Genotype-specific methods and systems for treating neurodegenerative diseases

Abstract

The present disclosure provides methods of treating a neurodegenerative disease in a subject in need thereof. A therapeutically effective dose of a combination of a suitable mast cell stabilizer and an NSAID may be administered to a suitable subject, wherein the suitability of the subject is determined by the subject genotype. In certain embodiments, the combination therapy may comprise a combination of a cromoglycin homolog salt and an NSAID, and a suitable subject is a person that is not a carrier of an APOE [epsilon] 4 variant of the APOE gene.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefits from U.S. Provisional Application No. 63 / 494,064, filed April 4, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure relates to methods for treating neurodegenerative diseases in suitable subjects who require treatment. Background Technology

[0004] Alzheimer's disease is a neurodegenerative disorder of the brain characterized by the decline in short-term memory formation and recall, the decline in long-term memory recall, behavioral impairments, disorientation, impairment of daily activities and functions of daily living, loss of independence, and even death. As of the end of 2020, an estimated 55 million people worldwide had some form of Alzheimer's disease (see ALZHEIMER'S DISEASE INT'L, Numbers of people with dementia around the world, https: / / www.alzint.org / resource / numbers-of-people-with-dementia-worldwide / (November 30, 2020)). This number is projected to roughly double every 20 years.

[0005] Alzheimer's disease is complex. It may not be a "single" disease, but rather a series or class of diseases with similar causes and manifestations. The causes are likely multifactorial. There is a consensus that Alzheimer's disease can be characterized by the accumulation of insoluble aggregates of amyloid-β peptide (Aβ), such as Aβ oligomers. These aggregates or oligomers are associated with cellular inflammatory responses and are thought to bind to surface receptors on neurons and alter the structure of neuronal synapses, thereby disrupting neuronal communication. This daily inflammatory response is barely visible and unrelated to any major symptoms due to the tiny amounts of Aβ produced daily (estimated at 22–27 ng / day throughout the brain) and accumulated over several years (approximately 7–10 mg in the brains of Alzheimer's patients). Furthermore, abnormalities in microtubule-associated unit proteins ("tau proteins" or "τ proteins") are thought to play a role in the disease cascade leading to the onset and progression of Alzheimer's disease. Hyperphosphorylated tau proteins are thought to pair with other filaments of tau. Finally, they form neurofibrillary tangles inside the neuronal cell body. When this occurs, microtubules disintegrate, causing the neuron's transport system to collapse. This can initially lead to a breakdown in biochemical communication between neurons, subsequently resulting in cell death.

[0006] In addition to the still-evolving understanding of the etiology and progression of Alzheimer's disease, including the importance of Aβ and tau proteins, some genetic predictors of the onset of Alzheimer's disease have been discovered. While in most cases Alzheimer's disease does not appear to be primarily genetically caused, many people do carry a genetic predisposition to Alzheimer's disease. In some cases, a subject's genetic predisposition to Alzheimer's disease can be strong, and can highly predict that a person will eventually have Alzheimer's disease.

[0007] Despite the understanding of certain characteristics of Alzheimer's disease as described above, effective treatments remain elusive. Promising drug candidates have failed, prompting an even more urgent search for new targets. There is a great need for new therapies. To date, researchers searching for drug candidates have not taken into account the subject's genotype, despite the fact that researchers know that genotype can significantly affect the expected progression of the disease. Because the etiology of Alzheimer's disease is multifactorial, and includes at least some genetic predisposition factors, there is a great unmet need for more personalized treatment approaches tailored to a subject's genotype. SUMMARY

[0008] In one aspect, the disclosure relates to embodiments of a method of treating a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject an effective dose of a combination of a mast cell stabilizer and a non-steroidal anti-inflammatory drug; wherein the subject is not a carrier of a neurodegenerative disease susceptibility genotype.

[0009] In any embodiment of the method of treatment, the neurodegenerative disease can be Alzheimer's disease ("AD"). In any embodiment of the method of treatment, the method can treat an ongoing neurodegenerative disease and / or prevent a future onset of a neurodegenerative disease. In any embodiment, the neurodegenerative disease can be diagnosed or not diagnosed at the time of treatment. The neurodegenerative disease can be early onset at the time of treatment. In any embodiment, the mast cell stabilizer can be cromolyn; a cromolyn derivative; a cromolyn homolog; a salt of any of cromolyn, a cromolyn derivative, or a cromolyn homolog; or any combination thereof. In any embodiment, the salt can be a biocompatible salt. In any embodiment, the biocompatible cromolyn salt can be sodium cromoglycate.

[0010] In any embodiment of the method of treatment, the subject can not be a carrier of any variant of apolipoprotein E that makes the subject susceptible to the onset of a neurodegenerative disease, including Alzheimer's disease. In any embodiment, the subject can not be a carrier of APOE ε4.

[0011] In any embodiment of the method of treatment, cromolyn or a biocompatible salt thereof is formulated as a dry powder for inhalation. In any such embodiment, cromolyn or a biocompatible salt thereof can be formulated as a dry powder for inhalation as a particle size of less than about 3 microns.

[0012] In any embodiment of the method of treatment, cromolyn or a biocompatible salt thereof can be administered at a dose of about 16 mg / day to about 20 mg / day. BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 An exemplary primary structure schematic of the general human ApoE protein is depicted, noting positions where certain differences exist among common ApoE subtypes. Although many of the described subtypes exist, by far the most prevalent are the ApoE2, ApoE3, and ApoE4 subtypes, which are encoded by the ε2, ε3, and ε4 homologs, respectively, of the APOE gene. The E2, E3, and E4 subtypes differ from one another at amino acid residues 112 and / or 158 (shown as gray circles in Figure 1 ApoE2 has cysteine residues at both 112 and 158; ApoE3 has a cysteine residue at 112 and an arginine residue at 158; and ApoE4 has arginine residues at both 112 and 158. The ApoE protein has two domains: an N-terminal domain containing a receptor-binding region (at residues 136-150) and a C-terminal domain containing a lipid-binding region (at residues 244-272); the two domains are connected by a “hinge” region. Analysis has shown a significant positive correlation between carrying one or two ApoE4 alleles and early onset of Alzheimer’s disease.

[0014] Figure 2 A table depicting approximate frequency and average age of onset of Alzheimer’s disease in humans not carrying any apoE ε4 alleles, those who are heterozygous for apoE ε4, and those who are homozygous for apoE ε4 is depicted.

