CN111617255B - Combination therapy for the treatment of central nervous system disorders - Google Patents

Combination therapy for the treatment of central nervous system disorders Download PDF

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CN111617255B
CN111617255B CN202010114379.4A CN202010114379A CN111617255B CN 111617255 B CN111617255 B CN 111617255B CN 202010114379 A CN202010114379 A CN 202010114379A CN 111617255 B CN111617255 B CN 111617255B
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CN111617255A (en
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李嘉强
陈素珍
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1Globe Biomedical Co Ltd
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Abstract

The present invention provides novel compositions, pharmaceutical compositions and uses thereof consisting of metformin (Met) and Disease Modifying Therapies (DMTs) (e.g., dimethyl fumarate, DMF) for the treatment of diseases affecting the central nervous system, such as multiple sclerosis.

Description

Combination therapy for the treatment of central nervous system disorders
Technical Field
The present invention relates to combinations of Metformin (Metformin, met) and Disease modifying therapies (diseases-modifying Treatments, DMTs) (e.g., dimethyl fumarate (dimethyl fumarate, DMF)), pharmaceutical compositions and methods of use thereof for the combined treatment of neurological disorders such as multiple sclerosis (Multiple Sclerosis, MS).
Background
Multiple Sclerosis (MS) is a demyelinating disease of the Central Nervous System (CNS) that can cause progressive motor and sensory deficits. It is the most common and debilitating neurological disease in young people in the united states. Seventeen FDA approved therapies are currently available for the treatment of relapsing-remitting multiple sclerosis (RRMS), which are developed based on the theory that MS is an autoimmune disease. Unfortunately, all of these therapies are Disease Modifying Treatments (DMTs) that bring little and ambiguous benefit to the patient and do not cure MS. Many patients discontinue DMTs due to serious side effects (Filippini G et al, 2017). An unmet need for treatment of MS is a treatment that can prevent the continued progression and accumulation of disability in MS patients and can ultimately cure the disease. The pathological features of MS are focal inflammation, gliosis (Gliosis), oligodendropathy (oligoglia), demyelination, and axonal injury. Methods of treatment that prevent the development of these pathological features may hold promise for curing MS.
The pathogenesis of MS is largely unknown and the molecular mechanism underlying the progression of MS remains elusive. MS is widely recognized as a T cell mediated autoimmune disease. However, this theory does not fully explain the progressive myelin damage, oligodendrocyte death, and axonal damage observed in MS patients. It is highly likely that various pathogenic processes lead to demyelination and degeneration of the CNS in MS patients. Glioblast proliferation, including astrocyte proliferation and microglial proliferation, are prominent features of many CNS disorders, playing an important role in the pathogenesis of MS (see for comments Burda JE and Sofroniew MV,2014;Dossi E et al,2018). Astrocytes are increasingly thought to be a key to providing peripheral immune cells with access to the central nervous system pathway and an early, highly active factor in the formation of MS lesions (see Pekny M and Pekna M,2016;Kiray H et al,2016;Ponath G et al,2018 for comments). In order to prevent MS progression, drugs targeting a variety of pathways, such as modulation of glioblast proliferation, enhancement of myelin and axon regeneration, are highly desirable. Combination therapy of MS with drugs tests have been performed in animal models of MS and in small-scale clinical trials on MS patients (Fernandez O,2007;Kim MJ et al,2017). Unfortunately, no combination therapy regimen has been approved for MS because of unsatisfactory test results. Thus, there remains a need to continue to explore new, effective combination therapy regimens that can benefit greatly from patients in need thereof.
Dimethyl fumarate (DMF) was marketed in 2013 as a small molecule drug for the treatment of RRMS. Although the therapeutic mechanism of DMF has not been fully elucidated, it has been shown to be immunomodulatory and antioxidant stressed (Mills EA et al, 2018).
