Methods and compositions for slowing myopia progression

Abstract

Methods for slowing myopia progression. Specifically, the method comprises administering to a subject a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, or a composition comprising an effective amount of a compound represented by the following formula, or a pharmaceutically acceptable salt thereof: # imgabs0 wherein the compound can target and inhibit catechol-O-methyltransferase, retinal dopamine expression is upregulated and choroidal thickness in the eyeball structure of a subject is altered, where increase in choroidal thickness may be considered as a predictive indicator of retinal progression slowing.

Description

Technical Field

[0001] The present disclosure generally relates to catechol-O-methyltransferase (COMT) inhibitors for slowing myopia progression, and more particularly, to celastrol or a pharmaceutically acceptable salt thereof for slowing myopia progression. Background Art

[0002] References cited in this article:

[0003] 1. FELDKAEMPER, M. & SCHAEFFEL, F. 2013. An updated view on the role of dopamine in myopia. Exp Eye Res, 114, 106-19.

[0004] 2.ZHOU,

[0005] 3 STONE, RA, LIN, T., LATIES, AM & IUVONE, PM 1989. Retinal dopamine and form-deprivation myopia. Proc Natl Acad Sci USA, 86, 704-6.4. SCHMID, KL & WILDSOET, CF2004. Inhibitory effects of apomorphine and atropine and their combination on myopia in chicks. Optometry and Vision Science, 81, 137-147.

[0006] 5.DONG,F.,ZHI,Z.N.,PAN,M.Z.,XIE,R.Z.,QIN,X.Y.,LU,R.X.,MAO,X.J.,CHEN,J.F.,WILLCOX,M.D.P.,QU,J.&ZHOU,X.T.2011.Inhibition of experimental myopia bya dopamine agonist:different effectiveness between form deprivation andhYPeropic defocus in guinea pigs.Molecular Vision,17,2824-2834.

[0007] 6.IUVONE,P.M.,TIGGES,M.,STONE,R.A.,LAMBERT,S.&LATIES,A.M.1991.Effectsof Apomorphine,a Dopamine Receptor Agonist,on Ocular Refraction and AxialElongation in a Primate Model of Myopia.Investigative Ophthalmology&VisualScience,32,1674-1677.

[0008] 7.YAN,T.T.,XIONG,W.W.,HUANG,F.R.,ZHENG,F.,YING,H.F.,CHEN,J.F.,QU,J.&ZHOU,X.T.2015.Daily Injection But Not Continuous Infusion of ApomorphineInhibits Form-Deprivation Myopia in Mice.Investigative Ophthalmology&VisualScience,56,2475-2485.

[0009] 8.FAUST,K.,GEHRKE,S.,YANG,Y.F.,YANG,L.C.,BEAL,M.F.&LU,B.W.2009.Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson′s disease.BmcNeuroscience.10.

[0010] 9.KYUNG,H.,KWONG,J.M.,BEKERMAN,V.,GU,L.,YADEGARI,D.,CAPRIOLI,J.&PIRI,N.2015.Celastrol supports survival of retinal ganglion cells injured by opticnerve crush.Brain Res,1609,21-30.

[0011] 10.ZHANG,J.,ZHOU,K.,ZHANG,X.,ZHOU,Y.,LI,Z.&SHANG,F.2019.CelastrolAmeliorates Inflammation in Human Retinal Pigment Epithelial Cells bySuppressing NF-kappaB Signaling.J Ocul Pharmacol Ther,35,116-123.

[0012] 11.ZHOU,Y.,ZHOU,L.,ZHOU,K.,ZHANG,J.,SHANG,F.&ZHANG,X.2019.CelastrolProtects RPE Cells from Oxidative Stress-Induced Cell Death via ActiVation ofNrf2 Signaling Pathway.Curr Mol Med,19,172-182.

[0013] 12.GUO, HJ, YANG, Y., ZHANG, Q., DENG, JR, YANG, Y., LI, SQ, SO, PK, LAM, TC, WONG, MK&ZHAO, Q. 2022. Integrated Mass Spectrometry Reveals Celastrol Asa Novel Catechol-O-methyltransferase Inhibitor.Acs Chemical Biology.

