suppository or inhalation, with the oral administration being the most preferred.
- the administration of the compounds of the present invention can be undertaken at various intervals such as once a day, twice per day, once per week, once a month or continuously.
- the compounds of the present invention are administered in combination with other treatments such as beta-secretase inhibitors, gamma-secretase inhibitors (APP-specific or non-specific), epsilon-secretase inhibitors (APP-specific or non-specific), other inhibitors of beta-sheet aggregation/fibrillogenesis/ADDL formation (e.g. Alzhemed), NMDA antagonists (e.g. memantine), non-steroidal anti-inflammatory compounds (e.g. Ibuprofen, Celebrex), anti-oxidants (e.g. Vitamin E), hormones (e.g. estrogens), nutrients and food supplements (e.g.
- other treatments such as beta-secretase inhibitors, gamma-secretase inhibitors (APP-specific or non-specific), epsilon-secretase inhibitors (APP-specific or non-specific), other inhibitors of beta-sheet aggregation/fibrillogenesis/ADDL formation (e.g. Alzhemed),
- Gingko biloba Gingko biloba
- acetylcholinesterase inhibitors e.g. donezepil
- muscarinic agonists e.g. AF102B (Cevimeline, EVOXAC), AF150(S), and AF267B
- anti-psychotics e.g. haloperidol, clozapine, olanzapine
- anti-depressants including tricyclics and serotonin reuptake inhibitors (e.g.
- Sertraline and Citalopram Hbr gene therapy and/or drug based approaches to upregulate neprilysin (an enzyme which degrades A ⁇ ); gene therapy and/or drug based approaches to upregulate insulin degrading enzyme (an enzyme which degrades A ⁇ ), vaccines, immunotherapeutics and antibodies to A ⁇ (e.g. ELAN AN-1792), statins and other cholesterol lowering drugs (e.g. Lovastatin and Simvastatin), stem cell and other cell-based therapies, inhibitors of kinases (CDK5, GSK3 ⁇ , GSK3 ⁇ ) that phosphorylate TAU protein (e.g. Lithium chloride), or inhibitors of kinases that modulate A ⁇ production (GSK3 ⁇ , GSK3 ⁇ , Rho/ROCK kinases) (e.g. lithium Chloride and Ibuprofen).
- CDK5 inhibitors of kinases
- GSK3 ⁇ , GSK3 ⁇ that phosphorylate TAU protein
- the compounds of the present invention are also useful in diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in a subject using a method that comprises administering to said subject a radioactive compound or compound tagged with a substance that emits a detectable signal in a quantity sufficient and under conditions to allow for the binding of said compound to the abnormally folded or aggregated protein and/or fibrils or amyloid, if present; and detecting the radioactivity or the signal from the compound bound to the abnormally folded or aggregated protein and/or fibrils or amyloid, thus diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid.
- a sample suspected of containing abnormally folded or aggregated protein and/or amyloid fibril or amyloid is collected from a subject and is contacted with a radioactive compound or compound tagged with a substance that emits a detectable signal under conditions to allow the binding of said compound to the abnormally folded or aggregated protein and/or amyloid fibril or amyloid if present; and thereafter detect the radioactivity or the signal from the compound bound to the abnormally folded or aggregated protein and/or fibrils or amyloid, thus diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in said subject.
- said detectable signal is a fluorescent or an enzyme-linked immunosorbent assay signal and said sample is whole blood (including all cellular constituents) or plasma.
- the compounds of the present invention can abrogate the cerebral accumulation of A ⁇ , the deposition of cerebral amyloid plaques, and cognitive decline in a transgenic mouse model of Alzheimer Disease when given during the “late presymptomatic” phase, prior to the onset of overt cognitive deficits and amyloid neuropathology in these mice. Furthermore, even when these compounds are given after the onset of cognitive deficits and amyloid plaque neuropathology, they can effectively reverse the amyloid deposition and neuropathology. Importantly, the mechanism of action of these compounds follows a rational design based upon their capacity to modulate the assembly of A ⁇ monomers into neurotoxic oligomers and/or protofibrils.
- TgCRND8 mice are a robust murine model of Alzheimer's disease as described by Janus et al. ( Nature 408:979-982 (2000). They express a human amyloid precursor protein (APP695) transgene under the regulation of the Syrian hamster prion promoter on a C3H/B6 outbred background. The human APP695 transgene bears two mutations that cause AD in humans (K670N/M671L and V717F). Beginning at about 3 months of age, TgCRND8 mice have progressive spatial learning deficits that are accompanied by rising cerebral A ⁇ levels and by increasing number of cerebral extracellular amyloid plaques that are similar to those seen in the brains of humans with AD (C. Janus et al., Nature 408:979-982 (2000)).
- APP695 human amyloid precursor protein
- mice and non-transgenic littermates were either untreated, or were given a compound of the present invention as indicated below at 30 mg/day/mouse beginning at age of about 6 weeks. The mice were followed for outcome measures cognitive function, brain A ⁇ levels, brain pathology, and survival at 4 months and 6 months of age.
- mice Experimental groups of TgCRND8 mice were fed myo-, epi- and scyllo-inositol at 30 mg/mouse/day. Two cohorts entered the study at 6 weeks of age and outcomes were analyzed at 4- and 6-months of age. The body weight, coat characteristics and in cage behavior was monitored. All experiments were performed according to the Canadian Council on Animal Care guidelines.
- mice After non-spatial pre-training, mice underwent place discrimination training for 5 days with 4 trials per day. Behavioral data was analyzed using a mixed model of factorial analysis of variance (ANOVA) with drug or genotype and training sessions as repeated measure factors.
- ANOVA factorial analysis of variance
- Cerebral amyloid burden Brains were removed and one hemisphere was fixed in 4% paraformaldehyde and embedded in paraffin wax in the mid saggital plane. To generate sets of systematic uniform random sections, 5 ⁇ m serial sections were collected across the entire hemisphere. Sets of sections at 50 mm intervals were used for analyses (10-14 sections/set). Plaque were identified after antigen retrieval with formic acid, and incubated with primary anti-A ⁇ antibody (Dako M-0872), followed by secondary antibody (Dako StreptABCcomplex/horseradish kit). End products were visualized with DAB counter-stained with hematoxylin. Amyloid plaque burden was assessed using Leco IA-3001 image analysis software interfaced with Leica microscope and Hitachi KP-M1U CCD video camera. Vascular burden was analyzed similarly and a dissector was used to measure the diameter of affected vessels.
- Plasma and Cerebral A ⁇ Content Plasma and Cerebral A ⁇ Content—Hemi-brain samples were homogenized in a buffered sucrose solution, followed by either 0.4% diethylamine/100 mM NaCl for soluble A ⁇ levels or cold formic acid for the isolation of total A ⁇ . After neutralization the samples were diluted and analyzed for A ⁇ 40 and A ⁇ 42 using commercially available kits (BIOSOURCE International). Each hemisphere was analyzed in triplicate with the mean ⁇ SEM reported. Western blot analyses were performed on all fractions using urea gels for A ⁇ species analyses. A ⁇ was detected using 6E10 (BIOSOURCE International) and Enhanced Chemiluminenscence (Amersham).
- Gliosis Quantitation Five randomly selected, evenly spaced, sagittal sections were collected from paraformaldehyde-fixed and frozen hemispheres of treated and control mice. Sections were immunolabelled for astrocytes with anti-rat GFAP IgG 2a (Dako; diluted 1:50) and for microglia with anti-rat CD68 IgG2b (Dako; 1:50). Digital images were captured using a Coolsnap digital camera (Photometrics, Tuscon, Ariz.) mounted to a Zeiss Axioscope 2 Plus microscope. Images were analysed using Openlab 3.08 imaging software (Improvision, Lexington Mass.).
- ANOVA analysis of variance
- epi-inositol treated TgCRND8 mice When compared to treated or non-treated non-Tg littermates, epi-inositol treated TgCRND8 mice had a slightly slower learning curve during the first three days of training. However, after 4 days of training, epi-inositol treated TgCRND8 mice were not statistically different from their non-Tg littermates ( FIG. 2E ). In contrast, scyllo-inositol treated TgCRND8 mice were indistinguishable from non-Tg littermates on all days.
- Inositol treatment decreases A ⁇ 40 and A ⁇ 42 Levels Total Plaque A ⁇ 40 A ⁇ 42 Plaque Area/Total (ng/gm wet brain ⁇ sem) (ng/gm wet brain ⁇ sem) Total Plaque Area Brain Area Soluble Insoluble Soluble Insoluble A ⁇ Count ( ⁇ m 2 ) (%) 4 month prevention Control 75 ⁇ 6 1163 ⁇ 9 273 ⁇ 18 5658 ⁇ 248 7169 ⁇ 284 696 ⁇ 25 100766 ⁇ 7564 0.026 ⁇ 0.004
- Astroglial and microglial reactions are neuropathological features both of human AD and of all amyloid mouse models (Irizarry et al., J Neuropathol Exp Neurol. 56, 965, 1997; K. D. Bornemann et al. Ann NY Acad Sci. 908, 260, 2000). Therefore, the effect of epi- and scyllo-inositol treatment was investigated on astrogliosis and microgliosis in the brains of TgCRND8 mice ( FIGS. 3A-3D ). Serial sagittal sections were stained with the astrocytic marker glial fibrillary acidic protein (GFAP) and quantitated for percent brain area covered by astrogliosis.
- GFAP astrocytic marker glial fibrillary acidic protein
- TgCRND8 mice have a high basal astrogliosis at 4-months of age (0.459 ⁇ 0.048%), which increases slightly by 6-months of age (0.584 ⁇ 0.089%), and which is not restricted to plaque areas ( FIGS. 2A-C ).
- Microglial activation was also significantly attenuated in scyllo-inositol treated TgCRND8 mice (0.20 ⁇ 0.008% brain area) when compared to age- and sex-matched untreated TgCRND8 mice (0.31 ⁇ 0.01%; p ⁇ 0.001).
- scyllo-inositol treatment decreases the A ⁇ -induced inflammatory response within the CNS.
- Alzheimer's disease is characterized by the presence of both parenchymal and vascular amyloid deposits.
- untreated 6 month old TgCRND8 mice approximately 0.03% of the brain area is associated with vascular amyloid. No difference could be detected in the vascular amyloid burden after epi-inositol treatment at 6 months of age ( FIG. 3C ).
- Treatment with myo-inositol did not affect overall survival significantly ( FIG. 10A ).
- treatment of wild type mice with scyllo-inositol had no effect either on survival or on other parameters such as weight, fur condition or cage behavior.
- mice Experimental groups of TgCRND8 mice were fed myo-, epi- and scyllo-inositol at 30 mg/mouse/day. A cohort entered the study at 5 months of age and outcomes were analyzed at 6-months of age. The body weight, coat characteristics and in cage behavior was monitored. All experiments were performed according to the Canadian Council on Animal Care guidelines.
- Behavioral. Test Reversal Study—Mice entered the Morris water maze test with a hidden platform on day one without pretraining. Mice were tested for 3 days with six trials per day. On the fourth day, the platform was removed from the pool and each mouse received one 30-s swim probe trial. On the last day the animals underwent a cue test in order to evaluate swimming ability, eye sight and general cognition. The cue test is composed at the platform being placed in a different quadrant than that used for testing and is tagged with a flag. Animals are allowed 60 s to find the platform. Animals that do not find the platform are not used in the final analyses of spatial memory. Behavioural data was analysed using a mixed model of factorial analysis of variance (ANOVA) with drug or genotype and training sessions as repeated measure factors.
- ANOVA factorial analysis of variance
- Cerebral amyloid burden Brains were removed and one hemisphere was fixed in 4% paraformaldehyde and embedded in paraffin wax in the mid saggital plane. To generate sets of systematic uniform random sections, 5 ⁇ m serial sections were collected across the entire hemisphere. Sets of sections at 50 mm intervals were used for analyses (10-14 sections/set). Plaque were identified after antigen retrieval with formic acid, and incubated with primary anti-A ⁇ antibody (Dako M-0872), followed by secondary antibody (Dako StreptABCcomplex/horseradish kit). End products were visualized with DAB counter-stained with hematoxylin. Amyloid plaque burden was assessed using Leco IA-3001 image analysis software interfaced with Leica microscope and Hitachi KP-M1U CCD video camera.
- Plasma and Cerebral A ⁇ Content Plasma and Cerebral A ⁇ Content—Hemi-brain samples were homogenized in a buffered sucrose solution, followed by either 0.4% diethylamine/100 mM NaCl for soluble A ⁇ levels or cold formic acid for the isolation of total A ⁇ . After neutralization the samples were diluted and analyzed for A ⁇ 40 and A ⁇ 42 using commercially available kits (BIOSOURCE International). Each hemisphere was analyzed in triplicate with the mean ⁇ SEM reported.
- TgCRND8 mice All animals that entered the reversal study survived and did not display outward signs of distress or toxicity.
- ANOVA analysis of variance
- TgCRND8 mice were significantly impaired in comparison to wild type littermates ( FIG. 4 ).
- scyllo-inositol can abrogate the cerebral accumulation of A ⁇ , the deposition of cerebral amyloid plaques, and cognitive decline in a transgenic mouse model of Alzheimer Disease when given during the “late presymptomatic” phase, prior to the onset of overt cognitive deficits and amyloid neuropathology in these mice. Furthermore, even when scyllo-inositol is given after the onset of cognitive deficits and amyloid plaque neuropathology, these compounds can effectively reverse the amyloid deposition, neuropathology and cognitive deficits. Therefore, these results indicate that scyllo-inositol is effective at both prevention of disease and in the treatment of existing disease in patients already diagnosed with AD.
- Inositol treatment decreases A ⁇ 40 and A ⁇ 42 Levels Total Plaque A ⁇ 40 A ⁇ 42 Plaque Area/Total (ng/gm wet brain ⁇ sem) (ng/gm wet brain ⁇ sem) Total Plaque Area Brain Area Soluble Insoluble Soluble Insoluble A ⁇ Count ( ⁇ m 2 ) (%) 4 month prevention Control 75 ⁇ 6 1163 ⁇ 9 273 ⁇ 18 5658 ⁇ 248 7169 ⁇ 284 696 ⁇ 25 100766 ⁇ 7564 0.026 ⁇ 0.004 Myo-Inositol 42 ⁇ 6 485 ⁇ 143 174 ⁇ 9 4268 ⁇ 308 4969 ⁇ 434 649 ⁇ 50 91902 ⁇ 7453 0.023 ⁇ 0.004 Epi-Inositol 43 ⁇ 7* 615 ⁇ 32 ⁇ 85 ⁇ 7 ⁇ 4059 ⁇ 179* 4802 ⁇ 176 678 ⁇ 64 65042 ⁇ 5199 0.020 ⁇ 0.001 Scyllo
- TgCRND8 mice treated for two months with scyllo-inositol were indistinguishable from scyllo-inositol treated non-Tg littermates ( FIG. 12B ).
- a ⁇ 40 and A ⁇ 42 levels were analysed in the brain (Table 3). Both insoluble A ⁇ 40 and A ⁇ 42 levels were decreased 20% after scyllo-inositol treatment.
- Inositol treatment decreases A ⁇ 40 and A ⁇ 42 Levels Brain A ⁇ 40 Brain A ⁇ 42 Plasma (ng/gm wet (ng/gm wet A ⁇ Levels brain ⁇ sem) brain ⁇ sem) (pg/ml) 2 month treatment Soluble Insoluble Soluble Insoluble A ⁇ 40 A ⁇ 42 Control 487 ⁇ 14 6924 ⁇ 287 764 ⁇ 51 25827 ⁇ 1238 5212 ⁇ 219 3455 ⁇ 331 Scyllo-inositol 395 ⁇ 60 5703 ⁇ 612* 688 ⁇ 28 20818 ⁇ 1404* 4507 ⁇ 207 3035 ⁇ 236 ANOVA with Fisher's PLSD, *p ⁇ 0.05.
- Allo-Inositol treatment decreases A ⁇ 42 levels Brain A ⁇ 40 Brain A ⁇ 42 (ng/gm wet (ng/gm wet Plasma brain ⁇ sem) brain ⁇ sem) A ⁇ Levels 1 month treatment Soluble Insoluble Soluble Insoluble (pg/ml) Control 252 ⁇ 48 4105 ⁇ 851 666 ⁇ 39 16448 ⁇ 2120 2359 ⁇ 147 Allo-inositol 281 ⁇ 21 3787 ⁇ 342 547 ⁇ 47* 16336 ⁇ 910 2458 ⁇ 95 ANOVA with Fisher's PLSD, *p ⁇ 0.05.
- Tg PS1 ⁇ APP mice are an enhanced model of Alzheimer's disease which express a mutant human PS1 transgene encoding two familial mutations (M146L and L286V) in conjunction with the human APP transgene encoding the Indiana and Swedish familial mutations. These animals develop robust expression of cerebral A ⁇ levels and amyloid deposition by 30-45 days of age. In a prophylactic trial, TgPS1 ⁇ APP mice were treated with scyllo-inositol from weaning and were assessed for effects on neuropathology at 2 months of age ( FIGS. 16 and 17 ).
- TgCRND8 mice were treated with a simple sugar of similar molecular weight, mannitol. At 6 months of age, mannitol treated TgCRND8 mice were indistinguishable from untreated TgCRND8 mice ( FIG. 11A ) and were significantly different from mannitol treated non-Tg littermates ( FIG. 11B ). Mannitol had no effect on the behaviour of non-Tg mice, since mannitol treated non-Tg mice were indistinguishable from untreated non-Tg mice. These results correlate with the pathological studies that indicate mannitol did not alter the plaque load in TgCRND8 mice ( FIG. 11C ). Simultaneous monitoring of survival demonstrated that mannitol had no effect on the survival of TgCRND8 mice ( FIG. 11D ).
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Immunology (AREA)
- Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Pathology (AREA)
- Analytical Chemistry (AREA)
- Food Science & Technology (AREA)
- Microbiology (AREA)
- Cell Biology (AREA)
- Diabetes (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Oncology (AREA)
Abstract
Disclosed are methods of preventing, treating, or diagnosing in a subject a disorder in protein folding or aggregation, or amyloid formation, deposition, accumulation, or persistence consisting of administering to said subject a pharmaceutically effective amount of inositol stereoisomers, enantiomers or derivatives thereof.
Description
- This application claims the priority of U.S. Provisional Application Ser. Nos. 60/451,363, 60/520,958 and 60/523,534, filed Feb. 27, 2003, Nov. 17, 2003 and Nov. 19, 2003, respectively.
- The invention relates to methods for treating Alzheimer's Disease and other amyloidoses; more particularly, it relates to methods for inhibiting and reducing amyloid fibril formation in therapeutic intervention in Alzheimer's disease and other amyloidoses.
- Alzheimer's disease is characterized neuropathologically by amyloid deposits, neurofibrillary tangles, and selective neuronal loss. The major component of the amyloid deposits is amyloid-β (Aβ, a 39-43 residue peptide. Soluble forms of Aβ generated from cleavage of amyloid precursor protein are normal products of metabolism. The importance of residues 1-42 (Aβ42) in Alzheimer's disease was highlighted in the discovery that mutations in codon 717 of the amyloid precursor protein gene,
presenilin 1 andpresenilin 2 genes result in an increased production of Aβ42 over Aβ1-40. These results in conjunction with the presence of Aβ42 in both mature plaques and diffuse amyloid lead to the hypothesis that this more amyloidogenic species may be the critical element in plaque formation. This hypothesis was supported by the fact that Aβ42 deposition precedes that of Aβ40 in Down's syndrome in PS1 mutations and in hereditary cerebral hemorrhage with amyloidosis. - Many in vitro studies have demonstrated that Aβ can be neurotoxic or enhance the susceptibility of neurons to excitotoxic, metabolic, or oxidative insults. Initially it was thought that only the fibrillar form of A was toxic to neurons but more thorough characterization of Aβ structures demonstrated that dimers and small aggregates of Aβ are also neurotoxic. These data suggested that prevention of Aβ oligomerization would be a likely strategy to prevent AD-related neurodegeneration. Several studies have demonstrated that in vitro Aβ-induced neurotoxicity can be ablated by compounds that can increase neuronal resistance by targeting cellular pathways involved in apoptosis, block downstream pathways after Aβ induction of destructive routes, or block Aβ oligomerization and ultimately fibril formation. The site at which Aβ acts to induce neurotoxicity has yet to be elucidated but its toxic effects have been blocked by a variety of disparate agents.
