WO2023165619A1 - 艾普拉唑用于调节消化道微生态的用途 - Google Patents
艾普拉唑用于调节消化道微生态的用途 Download PDFInfo
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- WO2023165619A1 WO2023165619A1 PCT/CN2023/079657 CN2023079657W WO2023165619A1 WO 2023165619 A1 WO2023165619 A1 WO 2023165619A1 CN 2023079657 W CN2023079657 W CN 2023079657W WO 2023165619 A1 WO2023165619 A1 WO 2023165619A1
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- Prior art keywords
- ilaprazole
- bacteria
- flora
- pharmaceutically acceptable
- acceptable salt
- Prior art date
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- HRRXCXABAPSOCP-UHFFFAOYSA-N ilaprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC(=CC=C3N=2)N2C=CC=C2)=C1C HRRXCXABAPSOCP-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 229950008491 ilaprazole Drugs 0.000 title claims abstract description 64
- 230000001105 regulatory effect Effects 0.000 title claims abstract description 18
- 230000000968 intestinal effect Effects 0.000 title claims abstract description 16
- 102100021022 Gastrin Human genes 0.000 claims abstract description 35
- 108010052343 Gastrins Proteins 0.000 claims abstract description 35
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 claims abstract description 35
- 210000002966 serum Anatomy 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 24
- 241000894006 Bacteria Species 0.000 claims abstract description 18
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims abstract description 16
- 241000590002 Helicobacter pylori Species 0.000 claims abstract description 7
- 229940037467 helicobacter pylori Drugs 0.000 claims abstract description 7
- 208000015181 infectious disease Diseases 0.000 claims abstract description 7
- 230000002685 pulmonary effect Effects 0.000 claims abstract description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 27
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 26
- 241000192125 Firmicutes Species 0.000 claims description 21
- 229940126409 proton pump inhibitor Drugs 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 16
- 241000605059 Bacteroidetes Species 0.000 claims description 14
- 239000000612 proton pump inhibitor Substances 0.000 claims description 14
- 241000606125 Bacteroides Species 0.000 claims description 10
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- 238000002360 preparation method Methods 0.000 claims description 5
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- 241001141113 Bacteroidia Species 0.000 claims description 3
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- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
- 201000008629 Zollinger-Ellison syndrome Diseases 0.000 claims description 3
- 230000001580 bacterial effect Effects 0.000 claims description 3
- 230000007423 decrease Effects 0.000 claims description 3
- 241000692822 Bacteroidales Species 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 206010013839 Duodenal ulcer haemorrhage Diseases 0.000 claims description 2
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- 241001468155 Lactobacillaceae Species 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 2
- 206010034344 Peptic ulcer haemorrhage Diseases 0.000 claims description 2
- 208000035109 Pneumococcal Infections Diseases 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 206010049416 Short-bowel syndrome Diseases 0.000 claims description 2
- 206010042220 Stress ulcer Diseases 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 208000001288 gastroparesis Diseases 0.000 claims description 2
- 208000024798 heartburn Diseases 0.000 claims description 2
- 230000002458 infectious effect Effects 0.000 claims description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 230000000306 recurrent effect Effects 0.000 claims description 2
- ZQGDDMFDBZPGCD-UHFFFAOYSA-N sodium 2-[(4-methoxy-3-methylpyridin-2-yl)methylsulfinyl]-5-pyrrol-1-ylbenzimidazol-3-ide Chemical group [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(C=C3N=2)N2C=CC=C2)=C1C ZQGDDMFDBZPGCD-UHFFFAOYSA-N 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 208000025865 Ulcer Diseases 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 206010009887 colitis Diseases 0.000 claims 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims 2
- 230000003628 erosive effect Effects 0.000 claims 1
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- 231100000397 ulcer Toxicity 0.000 claims 1
- 230000002496 gastric effect Effects 0.000 abstract description 15
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- 208000004300 Atrophic Gastritis Diseases 0.000 description 3
- 241000186000 Bifidobacterium Species 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
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- 241000606790 Haemophilus Species 0.000 description 2
- 241000588748 Klebsiella Species 0.000 description 2
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- 241000425347 Phyla <beetle> Species 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
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- 206010002243 Anastomotic ulcer Diseases 0.000 description 1
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- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
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- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
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Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to the use of ilaprazole or a pharmaceutically acceptable salt thereof for regulating intestinal microecology, and also relates to the use of ilaprazole or a pharmaceutically acceptable salt thereof in reducing the risk of lung infection and regulating gastric microecology And the use of serum gastrin.
