Application of 11β-HSD1 pathway activity inhibitors in the preparation of drugs for the treatment of glaucoma-cyclitis syndrome

Abstract

The invention relates to the use of an 11β-HSD1 pathway activity inhibitor in the preparation of a drug for treating glaucomatous cyclitis syndrome. By specifically inhibiting 11β-HSD1 activity in the eye, the drug can effectively correct the imbalance of local corticosteroid metabolism in the eye, alleviate the physiological effects of excess mineralocorticoids, and simultaneously reduce aqueous humor production and alleviate eye inflammation. The drug is suitable for treating glaucomatous cyclitis syndrome and other diseases related to increased 11β-HSD1 activity in the eye. The invention has the advantages of novel targets, high efficiency and safety, and long-term intraocular pressure reduction, and has important clinical application value.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to the use of an 11β-HSD1 pathway activity inhibitor in the preparation of a drug for treating glaucoma-cyclitis syndrome. Background Art

[0002] Glaucoma-cyclitis syndrome (PSS), also known as glaucoma syndrome, is a recurrent, self-limited anterior uveitis. The clinical manifestations of PSS are primarily characterized by a dramatic increase in intraocular pressure (IOP), the formation of mutton-fat posterior corneal deposits (KP), and mild visual impairment. Previously, PSS was considered to have a favorable prognosis, but recent studies have revealed that recurrent episodes can lead to irreversible visual impairment in a significant proportion of patients, severely impacting visual quality and quality of life. The pathogenesis of PSS remains unclear, and ideal treatment options are lacking. Current clinical treatment focuses primarily on symptomatic treatment with steroids, anti-inflammatory drugs, and ocular hypotensive medications. While steroid therapy can shorten the course of the disease, it cannot prevent or reduce recurrences. Long-term steroid use can also lead to steroid dependence and steroid-induced glaucoma, as well as inducing and accelerating cataract formation, further exacerbating visual impairment. Because ocular hypotensive medications do not address the underlying cause, they are typically used as an adjunct therapy. Cytomegalovirus (CMV) infection has recently been recognized as a significant cause of PSS, but viral infection cannot explain all cases of PSS; other pathogenic factors exist. At the same time, although antiviral treatment can reduce disease recurrence to a certain extent, its therapeutic effect when used alone is not ideal. Therefore, in-depth exploration of the pathogenesis of PSS, the development of effective therapeutic targets and strategies, and the reduction of PSS attack frequency and the reduction or avoidance of visual function damage are important needs in the field of ophthalmology. Summary of the Invention

[0003] In order to address the technical defects of the existing technology, the present invention provides an application of an 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) pathway activity inhibitor in the preparation of a drug for treating glaucomatous cyclitis syndrome, and the application of drugs and other strategies that correct local corticosteroid metabolic imbalance by inhibiting 11β-HSD1 activity, thereby reducing aqueous humor production and alleviating ocular inflammation. This type of drug can be used to treat glaucomatous cyclitis syndrome and other diseases related to increased 11β-HSD1 activity in the eye, and has significant clinical therapeutic potential.

[0004] The technical solution adopted by the present invention is: application of 11β-HSD1 pathway activity inhibitor in the preparation of medicine for treating glaucoma cyclitis syndrome.

[0005] Furthermore, the 11β-HSD1 pathway activity inhibitor is the 11β-HSD1 inhibitor CBX or AZD4017 and its analogs.

[0006] Furthermore, the concentration of the 11β-HSD1 inhibitor CBX or AZD4017 and its analogs is 0.1-20 mg / ml.

[0007] Furthermore, the medicine for treating glaucoma-cyclitis syndrome is eye drops.

[0008] Furthermore, the drug for treating glaucomatous cyclitis syndrome is a drug for treating glaucomatous cyclitis syndrome caused by enhanced 11β-HSD1 activity.

[0009] Application of 11β-HSD1 pathway activity inhibitors in the preparation of drugs for treating diseases associated with enhanced 11β-HSD1 activity in the eye.