[0015] Figure 3An exemplary schematic depicting the clearance pathway of amyloid beta protein. These include receptor-mediated uptake by neurons and glia, efflux into the interstitial fluid or out of the brain by the blood brain barrier (BBB), and proteolytic degradation by insulin-degrading enzyme (IDE) and neprilysin (NEP). Impairment of Aβ clearance can cause accumulation of Aβ in the brain parenchyma, leading to the formation of neurotoxic Aβ oligomers and amyloid plaques. Accumulation of Aβ in the perivascular space leads to cerebral amyloid angiopathy (CAA), which interferes with vascular function. ApoE is primarily synthesized by astrocytes and microglia and lipidated by the ATP-binding cassette Al (ABCA1) transporter protein to form lipoprotein particles. Lipidated ApoE binds soluble Aβ and facilitates Aβ uptake by cell surface receptors, including low-density lipoprotein receptor-related protein 1 (LRP1), low-density lipoprotein receptor (LDLR), heparan sulfate proteoglycans (HSPGs) 175, and HSPG 177, in a manner that can depend on the ApoE isoform and its level of lipidation. ApoE facilitates binding and internalization of soluble Aβ by glial cells, interferes with Aβ clearance at the BBB in a isoform-dependent manner (ApoE4 > ApoE3 > ApoE2), and influences CAA pathogenesis. As Figure 3 As used in the present disclosure, LXR refers to a liver X receptor. DETAILED DESCRIPTION

[0016] The present disclosure provides methods of treating a neurodegenerative disease in a subject in need thereof.

[0017] Failure to develop safe and effective treatments for neurodegenerative diseases

[0018] Neurodegenerative diseases, such as Alzheimer’s disease (AD), have been of interest to the medical and pharmaceutical industries since at least the 19th century. In the 21st century, there has been significant progress in basic science and therapeutic approaches, but safe and effective treatment options remain in their infancy at best. For neurodegenerative diseases, despite an estimated 55 million people worldwide afflicted, there are few therapies. In addition to the controversial 2021 U.S. Food and Drug Administration approval of aducanumab, the most recent drug approved by the FDA for the treatment of Alzheimer’s disease was memantine in 2003, and despite memantine addressing some symptoms, current therapies offer no hope of reversing disease progression.

[0019] Why are neurodegenerative diseases still incurable? One issue is that designing and implementing clinical studies with appropriate clinical benefit endpoints is challenging. Researchers lack the necessary diagnostic and quantitative measurement tools to describe and assess disease progression. Moreover, the etiology of neurodegenerative diseases is multifactorial, and measurement of one factor can miss other factors. Thus, depending on the readout selected, a clinical trial can appear to fail to refute the null hypothesis. But if designed and interpreted from another perspective, the same study can show efficacy, e.g., for some subpopulation of clinical subjects.

[0020] Finding safe and effective therapies for neurodegenerative diseases is challenging because, among other reasons, neurodegenerative diseases are complex health problems with more than 50 potential contributing factors, not a single diagnosable disease. Alzheimer’s disease is the most prevalent form of neurodegenerative disease, and is better understood as a generic term for progressive neurodegenerative conditions that manifest as deterioration of short-term memory formation and recall, gradual decline in long-term memory recall, behavioral disturbances, disorientation, impaired daily activities and life functions, loss of independence, and even death. Alzheimer’s disease accounts for 60-70% of all dementia cases, and is the focus of most drug therapy research. The scientific system supporting Alzheimer’s disease drug development is robust, conceptually based on a solid foundation of basic science, and well-validated in vitro and in vivo in animal models. In practice, however, clinical trial results have consistently failed to match potential assumptions and theoretical underpinnings, and have failed to reach predetermined clinical benefit endpoints since the 1990s.

[0021] There are many obstacles to developing promising neurodegenerative disease therapies. These include, among others, (1) insufficient basic scientific understanding of the complex physiology of neurodegenerative diseases; (2) lack of practical primary efficacy measures; and (3) over-reliance on biomarkers as surrogates for clinical efficacy.

[0022] Regarding the first obstacle, insufficient basic scientific understanding of the complex physiology of neurodegenerative diseases, despite significant advances by the scientific community in understanding the biology behind the diseases and the multifactorial etiology of the diseases, there are still many questions to be answered. For example, scientists have not fully understood what controls the toxic accumulation of amyloid plaques and tau tangles in the brains of Alzheimer’s patients, the causes and effects behind genetic predisposition, environmental influences, or why the rate of disease progression differs among individuals. However, researchers have developed sound scientific approaches for drug development, and validated these approaches in vitro and in animal models; thus, failure is unlikely to be due solely to the science that follows.

[0023] With respect to the primary efficacy measure of lack of utility, study design, and the tools needed to accurately diagnose and assess disease progression remain the most significant challenges. Most, if not all, clinical trial designs and available measurement tools (i.e., CDR-SB and all ADS-cogs) yield failed results to a greater extent than readouts of substantial clinical benefit. The reasons are related to many imperfect measurement tools and the multifactorial etiology of disease progression. For example, Alzheimer’s Disease Clinical Dementia Rating (CDR) readouts are susceptible to many variables, such as mood or caregiver’s assessment. These tools do not capture absolute measurable changes, as in the case of, for example, cancer, where differences in tumor size or its spread are measurable. Available Alzheimer’s CDR measurements are at best semi-quantitative.

[0024] Furthermore, the likelihood that any new drug will significantly reverse the chronic cognitive and functional decline of the impaired brain of an Alzheimer’s patient is far lower than stabilizing or slowing its progression; thus, cognitive scales, such as CDR-SB, for example, are more likely to measure significant decline in Alzheimer’s rather than a cognitive scale that measures stabilization, slowing, or mild improvement, can not be the best endpoint for many new therapies. In other words, for a disease that takes many years to manifest clinically, expecting a therapeutic intervention to achieve a measurable reversal can not be realistic. Evaluating treatment effects in pre-symptomatic populations is even more complex. Many cognitive scales that are useful outcome measures in established neurodegenerative diseases can not be sensitive enough in the preclinical stage of the disease. (See Vellas B et al., Endpoints for Pre-Dementia Alzheimer’s Disease Trials: A Report From the EU / US / CTAD Task Force, J PREV ALZHEIMERS DIS 2015 Jun; 2(2): 128-35). Other factors that affect trial outcomes are significant variations in subjects and within subjects due to disease heterogeneity and covariates such as age, rate of progression diagnosis, and other enrollment criteria.

[0025] Finally, regarding the over-reliance on biomarkers as surrogates for clinical efficacy, biomarkers cannot replace clinical symptom benefit as an efficacy readout. Biomarkers can help to predict the direction of drug development to achieve efficacy, but protein measurements alone cannot indicate a patient’s experience in terms of cognition. However, some clinical studies rely on an accepted change in biomarker levels (e.g., amyloid beta and / or tau) as a surrogate clinical endpoint when deciding to move forward to pivotal trials, without sufficient evidence of confirmatory changes in cognitive / functional / overall neurological performance. In fact, these performance tests are the primary clinical measures in Phase III clinical trials for dementia-type neurodegenerative diseases. Ultimately, these trials fail due to not meeting the clinical efficacy endpoint. (See Kim CK et al., Alzheimer’s Disease: Key Insights from Two Decades of Clinical Trial Failures, J ALZHEIMERS DIS 2022 May 8 7(1) 83-100).