- Proton Pump Inhibitors can selectively inhibit the H + /K + -ATPase on the secretory tubule membrane of human gastric mucosal cells. Since this H + /K + -ATPase is the ultimate way to inhibit gastric acid secretion, its inhibition can significantly reduce the secretion of gastric acid, so proton pump inhibitors are usually used to treat related diseases induced or caused by the action of gastric acid in the digestive tract. Diseases (i.e., acid-related diseases), including gastric and duodenal ulcers, gastroesophageal reflux disease (GERD), surgical anastomotic ulcers, and Zollinger-Ellison syndrome, etc., as well as resistance to Helicobacter pylori.
- GDD gastroesophageal reflux disease
- Zollinger-Ellison syndrome etc.
- non-reversible PPIs can be divided into non-reversible PPIs and reversible PPIs (Reversible PPIs, RPPIs); among them, non-reversible PPIs are mainly benzimidazole derivatives, which can quickly pass through the parietal cell membrane and accumulate In the strongly acidic secretory tubules, it is then protonated into a sulfenamide compound, which can form a covalently bonded disulfide with the sulfhydryl group on the cysteine residue in the H + /K + -ATPase subunit. Sulfur bonds, thereby irreversibly inactivating the H + /K + -ATPase and thereby inhibiting its acid secretion activity.
- RPPIs reversible PPIs
- PPI is still the drug of choice for the treatment of GERD.
- the consensus in treatment suggests that if a single dose of PPI is ineffective, double doses can be used; if one PPI is ineffective, other PPIs can be used for treatment.
- serum gastrin concentration is to nourish the gastrointestinal mucosa and stimulate the secretion of pancreatic juice and gastric acid. Elevated serum gastrin is more likely to suffer from gastritis, gastric ulcer and other diseases, atrophic gastritis, and gastrinoma.
- Ilaprazole or a pharmaceutically acceptable salt thereof as a proton pump inhibitor is capable of modulating Bacteroidetes and Firmicutes in intestinal flora during use (Firmicutes), and thus have important implications for individuals who need to regulate both.
- the inventors also unexpectedly found that compared with the acid-suppressing drug Vonorasan fumarate, ilaprazole has less effect on the gastrointestinal flora in individuals, thereby reducing the risk of patients undergoing acid-suppressing-related activities.
- ilaprazole or a pharmaceutically acceptable salt thereof affects serum gastrin levels less during use, it can be used in individuals using ilaprazole or a pharmaceutically acceptable salt thereof compared to other Azole drugs reduce the individual's risk of suffering from gastritis, gastric ulcer and other diseases, atrophic gastritis, and gastrinoma.
- the present invention provides the use of ilaprazole or a pharmaceutically acceptable salt thereof in the preparation of a medicament for regulating flora in an individual, especially in the preparation of a medicament for regulating the digestive tract in an individual. , preferably for use in medicine of the gastrointestinal flora.
- the present invention also provides the use of ilaprazole or a pharmaceutically acceptable salt thereof in the preparation of a medicament for regulating the abundance of Bacteroides bacteria and Firmicutes bacteria in the intestinal tract of an individual .
- the present invention provides the use of ilaprazole or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing intestinal bacteria of the phylum Bacteroidetes and increasing intestinal bacteria of the phylum Firmicutes in an individual .
- the subject has a gastrointestinal dysbiosis due to use of a proton pump inhibitor or antacid other than ilaprazole or a pharmaceutically acceptable salt thereof.
