WO2005051378A1 - Procede et composition pour traiter de troubles neurodegeneratifs - Google Patents

Procede et composition pour traiter de troubles neurodegeneratifs Download PDF

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Publication number
WO2005051378A1
WO2005051378A1 PCT/US2004/039195 US2004039195W WO2005051378A1 WO 2005051378 A1 WO2005051378 A1 WO 2005051378A1 US 2004039195 W US2004039195 W US 2004039195W WO 2005051378 A1 WO2005051378 A1 WO 2005051378A1
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inhibitor
selective cox
flurbiprofen
composition
cox
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PCT/US2004/039195
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English (en)
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Gaylen Zentner
Kenton Zavitz
Adrian Hobden
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Myriad Genetics, Inc.
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Publication of WO2005051378A1 publication Critical patent/WO2005051378A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings

Definitions

  • the invention relates to compositions and methods for the treatment of diseases.
  • the invention particularly relates to compositions having R-flurbiprofen and a selective COX-2 inhibitor which are useful for the prevention and/or treatment of neurodegenerative diseases.
  • Neurodegenerative disorders gravely affect many individuals and their ability to carry out normal daily activities. Neurodegenerative disorders have a variety of manifestations specific manifestations, but are generally characterized by the loss of nerve cells or neural tissue. However, the pathogenesis and molecular mechanisms of many neurodegenerative disorders is unknown. Neurodegenerative brain disorders such as dementia, and its most common form Alzheimer's disease (AD), involve parts of the brain that control thought, memory, and language. Despite intensive research throughout the world, the causes of AD and other neurodegenerative diseases are still unknown, and there is no cure. AD most commonly begins after the age of 60 with the risk increasing with age. Younger people can also get AD, but it is much less common.
  • AD most commonly begins after the age of 60 with the risk increasing with age. Younger people can also get AD, but it is much less common.
  • AD Alzheimer's disease
  • a ⁇ is a peptide of varying lengths up to 42 amino acids long.
  • a ⁇ is produced by the intracellular processing of its precursor, APP, the amyloid deposits forming the core of the plaques are extracellular.
  • studies have shown that the longer form of A ⁇ (A ⁇ 42 ) is much more amyloidogenic than the shorter forms (A ⁇ 40 or A ⁇ 39 ). Both plaques and tangles are found in the same brain regions affected by neuronal and synaptic loss.
  • abnormal processing of A ⁇ may be a cause of AD and A ⁇ formation is a target for affecting Alzheimer's disease progression. It has also been shown that the toxicity of some compounds (amyloid or tangles) could be aggravated by activation of the complement cascade (Rogers et al, Res Immunol 143:624-630 (1992); Rozemuller et al, Res Immunol 143:646-649 (1992)), suggesting the possible involvement of inflammatory process in the neuronal death (Fagarasan, Aisen, Brain Res 723:231-234 (1996); Kalaria et al, Neurodegeneration 5:497-503 (1996); Kalaria et al, Neurobiol Aging 17:687-693 (1996); Farlow, Am JHealth Syst Pharm 55 Suppl 2:S5-10 (1998)).
  • the chronic neuroinflammation seen in neurodegenerative disorders such as AD and Parkinson's disease (PD) further indicates that inflammation may be involved in the pathogenesis of neurodegenerative disorders (Eikelenboom et al, Glia 40(2):232-239; Gao et al, Trends Pharmacol Sci. 24(8):395-401).
  • overexpression of cyclooxygenase-2 (COX-2), an enzyme involved in inflammation was recently reported to be related to the neuropathology of AD in mouse models of AD (Xiang et al Neurobiol. Aging 23:327-34 (2002)).
  • NSAID non-steroidal anti- inflammatory drug
  • COX cyclooxygenase
  • COX-2 selective inhibitors have become attractive candidates for long-term drug use since they appear to be less-toxic than non-selective COX inhibitors.
  • studies have shown that NSAIDs selectively inhibiting COX-2 rather than COX-1 enzymes do not appear to reduce the incidence of symptomatic side-effects such as nausea, vomiting, epigastric pain/heartburn, abdominal discomfort. See Rainsford, J. Physiol Paris, 95:11-19 (2001).
  • the selective COX-2 inhibitor rofecoxib may be associated with an increased risk of myocardial infarction. Shoor, Curr. Sports. Med. Rep., 1:107-115 (2002).
  • AD patients have a loss of nerve cells (particularly cholinergic neurons) in areas of the brain that are vital to memory and other mental abilities.
  • levels of the neurotransmitter acetylcholine are markedly reduced in AD brains compared to controls.
  • the progressive loss of cholinergic neurons appears to accompany the progressive loss in memory and cognitive function in AD patients. It is thought that one reason for the decline of cholinergic neurons is the loss or decreased function of acetylcholine.
  • the level of acetylcholme in a neuron is typically controlled by the equilibrium between its biosynthesis and bio-degradation.
  • the enzyme acetylcholine esterase (AChE) is primarily responsible for the degradation of acetylcholine.
  • AChE has been found to be associated with neuritic plaques (Inestrosa, Alarcon, J Physiol Paris 92:341-344 (1998)), and APP has been found to interact with AChE (Alvarez et al, JNeurosci 18:3213-3223 (1998)).
  • AChE acetylcholine esterase
  • the invention generally relates to compositions and therapeutic treatments for neurodegenerative disorders. More specifically, the invention provides compositions for treating and/or slowing the progression of neurodegenerative disorders, or symptoms thereof.
  • the compositions of the invention have R-flurbiprofen and at least one cyclooxygenase-2 (COX-2) inhibitor or salt, derivative, analogue, metabolite, or hydrate thereof.
  • COX-2 cyclooxygenase-2
  • the methods of the invention involve treating an individual in need of treatment (or prophylaxis) with an effective amount of R-flurbiprofen and at least one selective COX-2 inhibitor, or salt, derivative, analogue, metabolite, or hydrate thereof.
  • the invention provides a composition comprising R-flurbiprofen or a pharmaceutically acceptable salt thereof and at least one selective COX-2 inhibitor or salt, derivative, analogue, metabolite, or hydrate thereof.
  • the composition comprises R-flurbiprofen and celecoxib.
  • the composition comprises a derivative or analogue of R-flurbiprofen and/or a selective COX-2 inhibitor.
  • the compositions of the invention can provide the two components together in a single dose or separately.
  • the compositions of the invention can also provide the components with a pharmaceutically acceptable carrier.
  • the invention provides a method for treating and/or slowing the onset of neurodegenerative disorders.
  • an effective amount of R-flurbiprofen or a pharmaceutically acceptable salt thereof and at least one selective COX-2 inhibitor or salt, derivative, analogue, metabolite, or hydrate thereof, is administered to an individual in need of such treatment.
  • the individual in need of treatment can have a neurodegenerative disorder, a predisposition to a neurodegenerative disorder, and/or desire prophylaxis against neurodegenerative disorders.
  • the method is capable of reducing at least one symptom of the neurodegenerative disorder.
  • the method is capable of slowing the progression of at least one symptom of the neurodegenerative disorder.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, dementia, mild cognitive impairment and Down's Syndrome.
  • the invention provides a method for the treatment or prophylaxis of Alzheimer's disease through the administration of an effective amount of R-flurbiprofen and celecoxib, R-flurbiprofen and rofecoxib, or R-flurbiprofen and lumiracoxib.
  • the invention provides a method of reducing amyloid ⁇ (A0 ) protein levels in the plasma or CSF of a human patient.
  • the method relates to decreasing or slowing an increase in A/3 42 protein levels, in an individual in need of such treatment, by administering to the individual an effective amount of R-flurbiprofen or a pharmaceutically acceptable salt thereof and at least one selective COX-2 inhibitor or salt, derivative, analogue, metabolite, or hydrate thereof.
  • the individual in need of treatment can have a neurodegenerative disorder, a predisposition to a neurodegenerative disorder, and/or desire prophylaxis against neurodegenerative disorders, where the disorder is characterized by increased A ⁇ 42 protein levels.
  • the effective amount is an amount of R-flurbiprofen and at least one selective COX-2 inhibitor sufficient for reducing A/3 42 protein levels.
  • the effective amount is an amount of R-flurbiprofen and at least one selective COX-2 inhibitor, sufficient for slowing an increase in A ⁇ 42 protein levels or an increase in the rate of A/3 42 increase.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, dementia, mild cognitive impairment and Down's Syndrome.
