Application of gemcitabine hydrochloride in the preparation of medicines for preventing and / or treating alcoholic gastric ulcer

Abstract

The present invention relates to the field of medical technology, and more particularly to the use of gemcitabine hydrochloride in the preparation of a medicament for preventing and / or treating alcoholic gastric ulcers. Experimental results show that the gemcitabine hydrochloride has significant therapeutic effects on peptic ulcer disease and inflammatory bowel disease, can effectively improve mucosal integrity, promote tissue morphology improvement, and restore animal weight, and has good clinical application prospects.

Description

[0001] This application is a divisional application of the invention patent (CN202110132629.1). The application date of the original application is January 31, 2021, the application number is CN202110132629.1, and the name of the invention is: Use of nucleoside analogs in the preparation of drugs for preventing or treating gastrointestinal diseases. Technical Field

[0002] The present invention relates to the field of medical technology, and in particular to application of gemcitabine hydrochloride in preparing a medicament for preventing and / or treating alcoholic gastric ulcer. Background Art

[0003] Gastrointestinal diseases encompass conditions of the esophagus, stomach, small intestine, colon, and rectum. Common symptoms include rhythmic and cyclical upper abdominal pain, diarrhea, hunger-induced abdominal pain, acid reflux, fever, bloody stools with melena, gastrointestinal bleeding, and intestinal obstruction. Gastrointestinal diseases are among the most common human illnesses, with the most common including dysphagia, gastric ulcers, peptic ulcers, gastroparesis, delayed gastric emptying, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD). Peptic ulcers primarily include gastric ulcers, duodenal ulcers, and combined ulcers. Gastric ulcers are currently believed to be primarily caused by a weakened gastric mucosal barrier and increased gastrin secretion, while duodenal ulcers are primarily caused by an increase in the total volume of parietal cells. Furthermore, exogenous factors such as excessive alcohol consumption, irregular eating habits, chronic mental stress, and long-term use of nonsteroidal anti-inflammatory drugs (such as aspirin), glucocorticoids, and clopidogrel have all been implicated in the development of peptic ulcers. Inflammatory bowel disease (IBD) can be caused by organisms such as bacteria, fungi, viruses, parasites, and protozoa, as well as by allergic reactions and physicochemical factors. Depending on the etiology, it can be divided into specific inflammatory lesions and nonspecific inflammatory lesions. The former refers to infectious colitis, ischemic colitis, and pseudomembranous colitis, while the latter mainly includes ulcerative colitis (UC) and Crohn's disease (CD). UC is an inflammatory bowel disease (IBD), a common condition in gastroenterology that causes long-term inflammation and ulcers in the digestive tract. It is characterized by chronic recurrent intestinal inflammation and intestinal epithelial cell damage. It often occurs in patients between the ages of 20 and 30, and clinical symptoms include diarrhea, abdominal pain, bloody stools, and intestinal obstruction. Numerous studies have shown that the pathogenesis of UC is associated with immune factors, inflammation, environmental genetics, stress, and infection. Gastritis includes chronic gastritis and acute gastritis.

[0004] Currently, the main types of Western medicine used to treat gastrointestinal diseases include prokinetic drugs, antispasmodics, antiemetics, peptic ulcer drugs, gastric mucosal protectants, digestive aids, and proecological preparations. Among them, drugs for treating peptic ulcers mainly include proton pump inhibitors, H2-receptor antagonists, bismuth preparations, and prostaglandins. They mainly neutralize gastric acid by using raw materials containing calcium. Although they can improve and relieve symptoms, it is difficult to completely cure them, the efficacy is unsatisfactory, and they are prone to recurrence. Inflammatory bowel disease is listed as one of the modern intractable diseases by the World Health Organization, and its incidence rate is on the rise worldwide. The pathogenesis of colitis has not yet been fully elucidated. Commonly used drugs for clinical treatment include aminosalicylic acid preparations, glucocorticoids, and immunosuppressants. Short-term use can control the symptoms of colitis, but the cure rate is extremely low. Long-term use can induce a variety of adverse reactions, and discontinuation of the drug can cause recurrence. Severe cases can cause cancer. Therefore, the development of a new drug for the treatment of gastrointestinal diseases is a technical problem that needs to be solved urgently.

[0005] Nucleoside analogs have some special effects. 2'-deoxynucleoside drugs can specifically inhibit the replication of infected viruses. Currently, a large proportion of drugs used clinically to treat viral diseases such as hepatitis, AIDS, and herpes are nucleoside compounds. They generally act as inhibitors of enzymes in the viral replication process, blocking the virus from infecting target cells. Common nucleoside antiviral compounds mainly include lamivudine (3-TC), telbivudine (LDT), zidovudine (AZT), famciclovir (FCV), PMPA, and PMEA. Telbivudine is used for adult patients with chronic hepatitis B who have evidence of viral replication and persistent elevation of serum transaminases (ALT or AST) or active liver tissue lesions. Zidovudine, also known as azidothymidine, is used for the treatment of patients with AIDS or AIDS-related syndromes and immunodeficiency virus (HIV) infection. Zidovudine is the world's first anti-AIDS drug approved by the US FDA. Its mechanism of action is mainly to bind to the viral DNA polymerase, stop the growth of the DNA chain, and thus prevent viral replication. Lamivudine is an antiviral drug that competes with the synthesis and extension of the viral DNA chain. It has a competitive inhibitory effect and is mainly used to treat hepatitis B and liver and gallbladder diseases. It is the most effective and representative nucleoside analog in clinical applications. Acyclovir is a highly effective, low-toxic, broad-spectrum antiviral drug and is currently the first choice for the treatment of herpes. Famciclovir is the first oral drug approved in the United States for recurrent herpes simplex virus infection in AIDS patients. It not only has a high absorption rate in the human body, but also has a long duration of action. It is the only effective drug for reducing post-herpetic neuralgia. Adefovir is an adenine nucleoside derivative with broad-spectrum antiviral activity that can effectively inhibit the replication and expression of retroviral genes.

[0006] In addition to common antiviral nucleoside compounds, some 2' and 3'-deoxynucleoside drugs have been reported to specifically interfere with viral replication and selectively guide diseased cancer cells to differentiate into normal cells.

