Use of nerolidol in the preparation of a medicament for treating radiation dry eye

Abstract

This invention discloses the application of nerolidol in the preparation of drugs for treating radiation-induced dry eye, including the following steps: S1, Preparation of 7% nerolidol solution: Dissolve 80 μL of nerolidol stock solution in 1 mL of sterile water; S2, Establishment of dry eye model: Radiation dose from the eyes to the back of the head of dry eye model mice is 10 Gy; S3, Modeling time: 2 weeks after irradiation with 10 Gy; S4, Grouping: IR + nerolidol group - after irradiation, each eye is given 10 μL of 7% nerolidol solution once every 20 min / day for 7 days; IR + sodium hyaluronate group - after irradiation, each eye is given 10 μL of 0.1% sodium hyaluronate eye drops once every 20 min / day for 7 days; IR group - no treatment after irradiation; NC group - normal, no irradiation treatment. This invention, through measurement of tear secretion time, found that nerolitin has a more significant effect on increasing tear secretion; in a radiation-induced dry eye model, the effect is better and more profound than the currently commonly used 0.1% sodium hyaluronate eye drops.

Description

Technical Field

[0001] This invention relates to the field of drug preparation for treating radiation-induced dry eye, specifically the application of nerolidol in the preparation of drugs for treating radiation-induced dry eye. Background Technology

[0002] The International Commission on Radiological Protection (ICRP) has identified the lens of the eye as one of the most radiation-sensitive tissues in the human body.

[0003] X-rays primarily cause denaturation of lens proteins, leading to cataracts. Radiation-induced cataracts are a legally recognized occupational eye disease. Cataracts can be treated with phacoemulsification surgery. However, after cataract surgery, some patients complain of discomfort such as dryness, foreign body sensation, and burning in the operated eye, i.e., dry eye. Furthermore, 11 out of 15 radiographers (average work experience of 6.36 years, personal dose less than 0.10 mSv for three months, and personal dose less than 0.40 mSv for one year) developed dry eye, compared to only 2 out of 15 in the control group. All 15 radiographers also exhibited corneal squamous metaplasia and intraepithelial lymphocytic infiltration. 21 out of 36 radiologists (average experience of 5.3 years) developed dry eye, compared to only 4 out of 35 in the control group (non-radiation workers) (11.4%). Dry eye can be considered an occupational disease related to radiation, with a low dose threshold and a high incidence rate. Patients are not only hindered from living a normal life, but may even develop corneal ulcers that are difficult to cure and lead to blindness.

[0004] In addition, during radiotherapy for orbital tumors, the lacrimal glands are usually also within the irradiation field. The dry eye syndrome caused by the irradiation of the lacrimal glands aggravates the side effects of irradiation, making patients suffer greatly.

[0005] The first generation of medications for dry eye were artificial tears. Since they only provided exogenous fluid replenishment, they only offered temporary relief. Examples include aqueous sodium hyaluronate, exogenous mucin-replenishing polyethylene glycol, lipid-based carbomer ophthalmic gel, and growth factor eye drops. The second generation of medications promoted the body's own tear production, such as diquafosol sodium eye drops. The third generation consisted of immunosuppressants with anti-inflammatory effects, such as 0.1% cyclosporine eye drops. Current drug development focuses on combinations of soft steroids and anti-inflammatory drugs (such as cyclosporine A), with the addition of new polyvalent mucins and tear secretion promoters. Some traditional Chinese medicine extracts are also used in dry eye treatment. Additionally, there are reports of chondrocyte-derived extracellular matrix, carboxymethyl cellulose, and hyaluronic acid being used to treat dry eye.

[0006] Most medications for dry eye disease do not contain substances already present in the human body, especially in tears. Treatment for dry eye disease can only supplement one or a few substances, which is insufficient and fails to solve the problem. For moderate to severe dry eye disease, the causes are complex, and most cases are irreversible, making effective drugs scarce and treatment difficult. Because radiation-induced dry eye disease also involves radiation damage to the lacrimal glands, drugs that promote tear secretion are also unlikely to be very effective. Summary of the Invention

[0007] The purpose of this invention is to provide the application of nerolidol in the preparation of drugs for treating radiation-induced dry eye, in order to solve the problems in the prior art.

[0008] To achieve the above objectives, the present invention provides the following technical solution: the application of nerolidol in the preparation of drugs for treating radiation-induced dry eye, comprising the following steps:

[0009] Preparation of S1, 7% nerolidol solution: Dissolve 80 μL of nerolidol stock solution in 1 mL of sterile water;

[0010] S2. Establishment of the dry eye model: The radiation dose from the eyes to the back of the head of the dry eye model mice was 10 Gy;

[0011] S3, Modeling time: 2 weeks after irradiation with 10 Gy;

[0012] S4, Grouping:

[0013] IR + nerolidol group – 10 μL of 7% nerolidol solution was administered to each eye once a day for 20 minutes after irradiation; for a total of 7 days;

[0014] IR + Sodium Hyaluronate Group – After irradiation, each eye was given 10 μL of 0.1% sodium hyaluronate eye drops once every 20 minutes for a total of 7 days;

[0015] IR group – No treatment was given after irradiation;

[0016] NC group – Normal, unirradiated treatment.