[0026] A cure for neurodegenerative diseases - or more likely, a safe and effective therapy that can slow disease progression and positively impact the quality of life of patients and their families - is complex. However, it is achievable.

[0027] Neurodegenerative diseases, such as Alzheimer’s disease, are typically chronic diseases with insidious, protracted onset. Alzheimer’s disease typically goes through a long preclinical and prodromal phase of about 20 years before the onset of overt symptoms. The appearance of symptoms reflects a brain network that has already been damaged and is accompanied by substantial neuronal loss and rapid spread of neuroinflammatory reactions. Unfortunately, with the current state of science, we cannot diagnose Alzheimer’s disease 20 years before the first symptoms appear.

[0028] Currently available drugs, such as those that block the action of enzymes that reduce the active chemical messenger for memory in the brain (acetylcholinesterase inhibitors) or those that prevent the toxic effects of another messenger, glutamate (memantine), only provide temporary relief of symptoms. The recently approved biologic, aducanumab, is a monoclonal Ig1 antibody that binds amyloid beta protein and is expected to cause dose-dependent removal of beta amyloid pathology, but the evidence of clinical efficacy is arguably insufficient. (See Tampi RR et al., Aducanumab: Evidence from Clinical Trial Data and Controversies, DRUGS CONTEXT 2021 Oct 4; 10:2021-7-3). However, emerging therapies will address the underlying biology to stop or mildly reverse the disease process.

[0029] Moreover, due to the chronic nature of Alzheimer's disease and its multifactorial causation, newly developed therapies are addressing more than one pathway of treatment, such as combining therapies that inhibit plaques and tangles or their removal with simultaneous prevention or treatment of neuroinflammatory spread, or enhancing microglial and macrophage clearance of damaged neurons and toxic debris. Unfortunately, the lengthy and expensive research that can precede proven therapies by years discourages investment enthusiasm. In contrast, drug development where researchers can quickly determine whether a drug works, such as antibiotics, becomes more attractive. The technology giant Pfizer decided to stop cure research for Alzheimer's and Parkinson's disease after many expensive and unsuccessful attempts, and to develop therapies that are easier to drug develop and approve. Nonetheless, the potential unmet need for neurodegenerative disorders will continue to attract innovative treatment approaches by governments and industry.

[0030] In response to the long-standing challenges and industry failures described above, the present disclosure provides methods of treating neurodegenerative diseases that can be tailored according to certain multivariate factors. In particular, clinical studies and treatment designs for treating neurodegenerative diseases can be tailored according to patient genotypes, as will be detailed hereafter.

[0031] Therapeutic agent

[0032] The present disclosure features methods of treating or preventing a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least a mast cell stabilizer and a non-steroidal anti-inflammatory drug (NSAID) in a subject who is not a susceptible genotype carrier.

[0033] The mast cell stabilizer can be any biocompatible salt of cromolyn, a cromolyn derivative, or a cromolyn homolog. The cromolyn homologs can be generally defined according to the following Formula I:

[0034] I

[0035]

[0036] wherein R1, R2, and R3 can be the same or different from each other, and wherein each can be any one of -H, -OH, -F, -CI, -Br, -I, -NH2, -NO2, -SH, -C(O)NH2, -CN, alkyl, haloalkyl, aryl, haloaryl, ether, ester, or aldehyde.

[0037] The NSAID is an anti-inflammatory compound that is not in the steroidal class of compounds, which tends to reduce pain, reduce inflammation, reduce fever, and prevent blood clotting. NSAIDs generally inhibit the enzyme cyclooxygenase

[0038] COX-1 and / or COX-2. Exemplary NSAIDs include, but are not limited to, acetyl salicylic acid, celecoxib, dexibuprofen, dexketoprofen, diclofenac, diflunisal, droxicam, etodolac, fenoprofen, goldenseal, flufenamic acid, flurbiprofen, hyperforin, ibuprofen, indomethacin, isoxicam, ketoprofen, ketorolac, licofelone, lomoxicam, loxoprofen, meclofenamic acid, mefenamic acid, meloxicam, nalfon, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tenoxicam, tolmetin, and tolfenamic acid.

[0039] Genetic factors

[0040] As early as the early 1990s, researchers noted an association between certain genotypes and the onset of Alzheimer’s disease. (See, e.g., Pericak-Vance M.A., et al. (1991) Linkage studies in familial Alzheimer’s disease: evidence for chromosome 19 linkage. AM. J. HUM. GENET. 48, 1034-50). Further research found that the primary predictor of Alzheimer’s disease was the genotype of the cholesterol transporter apolipoprotein E (apoE). (See Strittmatter W.J., et al., Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer’s disease. PROC. NATL. ACAD. SCI. USA 1993; 90, 1977-81).

[0041] ApoE is one of several types of apolipoproteins (including apoA, apoB, apoD, and apoJ) responsible for transporting lipids within and between cells. ApoE is an important cholesterol transport protein, synthesized primarily in liver parenchymal cells, but also in the adrenal gland, brain, fat, kidney, lung, and spleen. ApoE is polymorphic, existing in three major isoforms, the major protein isoforms being referred to as "apoE2," "apoE3," and "apoE4." The corresponding genetic variants are referred to as APOE ε2, APOE ε3, and APOE ε4, respectively. The APOE gene is located on the long arm of chromosome 19, contains four exons and three introns, and is approximately 3639 bp long. Since humans carry two copies of the gene on somatic chromosomes, the human APOE genotype can be represented as ε2 / ε2; ε2 / ε3; ε2 / ε4; ε3 / ε3; ε3 / ε4; or ε4 / ε4. Other apoE variants exist, but are considered to be very rare. Of the three major isoforms, the distribution of alleles in the general population is about 8% ε2, 78% ε3, and 14% ε4. About 86% of the general population are not carriers of APOE ε4.

[0042] APOE ε2 is underrepresented in the context of late-onset Alzheimer's disease. The APOE ε4 variant is significantly overrepresented in the context of late-onset Alzheimer's disease. This result is highly reliable and has been confirmed in ethnic and racial groups and for both early- and late-onset Alzheimer's disease. While about 14% of the general population carries APOE ε4, this number increases to about 40% in people diagnosed with Alzheimer's disease.

[0043] Suitable treatment subjects

[0044] For the methods of the present invention, it was surprisingly and unexpectedly discovered in human clinical trials that certain combinations of therapeutic agents have a significantly greater impact on non-carriers of APOE ε4.