[0007] Currently, dozens of nucleoside anti-tumor drugs are in clinical use or under investigation. Their primary function is to interfere with tumor DNA synthesis or affect nucleic acid transcription, inhibiting protein synthesis, thereby achieving a therapeutic effect. For example, cytarabine is a pyrimidine antimetabolite that primarily acts on cells during the S phase of proliferation. By inhibiting cellular DNA synthesis, it interferes with cell proliferation. It is primarily used for acute leukemias, with the greatest efficacy against acute myeloid leukemia, but also effective against acute monocytic leukemia and acute lymphoblastic leukemia. It also has some efficacy against malignant lymphomas, lung cancer, gastrointestinal cancer, head and neck cancer, and viral keratitis and epidemic conjunctivitis. Gemcitabine, a new cytosine nucleoside derivative, has a similar mechanism of action to cytarabine. Its primary metabolite is incorporated into DNA intracellularly, primarily acting during the G1 / S phase. Clinically, gemcitabine and cytarabine have different antitumor spectrums and are effective against a variety of solid tumors. They are used as second-line therapy for patients with advanced pancreatic cancer after failure of fluoropyrimidines, improving their lives. They are also used as first-line therapy for locally advanced and metastatic non-small cell lung cancer. Recent data suggest that this drug also has palliative efficacy in ovarian cancer, breast cancer, bladder cancer, cervical cancer, liver cancer, biliary tract cancer, nasopharyngeal carcinoma, testicular tumors, lymphoma, and head and neck cancer.

[0008] At present, researchers are focusing more on the research of nucleosides and their analogs, such as their dosage forms, detection methods, preparation methods, structural modifications and cancer treatment. For example, patent CN201880077576.4 discloses a method for preparing nucleotide analogs and their application in nucleic acid sequence determination; patent CN201780039312.5 discloses a method for nucleic acid detection using reversibly blocked nucleoside analogs; patent CN201810489585.6 discloses a functional nucleic acid with a nucleoside analog drug integrated into its skeleton and its derivatives and their preparation methods; patent CN20141 Patents 0169585.X disclose the use of N-fatty acid phosphates modified with cyclophosphitylation groups and attached to a fatty chain for the treatment of viral hepatitis and liver cancer; Patent CN201910892040.4 discloses drug aptamers constructed from nucleoside analog drug molecules, preparation methods, and their applications; and Patent CN201810077674.X discloses the use of 1,4-disubstituted 1,2,3-triazole nucleoside analogs as anti-tumor drugs, especially for gastric cancer. However, no researchers have conducted research on nucleoside analogs for the treatment of gastrointestinal diseases, nor have any relevant literature or patents disclosed their novel use for treating gastrointestinal diseases. During their research, the inventors unexpectedly discovered that nucleoside analogs have significant therapeutic effects on gastrointestinal diseases and have broad clinical application prospects. Summary of the Invention

[0009] In response to the above technical problems, the present invention discloses the use of nucleoside analogs or their tautomers, mesomers, racemates, enantiomers, diastereoisomers and mixtures thereof, and pharmaceutically acceptable salts thereof in the preparation of drugs for preventing and / or treating gastrointestinal diseases, wherein the gastrointestinal diseases do not include gastric cancer.

[0010] Preferably, the nucleoside analog is selected from any one of a cytosine analog, a thymidine analog, an adenine analog and a guanosine analog.

[0011] Preferably, the cytidine analog is selected from lamivudine, deoxycytidine, gemcitabine hydrochloride, cytarabine hydrochloride, cidofovir, eltracitabine, efcitabine, emtricitabine, acadesin, azacitidine, decitabine, thiarabine, ethynylcytidine, capecitabine, elcitabine, ancitabine, 4-S-β-D-arabinocytidine, 5-aza-4-thio-2-deoxycytidine, Any one of cis-1-[4-(hydroxy-methyl)-cyclopent-2-enyl]-5-I-iodocytosine and cis-1-[4-(hydroxy-methyl)-cyclopent-2-enyl]-5-(2-I-iodovinyl)cytosine; the thymidine nucleoside analogue is selected from zidovudine, telbivudine, sofosbuvir, 5-fluorouracil, deoxyuridine, clevudine, stavudine, flutolan, fufofuran, tegafur, fluorouracil, carmoxidine, telocycline ... Fluorine, 4-thiothymine, 5-taurine methyl-2-S-uridine, 2'-fluoro-5-methyl-β-L-arabinofuranosyl uridine, 2,3-thymine dideoxycarbocyclic nucleoside derivatives, 3-benzoylthymine and trifluorothymidine; the adenine nucleoside analogue is selected from adenosine, deoxyadenosine, deoxyadenosine, famciclovir, telofovir, telofovir dipivoxil, telofovir disoproxil fumarate, adefovir, adefovir dipivoxil, dihydroflavone Any one of adefovir phosphate, adefovir, clofarabine, cladribine, troxacitabine, aristeromycin and neplanocin A; the guanine nucleoside analog is selected from any one of 8-hydroxy-2-deoxyguanosine nucleoside, acyclovir, ganciclovir, entecavir, entecavir triphosphate, LB80380 / ANA380, nelarabine, 9-β-D-arabinofuranosylguanine, forodesine hydrochloride, mercaptoguanine, 6-mercaptoguanine, 6-thioguanine, 6-thioguanine nucleotide, 2-deoxyguanosine monophosphate and 5-(2-furyl)-2-deoxyguanosine.

[0012] Preferably, the cytidine nucleoside analog is selected from lamivudine or gemcitabine hydrochloride; the thymidine nucleoside analog is selected from zidovudine or telbivudine; the adenine nucleoside analog is selected from famciclovir, telofovir dipivoxil or adefovir dipivoxil; the guanine nucleoside analog is selected from acyclovir or 6-thioguanine.

[0013] Preferably, the gastrointestinal disease is peptic ulcer.

[0014] Preferably, the peptic ulcer is one or more of gastric ulcer, duodenal ulcer, postbulbar ulcer, pyloric ulcer, combined ulcer and kissing ulcer.

[0015] Preferably, the peptic ulcer is gastric ulcer and duodenal ulcer.

[0016] Preferably, the gastrointestinal disease is inflammatory bowel disease.

[0017] Preferably, the inflammatory bowel disease is ulcerative colitis and Crohn's disease.

