Use of magnetic resonance spectroscopy to calibrate and select doses, formulations, and devices for intranasal administration of n-acetylcysteine

Abstract

To provide the use of magnetic resonance spectroscopy to calibrate and select doses, formulations, and devices for intranasal administration of N-acetylcysteine.SOLUTION: The present disclosure describes methods of administering N-acetylcysteine (NAC) via intranasal administration. The effect of intranasal NAC administration can be monitored using an analytical technique, for example, magnetic resonance spectroscopy (MRS). In some embodiments, intranasal NAC can be used to treat a condition. In some embodiments, MRS can be used to monitor the effect of intranasal NAC administration or to modify the dosage of intranasal NAC administration to treat a condition.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Application No. 62 / 930,473, filed Nov. 4, 2019, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Background NAC is a precursor of L-cysteine that results in increased glutathione biosynthesis. NAC is a potent antioxidant that acts directly as a scavenger of free radicals, such as oxygen free radicals. NAC can be used as a treatment option for disorders resulting from the generation of free oxygen radicals. NAC has various multifaceted beneficial effects on acute and chronic central nervous system (CNS) disorders. A method of administering NAC and quantifying the effect of NAC on the brain is needed to improve the therapeutic use of NAC.

[0003] Incorporation by reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference.

Summary of the Invention

Means for Solving the Problems

[0004] Summary of the Invention Disclosed herein is a method of treating a condition, comprising: a) administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent, wherein the administering is intranasal; and b) quantifying, by magnetic resonance spectroscopy, the concentration of glutathione in a brain region after the administering.

Brief Description of the Drawings

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[0016] Detailed Description Concussion, also known as mild traumatic brain injury (mTBI), is a transient clinically detectable change in brain function caused by mechanical injury transmitted to the brain. The worldwide incidence of mTBI is approximately 42 million per year, with 100 to 300 per 100,000 individuals per year requiring medical treatment. The risk of mTBI, as well as repetitive mTBI and subconcussive injury, is increased in subgroups such as military personnel, athletes, and victims of domestic violence. mTBI in the general population can result from sustained blunt trauma in accidents, assaults, or participation in sports activities. The Centers for Disease Control (CDC) estimates that 1.6 to 3.8 million people in the United States experience sports- and recreation-related concussions each year. The direct and indirect costs attributable to concussion are estimated to exceed $17 billion per year in the United States alone.

[0017] In military personnel, blast injury is often the cause of concussion and more severe head injuries. 75 percent of head injuries due to blast are classified as mild. The incidence of mTBI in the military between 1997 and 2007 was approximately 6.6 per 1000 person-years, and 17% of Army veterans returning from Iraq or Afghanistan reported having persistent concussion, with over half reporting two or more persistent concussions.

[0018] N-acetylcysteine (NAC) is a synthetic small molecule. Figure 1 shows the biological activity of N-acetylcysteine. NAC has various pleiotropic beneficial effects on acute and chronic central nervous system (CNS) disorders through diverse biochemical and pharmacological mechanisms of action, including quenching of reactive oxygen species (ROS), chelation of oxidatively reactive metal ions, anti-inflammatory effects, and neuromodulation via the cystine-glutamate antiporter. NAC can also increase the concentration and bioavailability of the endogenous antioxidant glutathione (GSH), anti-excitotoxic activity, and heavy metal chelating activity.

[0019] This specification discloses a method of intranasally administering a compound of the disclosure and quantifying neurometabolites in the CNS using analytical techniques. This specification discloses a method of treating a condition, comprising: a) administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent in a step wherein the administering step is intranasal; and b) after the administering step, quantifying the concentration of NAC or NAC-neurometabolite in a brain region by magnetic resonance spectroscopy. This specification discloses a method of treating a condition, comprising: a) administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent in a step wherein the administering step is intranasal; and b) after the administering step, quantifying the concentration of glutathione in a brain region by magnetic resonance spectroscopy. In some embodiments, the therapeutic agent is NAC. In some embodiments, the therapeutic agent is NACA. In some embodiments, the therapeutic agent is an NAC derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the NAC derivative is GSH. In some embodiments, the therapeutic agent is an NAC homolog or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent is an NAC dendrimer (D-NAC) or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the disclosure provides a method of quantifying NAC-derived neurometabolites in the CNS using magnetic resonance spectroscopy (MRS). In some embodiments, MRS is used to determine the pharmacokinetics and pharmacodynamics of NAC, NACA, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, in healthy volunteers by quantifying NAC-derived neurometabolites. In some embodiments, MRS is used to determine the tolerable dose of intranasal NAC, NACA, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, by quantifying NAC-derived neurometabolites.

[0021] The present disclosure also describes methods of treating various brain disorders associated with oxidative stress or reactive oxygen species (ROS) that cause inflammation, excitotoxicity, and cell death. In some embodiments, an aqueous solution of volume-tolerated NAC, NACA, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof is administered to achieve a sufficient measure of brain bioactivity. In some embodiments, an aqueous solution of volume-tolerated NAC, NACA, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof may not be able to achieve a sufficient measure of bioactivity and may require the use of alternative delivery techniques and / or formulations. In some embodiments, novel combinations of formulations and devices are tested by monitoring MRS-GSH levels in the brain.

[0022] The methods described herein can administer NAC, NACA, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof. In some embodiments, NAC, NAC amide, NAC derivative, NAC metabolite, or an NAC homolog thereof is administered intranasally. In some embodiments, NAC, NAC amide, NAC derivative, NAC metabolite, or an NAC homolog thereof is administered intranasally using an atomizer, such as the Teleflex LMA® MAD Nasal™ intranasal mucosal spray device. In some embodiments, NAC, NACA, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof is administered intranasally using a nasal pump, such as the Aptar CPS 5mL nasal pump.

[0023] In some embodiments, the methods of the present disclosure can treat a brain condition. In some embodiments, the brain condition is a mild traumatic brain injury (mTBI). In some embodiments, the brain condition is cancer. In some embodiments, the brain condition is a central nervous system disorder. In some embodiments, the CNS disorder is Parkinson's disease.

[0024] Mechanism of action NAC, NACA, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, can treat a certain condition by acting as a cysteine or GSH precursor. GSH is an endogenous compound essential for intracellular defense against oxidative damage. GSH is a free radical scavenger and a very important component for maintaining the redox state of cells in the CNS. GSH contains three amino acids: glutamic acid, glycine, and cysteine. Cysteine exists at the lowest concentration intracellularly. In the presence of oxidative stress, the cysteine concentration becomes rate-limiting for GSH synthesis and thus depletes due to concussion-induced excitotoxicity and resulting changes in cell metabolism. The main mechanism of action of NAC is the ability of NAC-derived cysteine to act as a precursor for the synthesis and replenishment of cellular GSH stores. The strength of the effect of NAC on GSH concentration is partially controlled by the degree of endogenous cellular cysteine availability and the degree of endogenous GSH depletion. Correction of cellular GSH depletion is a major component of the putative neuroprotective effect of NAC in psychiatric and neurodegenerative disorders. The neuroprotective effect of NAC varies depending on the extent to which NAC and / or NAC-derived reduced sulfhydryl equivalents can access the central nervous system and enhance endogenous antioxidant activity.

[0025]

[0026] ​NAC can also reduce disulfide bonds in proteins, disrupt ligand binding, and alter protein structure. The ability of NAC to reduce disulfide bonds in mucolytic proteins is responsible for the action of NAC as an effective mucolytic agent. NAC can also act as a glutamatergic modulator. Cysteine in the nervous system can assist in regulating the intracellular and extracellular exchange of glutamate in neurons via a cystine-glutamate antiporter that is preferentially located on glial cells. Glial cells release glutamate into the extracellular space in response to cystine derived from NAC, stimulating inhibitory metabotropic glutamate receptors on glutamatergic nerve terminals, thereby reducing the synaptic release of glutamate, thereby affecting glutamatergic synaptic function and potentially improving post-injury neuroexcitotoxicity.

[0027] NAC acts as a free radical scavenger, directly quenching free radicals such as hydroxyl, nitrogen dioxide, carbonic acid, and thiyl radicals, and can detoxify semiquinone, hypochlorous acid, and nitrosyl hydride. Under physiological conditions, NAC does not react with nitric oxide, superoxide, hydrogen peroxide, or peroxynitrite. NAC can act as an anti-inflammatory agent. NAC has shown immunomodulatory activity in various experimental and clinical pro-inflammatory conditions, including human autoimmune disorders such as Sjögren's syndrome and systemic lupus erythematosus.

[0028] The compound of the present invention N-acetylcysteine (NAC) is a glutathione prodrug used to treat acetaminophen-induced liver failure and to alleviate individuals with thick mucus who have cystic fibrosis or chronic obstructive pulmonary disease. NAC can be administered intravenously, orally, or by inhalation as a mist. Common side effects of NAC include nausea and vomiting when administered orally. NAC can also cause skin flushing and itching, as well as non-immune type anaphylaxis. NAC has multiple putative targets of action and NAC has poor penetration into the CNS. NAC has been reported to cause nausea and vomiting, induce bronchospasm, delay blood clotting, and induce neurotoxicity in a dose-dependent manner. These problems can pose problems for patients with hemorrhagic stroke.

[0029] The present disclosure describes the use of at least one compound or a pharmaceutically acceptable salt thereof for treating a condition. In some embodiments, the compound is N-acetylcysteine (NAC), NAC amide (NACA), a NAC derivative, a NAC metabolite, a NAC homolog or a NAC dendrimer (D-NAC), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a NAC prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is NAC. In some embodiments, the compound is a NAC derivative. In some embodiments, the NAC derivative is GSH.

Chemical formula

[0030] In some embodiments, the compound is a NAC dendrimer. Dendrimer-NAC (D-NAC) is a dendrimer conjugate in which NAC is covalently attached to the surface of the dendrimer by a disulfide linkage. In some embodiments, D-NAC comprises a polyamidoamine (PAMAM) hydroxyl dendrimer. In some embodiments, D-NAC comprises a polyglycerol sulfate dendrimer. In some embodiments, D-NAC comprises a polyamine dendrimer. In some embodiments, D-NAC comprises a polyamide dendrimer. In some embodiments, D-NAC comprises a linker. In some embodiments, GABA comprises a gamma-aminobutyric acid (GABA) linker. In some embodiments, D-NAC comprises a succinimidyl 3-(2-pyridyldithio)propionate (SPDP) linker.

[0031] In some embodiments, D-NAC has the formula:

Chemical formula

[0032] In some embodiments, D-NAC has the formula:

Chemical formula

[0033] The purity of the compounds of the present invention Any compound of the present disclosure can be purified. The compounds herein are at least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 2 0% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure may be.

[0034] Detection method and clinical evaluation tool Magnetic resonance spectroscopy (MRS) is a technique related to magnetic resonance imaging (MRI). MRS, also known as nuclear magnetic resonance (NMR) spectroscopy, is a non-invasive analytical technique that does not use ionizing radiation and can detect and measure metabolic changes in organs, such as in the brain. MRS acquires signals from hydrogen protons in water and fat, which are approximately a thousand times more abundant than the molecules detected using MRS. In some embodiments, MRS is used to acquire signals from a single localized region of the brain, called a "voxel". In some embodiments, MRS can be used to determine the relative concentrations of biochemical substances within a region of the brain. In some embodiments, MRS can be used to determine the physical properties of a region of the brain.

[0035] In some embodiments, MRS can be used to determine the relative concentrations of metabolites within a region of the brain. In some embodiments, the methods of the present disclosure measure the concentration of a neurometabolic marker after intranasal administration of NAC, NACA, an NAC derivative, an NAC metabolite, an NAC homolog, or D-NAC, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods of the present disclosure measure the concentration of GSH after intranasal administration of NAC. In some embodiments, the methods of the present disclosure measure the change in the concentration of GSH after intranasal administration of NAC.

[0036] Also disclosed herein is a method of treating a brain disorder by monitoring the absorption of a compound of the present disclosure. In some embodiments, NAC, NACA, an NAC derivative, an NAC metabolite, an NAC homolog, or D-NAC, or a pharmaceutically acceptable salt thereof is administered to a subject, and the dosing of NAC, NACA, an NAC derivative, an NAC metabolite, an NAC homolog, or D-NAC, or a pharmaceutically acceptable salt thereof is It changes based on MRS analysis of the brain to determine the concentration of neurometabolites after intranasal administration of the salt. In some embodiments, the NAC derivative is GSH.

[0037] In some embodiments, the neurometabolic marker is an NAC neurometabolite. In some embodiments, the neurometabolite is N-acetylaspartic acid, lactate, glutamic acid, gamma-aminobutyric acid, or glutathione. In some embodiments, the NAC neurometabolite is glutathione. In some embodiments, the NAC neurometabolite is N-acetylaspartic acid.

[0038] In some embodiments, the methods of the present disclosure can detect the effects of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or pharmaceutically acceptable salts thereof as cysteine precursors. In some embodiments, NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or pharmaceutically acceptable salts thereof can increase GSH synthesis. In some embodiments, NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or pharmaceutically acceptable salts thereof can modulate gamma-aminobutyric acid (GABA) neurotransmission. In some embodiments, the effects of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or pharmaceutically acceptable salts thereof as cysteine precursors can be evaluated by measuring changes in GSH by quantifying the MRS signature of β-CH2 from the cysteine moiety.

[0039] The method of the present disclosure can further include Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS). In some embodiments, the method of the present disclosure can use MEGA-PRESS to separately but simultaneously measure changes in the MRS signature of β-CH2 common to both NAC and GSH after drug administration. In some embodiments, the method of the present disclosure can use MEGA-PRESS to determine the relative increase in the MRS signature of β-CH2 after dosing. In some embodiments, the method of the present disclosure can use MEGA-PRESS to region-specifically determine the conversion of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, to NAC-metabolites. In some embodiments, the method of the present disclosure can use MEGA-PRESS to region-specifically determine the conversion of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, to GSH. In some embodiments, the method of the present disclosure can use MEGA-PRESS to time-specifically determine the conversion of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, to GSH.

[0040] In some embodiments, the method of the present disclosure detects and quantifies changes in the concentration of NAC-neuro metabolites after administration of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, in order to at least optimize the delivery parameters for administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof. In some embodiments, the delivery parameter is the dose. In some embodiments, the delivery parameter is the dosing interval. In some embodiments, the delivery parameter is the dosing delivery system.

[0041] In some embodiments, the method of the present disclosure detects and quantifies changes in the concentration of NAC-neuro metabolites after administration of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, in order to optimize the presence of NAC in the brain. In some embodiments, the method of the present disclosure detects and quantifies changes in the concentration of NAC-neuro metabolites after administration of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC , or a pharmaceutically acceptable salt thereof, in order to optimize the presence of GSH in the brain. In some embodiments, the method of the present disclosure detects and quantifies changes in the concentration of NAC-neuro metabolites after administration of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, in order to optimize the presence of NAC and GSH in the brain.

[0042] In some embodiments, the method of the present disclosure detects and quantifies changes in the concentration of NAC-neuro metabolites after administration of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, in order to optimize the presence of NAC in a region of the brain. In some embodiments, the method of the present disclosure detects and quantifies changes in the concentration of NAC-neuro metabolites after administration of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, in order to optimize the presence of GSH in a region of the brain. In some embodiments, the method of the present disclosure detects and quantifies changes in the concentration of NAC-neuro metabolites after administration of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, in order to optimize the presence of NAC and GSH in a region of the brain.

