WO2023173261A1 - 羔羊胃提取物维b12制剂组方及其在治疗胃病中的用途 - Google Patents
羔羊胃提取物维b12制剂组方及其在治疗胃病中的用途 Download PDFInfo
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- WO2023173261A1 WO2023173261A1 PCT/CN2022/080776 CN2022080776W WO2023173261A1 WO 2023173261 A1 WO2023173261 A1 WO 2023173261A1 CN 2022080776 W CN2022080776 W CN 2022080776W WO 2023173261 A1 WO2023173261 A1 WO 2023173261A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/37—Digestive system
- A61K35/38—Stomach; Intestine; Goblet cells; Oral mucosa; Saliva
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention belongs to the medical field and relates to the use of a lamb stomach extract vitamin B12 preparation in treating moderate to severe chronic atrophic gastritis, reversing intestinal metaplasia and preventing gastric cancer.
- Chronic gastritis is the most common type of digestive system disease. Chronic atrophic gastritis is a type of chronic gastritis, accounting for about 1/3 of chronic gastritis. Clinically, some patients with chronic atrophic gastritis may have no obvious symptoms. However, most patients may have symptoms such as burning, distending pain, dull pain or fullness in the upper abdomen, loss of appetite, nausea, belching and other symptoms, especially after eating. Severe cases may include weight loss, anemia, brittle nails, glossitis or tongue papilla atrophy, etc.
- Chronic atrophic gastritis is characterized by reduction of gastric mucosal glands as the main pathological feature.
- the pathological characteristics are gastric gland atrophy, mucosal thinning, mucosal muscle layer thickening, intestinal metaplasia and atypical hyperplasia. . Its diagnosis mainly relies on gastroscopy findings and pathological findings of gastric mucosal biopsy.
- the disease development cycle from normal gastric mucosa to gastric cancer is as follows: normal gastric mucosa ⁇ non-atrophic gastritis ⁇ atrophic gastritis ⁇ intestinal metaplasia ⁇ intraepithelial neoplasia ⁇ gastric cancer.
- gastric diseases can be divided into non-atrophic gastritis, atrophic gastritis, intestinal metaplasia, intraepithelial neoplasia, and gastric cancer.
- the object of the present invention is to provide a lamb stomach extract vitamin B 12 preparation formula.
- Another object of the present invention is to provide a use of the above lamb stomach extract vitamin B 12 preparation.
- the present invention provides a lamb stomach extract vitamin B 12 preparation recipe, which lamb stomach extract vitamin B 12 preparation recipe consists of lamb stomach extract and vitamin B 12 , wherein the lamb stomach extract
- the chymosin activity of the substance is >40U/g
- the pepsin activity is >15U/g
- the weight ratio of lamb stomach extract and vitamin B12 is 100000:0.5-5.
- the weight ratio of the lamb stomach extract and vitamin B12 is 100000:1-4.5.
- the weight ratio of the lamb stomach extract and vitamin B12 is 100000:1, 100000:2, 100000:3, 100000:4 or 100000:4.5.
- the chymosin activity is >45 U/g, and the pepsin activity is >20 U/g; or the chymosin activity is >55 U/g, and the pepsin activity is >20 U/g.
- the relative molecular mass of the lamb stomach extract protein is 10,000 to 45,000.
- the ratio of the milk coagulation activity to the pepsin activity is 2.5 to 5.1.
- the pharmaceutically acceptable excipient is one or more of an excipient, a binder, a diluent, a glidant, a flavoring agent, an antioxidant, and a bacteriostatic agent.
- the dosage form of the preparation is capsule, tablet, suspension or granule.
- the present invention also provides a lamb stomach extract vitamin B 12 preparation composition for use in preparing a medicament for reversing gastric mucosal atrophy.
- the present invention also provides a lamb stomach extract vitamin B 12 preparation composition for use in preparing a medicine for treating moderate or severe chronic atrophic gastritis.
- the present invention also provides a lamb stomach extract vitamin B 12 preparation composition for use in preparing a medicine for treating intestinal metaplasia.
- the intestinal metaplasia is chronic atrophic gastritis with intestinal metaplasia.
- the present invention also provides the use of lamb stomach extract vitamin B12 preparation in preparing medicine for treating gastric intraepithelial neoplasia.
- the present invention also provides the use of lamb stomach extract vitamin B12 preparation in preparing gastric cancer prevention drugs.
- the treatment is effective treatment.
- the treatment is reversal therapy.
- the administration subjects are Helicobacter pylori-negative patients.
- the treatment, reversal, and prevention are carried out through antioxidant pathways.
- the treatment, reversal, and prevention are performed by regulating intestinal flora imbalance.
- the preparation formula was administered to the patient at 330U, 3 times/d.
- the proportion and dosage of the lamb stomach extract and the vitamin B 12 preparation provided by the present invention have a direct impact on the therapeutic effect.
- lamb stomach extract and vitamin B 12 produced a synergistic or synergistic effect in a specific ratio.
- the weight ratio of lamb stomach extract to vitamin B 12 in the range of 100000:4-100000:1 produced a synergistic effect.
- the combination of lamb stomach extract and vitamin B 12 at a lower weight ratio of 100,000:1 compared to a weight ratio of 100,000:4 showed advantages in controlling residual basal mucosal congestion. Further reducing the weight ratio of vitamin B 12 to 100000:0.2, the preparation formula did not produce a synergistic effect.
- the chymosin activity of the lamb stomach extract in the preparation is not less than 45 U/g, and the pepsin activity is not less than 20 U/g; or chymosin The activity is not less than 55U/g, and the pepsin activity is not less than 20U/g.
- the invention provides a lamb stomach extract vitamin B 12 preparation formula, which can effectively reverse gastric mucosal atrophy, intestinal metaplasia and intraepithelial neoplasia, can significantly reduce the OLGA and OLGIM staging of severe CAG patients, and can Effectively reduce the risk of gastric cancer.
- Figure 1 is a graph showing the comparison results of the gastric juice pH value of the lamb stomach extract vitamin B 12 preparation provided by the present invention on the negative control group, the administration group and the non-administration group of rats.
- Figure 2 (AF) is a diagram of the pathological changes in the gastric mucosa of rats in the negative control group, the administration group and the non-administration group caused by the lamb stomach extract vitamin B 12 preparation provided by the present invention.
- Figure 3 shows the effectiveness of the lamb stomach extract vitamin B 12 preparation provided by the present invention on chronic inflammation in various parts of patients with chronic atrophic gastritis.
- Figure 4 shows the lamb stomach extract vitamin B 12 preparation provided by the present invention on the reversal rate of chronic inflammation in various parts of patients with chronic atrophic gastritis/the effective rate of inflammatory activity in each part.
- Figure 5 shows the effectiveness of the lamb stomach extract vitamin B 12 preparation provided by the present invention on the atrophy of various parts of patients with chronic atrophic gastritis.
- Figure 6 shows the incidence of reversal of atrophy in various parts of patients with chronic atrophic gastritis using the lamb stomach extract vitamin B 12 preparation provided by the present invention.
- Figure 7 shows the effectiveness of the lamb stomach extract vitamin B 12 preparation provided by the present invention on intestinal metaplasia in various parts of patients with chronic atrophic gastritis.
- Figure 8 shows the incidence of reversal of intestinal metaplasia in various parts of patients with chronic atrophic gastritis using the lamb stomach extract vitamin B 12 preparation provided by the present invention.
- Figure 9 is a comprehensive evaluation of the effectiveness of the lamb stomach extract vitamin B 12 preparation provided by the present invention on chronic gastric inflammation, atrophy and intestinal metaplasia in patients with chronic atrophic gastritis.
- Figure 10 is a comprehensive evaluation of the incidence of gastric chronic inflammation, atrophy and intestinal metaplasia reversal in patients with chronic atrophic gastritis using the lamb stomach extract vitamin B 12 preparation provided by the present invention.
- Figure 11 shows the patient’s gastroscopy results on May 13, 2019, A gastric antrum, B gastric body.
- Figure 12 shows the pathological examination results of the patient’s biopsy on May 13, 2019. Hematoxylin-eosin staining and low-magnification magnification.
- A is the gastric antrum and B is the gastric body.
- Figure 13 shows the patient’s gastroscopy results on December 11, 2019, A gastric antrum, B gastric body.
- Figure 14 shows the pathological examination results of the patient’s biopsy on December 11, 2019. Hematoxylin-eosin staining and low-magnification magnification.
- A is the gastric antrum and B is the gastric body.
- Figure 15 shows the patient’s gastroscopy results on March 30, 2021, A gastric antrum, B gastric body.
- Figure 16 shows the pathological examination results of the patient’s biopsy on March 30, 2021. Hematoxylin-eosin staining and low-magnification magnification.
- A is the gastric antrum and B is the gastric body.
- the lamb stomach extract was defatted with petroleum ether and then extracted using 0.9% sodium chloride solution under low temperature conditions with ultrasound assistance.
- the extraction solution is 0.5 mol/L hydrochloric acid with a pH value of 4.6, and is sequentially precipitated with 30%, 50%, and 90% saturated ammonium sulfate. Finally, the 90% saturated ammonium sulfate precipitate is taken as the total enzyme active site.
- the precipitate was dissolved with deionized water, desalted in the dialysis bag and separated and purified using diethylaminoethyl (DEAE) cellulose 52 anion exchange resin.
- DEAE diethylaminoethyl
- the sample was eluted sequentially with equilibrium solution (0.05mol/L phosphate buffer with a pH value of 5.7) and equilibrium solution containing 0.1, 0.2, 0.3, 0.4, and 0.5mol/L sodium chloride solution. Detected at 280nm UV wavelength. Collect the effluent at a rate of 10 min/tube and measure the chymosin activity.
- the elution sites of 0.4 and 0.5 mol/L sodium chloride solutions (named F6 and F7) have chymosin activity, and are further eluted with 0.9% sodium chloride solution using a high pressure liquid chromatography (HPLC) gel chromatography column. As the eluent, separate and purify at a flow rate of 0.4mL/min.
- Detect protein absorption at dual wavelengths of 212 and 280 nm and collect samples.
- the chymosin activity of the samples was measured using the Arima method, and the pepsin activity was measured using the Mazorra Manzano method.
- the samples were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) using 15% separation gel.
- LC MS/MS analysis was performed on F6-2. F6-2 was hydrolyzed into small molecule peptides by trypsin.
- LC MS/MS analysis was performed on the peptide fragments.
- the similarity search tool of the SIB ExPASy bioinformatics database was used to analyze the data. Learn.
- the enzyme activities and yields in different separation and purification stages of lamb stomach extract are shown in Table 1.
- the chymosin activity of lamb stomach extract was (691.2 ⁇ 5.16) U/g. After one-step purification through saturated ammonium sulfate precipitation, the chymosin activity increased 26.5 times to (18341.61 ⁇ 4.1) U/g.
- the chromatographic results of the DEAE-cellulose 52 anion exchange column separation and purification of total enzyme active sites showed that among the seven elution sites, F6 and F7 had chymosin activity, and F7 also had pepsin activity.
- the isolated and purified chymosins F6-2 and F7-2 have high milk coagulation activity and low casein hydrolysis activity.
- Pepsin has bovine serum albumin hydrolysis activity, and F7-1 has this characteristic.
- F6-2 and F7-2 are chymosin
- F7-1 is pepsin.
- the enzyme activities are (27557.1 ⁇ 4.8) U/g, (17532.6 ⁇ 5.1) U/g and (17728.15 ⁇ 5.3) respectively. ) U/g.
- the relative molecular weights of F6-2, F7-2 and F7-1 are all between 35 000 and 40 000.
- the LC-MS/MS (nano LC-QE) analysis and database comparison results of chymosin are shown in Table 2.
- the relative molecular weight of chymosin F6-2 is 40 392.88, and the isoelectric point is 4.58.
- DEAE diethylaminoethyl
- HPLC-TSKgel high performance liquid chromatography gel chromatography column
- BSA bovine serum albumin
- the lamb stomach extract was acid hydrolyzed and derivatized with DNFB, and its amino acid composition was analyzed using HPLC Diamonsil AAA amino acid analysis column.
- the raw material drug is extracted with water, 0.1 mol/L phosphate buffer with a pH value of 7.0, and 0.01 mol/L ammonium bicarbonate aqueous solution in sequence to completely dissolve the raw material drug.
- the extract was desalted, freeze-dried, and stored at -20°C for later use.
- the analysis results of the amino acid composition of lamb stomach extract are shown in Table 3. Hydrophilic amino acids that directly participate in the antioxidant reaction process account for 33.04% of the total amino acid content.
- the sample concentration is 5g/L
- the in vitro antioxidant activity ABTS scavenging activities of the three extracts extracted from water, phosphate buffer saline and ammonium bicarbonate solution of the raw drug are (37.08 ⁇ 0.45)% and (23.20 ⁇ 0.78) respectively. )%, (62.80 ⁇ 0.74)%, and the DPPH scavenging activities were (57.87 ⁇ 0.55)%, (5.03 ⁇ 0.25)% and (26.67 ⁇ 0.21)% respectively.
- the comparative results of antioxidant activity showed that the water extract and the ammonium bicarbonate extract had higher ABTS and DPPH elimination abilities, and had higher antioxidant activity than the phosphate buffer extract.
- the SDS-PAGE results of the three extracts showed that the relative molecular mass of the protein in the raw material drug was 10 000 to 40 000.
- the results in Table 4 show that the glycoprotein crude extract has a growth-promoting effect on Bifidobacterium adolescentis, Lactobacillus delbrueckii subsp. bulgaricus, and Enterococcus faecalis, and has a growth-promoting effect on Lactobacillus delbrueckii subsp. bulgaricus and Enterococcus faecalis.
- the differences were all statistically significant (all P ⁇ 0.05).
- the elution peaks of proteins and sugars in the elution curve of the chromatogram overlap each other and are glycoproteins.
- GP is the glycoprotein purified by Sephadex G-50
- GP-1 is the glycoprotein separated and purified by DEAE-cellulose 52.
- the total sugar content of GP-1 is 70.24%, and the protein content is 16.39%; the polysaccharide chain is composed of two monosaccharides, lactose and glucose, and the amino acid composition is shown in Table 5.
- the antioxidant activity of the three extracts of the raw material showed that all three extracts had antioxidant activity.