- Docking of Aβ-fibrils to neuronal and glial cell membranes may be an early and intervenable step during the progression of AD. Formation of amyloid plaques, as well as neurotoxicity and inflammation may be direct or indirect consequences of the interaction of A with molecules containing sugar moieties. Previous studies have demonstrated that Aβ interaction with glycosaminoglycans results in aggregation of Aβ possibly adding to their insolubility and plaque persistence. Glycosaminoglycans have also been implicated in neuronal toxicity and microglial activation. Alternatively, interaction with glycolipids such as gangliosides results in the stabilization and prevention of Ab fibril formation, as well as, the site of Aβ production. The family of phosphatidylinositols, on the other hand, results in acceleration of fibril formation. The headgroup of phosphatidylinositol is myo-inositol, a naturally occurring simple sugar involved in lipid biosynthesis, signal transduction, and osmolarity control.
- It is also noteworthy that a variety of other human diseases also demonstrate amyloid deposition and usually involve systemic organs (i.e. organs or tissues lying outside the central nervous system), with the amyloid accumulation leading to organ dysfunction or failure. In Alzheimer's disease and “systemic” amyloid diseases, there is currently no cure or effective treatment, and the patient usually dies within 3 to 10 years from disease onset.
- U.S. Pat. No. 4,847,082 discloses the use of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid for the treatment of Alzheimer's disease. It also discloses that isomers of phytic acid or phytate salt comprise the hexakisphosphate myo-inositol, hexakisphosphate scyllo-inositol, hexakisphosphate D-chiro-inositol, hexakisphosphate L-chiro-inositol, hexakisphosphate neo-inositol and hexakisphosphate muco-inositol conformations. Phytic acid is inositol-hexakisphosphate (IP6).
- U.S. Pat. No. 5,112,814 discloses the use of phytic acid and isomers thereof for the treatment of Parkinson's disease. As is the case with U.S. Pat. No. 4,847,082, the phytic acid isomers disclosed in this patent retain the six phosphate groups on the six-carbon inositol sugar.
- It is noteworthy that in subsequent publications, the ability of inositol-monophosphate, inositol-1,4-bisphosphate and inositol-1,4,5-triphosphate to inhibit amyloid-beta peptide fibrillogenesis were investigated and found not to be effective (J. Mol. Biol. 278:183-194, 1998).
- Barak et al. disclose the use of inositol for the treatment of Alzheimer's Disease (AD). (Prog Neuro-psychoparmacol & Biol Psychiat. 20:729-735, 2000). However, this reference does not disclose the use of inositol isomers. Patients treated with inositol did not show any significant differences in overall cognitive function scores (CAMCOG index) between inositol and placebo (dextrose) in AD patients while two specific subscales of the CAMCOG index did show significant improvement (orientation and language).
- Levine J. reviews the above Barak et al. paper and specifically states that inositol treatment is not beneficial in AD or ECT-induced cognitive impairment (Eur Neuropsychoparm. 1997; 7,147-155, 1997).
- Colodny L, et al. suggests further studies for the usefulness of inositol in Alzheimer's disease by referring to the above Barak et al. paper and therefore does not disclose or suggest such use for inositol isomers (Altern Med Rev 3(6):432-47, 1998).
- McLaurin et al. disclosed that myo-inositol stabilizes a small micelle of Aβ42 (J. Mol. Biol. 278, 183-194, 1998). In addition, McLaurin et al. disclose that epi- and scyllo- but not chiro-inositol were able to induce a structural transition from random to β-structure in Aβ42 (J Biol Chem. Jun. 16; 275(24):18495-502, 2000; and J Struct Biol 130:259-270, 2000). Alternatively, none of the stereoisomers were able to induce a structural transition in Aβ40. Electron microscopy showed that inositol stabilizes small aggregates of Aβ42. These references also disclose that inositol-Aβ interactions result in a complex that is non-toxic to nerve growth factor-differentiated PC-12 cells and primary human neuronal cultures.
- Much work in Alzheimer's disease has been accomplished, but little is conventionally known about compounds or agents for therapeutic regimes to arrest or reverse amyloid formation, deposition, accumulation and/or persistence that occurs in Alzheimer's disease and other amyloidoses.
- New compounds or agents for therapeutic regimes to arrest or reverse amyloid formation, deposition, accumulation and/or persistence that occurs in Alzheimer's disease and other amyloidoses are therefore desperately needed.
- The present invention provides a method of treating or preventing in a subject a condition of the central or peripheral nervous system or systemic organ associated with a disorder in protein folding or aggregation, or amyloid formation, deposition, accumulation, or persistence comprising administering to said subject a pharmaceutically effective amount of compound selected having the following structure:
- wherein each of R1, R1′, R2, R2′, R3, R3′, R4, R4′, R5, R5′, R6, and R6′ is independently selected from the group of:
-
- (a) hydrogen atom;
- (b) NHR7, wherein said R7 is selected from the group of hydrogen; C2-C10 acyl and C1-C10 alkyl;
- (c) NR8R9, wherein said R8 is C2-C10 acyl or C1-C10 alkyl and said R9 is C2-C10 acyl or C1-C10 alkyl;
- (d) OR10, wherein said R10 is selected from the group of no group, hydrogen, C2-C10 acyl, C1-C10 alkyl and SO3H;
- (e) C5-C7 glycosyl;
- (f) C3-C8 cycloalkyl optionally substituted with a substituent selected from the group of hydrogen, OH, NH2, SH, OSO3H and OPO3H2;
- (g) SR11, wherein R11 is selected from the group of hydrogen, C1-C10 alkyl and O3H;
- (h) C1-C10 alkyl optionally substituted with a substituent selected from the group of hydrogen, OR10, NHR7, NR8R9 and SR11; and
- (i) C3-C8 cycloalkyl optionally substituted with a substituent selected from the group of hydrogen, OR10, NHR7, NR8R9 and SR11,
providing that the compound is not myo-inositol.
- The present invention also provides a method of preventing abnormal protein folding, abnormal protein aggregation, amyloid formation, deposition, accumulation, or persistence, or amyloid lipid interactions in a subject comprising administering to said subject a pharmaceutically effective amount of a compound having the following structure:
- wherein each of R1, R1′, R2, R2′, R3, R3′, R4, R4′, R5, R5′, R6, and R6′ is independently selected from the group of:
-
- (a) hydrogen atom;
- (b) NHR7, wherein said R7 is selected from the group of hydrogen; C2-C10 acyl and C1-C10 alkyl;
- (c) NR8R9, wherein said R8 is C2-C10 acyl or C1-C10 alkyl and said R9 is C2-C10 acyl or C1-C10 alkyl;
- (d) OR10, wherein said R10 is selected from the group of no group, hydrogen, C2-C10 acyl, C1-C10 alkyl and SO3H,
- (e) C5-C7 glycosyl;
- (f) C3-C8 cycloalkyl optionally substituted with a substituent selected from the group of hydrogen, OH, NH2, SH, OSO3H and OPO3H2;
- (g) SR11, wherein R11 is selected from the group of hydrogen, C1-C10 alkyl and O3H;
- (h) C1-C10 alkyl optionally substituted with a substituent selected from the group of hydrogen, OR10, NHR7, NR8R9 and SR11; and
- (i) C3-C8 cycloalkyl optionally substituted with a substituent selected from the group of hydrogen, OR10, NHR7, NR8R9 and SR11,
providing that the compound is not myo-inositol.
- The present invention further provides a method of causing the dissociation of abnormally aggregated proteins and/or dissolving or disrupting pre-formed or pre-deposited amyloid fibril or amyloid in a subject comprising administering to said subject a pharmaceutically effective amount of a compound having the following structure:
- wherein each of R1, R1′, R2, R2′, R3, R3′, R4, R4′, R5, R5′, R6, and R6′ is independently selected from the group of:
-
- (a) hydrogen atom;
- (b) NHR7, wherein said R7 is selected from the group of hydrogen; C2-C10 acyl and C1-C10 alkyl;
- (c) NR8R9, wherein said R8 is C2-C10 acyl or C1-C10 alkyl and said R9 is C2-C10 acyl or C1-C10 alkyl;
- (d) OR10, wherein said R10 is selected from the group of no group, hydrogen, C2-C10 acyl, C1-C10 alkyl and SO3H;
- (e) C5-C7 glycosyl;
- (f) C3-C8 cycloalkyl optionally substituted with a substituent selected from the group of hydrogen, OH, NH2, SH, OSO3H and OPO3H2;
- (g) SR11, wherein R11 is selected from the group of hydrogen, C1-C10 alkyl and O3H;
- (h) C1-C10 alkyl optionally substituted with a substituent selected from the group of hydrogen, OR10, NHR7, NR8R9 and SR11; and
- (i) C3-C8 cycloalkyl optionally substituted with a substituent selected from the group of hydrogen, OR10, NHR7, NR8R9 and SR11,
providing that the compound is not myo-inositol.
- The present invention also provides a method of diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in a subject comprising: (a) administering to said subject a radioactive compound or compound tagged with a substance that emits a detectable signal in a quantity sufficient and under conditions to allow for the binding of said compound to the abnormally folded or aggregated protein and/or fibrils or amyloid, if present; and (b) detecting the radioactivity or the signal from the compound bound to the abnormally folded or aggregated protein and/or fibrils or amyloid, thus diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in said subject, wherein said compound has the following structure:
- wherein each of R1, R1′, R2, R2′, R3, R3′, R4, R4′, R5, R5′, R6, and R6′ is independently selected from the group of:
-
- (a) hydrogen atom;
- (b) NHR7, wherein said R7 is selected from the group of hydrogen; C2-C10 acyl and C1-C10 alkyl;
- (c) NR8R9, wherein said R8 is C2-C10 acyl or C1-C10 alkyl and said R9 is C2-C10 acyl or C1-C10 alkyl;
- (d) OR10, wherein said R10 is selected from the group of no group, hydrogen, C2-C10 acyl, C1-C10 alkyl and SO3H;
- (e) C5-C7 glycosyl;
- (f) C3-C8 cycloalkyl optionally substituted with a substituent selected from the group of hydrogen, OH, NH2, SH, OSO3H and OPO3H2;
- (g) SR11, wherein R11 is selected from the group of hydrogen, C1-C10 alkyl and O3H;
- (h) C1-C10 alkyl optionally substituted with a substituent selected from the group of hydrogen, OR10, NHR7, NR8R9 and SR11; and
- (i) C3-C8 cycloalkyl optionally substituted with a substituent selected from the group of hydrogen, OR10, NHR7, NR8R9 and SR11,
providing that the compound is not myo-inositol.
- The present invention further provides a method of diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in a subject comprising: (a) collecting a sample from said subject; (b) contacting said sample with a radioactive compound or compound tagged with a substance that emits a detectable signal under conditions to allow the binding of said compound to the abnormally folded or aggregated protein and/or amyloid fibril or amyloid if present; and (c) detecting the radioactivity or the signal from the compound bound to the abnormally folded or aggregated protein and/or fibrils or amyloid, thus diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in said subject, wherein said compound has the following structure:
- wherein each of R1, R1′, R2, R2′, R3, R3′, R4, R4′, R5, R5′, R6, and R6′ is independently selected from the group of;
-
- (a) hydrogen atom;
- (b) NHR7, wherein said R7 is selected from the group of hydrogen; C2-C10 acyl and C1-C10 alkyl;
- (c) NR8R9, wherein said R8 is C2-C10 acyl or C1-C10 alkyl and said R9 is C2-C10 acyl or C1-C10 alkyl;
- (d) OR10, wherein said R10 is selected from the group of no group, hydrogen, C2-C10 acyl, C1-C10 alkyl and SO3H;
- (e) C5-C7 glycosyl;
- (f) C3-C8 cycloalkyl optionally substituted with a substituent selected from the group of hydrogen, OH, NH2, SH, OSO3H and OPO3H2;
- (g) SR11, wherein R11 is selected from the group of hydrogen, C1-C10 alkyl and O3H;
- (h) C1-C10 alkyl optionally substituted with a substituent selected from the group of hydrogen, OR10, NHR7, NR8R9 and SR11; and
- (i) C3-C8 cycloalkyl optionally substituted with a substituent selected from the group of hydrogen, OR10, NHR7, NR8R9 and SR11,
providing that the compound is not myo-inositol.
-
FIG. 1A shows the structure of myo-, epi- and scyllo-inositol whileFIGS. 1B-1H show the spatial reference memory version of the Morris water maze test in TgCRND8 mice. Myo-inositol treatment did not alter cognitive function (1B). At 6 months of age, non-treated TgCRND8 (n=10) show cognitive impairment relative to non-Tg controls and epi- (1C) and scyllo-inositol (1D) treated mice (n=10 per group, p<0.02 untreated vs treated). The performance of epi-inositol treated TgCRND8 mice remained impaired with respect to non-Tg littermates (1E) whereas the performance of scyllo-inositol TgCRND8 approached that of non-Tg littermates (1F). Non-Tg littermate behavior was not effected by either epi- (1G) or scyllo-inositol (1H) treatment. Vertical bars represent S.E.M. -
FIGS. 2A-2I show at 6 months of age, the plaque burden and astrogliosis in TgCRND8 treated with epi- and scyllo-inositol treated mice. Control animals have a high plaque load and astrogliosis in the hippocampus (2A) and cerebral cortex (2B). Higher magnification demonstrates that astrocytic activation is not only associated with plaque load (2C). Epi-inositol treatment has a modest effect on amyloid burden with a decrease in astrogliosis (2D, 2E and 2F). Scyllo-inositol treatment significantly decreased amyloid burden and gliosis (2G, 2H, and 2I). Higher magnification illustrates the smaller mean plaque size in scyllo-inositol treated mice (2I). Astrocytes were labeled using anti-GFAP antibody and plaque burden was identified using anti-Aβ antibody. Scale Bar 450 microns (A, B, D, E, G, H) and 94 microns (C, F, I). -
FIGS. 3A-3D show that the Aβ species, 1-42, 1-40 and 1-38, in control and treated TgCRND8 mice was indistinguishable (3A) as was the extent of APP processing (3B). Vascular amyloid burden was quantitated on serial sagittal sections in treated and untreated TgCRND8 mice. TgCRND8 mice have a significant vascular amyloid burden that is associated with small and medium sized vessels, the load is decreased in scyllo-inositol treated TgCRND8 mice (3A). Scyllo-inositol treatment significantly decreased the total vascular load in comparison to untreated and epi-inositol treated TgCRND8 mice (3C). Scyllo-inositol decreases plaque deposition as illustrated by the significant decrease in mean plaque size (3D). -
FIG. 4 shows the effect of water on the cognitive function of TgCRND8 and non-Tg mice using the spatial reference memory version of the Morris Water Maze in a three day trial paradigm. -
FIG. 5 shows the effect of scyllo-inositol on the cognitive function of TgCRND8 and non-Tg mice using the spatial reference memory version of the Morris Water Maze in a three day trial paradigm. -
FIG. 6 shows the effect of epi-inositol on the cognitive function of TgCRND8 and non-Tg mice using the spatial reference memory version of the Morris Water Maze in a three day trial paradigm. -
FIG. 7 shows the effect of myo-inositol on the cognitive function of TgCRND8 and non-Tg mice using the spatial reference memory version of the Morris Water Maze in a three day trial paradigm. -
FIG. 8 shows the effect of scyllo-inositol, epi-inositol and myo-inositol on the cognitive function of TgCRND8 (learning phase and memory test) and compared with wild type mice using the spatial reference memory version of the Morris Water Maze in a three-day trial paradigm. -
FIG. 9 shows the percentage of brain area covered with plaques in untreated TgCRND8 mice versus mice treated with scyllo-inositol, epi-inositol or myo-inositol. -
FIGS. 10A and 10B show the survival rates of TgCRND8 mice treated with water versus epi-inositol or myo-inositol (10A) or versus scyllo-inositol (10B). -
FIGS. 11A-D show the results of spatial reference memory version of the Morris Water Maze test in 6-month old TgCRND8 mice non-treated or treated with mannitol (A,B). Mannitol treated TgCRND8 mice were not significantly different from untreated TgCRND8 mice (p=0.89; A). The performance of mannitol treated TgCRND8 mice was significantly different from mannitol treated non-Tg littermates (p=0.05; B). Plaque burden was analyzed at 6 months of age using quantitative image analyses (C). Mannitol treated TgCRND8 mice were indistinguishable from untreated TgCRND8 mice when plaque count was used as a measure of total plaque burden (p=0.87). Vertical bars represent S.E.M. Kaplan-Meier Cumulative survival plots for TgCRND8 mice treated and untreated with mannitol (D). The two cohorts of animals, n=35 per group, were not significantly different as determined by the Tarone-Ware statistical test, p=0.87. -
FIGS. 12A and B show the results of a spatial reference memory test in the treatment studies when performed in a 3-day trial paradigm. The performance of scyllo-inositol treated TgCRND8 mice was comparable to scyllo-inositol treated non-Tg littermates (p=0.38; A). In agreement, scyllo-inositol treated TgCRND8 mice remained indistinguishable from non-Tg littermates after two months of treatment (p=0.67; B). -
FIGS. 13A and B show Aβ levels within the CNS after administration of various doses of scyllo-inositol were administered once daily for one month to five month old TgCRND8 mice. Soluble Aβ42 levels were decreased at all doses and were significantly different from untreated controls (A). In contrast, insoluble Aβ42 was not significantly different under all conditions (B). Vertical bars represent S.E.M. -
FIG. 14 . TgCRND8 mice administered various doses of scyllo-inositol once daily for one month were analyzed for levels of brain Aβ40. No difference was detected in soluble (A) and insoluble (B) levels of Aβ40 of untreated and scyllo-inositol treated TgCRND8 mice at all doses examined. -
FIG. 15 shows the cognitive performance of 6-month old allo-inositol-treated TgCRND8 mice compared with that of their non-transgenic littermates. -
FIGS. 6A-D show that at 2 months of age, the plaque burden in TgPS1×APP mice is decreased in scyllo-inositol treated mice. Control animals have a high plaque load in the hippocampus (A) and cerebral cortex (B). Scyllo-inositol treatment significantly decreased amyloid burden (C, D). Plaque burden identified using anti-Aβ antibody (brown).Scale Bar 300 μm. -
FIGS. 7A-C show the quantification of the plaque burden in TgPS1×APP mice after scyllo-inositol treatment. The percent brain area covered in plaques (A), mean plaque size (B) and plaque count (C) were significantly reduced. Vertical bars are S.E.M. - The present invention discloses novel, unpredictable and unexpected properties of certain inositol stereoisomers in relation to the treatment of amyloid-related disorders such as Alzheimer's Disease.
- It has been surprisingly discovered that certain stereoisomers of inositol and related compounds block Aβ-induced progressive cognitive decline and cerebral amyloid plaque pathology, and improve survival when given to a transgenic mouse model of human Alzheimer Disease during the nascent phase of Aβ deposition.
- As disclosed above, previous data suggested that some, but not all, inositol stereoisomers might have an effect on amyloid aggregation in cultured neuronal cells in vitro (McLaurin et al., J. Biol. Chem. 275(24): 18495-18502 (2000)). Those observations did not provide any method to predict which, if any, of the studied stereoisomers (myo-, epi-, scyllo- and chiro-inositols) would have such effects, nor whether any other stereoisomers would have such effects. Also, those studies could not predict if any inositol stereoisomers would have effects on amyloid deposition, cognitive defects or lifespan in vivo. The present invention describes the unpredictable results that only certain inositol stereoisomers, in particular scyllo- and allo-inositols reduce amyloid plaque burden, improve cognition and increase lifespan in animal models of amyloid-related disorders, whereas others studied did not have such effects.
- Previous studies also suggested only that certain inositol stereoisomers (e.g. epi- and scyllo-inositols) might inhibit de novo amyloid aggregation in vitro. The present invention describes the unexpected results that scyllo-inositol inhibits already established cerebral amyloid deposition, and does so in the living brain. This is not implied by the previously published in vitro data which considered only certain neuronal cell types in culture, not the complex tissues of the living brain, and only suggested that inositols might inhibit de novo aggregation, thereby having no relevance to established disease.
- Previous in vitro data also suggested that epi- and scyllo-inositol administration affects amyloid Aβ40 levels as well as Aβ42 levels. The in vivo dosing study of the present invention revealed the unpredictable result that administration of allo- or scyllo-inositol specifically reduced Aβ42 levels, whereas insoluble Aβ42 and either soluble or insoluble Aβ40 levels were unaffected.