[0043] The method of the present disclosure can further include the step of obtaining a biological sample for analysis. In some embodiments, the method further includes the step of quantifying the amount of free NAC in a plasma sample. In some embodiments, the method further includes the step of quantifying the amount of total NAC in a plasma sample. In some embodiments, the method further includes the step of quantifying the amount of plasma GSH. In some embodiments, the method further includes the step of quantifying the ratio of reduced GSH to oxidized GSH (GSH / GSSG). In some embodiments, the method further includes the step of quantifying the amount of NAC or NAC metabolite in a cerebrospinal fluid sample.

[0044] Several tools can be utilized to diagnose and evaluate the state of the brain, such as the clinical and neuropsychological characteristics of mild traumatic brain injury. In some embodiments, standard physical and neurological examinations, as well as neuropsychometric batteries and scales with broader applicability (e.g., Glasgow Coma Scale), can be used to diagnose and evaluate subjects with CNS conditions.

[0045] Post - concussion symptom score (PCSS): The PCSS score consists of 22 items that evaluate symptoms on a 7 - point scale. A score of 0 corresponds to no symptoms, and a score of 6 corresponds to severe symptoms. The PCSS score is useful in identifying individuals with clinically diagnosed concussion and predicting prolonged recovery in subjects 11 years of age and older. The PCSS score has also demonstrated test - retest reliability.

[0046] Graded Symptom Checklist (GSC): The GSC consists of 16 items scored on a 7-point scale. The GSC scale can be applied to subjects aged 13 and older and incorporates a three-factor structure (cognitive, physical, and neurokinetic). The GSC scale has demonstrated internal validity, test-retest reliability, and convergent validity with regard to balance and cognitive ability.

[0047] Standardized Concussion Assessment Tool (SCAT T): The SCAT is a standardized tool used by healthcare professionals and incorporates other assessment scales such as the GCS, Maddocks' questions for memory assessment, the PCSS, and other neurological and cognitive tests.

[0048] Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT): ImPACT is a computerized test battery that includes three components: demographic data, neuropsychological testing, and the PCSS. ImPACT has the advantage of including an assessment of cognition (e.g., attention, processing speed, impulsivity, and reaction time). ImPACT has a sensitivity of 81.9% and a specificity of 89.4% in combination with a scale for mTBI symptoms. There is no substantial implementation effect for ImPACT.

[0049] King-Devick Scale: The King-Devick Scale is a simple test that is acutely administered after a head injury, in which the subject must read a pattern of letters and numbers on a test card. The King-Devick Scale assesses language, attention, and eye movement, all of which can be impaired in CNS conditions such as concussion. The retest reliability of the King-Devick Scale over 1-2 years is equivalent to other standard assessment methods.

[0050] Biomarkers and Imaging: Electro-physiological techniques, imaging techniques, and blood tests can be used to evaluate the CNS status of a subject. Event-related potentials (ERPs) can be used to evaluate computer-processed electroencephalogram (EEG) signals with time locked to a permanent or cognitive task. In some embodiments, computed tomography (CT) and magnetic resonance imaging (MRI) can be used to diagnose or track the progression of a CNS condition. In some embodiments, diffusion tensor imaging can be used to diagnose or track the progression of a CNS condition.

[0051] Route of Administration The compounds of the present disclosure can be administered as a therapeutically effective amount in a pharmaceutical composition by various forms and routes, including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ocular, subcutaneous, transdermal, nasal, vaginal, and topical administration. In some embodiments, a therapeutically effective amount of the compounds of the present disclosure can be administered intranasally.

[0052] The compounds or pharmaceutical compositions of the present disclosure can be administered locally, for example, intranasally. Intranasal administration is an administration route in which the drug is insufflated through the nose. In some embodiments, intranasal administration can locally administer the compounds or pharmaceutical compositions of the present disclosure. In some embodiments, intranasal administration can systemically administer the compounds or pharmaceutical compositions of the present disclosure.

[0053] The rich vascular network of the nasal cavity that is readily accessible enables the locally administered drug to rapidly achieve therapeutically effective blood levels while at the same time avoiding the use of an intravenous catheter. In some embodiments, nasal administration can be used to deliver the compounds or pharmaceutical compositions of the present disclosure to the bloodstream. In some embodiments, nasal administration can be used to deliver the compounds or pharmaceutical compositions of the present disclosure to the blood. In some embodiments, nasal administration delivers the compounds or pharmaceutical compositions of the present disclosure to the blood, and thereby into the brain next. Intranasal administration of the compounds or pharmaceutical compositions disclosed herein avoids gastrointestinal tract destruction and first-pass metabolism in the liver, thereby enabling the compounds or pharmaceutical compositions to be most cost-effective and rapidly bioavailable compared to oral administration. In some embodiments, intranasal administration of the compounds or pharmaceutical compositions of the present disclosure can make the bioavailability of the compounds or pharmaceutical compositions more predictable compared to oral administration.

[0054] In some embodiments, intranasal administration of the compounds or pharmaceutical compositions of the present disclosure can have a higher absorption rate than subcutaneous or intramuscular administration. In some embodiments, intranasal administration of the compounds or pharmaceutical compositions of the present disclosure can result in a higher plasma concentration than subcutaneous or intramuscular administration. In some embodiments, intranasal administration of the compounds or pharmaceutical compositions of the present disclosure can rapidly achieve therapeutic drug concentrations in the brain and spinal cord.

[0055] The liquid pharmaceutical compositions of the present disclosure can be administered intranasally to a subject using a device. In some embodiments, the liquid formulation can be delivered as droplets using a pipette. In some embodiments, the liquid formulation can be delivered using a catheter and a delivery tube, such as a rhinyl catheter and delivery tube. In some embodiments, the liquid formulation can be delivered using a squeeze bottle.

[0056] In some embodiments, the liquid formulation can be administered intranasally using a mechanical spray pump. In some embodiments, the liquid formulation can be administered intranasally using a metered spray pump. In some embodiments, the liquid formulation can be delivered using a single-dose or two-dose spray device. In some embodiments, the liquid formulation can be delivered using a pressurized metered-dose inhaler (pMDI) for nasal use.

[0057] In some embodiments, the liquid formulation can be administered intranasally using a gas-driven spray system or an atomizer. In some embodiments, the liquid formulation can be administered intranasally using a nitrogen gas-driven system. In some embodiments, the liquid formulation can be administered intranasally using a powdered nebulizer or an atomizer. In some embodiments, the liquid formulation can be administered intranasally using a VibrENT pulsating membrane nebulizer. In some embodiments, the liquid formulation can be administered intranasally using an Aeroneb Solo vibrating mesh nebulizer. In some embodiments, the liquid formulation can be administered intranasally using a ViaNase atomizer. In some embodiments, the liquid formulation can be administered intranasally using a Teleflex LMA® MAD Nasal™ intranasal mucosal spray device. In some embodiments, the liquid formulation can be administered intranasally using an Aptar CPS 5mL nasal pump.

[0058] In some embodiments, the powder formulation can be administered intranasally using a device. In some embodiments, the powder formulation can be administered intranasally using a powder inhaler for nasal use. In some embodiments, the powder formulation can be administered intranasally using a powder sprayer for nasal use. In some embodiments, the powder formulation can be administered intranasally using a powder blower for nasal use. In some embodiments, the powder formulation can be administered intranasally using a Bi-Directional® technology device driven by respiration.

[0059] The compounds or pharmaceutical compositions of the present disclosure can be administered in various positions. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject in the supine position. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject in the sitting position. Pharmaceutical composition

[0060] The pharmaceutical compositions of the present invention may be a combination of any of the pharmaceutical compounds described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates the administration of the compound to an organism. The pharmaceutical compositions of the present invention can be used, for example, in combination with another pharmaceutical agent, for example, before, during, or after the treatment of a subject.

[0061] The subject may be, for example, an elderly person, an adult, a youth, a preadolescent youth, a child, an infant, a neonate, and a non-human animal. In some embodiments, the subject is a patient.

[0062] In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered to a subject having a disease or condition to be treated, in a pharmaceutical composition. In some embodiments, the subject is a mammal, such as a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, as well as other factors. The compound can be used singly or in combination with one or more therapeutic agents as components of a mixture.

[0063] The pharmaceutical composition can be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries that facilitate the processing of the active compound into a preparation that can be pharmaceutically used. The formulation can be modified according to the selected route of administration. The pharmaceutical compositions containing the compounds described herein can be manufactured, for example, by processes such as mixing, dissolving, emulsifying, encapsulating, entrapping, or compressing.

[0064] The pharmaceutical composition can include at least one pharmaceutically acceptable carrier, diluent or excipient, and the compounds described herein in free base or pharmaceutically acceptable salt form. The pharmaceutical composition can contain solubilizing agents, stabilizers, tonicity enhancing agents, buffers and preservatives. In some embodiments, the pharmaceutical composition of the present disclosure can include a stabilizer. In some embodiments, the stabilizer is Captisol®, Monosteol™, Vivapur® MCG591P, Vivapur® MCG611P, Vivapur® MCG811P, Neosorb sorbitol solution sweetener coating, HiCel MCG581, HiCel MCG591, or HiCel MCG611.

[0065] In some embodiments, the pharmaceutical composition of the present disclosure can include an absorption enhancer. In some embodiments, the absorption enhancer is a peptide or protein. In some embodiments, the absorption enhancer is calcitonin, desmopressin, insulin, leuprolide, or octreotide. In some embodiments, the absorption enhancer is a non-peptide macromolecule. In some embodiments, the absorption enhancer is heparin, low molecular weight heparin, enoxaparin, fondaparinux, oligonucleotide, or vancomycin. In some embodiments, the absorption enhancer is a hydrophilic small molecule. In some embodiments, the absorption enhancer is an aminoglycoside, amikacin, gentamicin, amphotericin B, or bisphosphonate.

[0066] The method for the preparation of a composition comprising a compound described herein involves formulating the compound together with one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, for example, solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, for example, gels, suspensions, and creams. The composition can exist as a liquid solution or suspension, a solid form suitable for dissolution or suspension in a liquid prior to use, or an emulsion. These compositions can also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives.

[0067] Non-limiting examples of dosage forms suitable for use in the present invention include liquids, powders, gels, nanosuspensions, nanoparticle formulations, microgels, aqueous or oily suspensions, emulsions, and any combination thereof.

[0068] Non-limiting examples of pharmaceutically acceptable excipients suitable for use in the present invention include binders, disintegrants, anti-adhesion agents, anti-static agents, surfactants, antioxidants, coating agents, colorants, plasticizers, preservatives, suspending agents, emulsifying agents, antibacterial agents, spheronization agents, and any combination thereof.

[0069] The pharmaceutical composition of the present disclosure may be in the form of an aqueous solution. In some embodiments, the pharmaceutical composition may contain about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, or about 25% to about 30% of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof in the aqueous solution. In some embodiments, the pharmaceutical composition of the present disclosure may contain about 5%, about 10%, about 15%, about 20%, about 25%, or about 30% of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof in the aqueous solution. In some embodiments, the pharmaceutical composition of the present disclosure may contain about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof in the aqueous solution. In some embodiments, the pharmaceutical composition of the present disclosure may contain about 15% of NAC, NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof in the aqueous solution. In some embodiments, the pharmaceutical composition of the present disclosure may contain about 20% of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof in the aqueous solution. In some embodiments, the pharmaceutical composition of the present disclosure may contain about 25% of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof in the aqueous solution.

[0070] The pharmaceutical composition of the present disclosure may be in the form of a dry powder. In some embodiments, the pharmaceutical composition can contain about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, or about 25% to about 30% of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof in the dry powder formulation. In some embodiments, the pharmaceutical composition of the present disclosure can contain about 5%, about 10%, about 15%, about 20%, about 25%, or about 30% of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof in the dry powder formulation. In some embodiments, the pharmaceutical composition of the present disclosure can contain about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof in the dry powder formulation. In some embodiments, the pharmaceutical composition of the present disclosure can contain about 15% of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof in an aqueous solution. In some embodiments, the pharmaceutical composition of the present disclosure can contain about 20% of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof in the dry powder formulation. In some embodiments, the pharmaceutical composition of the present disclosure can contain about 25% of NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof in the dry powder formulation.

[0071] Non-limiting examples of pharmaceutically acceptable excipients are, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 19 80, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), and they are hereby incorporated by reference in their entirety. Each of them is incorporated by reference in its entirety.

[0072] A plurality of therapeutic agents can be administered in any order or simultaneously. In some embodiments, the compounds of the present invention are administered before, after, or in combination with a treatment using another therapeutic agent. In the case of simultaneous administration, the plurality of therapeutic agents can be provided in an integrated single form or in multiple forms, such as multiple separate pills. The agents can be packaged together or separately in a single package or multiple packages. One or all of the therapeutic agents can be administered in multiple doses. If not simultaneous, the timing between multiple doses can vary up to a period of about one month.

[0073] The therapeutic agents described herein can be administered before, during, or after the onset of a disease or condition, and the timing of administration of the composition containing the therapeutic agent may vary. For example, the composition can be used as a prophylactic agent to reduce the likelihood of the occurrence of a disease or condition and can be administered continuously to a subject having a tendency for a condition or disease. The composition can be administered to the subject during the onset of symptoms or as soon as possible after the onset of symptoms. Administration of the therapeutic agent can be initiated within the first 48 hours, within the first 24 hours, within the first 6 hours, or within 3 hours of the onset of symptoms. The initial administration can be via any practical route, for example, using any of the formulations described herein by any of the routes described herein.

[0074] The compound can be administered as soon as possible after the onset of a disease or condition is detected or suspected for a period required for the treatment of the disease, for example, about 1 month to about 3 months, etc. In some embodiments, the period during which the compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years. The length of the treatment period can vary for each subject.

[0075] The compounds or pharmaceutical compositions of the present disclosure can be administered more than once. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure can be administered once a day. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure can be administered twice a day. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure can be administered three times a day. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure can be administered, and the administration can be repeated at least once. In some embodiments, the administration of the compound or pharmaceutical composition can be repeated once. In some embodiments, the administration of the compound or pharmaceutical composition can be repeated twice. In some embodiments, the administration of the compound or pharmaceutical composition can be repeated three times.

[0076] In some embodiments, the administration of the compound or pharmaceutical composition can be repeated after about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, or about 31 days. In some embodiments, the administration of the compound or pharmaceutical composition can be repeated after about 7 days. In some embodiments, the administration of the compound or pharmaceutical composition can be repeated after about 14 days.

[0077] The pharmaceutical compositions described herein may be in unit dosage forms suitable for single administration of precise dosages. In a unit dosage form, the formulation is divided into unit doses containing an appropriate amount of one or more compounds. The unit dosage may be in the form of a package containing separate amounts of the formulation. Non-limiting examples are packaged injections, vials, or ampoules. An aqueous suspension composition can be packaged in a non-resealable container for a single dose. A multi-dose resealable container can be used, for example, in combination with a preservative or without a preservative. Formulations for injection can be presented in unit dosage forms, for example in ampoules, or in multi-dose containers with a preservative.

[0078] The pharmaceutical compositions provided herein can be administered in combination with other treatments, such as chemotherapy, radiation, surgery, anti-inflammatory agents, and selected vitamins. The other agents can be administered before, after, or simultaneously with the pharmaceutical composition.

[0079] Depending on the intended mode of administration, the pharmaceutical composition can be in the form of a solid, semi-solid or liquid dosage form, for example, in a unit dosage form suitable for an exact dosage of a single administration, such as a powder, solution, suspension, lotion, cream, or gel.

