WO2025063698A1

WO2025063698A1 - Lamotrigine and rivastigmine combinations for treating neurodegenerative disorders

Info

Publication number: WO2025063698A1
Application number: PCT/KR2024/014111
Authority: WO
Inventors: Jai Jun Choung; Byoung Seok YE
Original assignee: Aribio Co. Ltd; Uif (University Industry Foundation), Yonsei University
Priority date: 2023-09-18
Filing date: 2024-09-19
Publication date: 2025-03-27

Abstract

The present disclosure provides a pharmaceutical composition for the prevention, alleviation, or treatment of neurodegenerative disorders. The composition comprises a therapeutically effective amount of Lamotrigine and Rivastigmine, wherein the molar ratio of Rivastigmine to Lamotrigine is in the range from 1:1 to 1:50. The composition may be formulated for oral administration and can be used to treat neurodegenerative disorders such as Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and Alzheimer's disease. The disclosure also provides a method of treating neurodegenerative disorders using the composition and a kit containing separate formulations of Lamotrigine and Rivastigmine along with instructions for administration.

Description

LAMOTRIGINE AND RIVASTIGMINE COMBINATIONS FOR TREATING NEURODEGENERATIVE DISORDERS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from Korean Provisional Application Serial No. 10-2023-0123921 filed on September 18, 2023, which is incorporated herein by reference in its entirety.

FIELD

The present disclosure relates to lamotrigine and rivastigmine combinations for treating neurodegenerative disorders.

Neurodegenerative disorders are a significant cause of morbidity and mortality worldwide. While the standards of care for many different neurodegenerative disorders have greatly improved over the years, current standards of care still fail to meet the need for effective therapies to improve treatment.

In pathological states, alpha-synuclein can undergo structural changes through interactions with various cellular components, leading to the formation of aggregates such as dimers, oligomers, and fibers. These aggregates have been associated with cellular toxicity and are a major component of Lewy bodies, abnormal protein aggregates found in neurons in various neurodegenerative disorders.

β-Amyloid (Aβ) pathology is also common in patients with dementia with Lewy bodies (DLB). It has been hypothesized that synuclein- and amyloid-pathology act synergistically aggravating cognitive decline in elderly patients, but their precise contribution to dementia is debated. Findings suggest that in Lewy Body Diseases, amyloid deposition enhances cognitive deficits, particularly attention-executive and language dysfunctions.　

Lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine) is an anticonvulsant drug that belongs to the drug class triazine anticonvulsants. The mechanism of action of lamotrigine may involve the inhibition of voltage-sensitive sodium channels which may stabilize neuronal membranes and modulate the release of excitatory neurotransmitters. In some cases, lamotrigine may also inhibit voltage-gated calcium channels and potassium channels, potentially contributing to its neuroprotective effects. Lamotrigine can be used to treat the following partial seizures, primary generalized tonic-clonic seizures, bipolar I disorder maintenance and Lennox-Gastaut syndrome. Off-label uses include treating acute bipolar depression, fibromyalgia, schizophrenia, and unipolar depression. The composition of matter and preparation of lamotrigine is described in U.S. Pat. No. 4,602,017, incorporated herein by reference in its entirety.

Rivastigmine ([3-[(1S)-1-(dimethylamino)ethyl]phenyl]　N-ethyl-N-methylcarbamate) is a cholinesterase inhibitor that belongs to the carbamate class. The mechanism of action of rivastigmine involves the inhibition of both acetylcholinesterase and butyrylcholinesterase, which may increase the levels of acetylcholine in the brain. In some cases, this increase in acetylcholine may enhance cholinergic neurotransmission. Rivastigmine is used to manage and treat neurodegenerative disease, specifically dementia, in patients with Alzheimer and Parkinson disease. The composition of matter and preparation of Rivastigmine is described in U.S. Pat. No. 5,602,176, incorporated herein by reference in its entirety.　

The clinical uses of lamotrigine and rivastigmine individually have resulted in improvements in the treatment of certain specific disorders. While these compounds have each, individually, produced clinical responses in those disorders, there is a need in the art for new therapies, including, for example, combination therapies for the treatment of neurodegenerative disorders. Provided herein are solutions to these and other problems in the art.

This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.

According to an aspect of the present disclosure, a pharmaceutical composition for the prevention, alleviation, or treatment of neurodegenerative disorders is provided. The pharmaceutical composition includes a therapeutically effective amount of Lamotrigine and Rivastigmine.

According to other aspects of the present disclosure, the pharmaceutical composition may include one or more of the following features. The molar ratio of Rivastigmine to Lamotrigine in the pharmaceutical composition may be in the range from 1:1 to 1:50. The neurodegenerative disorder may be selected from the group consisting of Parkinson's disease (PD) e.g., sporadic Parkinson disease/parkinsonism and familial Parkinson disease/parkinsonism; sporadic or heritable dementia with Lewy bodies (DLB) (aka diffuse Lewy body disease); pure autonomic failure (PAF) with αS deposition; multiple system atrophy (MSA) (of cerebellar, parkinsonian, or mixed type); hereditary neurodegeneration with brain iron accumulation (aka, Hallervordern Spatz disease or pantothenate kinase 2-linked neurodegeneration); and incidental Lewy body disease of advanced age. Alzheimer's disease of the Lewy body variant; Down's syndrome; progressive supranuclear palsy; essential tremor with Lewy bodies; familial parkinsonism with or without dementia resulting from a mutant gene and loci where no gene mutation has yet been identified; Creutzfeldt Jakob disease and related prion diseases such as bovine spongiform encephalopathy (mad cow disease); secondary Parkinson disease/parkinsonism resulting from neurotoxin exposure/drug-induced parkinsonism with α-synuclein deposition; sporadic or heritable spinocerebellar ataxia; amyotrophic lateral sclerosis (ALS); idiopathic rapid eye movement sleep behavior disorder; and other conditions associated with central and/or peripheral α-synuclein accumulation in mammals accompanying a primary disease process.

In various aspects, the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Vascular dementia, Frontotemporal dementia (FTD), Lewy body dementia (LBD), Mixed dementia, Posterior cortical atrophy (PCA), Primary progressive aphasia (PPA), Corticobasal degeneration (CBD), and Progressive supranuclear palsy (PSP), idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile　amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with　amyloidosis, Down's syndrome, Scrapie, medullary carcinoma of the thyroid, isolated atrial　amyloidosis, β₂-microglobulin　amyloidosis, inclusion body myositis, muscle wasting disease, Islets of Langerhans diabetes, Type 1 diabetes, insulinoma, Type 2 diabetes mellitus, hereditary cerebral hemorrhage　amyloidosis　(Dutch), amyloid A (reactive)　amyloidosis, secondary　amyloidosis, familial Mediterranean fever, familial amyloid nephropathy with urticaria and deafness (Muckle-wells Syndrome), amyloid lambda L-chain　amyloidosis, amyloid kappa L-chain　amyloidosis, idiopathic associated　amyloidosis, myeloma-associated　amyloidosis, macroglobulinemia-associated　amyloidosis, A beta 2M　amyloidosis　(chronic hemodialysis), ATTR　amyloidosis　(familial amyloid polyneuropathy (Portuguese, Japanese, Swedish)), familial amyloid cardiomyopathy (Danish), isolated cardiac　amyloidosis, systemic senile　amyloidosis, AIAPP or amylin insulinoma, atrial natriuretic factor　amyloidosis　(isolated atrial　amyloidosis), procalcitonin　amyloidosis　(medullary carcinoma of the thyroid), gelsolin　amyloidosis　(familial　amyloidosis　(Finnish)), cystatin C (hereditary cerebral hemorrhage with　amyloidosis　(Icelandic)), AApo-A-I　amyloidosis　(familial amyloidotic polyneuropathy-Iowa), AApo-A-II　amyloidosis, traumatic brain injury, fibrinogen-associated　amyloidosis, Creutzfeldt-Jakob disease, Gertsmann-Straussler-Scheinker syndrome, bovine spongiform encephalitis, condition associated with homozygosity for the apolipoprotein E4 allele, and Huntington's disease.

In yet other aspects, the neurodegenerative disorder is selected from the group consisting of Parkinson's Disease (PD), Parkinson's Disease Dementia (PDD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), and Lewy Body Variant of Alzheimer's Disease (LBV).

In yet other aspects, the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Vascular dementia, Frontotemporal dementia (FTD), Lewy body dementia (LBD), Mixed dementia, Posterior cortical atrophy (PCA), Primary progressive aphasia (PPA), Corticobasal degeneration (CBD), and Progressive supranuclear palsy (PSP).

More specifically, the neurodegenerative disorder is selected from the group consisting of Parkinson's disease and Alzheimer's disease.

The pharmaceutical composition may be for oral, parenteral, transcutaneous, mucosal, transdermal or inhalation administration. The pharmaceutical composition may be administered orally, non-orally, transcutaneously, mucosally, or by inhalation. The pharmaceutical composition may be administered with Lamotrigine at a dosage of 25 to 200 mg/day and Rivastigmine at a dosage of 1.0 to 15 mg/day. The Lamotrigine and Rivastigmine may be either in the form of a mixture or may be formulated separately administered simultaneously or sequentially.

According to another aspect of the present disclosure, a method of treating a neurodegenerative disorder is provided. The method includes administering to a subject in need thereof a therapeutically effective amount of Lamotrigine and Rivastigmine.

According to another aspect of the present disclosure, a kit is provided. The kit includes a pharmaceutical composition according to any one of the previously described aspects. The kit includes (i) a formulation containing Lamotrigine, and (ii) a formulation containing Rivastigmine.

According to other aspects of the present disclosure, the kit may include one or more of the following features. The Lamotrigine may be administered at a dosage of 25 to 200 mg/day, and Rivastigmine may be administered at a dosage of 1.0 to 15 mg/day. The kit may further include a packaging container, an instruction manual, and additional documents.

According to other aspects of the present disclosure, a Lamotrigine formulation for the treatment of neurodegenerative disorders, a method of treating neurodegenerative disorders using Lamotrigine, and a kit comprising lamotrigine is provided.

The foregoing general description of the illustrative embodiments and the following detailed description thereof are merely exemplary aspects of the teachings of this disclosure and are not restrictive.

Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

Fig. 1 depicts a bar graph showing effects of treatments on α-synuclein dimer levels, according to an embodiment.

Fig. 2 illustrates a bar graph showing effects of treatments on α-synuclein trimer levels, according to aspects of the present disclosure.

Fig. 3 shows a bar graph depicting effects of treatments on α-synuclein tetramer levels, according to aspects of the present disclosure.

Fig. 4 illustrates a bar graph showing JC-1 staining results in mouse primary neurons, according to an embodiment.

Abbreviations and Definitions

To facilitate understanding of the invention, a number of terms and abbreviations as used herein are defined below as follows:

All patents, applications, published applications and other publications cited herein are incorporated by reference in their entirety. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. Should a discrepancy exist between a depicted structure and a name given for that structure, the depicted structure is to be accorded more weight. Where the stereochemistry of a structure or a portion of a structure is not indicated in a depicted structure or a portion of the depicted structure, the depicted structure is to be interpreted as encompassing all of its possible stereoisomers.

Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this invention. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. Headings used herein are for organizational purposes only and in no way limit the invention described herein.

The term "neurodegenerative disorder" or "neurodegeneration" refers to a condition primarily characterized by neuron (i.e., neuronal cell) loss. The most common neurodegenerative disorders include Alzheimer's disease and Parkinson's disease. Although there are several medicines currently approved for managing neurodegenerative disorders, a large majority of them only help with associated symptoms. A listing of over 500 Neurological Disorders is provided by the US National Institute of Neurological Disorders and Stroke (NINDS) currently available at: https:/www.ninds.nih.gov/health-information/disorders. See also, Wolfe, M. The Molecular and Cellular Basis of Neurodegenerative Diseases: Underlying Mechanisms. Academic Press, April 18, 2018; Lewis, P. The Molecular and Clinical Pathology of Neurodegenerative Disease. Academic Press, December 14, 2018. For the purposes of the present disclosure, the term "neurodegenerative disorders" includes those disorders, and specifically the synucleinopathies and amyloidoses described herein.