[0010] Furthermore, the diseases associated with enhanced ocular 11β-HSD1 activity are diseases associated with enhanced ocular 11β-HSD1 activity and the resulting imbalance in local corticosteroid metabolism.

[0011] Furthermore, the 11β-HSD1 pathway activity inhibitor is the 11β-HSD1 inhibitor CBX or AZD4017 and its analogs.

[0012] Furthermore, the concentration of the 11β-HSD1 inhibitor CBX or AZD4017 and its analogs is 0.1-20 mg / ml.

[0013] The beneficial effects of the present invention are as follows: the present invention provides an application of an 11β-HSD1 pathway activity inhibitor in the preparation of a drug for treating glaucoma-cyclitis syndrome, which can effectively correct the imbalance of local corticosteroid metabolism in the eye and alleviate the physiological effects of excess mineralocorticoids by specifically inhibiting the activity of 11β-HSD1 in the eye, while simultaneously reducing aqueous humor production and alleviating eye inflammation. The present invention is suitable for treating glaucoma-cyclitis syndrome and other diseases related to increased 11β-HSD1 activity in the eye. The present invention has the advantages of novel targets, high efficiency and safety, and long-term intraocular pressure reduction, and has important clinical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Immunohistochemical staining was used to confirm that 11β-HSD1, glucocorticoid receptor GR, and mineralocorticoid receptor MR were highly expressed in the non-pigmented epithelium of the human ciliary body. However, 11β-HSD2 was only lowly expressed, suggesting that 11β-HSD1 plays a key regulatory role in corticosteroid metabolism in the ciliary body. Figure 1 A. Comparison of aqueous humor cortisol levels in patients with blue eyelash syndrome and controls; Figure 1 B. Comparison of aqueous cortisone content in patients with blue eyelash syndrome and control group; Figure 1 C. Comparison of 11β-HSD1 activity in aqueous humor between patients with blue eyelid syndrome and control group.

[0015] Figure 2 The levels of cortisol in the aqueous humor of patients with blue eyelash syndrome and the cortisol / cortisone ratio reflecting the activity of 11β-HSD1 were significantly increased compared with the control group (patients with simple cataract) and patients with primary open-angle glaucoma (POAG) and chronic angle-closure glaucoma (CACG) who also had significantly elevated intraocular pressure; Figure 1: Upper left: Human ciliary body morphology; Figure 1: Upper right: Western blot detection of the expression of mineralocorticoid receptor MR, glucocorticoid receptor GR, and 11β-HSD1 and 11β-HSD2 proteins in human ciliary body tissue; Figure 1: Immunohistochemical detection of the expression and localization of 11β-HSD1, 11β-HSD2, mineralocorticoid receptor MR, and glucocorticoid receptor GR in human ciliary body tissue.

[0016] Figure 3 This study tested the ocular surface toxicity of the 11β-HSD1 inhibitor CBX at doses ranging from 0.1 to 100 mg / ml in healthy mice. CBX eye drops at doses ranging from 0.1 to 20 mg / ml showed good safety, while 50 mg and 100 mg of CBX eye drops caused significant corneal epithelial damage.

[0017] Figure 4 The figure shows the effects of different concentrations of CBX eye drops on the intraocular pressure of healthy mice. It can be seen that local eye drops of 0.1-100 mg / ml CBX have no significant effect on the intraocular pressure of mice, and there is no obvious IOP-lowering effect compared with their baseline before medication and the contralateral control eyes.

