Application of sitagliptin in preparation of medicine for treating and / or preventing radiation-induced oral mucositis

Abstract

The invention discloses application of sitagliptin in preparation of a medicine for treating and / or preventing radiation-induced oral mucositis, and belongs to the technical field of biological pharmacy, and the medicine contains sitagliptin with a treatment effective amount and a pharmaceutically acceptable carrier and / or excipient. The application of sitagliptin in treatment and / or prevention of radiation-induced oral mucositis is provided for the first time, the sitagliptin has the advantages of being good in treatment effect, good in safety and the like, and the problem of treatment of radiation-induced oral mucositis is solved.

Description

Technical Field

[0001] The present invention belongs to the technical field of biopharmaceuticals, and in particular relates to the use of sitagliptin in the preparation of a drug for treating and / or preventing radiation oral mucositis. Background Art

[0002] Radiation-induced oral mucositis (RIOM) is the most common oral complication in cancer patients receiving radiotherapy, which is characterized by inflammation and mucosal damage of the oral mucosa. In particular, almost all patients receiving head and neck radiotherapy will experience RIOM. RIOM can cause pain, dysphagia, and malnutrition, seriously affecting the patient's quality of life and interrupting anticancer treatment. To date, there is no effective way to prevent RIOM, and the main method of preventing RIOM clinically is to maintain good oral care. Therefore, finding new drugs that can prevent RIOM is crucial to improving the quality of life of cancer patients receiving head and neck radiotherapy.

[0003] Sitagliptin is an FDA-approved oral hypoglycemic drug and is one of the dipeptidyl peptidase IV (DPP-4) inhibitors. With the progress of research, sitagliptin has been shown to play a therapeutic role in a series of diseases such as atherosclerosis, ischemia-reperfusion injury, acute lung injury, and fibrotic diseases.

[0004] Currently, there are no reports on the use of sitagliptin in the treatment and / or prevention of radiation-induced oral mucositis. Summary of the invention

[0005] The object of the present invention is to provide a new use of sitagliptin, namely, use of sitagliptin in preparing a drug for treating and / or preventing radiation oral mucositis.

[0006] In order to achieve the above purpose, this application adopts the following technical solutions:

[0007] The present invention provides the use of sitagliptin in preparing a medicine for treating and / or preventing radiation oral mucositis.

[0008] In the above technical solution, the drug contains a therapeutically effective amount of sitagliptin and a pharmaceutically acceptable carrier and / or excipient.

[0009] In the above technical solution, the dosage form of the drug includes at least one of an injection preparation, an oral preparation, a spray preparation and a flushing preparation.

[0010] In the above technical scheme, in the drug, the sitagliptin has any one or more of the following uses: for inhibiting the expression level of inflammatory factors, for inhibiting radiation-induced apoptosis of oral epithelial cells, for inhibiting oxidative stress damage, and for inhibiting the activation of the TLR2 / MyD88 / NFκB inflammatory pathway.

[0011] In the above technical solution, the inflammatory factors include but are not limited to at least one of TNFα, IL 6, and IL 1β.

[0012] The beneficial effects of the present invention are as follows: the present invention proposes for the first time the use of sitagliptin in the treatment and / or prevention of radiation oral mucositis, has the characteristics of good therapeutic effect and good safety, and solves the difficult problem of treating radiation oral mucositis. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 This is a graph showing the weight results of each group of mice in the examples of the present invention;

[0014] Figure 2 These are typical images of tongue ulcer staining in each group of mice in the examples of the present invention;

[0015] Figure 3 The results of H&E staining of pathological sections of mouse tongue tissues in each group in the embodiments of the present invention are shown;

[0016] Figure 4 The immunohistochemical staining results of Ki67 (cell proliferation) of tongue tissue of mice in each group in the embodiment of the present invention are shown in FIG.

[0017] Figure 5 The results of immunofluorescence TUNEL (apoptosis) staining of tongue tissues of mice in each group in the examples of the present invention are shown;

[0018] Figure 6 The immunofluorescence DHE (reactive oxygen species) staining results of the tongue tissues of mice in each group in the embodiment of the present invention are shown in FIG.

[0019] Figure 7 This is a heat map of the expression of inflammatory cytokines in the tongue tissue of each group of mice in the examples of the present invention;

[0020] Figure 8 GO and KEGG pathway enrichment diagrams of transcriptome sequencing of mouse tongue tissues in each group in the embodiment of the present invention;

[0021] Fig. 9 The expression diagrams of TLR2, MyD88, p65, and p-p65 proteins in the tongue tissues of mice in each group in the examples of the present invention are shown;

[0022] Fig.10These are the results of body weight and postprandial blood glucose of each group of mice in the examples of the present invention, as well as the results of H&E staining of pathological sections of heart, liver, spleen, lung and kidney tissues. DETAILED DESCRIPTION

[0023] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments. The present invention can be implemented in many different forms and should not be construed as being limited to the embodiments set forth herein. On the contrary, these embodiments are provided so that this disclosure will be thorough and complete, and the concept of the present invention will be fully conveyed to those skilled in the art, and the present invention will only be limited by the claims.