  • the invention provides a method for the treatment or prophylaxis of Alzheimer's disease through the administration of an A/3 42 protein lowering effective amount of R-flurbiprofen and celecoxib, R-flurbiprofen and rofecoxib, or R-flurbiprofen and lumiracoxib.
  • the invention provides a method for treating neurodegenerative disorders while avoiding and/or reducing the side-effects associated with higher levels of R-flurbiprofen or a pharmaceutically acceptable salt thereof and a selective COX-2 inhibitor.
  • a disease treating or preventing effective amount of R-flurbiprofen and at least one selective COX-2 inhibitor is administered to an individual in need of such treatment, at levels (or by treatment regimes) that avoid or reduce the side-effects associated with these treatments.
  • the individual in need of treatment can have a neurodegenerative disorder, a predisposition to a neurodegenerative disorder, and/or desire prophylaxis against neurodegenerative disorders.
  • the effective amount of R-flurbiprofen or a pharmaceutically acceptable salt thereof and at least one selective COX-2 inhibitor is capable of reducing at least one symptom of the neurodegenerative disorder.
  • the effective amount of R- flurbiprofen or a pharmaceutically acceptable salt thereof and at least one selective COX- 2 inhibitor is capable of slowing the progression, slowing the rate of progression, or lessening the severity of at least one symptom of the neurodegenerative disorder.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, dementia, mild cognitive impairment and Down's
  • the invention provides a method for the treatment or prophylaxis of Alzheimer's disease through the administration of an effective amount of R-flurbiprofen and celecoxib, R-flurbiprofen and rofecoxib, or R-flurbiprofen and lumiracoxib.
  • the invention provides a method for slowing the death of neurons in the brain, or lowering the level or slowing the growth of neuritic plaques in an individual.
  • the method relates to decreasing or slowing an increase in neuron death or neuritic plaque formation, in an individual in need of such treatment, by administering to the individual an effective amount of R-flurbiprofen or a pharmaceutically acceptable salt thereof and at least one selective COX-2 inhibitor, or salt, derivative, analogue, metabolite, or hydrate thereof.
  • the individual in need of treatment can have a neurodegenerative disorder, a predisposition to a neurodegenerative disorder, and/or desire prophylaxis against neurodegenerative disorders, where the disorder is characterized by neuron death or a buildup of neuritic plaques.
  • the effective amount is an amount of R-flurbiprofen or a pharmaceutically acceptable salt thereof and at least one selective COX-2 inhibitor sufficient for decreasing neuron death or neuritic plaque formation.
  • the effective amount is an amount of R-flurbiprofen or a pharmaceutically acceptable salt thereof and at least one selective COX-2 inhibitor, sufficient for decreasing or slowing an increase in neuron death or neuritic plaque formation.
  • the selective COX-2 inhibitor is celecoxib.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, dementia, mild cognitive impairment or Down's Syndrome.
  • the invention provides a composition comprising R-flurbiprofen or a pharmaceutically acceptable salt thereof and an NSAID capable of reducing inflammation or inhibiting COX, or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method for treating and/or slowing the onset of neurodegenerative disorders. According to this method, an effective amount of R- flurbiprofen or a pharmaceutically acceptable salt thereof and an NSAID capable of reducing inflammation or inhibiting COX, or a pharmaceutically acceptable salt thereof, is administered to an individual in need of such treatment.
  • the individual in need of treatment can have a neurodegenerative disorder, a predisposition to a neurodegenerative disorder, and/or desire prophylaxis against neurodegenerative disorders.
  • the method is capable of reducing at least one symptom of the neurodegenerative disorder.
  • the invention generally relates to compositions and therapeutic treatments for neurodegenerative disorders.
  • the compositions of the invention have R-flurbiprofen or a pharmaceutically acceptable salt thereof and at least one selective COX-2 inhibitor, or salt, derivative, analogue, metabolite, or hydrate thereof.
  • the methods of the invention involve treating an individual in need of treatment (or prophylaxis) with an effective amount of R-flurbiprofen or a pharmaceutically acceptable salt thereof and at least one selective COX-2 inhibitor, or salt, derivative, analogue, metabolite, or hydrate thereof.
  • the invention provides a composition comprising R-flurbiprofen or a pharmaceutically acceptable salt thereof and at least one selective COX-2 inhibitor or salt, ester, derivative, analogue, or metabolite thereof.
  • R- flurbiprofen refers to the R-enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen.
  • R-flurbiprofen or a pharmaceutically acceptable salt thereof can be administered in a composition substantially free of S-enantiomer or a salt or ester thereof.
  • selective COX-2 inhibitor refers to a class of compounds capable of inhibiting the activity of the COX-2 enzyme more than the COX-1 enzyme as determined by performing the COX 1/2 activity assays provided in Example 1 below.
  • the ratio of IC 50 values for COX-2 inhibition over COX-1 inhibition is at least 5, more preferably at least 10.
  • the ratio of IC 50 values for COX-2 inhibition over COX-1 inhibition is at least 15, preferably at least 20, and more preferably at least 40 or 50. Examples of selective COX-2 inhibitors have been described in U.S. Pat. Nos.
  • selective COX-2 inhibitors include several classes of compounds including but not limited to, heterocydic aromatic oxazoles, oxazolone derivatives, substituted oxazoles, sulfonylphenylpyrazoles, pyrazolyl benzenesulfonamides, and benzylidene derivatives.
  • selective COX-2 inhibitors may have the formula as described in U.S. Pat. No. 6,362,209:
  • Z is an oxygen atom; one of R and R) is a group of the formula
  • R 3 is lower alkyl, amino or lower alkylamino
  • R 4 , R 5 , R ⁇ and R 7 are the same or different and each is hydrogen atoms, halogen atom, lower alkyl, loweralkoxy, trifluorometyyl, hydroxyl or amino, provided that at least one of R 4 , R 5 , R ⁇ and R 7 is not hydrogen atom, and the other is an optionally substituted cycloalkyl, an optionally substituted heterocydic group or an optionally substituted aryl; and R 2 is a lower alkyl or a halogenated lower alkyl; as described in U.S. Pat. No. 6,362,209.
  • Specific examples of selective COX-2 inhibitors included in the present invention are compounds of the following formulas:
  • selective COX-2 inhibitors included in the present invention are: celecoxib (Celebrex® by Pfizer), rofecoxib (Vioxx® by Merck), valdecoxib (Bextra® by Pfizer), tilmacoxib (described in U.S. Pat. No. 6,362,209 by Japan Tobacco), etoricoxib (Arcoxia® by Merck), parecoxib (Dynastat® by Pfizer), deracoxib, S-2474 (described in U.S. Pat. No. 5,418,230 by Shionogi), L-745337
  • the COX-2 inhibitor is celecoxib, rofecoxib, valdecoxib, tilmacoxib, etoricoxib, lumiracoxib, parecoxib, deracoxib, S-2474, L-745337, SVT-2016, CS-502, LAS-34475, ABT-963, GW-406381, DFP, BMS-347070, P54, NS- 398, nimesulide, etodolac, or meloxicam.
  • the selective COX-2 inhibitor is selected from the group consisting of valdecoxib, parecoxib, etoricoxib, lumiracoxib, or meloxicam. In a further embodiment the selective COX-2 inhibitor is selected from the group consisting of L-745337, DFP, tilmacoxib, S-2474, NS-398, nimesulide, and etodolac.
  • the composition of the present invention comprises R-flurbiprofen or a pharmaceutically acceptable salt thereof and celecoxib. In another specific embodiment the composition includes R-flurbiprofen and rofecoxib. In yet another embodiment the composition includes R-flurbiprofen and valdecoxib.
  • the selective COX-2 inhibitor can inhibit the function of COX-2 at least five fold more than COX-1. In another embodiment, the selective COX-2 inhibitor can inhibit the function of COX-2 at least twenty, thirty, forty, or fifty fold more than COX-1. In another embodiment, the compositions of the present invention is substantially free of the (S)-stereoisomer of R-flurbiprofen. In a specific embodiment, the ratio of R- flurbiprofen to S-flurbiprofen is at least 70:30 by weight. In another specific embodiment, the ratio of R-flurbiprofen to S-flurbiprofen is at least 80:20 by weight.
  • the ratio of R-flurbiprofen to S-flurbiprofen is at least 90:10 by weight. In another specific embodiment, the ratio of R-flurbiprofen to S-flurbiprofen is at least 99:1 by weight.
  • the compositions of the present invention may be a derivative or analogue of R-flurbiprofen or the selective COX-2 inhibitor.