[0080] In the solid composition, non-toxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.

[0081] Non-limiting examples of dosage forms suitable for use in the present disclosure include solutions, elixirs, nano-suspensions, aqueous or oily suspensions, drops, syrups, and any combination thereof. Non-limiting examples of pharmaceutically acceptable excipients suitable for use in the present disclosure include granulating agents, binders, lubricants, disintegrants, sweeteners, glidants, anti-adhesion agents, anti-static agents, surfactants, antioxidants, gums, coating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulose materials and spheronizing agents, and any combination thereof.

[0082] The composition of the present invention can be packaged as a kit. In some embodiments, the kit includes written instructions regarding the administration / use of the composition. The written material can be, for example, a label. The written material can suggest the conditions and methods of administration. The instructions provide the best guidance for the subject and the supervising physician to achieve the optimal clinical outcome from the administration of the treatment. The written material can be a label. In some embodiments, the label can be approved by a regulatory agency, such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies.

[0083] Dosage The compounds or pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of an exact dosage. In a unit dosage form, the formulation is divided into unit doses containing an appropriate amount of one or more compounds. The unit dosage can be in the form of a package containing separate amounts of the formulation. Non-limiting examples are liquids in vials or ampoules. An aqueous suspension composition can be packaged in a non-resealable container for a single dose. A multi-dose resealable container can be used, for example, in combination with a preservative. Formulations for parenteral injection can be in unit dosage forms, for example, in ampoules, or in multi-dose containers with a preservative. shown.

[0084] The dosage can be expressed, for example, in milligrams of drug per kilogram of the subject's body weight, with respect to the amount of drug divided by the mass of the subject. The compounds described herein are present in the composition in an amount of about 1 mg to about 2000 mg, about 100 mg to about 2000 mg, about 10 mg to about 2000 mg, about 5 mg to about 1000 mg, about 10 mg to about 500 mg, about 50 mg to about 250 mg, about 100 mg to about 200 mg, about 1 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 300 mg to about 350 mg, about 350 mg to about 400 mg, about 400 mg to about 450 mg, about 450 mg to about 500 mg, about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1000 mg. In some embodiments, the methods of the disclosure administer a therapeutically effective amount of about 100 mg to about 400 mg.

[0085] In some embodiments, the compound is administered in an amount in the range of about 5 mg / kg to about 50 mg / kg, 250 mg / kg to about 2000 mg / kg, about 10 mg / kg to about 800 mg / kg, about 50 mg / kg to about 400 mg / kg, about 100 mg / kg to about 300 mg / kg, or about 150 mg / kg to about 200 mg / kg. In some embodiments, the compounds described herein can be present in the composition in the range of about 20 mg / kg to about 400 mg / kg. In some embodiments, the compounds described herein can be present in the composition in the range of about 20 mg / kg to about 240 mg / kg. In some embodiments, the compounds described herein can be present in the composition in the range of about 75 mg / kg to about 150 mg / kg. In some embodiments, the compounds described herein can be present in the composition in the range of about 75 mg / kg to about 150 mg / kg. In some embodiments, the compounds described herein can be present in the composition in the range of about 100 mg / kg to about 150 mg / kg.

[0086] In some embodiments, the compounds described herein can be present in the composition in an amount of about 75 mg / kg. In some embodiments, the compounds described herein can be present in the composition in an amount of about 100 mg / kg. In some embodiments, the compounds described herein can be present in the composition in an amount of about 150 mg / kg. In some embodiments, the compounds described herein can be present in the composition in an amount of about 200 mg / kg. In some embodiments, the compounds described herein can be present in the composition in an amount of about 250 mg / kg. In some embodiments, the compounds described herein can be present in the composition in an amount of about 400 mg / kg.

[0087] The compounds described herein can be present in the composition in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, or about 2000 mg.

[0088] In some embodiments, the compounds described herein can be present in the composition in an amount of about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg. In some embodiments, the compounds described herein can be present in the composition in an amount of about 150 mg. In some embodiments, the compounds described herein can be present in the composition in an amount of about 170 mg. In some embodiments, the compounds described herein can be present in the composition in an amount of about 280 mg. In some embodiments, the compounds described herein can be present in the composition in an amount of about 300 mg. In some embodiments, the compounds described herein can be present in the composition in an amount of about 350 mg. In some embodiments, the compounds described herein can be present in the composition in an amount of about 400 mg.

[0089] Combination therapy The compounds or pharmaceutical compositions of the present disclosure can be administered together with at least one additional therapeutic agent. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure can be administered together with one additional therapeutic agent. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure can be administered together with two additional therapeutic agents. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure can be administered together with three additional therapeutic agents.

[0090] In some embodiments, the therapeutic agent is a 5-lipogenase activating protein (FLAP) inhibitor. In some embodiments, the FLAP inhibitor is MK-866 (L663536), quiflapon (MK-591), fiboflapon (GSK2190915, AM-803), veriflapon (BAY X1005, DG-031), AM679, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent is glutathione. In some embodiments, the therapeutic agent is nanoparticles decorated with glutathione.

[0091] In some embodiments, the therapeutic agent is a cathepsin B inhibitor. In some embodiments, the cathepsin B inhibitor is antipain dihydrochloride, CA-074, CA-074 methyl ester, calpain inhibitor I, calpain inhibitor II, chymostatin, cystatin, E-64, leupeptin trifluoroacetate, procathepsin B fragment, Z-Leu-Leu-Leu fluoromethyl ketone. In some embodiments, the cathepsin B inhibitor is antipain dihydrochloride. In some embodiments, the cathepsin B inhibitor is CA-074. In some embodiments, the cathepsin B inhibitor is cystatin. In some embodiments, the cathepsin B inhibitor is chymostatin.

[0092] In some embodiments, the therapeutic agent is a poly(ADP-ribose) polymerase (PARP) inhibitor. In some embodiments, the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, rucaparib, CEP9722, E7016, iniparib, or 3-aminobenzamide. In some embodiments, the PARP inhibitor is olaparib. In some embodiments, the PARP inhibitor is rucaparib. In some embodiments, the PARP inhibitor is niraparib. In some embodiments, the PARP inhibitor is talazoparib.

[0093] In some embodiments, the therapeutic agent is probenecid. In some embodiments, the therapeutic agent is fenceline. In some embodiments, the therapeutic agent is a dopaminergic agent.

[0094] Treatment method The present disclosure describes the use of a compound for treating a brain condition. In some embodiments, the brain condition is a neurological disorder. A neurological disorder is any disorder of the nervous system. Structural, biochemical, or electrical abnormalities in the brain, spinal cord, or other nerves can result in various symptoms. Examples of symptoms resulting from neurological disorders include paralysis, muscle weakness, poor coordination, loss of sensation, seizures, confusion, pain, and changes in the level of consciousness. In some embodiments, the present disclosure describes the use of a compound for treating a brain injury, such as an injury to a lobe of the brain (e.g., the basal ganglia, cerebellum, or brainstem), frontal lobe injury, parietal lobe injury, temporal lobe injury, or occipital lobe injury. In some embodiments, the present disclosure describes the use of a compound for treating brain dysfunction of the type of aphasia (language), agraphia (writing), dysarthria (speech), apraxia (pattern of movement sequence), agnosia (recognition of things or people), or amnesia (memory). In some embodiments, the present disclosure describes the use of a compound for treating spinal cord disorders, peripheral nerve disorders and other peripheral nervous system disorders, cranial nerve disorders (e.g., trigeminal neuralgia), autonomic nervous system disorders (e.g., autonomic neuropathy, multiple system atrophy), or seizure disorders (i.e., epilepsy).

[0095] In some embodiments, the brain condition is a movement disorder of the central and peripheral nervous systems, such as essential tremor, amyotrophic lateral sclerosis (ALS), Tourette syndrome, multiple sclerosis, Parkinson's disease, or peripheral neuropathy. In some embodiments, the movement disorder is Parkinson's disease. In some embodiments, the present disclosure describes the use of a compound for treating a sleep disorder (e.g., narcolepsy), migraine and other types of headache, or a central nervous disorder. In some embodiments, the present disclosure describes the use of a compound for treating a neuropsychiatric disorder, such as attention deficit hyperactivity disorder, autism, or obsessive-compulsive disorder.

[0096] In some embodiments, the brain condition is a CNS condition. CNS disorders are a group of neurological disorders that affect the structure or function of the brain or spinal cord that collectively form the CNS. The present disclosure describes the use of a compound for treating CNS disorders caused by traumatic brain injury, concussion, post-concussion syndrome, infection, degeneration (e.g., degenerative spinal disorders), structural defects (e.g., anencephaly, hypospadias, split spine, cerebellar hypoplasia, polymicrogyria, bilateral frontoparietal polymicrogyria, or pachgyria), tumors, autoimmune disorders, or stroke. In some embodiments, the present disclosure describes the use of a compound for treating traumatic brain injury. In some embodiments, the present disclosure describes the use of a compound for treating subarachnoid hemorrhage. In some embodiments, the present disclosure describes the use of a compound for treating concussion. In some embodiments, the present disclosure describes the use of a compound for treating post-concussion syndrome.

[0097] In some embodiments, the present disclosure describes the use of compounds for treating stroke. Stroke is a medical condition in which a reduction in blood flow to the brain results in cell death. The two main types of stroke are ischemic stroke, which results from a lack of blood flow, and hemorrhagic stroke, which results from bleeding. Symptoms and signs of stroke can include the inability to move or feel one side of the body, problems with understanding or speaking, and blindness in one eye. In some embodiments, the present disclosure describes the use of compounds for treating hemorrhagic stroke. In some embodiments, the present disclosure describes the use of compounds for treating ICH stroke.

[0098] In some embodiments, the compounds of the present disclosure can be used to treat cerebral insufficiency. In some embodiments, the compounds of the present disclosure can be used to treat aphasia (language), dysgraphia (writing), dysarthria (speech), apraxia (motor sequencing patterns), agnosia (recognition of things or people), or amnesia (memory). In some embodiments, the compounds of the present disclosure can be used to treat spinal cord disorders, peripheral nerve disorders, peripheral nervous system disorders, cranial nerve disorders, autonomic nervous system disorders, or seizure disorders. In some embodiments, the compounds of the present disclosure can be used to treat cranial nerve disorders, such as trigeminal neuralgia. In some embodiments, the compounds of the present disclosure can be used to treat autonomic nervous system disorders, such as autonomic neuropathy or multiple system atrophy. In some embodiments, the compounds of the present disclosure can be used to treat seizure disorders, such as epilepsy.

[0099] In some embodiments, the present disclosure describes the use of a compound for treating brain cancer. In some embodiments, the brain cancer is an astrocytoma of the brain or spinal cord. In some embodiments, the brain cancer is a brainstem glioma. In some embodiments, the brain cancer is a glioblastoma multiforme. In some embodiments, the brain cancer is a meningioma. In some embodiments, the brain cancer is an ependymoma. In some embodiments, the brain cancer is an oligodendroglioma. In some embodiments, the brain cancer is a mixed glioma. In some embodiments, the brain cancer is a pituitary cancer. In some embodiments, the brain cancer is a craniopharyngioma. In some embodiments, the brain cancer is a germ cell tumor, a tumor in the pineal region, a medulloblastoma, or a primary CNS lymphoma.

[0100] Administering NAC, NACA, an NAC derivative, an NAC metabolite, an NAC homolog or D-NAC, or a pharmaceutically acceptable salt thereof can change the concentration of NAC neuro-metabolites in the brain region. In some embodiments, administering increases the concentration of NAC neuro-metabolites in the brain region. In some embodiments, administering increases the concentration of NAC neuro-metabolites in the brain region by about 20% to about 300%. In some embodiments, administering increases the concentration of NAC neuro-metabolites in the brain region by about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, or about 95% to about 100%. In some embodiments, administering increases the concentration of NAC neuro-metabolites in the brain region by about 100% to about 110%, about 110% to about 120%, about 120% to about 140%, about 140% to about 160%, about 160% to about 180%, about 180% to about 200%, about 200% to about 220%, about 220% to about 240%, about 240% to about 260%, about 260% to about 280%, or about 280% to about 300%.

[0101] In some embodiments, administering increases the concentration of NAC neuro-metabolites in the brain region by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, or about 300%. In some embodiments, administering increases the concentration of NAC neuro-metabolites in the brain region by about 20%. In some embodiments, administering increases the concentration of NAC neuro-metabolites in the brain region by about 50%. In some embodiments, administering increases the concentration of NAC neuro-metabolites in the brain region by about 100%. In some embodiments, administering increases the concentration of NAC neuro-metabolites in the brain region by about 150%. In some embodiments, administering increases the concentration of NAC neuro-metabolites in the brain region by about 200%.

[0102] In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof modulates the NAC neuro-metabolite / water ratio in the brain region. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof modulates the GSH / water ratio in the brain region. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof increases the GSH / water ratio in the brain region. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof modulates the NAA / water ratio in the brain region. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof increases the NAA / water ratio in the brain region. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof increases the GSH / water ratio in the brain region. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof modulates the NAA / water ratio in the brain region. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof increases the NAA / water ratio in the brain region.

[0103] In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof increases the GSH / water ratio in the region of the brain by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In some embodiments, administering increases the GSH / water ratio in the region of the brain by about 10%. In some embodiments, administering increases the GSH / water ratio in the region of the brain by about 20%. In some embodiments, administering increases the GSH / water ratio in the region of the brain by about 30%. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof decreases the GSH / water ratio in the region of the brain by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In some embodiments, administering decreases the GSH / water ratio in the region of the brain by about 10%. In some embodiments, administering decreases the GSH / water ratio in the region of the brain by about 20%. In some embodiments, administering decreases the GSH / water ratio in the region of the brain by about 30%.

[0104] In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, increases the NAA / water ratio in a region of the brain by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In some embodiments, administering increases the NAA / water ratio in a region of the brain by about 10%. In some embodiments, administering increases the NAA / water ratio in a region of the brain by about 20%. In some embodiments, administering increases the NAA / water ratio in a region of the brain by about 30%. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, decreases the NAA / water ratio in a region of the brain by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In some embodiments, administering decreases the NAA / water ratio in a region of the brain by about 10%. In some embodiments, administering decreases the NAA / water ratio in a region of the brain by about 20%. In some embodiments, administering decreases the NAA / water ratio in a region of the brain by about 30%.

[0105] In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, modulates the NAC metabolite / creatine ratio within a brain region. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, modulates the GSH / creatine ratio within a brain region. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, increases the GSH / creatine ratio within a brain region. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, modulates the NAA / creatine ratio within a brain region. In one In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, increases the NAA / creatine ratio within a brain region.

[0106] In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, increases the GSH / creatine ratio in a region of the brain by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In some embodiments, administering increases the GSH / creatine ratio in a region of the brain by about 10%. In some embodiments, administering increases the GSH / creatine ratio in a region of the brain by about 20%. In some embodiments, administering increases the GSH / creatine ratio in a region of the brain by about 30%. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, decreases the GSH / creatine ratio in a region of the brain by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In some embodiments, administering decreases the GSH / creatine ratio in a region of the brain by about 10%. In some embodiments, administering decreases the GSH / creatine ratio in a region of the brain by about 20%. In some embodiments, administering decreases the GSH / creatine ratio in a region of the brain by about 30%.