Recent studies have shown that metabolic disorders are involved in the pathology of Multiple Sclerosis (MS) and affect the sensitivity of the treatment. Metformin is an oral drug widely used for the treatment of type 2 diabetes and shows a wide range of therapeutic effects on other diseases, such as neurodegenerative diseases. Animal and retrospective human studies have shown that metformin has neuroprotective effects on Parkinson's Disease (PD). Metformin has the property of having mild side effects and rapidly crossing the blood brain barrier, which makes the drug an excellent candidate for the treatment of brain disorders. Studies have shown that metformin reduces MS disease activity in the mouse EAE model (Nath N et al,2009;Sun Y et al,2016). Recent studies have shown that metformin can readjust oligodendrocyte precursor cells (Oligodendrocyte Precursor Cells, OPCs), regenerate axonal myelin, and promote remyelination in older rodents (Franklin R, 2018). Even, metformin can help control disease activity in MS patients who are obese and suffering from metabolic syndrome. One human study showed that patients had significantly less T2 injury and gadolinium-enhanced injury when treated with metformin (Negrotto L et al 2016). However, metformin in combination with DMTs (e.g., DMF) has not been studied and reported as a new therapeutic modality for the treatment of MS.
Summary of The Invention
We have found that the combination treatment of metformin and DMTs (e.g., DMF) produces unexpected synergistic effects on one or more of the following functions in a variety of experimental settings, such as inhibiting damage to myelin, axons, and brain cells, preventing demyelination and promoting toxicity-mediated demyelination, inducing death of activated astrocytes and microglia, inhibiting inflammatory responses of glial cells, promoting oligodendrocyte maturation, promoting axon health and regeneration, and helping neurons survive.
In one aspect, the present invention relates to novel compositions and their use as novel methods of treatment in the treatment of CNS disorders (e.g., multiple sclerosis).
In one embodiment, the present invention relates to novel compositions comprising a first agent comprising metformin and a second agent comprising one or more DMTs, and their use as novel methods of treatment in the treatment of CNS disorders (e.g., multiple sclerosis). In one embodiment, the DMTS comprises dimethyl fumarate, interferon beta-1a (interferon beta-1 a), interferon beta-1b (interferon beta-1 b), glatiramer acetate (glatiramer acetate), natalizumab (natalizumab), fingolimod, teriflunomide (teriflunomide), alemtuzumab (alemtuzumab), daclizumab (daclizumab), omelizumab (ocrelizumab), polyethylene glycol interferon beta-1a (pegylated interferon beta-1 a), cladribine (cladribine) or mitoxantrone (mitoxantrone), and the like. In one embodiment, the second agent comprises a DMTs. In one embodiment, the composition has anti-inflammatory, neuroprotective, and nerve regeneration benefits for other neurological disorders resulting from neuroinflammation and neurodegeneration.
In one embodiment, the disclosure of the present invention relates to a novel composition comprising a first agent selected from metformin, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; and a second agent selected from the group consisting of dimethyl fumarate, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing. In one embodiment, the presently disclosed compositions are useful for treating neurological disorders, in particular, multiple sclerosis.
In one embodiment, the presently disclosed compositions are used to treat or ameliorate one or more central nervous system diseases or disorders, or, more specifically, demyelinating diseases. In one embodiment, the composition is effective in treating or alleviating multiple sclerosis.
In one aspect, the disclosure of the present invention relates to a pharmaceutical composition comprising a first agent selected from metformin or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; a second agent selected from a DMTs for the treatment of MS, such as dimethyl fumarate, interferon beta-1a, interferon beta-1b, glatiramer acetate, natalizumab, fingolimod, teriflunomide, alemtuzumab, daclizumab, omentulmoschus, polyethylene glycol interferon beta-1a, cladribine or mitoxantrone, and the like; and a pharmaceutically acceptable excipient, carrier or diluent. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of metformin, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; a therapeutically effective amount of dimethyl fumarate, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; and a pharmaceutically acceptable excipient, carrier or diluent. In one embodiment, the presently disclosed pharmaceutical compositions are used to treat or ameliorate one or more central nervous system diseases or disorders. In one embodiment, the pharmaceutical compositions disclosed herein are useful for treating neurological disorders, in particular, multiple sclerosis.