- The observation of the present invention showing changes in glial activity and inflammation is novel and surprising, and could not have been predicted by the in vitro data previously published.
- The observation of the present invention demonstrating that scyllo-inositol improves lifespan in transgenic model animals is also novel and surprising, since no drug for Alzheimer's Disease has previously been shown to increase survival and extend lifespan in vivo.
- Preferably, the compounds of the present invention are 1,2,3,4,5,6-cyclohexanehexyls, more preferably selected from the group of cis-, epi-, allo-, muco-, neo-, scyllo-, D-chiro- and L-chiro-inositols.
- Also preferably, these compounds are 1,2,3,4,5-cyclohexanepentols (quercitols), more preferably selected from the group of epi-, vibo-, scyllo-, allo-, talo-, gala-, cis-, muco-, neo-, proto-quercitols and enantiomers thereof.
- Also preferably, these compounds are selected from the group of a cyclohexanetetrol, a cyclohexanetriol, stereoisomer of cyclohexanetetrol, stereoisomer of cyclohexanetriol, enantiomer of cyclohexanetetrol, and enantiomer of cyclohexanetriol.
- These compounds may also be compound is pentahydxycyclohexanones or stereoisomers or enantiomers thereof.
- Yet again preferably, these compounds are inosose compounds selected from the group of scyllo-inosose, L-chiro-inosose-1 and L-epi-inosose.
- Also preferably, these compounds are trihydroxyxcyclohexanones, or stereoisomers or enantiomers thereof. More preferably, (−)-1-deoxy-scyllo-inosose.
- Also preferably, these compounds are pentahydxycyclohexanones (inosose), or stereoisomers or enantiomers thereof, more preferably selected from the group of scyllo-inosose, L-chiro-inosose-1 and L-epi-inosose.
- Optionally, these compounds are trihydroxyxcyclohexanones or stereoisomers or enantiomers thereof such as (−)-1-deoxy-scyllo-inosose.
- Also preferably, these compounds are O-monomethyl-cyclohexanehexyls or stereoisomers or enantiomers thereof, more preferably selected from the group of D-pinitol, L-quebrachitol and D-bornesitol.
- Again, these compounds may be selected from the group of monoaminocyclohexanepentols (inosamines), diaminocyclohexanetetrols (inosadiamines), diaminocyclohexanetriols, stereoisomers thereof, and enantiomers thereof, and pharmaceutically acceptable salts thereof such as L-neo-inosamine, D,L-epi-inosamine-2, streptamine and deoxystreptamine.
- Yet again preferably, these compounds are monomercapto-cyclohexanepentols or stereoisomers or enantiomers thereof, more preferably 1L-1-deoxy-1-mercapto-8-O-methyl-chiro-inositol.
- The most preferred compounds of the present invention are allo-inositol and scyllo-inositol, with scyllo-inositol being the most preferred. As indicated above, the inositol stereoisomers of the present invention exclude myo-inositol and may also exclude epi-inositol.
- Even when given after the amyloid pathology has been well established for several months, these compounds effectively reverse cerebral Aβ accumulation and amyloid pathology.
- Accordingly, these compounds are found to be useful in treating or preventing in a subject a condition of the central or peripheral nervous system or systemic organ associated with a disorder in protein folding or aggregation, or amyloid formation, deposition, accumulation, or persistence. These compounds are also found to be useful in preventing abnormal protein folding, abnormal protein aggregation, amyloid formation, deposition, accumulation, or persistence, or amyloid lipid interactions as well as causing the dissociation of abnormally aggregated proteins and/or dissolving or disrupting pre-formed or pre-deposited amyloid fibril or amyloid in a subject.
- Preferably, the condition of the central or peripheral nervous system or systemic organ results in the deposition of proteins, protein fragments and peptides in beta-pleated sheats and/or fibrils and/or aggregates. More preferably, the condition of the central or peripheral nervous system or systemic organ is selected from the group of: Alzheimer's disease, presenile and senile forms; amyloid angiopathy; mild cognitive impairment; Alzheimer's disease-related dementia; tauopathy; α-synucleinopathy; Parkinson's disease; Amyotrophic Lateral Sclerosis; motor neuron Disease; Spastic paraplagia; Huntington's Disease, spinocerebellar ataxia, Freidrich's Ataxia; neurodegenerative diseases associated with intracellular and/or intraneuronal aggregates of proteins with polyglutamine, polyalanine or other repeats arising from pathological expansions of tri- or tetra-nucleotide elements within corresponding genes; cerebrovascular diseases; Down's syndrome; head trauma with post-traumatic accumulation of amyloid beta peptide; Prion related disease; Familial British Dementia; Familial Danish Dementia; Presenile Dementia with Spastic Ataxia; Cerebral Amyloid Angiopathy, British Type; Presenile Dementia With Spastic Ataxia Cerebral Amyloid Angiopathy, Danish Type; Familial encephalopathy with neuroserpin inclusion bodies (FENIB); Amyloid Polyneuropathy; Inclusion Body myositis due to amyloid beta peptide; Familial and Finnish Type Amyloidosis; Systemic amyloidosis associated with multiple myeloma; Familial Mediterranean Fever; chronic infections and inflammations; and Type II Diabetes Mellitus associate with islet amyloid polypeptide (IAPP).
- Also preferably, the Alzheimer's disease-related dementias are vascular or Alzheimer dementia and tauopathy selected from the group of argyrophilic grain dementia, corticobasal degeneration, dementia pugilistica, diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism, Prion-related disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian Motor Neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and tangle only dementia.
- Also preferably, the α-synucleinopathy is selected from the group of dementia with Lewy bodies, multiple system atrophy with glial cytoplasmic inclusions, Shy-Drager syndrome, striatonigral degeneration, olivopontocerebellar atrophy, neurodegeneration with brain iron accumulation type I, olfactory dysfunction, and amyotrophic lateral sclerosis.
- Again preferably, the Motor Neuron Disease is associated with filaments and aggregates of neurofilament and/or superoxide dismutase proteins, the Spastic paraplegia is associated with defective function of chaperones and/or triple A proteins and the spinocerebellar ataxia is DRPLA or Machado-Joseph Disease.
- Also preferably, the Prion related disease is selected from the group of Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, and variant Creutzfeldt-Jakob disease and the Amyloid Polyneuropathy is Senile amyloid polyneuropathy or Systemic Amyloidosis.
- More preferably, the condition of the central or peripheral nervous system or systemic organ is Parkinson's disease including familial and non-familial types. Most preferably, said condition of the central or peripheral nervous system or systemic organ is Alzheimer's disease.
- Preferably, the compound is administered to the subject at a dose of about 1 mg to about 1 g per kg, preferably 1 mg to about 200 mg per kg, more preferably about 10 mg to about 100 mg per kg and most preferably about 30 mg to 70 mg per kg of the weight of said subject. The administration can be accomplished by a variety of ways such as orally (oral pill, oral liquid or suspension), intravenously, intramuscularly, intraperitoneally, intradermally, transcutaneously, subcutaneously, intranasally, sublingually, by rectal suppository or inhalation, with the oral administration being the most preferred. The administration of the compounds of the present invention can be undertaken at various intervals such as once a day, twice per day, once per week, once a month or continuously.
- Preferably, the compounds of the present invention are administered in combination with other treatments such as beta-secretase inhibitors, gamma-secretase inhibitors (APP-specific or non-specific), epsilon-secretase inhibitors (APP-specific or non-specific), other inhibitors of beta-sheet aggregation/fibrillogenesis/ADDL formation (e.g. Alzhemed), NMDA antagonists (e.g. memantine), non-steroidal anti-inflammatory compounds (e.g. Ibuprofen, Celebrex), anti-oxidants (e.g. Vitamin E), hormones (e.g. estrogens), nutrients and food supplements (e.g. Gingko biloba); acetylcholinesterase inhibitors (e.g. donezepil), muscarinic agonists (e.g. AF102B (Cevimeline, EVOXAC), AF150(S), and AF267B), anti-psychotics (e.g. haloperidol, clozapine, olanzapine); anti-depressants including tricyclics and serotonin reuptake inhibitors (e.g. Sertraline and Citalopram Hbr), gene therapy and/or drug based approaches to upregulate neprilysin (an enzyme which degrades Aβ); gene therapy and/or drug based approaches to upregulate insulin degrading enzyme (an enzyme which degrades Aβ), vaccines, immunotherapeutics and antibodies to Aβ (e.g. ELAN AN-1792), statins and other cholesterol lowering drugs (e.g. Lovastatin and Simvastatin), stem cell and other cell-based therapies, inhibitors of kinases (CDK5, GSK3α, GSK3β) that phosphorylate TAU protein (e.g. Lithium chloride), or inhibitors of kinases that modulate Aβ production (GSK3α, GSK3β, Rho/ROCK kinases) (e.g. lithium Chloride and Ibuprofen).
- It is believed that these other therapies act via a different mechanism and may have additive/synergistic effects with the present invention. In addition, many of these other therapies will have mechanism-based and/or other side effects which limit the dose or duration at which they can be administered alone.
- Because of their ability to bind amyloids in vivo as discussed hereinbelow in more detail, the compounds of the present invention are also useful in diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in a subject using a method that comprises administering to said subject a radioactive compound or compound tagged with a substance that emits a detectable signal in a quantity sufficient and under conditions to allow for the binding of said compound to the abnormally folded or aggregated protein and/or fibrils or amyloid, if present; and detecting the radioactivity or the signal from the compound bound to the abnormally folded or aggregated protein and/or fibrils or amyloid, thus diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid.
- Alternatively, a sample suspected of containing abnormally folded or aggregated protein and/or amyloid fibril or amyloid is collected from a subject and is contacted with a radioactive compound or compound tagged with a substance that emits a detectable signal under conditions to allow the binding of said compound to the abnormally folded or aggregated protein and/or amyloid fibril or amyloid if present; and thereafter detect the radioactivity or the signal from the compound bound to the abnormally folded or aggregated protein and/or fibrils or amyloid, thus diagnosing the presence of abnormally folded or aggregated protein and/or amyloid fibril or amyloid in said subject.
- Preferably, said detectable signal is a fluorescent or an enzyme-linked immunosorbent assay signal and said sample is whole blood (including all cellular constituents) or plasma.
- As shown hereinbelow, the compounds of the present invention can abrogate the cerebral accumulation of Aβ, the deposition of cerebral amyloid plaques, and cognitive decline in a transgenic mouse model of Alzheimer Disease when given during the “late presymptomatic” phase, prior to the onset of overt cognitive deficits and amyloid neuropathology in these mice. Furthermore, even when these compounds are given after the onset of cognitive deficits and amyloid plaque neuropathology, they can effectively reverse the amyloid deposition and neuropathology. Importantly, the mechanism of action of these compounds follows a rational design based upon their capacity to modulate the assembly of Aβ monomers into neurotoxic oligomers and/or protofibrils.
- Other advantages of the compounds of the present invention include the fact that they are transported into the CNS by both known transporters and by passive diffusion, and therefore provide ready CNS bioavailablility. Second, these compounds are catabolized to glucose. Third, as a class, these compounds generally have low toxicity profiles, and some of them have previously been given to humans albeit for a different purpose.
- TgCRND8 mice are a robust murine model of Alzheimer's disease as described by Janus et al. (Nature 408:979-982 (2000). They express a human amyloid precursor protein (APP695) transgene under the regulation of the Syrian hamster prion promoter on a C3H/B6 outbred background. The human APP695 transgene bears two mutations that cause AD in humans (K670N/M671L and V717F). Beginning at about 3 months of age, TgCRND8 mice have progressive spatial learning deficits that are accompanied by rising cerebral Aβ levels and by increasing number of cerebral extracellular amyloid plaques that are similar to those seen in the brains of humans with AD (C. Janus et al., Nature 408:979-982 (2000)).
- Age and sex-matched cohorts of TgCRND8 mice and non-transgenic littermates (n=35 in each cohort) were either untreated, or were given a compound of the present invention as indicated below at 30 mg/day/mouse beginning at age of about 6 weeks. The mice were followed for outcome measures cognitive function, brain Aβ levels, brain pathology, and survival at 4 months and 6 months of age.
- Mice—Experimental groups of TgCRND8 mice were fed myo-, epi- and scyllo-inositol at 30 mg/mouse/day. Two cohorts entered the study at 6 weeks of age and outcomes were analyzed at 4- and 6-months of age. The body weight, coat characteristics and in cage behavior was monitored. All experiments were performed according to the Canadian Council on Animal Care guidelines.
- Behavioral tests—After non-spatial pre-training, mice underwent place discrimination training for 5 days with 4 trials per day. Behavioral data was analyzed using a mixed model of factorial analysis of variance (ANOVA) with drug or genotype and training sessions as repeated measure factors.
- Cerebral amyloid burden—Brains were removed and one hemisphere was fixed in 4% paraformaldehyde and embedded in paraffin wax in the mid saggital plane. To generate sets of systematic uniform random sections, 5 μm serial sections were collected across the entire hemisphere. Sets of sections at 50 mm intervals were used for analyses (10-14 sections/set). Plaque were identified after antigen retrieval with formic acid, and incubated with primary anti-Aβ antibody (Dako M-0872), followed by secondary antibody (Dako StreptABCcomplex/horseradish kit). End products were visualized with DAB counter-stained with hematoxylin. Amyloid plaque burden was assessed using Leco IA-3001 image analysis software interfaced with Leica microscope and Hitachi KP-M1U CCD video camera. Vascular burden was analyzed similarly and a dissector was used to measure the diameter of affected vessels.
- Plasma and Cerebral Aβ Content—Hemi-brain samples were homogenized in a buffered sucrose solution, followed by either 0.4% diethylamine/100 mM NaCl for soluble Aβ levels or cold formic acid for the isolation of total Aβ. After neutralization the samples were diluted and analyzed for Aβ40 and Aβ42 using commercially available kits (BIOSOURCE International). Each hemisphere was analyzed in triplicate with the mean±SEM reported. Western blot analyses were performed on all fractions using urea gels for Aβ species analyses. Aβ was detected using 6E10 (BIOSOURCE International) and Enhanced Chemiluminenscence (Amersham).
- Analysis of APP in brain—Mouse hemi-brain samples were homogenized in 20 mM Tris pH7.4, 0.25M sucrose, 1 mM EDTA and 1 mM EGTA, and a protease inhibitor cocktail, mixed with 0.4% DEA (diethylamine)/100 mM NaCl and spun at 109,000×g. The supernatants were analysed for APPs levels by Western blotting using mAb 22C11, while the pellets were analysed for APP holoprotein using mAb C1/6.1.
- Gliosis Quantitation—Five randomly selected, evenly spaced, sagittal sections were collected from paraformaldehyde-fixed and frozen hemispheres of treated and control mice. Sections were immunolabelled for astrocytes with anti-rat GFAP IgG2a (Dako; diluted 1:50) and for microglia with anti-rat CD68 IgG2b (Dako; 1:50). Digital images were captured using a Coolsnap digital camera (Photometrics, Tuscon, Ariz.) mounted to a
Zeiss Axioscope 2 Plus microscope. Images were analysed using Openlab 3.08 imaging software (Improvision, Lexington Mass.). - Survival Census—The probability of survival was assessed by the Kaplan-Meier technique, computing the probability of survival at every occurrence of death, thus making it suitable for small sample sizes. For the analyses of survival, 35 mice were used for each treatment group. The comparison between treatments was reported using the Tarone-Ware test.
- The cognitive function of TgCRND8 mice was assessed using the spatial reference memory version of the Morris Water Maze using a five-day trial paradigm (
FIGS. 1C-1H ). Data from treated and non-treated TgCRND8 mice, and from treated and non-treated non-Tg littermates (n=10 for all combinations) were analyzed using a mixed model of analysis of variance (ANOVA) with treatment (untreated, epi- or scyllo-inositol) and genotype (TgCRND8 versus non-Tg) as ‘between-subject’ factors. TgCRND8 mice treated with either epi- or scyllo-inositol performed significantly better than untreated TgCRND8 mice (p<0.02;FIGS. 1C and D). When compared to treated or non-treated non-Tg littermates, epi-inositol treated TgCRND8 mice had a slightly slower learning curve during the first three days of training. However, after 4 days of training, epi-inositol treated TgCRND8 mice were not statistically different from their non-Tg littermates (FIG. 2E ). In contrast, scyllo-inositol treated TgCRND8 mice were indistinguishable from non-Tg littermates on all days. Thus both stereoisomers inhibited the development of cognitive deficits, and scyllo-inositol actually prevented the deficits to such a degree that the scyllo-inositol treated TgCRND8 mice were indistinguishable from normal mice. This improved performance was not due to a non-specific effect on behavioral, motoric, or perceptual systems because epi- and scyllo-inositol treatment had no effect on the performance of non-Tg mice (FIGS. 2G and 2H ). The improved performance was also not due to nutritional or caloric effects because body weight, activity, and coat condition were not different between treated and untreated cohorts. Furthermore, treatment with mannitol (a sugar of similar molecular weight) had no effect on behavior. Gender effects were not significant between any treatment group (p=0.85). - At four months of age, untreated TgCRND8 mice have a robust expression of both Aβ40 and Aβ42 (Table 1). Epi-inositol treatment as described in Example 1 reduced both Aβ40 (43±2% reduction in both soluble and insoluble pools; p≦0.05) and Aβ42 levels (69% reduction in soluble pool, p=0.005; 28% reduction in insoluble pool, p=0.02) at 4-months of age. However, these improvements were not sustained, and by 6 months of age, brain Aβ levels rose to levels similar to those observed in untreated TgCRND8 mice (Table 1).
- In contrast, at four months of age, scyllo-inositol treatment decreased total brain Aβ40 by 62% (p=0.0002) and total brain Aβ42 by 22% (p=0.0096; Table 1). At 6 months of age, scyllo-inositol treatment caused a 32% reduction in Aβ40 levels (p=0.04) and 20% reduction in Aβ42 (p=0.02) compared to untreated TgCRND8 mice.
- Because the decreased Aβ concentrations detected after inositol treatment could have resulted from altered efflux of Aβ into the plasma, Aβ-β levels in the plasma were examined at 4- and 6-months of age (Table 1). TgCRND8 mice have high plasma Aβ concentrations at 4-months of age and remain constant at 6 months of age even though CNS plaque load is still rising at 6-months of age (Table 1). Neither epi-inositol nor scyllo-inositol treatment had any effect on plasma Aβ levels in comparison to untreated TgCRND8 mice (p=0.89). The most parsimonious explanation for this observation is that the inositols have selectively altered the fibrillization of Aβ in the CNS, but have not affected β- or γ-secretase activity, or the normal mechanisms for clearance of Aβ into plasma. Nevertheless, this observation is significant for two reasons. First, a drop in plasma and CSF Aβ levels is usually detected as the clinical course progresses in untreated AD patients (Mayeux, et al., Ann. Neurol 46, 412, 2001). Secondly, patients in the AN1792 immunization study who developed a strong antibody response and an apparent clinical response did not have altered plasma Aβ-β levels (Hock et al., Neuron 38, 547 2003). Therefore, these results indicate that it is not necessary to change plasma Aβ levels to obtain an effective therapeutic outcome.