- said imbalance comprises an imbalance in the abundance of Bacteroidetes and Firmicutes in the gut. More preferably, the dysbiosis in the abundance of Bacteroidetes and Firmicutes in the gut is an increase in Bacteroidetes and a decrease in Firmicutes in the gut relative to a healthy individual.
- the individual is at risk of or has a pulmonary infection due to use of a proton pump inhibitor or antacid other than ilaprazole or a pharmaceutically acceptable salt thereof. More preferably, said pulmonary infection is a pneumococcal infection.
- the individual is poorly tolerated due to use of a proton pump inhibitor or acid suppressant other than ilaprazole or a pharmaceutically acceptable salt thereof, such as requiring treatment for H. pylori or requiring Long-term medication.
- the pharmaceutically acceptable salt of ilaprazole may be selected from ilaprazole sodium, ilaprazole magnesium, ilaprazole zinc, ilaprazole potassium, ilaprazole lithium or Ilaprazole calcium, etc.
- the individual may be a healthy human or a human suffering from the following gastrointestinal disorders: heartburn, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic Ulcers, stress ulcers, bleeding peptic ulcers, duodenal ulcers and recurrent duodenal ulcers, gastric ulcers associated with nonsteroidal anti-inflammatory drugs (NSAIDs), active benign gastric ulcers in adults, infectious Enteritis, knot Enteritis, hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease (GERD), Helicobacter pylori-related disorders, erosive esophagitis, short bowel syndrome, Or any combination of the above diseases.
- NSAIDs nonsteroidal anti-inflammatory drugs
- the bacteria of the phylum Bacteroides comprise bacteria of the class Bacteroidia, preferably of the order Bacteroidales, more preferably of the family Bacteroidaceae, still more preferably of the genus Bacteroides.
- the Firmicutes bacteria preferably comprise Bacilli (Bacilli), preferably Lactobacillales (Lactobacillales), more preferably Lactobacillus (Lactobacillaceae), still more preferably Lactobacillus (Lactobacillus) bacteria, most Lactobacillus (Bacillus acidi lactici) is preferred.
- the medicine includes tablet, preferably bilayer tablet, chewable tablet, orally disintegrating tablet, buccal tablet, sugar-coated pill, emulsion, suspension, solution, granule, drop pill, and pellet preferably Enteric-coated pellets or sustained-release pellets, freeze-dried powder injections, injections, soft capsules or capsules.
- the medicament comprises 1 mg to 20 mg unit dose of ilaprazole or a pharmaceutically acceptable salt thereof, preferably, the unit dose may be 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg , 3.5mg, 4mg, 4.5mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg or 20mg.
- the dose of ilaprazole or a pharmaceutically acceptable salt thereof is 1-40 mg/day, preferably 2.5-20 mg/day, more preferably about 5-10 mg/day. day, most preferably about 5 mg/day or 10 mg/day.
- the duration of medication depends on the needs, at least one week, two weeks, or one month, and the longest may be for life as needed.
- the antacid is Vonorasan fumarate.
- the present invention provides the use of ilaprazole or a pharmaceutically acceptable salt thereof for regulating serum gastrin levels in an individual, preferably regulating serum gastrin levels due to the use of antacids Elevated levels of use.
- the acid suppressant is vonorasan fumarate.
- the adjustment includes reducing the serum gastrin level, or returning the increase of the serum gastrin level caused by the use of an acid suppressant to a normal level.
- the present invention also provides a kit comprising ilaprazole or a pharmaceutically acceptable salt thereof alone or in combination with other active ingredients, and the instructions indicate that ilaprazole or Its pharmaceutically acceptable salts are used to reduce the number of Bacteroidetes and increase Firmicutes in the gut Bacterial counts, and/or for individuals susceptible to pneumococcus, and/or for lowering serum gastrin levels, preferably returning elevated serum gastrin levels due to the use of antacids to normal levels.
- the acid suppressant is vonorasan fumarate.
- the adjustment includes reducing the serum gastrin level, or returning the increase of the serum gastrin level caused by the use of an acid suppressant to a normal level.