The term "alpha-synuclein" refers to a protein or polypeptide (αS or αS protein), as used herein, includes a single, monomeric protein or polypeptide, as well as such αS proteins and polypeptides in the form of oligomers, e.g., in the form of dimers, trimers, tetramers, or in the form of lipid-associated complexes, or lipid-free forms, or in the form of aggregates, and any of these forms can be soluble or insoluble. The terms also include the αS proteins found in complexes with other molecules.

The term "synucleinopathy" is used herein to name a group of neurodegenerative disorders characterized by the presence of increased levels, e.g., steady-state levels, of any one or more of soluble non-fibrillary variants, soluble oligomeric isoforms, insoluble non-fibrillary variants, complexes, and insoluble fibrillary aggregates of αS protein within cellular compartments of selective populations of neurons and glia. Thus, the αS steady-state level is understood to encompass all soluble as well as insoluble and intermediate (metastable) forms of the SNCA gene product. See, UniProt P37840; Gene ID: 6622; NCBI Reference Sequence: NG_011851.1. These disorders include any one of the following grouped as "invariable" (or "primary") synucleinopathies: Parkinson's disease (PD) e.g., sporadic Parkinson disease/parkinsonism and familial Parkinson disease/parkinsonism; sporadic or heritable dementia with Lewy bodies (DLB) (aka diffuse Lewy body disease); pure autonomic failure (PAF) with αS deposition; multiple system atrophy (MSA) (of cerebellar, parkinsonian, or mixed type); hereditary neurodegeneration with brain iron accumulation (aka, Hallervordern Spatz disease or pantothenate kinase 2-linked neurodegeneration); and incidental Lewy body disease of advanced age. Furthermore, "variable" (or "secondary") synucleinopathies have been identified, where dysregulation of the alpha-synuclein metabolism is recognized to be a secondary event (given the abundance of the protein in the nervous system), which nevertheless contributes significantly to the course, penetrance, age-of-onset, severity and expressivity of the primary illness. Disorders with variable synucleinopathy include, but are not limited to, Alzheimer's disease of the Lewy body variant; Down's syndrome; progressive supranuclear palsy; essential tremor with Lewy bodies; familial parkinsonism with or without dementia resulting from a mutant gene and loci where no gene mutation has yet been identified; Creutzfeldt Jakob disease and related prion diseases such as bovine spongiform encephalopathy (mad cow disease); secondary Parkinson disease/parkinsonism resulting from neurotoxin exposure/drug-induced parkinsonism with α-synuclein deposition; sporadic or heritable spinocerebellar ataxia; amyotrophic lateral sclerosis (ALS); idiopathic rapid eye movement sleep behavior disorder; and other conditions associated with central and/or peripheral α-synuclein accumulation in mammals accompanying a primary disease process. See, Schlossmacher MG α-synuclein and synucleinopathies. The Dementias 2 Blue Books of Practical Neurology; Editors: Growdon J H & Rossor M N. Butterworth Heinemann, Inc., Oxford. 2007; Chapter 8: pp 184-213. Clinically, all of these related disorders are characterized by a chronic and progressive decline in motor, cognitive, behavioral, and/or autonomic functions, depending on the distribution of the alpha-synuclein abnormalities.

The term "amyloidosis" refers to a group of diseases that involve the accumulation of amyloid proteins in the body. Amyloid proteins can be deposited in one part of the body, called localized amyloidosis, or in multiple parts, called systemic amyloidosis. Many forms of　amyloidosis　exist, and the disease can be classified into four groups: primary　amyloidosis, secondary　amyloidosis, hereditary　amyloidosis, and　amyloidosis　associated with normal aging. Primary　amyloidosis　(light chain　amyloidosis) occurs with abnormalities of plasma cells, and some people with primary　amyloidosis　also have multiple myeloma (cancer of the plasma cells). Typical sites of amyloid buildup in primary　amyloidosis　are the heart, lungs, skin, tongue, thyroid gland, intestines, liver, kidneys, and blood vessels. Secondary　amyloidosis　may develop in response to various diseases that cause persistent infection or inflammation, such as tuberculosis, rheumatoid arthritis, and familial Mediterranean fever. Typical sites of amyloid buildup in secondary　amyloidosis　are the spleen, liver, kidneys, adrenal glands, and lymph nodes. Hereditary　amyloidosis　has been noted in some families, particularly those from Portugal, Sweden, and Japan. The amyloid-producing defect occurs because of mutations in specific proteins in the blood. Typical sites for amyloid buildup in hereditary　amyloidosis　are the nerves, heart, blood vessels, and kidneys. Alzheimer's disease is a type of localized amyloidosis where amyloid-beta proteins build up in the brain. This is the most common type of amyloidosis in humans and the most common form of dementia. The "amyloid hypothesis" is the prevailing theory that Alzheimer's disease is caused by the accumulation of beta-amyloid proteins in the brain. Some studies have shown that amyloid triggers a binding of two proteins in the brain's neurons, which can lead to the rapid accumulation of tau proteins. Tau proteins are a primary driver of neurodegeneration in Alzheimer's disease. Amyloidosis can be caused by chronic inflammation or genetic mutation. There are many different types of amyloid proteins involved in amyloidosis, and each type of amyloid deposit can characterize a different disease.

The term "amyloidosis-associated condition" refers to a disease that is associated with amyloid deposition and can include but not be limited to　Alzheimer's Disease, idiopathetic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile　amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with　amyloidosis, Down's syndrome, Scrapie, medullary carcinoma of the thyroid, isolated atrial amyloid, β₂-microglobulin amyloid in dialysis patients, inclusion body myositis, β2-amyloid deposits in muscle wasting disease, and Islets of Langerhans diabetes Type I1 insulinoma.　Type　2 diabetes mellitus, hereditary cerebral hemorrhage　amyloidosis　(Dutch), 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-associated) A beta 2M (chronic hemodialysis), ATTR (familial amyloid polyneuropathy (Portuguese, Japanese, Swedish)), familial amyloid cardiomyopathy (Danish), isolated cardiac amyloid, systemic senile amyloidoses, AIAPP or amylin insulinoma, atrial naturetic factor (isolated atrial amyloid), procalcitonin (medullary carcinoma of the thyroid), gelsolin (familial　amyloidosis　(Finnish)), cystatin C (hereditary cerebral hemorrhage with　amyloidosis　(Icelandic)), AApo-A-1 (familial amyloidotic polyneuropathy-Iowa), AApo-A-II (accelerated senescence in mice), head injuries (traumatic brain injury), dementia, fibrinogen-associated amyloid; and Asor or Pr P-27 (scrapie, Creutzfeld Jacob disease, Gertsmann-Straussler-Scheinker syndrome, bovine spongiform encephalitis) or in cases of persons who are homozygous for the apolipoprotein E4 allele, and the condition associated with homozygosity for the apolipoprotein E4 allele or Huntington's disease.

The term "anti-neurodegenerative agent" is used in accordance with its plain ordinary meaning and refers to a composition having neuronal protective properties or the ability to inhibit degeneration of neuronal cells. The term can include neuroprotective agents known to those of skill in the art. In embodiments, an anti-neurodegenerative agent is an agent identified herein having utility in methods of treating neurodegeneration. In embodiments, an anti-neurodegenerative agent is an agent approved by the US FDA or similar regulatory agency of a country other than the US, for treating neurodegeneration. This term includes, but is not limited to, the combinations described herein, and in the context of the present disclosure other anti-neurodegenerative agents.

The term "effective amount" refers to the amount of a therapy (e.g., a combination provided herein or another active agent such as an anti-neurodegenerative agent described herein) which is sufficient to accomplish a stated purpose or otherwise achieve the effect for which it is administered. An effective amount can be sufficient to reduce and/or ameliorate the progression, development, recurrence, severity and/or duration of a given disease, disorder or condition and/or a symptom related thereto. An effective amount can be a "therapeutically effective amount" which refers to an amount sufficient to provide a therapeutic benefit such as, for example, the reduction or amelioration of the advancement or progression of a given disease, disorder or condition, reduction or amelioration of the recurrence, development or onset of a given disease, disorder or condition, and/or to improve or enhance the prophylactic or therapeutic effect(s) of another therapy. A therapeutically effective amount of a composition described herein can enhance the therapeutic efficacy of another therapeutic agent.

The term "regimen" refers to a protocol for dosing and timing the administration of one or more therapies (e.g., combinations described herein including, optionally, another active agent such as an anti-neurodegenerative agent described herein) for treating a disease, disorder, or condition described herein. A regimen can include periods of active administration and periods of rest as known in the art. Active administration periods include administration of combinations and compositions described herein and the duration of time of efficacy of such combinations and compositions. Rest periods of regimens described herein include a period of time in which no compound is actively administered, and in certain instances, includes time periods where the efficacy of such compounds can be minimal. Combination of active administration and rest in regimens described herein can increase the efficacy and/or duration of administration of the combinations and compositions described herein.

The terms "therapies" and "therapy" refer to any protocol(s), method(s), and/or agent(s) that can be used in the prevention, treatment, management, and/or amelioration of a disease, disorder, or condition or one or more symptoms thereof. In certain instances the term refers to active agents such as an anti-neurodegenerative agent described herein. The terms "therapy" and "therapy" can also refer to anti-viral therapy, anti-bacterial therapy, anti-fungal therapy, anti-neurodegenerative therapy, biological therapy, supportive therapy, and/or other therapies useful in treatment, management, prevention, or amelioration of a disease, disorder, or condition or one or more symptoms thereof known to one skilled in the art, for example, a medical professional such as a physician.

The term "patient" or "subject" refers to a mammal, such as a human, bovine, rat, mouse, dog, monkey, ape, goat, sheep, cow, or deer. Generally a patient as described herein is human.

The terms "inhibition", "inhibit", and "inhibiting" refer to a reduction in the activity, binding, or expression of a polypeptide or reduction or amelioration of a disease, disorder, or condition or a symptom thereof. Inhibiting as used here can include partially or totally blocking stimulation, decreasing, preventing, or delaying activation or binding, or inactivating, desensitizing, or down-regulating protein or enzyme activity or binding.

The terms "treating" or "treatment" refer to any indicia of success or amelioration of the progression, severity, and/or duration of a disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a patient's physical or mental well-being.

The term "enhance" refers to an increase or improvement in the function or activity of a protein or cell after administration or contacting with a combination described herein compared to the protein or cell prior to such administration or contact.

The term "administering" refers to the act of delivering a combination or composition described herein into a subject by such routes as oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration. Parenteral administration includes intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Administration generally occurs after the onset of the disease, disorder, or condition, or its symptoms but, in certain instances, can occur before the onset of the disease, disorder, or condition, or its symptoms (e.g., administration for patients prone to such a disease, disorder, or condition).

The term "coadministration" refers to administration of two or more agents (e.g., a combination described herein including, optionally, another active agent such as an anti-neurodegenerative agent described herein). The timing of coadministration depends in part of the combination and individual compositions administered and can include administration at the same time, just prior to, or just after the administration of one or more additional therapies, for example therapies such as an anti-neurodegenerative agent including, for example, immunotherapy. Coadministration is meant to include simultaneous or sequential administration of each compound of the combination. Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating neurodegeneration.

Lamotrigine and Rivastigmine Combinations for Treating Neurodegenerative Disorders

The following description sets forth exemplary aspects of the present disclosure. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure. Rather, the description also encompasses combinations and modifications to those exemplary aspects described herein.