- To confirm that inositol stereoisomers had no effect on either the expression or proteolytic processing of APP, the levels of APP holo-protein, sAPP-α, and various Aβ species were examined within the brain of inositol-treated and untreated TgCRND8 mice. Consistent with our previously reported data (McLaurin, et al., Nat. Med. 8, 1263, 2002), Aβ42, Aβ40 and Aβ38 are the predominant species in the brain of TgCRND8 mice (
FIG. 3A ), and the CNS levels of immature and mature glycolyslated APP (FIG. 3B ), and of sAPP-α were indistinguishable regardless of treatment. In combination, these results indicate that epi- and scyllo-inositol have a direct and selective effect on Aβ oligomerization and not the processing of APP. - The changes in Aβ-β peptide load were accompanied by a significant decrease in plaque burden (Table 1;
FIGS. 2A-2I ). In epi-inositol treated TgCRND8 mice, there was a significant decrease in the mean plaque size at 4- but not 6-months of age compared with untreated TgCRND8 mice (95±4.3 μm2 versus 136±15 μm2, p=0.04; 370±9 μm2 versus 423±22 μm2, p=0.06, respectively). These results indicate that at modest Aβ levels, epi-inositol prevents Aβ oligomerization but once initiated at higher Aβ concentrations, epi-inositol is unable to inhibit fibrillogenesis. Scyllo-inositol treatment decreased the mean plaque size from 136±15 μm2 to 103±4 μm2 (p=0.01) at 4 months of age. In scyllo-inositol treated TgCRND8 mice at 6 months of age, the decrease in Aβ peptide levels was accompanied by a 20% reduction in plaque number (p=0.005), a 35% decrease in brain area covered with plaques (p=0.015) and a decreased mean plaque size (339±10 vs. 423±21 m2, p=0.009). These results demonstrate that by every measure there was a reduction in plaque burden after scyllo-inositol treatment. -
TABLE 1 Inositol treatment decreases Aβ40 and Aβ42 Levels Total Plaque Aβ40 Aβ42 Plaque Area/Total (ng/gm wet brain ± sem) (ng/gm wet brain ± sem) Total Plaque Area Brain Area Soluble Insoluble Soluble Insoluble Aβ Count (μm2) (%) 4 month prevention Control 75 ± 6 1163 ± 9 273 ± 18 5658 ± 248 7169 ± 284 696 ± 25 100766 ± 7564 0.026 ± 0.004 Epi-Inositol 43 ± 7* 615 ± 32† 85 ± 7† 4059 ± 179* 4802 ± 176 678 ± 64 65042 ± 5199 0.020 ± 0.001 Scyllo-Inositol 37 ± 5* 437 ± 80† 206 ± 8* 4409 ± 135* 5089 ± 173 598 ± 19* 63847 ± 2895 0.015 ± 0.001* 6 month prevention Control 187 ± 29 3576 ± 172 626 ± 87 15802 ± 237 20191 ± 211 960 ± 44 411288 ± 11912 0.120 ± 0.001 Epi-Inositol 188 ± 24 3668 ± 149 665 ± 39 13943 ± 277† 18464 ± 229 979 ± 32 380456 ± 13498 0.096 ± 0.04 Scyllo-Inositol 105 ± 8* 2453 ± 251*† 475 ± 26* 12588 ± 82† 15621 ± 151 774 ± 10*† 262379 ± 5373† 0.079 ± 0.013† Plasma Aβ Levels (pg/ml) 4 month prevention 6 month prevention Control 1018 ± 27 915 ± 59 Epi-Inositol 1082 ± 164 952 ± 56 Scyllo-Inositol 952 ± 49 905 ± 55 Anova with Fisher's PLSD, †p < 0.001 and *p < 0.05 - Astroglial and microglial reactions are neuropathological features both of human AD and of all amyloid mouse models (Irizarry et al., J Neuropathol Exp Neurol. 56, 965, 1997; K. D. Bornemann et al. Ann NY Acad Sci. 908, 260, 2000). Therefore, the effect of epi- and scyllo-inositol treatment was investigated on astrogliosis and microgliosis in the brains of TgCRND8 mice (
FIGS. 3A-3D ). Serial sagittal sections were stained with the astrocytic marker glial fibrillary acidic protein (GFAP) and quantitated for percent brain area covered by astrogliosis. TgCRND8 mice have a high basal astrogliosis at 4-months of age (0.459±0.048%), which increases slightly by 6-months of age (0.584±0.089%), and which is not restricted to plaque areas (FIGS. 2A-C ). Epi-inositol decreased the astrogliotic response to 0.388±0.039% at 6-months of age (p=0.04;FIG. 2D-F ). Scyllo-inositol, on the other hand, decreased astrogliosis much more efficiently to 0.269±0.028% at 6-months of age, (p=0.006) (FIG. 2G-I ). Microglial activation was also significantly attenuated in scyllo-inositol treated TgCRND8 mice (0.20±0.008% brain area) when compared to age- and sex-matched untreated TgCRND8 mice (0.31±0.01%; p<0.001). However, epi-inositol treated mice demonstrated no significant reduction in microglial activation at 6 months (0.248±0.02%; p=NS). Taken together these data indicate that scyllo-inositol treatment decreases the Aβ-induced inflammatory response within the CNS. - Alzheimer's disease is characterized by the presence of both parenchymal and vascular amyloid deposits. In untreated 6 month old TgCRND8 mice approximately 0.03% of the brain area is associated with vascular amyloid. No difference could be detected in the vascular amyloid burden after epi-inositol treatment at 6 months of age (
FIG. 3C ). In contrast, scyllo-inositol treatment significantly decreased the vascular amyloid burden (p=0.05) (FIG. 3C ), and the amyloid deposition was predominantly localized to smaller vessels, <25 m2 in diameter (56±2% versus 70±8% in small vessels in untreated TgCRND8 mice). The mean size of cerebrovascular plaques was significantly decreased in the scyllo-inositol treated mice in comparison to untreated mice (154±16 vs. 363±34, p=0.008;FIG. 3D ). - TgCRND8 mice have a 50% survival at 175 days, which after treatment was improved to 72% with scyllo-inositol (n=35 per group, p<0.02 for scyllo-inositol vs. control,
FIG. 10B ). Treatment with myo-inositol did not affect overall survival significantly (FIG. 10A ). Control experiments confirmed that the enhanced survival of scyllo-inositol treated mice was not an indirect effect of increased caloric intake. Thus, treatment of wild type mice with scyllo-inositol had no effect either on survival or on other parameters such as weight, fur condition or cage behavior. Furthermore, the weight, fur condition and home-cage behavior of the inositol-treated TgCRND8 mice did not vary from untreated TgCRND8 mice. Simultaneous experiments with mannitol, a simple sugar of similar molecular weight, also had no effect on survival of TgCRND8 mice. - Taken together, the prevention studies demonstrate that scyllo-inositol inhibits both parenchymal and cerebrovascular amyloid deposition and results in improved survival and cognitive function in the TgCRND8 mouse model of Alzheimer disease. However, most Alzheimer's disease patients will likely seek treatment only once symptomatic, and when Aβ oligomerization, deposition, toxicity and plaque formation are already well advanced within the CNS. A pilot study was therefore initiated on 5 month old TgCRND8 mice. These mice have significant Aβ and plaque burdens that are comparable to those in the brain of humans with AD.
- Mice—Experimental groups of TgCRND8 mice were fed myo-, epi- and scyllo-inositol at 30 mg/mouse/day. A cohort entered the study at 5 months of age and outcomes were analyzed at 6-months of age. The body weight, coat characteristics and in cage behavior was monitored. All experiments were performed according to the Canadian Council on Animal Care guidelines.
- Survival Census—The probability of survival was assessed by the Kaplan-Meier technique, computing the probability of survival at every occurrence of death, thus making it suitable for small sample sizes. For the analyses of survival, 35 mice were used for each treatment group. The comparison between treatments was reported using the Tarone-Ware test.
- Behavioral. Test—Reversal Study—Mice entered the Morris water maze test with a hidden platform on day one without pretraining. Mice were tested for 3 days with six trials per day. On the fourth day, the platform was removed from the pool and each mouse received one 30-s swim probe trial. On the last day the animals underwent a cue test in order to evaluate swimming ability, eye sight and general cognition. The cue test is composed at the platform being placed in a different quadrant than that used for testing and is tagged with a flag. Animals are allowed 60 s to find the platform. Animals that do not find the platform are not used in the final analyses of spatial memory. Behavioural data was analysed using a mixed model of factorial analysis of variance (ANOVA) with drug or genotype and training sessions as repeated measure factors.
- Cerebral amyloid burden—Brains were removed and one hemisphere was fixed in 4% paraformaldehyde and embedded in paraffin wax in the mid saggital plane. To generate sets of systematic uniform random sections, 5 μm serial sections were collected across the entire hemisphere. Sets of sections at 50 mm intervals were used for analyses (10-14 sections/set). Plaque were identified after antigen retrieval with formic acid, and incubated with primary anti-Aβ antibody (Dako M-0872), followed by secondary antibody (Dako StreptABCcomplex/horseradish kit). End products were visualized with DAB counter-stained with hematoxylin. Amyloid plaque burden was assessed using Leco IA-3001 image analysis software interfaced with Leica microscope and Hitachi KP-M1U CCD video camera.
- Plasma and Cerebral Aβ Content—Hemi-brain samples were homogenized in a buffered sucrose solution, followed by either 0.4% diethylamine/100 mM NaCl for soluble Aβ levels or cold formic acid for the isolation of total Aβ. After neutralization the samples were diluted and analyzed for Aβ40 and Aβ42 using commercially available kits (BIOSOURCE International). Each hemisphere was analyzed in triplicate with the mean±SEM reported.
- Results and Significance—All animals that entered the reversal study survived and did not display outward signs of distress or toxicity. The cognitive function of TgCRND8 mice was assessed using the spatial reference memory version of the Morris Water Maze using a three day trial paradigm (
FIGS. 4-8 ). Data from treated and non-treated TgCRND8 mice, and from treated and non-treated non-Tg littermates (n=10 for all combinations) were analyzed using a mixed model of analysis of variance (ANOVA) with treatment (untreated, myo-, epi- or scyllo-inositol) and genotype (TgCRND8 versus non-Tg) as ‘between-subject’ factors. In this paradigm TgCRND8 mice were significantly impaired in comparison to wild type littermates (FIG. 4 ). In contrast, scyllo-inositol treated TgCRND8 mice were indistinguishable from non-Tg littermates on all days. (p=0.38;FIG. 5 ). When compared to treated non-Tg littermates, epi-inositol treated TgCRND8 mice were almost significantly different (p=0.07;FIG. 6 ). Similarly, myo-inositol treated TgCRND8 mice were significantly different from treated non-Tg littermates (p=0.05,FIG. 7 ). When the learning phase of the Morris water maze test is compared between treatments, all mice behaved similarly (FIG. 8 ). In contrast, only scyllo-inositol was indistinguishable from non-Tg littermates (FIG. 8 ). Thus, scyllo-inositol actually reversed the cognitive deficits to such a degree that the scyllo-inositol treated TgCRND8 mice were indistinguishable from normal mice. This improved performance was not due to a non-specific effect on behavioral, motoric, or perceptual systems because epi- and scyllo-inositol treatment had no effect on the performance of non-Tg mice. The improved performance was also not due to nutritional or caloric effects because body weight, activity, and coat condition were not different between treated and untreated cohorts. - In order to determine if the improved cognition was associated with decreased plaque burden and Aβ load, brain tissue was examined post-mortem. The changes in cognition were accompanied by a corresponding change in plaque burden and Aβ load (
FIG. 9 and Table 2). Myo-inositol treatment did not affect the plaque burden or A load (FIG. 9 and Table 2). In epi-inositol treated TgCRND8 mice, there was not a significant decrease in the mean plaque size compared with untreated TgCRND8 mice (FIG. 9 ), yet the Aβ load was significantly decreased (Table 2). These results suggest that at modest Aβ levels, epi-inositol prevents Aβ oligomerization but at higher Aβ concentrations, epi-inositol is unable to inhibit fibrillogenesis completely. Scyllo-inositol treatment significantly decreased the plaque burden and the Aβ load. These results demonstrate that by every measure there was a reduction in plaque burden after scyllo-inositol treatment. These results are comparable in effect size to the 6-month prophylactic studies, and further support the potential for scyllo-inositol. - Because the decreased Aβ concentrations detected after inositol treatment could have resulted from altered efflux of Aβ into the plasma, we examined Aβ levels in the plasma (Table 2). TgCRND8 mice have high plasma Aβ concentrations at 6 months of age. Neither myo-inositol, epi-inositol nor scyllo-inositol treatment had any effect on plasma Aβ levels in comparison to untreated TgCRND8 mice (p=0.89). The most parsimonious explanation for this observation is that the inositols have selectively altered the fibrillization of Aβ in the CNS, but have not affected β- or γ-secretase activity, or the normal mechanisms for clearance of Aβ into plasma. Nevertheless, this observation is significant for two reasons. First, a drop in plasma and CSF Aβ levels is usually detected as the clinical course progresses in untreated AD patients. Secondly, patients in the AN1792 immunization study who developed a strong antibody response and an apparent clinical response did not have altered plasma Aβ levels. Therefore, these results further indicate that it is not necessary to change plasma Aβ levels to obtain an effective therapeutic outcome.
- Taken together, these data reveal that selected scyllo-inositol can abrogate the cerebral accumulation of Aβ, the deposition of cerebral amyloid plaques, and cognitive decline in a transgenic mouse model of Alzheimer Disease when given during the “late presymptomatic” phase, prior to the onset of overt cognitive deficits and amyloid neuropathology in these mice. Furthermore, even when scyllo-inositol is given after the onset of cognitive deficits and amyloid plaque neuropathology, these compounds can effectively reverse the amyloid deposition, neuropathology and cognitive deficits. Therefore, these results indicate that scyllo-inositol is effective at both prevention of disease and in the treatment of existing disease in patients already diagnosed with AD.
-
TABLE 2 Inositol treatment decreases Aβ40 and Aβ42 Levels Total Plaque Aβ40 Aβ42 Plaque Area/Total (ng/gm wet brain ± sem) (ng/gm wet brain ± sem) Total Plaque Area Brain Area Soluble Insoluble Soluble Insoluble Aβ Count (μm2) (%) 4 month prevention Control 75 ± 6 1163 ± 9 273 ± 18 5658 ± 248 7169 ± 284 696 ± 25 100766 ± 7564 0.026 ± 0.004 Myo-Inositol 42 ± 6 485 ± 143 174 ± 9 4268 ± 308 4969 ± 434 649 ± 50 91902 ± 7453 0.023 ± 0.004 Epi-Inositol 43 ± 7* 615 ± 32† 85 ± 7† 4059 ± 179* 4802 ± 176 678 ± 64 65042 ± 5199 0.020 ± 0.001 Scyllo-Inositol 37 ± 5* 437 ± 80† 206 ± 8* 4409 ± 135* 5089 ± 173 598 ± 19* 63847 ± 2895 0.015 ± 0.001* 6 month prevention Control 187 ± 29 3576 ± 172 626 ± 87 15802 ± 237 20191 ± 211 960 ± 44 411288 ± 11912 0.120 ± 0.001 Myo-Inositol 221 ± 19 3436 ± 189 543 ± 71 13289 ± 535 17489 ± 354 927 ± 78 400013 ± 19638 0.100 ± 0.005 Epi-Inositol 188 ± 24 3668 ± 149 665 ± 39 13943 ± 277† 18464 ± 229 979 ± 32 380456 ± 13498 0.096 ± 0.04 Scyllo-Inositol 105 ± 8* 2453 ± 251*† 475 ± 26* 12588 ± 82† 15621 ± 151 774 ± 10*† 262379 ± 5373† 0.079 ± 0.013† 1 month treatment Control 207 ± 16 4965 ± 457 426 ± 14 14503 ± 1071 20101 ± 854 1441 ± 29 486002 ± 16156 0.159 ± 0.014 Myo-Inositol 194 ± 12 4187 ± 226 487 ± 25 15622 ± 675 20490 ± 526 1324 ± 69 469968 ± 35664 0.153 ± 0.088 Epi-Inositol 264 ± 11 3637 ± 113 540 ± 14 12830 ± 330 17271 ± 415 1342 ± 114 459706 ± 49966 0.134 ± 0.017 Scyllo-Inositol 178 ± 11 3527 ± 241 374 ± 23 11115 ± 647 15194 ± 579 1260 ± 27* 420027 ± 14986* 0.119 ± 0.010* Plasma Aβ Levels (pg/ml) 4 month prevention 6 month prevention 1 month treatment Control 1018 ± 27 915 ± 59 2287 ± 151 Myo-Inositol 942 ± 30 969 ± 67 2110 ± 174 Epi-Inositol 1082 ± 164 952 ± 56 2158 ± 157 Scyllo-Inositol 952 ± 49 905 ± 55 1980 ± 146 Anova with Fisher's PLSD, †p < 0.001 and *p < 0.05; IP = in progress. - In order to determine longer efficacy ranges of scyllo-inositol for the treatment of disease, 5-month old TgCRND8 mice were fed scyllo-inositol or untreated for two months (n=10 per group). The cognitive function of 7-month old TgCRND8 mice treated with scyllo-inositol was compared to untreated TgCRND8 and treated non-Tg littermates in the three-day paradigm of the Morris Water Maze. Behavioural data was analysed using a mixed model of factorial analysis of variance (ANOVA) with drug and genotype as between subject variables and training sessions as within subject variable. As was seen with the 1-month treatment of scyllo-inositol (
FIG. 12A ), TgCRND8 mice treated for two months with scyllo-inositol were indistinguishable from scyllo-inositol treated non-Tg littermates (FIG. 12B ). In order to correlate the improved cognition with pathology, Aβ40 and Aβ42 levels were analysed in the brain (Table 3). Both insoluble Aβ40 and Aβ42 levels were decreased 20% after scyllo-inositol treatment. These results demonstrate that scyllo-inositol effects persist during disease progression. -
TABLE 3 Inositol treatment decreases Aβ40 and Aβ42 Levels Brain Aβ40 Brain Aβ42 Plasma (ng/gm wet (ng/gm wet Aβ Levels brain ± sem) brain ± sem) (pg/ml) 2 month treatment Soluble Insoluble Soluble Insoluble Aβ40 Aβ42 Control 487 ± 14 6924 ± 287 764 ± 51 25827 ± 1238 5212 ± 219 3455 ± 331 Scyllo-inositol 395 ± 60 5703 ± 612* 688 ± 28 20818 ± 1404* 4507 ± 207 3035 ± 236 ANOVA with Fisher's PLSD, *p < 0.05. - 5-month old TgCRND8 mice were gavaged once daily with scyllo-inositol in water at doses of 10 mg/Kg, 30 mg/Kg, 100 mg/Kg or untreated. Animals were sacrificed after one month of treatment and analysed for pathological outcomes. Analysis of the levels of Aβ within the brain of all the cohorts demonstrates that all drug doses were effective to the same extent on lowering soluble Aβ42 levels in comparison to untreated TgCRND8 mice (20% reduction, F3,15=3.1, p=0.07;
FIG. 13A ). Analyses of individual doses demonstrate that 10 mg/Kg and 30 mg/Kg doses were significantly different from untreated controls (p=0.03 and p=0.02, respectively). None of the doses chosen were significantly different from each other (F2,11=0.6, p=0.57;FIG. 13A ). Gavage dosing had no significant effect on insoluble Aβ42 (F3,15=0.69, p=0.58;FIG. 13B ) or soluble and insoluble Aβ40 (F3,15=0.04, p=0.99 and F3,15=0.36, p=0.79, respectively;FIGS. 14A and 14B ). - To assess whether allo-inositol might also be effective in preventing further progression and/or might partially reverse a well-established AD-like phenotype, the start of treatment of the TgCRND8 mice was delayed until 5 months of age. Cohorts of TgCRND8 and non-transgenic littermates were either treated for 28 days with allo-inositol, or were untreated. In these experiments, the dosage and oral administration of compounds, and the behavioral and neurochemical assays were the same as those employed in the above treatment experiments.
