Treatment of intracranial hemorrhage

Abstract

Described herein are compounds, pharmaceutical compositions, and methods of use for treating acute brain injury.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 313,078, entitled "Treatment of Intracranial Hemorrhage," filed February 23, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to methods for treating injuries and diseases of the nervous system, and more particularly to compounds for treating intracranial hemorrhage in humans, and their medical uses.

[0003] Research and Development This invention was made with Government support under Grant No. R01 AG069930 awarded by the National Institutes of Health. The Government has certain rights in this invention. [Background technology]

[0004] Acute brain injury resulting from trauma, e.g., traumatic brain injury (TBI) or non-traumatic cerebrovascular injury, e.g., intracranial hemorrhage, is a major medical problem that causes significant mortality and morbidity. In addition to the initial insult injury, downstream pathophysiological events can result in further brain damage leading to increased risk of long-term neurological complications. A key downstream injury response occurring within the time frame of the associated injury to treatment is the dysregulation of the inflammatory response (neuroinflammation) in the brain. A particular aspect of neuroinflammation, injury-induced overproduction of inflammatory cytokines from abnormally activated glia, is associated with subsequent neurological damage and cognitive deficits after acute brain injury. In both animal models and human patients, acute brain injury induces a robust increase in cytokine levels in the brain, which occurs in the first hours to days after the insult and then subsides. This acute inflammatory cytokine surge is the primary cause of subsequent brain edema, long-term neuronal dysfunction, and cognitive impairment. This mechanistic relevance and the attractive therapeutic time window of hours to days after an attack provide a rational therapeutic target for intervention in acute care settings.

[0005] Dysregulation of injury-induced glial activation is a key convergence point of diverse central nervous system (CNS) insults that can compromise neuronal survival, and excessive glial activation is a major factor contributing to unfavorable outcomes after acute brain injury. However, despite progress in understanding these cellular and molecular neuroinflammatory mechanisms underlying adverse neurological sequelae after injury, approved therapeutics targeting this pathological process are lacking. Thus, there is a clear and urgent need for CNS-penetrant small molecule drug candidates that improve neurological recovery and outcomes, especially in acute brain injury conditions in humans. Summary of the Invention

[0006] Described herein is a small molecule compound that is a CNS-permeable small molecule suitable for use in treating acute brain injury, preferably in humans.Therefore, the compounds and compositions described herein can be used to treat acute brain injury, such as, but not limited to, intracranial hemorrhage, including intracerebral hemorrhage or subarachnoid hemorrhage.

[0007] In some embodiments, described herein are pharmaceutical compositions comprising a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, and one or more pharma- ceutically acceptable carriers, diluents, and excipients suitable for administration to a patient in need of treatment for acute brain injury.

[0008] In some embodiments, provided herein is a method for the treatment or prevention of the consequences of acute brain injury in a patient in need thereof, comprising administering to the patient a therapeutically acceptable dose of MW189, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a method for the treatment or prevention of the consequences of acute brain injury in a patient in need thereof, comprising administering to the patient a pharmaceutical composition as described herein. In some embodiments, the acute brain injury is or comprises intracranial hemorrhage, including but not limited to epidural hematoma, subdural hematoma, subarachnoid hemorrhage, intracerebral hemorrhage, intraparenchymal hemorrhage, and intraventricular hemorrhage.

[0009] Other objects, features, and advantages of the methods and compositions described herein will become apparent from the following detailed description, however, it should be understood that while this detailed description and specific examples indicate particular embodiments, such embodiments are referred to by way of example only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description.

[0010] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification (if any) are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The compounds described herein can be used to treat acute brain injury, such as intracranial hemorrhage (e.g., hemorrhagic stroke), in subjects in need thereof.In some embodiments, the compounds described herein prevent death or significantly reduce the risk of death in subjects in need thereof.In some preferred embodiments, the subject is a human.

[0012] In some embodiments, the method of treating brain injury in a patient in need thereof comprises administering to the patient suffering from acute brain injury an effective amount of one or more of the compounds or compositions disclosed herein.In some embodiments, the compounds or compositions described herein reduce the risk of brain infection, for example, by preventing or reducing the inflammatory response to systemic infection.