[0024] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0025] The present invention provides a use of a drug, and specifically, provides for the first time a new use of sitagliptin to solve the problems related to the treatment and / or prevention of radiation oral mucositis.

[0026] Specifically, the present invention provides the use of sitagliptin in the preparation of a medicament for treating and / or preventing radiation oral mucositis.

[0027] This medicine includes:

[0028] (a) a therapeutically effective amount of sitagliptin; and

[0029] (b) pharmaceutically acceptable carriers and / or excipients.

[0030] In the present application, in some specific embodiments, depending on the specific field of product application, the drug may specifically be a pharmaceutical preparation used in the medical field, a dietary supplement used in the functional food field, etc.

[0031] In this application, "effective amount" may also be referred to as "therapeutically effective amount", which refers to the amount of an agent sufficient to provide a desired biological result. The result may be a reduction and / or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use refers to the amount of a composition comprising a compound as an active ingredient of the present invention that is required to clinically significantly reduce the disease. In any individual case, an appropriate "effective" amount can be determined by a person of ordinary skill in the art using routine experiments. Therefore, the expression "effective amount" generally refers to the amount of an active substance when it has a therapeutic effect.

[0032] In this application, "carrier" may also be referred to as "drug carrier", which refers to a system that can change the way drugs enter the human body and their distribution in the body, control the release rate of drugs and deliver drugs to targeted organs.

[0033] In this application, "excipients" can also be called "auxiliary materials", such as physiological saline, glucose, vitamin C, amino acids, etc., which refer to additives other than the main drug in pharmaceutical preparations. For example, adhesives, fillers, disintegrants, lubricants in tablets; wine, vinegar, medicinal juice, etc. in traditional Chinese medicine pills; matrix parts in semi-solid preparations such as ointments and creams; preservatives, antioxidants, flavoring agents, aromatics, cosolvents, emulsifiers, solubilizers, osmotic pressure regulators, colorants, etc. in liquid preparations can all be called excipients.

[0034] Furthermore, the dosage form of the drug includes at least one of an injection preparation, an oral preparation, a spray preparation and a flushing preparation.

[0035] In the present application, injectable preparations include freeze-dried powder injections, etc.; oral preparations include tablets, capsules or granules, etc.; spray preparations include atomizers, sprays, suspensions, etc.

[0036] Furthermore, in this drug, sitagliptin has any one or more of the following uses: for inhibiting the expression level of inflammatory factors, for inhibiting radiation-induced apoptosis of oral epithelial cells, for inhibiting oxidative stress damage, and for inhibiting the activation of the TLR2 / MyD88 / NFκB inflammatory pathway.

[0037] In the present application, inflammatory factors include but are not limited to at least one of TNFα, IL 6, and IL 1β. Sitagliptin treatment can effectively inhibit the expression level of inflammatory factors, providing a new treatment or prevention method for related diseases (including but not limited to radiation oral mucositis) caused by excessive expression of inflammatory factors.

[0038] Studies have shown that there is a correlation between the expression level of radiation-induced oral proinflammatory cytokines and the severity of oral mucositis. In the animal model of radiation-induced oral mucositis, inhibiting the expression of proinflammatory factors, inhibiting the level of oxidative stress, and inhibiting NF-κB can reduce the severity of radiation oral mucositis.

[0039] In the present application, sitagliptin can promote the proliferation of oral epithelial cells, inhibit apoptosis of oral epithelial cells, inhibit oxidative stress, and inhibit the activation of the TLR2 / MyD88 / NFκB inflammatory pathway, thereby inhibiting the expression of inflammatory factors and improving radiation oral mucositis.

[0040] The use of sitagliptin in the treatment of radiation oral mucositis has the characteristics of good therapeutic effect and good safety, which solves the treatment problem of radiation oral mucositis.

[0041] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only intended to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually measured according to national standards. If there is no corresponding national standard, then proceed according to general international standards, conventional conditions, or according to the conditions recommended by the manufacturer.

[0042] Example

[0043] Animal experiment: 30 male C57BL / 6 mice aged 6-8 weeks were randomly divided into 3 groups (control group, radiotherapy group, radiotherapy + sitagliptin group), with 10 mice in each group. The mice were raised normally for 1 week to adapt to the environment. The radiotherapy + sitagliptin group was first given sitagliptin (20 mg / kg) for 3 days, and then, except for the control group, the radiotherapy group and the radiotherapy + sitagliptin group received 20Gy head radiotherapy to construct a radiation oral mucositis model. The radiotherapy + sitagliptin group was given drugs every day, and the weight of mice in each group was weighed to observe the survival of the mice. On the day of taking the index, the mouse tongue tissue was collected for further study. Some fresh tongue tissues of mice were used for transcriptome sequencing to detect the regulatory effect of drugs on gene expression.

