Treatment of meniere's disease

Abstract

Disclosed herein are novel methods and compositions for treating MD and / or endolymphatic hydrops. The compositions comprise ebselen and optionally one or more glutathione peroxidase (GPx) modulators or mimetic compounds and / or one or more prescription diuretic compounds. Also disclosed are methods of increasing GPx activity and reducing free radical species and inflammation of the cochlea or vestibule in a subject.

Description

Invention Field

[0001] This disclosure relates to compositions and methods that can be used to treat Meniere's disease and / or endolymphedema.

[0002] Related technical descriptions

[0003] Meniere's disease (MD) is defined as a triad of episodic vertigo, hearing loss, and tinnitus. Ear pressure or aural fullness is frequently reported, and most auditory and vestibular symptoms fluctuate in frequency and intensity. While the etiology of MD is unknown, it is associated with endolymphatic edema, the swelling of the endolymphatic compartments of the inner ear. A chronic phase develops after an acute phase, with vertigo being the most common feature, during which hearing loss and tinnitus become the most common characteristics, although balance disorders are frequently reported. There are no FDA-approved medications for the prevention or treatment of MD. Most patients with MD receive medical treatment with a low-sodium diet and / or thiazide diuretics, but with limited effectiveness.

[0004] Overview

[0005] This disclosure addresses a clinical need for a treatment for MD and / or endolymphedema.

[0006] The inventors have discovered and demonstrated improvements in several auditory and vestibular symptoms after treating subjects with MD and / or idiopathic and non-idiopathic endolymphedema, said treatment comprising administration of an effective amount of ebuselin (SPI-1005) alone or in combination with one or more other glutathione peroxidase (GPx) modulators or mimics and / or one or more prescription diuretic compounds.

[0007] This disclosure provides: novel glutathione peroxidase (GPx) modulators or mimics available in pharmaceutical compositions for the treatment, prevention, and / or improvement of Meniere's disease and / or endolymphedema, said pharmaceutical compositions comprising ebuseline alone or in combination with one or more such glutathione peroxidase (GPx) modulators or mimics and / or one or more prescription diuretic compounds; methods for preparing such pharmaceutical compositions comprising ebuseline or comprising combinations of ebuseline with novel glutathione peroxidase (GPx) modulators or mimics and / or one or more prescription diuretic compounds; pharmaceutical compositions comprising ebuseline or comprising combinations of ebuseline with novel glutathione peroxidase (GPx) modulators or mimics and / or one or more prescription diuretic compounds; and methods for treating, preventing, and / or improving Meniere's disease and / or endolymphedema using these pharmaceutical compositions.

[0008] Some embodiments of the new combination composition contain at least two compounds or pharmaceutically acceptable salts thereof, wherein the first compound is ebuseline and the second compound is a glutathione peroxidase regulator or analog compound.

[0009] Another aspect of this disclosure is a method of treating a subject suffering from or diagnosed with MD and / or endolymphedema, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising ebuselin alone, or a combination of ebuselin, one or more other glutathione peroxidase modulators or analog compounds, and optionally one or more prescription diuretic compounds. The therapeutically effective amount of each compound included in the new combination may be from about 0.1 mg / day to about 5000 mg / day.

[0010] Another feature of this disclosure is a kit comprising any of the compositions described herein and instructions for use.

[0011] Another feature of this disclosure is a method for balancing inner ear pressure in a subject, the method comprising administering a therapeutically effective amount of a composition comprising ibuselenol and optionally one or more other glutathione peroxidase modulators or analog compounds and / or a composition of one or more prescription diuretic compounds.

[0012] In another aspect, this disclosure includes methods for reducing the production of free radicals and / or inflammation in the ear of a subject, including administering a therapeutically effective amount of a composition comprising ibuselenol and optionally one or more other glutathione peroxidase modulators or analog compounds.

[0013] This disclosure is further characterized by a method for preparing a pharmaceutical composition, the method comprising mixing ebuselenol and any one of a glutathione peroxidase regulator or analog compound or a prescription diuretic compound with one or more pharmaceutically acceptable carriers.

[0014] This disclosure provides a pharmaceutical composition comprising ebuseline and one or more other glutathione peroxidase (GPx) regulators or analogs; or pharmaceutically acceptable salts or solvates thereof.

[0015] This disclosure provides a composition in which one or more other glutathione peroxidase regulators or mimics are present as a compound and selected from the group consisting of:

[0016] 2,2'-Diseleno-bis-β-cyclodextrin;

[0017] in

[0018] R1 is H, methyl, ethyl, or isopropyl;

[0019] R2 is H or ethyl;

[0020] R3 represents H, acetyl, or phenylacetyl.

[0021]

[0022] in

[0023] R1 can be H, oxo, methyl, ethyl, n-propyl, n-pentyl, phenyl, or –(CHOH). n CH2OH or Where n is 1-5; R2 is H or –COOH;

[0024] And 6A,6B-diselenoic acid-6A',6B'-selenium-bridged β-cyclodextrin.

[0025] This disclosure provides a composition in which one or more other glutathione peroxidase regulators or mimic compounds are present as a compound and are 2,2'-diseleno-bis-β-cyclodextrin.

[0026] This disclosure provides a composition comprising ebuselenline or a pharmaceutically acceptable salt or solvate thereof.

[0027] This disclosure provides a composition, wherein the composition further comprises one or more diuretic compounds.

[0028] This disclosure provides kits containing compositions and instructions for use of any of the embodiments described herein.

[0029] This disclosure provides a method for treating, preventing, and / or improving Meniere's disease in a subject, the method comprising administering to a subject in need an effective amount of a composition comprising ebuseline, optionally in combination with a prescription diuretic compound.

[0030] This disclosure provides a method for treating, preventing, and / or improving Meniere's disease in a subject, the method comprising administering to a subject in need an effective amount of a composition comprising ibuselenone, optionally in combination with a prescription diuretic compound, and one or more other glutathione peroxidase modulators or analog compounds.

[0031] This disclosure provides a method for treating, preventing, and / or improving endolymphatic edema in a subject, the method comprising administering to a subject in need an effective amount of a composition comprising ebuselenol, optionally in combination with a prescription diuretic compound.

[0032] This disclosure provides methods for treating, preventing, and / or improving endolymphatic edema in subjects, the methods comprising administering to a subject in need an effective amount of a composition comprising ibuselenone, optionally in combination with a prescription diuretic compound, and one or more other glutathione peroxidase modulators or analog compounds.

[0033] This disclosure provides a method for any of the embodiments described herein, wherein one or more other glutathione peroxidase regulators or mimic compounds are present as a compound and selected from the group consisting of 2,2'-diseleno-bis-β-cyclodextrin;

[0034] in

[0035] R1 is H, methyl, ethyl, or isopropyl;

[0036] R2 is H or ethyl;

[0037] R3 represents H, acetyl, or phenylacetyl.

[0038]

[0039] in

[0040] R1 can be H, oxo, methyl, ethyl, n-propyl, n-pentyl, phenyl, or –(CHOH). n CH2OH or Where n is 1-5; R2 is H or –COOH;

[0041] And 6A,6B-diselenoic acid-6A',6B'-selenium-bridged β-cyclodextrin.

[0042] This disclosure provides a method for any of the embodiments described herein, wherein one or more other glutathione peroxidase regulators or mimic compounds are present as a compound and are 2,2'-diseleno-bis-β-cyclodextrin.

[0043] This disclosure provides a method for any of the embodiments described herein, wherein GPx activity is increased in subjects with Meniere's disease or endolymphedema.

[0044] This disclosure provides a method for any of the embodiments described herein, wherein administration is oral.

[0045] This disclosure provides a method for any of the embodiments described herein, wherein the effectiveness of the method is measured by a technique selected from the group consisting of pure-tone audiometry, speech discrimination testing, electrocochleography, or magnetic resonance imaging.

[0046] This disclosure provides a method for any of the embodiments described herein, wherein the treatment improves at least one of pure-tone audiometry, speech discrimination testing, electrocochleography, or magnetic resonance imaging of a subject.

[0047] This disclosure provides a method for any of the embodiments described herein, wherein the treatment increases at least one of the subject's test scores, the test scores being selected from a group consisting of the Vertigo Symptoms Scale (VSS), the Dizziness Handicap Inventory (DHI), the Tinnitus Functional Index (TFI), or the Tinnitus Handicap Inventory (THI).

[0048] This disclosure provides a method for reducing free radical production and / or inflammation in the inner ear of a subject, the method comprising administering to a subject in need an effective amount of a composition comprising ibuselenol and optionally one or more other glutathione peroxidase modulators or analog compounds.

[0049] This disclosure provides a method for any of the embodiments described herein, wherein the free radical is selected from the group consisting of peroxynitrite, hydrogen peroxide anion, superoxide anion, nitric oxide, nitrotyrosine, and hydroxyl groups.

[0050] This disclosure provides a method for balancing inner ear pressure, the method comprising administering to a subject with appropriate need an effective amount of a composition comprising ibuselenol and optionally one or more other glutathione peroxidase modulators or analogs and optionally a prescribed diuretic.

[0051] This disclosure provides a method for any of the embodiments described herein, wherein the subject suffers from vertigo.