[0013] In some preferred embodiments, the patient is a human.

[0014] In some embodiments, the compounds described herein can be used to treat acute brain injury, so that the symptoms, consequences or sequelae of acute brain injury are significantly reduced. In some embodiments, the cognitive and memory impairments associated with acute brain injury can be significantly alleviated after treatment with an effective amount of the compounds disclosed herein. In some embodiments, brain injury can be primary or secondary to a traumatic event, such as hemorrhagic stroke. Primary injury can include intracranial hematomas, including but not limited to epidural hematomas, subdural hematomas, subarachnoid hemorrhage, intracerebral hemorrhage, intraparenchymal hemorrhage, and intraventricular hemorrhage.

[0015] In some embodiments, secondary brain injury may include hypoxia and hypotension, ischemia, cerebral edema, hydrocephalus, expanding hemorrhage, or second impact syndrome. In some embodiments, secondary brain injury may also manifest as cognitive and behavioral problems.

[0016] In some embodiments, the severity of secondary brain damage is prevented or reduced after an initial seizure in a subject in need thereof.

[0017] The compounds described herein can be used to treat traumatic brain injury in a subject in need thereof.

[0018] The compounds described herein can also be used to treat spinal cord injury in a subject in need thereof.

[0019] In some embodiments, the compounds described herein regenerate cells or assist in regeneration in a subject in need thereof, hi embodiments, the compounds described herein regenerate brain cells or assist in regeneration in a subject in need thereof.

[0020] In some embodiments, methods of treating brain injury or intracranial hemorrhage can include selective inhibition of injury- and / or disease-induced glial inflammatory cytokine overproduction associated with a destructive glial inflammation / synaptic dysfunction cycle. In some embodiments, treating acute brain injury includes reducing perihematomal edema during and after treatment.

[0021] In some embodiments, a method of treating brain injury or intracranial hemorrhage includes reducing one or more proinflammatory cytokines or chemokines, including, but not limited to, interleukin-1 (IL-1) beta, IL-2, IL-6, IL-8, L-9, IL-12, IL-15, IL-17, IL-18, IL-33, MCP-1 (CCL2), IP-10 (CXCL10), tumor necrosis factor alpha (TNF-α), MIP-1a, MIP-2, interferon gamma (IFNγ), KC / GRO, or granulocyte macrophage colony stimulating factor (GM-CSF). In some embodiments, one or more proinflammatory cytokines can be used as biomarkers, which can be detected and / or quantified to diagnose acute brain injury, such as intracranial hemorrhage, evaluate the effectiveness of treatment, or both.

[0022] In some embodiments, methods of treating acute brain injury or intracranial hemorrhage may include increasing one or more anti-inflammatory cytokines, including interleukin (IL)-1 receptor antagonist, IL-4, IL-5, IL-10, IL-11, IL-13, or IL-35. In some embodiments, one or more anti-inflammatory cytokines may be used as biomarkers, which may be detected and / or quantified to diagnose acute brain injury, such as intracranial hemorrhage, evaluate the effectiveness of treatment, or both.

[0023] In some embodiments, basal physiological cytokine levels are not altered by administration of one or more compounds disclosed herein at effective dosage levels.

[0024] In some embodiments, the compounds disclosed herein can be used in combination with ion channel modulators. In some embodiments, the compounds disclosed herein can be used in combination with nimodipine to treat acute brain injury.

[0025] In some embodiments, the compounds disclosed herein can be used in combination with other therapeutic agents, such as antihypertensive agents, diuretics, antipyretics, analgesics, or anticonvulsants.

[0026] In some embodiments, methods of treating brain injury or intracranial hemorrhage include reducing neurofilament light chain polypeptide ("NfL" or "neurofilament light chain").

[0027] In some embodiments, the compounds of the present disclosure or pharma- ceutically acceptable salts or solvates thereof may be administered in an amount proportional to the patient's body weight in kilograms (kg) (measured in milligrams (mg)). Such amounts may be expressed in mg / kg or mpk. In some embodiments, the compounds described herein may be administered in an amount of at least about 0.01, 0.025mpk, 0.05mpk, 0.2mpk, 0.3mpk, 0.4mpk, 0.5mpk, 1mpk, 2mpk, 4mpk, 5mpk, 10mpk, 15mpk, 20mpk, or 30mpk. In some preferred embodiments, the compounds described herein may be administered in an amount of about 0.25mpk, about 0.5mpk, about 0.75mpk, about 1mpk, about 1.5mpk, about 2mpk, or about 2.5mpk.