[0044] Ten male C57BL / 6 mice aged 6-8 weeks were randomly divided into 2 groups (control group and sitagliptin group). The sitagliptin group was given sitagliptin (20 mg / kg) intervention until the day of index collection. The mice in each group were weighed, and the heart, liver, spleen, lung, kidney and venous blood of the mice were collected for further safety study.

[0045] Experimental results:

[0046] A single 20 Gy head irradiation dose induced radiation oral mucositis in C57BL / 6 mice, with weight loss starting around the fifth day (see Figure 1 ) and ulceration (see Figure 2 In mice treated with sitagliptin, weight loss was improved compared with that in mice treated with radiotherapy, and the area of ​​ulcer formation was also reduced (see Figure 1 , Figure 2 ).

[0047] Tongue histopathological examination of normal mice in the control group showed that the mucosal epithelial structure was intact, while the tongue mucosa of mice with radiotherapy-induced oral mucositis lost its integrity, the stratified squamous epithelium had completely disappeared, and a large number of inflammatory cells infiltrated. These histological changes were significantly improved after treatment with sitagliptin ( Figure 3 ).

[0048] Promoting oral epithelial cell proliferation: After the tongue tissue was fixed, it was embedded in paraffin and sliced ​​for Ki67 staining. The results showed that compared with the control group, radiation significantly inhibited epithelial cell proliferation; compared with the model group, the proliferation of tongue epithelial cells in mice treated with sitagliptin increased ( Figure 4 ).

[0049] Inhibition of radiation-induced apoptosis of tongue epithelial cells: After fixation, tongue tissue was embedded in paraffin and sliced ​​for TUNEL staining. The results showed that radiation significantly promoted epithelial cell apoptosis compared with the control group; compared with the model group, the apoptosis of tongue epithelial cells in mice treated with sitagliptin was reduced ( Figure 5 ).

[0050] Inhibition of radiation-induced oxidative stress: Tongue tissue was frozen in a minus 80 refrigerator, embedded in OCT, and sliced ​​for DHE staining. The results showed that compared with the control group, radiation significantly promoted the production of reactive oxygen species (ROS) in epithelial cells; compared with the model group, the ROS in the tongue epithelial cells of mice treated with sitagliptin was significantly reduced ( Figure 6 ).

[0051] The results of tongue tissue transcriptome sequencing showed that compared with the normal group, the expression of inflammatory factors in the radiotherapy group was significantly increased, including TNFα, IL6, IL1β and other inflammatory factors. Compared with the radiotherapy group, the sitagliptin treatment group had a significant downward trend ( Figure 7 In addition, GO and KEGG enrichment analysis results showed that MyD88-dependent toll-like receptor signaling pathway, toll-like receptor signaling pathway, and NF-kappa B signaling pathway were significantly activated in the radiotherapy group and inhibited in the sitagliptin group ( Figure 8 ). The above results indicate that sitagliptin may inhibit the expression of inflammatory factors through these pathways.

[0052] Western blot results showed that compared with the normal group, TLR2, MyD88 and p65 proteins in the tongue tissue of mice in the radiotherapy group were significantly increased. Compared with the radiotherapy group, these proteins in the sitagliptin treatment group were significantly reduced. This indicates that under the intervention treatment, sitagliptin improves radiation oral mucositis by inhibiting the TLR2 / MyD88 / NFκB inflammatory pathway. Fig. 9 ).

[0053] Safety study: Compared with the control group, the body weight and postprandial blood glucose of mice after sitagliptin intervention had no significant difference, and HE staining of the heart, liver, spleen, lung, and kidney also showed that sitagliptin did not cause organ damage. The above results show that sitagliptin has good safety ( Fig.10 ).

[0054] It should be understood that the endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0055] It should be noted that, in this article, relational terms such as "first" and "second" are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In addition, the term "and / or" appearing in this article is only a kind of association relationship describing associated objects, indicating that there can be three relationships. For example, A and / or B can represent: A exists alone, A and B exist at the same time, and B exists alone.

[0056] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. Use of sitagliptin in the preparation of drugs for treating and / or preventing radiation oral mucositis.

2. The application according to claim 1, characterized in that: The medicament contains a therapeutically effective amount of sitagliptin and a pharmaceutically acceptable carrier and / or excipient.

3. The application according to claim 1, characterized in that: The dosage form of the drug includes at least one of an injection preparation, an oral preparation, a spray preparation and a flushing preparation.

4. The application according to claim 1, characterized in that: In the drug, the sitagliptin has any one or more of the following uses: for inhibiting the expression level of inflammatory factors, for inhibiting radiation-induced apoptosis of oral epithelial cells, for inhibiting oxidative stress damage, and for inhibiting the activation of the TLR2 / MyD88 / NFκB inflammatory pathway.

5. The application according to claim 4, characterized in that: The inflammatory factors include but are not limited to at least one of TNFα, IL 6, and IL 1β.

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