[0052] This disclosure provides a method for any of the embodiments described herein, wherein the subject suffers from dizziness.

[0053] This disclosure provides a method for any of the embodiments described herein, wherein the subject has hearing loss.

[0054] This disclosure provides a method for any of the embodiments described herein, wherein the subject suffers from tinnitus.

[0055] This disclosure provides a method for any of the embodiments described herein, wherein inner ear pressure is displayed by electrocochleography or magnetic resonance imaging.

[0056] This disclosure provides a method for any of the embodiments described herein, wherein the pharmaceutical composition further comprises one or more diuretic compounds, including prescription diuretic compounds.

[0057] This disclosure provides compositions according to any of the embodiments described herein, wherein the compositions comprise ebuselenin and / or a dimer of ebuselenin, i.e., compounds represented by the following formula: The Se-Se bonds in this chemical structure are relatively weak. For example, it is known that the dimerization reaction forming Se-Se bonds from ebuselenoline will occur spontaneously at lower pH environments. It is also known that the dimerization reaction is thermodynamically controlled and reversible. This means that ebuselenoline can be made in a dimer form / compound and can exist in some equilibrium of dimer forms / compounds. Therefore, the inventors contemplate and disclose herein that, for such purposes as this disclosure, ebuselenoline and the dimer compound are equivalent. Thus, two active chemical substances for use, kits, methods, and compositions are disclosed herein. Therefore, it is contemplated herein that, whenever mentioned in this disclosure, the term ebuselenoline (which may be ) can be replaced with this dimer compound.

[0058] This disclosure provides a method for any of the embodiments described herein, wherein the pharmaceutical composition comprises a compound in the form of an ebuselenide dimer, i.e., a compound represented by the following formula:

[0059] Further embodiments and their advantages will become apparent from the following detailed discussion, schemes, embodiments and claims. Brief description of the attached diagram

[0061] This disclosure can be more fully understood by taking into account the following detailed description of various embodiments thereof in conjunction with the accompanying drawings, in which:

[0062] Figure 1 It is a table showing the clinical treatment results of Example 1, in which secondary endpoints of hearing loss were measured in human subjects.

[0063] Figure 2It is a table showing the clinical treatment results of Example 1, in which secondary endpoints of hearing loss were measured in human subjects.

[0064] Figure 3 This is a table showing the clinical treatment outcomes of Example 1, in which secondary endpoints of hearing loss were measured in human subjects. The measured secondary endpoints included: severity of sensorineural hearing loss using pure-tone audiometry (PTA) and speech discrimination using the Words-in-Noise Test (WINT) before, during, and after treatment; severity of tinnitus using the Tinnitus Function Index (TFI) and Tinnitus Loudness (TL) before, during, and after treatment; and severity of vertigo using the Vertigo Symptom Scale (VSS, shortened form) before, during, and after treatment.

[0065] Detailed description

[0066] In various embodiments, this disclosure provides methods for treating, preventing, and / or improving MD and / or endolymphatic edema, said methods comprising administering a therapeutically effective amount of a composition comprising ebuselenol.

[0067] Specific embodiments of this disclosure relate to methods and compositions that can be used to treat, prevent, and / or improve MD and / or endolymphatic edema, said compositions comprising a combination of at least two compounds, the first compound being ibuselenline and one or more other compounds being glutathione peroxidase modulators or analogs.

[0068] Representative compounds of the new combination are described throughout the specification and claims.

[0069] In some embodiments, the glutathione peroxidase regulator comprises compounds selected from the group consisting of: glutathione peroxidase mimics, glutathione, glutathione prodrugs, and cysteine ​​prodrugs.

[0070] In some embodiments, representative compounds of glutathione peroxidase mimics include ebuseline, (2-phenyl-1,2-benzisisoseleno-3(2H)-one), with the empirical formula C0. 13 H9NOSe has a molecular weight of 274.2 and the formula is:

[0071]

[0072] In some embodiments, the glutathione peroxidase mimicry compounds include 2,2'-diselenoyl-bis-β-cyclodextrin and 6A,6B-diselenoic acid-6A',6B'-selenium-bridged β-cyclodextrin.

[0073] Glutathione peroxidase regulators or mimics, such as glutathione peroxidase, reduce reactive oxygen species (ROS) by binding free radicals to their Se moiety. By reacting with glutathione, glutathione peroxidase mimics limit free radical toxicity, thus exhibiting strong activity against peroxynitrite. Ebuselenoline, a glutathione peroxidase mimic, reduces cytochrome C release and nuclear damage in mitochondria during lipid peroxidation, thereby mitigating neuronal apoptosis associated with oxidative stress. Agents that reduce the activity of ROS can improve the exacerbation of oxidative stress and the detrimental effects of diseases caused by such stress, including but not limited to other neurological disorders or ailments, and their associated symptoms or complications.

[0074] In some implementations, a representative glutathione prodrug comprises a compound of the following formula:

[0075]

[0076] in

[0077] R1 is H, methyl, ethyl, or isopropyl;

[0078] R2 is H or ethyl; and

[0079] R3 represents H, acetyl, or phenylacetyl.

[0080] In some implementations, a representative cysteine ​​prodrug comprises N-acetylcysteine ​​(NAC) having the following formula:

[0081]

[0082] Some embodiments of cysteine ​​prodrugs include N,N'-diacetylcysteine, N-acetylcysteine ​​amide, NAC esters (alkyl esters, hydroxyacetamide esters, and acycloxy methyl esters), S-allylcysteine, S-methylcysteine, S-ethylcysteine, S-propylcysteine, or compounds of the following formula:

[0083]

[0084] in

[0085] R1 can be H, oxo, methyl, ethyl, n-propyl, n-pentyl, phenyl, or –(CHOH). n CH2OH and

[0086] Where n is 1-5 or and

[0087] R2 is H or –COOH.

[0088] Some embodiments of cysteine ​​prodrugs comprise a 2-substituted thiazolidin-4-carboxylic acid having an aldose monosaccharide, such as glyceraldehyde, arabinose, lythose, ribose, xylose, galactose, glucose, and mannose.

[0089] Another feature of this disclosure is a pharmaceutical composition comprising a combination of a glutathione peroxidase modulator or analog compound and at least one pharmaceutically acceptable carrier.

[0090] This disclosure is further characterized by a method for preparing a pharmaceutical composition, including mixing any compound of the new combination with a pharmaceutically acceptable carrier.

[0091] In a further embodiment, a method for treating or improving MD and / or endolymphatic edema in a subject with appropriate need comprises administering to the subject a therapeutically effective amount of a composition comprising ebuselenol or a combination of ebuselenol with one or more other glutathione peroxidase modulators or analog compounds, wherein the therapeutically effective amount of each compound in the combination is from about 0.1 mg / dose to about 5 g / dose. Specifically, the therapeutically effective amount of each compound in the composition is from about 0.5 mg / dose to about 1000 mg / dose. More specifically, the therapeutically effective amount of each compound in the composition is from about 1 mg / dose to about 100 mg / dose. In another embodiment, the composition is administered 1 to 3 times per day. In another embodiment, the therapeutically effective amount of each compound in the composition is from about 0.001 mg / kg / day to about 30 mg / kg / day. More specifically, the therapeutically effective amount of each compound in the composition is from about 0.01 mg / kg / day to about 2 mg / kg / day.

[0092] In a further embodiment, a method for preventing or inhibiting the progression of MD and / or endolymphatic edema in subjects with appropriate need comprises administering to the subject a therapeutically effective amount of a composition comprising ebuselenol or a combination of ebuselenol with one or more other glutathione peroxidase modulators or analog compounds, wherein the therapeutically effective amount of each compound in the combination is from about 0.1 mg / dose to about 5 g / dose. Specifically, the therapeutically effective amount of each compound in the composition is from about 0.5 mg to about 1000 mg / dose. More specifically, the therapeutically effective amount of each compound in the composition is from about 1 mg / dose to about 100 mg / dose. In another embodiment, the composition is administered 1 to 3 times per day. In another embodiment, the therapeutically effective amount of each compound in the composition is from about 0.001 mg / kg / day to about 30 mg / kg / day. More specifically, the therapeutically effective amount of each compound in the composition is from about 0.01 mg / kg / day to about 2 mg / kg / day.

[0093] Definitions / Terms

[0094] Generally, the terms used in the claims and description are intended to be interpreted as having the ordinary meaning understood by one of ordinary skill in the art. Certain terms are defined below to provide additional clarity. If the ordinary meaning conflicts with the provided definition, the provided definition shall prevail. Unless otherwise stated, terms used in the claims and description are defined as listed below or as defined by their use throughout this disclosure.

[0095] Methods for determining an effective dose of a disclosed pharmaceutical composition or combination of pharmaceuticals (whether or not formulated in the same composition) for therapeutic and preventative purposes are known in the art. For therapeutic purposes, the term "therapeuticly effective amount" as used herein refers to the amount of each active compound or agent, alone or in combination, sought by a researcher, veterinarian, physician, or other clinician to elicit a biological or medical response in an tissue system, animal, or human, including the relief of symptoms of a disease or ailment being treated. For preventative purposes (i.e., suppression of the onset or progression of a disease), the term "therapeuticly effective amount" refers to the amount of each active compound or agent, alone or in combination, sought by a researcher, veterinarian, physician, or other clinician to treat or suppress the onset or progression of a disease in a subject. Therefore, this disclosure provides combinations of two or more drugs, wherein, for example, (a) each drug is administered in an independently therapeutic or preventative amount; (b) if administered alone, at least one drug in the combination is administered in a subtherapeutic or subpreventative amount, but is therapeutic or preventative when administered in combination with a second or additional drug according to this disclosure; or (c) if administered alone, two (or more) drugs are administered in a subtherapeutic or subpreventative amount, but are therapeutic or preventative when administered together.