- The cohort of 6-month old allo-inositol-treated TgCRND8 mice performed significantly better than untreated TgCRND8 mice (F1,13=0.45, p=0.05; data not shown). The cognitive performance of 6-month old allo-inositol-treated TgCRND8 mice was still significantly different from that of their non-transgenic littermates (F1,13=5.9, p=0.05;
FIG. 15 ). The beneficial effect of inositol treatment was not due to non-specific effects on behavioral, motor, or perceptual systems because inositol treatment had no effect on the cognitive performance of non-Tg mice (F1,12=0.98; p=0.49). Cerebral Aβ levels were analyzed for treatment versus untreated TgCRND8 mice to determine whether improved behavior could be correlated with changes in Aβ (Table 4). Allo-inositol treatment reduced soluble Aβ42 (20% reduction, p<0.05) an effect similar to that seen for scyllo-inositol. Allo-inositol did not significantly alter insoluble Aβ42 or Aβ40 (soluble and insoluble pools). One possible explanation for the decrease in Aβ42 is clearance of Aβ42 in the periphery with a subsequent increase in plasma Aβ42. The levels of Aβ42 in plasma after allo-inositol treatment were indistinguishable from untreated TgCRND8 plasma levels (Table 5). In agreement with the other inositol stereoisomers, these results demonstrate that plasma Aβ levels are unaffected by allo-inositol treatment. -
TABLE 4 Allo-Inositol treatment decreases Aβ42 levels Brain Aβ40 Brain Aβ42 (ng/gm wet (ng/gm wet Plasma brain ± sem) brain ± sem) Aβ Levels 1 month treatment Soluble Insoluble Soluble Insoluble (pg/ml) Control 252 ± 48 4105 ± 851 666 ± 39 16448 ± 2120 2359 ± 147 Allo-inositol 281 ± 21 3787 ± 342 547 ± 47* 16336 ± 910 2458 ± 95 ANOVA with Fisher's PLSD, *p < 0.05. -
TABLE 5 Blood Biochemistry - scyllo-inositol Dose Study Untreated 100 mg/Kg 30 mg/Kg 10 mg/Kg Reference Levels Biochemistry n = 4 n = 4 n = 3 n = 5 (Vita-Tech & CCAC) Total protein 46 ± 2 g/L 49 ± 2 50 ± 2.6 50 ± 3 35-72 Albumin 35 ± 0 g/L 31 ± 1 33 ± 2 33 ± 4 25-48 Globulin 12 ± 1 g/L 19 ± 2 17 ± 1 17 ± 2 18-82 Bilirubin 2.4 ± 1 umol/L 1.9 ± 0 2.0 ± 1 1.9 ± 0.6 2-15 ALP 81 ± 10 U/L 76 ± 11 81 ± 10 73 ± 22 28-94 ALT 42 ± 4 U/L 38 ± 4 42 ± 4 51 ± 20 28-184 Glucose 11 ± 2 mmol/L 11 ± 2 12 ± 2 7 ± 2 9.7-18.6 Urea 9 ± 3 mmol/L 7.4 ± 1 9 ± 3 10 ± 2 12.1-20.6 Creatinine 36 ± 5 umol/L 31 ± 4 35 ± 5 40 ± 5 26-88 Hemolysis Normal Normal Normal Normal Icteria Normal Normal Normal Normal Lipemia Normal Normal Normal Normal - In order to rule out any deleterious effects of inositol treatment on blood chemistry and organ function, blood was analyzed after one month treatment with both scyllo- and allo-inositol (Table 5,6). The total protein, albumin, globulin, bilirubin, alkaline phosphatase, glucose, urea and creatinine were not significantly different between treatment groups or from untreated TgCRND8 mice. All levels fell within the normal range as determined for non-transgenic wild type mice. In addition hemolysis, icteria and lipemia were all normal. These results suggest that allo- and scyllo-inositol do not exhibit obvious deleterious effects on blood chemistry or organ function.
-
TABLE 6 Blood Biochemistry - 1 Month Treatment Study Untreated Allo-Inositol Reference Levels Biochemistry n = 4 n = 4 (Vita-Tech & CCAC) Total protein 46 ± 2 g/L 48 ± 2 35-72 Albumin 35 ± 0 g/L 32 ± 2 25-48 Globulin 12 ± 1 g/L 17 ± 3 18-82 Bilirubin 2.4 ± 1 umol/L 2.9 ± 3 2-15 ALP 81 ± 10 U/L 95 ± 16 28-94 ALT 42 ± 4 U/L 44 ± 4 28-184 Glucose 11 ± 2 mmol/L 10 ± 3 9.7-18.6 Urea 9 ± 3 mmol/L 18.6 ± 13 12.1-20.6 Creatinine 36 ± 5 umol/L 69 ± 64 26-88 Hemolysis Normal Normal Icteria Normal Normal Lipemia Normal Normal - Tg PS1×APP mice are an enhanced model of Alzheimer's disease which express a mutant human PS1 transgene encoding two familial mutations (M146L and L286V) in conjunction with the human APP transgene encoding the Indiana and Swedish familial mutations. These animals develop robust expression of cerebral Aβ levels and amyloid deposition by 30-45 days of age. In a prophylactic trial, TgPS1×APP mice were treated with scyllo-inositol from weaning and were assessed for effects on neuropathology at 2 months of age (
FIGS. 16 and 17 ). Compared with untreated TgPS1×APP mice, scyllo-inositol treated TgPS1×APP mice displayed a significant decrease in all measures of plaque burden at 2 months of age (% brain area covered in plaques=0.157±0.007 vs 0.065±0.016, p<0.001; mean plaque size=177±8 μm2 vs 149±5 μm2, p<0.05; plaque count 3054±324 vs 1514±510, p<0.01; (FIG. 17 ). These results demonstrate that scyllo-inositol prevents amyloid deposition in two robust models of Alzheimer's disease. - In order to rule out the contribution of increased caloric intake or non-specific effects, TgCRND8 mice were treated with a simple sugar of similar molecular weight, mannitol. At 6 months of age, mannitol treated TgCRND8 mice were indistinguishable from untreated TgCRND8 mice (
FIG. 11A ) and were significantly different from mannitol treated non-Tg littermates (FIG. 11B ). Mannitol had no effect on the behaviour of non-Tg mice, since mannitol treated non-Tg mice were indistinguishable from untreated non-Tg mice. These results correlate with the pathological studies that indicate mannitol did not alter the plaque load in TgCRND8 mice (FIG. 11C ). Simultaneous monitoring of survival demonstrated that mannitol had no effect on the survival of TgCRND8 mice (FIG. 11D ). - Although the present invention has been described in relation to particular embodiments thereof, many other variations and modifications and other uses will become apparent to those skilled in the art. The present invention therefore is not limited by the specific disclosure herein, but only by the appended claims.
Claims (2)
1. A method of treating or preventing in a subject a condition of the central or peripheral nervous system or systemic organ associated with a disorder in protein folding or aggregation, or amyloid formation, deposition, accumulation, or persistence comprising administering to said subject a pharmaceutically effective amount of a compound having the following structure:
wherein each of R1, R1′, R2, R2′, R3, R3′, R4, R4′, R5, R5′, R6, and R6′ is independently selected from the group of:
(a) hydrogen atom;
(b) NHR7, wherein said R7 is selected from the group of hydrogen; C2-C10 acyl and C1-C10 alkyl;
(c) NR8R9, wherein said R8 is C2-C10 acyl or C1-C10 alkyl and said R9 is C2-C10 acyl or C1-C10 alkyl;
(d) OR10, wherein said R10 is selected from the group of no group, hydrogen, C2-C10 acyl, C1-C10 alkyl and SO3H;
(e) C5-C7 glycosyl;
(f) C3-C8 cycloalkyl optionally substituted with a substituent selected from the group of hydrogen, OH, NH2, SH, OSO3H and OPO3H2;
(g) SR11, wherein R11 is selected from the group of hydrogen, C1-C10 alkyl and O3H;
(h) C1-C10 alkyl optionally substituted with a substituent selected from the group of hydrogen, OR10, NHR7, NR8R9 and SR11; and
(i) C3-C8 cycloalkyl optionally substituted with a substituent selected from the group of hydrogen, OR10, NHR7, NR8, R9 and SR11,
providing that the compound is not myo-inositol.
2-201. (canceled)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/396,515 US20090227686A1 (en) | 2003-02-27 | 2009-03-03 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US13/408,337 US20120157549A1 (en) | 2003-02-27 | 2012-02-29 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US14/016,733 US20140073701A1 (en) | 2003-02-27 | 2013-09-03 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US14/608,617 US9833420B2 (en) | 2003-02-27 | 2015-01-29 | Methods of preventing, treating, and diagnosing disorders of protein aggregation |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US45136303P | 2003-02-27 | 2003-02-27 | |
US52095803P | 2003-11-17 | 2003-11-17 | |
US52353403P | 2003-11-19 | 2003-11-19 | |
US10/787,621 US7521481B2 (en) | 2003-02-27 | 2004-02-26 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US12/396,515 US20090227686A1 (en) | 2003-02-27 | 2009-03-03 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/787,621 Continuation US7521481B2 (en) | 2003-02-27 | 2004-02-26 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/408,337 Continuation US20120157549A1 (en) | 2003-02-27 | 2012-02-29 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
Publications (1)
Publication Number | Publication Date |
---|---|
US20090227686A1 true US20090227686A1 (en) | 2009-09-10 |
Family
ID=32931587
Family Applications (7)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/787,621 Active 2026-04-30 US7521481B2 (en) | 2003-02-27 | 2004-02-26 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US10/547,286 Active 2027-11-20 US8859628B2 (en) | 2003-02-27 | 2004-02-27 | Method for preventing, treating and diagnosing disorders of protein aggregation |
US12/396,515 Abandoned US20090227686A1 (en) | 2003-02-27 | 2009-03-03 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US13/408,337 Abandoned US20120157549A1 (en) | 2003-02-27 | 2012-02-29 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US14/016,733 Abandoned US20140073701A1 (en) | 2003-02-27 | 2013-09-03 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US14/475,859 Abandoned US20150031776A1 (en) | 2003-02-27 | 2014-09-03 | Method of preventing, treating and diagnosing disorders of protein aggregation |
US14/608,617 Expired - Lifetime US9833420B2 (en) | 2003-02-27 | 2015-01-29 | Methods of preventing, treating, and diagnosing disorders of protein aggregation |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/787,621 Active 2026-04-30 US7521481B2 (en) | 2003-02-27 | 2004-02-26 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US10/547,286 Active 2027-11-20 US8859628B2 (en) | 2003-02-27 | 2004-02-27 | Method for preventing, treating and diagnosing disorders of protein aggregation |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/408,337 Abandoned US20120157549A1 (en) | 2003-02-27 | 2012-02-29 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US14/016,733 Abandoned US20140073701A1 (en) | 2003-02-27 | 2013-09-03 | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US14/475,859 Abandoned US20150031776A1 (en) | 2003-02-27 | 2014-09-03 | Method of preventing, treating and diagnosing disorders of protein aggregation |
US14/608,617 Expired - Lifetime US9833420B2 (en) | 2003-02-27 | 2015-01-29 | Methods of preventing, treating, and diagnosing disorders of protein aggregation |
Country Status (15)
Country | Link |
---|---|
US (7) | US7521481B2 (en) |
EP (4) | EP2823813A1 (en) |
JP (4) | JP4999453B2 (en) |
AT (1) | ATE432694T1 (en) |
AU (2) | AU2004216544B2 (en) |
BR (1) | BRPI0407910A (en) |
CA (1) | CA2516563C (en) |
CY (2) | CY1109338T1 (en) |
DE (1) | DE602004021362D1 (en) |
DK (3) | DK2311445T3 (en) |
ES (3) | ES2520047T3 (en) |
IL (2) | IL170476A (en) |
PT (3) | PT2311445E (en) |
SI (3) | SI1608350T1 (en) |
WO (1) | WO2004075882A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110201060A1 (en) * | 2010-02-15 | 2011-08-18 | Abbott Laboratories | Process for the preparation of scyllo-inositol |
US9833420B2 (en) | 2003-02-27 | 2017-12-05 | JoAnne McLaurin | Methods of preventing, treating, and diagnosing disorders of protein aggregation |
Families Citing this family (60)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2003291063A1 (en) * | 2002-11-19 | 2004-06-15 | Board Of Trustees Operating Michigan State University | Antioxidant and antimicrobial agents and methods of use thereof |
US9592258B2 (en) | 2003-06-27 | 2017-03-14 | DePuy Synthes Products, Inc. | Treatment of neurological injury by administration of human umbilical cord tissue-derived cells |
US7510873B2 (en) | 2003-06-27 | 2009-03-31 | Ethicon, Incorporated | Postpartum cells isolated from umbilical cord tissue, and methods of making and using the same |
US8790637B2 (en) | 2003-06-27 | 2014-07-29 | DePuy Synthes Products, LLC | Repair and regeneration of ocular tissue using postpartum-derived cells |
US9572840B2 (en) | 2003-06-27 | 2017-02-21 | DePuy Synthes Products, Inc. | Regeneration and repair of neural tissue using postpartum-derived cells |
WO2005009291A2 (en) * | 2003-07-23 | 2005-02-03 | Synapse Biomedical, Inc. | System and method for conditioning a diaphragm of a patient |
US9017724B2 (en) | 2004-02-24 | 2015-04-28 | The General Hospital Corporation | Catalytic radiofluorination |
US8257680B1 (en) | 2004-02-24 | 2012-09-04 | The General Hospital Corporation | Catalytic radiofluorination |
US8193250B2 (en) * | 2004-10-22 | 2012-06-05 | Mount Sinai School Of Medicine | Compositions and methods for treating alzheimer's disease and related disorders and promoting a healthy nervous system |
JP2008520589A (en) * | 2004-11-17 | 2008-06-19 | ジョアン マクローリン, | Compositions comprising sylinositol derivatives and methods for treating protein aggregation disorders |
AU2006202209B2 (en) * | 2005-05-27 | 2011-04-14 | Lifescan, Inc. | Amniotic fluid derived cells |
US9050005B2 (en) | 2005-08-25 | 2015-06-09 | Synapse Biomedical, Inc. | Method and apparatus for transgastric neurostimulation |
EP1940373B8 (en) * | 2005-10-13 | 2015-06-24 | Waratah Pharmaceuticals, Inc. | 1-fluoro-1-deoxy-scyllo-inositol for the treatment of alzheimer's disease |
ES2407429T3 (en) * | 2005-12-12 | 2013-06-12 | Ac Immune S.A. | Therapeutic Vaccine |
CA2642647A1 (en) * | 2006-02-17 | 2007-11-15 | Joanne Mclaurin | Compositions and methods for treatment of disorders of protein aggregation |
EP1996284A2 (en) | 2006-03-09 | 2008-12-03 | Synapse Biomedical, Inc. | Ventilatory assist system and method to improve respiratory function |
BRPI0708725A2 (en) * | 2006-03-09 | 2011-06-07 | Waratah Pharmaceuticals Inc | cyclohexane polyalcohol formulation for the treatment of protein aggregation diseases |
CA2655632A1 (en) * | 2006-06-23 | 2008-01-03 | The Feinstein Institute For Medical Research | Inhibitors of a.beta. and synuclein aggregation |
US20080097153A1 (en) * | 2006-08-24 | 2008-04-24 | Ignagni Anthony R | Method and apparatus for grasping an abdominal wall |
WO2008034244A1 (en) * | 2006-09-21 | 2008-03-27 | Waratah Pharmaceuticals Inc. | The combination of a cyclohexanehexol and a nsaid for the treatment of neurodegenerative diseases |
US20080103116A1 (en) * | 2006-11-01 | 2008-05-01 | Jennings-Spring Barbara L | Method of treatment and compositions of D-chiro inositol and phosphates thereof |
US20110218176A1 (en) | 2006-11-01 | 2011-09-08 | Barbara Brooke Jennings-Spring | Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development |
US20090214474A1 (en) * | 2006-11-01 | 2009-08-27 | Barbara Brooke Jennings | Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development |
EP2091566A4 (en) * | 2006-11-24 | 2011-07-06 | Waratah Pharmaceuticals Inc | Combination treatments for alzheimer's disease and similar diseases |
US9079016B2 (en) * | 2007-02-05 | 2015-07-14 | Synapse Biomedical, Inc. | Removable intramuscular electrode |
JP2010518064A (en) | 2007-02-12 | 2010-05-27 | メルク・シャープ・エンド・ドーム・コーポレイション | Piperazine derivatives for the treatment of AD and related conditions |
CA2683548A1 (en) * | 2007-04-12 | 2008-10-23 | Joanne Mclaurin | Use of cyclohexanehexol derivatives for the treatment of polyglutamine diseases |
US20100168250A1 (en) * | 2007-04-12 | 2010-07-01 | Antonio Cruz | Use of cyclohexanehexol derivatives in the treatment of ocular disease |
CA2683546A1 (en) * | 2007-04-12 | 2008-10-23 | Joanne Mclaurin | Use of cyclohexanehexol derivatives in the treatment of .alpha.-synucleinopathies |
CA2683580A1 (en) * | 2007-04-12 | 2008-10-23 | Joanne Mclaurin | Treatment of amyotrophic lateral sclerosis |
US9820671B2 (en) * | 2007-05-17 | 2017-11-21 | Synapse Biomedical, Inc. | Devices and methods for assessing motor point electromyogram as a biomarker |
US8428726B2 (en) | 2007-10-30 | 2013-04-23 | Synapse Biomedical, Inc. | Device and method of neuromodulation to effect a functionally restorative adaption of the neuromuscular system |
WO2009059033A1 (en) * | 2007-10-30 | 2009-05-07 | Synapse Biomedical, Inc. | Method of improving sleep disordered breathing |
US20090131857A1 (en) * | 2007-11-20 | 2009-05-21 | Mark Geiger | Method and apparatus for introducing a medicinal dose directly into a mammalian patient's cerebrospinal fluid |
AT506535B1 (en) * | 2008-02-22 | 2010-04-15 | Affiris Forschungs & Entwicklungs Gmbh | VACCINE CONTAINING ALPHA SYNUCLEIN MIMOTOPES BASED ON PEPTIDES |
CA2978149C (en) * | 2008-03-21 | 2019-02-12 | The General Hospital Corporation | Inositol derivatives for the detection and treatment of alzheimer's disease and related disorders |
KR101021078B1 (en) | 2008-07-22 | 2011-03-14 | 포항공과대학교 산학협력단 | Inositol or trehalos derivatives and a pharmaceutical composition for treating neurodegenerative diseases containing same |
EP2349233A4 (en) * | 2008-10-09 | 2012-04-18 | Waratah Pharmaceuticals Inc | Use of scyllo-inositols for the treatment of macular degeneration-related disorders |
GB0821994D0 (en) * | 2008-12-02 | 2009-01-07 | Ge Healthcare Ltd | In viva imaging method |
US8722034B2 (en) | 2009-03-26 | 2014-05-13 | Depuy Synthes Products Llc | hUTC as therapy for Alzheimer's disease |
US20100249073A1 (en) * | 2009-03-27 | 2010-09-30 | Robert Sabin | Prophylactic and therapeutic treatment of Alzheimer's disease using phytic acid and phytate to reduce amyloid beta plaque and tau protein |
AU2011316540A1 (en) | 2010-10-13 | 2014-04-10 | Elan Pharmaceuticals, Inc. | Methods of synthesis of scyllitol and related compounds |
