CN-109475518-B - Treatment of meniere's disease

Abstract

Novel methods and compositions for treating MD and/or endolymphedema are disclosed herein. The composition comprises 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.

Inventors

• J. Chill

Assignees

• 桑得医药品公司

Dates

Publication Date

20260508

Application Date

20170518

Priority Date

20160518

Claims (13)

1. 1. Use of a composition comprising ebselen, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating meniere's disease in a subject.
2. 2. The use of claim 1, wherein the medicament is for oral administration.
3. 3. The use of claim 2, wherein the administration is 1 to 3 doses per day, 2 times per day (BID), 200mg ebselen BID,400mg ebselen BID, or 600mg ebselen BID.
4. 4. The use of claim 3, wherein the administration is 21 days.
5. 5. The use of claim 2, wherein the composition is formulated as a solid dosage form.
6. 6. The use of claim 5, wherein the solid dosage form is a capsule.
7. 7. The use of claim 1, wherein the treatment improves at least one of a score of a pure tone audiometry, a speech discrimination test, or a cochlear electrography test of the subject.
8. 8. The use of claim 1, wherein the treatment improves at least one of the subject's tested scores selected from the group consisting of Vertigo Symptom Scale (VSS), dizziness disability list (DHI), tinnitus Function Index (TFI), or tinnitus disability list (THI).
9. 9. The use of claim 1, wherein the composition further comprises one or more diuretic compounds.
10. 10. The use of claim 1, wherein the composition reduces hearing loss at a plurality of low frequencies.
11. 11. The use of claim 10, wherein the frequency is selected from the group consisting of 0.25 kHz, 0.5 kHz, and 1 kHz.
12. 12. The use of claim 1, wherein the composition reduces the occurrence of significant threshold shift by at least 10 dB from a baseline measurement.
13. 13. The use of claim 1, wherein the composition reduces VSS score from baseline measurement by at least six (6) points.

Description

Treatment of meniere's disease Technical Field The present disclosure relates to compositions and methods useful for treating meniere's disease and/or endolymphedema. Description of related Art Meniere's Disease (MD) is defined as a triple of episodic vertigo, hearing loss and tinnitus. Ear pressure or ear distension (aur) is often reported, and most auditory and vestibular symptoms fluctuate in frequency and intensity. Although the etiology of MD is unknown, it is associated with endolymphedema. Endolymphedema is a swelling of the endo-auricular lymphatic compartments. After the acute phase, which is most common with vertigo, the chronic phase occurs, in which hearing loss and tinnitus become the most common features, although balance disorders are often reported. There is no FDA approved drug for preventing or treating MD. Most MD patients are treated medically with low-salt diets and/or thiazide diuretics, but with limited success. SUMMARY The present disclosure addresses the clinical need for therapies to treat MD and/or endolymphedema. The inventors have found and shown an improvement in several auditory and vestibular symptoms after treatment of human subjects suffering from MD and/or idiopathic and non-idiopathic endolymphedema, said treatment comprising administration of an effective amount of ebselen (SPI-1005) alone or in combination with one or more other glutathione peroxidase (GPx) modulators or mimetic compounds and/or one or more prescription diuretic compounds. The present disclosure provides novel glutathione peroxidase (GPx) modulators or mimetic compounds useful in pharmaceutical compositions useful in the treatment, prevention, and/or amelioration of Meniere's disease and/or endolymphedema comprising ebselen alone or in combination with one or more such glutathione peroxidase (GPx) modulators or mimetic compounds and/or one or more prescription diuretic compounds, methods of preparing ebselen comprising ebselen or comprising a combination comprising ebselen and novel glutathione peroxidase (GPx) modulators or mimetic compounds and/or one or more prescription diuretic compounds, pharmaceutical compositions comprising ebselen or comprising a combination comprising ebselen and novel glutathione peroxidase (GPx) modulators or mimetic compounds and/or one or more prescription diuretic compounds, and methods of using these pharmaceutical compositions to treat, prevent, and/or ameliorate Meniere's disease and/or endolymphedema. Some embodiments of the new combination compositions comprise at least two compounds, or pharmaceutically acceptable salts thereof, wherein the first compound is ebselen and the second compound is a glutathione peroxidase modulator or mimetic compound. Yet another aspect of the disclosure features 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 ebselen alone, or a combination of ebselen, one or more other glutathione peroxidase modulators or mimetic compounds, and optionally one or more prescription diuretic compounds. The therapeutically effective amount of each compound included in the novel combination can be from about 0.1 mg/day to about 5000 mg/day, respectively. Another aspect of the disclosure features a kit that includes any of the compositions described herein and instructions for use. Another aspect of the disclosure features a method for balancing the pressure of the inner ear of a subject, the method including administering a therapeutically effective amount of a composition including ebselen and optionally one or more other glutathione peroxidase modulators or mimetic compounds and/or one or more prescription diuretic compounds. In yet another aspect, the present disclosure includes a method for reducing the production of free radical species and/or inflammation in the ear of a subject comprising administering a therapeutically effective amount of a composition comprising ebselen and optionally one or more other glutathione peroxidase modulators or mimetic compounds. The disclosure also features a method of preparing a pharmaceutical composition comprising mixing ebselen and any one of a glutathione peroxidase modulator or mimetic compound or a prescription diuretic compound with one or more pharmaceutically acceptable carriers. The present disclosure provides a pharmaceutical composition comprising ebselen and one or more other glutathione peroxidase (GPx) modulators or mimetic compounds, or a pharmaceutically acceptable salt or solvate thereof. The present disclosure provides a composition wherein one or more additional glutathione peroxidase modulator or mimetic compounds are present as one compound and are selected from the group consisting of: 2,2' -diseleno-bis- β -cyclodextrin; Wherein the method comprises the steps of R 1 is H, methyl, ethyl or isopropyl; r 2 is H or ethyl; R 3 is H, acetyl,