Treatment of neurodegenerative disorders with doxycycline alone or in combination with levodopa

Abstract

Provided herein are methods of treating a neurodegenerative disorder (e.g., Parkinson's Disease), or a symptom thereof, in a patient by administering doxycycline (or a pharmaceutically acceptable salt thereof) to the patient either alone or in combination with other therapeutic agents (e.g., levodopa).

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 484,286, filed on February 10, 2023. The entire contents of the foregoing application are incorporated herein by reference. Background Art

[0003] Neurodegenerative disorders affect millions of people worldwide, and the main feature is neuronal loss. The most common neurodegenerative disorders are Alzheimer's disease and Parkinson's disease (PD). Although there are currently several drugs approved for the management of neurodegenerative disorders, most of them only help with related symptoms. In addition, although surgery and other techniques have achieved some therapeutic success, due to potential damage to the brain barrier, these methods are still limited in clinical acceptance due to different concerns about their long-term benefits (see, for example, Lamptey RNL et al., "Common Neurodegenerative Disorders Review: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics", International Journal of Molecular Sciences (Int. J. Mol. Sci.) February 6, 2022; 23 (3): 1851). The lack of treatments targeting the pathogenesis is primarily due to the restrictive effects of the blood-brain barrier (BBB), which excludes nearly 99% of all "foreign substances" from the brain. The highly developed nature of the BBB, coupled with the poor penetration of most, if not all, drugs, has led to a lack of therapeutic options for neurodegenerative disorders.

[0004] It is therefore an object of the present disclosure to provide improved methods for treating patients suffering from neurodegenerative disorders, and in particular PD. Summary of the Invention

[0005] Provided herein are methods for treating various neurodegenerative disorders or symptoms by administering doxycycline (or a pharmaceutically acceptable salt thereof), alone or in combination with other therapeutic agents (eg, levodopa), to a patient in need thereof.

[0006] Exemplary neurodegenerative disorders include, but are not limited to, amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease (PD), supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, frontotemporal neurocognitive disorder, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment caused by Alzheimer's disease, ataxia, motor neuron disease, multiple system atrophy, hereditary ataxia, dementia, memory loss, mental retardation, Rett Syndrome, progressive supranuclear palsy, Creutzfeldt-Jakob disease, neurofibromatosis, brain injury, stroke, multiple sclerosis, and α-synuclein disease (e.g., Lewy body disease). In one embodiment, the neurodegenerative disorder is Alzheimer's disease. In another embodiment, the neurodegenerative disorder is PD.

[0007] Exemplary symptoms include, but are not limited to, movement abnormalities, balance abnormalities, movement abnormalities (e.g., tremors), swallowing abnormalities, bladder and bowel dysfunction (e.g., irritable bowel, abdominal pain, abdominal discomfort, diarrhea, abdominal bloating, abdominal gas, abdominal distension, and / or constipation), blood pressure fluctuations, sleep abnormalities, breathing abnormalities (e.g., shortness of breath), heart function abnormalities (e.g., palpitations), memory abnormalities, cognitive abnormalities, mood abnormalities, speech abnormalities, anxiety disorders, depression, stress, fatigue, feelings of panic, fear, restlessness, sleep problems, cold or sweaty hands and / or feet, mood swings, mania, impaired concentration or attention, cognitive problems, obsessions, compulsive behaviors, repetitive behaviors, aggression, social phobias or disorders, stage fright, inability to stay still and calm, dry mouth, numbness or tingling in the hands or feet, nausea, muscle tension, dizziness, apathy, euphoria, disinhibition, irritability, wandering, and / or combinations thereof.

[0008] Doxycycline (or a pharmaceutically acceptable salt thereof) can be administered to a patient by any suitable means. In one embodiment, doxycycline is formulated as a powder for suspension. In another embodiment, doxycycline is formulated as a capsule (e.g., extended release). In another embodiment, doxycycline is formulated as a tablet (e.g., delayed release). In another embodiment, doxycycline is formulated as a syrup.

[0009] In some embodiments, doxycycline is administered to the patient in a therapeutically active amount. In some embodiments, doxycycline is administered to the patient in a dose of between 50 mg and 200 mg once daily (e.g., 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg). In one embodiment, doxycycline is administered in a dose of 50 mg once daily. In another embodiment, doxycycline is administered in a dose of 100 mg once daily. In another embodiment, the patient is an adult patient and doxycycline is administered at a dose of 100 mg every 12 hours on the first day, followed by 100 mg once daily or 50 mg to 100 mg (e.g., 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg) every 12 hours. In another embodiment, doxycycline is administered to the patient at a subtherapeutic dose.

[0010] In some embodiments, the patient has previously been treated with levodopa (or a pharmaceutically acceptable salt thereof). For example, in some embodiments, the patient has been treated with levodopa for 3 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, or more prior to treatment according to the methods described herein.

[0011] Also provided herein are methods of treating a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor) in a patient by administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof) in combination with a therapeutically active amount of levodopa (or a pharmaceutically acceptable salt thereof). In one embodiment, doxycycline and levodopa are administered simultaneously. In another embodiment, doxycycline and levodopa are administered in chronological order. For example, in one embodiment, levodopa is administered prior to administering doxycycline. In another embodiment, doxycycline is administered prior to administering levodopa.

[0012] Levodopa (or a pharmaceutically acceptable salt thereof) can be administered to a patient by any suitable means. In one embodiment, levodopa is formulated as an oral tablet or capsule. In another embodiment, levodopa is formulated as an oral inhaler. In another embodiment, levodopa is formulated as an infusion.

[0013] In some embodiments, levodopa (or a pharmaceutically acceptable salt thereof) is administered to the patient in a therapeutically active amount. In some embodiments, levodopa is administered in combination (e.g., separately or in a single formulation) with the drug carbidopa, which reduces or prevents nausea that may be caused by levodopa alone.

[0014] In one embodiment, levodopa is administered at a total dose of 100 mg to 1,000 mg of levodopa per day (e.g., in divided doses 3 to 4 times a day in the form of immediate-release tablets). For example, levodopa can be administered at the following doses: 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg.

[0015] In another embodiment, levodopa is administered at a total daily dose of 100 mg to 1,600 mg (e.g., in divided doses as a controlled-release tablet). For example, levodopa can be administered at the following doses: 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg. In a specific embodiment, levodopa is administered at a dose of 100 mg once daily.

[0016] In another embodiment, levodopa is administered in a total daily dose of 100 mg to 1,000 mg (eg, in divided doses 3 to 4 times a day as an orally disintegrating tablet).

[0017] In another embodiment, levodopa is administered in doses up to 2,000 mg over 16 hours (eg, as an enteral suspension). For example, levodopa can be administered at a dose of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, or 2000 mg. In a specific embodiment, levodopa is administered in a dose of 100 mg once daily.

[0018] In another embodiment, levodopa is administered in a total daily dose of 855 mg to 2,340 mg levodopa (eg, administered in divided doses in extended-release capsules).

[0019] In another embodiment, levodopa is administered at a total daily dose of 100 mg to 1,600 mg (e.g., in tablet form). For example, levodopa can be administered at doses of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, or 1600 mg.

[0020] In another embodiment, levodopa is administered up to five times daily at a dose of 42 mg to 84 mg (e.g., in the form of an inhaled powder capsule). For example, levodopa can be administered at the following doses: 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, or 84 mg. In one embodiment, levodopa is administered once daily, twice daily, three times daily, four times daily, or five times daily.

[0021] In another embodiment, levodopa is administered to said patient in a subtherapeutic dose.

[0022] Also provided herein are methods of treating a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor) in a patient by administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof) in combination with a therapeutically active amount of levodopa (or a pharmaceutically acceptable salt thereof), wherein the combined administration of doxycycline and levodopa results in a synergistic therapeutic effect compared to administration of either doxycycline or levodopa alone.

[0023] Doxycycline or levodopa alone was administered.