[0107] In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, increases the NAA / creatine ratio in a region of the brain by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In some embodiments, administering increases the NAA / creatine ratio in a region of the brain by about 10%. In some embodiments, administering increases the NAA / creatine ratio in a region of the brain by about 20%. In some embodiments, administering increases the NAA / creatine ratio in a region of the brain by about 30%. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, decreases the NAA / creatine ratio in a region of the brain by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In some embodiments, administering decreases the NAA / creatine ratio in a region of the brain by about 10%. In some embodiments, administering decreases the NAA / creatine ratio in a region of the brain by about 20%. In some embodiments, administering decreases the NAA / creatine ratio in a region of the brain by about 30%.

[0108] In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, can increase the GSH / creatine ratio and decrease the NAA / creatine ratio within regions of the brain. In some embodiments, administering NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof, can increase the GSH / creatine ratio within regions of the brain by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, and decrease the NAA / creatine ratio by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% , or about 95%.

Example

[0109] (Example 1: Phase I Study of Intranasal NAC Brain Bioavailability and Safety) A single-site, single-blind, open-label, six-part Phase 1 study was conducted in healthy volunteers to evaluate the brain bioavailability, safety, and tolerability of IN NAC, as well as the 1 H-MRS measurements of NAC-derived neurometabolites. The brain bioavailability of NAC-derived neurometabolites was evaluated for three doses of IN NAC and compared to the effects of IN GSH. In addition, the effects of various formulations, dosing devices, and positioning during IN administration were evaluated. The comparative brain bioavailability of NAC was measured after administration of NAC by IN, IV, or oral administration. The effects of 7-day repeated dosing of NAC by IN, IV, or oral administration were determined using 1 H-MRS.

[0110] Measurements were made of pre- and post-dose NAC-derived brain metabolites during a single ascending repeated-dose study of IN NAC 1Obtained by H-MRS. Also obtain the blood levels of NAC (free and total), cysteine, GSH and the GSH / GSSG ratio, and obtain the measured values of cerebrospinal fluid (CSF) NAC before and after 7 days of repeated dosing. Evaluate safety and tolerability by reports of specific evaluations for adverse events, findings in physical neurological examinations, clinical test results, findings in electrocardiograms (ECGs), and nasal tolerability.

[0111] In each part of the study, participants undergo screening starting 28 days before the IP administration on Day 1. Subjects are required to sign an informed consent form (ICF) before receiving any study-specific procedures or evaluations. Based on inclusion and exclusion criteria, eligible participants are enrolled in the study. In each part of the study, monitor safety by evaluation of adverse events (AEs), the vulnerability assessment scoring tool (VAS-T), and the modified total nasal symptom (TNSS-M) score, electrocardiogram (ECG) results, vital signs, physical and neurological examinations, blood tests, and urine tests.

[0112] The pharmacokinetic (PK) and pharmacodynamic (PD) properties of single-dose IN GSH and single-dose escalating IN NAC are determined by measuring 1) the N-cysteinyl resonance of GSH and NAC and the N-acetyl resonance of NAC and N-acetylaspartic acid (NAA) as ratios to the water or creatine resonance of voxels in the dorsolateral prefrontal cortex (DLPF), occipital lobe, and striatum, represented as the 1 H-MRS measurements, and 2) the dose effect on NAC-derived neuro-metabolites as evaluated by the peripheral blood concentrations of GSH, free and total NAC, cysteine, and the GSH / GSSH ratio in RBCs. In each part of the study, complete the MRS analysis and collect PK samples before dosing and at 1, 3, 6, and 24 hours after dosing.

[0113] The effect of IN NAC administered using various devices and participant positioning during IP under different dosing conditions and formulations is determined by measuring NAC-derived neurometabolites in the voxels of interest using MRS. Measure the effect on the levels determined by MRS of 1) the aforementioned NAC-derived neurometabolites in the voxels of interest, 2) CSF NAC levels, and 3) peripheral blood concentrations of GSH, free and total NAC, cysteine, and the GSH / GSSH ratio of RBCs, for 7 days of twice-daily dosing of IN NAC.

[0114] Participant Population: The study is conducted with 72 healthy male and female volunteers included at the time of informed consent. Women of childbearing potential (WOCBP) may be included and must comply with contraception requirements during the study from screening through the follow-up period until study completion, and for at least 90 days after the final dosing of IP. WOCBP must demonstrate a negative pregnancy test at the time of screening and prior to the administration of IP. The maximum period of involvement for each participant from screening to study completion is approximately 64 - 78 days. Inclusion Criteria: 1) Volunteers between 18 and 45 years of age (inclusive) who are healthy at the time of informed consent; 2) Good general health as determined by medical history, physical examination, vital signs, clinical laboratory tests, and ECG. Isolated out-of-range values determined by the principal investigator (PI) or designated physician to be of no clinical significance may be permitted. The rationale for this determination must be documented in the participant's source data; 3) At screening, a body weight in the range of 50 - 120 kg (inclusive) and a body mass index (BMI) in the range of 19 - 28 kg / m

[0115] 2 ​Having a Body Mass Index (BMI) (including values at both ends); 4) Agreeing to refrain from alcohol intake for 24 hours before IP administration and for 24 hours before coming to all other outpatient medical treatments; 5) Agreeing not to use prescription drugs (except for contraception) within 14 days before IP administration and during the study period, except when approved by the PI and the sponsor's medical monitor; 6) Agreeing not to use over-the-counter (OTC) drugs (including corticosteroids, aspirin, pain medication, bloodletting agents, antihistamines) and herbal medications (including Hypericum perforatum) from within 14 days before IP administration until the 7-day follow-up visit, except when approved by the medical monitor. Occasional use of paracetamol (maximum 2 g / day) is permitted; 7) Agreeing to refrain from participating in contact sports from the start of the screening period until the 28-day follow-up; 8) WOCBP must not become pregnant from screening until the completion of the study including the follow-up period and must use a highly effective double-barrier contraception method that is permitted. The double-barrier contraception method is defined as the use of a condom (male or female, self-reported) and one of the following forms: an established hormonal contraception method (e.g., oral contraceptive pill [OCP], long-acting implantable hormone, injectable hormone, vaginal ring or intrauterine device [IUD]), evidence of a contraceptive surgery (e.g., tubal ligation, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) at least 6 months before screening. WOCBP who are in same-sex relationships or have no sexual relationships (abstinence from heterosexual intercourse, self-reported) do not need to use a contraception method if it is their preferred normal lifestyle not to use a contraception method. These WOCBP must agree to use the aforementioned highly effective permitted contraception method if they start or plan to start a heterosexual relationship from screening until 90 days after the final dosing of the study drug. WOCBP must have a negative pregnancy test at screening and on Day -1 and must be willing to undergo additional pregnancy tests as needed throughout the study.

[0116] Women who have no possibility of pregnancy (non-WOCBP) must be postmenopausal for at least 12 months after menopause. The postmenopausal state is confirmed by follicle-stimulating hormone (FSH) level testing at ≥40 IU / mL during screening for non-menstruating female participants. Non-WOCBP do not need to use contraception. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not considered highly effective methods of fertility regulation. Male participants involved in sexual relations with WOCBP must use an acceptable highly effective dual-barrier contraceptive method from screening until at least 90 days after the last dose of the study drug. The dual-barrier contraceptive method is defined as the use of a condom (male or female, self-reported) and, for WOCBP, the use of an effective contraceptive including being on OCP, long-acting implantable hormone, injectable hormone, vaginal ring or IUD (self-reported), or having had a contraceptive surgery (e.g., tubal ligation, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) (self-reported).

[0117] Men in same-sex relationships or with no sexual relationships at all (abstinence from heterosexual intercourse, self-reported) do not need to use contraception if it is their preferred normal lifestyle not to use contraception. These men must consent to use the aforementioned acceptable highly effective contraceptive methods if they start or plan to start a heterosexual relationship with a WOCBP from screening until 90 days after the last dose of the study drug.

[0118] Exclusion Criteria: 1) Women who are pregnant or lactating at the time of screening; 2) Those with nasal deformities, acute or chronic rhinosinusitis, which are known deviations of the nasal septum, or a history of recent (<5 years) surgery on the nasal cavity and / or nasopharynx; 3) A history of seizures or epilepsy within the past 5 years; 4) A history of moderate to severe traumatic brain injury; 5) A history of concussion within the past 1 year; 6) A history of any clinically significant medical disease or medical disorder that the investigator deems should exclude the participant, including but not limited to current cardiovascular, neurological, musculoskeletal, hematological, respiratory, skin, liver, or neoplastic diseases or immunodeficiency states; 7) A psychiatric or behavioral condition that may interfere with participation in the study; 8) Acute upper respiratory diseases including colds within 14 days prior to IP administration, or having had a serious illness or being hospitalized within 1 month of screening; 9) Major surgery within 12 weeks of screening; 10) Any participant who has a planned elective surgery before the end of the study including within 4 weeks prior to IP administration and the follow-up period; 11) Positive serological tests for HIV antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibodies at the time of screening; 12) A recent history of alcohol or drug abuse (within the past 6 months); 13) Having smoked tobacco or related products within 3 months prior to dosing; 14) Positive urine drug tests for substance abuse including but not limited to cocaine, cannabinoids, amphetamines, benzodiazepines, opioids, tricyclic antidepressants, and methadone at the time of screening and / or at any point during the study. Participants may be re-screened once at the discretion of the investigator after a positive result; 15) Positive alcohol breath tests at the time of screening and / or at any point during the study.Patients are required to refrain from alcohol for at least 24 hours before the first-day IP administration and the study evaluation day; 16) consuming an average of approximately more than 500 mg / day of caffeine per day (contained in 5 cups of tea or coffee, or 8 cans of soda or other caffeinated products); 17) donating blood within 60 days before screening; 18) having a history of active drug and / or food allergies or other active allergic diseases that require regular use of medications, or a history of severe allergic reactions, angioedema or anaphylaxis; 19) having received any other experimental treatment, including devices or investigational drugs, within 30 days or 5 half-lives (whichever is longer) of IP administration; 20) being unable to undergo an MRI scan due to the presence of non-removable metal implants, including but not limited to surgical staples, pacemakers, steel IUDs, claustrophobia or any other contraindications.

[0119] Statistical methods Pharmacokinetics: The changes in the MRS spectra of the targeted metabolites from baseline to each time point after dosing and the pharmacokinetic evaluation (concentrations of free and total NAC, cysteine and GSH, as well as the GSH / GSSG ratio, and the NAC level in CSF) are summarized using descriptive statistics.

[0120] Safety and tolerability: Participants are evaluated for IP tolerability several times during the study using a visual analog scale (VAS) where a value of 0 indicates very good tolerability and a value of 10 indicates very low tolerability. Subjects also complete the TNSS-M, thereby evaluating five specific nasal symptoms (i.e., congestion, rhinorrhea, sneezing, pain and painless burning) on a scale of 0 - 3. Only items scored as "3" (severe) on the TNSS-M are reported as adverse events.

[0121] Adverse events are coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA®). Provide a list of participant-specific AE data, including reporter terms, preferred terms (PTs), system organ classes (SOCs), severity, and relationship to the IP. Summarize the number of participants who experienced treatment-emergent adverse events (TEAEs) and the number of individual TEAEs by SOC, PT, and relationship to severity and the IP. Summarize clinical laboratory evaluations, vital sign evaluations, and ECG parameters for each scheduled visit. Present an overview of the changes from baseline at each time point specified by the protocol.

[0122] Previous medications and concomitant medications are coded using the latest version of the World Health Organization (WHO) Drug Dictionary available at the start of the study, listed by the participant, and summarized by treatment and preferred name using the Anatomical Therapeutic Chemical (ATC) (level 2). Medical history, pregnancy / FSH testing, urine drug screening / alcohol breath testing, physical and neurological examinations, and serology (HIV, hepatitis B, and hepatitis C screening) are listed by the participant.

[0123] Primary objective: The primary objective of the study is to evaluate the brain bioavailability of intranasal (IN) NAC using proton magnetic resonance spectroscopy ( 1 1H-MRS) assessment of changes from baseline in NAC-derived metabolic markers in healthy adult volunteers.

[0124] Secondary Objectives: The secondary objectives of the study include the following: 1) to evaluate the safety and tolerability of IN NAC; 2) to evaluate the time course and local CNS pharmacodynamic activity of IN NAC; 3) to compare the pharmacokinetics and pharmacodynamic activity of IN NAC with that of IN GSH; 4) to compare devices and positioning during administration of the investigational product (IP) for optimal delivery of IN NAC from nose to brain; 5) to evaluate the local CNS pharmacodynamic activity, safety, and tolerability of IN NAC after multiple repeated IN dosing; and 6) to evaluate the pharmacokinetic profile of NAC in blood and cerebrospinal fluid (CSF) after IN administration.

[0125] Screen Failure: Screen failure is defined as a volunteer who has consented to participate in a clinical study but is not subsequently enrolled. A transparent report of screen failure participants is required to ensure compliance with the public disclosure requirements of the Consolidated Standards of Reporting Trials (CONSORT) and to respond to questions from regulatory authorities. The minimum set of screen failure information includes details of the screen failure, eligibility criteria, and any serious adverse events (SAEs). Individuals who do not meet the eligibility criteria for participation in this study (screen failures) are re-screened at the discretion of the investigator in consultation with the medical monitor (MM) if possible during the recruitment period of the study. Participants who undergo re-screening are assigned the same number of participants as in the initial screening.

[0126] Participant Replacement: Participants who have signed and registered on the informed consent form (ICF) but have not received the IP may be replaced. Participants who have signed and registered on the ICF, received the IP, but subsequently withdraw, or are withdrawn or discontinued from the study, may be replaced at the discretion of the sponsor.

[0127] Participant Withdrawal Criteria: Participants may withdraw their consent to participate in the study at any time. If a participant withdraws their consent, the date and reason for the withdrawal are recorded. Participants are recommended to stay in the hospital until all necessary evaluations are completed and the researcher deems it safe for them to be discharged. Participant data is included in the analysis up to the date of withdrawal of consent.

[0128] Identify the main reasons for withdrawal and record them in the appropriate eCRF along with the withdrawal date. In accordance with the applicable rules, participants have the right to withdraw from the study at any time for any reason without prejudice to their right to future medical treatment. If a participant withdraws due to an AE, the researcher arranges for the participant to receive appropriate follow-up care until the AE resolves or stabilizes. Unresolved AEs are followed up until the scheduled final follow-up visit or until the PI and MM determine that no further follow-up is indicated. In addition to AEs, other reasons for participant discontinuation from the study may include, but are not limited to, withdrawal of consent, administrative decisions by the researcher or sponsor, protocol deviation, or participant non-compliance.

[0129] If a participant requests or decides to withdraw from the study, every effort is made to complete the observations as fully as possible up to the date of withdrawal, particularly for the specifically listed primary and secondary objectives, and to report them. Whenever possible, for all participants who discontinue before the study is completed, tests and evaluations are performed, including those listed for follow-up visits.

[0130] Participant Completion Criteria: Reasons for early termination of individual participants may include, but are not limited to, protocol deviation or participant non-compliance (which must be identified in the appropriate electronic case report form [eCRF]); pregnancy; serious or severe AE; administrative decisions by the researcher or sponsor; death; or other (which must be identified).