[0096] The term "Meniere's disease" refers to a progressive or non-progressive disease or disorder of the inner ear. The "classic" presentations of Meniere's disease are vertigo, hearing loss, and tinnitus. Here, the term Meniere's disease is not limited to being interpreted solely as a condition or disorder presenting with all three of the aforementioned symptoms. Rather, MD is considered to be a disorder diagnosed as described in Example 1.

[0097] The term "endolymphatic edema" refers to swelling of the endolymphatic compartment caused by the accumulation of endolymphatic fluid in the ear.

[0098] The term "pharmaceutically acceptable salt" refers to a non-toxic, pharmaceutically acceptable salt (see International J. Pharm., 1986, 33, 201-217; J. Pharm. Sci., 1997(January), 66, 1, 1). However, other salts well known in the art can be used to prepare compounds according to this disclosure or pharmaceutically acceptable salts thereof. Representative organic or inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, dihydroxynaphthyl acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfonic acid, salicylic acid, saccharinic acid, or trifluoroacetic acid. Representative organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine penicillin, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.

[0099] The term "composition" is intended to include products containing specified amounts of specified ingredients, as well as any products produced directly or indirectly from combinations of specified amounts of specified ingredients.

[0100] The term "subject" includes an organism, an animal, including mammals, humans or non-humans, males or females, that is the object of treatment, observation, clinical trials, or experiments. A subject can be a human patient. The term "human" generally refers to Homo sapiens. The term "mammal" as used herein includes, but is not limited to, humans, non-human primates, mice, rats, guinea pigs, chinchillas, and monkeys. Mammals other than humans can be advantageously used as subjects representing animal models of, for example, hearing loss, schizophrenia, bipolar disorder, and / or any other mental disorder.

[0101] The term "statistically significant" is defined as the probability that an outcome is not caused by random chance.

[0102] In the context of two or more nucleic acid or polypeptide sequences, the term "percentage of identity" or "sequence identity percentage" refers to two or more sequences or subsequences having a specified percentage of identical nucleotide or amino acid residues when compared and aligned for maximum correspondence, such as using one of the sequence comparison algorithms described below (e.g., BLASTP and BLASTN or other algorithms available to the technician) or by visual inspection. Depending on the application, the percentage of "identity" may be present in a region of the sequences being compared, for example, in a functional domain, or optionally across the entire length of the two sequences to be compared.

[0103] For sequence comparisons, typically one sequence serves as the reference sequence, and the test sequence is compared to it. When using a sequence comparison algorithm, the test and reference sequences are input into the computer, and subsequence coordinates are specified if necessary, along with the sequence algorithm program parameters. The sequence comparison algorithm then calculates the percentage of sequence identity of one or more test sequences relative to the reference sequence based on the specified program parameters.

[0104] The optimal alignment of sequences for comparison can be performed, for example, by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2: 482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48: 443 (1970), by the similarity search method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85: 2444 (1988), by the computerized implementation of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics software package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (generally see Ausubel et al. below).

[0105] An example of an algorithm suitable for determining the percentage of sequence identity and the percentage of sequence similarity is the BLAST algorithm, which is described in Altschul et al., J.Mol.Biol.215:403-410 (1990). The software used for BLAST analysis is publicly available through the website of the National Center for Biotechnology Information (NCBI).

[0106] The term "statistically significant" is defined as the probability that an outcome is not caused by random chance.

[0107] It must be noted that, unless the context clearly indicates otherwise, as used in the specification and appended claims, the singular forms “a,” “an,” and “the” include plural indicators.

[0108] The abbreviations or acronyms used throughout the instruction manual include:

[0109] ●AEC: List of Adverse Events

[0110] ●ECochG: Electrocochleography

[0111] ●EOS: Research concluded

[0112] ●GSH: Reduced form of glutathione

[0113] ●GSSG: Oxidized form of glutathione

[0114] ●GPx: Glutathione peroxidase

[0115] ●GR: Glutathione reductase

[0116] ●NAC: N-acetylcysteine

[0117] ●NC: Normal control

[0118] ●POC: Proof of Concept

[0119] ●Redox: Reduction / Oxidation

[0120] ●RNS: Reactive nitrogen substances

[0121] ●ROS: Reactive oxygen species

[0122] ●SOD: Superoxide dismutase

[0123] ●h or hr (hours)

[0124] ●LCMS (High-Performance Liquid Chromatography with Mass Spectrometer)

[0125] ●Me (methyl)

[0126] ●Mg (mg)

[0127] ●rt or RT (room temperature)

[0128] Treatment

[0129] In Meniere's disease, fluid buildup begins in the inner ear and flows into other areas, causing damage. This fluid buildup is called "edema." When pressure increases and drainage is blocked, the membranes swell (stretch and thin, like a balloon). This can be related to swelling of the endolymphatic sac or other tissues in the vestibular system of the inner ear, which is responsible for balance. Symptoms of Meniere's disease vary. Not all patients experience the same symptoms simultaneously.

[0130] Several preclinical animal studies have demonstrated the efficacy of glutathione peroxidase activity, particularly SPI-1005 (ebuselenone), in the prevention and treatment of various acquired forms of sensorineural hearing loss. GPx1 is the main catalytic antioxidant enzyme in the mammalian inner ear, and its activity decreases after ototoxic injury. Ebuselenone treatment has been shown to prevent or reverse pathological changes in the cochlea following noise or ototoxic damage.

[0131] In the cochlea, glutathione peroxidase (GPx) reacts with glutathione to limit free radical toxicity. Furthermore, GPx reduces reactive oxygen species by binding free radicals to their Se moieties. In this way, GPx can limit free radical toxicity from many cellular pathways. In normal functional cells, GPx functions at near-maximal capacity. However, GPx activity is severely reduced in the cochlear tissue of patients with myocardial infarction (MD) and / or endolymphatic edema. Restoration of cochlear GPx activity may then suppress or even reverse the effects of these conditions and associated inflammation.

[0132] Due to the large size and relative instability of enzymes, increasing GPx activity using the enzyme itself is impractical. However, many studies have synthesized and investigated small molecule modulators and / or mimics for GPx activity.

[0133] Ebuselenoline [SPI-1005 or 2-phenyl-1,2-benzisoselenazole-3(2H)-one] is a mimic of GPx activity and exhibits potent activity against peroxynitrite (ONOO-), a highly reactive oxygen species (ROS) formed by a combination of two free radicals, superoxide anion and nitric oxide (Noguchi et al., 1992; Noguchi et al., 1994). Ebuselenoline reduces cytochrome C release from mitochondria and nuclear damage during lipid peroxidation (Namura et al., 2001).

[0134] Therefore, this disclosure provides a method for treating, preventing, and / or improving MD and / or endolymphatic edema in a subject, the method comprising administering to a subject in need a therapeutically effective amount of a composition comprising ibuselenone or ibuselenone in combination with one or more other glutathione peroxidase modulators or analog compounds.

[0135] In one aspect, this disclosure provides for balancing pressure in the inner ear. The pressure system in the inner ear is highly complex and sensitive to subtle changes in middle ear hydrostatic pressure. Simultaneously, pressure balance in the inner ear is activated by the initiation of changes in the middle ear. Middle ear pressure is primarily governed by gas exchange with the middle ear tissues. Furthermore, the momentary opening of the Eustachian tubes also contributes to this pressure balance. Gas exchange can be triggered by chewing or yawning, but it is also sensitive to altitude, such as during flight or diving (ear clearing). Patients with Meniere's disease may experience significantly poorer middle ear pressure regulation. Middle ear ventilation (gas exchange) is influenced by endolymphatic fluid levels and is effective in the development and progression of Meniere's disease. Therefore, agents that lower endolymphatic fluid levels affect the preceding pathology and immediately induce Meniere's disease. Therefore, this disclosure provides a method for balancing pressure in the inner ear of a subject, comprising administering to a subject with appropriate need a therapeutically effective amount of a composition comprising ebuselenone or a combination of ebuselenone and one or more other glutathione peroxidase modulators or analogs.

[0136] In one aspect, this disclosure provides a method for reducing free radical production and / or inflammation in the cochlear tissue of a subject's ear, comprising administering to a subject in need an effective amount of a composition comprising ebuselenline and optionally one or more other glutathione peroxidase modulators or analogs. Specific free radical substances include reactive oxygen species. More specifically, free radicals include, but are not limited to, peroxynitrite, superoxide anion, nitric oxide, nitrotyrosine, and hydroxyl radicals.