- the water extract and the ammonium bicarbonate extract showed higher antioxidant activity, which may be due to the drug's role in the treatment and prevention of gastric cancer.
- Example 3 Subacute toxicity test of chymosin and pepsin activities in lamb stomach extract vitamin B 12 preparation
- Animals 30 healthy white rats (used for experiments after being fed for one week after being collected from the animal room) weighing 115 to 195 grams. Divided into three groups, each group contains 10 animals.
- the control group was orally infused with 1.5 ml of physiological saline every day for 30 days.
- the low-dose group was dosed with 500 mg/kg body weight daily for 30 days, and the samples were prepared into a 1.5 ml suspension with physiological saline.
- the high-dose group was dosed with 1500 mg/kg body weight daily for 30 days, and the samples were prepared into a 1.5 ml suspension with physiological saline.
- Serum alanine aminotransferase has the highest content in liver cells. When certain drugs cause liver damage or in the acute stage of viral hepatitis, liver cells are damaged and the enzyme overflows into the blood, which can significantly increase serum alanine aminotransferase activity. Therefore, changes in serum alanine aminotransferase activity can be used as one of the important indicators of subacute drug poisoning and liver disease.
- Pyruvate standard solution 23.5mg sodium pyruvate, dissolved in 0.1MPH7.4 phosphate buffer solution and diluted to 100ml.
- Substrate solution 87.6 mg of ketoglutarate and 5.34 g of dl-alanine, first dissolved in 90 ml of 0.1 ⁇ M, pH7.4 phosphate buffer, then adjusted to pH7.4 with 20%, NaOH solution, and then Dilute the above phosphate buffer to 300ml, store in the refrigerator, and can be used for one week.
- 2,4-dinitrophenylhydrazine solution 19.8mg, 2,4-dinitrophenylhydrazine, dissolved in 8.0ml concentrated hydrochloric acid, transferred to a 100ml volumetric flask, and diluted to the mark with distilled water.
- pH7.4 phosphate buffer 2.69 grams KH 2 PO 4 and 13.97 grams K 2 HPO 4. Dissolve in water and transfer to a 1000ml volumetric flask. Dilute to the mark with distilled water.
- Preparation of animal serum 0.5-1.0ml of blood was removed from the tail of the rat, coagulated and centrifuged at 3000rpm for 10 minutes, and the serum was taken for later use.
- Unit definition 1 ml of serum is incubated for 30 minutes at 37°C. Each 2.5ug of pyruvate produced is 1 SGPT unit. The SGPT value for normal people is between 2-40 units.
- Serum non-protein is a general term for nitrogen in substances such as urea, uric acid, amino acids, ammonia and bilirubin, mainly urea nitrogen.
- substances such as urea, uric acid, amino acids, ammonia and bilirubin, mainly urea nitrogen.
- measuring serum non-protein nitrogen content can be used to estimate the impact of subacute drug poisoning on the kidneys and the degree of renal disease.
- Nessler's reagent In a 500ml flask, add 22.5g iodine, 30g'Kl and 20ml water to dissolve, add 30g pure, shake thoroughly, cool intermittently with tap water, shake until the yellow color of the supernatant disappears. Pour the supernatant into a 200ml volumetric flask, dilute to the mark, mix well, add to 975ml 2.5N NaOH solution, mix well, store in a brown bottle, and set aside after clarification.
- Standard ammonium sulfate solution (containing 0.06 mg of nitrogen per milliliter): Place pure ammonium sulfate in a desiccator for several days, take 0.2834g in a 10ml volumetric flask, dilute to the mark, and mix (at this time, take this stock solution and dilute it once times to obtain an application solution containing 0.03mg nitrogen per ml)
- the non-protein nitrogen content in 100ml of blood of a normal person is 21-42.5 mg.
- the rats were sacrificed, and the liver, lungs, heart, spleen, kidneys, stomach and a section of the small intestine were immediately removed and fixed in 10% formaldehyde solution. After section observation, there was no significant difference between the control group and the administration group.
- the chymosin activity of the lamb stomach extract was 45U/g
- the pepsin activity was 20U/g
- the relative molecular mass of the protein was 10,000 to 40,000.
- Vitamin B 12 USP Vitamin B 12.
- control group (A) received only p.o water under the same conditions as the other groups.
- E used a combination of lamb stomach extract: vitamin B 12 in a weight ratio of 100,000:4.
- Each group was treated orally with the test compound as an aqueous suspension at a dose of 400 mg/kg, except for the group that was treated with only vitamin B 12 under the same conditions.
- the dosage of vitamin B 12 is (4ug/kg).
- the frequency of digestive mucosal ulcers and inflammation in different experimental groups is shown in Table 10. Each group contained four animals.
- treatment group B has a significant improvement effect on gastrointestinal mucosal inflammation. This effect is evident in all aspects of the digestive tract observed at autopsy.
- Treatment group E had the same clinical effect and similar protective effects as group B.
- Treatment group B had the lowest number of observed congestions in the residual basal mucosa than treatment group E.
- group C which was treated only with lamb stomach extract without vitamin B 12
- group F which was treated only with vitamin B 12 : Gastrointestinal tract of groups B and E
- the severity of the injury is the same.
- group D it was only slightly improved over the results of control group A.
- the treatment group with the lowest vitamin B 12 content (D) had no protective effect.
- the protective effect brought by the treatment group (E) is compared with that of the treatment group B.
- the number of hyperemia in the residual basal mucosa in the treatment group B is lower than that in the treatment group (E).
- the results showed that compared with the use of lamb stomach extract or vitamin B 12 alone, the weight ratio of lamb stomach extract to vitamin B 12 in the range of 100000:4-100000:1 produced a synergistic effect.
- the combination with a lower ratio of 100000:1 has advantages in controlling residual basal mucosal congestion. Further reducing the weight ratio of vitamin B 12 to 100000:0.2, the combination did not produce a synergistic effect.
- Lamb stomach extract vitamin B12 preparation was prepared according to the optimal combination B for subsequent research.
- Experimental animals 42 healthy, male Wistar rats aged 4 to 6 weeks and weighing 140 to 180g were selected. All rats were raised in the experimental animal center and kept Constant temperature and constant humidity (temperature is 20-23°C, humidity is about 50%), with a 12-hour light and 12-hour dark environment cycle to simulate day and night.
- mice Use methylnitrosoguanidine (N-methyl-N-nitro-N-nitrosoguanidine, MNNG) solution with a concentration of 1 ⁇ 10 5 ⁇ g/L or sterile tap water as drinking water for rats.
- ranitidine feed ranitidine hydrochloride at a concentration of 0.03%
- normal standard sterile rat feed was used as rat feed.
- Rats in the drug administration group were included in the drug intervention experiment. Rats in the drug administration group were administered 0.2g/kg lamb stomach extract vitamin A daily. B 12 preparation was administered once; the rats in the non-administration group and the negative control group were administered 0.2g/kg 0.9% sodium chloride solution once a day; the experiment lasted for 3 months.
- Observation and evaluation Observe the general status of the rats (coat color, daily activities, food intake, water intake, weight changes), death, gastric juice pH, and pathological changes in the gastric mucosa of rats in each group (observation of the general morphology of the mucosa, Mucosal inflammatory cell infiltration, number of hyperplasia nodules on the gastric mucosal surface, etc.).
- the evaluation of pathological changes in the gastric mucosa of rats was based on the "Expert Consensus on the Prevention, Control and Management of Helicobacter pylori Infection in Chinese Residential Households (2021)". Rats in the administration group and non-administration group were scored for gastric mucosal precancerous lesions (1 to 3 points). Rats without precancerous lesions (IN) were scored as 1 point, LGIN was scored as 2 points, and HGIN was scored as HGIN. 3 points.
- the gastric mucosa of the rats in the negative control group was darker orange-red, with no abnormal growths on the surface (Figure 2A); except for a few white spots, the gastric mucosa of the rats in the administration group showed no obvious abnormalities, which was different from that of the negative control group.
- the appearance and color of the gastric mucosal surface of the rats were similar ( Figure 2B); tumor-like hyperplasia nodules of varying sizes and numbers appeared on the gastric mucosal surfaces of the gastric fundus, gastric body, and gastric antrum of the rats in the non-drug group. Erosion, sinusoids, etc. appeared ( Figure 2C).
- the body weight gain of the rats in the drug group was greater than that of the non-drug group [(508.26 ⁇ 33.96)g vs. (495.50 ⁇ 23.01)g], and the pH value of gastric juice was lower than that of the non-drug group (3.07 ⁇ 0.55 vs. 4.45 ⁇ 0.72 ), the differences were all statistically significant (P ⁇ 0.05).
- the number of hyperplasia nodules on the gastric mucosal surface of rats in the drug group was less than that in the non-drug group [6.00 (3.00, 7.00) in the fundus of the stomach vs. 11.00 (7.00, 13.00) in the gastric antrum (0.00 in the gastric antrum).
- lamb stomach extract vitamin B 12 preparation can promote the secretion of gastric acid and pepsin, and promote chief cells, parietal cells, and G cells.
- the proliferation of D cells regulates the secretion of neuroendocrine hormones, gastrin, somatostatin, prostaglandin E2, epidermal growth factor and their receptors, protects the gastric mucosa, promotes the regeneration of gastric mucosal glands, and improves gastric mucosal bleeding. and bleeding status, and has a significant improvement and inhibitory effect on intestinal metaplasia subtypes.
- Example 5 The pathological effects and activity influencing factors of chymosin and pepsin activities in lamb stomach extract vitamin B 12 preparation on the treatment of chronic atrophic gastritis with intestinal metaplasia
- results After 6 months of treatment, the patient's OLGA stage effective rate was 49.7%, the OLGIM stage effective rate was 32.9%, and the total effective rate was 64.7%. After 12 months of treatment, the OLGA stage effective rate was 56.4%, the OLGIM stage effective rate was 41.8%, and the total effective rate was 70.9%.
- Exclusion criteria 1Previously diagnosed with malignant tumors; 2Having a history of gastric surgery; 3Lactating or pregnant; 4Suffering from hypothyroidism, adrenal insufficiency, systemic lupus erythematosus, ankylosing spondylitis, systemic vascular disease endocrine diseases or autoimmune diseases such as inflammation; 5 Suffering from severe mental illness; 6 Refuse drug treatment; 7 Patients diagnosed with gastric cancer or high-grade intraepithelial neoplasia by upper gastrointestinal endoscopy and pathological examination; 8 Patients with severe liver disease Patients with renal insufficiency; 9 Patients with incomplete clinical and pathological data.
- Treatment method All patients take 3-6 capsules of lamb stomach extract vitamin B 12 preparation (capsules, 55U/capsule), 3 times/d, for 12 months. At the same time, patients with Hp infection were given a bismuth-containing quadruple regimen and confirmed successful eradication. Gastroscopy and mucosal histopathological examination were reviewed at 6 months and 12 months of treatment respectively.
- Gastric mucosal tissue biopsy method Biopsies are taken according to the new Sydney system histological diagnostic criteria for chronic gastritis. The locations are the greater curvature of the gastric antrum, the lesser curvature of the gastric antrum, the greater curvature of the gastric body, the lesser curvature of the gastric body, and the stomach. 5 parts of the horn.
- Efficacy evaluation Calculate the patient's gastric mucosal atrophy and IM staging according to the OLGA and OLGIM gastric cancer risk staging assessment methods, and compare the staging changes before treatment and 6 months and 12 months after treatment. If the OLGA and OLGIM staging is reduced by one stage or more, the treatment is effective. If either stage is effective, the treatment is overall effective. If both are effective, the treatment is effective.
- SPSS 22.0 statistical software was used.
- the one-sample Kolmogorov-Smirnov test is used to test the normality of continuous variables. Non-normally distributed variables are represented by M, and normally distributed variables are represented by Expressed, comparisons between groups were performed using analysis of variance; count data were expressed as rates, comparisons between groups were performed using the ⁇ 2 test, and comparisons of multiple samples of hierarchical data were performed using the Kruskal-Wallis H test. Single factor analysis and multifactor regression analysis were used to explore the independent risk factors that affect the effectiveness of lamb stomach extract vitamin B 12 preparation, and the odds ratio (OR) value and its 95% CI were calculated. P ⁇ 0.05 means the difference is statistically significant.
- Hp infection The relationship between Hp infection and the efficacy of lamb stomach extract vitamin B 12 preparation.
- the patients were divided into three groups according to their Hp infection status, namely the Hp negative group (patients whose Hp test was always negative before enrollment) and the previous Hp eradication group (the three previous Hp eradication groups). Patients who have successfully eradicated Hp months ago and tested negative before enrollment), Hp eradication group before taking medication (patients who were Hp positive at enrollment and successfully eradicated Hp before taking lamb stomach extract vitamin B 12 preparation).
- Effective rate means that the histopathological score is reduced by ⁇ 1 point compared with the baseline.
- biopsies were taken from five locations: the lesser curvature of the gastric antrum, the greater curvature of the gastric antrum, the angle of the stomach, the lesser curvature of the gastric body, and the greater curvature of the gastric body, including chronic inflammation, activity, atrophy, and intestinal metaplasia, which were divided into There are 4 levels: normal (0 points), mild (1 point), moderate (2 points) and severe (3 points).
- the effective rate was calculated and evaluated at five sites: the lesser curvature of the gastric antrum, the greater curvature of the gastric antrum, the gastric angle, the lesser curvature of the gastric body, and the greater curvature of the gastric body. Cases whose histopathological evaluation was normal at the time of enrollment were not included in the calculation of the effective rate. .
- An efficient comprehensive evaluation adopts the following two methods:
- the comprehensive evaluation 1 method is used as the main indicator for efficiency evaluation.
- Incidence of reversal refers to a decrease in histopathological scores of ⁇ 2 points from baseline in moderate and severe patients within 180 days of enrollment.
- the incidence of reversal was calculated and evaluated at five sites: the lesser curvature of the gastric antrum, the greater curvature of the gastric antrum, the gastric angle, the lesser curvature of the gastric body, and the greater curvature of the gastric body. Cases with normal or mild histopathological evaluations at the time of enrollment were not included. Calculation of reversal incidence rates. The comprehensive evaluation of the incidence of reversal is carried out using the following two methods:
- the comprehensive evaluation 1 method is used as the main index for evaluating the incidence of reversal.