[0131] Lost to follow-up: A participant is considered lost to follow-up if they do not return for one of the scheduled visits and cannot be contacted by the study staff. If a participant is unable to return for the required study visits, the following actions are taken. The facility attempts to contact the participant, reschedules any missed visits within two days, advises the participant of the importance of maintaining the assigned visit schedule, and confirms whether the participant wishes to continue in the study. Before a participant is considered lost to follow-up, the investigator or designee makes every effort to re-establish contact with the participant (three telephone calls, as well as contact by email and text message). These attempts at contact are recorded in the participant's medical record or study file. A participant is considered to have withdrawn from the study for the primary reason of being lost to follow-up if the staff is unable to contact the participant.

[0132] (Example 2: Investigational Product, Dosage, and Route of Administration) Participants receive one or more of the IP formulations and dosages of NAC. The dose of IN NAC that results in an approximate 13% increase in brain GSH is considered the minimum effective dose.

[0133] NAC administered intranasally: For intranasal (IN) administration of NAC, a 20% aqueous solution of NAC or equivalent for inhalation is administered intranasally at the following dosages. i) 100 mg (0.5 mL) - approximately 0.25 mL per nostril per dose, ii) 200 mg (1.0 mL) - approximately 0.50 mL per nostril per dose, or iii) 400 mg (2.0 mL) - approximately 0.50 mL once in each nostril, with the administration repeated after 5 minutes. The 20% NAC solution is supplied as a colorless, clear solution in 4 mL or 30 mL glass vials. The solution contains acetylcysteine at 200 mg / mL (20% w / v) along with disodium edetate, sodium hydroxide, and water. The product may also contain hydrochloric acid for pH adjustment. The pH is maintained in the range of 6.0 - 7.5. The 20% solution of NAC is administered by one of two devices: a) Teleflex LMA® MAD Nasal™ intranasal mucosal spray device, or b) Aptar CPS 5 mL nasal pump.

[0134] GSH administered intranasally: For IN administration of GSH, a 20% aqueous solution of GSH or equivalent is administered intranasally at a dosage of 200 mg (1.0 mL), approximately 0.50 mL per nostril. IN GSH is administered using the Teleflex MAD device.

[0135] NAC administered orally: For oral administration of NAC, a 200 mg / mL solution of NAC (20% w / v) is used. NAC for oral administration is prepared by diluting 20 mL of a 20% NAC solution with 60 mL of diet soft drink, thereby providing a dosage of 4,000 mg of NAC in a 5% solution.

[0136] IV NAC: Use a 200 mg / mL NAC solution or equivalent for injection for IV administration. Dilute an amount of NAC solution equivalent to 150 mg / kg of NAC with 200 mL of 0.45% aqueous sodium chloride solution and administer IV over 1 hour. Provide 200 mg / mL NAC (acetylcysteine) injection solution as a colorless, clear, sterile solution containing 20% w / v acetylcysteine in a 30 mL vial. The solution also contains sodium hydroxide for pH adjustment and sterile water for injection.

[0137] Device for administration: IP is administered using 1) the LMA® MAD Nasal™ nasal mucosal spray device, or 2) the Aptar CPS 5 mL nasal pump.

[0138] Storage of investigational product: Upon receipt of the 20% acetylcysteine solution for inhalation, store at controlled room temperature in a light-protected area and maintain at a temperature below 25°C. The undiluted solution remaining in an opened vial is stored under refrigeration and used within 96 hours. The GSH solution is stored at controlled room temperature. Unopened IV NAC solution is stored at controlled room temperature, and an already-opened IN NAC vial is not used for IV administration.

[0139] (Example 3: Research evaluation and measurement) Pharmacodynamic evaluation: For pharmacodynamic evaluation, after a single dose of IN NAC to healthy volunteers, at 1, 3, 6, and 24 hours after dosing 1 Changes from baseline in the concentrations of NAC-derived neuro-metabolites in three brain regions (i.e., occipital cortex, striatum, and DLPF) using H-MRS are included.

[0140] 1H-MRS analysis is performed using a 3.0 cm × 3.0 cm × 2.5 cm voxel placed in the left dorsal striatum at the levels of the lens nucleus, occipital cortex, and dorsolateral prefrontal field (DLPF). The J-edited spin echo difference method is performed at an echo time (TE) of 70 ms and a repetition time (TR) of 1500 ms using 240 alternating excitations (total 480) during an acquisition time of 12.5 minutes per voxel. A pair of frequency-selective inversion pulses is inserted into the standard point-resolved spectroscopy to apply to the alternating scans at the frequency of the reduced form of the glutathione α-cysteinyl resonance at 4.56 ppm while avoiding excitation of the oxidized form of the glutathione α-cysteinyl resonance at 3.28 ppm. By subtracting the resulting two inverse sub-spectra of GSH, 1 H-MRS is obtained. The 32-channel phased array coil GSH data is combined with the non-suppressed voxel tissue water signal from each receiver coil element to obtain the required relative phased array coil sensitivity for a single regular time-domain free-induction decay signal. Metabolite concentrations are estimated by calculating the areas of the individual spectral peaks obtained by fitting each resonance to a Gauss-Lorentz lineshape function in the frequency domain using the Levenberg-Marquardt non-linear least squares algorithm.

[0141] Pharmacokinetic evaluation: Pharmacokinetic evaluation includes peripheral blood measurements of GSH, cysteine, free and total NAC, and the reduced GSH to oxidized GSH ratio (GSH / GSSG ratio) 1 hour, 3, 6, and 24 hours after IN NAC or GSH administration, and the NAC level in CSF obtained by lumbar puncture 6 hours after IP administration in parts 5 and 6 of the study.

[0142] Blood PK Sample Collection: Blood PK samples are collected, whenever possible, immediately prior to the acquisition of MRS data at each specified time point of the evaluation schedule. Blood PK measures the concentrations of free and total NAC, cysteine, and GSH, as well as the GSH / GSSG ratio. GSH / GSSG is measured in whole blood using high performance liquid chromatography (HPLC) coupled with a mass spectrometer (MS). The total protein-bound and total protein-unbound concentrations of NAC, Cys, and GSH are measured in plasma using a validated HPLC-MS assay.

[0143] Pharmacodynamic Endpoints: MRS of NAC-derived brain metabolites in the three target regions (occipital cortex, striatum, DLPF) at baseline and 1, 3, and 6 hours after IN NAC are summarized using descriptive statistics. The changes from baseline to each post-dose measurement are descriptively summarized. Statistical tests based on a priori inference are not planned. The target brain regions and the timing of MRS are revised based on the initial results.

[0144] Pharmacokinetic Endpoints: Descriptive summaries of quantifiable concentrations of the target metabolites are reported for the specified time points to evaluate the concentrations of free and total NAC, cysteine, and GSH, as well as the reduced GSH to oxidized GSH ratio (GSH / GSSG).

[0145] Safety and Tolerability: All safety evaluations, including previous medications and concomitant medications, AEs, clinical laboratory evaluations, vital signs, ECG, and other safety evaluations, are summarized using the safety population.

[0146] Previous Medications and Concomitant Medications: Previous medications and concomitant medications are coded using the latest version of the WHO Drug Dictionary available at the start of the study. Previous medications and concomitant medications are listed by the participants and summarized by treatment and basic terms using ATC (level 2).

[0147] Adverse Events: Adverse events are coded using the latest available version of MedDRA®. Provide a list of participant-specific AE data, including the relationship to reporter terms, PT, SOC, severity, and IP. Summarize the number of participants experiencing TEAEs and the number of individual TEAEs by relationship to SOC, PT, severity, and IP.

[0148] Other Safety Assessments: Other safety assessments enumerated by participants include medical history, pregnancy tests, urine drug screening, alcohol breath tests, physical and neurological examinations, and serology (e.g., HIV, hepatitis B, hepatitis C).

[0149] Safety Parameters: Complete the study procedures as described in the assessment schedule. If a participant is unable to attend within the specified time frame, the investigator or designee will discuss appropriate scheduling with the sponsor's MM or appropriate designee. Any unscheduled procedures necessary for the urgent assessment of safety concerns take precedence over all scheduled routine procedures.

[0150] Demographics and Medical History: Record medical history (e.g., concomitant medications, alcohol and smoking status, and drug use), date of birth, age (in years), sex, ethnicity, and race at screening time.

[0151] Vital Signs: Enumerate vital signs (e.g., blood pressure [systolic and diastolic], pulse rate, respiratory rate, and body temperature) and summarize at the collection time points specified by the protocol. Summarize changes from the observed baseline at each collection time point specified by the protocol. If the measurement time for vital signs is simultaneous with blood sampling, take the vital signs before the scheduled blood sampling, if possible, to ensure that blood sampling is performed within the time frame specified in the protocol. Take additional vital signs at other times if deemed necessary.

[0152] Weight and height: Measure height and weight at the time of screening and use them to calculate the BMI. The BMI is calculated by dividing the participant's weight in kilograms by the square of the participant's height in meters (kg / m2). Obtain weight and height with the participant having removed their shoes and jacket or coat.

[0153] Physical and neurological examinations: Comprehensive and brief physical and neurological examinations are performed by a qualified physician at specified time points in the evaluation schedule. The comprehensive physical examination includes general appearance, head, ears, eyes, nose, throat, dentition, thyroid, chest (heart, lungs), abdomen, skin, nerves, extremities, back, neck, musculoskeletal, and lymph nodes. The neurological examination includes assessment of mental status and cranial nerve function, motor and sensory systems, gait / coordination, and deep tendon reflexes. The brief physical examination includes the head, ears, eyes, nose, throat, chest (heart, lungs), abdomen, skin, musculoskeletal, and lymph nodes and any associated systems based on any past findings. The brief neurological examination includes assessment of eye movements, facial symmetry, drift of upper extremities, coordination (finger-to-nose and heel-to-toe tests), and deep tendon reflexes. Physical and neurological examinations are performed at various unscheduled times if considered necessary by the researcher.

[0154] Tolerance assessment: Participants rate their IP tolerance using the VAS-T, which uses values of 0 indicating very good tolerance and 10 indicating very low tolerance, at specified times during the study. Participants also complete the TNSS-M, thereby rating five specific nasal symptoms (congestion, rhinorrhea, sneezing, pain, and painless burning) on a scale of 0 to 3. Report only items scored as "3" (severe) on the TNSS-M as adverse events.

[0155] Electrocardiogram: Enumerate the ECG values and summarize them at the collection time points specified by the protocol. Summarize the changes from the observed baseline at each collection time point specified by the protocol. Take a 12-lead ECG at the time points described in the evaluation schedule. If deemed necessary, perform additional ECG monitoring at other times. The ECG is performed on the supine participant before the vital signs. The participant is in the supine position for at least 5 minutes before the reading is taken. All ECG tracings are reviewed by the PI or designee. If the time for ECG monitoring is concurrent with blood sampling, perform the ECG before the scheduled blood sampling and ensure that the blood sampling is carried out within the time frame specified in the protocol.

[0156] Clinical laboratory evaluation: Enumerate the clinical laboratory evaluations including hematology, serum biochemistry, and urine tests and summarize them at each collection time point specified by the protocol. Summarize the changes from the observed baseline clinical laboratory data at each collection time point specified by the protocol. Collect blood samples for safety clinical laboratory tests (hematology, serum biochemistry, and urine tests) at the time points specified in the evaluation schedule. If deemed necessary based on the participant's clinical status, perform additional clinical laboratory tests at other times.

[0157] The hematological parameters to be examined are hemoglobin (HGB); hematocrit (HCT); red blood cells (RBC); platelets (PLAT); and white blood cell fractions including eosinophils (ESN), neutrophils (NEUT), basophils (BASO), lymphocytes (LYM), and monocytes (MONO). The serum biochemical parameters to be examined are urea (BUN), creatinine (CREAT), total bilirubin (BILI) and direct bilirubin (BILIDIR), uric acid (URATE), albumin (ALB), globulin (GLOBUL), alkaline phosphatase (ALP), creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-GT (GGT), glucose (GLU), sodium (NA), potassium (K), calcium (CA), chloride (CL), phosphate (PHOS), bicarbonate (BICARB), and lactate dehydrogenase (LDH).

[0158] Urinalysis: A urinalysis test (urine test strip) is performed on each participant. Urine samples are taken at the time of screening. If abnormalities are observed for protein, blood, nitrite, or leukocyte esterase (at the discretion of the researcher), microscopic examination of red blood cells, white blood cells, bacteria, and casts is performed. The macroscopic urinalysis parameters to be examined are pH (PH), specific gravity (SPGRAV), creatinine (CREATININE), protein (PROT), glucose (GLUC), ketones (KETONES), total bilirubin (BILI), occult blood (OCCBLD), nitrite (NITRITE), urobilinogen (UROBIL), and white blood cells (WBC).

[0159] Viral serology: HBsAg, anti-HCV, and HIV antibody tests are performed at the time of screening.

[0160] Urinary drug screening and alcohol breath test: Urinary drug screening is performed at screening, before dosing on Day 1, and at the 7-day follow-up visit. Urinary drug screening includes, but is not limited to, cocaine, cannabinoid, amphetamine, benzodiazepine, opioid, tricyclic antidepressant, and methadone. Alcohol breath test is performed at screening, before dosing on Day 1, and at the 7-day follow-up visit.

[0161] Pregnancy test and follicle-stimulating hormone test: Serum pregnancy test is performed only for WOCBP at the screening visit. Urine pregnancy test is performed before dosing on Day 1. If the result is positive, a serum test is performed for confirmation. Women with no possibility of pregnancy must be postmenopausal (defined as at least 12 months of normal menstrual cycle cessation). The postmenopausal state is confirmed by testing FSH levels ≥ 40 IU / mL at screening.

[0162] Adverse and serious adverse events: AEs are reported for all participants from consent to the completion of the follow-up visit. Serious adverse events are reported for all participants (enrolled and unenrolled) from consent to the completion of the follow-up visit. Adverse events reported from consent to dosing are recorded as pre-treatment AEs. Treatment-emergent AEs (TEAEs) are evaluated from the first administration of the IP to the follow-up visit or up to 30 days of follow-up period for AEs considered related to the treatment. Adverse events ongoing at the final follow-up are marked as not recovered / resolved on the AE eCRF page. All spontaneously reported, queried, and observed AEs are recorded in the participant's medical record and eCRF.

[0163] An AE is any event, side effect, or other unfavorable medical occurrence associated with the use of a medicinal product in humans, regardless of whether it is considered to have a causal relationship with this treatment. It is an adverse event. An AE can be any unfavorable unintended sign that can include clinically significant abnormal clinical findings, symptoms, or diseases that are temporally related to the use of a pharmaceutical product, regardless of whether it is considered related to the pharmaceutical product.

[0164] Events that meet the definition of an AE include: 1) exacerbation of an existing chronic or intermittent condition, including either an increase in the frequency and / or intensity of the condition; 2) a new condition that occurs during the reporting period and is detected or diagnosed after IP administration, even if it was present before the start of the study; 3) signs, symptoms, or clinical sequelae of a suspected interaction; and 4) signs, symptoms, or clinical sequelae of a suspected overdose of either the IP or a concomitant medication (the overdose itself is reported as an AE / SAE).

[0165] Events that do not meet the definition of an AE include: 1) medical or surgical procedures (e.g., endoscopy, appendectomy), the conditions leading up to the procedure are reported as AEs if they meet the AE criteria; 2) situations where no adverse medical events occurred (e.g., social and / or convenience hospitalization); and 3) expected daily fluctuations of existing diseases or conditions that do not worsen and are present or detected at the start of the study. If there is evidence of an AE by report or observation, the investigator or designee further evaluates and records the following information: time of onset and resolution, severity, seriousness, causal relationship / relationship to the study treatment, actions taken regarding the IP, actions taken regarding the AE, and the outcome. Only items scored as "3" (severe) on the TNSS-M are reported as adverse events.