[0045] It is hypothesized that the mechanism of action of certain therapies can be suppressed by the influence of the apoE4 protein variant on the onset and progression of Alzheimer's disease in subjects who are carriers of APOE ε4. Thus, it was discovered that the combination therapies of the present disclosure are most effective in non-carriers of APOE ε4.

[0046] Definitions

[0047] As used herein, the following terms and phrases shall have the meanings provided below.

[0048] In the specification and claims, the indefinite articles "a" and "an," as used herein, should be understood to mean "at least one" unless explicitly indicated to the contrary.

[0049] For the purposes of the present disclosure, a "amyloidosis-related condition" is a disease associated with amyloid deposition, and can include, but is not limited to, Alzheimer's disease, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Down's syndrome, scrapie, medullary thyroid carcinoma, isolated atrial amyloid, beta2-microglobulin amyloid in dialysis patients, inclusion body myositis, beta2-amyloid deposition in muscle wasting diseases, and pancreatic islet type I diabetes isletoma. Type 2 diabetes, hereditary cerebral hemorrhage amyloidosis (Dutch type), amyloid A (reactive), secondary amyloidosis, familial Mediterranean fever, familial amyloid nephropathy with urticaria and deafness (Muckle-wells syndrome), amyloid lambda L-chain or amyloid kappa L-chain (idiopathic, myeloma- or macroglobulinemia-related) A beta2M (chronic hemodialysis), ATTR (familial amyloid polyneuropathy (Portuguese type, Japanese type, Swedish type)), familial amyloid cardiomyopathy (Danish type), isolated cardiac amyloid, systemic senile amyloidosis, AIAPP or amylin isletoma, atrial natriuretic factor (isolated atrial amyloid), procalcitonin (medullary thyroid carcinoma), gelsolin (familial amyloidosis (Finnish type)), cystatin C (hereditary cerebral hemorrhage with amyloidosis (Icelandic type)), AApo-A-1 (familial amyloid polyneuropathy - Iowa), AApo-A-II (mouse accelerated senescence), head injury (traumatic brain injury), dementia, fibrinogen-related amyloid; and

[0050] Asor or Pr P-27 (scrapie, Creutzfeldt-Jakob disease, Gertsmann-Straussler-Scheinker syndrome, bovine spongiform encephalopathy) or in the case of a human homozygous for the apolipoprotein E4 allele, as well as conditions associated with homozygosity for the apolipoprotein E4 allele or Huntington's disease.

[0051] "amyloidosis" is a condition characterized by the accumulation of various insoluble fibrillar proteins in the tissues of a patient. Amyloid deposition occurs through the aggregation of amyloid proteins, followed by the further assembly of aggregates and / or amyloid proteins.

[0052] There are many forms of amyloidosis, and the disease can be classified into four categories: primary amyloidosis, secondary amyloidosis, hereditary amyloidosis, and amyloidosis associated with normal aging. Primary amyloidosis (light chain amyloidosis) occurs in association with abnormalities in plasma cells, and some people with primary amyloidosis also have multiple myeloma (a cancer of plasma cells). Typical sites of amyloid accumulation in primary amyloidosis are the heart, lungs, skin, tongue, thyroid, intestines, liver, kidneys, and blood vessels. Secondary amyloidosis can occur in response to various diseases that result in persistent infection or inflammation (e.g., tuberculosis, rheumatoid arthritis, and familial Mediterranean fever). Typical sites of amyloid accumulation in secondary amyloidosis are the spleen, liver, kidneys, adrenal glands, and lymph nodes. Hereditary amyloidosis has been found in some families, particularly in families from Portugal, Sweden, and Japan. The amyloidogenic defect occurs due to mutations in specific proteins in the blood. Typical sites of amyloid accumulation in hereditary amyloidosis are the nerves, heart, blood vessels, and kidneys.

[0053] In the specification and claims, the phrase "and / or," as used herein, should be understood to mean "either or both of" i.e., "one or so" when used in a list of two or more items, "at least one of" the items, but not more than one, or "one, and optionally also the other" of one or more of the items. In addition, the phrase "and / or" as used herein assumes that the use of "only if" is explicitly denied. In addition to the explicitly identified elements, other elements can optionally be present, whether related to the explicitly identified elements or not. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer, in one embodiment, to only A (optionally including elements other than B); in another embodiment, to only B (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0054] In the specification and claims, the term "or" is understood to have the same meaning as “and / or” as defined above. For example, when used in the context of listing items paired with “and / or,” the term “or” should be interpreted as having an inclusive meaning, i.e., the selection of one or more of the listed items is permissible, and optional inclusion of additional items is also permissible. Only when the term “or” is explicitly stated to have an exclusive meaning, e.g., “only one of’ or “exactly one of,” or when used in the context of excluding additional symmetric possibilities, e.g., “none or one of’ should the term “or” be interpreted as having an exclusive meaning, i.e., the selection of exactly one of the listed items is permitted and no additional items are permitted. Generally, the term “or” as used herein should only be interpreted to indicate an exclusive option (i.e., “one or the other, but not both”) when preceded by terms of exclusivity, e.g., “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of’ when used in the claims, shall have its ordinary meaning as used in the patent law.

[0055] In the specification and claims, the phrase “at least one,” when used in reference to a list of one or more items should be understood to mean at least one of any one or more of the items in the list, but not necessarily including at least one of each and every item specifically listed, and not excluding additional or different items. This definition also allows that the

[0056] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of said method is not necessarily limited to the order in which the steps or acts are recited.

[0057] The term “augmentation” or “augment” refers to a combination in which one of the compounds increases or improves the therapeutic effect of another compound or compounds administered to a patient. In some cases, augmentation can result in improved efficacy, tolerability, or safety of a particular therapy, or any combination thereof.

[0058] In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "providing," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures (M.P.E.P.) § 2111.03.

[0059] Each recitation of a genus for a group of compounds, for example, alkyl, m, n, and the like, is intended to encompass each and every individual compound falling within that genus.

[0060] A complete list of abbreviations used by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled "Standard Abbreviations."

[0061] The terms "hydroxy" and "hydroxyl" mean the radical -OH.

[0062] The term "oxo" means the radical =0.

[0063] The term "carboxylate" or "carboxyl" means the radical -COO- or -COOH.

[0064] The term "cyano" means the radical -CN.

[0065] The term "nitro" means the radical -NO2.

[0066] The term "amino" means the radical -NH2.

[0067] The term "acyl" or "aldehyde" means the radical -C(=0)H.

[0068] The term "acylamino" or "amide" means the radical -C(O)NH2.

[0069] The term "aminoacyl" or "acylamino" means the radical -NHC(O)H.