- Histopathological score is the sum of the histopathological scores of the five parts of the gastric antrum, the greater curvature of the gastric antrum, the angle of the stomach, the lesser curvature of the gastric body and the greater curvature of the gastric body. The most severe pathology score and the histopathology score of each site were evaluated separately. Evaluation of histopathological evaluation included chronic inflammation, activity, atrophy, and intestinal metaplasia.
- Clinical symptom score including 7 items including abdominal discomfort, loss of appetite, bloating, indigestive diarrhea, abdominal tenderness, acid reflux, and nausea and vomiting.
- the total abdominal pain score includes three items: abdominal discomfort, abdominal distension, and abdominal tenderness
- the total non-abdominal pain score includes four items: loss of appetite, dyspeptic diarrhea, acid reflux, and nausea and vomiting.
- Laboratory tests blood routine (red blood cells, hemoglobin, white blood cells, platelets and neutrophils), blood biochemistry (ALT, AST, BUN, Cr and fasting blood glucose), urine routine (urinary white blood cells, urine red blood cells, urine glucose), stool Routine and occult blood tests, etc.;
- Measurement data are statistically described using mean, median, standard deviation, maximum value, minimum value, 25% and 75% quantile; count data or grade data are expressed with frequency and frequency.
- Lamb stomach extract vitamin B 12 preparation has a higher incidence rate of reversing chronic inflammation in the greater and lesser curvature of the gastric body in patients with chronic atrophic gastritis than the placebo group (P ⁇ 0.05). The results are shown in Figure 4.
- Lamb stomach extract vitamin B 12 preparation is more effective in treating atrophy of the greater curvature of the gastric body, lesser curvature of the gastric body, gastric angle, lesser curvature of the gastric antrum and greater curvature of the gastric antrum in patients with chronic atrophic gastritis than the placebo group (P ⁇ 0.05) , the results are shown in Figure 5.
- Lamb stomach extract vitamin B 12 preparation reversed atrophy of the greater curvature of the gastric body, lesser curvature of the gastric body, lesser curvature of the gastric antrum and greater curvature of the gastric antrum in patients with chronic atrophic gastritis than the placebo group (P ⁇ 0.05). The results See Figure 6.
- Lamb stomach extract vitamin B 12 preparation is more effective in treating intestinal metaplasia in the lesser curvature of the gastric body, gastric angle, lesser curvature of the gastric antrum and greater curvature of the gastric antrum in patients with chronic atrophic gastritis than in the placebo group (P ⁇ 0.05). The results See Figure 7.
- Lamb stomach extract vitamin B 12 preparation has a higher incidence of reversal of intestinal metaplasia in the lesser curvature of the gastric body, gastric angle, lesser curvature of the gastric antrum and greater curvature of the gastric antrum in patients with chronic atrophic gastritis than in the placebo group (P ⁇ 0.05). See Figure 8 for the results.
- the lamb stomach extract vitamin B 12 preparation is more effective in treating gastric chronic inflammation, atrophy and intestinal metaplasia in patients with chronic atrophic gastritis than the placebo group (P ⁇ 0.05). The results are shown in Figure 9.
- the adjusted mean difference (95% confidence interval) between placebo and lamb stomach was 0.24 (-0.40, 0.88) for FAS and 0.03 (-0.67, 0.74) for PPS. There was no statistically significant difference between the groups.
- the adjusted mean (95% confidence interval) of the change in the total clinical symptom score at the end of placebo treatment was -0.41 (-1.22, 0.40) for FAS and -0.37 (-1.35, 0.61) for PPS, with no statistical significance.
- the adjusted mean (95% confidence interval) of the change in the total clinical symptom score of the lamb stomach after treatment was -0.65 (-1.37, 0.07) for FAS and -0.41 (-1.32, 0.51) for PPS, with no statistical significance. .
- the adjusted mean difference (95% confidence interval) between placebo and lamb stomach was 0.38 (-0.07, 0.82) for FAS and 0.14 (-0.35, 0.63) for PPS. There was no statistically significant difference between the groups.
- the adjusted mean (95% confidence interval) of the change in total abdominal pain score at the end of placebo treatment was 0.07 (-0.50, 0.63) for FAS and -0.14 (-0.81, 0.54) for PPS, and the differences were not statistically significant.
- the adjusted mean (95% confidence interval) of the change in the total abdominal pain score of lambs after gastric treatment was -0.31 (-0.81, 0.20) for FAS and -0.27 (-0.91, 0.36) for PPS, with no statistical significance.
- the adjusted mean difference (95% confidence interval) between placebo and lamb stomach was -0.07 (-0.46, 0.32) for FAS and -0.11 (-0.53, 0.31) for PPS. There was no statistical difference between the groups. significance.
- the adjusted mean (95% confidence interval) of the change in the total score of clinical symptoms other than abdominal pain at the end of placebo treatment was -0.40 (-0.89, 0.09) for FAS and -0.21 (-0.80, 0.38) for PPS, with no statistical difference. learning meaning.
- the adjusted mean (95% confidence interval) of the change in the total score of clinical symptoms other than abdominal pain after gastric treatment in lambs was -0.33 (-0.77, 0.11), and the PPS result was -0.10 (-0.65, 0.45). There was no statistical difference. learning meaning.
- Lamb stomach extract vitamin B 12 preparation is generally effective in treating chronic atrophic gastritis, and the histological improvement effect is better.
- Treatment Lamb stomach extract vitamin B 12 preparation (capsule, 55U/capsule). Six months after regular treatment (110 U/time, 3 times/d), upper gastrointestinal endoscopy and gastric mucosal pathological tissue biopsy were performed to evaluate the therapeutic effect, and a urea breath test was performed to detect Helicobacter pylori infection. When starting treatment, if there is Helicobacter pylori infection, eradication treatment will be given first, and treatment with lamb stomach extract vitamin B 12 preparation will be started 2 weeks later.
- Endoscopic biopsy Take 5 biopsy specimens according to the requirements of the new Sydney standards, that is, the lesser curvature side of the gastric antrum is 2 to 3 cm away from the pylorus, the greater curvature side of the gastric antrum is 2 to 3 cm away from the pylorus, and the lesser curvature side of the gastric body is 4 cm away from the gastric angle. , the greater curvature side of the gastric body is 8cm away from the cardia and 5 gastric angles.
- the chronic gastritis OLGA grading system is used to evaluate the gastric mucosal inflammation status, which is divided into grades 0 to IV according to the score, and is recorded as 0 to 4 points, of which 1 to 2 points are defined as mild. Severe inflammation, 3 to 4 points are defined as severe inflammation; chronic gastritis OLGA and OLGIM staging systems are used to stage atrophy and intestinal metaplasia respectively.
- the comprehensive score results are divided into stages 0 to IV, stages 0 to II are defined as low stages, and stage III Or stage IV is a high stage.
- OLGA is a gastritis evaluation system
- OLGIM is a gastritis evaluation system based on intestinal metaplasia.
- Stages 0 to II are low OLGA or OLGIM stages; stages III to IV are high OLGA or OLGIM stages.
- Table 15 Gastric mucosal inflammation status and Helicobacter pylori infection in patients before and after treatment with lamb stomach extract vitamin B 12 preparation (example)
- the results of single factor analysis show that gender and vitamin supplementation are factors that affect the reversal of atrophic gastritis, while eating pickled foods, gastric mucosal inflammation status, and Helicobacter pylori infection are factors that affect the reversal of intestinal metaplasia (P All ⁇ 0.05).
- the results of multivariate logistic regression analysis showed that female gender, vitamin supplementation ( ⁇ 3 times/week), Helicobacter pylori negative or successful eradication, and mild inflammation (inflammation score of 1 to 2 points) were associated with lamb stomach extraction.
- the improvement of the efficacy of vitamin B 12 preparations was related, and the consumption of large amounts of pickled foods ( ⁇ 3 times/week) was related to the decrease of the efficacy (P ⁇ 0.05 for both).
- the stratified analysis results showed that there were no differences in the atrophy reversal rate and intestinal metaplasia reversal rate between the Helicobacter pylori-positive eradication treatment group (76 cases) and the Helicobacter pylori-negative non-eradication treatment group (164 cases).
- OLGIM gastritis evaluation system based on intestinal metaplasia. aThe total number of cases is less than 20, so it is not expressed as a percentage.
- the results of the present invention show that the total effective rate of the lamb stomach extract vitamin B12 preparation in treating atrophy and intestinal metaplasia is 62.9%, which is comparable to the results of previous studies.
- the present invention conducted risk stratification on CAG patients through the OLGA and OLGIM staging systems and found that the lamb stomach extract vitamin B 12 preparation has a high effective rate for patients with high OLGA and OLGIM staging (stages III and IV), among which patients with stage IV The effective rate is as high as about 70%. Treatment can reverse 54.5% (36/66) of patients with intestinal metaplasia from high OLGIM stage to low OLGIM stage, suggesting that treatment with lamb stomach extract vitamin B 12 preparation can reduce the risk of gastric cancer in CAG patients.
- Helicobacter pylori infection is the main cause of gastric cancer.
- the continuous activation of inflammatory-cancer pathways such as nuclear factor - KB, signal transducer and activator of transcription 3 and intracellular positive feedback under infection are the irreversible progression of gastric mucosal lesions.
- One of the important risk factors Eradicating Helicobacter pylori can effectively block the inflammation-cancer pathway and significantly reduce the incidence of gastric cancer in the population.
- intestinal metaplasia remains an important risk factor for the occurrence and development of gastric cancer.
- Multiple studies and meta-analyses have shown that eradication of Helicobacter pylori can only reverse gastric mucosal atrophy but not intestinal metaplasia.
- intestinal metaplasia is often regarded as the irreversible point of gastric mucosal lesions.
- present invention and other previous studies have confirmed that gastric mucosal atrophy and intestinal metaplasia can be reversed under drug intervention, indicating that it is inappropriate to regard intestinal metaplasia as the irreversible point of gastric mucosal lesions.
- Example 8 The reversal effect of lamb stomach extract vitamin B 12 preparation on chronic atrophic gastritis accompanied by severe intestinal metaplasia
- the C-UBT prompt was negative, and the results of gastroscopy are shown in Figure 11, which showed that the gastric mucosa was not smooth, with the body of the stomach being the most obvious, with distinct colors, submucosal vascular striae, and scattered spots of flaky erosion and old bleeding spots; There are multiple gray-white micro-bulges in the body, gastric angles and gastric antrum, and some surfaces are slightly sunken and red. Narrow-band endoscopy shows bright blue ridge-like changes, which are mostly intestinal metaplasia. Samples were taken from the large and small curvatures of the upper segment of the gastric body, the gastric angle and the large and small curvatures of the gastric antrum.
- the tissue was soft, had normal peristalsis, and the mucus lake was slightly turbid.
- the pathological examination results are shown in Figure 12, indicating that there is moderate chronic inflammation, severe atrophy, and severe intestinal metaplasia in the mucosa on the large and small curvatures of the upper gastric body; moderate chronic inflammation, moderate Atrophy, mild intestinal metaplasia.
- the gastritis assessment system (operative link on gastritis assessment, OLGA)/operative link on gastritis assessment based on intestinal metaplasia (OLGIM) stage is stage IV/stage III. Diagnosis: chronic atrophic gastritis with severe intestinal metaplasia.
- the patient was accompanied by upper abdominal discomfort such as abdominal distension and belching, and was treated with oral lamb stomach extract vitamin B12 preparation. After half a year of treatment, the C-UBT test was negative on December 11, 2019.
- the results of gastroscopy (Figure 13) showed that a shallow depression of flaky mucosa could be seen on the greater curvature of the lower part of the stomach, with no moss at the bottom, smooth and slightly congested mucosa at the edges, and soft tissue at the sampling site; slight bulges of flaky mucosa could be seen on the lesser curvature of the lower gastric body.
- the top is eroded, and the tissue where the material is taken is soft; the remaining gastric mucosa is still smooth, soft, red and white in color, and the sinus is scattered with flaky mucosal erythema, peristalsis is possible, and the mucus lake is slightly turbid.
- the pathological biopsy results on December 11, 2019 are shown in Figure 14, indicating moderate chronic inflammation of the lower gastric body mucosa, mild acute activity, moderate atrophy, moderate intestinal metaplasia, and foveolar epithelial hyperplasia; chronic inflammation of the cardia mucosa is acute.
- OLGA/OLGIM stage is stage III/stage II.
- Diagnosis chronic atrophic gastritis with intestinal metaplasia. The patient's gastric mucosal atrophy and intestinal metaplasia were less severe than before, and he was instructed to continue oral treatment with lamb stomach extract vitamin B 12 preparation and review after half a year. The reexamination on March 30, 2021 was negative for 3C-UBT.
- the pathological biopsy results showed moderate chronic inflammation of the gastric antrum and gastric horn mucosa, mild acute activity, mild atrophy, and foveolar epithelial hyperplasia; mild chronic inflammation of the gastric corpus mucosa.
- the OLGA/OLGIM stage is stage I/stage 0. Diagnosis: chronic atrophic gastritis, cardia.