[0018] Figure 5 In vivo experiments in mice confirmed that an animal model of blue eyelid syndrome was successfully established by upregulating the expression of 11β-HSD1 specifically in the non-pigmented ciliary epithelial cells of mice. Overexpression of 11β-HSD1 in non-pigmented ciliary epithelial cells can well simulate the main clinical features of patients with blue eyelid syndrome, namely, significantly increased intraocular pressure and the hypotensive effect of dexamethasone. At the same time, 10mg / ml of 11β-HSD1 inhibitors CBX and AZD4017 can effectively reduce the intraocular pressure of model mice. The above results further support the pathogenic role of 11β-HSD1 in blue eyelid syndrome and its feasibility as a target for therapeutic intervention. Figure 5 A. Intravitreal injection of transfectant virus; Figure 5 B. Western blot and immunofluorescence staining confirmed the specific transfection of mouse ciliary non-pigmented epithelial cells and the upregulation of 11β-HSD1 expression; Figure 5 C. The model mice exhibited two key clinical features of BLSS: elevated intraocular pressure and a hypotensive response to dexamethasone. Figure 5 D.11β-HSD1 inhibitors CBX and AZD407 can effectively reduce the intraocular pressure of model mice, and their effects are comparable to those of dexamethasone. DETAILED DESCRIPTION

[0019] The following will provide a clear and complete description of the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0020] Example 1

[0021] This part of the experiment observed the expression of 11β-HSDs and corticosteroid receptors in the human ciliary body. Ciliary tissues from the eyeballs of corneal transplant donors were collected from the hospital eye bank, and the expression of 11β-HSD1, 11β-HSD2, glucocorticoid receptor GR and mineralocorticoid receptor MR in the tissues was located and quantitatively detected by immunohistochemistry and western blot. The results showed that the human ciliary body had high expression of glucocorticoid receptor GR, mineralocorticoid receptor MR and 11β-HSD1, which were mainly located in the non-pigmented epithelium of the ciliary body. However, 11β-HSD2 was only lowly expressed in the ciliary body tissue of the human eye. These results suggest that 11β-HSD1 plays an important role in the regulation of corticosteroid metabolism in the human ciliary body (see Figure 1 ).

[0022] Example 2. This example uses high performance liquid chromatography tandem mass spectrometry to detect aqueous humor samples, demonstrating that patients with cyanosis have disease-specific ocular corticosteroid metabolic imbalance and increased 11β-HSD1 activity.

[0023] Experimental groups:

[0024] Control group: patients with simple age-related cataract who were scheduled to undergo cataract surgery

[0025] PSS acute attack group: eyes with acute attack of PSS who did not receive any treatment and had intraocular pressure > 21 mmHg

[0026] POAG group: patients with primary open-angle glaucoma who have not used any drugs that may affect the metabolism of corticosteroids in aqueous humor in the past month and whose intraocular pressure is greater than 21 mmHg

[0027] CACG group: patients with primary chronic angle-closure glaucoma who have not used any drugs that may affect the metabolism of corticosteroids in aqueous humor in the past month and whose intraocular pressure is greater than 21 mmHg

[0028] After informed consent was obtained from the patients, the periocular and conjunctival sac were irrigated and disinfected. A 1ml syringe was used to puncture the anterior chamber and withdraw 0.05-0.1ml of aqueous humor. This was injected into a sterile EP tube and frozen at -80°C. Cortisol and cortisone levels in aqueous humor samples from different groups were measured using high-performance liquid chromatography-tandem mass spectrometry, and the cortisol / cortisone ratio was calculated for evaluation of 11β-HSD1 activity. Results showed that compared with the control group, active cortisol levels in the aqueous humor of patients with PSS were significantly increased, whereas no significant changes were observed in patients with chronic angle-closure glaucoma (CACG) and primary open-angle glaucoma (POAG), who also had elevated intraocular pressure. Inactive cortisone levels in the aqueous humor of patients with PSS were not significantly different from those in the other groups. The cortisol / cortisone ratio, an indicator of 11β-HSD1 activity, was significantly elevated in the aqueous humor of patients with PSS, whereas it was not significantly altered in patients with CACG or POAG. These results suggest that enhanced 11β-HSD1 activity plays a specific role in the onset of PSS, and 11β-HSD1 may become a new therapeutic target for PSS.