WO2012061786A1 (en) | 2010-11-05 | 2012-05-10 | Brandeis University | Ice cleaved alpha-synuclein a biomarker |
JP2014515408A (en) * | 2011-06-03 | 2014-06-30 | エラン ファーマシューティカルズ,リミティド ライアビリティー カンパニー | Scyllo-inositol for the treatment of behavioral and mental disorders |
KR101365711B1 (en) * | 2013-04-30 | 2014-02-21 | 재단법인 경북해양바이오산업연구원 | A new biosurfactant isolated from yeast |
EP3161018A4 (en) | 2014-06-25 | 2018-01-24 | Rensselaer Polytechnic Institute | Oxetane polymers and methods of preparation thereof |
WO2016047823A1 (en) * | 2014-09-25 | 2016-03-31 | 영남대학교 산학협력단 | Composition for inhibiting cellular senescence containing melandrium firmum rohrbach extract or bornesitol separated from same as active ingredient |
US11191735B2 (en) | 2015-03-13 | 2021-12-07 | Nutrition 21, Llc | Arginine silicate for periodontal disease |
US20170135969A1 (en) | 2015-11-12 | 2017-05-18 | Jds Therapeutics, Llc | Topical arginine-silicate-inositol for wound healing |
WO2017147529A1 (en) * | 2016-02-24 | 2017-08-31 | The Trustees Of Columbia University In The City Of New York | Disruption of the interaction between amyloid beta peptide and dietary lipids |
WO2018045244A1 (en) | 2016-09-01 | 2018-03-08 | Jds Therapeutics, Llc | Magnesium biotinate compositions and methods of use |
US11883807B2 (en) | 2017-04-11 | 2024-01-30 | Colorado State University Research Foundation | Functionalization of metal-organic frameworks |
EP3793619A4 (en) | 2018-05-16 | 2022-01-12 | Emory University | Styrylbenzothiazole derivatives and uses in imaging |
AU2019371825B2 (en) * | 2018-11-02 | 2023-07-27 | Nutrition 21, Llc | Compositions containing inositol-stabilized arginine silicate complexes and inositol for improving cognitive function in video gamers |
US11471683B2 (en) | 2019-01-29 | 2022-10-18 | Synapse Biomedical, Inc. | Systems and methods for treating sleep apnea using neuromodulation |
EP3789018A1 (en) * | 2019-09-09 | 2021-03-10 | Servicio Andaluz De Salud | Composition and methods for enhancing or promoting the secretion of ghrelin to promote a healthy metabolic aging |
GB2613672A (en) | 2019-12-16 | 2023-06-14 | Nutrition 21 Llc | Methods of production of aginine-silicate complexes |
EP4084787A1 (en) * | 2020-01-03 | 2022-11-09 | Biosearch S.A. | Composition for use in the treatment of cognitive disorders |
WO2022059776A1 (en) * | 2020-09-17 | 2022-03-24 | 昭和電工株式会社 | Autophagy activator |
WO2024054415A1 (en) * | 2022-09-07 | 2024-03-14 | Eirgen Pharma, Ltd. | A combination of scyllo-inositol and flavones |
Citations (60)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4201706A (en) * | 1978-09-22 | 1980-05-06 | Burton, Parsons & Company, Inc. | Treatment of corneal edema |
US4474806A (en) * | 1982-05-10 | 1984-10-02 | Merck & Co., Inc. | Sulfonyl or carbonyl inositol derivatives useful as anti-inflammatory/analgesic agents |
US4515722A (en) * | 1982-03-30 | 1985-05-07 | Merck & Co., Inc. | Phosphatidyl inositol analogs useful as anti-inflammatory/analgesic agents |
US4734283A (en) * | 1984-10-23 | 1988-03-29 | Matti Siren | Method of making a food composition containing inosotoltriphosphate and the composition |
US4735902A (en) * | 1984-10-23 | 1988-04-05 | Matti Siren | Stabilized composition containing inositoltriphosphate |
US4758430A (en) * | 1987-01-21 | 1988-07-19 | Robert Sabin | Method of treatment of Alzheimer's disease using phytic acid |
US4758420A (en) * | 1986-07-14 | 1988-07-19 | The Dow Chemical Company | Solvent extraction of polychlorinated organic compounds from porous materials |
US4847082A (en) * | 1987-01-21 | 1989-07-11 | Robert Sabin | Method of treatment of Alzheimer's disease using phytic acid |
US4895841A (en) * | 1987-06-22 | 1990-01-23 | Eisai Co., Ltd. | Cyclic amine compounds with activity against acetylcholinesterase |
US4952396A (en) * | 1986-11-19 | 1990-08-28 | Linus Pauling Institute Of Science & Medicine | Method of using phytic acid for inhibiting tumor growth |
US5019566A (en) * | 1986-04-16 | 1991-05-28 | Perstorp Ab | Method of treating inflammation with inositol triphosphate |
US5023248A (en) * | 1984-10-23 | 1991-06-11 | Perstorp Ab | Method of treating diabetes with inositol triphosphate |
US5057507A (en) * | 1986-04-16 | 1991-10-15 | Perstorp Ab | Method of alleviating bone damage with inositoltriphosphate |
US5111814A (en) * | 1990-07-06 | 1992-05-12 | Thomas Jefferson University | Laryngeal pacemaker |
US5112814A (en) * | 1990-10-24 | 1992-05-12 | Robert Sabin | Method of treatment of Parkinson's disease using phytic acid |
US5128332A (en) * | 1984-10-23 | 1992-07-07 | Perstorp Ab | Method of treating cardiovascular diseases using inositoltrisphosphate |
US5135923A (en) * | 1986-04-16 | 1992-08-04 | Perstorp Ab | Method of treating cardiovascular diseases |
US5217959A (en) * | 1990-09-06 | 1993-06-08 | Robert Sabin | Method of treating multiple sclerosis with phytic acid |
US5306841A (en) * | 1991-07-03 | 1994-04-26 | Bundgaard Hans | Derivatives of inositol, preparations containing them and their use |
US5330979A (en) * | 1984-10-23 | 1994-07-19 | Perstorp Ab | Method of treating renal disorders with inositoltriphosphate |
US5342832A (en) * | 1989-12-21 | 1994-08-30 | Perstorp Ab | Use of mono and di inositolphosphates for treating inflammation |
US5407924A (en) * | 1984-10-23 | 1995-04-18 | Perstorp Ab | Method of treating pain using inositol triphosphate |
US5412080A (en) * | 1993-08-25 | 1995-05-02 | President And Fellow Of Harvard College | Enterobactin compounds |
US5545632A (en) * | 1984-10-23 | 1996-08-13 | Perstorp Ab | Method of treating retroviral disease |
US5554399A (en) * | 1993-04-05 | 1996-09-10 | Vanderbeke; E. M. M. | Process for hydrolyzing phytate with a synergetic enzyme composition |
US5614510A (en) * | 1992-02-25 | 1997-03-25 | Perstorp Ab | Pharmaceutical composition with improved bioavailability of inositol phosphate |
US5633412A (en) * | 1992-10-05 | 1997-05-27 | Virginia Tech Intellectual Properties | Syntheses of D-chiro-3-inosose and (+)-D-chiro inositol |
US5643562A (en) * | 1993-03-29 | 1997-07-01 | Queen's University Of Kingston | Method for treating amyloidosis |
US5714643A (en) * | 1993-08-11 | 1998-02-03 | Hokko Chemical Co., Ltd. | Processes for the preparation of D-chiro-inositol |
US5760022A (en) * | 1994-01-25 | 1998-06-02 | Perstorp Ab | Pharmaceutical composition with improved bioavailability of inositol phosphate |
US5840294A (en) * | 1993-03-29 | 1998-11-24 | Queen's University At Kingston | Method for treating amyloidosis |
US5858326A (en) * | 1995-06-06 | 1999-01-12 | Neurochem, Inc. | Methods of increasing amyloid deposition |
US5880099A (en) * | 1996-09-20 | 1999-03-09 | The Regents Of The University Of California | Inositol polyphosphates and methods of using same |
US5972328A (en) * | 1993-03-29 | 1999-10-26 | Queen's University At Kingston | Method for treating amyloidosis |
US5977078A (en) * | 1996-09-20 | 1999-11-02 | The Regents Of The Univesity Of California | Inositol polyphosphate derivatives and methods of using same |
US5998485A (en) * | 1997-06-16 | 1999-12-07 | Cedars-Sinai Medical Center | Method for modulating immune response with inositol |
US6153603A (en) * | 1997-06-27 | 2000-11-28 | Perstorp Ab | Method of treating angiogenesis in tumor tissue |
US6232486B1 (en) * | 1996-06-11 | 2001-05-15 | Nutrimed Biotech | Molecular probes and modulators for PI-PLC and PI 3-kinase |
US6310073B1 (en) * | 1998-07-28 | 2001-10-30 | Queen's University At Kingston | Methods and compositions to treat glycosaminoglycan-associated molecular interactions |
US20010041677A1 (en) * | 2000-05-12 | 2001-11-15 | Manuel Martin-Lomas | Compounds and their uses |
US6329256B1 (en) * | 1999-09-24 | 2001-12-11 | Advanced Micro Devices, Inc. | Self-aligned damascene gate formation with low gate resistance |
US20010053767A1 (en) * | 2000-05-12 | 2001-12-20 | Manuel Martin-Lomas | Compounds and their uses |
US20020013315A1 (en) * | 2000-07-06 | 2002-01-31 | Teall Martin Richard | Gamma secretase inhibitors |
US20020052311A1 (en) * | 1999-09-03 | 2002-05-02 | Beka Solomon | Methods and compostions for the treatment and/or diagnosis of neurological diseases and disorders |
US20030068316A1 (en) * | 1997-02-05 | 2003-04-10 | Klein William L. | Anti-ADDL antibodies and uses thereof |
US20030153512A1 (en) * | 2000-06-30 | 2003-08-14 | Manfred Hergenhahn | Curcumin derivatives with improved water solubility compared to curcumin and medicaments containing the same |
US20040028673A1 (en) * | 2002-01-04 | 2004-02-12 | William Netzer | Compositions and methods for prevention and treatment of amyloid-beta peptide-related disorders |
US6720190B1 (en) * | 1998-03-27 | 2004-04-13 | Ole Hindsgaul | Methods for screening compound libraries |
US20040204387A1 (en) * | 2003-02-27 | 2004-10-14 | Mclaurin Joanne | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US20040214307A1 (en) * | 1999-06-07 | 2004-10-28 | Atsushi Takahasi | Novel process for producing L-epi-2-inosose and novel process for producing epi-inositol using microorganisms |
US20040234626A1 (en) * | 1999-10-18 | 2004-11-25 | Gardiner Paul T. | Food supplement for increasing lean mass and strength |
US20050171112A1 (en) * | 2003-11-03 | 2005-08-04 | Probiodrug Ag | Combinations useful for the treatment of neuronal disorders |
US20060004096A1 (en) * | 2004-05-28 | 2006-01-05 | Joseph Larner | Method of Treating Endothelial Dysfunction, Oxidative Stress and Related Diseases |
US20060135624A1 (en) * | 2002-10-17 | 2006-06-22 | Jingyu Liang Et Al | Natural compound useful for treating diabetes, its preparation and use |
US20060148905A1 (en) * | 1999-10-22 | 2006-07-06 | Kim Darrick S H | Methods for treatment of beta-amyloid protein-induced ocular disease |
US20060189582A1 (en) * | 2004-11-17 | 2006-08-24 | Mclaurin Joanne | Compositions and methods for treatment of disorders of protein aggregation |
US20060240534A1 (en) * | 2003-10-14 | 2006-10-26 | Masanori Yamaguchi | Process for producing scyllo-inositol |
US20070111970A1 (en) * | 2005-10-13 | 2007-05-17 | Antonio Cruz | Inositol compounds and uses of same in the treatment of diseases characterized by abnormal protein folding or aggregation or amyloid formation, desposition, accumulation or persistence |
US20070197452A1 (en) * | 2006-02-17 | 2007-08-23 | Mclaurin Joanne | Treatment of amyloid-related diseases |
US20070197453A1 (en) * | 2006-02-17 | 2007-08-23 | Mclaurin Joanne | Compositions and methods for treatment of disorders of protein aggregation |
Family Cites Families (199)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2088897A (en) * | 1935-03-25 | 1937-08-03 | Goss Printing Press Co Ltd | Printing press |
US2557381A (en) * | 1946-08-09 | 1951-06-19 | William C Huebner | Multiple unit printing press |
DE2234089C3 (en) * | 1972-07-08 | 1975-01-23 | Automatic Druckmaschinenfabrik Dr. W. Hinniger U. Soehne, 1000 Berlin | Offset web-fed rotary printing press |
GB1581233A (en) * | 1976-06-02 | 1980-12-10 | Drg Uk Ltd | Printing press |
US4454151A (en) | 1982-03-22 | 1984-06-12 | Syntex (U.S.A.) Inc. | Use of pyrrolo pyrroles in treatment of ophthalmic diseases |
IT1164225B (en) | 1983-05-13 | 1987-04-08 | Anic Spa | INVERTED ANALOGS OF PENTAPEPTIDE ENHANCING BRADICHINA BPP5A AND METHODS FOR THEIR PREPARATION |
DE3405663A1 (en) | 1984-02-17 | 1985-08-22 | Merck Patent Gmbh, 6100 Darmstadt | Process for the preparation of scyllo-inositol |
IL74497A (en) | 1985-03-05 | 1990-02-09 | Proterra Ag | Pharmaceutical compositions containing phenyl carbamate derivatives and certain phenyl carbamate derivatives |
DE3610107A1 (en) * | 1986-03-26 | 1987-10-08 | Voith Gmbh J M | ACTUATING DEVICE FOR ADJUSTING A ROLLER |
NL195004C (en) | 1987-03-04 | 2003-11-04 | Novartis Ag | Pharmaceutical preparation containing phenyl carbamate. |
JPH067158Y2 (en) | 1987-03-18 | 1994-02-23 | 株式会社藤井合金製作所 | Waterproof structure of piping terminal |
DE3808142A1 (en) * | 1988-03-11 | 1989-09-21 | Goebel Gmbh Maschf | STORAGE FACILITIES |
DE3814752C1 (en) * | 1988-04-30 | 1989-08-31 | J.M. Voith Gmbh, 7920 Heidenheim, De | |
US5334618A (en) * | 1991-04-04 | 1994-08-02 | The Children's Medical Center Corporation | Method of preventing NMDA receptor-mediated neuronal damage |
JPH03102492A (en) | 1989-06-12 | 1991-04-26 | Mitsui Eng & Shipbuild Co Ltd | Data transmission system for automatic vending machine and compound function type automatic vending machine |
JP2984043B2 (en) | 1990-09-18 | 1999-11-29 | 旭化成工業株式会社 | Myo-inositol dehydrogenase and method for producing the same |
JPH05192163A (en) | 1991-09-30 | 1993-08-03 | Suntory Ltd | Inositol dehydrogenase gene |
CA2125964C (en) | 1991-12-18 | 2001-06-19 | Neng-Yang Shih | Imidazolyl-alkyl-piperazine and -diazepine derivatives as histamine h3 agonists/antagonists |
JP3251976B2 (en) | 1992-06-23 | 2002-01-28 | 旭化成株式会社 | Substantially pure microorganism producing myo-inositol dehydrogenase |
US5351616A (en) * | 1992-08-13 | 1994-10-04 | Man Roland Druckmaschinen Ag | Rotary web printing machine, particularly for printing on thick or carton-type stock webs with replaceable plate cylinders |
DE4229494A1 (en) | 1992-09-04 | 1994-03-10 | Basotherm Gmbh | Medicines for topical use on the eye to treat increased intraocular pressure |
DE4408025A1 (en) * | 1994-03-10 | 1995-09-14 | Koenig & Bauer Ag | Printing unit for a multi-color web-fed rotary printing machine |
DE4430693B4 (en) * | 1994-08-30 | 2005-12-22 | Man Roland Druckmaschinen Ag | Drives for a web-fed rotary offset printing machine |
US5550166A (en) | 1995-03-17 | 1996-08-27 | Ostlund; Richard E. | Pinitol and derivatives thereof for the treatment of metabolic disorders |
US6221645B1 (en) | 1995-06-07 | 2001-04-24 | Elan Pharmaceuticals, Inc. | β-secretase antibody |
JP3630344B2 (en) | 1995-11-17 | 2005-03-16 | 北興化学工業株式会社 | Process for producing inositol stereoisomers |
TW513409B (en) | 1996-06-07 | 2002-12-11 | Eisai Co Ltd | Polymorphs of donepezil hydrochloride |
WO1997046526A1 (en) | 1996-06-07 | 1997-12-11 | Eisai Co., Ltd. | Stable polymorphs of donepezil (1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine) hydrochloride and process for production |
TW506836B (en) | 1996-06-14 | 2002-10-21 | Janssen Pharmaceutica Nv | Fast-dissolving galanthamine hydrobromide tablet |
US6218506B1 (en) | 1997-02-05 | 2001-04-17 | Northwestern University | Amyloid β protein (globular assembly and uses thereof) |
ATE311865T1 (en) | 1997-03-10 | 2005-12-15 | Univ Loma Linda Med | USE OF R-ENANTIOMERIC NON-STEROIDAL ANTI-INFLAMMATORY TO PREVENT ALZHEIMER'S DISEASE |
GB9801899D0 (en) | 1998-01-29 | 1998-03-25 | Univ London | Neurotrophic properties of ipgs analogues |
DE19805898C2 (en) * | 1998-02-13 | 2003-09-18 | Roland Man Druckmasch | Printing unit for a web-fed rotary printing machine |
US5981168A (en) | 1998-05-15 | 1999-11-09 | The University Of British Columbia | Method and composition for modulating amyloidosis |
US6227110B1 (en) * | 1998-06-23 | 2001-05-08 | Heidelberger Druckmaschinen Ag | Wet printing press with throw-off mechanism |
AUPP589398A0 (en) | 1998-09-14 | 1998-10-08 | Walter And Eliza Hall Institute Of Medical Research, The | Immunogenic compositions and uses thereof |
CA2343004A1 (en) | 1998-09-24 | 2000-03-30 | Pharmacia & Upjohn Company | Alzheimer's disease secretase |
AUPP675898A0 (en) | 1998-10-27 | 1998-11-19 | Walter And Eliza Hall Institute Of Medical Research, The | A method of activating t cells and agents useful for same |
US6221856B1 (en) | 1999-02-03 | 2001-04-24 | Inologic, Inc. | Inositol derivatives for inhibiting superoxide anion production |
EP1165609A2 (en) | 1999-02-10 | 2002-01-02 | Elan Pharmaceuticals, Inc. | Human beta-secretase enzyme, inhibitors and their compositions and uses |
GB2389113B (en) | 1999-02-10 | 2004-02-04 | Elan Pharm Inc | B-secretase inhibitor |
CZ20013000A3 (en) | 1999-02-26 | 2002-02-13 | Merck & Co., Inc. | Novel sulfonamide compounds and use thereof |
US6864240B1 (en) | 1999-06-15 | 2005-03-08 | Elan Pharmaceuticals, Inc. | Dipeptide inhibitors of β-secretase |
CA2376420A1 (en) | 1999-06-15 | 2000-12-21 | Elan Pharmaceuticals, Inc. | Statine-derived tetrapeptide inhibitors of beta-secretase |
WO2001003680A2 (en) | 1999-07-09 | 2001-01-18 | Isis Innovation Limited | Compounds for inhibiting diseases and preparing cells for transplantation |
DE19937796B4 (en) * | 1999-08-10 | 2007-03-22 | Man Roland Druckmaschinen Ag | printing unit |
DE19937803A1 (en) * | 1999-08-10 | 2001-02-15 | Roland Man Druckmasch | Printing unit |
DE19937805A1 (en) * | 1999-08-10 | 2001-02-15 | Roland Man Druckmasch | Printing unit |
JP2001163810A (en) | 1999-09-30 | 2001-06-19 | Microbial Chem Res Found | Method for new synthesis of 1d-chiro-inositol and intermediate |
AU1569501A (en) | 1999-11-09 | 2001-06-06 | Eli Lilly And Company | Beta-aminoacid compounds useful for inhibiting beta-amyloid peptide release and/or its synthesis |
WO2001034639A2 (en) | 1999-11-09 | 2001-05-17 | Eli Lilly And Company | β-AMINOACID COMPOUNDS USEFUL FOR INHIBITING β-AMYLOID PEPTIDE RELEASE AND/OR ITS SYNTHESIS |
DE19963944C1 (en) * | 1999-12-31 | 2001-06-13 | Koenig & Bauer Ag | Method to adjust cylinders of printing machine; involves moving abutment to limit stroke of axle holder for adjustable cylinder at space from base plate and applying adjusting and holding forces |
JP2003520266A (en) | 2000-01-24 | 2003-07-02 | メルク シャープ エンド ドーム リミテッド | γ-secretase inhibitor |
DE10008215B4 (en) * | 2000-02-23 | 2013-03-28 | Manroland Web Systems Gmbh | Printing unit for a rotary printing press with cross slide |