The present disclosure provides pharmaceutical compositions that may be beneficial in the prevention, alleviation, or treatment of neurodegenerative disorders. More specifically, the compositions encompass combinations of Lamotrigine and Rivastigmine, which may be particularly effective in addressing synucleinopathies and amyloidoses. Synucleinopathies that are amenable to treatment include Parkinson's Disease (PD), Parkinson's Disease Dementia (PDD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), and Lewy Body Variant of Alzheimer's Disease (LBV). Amyloidoses that are amenable to treatment include Alzheimer's disease, Vascular dementia, Frontotemporal dementia (FTD), Lewy body dementia (LBD), Mixed dementia, Posterior cortical atrophy (PCA), Primary progressive aphasia (PPA), Corticobasal degeneration (CBD), and Progressive supranuclear palsy (PSP).

These combinations may offer a novel approach to managing these debilitating conditions by potentially reducing the levels of α-synuclein protein, a key factor in the pathogenesis of these disorders. In addition, the effects of Aβ appear to be modulated by administration of the combinations described herein. The compositions may be administered in various forms and dosages, providing flexibility in treatment options. In some cases, the compositions may be provided in a kit, which may include separate formulations of Lamotrigine and Rivastigmine, potentially allowing for simultaneous or sequential administration. The present disclosure thus offers a potential new avenue for the treatment of neurodegenerative disorders, particularly synucleinopathies and amyloidoses.

Provided herein are combinations (e.g., combination therapies and compositions) useful for treating a variety of diseases, disorders, and symptoms thereof, including for example, neurodegeneration. The combinations described herein include Lamotrigine and Rivastigmine. The combinations herein may also include an additional anti-neurodegenerative agent.

One aspect of the present disclosure is a combination that includes a therapeutically effective amount of Lamotrigine, a compound of Formula I:

6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine

Lamotrigine may be found commercially under the brand names: LAMICTAL®, LAMICTAL® ODT, LAMICTAL® XR, SUBVENITE®, LAMICTAL® CD, LAMICTAL® Starter Kit (Blue), LAMICTAL® Starter Kit (Green), LAMICTAL® Starter Kit (Orange), LAMICTAL® ODT Patient Titration Kit (Blue), LAMICTAL® ODT Patient Titration Kit (Orange), LAMICTAL® ODT Patient Titration Kit (Green), LAMICTAL® XR Patient Titration Kit (Blue), LAMICTAL® XR Patient Titration Kit (Orange), LAMICTAL® XR Patient Titration Kit (Green), LamoTRIgine Starter Kit (Blue) obsolete, SUBVENITE® Blue Starter Kit, SUBVENITE® Green Starter Kit, SUBVENITE® Orange Starter Kit.

Commercially available dosage forms of Lamotrigine include: oral tablet ((blue dose pack) 25 mg, (green dose pack) 25 mg-100 mg, (orange dose pack) 25 mg-100 mg, 100 mg, 150 mg, 200 mg, 25 mg), oral tablet, disintegrating ((blue dose pack) 25 mg-50 mg, (green dose pack) 50 mg-100 mg, (orange dose pack) 25 mg-50 mg-100 mg, 100 mg, 200 mg, 25 mg, 50 mg), oral tablet, dispersible (2 mg; 25 mg; 5 mg), oral tablet, extended release ((blue dose pack) 25 mg-50 mg, (green dose pack) 50 mg-100 mg-200 mg, (orange dose pack) 25 mg-50 mg-100 mg, 100 mg, 200 mg, 25 mg, 250 mg, 300 mg, 50 mg).

In another aspect of the present disclosure is a combination that includes a therapeutically effective amount of Rivastigmine, a compound of Formula II:

[3-[(1S)-1-(dimethylamino)ethyl]phenyl]　N-ethyl-N-methylcarbamate

Rivastigmine may be found commercially under the brand name: EXELON®, Commercially available dosage forms of Rivastigmine include: oral capsule (1.5 mg; 3 mg; 4.5 mg; 6 mg); and transdermal patches (4.6 mg/24 hr, 9.5 mg/24 hr, 13.3 mg/24 hr).

Compounds of Formulas I and II as described herein include pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, prodrugs, enantiomers, diastereomers, hydrates, co-crystals, and polymorphs thereof.

In certain instances, the combination includes a compound of Formula I present at an amount of greater than about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg. The combination can include a compound of Formula I present at an amount greater than about: 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, or 300 mg.

The combination can include a compound of Formula I present at an amount greater than about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, 100 mg to about 200 mg, or 200 mg to about 300 mg.

The combination can include a compound present in an amount of at least about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg. The combination can include a compound of Formula I present at an amount of at least about: 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, or 300 mg. The combination can include a compound of Formula I present at an amount of at least about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, 100 mg to about 200 mg, or 200 mg to about 300 mg.

The combination can include a compound present in an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg. The combination can include a compound of Formula I present at an amount of about: 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, or 300 mg. The combination can include a compound of Formula I present at an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, 100 mg to about 200 mg, or 200 mg to about 300 mg.

A compound of Formula I can be present in the combinations described herein relative to the weight of the patient (e.g., mg/kg). In some instances, the compound of Formula I is present in an amount equivalent to about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 150 mg/kg, 0.01 mg/kg to about 100 mg/kg, 0.01 mg/kg to about 50 mg/kg, 0.01 mg/kg to about 25 mg/kg, 0.01 mg/kg to about 10 mg/kg, or 0.01 mg/kg to about 5 mg/kg, 0.05 mg/kg to about 200 mg/kg, 0.05 mg/kg to about 150 mg/kg, 0.05 mg/kg to about 100 mg/kg, 0.05 mg/kg to about 50 mg/kg, 0.05 mg/kg to about 25 mg/kg, 0.05 mg/kg to about 10 mg/kg, or 0.05 mg/kg to about 5 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg. In other instances the compound of Formula I is present in an amount equivalent to about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg.

In certain instances, the combination includes a compound of Formula II present at an amount of greater than about: 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, or 100 mg. The combination can include a compound of Formula II present at an amount greater than about: 1.5 mg, 3 mg, 4.5 mg, or 6 mg.

The combination can include a compound of Formula II present at an amount greater than about: 0.1 mg to about 10 mg, 0.1 mg to about 25 mg, 0.1 mg to about 50 mg, 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 3 mg to about 25 mg, 3 mg to about 50 mg, 6 mg to about 10 mg, or 10 mg to about 20 mg.

The combination can include a compound present in an amount of at least about: 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, or 100 mg. The combination can include a compound of Formula II present at an amount of at least about: 1.5 mg, 3 mg, 4.5 mg, or 6 mg. The combination can include a compound of FormulaI II present at an amount of at least about: 0.1 mg to about 10 mg, 0.1 mg to about 25 mg, 0.1 mg to about 50 mg, 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 3 mg to about 25 mg, 3 mg to about 50 mg, 6 mg to about 10 mg, or 10 mg to about 20 mg.

The combination can include a compound present in an amount of about: 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, or 100 mg. The combination can include a compound of Formula II present at an amount of about: 1.5 mg, 3 mg, 4.5 mg, or 6 mg. The combination can include a compound of Formula II present at an amount of about: 0.1 mg to about 10 mg, 0.1 mg to about 25 mg, 0.1 mg to about 50 mg, 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 3 mg to about 25 mg, 3 mg to about 50 mg, 6 mg to about 10 mg, or 10 mg to about 20 mg.

A compound of Formula II can be present in the combinations described herein relative to the weight of the patient (e.g., mg/kg). In some instances, the compound of Formula II is present in an amount equivalent to about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 150 mg/kg, 0.01 mg/kg to about 100 mg/kg, 0.01 mg/kg to about 50 mg/kg, 0.01 mg/kg to about 25 mg/kg, 0.01 mg/kg to about 10 mg/kg, or 0.01 mg/kg to about 5 mg/kg, 0.05 mg/kg to about 200 mg/kg, 0.05 mg/kg to about 150 mg/kg, 0.05 mg/kg to about 100 mg/kg, 0.05 mg/kg to about 50 mg/kg, 0.05 mg/kg to about 25 mg/kg, 0.05 mg/kg to about 10 mg/kg, or 0.05 mg/kg to about 5 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg. In other instances the compound of Formula II is present in an amount equivalent to about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg.

In certain instances the therapeutically effective amount of combination hereof is determined as an amount provided in a package insert provided with the combination. The term package insert refers to instructions customarily included in commercial packages of medicaments approved by the FDA or a similar regulatory agency of a country other than the US, which contains information about, for example, the usage, dosage, administration, contraindications, and/or warnings concerning the use of such medicaments.

The compound of Formulas I can be provided in amounts that are synergistic with the amount of the compound of Formula II. The term synergistic refers to a combination described herein (e.g., a compound of Formula I and a compound of Formula II - including, optionally, coadministration with another active agent such as an anti-neurodegenerative agent described herein) or a combination of regimens such as those described herein that is more effective than the additive effects of each individual therapy or regimen.

A synergistic effect of a combination described herein can permit the use of lower dosages of one or more of the components of the combination (e.g., a compound of Formula I and a compound of Formula II). A synergistic effect can permit less frequent administration of at least one of the administered therapies (e.g., a compound of Formula I and a compound of Formula II) to a subject with a disease, disorder, or condition described herein. Such lower dosages and reduced frequency of administration can reduce the toxicity associated with the administration of at least one of the therapies (e.g., a compound of Formula I and a compound of Formula II) to a subject without reducing the efficacy of the treatment. A synergistic effect as described herein avoid or reduce adverse or unwanted side effects associated with the use of any therapy.

Pharmaceutical Compositions

Combinations described herein can be provided as a pharmaceutical composition suitable for administration via any route to a patient described herein including but not limited to: oral, mucosal (e.g., nasal, inhalation, pulmonary, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intra-arterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal or transcutaneous administration to a patient.

Exemplary of dosage forms include: tablets; caplets; capsules (e.g., gelatin capsules); cachets; lozenges; suppositories; powders; gels; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

Pharmaceutical compositions and dosage forms described herein typically include one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors such as, for example, the intended route of administration to the patient. Pharmaceutical compositions described herein can include other agents such as stabilizers, lubricants, buffers, and disintegrants that can reduce the rate by which an active ingredient can decompose in a particular formulation.

Pharmaceutical compositions described herein can in certain instances include additional active agents other than those in the combinations described herein (e.g., an anti-neurodegenerative agent such as those described herein) in an amount provided herein.

In one embodiment, the compound of Formula I is provided in an oral dosage form such as a tablet or capsule. In another embodiment, the compound of Formula I is supplied as a powder (e.g., lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration. In one embodiment, the compound of Formula II is provided in an oral dosage form such as a tablet or capsule. In another embodiment, the compound of Formula II is supplied as a powder (e.g., lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration.

The combinations described herein can be provided in forms convenient to or facilitate their administration to a patient. For example, the combination can be formulated as a tablet, capsule, or as a powder (e.g., lyophilized powder) that can be resuspended in a liquid suitable for parenteral administration. In one embodiment, the combination includes an Inhibitor Antibody formulated for intravenous administration.

Combinations described herein can be provided as controlled release pharmaceutical products, which have a goal of improving drug therapy over that achieved by their non-controlled counterparts. Controlled release formulations can extend activity of the drug, reduce dosage frequency, and increase subject compliance. In addition, controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

Methods

The combinations, pharmaceutical compositions, and kits described herein are useful for treating diseases, disorders, or alleviating, ameliorating, or eliminating the symptoms of diseases and disorders such as, for example, neurodegenerative disorders. It is to be understood that the methods described herein pertain to administration of combinations and pharmaceutical compositions described herein, and such combinations and pharmaceutical compositions can be provided in the form of a kit as described herein. Provided herein are methods of treating neurodegeneration by administering a therapeutically effective amount of a combination described herein to a patient in need thereof. Also provided herein are methods of managing neurodegeneration by administering therapeutically effective amount of a combination described herein to a patient in need thereof.