[0070] The term "thiol" means the radical -SH.

[0071] The term "thio" means the radical =S.

[0072] The term "sulfinyl" means the radical -S(=0)H.

[0073] The term "sulfonyl" means the radical -SO2H.

[0074] The term "sulfonamido" or "sulfonamide" refers to the group—SO2NH2.

[0075] The term "sulfonate" refers to the group SO3H and includes groups in which the hydrogen is replaced by, for example, C1-C6 alkyl ("alkyl sulfonate"), aryl ("aryl sulfonate"), aralkyl ("arylalkyl sulfonate"), and the like. C1-C3 sulfonates are preferred, such as SO3Me, SO3Et, and SO3Pr.

[0076] The term "isomer" as used herein refers to stereoisomers, diastereoisomers, enantiomers, and tautomers. "Tautomers" can be isomers that are readily interconvertible by a fast equilibrium. For example, carbonyl compounds with a hydrogen on the alpha-carbon are rapidly interconvertible with their corresponding enol.

[0077] As used herein, the terms "alkyl," "alkenyl," and the prefix "alk-" include straight-chain groups and branched-chain groups, as well as cyclic groups, such as cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain 1 to 20 carbon atoms, with alkenyl groups containing 2 to 20 carbon atoms. In some embodiments, these groups have up to 10 carbon atoms in total, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms. Cyclic groups can be monocyclic or polycyclic, and preferably have 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstituted isobornyl, norbornyl, and norbornenyl groups.

[0078] The term "heterocycle" includes cyclic alkyl or alkenyl non-aromatic rings or ring systems containing at least one ring heteroatom (e.g., O, S, N).

[0079] Unless otherwise specified, "alkylene" and "alkenylene" are the divalent versions of "alkyl" and "alkenyl" as defined above. When "alkylene" and "alkenylene" are substituted, the terms "alkylenyl" and "alkenylenyl" are used. For example, arylalkylene includes the aryl group and the alkylene portion to which it is attached.

[0080] The term "haloalkyl" includes groups substituted with one or more halogen atoms, including perfluorinated groups. Other groups that include the prefix "halo" are also such. Examples of suitable haloalkyl groups are difluoromethyl, trifluoromethyl, and the like. "Halogen" is the element including chlorine, bromine, fluorine, and iodine.

[0081] The term "aryl" as used herein includes monocyclic or polycyclic aromatic hydrocarbons or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl, and indenyl. Aryl groups can be substituted or unsubstituted. Aryl groups include aromatic wheels, fused aryl groups, and heteroaryl groups. Aryl groups are also referred to herein as aryl rings.

[0082] The term "heteroatom" means an atom O, S, or N, unless otherwise indicated.

[0083] The term "heteroaryl" includes aromatic rings or ring systems containing at least one ring heteroatom (e.g., O, S, N). In some embodiments, the term "heteroaryl" includes rings or ring systems containing 2 to 12 carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O, S, and / or N as the heteroatoms. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothienyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiodiazolyl, and the like.

[0084] The terms "arylene" and "heteroarylene" are the divalent versions of the "aryl" and "heteroaryl" defined above. The terms "arylenyl" and "heteroarylenyl" are used when "arylene" and "heteroarylene" are substituted. For example, an alkylarylene includes an alkyl group attached to an arylene moiety.

[0085] The term "fused aryl ring" includes fused carbocyclic aromatic rings or ring systems. Examples of fused aryl rings include benzo, naphtho, fluoreno, and indeno.

[0086] The term "wheel" refers to an aryl group that is a fully conjugated monocyclic hydrocarbon. Examples of wheels include cyclobutadiene, benzene, and cyclooctatetraene. Wheels present in aryl groups typically have one or more hydrogen atoms replaced with other atoms such as carbon.

[0087] When a group is present more than once in any formula or scheme depicted herein, each group (or substituent) is selected independently, whether or not explicitly stated. For example, for the formula — C(O)NR2, each of the two R groups is selected independently.

[0088] To simplify the discussion and recitation of certain terms used in the specification and claims, the terms "group" and "moiety" are used to distinguish between chemical species that allow substitution or that can be substituted, and those that do not allow such substitution or can not be substituted in a particular embodiment of the application. Thus, when the term "group" is used to describe a chemical substituent, the described chemical material includes substituted and unsubstituted species of the recited group. When the term "moiety" is used to describe a chemical compound or substituent, it is only intended to exclude un-substituted chemical species. For example, the phrase "alkyl" is intended to include both substituted and unsubstituted alkyl groups, e.g., methyl, ethyl, propyl, t-butyl, etc., as well as alkyl groups bearing further substitutents, e.g., hydroxy, alkoxy, alkylsulfonyl, halogen atoms, cyano, nitro, amino, carboxy, etc. Thus, "alkyl" includes ether groups, haloalkyl, nitroalkyl, carboxyalkyl, hydroxyalkyl, sulfoalkyl, etc. On the other hand, the phrase "alkyl moiety" is intended to limit the group to only include simple, open chain, saturated hydrocarbon alkyl substituents, e.g., methyl, ethyl, propyl, t-butyl, etc.

[0089] The present application includes the compounds described herein (including intermediates), in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), tautomers, salts, solvates, polymorphs, prodrugs, and the like. In particular, if a compound is optically active, the present application specifically includes each enantiomer of the compound, as well as racemic mixtures of the enantiomers. It is understood that the term "compound" includes any or all such forms, whether or not explicitly identified (although sometimes "salt" is explicitly identified).

[0090] "Pharmaceutically acceptable" as used herein means that which is suitable for administration to a subject to achieve the therapeutic effects described herein, without unduly deleterious side effects in light of the necessity of the therapy.

[0091] The term "therapeutically effective amount" or "pharmaceutically suitable dose" as used herein refers to the amount of a compound or dose that will elicit the biological or medical response of a subject, tissue or cell that is being sought by the researcher, veterinarian, medical doctor or other clinician.

[0092] As used herein, "pharmaceutically acceptable carrier" includes any and all dry powder agents, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of a pharmaceutically acceptable carrier in the methods of the present application is contemplated to be a material that is nontoxic to the subject in which it is administered, preferably is inert, and can be a solid, liquid, or gas material that is otherwise chemically and / or biologically inert and pharmaceutically acceptable, and is compatible with the compounds of the present application. Examples of such carriers include oils such as corn oil, buffers such as PBS, saline, polyethylene glycol, glycerol, polypropylene glycol, dimethyl sulfoxide, amides such as dimethylacetamide, proteins such as albumin, and detergents such as Tween 80, monosaccharides and oligosaccharides such as glucose, lactose, cyclodextrins, and starches.

[0093] The term "administering" or "administration" as used herein refers to providing a compound or pharmaceutical composition of the present application to a subject suffering from or at risk of a disease or condition to be treated or prevented.