- the invention provides a method for modulating serum gastrin levels in an individual, preferably a method of modulating elevated serum gastrin levels due to the use of antacids, the method comprising: Individuals in need thereof are administered ilaprazole or a pharmaceutically acceptable salt thereof.
- the acid suppressant is vonorasan fumarate.
- the adjustment includes reducing the serum gastrin level, or returning the increase of the serum gastrin level caused by the use of an acid suppressant to a normal level.
- the present invention provides the use of ilaprazole or a pharmaceutically acceptable salt thereof for regulating serum gastrin levels in an individual, preferably regulating serum gastrin due to the use of antacids Uses with elevated toxin levels.
- the acid suppressant is vonorasan fumarate.
- the adjustment includes reducing the serum gastrin level, or returning the increase of the serum gastrin level caused by the use of an acid suppressant to a normal level.
- the present inventors have found that, unlike other proton pump inhibitors or acid suppressants such as vornorazan fumarate, ilaprazole or a pharmaceutically acceptable salt thereof is capable of modulating Bacteroides in intestinal flora during use
- the bacterial abundances of both phyla and Firmicutes therefore have important implications for individuals with the need to regulate both.
- the present inventors also unexpectedly found that, compared with the acid-suppressing drug Vonolasan fumarate, ilaprazole or a pharmaceutically acceptable salt thereof has less effect on the gastrointestinal flora in the individual, thus It reduces the risk of lung infection, especially pneumonia, in patients undergoing acid suppression-related treatment, so it is expected to be used as an alternative to the use of vonolasan fumarate, thereby reducing the need for long-term use of acid suppressants or proton pump inhibitors It is also beneficial to the treatment of Helicobacter pylori, and it is more suitable for individuals who need long-term medication, such as patients with gastroesophageal reflux disease.
- ilaprazole or its pharmaceutically acceptable salt has less effect on the individual's serum gastrin level, thereby reducing the related effects of increased serum gastrin. Therefore, it is expected to be used to replace the use of vonolasan fumarate, thereby reducing the risk of gastritis, gastric ulcer and other diseases, atrophic gastritis, gastrin
- the improvement of intestinal microecology helps to enhance the digestive function.
- Figure 1 shows the effect of ilaprazole (left) and voranoxan fumarate (Right) On the 4th day after administration, the NMDS analysis of the differences in the flora in the feces of the subjects;
- Figure 2 shows the effect of ilaprazole (left) and voranoxan fumarate (Right) On the 7th day after administration, the NMDS analysis of the differences in the flora in the feces of the subjects;
- Figure 3 shows the effect of ilaprazole (left) and voranoxan fumarate (Right) On the 4th day after administration, the Anosim analysis of the differences in the flora in the feces of the subjects;
- Figure 4 shows the effect of ilaprazole (left) and voranoxan fumarate (Right) On the 7th day after administration, the Anosim analysis of the differences in the flora in the feces of the subjects;
- Figure 5 shows the Metastaststis analysis of the phylum-level flora in the feces of the subjects on the 7th day after ilaprazole administration, wherein the left side of the chart for each study is group A, and the right side is group E;
- Figure 6 shows the voranosan fumarate On the 7th day after administration, the Metastaststis analysis of the phylum-level flora in the feces of the subjects, in which the left side of the chart for each study is group B, and the right side is group F;
- Figure 7 shows the Metastaststis analysis of the species-level flora in the stool of the subject on the 7th day after ilaprazole administration, wherein the left side of the chart is group A, and the right side is group E;
- Figure 8 shows the voranosan fumarate On the 7th day after administration, the Metastaststis analysis of the species-level flora in the feces of the subjects, in which the left side of the chart for each study is group B, and the right side is group F.
- Example 1 Effects of ilaprazole and vonoranate fumarate on gastrointestinal flora
- Ilaprazole enteric-coated tablets (trade name: ): Specification: 5mg; produced by Livzon Group; store in a shading, sealed, and cool place (not exceeding 20°C);
- Vonola fumarate raw tablets (trade name: ): Specification: 20mg, batch number: 11848733, expiry date: December 2022, produced by Takeda Pharmaceutical Co., Ltd., and stored in airtight storage below 30°C.