[0014] 13. CASCAO, R., FONSECA, JE & MOITA, LF2017. Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases. Front Med (Lausanne), 4, 69.

[0015] 14. HOU, W., LIU, B. &

[0016] Myopia is a common refractive error characterized by the inability to see distant objects clearly. Myopia usually begins at the age of 5-6 and progresses (or worsens) every few months or every year. This is caused by the eyes growing too fast or too long beyond their normal growth rate. However, the molecular mechanism underlying myopia remains unclear, and no drug has been approved by the FDA for clinical use so far.

[0017] Catechol-O-methyltransferase (COMT) is a methyltransferase that metabolizes catechol estrogens and catechol neurotransmitters (such as dopamine). Some COMT inhibitors have been used in combination with the precursor of dopamine (levodopa) to control the motor symptoms of Parkinson's disease and other neurological diseases, but their clinical application is limited by their ability to penetrate the brain and adverse side effects. Extensive research has reported that dopamine serves as a "stop" signal for eye growth (Feldkaemper and Schaeffel, 2013a, Zhou et al., 2017). Reduced retinal dopamine levels have been found in various form deprivation myopia (FDM) models (such as chicks, rhesus monkeys, guinea pigs and tree shrews) and in LIM chicks. Stone et al. (1989), Schmid and Wildsoet (2004), Dong et al. (2011), Iuvone et al. (1991) and Yan et al. (2015) have reported that a non-selective dopamine receptor agonist (apomorphine) can prevent FDM in various animal models including chicks, guinea pigs, monkeys and mice.

[0018] Celastrol (a five-membered ring triterpene with an electrophilic quinone methide) is one of the five most promising natural products extracted from the roots and stems of Tripterygium wilfordii (or commonly referred to as Tripterygium wilfordii) for drug development. Celastrol has been found to have a broad spectrum of activity in anti-obesity, anti-cancer, antioxidant, anti-inflammatory and neuroprotective aspects. Its potent dopaminergic neuroprotective effects have been shown in a Drosophila Parkinson's disease model (Faust et al., 2009), but its molecular mechanism (such as binding target) in the brain by increasing dopamine levels is not yet clear.

[0019] Existing studies have tested tripterygium wilfordii in various eye disease models, revealing its great potential in treating various eye diseases. For example, in a glaucoma rat model, the average number of retinal ganglion cells (RGCs) increased by approximately 80% and 78% compared with the control using intravitreal injections of 1 mg / kg and 5 mg / kg tripterygium wilfordii (Kyung et al., 2015). Tripterygium wilfordii can also inhibit inflammatory effects in human retinal pigment epithelial (RPE) cells by inhibiting NF-κB signaling (Zhang et al., 2019). Zhou et al. (2019) further showed that tripterygium wilfordii can protect RPE cells from oxidative stress-induced cell death via activation of the Nrf2 signaling pathway. Guo et al. (2022) showed that low concentrations of tripterygium wilfordii (1 μM) resulted in a 6-fold increase in dopamine in neuroendocrine chromaffin cells and proposed COMT as the main binding target of tripterygium wilfordii identified by chemical proteomics. All these findings led to the hypothesis that tripterygium wilfordii could control or regulate myopia progression by upregulating retinal dopamine expression and thereby inhibiting COMT, including both the soluble isoform (S-COMT) and the membrane-bound form (MB-COMT). (2017) and Hou et al. (2020) reported that high doses of triptolide had adverse side effects as they found that triptolide had limited bioavailability, undesirable biodistribution, poor aqueous stability, and a narrow therapeutic range.

[0020] Therefore, clinically relevant treatment options using tripterygium wilfordii to slow or delay the progression of myopia are still needed. Summary of the invention

[0021] Accordingly, in a first aspect, the present disclosure provides a method for slowing the progression of myopia, comprising administering to a subject a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

[0022]

[0023] A second aspect of the present disclosure provides a composition comprising a therapeutically effective amount of a compound represented by the following formula or a pharmaceutically acceptable salt thereof, for slowing the progression of myopia in a subject:

[0024]

[0025] A third aspect of the present disclosure provides a method for increasing the choroidal thickness of the uveal tract of a subject, comprising contacting the vitreous body, cornea or conjunctiva or fascia bulbarum or retrobulbarum of the subject with a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

[0026]

[0027] In certain embodiments, a therapeutically effective amount of a compound is formulated into a composition that improves the bioavailability, biodistribution, and stability of the compound.