[0094] The term "systemic delivery" as used herein refers to any suitable method of administration by which a compound of the present application can be systemically delivered. In one embodiment, systemic delivery can be selected from oral, parenteral, intranasal, inhaler, sublingual, rectal, and transdermal administration.

[0095] Routes of administration in pharmacology and toxicology are the paths by which a drug, fluid, poison, or other substance enters the body. Routes of administration can be generally categorized by the location where the substance is applied. Common examples can include oral and intravenous administration. Routes can also be categorized based on the location of the target of action. The action can be local, enteral (systemic effect, but delivered through the gastrointestinal tract), or parenteral (systemic action, but delivered through a route other than the GI tract).

[0096] Local administration emphasizes a local effect, and the substance is applied directly to the location where its action is needed. Sometimes, however, the term local can be defined as applied to a localized area or surface of a body part of the body, not necessarily involving a target effect of the substance, making this classification more of a categorical variant based on the site of application. In enteral administration, the desired effect is systemic (non-local), and the substance is given through the digestive tract. In parenteral administration, the desired effect is systemic, and the substance is given through a route other than the digestive tract.

[0097] Examples of local administration can include epicutaneous (application to the skin), such as allergy testing or routine local anesthesia; inhalation, such as asthma medication; enemas, such as contrast agents for imaging of the intestinal tract; eye drops (to the conjunctiva), such as antibiotics for conjunctivitis; ear drops, such as antibiotics and corticosteroids for otitis externa; and those through mucous membranes in vivo.

[0098] Enteral administration can be any administration involving any part of the gastrointestinal tract and having a systemic effect. Examples include those administered orally (orally), such as many drugs as tablets, capsules, or drops; those administered via gastric tube, duodenal tube, or gastrostomy, such as many drugs and enteral nutrition products; and those administered rectally, such as various drugs in suppository form.

[0099] Examples of parenteral administration can include intravenous (to the vein), such as many medications and total parenteral nutrition; intra-arterial (to the artery), such as vasodilators for treating vasospasm and thrombolytics for treating embolism; intraosseous infusion (to the bone marrow); intramuscular; intracerebral (to the brain parenchyma); intraventricular (to the ventricular system); intrathecal (injected into the spinal canal); and subcutaneous (under the skin). Intraosseous infusion is essentially an indirect intravenous access because the bone marrow drains directly into the venous system. In emergency medicine and pediatrics, intraosseous infusion may occasionally be used for medications and fluids when intravenous access is difficult.

[0100] Any route of administration may be suitable for this invention. In one embodiment, the compound of the invention may be administered to the subject by intravenous injection. In another embodiment, the compound of the invention may be administered to the subject by any other suitable systemic delivery method, such as oral, parenteral, intranasal, sublingual, rectal, or transdermal administration.

[0101] In another embodiment, the compounds of the present invention may be administered to a subject via the nasal system or mouth, for example by inhalation.

[0102] In another embodiment, the compounds of the present invention can be administered to the subject by intraperitoneal injection or intraperitoneal injection (IP).

[0103] As used herein, the terms "intraperitoneal injection" or "IP injection" refer to the injection of a substance into the peritoneum (body cavity). IP injection is more commonly used in animals than in humans. Generally, IP injection may be preferred when a large amount of blood is needed to replace fluids or when low blood pressure or other problems prevent the use of a suitable blood vessel for intravenous injection.

[0104] In animals, IP injection is primarily used for veterinary drugs and for animal testing of systemic drugs and fluids due to its ease of administration compared to other parenteral methods.

[0105] In humans, the IP injection method is widely used to administer chemotherapy drugs to treat some cancers, particularly ovarian cancer. Despite controversy, this specific use has been recommended as a standard of care.

[0106] Certain compounds contained in the compositions of the present invention may be present in specific geometric or stereoisomeric forms. Furthermore, the polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, and mixtures thereof, are intended to be included in the present invention.

[0107] If, for example, a specific enantiomer of the compound of the present invention is required, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is isolated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, a diastereomeric salt is formed with a suitable optically active acid or base, followed by resolution of the resulting diastereomeric isomer by fractional crystallization or chromatographic means well known in the art, and subsequently recovery of the pure enantiomer.

[0108] It will be understood that “substitution” or “replacing with…” includes the implicit condition that such substitution is based on the allowed valence of the substituted atom and the substituent, and that the substitution results in a stable compound, for example, which does not spontaneously undergo conversion, such as by rearrangement, cyclization, elimination or other reactions.

[0109] The term "substituted" also considers all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described above. For suitable organic compounds, permissible substituents can be one or more, and can be the same or different. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein, satisfying the valence of the heteroatom. This invention is not intended to be limited in any way to permissible substituents of organic compounds.

[0110] For the purposes of this invention, chemical elements were identified according to the CAS version of the periodic table on the inner cover of "Handbook of Chemistry and Physics", 67th edition, 1986-87.

[0111] As used herein, the terms “subject” or “individual” refer to a human or other vertebrate. The term is intended to include “patient”.

[0112] The term "synergistic" refers to a combination that is more effective than the additive effect of any two or more individual agents. Synergistic effects allow for the effective treatment of disease using lower amounts (doses) of individual therapies. Lower doses result in lower toxicity without reduced efficacy. Furthermore, synergistic effects can lead to improved efficacy. Finally, synergistic effects can result in improved disease prevention or relief compared to any single therapy.

[0113] Compared to the normal requirement when each drug is used alone, combination therapy allows for a lower dose of either the first or second therapeutic agent (referred to herein as “apparent one-way synergy”) or a lower dose of both therapeutic agents (referred to herein as “two-way synergy”).

[0114] As used herein, "pharmaceuticalally acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delay agents, etc. A pharmaceutically acceptable carrier is a material used in the methods of the present invention for the purpose of administering a compound, preferably non-toxic, and may be otherwise inert and pharmaceutically acceptable solid, liquid, or gaseous material, and compatible with the compounds of the present invention. Examples of such carriers include oils such as corn oil, buffers such as PBS, saline, polyethylene glycol, glycerol, polypropylene glycol, dimethyl sulfoxide, amides such as dimethylacetamide, proteins such as albumin, and detergents such as Tween 80, monosaccharides and oligosaccharides such as glucose, lactose, cyclodextrin, and starch.

[0115] The formulations used in this invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those skilled in the art. Such media and reagents are well-known in the art for the use of pharmaceutically active substances. Additional active compounds may also be incorporated into the imaging agents of this invention. The imaging agents of this invention may be further administered to individuals in suitable diluents or adjuvants, co-administered with enzyme inhibitors, or in suitable carriers, such as human serum albumin or liposomes. Pharmaceutically acceptable diluents include sterile saline and other aqueous buffer solutions. Adjuvants considered herein include resorcinol, nonionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether. Enzyme inhibitors include trypsin inhibitors, diethyl pyrocarbonate, and aprotinin. Liposome inhibitors include water-in-oil-in-water CGF emulsions and conventional liposomes (see J. Neuroimmunol. 1984, 7, 27).