GB0005251D0 (en) | 2000-03-03 | 2000-04-26 | Merck Sharp & Dohme | Therapeutic compounds |
AU2001239052A1 (en) | 2000-03-06 | 2001-09-17 | Immune Network Ltd. | Compositions for prevention and treatment of dementia |
EP1268412B8 (en) | 2000-03-20 | 2007-02-21 | MERCK SHARP & DOHME LTD. | Sulphonamido-substituted bridged bicycloalkyl derivatives |
JP2003528071A (en) | 2000-03-23 | 2003-09-24 | エラン ファーマスーティカルズ インコーポレイテッド | Compositions and methods for treating Alzheimer's disease |
GB0008710D0 (en) | 2000-04-07 | 2000-05-31 | Merck Sharp & Dohme | Therapeutic compounds |
AU5702201A (en) | 2000-04-13 | 2001-10-30 | Mayo Foundation | Abeta<sub>42</sub> lowering agents |
AU2001258771A1 (en) | 2000-05-19 | 2001-11-26 | Takeda Chemical Industries Ltd. | -secretase inhibitors |
GB0015627D0 (en) | 2000-06-26 | 2000-08-16 | Rademacher Group Limited | Phosphoglycan messengers and their medical uses |
PE20020276A1 (en) | 2000-06-30 | 2002-04-06 | Elan Pharm Inc | SUBSTITUTE AMINE COMPOUNDS AS ß-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER |
WO2002002505A2 (en) | 2000-06-30 | 2002-01-10 | Elan Pharmaceuticals, Inc. | Compounds to treat alzheimer's disease |
US6846813B2 (en) | 2000-06-30 | 2005-01-25 | Pharmacia & Upjohn Company | Compounds to treat alzheimer's disease |
US6559891B1 (en) * | 2000-08-15 | 2003-05-06 | Sony Corporation | Method and apparatus to generate tri-level HDTV synchronization pulses |
EP1349858B1 (en) | 2000-11-02 | 2008-08-27 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Agents useful for reducing amyloid precursor protein and treating demantia and methods of use thereof |
ATE302753T1 (en) | 2000-11-02 | 2005-09-15 | Merck Sharp & Dohme | SULFAMIDES AS GAMMA SECRETASE INHIBITORS |
WO2002055715A1 (en) | 2001-01-15 | 2002-07-18 | Hokko Chemical Industry Co., Ltd. | Dna encoding d-myo-inositol 1-epimerase |
AU2002236988A1 (en) | 2001-02-06 | 2002-08-19 | Novartis Ag | Photodynamic therapy of occult choroidal neovascularization linked to age-related macular degeneration |
EP1233021A3 (en) | 2001-02-20 | 2002-11-20 | Pfizer Products Inc. | An inhibitor of Beta amyloid cleavage enzyme |
AU2002306848A1 (en) | 2001-03-23 | 2002-10-08 | Elan Pharmaceuticals, Inc. | Methods of treating alzheimer's disease with piperidin derivates |
EP1377453B2 (en) * | 2001-04-09 | 2009-09-16 | Koenig & Bauer Aktiengesellschaft | Printing group pertaining to a printing machine |
EP1389194A2 (en) | 2001-04-27 | 2004-02-18 | Vertex Pharmaceuticals Incorporated | Inhibitors of bace |
CA2448084A1 (en) | 2001-05-22 | 2002-11-28 | Elan Pharmaceuticals, Inc. | Aza hydroxylated ethyl amine compounds |
ATE413884T1 (en) | 2001-05-22 | 2008-11-15 | Merck & Co Inc | BETA-SECRETASE SUBSTRATE AND USE THEREOF |
ES2307764T3 (en) | 2001-06-01 | 2008-12-01 | Elan Pharmaceuticals, Inc. | DERIVATIVES OF HYDROXIALQUILAMINS AS INHIBITORS OF BETA-SECRETASE AND ITS USE FOR THE TREATMENT OF ALZHEIMER'S DISEASE AND SIMILAR DISEASES. |
US6684775B2 (en) * | 2001-06-07 | 2004-02-03 | Heidelberger Druckmaschinen Ag | Printing unit with roll-away inkers |
WO2002100410A1 (en) | 2001-06-08 | 2002-12-19 | Elan Pharmaceuticals, Inc. | Methods of treating alzheimer's disease |
JP2004535424A (en) | 2001-06-11 | 2004-11-25 | イーラン ファーマスーティカルズ、インコーポレイテッド | Substituted amino alcohols useful for treating Alzheimer's disease |
CA2450167A1 (en) | 2001-06-12 | 2002-12-19 | Elan Pharmaceuticals, Inc. | Macrocycles useful in the treatment of alzheimer's disease |
MXPA03011466A (en) | 2001-06-12 | 2004-07-01 | Elan Pharm Inc | Macrocycles useful in the treatment of alzheimer's disease. |
CA2450205A1 (en) | 2001-06-13 | 2002-12-19 | Elan Pharmaceuticals, Inc. | Aminediols for the treatment of alzheimer's disease |
JP3981597B2 (en) | 2001-06-25 | 2007-09-26 | 北興化学工業株式会社 | Method for producing scyllo-inosose and method for producing scyllo-inositol |
MXPA04000139A (en) | 2001-06-25 | 2004-06-03 | Pharmacia & Up John Company | Use of bicyclo compounds for treating alzheimer's disease. |
US6982264B2 (en) | 2001-06-27 | 2006-01-03 | Elan Pharmaceuticals, Inc. | Substituted alcohols useful in treatment of Alzheimer's disease |
CA2453451A1 (en) | 2001-07-10 | 2003-01-23 | Elan Pharmaceuticals, Inc. | Aminediols for the treatment of alzheimer's disease |
EP1404328A1 (en) | 2001-07-10 | 2004-04-07 | Elan Pharmaceuticals, Inc. | Alpha-hydroxyamide statine derivatives for the treatment of alzheimer's disease |
CA2453444A1 (en) | 2001-07-10 | 2003-01-23 | Elan Pharmaceuticals, Inc. | Diaminediols for the treatment of alzheimer's disease |
US20030181531A1 (en) | 2003-02-11 | 2003-09-25 | David Sherris | Compositions and methods of administering tubulin binding agents for the treatment of ocular diseases |
WO2003007944A1 (en) | 2001-07-20 | 2003-01-30 | Qlt, Inc. | Treatment of macular edema with photodynamic therapy |
EP1411944A1 (en) | 2001-08-03 | 2004-04-28 | Schering Corporation | Sulfonamide derivatives as gamma secretase inhibitors |
EP1492765B1 (en) | 2001-08-03 | 2011-07-06 | Schering Corporation | Novel gamma secretase inhibitors |
EP1423167A1 (en) | 2001-08-28 | 2004-06-02 | Elan Pharmaceuticals, Inc. | Method for treating alzheimer's disease using quinaldoyl-amine derivatives of oxo- and hydroxy-substituted hydrocarbons |
DE10145322A1 (en) * | 2001-09-14 | 2003-04-03 | Ina Schaeffler Kg | Bearing arrangement for cylinders, rollers or drums |
MXPA04002785A (en) | 2001-09-24 | 2004-07-29 | Elan Pharm Inc | Substituted amines for the treatment of alzheimer's disease. |
MXPA04003245A (en) | 2001-10-04 | 2004-08-11 | Elan Pharm Inc | Hydroxypropylamines. |
MXPA04003244A (en) | 2001-10-05 | 2004-07-08 | Elan Pharm Inc | Allylamides useful in the treatment of alzheimer's disease. |
AU2002359301B2 (en) | 2001-10-23 | 2008-07-03 | Comentis, Inc. | Beta-secretase inhibitors and methods of use |
US20050038019A1 (en) | 2001-10-29 | 2005-02-17 | Beck James P. | Hydroxy substituted amides for the treatment of alzheimer's disease |
NZ533107A (en) | 2001-11-08 | 2007-04-27 | Upjohn Co | N, N'-substituted-1,3-diamino-2-hydroxypropane derivatives |
NZ533158A (en) | 2001-11-19 | 2006-09-29 | Elan Pharm Inc | 3,4-Disubstituted, 3,5-disubstituted and 3,4,5-substituted piperidines and piperazines |
US20060079550A1 (en) | 2001-11-21 | 2006-04-13 | Varghese John | Amino acid derivatives useful for the treatment of alzheimer's disease |
AU2002357232A1 (en) | 2001-12-04 | 2003-06-17 | Elan Pharmaceuticals, Inc. | Peptide isosteres containing a heterocycle useful in the treatment of alzheimer's disease |
MXPA04005428A (en) | 2001-12-06 | 2004-12-06 | Elan Pharm Inc | Substituted hydroxyethylamines. |
CH698246B1 (en) | 2001-12-20 | 2009-06-30 | Hoffmann La Roche | Test to identify inhibitors of beta secretases. |
BR0306724A (en) | 2002-01-04 | 2006-04-11 | Elan Pharm Inc | amino substituted carboxamides for treatment of alzheimer's disease |
JP2005516967A (en) | 2002-01-18 | 2005-06-09 | ザ ジェネティクス カンパニー インコーポレーティッド | β-secretase inhibitor |
US7053220B2 (en) | 2002-02-01 | 2006-05-30 | Elan Pharmaceuticals, Inc. | Hydroxyalkanoyl aminopyrazoles and related compounds |
US7256186B2 (en) | 2002-02-06 | 2007-08-14 | Schering Corporation | Gamma secretase inhibitors |
TW200302717A (en) | 2002-02-06 | 2003-08-16 | Schering Corp | Novel gamma secretase inhibitors |
US20040171614A1 (en) | 2002-02-06 | 2004-09-02 | Schering-Plough Corporation | Novel gamma secretase inhibitors |
US20040058313A1 (en) | 2002-04-24 | 2004-03-25 | Abreu Marcio Marc | Compositions, targets, methods and devices for the therapy of ocular and periocular disorders |
US7585938B2 (en) | 2002-04-24 | 2009-09-08 | Hiroshi Mori | Gamma-secretase inhibitors |
EP1503998B1 (en) | 2002-05-01 | 2009-07-01 | MERCK SHARP & DOHME LTD. | Heteroaryl substituted spirocyclic sufamides for inhibition of gamma secretase |
US6974829B2 (en) | 2002-05-07 | 2005-12-13 | Elan Pharmaceuticals, Inc. | Succinoyl aminopyrazoles and related compounds |
DE10223666B4 (en) * | 2002-05-28 | 2006-06-14 | Windmöller & Hölscher Kg | Inking system for flexo printing machines |
US6723755B2 (en) | 2002-06-12 | 2004-04-20 | Piotr Chomczynski | Method of treating rosacea |
WO2003103653A1 (en) | 2002-06-11 | 2003-12-18 | Elan Pharmaceuticals, Inc. | Methods of treating alzheimer's disease using aryl alkanoic acid amides |
AU2003237546A1 (en) | 2002-06-11 | 2003-12-22 | Elan Pharmaceuticals, Inc. | METHODS OF TREATING ALZHEIMER'S DISEASE USING AROMATICALLY SUBSTITUTED Omega-AMINO-ALKANOIC ACID AMIDES AND ALKANOIC ACID DIAMIDES |
WO2004002478A1 (en) | 2002-06-27 | 2004-01-08 | Elan Pharmaceuticals, Inc. | Methods for treating alzheimer's disease using hydroxyethylene compounds containing a heterocyclic amide bond isostere |
GB0217909D0 (en) | 2002-08-01 | 2002-09-11 | Du Pont | Chintzed stretch fabrics |
GB0218041D0 (en) | 2002-08-02 | 2002-09-11 | Merck Sharp & Dohme | Chemical process |
US7557137B2 (en) | 2002-08-05 | 2009-07-07 | Bristol-Myers Squibb Company | Gamma-lactams as beta-secretase inhibitors |
BR0314071A (en) | 2002-09-06 | 2005-07-05 | Pharmacia & Upjohn Co Llc | 1,3-Diamino-2-hydroxypropane prodrug derivatives |
UY27967A1 (en) | 2002-09-10 | 2004-05-31 | Pfizer | 2-HINDROXI-1,3-DIAMINOALCANE OIL |
WO2004029019A2 (en) | 2002-09-27 | 2004-04-08 | Elan Pharmaceuticals, Inc. | Compounds for the treatment of alzheimer’s disease |
CN100520260C (en) | 2002-09-30 | 2009-07-29 | Bp北美公司 | Reduced carbon dioxide emission system and method for providing power for refrigerant compression and electrical power for a light hydrocarbon gas liquefaction process |
AU2003279728B2 (en) | 2002-10-01 | 2007-09-27 | Northwestern University | Amyloid beta-derived diffusible ligands (addls), addl-surrogates, addl-binding molecules, and uses thereof |
GB0223038D0 (en) | 2002-10-04 | 2002-11-13 | Merck Sharp & Dohme | Therapeutic compounds |
GB0223039D0 (en) | 2002-10-04 | 2002-11-13 | Merck Sharp & Dohme | Therapeutic compounds |
WO2004050609A1 (en) | 2002-11-27 | 2004-06-17 | Elan Pharmaceutical, Inc. | Substituted ureas and carbamates |
KR20050085535A (en) | 2002-12-11 | 2005-08-29 | 파마시아 앤드 업존 캄파니 엘엘씨 | Treatment of diseases with combinations of alpha 7 nicotinic acetylcholine receptor agonists and other compounds |
FR2848452B1 (en) | 2002-12-12 | 2007-04-06 | Aventis Pharma Sa | APPLICATION OF INTESTINAL BILIARY ACID RECAPTURE INHIBITORS FOR THE PREVENTION AND TREATMENT OF ALZHEIMER'S DISEASE |
JP4662914B2 (en) | 2003-02-04 | 2011-03-30 | エフ.ホフマン−ラ ロシュ アーゲー | Malonamide derivatives as gamma-secretase inhibitors |
EP1603548A4 (en) | 2003-02-05 | 2007-10-10 | Myriad Genetics Inc | Method and composition for treating neurodegenerative disorders |
GB0308318D0 (en) | 2003-04-10 | 2003-05-14 | Merck Sharp & Dohme | Therapeutic agents |
CL2004000849A1 (en) | 2003-04-21 | 2005-01-28 | Elan Pharmaceuticals Inc Pharm | COMPOUNDS DERIVED FROM BENZAMIDAS-2-HIDROXI-3-DIAMINOALCANS, USEFUL FOR THE TREATMENT OR PREVENTION OF ALZHEIMER, DOWN SYNDROME, HEREDITARY CEREBRAL HEMORRAGY, DEGENERATIVE DEMENCIES AND OTHERS. |
EP1615915A1 (en) | 2003-04-21 | 2006-01-18 | Elan Pharmaceuticals, Inc. | Phenacyl 2-hydroxy-3-diaminoalkanes |
TW200510405A (en) | 2003-05-13 | 2005-03-16 | Schering Corp | Bridged n-arylsulfonylpiperidines as gamma-secretase inhibitors |
CA2525841C (en) | 2003-05-16 | 2012-10-16 | Merck Sharp & Dohme Limited | Cyclohexyl sulphones as gamma-secretase inhibitors |
US7060698B2 (en) | 2003-05-19 | 2006-06-13 | Hoffmann-La Roche Inc. | Benzoxazepinone derivatives |
JP4220548B2 (en) | 2003-06-05 | 2009-02-04 | エラン ファーマシューティカルズ,インコーポレイテッド | Acylated amino acids, amidylpyrazole, and related compounds |
AU2004255183A1 (en) | 2003-06-30 | 2005-01-20 | Merck & Co., Inc. | N-alkyl phenylcarboxamide beta-secretase inhibitors for the treatment of Alzheimer's disease |
AU2004255191A1 (en) | 2003-07-01 | 2005-01-20 | Merck & Co., Inc. | Phenylcarboxylate beta-secretase inhibitors for the treatment of Alzheimer's disease |
EP1671129A1 (en) | 2003-07-21 | 2006-06-21 | Angiogenetics Sweden AB | Compounds and methods for promoting angiogenesis by using a gamma-secretase inhibitor or inhibiting the gamma-secretase pathway |
GB0318447D0 (en) | 2003-08-05 | 2003-09-10 | Merck Sharp & Dohme | Therapeutic agents |
TW200519084A (en) | 2003-08-08 | 2005-06-16 | Schering Corp | Cyclic amine bace-1 inhibitors having a benzamide substituent |
US7329746B2 (en) | 2003-08-14 | 2008-02-12 | Merck & Co., Inc. | Macrocyclic beta-secretase inhibitors for the treatment of Alzheimer's disease |
JP2007506715A (en) | 2003-09-24 | 2007-03-22 | メルク シャープ エンド ドーム リミテッド | Gamma secretase inhibitor |
KR100793095B1 (en) | 2003-10-01 | 2008-01-10 | 주식회사 프로메디텍 | Novel Sulfone Amide Derivatives Capable Of Inhibiting BACE |
DE602004014170D1 (en) | 2003-10-03 | 2008-07-10 | Merck & Co Inc | BENZYL ETHER AND BENZYLAMINO BETA SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER DISEASE |
GB0323258D0 (en) | 2003-10-04 | 2003-11-05 | Merck Sharp & Dohme | Therapeutic compounds |
SI1673347T1 (en) | 2003-10-06 | 2015-10-30 | F. Hoffmann - La Roche Ag | Substituted dibenzo-azepine and benzo-diazepine derivatives useful as gamma-secretase inhibitors |
GB0326039D0 (en) | 2003-11-07 | 2003-12-10 | Merck Sharp & Dohme | Therapeutic agents |
ES2232302B1 (en) | 2003-11-07 | 2006-08-01 | Universitat De Les Illes Balears | MYO-INOSITOL HEXAFOSFATO FOR TOPICAL USE. |
ATE383160T1 (en) | 2003-11-11 | 2008-01-15 | Hoffmann La Roche | PHOSPHINE ACID DERIVATIVES, INHIBITORS OF BETA-SECRETASE FOR THE TREATMENT OF ALZHEIMER'S DISEASE |
WO2005051914A1 (en) | 2003-11-24 | 2005-06-09 | Merck & Co., Inc. | Benzylether and benzylamino beta-secretase inhibitors for the treatment of alzheimer's disease |
JP2007512281A (en) | 2003-11-28 | 2007-05-17 | エフ.ホフマン−ラ ロシュ アーゲー | Tetronic and tetramic acids as inhibitors of β-secretase |
AU2004311749A1 (en) | 2003-12-19 | 2005-07-21 | Merck & Co., Inc. | Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of Alzheimer's disease |
WO2005063796A1 (en) | 2003-12-31 | 2005-07-14 | Posco | Inhibitors of amyloid precursor protein processing |
AU2004315111B2 (en) | 2004-01-29 | 2010-03-04 | Cellzome Ag | Treatment of neurodegenerative diseases by the use of GPR49 |
AU2004315399B2 (en) | 2004-01-29 | 2009-08-06 | Cellzome Ag | Treatment of neurodegenerative diseases by the use of ATP7A-modulators |
US7544717B2 (en) | 2004-03-25 | 2009-06-09 | Elan Pharmaceuticals, Inc. | 2-amino- and 2-thio- substituted 1,3-diaminopropanes |
WO2005097767A1 (en) | 2004-03-30 | 2005-10-20 | Merck & Co., Inc. | 2-aminothiazole compounds useful as aspartyl protease inhibitors |
TWI300410B (en) | 2004-04-05 | 2008-09-01 | Schering Corp | Novel gamma secretase inhibitors |
AU2005236063A1 (en) | 2004-04-20 | 2005-11-03 | Merck & Co., Inc. | 2, 4, 6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease |
AU2005236020A1 (en) | 2004-04-20 | 2005-11-03 | Merck & Co., Inc. | 1,3,5-substituted phenyl derivative compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease |
US7449599B2 (en) | 2004-05-13 | 2008-11-11 | Merck + Co Inc. | Phenyl carboxamide compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease |
JP4406327B2 (en) | 2004-06-29 | 2010-01-27 | 儀昭 新田 | Tire chip manufacturing equipment |
US8193250B2 (en) | 2004-10-22 | 2012-06-05 | Mount Sinai School Of Medicine | Compositions and methods for treating alzheimer's disease and related disorders and promoting a healthy nervous system |
WO2006088705A1 (en) | 2005-02-14 | 2006-08-24 | Wyeth | Terphenyl guanidines as [beta symbol] -secretase inhibitors |
WO2006112000A1 (en) | 2005-03-30 | 2006-10-26 | The Niigata Institute Of Science And Technology | Method of synthesizing 2-deoxy-scyllo-inosose by modified strain of e. coli, method of purifying the same and obtained 2-deoxy-scyllo-inosose |
KR20060105233A (en) | 2005-04-02 | 2006-10-11 | 삼성전자주식회사 | Hybrid disc and recording and/or reproducing apparatus and method for the same |
WO2007002220A2 (en) | 2005-06-21 | 2007-01-04 | Bristol-Myers Squibb Company | Aminoacetamide acyl guanidines as beta-secretase inhibitors |
CA2615656A1 (en) | 2005-07-18 | 2007-01-25 | Merck & Co., Inc. | Spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease |
WO2007019080A2 (en) | 2005-08-03 | 2007-02-15 | Merck & Co., Inc. | Tricyclic beta-secretase inhibitors for the treatment of alzheimer's disease |
US7338974B2 (en) | 2005-08-12 | 2008-03-04 | Bristol-Myers Squibb Company | Macrocyclic diaminopropanes as beta-secretase inhibitors |
ES2360957T3 (en) | 2005-10-25 | 2011-06-10 | Janssen Pharmaceutica Nv | DERIVATIVES OF 2-AMINO-3,4-DIHIDRO-PIRIDO (3,4-D) -PIRIMIDINE USEFUL AS INHIBITORS OF THE BETA-SECRETASE (BACE). |
CA2579188A1 (en) | 2006-02-17 | 2007-08-17 | Joanne Mclaurin | Treatment of amyloid-related diseases |
BRPI0708725A2 (en) | 2006-03-09 | 2011-06-07 | Waratah Pharmaceuticals Inc | cyclohexane polyalcohol formulation for the treatment of protein aggregation diseases |
CA2652238A1 (en) | 2006-05-18 | 2007-11-29 | Merck Frosst Canada Ltd. | Phenanthrene derivatives as mpges-1 inhibitors |
CA2652449A1 (en) | 2006-05-19 | 2007-11-29 | Waratah Pharmaceuticals Inc. | Screening methods for amyloid beta modulators |
EP1884531A1 (en) | 2006-07-30 | 2008-02-06 | Lonza Compounds GmbH & Co. KG | Sheet molding compounds (smc) comprising thermosetting resins based on renewable resources |
EP2061317A4 (en) | 2006-08-25 | 2010-06-30 | Allan Basbaum | Intrathecal administration of triptan compositions to treat non-migraine pain |