[0137] In one aspect, this disclosure provides methods for treating, preventing, and / or improving MD and / or endolymphatic edema in a subject, wherein said methods restore or partially restore hearing loss or prevent hearing loss in the subject. This disclosure provides methods in which swelling of the endolymphatic compartments or other tissues in the vestibular system of the inner ear is reduced, improved, stopped, or otherwise eliminated. This disclosure provides methods in which a subject experiences reduced vertigo and / or tinnitus. This disclosure provides methods in which the method reduces inflammation in the tissues of the ear.

[0138] Furthermore, in any of the methods described herein, one or more GPx modifiers or analogues may be co-administered with ebuselenol in each single dose or intermittently, for example, every other dose, or every three doses, or every four doses, or every five doses, or every six to twenty doses. Of course, it is anticipated that one or more GPx modifiers or analogues may be administered periodically, which may or may not overlap with the administration of ebuselenol. In this case, the GPx analogue or modifier may be administered every 4 hours, every 6 hours, every 12 hours, once daily, every other day, every three days, every five days, once weekly, every ten days, every two weeks, or up to once monthly.

[0139] In any of the methods described herein, ibuselenone and one or more GPx modifiers or analogs, or their pharmaceutically acceptable salts, esters, or prodrugs, are administered orally, nasally, transdermally, pulmonaryly, by inhalation, sublingually, intraorally, intracochlearly, intratympanicly, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, or parenterally. The compound is administered orally. In another embodiment, the compound is administered topically to the inner, middle, or outer ear.

[0140] In any of the methods described herein, ebuselenline and one or more GPx modifiers or analogues can be administered via various routes, including parenteral, enteral, and local administration. Parenteral delivery methods include intramuscular, intrathecal, intraventricular, intra-arterial, subcutaneous, intramedullary, intravenous, or intranasal administration. Additionally, the composition may contain a suitable pharmaceutically acceptable carrier comprising excipients and other compounds that facilitate administration to mammalian subjects.

[0141] In any of the methods described herein, one or more prescription diuretic compounds may be used in combination with ibuselenol, or in combination with ibuselenol and one or more other glutathione peroxidase modulators or mimics, to prepare a composition that can be administered to a subject.

[0142] compound

[0143] Representative compounds of this disclosure are described throughout the specification and claims.

[0144] Representative compounds of glutathione peroxidase (GPx) mimics include ibuseline, (2-phenyl-1,2-benzisisoseleno-3(2H)-one), with the empirical formula C0. 13 H9NOSe, with a molecular weight of 274.2, has the following formula:

[0145]

[0146] In some embodiments, ebuselenline is the sole active ingredient administered in the formulation. Ebuselenline is slightly soluble in aqueous solution at 25°C. Ebuselenline acts as a catalyst and is not consumed during the detoxification reaction (Muller et al., 1988). One embodiment of the ebuselenline formulation was confirmed by HPLC to have a purity >99%. The synthesis of this formulation was provided by Rhodia PharmaSolutions and comprises capsules sealed in blister packs. Each capsule contains 200 mg of the ebuselenline formulation or SPI-1000 (placebo).

[0147] Other representative compounds of glutathione peroxidase (GPx) mimics include 2,2'-diseleno-bis-β-cyclodextrin and 6A,6B-diselenoic acid-6A',6B'-selenium-bridged β-cyclodextrin.

[0148] Representative compounds of the GPx modulators in the combination include glutathione (GSH), glutathione prodrugs listed in Table 1, and cysteine ​​prodrugs listed in Table 2.

[0149] Table 1 - Glutathione prodrugs

[0150]

[0151]

[0152] Table 2 – Cysteine ​​Prodrugs

[0153]

[0154]

[0155]

[0156]

[0157] Some other embodiments of cysteine ​​prodrugs include 2-substituted thiazolidin-4-carboxylic acids with aldose monosaccharides such as glyceraldehyde, arabinose, lythose, ribose, xylose, galactose, glucose, and mannose.

[0158] This disclosure provides one or more diuretic compounds. Diuretics are drugs used to treat hypertension, heart disease, and certain types of kidney or liver disease. They stimulate the kidneys to remove water from the body. These compounds are well known in the art and are generally classified into three classes: thiazide diuretics, potassium-sparing agents, and long-acting diuretics. Examples of compounds that are diuretic compounds include, but are not limited to, Aquatensen, Diucardin, Diulo, Diuril, Enduron, Esidrix, Hydro-chlor, Hydro-D, HydroDIURIL, Hydrochlorothiazide, Hydrogroton, Metahydrin, Microzide, and Mykrox. Naqua (trichlorothiazide), Naturetin (benzylfluorothiazide), Oretic (hydrochlorothiazide), Renese (polithiazide), Saluron (hydrofluorothiazide), Thalitone (chlorothiazide), Trichlorex (trichlorothiazide), Zaroxolyn (metoprazine), Aldactone (spironolactone), Dyrenium (triamterene), Midamor (amiloride), Bumex (bumetanide), Demadex (tosemide), Edecrin (ethacrynic acid), and Lasix (furosemide), Myrosemide (furosemide). Prescription diuretic compounds are commercially available.

[0159] In one aspect, this disclosure provides glutathione peroxidase (GPx) regulators or mimics, including but not limited to 2-phenyl-1,2-benzisoselenazole-3(2H)-one (ebuselenone); 6A,6B-diselenoic acid-6A',6B'-selenium-bridged β-cyclodextrin (6-diSeCD); and 2,2'-diselenoyl-bis-β-cyclodextrin (2-diSeCD).

[0160] In one aspect, this disclosure provides amino acids or peptides having at least 90%, more preferably 95%, still more preferably 98%, still more preferably 99%, and still more preferably 100% sequence identity with the amino acids or peptides disclosed herein.

[0161] When the compounds according to this disclosure have at least one chiral center, they can therefore exist as enantiomers. In the case of compounds having two or more chiral centers, they can additionally exist as diastereomers. In cases where the preparation method of the compounds according to this disclosure provides a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds can be prepared in racemic form or by stereospecific synthesis or by resolution as separate enantiomers or diastereomers. The compounds can be, for example, resolved into their component enantiomers or diastereomers by standard techniques, such as by forming a salt with an optically active base to form a stereoisomer pair, followed by fractional crystallization and regeneration of the free acid. The compounds can also be resolved by forming stereoisomeric esters or amides, followed by chromatographic separation and removal of chiral auxiliaries. Optionally, a chiral HPLC column can be used to resolve the compounds. It should be understood that all stereoisomers, racemic mixtures, diastereomers, geometric isomers, and their enantiomers are included within the scope of this disclosure.

[0162] Furthermore, some crystalline forms of the compounds can exist as polymorphs and are therefore intended to be included in this disclosure. Additionally, some compounds can form solvates with water (i.e., hydrates) or common organic solvents, and these solvates are also intended to be included within the scope of this disclosure.

[0163] In one aspect, ibuselenone, alone or in combination with one or more GPx regulators or analogs or one or more prescription diuretic compounds, can be used to prepare pharmaceutical compositions by mixing the compound with one or more adjuvants and / or excipients.

[0164] Compound Synthesis

[0165] Generally, the ebuselenoid and GPx compounds disclosed herein are commercially available but have not been approved as prescription drugs. Optionally, the ebuselenoid and GPx modifiers and analogs described herein have been prepared or synthesized in U.S. Patent Nos. 5,008,394, 5,399,573, International Patent Publication Nos. WO2010 / 074992, WO2013 / 016727, and Chinese Patent Application No. 201410299898 and U.S. Patent Application No. 10 / 750,005, the full text of which is hereby incorporated. Any necessary modifications to these compounds, such as the conversion of one or more organic functional groups or protecting groups to the necessary R groups for the preparation of compounds of the formula disclosed herein, can be readily performed by those skilled in the art using the organic synthesis techniques described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999.

[0166] General application, formulation and dosage

[0167] The compounds disclosed herein are GPx modulators or analogs and are therefore used to treat, prevent or inhibit the progression of MD and / or endolymphedema.

[0168] One embodiment is characterized by a method for treating a subject suffering from MD and / or endolymphedema, the method comprising administering to the subject in need a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds disclosed herein.

[0169] The implementation scheme also includes prodrugs of the compounds disclosed herein. Typically, such prodrugs are functional derivatives of compounds that are readily converted into the desired compound in vivo. Therefore, in the treatment methods described in this disclosure, the term "administration" will include treating the various conditions with a specifically disclosed compound or with a compound that may not be specifically disclosed but is converted into the designated compound in vivo after administration to a subject. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundara, Elsevier, 1985.

[0170] Some crystalline forms of the compounds may exist in polymorphic forms and are therefore intended to be included in this disclosure. Furthermore, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and these solvates are intended to be covered by some embodiments.

[0171] When the methods for preparing the compounds disclosed herein produce mixtures of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds can be prepared in racemic form or by stereospecific synthesis or by resolution as separate enantiomers or diastereomers. The compounds can, for example, be resolved into their component enantiomers or diastereomers by standard techniques, such as by forming a salt with an optically active base to form a stereoisomer pair, followed by fractional crystallization and regeneration of the free acid. The compounds can also be resolved by forming stereoisomeric esters or amides, followed by chromatographic separation and removal of chiral auxiliaries. Optionally, a chiral HPLC column can be used to resolve the compounds. It should be understood that all stereoisomers, racemic mixtures, diastereomers, cis-trans isomers, and their enantiomers are covered by some embodiments.