[0029] Example 3

[0030] In some experiments, we first tested the ocular surface toxicity of topical CBX, an 11β-HSD1 inhibitor. CBX powder was dissolved in DMSO and then prepared in sterile PBS to prepare eye drops at concentrations of 0.1 mg / ml, 1 mg / ml, 10 mg / ml, 20 mg / ml, 50 mg / ml, and 100 mg / ml. Healthy adult C57BL / 6J female mice, aged 6-8 weeks, were administered CBX eye drops of varying concentrations twice daily (8-9 am and 1-2 pm). Ocular surface slit lamp observation and fluorescein staining were performed before intervention and on days 3, 6, 9, and 15 after instillation. Results showed that mice treated with 0.1-20 mg / ml CBX eye drops maintained intact, smooth, and transparent corneal epithelium during the observation period, demonstrating a relatively safe treatment profile. However, 50 and 100 mg / ml CBX eye drops caused significant corneal epithelial damage. Six days after instillation, corneal roughness, localized epithelial defects, and localized accumulation of fluorescein staining were observed in the mice. At the end of the observation period, corneal opacity and clouding were observed, suggesting ocular surface toxicity. Therefore, the recommended safe working concentration range for CBX in in vivo mouse studies is 0.1-20 mg / ml.

[0031] Example 4

[0032] In some experiments, we investigated the effects of the 11β-HSD1 inhibitor CBX on the intraocular pressure (IOP) of healthy mice. CBX eye drops of varying concentrations were prepared as described in Example 3. Six- to eight-week-old healthy adult C57BL / 6J female mice were administered CBX eye drops twice daily (8-9 AM and 1-2 PM) at doses of 0.1 mg / ml, 1 mg / ml, 10 mg / ml, and 100 mg / ml. IOP was measured using an icare tonometer before treatment and on days 3, 6, 9, 12, and 15 after the instillation. Results showed that topical CBX infusions of 0.1-100 mg / ml had no significant effect on IOP in mice, with no significant IOP-lowering effect compared to baseline and the contralateral control eye.

[0033] Example 5

[0034] This study established an animal model of blue eyelid syndrome by specifically upregulating 11β-HSD1 in the non-pigmented ciliary epithelium of mice and evaluated the model. The therapeutic effects of the 11β-HSD1 inhibitors CBX and AZD407 on the model mice were observed.

[0035] The study involved healthy adult C57BL / 6J female mice aged 6-8 weeks. Two microliters of AAV-CAG-11β-EGPF virus were injected intravitreally, while a control group of mice received 2 microliters of blank AAV-CAG-EGPF virus. Intraocular pressure (IOP) was measured using an icare tonometer before and at various time points after injection. Four weeks after modeling, eyeballs were harvested, and the expression and localization of 11β-HSD1 in the ciliary body of the model mice were assessed by western blot and immunofluorescence staining. The results showed that a single intravitreal viral transfection effectively and specifically increased 11β-HSD1 expression in the non-pigmented ciliary epithelial cells of the mice. A gradual increase in IOP was observed in the model mice starting one week after transfection, reaching a peak at four weeks and maintaining a plateau. At week 4, when IOP peaked, 0.1% dexamethasone gel was administered twice daily. This significantly reduced IOP in the model mice, whereas normal mice exhibited significant IOP elevations following administration of the same 0.1% dexamethasone gel. These findings are highly consistent with those observed in patients with glaucoma. This finding not only further supports the pathogenic role of 11β-HSD1 in glaucoma but also provides a basis for the development of novel therapeutic strategies targeting 11β-HSD1. To test this hypothesis, we further administered 10 mg / ml of the 11β-HSD1 inhibitors CBX and AZD407 twice daily. These results demonstrated that this treatment significantly reduced IOP in the model mice, comparable to the IOP-lowering effect of dexamethasone in this model.