[0024] Further provided are methods of treating a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor) in a patient by administering doxycycline (or a pharmaceutically acceptable salt thereof) in combination with levodopa, wherein a dose of doxycycline or levodopa that is typically subtherapeutic alone is rendered effective by the combination. Thus, when doxycycline and levodopa are administered in combination, doses of doxycycline below the standard therapeutic dose and / or doses of levodopa below the standard therapeutic dose that are typically not therapeutically effective in humans are found to be therapeutically effective. In other words, by administering doxycycline and levodopa in combination, at least one or both of doxycycline and / or levodopa can be administered at a subtherapeutic dose while still producing similar efficacy.

[0025] Thus, in one aspect, a method of treating a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor) in a patient is provided, the method comprising administering to the patient a combination of doxycycline (or a pharmaceutically acceptable salt thereof) and levodopa (or a pharmaceutically acceptable salt thereof), wherein at least one of the doxycycline and / or levodopa is administered at a subtherapeutic dose. In some embodiments, the subtherapeutic dose of doxycycline and / or the subtherapeutic dose of levodopa is a dose that is lower than the dose of doxycycline and / or the dose of levodopa required to achieve a therapeutic effect in the patient when administered alone.

[0026] The efficacy of the therapeutic methods provided herein can be assessed using any suitable means. In one embodiment, the neurodegenerative disorder is PD, and the treatment results in an improvement according to a recognized clinical scale for assessing PD. For example, in one embodiment, the neurodegenerative disorder is PD, and the treatment results in an improvement according to the Unified Parkinson's Disease Rating Scale (UPDRS). On the UPDRS scale, a score of 199 represents the worst (complete disability) and a score of zero represents (no disability). Thus, in one embodiment, the treatment results in a decrease in score of, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 199 points compared to baseline. In another embodiment, the treatment results in a decrease in score of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% compared to baseline.

[0027] In another embodiment, the neurodegenerative disorder is PD and the treatment results in an improvement according to the Hoehn and Yahr Staging Scale. The Hoehn and Yahr Staging Scale includes 7 different stages ranging from no disease (Stage 1) to wheelchair or bed confined (Stage 5), i.e., Stage 0, Stage 1, Stage 1.5, Stage 2, Stage 2, Stage 2.5, Stage 3, Stage 4, and Stage 5. In one embodiment, the treatment results in a decrease in one or more stages (e.g., a decrease of one, two, three, four, five, six, seven, or eight stages) compared to baseline.

[0028] In another embodiment, the neurodegenerative disorder is PD and the treatment results in an improvement on the Schwab and England Rating of Activities of Daily Living. This rating ranges from 0% (complete independence) to 100% (vegetative function) in 10% increments and includes 11 possible ratings, namely 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and 100%. In one embodiment, the treatment results in a decrease in one or more ratings (e.g., a decrease in one, two, three, four, five, six, seven, eight, one or ten ratings) compared to baseline.

[0029] In some embodiments, the neurodegenerative disorder is PD, and the treatment causes an improvement in tremor (e.g., a reduction in tremor), such as a reduction of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. The improvement can be assessed by any suitable means, including but not limited to electromyography (EMG), electromagnetic motion tracker, non-contact measurement results obtained from a device (e.g., Kinect), laser Doppler vibrometer, accelerometer, gyroscope, or smart wearable technology device.

[0030] Doxycycline (or a pharmaceutically acceptable salt thereof) can be administered according to the methods described herein: (1) alone; (2) in combination with levodopa (or a pharmaceutically acceptable salt thereof); (3) in combination with one or more other therapeutic agents; or (4) in combination with levodopa and one or more other therapeutic agents.

[0031] Any other suitable therapeutic agent may be administered. In one embodiment, the other therapeutic agent is a Kv7 channel activator (eg, retigabine, flupirtine, or an endocannabinoid-like molecule).

[0032] In another embodiment, the other therapeutic agent is an anti-α-synuclein antibody (e.g., "Syn204" from Abeam, "15G 7" from Alexis, "42" from Becton Dickinson, "7B 2, 12" from Chemicon, "KM51" from NovaCastra, "Syn211" from Santa Cruz, or "LB509" from Zymed).

[0033] In another embodiment, the additional therapeutic agent is a decarboxylase inhibitor, such as carbidopa.

[0034] In another embodiment, the additional therapeutic agent is a dopamine agonist (e.g., bromocriptine (Parlodel, ), Cabergoline, Apokyn, ), Mirapex, ), Requip, ) or Neupro, )).

[0035] In another embodiment, the additional therapeutic agent is a monoamine oxidase (MAO) B inhibitor (e.g., socarboxazid, ), phenelzine Selegiline ), Tranylcypromine ), Selegiline hydrochloride Selegiline hydrochloride Rasagiline ) or SAFINAMIDE ( )).

[0036] In another embodiment, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor (e.g., entacapone, ), nebicapone, nitecapone, opicapone, ) or tolcapone )).

[0037] In another embodiment, the additional therapeutic agent is an anticholinergic agent (e.g., (1) an antimuscarinic agent, such as an antipsychotic Atropine, benztropine ), biperiden, chlorpheniramine, some SSRIs Dicyclomine dimenhydrinate, diphenhydramine, doxepin, doxylamine, flavoxate, glycopyrronium / -late, hyoscyamine, ipratropium, orphenadrine, oxitropium, oxybutynin, promethazine, propantheline bromide bromide, scopolamine, solifenacin, tolterodine, tiotropium, tricyclic antidepressants, trihexyphenidyl, amantadine, tropicamide, and umeclidinium; or (2) antinicotinic agents, such as bupropion, dextromethorphan, doxacurium, dexamethonium, mecamylamine, and tubocurarine).

[0038] In another embodiment, the additional therapeutic agent is an adenosine receptor antagonist (A2A receptor antagonist) (e.g., caffeine, theophylline, or istradefylline, ) or pimavanserin (Nuplazid, )).

[0039] In another embodiment, the additional therapeutic agent is a TNF-α targeting agent or inhibitor (e.g., liximab, ), adalimumab (adalimumab, ), certolizumab pegol ), golimumab ( ) and etanercept )).

[0040] In another embodiment, the additional therapeutic agent is an IL17A targeting agent or inhibitor (e.g., Secukinumab, ), Ixekizumab ), Bimekizumab, ) or brodalumab (Brodalumab, )).

[0041] In another embodiment, the additional therapeutic agent is deep brain stimulation.

[0042] Further provided are kits comprising a dose of doxycycline suitable for use in the methods described herein, e.g., for effectively treating a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor). In one embodiment, the kit comprises: (a) a dose of doxycycline; and (b) instructions for using doxycycline in the methods described herein. In another embodiment, the kit comprises: (a) a dose of doxycycline, (b) a dose of levodopa, and (c) instructions for using doxycycline and levodopa in the methods described herein. In one embodiment, the dose of doxycycline is a therapeutically effective amount. In one embodiment, the dose of levodopa is a therapeutically effective amount. In one embodiment, the dose of doxycycline and / or levodopa is a subtherapeutic dose.

[0043] Also provided is the use of doxycycline for treating a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor), wherein doxycycline (or a pharmaceutically acceptable salt thereof) is administered to the patient in an amount and frequency sufficient to treat the neurodegenerative disorder or symptom. Further provided is the use of a combination of doxycycline and levodopa (or a pharmaceutically acceptable salt thereof) for treating a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor), wherein doxycycline and levodopa are administered to the patient in an amount and frequency sufficient to treat the neurodegenerative disorder or symptom. In one embodiment, the combination of doxycycline and levodopa produces a synergistic therapeutic effect compared to the administration of doxycycline or levodopa alone. In another embodiment, the combination of doxycycline and levodopa allows for the administration of doxycycline and / or levodopa at subtherapeutic doses. DETAILED DESCRIPTION

[0044] The following detailed description is provided to assist those skilled in the art in practicing the present invention. Exemplary embodiments are described in detail below. However, these embodiments are merely exemplary, and the present disclosure is not limited thereto but rather by the scope of the appended claims. Modifications and variations to the embodiments described herein may be made by those skilled in the art without departing from the spirit or scope of the present disclosure.