[0172] dose

[0173] Those skilled in the art of treating MD and / or endolymphedema can determine the effective daily dose from the test results and other information provided below. It is well known to those skilled in the art that the exact dosage and frequency of administration depend on the specific compound used in this disclosure, the specific condition being treated, the severity of the condition, the age, weight, general condition of the particular patient, and other medications the patient may be taking. Furthermore, it is apparent that the effective daily dose may be reduced or increased based on the patient's response to treatment and / or on the evaluation of the physician who prescribed the compound of this disclosure. Therefore, the effective daily dose ranges mentioned herein are merely guidelines for implementing this disclosure.

[0174] For any method of treating MD and / or endolymphatic edema described herein using any of the compounds disclosed herein, the dosage form will contain a pharmaceutically acceptable carrier containing from about 0.1 mg to about 5000 mg; particularly from about 0.5 mg to about 1000 mg; and, more particularly, from about 1 mg to about 100 mg of the compound, and may be configured in any form suitable for the chosen mode of administration. However, the dosage may vary depending on the needs of the subject, the severity of the condition being treated, and the compound used. Administration may be daily or post-periodic.

[0175] The pharmaceutical compositions described herein will contain tablets, capsules, powders, injections, suppositories, teaspoonfuls, etc., with a dosage unit ranging from about 0.001 mg / kg / day to about 10 mg / kg / day (particularly from about 0.01 mg / kg / day to about 1 mg / kg / day; and more specifically, from about 0.1 mg / kg / day to about 0.5 mg / kg / day), and can be administered at a dosage ranging from about 0.001 mg / kg / day to about 30 mg / kg / day (particularly from about 0.01 mg / kg / day to about 2 mg / kg / day, more particularly from about 0.1 mg / kg / day to about 1 mg / kg / day, and even more particularly from about 0.5 mg / kg / day to about 1 mg / kg / day).

[0176] These compositions are in unit dosage forms, such as tablets, pills, capsules, dry powders for reconstitution or inhalation, granules, lozenges, sterile parenteral solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, auto-injection devices, or suppositories, for administration via oral, intranasal, sublingual, intraocular, transdermal, parenteral, rectal, vaginal, dry powder inhaler, or other inhalation or blowing routes. Optionally, the compositions may be presented in a form suitable for weekly or monthly administration; for example, insoluble salts of the active compound, such as decanoates, may be suitable for providing long-acting products for intramuscular injection.

[0177] To prepare solid pharmaceutical compositions such as tablets, the main active ingredient is mixed with a drug carrier, such as conventional tableting components, including diluents, binders, adhesives, disintegrants, lubricants, anti-adhesion agents, and flow aids. Suitable diluents include, but are not limited to, starch (i.e., corn, wheat, or potato starch, which can be hydrolyzed), lactose (granular, spray-dried, or anhydrous), sucrose, sucrose-based diluents (confectioner's sugar; sucrose plus about 7%-10% by weight of invert sugar; sucrose plus about 3% by weight of modified dextrin; sucrose plus invert sugar, about 4% by weight of invert sugar, about 0.1% to 0.2% by weight of corn starch and magnesium stearate), dextran, inositol, mannitol, sorbitol, and microcrystalline cellulose (i.e., AVICEL, available from FMC Corp.). TM Microcrystalline cellulose), dicalcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate, etc. Suitable adhesives and binders include, but are not limited to, gum arabic, guar gum, tragacanth gum, sucrose, gelatin, glucose, starch and cellulose (i.e., methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, etc.), water-soluble or water-dispersible adhesives (i.e., alginate and its salts, magnesium aluminum silicate, hydroxyethylcellulose [i.e., TYLOSE available from Hoechst Celanese]).TM Suitable disintegrants include, but are not limited to, starch (corn starch, potato starch, etc.), sodium glycolate, pregelatinized starch, clay (magnesium aluminum silicate), cellulose (such as croscarmellose sodium and microcrystalline cellulose), alginate, pregelatinized starch (i.e., corn starch, etc.), gums (i.e., agar, guar gum, locust bean gum, ark sylvestris gum, pectin and tragacanth gum), croscarmellose, etc. Suitable lubricants and anti-sticking agents include, but are not limited to, stearates (magnesium stearate, calcium stearate and sodium stearate), stearic acid, talc, stearrowet, boric acid, sodium chloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate, sodium benzoate, sodium acetate, sodium dodecyl sulfate, magnesium dodecyl sulfate, etc. Suitable flow aids include, but are not limited to, talc, corn starch, and silica (i.e., CAB-O-SIL obtained from Cabot). TM Silica, available from WRGrace / Davison SYLOID TM Silica and AEROSIL available from Degussa TM Silicon dioxide, etc. Sweeteners and flavorings can be added to chewable solid dosage forms to improve the palatability of oral dosage forms. Additionally, colorants and coatings can be added to or applied to solid dosage forms to facilitate drug labeling or for aesthetic purposes. These carriers are formulated together with the active pharmaceutical ingredient to provide an accurate and appropriate dose of the active pharmaceutical ingredient with a therapeutic release profile.

[0178] These carriers are typically mixed with the pharmaceutically active substance to form a solid preformation composition containing a homogeneous mixture of the pharmaceutically active form of the present disclosure or a pharmaceutically acceptable salt thereof. Typically, the preformation is formed by one of three common methods: (a) wet granulation, (b) dry granulation, and (c) dry mixing. When these preformation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, allowing for easy further fractionation into equivalent dosage forms such as tablets, pills, and capsules. This solid preformation composition is then further fractionated into unit dosage forms of the type described above, containing about 0.1 mg to about 5000 mg of the active ingredient of the present disclosure. Tablets or pills containing this novel composition may also be formulated into multilayer tablets or pills to provide sustained or dual-release products. For example, dual-release tablets or pills may contain an inner dose component and an outer dose component, the latter being encapsulated on the former. The two components are separated by an enteric coating layer, which resists breakdown in the stomach and allows the inner component to pass intact into the duodenum or be released with a delay. Various materials can be used for such enteric coatings or coatings, including many polymeric materials such as shellac, cellulose acetate (i.e., cellulose acetate phthalate, cellulose trimellitate acetate), polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylate and ethyl acrylate copolymers, methacrylate and methyl methacrylate copolymers, etc. Sustained-release tablets can also be formulated using slightly soluble or insoluble substances in solution (used as binders in wet granulation) or low-melting-point solid melt forms (incorporating the active ingredient in wet granulation) through film coating or wet granulation. These materials include natural and synthetic polymeric waxes, hydrogenated oils, fatty acids and alcohols (i.e., beeswax, carnauba wax, cetyl alcohol, cetyl stearyl alcohol, etc.), esters of fatty acid metal soaps, and other acceptable materials that can be used for granulation, coating, embedding, or otherwise limiting the solubility of the active ingredient to achieve prolonged or sustained release.

[0179] The novel compositions disclosed herein can be incorporated into liquid forms for oral or injectable administration, including but not limited to aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar drug carriers. Suitable suspending agents for aqueous suspensions include synthetic and natural gums such as gum arabic, agar, alginate (i.e., propylene alginate, sodium alginate, etc.), guar gum, black privet gum, locust bean gum, pectin, tragacanth gum, and xanthan gum; celluloses such as sodium carboxymethyl cellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose and combinations thereof; synthetic polymers such as polyvinylpyrrolidone, carbomer (i.e., polycarboxyethylene), and polyethylene glycol; clays such as bentonite, lithium montmorillonite, palygorskite, or sepiolite; and other pharmaceutically acceptable suspending agents such as lecithin, gelatin, etc. Suitable surfactants include, but are not limited to, sodium docusate, sodium lauryl sulfate, polysorbate, octyl phenyl alcohol-9, nonyl phenyl alcohol ether-10, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer 188, poloxamer 235, and combinations thereof. Suitable antiflocculating or dispersing agents include pharmaceutical-grade lecithin. Suitable flocculants include, but are not limited to, simple neutral electrolytes (i.e., sodium chloride, potassium chloride, etc.), highly charged insoluble polymers and polyelectrolytes, and water-soluble divalent or trivalent ions (i.e., calcium salts, alum or sulfates, citrates, and phosphates, which can be used together as pH buffers and flocculants in formulations). Suitable preservatives include, but are not limited to, parabens (i.e., methylparaben, ethylparaben, n-propylparaben, and n-butylparaben), sorbic acid, thimerosal, quaternary ammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate, phenethyl alcohol, etc. Many liquid mediators are available for liquid drug dosage forms; however, the liquid mediator used in a particular dosage form must be compatible with the suspending agent. For example, nonpolar liquid mediators such as fatty esters and oil-based liquid mediators are best used with surfactants such as low HLB (hydrophilic-lipophilic balance) surfactants, stearalkonium chloride, etc. Suspensions such as hectorite, water-insoluble resins, and water-insoluble film-forming polymers are used together. Conversely, polar liquids such as water, alcohols, polyols, and glycols are best used with suspensions such as high-HLB surfactants, clay silicates, colloids, water-soluble cellulose, and water-soluble polymers. For parenteral administration, sterile suspensions and solutions are required. Liquid forms suitable for parenteral administration include sterile solutions, emulsions, and suspensions. When intravenous administration is required, isotonic preparations, typically containing suitable preservatives, are used.