In an aspect the methods of treating neurodegeneration provide for methods for reducing amyloid or Aβ burden in an individual by administering a therapeutically effective amount of a combination described herein. In some embodiments, neurodegeneration is reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

The methods of treating neurodegeneration described herein also provide for methods for increasing or otherwise prolonging time to neurodegenerative disease progression. Time to disease progression can be prolonged in a patient by administering a therapeutically effective amount of a combination described herein. In some embodiments, the increase is a comparison between the time to disease progression without treatment and with treatment with a combination described herein. In some embodiments, the methods described herein prolong the time to disease progression by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 15 years, 20 years, 25 years, or more, including values therein.

The methods of treating neurodegeneration described herein also provide for methods for increasing or otherwise prolonging survival of patients diagnosed with neurodegenerative disorders as described herein. Patient survival can be prolonged by administering a therapeutically effective amount of a combination described herein. In some embodiments, the increase is a comparison between the survival without treatment and with treatment with a combination as described herein. In some embodiments, the methods described herein prolong survival by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 15 years, 20 years, 25 years, or more, including values therein.

The methods of treating neurodegeneration described herein also provide for methods for increasing progression-free survival of patients diagnosed with neurodegenerative disorders as described herein. Patient progression-free survival can be prolonged by administering a therapeutically effective amount of a combination described herein. In some embodiments, the increase is a comparison between the progression-free survival without treatment and with treatment with a combination as described herein. In some embodiments, the methods described herein increase progression-free survival by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 15 years, 20 years, 25 years, or more, including values therein.

Target Neurodegenerative Disorders

Synucleinopathies are a group of neurodegenerative disorders characterized by the abnormal accumulation and aggregation of alpha-synuclein protein in various parts of the nervous system. In some cases, these disorders may share common pathological mechanisms, but they often present with distinct clinical features. The following outlines several known synucleinopathies:

Parkinson's Disease (PD): PD may be characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies containing aggregated alpha-synuclein. In some cases, patients may experience motor symptoms such as tremor, rigidity, bradykinesia, and postural instability. Non-motor symptoms may include cognitive impairment, depression, sleep disorders, and autonomic dysfunction.

Parkinson's Disease Dementia (PDD): PDD may develop in some patients with long-standing PD. It may be characterized by cognitive decline, including impairments in attention, executive function, and visuospatial abilities. In some cases, PDD may be associated with a more widespread distribution of Lewy bodies in cortical and limbic regions.

Dementia with Lewy Bodies (DLB): DLB may share features with both PD and Alzheimer's disease. It may be characterized by fluctuating cognition, visual hallucinations, and parkinsonism. In some cases, patients may experience rapid eye movement (REM) sleep behavior disorder. The distribution of Lewy bodies in DLB may be more widespread than in PD, often affecting cortical areas.

Multiple System Atrophy (MSA): MSA may be characterized by a combination of parkinsonian, cerebellar, and autonomic symptoms. In some cases, it may be divided into two subtypes: MSA-P (predominant parkinsonism) and MSA-C (predominant cerebellar ataxia). Alpha-synuclein aggregates in MSA may primarily affect oligodendrocytes, forming glial cytoplasmic inclusions.

Pure Autonomic Failure (PAF): PAF may be characterized by progressive autonomic dysfunction without significant central nervous system involvement. In some cases, patients may experience orthostatic hypotension, gastrointestinal disturbances, and urogenital dysfunction. Alpha-synuclein aggregates may be found in peripheral autonomic neurons.

Lewy Body Variant of Alzheimer's Disease (LBV): LBV may represent a condition where patients exhibit pathological features of both Alzheimer's disease and DLB. In some cases, patients may show cognitive decline typical of Alzheimer's disease along with some features of DLB, such as visual hallucinations or fluctuating cognition.

In some aspects, these synucleinopathies may share common pathological mechanisms related to alpha-synuclein aggregation and neuronal dysfunction. However, the specific distribution of alpha-synuclein pathology and the affected cell types may vary among these disorders, contributing to their distinct clinical presentations.

The development of therapeutic strategies targeting alpha-synuclein aggregation, such as the combination of Lamotrigine and Rivastigmine described in this disclosure, may have potential applications across various synucleinopathies. In some cases, such approaches may address the underlying pathological processes common to these disorders, potentially offering new avenues for prevention, alleviation, or treatment of these debilitating neurodegenerative conditions.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that may be characterized by cognitive decline, memory loss, and behavioral changes. In some cases, AD may be the most common cause of dementia in older adults. The disease may be associated with the accumulation of Aβ plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein in the brain.

In some aspects, the pathological hallmarks of AD may include:

Aβ plaques: These extracellular deposits may consist of aggregated beta-amyloid peptides, which may be derived from the amyloid precursor protein (APP).

Neurofibrillary tangles: These intracellular aggregates may be composed of hyperphosphorylated tau protein, which may disrupt normal neuronal function.

Neuronal loss: Progressive degeneration of neurons, particularly in regions such as the hippocampus and cortex, may occur.

Synaptic dysfunction: Impairment of synaptic transmission and plasticity may contribute to cognitive decline.

In some cases, AD may progress through several stages, from mild cognitive impairment to severe dementia. The disease may affect various cognitive domains, including memory, language, executive function, and visuospatial abilities.

Other neurodegenerative diseases related to AD may include:

Vascular dementia: This form of dementia may be caused by reduced blood flow to the brain, often due to stroke or other vascular issues.

Frontotemporal dementia (FTD): FTD may be characterized by changes in behavior, personality, and language abilities, often with an earlier onset than AD.

Lewy body dementia (LBD): This condition may share features with both AD and Parkinson's Disease, and may be characterized by cognitive fluctuations, visual hallucinations, and parkinsonism.

Mixed dementia: In some cases, individuals may exhibit pathological features of multiple types of dementia, such as AD and vascular dementia.

Posterior cortical atrophy (PCA): This rare form of dementia may primarily affect visual processing and spatial awareness.

Primary progressive aphasia (PPA): PPA may be characterized by progressive language impairment, which may be a variant of FTD or AD.

Corticobasal degeneration (CBD): This rare neurological disorder may affect movement and cognition, often presenting with asymmetric motor symptoms and cognitive impairment.

Progressive supranuclear palsy (PSP): PSP may be characterized by problems with balance, eye movements, and cognitive function.

In some aspects, these neurodegenerative diseases may share common pathological mechanisms, such as protein aggregation, mitochondrial dysfunction, and neuroinflammation, including mechanisms involved in synucleinopathies. However, the specific proteins involved, the regions of the brain affected, and the clinical presentations may vary among these disorders.

The development of therapeutic strategies targeting multiple pathological processes, such as the combination of Lamotrigine and Rivastigmine described in this disclosure, may have potential applications across various neurodegenerative diseases. In some cases, such approaches may address the underlying pathological processes common to these disorders, potentially offering new avenues for prevention, alleviation, or treatment of these debilitating conditions.

The combinations described herein can include administration of each therapy (e.g., a compound of Formula I and a compound of Formula II, optionally including another anti-neurodegenerative agent), where the administration is performed simultaneously or sequentially (in either order). In one embodiment, the compound of Formula I and the compound of Formula II are administered simultaneously (e.g., within at least 1 to 5 min of each other). In another embodiment, the compound of Formula I and the compound of Formula II are administered sequentially (e.g., within at least 10 min, 15 min, 30 min, 1 h, 2 h, 5 h, 10 h, 12 h, 1 day, 2 days, 5 days, 7 days, 14 days, or 21 days of each other).

The compound of Formula I can be administered, for example, once a day (QD), twice daily (BID), once a week (QW), twice weekly (BIW), three times a week (TIW), or monthly (QM) regularly on a continuous base or intermittent base such as BIW for 3 months then resume a month later. For example, the compound of Formula I can be administered BID. The compound of Formula I can be administered TIW. In certain instances, the compound of Formula I is administered 2 to 3 times a week. In another embodiment, the compound of Formula I is administered QD. The compound can be administered QD for about: 1 day to about 7 days, 1 day to about 14 days, 1 day to about 21 days, 1 day to about 28 days, or daily until disease progression changes or unacceptable toxicity occurs. The administration of a compound of Formula I can, in part, depend upon the tolerance of the patient where greater tolerance can allow greater or more frequent administration. Alternatively, where a patient shows poor tolerance to a compound of Formula I, a less amount of the compound or a less frequent dosing can be performed. Compounds of Formula I can be administered in any regimen as described herein.

For example, a compound of Formula I can be administered at an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, QD. For example, a compound of Formula I can be administered at an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, BIW. For example, a compound of Formula I can be administered at an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, TIW. For example, a compound of Formula I can be administered at an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, QW. For example, a compound of Formula I can be administered at an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, Q2W. For example, a compound of Formula I can be administered at an amount of about 5 mg or about 10 mg, QD. For example, a compound of Formula I can be administered at an amount of about 5 mg or about 10 mg, BIW. For example, a compound of Formula I can be administered at an amount of about 5 mg or about 10 mg, TIW. For example, a compound of Formula I can be administered at an amount of about 5 mg or about 10 mg, QW. For example, a compound of Formula I can be administered at an amount of about 5 mg or about 10 mg, Q2W. Administration of a compound of Formula I can be continuous. Administration of a compound of Formula I can be intermittent.

For example, a compound of Formula I can be administered at an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg, QD. For example, a compound of Formula I can be administered at an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg, BIW. For example, a compound of Formula I can be administered at an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg, TIW. For example, a compound of Formula I can be administered at an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg, QW. For example, a compound of Formula I can be administered at an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg, Q2W. Administration of a compound of Formula I can be continuous. Administration of a compound of Formula I can be intermittent.

For example, a compound of Formula I can be administered at an amount of about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 150 mg/kg, 0.01 mg/kg to about 100 mg/kg, 0.01 mg/kg to about 50 mg/kg, 0.01 mg/kg to about 25 mg/kg, 0.01 mg/kg to about 10 mg/kg, or 0.01 mg/kg to about 5 mg/kg, 0.05 mg/kg to about 200 mg/kg, 0.05 mg/kg to about 150 mg/kg, 0.05 mg/kg to about 100 mg/kg, 0.05 mg/kg to about 50 mg/kg, 0.05 mg/kg to about 25 mg/kg, 0.05 mg/kg to about 10 mg/kg, or 0.05 mg/kg to about 5 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, QD. For example, a compound of Formula I can be administered at an amount of about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, BIW. For example, a compound of Formula I can be administered at an amount of about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, TIW. For example, a compound of Formula I can be administered at an amount of about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, QW. For example, a compound of Formula I can be administered at an amount of about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, Q2W. In one example, a compound of Formula I can be administered at an amount of about 15 mg/kg to about 75 mg/kg, QD. In another example, a compound of Formula I can be administered at an amount of about 20 mg/kg to about 50 mg/kg. In still another example, a compound of Formula I can be administered at an amount of about 0.001 mg/kg, 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, or 200 mg/kg. Administration of a compound of Formula I can be continuous. Administration of a compound of Formula I can be intermittent.

For example, a compound of Formula I can be administered at an amount of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg, QD. For example, a compound of Formula I can be administered at an amount of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg, BIW. For example, a compound of Formula I can be administered at an amount of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg, TIW. For example, a compound of Formula I can be administered at an amount of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg, QW. For example, a compound of Formula I can be administered at an amount of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg, Q2W. In one example, a compound of Formula I can be administered at an amount of about 15 mg/kg to about 75 mg/kg, QD. In another example, a compound of Formula I can be administered at an amount of about 20 mg/kg to about 50 mg/kg. In still another example, a compound of Formula I can be administered at an amount of about 0.001 mg/kg, 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, or 200 mg/kg. Administration of a compound of Formula I can be continuous. Administration of a compound of Formula I can be intermittent.