- the subject fasted for at least 10 hours before the administration took the test drug orally with about 240 mL of water on an empty stomach on the morning of each cycle of administration, and abstained from drinking from 1 hour before the administration to 2 hours after the start of the administration (about 240 mL except water). You need to keep your upper body upright for 4 hours after taking the medicine (except for necessary activities).
- One day before the administration of the first cycle keep the upper body upright during the day on the first day, the seventh day and the eighth day of the gastric pH monitoring day (except for necessary activities).
- the emergency room should be equipped with first-aid equipment and first-aid medicine. Subjects were cared for by trained physicians and nurses.
- the first batch consisted of 4 subjects, and a randomized, open, multiple-dose, two-dose, two-sequence trial design was adopted. Divided into the first group and the second group on average, the first group took 1 tablet of ilaprazole enteric-coated tablet every day, specification: 5mg; The second group took 1 tablet of vornolan fumarate every day, specification: 20 mg. The second batch consisted of 8 subjects, who were equally divided into the third group and the fourth group. The third group took 2 tablets of ilaprazole enteric-coated tablets every day, specification: 5mg; the fourth group took voroxofumarate every day. Lasheng tablets 1 piece, specification: 20mg.
- the first batch and the second batch of subjects were all collected the feces of the subjects one day before the administration and in the morning of the 4th day and the 7th day after the administration for the detection of the intestinal microbiota (flora).
- Collect the feces in the disposable feces collection device use the sterile spoon in the disposable feces collection tube to sample from the middle of the feces sample, dig out 2 scoops (3-5g) and put them into the marked sample tube and backup tube respectively. It should be placed vertically, and transferred to a low-temperature thermos as soon as possible to store for testing.
- ilaprazole basically does not cause the flora of other bacteria to be overly affected, that is, it will not cause flora imbalance and induce related diseases, so its safety is significantly higher than that of vonolasan, thereby reducing the The risk of lung infection, especially pneumonia, in patients undergoing acid suppression-related treatment is also conducive to the treatment of Helicobacter pylori, and it is more suitable for individuals who need long-term medication, such as patients with gastroesophageal reflux disease. Given that the flora in the individual is in a state of balance without being disturbed, and both ilaprazole and vonolasan lead to an increase in gastric pH, the flora imbalance is generally induced first. However, as can be seen from the comparison of day 4 and day 7 in Tables 3 to 7 above, ilaprazole was able to return the flora in individuals to normal levels more quickly than vonolasan.
- the first batch of subjects and the second batch of subjects took gastric juice 1 day before administration, 2 days before administration, and 7 days before administration, and 12mL gastric juice was extracted with a 20mL syringe, placed in the sample tube, and transferred to a low temperature Store in a thermos for testing.
- the flora in the gastric juice was compared and analyzed, and according to the statistical results, the flora with significant differences in the abundance of bacteria before and after administration were classified and graded.
- the summary statistics of the test results are shown in Table 9 below.
- Table 9 The number of flora with significant differences in the abundance of gastric juice flora before the 2nd and 7th days of administration and the 1st day before administration
- NMDS analysis showed that compared with the ilaprazole group, there was a significant difference in the flora of the vonolasan group after the 7th day of administration. Further LEfSe discriminant analysis showed that Bifidobacteria, Escherichia coli and Klebsiella decreased after 7 days of Aipu administration; Bifidobacteria, Escherichia coli, Klebsiella, Enterococcus, Mycobacterium Bacillus and Salmonella decreased.