[0180] Furthermore, the compounds disclosed herein can be administered in intranasal formulations via topical application of a suitable intranasal medium or via transdermal patches, and the compositions are well known to those skilled in the art. For administration via a transdermal delivery system, the therapeutic dose will naturally be administered continuously rather than intermittently throughout the administration regimen.

[0181] The compounds disclosed herein can also be administered via liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearamide, and phosphatidylcholine.

[0182] The daily dose of the pharmaceutical compositions disclosed herein can vary over a wide range from about 0.1 mg to about 5000 mg; preferably, for the average person, the dose will be in the range of about 1 mg to about 100 mg per day. For oral administration, the compositions are preferably provided in tablet form containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500, 750, 1000, 1250, 1500, 1750, 2000, 2500 or 3000 mg of the active ingredient for symptomatic dose adjustment in treated subjects. Advantageously, the compounds of this disclosure can be administered in a single daily dose, or the total daily dose can be administered in divided doses twice, three or four times daily.

[0183] The therapeutically effective dose of the active compounds or pharmaceutical compositions thereof disclosed herein can vary depending on the desired effect. Therefore, the optimal dose to be administered can be readily determined by those skilled in the art and can vary depending on the specific compound used, the method of administration, the strength of the product, and the progression of the disease condition. Furthermore, factors relevant to the specific subject being treated, including the subject's age, weight, diet, and time of administration, will necessitate adjustments to the dose to an appropriate therapeutic level. Therefore, the doses described above are examples of typical cases. Of course, there may be individual cases where higher or lower dose ranges are worthwhile, and such cases are within the scope of this disclosure.

[0184] The compounds disclosed herein may be administered in any of the foregoing compositions and administration regimens, or by those compositions and administration regimens established in the art, provided that a subject with a corresponding need requires the use of the compounds disclosed herein as a GPx modulator or analogue.

[0185] preparation

[0186] To prepare the pharmaceutical compositions disclosed herein, one or more of the compounds disclosed herein, or salts thereof, are tightly mixed as active ingredients with a pharmaceutical carrier, which may take various forms depending on the desired form of administration (e.g., oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0187] The compounds disclosed herein can be formulated into various pharmaceutical forms for administration purposes. Methods for formulating pharmaceutical compositions have been described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, 2nd Edition, Revised and Expanded, Volumes 1–3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1–2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1–2, edited by Lieberman et al., published by Marcel Dekker, Inc.

[0188] Ebuselenin was prepared in capsule form for the following examples, which investigated ebuselenin as a novel therapeutic agent for MD and / or endolymphatic edema. Ebuselenin may or may not be the sole active ingredient in the formulation and may act as a catalyst for biochemical reactions in which case it is not consumed during detoxification. The purity of the formulation was determined by HPLC to be >99%. The capsules were sealed in blister packs. Each capsule contained 200 mg of ebuselenin, which has low toxicity due to its unique structural stability. Its selenium (Se) moiety is not released during biotransformation and therefore does not enter selenium metabolism. Unbound selenium may be present during the manufacturing process. The manufacturing standard is that each capsule contains less than 1 microgram of inorganic selenium. In humans, long-term intake of large amounts of selenium can lead to selenium toxicity or selenium poisoning. The recommended daily allowance (RDA) for selenium in adults is 55 micrograms per day. The dosage was adjusted so that the total selenium exposure monitored during the study period was significantly lower than the RDA. Example

[0189] The following are examples of specific implementation schemes for carrying out the present disclosure. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way. Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental error and bias should of course be tolerated.

[0190] Unless otherwise stated, practice of this disclosure will employ conventional methods of protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology within the scope of the art. Such techniques are well explained in the literature. See, for example, TECreighton, Proteins: Structures and Molecular Properties (WH Freeman and Company, 1993); ALLehninger, Biochemistry (Worth Publishers, Inc., latest edition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd edition, 1989); Methods in Enzymology (edited by S. Colowick and N. Kaplan, Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry, 3rd edition (Plenum Press), Vols A and B (1992).

[0191] Example 1: Clinical treatment of patients with Meniere's disease

[0192] introduction

[0193] Meniere's disease (MD) is defined as a triad of episodic vertigo, hearing loss, and tinnitus. Ear pressure or fullness is frequently reported, and most auditory and vestibular symptoms fluctuate in frequency and intensity. Endolymphedema, swelling of the endolymphatic compartments of the inner ear, is directly associated with MD. Most patients with MD are treated medically with a low-sodium diet and / or thiazide diuretics, but with limited effectiveness. A chronic phase develops after an acute phase, in which vertigo is the most common feature, and hearing loss and tinnitus become the most common features, although balance disorders are frequently reported.

[0194] MD Standard

[0195] AAO-HNS 1995 diagnostic criteria for Meniere's disease

[0196] Possible Meniere's disease

[0197] Paroxysmal vertigo of the Meniere's disease type, with no recorded hearing loss, or

[0198] Fluctuating or fixed sensorineural hearing loss, with balance disorder, but without ruling out other definite causes of onset.

[0199] High probability of Meniere's disease

[0200] A definite vertigo event

[0201] Hearing loss recorded in at least one hearing test

[0202] Tinnitus or ear fullness in the ear being treated.

[0203] Excluding other causes

[0204] Definite Meniere's disease

[0205] Two or more distinct spontaneous episodes of vertigo lasting 20 minutes or longer.

[0206] Hearing loss recorded in at least one hearing test

[0207] Tinnitus or ear fullness in the ear being treated.

[0208] Excluding other causes

[0209] Certain Meniere's disease

[0210] A confirmed diagnosis of Meniere's disease, plus histopathological confirmation.

[0211] American Academy of Otolaryngology-Head and Neck Foundation,Inc.Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Meniere's disease. Otolaryngol Head Neck Surg.1995 Sep;113(3):181-5 .

[0212] Thorp MA, Shehab ZP, Bance ML, Rutka JA; AAO-HNS Committee on Hearing and Equilibrium. The AAO-HNS Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Meniere's disease: have they been applied in the published literature of the last decade? Clin Otolaryngol Allied Sci. 2003 Jun;28(3):173-6 .

[0213] The general approach to investigating the safety and efficacy of SPI-1005 in Meniere's disease was to conduct this Phase 1b safety, pharmacokinetic, and pharmacodynamic study in 40 adults with Meniere's disease. This study evaluated the effects of escalating doses of SPI-1005, administered orally twice daily at 200, 400, or 600 mg versus placebo for 21 days on patient-reported outcomes of pure-tone audiometry, speech discrimination, electrocochleography, and assessment of vertigo and tinnitus using a validated questionnaire. Hornibrook, et al. 2012 ; Meikle et al., 2011 ; Yardley et al., 2004 This study is ongoing and is being conducted in accordance with Good Clinical Practice (GCP) protocols and applicable regulatory requirements.

[0214] Research Objectives

[0215] The aim of this study was to evaluate the safety, pharmacokinetic (PK) and PD of three dose levels of SPI-1005 (administered for 21 days) in patients with Meniere's disease compared with placebo.

[0216] Main purpose

[0217] The safety and tolerability of SPI-1005 were determined by examining toxicities and adverse events attributable to treatment. Safety parameters included assessment of clinical signs and symptoms during medical history and physical examination; vital signs; incidence of adverse events; and abnormal laboratory test results.

[0218] Second objective

[0219] The second objective of this study was to determine the pharmacokinetics of SPI-1005 at various dose levels; the severity of sensorineural hearing loss using pure-tone audiometry and speech discrimination tests using the Word Noise Test (WINT) before, during, and after treatment; the severity of vertigo using the Vertigo Symptom Scale (VSS) before, during, and after treatment; the severity of tinnitus using the Tinnitus Function Index (TFI) before, during, and after treatment; and the pharmacodynamic response using electrocochleography (ECochG) before, during, and after treatment.

[0220] Research Design

[0221] In this double-blind, dose-escalation study, participants were randomized to receive either SPI-1005 or placebo to assess its safety and preliminary efficacy. Patients aged 19–70 years with a high probability or confirmed Meniere's disease underwent baseline testing to obtain the severity of their sensorineural hearing loss, tinnitus, and vertigo, which were determined prior to the start of study treatment (see Table 3: Assessment Timeline).

[0222] Patient safety was assessed before, during, and for 28 days after SPI-1005 administration via medical history, physical examination, vital signs, and blood tests (complete blood count [CBC], Chemistry-20 [Chem-20]). Peak and trough plasma levels of ebuselenin and its major metabolites were determined using liquid chromatography-mass spectrometry (LCMS) at certain time points. Additionally, total selenium in plasma was analyzed by high-performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP-MS) at the corresponding time points. Adverse events were monitored at each outpatient visit. Pregnancy testing was performed on female patients, and those found to be pregnant were excluded from the study or the study was terminated, with adverse events monitored in these patients. Safety monitoring was extended for four weeks after completion of treatment.

[0223] The effects of SPI-1005 on hearing and vertigo were assessed at baseline, at the end of 21 days of treatment, and 28 days after treatment completion. Tinnitus was assessed at baseline, weekly during treatment, and 7 and 28 days after treatment. Hearing was assessed using pure-tone audiometry at 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz and speech discrimination using WINT with signal-to-noise ratios (SNR) of 24, 20, 16, 12, 8, 4, and 0. Vertigo severity was assessed using VSS. Tinnitus severity was assessed using TFI. In addition, ECochG was performed at baseline, at the end of treatment, and 28 days after treatment completion to measure pharmacodynamic response.