[0028] In some embodiments, the compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof is administered in an effective amount of about 0.01 to about 1 mpk. Preferably, the effective amount is about 0.1 to about 0.5 mg / kg of patient body weight (mpk). More preferably, the effective amount is about 0.15 to about 0.3 mg / kg of patient body weight (mpk).

[0029] In some embodiments, a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof is administered to a human subject having a cerebral hemorrhage of 10 mL to 60 mL in volume, confirmed via diagnostic and stable computed tomography (CT) using volumetric assessment, within 24 hours of the first attack or onset of symptoms and about every 12 hours thereafter for up to 5 days (10 doses total), or until the human subject is discharged from the hospital (if earlier than 5 days). In some embodiments, the volume of the cerebral hemorrhage can be 1 mL to 100 mL.

[0030] In some embodiments, the compound of the present disclosure or its pharma- ceutically acceptable salt or solvate is administered about 1 to 4 times per day. In some embodiments, the compound of the present disclosure or its pharma- ceutically acceptable salt or solvate is administered about 1 or 2 times per day. In some preferred embodiments, the compound of the present disclosure or its pharma- ceutically acceptable salt or solvate is administered 2 times per day.

[0031] In some embodiments, the compounds of the present disclosure, or pharma- ceutically acceptable salts or solvates thereof, can be administered in a dosing regimen. The regimen can be configured to provide a therapeutically effective amount of the compound over a predefined period (e.g., administration time). The regimen can be structured to limit or prevent side effects or undesirable complications of the compounds disclosed herein. A regimen useful for treating acute brain injury can include any number of days of administration, which can be repeated as needed. The administration period can be separated by a rest period that does not include administration. For example, the regimen can include an administration period that includes 2, 3, 5, 7, 10, 15, 21, 28, or more days. These periods can be repeated. For example, the regimen can include days set forth above, which are repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more times.

[0032] In some embodiments, administration of the disclosed compound may be delayed up to about 4-8 hours after injury. In some embodiments, administration of the disclosed compound, or a pharma- ceutically acceptable salt, or solvate thereof, may be delayed up to about 10 hours after injury. In some preferred embodiments, administration of the disclosed compound (e.g., MW189), or a pharma- ceutically acceptable salt, or solvate thereof, may be delayed up to about 24 hours after injury. In some embodiments, administration of the disclosed compound may be administered up to about 8, 16, 24, 36, or 48 hours after injury.

[0033] In some embodiments, administration of the disclosed compounds begins within about 1 minute to 24 hours, about 10 minutes to about 12 hours, or about 30 minutes to 6 hours after the patient suffers from acute brain injury, hi some embodiments, administration of the disclosed compounds begins within about 4 to 6 hours, or about 6 to 12 hours, or about 12 to 24 hours, or about 24 to 36 hours.

[0034] In some embodiments, administration of a compound of the disclosure begins within about 2-36 hours, about 4-36 hours, about 6-36 hours, about 6-18 hours, about 6-8 hours, or 2-24 hours, about 4-12 hours, about 4-24 hours, 4-36 hours, about 6-12 hours, about 6-24 hours, about 6-36 hours, about 8-12 hours, about 8-24 hours, about 8-36 hours, about 10-12 hours, about 10-18 hours, about 10-24 hours, about 10-36 hours, about 12-24 hours, about 12-36 hours, about 18 hours to 24 hours, or about 18-36 hours after the patient suffers from acute brain injury.

[0035] In some embodiments, a typical daily dosage of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof will vary within a wide range and will depend on a variety of factors, such as the relevant indication, the severity of the disease being treated, the route of administration, the age, weight, and sex of the patient, as well as the particular compound used, and can be determined by a physician.