The compound of Formula II can be administered, for example, once a day (QD), twice daily (BID), once a week (QW), twice weekly (BIW), three times a week (TIW), or monthly (QM) regularly on a continuous base or intermittent base such as BIW for 3 months then resume a month later. For example, the compound of Formula II can be administered BID. The compound of Formula II can be administered TIW. In certain instances, the compound of Formula II is administered 2 to 3 times a week. In another embodiment, the compound of Formula II is administered QD. The compound can be administered QD for about: 1 day to about 7 days, 1 day to about 14 days, 1 day to about 21 days, 1 day to about 28 days, or daily until disease progression changes or unacceptable toxicity occurs. The administration of a compound of Formula II can, in part, depend upon the tolerance of the patient where greater tolerance can allow greater or more frequent administration. Alternatively, where a patient shows poor tolerance to a compound of Formula II, a less amount of the compound or a less frequent dosing can be performed. Compounds of Formula II can be administered in any regimen as described herein.

For example, a compound of Formula II can be administered at an amount of about: 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, or 100 mg, QD. For example, a compound of Formula II can be administered at an amount of about: 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, or 100 mg, BIW. For example, a compound of Formula II can be administered at an amount of about: 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, or 100 mg, TIW. For example, a compound of Formula II can be administered at an amount of about: 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, or 100 mg, QW. For example, a compound of Formula II can be administered at an amount of about: 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, or 100 mg, Q2W. For example, a compound of Formula II can be administered at an amount of about 1.5 mg, 3 mg, 4.5 mg, or 6 mg, QD. For example, a compound of Formula II can be administered at an amount of about 1.5 mg, 3 mg, 4.5 mg, or 6 mg, BIW. For example, a compound of Formula II can be administered at an amount of about 1.5 mg, 3 mg, 4.5 mg, or 6 mg, TIW. For example, a compound of Formula II can be administered at an amount of about 1.5 mg, 3 mg, 4.5 mg, or 6 mg, QW. For example, a compound of Formula II can be administered at an amount of about 1.5 mg, 3 mg, 4.5 mg, or 6 mg, Q2W. Administration of a compound of Formula II can be continuous. Administration of a compound of Formula II can be intermittent.

For example, a compound of Formula II can be administered at an amount of about: 0.1 mg to about 10 mg, 0.1 mg to about 25 mg, 0.1 mg to about 50 mg, 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 3 mg to about 25 mg, 3 mg to about 50 mg, 6 mg to about 10 mg, or 10 mg to about 20 mg, QD. For example, a compound of Formula II can be administered at an amount of about: 0.1 mg to about 10 mg, 0.1 mg to about 25 mg, 0.1 mg to about 50 mg, 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 3 mg to about 25 mg, 3 mg to about 50 mg, 6 mg to about 10 mg, or 10 mg to about 20 mg, BIW. For example, a compound of Formula II can be administered at an amount of about: 0.1 mg to about 10 mg, 0.1 mg to about 25 mg, 0.1 mg to about 50 mg, 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 3 mg to about 25 mg, 3 mg to about 50 mg, 6 mg to about 10 mg, or 10 mg to about 20 mg, TIW. For example, a compound of Formula II can be administered at an amount of about: 0.1 mg to about 10 mg, 0.1 mg to about 25 mg, 0.1 mg to about 50 mg, 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 3 mg to about 25 mg, 3 mg to about 50 mg, 6 mg to about 10 mg, or 10 mg to about 20 mg, QW. For example, a compound of Formula II can be administered at an amount of about: 0.1 mg to about 10 mg, 0.1 mg to about 25 mg, 0.1 mg to about 50 mg, 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 3 mg to about 25 mg, 3 mg to about 50 mg, 6 mg to about 10 mg, or 10 mg to about 20 mg, Q2W. Administration of a compound of Formula II can be continuous. Administration of a compound of Formula II can be intermittent.

For example, a compound of Formula II can be administered at an amount of about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 150 mg/kg, 0.01 mg/kg to about 100 mg/kg, 0.01 mg/kg to about 50 mg/kg, 0.01 mg/kg to about 25 mg/kg, 0.01 mg/kg to about 10 mg/kg, or 0.01 mg/kg to about 5 mg/kg, 0.05 mg/kg to about 200 mg/kg, 0.05 mg/kg to about 150 mg/kg, 0.05 mg/kg to about 100 mg/kg, 0.05 mg/kg to about 50 mg/kg, 0.05 mg/kg to about 25 mg/kg, 0.05 mg/kg to about 10 mg/kg, or 0.05 mg/kg to about 5 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, QD. For example, a compound of Formula II can be administered at an amount of about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, BIW. For example, a compound of Formula II can be administered at an amount of about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, TIW. For example, a compound of Formula II can be administered at an amount of about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, QW. For example, a compound of Formula II can be administered at an amount of about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, Q2W. In one example, a compound of Formula II can be administered at an amount of about 15 mg/kg to about 75 mg/kg, QD. In another example, a compound of Formula II can be administered at an amount of about 20 mg/kg to about 50 mg/kg. In still another example, a compound of Formula II can be administered at an amount of about 0.001 mg/kg, 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, or 200 mg/kg. Administration of a compound of Formula II can be continuous. Administration of a compound of Formula II can be intermittent.

For example, a compound of Formula II can be administered at an amount of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg, QD. For example, a compound of Formula II can be administered at an amount of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg, BIW. For example, a compound of Formula II can be administered at an amount of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg, TIW. For example, a compound of Formula II can be administered at an amount of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg, QW. For example, a compound of Formula II can be administered at an amount of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg, Q2W. In one example, a compound of Formula II can be administered at an amount of about 15 mg/kg to about 75 mg/kg, QD. In another example, a compound of Formula II can be administered at an amount of about 20 mg/kg to about 50 mg/kg. In still another example, a compound of Formula II can be administered at an amount of about 0.001 mg/kg, 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, or 200 mg/kg. Administration of a compound of Formula II can be continuous. Administration of a compound of Formula II can be intermittent.

As used herein, the term daily is intended to mean that a therapeutic compound of a combination described herein, such as a compound of Formula I and a compound of Formula II, is administered once or more than once each day for a period of time. The term continuous is intended to mean that a therapeutic compound of a combination described herein, such as a compound of Formula I and a compound of Formula II, is administered daily for an uninterrupted period of at least 10 days to 52 weeks, to multiple years. The term intermittent or intermittently as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a therapeutic compound of a combination described herein, such as a compound of Formula I and a compound of Formula II, includes administration for one to six days per week (e.g., 2 to 3 times per week or QD), administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration at least one day), or, for example, administration on alternate days.

The combinations described herein can be administered in a regimen. The regimen can be structured to provide therapeutically effective amounts of a compound of Formula I and a compound of Formula II, optionally including another anti-neurodegenerative agent, over a predetermined period of time (e.g., an administration time). The regimen can be structured to limit or prevent side-effects or undesired complications of each of the components of the combination described herein. The regimen can be structured in a manner that results in increased effect for both therapies of the combination (e.g., synergy). Regimens useful for treating neurodegeneration can include any number of days, months or years of administration which can be repeated as necessary. Administration periods can be broken by a rest period that includes no administration of at least one therapy. For example, a regimen can include administration periods that include 2, 3, 5, 7, 10, 15, 21, 28, or more days. These periods can be repeated. For example, a regimen can include a set number of days as previously described where the regimen is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more times.

Regimens can include a rest period of at least 1, 2, 3, 5, 7, 10, or more days, where at least one therapy is no longer administered to a patient. The rest period can be determined by, for example, monitoring the reaction of the patient to the drug or by measuring the efficacy of the treatment. A rest period can be applicable to a single therapy, such that only one therapy of a combination described herein is discontinued in the rest period but the other therapy(ies) are still administered. Rest periods can be applied to all of the therapies administered to the subject such that the subject receives no therapy for a set period of time during the rest period.

Regimens described herein for the treatment of neurodegeneration using the combinations described herein can be continued until disease progression is changed or unacceptable toxicity occurs.

Regimens for administration of combinations described herein include, for example administration of a compound of Formula I BIW or TIW and administration of a compound of Formula II. For example, a compound of Formula I can be administered QD for about 21 days and a compound of Formula II can be administered Q2W or Q4W. For example, a compound of Formula I can be administered BIW or TIW and a compound of Formula II can be administered Q2W. In another exemplary regimen, a compound of Formula I can be administered BIW or TIW and a compound of Formula II can be administered BIW for 2 or 3 weeks. In still another exemplary regimen, a compound of Formula I can be administered BIW or TIW and a compound of Formula II can be administered Q4W. In still another exemplary regimen, a compound of Formula I can be administered BIW and a compound of Formula II can be administered Q2W, Q3W, or Q4W. In certain instances, such regimens include administration of another anti-neurodegenerative agent administered Q2W, Q3W, or Q4W. In yet another exemplary regimen, a compound of Formula I can be administered TIW and a compound of Formula II can be administered Q2W, Q3W, or Q4W.

It should also be appreciated that the combinations described herein for treating neurodegeneration can be coadministered with other active agents other than those present in the combinations described herein (e.g., anti-neurodegenerative agents). Regimens for administration of a combination described herein, including the exemplary regimens set forth above, can be modified as necessary to include administration of such active agents. Administration of such active agents, e.g., anti-neurodegenerative agents, can be performed QD, QW, QM, BID, BIW, TIW, Q2W, Q3W, or Q4W, or in accordance with prescribing information for such anti-neurodegenerative agents as set forth, for example, in a package insert. Exemplary anti-neurodegenerative agents include but are not limited

Referring to Figure 1, the bar graph illustrates the effects of various treatments on α-synuclein dimer levels in a neurodegenerative disease model. In some cases, the treatments may include Rivastigmine and Lamotrigine, administered either individually or in combination. The y-axis of the graph represents the fold change in α-synuclein/β-actin ratio, providing a measure of α-synuclein dimer levels relative to the control condition. The x-axis represents the different treatment conditions, allowing for comparison of the effects of various treatments.

In some aspects, the graph shows a significant reduction in α-synuclein dimer levels following treatment with Rivastigmine and Lamotrigine alone, as compared to the control condition. This decrease may be indicative of the pathological state associated with neurodegenerative disorders, particularly synucleinopathies.

In some aspects, combination treatments of Lamotrigine and Rivastigmine at various concentrations may result in a more significant reduction of α-synuclein dimer levels compared to individual treatments. For instance, the combination of Lamotrigine at 0.5 μM and Rivastigmine at 0.025 μM may result in a greater reduction of α-synuclein dimer levels than either drug alone at the same concentrations. Similarly, the combination of Lamotrigine at 0.5 μM and Rivastigmine at 0.05 μM, Lamotrigine at 1.0 μM and Rivastigmine at 0.025 μM, and Lamotrigine at 1.0 μM and Rivastigmine at 0.05 μM may each result in a greater reduction of α-synuclein dimer levels than either drug alone at the same concentrations.

In some cases, the combination treatments may exhibit a synergistic effect, where the reduction in α-synuclein dimer levels is greater than the sum of the reductions observed with each drug alone. This synergistic effect may provide a more effective approach to the prevention, alleviation, or treatment of neurodegenerative diseases, particularly synucleinopathies.

Referring to Figure 2, the bar graph illustrates the effects of various treatments on α-synuclein trimer levels in a neurodegenerative disease model. In some cases, the treatments may include Rivastigmine and Lamotrigine, administered either individually or in combination. The y-axis of the graph represents the fold change in α-synuclein/β-actin ratio, providing a measure of α-synuclein trimer levels relative to the control condition. The x-axis represents the different treatment conditions, allowing for comparison of the effects of various treatments.