[0224] Treatment instructions

[0225] compound

[0226] SPI-1005 is a patented formulation of the compound ibuselenin, consisting of gelatin capsules containing 200 mg of the active pharmaceutical ingredient ibuselenin and 150 mg of excipients, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0227] Dosage level

[0228] There are three dosage levels of SPI-1005: 200 mg, 400 mg, and 600 mg.

[0229] Dosing regimen

[0230] Patients were randomly assigned to SPI-1005 or placebo in three consecutive dose-escalation cohorts: Cohort 1: 200 mg orally twice daily (n=10) or placebo (n=3) for 21 days; Cohort 2: 400 mg orally twice daily (n=10) or placebo (n=3) for 21 days; Cohort 3: 600 mg orally twice daily (n=10) or placebo (n=4) for 21 days.

[0231] Each dose is administered as three capsules before meals in the morning and three capsules before meals in the evening. The three capsules consist of a combination of SPI-1005 and / or the same placebo capsules to provide the target dose level.

[0232] Dosage form

[0233] Capsule #1 contains 200 mg of ebuseline or a matching placebo.

[0234] Manufacturer

[0235] SPI-1005 is manufactured by Catalent Pharma Solutions, Somerset, NJ.

[0236] Application route

[0237] SPI-1005 (or a matching placebo) was delivered orally.

[0238] Research Procedures

[0239] Treatment duration

[0240] The study treatment was administered over a 21-day period starting from day 1 of the study.

[0241] Study duration

[0242] Patients will participate in this clinical trial for approximately 7 to 9 weeks, starting with baseline testing and continuing for more than 4 weeks beyond the final dose to allow for drug safety monitoring. A two-week window (days -14 to -1 of the study) is allowed to complete the baseline testing. Each patient will have six clinical visits during the study period (see Table 3, Assessment Schedule).

[0243] Initial screening is conducted by telephone to obtain a brief medical history, review inclusion and exclusion criteria, discuss informed consent forms, explain the costs of outpatient visits and blood tests, and, if appropriate and agreed, schedule the first outpatient visit.

[0244] Outpatient visit 1 (Day -14 to Day -1)

[0245] Informed consent was obtained from participants prior to study evaluation. Medical history and physical examination, vital signs, height / weight, blood tests (Chem-20, CBC), and urine pregnancy tests were performed up to 14 days prior to treatment initiation (Day 1 of the study). Baseline symptoms and concomitant medications were recorded. Total selenium levels in the blood were obtained. Baseline hearing assessment consisted of otoscopy, tympanic pressure measurement, pure-tone audiometry at 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz, and speech discrimination using WINT at 24, 20, 16, 12, 8, 4, and 0 SNR. Baseline vertigo was assessed using VSS. Baseline tinnitus was assessed using TFI. Baseline ECochG was performed.

[0246] After receiving informed consent, blood tests, medical history, physical examination, baseline hearing test, study registration, and verbal explanation of the protocol, each patient received a medication card containing SPI-1005 and / or a placebo capsule. The dispensing clinician recorded the subject identification code, date of issue, and card number for each card. Patients were advised not to take their morning dose before returning to the clinic on the morning of their next outpatient appointment.

[0247] Outpatient visit 2 (Day 7, before morning dose)

[0248] Perform a medical history and physical examination, and assess vital signs. Record adverse events. Record concomitant medications. Measure treatment adherence using patient history and pill count. Perform blood tests, including but not limited to Chem-20 and CBC. Draw a trough blood sample for total selenium and ebuselin and its metabolites levels before the morning dose of the study drug. Assess tinnitus using TFI. Patients are advised not to take their morning dose before returning to the clinic on the morning of their next outpatient visit.

[0249] Outpatient visit 3 (Day 14, before morning dose)

[0250] Perform a medical history and physical examination, and assess vital signs. Record adverse events. Record concomitant medications. Measure treatment adherence using patient history and pill count. Draw a glutar blood sample for total selenium and ebuselin and its metabolites levels before the morning dose of the study medication. Assess tinnitus using TFI. The patient is advised not to take their morning dose before returning to the clinic on the morning of their next outpatient visit.

[0251] Outpatient visit 4 (Day 21, before and after the morning dose on the last day of administration).

[0252] Perform a medical history and physical examination, and assess vital signs. Record adverse events. Record concomitant medications. Measure treatment adherence using patient history and pill count. Perform blood tests, including but not limited to Chem-20 and CBC. Draw a trough blood sample for total selenium and ebuselenin and its metabolites levels before the morning dose of the study drug. Draw a peak blood sample for total selenium and ebuselenin and its metabolites levels 2 hours after administration of the study drug. Hearing assessment consists of pure-tone audiometry at 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz and speech discrimination using WINT at 24, 20, 16, 12, 8, 4, and 0 SNR. Evaluate vertigo using VSS. Evaluate tinnitus using TFI. Perform ECochG at the end of treatment.

[0253] Outpatient visit 5 (Day 28, 7 days after the last dose of SPI-1005)

[0254] Perform a medical history and physical examination, and assess vital signs. Record adverse events. Record concomitant medications. Assess treatment adherence using patient history and pill count. Draw blood samples for total selenium and ebuselenline and its metabolites levels. Perform tinnitus assessment using TFI.

[0255] Outpatient visit 6 (Day 49, 28 days after the last dose of SPI-1005)

[0256] Perform a medical history and physical examination, and assess vital signs. Record adverse events. Record concomitant medications. Measure treatment adherence using patient history and final pill count. Perform blood tests, including but not limited to Chem-20 and CBC. Draw blood samples for total selenium and ebuselin and its metabolites levels. Hearing assessment consists of pure-tone audiometry at 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz and speech discrimination using WINT at 24, 20, 16, 12, 8, 4, and 0 SNR. Evaluate vertigo using VSS. Evaluate tinnitus using TFI. Perform ECochG post-treatment.

[0257] Safety and effectiveness evaluation

[0258] Medical assessment

[0259] Medical history and physical examination, vital signs, and laboratory reports were analyzed to assess the safety of SPI-1005. A licensed physician (MD) or physician assistant (PA) performed the physical examination using standard clinical equipment at designated study intervals. Blood test results were analyzed according to currently established laboratory protocols. Adverse events were inquired about at each outpatient visit.

[0260] Laboratory testing

[0261] Blood tests were performed at prescribed time intervals to assess the safety of SPI-1005. Qualified medical laboratory technicians performed the laboratory tests using standard equipment and established general safety precautions for collecting and handling blood samples. The blood tests performed included CBC and Chem-20. Blood was collected and transported to a designated CRO for quantification of ebuselenin, ebuselenin metabolites, and total selenium.

[0262] Hearing test

[0263] Hearing assessments were performed at specified time intervals to evaluate the effectiveness of the SPI-1005. Tests included otoscopy, tympanic pressure measurement, pure-tone audiometry, bone conduction, and speech discrimination, all performed by a physician or qualified audiologist. Wilson and Burks, 2005 ECochG was performed by a physician specialist at specified time intervals. Patient-reported results from the self-assessment questionnaire included VSS (Various Situations). Yardley et al., 2004 ) and TFI ( Meikle et al., 2011 These are rated by researchers.

[0264] analyze

[0265] Multiple clinical evaluations and auditory and vestibular function analyses

[0266] Pure-tone audiometry and word recognition scores: baseline, day 21 of treatment (21d tx), and day 28 post-treatment (28d post-tx)

[0267] ● Hearing loss is usually unilateral and occurs at low frequencies (0.25, 0.5, and 1 kHz).

[0268] √ Significant hearing improvement with a reduction of ≥10 dB from baseline

[0269] ● Word Noise Test (WINT): 35 words (0-35) at 7 different SNRs for each ear.

[0270] √ Significant improvement in WINT, with an increase of ≥10% from baseline

[0271] Tinnitus Function Index (TFI): baseline, and on days 7, 14, and 21 of treatment, and on days 7 and 28 after treatment.

[0272] ● The patient answers 25 questions (0-100) about the severity of their tinnitus.

[0273] √ Significant improvement in TFI, a reduction of ≥10 pt from baseline

[0274] ● The patient answered the tinnitus loudness (TL) (0-10) using the visual analog scale.

[0275] √ Significant improvement in TL, a reduction of ≥2 pt from baseline

[0276] Vertigo Symptom Scale (VSS): baseline, day 21 of treatment, and day 28 after treatment

[0277] ● The patient answers 15 questions about the severity of dizziness (0-60).

[0278] √ Significant improvement in VSS, a reduction of ≥6 pt from baseline

[0279] Statistical analysis of study endpoints

[0280] Adverse events were coded using MedDRA (version 18.1 or later), and the number of adverse events was summed for each dose level (placebo, 200, 400, and 600 mg twice daily). Comparisons were made between baseline, treatment duration, and follow-up values ​​at 7 and 28 days.

[0281] Vital signs and clinical laboratory results were summarized for each dose level. Comparisons were made between baseline, treatment, 7-day, and 28-day follow-up values. Outliers were identified and categorized by severity.