[0036] In some embodiments, the compounds described herein are formulated in pharmaceutical compositions. In some embodiments, the pharmaceutical compositions comprising the compounds described herein are administered to a subject in a variety of ways by multiple routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, or intralymphatic injection), intranasal, buccal, topical, or transdermal routes of administration. In some embodiments, the pharmaceutical compositions comprising the compounds described herein are administered to a subject parenterally. In some preferred embodiments, the pharmaceutical compositions comprising the compounds described herein are administered to a subject intravenously.

[0037] In some embodiments, the compounds described herein are formulated in pharmaceutical compositions that are capable of crossing the blood-brain barrier.

[0038] In some embodiments, compounds of the present disclosure include MW01-6-189WH (MW189): [ka]

[0039] In some embodiments, the compounds described herein include MW189 and pharma- ceutically acceptable salts, solvates, polymorphs, or prodrugs thereof.

[0040] In some preferred embodiments, MW189 may be administered as part of a method for treating acute brain injury in a patient in need thereof, the method comprising administering to a patient suffering from acute brain injury an effective amount of a compound described herein, such as MW189.

[0041] In some embodiments, the acute brain injury comprises an intracranial hemorrhage, including but not limited to an epidural hematoma, a subdural hematoma, a subarachnoid hemorrhage, an intracerebral hemorrhage, an intraparenchymal hemorrhage, and an intraventricular hemorrhage.

[0042] Pharmaceutical Compositions In some embodiments, the compounds described herein are formulated in pharmaceutical compositions. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharma- ceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharma- ceutically usable preparations. Appropriate formulations vary according to the route of administration selected. Summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteeth Ed (Easton, PA: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams&Wilkins 1999), which are incorporated herein by reference.

[0043] The pharmaceutical composition disclosed herein refers to a mixture of the compounds disclosed herein with other chemical components (i.e., pharma- ceutically acceptable inactive components), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, permeation enhancers, humectants, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. The pharmaceutical composition facilitates administration of the compounds to an organism, including a human subject.

[0044] The pharmaceutical formulations described herein may be administered to a subject in a variety of ways by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic injection), intranasal, buccal, topical, or transdermal routes of administration. Pharmaceutical formulations described herein include, but are not limited to, aqueous dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0045] In some embodiments, the compounds disclosed herein may be administered orally.

[0046] In some embodiments, the compounds disclosed herein are administered topically.In such embodiments, the compounds disclosed herein can be formulated into various compositions that can be administered topically, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated dressings, balms, creams, or ointments.In some embodiments, the compounds disclosed herein can be administered topically to the skin.

[0047] In another aspect, the compounds disclosed herein may be administered by inhalation.

[0048] In another aspect, the compounds disclosed herein are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.

[0049] In another aspect, the compounds disclosed herein are formulated as eye drops.

[0050] In any of the foregoing aspects, there are further embodiments in which an effective amount of a compound disclosed herein (e.g., MW189) is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by inhalation to a mammal, and / or (e) administered by nasal administration to a mammal, and / or (f) administered by injection to a mammal, and / or (g) administered topically to a mammal, and / or (h) administered by ophthalmic administration, and / or (i) administered rectally to a mammal, and / or (j) administered non-systemically or topically to a mammal.

[0051] In any of the foregoing aspects, further embodiments include a single administration of an effective amount of a compound disclosed herein (e.g., MW189), including further embodiments in which (i) the compound is administered once, (ii) the compound is administered to the mammal multiple times over the course of a day, (iii) the compound is administered continuously for a period of 1-10 days, 1-10 weeks, 1-20 weeks, 1-30 weeks, etc., or (iv) the compound is administered continuously indefinitely.

[0052] In any of the foregoing aspects, further embodiments include multiple administrations of an effective amount of a compound disclosed herein (e.g., MW189), including further embodiments in which (i) the compound is administered continuously or intermittently as a single dose, (ii) the multiple administrations are spaced apart by 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the mammal every 12 hours, or (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of the compound disclosed herein is temporarily suspended or the dose of the compound administered is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In some embodiments, the length of the drug holiday varies from 2 days to up to 1 year.

[0053] In certain embodiments, the compounds disclosed herein are administered locally rather than systemically.

[0054] In some embodiments, the compounds disclosed herein may be administered locally.

[0055] In some embodiments, the compounds disclosed herein may be administered systemically.