In one aspect, the disclosure relates to a combination therapy for treating or alleviating one or more central nervous system diseases or disorders comprising administering to a subject in need thereof: a therapeutically effective amount of a first agent selected from metformin, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; and a therapeutically effective amount of a second agent selected from a DMTS for the treatment of MS, such as dimethyl fumarate, interferon beta-1a, interferon beta-1b, glatiramer acetate, natalizumab, fingolimod, teriflunomide, alemtuzumab, daclizumab, omentum bemtuzumab, polyethylene glycol interferon beta-1a, cladribine or mitoxantrone, and the like. In some embodiments, the disclosure relates to a combination therapy for treating or alleviating one or more central nervous system diseases or disorders comprising administering to a subject in need thereof: a therapeutically effective amount of a first agent selected from metformin, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; and a therapeutically effective amount of a second agent selected from the group consisting of dimethyl fumarate, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing.
In one aspect, the present disclosure relates to a method of treatment for treating or alleviating one or more central nervous system diseases or disorders comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising metformin and dimethyl fumarate.
In some embodiments, the central nervous system disease or disorder is multiple sclerosis.
In some embodiments, the first agent and the second agent may be administered to the subject simultaneously or sequentially.
The foregoing and other objects, aspects, features, and advantages of the present invention will become more apparent from the following description and from the claims.
Brief Description of Drawings
The objects and features of the present invention may be better understood with reference to the drawings and claims described below. The drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention.
Fig. 1 shows the effect of DMF, metformin (Met), and combinations thereof on survival of activated astrocytes. * p <0.05 compared to control, #p <0.01 compared to Met or DMF single drug (n=4).
Fig. 2 shows the effect of DMF, metformin (Met), and combinations thereof on survival of activated microglia. * P <0.01 compared to control plus LPS/IFN, #p <0.05 between experimental groups (n=4-8).
Detailed Description
I. Definition of the definition
As used in the specification and in the claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "cell" includes a variety of cells, including mixtures thereof.
When dimensional measurements are given herein for a component, unless explicitly stated or clear from the context, the values are intended to describe the average of the necessary parts of the component, i.e. the average of the parts of the component that are required for the purpose. Any accessory or excess parts are not included in the calculation of the value.
As used herein, "about" means within ±10%. For example, "about 1" means "0.9 to 1.1", "about 2%" means "1.8% to 2.2%", "about 2% to 3%" means "1.8% to 3.3%", and "about 3% to about 4%" means "2.7% to 4.4%".
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The general principles of organic chemistry and specific functional moieties and reactivities are described in "organic chemistry", thomas Sorrell, university Science Books, sausalato (2006).
The term "effective amount" of an active agent refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the present invention may vary depending upon the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient.
The term "treatment" or "treating" a disease or disorder refers to a method of reducing, delaying or ameliorating a condition before or after such condition occurs. Treatment may be directed to one or more effects or symptoms of the disease and/or underlying pathology. Treatment may be any reduction and may be, but is not limited to, a disease or complete elimination of symptoms of a disease. This reduction or prevention, as measured by any standard technique, is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95% or 100% as compared to an equivalent untreated control.
The term "subject" refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., that is the recipient of a particular treatment. In general, the terms "subject" and "patient" are used interchangeably herein to refer to a human subject.
The term "demyelinating disease" refers to a condition or disease caused by damage or loss of myelin sheath around neurons. Multiple sclerosis is the most common demyelinating disease. Other examples of demyelinating diseases include: neuromyelitis optica (NMO and NMO disease spectrum), progressive Multifocal Leukoencephalopathy (PML), transverse myelitis, acute Disseminated Encephalomyelitis (ADEM), acute Hemorrhagic Leukoencephalitis (AHL), balo's disease, schilder's disease, central and external pontine myelinolysis (Central Pointine and Extra Myelinolysis, CPM), recurrent isolated optic neuritis, and neoplastic demyelination.
The term "disease modifying treatment" or "DMTs" refers to known FDA or EMA approved disease modifying treatments, disease modifying therapies or disease modifying drugs for Multiple Sclerosis (MS). These treatments or therapies fail to cure MS. Examples of "DMTs" include, but are not limited to: interferon beta-1aInterferon beta-1b (Betaferon/->) Glatiramer acetate->NatalizumabFengomod->Teriflunomide->Fumaric acid dimethyl esterAlemtuzumab->Darcy bead mab->Omeprazole monoclonal antibodyPolyethylene glycol interferon beta-1 a->Cladribine>Or mitoxantrone
As used herein, "composition" or "combination" therapy or treatment refers to the administration of at least two different drugs to treat a disorder, condition or symptom, e.g., a multiple sclerosis disorder. Such combination therapy may comprise administration of one drug before, during and/or after administration of another drug. The interval between drug administrations may be up to several weeks, but is more typically within 48 hours, most typically within 24 hours.