[0028] In certain embodiments, the composition is administered via intravitreal injection, intravenous injection, oral administration, or topically administered to the eye.

[0029] In certain embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0030] In certain embodiments, pharmaceutically acceptable carriers are based on nanomedicines, including but not limited to standard and core-cross-linked polymeric micelles, polymer-drug conjugates, polymer-protein conjugates, antibody-drug conjugates, dendrimer drugs, polymer vesicles, liposomes, pegylated liposomes, and organic / inorganic colloids.

[0031] In certain embodiments, the pharmaceutically acceptable carrier comprises cyclodextrin (CD), including β-cyclodextrin (β-CD).

[0032] In certain embodiments, the subject includes non-human animals and humans.

[0033] In certain embodiments, the subject is a chicken, and the therapeutically effective amount of the compound is 74 μM, which is administered once a day (qd) for four days via intravitreal injection.

[0034] In certain embodiments, the subject is a human and the therapeutically effective amount of the compound is about 1.665 mM, which is administered via eye drops.

[0035] In certain embodiments, when the subject is a chicken, the compound directly contacts the vitreous of the subject.

[0036] In certain embodiments, when the subject is a human, the compound is contacted with the cornea or conjunctiva of the subject via a non-invasive administration route (such as eye drops containing a therapeutically effective amount of the compound) once a day.

[0037] In certain embodiments, human subjects are generally 18 years of age or younger.

[0038] In certain embodiments, the human subject is between 6 and 18 years old.

[0039] The present invention summary provides a selection of the concepts that will be further described below in the detailed description in a simplified form. The present invention summary is not intended to identify the key features or essential features of the claimed subject matter, nor is it intended to be used to help determine the scope of the claimed subject matter. Other aspects of the present disclosure are disclosed as illustrated by the following embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The accompanying drawings, in which the same reference numerals refer to the same or functionally similar elements, contain diagrams of certain embodiments to further illustrate and clarify the above and other aspects, advantages and features of the present disclosure. It should be appreciated that these drawings depict embodiments of the present disclosure and are not intended to limit the scope thereof. The present invention will be described and explained in additional detail and in detail through the use of the accompanying drawings, in which:

[0041] Figure 1 Shown is a scheme for in vivo study of tripterygium wilfordii on the chick model of unilateral lens-induced myopia (LIM);

[0042] Figure 2A The effect of triptolide on refractive error in the unilateral LIM chick model is shown;

[0043] Figure 2B The effect of celastrol on vitreous cavity depth (VCD) in the unilateral LIM chick model is shown;

[0044] Figure 2C shows the effect of celastrol on axial length (AL) in a unilateral LIM chick model; and

[0045] Figure 2D Shown is the effect of celastrol on choroidal thickness in the unilateral LIM chick model.

[0046] Those skilled in the art will appreciate that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. DETAILED DESCRIPTION

[0047] definition

[0048] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for contacting a subject's tissue without excessive toxicity, irritation, allergic reaction, etc., and that are matched to a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include salts derived from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. In certain embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0049] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4Alkyl) 4 salts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Where appropriate, further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions (such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates). Organic bases from which salts can be derived include, for example, primary amines, secondary amines and tertiary amines, including substituted amines of naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In certain embodiments, pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts.

[0050] As used herein, the term "treatment" and the like refers to slowing down or alleviating the discomfort / disease and / or symptoms associated therewith. It will be understood that, although not excluded, treating discomfort or conditions does not require that the discomfort, condition or symptoms associated therewith are completely eliminated. In certain embodiments, treatment includes prevention of discomfort or conditions and / or symptoms associated therewith. As used herein, the term "prevention" refers to any action that inhibits or at least delays the development of discomfort, condition or symptoms associated therewith. Prevention may include primary prevention levels, secondary prevention levels, and tertiary prevention levels, wherein: a) primary prevention avoids the development of the disease; b) secondary prevention activities are aimed at early disease treatment, thereby increasing intervention to prevent the progression of the disease and the chance of symptoms; and c) tertiary prevention reduces the negative effects of the already formed disease by restoring function and reducing complications associated with the disease.