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Abstract
一种羔羊胃提取物维B 12制剂组方，由羔羊胃提取物和维生素B 12组成，其中，所述羔羊胃提取物的凝乳酶活力>40U/g，胃蛋白酶活力>15U/g，羔羊胃提取物和维生素B 12的重量比为100000:0.5-5，其在治疗中重度慢性萎缩性胃炎、肠化生逆转及预防胃癌的用途。羔羊胃提取物与维生素B 12在特定比例下产生了协同或增效作用。
Description
本发明属于医学领域，涉及一种羔羊胃提取物维B
12制剂组方在治疗中重度慢性萎缩性胃炎、肠化生逆转及预防胃癌的用途。
慢性胃炎是最常见的一类消化系统疾病，慢性萎缩性胃炎是慢性胃炎的一种类型，约占慢性胃炎的1/3。临床上，有些慢性萎缩性胃炎患者可无明显症状。但大多数患者可有上腹部灼痛、胀痛、钝痛或胀满，食欲不振、恶心、嗳气等症状，尤以食后为甚。严重者可有消瘦、贫血、脆甲、舌炎或舌乳头萎缩等。
慢性萎缩性胃炎(chronic atrophic gastritis，CAG)以胃黏膜腺体减少为主要病理特征，病理特点为胃腺体萎缩，粘膜变薄，粘膜肌层增厚及伴有肠上皮化生、不典型增生。其诊断主要依靠胃镜发现和胃粘膜活组织检查的病理所见。
正常胃粘膜到胃癌的疾病发展周期如下：正常胃粘膜→非萎缩性胃炎→萎缩性胃炎→肠化生→上皮内瘤变→胃癌。按照上述疾病进展，胃部疾病可以分成非萎缩性胃炎、萎缩性胃炎、肠化生、上皮内瘤变、胃癌。针对萎缩性胃炎、肠化生、上皮内瘤变的逆转，临床尚无有效的治疗药物。
发明内容
为了解决上述问题，本发明的目的在于提供一种羔羊胃提取物维B
12制剂组方。
本发明的另一目的在于提供一种上述羔羊胃提取物维B
12制剂组方的用途。
为了实现上述目的，本发明提供一种羔羊胃提取物维B
12制剂组方，该羔羊胃提取物维B
12制剂组方由羔羊胃提取物和维生素B
12组成，其中，所述羔羊胃提取物的凝乳酶活力>40U/g，胃蛋白酶活力>15U/g，羔羊胃提取物和维生素B
12的重量比为100000:0.5-5。
优选地，所述羔羊胃提取物和维生素B
12的重量比为100000:1-4.5。
更优选地，所述羔羊胃提取物和维生素B
12的重量比为100000:1、100000:2、100000:3、100000:4或100000:4.5。
优选地，所述凝乳酶活力>45U/g，所述胃蛋白酶活力>20U/g；或者所述 凝乳酶活力>55U/g，所述胃蛋白酶活力>20U/g。
优选地，所述羔羊胃提取物蛋白质的相对分子质量为10000～45000。
优选地，所述凝乳活力与所述胃蛋白酶活力的比值为2.5～5.1。
如上所述地，进一步包括药学上可接受的辅料。优先地，所述药学上可接受的辅料为赋形剂、粘合剂、稀释剂、助流剂、矫味剂、抗氧化剂、抑菌剂中的一种或多种。
如上所述地，所述制剂组方的剂型为胶囊剂、片剂、混悬剂或颗粒剂。
本发明还提供羔羊胃提取物维B
12制剂组方作为制备逆转胃黏膜萎缩的药物中的用途。
本发明还提供羔羊胃提取物维B
12制剂组方作为制备治疗中度或重度慢性萎缩性胃炎的药物中的用途。
本发明还提供羔羊胃提取物维B
12制剂组方作为制备治疗肠化生的药物中的用途。
如上所述地，所述肠化生为慢性萎缩性胃炎伴肠化。
本发明还提羔羊胃提取物维B
12制剂组方在制备治疗胃上皮内瘤变的药物中的用途。
本发明还提羔羊胃提取物维B
12制剂组方在制备预防胃癌药物中的用途。
如上所述地，所述的治疗为有效性治疗。
如上所述地，所述的治疗为逆转性治疗。
如上所述地，施用对象为幽门螺旋杆菌阴性的患者。
如上所述地，通过抗氧化途径进行所述治疗、逆转、预防。
如上所述地，通过调节肠道菌群失调进行所述治疗、逆转、预防。
如上所述地，所述制剂组方以330U,3次/d的方式给与患者。
本发明所提供的羔羊胃提取物与维生素B
12制剂组方的比例用量对治疗效果产生直接影响。具体的，羔羊胃提取物与维生素B
12在特定比例下产生了协同或增效作用。相对于单独使用羔羊胃提取物或维生素B
12，羔羊胃提取物与维生素B
12的重量比100000：4-100000：1的范围内的产生了协同增效作用。相对100000：4的重量比例，羔羊胃提取物与维生素B
12在更低重量比例100000：1组合时，在控制残余基底粘膜充血方面存在优势。进一步降低维生素B
12的重量比至100000：0.2，制剂组方没有产生协同增效作用。
本发明的羔羊胃提取物维B
12制剂组方，所述制剂组方中羔羊胃提取物的凝乳酶活力不少于45U/g，胃蛋白酶活力不少于20U/g；或者凝乳酶活力不少于55U/g，胃蛋白酶活力不少于20U/g。
本发明的有益效果在于：
本发明提供的一种羔羊胃提取物维B
12制剂组方，该制剂组方可以有效逆转胃黏膜萎缩、肠化生和上皮内瘤变，可以显著降低重度CAG患者的OLGA和OLGIM分期，可有效降低胃癌发病风险。
图1为本发明提供的羔羊胃提取物维B
12制剂对阴性对照组、给药组和非给药组大鼠的胃液pH值比较结果图。
图2(A-F)为本发明提供的羔羊胃提取物维B
12制剂对阴性对照组、给药组和非给药组大鼠的胃黏膜病理改变情况图。
图3为本发明提供的羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者各部位慢性炎症有效率。
图4为本发明提供的羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者各部位慢性炎症逆转发生率/各部位炎症活动性有效率。
图5为本发明提供的羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者各部位萎缩有效率。
图6为本发明提供的羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者各部位萎缩逆转发生率。
图7为本发明提供的羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者各部位肠上皮化生有效率。
图8为本发明提供的羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者各部位肠上皮化生逆转发生率。
图9为本发明提供的羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者胃慢性炎、萎缩及肠化生有效率综合评价。
图10为本发明提供的羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者胃慢性炎、萎缩及肠化生逆转发生率综合评价。
图11为患者2019年5月13日胃镜检查结果，A胃窦部，B胃体部。
图12为患者2019年5月13日活体组织病理检查结果，苏木精-伊红染色低倍放大，A胃窦部，B胃体部。
图13为患者2019年12月11日胃镜检查结果，A胃窦部，B胃体部。
图14为患者2019年12月11日活体组织病理检查结果，苏木精-伊红染色低倍放大，A胃窦部，B胃体部。
图15为患者2021年3月30日胃镜检查结果，A胃窦部，B胃体部。
图16为患者2021年3月30日活体组织病理检查结果，苏木精-伊红染 色低倍放大，A胃窦部，B胃体部。
下面将对本发明的实施例进行详细、完善的描述，以使本发明的优点和特征能更易于被本领域技术人员理解，从而对本发明的保护范围做出更为清楚明确的界定。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
羔羊胃提取物维B
12口服制剂或颗粒，其主要成份为新疆天山绵羊第4胃(皱胃)提取出来的高活性生物(含凝乳酶、胃蛋白酶、粘蛋白、双歧因子等多种生物活性成份)和维生素B
12。
实施例1羔羊胃提取物中皱胃中酶的提取和分离、纯化
羔羊胃提取物经石油醚脱脂后，用0.9％氯化钠溶液在低温条件下进行超声波辅助提取。提取液为pH值为4.6的0.5mol/L盐酸，依次用30％、50％、90％饱和度的硫酸铵沉淀，最后取90％饱和硫酸铵沉淀物为总酶活性部位。沉淀物用去离子水溶解，透析袋脱盐后用二乙基氨乙基(diethylaminoethyl，DEAE)纤维素52阴离子交换树脂分离、纯化。样品依次用平衡液(pH值为5.7的0.05mol/L磷酸盐缓冲液)和含0.1、0.2、0.3、0.4、0.5mol/L氯化钠溶液的平衡液梯度洗脱，对洗脱液在280nm紫外波长处检测。以10min/管的速度收集流出液，测定凝乳酶活力。0.4和0.5mol/L的氯化钠溶液洗脱部位(命名为F6和F7)具有凝乳酶活性，进一步用高压液相色谱(highpressure chromatography，HPLC)凝胶色谱柱以0.9％氯化钠溶液为洗脱剂，以0.4mL/min的流速分离、纯化。在212和280nm双波长处检测蛋白吸收，收集样品。样品的凝乳酶活力采用Arima法测定，胃蛋白酶活力用Mazorra Manzano方法测定。样品用15％分离胶进行十二烷基硫酸钠聚丙烯酰胺凝胶电泳(sodium dodecyl sulfate polyacrylamide gel electrophoresis，SDS-PAGE)。对F6-2进行LC MS/MS分析，F6-2通过胰蛋白酶酶解成小分子肽，对肽段进行LC MS/MS分析，利用SIB ExPASy生物信息学数据库的相似性搜索工具对分析数据进行鉴。
羔羊胃提取物不同分离、纯化阶段中酶活性和得率参见表1。羔羊胃提取物的凝乳酶活力为(691.2±5.16)U/g，通过饱和硫酸铵沉淀一步纯化后凝乳酶活力凝乳酶提高了26.5倍，为(18341.61±4.1)U/g。总酶活性部位的DEAE-纤维素52阴离子交换柱分离纯化的色谱结果表明，7个洗脱部位中F6和F7有凝乳酶活力，F7同时有胃蛋白酶活力。分离、纯化的凝乳酶F6-2和F7-2有高凝乳活力和低酪蛋白水解活力，胃蛋白酶具有牛血清白蛋白水解活力，F7-1有此测特性。HPLC分离纯化图谱中F6-2和F7-2为凝乳酶，F7-1为胃蛋白酶，酶活力分别为(27557.1±4.8)U/g、(17532.6±5.1)U/g和(17728.15±5.3) U/g。F6-2、F7-2和F7-1的相对分子量均在35 000～40 000。凝乳酶的LC-MS/MS(nano LC-QE)分析和数据库对比结果见表2，凝乳酶F6-2的相对分子量为40 392.88，等电点为4.58。
表1 羔羊胃提取物不同分离纯化阶段中酶活性和得率
注：“－”为无此值。同一列中的不同字母表示两者之间具有统计学差异差异(P<0.05)。DEAE为二乙基氨乙基；HPLC-TSKgel为高效液相色普凝胶色谱柱；BSA为牛血清白蛋白
表2 凝乳酶F6-2的液相色谱-串联质谱鉴定结果
实施例2羔羊胃提取物的抗氧化活性成分分析
羔羊胃提取物酸水解后进行DNFB衍生化，用HPLC Diamonsil AAA氨基酸分析柱对其氨基酸组成进行分析。原料药依次用水，pH值为7.0的0.1mol/L的磷酸盐缓冲液，以及0.01mol/L的碳酸氢铵水溶液提取，使原料药完全溶解。提取物脱盐、冷冻干燥、-20℃保存备用。采用文献[13]报道的方法对3种提取物进行1，1- 二苯基-2-三硝基苯肼[1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl，DPPH]和2，2’-联氮-双(3-乙基苯并噻唑啉-6-磺酸)二铵盐[2,2’-azinobis-(3-ethylbenzthiazoline-6-sulphonate)，ABTS]自由基体外抗氧化活性测定。采用15％分离胶进行SDS-PAGE分析3种提取物中蛋白质的相对分子质量范围。
羔羊胃提取物的氨基酸组成分析结果见表3，直接参与抗氧化反应过程的亲水性氨基酸占总氨基酸含量的33.04％。当样品浓度为5g/L时，原料药的水、磷酸盐缓冲液和碳酸氢铵溶液提取的3种提取物的体外抗氧化活性ABTS清除活力分别为(37.08±0.45)％、(23.20±0.78)％、(62.80±0.74)％，DPPH清除活力分别为(57.87±0.55)％、(5.03±0.25)％和(26.67±0.21)％。抗氧化活性对比结果表明，其中水提物和碳酸氢铵提取部位具有的ABTS和DPPH消除能力均较高，与磷酸盐缓冲液提取物相比有较高的抗氧化活性。3种提取物的SDS-PAGE结果显示，原料药中蛋白质的相对分子质量为10 000～40 000。
表3 羔羊胃提取物的氨基酸组成
羔羊胃糖蛋白粗提取物及其益生菌活性分析
表4结果显示，糖蛋白粗提取物对青春双歧杆菌，德氏乳杆菌保加利亚亚种和粪肠球菌都有促生长作用，其中对德氏乳杆菌保加利亚亚种和粪肠球菌的促生长作用差异均有统计学意义(P均＜0.05)。色谱图洗脱曲线中蛋白质和糖的洗脱峰相互重叠为糖蛋白，GP为Sephadex G-50纯化得到的糖蛋白，GP-1为DEAE-纤维素52分离、纯化的糖蛋白。GP-1的总糖含量为70.24％，蛋白质含量为16.39％；多糖链由乳糖和葡萄糖2种单糖组成，氨基酸组成如表5。
表4 糖蛋白的促肠道益生菌生长活性结果
注：
a与阴性对照比较
表5 二乙基氨乙基纤维素52分离、纯化的糖蛋白中蛋白质链的氨基酸组成