The term "pharmaceutically acceptable excipient, carrier or diluent" as used herein refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a subject agent from one organ or body part to another organ or body part. Each carrier must be "acceptable", that is, must be compatible with the other ingredients of the formulation and not deleterious to the patient. Some examples of materials that may be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderized gum tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; diols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; non-thermal raw water; isotonic saline; ringer's solution; ethanol; phosphate buffers and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate, magnesium stearate and polyethylene oxide-polypropylene oxide copolymers, colorants, mold release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives and antioxidants can also be present in the compositions.
The compounds of the present invention may form salts which are also within the scope of the present invention. Unless otherwise indicated, references herein to the compounds of the present invention are to be understood as including salts thereof. The term "salt" as used herein means an acidic and/or basic salt formed with inorganic and/or organic acids and bases. Furthermore, when the compounds of the present invention comprise a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, carboxylic acid), a zwitterionic ("inner salt") may be formed and included in the term "salt" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps in the preparation process. Salts of the compounds of the invention may be formed, for example, by reacting the compounds with an amount of an acid or base (e.g., an equivalent amount) in a medium such as a salt precipitate or in an aqueous medium, followed by lyophilization.
The term "pharmaceutically acceptable salts" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, berge et al describe pharmaceutically acceptable salts in detail in J.pharmaceutical Sciences (1977) 66:1-19. (see also P.H.Stahl and C.G.Wermuth, editors, handbook of Pharmaceutical Salts: properties, selection and Use, weinheim/Zurich: wiley-VCH/VHCA, 2002.)
The term "metabolites" refers to those compounds which are converted from the compounds of the invention under certain conditions (e.g. enzymes) and which may have similar functions as the compounds of the invention, e.g. one metabolite of dimethyl fumarate (DMF) is monomethyl fumarate (MMF).
Solvates of the compounds of the present invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.
The compounds of the invention and salts thereof may exist in their tautomeric forms (e.g., as amides or iminoethers). All of these tautomeric forms are considered herein to be part of the present invention.
All stereoisomers of the compounds of the invention (e.g., those that may exist due to asymmetric carbon atoms on various substituents), including enantiomeric and diastereomeric forms, are included within the scope of the invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers having a particular activity); or may be mixed, for example as racemate or with all other isomers; or other selected stereoisomers. The chiral centers of the present invention may have the S or R configuration defined by IUPAC 1974 Recommendations. The racemic forms can be resolved by physical methods such as fractional crystallization, separation or crystallization of diastereoisomeric derivatives or separation by chiral chromatography columns. The various optical isomers may be obtained from the racemates by any suitable method, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
All configurational isomers of the compounds of the present invention are contemplated, as are mixtures, as well as pure or substantially pure forms. The definition of compounds of the invention includes cis (Z) and trans (E) olefin isomers, and cis and trans isomers of cyclic or heterocyclic hydrocarbons.
Throughout the specification, the groups and substituents thereof may be selected to provide stable moieties and compounds.
II, composition, pharmaceutical composition and use
The present invention provides novel compositions, pharmaceutical compositions and novel uses thereof in the treatment of CNS disorders (e.g., multiple sclerosis). In one embodiment, the composition or pharmaceutical composition is used for neurological disorders resulting from neuroinflammation and neurodegeneration.
In one aspect, the present invention provides a novel composition comprising a first agent selected from metformin, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; and a second agent selected from DMTs for treating MS. In one embodiment, the DMTs are one or more drugs selected from dimethyl fumarate, interferon beta-1a, interferon beta-1b, glatiramer acetate, natalizumab, fingolimod, teriflunomide, alemtuzumab, daclizumab, omentulmoschus mab, polyethylene glycol interferon beta-1a, cladribine, or mitoxantrone, and the like. In one embodiment, the present invention provides a novel composition comprising a first agent selected from metformin, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; and a second agent selected from the group consisting of dimethyl fumarate, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing.