  • analogue encompasses a chemical compound that is structurally similar to another but differs slightly in composition. Such differences can be the replacement of one atom or functional group by an atom or functional group of a different element. Such differences can also be the addition of molecular groups such as sulfur or nitrogen containing groups.
  • an analogue also includes chemical compounds that are linked together to form larger molecules containing the compound, e.g. polymers.
  • the term "derivative" as used herein, encompasses a chemical substance related structurally to another substance, in which the chemical substance is able to be made from the related substance.
  • the selective COX-2 inhibitor is a derivative or analogue of the selective COX-2 inhibitor selected from the group consisting of celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib (Bextra®), tilmacoxib, etoricoxib
  • the analogue or derivative of R-flurbiprofen or a selective COX-2 inhibitor may be a nitrosated or nitrosylated selective COX-2 inhibitor and/or R-flurbiprofen.
  • Nitrosation refers to linking a nitrogen monoxide group (NO) to a compound.
  • Nitrosylation refers to linking a nitrogen dioxide group (NO 2 ) to a compound.
  • Nitrosated and/or nitrosylated non steroidal anti-inflammatory drugs (NSAIDs) and nitrosated and/or nitrosylated R-flurbiprofen derivatives are known to release nitric oxide, which may increase the efficacy of clearing A ⁇ deposits in an individual.
  • one of the analogues of R-flurbiprofen or selective COX-2 inhibitor of the composition has a sulfur-containing functional group containing a hydrocarbyl moiety attached.
  • the composition of the present invention includes an analogue of R-flurbiprofen with the structure: X— L— Y— S(O) n — Y'— Q wherein: X is an R-flurbiprofen; L is an optional linker/spacer; Y and Y' are optionally present, and when present are independently — O — or — NR' — , wherein R' is H or an optionally substituted hydrocarbyl moiety; n is 1 or 2; and Q is H or an optionally substituted hydrocarbyl moiety.
  • the composition of the present invention contains polymers of R-flurbiprofen and/or a selective COX-2 inhibitor.
  • the polymer can be made up of R-flurbiprofen, a selective COX-2 inhibitor, or a combination thereof.
  • a specific embodiment contains a polymer of R-flurbiprofen.
  • Another specific embodiment contains a polymer of a selective COX-2 inhibitor, such as celecoxib.
  • the composition contains a polymer of alternating rofecoxib and R-flurbiprofen compounds.
  • the composition contains a polymer of alternating celecoxib and valdecoxib molecules.
  • the composition of the present invention contains a salt of a selective COX-2 inhibitor or R-flurbiprofen.
  • the composition may contain a salt of paracoxib or valdecoxib.
  • R-flurbiprofen and the selective COX-2 inhibitor may or may not be chemically linked together.
  • the compositions of the invention can provide the two components together in a single dose or separately.
  • the compositions of the invention can also provide the components with a pharmaceutically acceptable carrier.
  • the invention provides a method for treating neurodegenerative disorders by administering compounds or compositions of the present invention.
  • neurodegenerative diseases and “neurodegenerative disorders” include central nervous system disorders that can be characterized by a gradual loss of nerve cells or neural tissues and specifically include such diseases and impairments as Alzheimer's disease, dementia, MCI, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, neuropathies, Creutzfeld- Jacob disease, Pick's disease and Down's Syndrome.
  • treating Alzheimer's disease or “treating neurodegenerative disorders” refer to a slowing of or a reversal of the progress of the disease or disorder. Treating Alzheimer's disease or neurodegenerative disorders also includes reducing the symptoms of the disease.
  • preventing an increase in a symptom refers to not allowing a symptom to increase or worsen, as well as reducing the rate of increase in the symptom.
  • a symptom can be measured as the amount of particular disease marker, i.e., a protein.
  • Preventing an increase means that the amount of the protein does not increase or that the rate at which it increases is reduced.
  • the term "preventing Alzheimer's disease” or “preventing "neurodegeneratives disorders” refers to a slowing of disease progression, delaying the onset of the disease, or the symptoms thereof. It is believed that administration of the compositions of the present invention is unexpectedly useful for treating or preventing neurodegenerative disorders.
  • R- flurbiprofen and at least one selective non-steroidal anti-inflammatory agent acts synergistically to lower levels of A/3 42; slow the death or decline of neurons in the brain, and/or to lower the level or slow the growth of neuritic plaques.
  • NSAID selective non-steroidal anti-inflammatory agent
  • R-flurbiprofen and various NSAIDs decrease the secretion of A ⁇ from cultured cells (Gasparini et al, J. ofNeurochemistry 91 :521-536 (2004)).
  • R-flurbiprofen may not adequately inhibit COX-2 induced inflammation or production of oxidative species that lead to neurodegeneration.
  • administration of R-flurbiprofen and a NSAID such as a selective COX-2 inhibitor is thought to be particulary effective in treating neurodegenerative diseases.
  • Individuals having neurodegenerative disorders such as mild-to-moderate Alzheimer's disease can be diagnosed by any method available to the ordinary artisan skilled is such diagnoses. For example, progression or severity of AD can be determined using Mini Mental State Examination (MMSE) as described by Mohs et al. Int Psychogeriatr 8:195-203 (1996); Alzheimer's Disease Assessment Scale-cognitive component (ADAS-cog) as described by Galasko et al.
  • MMSE Mini Mental State Examination
  • ADAS-cog Alzheimer's Disease Assessment Scale-cognitive component
  • Alzheimer Dis Assoc Disord 11 suppl 2:S33-9 (1997); the Alzheimer's Disease Cooperative Study Activities of Daily Living scale (ADCS-ADL) as described by McKhann et al. Neurology 34:939-944 (1984); and the NINCDS-ADRDA criteria as described by Folstein et al J. Psychiatr. Res. 12:189-198 (1975).
  • ADCS-ADL Alzheimer's Disease Cooperative Study Activities of Daily Living scale
  • NINCDS-ADRDA criteria as described by Folstein et al J. Psychiatr. Res. 12:189-198 (1975).
  • methods that allow for evaluating different regions of the brain and estimating plaque and tangle frequencies can be used. These methods are described by Braak et al Acta Neuropathol 82:239-259 (1991); Khachaturian Arch. Neuro. 42:1097-1105 (1985); Mina et al.
  • individuals with probable mild-to-moderate AD take an oral dose of a pharmaceutical composition once-a-day for at least 90 days, preferably 120 days, more preferably at least 180 days and even more desirably at least 365 days.
  • Individuals undergoing such treatment are likely to see an improvement or lessening in decline of cognitive function, an improvement or lessening in decline in biochemical disease marker progression, and/or an improvement or lessening decline in plaque pathology.
  • a lessening in decline in cognitive function can be assessed using test of cognitive function like the ADAS-cog.
  • an individual treated with placebo having probable mild-to-moderate Alzheimer's disease is expected to score preferably approximately 5.5 points lower on the ADAS-cog test after a specified period of time of treatment (e.g., 1 year) whereas an individual treated with the composition of this aspect of the invention for the same period of time will score approximately 2.2 points lower on the ADAS-cog scale with a 60% decrease in decline or 3.3 points lower with a 40% decrease in decline in cognitive function when treated with the composition for the same specified period of time.
  • an effective amount of R-flurbiprofen and at least one selective COX-2 inhibitor, or salt, derivative, analogue, metabolite, or hydrate thereof is administered to an individual in need of such treatment.
  • the individual in need of treatment can have a neurodegenerative disorder, a predisposition to a neurodegenerative disorder, and/or desire prophylaxis against neurodegenerative disorders.
  • the effective amount R-flurbiprofen and selective COX-2 inhibitor is capable of slowing the onset or reducing at least one symptom of the neurodegenerative disorder.
  • Symptoms of neurodegenerative diseases include cognitive decline, gradual memory loss, disorientation, personality changes, loss of language skills, and tremors.
  • R-flurbiprofen and a selective COX-2 inhibitor are administered to slow the rate of cognitive decline.
  • the administered compounds may slow the rate of cognitive decline by about 10%, 25%, 40%, 50% or 60%.
  • the individual in need of treatment can have a neurodegenerative disorder, a predisposition to a neurodegenerative disorder, and/or desire prophylaxis against neurodegenerative disorders.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, dementia, and mild cognitive impairment.
  • the invention provides a method for the treatment or prophylaxis of Alzheimer's disease through the administration of an effective amount of R-flurbiprofen and celecoxib, R-flurbiprofen and rofecoxib, or R-flurbiprofen and lumiracoxib.