[0018] Preferably, the nucleoside analog or its tautomers, mesomers, racemates, enantiomers, diastereomers and mixtures thereof, and pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers constitute a pharmaceutical composition, and the dosage form of the pharmaceutical composition is injection, tablet, capsule, granule or pill.

[0019] The beneficial effects of the present invention are as follows: the present invention provides the use of nucleoside analogs in the preparation of drugs for preventing or treating gastrointestinal diseases, and specifically provides some classic nucleoside analogs such as lamivudine, telbivudine, famciclovir, telofovir dipivoxil, adefovir dipivoxil, acyclovir, gemcitabine hydrochloride, zidovudine and 6-mercaptoguanine. Under different feeding conditions, DAI scores and colon morphology measurements are performed on colitis mice, and the results show that drugs such as lamivudine, telbivudine, famciclovir, telofovir dipivoxil, adefovir dipivoxil, acyclovir, gemcitabine hydrochloride, zidovudine and 6-mercaptoguanine are all effective for ulcerative colitis. At the same time, under different feeding conditions, ulcer index, inhibition rate and tissue morphology examination were performed on mice with gastric ulcers. The experimental results showed that lamivudine, telbivudine, famciclovir, telofovir dipivoxil, adefovir dipivoxil, acyclovir, gemcitabine hydrochloride, zidovudine and 6-mercaptoguanine all have the effect of preventing and treating gastric ulcers, and the effects of most drugs are stronger than the efficacy of the existing clinical drug cimetidine. That is, the nucleoside analogs lamivudine, telbivudine, famciclovir, telofovir dipivoxil, adefovir dipivoxil, acyclovir, gemcitabine hydrochloride, zidovudine and 6-mercaptoguanine described in the present invention are effective for both ulcerative colitis and gastric ulcers, and the therapeutic effect is 40 times higher than that of existing clinical drugs, and has good clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 Effects of lamivudine on body weight and DAI scores in C57BL / 6N colitis mice;

[0021] Figure 2 Effects of lamivudine on colon morphology and colon length in C57BL / 6N colitis mice;

[0022] ### p<0.001 vs. Control group; *p<0.05, **p<0.01 and ***p<0.001 vs. DSS group.

[0023] Figure 3 Effects of lamivudine on gastric tissue morphology in mice with gastric ulcer;

[0024] Figure 4 The effect of lamivudine on gastric ulcer index, gastric ulcer area and gastric ulcer inhibition rate;

[0025] ### p<0.001 vs. Control group; **p<0.01 and ***p<0.001 vs. Ethanol group.

[0026] Figure 5 Effects of adefovir dipivoxil, telofovir dipivoxil, famciclovir, and telbivudine on body weight, DAI score, colon morphology, and colon length in KM colitis mice;

[0027] ### p<0.001 vs. blank control group; *p<0.05, **p<0.01 and ***p<0.001 vs. DSS model group.

[0028] Figure 6 Effects of acyclovir, gemcitabine hydrochloride, zidovudine, and 6-thioguanine on body weight, DAI score, colon morphology, and colon length in KM colitis mice;

[0029] ### p<0.001 vs. blank control group; *p<0.05, **p<0.01 and ***p<0.001 vs. DSS model group.

[0030] Figure 7 Effects of telbivudine, gemcitabine hydrochloride, and zidovudine on gastric tissue morphology, ulcer index, ulcer area, and ulcer inhibition rate in KM gastric ulcer mice;

[0031] ### p<0.001 vs. blank control group; *p<0.05, **p<0.01 and ***p<0.001 vs. ethanol model group.

[0032] Figure 8 Effects of adefovir dipivoxil, telofovir dipivoxil, acyclovir, famciclovir and 6-thioguanine on gastric tissue morphology, ulcer index, ulcer area and ulcer inhibition rate in KM gastric ulcer mice;

[0033] ### p<0.001 vs. blank control group; *p<0.05, **p<0.01 and ***p<0.001 vs. ethanol model group. DETAILED DESCRIPTION

[0034] The scope of protection of the present invention is described in detail below with reference to specific examples. However, it should be noted that the scope of protection of the present invention is not limited to the following examples. The scope of protection of the present invention also protects the therapeutic effects of a class of nucleoside analogs in all gastrointestinal diseases, especially peptic ulcer disease and inflammatory bowel disease, including different dosage forms, dosages, and combination therapies. Any technical solutions derived by those skilled in the art based on the principles of the present invention through logical analysis, inference, and experimentation on the existing technology shall fall within the scope of protection claimed by the present invention.

[0035] It should be understood that the above summary and the following detailed description are exemplary and explanatory only and do not limit the subject matter of the present invention in any way. In this application, it must be noted that unless otherwise clearly indicated, the singular forms used in this specification and claims include the plural forms of the referents. It should also be noted that unless otherwise indicated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "comprising", "including" and "containing" are not limiting.

[0036] The C57BL / 6N mouse described in the present invention is one of the most widely used strains of mice and is also the mother of transgenic or gene knockout mice most commonly used in genetic engineering.

[0037] The KM mice described in the present invention refer to Kunming mice.

[0038] The following examples of the present invention use dextran sulfate sodium for the establishment of a colitis model in mice.

[0039] In the following examples of the present invention, the indications of sulfasalazine enteric-coated tablets are (1) ulcerative colitis for the treatment of mild to moderate ulcerative colitis; it can be used as an adjuvant therapy in severe ulcerative colitis. It can also be used for maintenance treatment of ulcerative colitis in the remission phase; (2) Crohn's disease for the treatment of active Crohn's disease, especially those involving the colon; (3) rheumatoid arthritis for rheumatoid arthritis and juvenile rheumatoid arthritis (polyarticular type) that are not significantly responsive to salicylates or other nonsteroidal anti-inflammatory drugs. In Example 1 of the present invention, sulfasalazine enteric-coated tablets are used as the positive drug.

[0040] Cimetidine, also known as cimetidine, in the following embodiments of the present invention is a histamine H2 receptor antagonist that is primarily used to inhibit gastric acid secretion. It can significantly inhibit basal and nocturnal gastric acid secretion, as well as gastric acid secretion caused by stimulation such as histamine, gastrin, insulin, and food, and reduces its acidity. It has a preventive and protective effect on corrosive gastritis caused by chemical stimulation, and also has a significant therapeutic effect on stress-induced gastric ulcers and upper gastrointestinal bleeding. In the embodiments of the present invention, cimetidine is used as a positive drug.