[0056] In some embodiments, the pharmaceutical formulation may be in the form of a tablet or capsule.

[0057] In some embodiments, the dosage form of the liquid formulation for oral administration is in the form of an aqueous suspension or solution selected from the group including, but not limited to, aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.

[0058] For administration by inhalation, the compounds disclosed herein (eg, MW189) can be formulated for use as an aerosol, mist, or powder.

[0059] For buccal or sublingual administration, compositions containing a compound disclosed herein (eg, MW189) may take the form of tablets, lozenges, or gels formulated in a conventional manner.

[0060] In some embodiments, the compounds disclosed herein may be formulated as transdermal dosage forms.

[0061] In some embodiments, the compounds disclosed herein can be formulated into pharmaceutical compositions suitable for intramuscular, subcutaneous, or intravenous injection.

[0062] In some embodiments, the compounds disclosed herein may be administered topically and may be formulated into a variety of topically administrable compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments.

[0063] In some embodiments, the compounds disclosed herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas.

[0064] Dosage and Treatment Regimens In some embodiments, the compounds disclosed herein are used in the preparation of medicaments for treating the diseases or conditions described herein.Furthermore, the method for treating any of the diseases or conditions described herein comprises administering to a subject in need of such treatment a pharmaceutical composition comprising at least one compound disclosed herein, or its pharmaceutically acceptable salt, active metabolite, prodrug, or solvate, in a therapeutically effective amount.

[0065] In certain embodiments, compositions comprising a compound disclosed herein (e.g., MW189) are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions may be administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or condition. Amounts effective for this use will vary depending on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, response to drugs, and the judgment of the treating physician. Therapeutically effective amounts may optionally be determined by methods including, but not limited to, dose escalation clinical trials.

[0066] In prophylactic applications, compositions containing the compounds disclosed herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.

[0067] In certain embodiments, the dose of drug being administered may be temporarily reduced or temporarily stopped for a period of time (ie, a "drug holiday").

[0068] Doses used for adult treatment typically range from 0.05mpk to 2.5mpk and may be administered 1 to 6 times daily.

[0069] Treatment methods Described herein is a method for treating acute brain injury, including intracranial hemorrhage, such as intracerebral hemorrhage or subarachnoid hemorrhage. In some embodiments, described herein is a method for treating a disease or condition, comprising administering an effective amount of a compound disclosed herein to a subject in need thereof.

[0070] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise. Moreover, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0071] "Co-administration" and like terms, as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which agents are administered by the same or different routes of administration or at the same or different times.

[0072] The term "effective amount" or "therapeutically effective amount" as used herein refers to the administration of an amount of an agent or compound sufficient to alleviate to some extent one or more of the symptoms of the disease or condition being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or pathogenesis of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to produce a clinically significant reduction in the symptoms and / or consequences of the disease. The appropriate "effective" amount in any individual case may be determined using techniques such as dose escalation studies. An "effective amount" is an amount sufficient for the compound to achieve the stated purpose compared to the absence of the compound (e.g., the compound achieves the effect for which it is administered, treats the disease, reduces enzyme activity, increases enzyme activity, reduces a signal pathway, or reduces one or more symptoms and / or consequences of the disease or condition, reduces or increases one or more biomarkers indicative of the occurrence or severity of the disease or condition, or a combination of two or more thereof). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom(s) of a disease, which may also be referred to as a "therapeutically effective amount."

[0073] "Relief" of a symptom(s) (and grammatical equivalents of this phrase) means a decrease in the severity or frequency of the symptom(s), or the elimination of the symptom(s).

[0074] A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, has an intended prophylactic effect, such as, for example, preventing or delaying the onset (or recurrence) of an injury, disease, condition, or illness, or reducing the likelihood of the onset (or recurrence) of an injury, disease, condition, or illness, or their symptoms. A complete prophylactic effect does not necessarily occur by administration of one dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount can be administered in one or more administrations. The prophylactic effect can be total or partial. "Activity reduction amount" as used herein refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of antagonist.