  • the effective amount of R-flurbiprofen and at least one selective COX-2 inhibitor is capable of reducing at least one symptom of the neurodegenerative disorder.
  • the effective amount of R- flurbiprofen and the selective COX-2 inhibitor is capable of slowing the progression of at least one symptom of the neurodegenerative disorder.
  • the administered COX-2 inhibitor is celecoxib, rofecoxib, valdecoxib, tilmacoxib, etoricoxib, lumiracoxib, parecoxib, deracoxib, S-2474, L-745337, SVT-2016, CS-502, LAS-34475, ABT-963, GW-406381, DFP, BMS-347070, P54, NS-398, nimesulide, etodolac, or meloxicam.
  • the administered selective COX-2 inhibitor is selected from the group consisting of valdecoxib, parecoxib, etoricoxib, lumiracoxib, or meloxicam.
  • the administered selective COX-2 inhibitor is selected from the group consisting of L- 745337, DFP, tilmacoxib, S-2474, NS-398, nimesulide, and etodolac.
  • the R-flurbiprofen and celecoxib are administered to an individual in need thereof.
  • R-flurbiprofen and rofecoxib is administered to an individual in need thereof.
  • R-flurbiprofen and valdecoxib are administered to an individual in need thereof.
  • the invention provides a method of reducing A/3 42 protein levels in a cell, tissue or bodily fluid.
  • A/3 42 lowering refers to the capability to reduce the amount of A/3 42 present and/or being produced. Levels of A 42 can be determined with an ELISA assay configured to detect A/3 42 . Methods of determining Aj3 42 levels are described in the examples and references cited herein. In particular, the method relates to decreasing or slowing an increase in A/3 42 protein levels, in an individual in need of such treatment, by administering to the individual an effective amount of R-flurbiprofen and at least one selective COX-2 inhibitor, or salt, derivative, analogue, metabolite, or hydrate thereof. In one embodiment R-flurbiprofen is administered simultaneously with a selective COX-2 inhibitor.
  • R-flurbiprofen is administered in the morning and a selective COX-2 inhibitor is administered at night.
  • the individual in need of treatment can have a neurodegenerative disorder, a predisposition to a neurodegenerative disorder, and/or desire prophylaxis against neurodegenerative disorders, where the disorder is characterized by increased A ⁇ 42 protein levels.
  • an effective amount of R-flurbiprofen sufficient for reducing A/3 42 protein levels is administered.
  • An effective amount of a selective COX-2 inhibitor sufficient for inhibiting inflammation is also administered.
  • an effective amount of R-flurbiprofen sufficient for slowing an increase in A/3 42 protein levels or an increase in the rate of A/3 42 increase is administered.
  • An effective amount of a selective COX-2 inhibitor sufficient for inhibiting inflammation is also administered.
  • the invention provides a method of lowering
  • the neurodegenerative disease is selected from the group consisting of AD, dementia, mild cognitive impairment and Down's Syndrome.
  • the neurodegenerative disease is inclusion body myositis.
  • the invention provides a method for the treatment or prophylaxis of AD through the administration of an A/?
  • the invention provides a method for treating neurodegenerative disorders while avoiding and/or reducing the side-effects associated with higher levels of R-flurbiprofen and a selective COX-2 inhibitor, or salt, derivative, analogue, metabolite, or hydrate thereof.
  • the selective COX-2 inhibitor rofecoxib may be associated with an increased risk of myocardial infarction (Shoor, Curr. Sports. Med. Rep., 1 : 107- 115 (2002)) and NSAIDs selectively inhibiting COX-2 do not appear to reduce the incidence of symptomatic side-effects such as nausea, vomiting, epigastric pain/heartburn, abdominal discomfort. See Rainsford, J. Physiol Paris, 95:11-9 (2001 ).
  • COX inhibition by racemic flurbiprofen is found specifically in the S- enantiomer, whereas levels of A ⁇ 2 are able to be lowered by administering R-flurbiprofen or metabolites of R-flurbiprofen.
  • a selective COX-2 inhibitor, or derivative thereof may be administered in conjunction with R-flurbiprofen, or derivative thereof, to achieve the neuroprotective and/or A 3 42 -lowering effect usually achieved by administering a larger dose of either the selective COX-2 inhibitor or R- flurbiprofen.
  • the side effects associated with R-flurbiprofen or COX-2 inhibition may be reduced when R-flurbiprofen is administered with a selective COX-2 inhibitor because the synergistic effect of compositions of the present invention allow a smaller dosage of selective COX-2 inhibitors and/or R-flurbiprofen to be administered.
  • compositions of derivatives of R-flurbiprofen and at least one selective COX-2 inhibitor will have less severe side effects when administered to an individual.
  • the change in side effects associated with R-flurbiprofen and/or selective COX-2 inhibitors can be measured by a variety of methods known in the art. For example, the ulcerogenicity of compounds of the present invention may be measured by the small bowel ulcer score.
  • the small bowel ulcer score of a compound is determined by treating a rat daily with the oral administration of the compound for 30 days. At the end of the 30 days, the rat is sacrificed and the intestines removed. Lesions of appreciable size in the mucosa are measured. A cumulative score equaling the sum of the diameters of the ulcers measured are reported as the ulcer score.
  • both A ⁇ 42 and inflammation have been implicated in AD.
  • R-flurbiprofen lowers A ⁇ 42 whereas COX- 1/2 inhibition reduces inflammation thereby exhibiting a synergistic effect.
  • a disease treating or preventing effective amount of R-flurbiprofen and at least one selective COX-2 inhibitor is administered to an individual in need of such treatment, at levels (or by treatment regimes) that avoid or reduce the side-effects associated with these treatments.
  • the amount of administered R-flurbiprofen is reduced in order to achieve a reduction of side effects.
  • the amount of a selective COX-2 inhibitor is reduced in order to achieve a decrease in unwanted side effects.
  • a derivative or analogue of R-flurbiprofen or a selective COX-2 inhibitor are administered in order to achieve a reduction in unwanted side effects associated with R-flurbiprofen or COX-2 therapy.
  • the effective amount of R-flurbiprofen and at least one selective COX-2 inhibitor is capable of reducing at least one symptom of the neurodegenerative disorder.
  • the effective amount of R-flurbiprofen and at least one selective COX-2 inhibitor is capable of slowing the progression or severity at least one symptom of the neurodegenerative disorder.
  • the invention provides a method for the treatment or prophylaxis of AD with less severe side effects by administering an effective amount of R-flurbiprofen and celecoxib, R-flurbiprofen and rofecoxib, R-flurbiprofen and lumiracoxib, R-flurbiprofen and meloxicam, R-flurbiprofen and etoricoxib, or R-flurbiprofen and parecoxib
  • the invention provides a method for slowing the death or decline of neurons in the brain, or lowering the level or slowing the growth of neuritic plaques in an individual.
  • the method relates to decreasing or slowing an increase in neuron death or neuritic plaque formation, in an individual in need of such treatment, by administering to the individual an effective amount of R-flurbiprofen and at least one selective COX-2 inhibitor, or salt, derivative, analogue, metabolite, or hydrate thereof.
  • the individual in need of treatment can have a neurodegenerative disorder, a predisposition to a neurodegenerative disorder, and/or desire prophylaxis against neurodegenerative disorders, where the disorder is characterized by neuron death or a buildup of neuritic plaques.
  • the selective COX-2 inhibitor is selected from the group consisting of celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib (Bextra®), tilmacoxib, etoricoxib (Arcoxia®), parecoxib (Dynastat®), deracoxib, etodolac, meloxicam, nimesulide, NS-398, S-2474 (by Shionogi), L-745337 (by Merck), SVT-2016 (by Laboratorios S.A.L.V.A.T., S.A.), CS-502 (by Sankyo), LAS-34475 (by Almirall Prodesfarma), ABT-963 (by Abbott Laboratories), GW-406381 (by
  • the selective COX-2 inhibitor is celecoxib.
  • the selective COX-2 inhibitor is paracoxib.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, dementia, mild cognitive impairment and Down's Syndrome.
  • the invention provides a composition comprising R-flurbiprofen or a pharmaceutically acceptable salt thereof and an NSAID capable of reducing inflammation or inhibiting COX, or a pharmaceutically acceptable salt thereof.
  • NSAIDs capable of reducing inflammation or inhibiting COX include selective COX-2 inhibitors, non-selective COX inhibitors and COX-1 selective inhibitors.