[0051] As used herein, the term "subject" refers to any animal (eg, mammal), including, but not limited to, humans, non-human primates, canines, felines, and rodents.

[0052] In this article, the use of the singular includes the plural (and vice versa), unless otherwise specifically stated. In addition, where the term "about" is used before a quantitative value, the present teachings also include the specific quantitative value itself, unless otherwise specifically stated. As used herein, the term "about" refers to a variation of ±10%, ±7%, ±5%, ±3%, ±1% or ±0% from the nominal value, unless otherwise indicated or stated.

[0053] It will be apparent to those skilled in the art that modifications (including additions and / or substitutions) may be made without departing from the scope and spirit of the invention. Specific details may be omitted so as not to obscure the invention; however, this disclosure is written to ensure that those skilled in the art can practice the teachings herein without undue experimentation.

[0054] The present disclosure provides a method for slowing down the progression of myopia by administering a therapeutically effective amount of tripterine via intravitreal injection into the vitreous or via a non-invasive route (such as topical administration). For example, the method for slowing down the progression of myopia includes administering an eye drop containing a therapeutically effective amount of tripterine to the cornea or conjunctiva or fascia bulbi or posterior bulbi of the subject's eye. In the following examples, an induced monocular animal model of lens-induced myopia (LIM) (or unilateral LIM model) was used to study the beneficial effects of tripterine on slowing down the progression of myopia from the perspective of refractive error and eye parameters (e.g., vitreous cavity depth (VCD) and axial length (AL) of unilateral LIM chicks) compared to the baseline (before induction of unilateral LIM). The changes in body weight before and 7 days after LIM and the choroidal thickness of the uvea of ​​the tripterine group 2 hours after the lens was removed from the unilateral LIM chicks after 7 days of LIM were also quantified, showing no adverse side effects, but low doses of tripterine induced an increase in choroidal thickness. Animal doses and human equivalent doses of tripterygium wilfordii may also be derived from the results of in vivo studies in the present disclosure. For example, if tripterygium wilfordii is administered via intravitreal injection, then based on the difference in vitreous volume between the tested animal model and humans, a human equivalent dose of tripterygium wilfordii may be determined. Taking the vitreous volume of a chicken as an illustrative example, if tripterygium wilfordii is administered via intravitreal injection into the vitreous of a chicken at about 74 μM, assuming that the vitreous volume of a chicken is typically about 200 μl, based on the estimated human vitreous volume (about 4.5 ml), the human equivalent dose of tripterygium wilfordii injected via intravitreal injection is determined to be about 1.665 mM.

[0055] In certain embodiments, tripterygium wilfordii is administered to a subject once, twice, three times, four times or more per day for a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days or more. In certain embodiments, tripterygium wilfordii is administered to a subject once, twice, three times, four times or more per day for a period of 1 day to 28 days, 1 day to 21 days, 1 day to 14 days, 1 day to 7 days, 2 days to 7 days, 3 days to 7 days, 3 days to 6 days, 2 days to 6 days, 3 days to 7 days or 3 days to 5 days.

[0056] In the case where tripterygium wilfordii is formulated as an eye drop formulation and topically applied to the subject's eye, the eye drop formulation may include tripterygium wilfordii at a concentration of between 0.1 mM-10 mM, between 0.1 mM-9 mM, between 0.1 mM-8 mM, between 0.1 mM-7 mM, between 0.1 mM-5 mM, between 0.5 mM-5 mM, between 1 mM-5 mM, between 1 mM-4 mM, between 1 mM-3 mM, between 1 mM-2 mM, between 1.1 mM-2 mM, between 1.2 mM-1.9 mM, between 1.3 mM-1.8 mM, between 1.4 mM-1.7 mM, or between 1.5 mM-1.7 mM. In certain embodiments, the eye drop formulation includes tripterygium wilfordii at a concentration of about 1.665 mM. 10 μl-200 μl, 10 μl-150 μl, 10 μl-100 μl, 25 μl-75 μl, or 25 μl-50 μl of the eye drop formulation may be administered to the subject's eye.