[0017] Preferably, the osmotic pressure in S1 is 300 mmol / L, which is within the normal plasma osmotic pressure range.

[0018] Preferably, the mouse breed in S2 is a female C57BL / 65w mouse.

[0019] Preferably, the IR+nerolidol group uses 4 mice; the IR+sodium hyaluronate group uses 4 mice; the IR group uses 3 mice; and the NC group uses 4 mice.

[0020] Preferably, it also includes S5, tear secretion time measurement: the lower eyelid of the mouse to be tested is rolled down, the tear test strip is placed in the conjunctival sac of the lower eyelid, and the strip is removed when the tear secretion reaches 2.3 μL, and the time is recorded.

[0021] Preferably, it also includes S6, corneal fluorescein sodium staining assay.

[0022] Preferably, it also includes S7, corneal confocal measurement.

[0023] Preferably, it also includes S8, tear film breakup time measurement: the cornea is stained with sodium fluorescein, and the time of formation of the first black spot is observed under cobalt blue light, with 3 measurements for each eye.

[0024] Compared with the prior art, the beneficial effects of the present invention are:

[0025] 1. Nerolidol exists in human tears and can promote the recovery of endothelial cells and optic nerve cells after irradiation, and increase tear secretion. Through corneal confocal microscopy, it was found that after irradiation, endothelial cells are disordered, have different shapes, larger volume, and swelling, with increased inflammatory cells and decreased nerve fiber density. Nerolidol's repair function is superior to that of sodium hyaluronate. Through the measurement of tear secretion time, it was found that nerolidol has a more significant effect on increasing tear secretion. In the radiation-induced dry eye model, the effect is better and more profound than the currently commonly used 0.1% sodium hyaluronate eye drops.

[0026] 2. Nerolidol is one of the tear components that are significantly reduced in a mouse model of radiation-induced dry eye. Currently, there is no literature on its association with dry eye. Data on the relief of radiation-induced dry eye provides an innovative drug for patients with occupational radiation-related diseases and orbital tumors undergoing radiotherapy, especially those with moderate to severe radiation-induced dry eye. Attached Figure Description

[0027] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings:

[0028] Figure 1 These are before-and-after comparison images of corneal confocal treatment according to the present invention;

[0029] Figure 2 This is an endothelial cell counting diagram of the present invention;

[0030] Figure 3 This is a tear secretion time diagram of the present invention;

[0031] Figure 4 This is a fluorescein sodium staining image of the IR+ nerolidol group before treatment according to the present invention;

[0032] Figure 5This is a fluorescein sodium staining image after treatment with IR+ nerolidol group according to the present invention. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Therefore, the following detailed description of the embodiments of the present invention provided in the accompanying drawings is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention.

[0034] Please see Figure 1-5 In this embodiment of the invention, the application of nerolidol in the preparation of a drug for treating radiation-induced dry eye includes the following steps:

[0035] Preparation of S1, 7% nerolidol solution: Dissolve 80 μL of nerolidol stock solution in 1 mL of sterile water; the osmotic pressure is 300 mmol / L, which is within the normal plasma osmotic pressure range;

[0036] S2. Establishment of the dry eye model: The radiation dose from the eyes to the back of the head of the dry eye model mice was 10 Gy; the mouse breed was C57BL / 65w female mice;

[0037] S3, Modeling time: 2 weeks after irradiation with 10 Gy;

[0038] S4, Grouping:

[0039] IR + nerolidol group – 10 μL of 7% nerolidol solution was administered to each eye once a day for 20 minutes after irradiation; for a total of 7 days;

[0040] IR + Sodium Hyaluronate Group – After irradiation, each eye was given 10 μL of 0.1% sodium hyaluronate eye drops once every 20 minutes for a total of 7 days;

[0041] IR group – No treatment was given after irradiation;

[0042] NC group – Normal, unirradiated treatment.

[0043] Preferably, the IR+nerolidol group uses 4 mice; the IR+sodium hyaluronate group uses 4 mice; the IR group uses 3 mice; and the NC group uses 4 mice.

[0044] Preferably, it also includes S5, tear secretion time measurement: the lower eyelid of the mouse to be tested is rolled down, the tear test strip is placed in the conjunctival sac of the lower eyelid, and the strip is removed when the tear secretion reaches 2.3 μL, and the time is recorded.

[0045] Preferably, it also includes S6, corneal fluorescein sodium staining assay.

[0046] Preferably, it also includes S7, corneal confocal measurement.

[0047] Preferably, it also includes S8, tear film breakup time measurement: the cornea is stained with sodium fluorescein, and the time of formation of the first black spot is observed under cobalt blue light, with 3 measurements for each eye.