[0282] Hearing data were collected as categorical and continuous variables. Categorical data were analyzed using a chi-square distribution. Continuous data were analyzed using mixed-effects repeated measures and post-hoc analysis, with adjustments made using the Bonferroni application where necessary. Nonparametric tests included the Mann-Whitney U test. Calculated p-values ​​were considered statistically significant at α of 0.05 or less. The final model was determined using inverse stepwise regression, and included only variables significant at the .05 level. A sample size of 40 patients was sufficient to provide safety, p-value, and PD results to guide future dose selection.

[0283] Example 2: Clinical Treatment Data

[0284] Preliminary safety, auditory and vestibular findings

[0285] The drug was well tolerated after 21 days of oral administration, and no adverse events were caused by the study drug.

[0286] Pure-tone audiometry (PTA) and word recognition scoring (WRS) showed some consistency.

[0287] ● Improvement of up to 35 dB in low-frequency (.25, .5, and 1 kHz) hearing.

[0288] √60% of the active substance group showed significant hearing improvement ≥10 dB

[0289] √ No significant improvement was observed in the placebo group.

[0290] ● Improvement of up to 120% compared to baseline WRS

[0291] √ The 35% active ingredient group showed a significant improvement in WINT, with an increase of ≥10%.

[0292] √ No significant improvement was observed in the placebo group.

[0293] Compared to placebo, the improvement in PTA / WINT for the active substance was significant and specific.

[0294] Improvement in low-frequency hearing can precede improvement in WRS.

[0295] Tinnitus Function Index (TFI) and Tinnitus Loudness (TL) show some consistency

[0296] ● TFI score improvement of up to 62pt decrease (0-100)

[0297] √40% active ingredient group, significant improvement in TFI (≥10pt reduction)

[0298] √ The placebo group showed a significant improvement in TFI of 50%.

[0299] √ Tinnitus loudness improved by up to 8pt (0-10).

[0300] The 70% active ingredient group showed a significant improvement in TL (transfer volume) with a reduction of ≥2 pt.

[0301] The placebo group showed a significant improvement in TFI of 33%.

[0302] Vertigo Symptom Scale (VSS)

[0303] ■ Improvement of up to 33pt reduction (0-60)

[0304] √55% active ingredient group showed significant improvement in VSS (≥6pt reduction).

[0305] √The placebo group showed a significant improvement in VSS of 33%.

[0306] Improvements in TL and VSS were greater in the active substance group than in the placebo group.

[0307] TFI, TL, and VSS all showed a placebo effect.

[0308] Results Discussion

[0309] As stated above, forty (40) adult volunteers who met the AAO-HNS 1995 criteria in the past 12 months participated in the clinical treatment. Clinical outcomes from a subset of twenty-six (26) of the forty (40) adult subjects are presented in Figure 1-3 Data from the first two groups indicate that ebuselenide administration is safe and well-tolerated, as no significant adverse events were observed. Furthermore, no drug-related adverse events occurred.

[0310] Initial efficacy analysis showed that ebuseline achieved several secondary endpoints compared to placebo.

[0311] Ibuselenium treatment showed clinically relevant improvements in hearing, tinnitus, and vertigo in both analyzed groups.

[0312] Data from this clinical treatment support the use of ibuselenone, and more generally, glutathione peroxidase (GPx) modulators and mimics, to limit free radical damage, cochlear or vestibular inflammation. In summary, GPx modulators, ibuselenone, have demonstrated good clinical efficacy in these groups for the treatment, prevention, and / or improvement of MD and / or endolymphedema.

[0313] For all purposes, all references, patents and patent applications cited in the body of this specification are hereby incorporated in their entirety by reference.

[0314] Reference List

[0315] American Academy of Otolaryngology-Head and Neck Foundation .Committeeon Hearing and Equilibrium guidelines for the diagnosis and evaluation oftherapy in Meniere's disease.Otolaryngol Head Neck Surg.1995;113:181-5.

[0316] Hornibrook J,Kalin C,Lin E,et al. Transtympanic electrocochleography for the diagnosis of Meniere's disease.Int J Otolaryngol 2012; article 852714:1-11.

[0317] Kil J,Pierce C,Tran H,Gu R,Lynch ED.Ebselen treatment reduces noise-induced hearing loss via the mimicry and induction of glutathioneperoxidase.Hearing Res 2007;226:44-51.

[0318] Lee JE,Nakagawa T,Kim TS,Endo T,Shiga A,Iguchi F,Lee SH,Ito J. Role ofreactive radicals in degeneration of the auditory system of mice followingcisplatin treatment.Acta Otolaryngol.2004Dec;124(10):1131-5.

[0319] fLynch ED,Gu R,Pierce C,Kil J. Reduction of acute cisplatinototoxicity and nephrotoxicity in rats by oral administration of allopurinoland ebselen.Hear Res.2005bMar;201(1-2):81-9.

[0320] Meikle MB, Henry JA, Greist SE, et al. Tinnitus Functional Index:Developmentof a new clinical measure for chronic,intrusive tinnitus Ear Hearing 2011;33:153-176.

[0321] Müller A,Cadenas E,Graf P,Sies H. A novel biologically active seleno-organic compound—I.Glutathione peroxidase-like activity in vitro andantioxidant capacity of PZ51(ebselen).Biochem Pharmacol 1984;(33):3235-9.

[0322] Müller A,Gabriel H,Sies H,Terlinden R,Fischer H,Romer A.A novelbiologically active seleno-organic compound--VII.Biotransformation of ebselenin perfused rat liver.Biochem Pharmacol.1988Mar 15;37(6):1103-9.

[0323] Namura S,Nagata I,Takami S,Masayasu H,Kikuchi H. Ebselen reducescytochromec release from mitochondria and subsequent DNA fragmentation aftertransient focal cerebral ischemia in mice.Stroke 2001 Aug;32(8):1906-11.

[0324] Noguchi N,Yoshida Y,Kaneda H,Yamamoto Y,Niki E. Action of ebselen asan antioxidant against lipid peroxidation.Biochem Pharmacol.1992 Jul 7;44(1):39-44.

[0325] Noguchi N, Gotoh N, Niki E. Effects of ebselen and probucol onoxidativemodifications of lipid and protein of low density lipoproteininduced by free radicals.Biochim Biophys Acta.1994 Jul 14;1213(2):176-182.

[0326] Reiter R, Wendel A. Selenium and drug metabolism--II.Independence ofglutathione peroxidase and reversibility of hepatic enzyme modulations indeficient mice.Biochem Pharmacol 1984 Jun 15;33(12):1923-8.

[0327] Thorp MA,Shehab ZP,Bance ML,Rutka JA.AAO-HNS Committee on Hearing andEquilibrium.The AAO-HNS Committee on Hearing and Equilibrium guidelines forthe diagnosis and evaluation of therapy in Meniere’s disease:have they beenapplied in the published literature of the last decade?Clin OtolaryngolAllied Sci 2003;28:173-6.

[0328] Wendel A,Fausel M,Safayhi H,Tiegs G,Otter R. A novel biologicallyactive seleno-organic compound--II.Activity of PZ 51 in relation toglutathione peroxidase.Biochem Pharmacol 1984 Oct 15;33(20):3241-5.

[0329] Wilson RH, Burks CA. Use of 35 words for evaluation of hearing loss insignal-to-noise babble ratio:A clinical protocol.JRRD 2005;42:839-52.

[0330] Yardley L,Donovan-Hall M,Smith HE,Walsh BM,Mullee M,Bronstein AM. Effectiveness of primary care-based vestibular rehabilitation for chronicdizziness.Ann Intern Med 2004;141:598-605.

Claims

1. Use of the composition in the preparation of a medicament for treating Meniere's disease in a subject, said composition comprising ebuselenline; or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein the drug is for oral administration.

3. The use according to claim 2, wherein the administration is 1 to 3 doses / day, twice daily (BID), 200 mg ebuselenium BID, 400 mg ebuselenium BID, or 600 mg ebuselenium BID.

4. The use according to claim 3, wherein the application is performed over 21 days.

5. The use according to claim 2, wherein the composition is formulated as a solid dosage form.

6. The use according to claim 5, wherein the solid dosage form is a capsule.

7. The use according to claim 1, wherein the treatment improves at least one of the scores of pure tone audiometry, speech discrimination test, or electrocochleography test of the subject.

8. The use according to claim 1, wherein the treatment improves the score of at least one of the following tests selected from the group consisting of: Vertigo Symptom Scale (VSS), Dizziness Disability Inventory (DHI), Tinnitus Function Index (TFI), or Tinnitus Disability Inventory (THI).

9. The use as claimed in claim 1, wherein the composition further comprises one or more diuretic compounds.

10. The use as claimed in claim 1, wherein the composition reduces hearing loss at multiple low frequencies.

11. The use as claimed in claim 10, wherein the frequency is selected from the group consisting of: 0.25 kHz, 0.5 kHz, and 1 kHz.

12. The use as claimed in claim 1, wherein the composition reduces the occurrence of significant threshold shift from baseline measurements by at least 10 dB.

13. The use according to claim 1, wherein the composition reduces the VSS score from the baseline measurement by at least six (6) points.

Images