原料药的3种提取物的抗氧化活性显示，3个提取物都有抗氧化活性，其中水提物和碳酸氢铵提取部位显示更高的抗氧化活性，可能是该药物对治疗和预防胃溃疡，慢性萎缩性胃炎，胃癌等中起药效作用的主要成分。
实施例3羔羊胃提取物维B
12制剂中凝乳酶、胃蛋白酶活性亚急性毒性试验
一、材料与方法
1.动物：健康大白鼠30只(自动物房领取后再喂养一星期始用于实验)体重115～195克。共分三组，每组10只。
2.样品：羔羊胃提取物维B
12制剂
3.方法：三组动物分为对照组，低剂最组及高剂最组。
对照组每日经口灌入1.5ml生理盐水，共30天。
低剂量组每日按500毫克/根公斤体重灌药30天，样品用生理盐水配成1.5ml混悬液。
高剂量组每日按1500毫克/根公斤体重灌药30天，样品用生理盐水配成1.5ml混悬液。
4.观察项目：给药前及给药30天后，分别测定动物血清谷丙金氨酶(SGPT)活性及血清非蛋白氮含量，及给药30天后动物肝、脾、心、肾、少、小肠、胃等器官的病理切片检查，以观察药物对肝、肾功能的影响及动物各器官麻理金化。
二、血清谷丙转氨酶(SGPT)活力测定
血清谷丙转氢酶在肝细胞中含量最高，当某些药物造成肝损害或处于病毒性肝炎急性阶段时，肝细胞损坏，该酶溢入血液，可使血清谷丙转氨酶活 性明显升高。因此，血清谷丙转氨酶活力的变化可作为药物亚急性中毒及肝脏病变的重要指标之一。
测定方法
(一)试剂：
1.丙酮酸标准溶液：23.5mg丙酮酸钠，用0.1MPH7.4磷酸缓冲溶液溶解并定容至100ml。
2.底物溶液：酮戊二酸87.6mg及dl-丙氨酸5.34g，先以90ml 0.Im，PH7.4磷酸缓冲液溶解，以20％,，NaOH溶液调PH7.4，再以上述磷酸缓冲液稀释至300ml，冰箱保存，可使用一周。
3. 2,4-二硝基苯肼溶液：19 8mg，2,4-二硝基苯肼，用8.0ml浓盐酸溶解，转移至100ml容量瓶中，用蒸馏水定容至刻度。
4. 0.4N NaOH溶液
5. 0IM,PH7.4磷酸缓冲液：2.69克KH
2PO
4及13.97克K
2HPO
4，加水溶解后，转移至1000ml容量瓶中，用蒸馏水稀释至刻度。
(二)标准曲线的制备：
取干燥洁净试管6支，编号为0、1、2、3、4、5，向各管中依次加入丙酮酸标准溶液0、0.05、0.10、0.15、0.20、0.25ml，在依次向各管中加入0.1M,PH7.4磷酸缓冲液0.25、0.20、0.15、0.10、0.05、0ml，然后向各管中加入SGPT底物溶液0.25ml及2,4-二硝基苯肼溶液0.5ml混匀，37℃水浴中保温20分钟，各管均加入0.4N NaOH rye 5.0ml混匀，室温放置10分钟后，以蒸馏水调零点，在750分光光度计上用200u微量池，于520nm波长处测定光吸收以各管与“0”号管光密度差值为纵坐标，相应丙酮酸微克数为横坐标，描绘标准曲线。
(三)SGPT活力测定
动物血清制备：大鼠断尾去血0.5—1.0ml，凝血3000rpm离心10分钟，取血清备用。
取干燥洁净试管若干支，其中一支为对照管。其余为测定管，用微量注射胃向各管中加入相应血清0.02ml，向测定管加入SGPT底物溶液0.10ml，混匀：37℃水浴保温30分钟，向各管中加入2,4-二硝基苯肼溶液0.10ml同时向对照管中加入SGPT底物溶液0.10ml，混匀，37℃水浴保温20分钟，然后向各管加入0.4N NaOH溶液1.0ml，混匀，室温放置10分钟。以蒸馏水调零点，于520n波长处测光吸收。由标准曲线上查得丙酮酸微克数，依下列公式计算SGPT活力。
单位定义：在37℃条件下，1毫升血清与第五作用30分钟。每产生2.5ug丙酮酸者为1个SGPT单位。正常人SGPT值在2-40单位之间。
三、血清非蛋白氮含量测定
血清非蛋白务为尿素、尿酸、氨基酸，氨及胆红素等物质中氮的总称，主要是尿素氮。当血清中非蛋白氮有明显升高时，表明肾脏受损害。故测定血清非蛋白氮含量可用于估计药物亚急性中毒对肾脏的影响及肾脏病变的程度。
测定方法
(―)试剂
1. 10％钨酸钠溶液
2. 2/3N NaOH溶液
3. 1:1硫酸
4.奈氏试剂：在500ml烧瓶中，加22.5g碘，30g`Kl及水20ml使溶解，加纯30g，充分摇荡，用自来水间歇冲冷，摇荡至上清液的黄色消失为止。上清液倾入200ml容量瓶中，稀释至刻度，混匀，加入到975ml 2.5N NaOH溶液中混匀，贮于棕色瓶中，澄清后备用。
5.标准硫酸铵溶液(每毫升含氮0.06mg)：将纯硫酸铵置于干燥器内数日，取0.2834g于10ml容量瓶中，稀释至刻度，混匀(此时取此原液稀释一倍即成每毫升含0.03mg氮的应用液)
(二)测定
1.无蛋白滤液制备：向5ml干燥洁净小离心管中加入水0.7ml，血清0.1ml,，10％钨酸钠0.1ml，混匀，再加入2/3N H
2SO
4溶液0.1ml，混匀，放置10分钟，以3000RPM离心10分钟，取上清液备用。
2.取硬质试管三支，一支为测定管，一支为标准管，一支为空白管。
向测定管内加入上述无蛋白滤液0.5ml,，1:1硫酸0.1ml，混匀，于酒精灯上小火消化至无色，冷却。定容至5.0ml，向标准管中加入标准硫酸铵应用液0.5ml及1:1硫酸0.1ml,蒸馏水4.4ml。空白管中加入5.0ml蒸馏水。
上述三管分别加入1.5ml奈氏试剂，混匀，以空白管调零点于420nm波长处测定吸收，并依下列公式计算每100ml血清中非蛋白氮含量。
正常人100ml血中非蛋白氮含屋为21-42.5毫克。
四、结果讨论
表6 给予1.5ml生理盐水前后，对照组SGPT活力及N·P·N含量比较。
| 鼠号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | |
| SGPT | 给前 | 29 | 33 | 27 | 37 | 33 | 48 | 49 | 21 | 33 |
| 活力(u) | 给后 | 22 | 22 | 14 | 26 | 18 | 14 | 20 | 32 | 28 |
| N·P·N含量 | 给前 | 39.1 | 39.1 | 36.5 | 30.1 | 44.0 | 36.6 | 46.6 | 34.4 | 50.0 |
| (mg％) | 给后 | 36.7 | 36.0 | 29.5 | 34.8 | 27.8 | 44.6 | 41.7 | 44.6 | 41.1 |
[注]中途一只老鼠灌胃时死亡
表7 低剂量(500mg原药/公斤体重)组SGPT活力剂NPN含量比较
表8 高剂量(1500mg原药/公斤体重)组SGPT活力剂NPN含量比较
[注]中途两只老鼠因灌药死亡
表9 各组数
由表6-9可以看出，与正常大鼠相比，在给药前，30只大鼠中有两只SGPT活力大于40个单位，有10只大鼠NPN含量超过42.5mg％，但给药后，所有大鼠SGPT活力都在40单位以下。至于NPN含量，给药后，除对照组两只大鼠在42.5mg％以上外，其余所有大鼠的血清NPN含量均在正常范围。说明羔羊胃提取物维B
12制剂对大鼠肝、肾无损害。
五、病理切片观察
给药30天后，将大鼠处死，立即取出肝、肺、心、脾、肾、胃及小肠一段，于10％甲醛溶液中固定，经切片观察，对照组与给药组无明显差异。
实施例4羔羊胃提取物维B
12制剂对大鼠胃黏膜癌前病变的治疗作用
研究方法一：
供试药物：
试验中羔羊胃提取物的凝乳酶活力为45U/g，胃蛋白酶为20U/g，蛋白质的相对分子质量为10000～40000。维生素B
12，为U.S.P维生素B
12。
控组和治疗组
动物按如下方式进行分配：
-控组(A)在与其他组相同的条件下仅接收p.o水。
-治疗组(B)使用羔羊胃提取物：维生素B
12重量比为100000：1的组合。
-治疗组(C)仅使用羔羊胃提取物而不使用维生素B
12。
-治疗组(D)使用用羔羊胃提取物：维生素B
12重量比为100000：0.2的组合。
-治疗组(E)使用羔羊胃提取物：维生素B
12重量比为100000：4的组合。
每组的治疗都是通过口服，剂量按400mg/kg，把测试复合药物配成水悬浮液使用，不过在相同的条件下仅使用维生素B
12进行治疗的组除外。维生素B
12的剂量按(4ug/kg)进行。
通过运用针对每天数据的协方差分析，来对不同实验组的体重变化进行统计学比较。
不同实验组消化粘膜溃疡和炎症出现的次数参见表10。每组含四只动物。
表10
从表6可以看出，治疗组B对胃肠粘膜炎症出现有明显的改善作用。这种作用在尸体解剖中观察到的消化道的各个方面都有体现。治疗的组E与组B有着相同的临床效果和相似的保护作用。治疗组B比治疗组E在残余基底粘膜充血观察到的次数最低。
根据对比，仅使用羔羊胃提取物而不使用维生素B
12进行治疗的组C与控组A相似，控组A与仅使用维生素B
12进行治疗的组F相同：组B和组E的胃肠损伤的严重程度相同。对于组D，它只比控组A的结果稍有改善。
从表6可以看出，应当同时使用羔羊胃提取物和维生素B
12。在疗效上，在相同的实验条件下，治疗组C(羔羊胃提取物无维生素B
12)对苯基丁氮酮所致的溃疡没有保护作用，而治疗组B(羔羊胃提取物)却有非常大的保护作用(P<0.00001)。
维生素B
12含量最低的治疗的组(D)没有保护作用。而治疗组(E)所带来的保护作用与治疗组B相比，治疗组B在残余基底粘膜充血观察到的次数低于治疗组(E)。结果表明相对于单独使用羔羊胃提取物或维生素B
12，羔羊胃提取物与维生素B
12的重量比100000：4-100000：1的范围的产生了协同增效作用。相对100000：4，更低比例100000：1的组合在控制残余基底粘膜充血方面存在优势。进一步降低维生素B
12的重量比至100000：0.2，组合没有产生协同增效作用。按照最优组合B制备羔羊胃提取物维B12制剂进行后续研究。
研究方法二：
1.实验动物：选取鼠龄在4～6周、体重在140～180g的无特定病原体(specific pathogen free)级、健康、雄性Wistar大鼠42只，将所有大鼠饲养于实验动物中心，保持恒温、恒湿(温度为20～23℃，湿度约为50％)，予12h光照与12h黑暗环境循环，模拟白天和黑夜。
2.实验材料：采用浓度为1×10
5μg/L的甲基硝基亚硝基胍(N-methyl-N-nitro-N-nitrosoguanidine，MNNG)溶液或无菌自来水作为大鼠饮用水。采用含浓度为0.03％的盐酸雷尼替丁的无菌大鼠饲料(以下简称为雷尼替丁饲料)或正常标准的无菌大鼠饲料作为大鼠饲料。采用浓度为50％的 乙醇溶液或羔羊胃提取物维B
12制剂内容物稀释于0.9％氯化钠溶液或0.9％氯化钠溶液进行灌胃。
构建大鼠癌前病变模型和药物干预实验：将给药组、非给药组和阴性对照组大鼠纳入药物干预实验，给药组大鼠每日灌胃0.2g/kg羔羊胃提取物维B
12制剂1次；非给药组和阴性对照组大鼠均每日灌胃0.2g/kg 0.9％氯化钠溶液1次；实验持续3个月。
标本收集和处理：药物干预实验结束后，3组大鼠禁食不禁水24～36h后麻醉、处死，收集大鼠血液标本、胃液和胃组织标本，胃组织标本送病理科，经脱水、石蜡包埋、切片，行苏木精-伊红染色行病理检查。
观察和评估：观察大鼠的一般状态(毛色、平时活动情况、进食量、饮水量、体重变化)，死亡情况，胃液pH值，以及各组大鼠胃黏膜的病理改变(黏膜大体形态观察，黏膜炎症细胞浸润情况，胃黏膜表面增生结节数目等)。大鼠胃黏膜病理改变的评估参照《中国居民家庭幽门螺杆菌感染的防控和管理专家共识(2021年)》。对给药组和非给药组大鼠进行胃黏膜癌前病变评分(1～3分)，大鼠无癌前病变(IN)记为1分，出现LGIN记为2分，出现HGIN记为3分。
给药组、非给药组和阴性对照组大鼠的胃液pH值比较，结果如图1所示。
从图1可以看出，给药组大鼠的胃液pH值高于阴性对照组(3.07±0.55比2.11±0.33)、低于非给药组(3.07±0.55比4.45±0.72)，差异均有统计学意义(t＝3.45、2.80，P均<0.05)。给药组大鼠胃酸分泌得到改善，进而反映胃黏膜上皮细胞的分泌功能甚至类型可能也得到改善。
给药组、非给药组和阴性对照组大鼠胃黏膜的病理改变情况和癌前病变评分。
阴性对照组大鼠的胃黏膜呈较深的暗橘红色，表面无异常增生物(图2A)；给药组大鼠胃黏膜除个别有白点外，其他未见明显异常，与阴性对照组大鼠胃黏膜表面外观、颜色相近(图2B)；非给药组大鼠胃底、胃体和胃窦3处胃黏膜表面均出现大小不等、数量不一的瘤样增生结节，个别出现糜烂、血窦等(图2C)。阴性对照组大鼠胃黏膜层腺体结构正常，基本无炎症细胞浸润或腺体缺失(图2D)；给药组大鼠胃黏膜层有少许炎症细胞浸润，固有层腺体萎缩，与造模结束时相比无加重，一些个体的黏膜固有层腺体密度较前更丰富(图2E)；非给药组大鼠的胃黏膜萎缩未见明显恢复甚至有加重，并出现较多不典型增生(图2F)。上述结果表明羔羊胃提取物维B
12制剂可显著降低大鼠从胃癌癌前状态向癌前病变的进展风险，提示羔羊胃提取 物维B
12制剂可能预防癌前病变的发生。