[0045] Thus, the embodiments are merely described below, by referring to the constructions and arrangements, to explain aspects of the present description.

[0046] I. definition

[0047] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. The term "or" means "and / or." Expressions such as "at least one of..." that precede a list of elements modify the entire list of elements and do not modify the individual elements of the list.

[0048] It will be understood that when an element is referred to as being "on" another element, it can be directly in contact with the other element or intervening elements may be present therebetween. In contrast, when an element is referred to as being "directly on" another element, there are no intervening elements present.

[0049] It will be understood that although the terms first, second, third, etc. can be used to describe various elements, components, regions, layers and / or parts in this article, these elements, components, regions, layers and / or parts should not be limited by these terms. These terms are only used to distinguish an element, component, region, layer or part from another element, component, region, layer or part. Therefore, without departing from the teaching of the present embodiment, the first element, component, region, layer or part discussed below can be referred to as the second element, component, region, layer or part.

[0050] It will be understood that when used in this specification, the terms “comprises” and / or “comprising” or “includes” and / or “including” specify the presence of stated features, regions, integers, steps, operations, elements and / or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components and / or groups thereof.

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this disclosure belongs. The terms used in this specification are only used to describe specific embodiments and are not intended to be limiting. It will be further understood that terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant art and in this disclosure, and will not be interpreted in an idealized or overly formal sense unless explicitly defined as such herein.

[0052] As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application. Where a term is not specifically defined herein, it is to be given its art-recognized meaning as applied by one of ordinary skill in the art to the context in which it is used to describe the present invention.

[0053] Unless the context clearly indicates otherwise, the articles "a" and "an" refer to one or to more than one (ie, to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0054] II. Neurodegenerative conditions and symptoms

[0055] Neurons are essential for the normal function of the human brain because they play a key role in information transmission (see, for example, Lamptey RNL et al., 2022; and Van den Heuvel MP et al., "Network hubs in the human brain", Trends Cogn. Sci. 2013; 17: 683-696). Although most neurons originate in the brain, they are present throughout the body. In childhood, neural stem cells produce most neurons, and in adulthood, the number of neurons decreases significantly (see, for example, Ganat YM et al., "Early postnatal astroglial cells produce multilineage precursors and neural stem cells in vivo", J. Neurosci. 2006; 26: 8609-862). Neurons are not immortal. However, the progressive loss of neurons, neuronal structure and / or their function (referred to as "neurodegeneration") is at the heart of the pathophysiology of various brain disorders and remains a significant health concern (see, e.g., Przedborski S. et al., "Series Introduction: Neurodegeneration: What is it and where are we?", J. Clin. Investig. 2003; 111: 3-10). Neurodegeneration is associated with synaptic and neural network dysfunction and the deposition of physiochemically altered protein variants in the brain. Diseases characterized by neurodegeneration are collectively referred to as ND (see, e.g., Lamptey RNL et al., 2022).

[0056] Any neurodegenerative disorder or symptom can be treated according to the methods described herein. Exemplary neurodegenerative disorders include, but are not limited to, amyotrophic lateral sclerosis (ALS), Huntington's disease, PD, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment caused by Alzheimer's disease, ataxia, hereditary ataxia, dementia, memory loss, mental retardation, and Rett syndrome.

[0057] The methods described herein can also be used to treat one or more symptoms of a neurodegenerative disorder. Exemplary neurodegenerative disorders include, but are not limited to, anxiety, depression, stress, fatigue, feelings of panic, fear, restlessness, sleep problems, cold or sweaty hands and / or feet, mood swings, mania, impaired concentration or attention, cognitive problems, obsessions, compulsive behaviors, repetitive behaviors, aggression, social phobias or disorders, stage fright, shortness of breath, palpitations, inability to remain still and calm, dry mouth, numbness or tingling in the hands or feet, nausea, muscle tension, dizziness, apathy, euphoria, disinhibition, irritability, wandering, irritable bowel, abdominal pain, abdominal discomfort, diarrhea, changes in bowel habits, abdominal bloating, abdominal gas, abdominal distension, and / or constipation.

[0058] A. Parkinson's disease

[0059] PD is a neurodegenerative disease that typically develops around age 60 and causes slow movement (bradykinesia), muscle stiffness (rigidity), tremors, poor postural stability, a low, weak voice, a dragging gait, sudden cessation of movement (called freezing), and decreased spontaneous movement (akinesia) (see, e.g., Fahn S., "Description of Parkinson's disease as a clinical syndrome," Ann. NY Acad. Sci. 2003; 991: 1-14). Motor manifestations typically begin on one side of the body, only later affecting the other side as well (see, e.g., Rajput AH et al., "Accuracy of clinical diagnosis in parkinsonism—A prospective study," Can. J. Neurol. Sci. 1991; 18: 275-278). The underlying degeneration of dopaminergic nigrostriatal neurons and subsequent striatal dopamine deficiency forms the basis of pharmacotherapy (see, e.g., McColl CD et al., "Motor response to levodopa and the evolution of motor fluctuations in the first decade of treatment of Parkinson's disease," Mov. Disord. 2002; 17: 1227-1234).

[0060] As used herein, the term "tremor" refers to involuntary, oscillatory, and rhythmic movements produced by the synchronous or alternating contraction of agonist / antagonist muscles (see, e.g., Sigcha L et al., "Automatic Resting Tremor Assessment in Parkinson's Disease Using Smartwatches and Multitask Convolutional Neural Networks," Sensors (Basel). 2021 Jan 4; 21(1): 291). Tremors can occur in the hands, head, trunk, or legs (see, e.g., Puschmann A. et al., "Diagnosis and Treatment of Common Forms of Tremor," Semin. Neurol. 2011; 31: 65-77). In PD, tremor can appear in the early stages of the disease and reduce quality of life by interfering with activities such as reading, writing, and eating (see, e.g., Hssayeni MD et al., "Wearable Sensors for Estimation of Parkinsonian Tremor Severity during Free Body Movements," Sensors. 2019;19:4215). More than 70% of all PD patients experience resting tremor during the course of the disease, and the effects of tremor tend to become more severe with age (see, e.g., Baumann CR, "Epidemiology, diagnosis and differential diagnosis in Parkinson's disease tremor," Parkinsonism Relat. Disord. 2012;18:S90-S92).Tremor in PD can be divided into: (1) resting tremor, which occurs when the patient relaxes his muscles; and (2) action tremor (postural and kinetic), which occurs when the subject makes voluntary muscle movements (see, e.g., Bhidayasiri R., "Differential Diagnosis of Common Tremor Syndromes", Postgrad. Med. J. 2005;81:756-762).

[0061] Exemplary technologies for assessing tremor in PD include, but are not limited to, sensor technologies such as electromyography (EMG) (see, e.g., Mailankody P. et al., “Re-emergent tremor in Parkinson's disease: A clinical and electromyographic study,” J. Neurol. Sci. 2016;366:33–36; Palmes P. et al., “Pattern Mining of Multichannel sEMG for Tremor Classification,” IEEE Trans. Biomed. Eng. 2010;57:2795-2805; and Kwon K. et al., “Comparison of motor and non-motor features between essential tremor and tremor dominant Parkinson's disease.” disease,” J Neurosci 2016;361:34-38), electromagnetic motion trackers (see, e.g., Perera T. et al., “Clinical validation of a precision electromagnetic tremor measurement system in participants receiving deep brain stimulation for essential tremor,” Physiol. Meas. 2016;37:1516-1527), contactless measurements from devices such as Kinect (see, e.g., Sooklal S.et al., “Using the Kinect for detecting tremors: Challenges and opportunities”; Proceedings of the IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI); Valencia, Spain. June 1-4, 2014; pp. 768-771), laser Doppler vibrometers (see, e.g., Sooklal S. et al., “Using the Kinect for detecting tremors: Challenges and opportunities”; Proceedings of the IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI); Valencia, Spain. June 1-4, 2014; pp. 768-771), accelerometers or gyroscopes (see, e.g., Ossig AAC et al., “Wearable sensor-based objective assessment of motor symptoms in Parkinson’s disease” Motor symptoms in Parkinson's disease," Journal of Neurotransmission (J. Neural Transm.), 2016; 123:57-64; and Rovini E. et al., "How Wearable Sensors Can Support Parkinson's Disease Diagnosis and Treatment: A Systematic Review," Frontiers in Neuroscience (Front. Neurosci.), 2017; 11:555) and smart wearable technology.