[0041] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0042] The term "pharmaceutical composition" refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component or agent, namely a "carrier", which facilitates the introduction of the compound into cells or tissues, including but not limited to stabilizers, diluents, suspending agents, thickening agents and / or excipients.

[0043] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acid and free base of the specified compound and has no adverse biological or other effects. Unless otherwise indicated, the salts of the present invention may include metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, and the like.

[0044] Pharmaceutically acceptable salts can be synthesized from parent compounds containing acid or basic groups by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0045] The term "treat" and other similar synonyms include alleviating, reducing or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, such as preventing the development of the disease or condition, alleviating the disease or condition, making the disease or condition better, alleviating the symptoms caused by the disease or condition, or stopping the symptoms of the disease or condition. In addition, the term may also include the purpose of prevention. The term also includes obtaining a therapeutic effect and / or a prophylactic effect. The therapeutic effect refers to curing or improving the underlying disease being treated. In addition, the cure or improvement of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, the patient's condition is observed to improve. In terms of prophylactic effect, the composition or compound can be administered to a patient at risk for a particular disease, or even if a diagnosis of the disease has not yet been made, the composition or compound can be administered to a patient who has one or more physiological symptoms of the disease.

[0046] In the following examples of the present invention, the specific small molecule active compounds are shown in Table 1.

[0047] Table 1 List of active small molecules in the examples

[0048]

[0049]

[0050] Example 1: Therapeutic Effect of Lamivudine on C57BL / 6N Colitis Mice

[0051] 1. Animal feeding

[0052] SPF-grade healthy male C57BL / 6N mice, weighing 18-22 g, were provided by the Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, and were drug-naive. The animals were acclimated for one week in an environment with a 12-hour day / night cycle and a temperature of 24-26°C. They were provided with free access to food and water before being grouped for the experiments.

[0053] 2. Drugs and reagents

[0054] Lamivudine (3-TC, HPLC ≥ 98%) was purchased from MacLean Biotechnology Co., Ltd., batch number: C10102050, molecular weight 229.25; salazosulfapyridine enteric-coated tablets (SASP) were purchased from Shanghai Xinyi Tianping Pharmaceutical Co., Ltd.; dextran sulfate sodium (DSS), MW: 40000, was purchased from Aladdin Biotechnology Co., Ltd.

[0055] 3. Experimental Grouping and Oral Administration Dosage

[0056] Forty 8-week-old male C57BL / 6N mice were randomly divided into five groups according to body weight, with 8 mice in each group. The grouping and dosage were as follows:

[0057] Normal control group (Control, oral administration of equal volume of 0.9% normal saline);

[0058] Normal mice were given lamivudine (C+3-TC, dosage 2mg / kg / day)

[0059] DSS model control group (DSS, orally administered with an equal volume of 0.9% saline);

[0060] positive drug group (SASP, oral administration of sulfasalazine, 80 mg / kg / day);

[0061] The model mice were given lamivudine (D+3-TC, dosage was 2 mg / kg / day).

[0062] 4. Preparation of Ulcerative Colitis Model

[0063] A 4% DSS distilled water solution was prepared, and the mice in the DSS model group drank the DSS water solution freely to establish the model, and maintained regular feed for 7 consecutive days.

[0064] 5. Time and method of administration

[0065] Mice in the DSS control group were given free access to DSS solution to establish the DSS model, while mice in the DSS+3-TC group were given free access to DSS solution to establish the DSS model and were also given 2 mg / kg / day of 3-TC. Mice in the DSS+SASP group were given free access to DSS solution to establish the DSS model and were also given 80 mg / kg / day of SASP. Mice in the blank control group were given free access to distilled water, while mice in the blank control+3-TC group were given 2 mg / kg / day of 3-TC to establish the DSS model. All mice were fed a regular diet for 7 consecutive days. Serum and colon tissue were isolated 2 hours after the last dose on the seventh day for future use.

[0066] 6. Clinical indicator detection of ulcerative colitis

[0067] 6.1 Weight Loss

[0068] The score was calculated based on the percentage (%) of body weight loss of each mouse: no weight loss was scored as 0 points, 1%-5% weight loss was scored as 1 point, 6%-10% weight loss was scored as 2 points, 11%-15% weight loss was scored as 3 points, and weight loss greater than 15% was scored as 4 points.

[0069] 6.2 Stool consistency

[0070] Normal stool was scored as 0 points, loose stool as 2 points, and diarrhea as 4 points.

[0071] 6.3 Blood in stool and occult blood

[0072] Normal stool score is recorded as 0 points, occult blood is recorded as 1 point (judged according to the occult blood test results), and blood in stool visible to the naked eye is recorded as 3 points. The average of the above three items is DAI.

[0073] 6.4 Measurement of colon length

[0074] After killing the mice, the colon was separated. The ileum was cut at the junction of the ileum and colon, and then the colon was cut near the anus. The fascia outside the colon was separated to fully stretch the colon. The length of the mouse colon from the ileum to the anus was measured with a ruler and photographed for record.

[0075] 7. Data Processing

[0076] The experimental data were statistically analyzed using SPSS 23.0 software. Data are expressed as (x ± s). One-way ANOVA and the LSD-t method were used for pairwise comparisons between groups. p < 0.05 was considered statistically significant.

[0077] 8. Results Analysis

[0078] 8.1 Effects of lamivudine on body weight and disease activity index in C57BL / 6N colitis mice

[0079] During the experiment, the weight, stool viscosity, blood in stool and occult blood of the above mice were monitored, and the data were statistically analyzed by one-way analysis of variance using SPSS23.0 software.

[0080] The significant differences in weight and DAI scores of mice in each group are indicated as *p<0.05, **p<0.01 and ***p<0.001. The weight differences and DAI scores of mice in each group of different strains of UC mice are shown in Figure 1 .

[0081] As can be seen from the above data, compared with the blank control group, the blank control + lamivudine group showed no statistical difference in body weight and DAI score indicators, indicating that lamivudine has no toxic side effects on normal mice; compared with the blank control group, the body weight of the DSS model group decreased significantly, which is consistent with the law of weight loss in patients with colitis, and the DAI score showed a significant upward trend (###p<0.001), indicating that the DSS model was successfully prepared; compared with the DSS model control group, both the sulfasalazine group and the lamivudine group could significantly improve body weight loss and DAI score (*p<0.05), and the efficacy of lamivudine was stronger than that of the clinical drug sulfasalazine.