[0075] The precise amount that corresponds to an "effective amount" or a "therapeutically effective amount" will depend on the purpose of the treatment and can be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0076] The term "brain injury" refers to a state in which the brain is damaged by an injury caused by an event. As used herein, "injury" is a change in the integrity, activity, level, robustness, state, or other changes of cells or molecules that can be traced to the injury that causes the injury. For example, injury includes physical, mechanical, chemical, biological, functional, infectious, or other modulatory properties of cells or molecules. Injury can include physical trauma, such as a single or repeated impact (percussion), or biological abnormalities, such as stroke, caused by either occlusion or leakage of blood vessels. Injury can be or include infection by infectious agents. Those skilled in the art will recognize the many events that are encompassed by the term injury or injury.

[0077] More specifically, the term "brain injury" refers to a condition that results in damage to the central nervous system, regardless of its pathophysiological basis. Stroke is one of the most frequent causes of "brain injury". "Stroke" can be classified into hemorrhagic stroke and non-hemorrhagic stroke. Examples of hemorrhagic stroke include cerebral hemorrhage, subarachnoid hemorrhage, and intracranial hemorrhage secondary to cerebral artery deformation, while examples of non-hemorrhagic stroke include cerebral infarction.

[0078] The term "subject" or "patient" encompasses organisms, including mammals. By way of example, and not limitation, mammals include humans. In some preferred embodiments, the mammal is a human.

[0079] The terms "treat", "treating" or "treatment" as used herein include reducing, eliminating or ameliorating one or more symptoms, results, outcomes and / or sequelae of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., arresting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, preventing the onset or progression of a condition caused by a disease or condition, or arresting a symptom of a disease or condition either prophylactically and / or therapeutically. The effectiveness of treating brain injury can be assessed in a variety of ways, which may include detecting and / or quantifying one or more biomarkers in one or more tissues and / or body fluids, such as blood, serum, cerebrospinal fluid (CSF), etc. Biomarker levels can be used to diagnose and / or assess the severity of acute brain injury, for example, by determining the amount of the biomarker in a biological fluid, such as plasma or CSF, and comparing the amount to a normal amount of the biomarker in tissue and / or biological fluid from one or more uninjured subjects of the same species of patient (e.g., human). Such biomarkers can include, for example, neurofilament light polypeptide (NfL), which can be detected in serum and / or CSF. Such biomarkers can also include one or more inflammatory cytokines as described herein.

[0080] Working Example The compounds disclosed herein can be used to treat acute brain injury, preferably in a human patient.

[0081] MW189 is a novel small molecule drug candidate developed as a selective inhibitor of disease- and injury-induced inflammatory cytokine overproduction associated with the destructive neuroinflammation / synaptic dysfunction cycle. In animal models of acute brain injury, such as intracranial hemorrhage, MW189 attenuates neuroinflammation, reduces cerebral edema, and improves functional and cognitive performance. Researchers are seeking to determine whether these targets are modified in humans with intracranial hemorrhage.

[0082] Experimental Method: To determine the safety, tolerability, biological response, and pharmacokinetic outcomes of MW189 in the treatment of acute brain injury, MW189 will be administered intravenously to human subjects suffering from intracranial hemorrhage. In this study, MW189 (0.25 mg / kg) will be administered to human subjects with cerebral hemorrhage measuring 10 mL-60 mL in size, confirmed via diagnostic and stable CT scan utilizing volumetric assessment, within 24 hours of the first seizure or onset of symptoms and approximately every 12 hours thereafter for up to 5 days (10 doses total) or until the human subject is discharged from the hospital (if earlier than 5 days).

[0083] Results: Biochemical biomarkers such as NfL and cytokines are used to demonstrate target binding and biological response. Safety and tolerability of MW189 will be assessed, for example, by monitoring patient health or pharmacokinetic parameters and / or one or more biomarkers. Exploratory radiographic and clinical endpoints will also be monitored. Production of inflammatory cytokines will also be observed. Secondary brain tissue damage due to intracranial hemorrhage will also be observed.

[0084] The examples and embodiments described herein are for illustrative purposes only, and various modifications or variations to the specific embodiments described herein will be apparent to those skilled in the art and are to be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. 11. A method for treating acute brain injury in a patient in need thereof, comprising administering to the patient suffering from acute brain injury an effective amount of MW189.