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Abstract
涉及艾普拉唑或其药学上可接受的盐用于调节肠道微生态,特别是调节拟杆菌门细菌和厚壁菌门细菌丰度的用途,还涉及艾普拉唑在降低肺部感染风险、调节胃微生态及血清胃泌素方面的用途,艾普拉唑尤其有利于对于幽门螺旋杆菌的治疗,更适合需要长期用药的个体,如胃食管反流症患者。
Description
本申请要求享有于2022年3月4日向中国国家知识产权局提交的,专利申请号为202210211033.5,发明名称为“艾普拉唑用于调节消化道微生态的用途”的在先申请的优先权,该在先申请的全文通过引用的方式结合于本申请中。
本发明涉及艾普拉唑或其药学上可接受的盐用于调节肠道微生态的用途,还涉及艾普拉唑或其药学上可接受的盐在降低肺部感染风险、调节胃微生态及血清胃泌素方面的用途。
质子泵抑制剂(Proton Pump Inhibitors,PPIs)能够选择性抑制人体胃黏膜细胞分泌小管膜上的H+/K+-ATP酶。由于该H+/K+-ATP酶是抑制胃酸分泌的最终途径,对其进行抑制可明显降低胃酸的分泌,因此质子泵抑制剂通常被用于治疗消化道由于胃酸作用而诱发或导致的相关疾病(即酸相关疾病),包括胃和十二指肠溃疡、胃食管反流病(GERD)、手术吻合口溃疡和卓-艾综合症等以及抗幽门螺杆菌。
根据作用机理,可以将已知的PPI分为非可逆性PPI和可逆性PPI(Reversible PPI,RPPIs);其中,非可逆性PPIs主要为苯并咪唑衍生物,它们能迅速穿过壁细胞膜并蓄积在强酸性的分泌小管中,然后质子化转化为次磺酰胺类化合物,后者可与H+/K+-ATP酶亚基中的半胱氨酸残基上的巯基形成共价结合的二硫键,由此使H+/K+-ATP酶不可逆地失活并且由此抑制其泌酸活性。
健康人群的肠道中存在与机体处于动态平衡状态下的各种菌群,它们共同参与机体的物质代谢并且维持人体正常的生理活动,对胃肠道的消化和免疫作用发挥重要作用。已知的是,肠道中存在的中性菌通常包括拟杆菌门和厚壁菌门的各种细菌,其中拟杆菌门的细菌有助于从膳食纤维和淀粉中释放能量并且
因此吸收营养的效率低,而厚壁菌门的细菌则正好相反,具有从少量食物中吸收大量能量的作用。然而在受到外来因素刺激时,可能导致这些菌群之间失去原有的平衡状态而引起一定的后果。在长期使用PPI的过程中,已经发现其可能造成胃内长期的低酸环境,即胃内pH值升高,导致胃肠道菌群失调,即不同菌群的比例和含量发生变化。另外,根据现有技术报道(参见陈李燊等,“质子泵抑制剂诱发感染危险性研究进展”《中国卫生标准管理》,第6卷,第28期,第136-137页),随着质子泵抑制剂临床使用越来越广泛,一些患者使用过程中出现并发肺炎状况,患者中使用质子泵抑制剂患者出现肺炎的发生率可达55%,有研究结果显示治疗组患儿使用质子泵抑制剂治疗后出现医院获得性肺炎的危险性与对照组患儿相比提升6.39倍。
PPI仍然是治疗GERD的首选药物,治疗中的共识意见建议,如单剂量PPI治疗无效可换用双倍剂量;如一种PPI治疗无效,可选用其他PPI进行治疗。研究显示,GERD治疗中最优胃酸抑制需要在24h中使胃内pH>4的时间达到16h,在疗程方面,共识意见认为PPI治疗GERD使用疗程至少8周。(参见中国医师协会外科医师分会胃食管反流病专业委员会.胃食管反流病外科诊疗共识(2019版)[J/CD].中华胃食管反流病电子杂志,2019,6(1):3-9.)