[0062] Several scales have been established as a way to assess the severity of PD, for example by measuring motor performance, assessing the ability to perform daily functional activities, and symptomatic response to medication. The most commonly used rating scales are the Unified Parkinson's Disease Rating Scale (UPDRS), the Hoehn and Yahr Staging Scale, and the Schwab and England Activities of Daily Living Assessment (see, e.g., Perlmutter JS, "Assessment of Parkinson disease manifestations," Curr. Protoc Neurosci. October 2009; Chapter 10: Unit 10.1).

[0063] The Unified Parkinson's Disease Rating Scale (UPDRS) is the most widely accepted tool for evaluating interventions and following up on patients (see, e.g., Martinez-Martin P et al., "The Cooperative Multicentric Group Unified Parkinson's Disease Rating Scale characteristics and structure," Mobility Disorders 1994; 9:76-8). A detailed description of the UPDRS is set forth in Perlmutter JS ("Assessment of Parkinson's Disease Manifestations," Current Neuroscience Protocols October 2009; Chapter 10: Unit 10.1), the contents of which are expressly incorporated herein by reference.

[0064] The current UPDRS consists of four subscales. Subscale 1 covers psychological state, behavior, and mood. Subscale 2 assesses activities of daily living. Subscale 3 is the clinician's assessment of motor performance in PD. Subscale 4 covers complications of therapy. Data for subscales 1, 2, and 4 are collected from patients and caregivers, while data for subscale 3 are based on examinations. Training videos are available for UPDRS subscales 2 and 3, and viewing these videos can improve measurement reliability (see, e.g., Goetz CG et al., "Standardized training tools for the UPDRS activities of daily living scale: Newly available teaching program," Mobil Disord 2003;18:1455-1458; Goetz CG et al., "Teaching tape for the motor section of the unified Parkinson's disease rating scale," Mobil Disord 1995;10:263-266; and e.g., Goetz CG et al., "Assuring interrater reliability for the UPDRS motor section: Utility of the UPDRS teaching tape," Mobil Disord 2004;19:1453-1456). However, the reliability of the other subscales depends on patient reporting and examiner skill, but there are training videos for subscale 2 of the activities of daily living section (see, for example, Louis ED et al., "Reliability of patient completion of the historical section of the Unified Parkinson's Disease Rating Scale", "Mobility Disorders" 1996; 11: 185-192). The UPDRS total score and UPDRS subscale scores are not equal interval scales, which means that there is no quantitative, equal distance between the values ​​on these scales. For example, a score of 4 is greater than a score of 2, but it does not necessarily indicate that the severity is twice as great. Each part of the assessment is a rank order measurement, not an exact equal interval change. This must be taken into account when using these data for statistical analysis.Some sections of the UPDRS scale require that each limb be assigned multiple grades, with a possible maximum of 199. On the UPDRS scale, a score of 199 represents the worst possible outcome (total disability) and a score of zero represents the worst possible outcome (no disability).

[0065] The Hoehn and Yahr scale is the first rating scale for describing the progression of PD and describes the five stages of PD progression. The motor performance of PD was simply graded from 0 to 5, aiming to reflect the degree of progression and combining the characteristics of movement disorders and disability. However, the scale is not linear and may not even be ranked, with some people being classified as stage 3 (falling in the traction test, but with relatively mild bradykinesia and stiffness) compared to those who are in stage 2 (significant bradykinesia, but with good stability in the traction test) with higher disability. The assessment was subsequently revised to include two and a half scores, as shown in Table 1 below (see Goetz CG et al., Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: Status and recommendations. "Mobility Disorders" 2004; 19: 1020-1028).

[0066] Table 1: Revised Hoehn and Yahr Scale

[0067]

[0068]

[0069] The Schwab and England Scale is an Activities of Daily Living (ADL) scale that is often used to provide a single estimate of a patient's functional ability. This assessment is made by interviewing the patient and often by a collateral source, such as a spouse. This assessment ranges from 0% to 100% in 5% increments and is shown in Table 2 below.

[0070] Table 2: Schwab and England Scales

[0071]

[0072] III. Doxycycline and its pharmaceutically acceptable salts

[0073] As used herein, the term doxycycline ( ADOXA ADOXA ADOXA VIBRAMYCIN VIBRAMYCIN and ) include doxycycline and its pharmaceutically acceptable salts. Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline. It is included in the World Health Organization's list of essential medicines and is available as a generic drug.

[0074] Doxycycline belongs to a class of drugs known as tetracycline antibiotics. It is a second-generation tetracycline, first discovered in 1967. Second-generation tetracyclines exhibit less toxicity than first-generation tetracyclines. Doxycycline is used to treat a variety of gram-positive and gram-negative bacterial infections.

[0075] Doxycycline is a broad-spectrum tetracycline antibiotic used to treat infections caused by bacteria and certain parasites. According to the National Library of Medicine of the National Institute of Health, doxycycline is also used to treat or prevent anthrax (a serious infection that could be intentionally spread as part of a bioterrorism attack) in people who may have been exposed to airborne anthrax, as well as for the treatment of plague and tuleramia (a serious infection that could be intentionally spread as part of a bioterrorism attack). Doxycycline is also used to prevent malaria. When used with other medications, doxycycline is used to treat acne and rosacea (a skin disease that causes facial redness, flushing, and pimples).

[0076] Because doxycycline is a highly lipophilic drug, it crosses the membranes of multiple target molecules. Doxycycline shows good intracellular penetration and has bacteriostatic activity against a variety of bacteria. Doxycycline also exhibits antiparasitic properties and anti-inflammatory effects. Its anti-inflammatory effects have been studied in various inflammatory skin conditions, such as bullous skin diseases and rosacea.

[0077] Protein synthesis is essential for the survival and function of cells, including bacteria. Doxycycline inhibits bacterial protein synthesis by allosterically binding to the 30S prokaryotic ribosomal subunit. The drug blocks the association of charged aminoacyl-tRNA (aa-tRNA) with the ribosomal A site, an acceptor site on the mRNA-ribosome complex. Ultimately, doxycycline hinders the elongation phase of protein synthesis and halts the production of key proteins required for bacterial survival and function.

[0078] Doxycycline mediates its anti-inflammatory effects by preventing calcium-dependent microtubule assembly and lymphocyte proliferation, thereby inhibiting the migration of white blood cells during inflammation. It also inhibits nitric oxide synthase, an enzyme that produces nitric oxide, an inflammatory signaling molecule.

[0079] Doxycycline can be in a variety of forms. These forms include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends in part on the intended mode of administration and therapeutic application. Doxycycline intended for systemic or local delivery, for example, can be in the form of injectable and infusible solutions. Thus, doxycycline can be formulated for administration by parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal or intramuscular injection). As used herein, "parenteral administration," "parenterally administered," and other grammatically equivalent phrases refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injection and infusion.

[0080] In one embodiment, doxycycline is formulated as a powder for suspension. In another embodiment, doxycycline is formulated as a capsule (e.g., extended release). In another embodiment, doxycycline is formulated as a tablet (e.g., delayed release). In another embodiment, doxycycline is formulated as a syrup.

[0081] IV. Levodopa

[0082] As used herein, the term levodopa ( and ) includes levodopa and its pharmaceutically acceptable salts. Levodopa is a dopamine precursor used to manage PD, usually in combination with carbidopa, and is also used for other related conditions. Since levodopa can be metabolized to dopamine on both sides of the blood-brain barrier, it is usually administered together with a dopa decarboxylase inhibitor (e.g., carbidopa) to prevent it from being metabolized before crossing the blood-brain barrier (see, for example, Djamshidian A, Poewe W, Parkinsonism Relat Disord. 2016 Dec; 33 Suppl 1: S9-S12). Once across the blood-brain barrier, levodopa is metabolized to dopamine and replenishes low endogenous dopamine levels, thereby treating the symptoms of PD.