  • Examples of NSAIDs capable of reducing inflammation or inhibiting COX include: diclofenac, sulindac, meclofenamate, tomoxiprol, piroxicam, diflunisal, sodium salicylate, niflumic acid, zomepirac, fenoprofen, ampyrone, ibuprofen, tolmetin, naproxen, aspirin, indomethacin, ketoprofen, suprofen, flurbiprofen and ketorolac.
  • the invention also provides a method for treating and/or slowing the onset of neurodegenerative disorders.
  • an effective amount of R-flurbiprofen or a pharmaceutically acceptable salt thereof and an NSAID capable of reducing inflammation or inhibiting COX, or a pharmaceutically acceptable salt thereof is administered to an individual in need of such treatment.
  • the individual in need of treatment can have a neurodegenerative disorder, a predisposition to a neurodegenerative disorder, and/or desire prophylaxis against neurodegenerative disorders.
  • the method is capable of reducing at least one symptom of the neurodegenerative disorder.
  • the method is capable of slowing the progression of at least one symptom of the neurodegenerative disorder.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, dementia, mild cognitive impairment and Down's Syndrome.
  • the composition and/or method provides about 100 mg to about 1600 mg of R-flurbiprofen (e.g. 200 mg, 400 mg or 800 mg) and no greater than about 50% of the U.S. FDA approved dosage unit of an NSAID capable of reducing inflammation or inhibiting COX.
  • the dosage of ibuprofen is no greater than about 12.5 mg, 25 mg, 50 mg orlOO mg.
  • the unit dosage of naproxen is no greater than about 50 mg, 100 mg, 125 mg or 250 mg.
  • the unit dosage of diclofenac is no greater than about 10 mg, 12.5 mg, 25 mg or 50 mg.
  • the unit dosage of sulindac is no greater than about 50 mg, 75 mg or 150 mg.
  • the unit dosage of meclofenamate is no greater than about 10 mg, 25 mg or 50 mg.
  • the unit dosage of diflunisal is no greater than about 50 mg, 100 mg, 125 mg or 250 mg; the unit dosage of fenoprofen is no greater than about 50 mg, 100 mg or 150 mg; the unit dosage of tolmetin is no greater than about 50 mg, 100 mg or 200 mg; the unit dosage of flurbiprofen is no greater than about 10 mg, 25 mg or 50 mg; the unit dosage of ketorolac is no greater than about 5 mg or 10 mg; the unit dosage of ketoprofen is no greater than about 5 mg, 10 mg, 12.5 mg or 25 mg; the unit dosage of indomethacin is no greater than about 5 mg, 10 mg, 12.5 mg or 25 mg; the unit dosage of aspirin is no greater than about 125 mg, 250 mg or 500 mg; and the unit dosage of piroxicam is no greater than about 5 mg or 10 mg.
  • prostaglandin H synthase catalyze the rate-limiting step in prostaglandin synthesis from arachidonic acid.
  • Cell lines are known and available that express at least one form of the enzyme.
  • a human skin fibroblast line can be induced with IL-1 to synthesize COX-2, and a kidney epithelial cell line 293 has been stably transfected to constitutively express COX-1.
  • arachidonic acid can be added exogenously to increase signal to readably detectable levels.
  • the amount of prostaglandin-E 2 in the extracellular medium can be assayed by radioimmunoassay, for measuring COX activity.
  • IC 50 values for compounds for COX-1 and COX-2 can be determined by an ordinary skilled artisan.
  • the effects of the compositions and compounds of the invention can be determined by examining the secretion of A/3 42 by a CHO cell line that expresses APP. Untreated cell cultures, cell cultures treated with a compound of the invention and a carrier, carrier treated cell cultures can be examined and compared, and A/3 42 levels secretion levels can be determined.
  • a CHO (Chinese hamster ovary) cell line expressing APP can be culture for an appropriate amount of time and the supernatants analyzed for A/? 42 and A/3 40 levels using end-specific A ⁇ ⁇ 2 and Aj3 40 ELISAs (Suzuki et al (1994J Science 264:336-340).
  • the compounds of the invention can be prepared by a variety of procedures known in the art. A description of racemic flurbiprofen and its preparation is described in U.S. Pat. No. 3,755,427, which is incorporated herein by reference. Racemates of flurbiprofen can be obtained through Sigma Chemical Co. Additionally, many commercial sources exist for the stereospecific R-isomers of R-flurbiprofen. For example, R-flurbiprofen is available through Sepracor, Inc. Many commercial sources also exist for selective COX-2 inhibitors.
  • celecoxib Celebrex®
  • valdecoxib Bextra®
  • parecoxib Dynastat®
  • Rofecoxib Vioxx®
  • etoricoxib Arcoxia®
  • Other selective COX-2 inhibitors and methods of producing selective COX-2 inhibitors can be found in U.S. Pat. Nos.
  • Derivatives and analogues of R-flurbiprofen and/or selective COX-2 inhibitors of the present invention can be prepared by a variety of procedures known in the art. Chemical derivatives are typically generated by modifying functional groups of known chemicals. For example, substitutions to the aminocarboxylic acid, arylacetic acid, and arylpropionic acid groups are typically performed to produce a derivative or analogue. Modifications and additions to indole compounds are typical ways of producing analogues.
  • alkyl, hydroxyl alkyl, phenyl, benzyl, or thienyl groups may be added to indoles in various combinations in order to prepare derivatives and analogues of R-flurbiprofen or selective COX-2 inhibitors.
  • structural analogues can be identified by commercially available computer modeling programs.
  • R-flurbiprofen derivatives and analogues can be obtained from Sigma, Biomol, Cayman Chemical, ICN, or from the web through the Chemnavigator website. Novel R- flurbiprofen derivatives and analogues can be chemically synthesized using methods described in many published protocols and the starting materials for the synthesis of the compounds of the invention are available or readily preparable.
  • flurbiprofen, derivatives can be prepared by performing modifications including, but not limited to: (1) altering the position of the propionic acid substituent on the phenyl ring, (2) altering the position or type of substituents on the phenyl ring opposite the propionic acid substituent, (3) altering the bond connecting the two phenyl rings, (4) replacing the acetic acid substituent with a carboxylic acid substituent or other derivative.
  • a derivative of R-flurbiprofen or a selective COX-2 inhibitor can also be prepared by one skilled in the art by nitrosating and/or nitrosylating the compound.
  • R-flurbiprofen can be nitrosated and/or nitrosylated at locations such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon, and/or nitrogen.
  • nitroxybutyl ester may be coupled to flurbiprofen through a methoxyphenyl linker.
  • Other examples and methods of preparing nitrosated and or nitrosylated R- flurbiprofen can be found in U.S. Pat. App. Serial No. 938,560, which is incorporated herein by reference. Examples and method of preparing nitrosated and nitrosylated selective COX-2 inhibitors are found in U.S. Pat. App. Serial No.
  • the an analogue of R-flurbiprofen has the structure: X— L— Y— S(O) n — Y'— Q wherein: X is a R-flurbiprofen; L is an optional linker/spacer; Y and Y' are optionally present, and when present are independently — O — or — NR' — , wherein R' is H or an optionally substituted hydrocarbyl moiety; n is 1 or 2; and Q is H or an optionally substituted hydrocarbyl moiety.
  • Manufacturing derivatives of R-flurbiprofen and/or selective COX-2 inhibitors may be less expensive than manufacturing the parent compounds.
  • R-flurbiprofen and/or selective COX-2 inhibitors are thought to have desirable compounding, solubility, delivery, and/or formulation advantages over the parent compounds.
  • derivatives of R-flurbiprofen and/or selective COX-2 inhibitors typically have hydrophilic groups attached to the parent compound. By increasing the hydrophilic content of the compound, the derivative will be more soluble and easier to formulate.
  • manufacturing the combination therapeutic of R- flurbiprofen and a selective COX-2 inhibitor may be less expensive than the manufacture of the more expensive component thereby producing an advantage over the single compound therapy.
  • the invention further provides additional combination therapy strategies for treating neurodegenerative disorders such as Alzheimer's disease, MCI, and dementia.
  • an individual in need of treatment is administered an effective amount of an R-flurbiprofen, at least one selective COX-2 inhibitor, and optionally at least one compound selected from the group consisting of statins (such as atorvastatin, simvastatin, lovastatin, fluvastatin, pravastatin, cerivastatin, rosuvastatin, and pitavastatin), NMDA antagonists (such as memantine, adamantane, amantadine, an adamantane derivative, dextromethorphan, dextrorphan, dizocilpine, ibogaine, ketamine, remacemide, phencyclidine), NSAIDs, /3-secretase inhibitors, ⁇ - secretase inhibitors, acetylcholine esterase inhibitor
  • Preferred acetylcholine esterase inhibitors include tacrine, donepezil, rivastigmine, and galantamine.