US20100256752A1 (en) | 2006-09-06 | 2010-10-07 | Forster David C | Prosthetic heart valves, support structures and systems and methods for implanting the same, |
WO2008034244A1 (en) | 2006-09-21 | 2008-03-27 | Waratah Pharmaceuticals Inc. | The combination of a cyclohexanehexol and a nsaid for the treatment of neurodegenerative diseases |
EP2091566A4 (en) | 2006-11-24 | 2011-07-06 | Waratah Pharmaceuticals Inc | Combination treatments for alzheimer's disease and similar diseases |
CA2674048A1 (en) | 2006-12-29 | 2008-07-10 | Normoxys, Inc. | Cyclitols and their derivatives and their therapeutic applications |
WO2008098371A1 (en) | 2007-02-16 | 2008-08-21 | The Royal Institution For The Advancement Of Learning/Mcgill University | Compositions and method for reducing amyloid beta in a mammal |
US20100168250A1 (en) | 2007-04-12 | 2010-07-01 | Antonio Cruz | Use of cyclohexanehexol derivatives in the treatment of ocular disease |
CA2683580A1 (en) | 2007-04-12 | 2008-10-23 | Joanne Mclaurin | Treatment of amyotrophic lateral sclerosis |
CA2683548A1 (en) | 2007-04-12 | 2008-10-23 | Joanne Mclaurin | Use of cyclohexanehexol derivatives for the treatment of polyglutamine diseases |
CA2683546A1 (en) | 2007-04-12 | 2008-10-23 | Joanne Mclaurin | Use of cyclohexanehexol derivatives in the treatment of .alpha.-synucleinopathies |
JP5034916B2 (en) | 2007-12-10 | 2012-09-26 | 富士通セミコンダクター株式会社 | Performance evaluation model generation method, system performance evaluation method, and performance evaluation model generation apparatus |
JP6026742B2 (en) | 2008-08-06 | 2016-11-16 | インヴィスタ テクノロジーズ エスアエルエル | Method for producing an elastic composite structure useful as a component for disposable hygiene products and clothing |
TW201016208A (en) | 2008-09-15 | 2010-05-01 | Elan Pharm Inc | Methods of treatment of hyperuricemia and associated disease states |
EP2349233A4 (en) | 2008-10-09 | 2012-04-18 | Waratah Pharmaceuticals Inc | Use of scyllo-inositols for the treatment of macular degeneration-related disorders |
JP2014515408A (en) | 2011-06-03 | 2014-06-30 | エラン ファーマシューティカルズ,リミティド ライアビリティー カンパニー | Scyllo-inositol for the treatment of behavioral and mental disorders |
-
2004
- 2004-02-26 US US10/787,621 patent/US7521481B2/en active Active
- 2004-02-27 PT PT100104777T patent/PT2311445E/en unknown
- 2004-02-27 EP EP14170801.6A patent/EP2823813A1/en not_active Withdrawn
- 2004-02-27 SI SI200431216T patent/SI1608350T1/en unknown
- 2004-02-27 ES ES09005295.2T patent/ES2520047T3/en not_active Expired - Lifetime
- 2004-02-27 WO PCT/CA2004/000272 patent/WO2004075882A1/en active Application Filing
- 2004-02-27 SI SI200432169T patent/SI2311445T1/en unknown
- 2004-02-27 AT AT04715226T patent/ATE432694T1/en active
- 2004-02-27 AU AU2004216544A patent/AU2004216544B2/en not_active Expired
- 2004-02-27 EP EP09005295.2A patent/EP2153829B1/en not_active Expired - Lifetime
- 2004-02-27 SI SI200432192T patent/SI2153829T1/en unknown
- 2004-02-27 CA CA2516563A patent/CA2516563C/en not_active Expired - Lifetime
- 2004-02-27 DE DE602004021362T patent/DE602004021362D1/en not_active Expired - Lifetime
- 2004-02-27 JP JP2006501433A patent/JP4999453B2/en not_active Expired - Lifetime
- 2004-02-27 PT PT04715226T patent/PT1608350E/en unknown
- 2004-02-27 DK DK10010477.7T patent/DK2311445T3/en active
- 2004-02-27 DK DK04715226T patent/DK1608350T3/en active
- 2004-02-27 DK DK09005295.2T patent/DK2153829T3/en active
- 2004-02-27 EP EP04715226A patent/EP1608350B1/en not_active Expired - Lifetime
- 2004-02-27 BR BRPI0407910-8A patent/BRPI0407910A/en not_active Application Discontinuation
- 2004-02-27 US US10/547,286 patent/US8859628B2/en active Active
- 2004-02-27 ES ES04715226T patent/ES2327521T3/en not_active Expired - Lifetime
- 2004-02-27 EP EP10010477.7A patent/EP2311445B1/en not_active Expired - Lifetime
- 2004-02-27 PT PT90052952T patent/PT2153829E/en unknown
- 2004-02-27 ES ES10010477.7T patent/ES2475977T3/en not_active Expired - Lifetime
-
2005
- 2005-08-24 IL IL170476A patent/IL170476A/en active IP Right Grant
-
2009
- 2009-03-03 US US12/396,515 patent/US20090227686A1/en not_active Abandoned
- 2009-09-01 CY CY20091100910T patent/CY1109338T1/en unknown
- 2009-12-18 AU AU2009251035A patent/AU2009251035B2/en not_active Expired
-
2010
- 2010-12-28 JP JP2010294145A patent/JP2011105733A/en not_active Withdrawn
-
2012
- 2012-02-29 US US13/408,337 patent/US20120157549A1/en not_active Abandoned
- 2012-05-30 IL IL220065A patent/IL220065A/en active IP Right Grant
-
2013
- 2013-09-03 US US14/016,733 patent/US20140073701A1/en not_active Abandoned
- 2013-12-13 JP JP2013257712A patent/JP2014065731A/en active Pending
-
2014
- 2014-09-03 US US14/475,859 patent/US20150031776A1/en not_active Abandoned
- 2014-11-11 CY CY20141100936T patent/CY1115732T1/en unknown
-
2015
- 2015-01-29 US US14/608,617 patent/US9833420B2/en not_active Expired - Lifetime
-
2016
- 2016-01-18 JP JP2016006804A patent/JP2016117743A/en active Pending
Patent Citations (77)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4201706A (en) * | 1978-09-22 | 1980-05-06 | Burton, Parsons & Company, Inc. | Treatment of corneal edema |
US4515722A (en) * | 1982-03-30 | 1985-05-07 | Merck & Co., Inc. | Phosphatidyl inositol analogs useful as anti-inflammatory/analgesic agents |
US4474806A (en) * | 1982-05-10 | 1984-10-02 | Merck & Co., Inc. | Sulfonyl or carbonyl inositol derivatives useful as anti-inflammatory/analgesic agents |
US5545632A (en) * | 1984-10-23 | 1996-08-13 | Perstorp Ab | Method of treating retroviral disease |
US5003098A (en) * | 1984-10-23 | 1991-03-26 | Perstorp Ab | Method of reducing or eliminating adverse effects of a pharmaceutical composition or a drug |
US4735902A (en) * | 1984-10-23 | 1988-04-05 | Matti Siren | Stabilized composition containing inositoltriphosphate |
US5330979A (en) * | 1984-10-23 | 1994-07-19 | Perstorp Ab | Method of treating renal disorders with inositoltriphosphate |
US5128332A (en) * | 1984-10-23 | 1992-07-07 | Perstorp Ab | Method of treating cardiovascular diseases using inositoltrisphosphate |
US4777134A (en) * | 1984-10-23 | 1988-10-11 | Matti Siren | Inositoltriphosphate |
US4793945A (en) * | 1984-10-23 | 1988-12-27 | Matti Siren | Use of inositol triphosphate as a stabilizer and compositions formed therefrom |
US4794014A (en) * | 1984-10-23 | 1988-12-27 | Matti Siren | Food compositions containing inositol triphosphate and method for making same |
US4734283A (en) * | 1984-10-23 | 1988-03-29 | Matti Siren | Method of making a food composition containing inosotoltriphosphate and the composition |
US5407924A (en) * | 1984-10-23 | 1995-04-18 | Perstorp Ab | Method of treating pain using inositol triphosphate |
US4851560A (en) * | 1984-10-23 | 1989-07-25 | Matti Siren | Inositol triphosphates |
US4735936A (en) * | 1984-10-23 | 1988-04-05 | Matti Siren | Pharmaceutical composition containing inositol triphosphate |
US4797390A (en) * | 1984-10-23 | 1989-01-10 | Matti Siren | Inositol triphosphate pharmaceutical compositions |
US5023248A (en) * | 1984-10-23 | 1991-06-11 | Perstorp Ab | Method of treating diabetes with inositol triphosphate |
US5019566A (en) * | 1986-04-16 | 1991-05-28 | Perstorp Ab | Method of treating inflammation with inositol triphosphate |
US5135923A (en) * | 1986-04-16 | 1992-08-04 | Perstorp Ab | Method of treating cardiovascular diseases |
US5057507A (en) * | 1986-04-16 | 1991-10-15 | Perstorp Ab | Method of alleviating bone damage with inositoltriphosphate |
US4758420A (en) * | 1986-07-14 | 1988-07-19 | The Dow Chemical Company | Solvent extraction of polychlorinated organic compounds from porous materials |
US4952396A (en) * | 1986-11-19 | 1990-08-28 | Linus Pauling Institute Of Science & Medicine | Method of using phytic acid for inhibiting tumor growth |
US4847082A (en) * | 1987-01-21 | 1989-07-11 | Robert Sabin | Method of treatment of Alzheimer's disease using phytic acid |
US4758430A (en) * | 1987-01-21 | 1988-07-19 | Robert Sabin | Method of treatment of Alzheimer's disease using phytic acid |
US4895841A (en) * | 1987-06-22 | 1990-01-23 | Eisai Co., Ltd. | Cyclic amine compounds with activity against acetylcholinesterase |
US5342832A (en) * | 1989-12-21 | 1994-08-30 | Perstorp Ab | Use of mono and di inositolphosphates for treating inflammation |
US5111814A (en) * | 1990-07-06 | 1992-05-12 | Thomas Jefferson University | Laryngeal pacemaker |
US5217959A (en) * | 1990-09-06 | 1993-06-08 | Robert Sabin | Method of treating multiple sclerosis with phytic acid |
US5112814A (en) * | 1990-10-24 | 1992-05-12 | Robert Sabin | Method of treatment of Parkinson's disease using phytic acid |
US5306841A (en) * | 1991-07-03 | 1994-04-26 | Bundgaard Hans | Derivatives of inositol, preparations containing them and their use |
US5614510A (en) * | 1992-02-25 | 1997-03-25 | Perstorp Ab | Pharmaceutical composition with improved bioavailability of inositol phosphate |
US5633412A (en) * | 1992-10-05 | 1997-05-27 | Virginia Tech Intellectual Properties | Syntheses of D-chiro-3-inosose and (+)-D-chiro inositol |
US20030108595A1 (en) * | 1993-03-29 | 2003-06-12 | Queen's University At Kingston | Method for treating amyloidosis |
US5643562A (en) * | 1993-03-29 | 1997-07-01 | Queen's University Of Kingston | Method for treating amyloidosis |
US5728375A (en) * | 1993-03-29 | 1998-03-17 | Queen's University At Kingston | Method for treating amyloidosis |
US5972328A (en) * | 1993-03-29 | 1999-10-26 | Queen's University At Kingston | Method for treating amyloidosis |
US5840294A (en) * | 1993-03-29 | 1998-11-24 | Queen's University At Kingston | Method for treating amyloidosis |
US20010048941A1 (en) * | 1993-03-29 | 2001-12-06 | Queen's University Of Kingston | Method for treating amyloidosis |
US5554399A (en) * | 1993-04-05 | 1996-09-10 | Vanderbeke; E. M. M. | Process for hydrolyzing phytate with a synergetic enzyme composition |
US5714643A (en) * | 1993-08-11 | 1998-02-03 | Hokko Chemical Co., Ltd. | Processes for the preparation of D-chiro-inositol |
US5412080A (en) * | 1993-08-25 | 1995-05-02 | President And Fellow Of Harvard College | Enterobactin compounds |
US5760022A (en) * | 1994-01-25 | 1998-06-02 | Perstorp Ab | Pharmaceutical composition with improved bioavailability of inositol phosphate |
US5858326A (en) * | 1995-06-06 | 1999-01-12 | Neurochem, Inc. | Methods of increasing amyloid deposition |
US6384260B1 (en) * | 1996-06-11 | 2002-05-07 | Nutrimed Biotech | Molecular probes and modulators for PI-PLC and PI 3-kinase |
US6232486B1 (en) * | 1996-06-11 | 2001-05-15 | Nutrimed Biotech | Molecular probes and modulators for PI-PLC and PI 3-kinase |
US5880099A (en) * | 1996-09-20 | 1999-03-09 | The Regents Of The University Of California | Inositol polyphosphates and methods of using same |
US5977078A (en) * | 1996-09-20 | 1999-11-02 | The Regents Of The Univesity Of California | Inositol polyphosphate derivatives and methods of using same |
US20030068316A1 (en) * | 1997-02-05 | 2003-04-10 | Klein William L. | Anti-ADDL antibodies and uses thereof |
US5998485A (en) * | 1997-06-16 | 1999-12-07 | Cedars-Sinai Medical Center | Method for modulating immune response with inositol |
US6153603A (en) * | 1997-06-27 | 2000-11-28 | Perstorp Ab | Method of treating angiogenesis in tumor tissue |
US6720190B1 (en) * | 1998-03-27 | 2004-04-13 | Ole Hindsgaul | Methods for screening compound libraries |
US6310073B1 (en) * | 1998-07-28 | 2001-10-30 | Queen's University At Kingston | Methods and compositions to treat glycosaminoglycan-associated molecular interactions |
US20020193395A1 (en) * | 1998-07-28 | 2002-12-19 | Queen's University | Methods and compositions to treat glycosaminoglycan-associated molecular interactions |
US7157268B2 (en) * | 1999-06-07 | 2007-01-02 | Hokko Chemical Industry Co., Ltd. | Process for producing L-epi-2-inosose and novel process for producing epi-inositol using microorganisms |
US20040214307A1 (en) * | 1999-06-07 | 2004-10-28 | Atsushi Takahasi | Novel process for producing L-epi-2-inosose and novel process for producing epi-inositol using microorganisms |
US20020052311A1 (en) * | 1999-09-03 | 2002-05-02 | Beka Solomon | Methods and compostions for the treatment and/or diagnosis of neurological diseases and disorders |
US6329256B1 (en) * | 1999-09-24 | 2001-12-11 | Advanced Micro Devices, Inc. | Self-aligned damascene gate formation with low gate resistance |
US20040234626A1 (en) * | 1999-10-18 | 2004-11-25 | Gardiner Paul T. | Food supplement for increasing lean mass and strength |
US20060148905A1 (en) * | 1999-10-22 | 2006-07-06 | Kim Darrick S H | Methods for treatment of beta-amyloid protein-induced ocular disease |
US20010053767A1 (en) * | 2000-05-12 | 2001-12-20 | Manuel Martin-Lomas | Compounds and their uses |
US20010041677A1 (en) * | 2000-05-12 | 2001-11-15 | Manuel Martin-Lomas | Compounds and their uses |
US20030153512A1 (en) * | 2000-06-30 | 2003-08-14 | Manfred Hergenhahn | Curcumin derivatives with improved water solubility compared to curcumin and medicaments containing the same |
US20020013315A1 (en) * | 2000-07-06 | 2002-01-31 | Teall Martin Richard | Gamma secretase inhibitors |
US20040028673A1 (en) * | 2002-01-04 | 2004-02-12 | William Netzer | Compositions and methods for prevention and treatment of amyloid-beta peptide-related disorders |
US20060135624A1 (en) * | 2002-10-17 | 2006-06-22 | Jingyu Liang Et Al | Natural compound useful for treating diabetes, its preparation and use |
US20070078099A1 (en) * | 2003-02-27 | 2007-04-05 | Mclaurin Joanne | Method of preventing, treating and diagnosing disorders of protein aggregation |
US20040204387A1 (en) * | 2003-02-27 | 2004-10-14 | Mclaurin Joanne | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US7521481B2 (en) * | 2003-02-27 | 2009-04-21 | Mclaurin Joanne | Methods of preventing, treating and diagnosing disorders of protein aggregation |
US20060240534A1 (en) * | 2003-10-14 | 2006-10-26 | Masanori Yamaguchi | Process for producing scyllo-inositol |
US20050171112A1 (en) * | 2003-11-03 | 2005-08-04 | Probiodrug Ag | Combinations useful for the treatment of neuronal disorders |
US20060004096A1 (en) * | 2004-05-28 | 2006-01-05 | Joseph Larner | Method of Treating Endothelial Dysfunction, Oxidative Stress and Related Diseases |
US20080306166A1 (en) * | 2004-11-17 | 2008-12-11 | Mclaurin Joanne | Compositions and Methods For Treatment of Disorders of Protein Aggregation |
US20090062403A1 (en) * | 2004-11-17 | 2009-03-05 | Mclaurin Joanne | Compositions and Methods for Treatment of Disorders of Protein Aggregation |
US20060189582A1 (en) * | 2004-11-17 | 2006-08-24 | Mclaurin Joanne | Compositions and methods for treatment of disorders of protein aggregation |
US20070111970A1 (en) * | 2005-10-13 | 2007-05-17 | Antonio Cruz | Inositol compounds and uses of same in the treatment of diseases characterized by abnormal protein folding or aggregation or amyloid formation, desposition, accumulation or persistence |
US20070197452A1 (en) * | 2006-02-17 | 2007-08-23 | Mclaurin Joanne | Treatment of amyloid-related diseases |
US20070197453A1 (en) * | 2006-02-17 | 2007-08-23 | Mclaurin Joanne | Compositions and methods for treatment of disorders of protein aggregation |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9833420B2 (en) | 2003-02-27 | 2017-12-05 | JoAnne McLaurin | Methods of preventing, treating, and diagnosing disorders of protein aggregation |
US20110201060A1 (en) * | 2010-02-15 | 2011-08-18 | Abbott Laboratories | Process for the preparation of scyllo-inositol |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9833420B2 (en) | Methods of preventing, treating, and diagnosing disorders of protein aggregation | |
Ludolph et al. | Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options | |
Dorninger et al. | Disturbed neurotransmitter homeostasis in ether lipid deficiency | |
Sudduth et al. | β-amyloid deposition is shifted to the vasculature and memory impairment is exacerbated when hyperhomocysteinemia is induced in APP/PS1 transgenic mice | |
US20060189582A1 (en) | Compositions and methods for treatment of disorders of protein aggregation | |
Wildburger et al. | Amyloid-β plaques in clinical Alzheimer’s disease brain incorporate stable isotope tracer in vivo and exhibit nanoscale heterogeneity | |
Kang et al. | Tau modification by the norepinephrine metabolite DOPEGAL stimulates its pathology and propagation | |
US20070197452A1 (en) | Treatment of amyloid-related diseases | |
Dehelean et al. | Trends in glycolipid biomarker discovery in neurodegenerative disorders by mass spectrometry | |
Gómez-Pinedo et al. | Immununochemical markers of the amyloid cascade in the hippocampus in motor neuron diseases | |
Gong et al. | p47 phox deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD | |
Zhang et al. | Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairment | |
US20070197453A1 (en) | Compositions and methods for treatment of disorders of protein aggregation | |
Mousa et al. | Amylin and pramlintide modulate γ-secretase level and APP processing in lipid rafts | |
Hedera et al. | Inherited dementias | |
Fu et al. | Heart fatty acid-binding protein is associated with phosphorylated tau and longitudinal cognitive changes | |
CN101385722A (en) | Method of preventing, treating and diagnosing disorders of protein aggregation | |
Ni | Multiple amyloid binding sites in Alzheimer brain and their interaction with synaptic and inflammatory mechanisms |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: EXPRESSLY ABANDONED -- DURING PUBLICATION PROCESS |