[0036] By targeting and upregulating the expression of 11β-HSD1 in the non-pigmented ciliary epithelial cells of mice, we successfully induced PSS-specific clinical features of increased intraocular pressure and an intraocular pressure-lowering response to hormones, further proving the key role of 11β-HSD1 in the pathogenesis of PSS. We then treated the model mice with eye drops prepared with different 11β-HSD1 inhibitors, CBX and AZD4017, and observed that both 11β-HSD1 inhibitors could successfully reduce the intraocular pressure of the model mice, with an effect comparable to that of hormone gel. Figure 3 As shown, specific upregulation of 11β-HSD1 in ciliary non-pigmented epithelial cells can successfully induce a mouse model with clinical features highly consistent with those of PSS in clinical settings. The 11β-HSD1 inhibitors CBX and AZD4017 exhibited therapeutic efficacy comparable to dexamethasone in PSS model mice. Based on this, the present invention proposes the use of local ocular administration of 11β-HSD1 inhibitory drugs or genetic intervention strategies to treat PSS and diseases associated with increased local 11β-HSD1 activity, improving the safety and efficacy of treatment.

[0037] in conclusion

[0038] This invention demonstrates the key role of 11β-HSD1 in the pathogenesis of PSS. Furthermore, eye drops prepared with two 11β-HSD1 inhibitors, CBX and AZD4017, were used to treat the model mice. Both 11β-HSD1 inhibitors successfully reduced intraocular pressure in the model mice, with efficacy comparable to that of hormone gel. Based on this, the present invention proposes the use of topical administration of 11β-HSD1 inhibitory drugs or genetic intervention strategies for the treatment of PSS and diseases associated with localized 11β-HSD1 activity, improving the safety and efficacy of treatment.

[0039] The innovation of the present invention is:

[0040] 1. Theoretical Innovation: The pathogenesis of PSS remains unclear, and for decades, there has been no breakthrough in its pathogenesis theory. The core of this invention is that 11β-HSD1 plays a key pathogenic role in the pathogenesis of PSS, which is innovative in the theory of PSS pathogenesis.

[0041] 2. Novel target: Compared with the current lack of specific broad-spectrum immune inflammation inhibition methods, it is proposed for the first time that enhanced 11β-HSD1 activity may serve as a specific intervention target for diseases such as PSS.

[0042] 3. Dosage Form Innovation: Previous studies have mostly used systemic administration, resulting in systemic 11β-HSD1 inhibition and potential side effects. This invention addresses conditions such as PSS, where local 11β-HSD1 function is upregulated, by providing CBX and AZD4017 eye drops at concentrations of 0.1-20 mg / ml as therapeutic agents. These eye drops demonstrate excellent IOP-lowering effects with minimal local and systemic side effects. This approach also avoids the hormone-related complications associated with current conventional hormone treatments.

[0043] 4. Strategic Innovation: The present invention aims to protect drugs and other strategies that have the effect of inhibiting ocular 11β-HSD1 activity, such as gene intervention, for the treatment of diseases related to enhanced ocular 11β-HSD1 activity, such as PSS.

[0044] The scope of protection of the present invention is not limited to the above-mentioned embodiments. All technical solutions within the scope of protection of the present invention are within the scope of protection of the present invention. It should be noted that for those skilled in the art, various improvements and modifications that do not depart from the principles of the present invention should be considered as within the scope of protection of the present invention.

Claims

1. Use of an 11β-HSD1 pathway activity inhibitor in the preparation of a drug for treating glaucoma-cyclitis syndrome, characterized in that: The 11β-HSD1 pathway activity inhibitor is the 11β-HSD1 inhibitor CBX or AZD4017.

2. The use according to claim 1, characterized in that The concentration of the 11β-HSD1 inhibitor CBX or AZD4017 is 0.1-20 mg / ml.

3. The use according to claim 1, characterized in that The medicine for treating glaucoma-cyclitis syndrome is eye drops.

4. The use according to claim 3, characterized in that The drug for treating glaucoma-cyclitis syndrome is a drug for treating glaucoma-cyclitis syndrome caused by enhanced 11β-HSD1 activity.

5. The use according to claim 2, characterized in that The drug for treating glaucomatous cyclitis syndrome is a drug for treating the disease-specific local ocular corticosteroid metabolic imbalance existing in patients with glaucomatous cyclitis syndrome.

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