给药组大鼠的第6周体重增量大于非给药组[(508.26±33.96)g比(495.50±23.01)g]，胃液pH值低于非给药组(3.07±0.55比4.45±0.72)，差异均有统计学意义(P均<0.05)。给药组大鼠的各区域胃黏膜表面增生结节数目均少于非给药组[胃底6.00个(3.00个，7.00个)比11.00个(7.00个，13.00个).胃窦0.00个(0.00个.1.00个)比3.00个(2.00个，4.00个)，全胃7.00个(3.00个，10.00个)比15.00个(13.00个，17.00个)]，差异均有统计学意义(U＝43.50、49.00、49.00，P均<0.05)。给药组大鼠的胃黏膜癌前病变评分低于非给药组[(1.00±0.00)分比(1.14±0.38)分]，癌前病变发生率低于非给药组(1/7比5/7)，差异均有统计学意义(t＝2.45、χ
2＝4.67，P均＝0.031)。
通过建立慢性萎缩性胃炎、肠化的大鼠模型研究(研究方法一和二)，实验证明羔羊胃提取物维B
12制剂能够促进胃酸和胃蛋白酶的分泌，促进主细胞、壁细胞、G细胞、D细胞的增值，调节神经内分泌激素和胃泌素、生长抑素、前列腺素E2、表皮生长因子及其受体的分泌，发挥保护胃粘膜，促进胃粘膜腺体再生，改善胃粘膜流血量及流血状态，对肠化亚型有明显的改善和阻抑作用，同时明显提高大鼠血液LPOSODJSH-PX水平，促进胃粘膜腺体细胞生长，提高胃粘膜细胞合成，清除自由基起到保护胃粘膜的作用，治疗逆转大鼠慢性萎缩性胃炎、肠化，对CAG产生治疗作用。
实施例5羔羊胃提取物维B
12制剂中凝乳酶、胃蛋白酶活性对治疗慢性萎缩性胃炎伴肠化生的病理效果及活性影响因素
试验：羔羊胃提取物维B
12制剂对中重度萎缩性胃炎肠化生患者的治疗及合理的用法用量
背景：慢性萎缩性胃炎伴肠化生与胃癌的发生关系密切。研究发现，羔羊胃提取物维B
12制剂中含有的生物活性酶可能通过促进大鼠胃黏膜腺体增殖、抑制腺体凋亡以及抑制氧化应激反应从而逆转胃黏膜萎缩和肠化生。
目的：探讨羔羊胃提取物维B
12制剂生物活性对治疗慢性萎缩性胃炎伴肠化生的病理效果及其影响因素。
方法：纳入2018年6月—2019年6月至西京医院就诊的173例慢性萎缩性胃炎伴肠化生患者，所有患者均口服羔羊胃3-6粒，3次/d，采用增加服用剂量(或服用次数)，分别于治疗6个月和12个月行胃镜检查和胃黏膜组织活检，根据治疗前后OLGA分期和OLGIM分期变化来评估治疗效果，采用单因素分析和多因素分析探讨影响疗效的因素。
结果：治疗6个月后，患者的OLGA分期有效率为49.7％，OLGIM分期有效率为32.9％，总有效率为64.7％。治疗12个月后，OLGA分期有效率为56.4％，OLGIM分期有效率为41.8％，总有效率为70.9％。
结论：羔羊胃能显著降低慢性萎缩性胃炎伴肠化生患者的OLGA和OLGIM分期，提示该药物可能降低患者的胃癌发病风险，在胃癌的预防方面具有较好的临床应用前景。
对象与方法
一、研究对象
纳入并随访2018年6月—2019年6月至空军军医大学西京医院消化内科门诊就诊的173例CAG伴IM患者。纳入标准：①年龄18～70岁；②近三个月内经上消化道内镜检查和组织病理活检诊断为CAG伴IM。排除标准：①既往诊断为恶性肿瘤；②既往有胃部手术史；③处于哺乳或妊娠期；④患有甲状腺功能减退症、肾上腺功能不全、系统性红斑狼疮、强直性脊柱炎、系统性血管炎等内分泌疾病或自身免疫病；⑤患有严重精神疾病；⑥拒绝药物治疗；⑦上消化道内镜和病理检查诊断为胃癌或伴有高级别上皮内瘤变的患者；⑧患有严重肝肾功能不全的患者；⑨临床病理资料不全者。收集患者的一般情况、饮食习惯、行为特征(吸烟、饮酒)、疾病史、用药史等资料。纳入病例中男性117例，女性56例；平均年龄(54.4±8.8)岁；Hp感染率为79.8％(138/173)。
二、研究方法
1.治疗方法：所有患者口服羔羊胃提取物维B
12制剂(胶囊，55U/粒)3-6粒，3次/d，疗程12个月。同时，对Hp感染的患者给予含铋剂的四联方案并确认根除成功。分别于治疗6个月和治疗12个月时复查胃镜及其黏膜组织病理学检查。
2.胃黏膜组织活检方法：根据慢性胃炎新悉尼系统组织学诊断标准进行活检取材，部位分别为胃窦大弯侧、胃窦小弯侧、胃体大弯侧、胃体小弯侧、胃角5个部位。
3.疗效评估：根据OLGA和OLGIM胃癌风险分期评估方法计算患者的胃黏膜萎缩和IM分期，并比较治疗前以及治疗后6个月和12个月的分期变化。OLGA和OLGIM分期降低1期及以上为治疗有效，任一分期有效为总体有效，两者都有效为均有效。
三、统计学分析
应用SPSS 22.0统计学软件。采用单样本Kolmogorov-Smirnov检验来检 验连续变量的正态性，非正态分布变量以M表示，正态分布的变量以
表示，组间比较采用方差分析；计数资料以率表示，组间比较采用χ
2检验，等级资料的多个样本比较采用Kruskal-Wallis H检验。采用单因素分析、多因素回归分析探讨影响羔羊胃提取物维B
12制剂有效率的独立危险因素，计算比值比(OR)值及其95％CI。P＜0.05为差异有统计学意义。
结果
一、羔羊胃提取物维B
12制剂治疗后患者OLGA分期和OLGIM分期变化
173例CAG伴IM患者完成了6个月的治疗和随访，110例完成了12个月的治疗和随访。治疗6、12个月后，OLGA和OLGIM分期的0期、Ⅰ期患者明显增多、而Ⅱ、Ⅲ、Ⅳ期患者明显减少(表11、表12)。
表11 治疗6个月前后OLGA、OLGIM分期分布情况(n)
表12 治疗12个月前后OLGA、OLGIM分期分布情况(n)
进一步分析发现，羔羊胃提取物维B
12制剂治疗6个月后，49.7％(86/173)的患者OLGA分期降低，32.9％(57/173)的患者OLGIM分期降低，64.7％(112/173)的患者OLGA和(或)OLGIM分期降低，17.9％(31/173)的患者OLGA和OLGIM分期均降低(图1)；羔羊胃提取物维B
12制剂治疗12个月后，56.4％(62/110)的患者OLGA分期降低，41.8％(46/110)的患者OLGIM分期降低，70.9％(78/110)的患者OLGA和(或)OLGIM分期降低，27.3％(30/110)的患者OLGA和OLGIM分期均降低(图2)。羔羊胃提取物维B
12制剂治疗6个月与12个月的疗效相比差异无统计学意义(P＞0.05)。
治疗前，OLGA、OLGIM的高危分期(Ⅲ期和Ⅳ期)比例较高；治疗后，高危分期比例明显下降，而低危分期比例明显升高；治疗后与治疗前的分期分布相比差异有统计学意义(P＜0.01；图3、图4)。说明羔羊胃提取物维B
12制剂对萎缩和IM有明显的逆转作用。进一步分析显示，治疗6个月和12个月后OLGA高危分期比例较OLGIM分期降低更明显，差异有统计学意义(P＜0.05)。提示羔羊胃提取物维B
12制剂治疗萎缩的疗效优于IM。此外，治疗12个月的萎缩完全消失(OLGIM 0期)和IM完全消失(OLGIM 0期)的比 例高于治疗6个月，但差异无统计学意义(P＞0.05)。
二、Hp感染与羔羊胃提取物维B
12制剂疗效的关系患者根据Hp感染情况分为三组，分别为Hp阴性组(入组前Hp检测始终阴性的患者)、既往Hp根除组(既往三个月前已成功根除Hp且入组前检测为阴性的患者)、服药前Hp根除组(入组时Hp为阳性，服用羔羊胃提取物维B
12制剂前成功根除Hp的患者)。三组患者治疗6个月时的OLGA和OLGIM分期有效率差异均无统计学意义(P＞0.05)；治疗12个月，各组OLGA分期和OLGIM分期有效率差异无统计学意义(P＞0.05)。虽然根除Hp后使用羔羊胃提取物维B
12制剂对OLGA分期的有效率无明显影响，但可更有效地降低患者OLGIM分期(P＜0.05；表13)。
表13 不同Hp状态患者治疗后OLGA和OLGIM有效率分析n(％)
实施例6羔羊胃提取物维B
12制剂用于治疗慢性萎缩性胃炎的Ⅳ期临床研究
为了评价羔羊胃提取物维B
12制剂用于治疗慢性萎缩性胃炎的有效性和安全性，研究羔羊胃提取物维B
12制剂对慢性萎缩性胃炎腺体萎缩的逆转效果，并收集治疗过程中的药物经济学数据。
研究方法
以安慰剂为对照，以组织病理学改变为主要疗效指标，进行随机、双盲的多中心临床研究，对筛选成功的受试者将以2：1的比例随机分到试验组和安慰剂组。
评价标准
疗效指标:
(1)有效率：有效率是指组织病理学评分较基线降低≥1分。组织病理学评价分别在胃窦小弯、胃窦大弯、胃角、胃体小弯和胃体大弯5个部位取材活检，包括慢性炎症、活动性、萎缩和肠上皮化生，分为正常(0分)、轻度(1分)、中度(2分)和重度(3分)4级。
有效率分别在胃窦小弯、胃窦大弯、胃角、胃体小弯和胃体大弯5个部位进行计算评价，入组时组织病理学评价为正常的病例不纳入有效率的计算。有效率的综合评价采取以下两种方法进行：
①综合评价1：分别选取治疗前后最严重部位的评分计算有效率；
②综合评价2：分别选取入组时受试者慢性炎症、活动性、萎缩和肠上皮化生最严重的部位为目标观察部位，对目标观察部位治疗180天后的有效率进行评价。当多个部位入组时评分相等时，选取其中治疗前后分值变化最小者进行评价。
其中，以综合评价1方法作为有效率评价的主要指标。
(2)逆转发生率：逆转发生率是指入组中度、重度患者180天组织病理学评分较基线降低≥2分。
逆转发生率分别在胃窦小弯、胃窦大弯、胃角、胃体小弯和胃体大弯5个部位进行计算评价，入组时组织病理学评价为正常、轻度的病例不纳入逆转发生率的计算。逆转发生率的综合评价采取以下两种方法进行：
①综合评价1：分别选取治疗前后最严重部位的评分计算逆转发生率；
②综合评价2：分别选取入组时受试者慢性炎症、活动性、萎缩和肠上皮化生最严重的部位为目标观察部位，对目标观察部位治疗180天后的逆转发生率进行评价。当多个部位入组时评分相等时，选取其中治疗前后分值变化最小者进行评价。
其中，以综合评价1方法作为逆转发生率评价的主要指标。
(3)组织病理学评分：组织病理学评分分别对胃窦小弯、胃窦大弯、胃角、胃体小弯和胃体大弯5个部位的组织病理学评分之和、各部位中最严重的病理学评分以及各部位的组织病理学评分分别进行评价。组织病理学评价的评价包括慢性炎症、活动性、萎缩和肠上皮化生。
(4)胃镜下胃黏膜变化：包括萎缩性胃炎内镜下表现(黏膜红白相间、黏膜以白为主、皱襞扁平、皱襞消失、血管显露和黏膜呈颗粒或结节状)和伴有内镜下糜烂或胆汁反流(平坦糜烂、隆起糜烂、出血点斑、黏膜充血和胆汁反流)。分别为贲门、胃体、胃角、胃窦、胃底和幽门进行评价。
(5)临床症状评分：包括腹部不适、食欲不振、腹胀、消化不良性腹泻、腹部压痛、反酸和恶心呕吐7项。其中，腹痛总评分包括腹部不适、腹胀和腹部压痛3项，腹痛外总评分包括食欲不振、消化不良性腹泻、反酸和恶心呕吐4项。
安全性指标
不良事件；
实验室检查：血常规(红细胞、血红蛋白、白细胞、血小板和中性粒细胞)、血生化(ALT、AST、BUN、Cr和空腹血糖)、尿常规(尿白细胞、 尿红细胞、尿糖)、便常规和隐血试验等；
心电图检查；
一般检查：包括体温、脉搏、血压、呼吸。
统计方法：所有的统计检验均采用双侧检验，P值小于或等于0.05将被认为所检验的差别有统计意义。(特别说明的除外)。
计量资料用均数、中位数、标准差、最大值、最小值、25％和75％分位数进行统计描述；计数资料或等级资料用频数、频率表述。
疗效的分析
1.各部位慢性炎症有效率
羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者胃窦大弯及胃体大弯慢性炎症的有效率高于安慰剂组(P<0.05)，结果参见图3。
2.各部位慢性炎症逆转发生率
羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者胃体大弯及胃体小弯慢性炎症的逆转发生率高于安慰剂组(P<0.05)，结果参见图4。
3.各部位萎缩有效率
羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者胃体大弯、胃体小弯、胃角、胃窦小弯及胃窦大弯萎缩有效率均高于安慰剂组(P<0.05)，结果参见图5。
4.各部位萎缩逆转发生率
羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者胃体大弯、胃体小弯、胃窦小弯及胃窦大弯萎缩逆转发生率均高于安慰剂组(P<0.05)，结果参见图6。
5.各部位肠上皮化生有效率
羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者胃体小弯、胃角、胃窦小弯及胃窦大弯肠上皮化生的有效率高于安慰剂组(P<0.05)，结果参见图7。
6.各部位肠上皮化生逆转发生率
羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者胃体小弯、胃角、胃窦小弯及胃窦大弯肠上皮化生的逆转发生率高于安慰剂组(P<0.05)，结果参见图8。
7.有效率综合评价
羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者胃慢性炎、萎缩及肠化生有效率高于安慰剂组(P<0.05)，结果参见图9。
8.逆转发生率综合评价
羔羊胃提取物维B
12制剂对慢性萎缩性胃炎患者胃慢性炎、萎缩及肠化生 逆转发生率高于安慰剂组(P<0.05)，结果参见图10。
有效性结果：
有效率
采用综合评价1，即取治疗前后组织病理学评价最重者计算有效率：
组间慢性炎症有效率比较：有效率FAS(PPS),安慰剂10.60％(12.13％)、羔羊胃15.70％(17.86％)，经双向无序CMH-χ