  • the NSAID is selected from the group consisting of 5,5-dimethyl-3-(3- fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone, 5,5-dimethyl-3-isopropyloxy- 4-(4'-methylsulfonylphenyl)-2(5H)-furanone, resveratrol, flufemic acid, meclofenamic acid, fenoprofen, carprofen, ibuprofen, ketoprofen, sulindac, flurbiprofen, indomethacin, naproxen, etolodac, tiaprofenic, suprofen, ketorolac, pirprofen, indoprofen, benoxaprof
  • the combination therapy of the invention in theory, is thought to provide a synergistic effect in reducing A/? 42 levels and is thought to be especially effective for treating and preventing neurodegenerative disorders including Alzheimer's disease, dementia, and MCI.
  • the invention further encompasses compositions comprising the combination of active ingredients of this aspect of the invention.
  • compositions according to the invention can be administered enterally, such as orally or rectally, transdermally, topically, and parenterally to an individual, for the prevention and/or treatment of neurodegenerative disorders including AD, PD, dementia, MCI, Down's Syndrome and inclusion body myositis.
  • Such compositions can comprise an effective amount of a compound or compounds as described herein, alone or in combination, and with one or more pharmaceutically acceptable carriers.
  • a compound of the invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
  • the administration of the active ingredients can be performed at different times and/or different routes.
  • a composition having an active ingredient can be administered in the morning, and a composition having the other active ingredientscan be administered in the evening.
  • Another example would involve the administration of a composition having an active ingredient orally while another active ingredient is administered intravenously.
  • R- flurbiprofen is administered in the morning and a selective COX-2 inhibitor is administered at night.
  • R-flurbiprofen is administered simultaneously with a selective COX-2 inhibitor.
  • a selective COX-2 inhibitor and R-flurbiprofen are administered on alternating days.
  • the dosage of active compound(s) administered is dependent on the body weight, age, individual condition, and on the form of administration.
  • a unit dosage for oral administration to a mammal of about 50 to 70 kg may contain between about 0.1 mg to about 2000 mg.
  • an individual desiring or needing preventative treatment against the onset of AD is administered a daily dose having from about 1 mg to about 1600 mg of R-flurbiprofen and about 1 mg to about 800 mg of a selective COX-2 inhibitor.
  • Other exemplary daily dosages are from about 200 mg to about 1600 mg of R-flurbiprofen and from about 0.5 mg to about 30 mg of the selective COX-2 inhibitor.
  • Another exemplary daily dosages is about 400 mg to about 800 mg of R-flurbiprofen and from about 1.0 mg to about 20 mg of the selective COX-2 inhibitor.
  • the unit dosage of R-flurbiprofen and a selective COX-2 inhibitor can be about 100 mg to about 1600 mg of R-flurbiprofen (e.g. 200 mg, 400 mg, or 800 mg) and a sufficient amount of COX- 1/2 inhibition to reduce inflammation.
  • Exemplary daily dosages of celecoxib are from about 1 mg to about 400 mg, from about 1 mg to about 200 mg, from about 1 mg to about 100 mg, and from about 1 mg to about 50 mg. In one embodiment, the daily dosage of celecoxib is about 50 mg, about 100 mg, about 200 mg, or about 400 mg.
  • Exemplary daily dosages of rofecoxib are from about 1 mg to about 50 mg, from about 1 mg to about 25 mg, from about 1 mg to about 12.5 mg, and from about 1 mg to about 5 mg.
  • Exemplary daily dosages of valdecoxib are from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, and from about 1 mg to about 5 mg. In one embodiment, the daily dosage of valdecoxib is about 10 mg or about 20 mg.
  • Exemplary daily dosages of etoricoxib are from about 1 mg to about 120 mg, from about 1 mg to about 90 mg, from about 1 mg to about 75 mg, and from about 1 mg to about 50 mg.
  • the daily dosage of etoricoxib is about 30 mg, about 60 mg, about 90 mg, or about 120 mg.
  • Exemplary daily dosages of lumiracoxib are from about 1 mg to about 400 mg, from about 1 mg to about 200 mg, from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg. In one embodiment, the daily dosage of lumiracoxib is about 50 mg, about 100 mg, about 200 mg, or about 400 mg.
  • Exemplary daily dosages of DFP are from about 1 mg to about 50 mg, from about 1 mg to about 25 mg, or from about 1 mg to about 12.5 mg. In one embodiment, the daily dosage of DFP is about 10 mg, about 25 mg, or about 50 mg.
  • R-flurbiprofen and a selective COX-2 inhibitor may be applied as such or in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to salt forms that are pharmacologically acceptable and substantially non- toxic to the subject being administered the composition of the present invention.
  • a salt is formed when the hydrogen of an acid is replaced by a metal or its equivalent and an ester formed through the exchange of a replaceable hydrogen of an acid for an organic radical, usually using an alcohol or other organic compound rich in OH groups.
  • Pharmaceutically acceptable salts include conventional acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or inorganic bases.
  • acid-addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and those derived from organic acids such as p- toluenesulfonic acid, methanesulfonic acid, ethane-disulfonic acid, isethionic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid, propionic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, glutamic acid, salicylic acid, sulfanilic acid, and famaric acid.
  • inorganic acids such as hydrochloric acid,
  • base-addition salts include salts derived from ammonium hydroxides (e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide), salts derived from inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and salts derived from organic bases such as amines, benzylamines, piperidines, and pyrrolidines.
  • ammonium hydroxides e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide
  • inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides
  • salts derived from organic bases such as amines, benzylamines, piperidines, and pyrrolidines.
  • R-flurbiprofen and a selective COX-2 inhibitor may be applied in the form of their hydrochlorides, hydrobromides, sulfates, acetates, succinates or tartrates, or their acid addition salts with fumaric, maleic, citric, or phosphoric acids.
  • Appropriate presentation forms are, for example, combinations of the active substance with common pharmaceutical carriers and adjuvants in the form of tablets, coated tablets, and sterile solutions or suspensions for injection.
  • Pharmaceutically- acceptable carriers are, for example, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, gum arabic, corn starch, or cellulose, combined with diluents such as water, polyethylene glycol, etc.
  • Solid presentation forms are prepared according to common methods and may contain up to 50 mg of the active ingredient per unit.
  • the pharmacologically active compound(s) of the invention can be manufactured as a pharmaceutical composition comprising an effective amount of the compound(s) in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application. Prefened are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g.
  • lactose dextrose, sucrose, mannitol, sorbitol, cellulose and or glycine
  • lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol
  • binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone
  • disintegrants e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient. Tablets may be either film coated or enteric coated according to methods known in the art.
  • Suitable formulations for transdermal application include an effective amount of a compound(s) of the invention with carrier.
  • Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • the compositions of the present invention can be prepared in any desired form, for example, tablets, powders, capsules, suspensions, solutions, elixirs, and aerosols.
  • Carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used in the cases of oral solid preparations.
  • Oral solid preparations (such as powders, capsules, and tablets) are prefened over oral liquid preparations. The most prefened oral solid preparations are tablets. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Tablets may also be formulated having an inner core of R-flurbiprofen (or a selective COX-2 inhibitor) and outer layer of a selective COX-2 inhibitor (or R-flurbiprofen), respectively.
  • the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, the disclosures of which are hereby incorporated by reference in their entireties.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the conventional methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient with liquid earners or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally, with one or more additional ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from about 0.5 mg to about 2000 mg of the active ingredient(s), and each cachet or capsule contains from about 0.5 mg to about 1000 mg of the active ingredient.
  • suitable formulations for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, for example, for delivery by aerosol or the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Formulations suitable for topical application can be prepared e.g. as described in U.S. Pat. No. 4,784,808.
  • Formulations for ocular administration can be prepared, e.g., as described in U.S. Pat. Nos. 4,829,088 and 4,960,799. 5.0. Examples
  • Example 1 Determination of COX inhibition activity
  • the present invention provides compositions and methods that inhibit COX-2.
  • In vitro cellular COX inhibition can be determined using specific assays for inhibition of COX-1 and COX-2 (Kalgutkar et al. J. Med Chem., 43:2860-2870 (2000)).