In some cases, treatment with Lamotrigine alone at concentrations of 0.5 and 1.0 μM may result in a reduction of α-synuclein trimer levels compared to the α-synuclein treatment alone. Similarly, treatment with Rivastigmine alone at concentrations of 0.025 and 0.05 μM may also result in a reduction of α-synuclein trimer levels compared to the α-synuclein treatment alone.

In some aspects, combination treatments of Lamotrigine and Rivastigmine at various concentrations may result in a more significant reduction of α-synuclein trimer levels compared to individual treatments. For instance, the combination of Lamotrigine at 0.5 μM and Rivastigmine at 0.025 μM may result in a greater reduction of α-synuclein trimer levels than either drug alone at the same concentrations. Similarly, the combination of Lamotrigine at 0.5 μM and Rivastigmine at 0.05 μM, Lamotrigine at 1.0 μM and Rivastigmine at 0.025 μM, and Lamotrigine at 1.0 μM and Rivastigmine at 0.05 μM may each result in a greater reduction of α-synuclein trimer levels than either drug alone at the same concentrations.

In some cases, the combination treatments may exhibit a synergistic effect, where the reduction in α-synuclein trimer levels is greater than the sum of the reductions observed with each drug alone. This synergistic effect may provide a more effective approach to the prevention, alleviation, or treatment of neurodegenerative diseases, particularly synucleinopathies and amyloidoses.

Referring to Figure 3, the bar graph illustrates the effects of various treatments on α-synuclein tetramer levels in a neurodegenerative disease model. In some cases, the treatments may include Rivastigmine and Lamotrigine, administered either individually or in combination. The y-axis of the graph represents the fold change in α-synuclein/β-actin ratio, providing a measure of α-synuclein tetramer levels relative to the control condition. The x-axis represents the different treatment conditions, allowing for comparison of the effects of various treatments.

In some aspects, combination treatments of Lamotrigine and Rivastigmine at various concentrations may result in a more significant reduction of α-synuclein tetramer levels compared to individual treatments. For instance, the combination of Lamotrigine at 0.5 μM and Rivastigmine at 0.025 μM may result in a greater reduction of α-synuclein tetramer levels than either drug alone at the same concentrations. Similarly, the combination of Lamotrigine at 0.5 μM and Rivastigmine at 0.05 μM, Lamotrigine at 1.0 μM and Rivastigmine at 0.025 μM, and Lamotrigine at 1.0 μM and Rivastigmine at 0.05 μM may each result in a greater reduction of α-synuclein tetramer levels than either drug alone at the same concentrations.

In some cases, the combination treatments may exhibit a synergistic effect, where the reduction in α-synuclein tetramer levels is greater than the sum of the reductions observed with each drug alone. This synergistic effect may provide a more effective approach to the prevention, alleviation, or treatment of neurodegenerative diseases, particularly synucleinopathies.

Referring to Figure 4, the bar graph illustrates the effects of various treatments on the JC-1 ratio in mouse primary neurons after two days of treatment. The y-axis represents the fold change in the JC-1 ratio (Aggregate/Monomer), providing a measure of mitochondrial membrane potential relative to the control condition. The x-axis represents the different treatment conditions, allowing for comparison of the effects of various treatments.

In some aspects, the graph shows a decrease in the JC-1 ratio following exposure with Aβ alone, as compared to the control condition. This decrease may be indicative of a decrease in mitochondrial membrane potential, which could potentially contribute to the pathogenesis of neurodegenerative diseases, particularly synucleinopathies and amyloidoses.

In some cases, treatment with Lamotrigine alone at a concentration of 5 μM may result in an increase in the JC-1 ratio compared to the Aβ exposure alone. Similarly, treatment with Rivastigmine alone at concentrations of 0.1, 0.5, 1, and 5 μM may also result in an increase in the JC-1 ratio compared to the Aβ exposure alone.

In some aspects, combination treatments of Lamotrigine and Rivastigmine at various concentrations may result in a more significant increase in the JC-1 ratio compared to individual treatments. For instance, the combination of Lamotrigine at 5 μM and Rivastigmine at 0.1 μM may result in a greater increase in the JC-1 ratio than either drug alone at the same concentrations. Similarly, the combinations of Lamotrigine at 5 μM and Rivastigmine at 0.5, 1, and 5 μM may each result in a greater increase in the JC-1 ratio than either drug alone at the same concentrations.

In some cases, the combination treatments may exhibit a synergistic effect, where the increase in the JC-1 ratio is greater than the sum of the increases observed with each drug alone. This synergistic effect may provide a more effective approach to the prevention, alleviation, or treatment of neurodegenerative diseases, particularly synucleinopathies and amyloidoses, by potentially improving mitochondrial function.

In some aspects, the pharmaceutical composition may include Lamotrigine and Rivastigmine in specific molar ratios. The molar ratio of Rivastigmine to Lamotrigine in the pharmaceutical composition may be 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, 1:50, 1:51, 1:52, 1:53, 1:54, 1:55, 1:56, 1:57, 1:58, 1:59, 1:60, 1:61, 1:62, 1:63, 1:64, 1:65, 1:66, 1:67, 1:68, 1:69, 1:70, 1:71, 1:72, 1:73, 1:74, 1:75, 1:76, 1:77, 1:78, 1:79, 1:80, 1:81, 1:82, 1:83, 1:84, 1:85, 1:86, 1:87, 1:88, 1:89, 1:90, 1:91, 1:92, 1:93, 1:94, 1:95, 1:96, 1:97, 1:98, 1:99, or 1:100, and values in between. These specific molar ratios may provide different balances between the two active ingredients, potentially allowing for optimization of the therapeutic efficacy of the composition for different patients or conditions.

Aspects of the present teachings may be further understood in light of the following examples, which should not be construed as limiting the scope of the present teachings in any way.

Example 1

1. Brain slice culture and drug treatment

For the brain slice culture, adult male (6-8 weeks) mice were used. The animals were anesthetized, decapitated and the brains was dissected out as per the Institutional Animal Ethical Guidelines. The brains were immediately transferred in artificial cerebrospinal fluid [(ACSF) NaCl (125 mM, Sigma-Aldrich), KCl (2.5 mM, Sigma-Aldrich), NaHCO₃ (25 mM, Sigma-Aldrich), NaH₂PO₄ (1.25 mM, Sigma-Aldrich), MgCl2 (0.1 mM, Sigma-Aldrich), CaCl₂ (0.2 mM, Sigma-Aldrich), D-Glucose (2.5 mM, Sigma-Aldrich) and penicillin/streptomycin (1%, HyClone)]. The ACSF was incubated for 1 h in CO₂ incubator (95% O₂ and 5% CO₂) before use. Further, the brains were washed quickly with 4% low melting point (LMP) agarose and then embedded in fresh LMP agarose. The brain sections were prepared (200 μM thick) using vibratome (Leica VT-1200S) and incubated in the brain slice culture media [Hanks' balanced Salt solution (25%, Gibco), DMEM high glucose (70%, HyClone), HEPES (1%, Sigma-Aldrich), B27 supplement (0.5%, Gibco), L-glutamine (1%, Gibco), 25 mM D-Glucose (1.5%, Sigma-Aldrich) and penicillin/streptomycin (1%, HyClone)] in CO₂ incubator at 37℃. After three days, the brain sections were divided into 10 groups and treated with human α-synuclein (2 μg/mL, NKMAX) as well as Lamotrigine (LMT; 0.5 and 1.0 μM) and Rivastigmine (RV; 0.025 and 0.05 μM) individually or in combination:

(i) Control,

(ii) α-syn,

(iii) α-syn + LMT (0.5 μM),

(iv) α-syn + LMT (1.0 μM),

(v) α-syn + RV (0.025 μM),

(vi) α-syn + RV (0.5 μM)

(vii) α-syn + LMT (0.5 μM)/RV (0.025 μM),

(viii) α-syn + LMT (0.5 μM)/RV (0.05 μM),

(ix) α-syn + LMT (1.0 μM) /RV 0.025 μM and

(x) α-syn + LMT (1.0 μM)/RV (0.5 μM)

at the ratio of LMT/RV 1:10, 1:20 and 1:40. After 8 days of treatment, the brain slices were harvested and proteins were isolated.

2. Protein isolation and quantification

After 8 days, the brain slices were taken out of the culture media and transferred to 1.5 mL microfuge tubes. Lysis buffer [(400 μL for each tube); DyneBio, MOPS (20mM), β-glycerolphosphate (50mM), EGTA (5 mM), EDTA (2mM), NP-40 (1%) and DTT (1mM)] containing protease inhibitor (1X) and phosphatase inhibitor (1X) was added in each microcentrifuge tube. Then brain slices were homogenized using bioruptor (Cosmobio) for 15 min at 4℃. The homogenates were centrifuged at 13,000X g for 12 min at 4℃ and the supernatant was collected in the fresh 1.5 mL microfuge tubes. Protein estimation was done by bicinchoninic acid protein (BCA) assay method. Briefly, 25 μL of protein sample and 200 μL of BCA assay buffer was added to each well in a 96 well plate. The mixture was incubated for 30 min at 37℃ and OD was taken at 592 nm using the microplate reader (Varioskan LUX). Bovine serum albumin (BSA) was used as standard.

3. Immunoblotting of α-synuclein

After estimation, proteins were denatured, and resolved by 12% SDS-polyacrylamide gel electrophoresis, transferred to PVDF membrane. Further, the membrane was blocked with 5% BSA for 1 h, probed with primary anti-human mouse monoclonal α-synuclein antibody (ab80627, Abcam; 1: 5000) and anti-mouse HRP conjugated secondary antibody (1:6000), and detected using Chemidoc (Vilber, Fusion Solo S) using Super Signal West Femto Maximum sensitivity substrate (Thermo Scientific).

4. Measurement of α-synuclein level and statistical analysis

Signal intensities of the blots from three independent experiments were analyzed using Image J software. Signal intensities of α-synuclein dimer, trimer and tetramer bands were normalized using the signal intensities of β actin and bar diagram were plotted as relative density value. The values were represented as Mean ± SEM and statistical significance was analyzed by independent t-test.

Results

In order to assess whether combination of Lamotrigine and Rivastigmine treatment affects α-synuclein level in the brain slice culture, western blot analysis was performed. α-synuclein treated brain slices showed increased α-synuclein protein level (dimer - 262%, trimer - 1310% and tetramer - 491%).

Lamotrigine alone treatment significantly reduced α-synuclein protein level at 0.5 μM (dimer - 48%, trimer - 82% and tetramer - 41%) and 1.0 μM (dimer - 42%, trimer - 50% and tetramer - 41%) dose as compared to α-synuclein treated group. Similarly, Rivastigmine alone treatment significantly reduced α-synuclein protein level at 0.025 μM (dimer - 35%, trimer - 65% and tetramer - 34%) and 0.05 μM (dimer - 32%, trimer - 56% and tetramer - 35%) dose as compared to α-synuclein treated group.

Combination treatment showed significant reduction in α-synuclein protein level at Lamotrigine 0.5 μM and Rivastigmine 0.025 μM (dimer - 64%, trimer - 96% and tetramer - 89%), Lamotrigine 0.5 μM and Rivastigmine 0.05 μM (dimer - 80%, trimer - 98% and tetramer - 92%), Lamotrigine 1.0 μM and Rivastigmine 0.025 μM (dimer - 83%, trimer - 98% and tetramer - 94%), Lamotrigine 1.0 μM and Rivastigmine 0.05 μM (dimer - 93%, trimer - 99% and tetramer - 98%) dose as compared to α-synuclein treated group.