2. 13. The method of claim 1, further comprising detecting one or more biomarkers to diagnose or assess the severity of acute brain injury, assess the patient's response to MW189, or a combination thereof.

3. 3. The method of claim 2, wherein the biomarker levels indicate the occurrence, severity, or both of acute brain injury, and a change in one or more biomarker levels indicates the patient's response to MW189.

4. a. detecting one or more biomarkers for diagnosing and assessing the severity of acute brain injury prior to administration of MW189; b. administering MW189; c. detecting said one or more biomarkers to assess changes in the severity of acute brain injury at a time point following administration of MW189; and d. The method of any one of claims 1 to 3, comprising continuing, ceasing, increasing, or decreasing administration of MW189.

5. The method of any one of claims 1 to 4, wherein the biomarker comprises neurofilament light chain.

6. The method according to any one of claims 1 to 5, wherein the acute brain injury is a hemorrhagic stroke.

7. The method of any one of claims 1 to 6, wherein the patient is a human.

8. 8. The method of any one of claims 1 to 7, wherein the administration is initiated within about 4 to 6 hours, about 6 to 12 hours, about 12 to 24 hours, or about 24 to 36 hours after the patient suffers from an acute brain injury.

9. 9. The method of any one of claims 1 to 8, wherein treating acute brain injury or intracranial hemorrhage comprises preventing morbidity and / or mortality or reducing the risk of morbidity and / or mortality.

10. 10. The method of any one of claims 1 to 9, wherein treating brain injury or intracranial hemorrhage comprises reducing the risk of morbidity and / or mortality in said patient.

11. The method of any one of claims 1 to 10, wherein treating brain injury or intracranial hemorrhage comprises reducing one or more inflammatory cytokines.

12. The method of claim 11, wherein the one or more inflammatory cytokines include TNF-α.

13. The method of any one of claims 1 to 12, wherein treating brain injury or intracranial hemorrhage comprises increasing one or more anti-inflammatory cytokines.

14. The method of claim 13, wherein the one or more anti-inflammatory cytokines include IL-10.

15. 15. The method of any one of claims 1 to 14, wherein the effective amount of MW189 is about 0.025 to 30 mg / kg.

16. 16. The method of claim 15, wherein the effective amount of MW189 is about 0.25 mg / kg.

17. 17. The method of any one of claims 1 to 16, comprising administering MW189 1 to 4 times per day.

18. 18. The method of claim 17, wherein MW189 is administered once or twice per day.

19. 20. The method of claim 18, wherein MW189 is administered twice per day.

20. 20. The method of any one of claims 1-19, wherein administering MW189 to the patient comprises administering MW189 to the patient for at least two consecutive days.

21. 21. The method of claim 20, comprising administering MW189 to the patient for 2, 3, 4, 5, 6, 7, 8, 9, 10 or more consecutive days.

22. 22. The method of any one of claims 1 to 21, wherein treating acute brain injury comprises preventing or reducing the risk of a brain infection.

23. 23. The method of any one of claims 1 to 22, wherein treating acute brain injury comprises reducing intracranial bleeding, preventing or reducing the risk of spreading bleeding, or both.

24. 24. The method of any one of claims 1 to 23, wherein treating acute brain injury comprises reducing perihematomal edema during and after treatment.

25. 25. The method of any one of claims 1 to 24, wherein treating acute brain injury comprises reducing secondary brain tissue damage caused by or resulting from acute brain injury.

26. 26. The method of any one of claims 1 to 25, comprising administering to a patient suffering from acute brain injury an effective amount of MW189 in combination with a therapeutic agent.

27. 26. The method of any one of claims 1 to 25, comprising administering to a patient suffering from acute brain injury an effective amount of MW189 in combination with an ion channel modulator.

28. 26. The method of any one of claims 1 to 25, comprising administering to a patient suffering from acute brain injury an effective amount of MW189 in combination with an ion channel modulator and a therapeutic agent.

29. 27. The method of claim 26, wherein the therapeutic agent comprises an antihypertensive agent, a diuretic agent, an antipyretic agent, an analgesic agent, or an anticonvulsant agent.

30. 28. The method of claim 27, wherein the ion channel modulator comprises nimodipine.

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