[0166] Severity of Adverse Events: The severity of an AE is graded by the investigator as one of the following: 1) Mild (Grade 1): An AE that is typically transient and may require minimal treatment or therapeutic intervention. The event generally does not interfere with normal activities of daily living. 2) Moderate (Grade 2): An AE that is typically alleviated by additional specific therapeutic intervention. The event interferes with normal activities of daily living and causes discomfort but does not pose a significant or permanent harm risk to the study participant. 3) Severe (Grade 3): An AE that interferes with normal activities of daily living, or significantly affects the clinical condition, or may require intensive therapeutic intervention. 4) Life-threatening (Grade 4): An AE that exposes the participant to an imminent risk of death. And 5) Death (Grade 5): An event that results in death.

[0167] Causality of Adverse Events: Researchers evaluate the relationship between the IP and the occurrence of each AE. The researchers' evaluation of the relationship between each AE and the IP is recorded in the source materials and eCRF. When appropriate, other causes such as medical history, concomitant treatments, other risk factors, and the temporal relationship with the IP of the event are considered and investigated. The following definitions are general guidelines to assist in the assignment of grades of attributes. 1) Unrelated: The event is clearly related to other factors such as the participant's environment or clinical condition, treatment intervention, or concomitant medications administered to the participant. This is particularly applicable when the event occurs prior to the initiation of the treatment using the IP. 2) Low probability: The temporal association, the participant's medical history, and / or the surrounding circumstances are such that it is unlikely that the IP is related to the observed event. Other conditions, including co-existing diseases, progression or emergence of the medical condition, or reaction to the concomitant medications administered, are thought to explain the event. 3) Possible: The event follows a reasonable time series from the time of IP administration or follows a known response to the IP, but may have been caused by other factors such as the participant's clinical condition, other treatment interventions, or concomitant medications administered to the participant. 4) High probability: The event follows a reasonable time series from the time of IP administration and follows a known response to the IP and cannot be reasonably explained by other factors such as the participant's clinical condition, other treatment interventions, or concomitant medications administered to the participant. And 5) Definite: The event follows a reasonable time series from the time of IP administration or resolves under control upon discontinuation or cannot be explained by the known characteristics of the participant's clinical condition.

[0168] Predictable: MM is involved in determining whether an AE is predicted or not. If the nature, severity, or frequency of the event does not match the risk information, the AE is considered not to be predicted.

[0169] Outcome: The outcome of the AE is recorded in the AE's eCRF as follows: Recovered / resolved, Recovering / resolving, Recovered / resolved with sequelae, Not recovered / not resolved, Fatal, and Unknown.

[0170] Definition of Serious Adverse Event: An SAE is an AE that occurs during any stage of the study (i.e., baseline, treatment, or follow-up) at any dose of the IP and meets one or more of the following: results in death, immediately threatens life, requires readmission of an inpatient or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital anomaly or congenital defect, is a significant medical event that may place the participant at risk or may require medical intervention to prevent one of the previously listed outcomes. An AE is considered "life-threatening" by the opinion of either the investigator or the sponsor if its occurrence places the participant at immediate risk of death. SAE does not include an AE that, if it had occurred in a more severe form, might have caused death.

[0171] Notification of Serious Adverse Event: All SAEs are reported within 24 hours from the time the institutional research team becomes aware of an event that meets the requirements for urgent reporting of the SAE to the appropriate regulatory authorities and the institutional review board. The initial report is accomplished by completing the SAE reporting form and sending it by email to the assigned project's email address provided at the time of study setup. If it is not possible to complete the SAE form and send the email, reporting by telephone is required and the completed SAE form must be sent by email at the first opportunity. The initial telephone notification of an SAE is confirmed in writing within 24 hours from the time the institutional research team first becomes aware of the event using the aforementioned SAE reporting form. When additional information regarding the SAE becomes available, such follow-up information is recorded on a new SAE reporting form, marked as a follow-up report, reviewed, and sent by email to the address at the bottom of the form.

[0172] Withdrawal from the study in the event of an SAE and the treatment measures taken are at the discretion of the investigator. A sufficient explanation for the discontinuation of the study is made in the participant's medical records and CRF. The sponsor or their designee has the responsibility to notify the relevant regulatory authorities of a specific event. The investigator is also notified of all serious events related to the drug that occur during the clinical trial and were not expected. The trial facility has the responsibility to notify its IRB / EC of these additional SAEs as necessary.

[0173] Clinical laboratory abnormalities, as well as other abnormal evaluations as adverse events and serious adverse events: Abnormal clinical laboratory findings (e.g., serum biochemistry and hematology) or other abnormal evaluations (e.g., ECG and vital signs) themselves are not reported as AEs. However, abnormal findings considered clinically significant by the PI and / or agent, or associated with signs and / or symptoms, are recorded as AEs as already described (recorded as SAEs if they meet the criteria for being serious) if they meet the definition of an AE. Clinically significant abnormal clinical laboratory tests or other abnormal findings detected after consent or present at baseline and worsening after consent are included as AEs (SAEs if serious). The investigator makes a medical and scientific judgment in determining whether an abnormal clinical laboratory finding or other abnormal evaluation is clinically significant. For an abnormality to be considered clinically significant, it must be associated with clinically obvious signs or symptoms or have the potential to result in obvious signs or symptoms in the near future. Clinically significant clinical laboratory abnormalities in the absence of clinical symptoms may put the participant at risk and may require intervention to prevent direct consequences. For example, a significantly low serum glucose concentration may not be accompanied by coma or convulsions but may be of a magnitude that requires glucose administration to prevent such sequelae. Clinical laboratory abnormalities that are clinically significant in the absence of clinical symptoms may put the participant at risk and may require intervention to prevent direct consequences. For example, a significantly low serum glucose concentration may not be accompanied by coma or convulsions but may be of a magnitude that requires glucose administration to prevent such sequelae.

[0174] Recording of Adverse Events: Adverse events reported spontaneously by participants and / or in response to open questions from the researcher, or revealed by observation, are recorded on the AE page of the eCRF during the study at the trial site in accordance with the researcher's normal clinical practice. Abnormal values that constitute an SAE or lead to discontinuation of IP administration must be reported and recorded as an AE. Information on AEs and SAEs is collected from consent until the end of the study. AE terms are reported in standard medical terms whenever possible. For each AE, the researcher evaluates and reports the onset (date and time), resolution (date and time), intensity, causality, actions taken, serious outcome (where applicable), and whether the participant discontinued the study due to the AE. AEs occurring during the study are recorded in the participant's medical record, on the AE eCRF, and in the SAE reporting form. When the SAE report is complete, relevant clinical laboratory data are recorded in the SAE form, preferably with a copy of the baseline values and clinical laboratory reports.

[0175] If the criteria for the abnormal assessment being severe are met, the SAE form is also completed. The AE / SAE page is completed using the diagnosis if known, or clinical signs or symptoms if the diagnosis is unknown. If the diagnosis is unknown and there are no clinical signs or symptoms, the abnormal findings are recorded.

[0176] Follow-up of Adverse Events and Serious Adverse Events: All AEs and SAEs related to, potentially related to, or considered potentially related to the IP are followed up until resolved, until the condition stabilizes, until the event is otherwise explained, or until the participant dies or is lost to follow-up. The investigator is responsible for ensuring that any supplementary investigations that may be indicated to elucidate as fully as possible the nature and / or causality of the AE / SAE are included in the follow-up. This includes additional clinical tests or investigations or advice from other medical specialists. The sponsor may request that the investigator perform or arrange for the performance of supplementary measurements and / or evaluations. If a participant dies during the course of the study or during the recognized follow-up period, the sponsor is provided with a copy of any postmortem findings, including histopathology.

[0177] Pregnancy: Pregnancy tests are performed on all WOCBP at screening and on Day 1 as per the assessment schedule, and the pregnancy outcome is captured in the eCRF. All WOCBP are instructed to contact the investigator immediately if they suspect they may be pregnant at any time during the course of the trial (e.g., loss or delay of menstrual cycle). Male participants are instructed to contact the investigator immediately if they suspect they have become fathers during the study treatment period. If possible, the pregnancy of the partner is followed up (until delivery) to determine the outcome. If a pregnancy occurs, it must be reported and recorded on the pregnancy form. Pregnancy is not considered an AE, except in cases where there is a suspicion that the IP has interfered with the effectiveness of contraceptives. The investigator reports the details on the pregnancy form to the sponsor / assigned designee within 24 hours of becoming aware of the pregnancy. Even if a participant withdraws from or consents to end the clinical trial, the investigator follows up and records the course and outcome of all pregnancies.

[0178] If the female partner of a male participant becomes pregnant while enrolled in the clinical trial, complete the Pregnancy Form promptly and send it to the Clinical Research Organization (CRO), regardless of whether the criteria for urgent reporting are met. Miscarriages (spontaneous, accidental, or therapeutic) are also reported. Congenital anomalies / congenital defects always meet the SAE criteria and, therefore, are reported as SAEs using the process already described for SAEs. The Pregnancy Form is updated to reflect the outcome of the pregnancy. The investigator reports any pregnancy (including pregnancy of the partner of the male participant) on the Pregnancy Report Form within 24 hours of becoming aware of the pregnancy, even if no AE has occurred. For congenital anomalies / congenital defects, use the process already described for SAEs to report them promptly as SAEs. The Pregnancy Form is updated to reflect the outcome of the pregnancy. The investigator reports any pregnancy (including pregnancy of the partner of the male participant) on the Pregnancy Report Form within 24 hours of becoming aware of the pregnancy, even if no AE has occurred.

[0179] (Example 4: Single ascending dose study) Conduct the single ascending dose study as a single-blind study in study participants blinded to treatment assignment. Figure 2 shows a schematic diagram of a single ascending dose study for intranasal administration of N-acetylcysteine. The radiologist providing the review and interpretation of the MRS study is blinded to treatment assignment, the IP administered, the timing of the MRS, and other details of the IP administration. Randomize 20 subjects in a 1:1 fashion to one of two dosing cohorts.

[0180] Administer IN NAC and IN GSH using a Teleflex MAD device. The investigational drug, IN GSH 200 mg, and IN NAC 100, 200, and 400 mg are supplied in identical-looking nasal administration devices. The dosing procedure is the same for the 200 mg dose of NAC and GSH (0.5 mL once per nostril). The dosing procedure is 0.25 mL per nostril for the 100 mg dose of NAC and 0.5 mL per nostril twice for the 400 mg dose of NAC. The participants receive four sequential doses of the investigational drug, with a 1-week interval between each dosing. Otherwise, the subjects are blinded to treatment assignment.

[0181] Twenty healthy volunteers are randomized 1:1 to one of two regimens consisting of escalating sequential single doses of IN NAC 200 mg and IN NAC 400 mg, following either low-dose IN NAC (100 mg) or IN GSH 200 mg, given on days 8, 15, and 22 at 7-day intervals. Cohort 1A receives IN GSH 200 mg, followed by sequential doses of IN NAC 100 mg, IN NAC 200 mg, and IN NAC 400 mg at 1-week intervals. Cohort 1B receives IN NAC 100 mg, followed by sequential doses of IN GSH 200 mg, IN NAC 200 mg, and IN NAC 400 mg at 1-week intervals. Both NAC and GSH are administered as 20% aqueous solutions. On each dosing day of the investigational product, MRS is performed and blood samples are collected before dosing and at 1, 3, 6, and 24 hours after dosing to determine the peripheral blood concentrations of GSH, cysteine, free and total NAC, and the GSH / GSSG ratio of RBG. Table 1

Table 1

[0182] Changes from baseline in the relative levels of NAC-derived neuro-metabolites are evaluated after administration of a single dose of IN NAC or IN GSH, followed by single escalating doses of IN NAC at 1-week intervals, and changes in peripheral blood measurements from PK clinical assays are also evaluated.

[0183] Participants are asked to remain in the supine position as much as possible from the baseline scan until the final 6-hour scan. Safety and tolerability are monitored as outlined in Table 2. If tolerability is acceptable, participants proceed to the next planned dose of the investigational product. Participants experiencing harmful effects that limit treatment discontinue the study and do not proceed to the next dose. Participants return for a follow-up visit 7 days after the final dosing of IP (day 30 ± 3 days) and receive a follow-up phone call for safety evaluation on day 51 (± 2 days). Table 2

Table 2-1

Table 2-2

[0184] (Example 5: Comparison of Devices) Figure 3 shows a schematic diagram of the device comparison study. Ten study participants are randomized in a 1:1 ratio to receive IN NAC (20% aqueous solution of acetylcysteine) using either the Teleflex LMA® MAD Nasal™ intranasal mucosal spray device or the Aptar CPS 5 mL nasal pump on Day 1. Each cohort receives IN NAC with device exchange on Day 8. Doses of 100, 200 or 400 mg of IN NAC are selected based on the results of a single ascending dose study. Table 3 shows the dosing cohorts used for the device comparison study Table 3

Table 3

[0185] ​ Perform MRS and draw blood before IP administration to determine the peripheral blood concentrations of GSH, cysteine, free and total NAC, and the GSH / GSSG ratio of RBG. Repeat MRS 1, 3, 6, and 24 hours after dosing. Evaluate the change from baseline in the relative levels of NAC-derived neuro-metabolites after administration of a single dose of IN NAC using the Teleflex LMA® MAD Nasal™ intranasal mucosal spray device or the Aptar CPS 5 mL nasal pump.

[0186] IN NAC is administered as a 20% solution of NAC according to the instructions for using each device. After each administration, the mouth may be rinsed with approximately 200 mL of water. Monitor safety and tolerability according to the evaluation schedule in Table 4. Participants who experience harmful effects that limit treatment withdraw from the study. Participants return for a follow-up visit 7 days after the final dose of IP (day 15 ± 3 days) and receive a follow-up phone call for safety evaluation on day 36 (± 2 days). Table 4

Table 4-1

Table 4-2

[0187] (Example 6: Comparative Study of Formulations) Ten study participants are randomized at a 1:1 ratio into two dosing cohorts. One cohort receives a 20% solution of acetylcysteine on day 1, followed by IV NAC seven days later, and the other cohort is assigned the reverse formulation dosing. The dose of IN NAC at 100, 200, or 400 mg, and the device to be used for IP administration are selected based on the results of single ascending dose studies and dose comparison studies. A 200 mg / mL NAC injection or equivalent is administered by the facility staff. NAC is hypertonic (2000 mOsm / L), and thus NAC is diluted prior to injection. NAC is diluted with a 0.45% aqueous sodium chloride solution (1 / 2 normal saline). The dose of IV NAC administered is 150 mg / kg, which is diluted in 200 mL of 0.45% aqueous sodium chloride solution and infused over 1 hour. Table 5 lists exemplary doses of 200 mg / mL IV NAC by body weight. Table 5

Table 5

[0188] MRS is performed, and prior to IP administration, blood samples are collected to determine the peripheral blood concentrations of GSH, cysteine, free and total NAC, and the GSH / GSSG ratio of RBG. MRS is repeated at 1, 3, 6, and 24 hours after dosing. The change from baseline in the relative levels of NAC-derived neuro-metabolites is evaluated after administration of a single dose of IN NAC or IV NAC as a 20% solution.