  • Another art- known cellular assay for determining COX inhibition is based on the production of prostaglandin-E 2 from exogenous arachidonic acid in cells expressing COX-1, COX-2, or a combination thereof.
  • COX enzymes prostaglandin H synthase catalyze the rate- limiting step in prostaglandin synthesis from arachidonic acid.
  • Cell lines are known and available that express at least one form of the enzyme.
  • a human skin fibroblast line can be induced with IL-1 to synthesize COX-2, and a kidney epithelial cell line 293 has been stably transfected to constitutively express COX-1.
  • arachidonic acid can be added exogenously to increase signal to readably detectable levels.
  • the amount of prostaglandin-E 2 in the extracellular medium can be assayed by radioimmunoassay, for measuring COX activity.
  • IC 0 values for compounds for COX-1 and COX-2 can be determined by an ordinary skilled artisan.
  • Example 2 Selective COX-2 inhibitor assay The inhibition of COX-2 can be determined by the TCP binding displacement assay.
  • phencyclidine a known selective COX-2 inhibitor, binds to the NMDA receptor-associated ionic channel and blocks ionic transport (Garthwaite et al, Neurosci. Lett. 83: 241-246 (1987)).
  • the interaction between selective COX-2 inhibitors and the PCP bond is examined as follows. A membrane preparation of rat cortex is incubated with H-TCP which is an analogue of phencyclidine (PCP) (Quirion et al. Eur. J. Pharmacol. 83:155 (1982)).
  • test compounds i.e., l-amino-3,5-dimethyl adamantane
  • IC 50 values for test compounds of 100 micromolar or less are desirable. More desirable are those test compounds having an IC 50 values of less than 1 micromolar.
  • Example 3 Neuroprotection Assay The present invention provides compositions and methods for slowing the death or decline of neurons. To test the ability of compositions of the present invention to protect against neurotoxicity, adult female Sprague Dawley rats are obtained and injected intraperitoneally with various doses of a composition of the present invention.
  • test animals also receive a subcutaneous injection of MK-801 (0.5 mg/kg), which has been shown to consistently induce, in all treated rats, a fully developed neurotoxic reaction consisting of acute vacuole formation in the majority of pyramidal neurons in layers III and IV of the posterior cingulate and retrosplenial (PC/RS) cortices.
  • Control animals are administered the liquid which was used to dissolve the test agent and the same dosage of MK-801 (0.5 mg/kg sc).
  • the animals are sacrificed four hours after treatment and the number of vacuolated PC/RS neurons are counted on each side of the brain, at a rostrocaudal level immediately posterior to where the corpus callosum ceases decussating across the midline (approximately 5.6 mm caudal to bregma).
  • the toxic reaction approaches maximal severity at this level and shows very little variability between different animals.
  • Percentage reduction in neurotoxicity is calculated by dividing the mean number of vacuolated neurons in a given treatment group, by the mean number of vacuolated neurons in control animals that were treated with MK-801 but not the protective agent. The result is subtracted from one and multiplied by 100, to calculate a percentage.
  • Linear regression analysis can be used to determine an ED 50 (i.e., the dosage of a given compound that reduces the mean number of vacuolated neurons to 50% of the value in control animals), with the 25th and 75th percentiles defining the confidence limits.
  • ED 50 i.e., the dosage of a given compound that reduces the mean number of vacuolated neurons to 50% of the value in control animals
  • Example 4 A ⁇ Secretion Assay The present invention provides compositions and methods for lowering A ⁇ 42 levels. To test whether compounds and compositions are capable of modulating A ⁇ levels, H4 neuroglioma cells expressing APP695NL and CHO cells stably expressing wild-type human APP751 and human mutant presenilin 1 (PS1) M146L are used. Generation and culture of these cells have been described. See Murphy et al, J. Biol. Chem., 274(17):11914-11923 (1999); Murphy et al, J. Biol. Chem., 275(34):26277- 26284 (2000).
  • PS1 presenilin 1
  • the H4 cells are incubated for 6 hours in the presence of the various compositions and compounds.
  • additional aliquots of cells are incubated in parallel with each composition or compound.
  • the supernatants are analyzed for the presence of lactate dehydrogenase (LDH) as a measure of cellular toxicity.
  • LDH lactate dehydrogenase
  • sandwich enzyme-linked immunosorbent assay ELISA is employed to measure secreted A ⁇ (A ⁇ 42 and/or A ⁇ 40) levels as described previously. Murphy et al, J. Biol. Chem., 275(34):26277-26284 (2000).
  • Antibody 3160 is an affinity purified polyclonal antibody raised against A ⁇ l-40. HRP conjugated monoclonal antibodies BA27 for detection of A ⁇ 40 and BC05 for detection of A ⁇ 42 have been previously described. Suzuki et al, Science, 264(5163):1336-1340 (1994).
  • Example 5 Treatment of Animals with a Compound to Determine the Compound's Effect on Levels of A ⁇ 42 and Alzheimer's Disease
  • an animal is treated with the compound and the levels of A ⁇ 42 in the brain are measured.
  • Three month-old TG2576 mice that overexpress APP(695) with the "Swedish” mutation (APP695NL) are used.
  • Mice overexpressing APP(695) with the "Swedish” mutation have high levels of soluble A ⁇ in the their brains and develop memory deficits and plaques with age, making them suitable for examining the effect of compounds on levels of A ⁇ 42 and Alzheimer's Disease.
  • Test mice are treated with the compound and "control” TG25276 mice are not.
  • the brain levels of SDS-soluble A ⁇ 40 and A ⁇ 42 for "test” mice are compared to "control” mice using ELISA.
  • Test mice that have a reduction in A ⁇ 42 levels suggest that treatment with the compound could prevent amyloid pathology by decreasing the ratio of A ⁇ 42 to A ⁇ 40 in the brain.
  • Example 6 Treatment of Animals with a Compound to Determine the Compound's Effect on Memory and Alzheimer's Disease
  • the present invention provides compositions and methods for treating or preventing Alzheimer's Disease.
  • TG2576 mice that overexpress APP(695) with the "Swedish” mutation (APP695NL) are used.
  • Mice overexpressing APP(695) with the "Swedish” mutation develop memory deficits and plaques with age, making them suitable for examining the effect of compounds on memory and Alzheimer's Disease.
  • the test compound is administered daily for two weeks to test groups of the TG2576 mice in age groups of: 1) 4-5 months, 2) 6-11 months, 3) 12-18 months, and 4) 20-25 months.
  • mice of corresponding ages are not administered the compound. Both control and test groups then have memory tested in a version of the Morris water maze (Mo is, J. Neurosci. Methods, 11 :47-60 (1984)) that is modified for mice.
  • the water maze contains a metal circular pool of about 40 cm in height and 75 cm in diameter. The walls of the pool have fixed spatial orientation clues of distinct patterns or shelves containing objects.
  • the pool is filled with room temperature water to a depth of 25cm and an escape platform is hidden 0.5 cm below the surface of the 25-cm-deep water at a fixed position in the center of one of the southwest quadrant of pool.
  • the test and control mice are trained for 10 days in daily sessions consisting of four trials in which the mouse starts in a different quadrant of the pool for each trial.
  • the mice are timed and given 60 seconds to find the escape platform in the pool. If the mice have not found the escape platform after 60 seconds, they are guided into it. The mice are then allowed to rest on the platform for 30 seconds and the amount of time it takes the mice to find the platform is recorded.
  • Probe trials are run at the end of the trials on the 4th, 7 th , and 10 th days of training, in which the platform is removed and the mice are allowed to search for the platform for 60 sec. The percentage of time spent in the quadrant where the platform was in previous trials is calculated.
  • test mice In training trials, the time it takes test group mice to reach the escape platform is compared to the time taken by control group mice of conesponding ages. In probe trials, the percentage of time spent by test group mice in the quadrant where the platform was in previous trials is compared to the percentage time spent by control mice. Quicker location of the escape platform in training trials and/or an increased percentage time spent in the previous quadrant of the maze during probe trials is indicative of spatial learning and memory. Because memory loss is a hallmark of Alzheimer's Disease, test mice that have better learning and memory when compared to control mice indicate that the compound may be effecting in treating or slowing Alzheimer's Disease and/or its symptoms.
  • Tablets 1 tablet contains: Active COX-2 ingredient 100.0 mg (i.e., celecoxib) Active R-flurbiprofen 200 mg Lactose 300 mg Microcrystalline cellulose 180 mg Talc 45 mg Total 825 mg
  • the substances are mixed and the mixture compressed into 825-mg tablets in a direct procedure without granulation.