[0083] Levodopa is generally considered a first-line medication for managing the motor symptoms of PD. Levodopa is almost always given in combination with the drug carbidopa, which reduces or prevents nausea that can occur with levodopa alone. Carbidopa-levodopa is delivered in a variety of forms, including immediate-release, controlled-release, or extended-release oral tablets or capsules. In addition to pills and capsules, it is also available as an enteral gel. and inhalers get.

[0084] Carbidopa-levodopa immediate-release tablets It can be obtained in doses of 10 mg to 100 mg, 25 mg to 100 mg, or 25 mg to 250 mg. A typical treatment regimen is a total of 100 mg to 1,000 mg of levodopa per day (divided into 3 to 4 doses). In one embodiment, levodopa is administered in a dose of 100 mg once daily.

[0085] In one embodiment, levodopa is administered at a total dose of 100 mg to 1,000 mg of levodopa per day (e.g., in divided doses 3 to 4 times a day in the form of immediate-release tablets). For example, levodopa can be administered at the following doses: 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg.

[0086] Carbidopa-levodopa controlled-release tablets (SINEMET ) is available in doses of 25mg-100mg or 50mg-200mg. A typical treatment regimen is 400mg to 1,600mg of levodopa in divided doses, depending on daily needs.

[0087] In one embodiment, levodopa is administered at a total daily dose of 100 mg to 1,600 mg (e.g., in divided doses in the form of controlled-release tablets). For example, levodopa can be administered at the following doses: 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg. In one embodiment, levodopa is administered at a dose of 100 mg once daily.

[0088] Carbidopa-levodopa orally disintegrating tablets It is available in doses of 10 mg-100 mg, 25 mg-100 mg, or 25 mg-250 mg. A typical treatment regimen is a total of 100 mg to 1,000 mg of levodopa per day (divided into 3 to 4 doses).

[0089] In one embodiment, levodopa is administered in a total daily dose of 100 mg to 1,000 mg (eg, in divided doses 3 to 4 times a day as an orally disintegrating tablet).

[0090] Carbidopa-levodopa enteral suspension It is available in a dose of 4.86 / 20 per milliliter (mL). This form of carbidopa-levodopa is delivered via a surgically implanted tube in the small intestine, rather than via a pill. After surgery, this delivery method increases "on" time (the time a patient's symptoms are well controlled and they can move and function well without troublesome, involuntary dyskinesias). A typical treatment regimen is up to 2,000 mg of levodopa over 16 hours.

[0091] In one embodiment, levodopa is administered in doses up to 2,000 mg over 16 hours (eg, as an enteral suspension). For example, levodopa can be administered in doses of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg or 2000 mg. In one embodiment, levodopa is administered in a dose of 100 mg once daily.

[0092] Carbidopa-levodopa extended-release (ER) capsules Available in doses of 23.75 mg to 95 mg, 36.25 mg to 145 mg, 48.75 mg to 195 mg, or 61.25 mg to 245 mg. This form of carbidopa-levodopa contains microparticles of the two drugs that dissolve and are absorbed at different rates. This can improve "on" time while requiring a lower drug dose. Carbidopa-levodopa ER capsules are not interchangeable with doses of other carbidopa-levodopa products. A typical treatment regimen is 855 mg to 2,340 mg of levodopa in divided doses, depending on daily needs.

[0093] In one embodiment, levodopa is administered at a total daily dose of 855 mg to 2,340 mg levodopa (eg, administered in divided doses in extended-release capsules).

[0094] Carbidopa-levodopa entacapone tablets It is available in doses of 12.5mg-50mg-200mg, 18.75mg-75mg-200mg, 25mg-100mg-200mg, 31.25mg-125mg-200mg, 37.5mg-150mg-200mg, and 50mg-200mg-200mg. This is a combination medication that includes entacapone and carbidopa-levodopa in a single pill. This is more convenient than taking carbidopa-levodopa and entacapone separately. A typical treatment regimen is a total daily dose of 150mg to 1,600mg of levodopa, depending on daily needs (up to 8 tablets per day).

[0095] In one embodiment, levodopa is administered at a total daily dose of 100 mg to 1,600 mg (e.g., in tablet form). For example, levodopa can be administered at the following doses: 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, or 1600 mg. In one embodiment, levodopa is administered at a dose of 100 mg once daily.

[0096] Levodopa inhalation powder Available in doses of 42 mg or 84 mg. This is an inhaled form of levodopa that is most commonly used for early morning "off" time or sudden "off" (e.g., PD motor and / or non-motor symptoms occur between drug administrations), thereby giving a low but faster-acting dopamine supplement. This is usually combined with a more stable regimen. The inhaled oral formulation of levodopa was approved by the US Food and Drug Administration in 2018 for adjunctive therapy with levodopa / carbidopa for the treatment of PD. Inhaled levodopa bypasses the intestinal absorption and hepatic metabolism of oral levodopa, and it is available in dry powder form (see, for example, LeWitt PA et al., Lancet Neurol. February 2019; 18(2): 145-154). A typical treatment regimen is 42 mg to 84 mg (1 to 2 capsules), up to 5 times a day.

[0097] In one embodiment, levodopa is administered up to 5 times daily at a dosage of 42 mg to 84 mg (e.g., in the form of an inhaled powder capsule). For example, levodopa can be administered at the following dosages: 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, or 84 mg. In one embodiment, levodopa is administered once daily, twice daily, three times daily, four times daily, or five times daily.

[0098] In one embodiment, levodopa is administered to the patient in a subtherapeutic dose.

[0099] V. Treatment

[0100] Provided herein are methods for treating a neurodegenerative disorder (e.g., PD) or a symptom thereof (e.g., tremor) by administering doxycycline (or a pharmaceutically acceptable salt thereof), alone or in combination with other therapeutic agents (e.g., levodopa), to a patient in need thereof.

[0101] As used herein, the term "subject" or "patient" is a human patient (eg, a patient suffering from a neurodegenerative disorder or condition).

[0102] As used herein, the term "pediatric" patient is a human patient classified by a physician or caregiver as belonging to a non-adult category, and can include, for example, newborns (both premature and full-term), infants, children, and adolescents. Typically, a pediatric patient is a patient less than 18 years of age (age < 18 years).

[0103] As used herein, the term "adult" patient is a human patient who is categorized by a physician or caregiver as not being a newborn, infant, child, or adolescent, e.g., based on age, developmental status, physiological characteristics, etc. Typically, an adult patient is a patient 18 years of age or older (age ≥ 18 years).

[0104] As used herein, the terms "treat," "treating," and "treatment" refer to any type of intervention or procedure performed on a subject or the administration of an agent or combination of agents to a subject with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing, or preventing the progression, development, severity, or recurrence of symptoms, complications, conditions, or biochemical markers associated with a disease.

[0105] As used herein, "effective treatment" refers to treatment that produces a beneficial effect, such as an improvement in at least one symptom of a disease or condition. The beneficial effect can take the form of an improvement relative to a baseline, such as an improvement relative to a measurement or observation made before initiating therapy according to the method. Effective treatment can refer to alleviation of at least one symptom of a neurodegenerative disorder.

[0106] The term "effective amount" refers to the amount of an agent that provides a desired biological, therapeutic, and / or prophylactic outcome. This outcome can be a reduction, improvement, alleviation, reduction, delay, and / or relief of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In one example, an "effective amount" is an amount that has been clinically demonstrated to alleviate at least one symptom of a neurodegenerative disorder. An effective amount can be administered in one or more administrations.