In one embodiment, the present invention provides a novel composition comprising a therapeutically effective amount of a first agent selected from metformin, or an enantiomer, diastereomer, tautomer, metabolite, or pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of a second agent selected from dimethyl fumarate, or an enantiomer, diastereomer, tautomer, metabolite, or pharmaceutically acceptable salt or solvate thereof.
In one embodiment, the second agent is selected from the group consisting of a metabolite of dimethyl fumarate, which metabolite is monomethyl fumarate (MMF).
In one embodiment, the pharmaceutically acceptable salt is the hydrochloride salt.
In one embodiment, the first agent is 1, 1-dimethylbiguanide hydrochloride.
In one aspect, the present invention provides a novel pharmaceutical composition comprising a first agent selected from metformin or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; a second agent selected from DMTs for the treatment of MS; and a pharmaceutically acceptable excipient, carrier or diluent. In one embodiment, the DMTs are one or more drugs selected from dimethyl fumarate, interferon beta-1a, interferon beta-1b, glatiramer acetate, natalizumab, fingolimod, teriflunomide, alemtuzumab, daclizumab, omentulmoschus mab, polyethylene glycol interferon beta-1a, cladribine or mitoxantrone, and the like. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of metformin, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; a therapeutically effective amount of dimethyl fumarate, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; and a pharmaceutically acceptable excipient, carrier or diluent.
In one embodiment, the disclosed compositions or pharmaceutical compositions are used to treat neurological disorders. In some embodiments, the disclosed compositions or pharmaceutical compositions are used to treat or ameliorate one or more central nervous system diseases or disorders, or diseases caused by demyelination of neurons. In one embodiment, the disclosed compositions or pharmaceutical compositions are useful for treating or alleviating multiple sclerosis.
In one embodiment, the disclosed compositions or pharmaceutical compositions are used to induce death of activated astrocytes and microglia.
In one embodiment, the disclosed compositions or pharmaceutical compositions are used to inhibit myelin sheath, axons, and brain cell damage caused by defects in the immune system.
In one embodiment, the disclosed compositions or pharmaceutical compositions are used to prevent demyelination and promote remyelination of toxicity-mediated demyelination.
In one embodiment, the disclosed compositions or pharmaceutical compositions are used to inhibit the inflammatory response of glial cells.
In one embodiment, the disclosed compositions or pharmaceutical compositions are used to promote oligodendrocyte maturation.
In one embodiment, the disclosed compositions or pharmaceutical compositions are used to promote axonal health and regeneration.
In one embodiment, the disclosed compositions or pharmaceutical compositions do not exhibit novel adverse events and have similar safety characteristics as each drug in the combination alone.
In one embodiment, the disclosed compositions or pharmaceutical compositions are used to inhibit the production of inflammatory factors by activated glial cells.
In one embodiment, the disclosed compositions or pharmaceutical compositions are used to treat demyelination and/or axonal injury and diseases caused thereby.
In one embodiment, the disclosed compositions or pharmaceutical compositions have anti-inflammatory, neuroprotective, and neuroregenerative effects on other neurological disorders resulting from neuroinflammation and neurodegeneration.
In one aspect, the disclosure relates to a method of treatment for treating or alleviating one or more central nervous system diseases or disorders comprising administering to a subject in need thereof: a first agent selected from metformin, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; and a second agent selected from DMTs for the treatment of MS, such as dimethyl fumarate, interferon beta-1a, interferon beta-1b, glatiramer acetate, natalizumab, fingolimod, teriflunomide, alemtuzumab, daclizumab, omentulmoschus, polyethylene glycol interferon beta-1a, cladribine, or mitoxantrone, and the like. In some embodiments, a method of treating or alleviating one or more central nervous system diseases or disorders, comprising administering to a subject in need thereof: a therapeutically effective amount of a first agent selected from metformin, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing; and a therapeutically effective amount of a second agent selected from the group consisting of dimethyl fumarate, or a prodrug, metabolite, derivative, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salt of any of the foregoing, and solvate of any of the foregoing.
In one aspect, the present disclosure relates to a method of treatment for treating or alleviating one or more central nervous system diseases or disorders comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising metformin and dimethyl fumarate.