[0082] 8.2 Effects of lamivudine on colon morphology and length in C57BL / 6N colitis mice

[0083] After the mice in each group were sacrificed, their colon tissues were quickly removed to observe their morphological changes and measure their lengths. The data of each group were statistically analyzed. Significant differences in colon length between groups of mice are indicated as *p<0.05, **p<0.01, and ***p<0.001. The results of colon morphology and colon length monitoring of each group of mice with UC colitis are shown in Figure 2 .

[0084] Compared with the blank control group, there was no significant change in the colon length of mice in the blank control + lamivudine treatment group, indicating that lamivudine has no toxic side effects on normal mice; compared with the blank control group, the colon length of the DSS model group was significantly shortened (###p<0.001), indicating that the DSS model was successfully prepared; compared with the DSS model control group, both the sulfasalazine treatment group and the lamivudine treatment group could significantly improve colon edema and shortening, with significant differences (*p<0.05 and ***p<0.001), and the efficacy of lamivudine was stronger than that of the clinical drug sulfasalazine.

[0085] The weight difference, DAI score, colon morphology and colon length measurements showed that lamivudine had a therapeutic effect on DSS-induced colitis mice without obvious toxic side effects, and its efficacy was significantly stronger than that of the clinical drug sulfasalazine. Example 2: Therapeutic effect of lamivudine on KM gastric ulcer mice

[0086] 1. Source of experimental animals

[0087] Experimental animals: 8-week-old, SPF-grade Kunming (KM) male mice weighing 18–22 g were purchased from the Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, and had not received any medication prior to the experiment. The animals were acclimated for one week in an environment with a 12-hour day / night cycle and a temperature of 24–26°C. They were provided with a diet and free access to distilled water before being divided into groups for the experiments.

[0088] 2. Drugs and reagents

[0089] Lamivudine (3-TC, HPLC≥98%) was purchased from MacLean Biotechnology Co., Ltd.; anhydrous ethanol was purchased from Tianjin Damao Chemical Reagent Co., Ltd.; and cimetidine tablets (CIM) were purchased from Shanghai Xinyi Tianping Pharmaceutical Co., Ltd.

[0090] 3. Preparation of Alcoholic Gastric Ulcer Model in KM Mice

[0091] Forty KM male mice (20-25 g) were housed in the experimental animal room of Lanzhou University. After one week of adaptive feeding, the mice were randomly divided into five groups, with eight mice in each group. The grouping and drug dosage are shown in Table 2.

[0092] Table 2 Experimental groups of KM male mice and the dosage of each group

[0093] Group Dosage Blank control group 0.3 mL / mouse oral administration of 0.9% saline Blank+lamivudine 2mg / kg / day 3-TC was administered by injection, and 2 hours later 0.3mL / animal was gavaged with normal saline Ethanol model group 0.3 mL / mouse oral administration of anhydrous ethanol Cimetidine positive group 80 mg / kg / day of cimetidine was administered orally, and 2 hours later, 0.3 mL of anhydrous ethanol was administered orally per mouse. Lamivudine group 2mg / kg / day 3-TC was administered by injection, and 2 hours later, 0.3mL / animal was gavaged with anhydrous ethanol

[0094] The experiment was terminated after 2 hours of stimulation in each group of mice, and the serum and gastric tissues were separated to measure various indicators.

[0095] 4. Ulcer area, ulcer index and inhibition rate

[0096] The stomach was taken out and cut open along the greater curvature of the stomach. The contents were rinsed clean and the gastric mucosal ulcer was observed. The horizontal and vertical diameters of the ulcer were measured with a ruler. The product of the two was the ulcer area (mm 2 ), as shown in Formula 1; the ulcer area of ​​the entire gastric tissue was then calculated, and the ulcer inhibition rate (%) was calculated, as shown in Formula 2. The mean of the sum of the ulcer points in each group of mice was used as the ulcer index (healing was scored as 0, superficial mucosal erosion was scored as 1, deep ulcer or transmural necrosis was scored as 2, and perforation or penetrating ulcer was scored as 3).

[0097] Ulcer area (mm2) = maximum length of ulcer * maximum width perpendicular to the maximum length (1)

[0098]

[0099] 5. Data Processing

[0100] The experimental data were statistically analyzed using SPSS 23.0 software. Data are expressed as (x ± s). One-way ANOVA and the LSD-t method were used for pairwise comparisons between groups. p < 0.05 was considered statistically significant.

[0101] 6. Effects of lamivudine on gastric tissue morphology, ulcer index, ulcer area and ulcer inhibition rate in mice with gastric ulcer

[0102] After the mice in each group were killed, their gastric tissues were quickly taken to observe their morphological changes and ulcer damage, and their ulcer areas and ulcer indices were statistically analyzed. The experimental results are shown in Table 2. Figure 3 and Figure 4 As shown. Figure 3It can be seen that the macroscopic morphology of the gastric tissue of the normal group mice and the normal group given lamivudine was normal, without obvious hemorrhagic lesions, while the gastric tissue of the ethanol model group mice was obviously hemorrhagic, and the ulcers were the most severe, indicating that the ethanol gastric ulcer model was successfully prepared. At the same time, lamivudine had no obvious damaging effect on the gastric tissue of healthy mice; compared with the ethanol model group, the lamivudine and cimetidine groups were able to significantly improve the degree of damage to the gastric mucosa and reduce the ulcer area, and the ulcer inhibition rate of lamivudine (79.2%) was higher than the ulcer inhibition rate of the clinical drug cimetidine (CIM) (73.25%). The above-mentioned ulcer area, ulcer index and inhibition rate, as well as gastric tissue morphological measurements show that lamivudine is effective in preventing and treating gastric ulcers, and its efficacy is significantly stronger than that of the clinical drug cimetidine. Example 3. The therapeutic effect of adefovir dipivoxil, telofovir dipivoxil, famciclovir and telbivudine on KM colitis mice 1. Drugs and reagents

[0103] Telofovir disoproxil fumarate (PMPA, HPLC ≥ 98%), adefovir disoproxil fumarate (PMEA, HPLC ≥ 98%), famciclovir (FCV, HPLC ≥ 98%), and telbivudine (LDT, HPLC ≥ 98%) were purchased from Aladdin Biotechnology Co., Ltd.; sulfasalazine enteric-coated tablets (Salazosulfapyridine, SASP) were purchased from Shanghai Xinyi Tianping Pharmaceutical Co., Ltd.; dextran sulfate sodium (DSS), MW: 40000, was purchased from Aladdin Biotechnology Co., Ltd.