[0057] Example

[0058] Example 1 - Study of in vivo myopia model and the effect of tripterygium wilfordii on myopia progression:

[0059] To establish the lens-induced myopia (LIM) animal model, -5D concave lenses were applied to Leghorn chickens (Gallus gallus) hatched from specific pathogen-free eggs (SPF, Jinan, China) until they were ten days old (PN10, baseline). All animals were housed in standard cages at 25°C, with adequate food and water, and experienced a 12-hour: 12-hour light / dark cycle every day. The central ambient brightness above the cage was maintained at approximately 260 lux.

[0060] Reference Figure 1Starting from ten days of age (PN10), LIM chicks received four intravitreal injections for four consecutive days, i.e., PN10, PNl1, PN12 and PN13 (s101). LIM chicks were randomly assigned to two groups, including vehicle-injected (1% DMSO with 1% β-CD) LIM chicks (n=6) (101b) and tripterygium wilfordii-injected (74 μM tripterygium wilfordii dissolved in 1% DMSO with 1% β-CD) LIM chicks (n=7) (101a), and there was no gender preference in the experimental grouping. β-CD was selected as the drug carrier of tripterygium wilfordii because it has a ring-shaped cavity with a hydrophilic outer surface and a hydrophobic inner surface to form a complex with tripterygium wilfordii to improve the solubility, stability and permeability of tripterygium wilfordii in vivo. Freshly prepared solution (10 μl) was injected monocularly into the vitreous body through the sclera, choroid and retina near the upper eyelid margin using a 0.3-mL syringe (31 gauge, BD Medical, Le Pont de Claix, France). After the first injection at PN10, the right eye (or left eye) of the LIM chick was immediately assigned a -5D lens (treated eye 102a), and no lens was applied to the other eye (control eye 102b) (s102). The treated eye 102a covered with the lens in each LIM chick (unilateral LIM) received subsequent celastrol injections 101a or vehicle 101b at PN11, PN12 and PN13, while there was no treatment for the contralateral (control) eye 102b.

[0061] After 7 days of LIM (PN17), the lens was removed for 2 hours (s103). Refractive error and eye parameters were recorded using linear retinoscopy and high-frequency ultrasound at baseline (PN10), 7 days of LIM (PN17), and 2 hours after recovery (PN17+2hr) (s104). Refractive error was detected using linear retinoscopy before and after treatment, and eye parameters were measured using a high-frequency A-scan ultrasound system equipped with a 30MHz converter (Panametrics, Inc., Waltham, MA). The spherical equivalent (SE) was calculated from the refractive state (SE=spherical power+1 / 2 cylindrical power). The axial length (AL) was defined from the anterior part of the cornea to the posterior part of the vitreous chamber.

[0062] Example 2 - Analysis of biometric measurements from LIM chicks treated with tripterine:

[0063] Analysis according to Example 1 and Figure 1Biometric data were obtained for unilateral LIM chicks treated with or without tripterine according to the protocol depicted in . First, the interocular difference (difference between the lens-treated eye and the contralateral eye) was calculated for three eye parameters (refractive error, vitreous cavity depth, and axial length) during the 7-day lens treatment period (PN17), and the results are shown in FIG. 2A to FIG. 2C Because increased choroidal thickness can be considered a predictor of slowed myopia progression, choroidal thickness was measured two hours after lens removal and the results are shown in Figure 2D Mean inter-eye differences and changes in choroidal thickness are presented as ± SD. Unpaired t-test with equal variance was used to analyze the significance between the tripterygium wilfordii group and the vehicle group.