[0107] As used herein, the phrase "optimal biological dose (OBD)" is defined as the minimum dose of an agent or combination of agents that produces an optimal and sustained in vivo response without clinically unacceptable toxicity. Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the LD50 (the dose that is lethal to 50% of a population) and the ED50 (the dose that is therapeutically effective to 50% of a population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the therapeutic index can be expressed as the ratio LD50 / ED50.

[0108] As used herein, the terms "synergy," "therapeutic synergy," and "synergistic effect" refer to the phenomenon that when a patient is treated with a combination of therapeutic agents (e.g., doxycycline and levodopa), a therapeutic outcome is achieved that is superior to the outcome achieved when each component of the combination is used alone (see, for example, TH Corbett et al., 1982, Cancer Treatment Reports, 66, 1187). In this context, a therapeutically superior outcome includes one or more of the following: (a) an enhancement of the therapeutic response that is greater than the sum of the effects of each individual agent at the same dose as in the combination; (b) a reduction in the dose of one or more agents in the combination without reducing therapeutic efficacy; (c) a reduction in the incidence of adverse events while achieving a therapeutic benefit that is equal to or greater than that achieved by monotherapy of each agent at the same dose as in the combination; (d) a reduction in dose-limiting toxicity while achieving a therapeutic benefit that is greater than that achieved by monotherapy of each agent; and (e) a delay or minimization of the induction of drug resistance. Synergy of a drug combination can be determined, for example, according to the Chou-Talalay Combination Index (CI) theorem (Chou et al., Adv. Enzyme Regul. 1984; 22: 27-55; Chou, Cancer Res. 2010; 70(2): 440-446).

[0109] "Relapse" or "recurrence" or "resurgence" are used interchangeably herein and refer to the return of diagnosed signs and symptoms after a period of improvement or response.

[0110] As used herein, a "subtherapeutic dose" of a therapeutic compound (eg, doxycycline or levodopa) is a dose that is lower than the usual / typical dose of the compound required to achieve a therapeutic effect.

[0111] The term "subtherapeutic amount" of a compound means an amount that is less than what is accepted as a therapeutically effective amount. A subtherapeutic amount can be defined as an amount that is less than one or more doses approved by the FDA for a specific disease. Additionally, given that many drugs are used off-label, a subtherapeutic amount can be defined as less than the amount a doctor would typically prescribe for a specific disease. A subtherapeutic amount can also take into account factors such as weight, sex, age, kidney or liver damage, and other parameters that may affect the effectiveness of a given amount of a specific drug. In some embodiments, a subtherapeutic amount can be 85% of a therapeutically effective amount. In other embodiments, a subtherapeutic amount can be 70% of a therapeutically effective amount. In other embodiments, a subtherapeutic amount can be 60% of a therapeutically effective amount. In other embodiments, a subtherapeutic amount can be 50% of a therapeutically effective amount. In other embodiments, a subtherapeutic amount can be 40% of a therapeutically effective amount. In other embodiments, a subtherapeutic amount can be 30% of a therapeutically effective amount. In other embodiments, it can be even lower.

[0112] In other words, a subtherapeutic dose is an amount of a therapeutic compound (e.g., doxycycline or levodopa) that, when administered to a patient, is not by itself sufficiently effective in treating the claimed condition (e.g., a neurodegenerative condition such as PD). However, even if one or more of the therapeutic compounds (e.g., doxycycline or levodopa) is administered at a dose that is not sufficiently effective in treating the claimed condition, the combination is surprisingly still sufficiently effective in treating the condition.

[0113] In one embodiment, a method of treating a neurodegenerative disorder or a symptom thereof in a patient is provided, the method comprising administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof).

[0114] In one embodiment, a method of treating PD or a symptom thereof (eg, tremor) in a patient is provided, the method comprising administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof).

[0115] In one embodiment, a method of treating a neurodegenerative disorder or a symptom thereof in a patient is provided, the method comprising administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof) in combination with a therapeutically active amount of levodopa (or a pharmaceutically acceptable salt thereof).

[0116] In one embodiment, a method of treating PD or a symptom thereof (e.g., tremor) in a patient is provided, the method comprising administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof) in combination with a therapeutically active amount of levodopa (or a pharmaceutically acceptable salt thereof).

[0117] In one embodiment, a method of treating a neurodegenerative disorder or a symptom thereof in a patient is provided, the method comprising administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof) in combination with a therapeutically active amount of levodopa (or a pharmaceutically acceptable salt thereof), wherein the combined administration of doxycycline and levodopa produces a synergistic therapeutic effect compared to administration of either doxycycline or levodopa alone.

[0118] In one embodiment, a method of treating PD or a symptom thereof (e.g., tremor) in a patient is provided, the method comprising administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof) in combination with a therapeutically active amount of levodopa (or a pharmaceutically acceptable salt thereof), wherein the combined administration of doxycycline and levodopa produces a synergistic therapeutic effect compared to administration of either doxycycline or levodopa alone.

[0119] In one embodiment, a method of treating a neurodegenerative disorder or a symptom thereof in a patient is provided, the method comprising administering doxycycline (or a pharmaceutically acceptable salt thereof) and levodopa in combination, wherein a dose of doxycycline or levodopa that is normally subtherapeutic alone is rendered effective by the combination. Thus, when doxycycline and levodopa are administered in combination, doses of doxycycline below the standard therapeutic dose and / or doses of levodopa below the standard therapeutic dose that are normally not therapeutically effective in humans are found to be therapeutically effective. In other words, by administering doxycycline and levodopa in combination, at least one or both of doxycycline and / or levodopa can be administered at a subtherapeutic dose while still producing similar efficacy.

[0120] In one embodiment, a method of treating PD or a symptom thereof (e.g., tremor) in a patient is provided, the method comprising administering doxycycline (or a pharmaceutically acceptable salt thereof) and levodopa in combination, wherein a dose of doxycycline or levodopa that is typically subtherapeutic alone is rendered effective by the combination. Thus, when doxycycline and levodopa are administered in combination, doses of doxycycline below the standard therapeutic dose and / or doses of levodopa below the standard therapeutic dose that are typically not therapeutically effective in humans are found to be therapeutically effective. In other words, by administering doxycycline and levodopa in combination, at least one or both of doxycycline and / or levodopa can be administered at a subtherapeutic dose while still producing similar efficacy.

[0121] In one embodiment, a method of treating a neurodegenerative disorder or a symptom thereof in a patient is provided, the method comprising administering to the patient a combination of doxycycline (or a pharmaceutically acceptable salt thereof) and levodopa (or a pharmaceutically acceptable salt thereof), wherein at least one of the doxycycline and / or levodopa is administered at a subtherapeutic dose. In some embodiments, the subtherapeutic dose of doxycycline and / or the subtherapeutic dose of levodopa is a dose that is lower than the dose of doxycycline and / or the dose of levodopa required to achieve a therapeutic effect in the patient when administered alone.

[0122] In one embodiment, a method of treating PD or a symptom thereof (e.g., tremor) in a patient is provided, the method comprising administering to the patient a combination of doxycycline (or a pharmaceutically acceptable salt thereof) and levodopa (or a pharmaceutically acceptable salt thereof), wherein at least one of the doxycycline and / or levodopa is administered at a subtherapeutic dose. In some embodiments, the subtherapeutic dose of doxycycline and / or the subtherapeutic dose of levodopa is a dose that is lower than the dose of doxycycline and / or the dose of levodopa required to achieve a therapeutic effect in the patient when administered alone.

[0123] VI. Other combination treatments

[0124] Doxycycline (or a pharmaceutically acceptable salt thereof) can be administered according to the methods described herein: (1) alone; (2) in combination with levodopa (or a pharmaceutically acceptable salt thereof); (3) in combination with one or more other therapeutic agents; or (4) in combination with levodopa and one or more other therapeutic agents. Any other suitable therapeutic agent may be administered.

[0125] In one embodiment, the additional therapeutic agent is a Kv7 channel activator (eg, retigabine, flupirtine, or an endocannabinoid-like molecule).