  • the components can be mixed and divided into two 412.5 mg tablets.
  • the above described tablets or similar co- formulations can be used according to therapeutic treatments of the invention, such as described in Examples 8-12.
  • Capsules 11 ccaapsule contains: Active COX-2 ingredient 50 mg (i.e., rofecoxib) Active R-flurbiprofen 400 mg Microcrystalline cellulose 500 mg Com starch 100 mg Magnesium stearate 800 mg Total 1850 mg
  • a formulation of gelatin capsules can be prepared by mixing 400 mg of R- flurbiprofen and 50 mg of a selective COX-2 inhibitor with 500 mg of microcrystalline cellulose and 100 mg of com starch. 800 mg of magnesium stearate is then blended into the mixture and the resulting blend is encapsulated into a gelatin capsule. Doses of varying strengths can be prepared by altering the ratio of R-flurbiprofen and COX-2 inhibitors to pharmaceutically acceptable carriers or changing the size of the capsule.
  • Tablets 1 tablet contains: Active COX-2 ingredient 35 mg (i.e., rofecoxib) Active R-flurbiprofen 800 mg Lactose 200 mg Microcrystalline cellulose 100 mg Talc 25 mg Total 1160 mg The substances are mixed and the mixture compressed into 1160-mg tablets in a direct procedure without granulation.
  • Example 10 Combination Formulation Capsules 1 capsule contains: Active COX-2 ingredient 25 mg (i.e., celecoxib) Active R-flurbiprofen 200 mg Microcrystalline cellulose 400 mg Com starch 50 mg Magnesium stearate 700 mg Total 1375 mg
  • a formulation of gelatin capsules can be prepared by mixing 200 mg of R- flurbiprofen and 25 mg of a selective COX-2 inhibitor with 400 mg of microcrystalline cellulose and 50 mg of com starch. 700 mg of magnesium stearate is then blended into the mixture and the resulting blend is encapsulated into a gelatin capsule. Doses of varying strengths can be prepared by altering the ratio of R-flurbiprofen and COX-2 inhibitors to pharmaceutically acceptable carriers or changing the size of the capsule.
  • Tablets 1 tablet contains: Active COX-2 ingredient 100.0 ⁇ . (i.e., valdecoxib) Active R-flurbiprofen 400 mg Lactose 300 mg Microcrystalline cellulose 200 mg Talc 50 mg Total 1150 mg
  • the substances are mixed and the mixture compressed into 1150-mg tablets in a direct procedure without granulation.
  • the components can be mixed and divided into two 575 mg tablets.
  • Example 12 Combination Formulation Capsules 1 capsule contains: Active COX-2 ingredient 30 mg (i.e., etoricoxib) Active R-flurbiprofen 800 mg Microcrystalline cellulose 450 mg Com starch 120 mg Magnesium stearate 600 mg Total 2000 mg
  • a formulation of gelatin capsules can be prepared by mixing 800 mg of R- flurbiprofen and 30 mg of a selective COX-2 inhibitor with 450 mg of microcrystalline cellulose and 120 mg of com starch. 600 mg of magnesium stearate is then blended into the mixture and the resulting blend is encapsulated into a gelatin capsule. Doses of varying strengths can be prepared by altering the ratio of R-flurbiprofen and COX-2 inhibitors to pharmaceutically acceptable earners or changing the size of the capsule.
  • Example 13 Treatment of MCI R-flurbiprofen and a selective COX-2 inhibitor (i.e., celecoxib) can be administered as tablets containing 100 mg of the selective COX-2 inhibitor and 200 mg of R-flurbiprofen, and as oral gel capsules containing 100 mg of the selective COX-2 inhibitor and 200 mg of R-flurbiprofen to treat MCI.
  • the typical dosage may be 300 or 600 mg of active ingredients daily. These dosages can also be divided or modified, and taken with or without food.
  • R-flurbiprofen and a selective COX-2 inhibitor can also be administered separately.
  • a typical dosage regimen may have 200 mg of R-flurbiprofen taken daily (100 mg twice daily) and 100 mg of a selective COX-2 inhibitor taken daily (50 mg twice daily).
  • the dosage regimen may alternatively have 200 mg of R-flurbiprofen taken in the morning and 100 mg of the selective COX-2 inhibitor taken at night. These dosages can also be divided or modified, and taken with or without food.
  • Example 14 Preventive treatment of Alzheimer's Disease
  • patients desiring prophylaxis against Alzheimer's disease can be treated with a combination of R-flurbiprofen and selective COX-2 inhibitor.
  • Those needing prophylaxis can be assessed by monitoring assayable disease markers, detection of genes conferring a predisposition to the disease, other risks factors such as age, diet, other disease conditions associated with Alzheimer's.
  • the patient can be treated with a combination of selective COX-2 inhibitor and R-flurbiprofen to delay or prevent the onset of Alzheimer's disease or symptoms thereof.
  • the patient desiring prophylaxis against Alzheimer's disease or prophylaxis of a worsen of the symptoms of Alzheimer's disease can be treated with a combination of R- flurbiprofen and selective COX-2 inhibitor sufficient to delay the onset or progression of symptoms of Alzheimer's disease.
  • a patient can be treated with 200 mg of R-flurbiprofen per day and 100 mg of selective COX-2 inhibitor (i.e., celecoxib) per day.
  • selective COX-2 inhibitor i.e., celecoxib
  • R-flurbiprofen per day and 50 mg of selective COX-2 inhibitor per day can be administered to reduce sides- effects associated with the use of higher levels of the active ingredients.
  • the R- flurbiprofen or selective COX-2 inhibitors can be administered on different days.
  • the preventive treatment can also be, e.g., treatment with R-flurbiprofen for one week followed by treatment with selective COX-2 inhibitor for one week, treatment with R- flurbiprofen for a month, followed by treatment with selective COX-2 inhibitor for one month, and the such.
  • Example 15 Treatment of Alzheimer's Disease R-flurbiprofen and a selective COX-2 inhibitor (i.e., celecoxib) can be administered as tablets containing 100 mg of the selective COX-2 inhibitor and 200 mg of R-flurbiprofen, and as oral gel capsules containing 100 mg of the selective COX-2 inhibitor and 200 mg of R-flurbiprofen to treat Alzheimer's Disease, or a symptom thereof.
  • the typical dosage may be 300, 600, 900, or 1200 mg of active ingredients daily.
  • the individual with AD may take 400 mg of R-flurbiprofen and 200 mg of a selective COX-2 inhibitor daily (200 mg of R-flurbiprofen and 100 mg of a selective COX-2 inhibitor twice daily).
  • the individual with AD may alternatively take 300 mg of R- flurbiprofen and 300 mg of a selective COX-2 inhibitor daily. These dosages can also be divided or modified, and taken with or without food. R-flurbiprofen and a selective COX-2 inhibitor can also be administered separately.
  • a typical dosage regimen may have 800 mg of R-flurbiprofen taken daily (400 mg twice daily) and 400 mg of a selective COX-2 inhibitor taken daily (200 mg twice daily).
  • Another typical dosage regimen may have 1600 mg of R-flurbiprofen taken daily and 20 mg of a selective COX-2 inhibitor.
  • the dosage regimen may alternatively have 400 mg of R-flurbiprofen taken in the morning and 200 mg of the selective COX-2 inhibitor taken at night.
  • R-flurbiprofen or selective COX-2 inhibitors can be administered on different days, e.g. 600 mg of R-flurbiprofen one day and 600 mg of a selective COX-2 inhibitor the next day. These dosages can also be divided or modified, and taken with or without food.
  • All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The mere mentioning of the publications and patent applications does not necessarily constitute an admission that they are prior art to the instant application.

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Abstract

L'invention concerne des procédés et compositions pour traiter des troubles neurodégénératifs. Le procédé de l'invention consiste à administrer à un individu nécessitant un traitement une composition possédant R-flurbiprofène et un inhibiteur sélectif de COX-2. Les procédés et compositions de l'invention sont utiles pour traiter et ralentir l'évolution des maladies neurodégénératives tels que la maladie d'Alzheimer, la démence et la déficiente intellectuelle légère.
PCT/US2004/039195 2003-11-21 2004-11-22 Procede et composition pour traiter de troubles neurodegeneratifs WO2005051378A1 (fr)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
US6245802B1 (en) * 1998-11-13 2001-06-12 Eli Lilly And Company Method for treating pain

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245802B1 (en) * 1998-11-13 2001-06-12 Eli Lilly And Company Method for treating pain

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