[0048] Nerolidol is present in human tears: Most previous medications for dry eye were not substances already present in the human body, especially in tears. Examples include aqueous sodium hyaluronate, exogenous mucin-supplementing polyethylene glycol, lipid-based carbomer ophthalmic gel, growth factor eye drops, diquafosol sodium eye drops, and 0.1% cyclosporine eye drops. However, by examining metabolomics changes in tears before and after irradiation, we used the small molecules we discovered to treat radiation-induced dry eye in mice. Through tear secretion assays and other methods, we demonstrated that nerolidol is one of the tear components that was significantly reduced in the mouse model of radiation-induced dry eye.

[0049] Nerolidol has a broad range of effects: Currently, the main mechanisms of action for treating dry eye drugs are: exogenous fluid replenishment, promotion of endogenous tear secretion, anti-inflammatory effects, replenishment of polyvalent mucins, and traditional Chinese medicine extracts. These drugs can only replenish one or a few substances for the treatment of dry eye disease, and for moderate to severe dry eye syndrome with complex etiologies and often irreversible causes, clinically effective drugs are scarce, making treatment difficult. Because radiation-induced dry eye disease also involves radiation damage to the lacrimal glands, drugs that promote tear secretion are also unlikely to be very effective. However, nerolidol can promote the recovery of endothelial cells and optic nerve cells after irradiation, thereby increasing tear secretion.

[0050] Nerolidol is one of the tear components that are significantly reduced in a mouse model of radiation-induced dry eye. Currently, there is no literature on its association with dry eye. Data on its relief of radiation-induced dry eye provides an innovative drug for patients with occupational radiation-related diseases and those undergoing radiotherapy for orbital tumors, especially those with moderate to severe radiation-induced dry eye.

[0051] Currently, there is no literature on nerolidol for treating radiation-induced dry eye. Nerolidol is present in human tears and can promote the recovery of endothelial cells and optic nerve cells after irradiation, increasing tear secretion. Our corneal confocal microscopy revealed that after irradiation, endothelial cells exhibit disordered arrangement, inconsistent morphology, increased size, swelling, increased inflammatory cells, and decreased nerve fiber density. Nerolidol showed superior repair function compared to sodium hyaluronate. Measurements of tear secretion time showed that nerolidol had a more significant effect on increasing tear secretion. In a radiation-induced dry eye model, the effect was better and more profound than the currently commonly used 0.1% sodium hyaluronate eye drops.

[0052] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. Use of nerolidol for the preparation of a medicament for the treatment of radiation dry eye, characterized in that, Includes the following steps: Preparation of S1, 7% nerolidol solution: Dissolve 80 μL of nerolidol stock solution in 1 mL of sterile water; S2. Establishment of the dry eye model: The radiation dose from the eyes to the back of the head of the dry eye model mice was 10 Gy; S3, Modeling time: 2 weeks after irradiation with 10 Gy; S4, Grouping: IR + nerolidol group – 10 μL of 7% nerolidol solution was administered to each eye once a day for 20 minutes after irradiation; for a total of 7 days; IR + Sodium Hyaluronate Group – After irradiation, each eye was given 10 μL of 0.1% sodium hyaluronate eye drops once every 20 minutes for a total of 7 days; IR group – No treatment was given after irradiation; NC group – Normal, unirradiated treatment.

2. Use of nerolidol according to claim 1 for the preparation of a medicament for the treatment of radiation dry eye, characterized in that, The osmotic pressure in S1 is 300 mmol / L, which is within the normal plasma osmotic pressure range.

3. Use of nerolidol according to claim 1 for the preparation of a medicament for the treatment of radiation dry eye, characterized in that, The mice in S2 are female C57BL / 65w mice.

4. Use of nerolidol according to claim 1 for the preparation of a medicament for the treatment of radiation dry eye, characterized in that, The IR+nerolidol group used 4 mice; the IR+sodium hyaluronate group used 4 mice; the IR group used 3 mice; and the NC group used 4 mice.

5. Use of nerolidol according to claim 1 for the preparation of a medicament for the treatment of radiation dry eye, characterized in that, It also includes S5, tear secretion time measurement: the lower eyelid of the mouse to be tested is rolled down, the tear test strip is placed in the conjunctival sac of the lower eyelid, and it is removed when the tear secretion reaches 2.3μL, and the time is recorded.

6. The application of nerolidol according to claim 1 in the preparation of a drug for treating radiation-induced dry eye, characterized in that, It also includes S6 and corneal fluorescein sodium staining assay.

7. The application of nerolidol according to claim 1 in the preparation of a drug for treating radiation-induced dry eye, characterized in that, It also includes S7 and corneal confocal measurement.

8. The application of nerolidol according to claim 1 in the preparation of a drug for treating radiation-induced dry eye, characterized in that, It also includes S8, tear film breakup time measurement: the cornea is stained with sodium fluorescein, and the time of formation of the first black spot is observed under cobalt blue light, with 3 measurements for each eye.

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