[0126] In another embodiment, the other therapeutic agent is an anti-α-synuclein antibody (e.g., "Syn204" from Abeam, "15G 7" from Alexis, "42" from Becton Dickinson, "7B 2, 12" from Chemicon, "KM51" from NovaCastra, "Syn211" from Santa Cruz, or "LB509" from Zymed).

[0127] In another embodiment, the additional therapeutic agent is a decarboxylase inhibitor, such as carbidopa.

[0128] In another embodiment, the additional therapeutic agent is a dopamine agonist (e.g., bromocriptine cabergoline, apokin Merepit Ricopine or Yopro ).

[0129] In another embodiment, the additional therapeutic agent is a monoamine oxidase (MAO) B inhibitor (e.g., socarbosazole Phenelzine Selegiline Tranylcypromine Selegiline hydrochloride Selegiline hydrochloride Rasagiline or safinamide ).

[0130] In another embodiment, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor (e.g., entacapone Nibicapone, Niticapone, and Opicapone or tolcapone ).

[0131] In another embodiment, the additional therapeutic agent is an anticholinergic agent (e.g., (1) an antimuscarinic agent, such as an antipsychotic Atropine, benztropine Biperiden, chlorpheniramine, and some SSRIs Dicyclomine dimenhydrinate, diphenhydramine, doxepin, doxylamine, flavoxate, glycopyrronium / glycopyrronium salts, hyoscyamine, ipratropium, orphenadrine, oxitropium, oxybutynin, promethazine, propantheline bromide, scopolamine, solifenacin, tolterodine, tiotropium bromide, tricyclic antidepressants, trihexyphenidyl, amantadine, tropicamide, and umeclidinium; or (2) antinicotinic agents, such as bupropion, dextromethorphan, doxacurium, dextromethorphanium, mecamylamine, and tubocurarine).

[0132] In another embodiment, the additional therapeutic agent is an adenosine receptor antagonist (A2A receptor antagonist) (e.g., caffeine, theophylline, or etretinate) or pimavanserin ).

[0133] In another embodiment, the additional therapeutic agent is a TNF-α targeting agent or inhibitor (e.g., rituximab Adalimumab Certolizumab Golimumab and etanercept ).

[0134] In another embodiment, the additional therapeutic agent is an IL17A targeting agent or inhibitor (e.g., secukinumab Ixibezumab Bimeigezumab Brodalumab ).

[0135] In another embodiment, the additional therapeutic agent is deep brain stimulation.

[0136] VII. result

[0137] Provided herein are methods for treating a neurodegenerative disorder (e.g., PD) or symptom in a patient, comprising administering doxycycline (or a pharmaceutically acceptable salt thereof), alone or in combination with another therapeutic agent (e.g., levodopa), to the patient. Patients treated according to the methods disclosed herein experience improvement in at least one symptom of the neurodegenerative disorder.

[0138] Exemplary neurodegenerative disorder symptoms include, but are not limited to, abnormal movement, abnormal balance, abnormal movement (e.g., tremors), abnormal swallowing, abnormal bladder and bowel function (e.g., irritable bowel, abdominal pain, abdominal discomfort, diarrhea, abdominal bloating, abdominal gas, abdominal distension, and / or constipation), blood pressure fluctuations, abnormal sleep, abnormal breathing (e.g., shortness of breath), abnormal heart function (e.g., palpitations), abnormal memory, abnormal cognitive ability, abnormal mood, abnormal speech, anxiety, depression, stress, fatigue, feelings of panic, fear, restlessness, sleep problems, cold or sweaty hands and / or feet, mood swings, mania, impaired concentration or attention, cognitive problems, obsessions, compulsive behaviors, repetitive behaviors, aggression, social phobias or disorders, stage fright, inability to stay still and calm, dry mouth, numbness or tingling in the hands or feet, nausea, muscle tension, dizziness, apathy, euphoria, disinhibition, irritability, wandering, and / or combinations thereof.

[0139] In one embodiment, the patient is a PD patient. Exemplary PD symptoms include, but are not limited to, tremors, slow movement (bradykinesia), muscle stiffness, posture and balance disorders, loss of automatic movement, speech changes, and handwriting changes. Thus, in some embodiments, PD patients treated according to the methods described herein experience improvement in one or more of these symptoms.

[0140] In another embodiment, the patient is a PD patient, and the treatment results in an improvement according to a recognized clinical scale for assessing PD. For example, in one embodiment, the treatment results in an improvement according to the Unified Parkinson's Disease Rating Scale (UPDRS). On the UPDRS scale, a score of 199 represents the worst (total disability) and a score of zero represents (no disability). Thus, in one embodiment, the treatment results in a decrease in score of, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 199 points compared to baseline. In another embodiment, the treatment results in a decrease in score of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% compared to baseline.

[0141] In another embodiment, the patient is a PD patient and the treatment results in an improvement according to the Hoehn and Yahr staging scale. The Hoehn and Yahr staging scale includes 7 different stages ranging from no disease (stage 1) to wheelchair or bed confined (stage 5), namely stage 0, stage 1, stage 1.5, stage 2, stage 2, stage 2.5, stage 3, stage 4, and stage 5. In one embodiment, the treatment results in a decrease in one or more stages (e.g., a decrease of one, two, three, four, five, six, seven, or eight stages) compared to baseline.

[0142] In another embodiment, the patient is a PD patient and the treatment results in an improvement on the Schwab and England Activities of Daily Living Scale. This scale ranges from 0% (complete independence) to 100% (vegetative function) in 10% increments and includes 11 possible scales, namely 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 100%. In one embodiment, the treatment results in a decrease in one or more scales compared to baseline (e.g., a decrease in one, two, three, four, five, six, seven, eight, one, or ten scales).

[0143] In some embodiments, the patient is a PD patient, and the treatment causes an improvement in tremor (e.g., a reduction in tremor), such as a reduction of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. The improvement can be assessed by any suitable means, including but not limited to electromyography (EMG), electromagnetic motion tracking, contactless measurements obtained from a device (e.g., Kinect), laser Doppler vibrometer, accelerometer, gyroscope, or smart wearable technology device.

[0144] VIII. Kits and Unit Dosage Forms

[0145] Also provided herein are kits suitable for the aforementioned methods, comprising a dose of doxycycline. In some embodiments, the kit further comprises a dose of levodopa. The kit may optionally further comprise instructions, such as an administration protocol, to allow a practitioner (e.g., a doctor, nurse, or patient) to administer the composition contained therein to a patient suffering from a neurodegenerative disorder such as PD, thereby administering the composition. The kit may further comprise a syringe.

[0146] In one embodiment, the kit comprises: (a) a dose of doxycycline; and (b) instructions for using the doxycycline in the methods described herein.

[0147] In another embodiment, the kit comprises: (a) a dose of doxycycline, (b) a dose of levodopa, and (c) instructions for using the doxycycline and levodopa in the methods described herein. In one embodiment, the dose of doxycycline is a therapeutically effective amount. In one embodiment, the dose of levodopa is a therapeutically effective amount. In one embodiment, the dose of doxycycline and / or levodopa is a subtherapeutic dose.

[0148] IX. use

[0149] Provided herein are uses of doxycycline for treating a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor), wherein doxycycline (or a pharmaceutically acceptable salt thereof) is administered to a patient in an amount and at a frequency to treat the neurodegenerative disorder or symptom.

[0150] Further provided is the use of a combination of doxycycline and levodopa (or a pharmaceutically acceptable salt thereof) for treating a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor), wherein doxycycline and levodopa are administered to the patient in an amount and frequency effective to treat the neurodegenerative disorder or symptom. In one embodiment, the combination of doxycycline and levodopa produces a synergistic therapeutic effect compared to administration of doxycycline or levodopa alone. In another embodiment, the combination of doxycycline and levodopa allows for administration of doxycycline and / or levodopa at subtherapeutic doses.

[0151] The following examples are illustrative only and should not be construed in any way as limiting the scope of the present disclosure, as many variations and equivalents will become apparent to those skilled in the art after reading this disclosure. The contents of all references, Genbank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.