[0116] As described herein, certain embodiments of the compounds of the present invention may contain a basic functional group, such as an amino or alkylamino group, and thus be able to form pharmaceutically acceptable salts with pharmaceutically acceptable acids. In this respect, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic and organic acid addition salt of the compounds of the present invention. These salts may be prepared in situ during the manufacture of the administration medium or dosage form, or by reacting the purified compounds of the present invention in their free basic form with a suitable organic or inorganic acid, and then separating the resulting salt in a subsequent purification. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, p-toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, and laurylsulfonate, etc. See J. Pharm. Sci. 1977, 66, 1-19.

[0117] Pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothiosulfate, etc.

[0118] In other cases, the compounds of the present invention may contain one or more acidic functional groups, thus enabling them to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic base addition salt of the compounds of the present invention. These salts may be prepared in situ during the manufacture of the administration medium or dosage form, or by reacting a purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (See, for example, J. Pham. Sci. 1977., ibid.).

[0119] More specifically, the compounds that can be formulated into pharmaceutical compositions include a therapeutically effective amount of a first compound, a therapeutically effective amount of a second compound, and a pharmaceutically acceptable carrier. The therapeutically effective amount of the compound and the specific pharmaceutically acceptable carrier will vary depending on, for example, the subject's age, weight, sex, route of administration, and type of viral condition being treated.

[0120] In one specific aspect, the pharmaceutical compositions that may be used include compounds of the present invention in the form of an effective unit dosage form. As used herein, the terms “effective unit dose” or “effective unit dose” are used to refer to a predetermined amount sufficient to effectively target AD, etc. Examples include amounts capable of treating amyloid deposition in vivo or in vitro, producing acceptable levels of toxicity and bioavailability for pharmaceutical use, and / or preventing cell degeneration and toxicity associated with fibrillation.

[0121] The pharmaceutical composition may contain 0.01-99% by weight of the total composition, preferably 0.1-80% by weight of the total composition, of the first or second compound used in the method of the present invention. For oral administration, the first or second compound is typically administered at an amount of 0.1 g / body to 15 g / body, preferably 0.5 g / body to 5 g / body. For intravenous injection, the dose may be from about 0.1 to about 30 mg / kg / day, preferably from about 0.5 to about 10 mg / kg / day. If applied topically as a liquid, ointment, or cream, the first or second compound may be present at an amount of about 0.1 to about 50 mg / mL, preferably from about 0.5 to 30 mg / mL of the composition.

[0122] For systemic administration, the daily dose range for adult treatment is from about 0.1 mg / kg to about 150 mg / kg, preferably from about 0.2 mg / kg to about 80 mg / kg.

[0123] All U.S. patent and U.S. patent application publications cited in this article are incorporated herein by reference.

[0124] Using no more than conventional experiments, those skilled in the art will recognize or be able to identify numerous equivalents of specific embodiments of the invention described herein. Such equivalents are intended to be covered by the appended claims.

[0125] Treatment

[0126] The combination of compounds described above can be administered to a subject as a single dosage form or by administering each active agent separately. The reagents can be formulated as single tablets, pills, capsules, or solutions for parenteral administration, etc. In a single dosage form, each therapeutic agent can be separated from the others. Formulation in this manner helps maintain the structural integrity of potentially reactive therapeutic agents until they are administered. The therapeutic agents can be contained in a separate region within a capsule or in different tablets, etc. The therapeutic agents can also be provided in tablets as separate layers.

[0127] Alternatively, the therapeutic agents may be administered as separate compositions, such as as separate tablets or solutions. One or more active agents may be administered simultaneously with other active agents, or the active agents may be administered intermittently. The duration between administrations of the therapeutic agents may be adjusted to achieve the desired therapeutic effect. In some cases, one or more therapeutic agents may be administered only a few minutes (e.g., about 1, 2, 5, 10, 30, or 60 minutes) after administration of other therapeutic agents. Alternatively, one or more therapeutic agents may be administered several hours (e.g., about 2, 4, 6, 10, 12, 24, or 36 hours) after administration of other therapeutic agents. In some embodiments, it may be advantageous to administer more than one dose of one or more therapeutic agents between administrations of the remaining therapeutic agents. For example, a therapeutic agent may be administered 2 hours after administration of other therapeutic agents, and then again 10 hours later. The therapeutic effects of each active ingredient should overlap for at least a portion of the time, such that the overall therapeutic effect of the combination therapy is partly attributable to the combination or synergistic effect of the combination therapy.

[0128] The dosage of an active agent typically depends on many factors, including the pharmacodynamic characteristics of each agent in the combination, the manner and route of administration, the health of the patient being treated, the extent of treatment required, the nature and type of concurrent therapies (if any), and the frequency of treatment and the nature of the desired effect. Generally, the dosage range of an active agent is typically from about 0.001 to about 250 mg / kg body weight / day. For a normal adult with a body weight of about 70 kg, the dosage range may be from about 0.1 to about 25 mg / kg body weight. However, some variation within this general dosage range may be necessary depending on the age and weight of the subject being treated, the intended route of administration, the specific agent being administered, etc. Since two or more different active agents are used together in combination therapy, the potency of each agent and the interaction effects achieved by using them together must be considered. Importantly, the determination of the dosage range and optimal dosage for a particular mammal is also entirely within the capabilities of those skilled in the art who have benefited from this disclosure.

[0129] The dosage range for the reagent can be as low as 5 ng / day. In some embodiments, the dosage is approximately 10 ng / day, approximately 15 ng / day, approximately 20 ng / day, approximately 25 ng / day, approximately 30 ng / day, approximately 35 ng / day, approximately 40 ng / day, approximately 45 ng / day, approximately 50 ng / day, approximately 60 ng / day, approximately 70 ng / day, approximately 80 ng / day, approximately 90 ng / day, approximately 100 ng / day, approximately 200 ng / day, approximately 300 ng / day, approximately 400 ng / day, approximately 500 ng / day, approximately 600 ng / day, approximately 700 ng / day, approximately 800 ng / day, approximately 900 ng / day, approximately 1 μg / day, approximately 2 μg / day, approximately 3 μg / day, approximately 4 μg / day, approximately 5 μg / day, approximately 10 μg / day, approximately 1 The reagents of the present invention are available in the following doses: 5 μg / day, about 20 μg / day, about 30 μg / day, about 40 μg / day, about 50 μg / day, about 60 μg / day, about 70 μg / day, about 80 μg / day, about 90 μg / day, about 100 μg / day, about 200 μg / day, about 300 μg / day, about 400 μg / day, about 500 μg / day, about 600 μg / day, about 700 μg / day, about 800 μg / day, about 900 μg / day, about 1 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 10 mg / day, about 15 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, or about 50 mg / day.