[0104] 2. Experimental grouping and dosage: Standard weight KM male mice were randomly divided into 7 groups, 8 mice in each group. The grouping and dosage were as follows:

[0105] Normal control group (Control, oral administration of equal volume of 0.9% normal saline);

[0106] DSS model control group (DSS, orally administered with an equal volume of 0.9% saline);

[0107] positive drug group (SASP, oral administration of sulfasalazine, 80 mg / kg / day);

[0108] Telofovir disoproxil fumarate group (PMPA, dose of 2 mg / kg / day, intraperitoneal injection);

[0109] Adefovir dipivoxil group (PMEA, dosage 2 mg / kg / day, intraperitoneal injection);

[0110] famciclovir group (FCV, dose of 2 mg / kg / day, intraperitoneal injection);

[0111] Telbivudine group (LDT, dosage of 2 mg / kg / day, intraperitoneal injection).

[0112] 3. Preparation of ulcerative colitis model and clinical index detection methods are as shown in "4-6 Experimental Methods" in Example 1.

[0113] 4. Results Analysis

[0114] During the experiment, the weight, stool viscosity, blood in stool and occult blood, colon morphology and length of the mice in the above groups were monitored, and the data were statistically analyzed by one-way analysis of variance using SPSS23.0 software. Figure 5 It can be seen that compared with the blank control group, the body weight of the DSS model group was significantly reduced, which is consistent with the law of weight loss in patients with colitis. The DAI score showed a significant upward trend (###p<0.001), and the colon length was significantly shortened (###p<0.001), indicating that the DSS model was successfully prepared; compared with the DSS model control group, the telofovir dipivoxil, adefovir dipivoxil, telbivudine and famciclovir administration groups were able to significantly improve weight loss, DAI score, colon edema and shortening, indicating that telofovir dipivoxil, adefovir dipivoxil, telbivudine and famciclovir have therapeutic effects on ulcerative colitis, among which the efficacy of telbivudine is stronger than that of the clinical drug sulfasalazine. Example 4 The therapeutic effect of acyclovir, gemcitabine hydrochloride, zidovudine and 6-thioguanine on KM colitis mice

[0115] 1. Drugs and reagents

[0116] Gemcitabine hydrochloride (Gemzar, HPLC ≥ 98%), zidovudine / 3-azido-3-deoxythymidine (AZT, HPLC ≥ 98%), and 6-thioguanine (6-TG, HPLC ≥ 98%) were purchased from Aladdin Biotechnology Co., Ltd.; acyclovir (ACV, HPLC ≥ 97%) was purchased from MacLean Biotechnology Co., Ltd.; salazosulfapyridine enteric-coated tablets (SASP) were purchased from Shanghai Xinyi Tianping Pharmaceutical Co., Ltd.; dextran sulfate sodium (DSS), MW: 40000, was purchased from Aladdin Biotechnology Co., Ltd.

[0117] 2. Experimental grouping and dosage: Standard weight KM male mice were randomly divided into 7 groups, 8 mice in each group. The grouping and dosage were as follows:

[0118] Normal control group (Control, oral administration of equal volume of 0.9% normal saline);

[0119] DSS model control group (DSS, orally administered with an equal volume of 0.9% saline);

[0120] positive drug group (SASP, oral administration of sulfasalazine, 80 mg / kg / day);

[0121] gemcitabine hydrochloride group (Gemzar, dosage 2 mg / kg / day, intraperitoneal injection);

[0122] Zidovudine group (AZT, dosage 2 mg / kg / day, intraperitoneal injection);

[0123] acyclovir group (ACV, dose of 2 mg / kg / day, intraperitoneal injection);

[0124] 6-thioguanine group (6-TG, dosage of 2 mg / kg / day, administered by oral gavage).

[0125] 3. Preparation of ulcerative colitis model and clinical index detection methods are as shown in "4-6 Experimental Methods" in Example 1.

[0126] 4. Results Analysis

[0127] During the experiment, the body weight, stool viscosity, blood in stool and occult blood, colon morphology and length of the mice in the above groups were monitored, and the data were statistically analyzed by one-way analysis of variance using SPSS23.0 software.

[0128] Depend on Figure 6 It can be seen that compared with the blank control group, the DAI score showed a significant upward trend (###p<0.001), and the colon length was significantly shortened (###p<0.001), indicating that the DSS model was successfully established. Compared with the DSS model control group, the acyclovir, gemcitabine hydrochloride, zidovudine and 6-thioguanine treatment groups all significantly increased the DAI score (***p<0.001, **p<0.01, *p<0.05 and *p<0. 05), improved colon edema and shortening (***p<0.001, **p<0.01, **p<0.01 and **p<0.01), indicating that acyclovir, gemcitabine hydrochloride, zidovudine and 6-mercaptoguanine have therapeutic effects on ulcerative colitis, among which the efficacy of acyclovir is stronger than that of the clinical drug sulfasalazine. The comparison of the efficacy of each drug-administered group is: acyclovir>sulfasalazine>6-mercaptoguanine>gemcitabine hydrochloride>zidovudine.

[0129] Example 5: Protective Effects of Telbivudine, Gemcitabine Hydrochloride, and Zidovudine on KM Gastric Ulcer Mice

[0130] 1. Source of experimental animals

[0131] Experimental animals: 8-week-old SPF male Kunming (KM) mice weighing 18-22 g were purchased from the Lanzhou Veterinary Research Institute of the Chinese Academy of Agricultural Sciences without any medication before the experiment.

[0132] 2. Drugs and reagents

[0133] Gemcitabine hydrochloride (Gemzar, HPLC ≥ 98%), zidovudine / 3-azido-3-deoxythymidine (AZT, HPLC ≥ 98%), and telbivudine (LDT, HPLC ≥ 98%) were purchased from Aladdin Biotechnology Co., Ltd.; anhydrous ethanol was purchased from Tianjin Damao Chemical Reagent Company; and cimetidine tablets (CIM) were purchased from Shanghai Xinyi Tianping Pharmaceutical Co., Ltd.