[0189] Administer 20% NAC solution intranasally to participants who are in the supine or seated position as instructed. During the study, participants receive either 0.5 mL, 1 mL, or 2 mL of 20% NAC solution, or 1 mL of 20% GSH solution. For all doses, approximately half of the total dose is administered to each nostril. Using a Teleflex MAD device, administer the NAC doses as follows: 1) IN NAC 100 mg (0.5 mL): 0.25 mL per spray, one spray into each nostril, 2) IN NAC 200 mg (1 mL) or IN GSH 200 mg (1 mL): 0.25 mL per spray, two sprays into each nostril, or 3) IN NAC 400 mg (2 mL): 0.5 mL per spray, two sprays into each nostril, and repeat two sprays into each nostril after 5 minutes. Using an Aptar CPS nasal pump, administer the NAC doses as follows: 1) IN NAC 100 mg (0.5 mL): 0.14 mL per spray, two sprays into each nostril, 2) IN NAC 200 mg (1 mL) or IN GSH 200 mg (1 mL): 0.14 mL per spray, four sprays into each nostril, or 3) IN NAC 400 mg (2 mL): 0.14 mL per spray, four sprays into each nostril, and repeat four sprays into each nostril after 5 minutes.

[0190] Participants self-administer up to 400 mg of IN NAC once to three times a day using an Aptar CPS nasal pump. On the evaluation day, IN NAC is administered by the facility staff. Participants receive training from the facility staff on the use of the Aptar CPS nasal pump.

[0191] Monitor safety and tolerability as outlined in Table 6. Participants who experience adverse effects that limit treatment discontinue the study. Participants return for a follow-up visit 7 days after the last dose of IP (day 36 ± 3 days) and receive a follow-up phone call for safety assessment on day 57 (± 2 days).

[0192] The effect of oral administration of NAC will also be compared to IN NAC. 200 mg / mL of acetylcysteine as a 20% w / v solution will be used. NAC will be administered orally by diluting the NAC solution to a 5% concentration in a diet soft drink. The oral dose studied will be a 4,000 mg dose, which will be prepared by adding 20 mL of the 20% NAC solution to 60 mL of diet soda to obtain 80 mL of a 5% NAC solution. . Table 6 [Table 6-1] [Table 6-2] Abbreviations: ECG, electrocardiogram; GSH, glutathione; GSH / GSSG, reduced glutathione vs. oxidized glutathione ON; MRS, magnetic resonance spectroscopy; NAC, N-acetylcysteine; TNSS-M, modified total nasal symptoms scale; VAS-T, visual analog scale for tolerability 1 Screening procedures must be performed within 28 days of the Day 1 IP dose 2 See Clinical Laboratory Evaluation for a list of tests to be completed. 3 ECG will be performed pre-dose on days 1 and 7 4 BID or TID dosing will depend on Parts 1 and 2 5 MRS was performed before dosing, and at 1, 3, 6, and 24 hours after the morning dosing on Day 1 and the morning dosing on Day 7. Shortly after 6 CSF sampling was performed after MRS 6 hours after dosing on days 1 and 7. 7 Blood samples for NAC, cysteine, GSH, and RBC GSH / GSSG were collected before each MRS session. do

[0193] To determine whether a participant is suitable for inclusion in the study, all medications, including over-the-counter drugs, vitamins, and herbal supplements taken during the 30 days prior to the first NAC administration, are recorded and reviewed by the investigator. Concurrent therapy with any medications, including past treatments or both prescription and over-the-counter drugs, is discussed between the investigator and the sponsor's medical monitor (MM) prior to IP administration, except when treatment of an adverse event (AE) is essential or when treatment needs to be initiated by appropriate medical care before the investigator can consult with the MM. The use of any NAC or investigational medical device within 30 days prior to screening is prohibited. Paracetamol / acetaminophen (one to two therapeutic doses per week) can be used at the discretion of the investigator for minor illnesses during the course of the study without prior consultation with the sponsor's MM.

[0194] (Example 7: Comparison of Brain Bioavailability of IN NAC in Different Positions of Participants During Administration) Figure 4 shows a schematic diagram for studying the effect of the position of the subject during IP administration. The formulation, dosage, and administration of IN NAC are determined based on the results of Examples 1 to 6. Participants are randomized in a 1:1 ratio to different sequences of IN NAC dosing parameters with different head positions during IP administration. Participants receive IN NAC in the supine position, where permitted activities are restricted after dosing, or in the seated position, where after dosing, study participants are permitted to remain seated, stand up, or walk between MRS sessions. One cohort is assigned to IP administration in the supine position on Day 1 and to seated administration on Day 8, and the other cohort is assigned the dosing conditions with the order reversed.

[0195] Participants receiving IP in the supine position are requested to maintain the supine position as much as possible from the baseline scan until the completion of MRS 6 hours after dosing. Participants receiving IP in the seated position may sit, stand up, or walk between MR sessions and are encouraged to stand up or walk for 10 minutes every hour from the completion of MRS 1 hour after dosing until the completion of the scan 6 hours after dosing.

[0196] Perform MRS and collect blood samples before IP administration to determine the peripheral blood concentrations of GSH, cysteine, free and total NAC, and the GSH / GSSG ratio of RBG. Repeat MRS and blood sample analysis at 1, 3, 6, and 24 hours after dosing. Evaluate changes from baseline in the relative levels of NAC-derived neurometabolites after IP administration in participants who are in one of the following two positions during IN NAC administration: 1) Supine position - Administer IP to participants in the supine position, and the participants remain in the supine position as much as possible until after MRS 6 hours after IP. And 2) Sitting position - Administer IP to participants in the sitting position, and then the participants are encouraged to stand up or walk for at least 10 minutes per hour until completion of MRS 6 hours after IP. Table 7 shows the dosing cohorts for comparison of participant positioning during NAC administration. Table 7

Table 7

[0197] The NAC dosage, formulation, and device for administration are determined based on the results of Examples 1-6. Monitor safety and tolerability as outlined in Table 8. Participants who experience harmful effects that limit treatment discontinue the study. Participants return for follow-up clinic visits 7 days after the final dose of IP (Day 36 ± 3 days) and receive a follow-up phone call for safety assessment on Day 57 (± 2 days). Table 8

Table 8-1

Table 8-2

[0198] (Example 8: Repeated dosing study) Figure 5 shows a schematic diagram for studying the effect of repeated dosing of intranasal N-acetylcysteine administration. Ten healthy volunteers are evaluated for changes from baseline in the relative levels of NAC-derived neuro-metabolites before and after 7 days of repeated dosing of up to 400 mg of IN NAC 1 to 3 times a day. The ten study participants undergo MRS and other evaluations before and after 7 days of repeated dosing of up to 400 mg of IN NAC 1 to 3 times a day. The dose, formulation, and administration of NAC are determined based on the results of Examples 1 to 6.

[0199] On day 1, MRS is performed, and blood samples are collected for the determination of GSH, cysteine, peripheral blood concentrations of free and total NAC, and GSH / GSSG ratio of RBG before dosing and 1, 3, and 6 hours after IP administration. CSF samples are collected 6 hours after IN NAC dosing using a 22-gauge non-invasive needle to measure NAC concentration. On day 2, MRS and other evaluations 24 hours after dosing are performed, and the participants start self-administering IN NAC at a dose of up to 400 mg 1 to 3 times a day. The participants continue self-administering IN NAC on days 3 to 8 for a total of 7 days of repeated dosing. On day 9, the study participants return for IN NAC administration, MRS, and other evaluations according to the same schedule as on day 1. Blood sampling for MRS and clinical tests 24 hours after dosing is performed on day 10.

[0200] Safety and tolerability are monitored as outlined in the assessment schedule in Table 9. Participants experiencing adverse effects that limit treatment discontinue the study. There is a follow-up visit 7 days after the final dose of IP (day 17 ± 3 days), and subjects receive a follow-up phone call for safety assessment on day 38 (± 2 days). Table 9

Table 9-1

Table 9-2

[0201] (Example 9: Comparison of IN, IV, and oral dosing of NAC) Figure 6 shows a schematic diagram for comparing the effects of intranasal, intravenous, and oral administration of N-acetylcysteine. The change from baseline in the relative levels of NAC-derived neuro-metabolites is determined after administration of IN, oral, or IV NAC. Twelve study participants are randomized in a 1:1:1 ratio to weekly NAC dosing in different sequences with three different formulations: IN NAC, an oral NAC dose of 4,000 mg, or 150 mg / kg of IV NAC. The oral NAC dose of 4,000 mg is given as a 20 mL solution of 200 mg / mL acetylcysteine (20% w / v). The IV NAC formulation is given as a dose of 150 mg / kg of NAC in 200 mL of sterile water, 0.45% saline, or 5% glucose in water. The dosing sequences at intervals are outlined in Table 10. The formulation, dose, and administration for IN NAC are determined based on the results of Examples 1-6.

[0202] MRS is performed on each dosing day, and blood samples are collected before dosing and at 1, 3, 6, and 24 hours after IP administration to determine the peripheral blood concentrations of GSH, cysteine, free and total NAC, and the GSH / GSSG ratio of RBG. CSF samples are collected 6 hours after IP administration using a 22-gauge non-invasive needle by lumbar puncture. The CSF samples are used to measure the NAC concentration 6 hours after dosing. Table 10

Table 10

[0203] Safety and tolerability are monitored by AE reports, ECG, vital signs, physical and neurological examinations, and safety blood and urine tests. The tolerability of IP IN administration is further evaluated using the Visual Analogue Scale for Tolerability (VAS-T) and the Modified Total Nasal Symptom Score (TNSS-M). Participants experiencing harmful effects that limit treatment discontinue the study. There is a follow-up visit 7 days after the final dose of IP (day 22 ± 3 days), and patients receive a follow-up phone call for safety evaluation on day 43 (± 2 days). Table 11 shows the evaluation schedule for comparison of IN, IV, and oral NAC administration. Table 11

Table 11-1

Table 11-2

[0204] (Example 10: Optimization of Therapeutic Agents and Drug Delivery Using MEGA-PRESS) Patients with Parkinson's disease are treated with intranasal NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof. MEGA-PRESS is used to quantify the amount of GSH in the substantia nigra and stratum regions of the brain. The therapeutic agent, dosage, dosing interval, and dosage delivery system are optimized to deliver the maximum amount of GSH to the substantia nigra and stratum regions of the brain to treat Parkinson's disease.

[0205] Patients with hemorrhagic stroke are treated with intranasal NAC, NACA, NAC derivatives, NAC metabolites, NAC homologs or D-NAC, or a pharmaceutically acceptable salt thereof. MEGA-PRESS is used to quantify the amount of NAC within the regions of the brain. The therapeutic agent, dosage, dosing interval, and dosage delivery system are optimized to deliver the maximum concentration of NAC to the site of bleeding.

[0206] (Example 11: Local and Temporal Changes in NAC Metabolites) A 1 mL solution of 200 mg / mL NAC was delivered intranasally to 5 subjects at 0.5 mL per nostril using a Teleflex mucosal atomizer (MAD). MRS analysis was used to determine the concentrations of GSH, NAA, water, and creatine before dosing and 1, 3, and 6 hours after NAC administration. The ratios of GSH / water (I.U.), GSH / creatine, NAA / water, and NAA / creatine were determined.

[0207] Figure 7A shows the changes in the GSH / water (I.U.) ratio in the dorsolateral prefrontal (DLPF), occipital (OCC), and striatal regions of the brain. Figure 7B shows the percent change in the GSH / water ratio in the DLPF, OCC, and striatum.

[0208] Figure 8A shows the changes in the GSH / creatine ratio in the dorsolateral prefrontal (DLPF), occipital (OCC), and striatal regions of the brain. Figure 8B shows the percent change in the GSH / creatine ratio in the DLPF, OCC, and stratum regions of the brain.

[0209] Figure 9A shows the N-acetylaspartic acid (NAA) / water ratio in the dorsolateral prefrontal cortex (DLPF), occipital lobe (OCC), and striatal region of the brain. Figure 9B shows the percentage change in the NAA / water ratio in the dorsolateral prefrontal cortex (DLPF), occipital lobe (OCC), and striatal region of the brain.

[0210] Figure 10A shows the N-acetylaspartic acid (NAA) / creatine ratio in the dorsolateral prefrontal cortex (DLPF), occipital lobe (OCC), and striatal region of the brain. Figure 10B shows the percentage change in the NAA / creatine ratio in the dorsolateral prefrontal cortex (DLPF), occipital lobe (OCC), and striatal region of the brain.

[0211] Figure 11A shows the percentage change in GSH / creatine and the percentage change in NAA / creatine in the dorsolateral prefrontal cortex (DLPF) region of the brain. Figure 11B shows the percentage change in GSH / creatine and the percentage change in NAA / creatine in the occipital lobe (OCC) region of the brain. Figure 11C shows the percentage change in GSH / creatine and the percentage change in NAA / creatine in the striatal region of the brain.

[0212] Embodiments The following non-limiting embodiments provide illustrative examples of the present invention but do not limit the scope of the present invention.

[0213] Embodiment 1. A method of treating a condition, comprising: a) administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent, wherein the administering is intranasal; and b) quantifying the concentration of glutathione in the brain region by magnetic resonance spectroscopy after the administering step.

[0214] Embodiment 2. The method of Embodiment 1, wherein the therapeutic agent is N-acetylcysteine (NAC).

[0215] Embodiment 3. The method of Embodiment 1, wherein the therapeutic agent is NAC amide (NACA).

[0216] The method of Embodiment 1, wherein the therapeutic agent is an NAC derivative or a pharmaceutically acceptable salt thereof.

[0217] The method of Embodiment 1, wherein the therapeutic agent is an NAC homolog or a pharmaceutically acceptable salt thereof.

[0218] The method of Embodiment 1, wherein the therapeutic agent is an NAC dendrimer or a pharmaceutically acceptable salt thereof.

[0219] The method according to any one of Embodiments 1 to 6, wherein the condition is a brain condition.

[0220] The method according to any one of Embodiments 1 to 7, wherein the brain condition is mild traumatic brain injury (mTBI).

[0221] The method according to any one of Embodiments 1 to 7, wherein the brain condition is cancer.

[0222] The method according to any one of Embodiments 1 to 7, wherein the brain condition is a central nervous system (CNS) disorder.

[0223] The method according to any one of Embodiments 1 to 7 and 10, wherein the CNS disorder is Parkinson's disease.

[0224] The method according to any one of Embodiments 1 to 11, wherein the therapeutically effective amount is from about 100 mg to about 400 mg.

[0225] The method according to any one of Embodiments 1 to 12, wherein the therapeutically effective amount is about 100 mg.

[0226] The method according to any one of Embodiments 1 to 12, wherein the therapeutically effective amount is about 200 mg.

[0227] The method according to any one of Embodiments 1 to 12, wherein the therapeutically effective amount is about 400 mg.

[0228] Embodiment 16. The method according to any one of Embodiments 1 to 15, wherein the therapeutic agent is administered using a nasal pump.

[0229] Embodiment 17. The method according to any one of Embodiments 1 to 15, wherein the therapeutic agent is administered using an atomizer.

[0230] Embodiment 18. The method according to any one of Embodiments 1 to 17, wherein the administration step is performed in the supine position.

[0231] Embodiment 19. The method according to any one of Embodiments 1 to 17, wherein the administration step is performed in the sitting position.

[0232] Embodiment 20. The method according to any one of Embodiments 1 to 19, further comprising the step of quantifying the amount of free NAC in the plasma sample.