2检验，FAS结果为P＝0.0411，PPS结果为P＝0.0492，组间差别均有统计学意义。
组间活动性有效率比较：有效率FAS(PPS),安慰剂34.48％(38.16％)、羔羊胃41.07％(45.58％)，经双向无序CMH-χ
2检验，FAS结果为P＝0.5336，PPS结果为P＝0.4601，组间差别均无统计学意义。
组间萎缩有效率比较：有效率FAS(PPS),安慰剂7.80％(8.79％)、羔羊胃16.01％(18.60％)，经双向无序CMH-χ
2检验，FAS结果为P＝0.0010，PPS结果为P＝0.0008，组间差别均有统计学意义。
经双向无序CMH-χ
2检验，FAS结果为P＝0.0003，PPS结果为P＝0.0003，组间差别均有统计学意义。由于肠上皮化生最严重者存在基线不均衡，因此，以基线肠上皮化生最严重者为协变量，肠上皮化生有效率为应变量拟合logistic回归模型，对肠上皮化生有效率进行进一步考察。结果显示：FAS结果为P＝0.0001，PPS结果为P＝0.0001，组间差别仍有统计学意义。
采用综合评价2，即取治疗前组织病理学评价最重的部位作为靶部位计算有效率：
组间慢性炎症有效率比较：有效率FAS(PPS),安慰剂39.93％(46.44％)、羔羊胃49.21％(57.56％)，经双向无序CMH-χ
2检验，FAS结果为P＝0.0103，PPS结果为P＝0.0063，组间差别均有统计学意义。
组间活动性有效率比较：有效率FAS(PPS),安慰剂58.62％(65.79％)、羔羊胃63.69％(70.07％)，经双向无序CMH-χ
2检验，FAS结果为P＝0.6068，PPS结果为P＝0.7386，组间差别均无统计学意义。
组间萎缩有效率比较：有效率FAS(PPS),安慰剂36.17％(41.84％)、羔羊胃59.61％(69.13％)，经双向无序CMH-χ
2检验，FAS结果为P<0.0001，PPS结果为P<0.0001，组间差别均有统计学意义。
组间肠上皮化生有效率比较：有效率FAS(PPS),安慰剂34.29％(38.31％)、羔羊胃62.24％(69.25％)，经双向无序CMH-χ
2检验，FAS结果为P<0.0001，PPS结果为P<0.0001，组间差别均有统计学意义。
逆转发生率
采用综合评价1，即取治疗前后组织病理学评价最重者计算逆转发生率：
组间慢性炎症逆转发生率比较：羔羊胃和安慰剂组均未发生逆转者。
组间活动性逆转发生率比较：发生逆转率FAS(PPS),安慰剂33.33％(35.48％)、羔羊胃20.73％(22.54％)，经双向无序CMH-χ
2检验，FAS结果为P＝0.1044，PPS结果为P＝0.3446，组间差别均无统计学意义。
组间萎缩逆转发生率比较：发生逆转率FAS(PPS),安慰剂0.00％(0.00％)、羔羊胃1.13％(1.34％)，经双向无序CMH-χ
2检验，FAS结果为P＝0.0818，PPS结果为P＝0.0810，组间差别均无统计学意义。
组间肠上皮化生逆转发生率比较：发生逆转率FAS(PPS),安慰剂3.64％(4.08％)、羔羊胃13.62％(14.67％)，经双向无序CMH-χ
2检验，FAS结果为P＝0.0079，PPS结果为P＝0.0139，组间差别均有统计学意义。
由于肠上皮化生最严重者存在基线不均衡，因此，以基线肠上皮化生最严重者为协变量，肠上皮化生逆转发生率为应变量拟合logistic回归模型，对肠上皮化生逆转发生率进行进一步考察。结果显示：FAS结果为P＝0.0083，PPS结果为P＝0.0104，组间差别仍有统计学意义。
采用综合评价2，即取治疗前组织病理学评价最重的部位作为靶部位计算逆转发生率：
组间慢性炎症逆转发生率比较：发生逆转率FAS(PPS),安慰剂1.59％(1.87％)、羔羊胃6.10％(6.68％)，经双向无序CMH-χ
2检验，FAS结果为P＝0.0057，PPS结果为P＝0.0082，组间差别均有统计学意义。
组间活动性逆转发生率比较：发生逆转率FAS(PPS),安慰剂63.89％(70.97％)、羔羊胃50.00％(53.52％)，经双向无序CMH-χ
2检验，FAS结果为P＝0.0424，组间差别有统计学意义；PPS结果为P＝0.0626，组间差别无统计学意义。
组间萎缩逆转发生率比较：发生逆转率FAS(PPS),安慰剂6.39％(7.14％)、羔羊胃19.96％(23.16％)，经双向无序CMH-χ
2检验，FAS结果为P<0.0001，PPS结果为P<0.0001，组间差别均有统计学意义。组间肠上皮化生逆转发生率比较：发生逆转率FAS(PPS),安慰剂11.82％(13.27％)、羔羊胃47.86％(53.33％)，经双向无序CMH-χ
2检验，FAS结果为P<0.0001，PPS结果为P<0.0001，组间差别均有统计学意义。
组织病理学评分
组间慢性炎症五个部位组织病理学评分之和比较：治疗前均数±SD，安慰剂FAS(PPS)8.32±2.35(8.33±2.33)、羔羊胃FAS(PPS)8.19±2.28(8.21±2.22)；治 疗后均数±SD，安慰剂FAS(PPS)8.63±2.28(8.72±2.25)、羔羊胃FAS(PPS)8.19±2.14(8.22±2.06)；(治疗后-治疗前)差值均数±SD，安慰剂FAS(PPS)0.31±1.72(0.38±1.81)、羔羊胃FAS(PPS)-0.00±2.04(0.00±2.20)，经成组t检验，FAS结果为P＝0.0246，PPS结果为P＝0.0203，组间差别均有统计学意义。
组间活动性五个部位组织病理学评分之和比较：治疗前均数±SD,安慰剂FAS(PPS)0.95±1.96(0.96±1.90)、羔羊胃FAS(PPS)1.01±2.03(1.02±1.98)；治疗后均数±SD,安慰剂FAS(PPS)1.21±2.32(1.28±2.38)、羔羊胃FAS(PPS)1.27±2.35(1.34±2.37)；(治疗后-治疗前)差值均数±SD,安慰剂FAS(PPS)0.26±2.11(0.32±2.20)、羔羊胃FAS(PPS)0.26±2.13(0.32±2.28)，经成组t检验，FAS结果为P＝0.9909，PPS结果为P＝0.9997，组间差别均无统计学意义。
组间萎缩五个部位组织病理学评分之和比较：治疗前均数±SD,安慰剂FAS(PPS)7.77±3.05(7.75±2.98)、羔羊胃FAS(PPS)8.21±3.00(8.25±3.00)；治疗后均数±SD,安慰剂FAS(PPS)9.17±2.86(9.38±2.66)、羔羊胃FAS(PPS)8.75±2.56(8.89±2.45)；(治疗后-治疗前)差值均数±SD,安慰剂FAS(PPS)1.40±2.53(1.63±2.59)、羔羊胃FAS(PPS)0.54±2.92(0.63±3.13)，经成组t检验，FAS结果为P<0.0001，PPS结果为P<0.0001，组间差别均有统计学意义。
组间肠上皮化生五个部位组织病理学评分之和比较：治疗前均数±SD,安慰剂FAS(PPS)2.31±2.75(2.45±2.79)、羔羊胃FAS(PPS)2.90±3.18(3.01±3.20)；治疗后均数±SD,安慰剂FAS(PPS)2.97±3.42(3.25±3.52)、羔羊胃FAS(PPS)2.78±3.07(2.89±3.09)；(治疗后-治疗前)差值均数±SD,安慰剂FAS(PPS)0.66±1.90(0.80±2.02)、羔羊胃FAS(PPS)-0.12±2.19(-0.13±2.36)，经成组t检验，FAS结果为P<0.0001，PPS结果为P<0.0001，组间差别均有统计学意义。
临床症状评分
治疗结束临床症状总评分变化，经协方差分析，分组间差别无统计学意义(FAS:P＝0.4637,PPS:P＝0.9235)，中心间组间差别趋势一致(FAS:P＝0.8169,PPS:P＝0.9044)；
安慰剂与羔羊胃间校正的差数均数(95％可信区间)FAS结果为0.24(-0.40,0.88)，PPS结果为0.03(-0.67,0.74)，组间差别均无统计学意义。
安慰剂治疗结束临床症状总评分变化的校正均数(95％可信区间)FAS结 果为-0.41(-1.22,0.40)，PPS结果为-0.37(-1.35,0.61)，差别均无统计学意义。羔羊胃治疗结束临床症状总评分变化的校正均数(95％可信区间)FAS结果为-0.65(-1.37,0.07)，PPS结果为-0.41(-1.32,0.51)，差别均无统计学意义。
治疗结束腹痛总评分变化，经协方差分析，分组间差别无统计学意义(FAS:P＝0.0976,PPS:P＝0.5786)，中心间组间差别趋势一致(FAS:P＝0.9651,PPS:P＝0.9743)；
安慰剂与羔羊胃间校正的差数均数(95％可信区间)FAS结果0.38(-0.07,0.82)，PPS结果0.14(-0.35,0.63)，组间差别均无统计学意义。
安慰剂治疗结束腹痛总评分变化的校正均数(95％可信区间)FAS结果为0.07(-0.50,0.63)，PPS结果为-0.14(-0.81,0.54)，差别均无统计学意义。羔羊胃治疗结束腹痛总评分变化的校正均数(95％可信区间)FAS结果为-0.31(-0.81,0.20)，PPS结果为-0.27(-0.91,0.36)，差别均无统计学意义。
治疗结束腹痛外临床症状总评分变化，经协方差分析，分组间差别无统计学意义(FAS:P＝0.7218,PPS:P＝0.6078)，中心间组间差别趋势一致(FAS:P＝0.4674,PPS:P＝0.7934)；
安慰剂与羔羊胃间校正的差数均数(95％可信区间)FAS结果为-0.07(-0.46,0.32)，PPS结果为-0.11(-0.53,0.31)，组间差别均无统计学意义。
安慰剂治疗结束腹痛外临床症状总评分变化的校正均数(95％可信区间)FAS结果为-0.40(-0.89,0.09)，PPS结果为-0.21(-0.80,0.38)，差别均无统计学意义。羔羊胃治疗结束腹痛外临床症状总评分变化的校正均数(95％可信区间)FAS结果为-0.33(-0.77,0.11)，PPS结果为-0.10(-0.65,0.45)，差别均无统计学意义。
从上述结果可以看出：
1.羔羊胃提取物维B
12制剂对慢性萎缩性胃炎总体有效，以组织学改善效果较好。
2.对慢性炎、萎缩、肠化组织学有效，尤其对肠化效果更好，并可有效逆转肠上皮化生。
实施例7大数据真实世界研究：羔羊胃提取物维B
12制剂对于慢性萎缩性胃炎、肠化生的逆转效果
对经羔羊胃提取物维B
12制剂治疗的CAG患者进行自身前后对照分析。
1.治疗：羔羊胃提取物维B
12制剂(胶囊，55U/粒)。规律治疗(110U/次，3次/d)半年后行上消化道内镜和胃黏膜病理组织活检评估治疗效果，并行尿素呼气试验以检测有无幽门螺杆菌感染。开始治疗时，如有幽门螺杆菌 感染则先予以根除治疗，2周后再启动羔羊胃提取物维B
12制剂治疗。
2.内镜活检：根据新悉尼标准的要求取5块活检标本，即胃窦小弯侧距幽门2～3cm、胃窦大弯侧距幽门2～3cm、胃体小弯侧距胃角4cm、胃体大弯侧距贲门8cm、胃角5处。
3.胃黏膜炎症状态和萎缩程度的判断：采用慢性胃炎OLGA分级系统评估胃黏膜炎症状态，依据评分高低分为0～Ⅳ级，并记为0～4分，其中1～2分定义为轻度炎症，3～4分定义为重度炎症；采用慢性胃炎OLGA、OLGIM分期系统分别对萎缩和肠化生进行分期，综合评分结果分为0～Ⅳ期，0～Ⅱ期定义为低分期，Ⅲ或Ⅳ期为高分期。
4.疗效指标：治疗后OLGA或OLGIM分期较治疗前降低≥1期为萎缩或肠化生有效逆转；治疗后OLGA或OLGIM分期较治疗前增加≥1期为萎缩或肠化生进展。有效逆转率(％)＝治疗后有效逆转病例数/总病例数×100％；进展率(％)＝治疗后进展的病例数/总病例数×100％；总逆转有效率(％)＝治疗后萎缩或肠化生有效逆转的病例数/总病例数×100％。
统计学方法
应用SPSS 25.0软件进行统计学分析。呈正态分布的计量资料用
表示，组间比较采用独立样本t检验。计数资料以例数和百分数表示，组间比较采用卡方检验；等级资料的组间比较采用Wilcoxon秩和检验。采用多因素logistic回归分析药物治疗效果的影响因素，计算比值比和95％可信区间(95％confidence interval，95％CI)。P<0.05为差异有统计学意义。
一般资料和临床特征
240例患者中，男性146例，女性94例；平均年龄为(53.8±8.0)岁；BMI<18.5kg/m
217例(7.1％)，BMI 18.5～<24.0kg/m
2 147例(61.2％)，BMI24.0～28.0kg/m
266例(27.5％)，BMI>28.0kg/m
210例(4.2％)；A型血44例(18.3％)，B型血47例(19.6％)，O型血52例(21.7％)，AB型血22例(9.2％)，血型不详75例(31.2％)；高中以上学历者155例(64.6％)；城镇居民165例(68.8％)；有胃癌家族史56例(23.3％)；有胆囊切除史14例(5.8％)；高血压43例(17.9％)；糖尿病14例(5.8％)；幽门螺杆菌阳性76例(31.7％)；胃黏膜炎症评分从低到高分别为1分4例(1.7％)，2分158例(65.8％)，3分65例(27.1％)，4分13例(5.4％)。