[0134] 3. Preparation of Alcoholic Gastric Ulcer Model in KM Mice

[0135] Forty-eight KM male mice (20-25 g) were housed in the experimental animal room of Lanzhou University. After one week of adaptive feeding, the mice were randomly divided into six groups, with eight mice in each group. The grouping and drug dosage are shown in Table 3.

[0136] Table 3 Experimental groups of KM male mice and the dosage of each group

[0137] Group Dosage Blank control group 0.25 mL / mouse oral administration of 0.9% saline Ethanol model group 0.25mL / mouse oral administration of anhydrous ethanol Cimetidine positive group 80 mg / kg / day of cimetidine was administered orally, and 2 hours later, 0.25 mL of anhydrous ethanol was administered orally per mouse. Gemcitabine group 2mg / kg / day Gemzar was injected, and 2 hours later, 0.25mL / animal was gavaged with anhydrous ethanol Zidovudine group AZT was administered by injection at 2 mg / kg / day, and 0.25 mL / animal was gavage-administered with anhydrous ethanol 2 hours later. Telbivudine group 2mg / kg / day LDT was administered by injection, and 2 hours later, 0.25mL / animal was gavaged with anhydrous ethanol

[0138] The experiment was ended 2 hours after the ethanol stimulation of the mice in the above groups, and the serum and gastric tissue were separated to measure various indicators.

[0139] 4. Ulcer area, ulcer index and inhibition rate

[0140] The stomach was taken out and cut open along the greater curvature of the stomach. The contents were rinsed clean and the gastric mucosal ulcer was observed. The horizontal and vertical diameters of the ulcer were measured with a ruler. The product of the two was the ulcer area (mm 2 ), as shown in Formula 1; the ulcer area of ​​the entire gastric tissue was then calculated, and the ulcer inhibition rate (%) was calculated, as shown in Formula 2. The mean of the sum of the ulcer points in each group of mice was used as the ulcer index (healing was scored as 0, superficial mucosal erosion was scored as 1, deep ulcer or transmural necrosis was scored as 2, and perforation or penetrating ulcer was scored as 3).

[0141] Ulcer area (mm2) = maximum length of ulcer * maximum width perpendicular to the maximum length (1)

[0142]

[0143] 5. Data Processing

[0144] The experimental data were statistically analyzed using SPSS 23.0 software. Data are expressed as (x ± s). One-way ANOVA and the LSD-t method were used for pairwise comparisons between groups. p < 0.05 was considered statistically significant.

[0145] 6. Effects of telbivudine, gemcitabine hydrochloride, and zidovudine on gastric tissue morphology, ulcer index, ulcer area, and ulcer inhibition rate in mice with gastric ulcer

[0146] After the mice in each group were killed, their gastric tissues were quickly taken to observe their morphological changes and ulcer damage, and their ulcer areas and ulcer indices were statistically analyzed. The experimental results are shown in Table 2. Figure 7 As shown. Figure 7 The results showed that the gastric tissue of the mice in the normal group showed normal macroscopic morphology and no obvious hemorrhagic lesions, while the gastric tissue of the mice in the ethanol model group showed obvious hemorrhagic lesions and the most severe ulcers, indicating that the ethanol gastric ulcer model was successfully established. Compared with the ethanol model group, the telbivudine, gemcitabine hydrochloride, zidovudine, and cimetidine groups all significantly improved the degree of gastric mucosal damage and reduced the ulcer area. Among them, the ulcer inhibition rate of gemcitabine hydrochloride (91.02%) and zidovudine (84.47%) were higher than the ulcer inhibition rate of the clinical drug cimetidine (CIM) (65.25%). The above-mentioned ulcer area, ulcer index and inhibition rate, as well as gastric tissue morphological measurements, showed that telbivudine, gemcitabine hydrochloride, and zidovudine are effective in preventing and treating gastric ulcers.

[0147] Example 6: Protective Effects of Adefovir Dipivoxil, Telofovir Dipivoxil, Acyclovir, Famciclovir, and 6-Mercaptoguanine on KM Gastric Ulcer Mice

[0148] 1. Source of experimental animals

[0149] Experimental animals: 8-week-old SPF male Kunming (KM) mice weighing 18-22 g were purchased from the Lanzhou Veterinary Research Institute of the Chinese Academy of Agricultural Sciences without any medication before the experiment.

[0150] 2. Drugs and reagents

[0151] Tilofovir disoproxil (PMPA, HPLC ≥ 98%), adefovir disoproxil (PMEA, HPLC ≥ 98%), famciclovir (FCV, HPLC ≥ 98%) and 6-thioguanine (6-TG, HPLC ≥ 98%) were purchased from Aladdin Biotechnology Co., Ltd.; acyclovir (ACV, HPLC ≥ 97%) was purchased from MacLean Biotechnology Co., Ltd.; anhydrous ethanol was purchased from Tianjin Damao Chemical Reagent Co., Ltd.; cimetidine tablets (CIM) were purchased from Shanghai Xinyi Tianping Pharmaceutical Co., Ltd.

[0152] 3. Preparation of Alcoholic Gastric Ulcer Model in KM Mice

[0153] 64 KM male mice (20-25 g) were housed in the experimental animal room of Lanzhou University. After one week of adaptive feeding, the mice were randomly divided into 8 groups, with 8 mice in each group. The grouping and drug dosage are shown in Table 4.

[0154] Table 4 Experimental groups of KM male mice and the dosage of each group

[0155] Group Dosage Blank control group 0.25 mL / mouse oral administration of 0.9% saline Ethanol model group 0.25mL / mouse oral administration of anhydrous ethanol Cimetidine positive group 80 mg / kg / day of cimetidine was administered orally, and 2 hours later, 0.25 mL of anhydrous ethanol was administered orally per mouse. Adefovir dipivoxil group 2mg / kg / day PMEA was administered by injection, and 0.25mL / animal was gavage with anhydrous ethanol 2 hours later. Telofovir disoproxil group 2mg / kg / day PMPA was injected, and 2 hours later, 0.25mL / animal was gavaged with anhydrous ethanol Acyclovir group 2mg / kg / day ACV injection, 2 hours later 0.25mL / animal anhydrous ethanol gavage Famciclovir group 2mg / kg / day FCV injection, 2 hours later, 0.25mL / animal anhydrous ethanol gavage 6-thioguanine group 2mg / kg / day 6-TG was administered by injection, and 0.25mL / animal was gavage-administered with anhydrous ethanol 2 hours later.