[0152] Examples

[0153] Patient A, 59 years old, was diagnosed with Parkinson's disease (PD) approximately a year and a half prior and was treated with levodopa. In addition to the typical tremor symptoms, the patient also exhibited seborrheic dermatitis, an inflammatory skin condition known to be associated with a higher incidence in Parkinson's disease. The patient also experienced intermittent symptoms of irritable bowel syndrome. Before starting doxycycline, the patient required increased levodopa dosage every approximately three months due to worsening PD, most notably tremor. In response to the skin symptoms, the patient was started on a 100 mg tablet of doxycycline once daily, and within three weeks, the seborrheic dermatitis resolved. Quite surprisingly and unexpectedly, after starting doxycycline, the patient also experienced a clinically significant reduction in tremor. Approximately eight weeks later, the patient discontinued doxycycline, and the seborrheic dermatitis recurred within two weeks, accompanied by a clinically worsening tremor. The patient restarted doxycycline and again experienced remission of the seborrheic dermatitis and improvement in tremor. The patient's inflammatory skin symptoms were relieved again, and the Parkinson's tremor improved clinically. The patient continued to use doxycycline for an additional two months, but then stopped using doxycycline due to nausea. Once doxycycline was discontinued again, the seborrheic dermatitis recurred within a month, and the tremor worsened clinically. The patient restarted doxycycline at 50 mg and showed partial improvement in skin symptoms and Parkinson's disease. The dose was increased again to 100 mg, with relief of seborrheic dermatitis and improvement of tremor. The patient continued to use doxycycline 100 mg tablets once daily for approximately two years and experienced complete remission of seborrheic dermatitis, disappearance of irritable bowel symptoms, and clinically significant improvement of tremor. In addition to the improvement in Parkinson's disease tremor, the patient did not need to increase any Parkinson's treatment and levodopa dose for the first time, and the dose remained stable for approximately two years after starting treatment with doxycycline 100 mg.

Claims

1. A method of treating a neurodegenerative disorder or symptom, the method comprising administering to a patient in need thereof a therapeutically active amount of doxycycline.

2. The method of claim 1 , wherein the neurodegenerative disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease (PD), supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, frontotemporal neurocognitive disorder, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease, ataxia, motor neuron disease, multiple system atrophy, hereditary ataxia, dementia, memory loss, mental retardation, Rett Syndrome, progressive supranuclear palsy, Creutzfeldt-Jakob disease, neurofibromatosis, brain injury, stroke, multiple sclerosis, and alpha-synucleinopathy (e.g., Lewy body disease).

3. The method of claim 1 or 2, wherein the neurodegenerative disorder is PD.

4. The method of claim 1 , wherein the symptom is selected from the group consisting of movement abnormalities, balance abnormalities, ambulation abnormalities, swallowing abnormalities, bladder and bowel dysfunction (e.g., irritable bowel, abdominal pain, abdominal discomfort, diarrhea, abdominal bloating, abdominal gas, abdominal distension, and / or constipation), blood pressure fluctuations, sleep abnormalities, breathing abnormalities (e.g., shortness of breath), cardiac dysfunction (e.g., palpitations), memory abnormalities, cognitive abnormalities, mood abnormalities, speech abnormalities, anxiety disorders, depression, stress, fatigue, feelings of panic, fear, restlessness, sleep problems, cold or sweaty hands and / or feet, mood swings, mania, impaired concentration or attention, cognitive problems, obsessions, compulsive behaviors, repetitive behaviors, aggression, social phobias or disorders, stage fright, inability to stay still and calm, dry mouth, numbness or tingling in the hands or feet, nausea, muscle tension, dizziness, apathy, euphoria, disinhibition, irritability, wandering, or a combination thereof.

5. The method of any one of the preceding claims, wherein the therapeutically active amount of doxycycline is between 50 mg and 200 mg once daily.

6. The method of any one of claims 1 to 4, wherein the therapeutically active amount of doxycycline is 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg once daily.

7. The method of claim 6, wherein the therapeutically active amount of doxycycline is 50 mg once daily.

8. The method of claim 6, wherein the therapeutically active amount of doxycycline is 100 mg once daily.

9. The method of any one of the preceding claims, wherein the patient has previously been administered levodopa.

10. The method of any one of the preceding claims, wherein the method further comprises administering levodopa to the patient.

11. The method of claim 10, wherein the doxycycline and the levodopa are administered simultaneously or chronologically.

12. The method of claim 10 or 11, wherein the levodopa is administered before the doxycycline.

13. The method of claim 10 or 11, wherein the doxycycline is administered prior to the administration of the levodopa.

14. The method of any one of claims 10 to 13, wherein levodopa is administered as an oral tablet or capsule, an oral inhaler, or an infusion.

15. The method of any one of claims 10 to 14, wherein levodopa is administered in a dose of between about 100 mg and 2,340 mg once daily.

16. The method according to any one of claims 10 to 14, wherein levodopa is administered in a dose of between about 100 mg once daily.

17. The method of any one of claims 11 to 16, wherein administration of doxycycline and levodopa produces a synergistic therapeutic effect compared to administration of doxycycline or levodopa alone.

18. The method of any one of claims 11 to 17, wherein doxycycline and levodopa are administered in combination, and wherein at least one of doxycycline and / or levodopa is administered in a subtherapeutic dose.

19. The method of claim 18, wherein the subtherapeutic dose of doxycycline and / or the subtherapeutic dose of levodopa is a dose that is lower than the dose of doxycycline and / or the dose of levodopa required to achieve a therapeutic effect in the patient when administered alone.

20. The method of any one of the preceding claims, wherein the neurodegenerative disorder is PD and the treatment results in an improvement according to the Unified Parkinson Disease Rating Scale (UPDRS), the Hoehn and Yahr Staging Scale and / or the Schwab and England Rating of Activities of Daily Living.

21. The method of any one of the preceding claims, wherein the neurodegenerative disorder is PD and the treatment results in improvement of tremor.

22. The method of claim 21, wherein improvement in the tremor is assessed by electromyography (EMG), an electromagnetic motion tracker, non-contact measurements obtained from a device (e.g., Kinect), a Doppler vibrometer, an accelerometer, a gyroscope, or a smart wearable technology device.

23. The method of any one of the preceding claims, wherein doxycycline is administered in combination with an additional therapeutic agent.

24. The method of claim 23, wherein the additional therapeutic agent is a Kv7 channel activator, an anti-α-synuclein antibody, carbidopa, a dopamine agonist, a monoamine oxidase (MAO) B inhibitor, a catechol O-methyltransferase (COMT) inhibitor, an anticholinergic agent, and an adenosine receptor antagonist (A2A receptor antagonist), or a combination thereof.

25. The method of claim 23, wherein the additional therapeutic agent is a TNF-α targeting agent, an IL17A targeting agent, or a combination thereof.

26. The method of any one of the preceding claims, wherein doxycycline is administered in combination with deep brain stimulation.

27. A kit comprising: (a) a dose of doxycycline; and (b) instructions for using the doxycycline in the method of any one of claims 1 to 26.

28. A kit comprising: (a) a dose of doxycycline; (b) a dose of levodopa; and (c) instructions for using the doxycycline and levodopa in the method of any one of claims 1 to 26.

29. Use of doxycycline for treating a neurodegenerative disorder or symptom, wherein doxycycline is administered to a patient in an amount and at a frequency useful for treating the neurodegenerative disorder or symptom.

30. Use of a combination of doxycycline and levodopa for treating a neurodegenerative disorder or condition, wherein the doxycycline and levodopa are administered to a patient in an amount and at a frequency useful for treating the neurodegenerative disorder or condition.

31. The use according to claim 28 or 29, wherein the neurodegenerative disorder is PD.

32. The use of any one of claims 28 to 30, wherein the combination of doxycycline and levodopa produces a synergistic therapeutic effect compared to administration of doxycycline or levodopa alone.

33. The use according to claim 29 or 30, wherein doxycycline and levodopa are administered in subtherapeutic doses.

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