治疗效果分析
见表14，经羔羊胃提取物维B
12制剂治疗半年后，OLGA和OLGIM低分期(0～Ⅱ期)的患者比例均高于治疗前[62.9％(151/240)比50.8％(122/240)、 80.8％(194/240)比72.5％(174/240)]，差异均有统计学意义(χ
2＝7.143、4.658，P均<0.05)。见表15，治疗后胃黏膜重度炎症(炎症评分为3～4分)的患者比例低于治疗前[23.3％(56/240)比32.5％(78/240)]，差异有统计学意义(χ
2＝5.011，P<0.05)。治疗后幽门螺杆菌阳性患者比例低于治疗前[10.8％(26/240)比31.7％(76/240)]，差异有统计学意义(χ
2＝31.124，P<0.05)。10例初始治疗时伴有低级别上皮内瘤变的患者中，8例在治疗后复查时未检测到异型增生。治疗期间，240例患者均无不良反应发生。
表14 羔羊胃提取物维B
12制剂治疗前后OLGA、OLGIM分期分布情况(例)
注：OLGA为胃炎评价系统；OLGIM为基于肠化生的胃炎评价系统。0～Ⅱ期为低OLGA或OLGIM分期；III～IV期为高OLGA或OLGIM分期
表15 羔羊胃提取物维B
12制剂治疗前后患者胃黏膜炎症状态和幽门螺杆菌感染情况(例)
羔羊胃提取物维B
12制剂治疗半年后，患者胃黏膜萎缩和肠化生的逆转率分别为45.4％(109/240)和37.9％(91/240)，总逆转率为62.9％(151/240)，其中35例萎缩完全消退，15例肠化生完全消退，8例萎缩、肠化生均完全消退；分别有21.3％(51/240)和21.3％(51/240)的患者萎缩和肠化生发生进展；33.3％(80/240)和40.8％(98/240)的患者萎缩和肠化生分期保持不变。治疗后，OLGA和OLGIM高分期的患者中，分别有53.4％(63/118)和54.5％(36/66)逆转为低分期，OLGA和OLGIM低分期的患者分别有27.0％(33/122)和15.5％(16/174)的患者进展为高分期。治疗前后患者的OLGA、OLGIM分期高低的构成比差异均有统计学意义(χ
2＝19.492、10.013，P均<0.05)。OLGA分期I～Ⅳ期的胃黏膜萎缩的逆转比例分别为4/13、30.3％(30/99)59.5％(50/84)、70.6％(24/34)，OLGIM分期I～Ⅳ期肠化生的逆转比例分别为11.5％(7/61)、49.4％(44/89)51.1％(24/47)、13/19。除OLGIMⅡ期与Ⅲ期患者的肠化生逆转率比较差异无统计学意义(P>0.05)外，高OLGA和OLGIM分期患者的逆转率均高于低分期者(P均<0.05)。
疗效相关影响因素分析
如表16所示，单因素分析结果显示，性别、补充维生素是影响萎缩性胃炎逆转的因素，而食用腌制食品、胃黏膜炎症状态和幽门螺杆菌感染是影响肠化生逆转的因素(P均<0.05)。如表17所示，多因素logistic回归分析结果显示，女性、补充维生素(≥3次/周)、幽门螺杆菌阴性或根除成功和轻度炎症(炎症评分为1～2分)与羔羊胃提取物维B
12制剂疗效的提高相关，大量食用腌制食品(≥3次/周)与疗效降低相关(P均<0.05)。
表16 影响羔羊胃提取物维B
12制剂疗效的单因素分析[例(％)]
注：
a总例数不足20，故不以百分数表示
表17 影响羔羊胃提取物维B
12制剂疗效的多因素分析
如表18所示，分层分析结果显示，幽门螺杆菌阳性根除治疗组(76例)与幽门螺杆菌阴性未经根除治疗组(164例)间萎缩逆转率和肠化生逆转率比较差异均无统计学意义(P均>0.05)；幽门螺杆菌阳性根除治疗组的总有效逆转率高于幽门螺杆菌阴性未经根除治疗组，差异有统计学意义(χ
2＝5.388，P<0.05)；幽门螺杆菌根除治疗组内根除成功与根除失败患者的总有效逆转率、萎缩逆转率和肠化生逆转率比较差异均无统计学意义(P均>0.05)；幽 门螺杆菌阴性未经根除治疗组内复查阴性与复查阳性患者的总有效逆转率、萎缩逆转率和肠化生逆转率比较差异均无统计学意义(P均>0.05)。
表18 根除幽门螺杆菌治疗对羔羊胃提取物维B
12制剂疗效的影响[例(％)]
注：
a与阴性未经根除治疗组比较，P<0.05
如表19所示，萎缩完全逆转患者中食用腌制食品的比例低于进展患者，食用水果、高OLGA分期和经幽门螺杆菌根除治疗的比例均高于进展患者，差异均有统计学意义(χ
2＝9.701、40.518、4.575、4.023，P均<0.05)。肠化生完全逆转患者中饮酒、食用腌制食品、高OLGA分期的比例均低于进展患者，差异均有统计学意义(χ
2＝5.315、3.958、40.518，P均<0.05)。性别、年龄、胃癌家族史、吸烟史、高盐饮食、食用蔬菜和OLGIM分期在萎缩和肠化生完全逆转组与进展组间比较差异均无统计学意义(P均>0.05)。
表19 萎缩和肠化生完全逆转患者与进展患者的临床特征
注：OLGA为胃炎评价系统；OLGIM为基于肠化生的胃炎评价系统。
a总例数不足20，故不以百分数表示
本发明结果显示，羔羊胃提取物维B
12制剂治疗萎缩和肠化生的总有效率为62.9％，与既往研究结果相当。此外，本发明通过OLGA、OLGIM分期系统对CAG患者进行风险分层后发现，羔羊胃提取物维B
12制剂对高OLGA、OLGIM分期(Ⅲ、Ⅳ期)患者的有效率高，其中Ⅳ期患者的有效率高达约70％。通过治疗可以使54.5％(36/66)的肠化生患者从高OLGIM分期逆转为低OLGIM分期，提示羔羊胃提取物维B
12制剂治疗能降低CAG患者的胃癌发病风险。
幽门螺杆菌感染是引起胃癌发病的最主要病因，感染状态下核因子
-KB、信号转导和转录激活因子3等炎-癌通路的持续激活和细胞内正反馈是胃黏膜病变不可逆进展的重要危险因素之一。根除幽门螺杆菌可以有效阻断炎-癌通路，显著降低人群胃癌发病率。在根除幽门螺杆菌后，肠化生仍然是胃癌发生和发展的重要危险因素。多篇研究和meta分析表明，根除幽门螺杆菌仅能逆转胃黏膜萎缩，不能逆转肠化生。因此在胃癌发展的Correa模型中，肠化生常被视为胃黏膜病变的不可逆转点。本发明和既往其他研究均证实了在药物的干预下可以使胃黏膜萎缩和肠化生得到逆转，说明将肠化生视为胃黏膜病变不可逆转点并不合适。也有研究指出，在随访5～10年后，幽门螺杆菌根除组在胃窦和胃体分别有33.9％(75/221)和44.4％(63/142)的肠化生发生逆转，提示根除幽门螺杆菌能够在一定程度上逆转萎缩和肠化生，但其逆转效应较弱且需要较长的时间效应的累积。结果显示，无论有无幽门螺杆菌感染，羔羊胃提取物维B
12制剂均能有效逆转萎缩和肠化生，而且根除治疗能 够提高羔羊胃提取物维B
12制剂对萎缩和肠化生的总逆转有效率。
综上所述，在根除幽门螺杆菌的基础上，羔羊胃提取物维B
12制剂治疗对萎缩和肠化生具有较好的逆转作用，并可能降低CAG患者的胃癌发病风险。高风险(OLGA、OLGIMⅢ、Ⅳ期)的CAG患者，应推荐使用羔羊胃提取物维B
12制剂进行治疗。
实施例8羔羊胃提取物维B
12制剂对慢性萎缩性胃炎伴重度肠化生的逆转效果
患者女，52岁，因“腹胀、嗳气等上腹部不适，加重1个月”于2018年3月13日就诊于空军军医大学西京医院消化内科门诊。
C-UBT提示阴性，胃镜检查结果如图11所示，提示胃黏膜欠光滑，以胃体部明显，色泽相间明显，黏膜下血管纹透见，散在点片状糜烂和陈旧性出血斑；胃体、胃角和胃窦部多发灰白色微隆起，部分表面略凹陷、发红，窄带内镜观察见亮蓝嵴样改变，多系肠化生。分别在胃体上段大小弯侧、胃角和胃窦大小弯侧取材，组织质软、蠕动正常，黏液湖微浊。病理检香结果如图12所示，提示胃体上部大小弯侧出现黏膜中度慢性炎，重度萎缩，重度肠化生；胃角和胃窦部大小弯侧黏膜出现中度慢性炎，中度萎缩，轻度肠化生。胃炎评价系统(operative link on gastritis assessment，OLGA)/基于肠化生的胃炎评价系统(operative link on gastritis assessment based on intestinal metaplasia，OLGIM)分期为Ⅳ期/Ⅲ期。诊断：慢性萎缩性胃炎伴重度肠化生。患者伴有腹胀、嗳气等上腹部不适，予以口服羔羊胃提取物维B
12制剂治疗。治疗半年后，于2019年12月11日复查C-UBT呈阴性。胃镜检查结果(图13)提示责门下大弯侧可见片状黏膜浅凹陷，底无苔，边缘黏膜尚光滑，略充血，取材处组织质软；胃体下段小弯侧可见片状黏膜微隆起，顶端糜烂，取材处组织质软；余胃黏膜尚光滑，柔软，色泽红白相间，窦部散在点片状黏膜红斑，蠕动可，黏液湖微浊。2019年12月11日病理活检结果如图14所示，提示胃体下段黏膜中度慢性炎，轻度急性活动，中度萎缩，中度肠化生，小凹上皮增生；贲门黏膜慢性炎急性活动，小凹上皮增生伴中度肠化生；胃窦、胃角黏膜轻度慢性炎，轻度急性活动，轻-中度萎缩；胃体上段黏膜轻度慢性炎。OLGA/OLGIM分期为Ⅲ期/Ⅱ期。诊断：慢性萎缩性胃炎伴肠化生。患者胃黏膜萎缩和肠化生程度较前减轻，嘱其继续口服羔羊胃提取物维B
12制剂治疗，半年后复查。2021年3月30日复查3C-UBT阴性。胃镜结果如图15所示，提示贲门局部黏膜充血；余胃黏膜柔软欠光滑，以胃体小弯侧明显，色泽红白相间明显，黏膜下血管纹透见，蠕动正常，黏液湖微浊。分别于胃体上段大 小弯侧、胃角和胃窦部大小弯侧取材，组织质软。病理活检结果(图16)提示胃窦、胃角黏膜中度慢性炎，轻度急性活动，轻度萎缩，小凹上皮增生；胃体黏膜轻度慢性炎。OLGA/OLGIM分期为Ⅰ期/0期。诊断：慢性萎缩性胃炎，贲门炎。经羔羊胃提取物维B
12制剂治疗1年半，患者胃黏膜OLGA分期从Ⅳ期降至I期，OLGIM分期从Ⅲ期降至0期，提示羔羊胃提取物维B
12制剂能有效降低CAG伴肠化生患者的OLGA和OLGIM分期，并有可能降低患者的胃癌发病风险。
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (21)
- 一种羔羊胃提取物维B 12制剂组方，其特征在于：该羔羊胃提取物维B 12制剂组方由羔羊胃提取物和维生素B 12组成，其中，所述羔羊胃提取物的凝乳酶活力>40U/g，胃蛋白酶活力>15U/g，羔羊胃提取物和维生素B 12的重量比为100000:0.5-5。
- 根据权利要求1所述的羔羊胃提取物维B 12制剂组方，其特征在于，所述羔羊胃提取物和维生素B 12的重量比为100000:1-4.5。
- 根据权利要求2所述的羔羊胃提取物维B 12制剂组方，其特征在于，所述羔羊胃提取物和维生素B 12的重量比为100000:1、100000:2、100000:3、100000:4或100000:4.5。
- 根据权利要求1至3任一项所述的羔羊胃提取物维B 12制剂组方，其特征在于，所述凝乳酶活力>45U/g，所述胃蛋白酶活力>20U/g；或者所述凝乳酶活力>55U/g，所述胃蛋白酶活力>20U/g。
- 根据权利要求1至3任一项所述的羔羊胃提取物维B 12制剂组方，其特征在于，所述羔羊胃提取物蛋白质的相对分子质量为10000～45000。
- 根据权利要求1至3任一项所述的羔羊胃提取物维B 12制剂组方，其特征在于，所述凝乳活力与所述胃蛋白酶活力的比值为2.5～5.1。
- 根据权利要求1至6任一项所述的羔羊胃提取物维B 12制剂组方，其特征在于，进一步包括药学上可接受的辅料。
- 根据权利要求7所述的羔羊胃提取物维B 12制剂组方，其特征在于，所述药学上可接受的辅料为赋形剂、粘合剂、稀释剂、助流剂、矫味剂、抗氧化剂、抑菌剂中的一种或多种。
- 根据权利要求1至6任意一项所述的羔羊胃提取物维B 12制剂组方，其特征在于，所述制剂组方的剂型为胶囊剂、片剂、混悬剂或颗粒剂。
- 羔羊胃提取物维B 12制剂组方作为制备逆转胃黏膜萎缩的药物中的用途。
- 羔羊胃提取物维B 12制剂组方作为制备治疗中度或重度慢性萎缩性胃炎的药物中的用途。
- 羔羊胃提取物维B 12制剂组方作为制备治疗肠化生的药物中的 用途。
- 根据权利要求12所述的用途，所述肠化生为慢性萎缩性胃炎伴肠化。
- 羔羊胃提取物维B 12制剂组方在制备治疗胃上皮内瘤变的药物中的用途。
- 羔羊胃提取物维B 12制剂组方在制备预防胃癌药物中的用途。
- 根据权利要求10-14中任一项所述的用途，其特征在于，所述的治疗为有效性治疗。
- 根据权利要求10-14中任一项所述的用途，其特征在于，所述的治疗为逆转性治疗。
- 根据权利要求10-14中任一项所述的用途，其特征在于，施用对象为幽门螺旋杆菌阴性的患者。
- 根据权利要求10-14中任意一项所述的用途，其特征在于，通过抗氧化途径进行所述治疗、逆转、预防。
- 根据权利要求10-14中任意一项所述的用途，其特征在于，通过调节肠道菌群失调进行所述治疗、逆转、预防。
- 根据权利要求8-20中任意一项所述的用途，其特征在于，所述制剂组方中羔羊胃提取物的凝乳酶活力不少于45U/g，胃蛋白酶活力不少于20U/g；或者凝乳酶活力不少于55U/g，胃蛋白酶活力不少于20U/g；以330U,3次/d的方式给与患者，并且羔羊胃提取物的蛋白质相对分子质量为10000～45000。
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