[0064] At baseline (PN10), there were no significant differences in all ocular parameters between the two groups. After 7 days of LIM (PN17), the body weight of the tripterine group was similar to that of the vehicle group. There was no delay in the growth of body weight after tripterine treatment. For ocular biometrics, hyperopia decreased in both groups. A mean shift in interocular relative myopia (-1.45 D, mean, 1.25 D) was observed in the vehicle group. Figure 2A )(Tripterine vs. Vehicle: -1.68±2.03D vs. -3.13±1.78D, mean±SD). A-scans also confirmed a corresponding enlargement of vitreous cavity depth in the vehicle group (Tripterine vs. Vehicle: 0.190±0.105mm vs. 0.260±0.194mm, mean±SD) and elongation of axial length (AL) in the vehicle group (Tripterine vs. Vehicle: 0.088±0.109mm vs. 0.262±0.178mm, mean±SD, P=0.054) compared with the tripterine group. Although the difference did not reach statistical significance, numerical elongation of AL (0.174mm, mean) and enlargement of VCD (0.070mm) were also observed in the vehicle group compared with the tripterine group (P>0.05, Figure 2B and Figure 2C ). Note that after 2 hours of recovery (PN17+2 hours) in 7-day LIM, the choroidal thickness in the tripterygium wilfordii group increased by about 1.52 times compared with the vehicle group (tripterygium wilfordii group vs. vehicle group: 65.98±20.89μm vs. 43.44±27.50μm, mean±SD, P=0.072, Figure 2D ). Based on the refractive error and axial length data, approximately 46.3% and 66.4% inhibition occurred in the tripterygium wilfordii group. Tripterygium wilfordii inhibited myopia progression by intravitreal injection at the tested dose.

[0065] From the results of this embodiment, it is suggested that at the low dose tested, tripterygium wilfordii can inhibit myopia progression (74 μM in the unilateral LIM chick model). Based on the refractive error and axial length data, there were about 43% and 46.2% inhibition in the tripterygium wilfordii group compared to the vehicle group, which is comparable to atropine treatment. It is also suggested that tripterygium wilfordii can induce choroidal thickness, i.e., the choroidal thickness increased by approximately 1.5 times after two hours of recovery from myopia, which is an indication of a protective effect against myopia, followed by inhibition of myopia progression. Tripterygium wilfordii can also be used as an antioxidant, exhibiting anti-inflammatory and neuroprotective effects on subjects by upregulating the expression of dopamine in particular areas or tissues.

[0066] Although the invention has been described in terms of certain embodiments, other embodiments that are apparent to those of ordinary skill in the art are also within the scope of the invention. Accordingly, the scope of the invention is intended to be limited only by the appended claims.

Claims

1. A method for slowing the progression of myopia, comprising administering to a subject a composition comprising a therapeutically effective amount of a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

2. The method of claim 1, wherein the composition is administered to the eye via intravitreal injection, intravenous injection, oral administration, or topical administration.

3. The method of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier.

4. The method of claim 1, wherein the subject comprises a non-human animal or a human.

5. The method of claim 1, wherein the subject is a chicken, and the therapeutically effective amount of the compound is 74 μM, which is administered via intravitreal injection once a day for four days.

6. The method of claim 1, wherein the subject is a human and the therapeutically effective amount of the compound is 1.665 mM, which is administered via eye drops.

7. A composition comprising a therapeutically effective amount of a compound represented by the following formula or a pharmaceutically acceptable salt thereof, for slowing the progression of myopia in a subject:

8. The composition according to claim 7, which is administered to the eye via intravitreal injection, subconjunctival injection, subbulbar injection or retrobulbar injection, intravenous injection, oral administration or topical eye drops or gel administration.

9. The composition according to claim 7, further comprising a pharmaceutically acceptable carrier.

10. The composition of claim 7, wherein the subject comprises non-human animals and humans.

11. The composition of claim 7, wherein the subject is a chicken, and the therapeutically effective amount of the compound is 74uM, which is administered via intravitreal injection once a day for four days.

12. The composition of claim 7, wherein the subject is a human, and the therapeutically effective amount of the compound is 1.665 mM, which is administered via eye drops.

13. A method for increasing choroidal thickness of a subject, comprising contacting the vitreous, cornea, conjunctiva, subconjunctival, subfascia bulbaris, or retrobulbar of the subject with a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

14. The method according to claim 13, wherein the compound is formulated in injectable form or eye drops or gel or aerosol.

15. The method of claim 13, wherein the subject comprises non-human animals and humans.

16. The method of claim 13, wherein the subject is a chicken and the compound is contacted with the vitreous of the subject at 74uM once a day for four days.

17. The method of claim 13, wherein the subject is a human, and the compound is contacted with the cornea or conjunctiva or fascia bulbarum or retrobulbarum of the subject via an eye drop solution containing a therapeutically effective amount of the compound.

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