[0130] In some embodiments, the reagent of the present invention is administered at a concentration of pM or nM. In some embodiments, the reagent is administered at concentrations of about 1 pM, about 2 pM, about 3 pM, about 4 pM, about 5 pM, about 6 pM, about 7 pM, about 8 pM, about 9 pM, about 10 pM, about 20 pM, about 30 pM, about 40 pM, about 50 pM, about 60 pM, about 70 pM, about 80 pM, about 90 pM, about 100 pM, about 200 pM, about 300 pM, about 400 pM, about 500 pM, about 600 pM, about 700 pM, about 800 pM, about 900 pM, about 100 pM, about 200 pM, about 300 pM, about 400 pM, about 500 pM, about 600 pM, about 700 pM, about 800 pM, about 900 pM, or about 100 pM. Apply at concentrations of approximately 0.00 pM, 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, or 900 nM.

[0131] In some embodiments, the size of the active agent is important. In some embodiments, the diameter of the active agent is less than about 3 μm, less than about 2 μm, or less than about 1 μm. In some embodiments, the diameter of the active agent is from about 0.1 μm to about 3.0 μm. In some embodiments, the diameter of the active agent is from about 0.5 μm to about 1.5 μm. In some embodiments, the diameter of the active agent is about 0.2 μm, about 0.3 μm, about 0.4 μm, about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8 μm, about 0.9 μm, about 1.0 μm, about 1.1 μm, about 1.2 μm, about 1.3 μm, about 1.4 μm, or about 1.5 μm.

[0132] It may be advantageous for the drug combination to contain a relatively large amount of the first component compared to the second component. In some cases, the ratio of the first active agent to the second active agent is about 200:1, 190:1, 180:1, 170:1, 160:1, 150:1, 140:1, 130:1, 120:1, 110:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1. Further preference may be given to having a more evenly distributed distribution of the agents. In some cases, the ratio of the first active agent to the second active agent is about 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, or 1:4. It may also be advantageous for the drug combination to have a relatively large amount of the second component compared to the first component. In some cases, the ratio of the second active agent to the first active agent is about 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1. In some cases, the ratio of the second active agent to the first active agent is about 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, or 40:1. In some cases, the ratio of the second active agent to the first active agent is about 200:1, 190:1, 180:1, 170:1, 160:1, 150:1, 140:1, 130:1, 120:1, or 110:1. Compositions containing any combination of the first and second therapeutic agents as defined above may be administered separately in doses about 1, 2, 3, 4, 5, 6, or more times daily, or in a form that provides a release rate that effectively achieves the desired results. The dosage form may contain both the first and second active agents. If the dosage form contains both the first and second active agents, it can be applied once daily.

[0133] For example, a formulation intended for oral administration to humans may contain about 0.1 mg to about 5 g of a first therapeutic agent and about 0.1 mg to about 5 g of a second therapeutic agent, both mixed with a suitable and convenient amount of carrier material varying from about 5% to about 95% of the total composition. A unit dose typically contains about 0.5 mg to about 1500 mg of the first therapeutic agent and about 0.5 mg to about 1500 mg of the second therapeutic agent. The dose may be about 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, up to about 1500 mg of the first therapeutic agent. The dose may be about 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, up to about 1500 mg of the second therapeutic agent.

[0134] In one aspect, this disclosure relates to embodiments of a method for treating a subject with neurodegenerative disease, the method comprising administering to the subject an effective dose of a combination of a mast cell stabilizer and a nonsteroidal anti-inflammatory drug; wherein the subject is not a carrier of a neurodegenerative disease susceptibility genotype.

[0135] In any embodiment of the treatment method, the neurodegenerative disease may be Alzheimer's disease (AD). In any embodiment of the treatment method, the method can treat an ongoing neurodegenerative disease and / or prevent future onsets of the neurodegenerative disease. In any embodiment, the neurodegenerative disease may be diagnosed or undiagnosed at the time of treatment. The neurodegenerative disease may be in its early stages at the time of treatment. In any embodiment, the mast cell stabilizer may be cromoglycine; cromoglycine derivatives; cromoglycine homologues; a salt of any one of cromoglycine, cromoglycine derivatives, or cromoglycine homologues; or any combination thereof. In any embodiment, the salt may be a biocompatible salt. In any embodiment, the biocompatible cromoglycate may be sodium cromoglycate.

[0136] In any implementation of the treatment method, the subject may not be a carrier of any variant of apolipoprotein E that susceptes the subject to the onset of Alzheimer's disease. In any implementation, the subject may not be a carrier of APOEε4.

[0137] In any embodiment of the treatment method, cromoglycine or a biocompatible salt thereof may be formulated as a dry powder for inhalation. In any such embodiment, cromoglycine or a biocompatible salt thereof may be formulated as a dry powder for inhalation with a particle size of less than about 3 micrometers.

[0138] In any embodiment of the treatment method, cromoglycine or a biocompatible salt thereof may be administered at a dose of about 1 mg / day to about 50 mg / day. In some embodiments, the dose may be about 16 to about 20 mg / day.

Claims

1. A method for treating a neurodegenerative disease in a subject of need, the method comprising: The subjects were administered an effective dose of a combination of mast cell stabilizers and nonsteroidal anti-inflammatory drugs. The subjects in question were not carriers of genotypes susceptible to neurodegenerative diseases.

2. The method according to claim 1, wherein the neurodegenerative disease is Alzheimer's disease.

3. The method according to claim 1, wherein the nonsteroidal anti-inflammatory drug is ibuprofen.

4. The method according to claim 1, wherein the mast cell stabilizer is cromoglycine or a biocompatible salt thereof.

5. The method of claim 2, wherein the subject is not a carrier of any variant of apolipoprotein E that makes the subject susceptible to the onset of Alzheimer's disease.

6. The method of claim 5, wherein the subject is not a carrier of APOEε4.

7. The method according to claim 4, wherein the cromoglycine or its biocompatible salt is sodium cromoglycate.

8. The method of claim 4, wherein the cromoglycine or its biocompatible salt is formulated as a dry powder for inhalation.

9. The method of claim 8, wherein the cromoglycine or its biocompatible salt is formulated as a dry powder with a particle size of less than about 3 micrometers for inhalation.

10. The method according to any one of claims 4-9, wherein the cromoglycine or its biocompatible salt is administered at a dose of about 16 mg / day to about 20 mg / day.

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