[0156] The experiment was ended 2 hours after the ethanol stimulation of the mice in the above groups, and the serum and gastric tissue were separated to measure various indicators.

[0157] 4. Ulcer area, ulcer index and inhibition rate

[0158] The stomach was taken out and cut open along the greater curvature of the stomach. The contents were rinsed clean and the gastric mucosal ulcer was observed. The horizontal and vertical diameters of the ulcer were measured with a ruler. The product of the two was the ulcer area (mm 2 ), as shown in Formula 1; the ulcer area of ​​the entire gastric tissue was then calculated, and the ulcer inhibition rate (%) was calculated, as shown in Formula 2. The mean of the sum of the ulcer points in each group of mice was used as the ulcer index (healing was scored as 0, superficial mucosal erosion was scored as 1, deep ulcer or transmural necrosis was scored as 2, and perforation or penetrating ulcer was scored as 3).

[0159] Ulcer area (mm2) = maximum length of ulcer * maximum width perpendicular to the maximum length (1)

[0160]

[0161] 5. Data Processing

[0162] The experimental data were statistically analyzed using SPSS 23.0 software. Data are expressed as (x ± s). One-way ANOVA and the LSD-t method were used for pairwise comparisons between groups. p < 0.05 was considered statistically significant.

[0163] 6. Effects of adefovir dipivoxil, telofovir dipivoxil, acyclovir, famciclovir and 6-thioguanine on gastric tissue morphology, ulcer index, ulcer area and ulcer inhibition rate in mice with gastric ulcer

[0164] After the mice in each group were killed, their gastric tissues were quickly taken to observe their morphological changes and ulcer damage, and their ulcer areas and ulcer indices were statistically analyzed. The experimental results are shown in Table 2. Figure 8 As shown. Figure 8The gastric tissue of mice in the normal group showed normal macroscopic morphology and no obvious hemorrhagic lesions, while the gastric tissue of mice in the ethanol model group showed obvious hemorrhagic lesions and the most severe ulcers, indicating that the ethanol gastric ulcer model was successfully established. Compared with the ethanol model group, adefovir dipivoxil, telofovir dipivoxil, acyclovir, famciclovir, 6-mercaptoguanine, and cimetidine significantly improved the degree of gastric mucosal damage, reduced the ulcer area, and inhibited the ulcer degree by more than 50%. The comparison of each drug group with the positive drug cimetidine was as follows: 6-mercaptoguanine > telofovir dipivoxil > famciclovir > acyclovir > cimetidine > adefovir dipivoxil. The above-mentioned ulcer area, ulcer index, inhibition rate, and gastric tissue morphology measurements indicate that adefovir dipivoxil, telofovir dipivoxil, acyclovir, famciclovir, and 6-mercaptoguanine are effective in preventing and treating gastric ulcers.

[0165] In summary, the nucleoside analogs lamivudine, telbivudine, famciclovir, telofovir dipivoxil, adefovir dipivoxil, acyclovir, gemcitabine hydrochloride, zidovudine and 6-mercaptoguanine described in the present invention were used to perform DAI scoring and colon morphology measurement on colitis mice under different feeding conditions. The results showed that lamivudine, telbivudine, famciclovir, telofovir dipivoxil, adefovir dipivoxil, acyclovir, gemcitabine hydrochloride, zidovudine and 6-mercaptoguanine were all effective for ulcerative colitis. At the same time, under different feeding conditions, ulcer index, inhibition rate and tissue morphology examination were performed on mice with gastric ulcers. The experimental results showed that lamivudine, telbivudine, famciclovir, telofovir dipivoxil, adefovir dipivoxil, acyclovir, gemcitabine hydrochloride, zidovudine and 6-mercaptoguanine have the effect of preventing and treating gastric ulcers, and the effects of most drugs are stronger than the efficacy of the existing clinical drug cimetidine. That is, the nucleoside analogs lamivudine, telbivudine, famciclovir, telofovir dipivoxil, adefovir dipivoxil, acyclovir, gemcitabine hydrochloride, zidovudine and 6-mercaptoguanine described in the present invention are effective for both ulcerative colitis and gastric ulcers, and have good clinical application prospects.

[0166] During the research process, the inventors unexpectedly discovered that lamivudine has significant therapeutic effects in treating gastrointestinal diseases. The experimental results are shown in Examples 1 and 2 above. Lamivudine is a classic cytidine nucleoside analog. Therefore, the inventors inferred that all cytidine nucleoside analogs have therapeutic effects in treating gastrointestinal diseases. To verify the above conclusion, the inventors selected another cytidine nucleoside analog, gemcitabine hydrochloride, for related experiments. The experimental results showed that gemcitabine hydrochloride also has therapeutic effects in treating gastrointestinal diseases. Therefore, the inventors further inferred that all nucleoside analogs have therapeutic effects in treating gastrointestinal diseases. At the same time, nucleoside analogs can be divided into cytidine analogs, thymidine analogs, adenine analogs, and guanine analogs. The inventors selected thymidine analogs from zidovudine or telbivudine; the adenine analogs from famciclovir, telofovir dipivoxil, or adefovir dipivoxil; and the guanine analogs from acyclovir or 6-thioguanine. Experiments related to gastrointestinal diseases were conducted, and the experimental results showed that telbivudine, famciclovir, telofovir dipivoxil, adefovir dipivoxil, acyclovir, gemcitabine hydrochloride, zidovudine, and 6-thioguanine all had significant effects in treating gastrointestinal diseases. The experimental results are shown in the above examples. The inventors confirmed the above inference and concluded that all nucleoside analogs are effective in treating gastrointestinal diseases and can be used to prepare drugs for treating gastrointestinal diseases, providing a new use for nucleoside analogs, which is recognized by those skilled in the art.

Claims

1. Use of gemcitabine hydrochloride in the preparation of a medicament for preventing and / or treating alcoholic gastric ulcer.

2. The use according to claim 1, characterized in that The gemcitabine hydrochloride and one or more pharmaceutically acceptable carriers form a pharmaceutical composition, and the dosage form of the pharmaceutical composition is injection, tablet, capsule, granule or pill.

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