In some embodiments, the central nervous system disease or disorder is multiple sclerosis.
In one embodiment, the first agent and the second agent may be administered to the subject simultaneously or sequentially.
III. Examples
Example 1 Effect of DMF, metformin (Met), and combinations thereof on the survival of activated astrocytes
Astrocytes from P7 mice were placed in DMF (50. Mu.M), metformin (Met, 1 mg/ml) or DMF+Met, respectively, for 48 hours. Cell survival was calculated and cell viability is shown in figure 1 compared to the control. * p <0.05 compared to control, #p <0.01 compared to Met or DMF single drug group (n=4). The results indicate that the Met or DMF single drug had no significant effect on survival of activated astrocytes; the combination of Met with DMF significantly induced death of activated astrocytes; and the composition has a significantly superior effect on inducing death of activated astrocytes compared to a single agent of Met or DMF.
Example 2 Effect of DMF, metformin (Met), and combinations thereof on survival of activated microglia
Microglia from P7 mice were treated with lipopolysaccharide (LPS, 10 ng/ml) and gamma interferon (IFN, 20 ng/ml) to induce microglial activation, respectively. To determine the effect of the drug on LPS/IFN-activated microglia, DMF (50 μm), metformin (Met, 1 mg/ml) or a combination of DMF and Met was added into the medium. Cell survival was calculated 48 hours after drug treatment. Cell viability is shown in figure 2 compared to the control. * P <0.01 compared to control plus LPS/IFN, #p <0.05 between experimental groups (n=4-8). The data indicate that DMF, met, and their compositions all significantly induced death of LPS/IFN-activated microglia. The composition of DMF and Met has significantly better effect than Met single drug and better effect than DMF single drug (the survival rate of the composition is 16.9% and the survival rate of DMF single drug is 34.4%).
The above studies show that a combination of DMF and metformin has a synergistic effect in reducing glioblast proliferation, in particular astrocyte proliferation. The combination of DMF and metformin has a superior effect on inducing death of activated astrocytes and microglia compared to DMF or Met single drugs. These demonstrate that the combined use of DMF and metformin may have better efficacy in reducing disease activity in MS patients by treating glioblastoma. Combination therapy with DMF and Met is a potential new treatment for CNS disorders (e.g., multiple sclerosis).
Applicants' disclosure is described herein in the preferred embodiments with reference to the accompanying drawings, wherein like numerals represent the same or similar elements. Reference throughout this specification to "one embodiment," "an embodiment," or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment," "in an embodiment," and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.
While the invention has been particularly shown and described with reference to the structures and methods disclosed herein and as shown in the drawings, the invention is not limited to the details set forth and is intended to cover any modifications and variations which fall within the scope and spirit of the appended claims.
All publications and patent documents described herein are incorporated by reference in their entirety to the extent permitted by applicable laws and regulations. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material set forth explicitly herein is only incorporated to the extent that no conflict arises between that incorporated material and the disclosure material. In the event of a conflict, the present disclosure will control to resolve the conflict as a preferred disclosure.

Claims (5)

1. A composition comprising a first agent, metformin; dimethyl fumarate as a second agent; wherein the first agent is 1mg/ml and the second agent is 50 μm.
2. A pharmaceutical composition comprising a therapeutically effective amount of a first agent metformin; a therapeutically effective amount of a second agent dimethyl fumarate; a pharmaceutically acceptable excipient, carrier or diluent; wherein the therapeutically effective amount of the first agent is 1mg/ml and the therapeutically effective amount of the second agent is 50 μm.
3. The pharmaceutical composition of claim 2, wherein the therapeutically effective amount of the first agent and the therapeutically effective amount of the second agent can be administered to the subject simultaneously or sequentially.
4. Use of a composition according to claim 1 or a pharmaceutical composition according to claim 2 or 3 in the manufacture of a medicament for the treatment or alleviation of multiple sclerosis.
5. Use of the composition of claim 1 or the pharmaceutical composition of claim 2 or 3 in the manufacture of a medicament for inducing death of activated astrocytes and microglia to treat or ameliorate multiple sclerosis.
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Citations (1)

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WO2016074684A1 (en) * 2014-11-11 2016-05-19 Syddansk Universitet Fumaric acid derivatives for medical use

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