[Table 1]

Therefore, Lamotrigine alone treatment significantly reduced the α-synuclein protein level. In addition, combination treatment of Lamotrigine and Rivastigmine showed a higher reduction rate in α-synuclein protein levels compared to the sum of the reduction rates from alone treatments of Lamotrigine or Rivastigmine. The combination treatment of Lamotrigine and Rivastigmine can show a synergistic effect compared to the alone treatment of Lamotrigine or Rivastigmine.

Example 2

1. Neuron cell culture plate coating

Prior to seeding, 96-well plates were coated with Poly-L-lysine. The Poly-L-lysine solution was thawed from -20℃ storage, and 100 μL was added to each well in a clean bench. Plates were incubated at room temperature for approximately 12 hours. After incubation, the wells were washed 2-3 times with distilled water and dried in the clean bench by partially opening the lids to allow airflow.

2. Mouse embryo brain dissection

Prior to dissection, 15 mL tubes and 100 mm dishes containing Neurobasal medium (other media could also be used at this stage) were prepared to store the dissected telencephalons. The dissection was performed on ice, and the embryos were carefully extracted from the pregnant mouse (TP14.5~15.5). Using a dissection microscope, the telencephalons of the brains were isolated. During this process, the meninges (the membrane surrounding the brain) were thoroughly removed to minimize cell debris. The dissected cortices were collected in 15 mL tubes containing Neurobasal medium and centrifuged at 1200 rpm for 2 minutes to pellet the tissue.

3. Single cell isolation

To dissociate the tissue into single cells, 5 mL of pre-warmed Trypsin (0.125%, diluted in DPBS) was added to the pellet, and the cells were incubated at 37℃ for 15 minutes. Trypsin activity was halted by adding 500 μL of FBS, and the cell suspension was transferred to a 50 mL tube. Neurobasal medium (10 mL) was added, and the cells were mechanically dissociated by pipetting with a 10 mL pipette followed by a 1000 μL pipette. An additional 20 mL of medium was added, and the cell suspension was filtered through a 70 μm cell strainer. The cells were centrifuged at 1500 rpm for 5 minutes, after which the supernatant was discarded, and the cells were resuspended in fresh Neurobasal medium. Cell counting was performed to ensure consistent seeding density.

4. Plate cell seeding and drug treatment

Cells were seeded in 96-well plates at a density of 3 Х 10⁴ cells per well in 100 μL of total volume. On day 6 of differentiation, the medium for the control group was replaced with fresh Neurobasal medium, while the treatment groups were exposed to Aβ (5 μM), Lamotrigine (LTG; 5 μM), and Rivastigmine (RV; 0.1, 0.5, 1, 5 μM) either individually or in combination:

(i) Control,

(ii) Aβ

(iii) Aβ + LTG (5 μM),

(iv) Aβ + RV (0.1 μM),

(v) Aβ + RV (0.5 μM),

(vi) Aβ + RV (1 μM),

(vii) Aβ + RV (5 μM),

(viii) Aβ + LTG (5 μM) / RV (0.1 μM),

(ix) Aβ + LTG (5 μM) / RV (0.5 μM),

(x) Aβ + LTG (5 μM) / RV (1 μM),

(xi) Aβ + LTG (5 μM) / RV (5 μM).

at the ratio of LMT/RV 1:1, 1:5, 1:10 and 1:50. After 2 days of treatment, the cells were assessed using the JC-1 assay.

5. Mitochondrial membrane potential (JC-1 assay)

Following 48 hours of incubation at 37℃ with 5% CO2, the mitochondrial membrane potential was assessed using the JC-1 assay. The JC-1 Mitochondrial Membrane Potential Assay Kit (ab113850, Abcam) was used according to the manufacturer's protocol, with the cells stained for 10 minutes in a CO2 incubator. Fluorescent measurements were taken using a microplate reader (Varioskan LUX), with results expressed as the ratio of aggregate (535 nm, red) to monomer (475 nm, green).

6. Statistical analysis

The values are indicated as Mean ± SEM and statistical significance was analyzed by One Way ANOVA.

Results

The decrease in JC-1 ratio (Aggregate/Monomer) in primary neurons following Aβ treatment was compared to the JC-1 ratio changes in the drug-treated groups. In the Aβ + LTG (5 μM) group, the JC-1 ratio changed by -2%, while in the Aβ + RV (0.1 μM) group, the JC-1 ratio increased by 24%. In the Aβ + RV (0.5 μM) group, the JC-1 ratio increased by 28%, and in the Aβ + RV (1 μM) group, the JC-1 ratio increased by 23%. In the Aβ + RV (5 μM) group, the JC-1 ratio increased by 35%.

On the other hand, in the Aβ + LTG (5 μM)/RV (0.1 μM) combination treatment group, the JC-1 ratio increased by 39%, while in the Aβ + LTG (5 μM)/RV (0.5 μM) combination treatment group, the JC-1 ratio increased by 35%. In the Aβ + LTG (5 μM)/RV (1 μM) combination treatment group, the JC-1 ratio increased by 32%, and in the Aβ + LTG (5 μM)/RV (5 μM) combination treatment group, the JC-1 ratio increased by 37%.

[Table 2]

Therefore, the combination treatment of Lamotrigine and Rivastigmine demonstrated a higher increase in the JC-1 ratio compared to the sum of the increases observed in each treatment alone. This indicates that the combination treatment of Lamotrigine and Rivastigmine exhibits a significantly enhanced effect compared to individual treatments.

As described above, specific parts of the present disclosure have been described in detail; however, it is obvious to those skilled in the art that these specific techniques are merely preferred exemplary embodiments and the scope of the present disclosure is not limited thereto. Accordingly, the actual scope of the present disclosure will be defined by the accompanying claims and equivalents thereof.

Other Embodiments

The detailed description set-forth above is provided to aid those skilled in the art in practicing the present invention. However, the invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended as illustration of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.

References Cited

All publications, patents, patent applications and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention.

The composition may be formulated for oral administration and can be used to treat neurodegenerative disorders such as Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and Alzheimer's disease.

Claims

A pharmaceutical composition for the treatment of a neurodegenerative disorder, the composition comprising:

a therapeutically effective amount of Lamotrigine and a therapeutically effective amount of Rivastigmine.
The pharmaceutical composition of claim 1, wherein the molar ratio of Rivastigmine to Lamotrigine is in the range from 1:1 to 1:50.
The pharmaceutical composition of claim 1, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson's disease (PD); sporadic or heritable dementia with Lewy bodies (DLB); pure autonomic failure (PAF) with αS deposition; multiple system atrophy (MSA); hereditary neurodegeneration with brain iron accumulation; and incidental Lewy body disease of advanced age; Alzheimer's disease of the Lewy body variant; Down's syndrome; progressive supranuclear palsy; essential tremor with Lewy bodies; familial parkinsonism with or without dementia resulting from a mutant gene and loci where no gene mutation has yet been identified; Creutzfeldt Jakob disease; bovine spongiform encephalopathy; secondary Parkinson disease/parkinsonism resulting from neurotoxin exposure/drug-induced parkinsonism with α-synuclein deposition; sporadic or heritable spinocerebellar ataxia; amyotrophic lateral sclerosis (ALS); idiopathic rapid eye movement sleep behavior disorder; and other conditions associated with central and/or peripheral α-synuclein accumulation in mammals accompanying a primary disease process.
The pharmaceutical composition of claim 1, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Vascular dementia, Frontotemporal dementia (FTD), Lewy body dementia (LBD), Mixed dementia, Posterior cortical atrophy (PCA), Primary progressive aphasia (PPA), Corticobasal degeneration (CBD), and Progressive supranuclear palsy (PSP), idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile　amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with　amyloidosis, Down's syndrome, Scrapie, medullary carcinoma of the thyroid, isolated atrial　amyloidosis, β₂-microglobulin　amyloidosis, inclusion body myositis, muscle wasting disease, Islets of Langerhans diabetes, Type 1 diabetes, insulinoma, Type 2 diabetes mellitus, hereditary cerebral hemorrhage　amyloidosis　(Dutch), amyloid A (reactive)　amyloidosis, secondary　amyloidosis, familial Mediterranean fever, familial amyloid nephropathy with urticaria and deafness (Muckle-wells Syndrome), amyloid lambda L-chain　amyloidosis, amyloid kappa L-chain　amyloidosis, idiopathic associated　amyloidosis, myeloma-associated　amyloidosis, macroglobulinemia-associated　amyloidosis, A beta 2M　amyloidosis　(chronic hemodialysis), ATTR　amyloidosis　(familial amyloid polyneuropathy (Portuguese, Japanese, Swedish)), familial amyloid cardiomyopathy (Danish), isolated cardiac　amyloidosis, systemic senile　amyloidosis, AIAPP or amylin insulinoma, atrial natriuretic factor　amyloidosis　(isolated atrial　amyloidosis), procalcitonin　amyloidosis　(medullary carcinoma of the thyroid), gelsolin　amyloidosis　(familial　amyloidosis　(Finnish)), cystatin C (hereditary cerebral hemorrhage with　amyloidosis　(Icelandic)), AApo-A-I　amyloidosis　(familial amyloidotic polyneuropathy-Iowa), AApo-A-II　amyloidosis, traumatic brain injury, fibrinogen-associated　amyloidosis, Creutzfeldt-Jakob disease, Gertsmann-Straussler-Scheinker syndrome, bovine spongiform encephalitis, condition associated with homozygosity for the apolipoprotein E4 allele, and Huntington's disease.
The pharmaceutical composition of claim 1, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson's Disease (PD), Parkinson's Disease Dementia (PDD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), and Lewy Body Variant of Alzheimer's Disease (LBV).
The pharmaceutical composition of claim 1, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Vascular dementia, Frontotemporal dementia (FTD), Lewy body dementia (LBD), Mixed dementia, Posterior cortical atrophy (PCA), Primary progressive aphasia (PPA), Corticobasal degeneration (CBD), and Progressive supranuclear palsy (PSP).
The pharmaceutical composition of claim 1, wherein the neurodegenerative disorder is selected from the group consisting of Dementia with Lewy Bodies and Alzheimer's disease.
The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for oral administration.
The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is in the form of a tablet or capsule.
The pharmaceutical composition of claim 1, wherein the Lamotrigine is present at a dosage of 25 to 300 mg/day and the Rivastigmine is present at a dosage of 1.0 to 15 mg/day.
The pharmaceutical composition of claim 1, wherein the Lamotrigine and Rivastigmine are formulated as a mixture in a single dosage form.
The pharmaceutical composition of claim 1, wherein the molar ratio of Rivastigmine to Lamotrigine is 1:20.
The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable carrier.
The pharmaceutical composition of claim 13, wherein the pharmaceutically acceptable carrier is selected from the group consisting of fillers, antioxidants, buffers, bacteriostats, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavors, glidants, release-controlling agents, wetting agents, stabilizers, suspending agents, and lubricants.
The pharmaceutical composition of claim 1, wherein the composition further includes another anti-neurodegenerative agent.
A pharmaceutical composition for the treatment of a neurodegenerative disorder, the composition comprising:

a therapeutically effective amount of Lamotrigine.
The pharmaceutical composition of claim 16, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson's disease (PD); sporadic or heritable dementia with Lewy bodies (DLB); pure autonomic failure (PAF) with αS deposition; multiple system atrophy (MSA); hereditary neurodegeneration with brain iron accumulation; and incidental Lewy body disease of advanced age; Alzheimer's disease of the Lewy body variant; Down's syndrome; progressive supranuclear palsy; essential tremor with Lewy bodies; familial parkinsonism with or without dementia resulting from a mutant gene and loci where no gene mutation has yet been identified; Creutzfeldt Jakob disease; bovine spongiform encephalopathy; secondary Parkinson disease/parkinsonism resulting from neurotoxin exposure/drug-induced parkinsonism with α-synuclein deposition; sporadic or heritable spinocerebellar ataxia; amyotrophic lateral sclerosis (ALS); idiopathic rapid eye movement sleep behavior disorder; and other conditions associated with central and/or peripheral α-synuclein accumulation in mammals accompanying a primary disease process.
The pharmaceutical composition of claim 16, wherein the neurodegenerative disorder is DLB.
A method of treating a neurodegenerative disorder, comprising:

administering to a subject in need thereof a therapeutically effective amount of Lamotrigine and a therapeutically effective amount of Rivastigmine.
The method of claim 19, wherein the molar ratio of Rivastigmine to Lamotrigine is in the range from 1:1 to 1:50.
The method of claim 19, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson's disease (PD); sporadic or heritable dementia with Lewy bodies (DLB); pure autonomic failure (PAF) with αS deposition; multiple system atrophy (MSA); hereditary neurodegeneration with brain iron accumulation; and incidental Lewy body disease of advanced age; Alzheimer's disease of the Lewy body variant; Down's syndrome; progressive supranuclear palsy; essential tremor with Lewy bodies; familial parkinsonism with or without dementia resulting from a mutant gene and loci where no gene mutation has yet been identified; Creutzfeldt Jakob disease; bovine spongiform encephalopathy; secondary Parkinson disease/parkinsonism resulting from neurotoxin exposure/drug-induced parkinsonism with α-synuclein deposition; sporadic or heritable spinocerebellar ataxia; amyotrophic lateral sclerosis (ALS); idiopathic rapid eye movement sleep behavior disorder; and other conditions associated with central and/or peripheral α-synuclein accumulation in mammals accompanying a primary disease process.
The method of claim 19, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Vascular dementia, Frontotemporal dementia (FTD), Lewy body dementia (LBD), Mixed dementia, Posterior cortical atrophy (PCA), Primary progressive aphasia (PPA), Corticobasal degeneration (CBD), and Progressive supranuclear palsy (PSP), idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile　amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with　amyloidosis, Down's syndrome, Scrapie, medullary carcinoma of the thyroid, isolated atrial　amyloidosis, β₂-microglobulin　amyloidosis, inclusion body myositis, muscle wasting disease, Islets of Langerhans diabetes, Type 1 diabetes, insulinoma, Type 2 diabetes mellitus, hereditary cerebral hemorrhage　amyloidosis　(Dutch), amyloid A (reactive)　amyloidosis, secondary　amyloidosis, familial Mediterranean fever, familial amyloid nephropathy with urticaria and deafness (Muckle-wells Syndrome), amyloid lambda L-chain　amyloidosis, amyloid kappa L-chain　amyloidosis, idiopathic associated　amyloidosis, myeloma-associated　amyloidosis, macroglobulinemia-associated　amyloidosis, A beta 2M　amyloidosis　(chronic hemodialysis), ATTR　amyloidosis　(familial amyloid polyneuropathy (Portuguese, Japanese, Swedish)), familial amyloid cardiomyopathy (Danish), isolated cardiac　amyloidosis, systemic senile　amyloidosis, AIAPP or amylin insulinoma, atrial natriuretic factor　amyloidosis　(isolated atrial　amyloidosis), procalcitonin　amyloidosis　(medullary carcinoma of the thyroid), gelsolin　amyloidosis　(familial　amyloidosis　(Finnish)), cystatin C (hereditary cerebral hemorrhage with　amyloidosis　(Icelandic)), AApo-A-I　amyloidosis　(familial amyloidotic polyneuropathy-Iowa), AApo-A-II　amyloidosis, traumatic brain injury, fibrinogen-associated　amyloidosis, Creutzfeldt-Jakob disease, Gertsmann-Straussler-Scheinker syndrome, bovine spongiform encephalitis, condition associated with homozygosity for the apolipoprotein E4 allele, and Huntington's disease.
The method of claim 19, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson's Disease (PD), Parkinson's Disease Dementia (PDD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), and Lewy Body Variant of Alzheimer's Disease (LBV).
The method of claim 19, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Vascular dementia, Frontotemporal dementia (FTD), Lewy body dementia (LBD), Mixed dementia, Posterior cortical atrophy (PCA), Primary progressive aphasia (PPA), Corticobasal degeneration (CBD), and Progressive supranuclear palsy (PSP).
The method of claim 19, wherein the neurodegenerative disorder is selected from the group consisting of Dementia with Lewy Bodies and Alzheimer's disease.
The method of claim 19, wherein the Lamotrigine is administered at a dosage of 25 to 300 mg/day and the Rivastigmine is administered at a dosage of 1.0 to 15 mg/day.
The method of claim 19, wherein the Lamotrigine and Rivastigmine are administered orally.
The method of claim 19, wherein the Lamotrigine and Rivastigmine are administered as a single dosage form.
The method of claim 28, wherein the single dosage form is a tablet or capsule.
The method of claim 19, wherein the molar ratio of Rivastigmine to Lamotrigine is 1:20.
A method of treating a neurodegenerative disorder, comprising:

administering to a subject in need thereof a therapeutically effective amount of Lamotrigine.
The method of claim 31, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson's disease (PD); sporadic or heritable dementia with Lewy bodies (DLB); pure autonomic failure (PAF) with αS deposition; multiple system atrophy (MSA); hereditary neurodegeneration with brain iron accumulation; and incidental Lewy body disease of advanced age; Alzheimer's disease of the Lewy body variant; Down's syndrome; progressive supranuclear palsy; essential tremor with Lewy bodies; familial parkinsonism with or without dementia resulting from a mutant gene and loci where no gene mutation has yet been identified; Creutzfeldt Jakob disease; bovine spongiform encephalopathy; secondary Parkinson disease/parkinsonism resulting from neurotoxin exposure/drug-induced parkinsonism with α-synuclein deposition; sporadic or heritable spinocerebellar ataxia; amyotrophic lateral sclerosis (ALS); idiopathic rapid eye movement sleep behavior disorder; and other conditions associated with central and/or peripheral α-synuclein accumulation in mammals accompanying a primary disease process.
The method of claim 31, wherein the neurodegenerative disorder is DLB.
A kit for the treatment of a neurodegenerative disorder, the kit comprising:

a formulation containing Lamotrigine;

a formulation containing Rivastigmine; and

instructions for administering the formulations, wherein the molar ratio of Rivastigmine to Lamotrigine when administered is in the range from 1:1 to 1:50.
The kit of claim 34, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson's disease (PD); sporadic or heritable dementia with Lewy bodies (DLB); pure autonomic failure (PAF) with αS deposition; multiple system atrophy (MSA); hereditary neurodegeneration with brain iron accumulation; and incidental Lewy body disease of advanced age; Alzheimer's disease of the Lewy body variant; Down's syndrome; progressive supranuclear palsy; essential tremor with Lewy bodies; familial parkinsonism with or without dementia resulting from a mutant gene and loci where no gene mutation has yet been identified; Creutzfeldt Jakob disease; bovine spongiform encephalopathy; secondary Parkinson disease/parkinsonism resulting from neurotoxin exposure/drug-induced parkinsonism with α-synuclein deposition; sporadic or heritable spinocerebellar ataxia; amyotrophic lateral sclerosis (ALS); idiopathic rapid eye movement sleep behavior disorder; and other conditions associated with central and/or peripheral α-synuclein accumulation in mammals accompanying a primary disease process.
The kit of claim 34, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Vascular dementia, Frontotemporal dementia (FTD), Lewy body dementia (LBD), Mixed dementia, Posterior cortical atrophy (PCA), Primary progressive aphasia (PPA), Corticobasal degeneration (CBD), and Progressive supranuclear palsy (PSP), idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile　amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with　amyloidosis, Down's syndrome, Scrapie, medullary carcinoma of the thyroid, isolated atrial　amyloidosis, β₂-microglobulin　amyloidosis, inclusion body myositis, muscle wasting disease, Islets of Langerhans diabetes, Type 1 diabetes, insulinoma, Type 2 diabetes mellitus, hereditary cerebral hemorrhage　amyloidosis　(Dutch), amyloid A (reactive)　amyloidosis, secondary　amyloidosis, familial Mediterranean fever, familial amyloid nephropathy with urticaria and deafness (Muckle-wells Syndrome), amyloid lambda L-chain　amyloidosis, amyloid kappa L-chain　amyloidosis, idiopathic associated　amyloidosis, myeloma-associated　amyloidosis, macroglobulinemia-associated　amyloidosis, A beta 2M　amyloidosis　(chronic hemodialysis), ATTR　amyloidosis　(familial amyloid polyneuropathy (Portuguese, Japanese, Swedish)), familial amyloid cardiomyopathy (Danish), isolated cardiac　amyloidosis, systemic senile　amyloidosis, AIAPP or amylin insulinoma, atrial natriuretic factor　amyloidosis　(isolated atrial　amyloidosis), procalcitonin　amyloidosis　(medullary carcinoma of the thyroid), gelsolin　amyloidosis　(familial　amyloidosis　(Finnish)), cystatin C (hereditary cerebral hemorrhage with　amyloidosis　(Icelandic)), AApo-A-I　amyloidosis　(familial amyloidotic polyneuropathy-Iowa), AApo-A-II　amyloidosis, traumatic brain injury, fibrinogen-associated　amyloidosis, Creutzfeldt-Jakob disease, Gertsmann-Straussler-Scheinker syndrome, bovine spongiform encephalitis, condition associated with homozygosity for the apolipoprotein E4 allele, and Huntington's disease.
The kit of claim 34, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson's Disease (PD), Parkinson's Disease Dementia (PDD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), and Lewy Body Variant of Alzheimer's Disease (LBV).
The kit of claim 34, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Vascular dementia, Frontotemporal dementia (FTD), Lewy body dementia (LBD), Mixed dementia, Posterior cortical atrophy (PCA), Primary progressive aphasia (PPA), Corticobasal degeneration (CBD), and Progressive supranuclear palsy (PSP).
The kit of claim 34, wherein the neurodegenerative disorder is selected from the group consisting of Dementia with Lewy Bodies and Alzheimer's disease.
The kit of claim 34, wherein the Lamotrigine formulation is configured for administration at a dosage of 25 to 300 mg/day and the Rivastigmine formulation is configured for administration at a dosage of 1.0 to 15 mg/day.
The kit of claim 34, wherein the Lamotrigine formulation and the Rivastigmine formulation are each in the form of tablets or capsules, and wherein the instructions indicate that the Lamotrigine formulation and the Rivastigmine formulation are to be administered orally.
A kit for the treatment of a neurodegenerative disorder, the kit comprising:

a formulation containing Lamotrigine; and

instructions for administering the formulation.
The kit of claim 42, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson's disease (PD); sporadic or heritable dementia with Lewy bodies (DLB); pure autonomic failure (PAF) with αS deposition; multiple system atrophy (MSA); hereditary neurodegeneration with brain iron accumulation; and incidental Lewy body disease of advanced age; Alzheimer's disease of the Lewy body variant; Down's syndrome; progressive supranuclear palsy; essential tremor with Lewy bodies; familial parkinsonism with or without dementia resulting from a mutant gene and loci where no gene mutation has yet been identified; Creutzfeldt Jakob disease; bovine spongiform encephalopathy; secondary Parkinson disease/parkinsonism resulting from neurotoxin exposure/drug-induced parkinsonism with α-synuclein deposition; sporadic or heritable spinocerebellar ataxia; amyotrophic lateral sclerosis (ALS); idiopathic rapid eye movement sleep behavior disorder; and other conditions associated with central and/or peripheral α-synuclein accumulation in mammals accompanying a primary disease process.
The kit of claim 42, wherein the neurodegenerative disorder is DLB.