[0233] Embodiment 21. The method according to any one of Embodiments 1 to 20, further comprising the step of quantifying the amount of total NAC in the plasma sample.

[0234] Embodiment 22. The method according to any one of Embodiments 1 to 21, further comprising the step of quantifying the amount of plasma GSH.

[0235] Embodiment 23. The method according to any one of Embodiments 1 to 22, further comprising the step of quantifying the ratio of reduced GSH to oxidized GSH (GSH / GSSG).

[0236] Embodiment 24. The method according to any one of Embodiments 1 to 23, further comprising the step of quantifying the amount of NAC or NAC metabolite in the cerebrospinal fluid sample.

[0237] Embodiment 25. The method according to any one of Embodiments 1 to 24, wherein the administration step is once a day.

[0238] Embodiment 26. The method according to any one of Embodiments 1 to 24, wherein the administration step is twice a day.

[0239] Embodiment 27. A method according to any one of Embodiments 1 to 24, wherein the administration step is three times a day.

[0240] Embodiment 28. A method according to any one of Embodiments 1 to 27, wherein the administration step is repeated at least once.

[0241] Embodiment 29. A method according to any one of Embodiments 1 to 28, wherein the administration step is repeated once.

[0242] Embodiment 30. A method according to any one of Embodiments 1 to 28, wherein the administration step is repeated twice.

[0243] Embodiment 31. A method according to any one of Embodiments 1 to 30, wherein the administration step is repeated approximately 7 days later.

[0244] Embodiment 32. A method according to any one of Embodiments 1 to 31, wherein the therapeutic agent is in a pharmaceutical composition.

[0245] Embodiment 33. A method according to any one of Embodiments 1 to 32, wherein the therapeutic agent is an aqueous solution.

[0246] Embodiment 34. A method according to any one of Embodiments 1 to 33, wherein the pharmaceutical composition contains approximately 5% to approximately 40% of the therapeutic agent.

[0247] Embodiment 35. A method according to any one of Embodiments 1 to 34, wherein the pharmaceutical composition contains approximately 20% of the therapeutic agent.

[0248] Embodiment 36. A method according to any one of Embodiments 1 to 35, wherein the pharmaceutical composition further contains a pharmaceutically acceptable excipient.

[0249] Embodiment 37. A method according to any one of Embodiments 1 to 36, wherein the pharmaceutically acceptable excipient is disodium edate.

[0250] Embodiment 38. The method according to any one of Embodiments 1 to 37, wherein the pharmaceutically acceptable excipient is sodium hydroxide.

[0251] Embodiment 39. The method according to any one of Embodiments 1 to 38, wherein the pharmaceutical composition further comprises a pH adjuster.

[0252] Embodiment 40. The method according to Embodiment 39, wherein the pH adjuster is hydrochloric acid.

[0253] Embodiment 41. The method according to any one of Embodiments 1 to 40, wherein the brain region is the cerebrum.

[0254] Embodiment 42. The method according to any one of Embodiments 1 to 40, wherein the brain region is the brainstem.

[0255] Embodiment 43. The method according to any one of Embodiments 1 to 40, wherein the brain region is the cerebellum.

[0256] Embodiment 44. The method according to any one of Embodiments 1 to 40, wherein the brain region is the pons.

[0257] Embodiment 45. The method according to any one of Embodiments 1 to 40, wherein the brain region is the medulla oblongata.

[0258] Embodiment 46. The method according to any one of Embodiments 1 to 40, wherein the brain region is the frontal lobe.

[0259] Embodiment 47. The method according to any one of Embodiments 1 to 40, wherein the brain region is the parietal lobe.

[0260] Embodiment 48. The method according to any one of Embodiments 1 to 40, wherein the brain region is the occipital lobe.

[0261] Embodiment 49. The method according to any one of Embodiments 1 to 40, wherein the brain region is the temporal lobe.

[0262] Embodiment 50. The method according to any one of Embodiments 1 to 40, wherein the brain region is the left dorsal striatum.

[0263] Embodiment 51. The method according to any one of Embodiments 1 to 40, wherein the brain region is the occipital cortex.

[0264] Embodiment 52. The method according to any one of Embodiments 1 to 40, wherein the brain region is the dorsolateral prefrontal cortex (DLPF).

[0265] Embodiment 53. The method according to any one of Embodiments 1 to 52, further comprising determining a change in the concentration of glutathione in the brain region over a period of time.

[0266] Embodiment 54. The method according to any one of Embodiments 1 to 53, wherein the step of administration increases the concentration of glutathione by about 20% to about 300%.

[0267] Embodiment 55. The method according to any one of Embodiments 1 to 54, wherein the step of administration increases the concentration of glutathione by about 30%.

[0268] Embodiment 56. The method according to any one of Embodiments 1 to 54, wherein the step of administration increases the concentration of glutathione by about 50%.

[0269] Embodiment 57. The method according to any one of Embodiments 1 to 54, wherein the step of administration increases the concentration of glutathione by about 100%.

[0270] Embodiment 58. A method of treating a condition, comprising: a) administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent; and b) quantifying, after the step of administration, the concentration of the therapeutic agent or a metabolite of the therapeutic agent in the brain region of the subject by at least two magnetic resonance spectroscopy signals.

[0271] Embodiment 59. The method of Embodiment 58, wherein the therapeutic agent is N-acetylcysteine (NAC).

[0272] Embodiment 60. The method of Embodiment 58, wherein the therapeutic agent is NAC amide (NACA).

[0273] Embodiment 61. The method of Embodiment 58, wherein the therapeutic agent is an NAC derivative.

[0274] Embodiment 62. The method of Embodiment 58, wherein the therapeutic agent is an NAC homolog or a pharmaceutically acceptable salt thereof.

[0275] Embodiment 63. The method of Embodiment 58, wherein the therapeutic agent is an NAC dendrimer or a pharmaceutically acceptable salt thereof.

[0276] Embodiment 64. The method according to any one of Embodiments 58 to 63, wherein the metabolite of the therapeutic agent is glutathione.

[0277] Embodiment 65. The method according to any one of Embodiments 58 to 64, wherein the condition is a brain condition.

[0278] Embodiment 66. The method according to Embodiments 58 to 64, wherein the condition is mild traumatic brain injury (mTBI).

[0279] Embodiment 67. The method according to Embodiments 58 to 64, wherein the condition is cancer.

[0280] Embodiment 68. The method according to Embodiments 58 to 64, wherein the condition is hemorrhagic stroke.

[0281] Embodiment 69. The method according to Embodiments 58 to 64, wherein the condition is a central nervous system (CNS) disorder.

[0282] Embodiment 70. The method of Embodiment 69, wherein the CNS disorder is Parkinson's disease.

[0283] Embodiment 71. The method according to any one of Embodiments 58 to 70, wherein the therapeutically effective amount is from about 100 mg to about 400 mg.

[0284] Embodiment 72. The method according to any one of Embodiments 58 to 71, wherein the therapeutically effective amount is about 100 mg.

[0285] Embodiment 73. The method according to any one of Embodiments 58 to 71, wherein the therapeutically effective amount is about 200 mg.

[0286] Embodiment 74. The method according to any one of Embodiments 58 to 71, wherein the therapeutically effective amount is about 400 mg.

[0287] Embodiment 75. The method according to any one of Embodiments 58 to 74, wherein the administration step is by a nasal pump.

[0288] Embodiment 76. The method according to any one of Embodiments 58 to 74, wherein the administration step is by an atomizer.

[0289] Embodiment 77. The method according to any one of Embodiments 58 to 76, wherein the administration step is performed on a supine subject.

[0290] Embodiment 78. The method according to any one of Embodiments 58 to 76, wherein the administration step is performed on a seated subject. Any one method.

[0291] Embodiment 79. The method according to any one of Embodiments 58 to 78, further comprising obtaining a plasma sample of the subject after the administration step and quantifying the amount of free NAC in the plasma sample.

[0292] Embodiment 80. The method according to any one of Embodiments 58 to 79, further comprising obtaining a plasma sample of the subject after the administration step and quantifying the amount of total NAC in the plasma sample.

[0293] Embodiment 81. The method according to any one of Embodiments 58 to 80, further comprising obtaining a plasma sample of the subject after the administration step and quantifying the amount of GSH in the plasma sample.

[0294] Embodiment 82. The method according to any one of Embodiments 58 to 81, further comprising quantifying the ratio of reduced GSH to oxidized GSH (GSH / GSSG) in the brain region after the administration step.

[0295] Method according to any one of Embodiments 58 to 82, further comprising the step of obtaining a cerebrospinal fluid sample of the subject after the administration step and quantifying the amount of NAC or NAC metabolite in the cerebrospinal fluid sample.

[0296] Method according to any one of Embodiments 58 to 83, wherein the administration step is once a day.

[0297] Method according to any one of Embodiments 58 to 84, wherein the administration step is twice a day.

[0298] Method according to any one of Embodiments 58 to 85, wherein the administration step is three times a day.

[0299] Method according to any one of Embodiments 58 to 86, wherein the administration step is repeated at least once.

[0300] Method according to any one of Embodiments 58 to 87, wherein the administration step is repeated once.

[0301] Method according to any one of Embodiments 58 to 87, wherein the administration step is repeated twice.

[0302] Method according to any one of Embodiments 58 to 89, wherein the administration step is repeated approximately 7 days later.

[0303] Method according to any one of Embodiments 58 to 90, wherein the therapeutic agent is in a pharmaceutical composition.

[0304] Method according to any one of Embodiments 58 to 91, wherein the therapeutic agent is an aqueous solution.

[0305] Method according to any one of Embodiments 58 to 92, wherein about 5% to about 40% of the pharmaceutical composition is the therapeutic agent.

[0306] Embodiment 94. A method according to any one of Embodiments 58 to 93, wherein about 20% of the pharmaceutical composition is a therapeutic agent.

[0307] Embodiment 95. A method according to any one of Embodiments 58 to 94, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0308] Embodiment 96. The method of Embodiment 95, wherein the pharmaceutically acceptable excipient is disodium edetate.

[0309] Embodiment 97. The method of Embodiment 96, wherein the pharmaceutically acceptable excipient is sodium hydroxide.

[0310] Embodiment 98. A method according to any one of Embodiments 58 to 97, wherein the pharmaceutical composition further comprises a pH adjuster.

[0311] Embodiment 99. The method of Embodiment 98, wherein the pH adjuster is hydrochloric acid.

[0312] Embodiment 100. A method according to any one of Embodiments 58 to 99, wherein the brain region is the cerebrum.

[0313] Embodiment 101. A method according to any one of Embodiments 58 to 99, wherein the brain region is the brainstem.

[0314] Embodiment 102. A method according to any one of Embodiments 58 to 99, wherein the brain region is the cerebellum.

[0315] Embodiment 103. A method according to any one of Embodiments 58 to 99, wherein the brain region is the pons.

[0316] Embodiment 104. A method according to any one of Embodiments 58 to 99, wherein the brain region is the medulla.

[0317] Embodiment 105. A method according to any one of Embodiments 58 to 99, wherein the brain region is the frontal lobe.

[0318] Embodiment 106. The method according to any one of Embodiments 58 to 99, wherein the brain region is the parietal lobe.

[0319] Embodiment 107. The method according to any one of Embodiments 58 to 99, wherein the brain region is the occipital lobe.

[0320] Embodiment 108. The method according to any one of Embodiments 58 to 99, wherein the brain region is the temporal lobe.

[0321] Embodiment 109. The method according to any one of Embodiments 58 to 99, wherein the brain region is the left dorsal striatum.

[0322] Embodiment 110. The method according to any one of Embodiments 58 to 99, wherein the brain region is the occipital cortex.

[0323] Embodiment 111. The method according to any one of Embodiments 58 to 99, wherein the brain region is the dorsolateral prefrontal cortex (DLPF).

[0324] Embodiment 112. The method according to any one of Embodiments 58 to 99, wherein the brain region is the substantia nigra.

[0325] Embodiment 113. The method according to any one of Embodiments 58 to 99, wherein the brain region is the striatum.

[0326] Embodiment 114. The method according to any one of Embodiments 58 to 113, further comprising determining a change in the concentration of glutathione in the brain region of the subject after administration over a period of time.

[0327] Embodiment 115. The method according to any one of Embodiments 58 to 114, further comprising determining a change in the concentration of NAC in the brain region of the subject after administration over a period of time.

[0328] Embodiment 116. The method according to any one of Embodiments 58 to 115, wherein the step of administration increases the concentration of glutathione in the brain region by about 20% to about 300%.

[0329] Embodiment 117. A method according to any one of Embodiments 58 to 116, wherein the administering step increases the concentration of NAC in the brain region by about 20% to about 300%.

[0330] Embodiment 118. A method according to any one of Embodiments 58 to 117, wherein the administering step increases the concentration of glutathione in the brain region by about 30%.

[0331] Embodiment 119. A method according to any one of Embodiments 58 to 117, wherein the administering step increases the concentration of NAC in the brain region by about 30%.

[0332] Embodiment 120. A method according to any one of Embodiments 58 to 117, wherein the administering step increases the concentration of glutathione in the brain region by about 50%.

[0333] Embodiment 121. A method according to any one of Embodiments 58 to 117, wherein the administering step increases the concentration of NAC in the brain region by about 50%.

[0334] Embodiment 122. A method according to any one of Embodiments 58 to 117, wherein the administering step increases the concentration of glutathione in the brain region by about 100%.

[0335] Embodiment 123. A method according to any one of Embodiments 58 to 117, wherein the administering step increases the concentration of NAC in the brain region by about 100%. The present invention provides, for example, the following items. (Item 1) A method of treating a condition, a) administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent, wherein the administering step is intranasal; b) quantifying, by magnetic resonance spectroscopy, the concentration of NAC or glutathione in the brain region after the administering step and comprising. (Item 2) The method according to Item 1, wherein the therapeutic agent is N-acetylcysteine (NAC) or a pharmaceutically acceptable salt thereof. (Item 3) The method according to item 1, wherein the therapeutic agent is an NAC derivative. (Item 4) The method according to item 1, wherein the state is a state of the brain. (Item 5) The method according to item 4, wherein the state of the brain is mild traumatic brain injury. (Item 6) The method according to item 4, wherein the state of the brain is cancer. (Item 7) The method according to item 4, wherein the state of the brain is a central nervous system (CNS) disorder. (Item 8) The method according to item 6, wherein the CNS disorder is Parkinson's disease. (Item 9) The method according to item 1, wherein the therapeutically effective amount is from about 100 mg to about 400 mg. (Item 10) The method according to item 1, wherein the therapeutic agent is administered using a nasal pump. (Item 11) The method according to item 1, wherein the therapeutic agent is administered using an atomizer. (Item 12) The method according to item 1, wherein the step of administering is repeated at least once. (Item 13) The method according to item 1, wherein the therapeutic agent is in a pharmaceutical composition, and the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. (Item 14) The method according to item 12, wherein the therapeutic agent is an aqueous solution. (Item 15) The method according to item 1, wherein the brain region is the cerebrum. (Item 16) The method according to item 1, wherein the brain region is the frontal lobe. (Item 17) The method according to item 1, wherein the brain region is the occipital lobe. (Item 18) The method according to item 1, wherein the brain region is the occipital cortex. (Item 19) The method according to item 1, further comprising the step of determining a change in the concentration of glutathione in the brain region over a period of time. (Item 20) The method according to item 19, wherein the step of administering increases the concentration of glutathione by about 20% to about 300%.

Claims

【Claim 1】 The invention described in the specification of this application.

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