此外,血清胃泌素浓度主要作用在于营养胃肠道黏膜、刺激胰液和胃酸分泌。血清胃泌素增高更容易患有胃炎、胃溃疡等疾病、萎缩性胃炎、胃泌素瘤。
因此,如何在PPI的使用过程中尽量避免其副作用而利用其有利之处始终是本领域关注的问题。
发明内容
本发明人出人意料地发现,作为质子泵抑制剂的艾普拉唑(Ilaprazole)或其药学上可接受的盐在使用期间能够调节肠道菌群中的拟杆菌门(Bacteroidetes)和厚壁菌门(Firmicutes)的细菌,因而对有需求调节二者的个体具有重要的意义。此外,本发明人还出人意料地发现,相对于抑酸药物富马酸伏诺拉生,艾普拉唑对个体中的胃肠道菌群影响更小,由此降低了患者在进行抑酸相关治疗时出现肺部感染,尤其是肺炎的风险,也有利于对于幽门螺旋杆菌的治疗,更适合需要长期用药的个体,如胃食管反流症患者。另外,由
于艾普拉唑或其药学上可接受的盐在使用过程中更少地影响血清胃泌素水平,因而在使用艾普拉唑或其药学上可接受的盐的个体中能够相对于其它拉唑类药物降低该个体罹患胃炎、胃溃疡等疾病、萎缩性胃炎、胃泌素瘤的风险。
因此,在一方面,本发明提供了艾普拉唑或其药学上可接受的盐在制备用于在个体中调节菌群的药物中的应用,尤其是在制备用于在个体中调节消化道,优选胃肠道菌群的药物中的应用。
在一个实施方案中,本发明还提供了艾普拉唑或其药学上可接受的盐在制备用于在个体中调节肠道中拟杆菌门细菌和厚壁菌门细菌丰度的药物中的应用。
在一个实施方案中,本发明提供了艾普拉唑或其药学上可接受的盐在制备用于在个体中减少肠道拟杆菌门细菌并且增加肠道厚壁菌门细菌的药物中的应用。
在一个实施方案中,所述个体由于使用了不同于艾普拉唑或其药学上可接受的盐的质子泵抑制剂或抑酸剂而导致胃肠道菌群失调。优选地,所述失调包括肠道中拟杆菌门细菌和厚壁菌门细菌丰度失调。更优选地,肠道中拟杆菌门细菌和厚壁菌门细菌丰度失调是相对于健康个体而言肠道中拟杆菌门细菌增加和肠道中厚壁菌门细菌减少。
在一个实施方案中,所述个体由于使用了不同于艾普拉唑或其药学上可接受的盐的质子泵抑制剂或抑酸剂而存在肺部感染的风险或患有肺部感染。更优选地,所述肺部感染是肺炎球菌感染。
在一个实施方案中,所述个体由于使用了不同于艾普拉唑或其药学上可接受的盐的质子泵抑制剂或抑酸剂而存在耐受性差,如需要幽门螺旋杆菌的治疗或需长期用药。
在一个实施方案中,艾普拉唑的药学上可接受的盐可以选自艾普拉唑钠、艾普拉唑镁、艾普拉唑锌、艾普拉唑钾、艾普拉唑锂或艾普拉唑钙等。
在一个实施方案中,个体可以是健康的人类或患有下述胃肠道疾病的人类:胃灼热、炎性肠病、克罗恩病、过敏性肠综合征、溃疡性结肠炎、消化性溃疡、应激性溃疡、出血性消化性溃疡、十二指肠溃疡及十二指肠溃疡复发、与非甾体抗炎药(NSAID)相关的胃溃疡、成人活动性良性胃溃疡、感染性肠炎、结
肠炎、胃酸过多症、消化不良、胃轻瘫、佐林格-埃利森综合征、胃食管返流疾病(GERD)、幽门螺旋杆菌相关的疾病、糜烂性食管炎、短肠综合征,或者任何以上疾病的组合。
在一个实施方案中,拟杆菌门细菌包括拟杆菌纲(Bacteroidia),优选拟杆菌目(Bacteroidales),更优选拟杆菌科(Bacteroidaceae),还更优选拟杆菌属(Bacteroides)的细菌。
在一个实施方案中,厚壁菌门细菌优选包括芽孢杆菌纲(Bacilli),优选乳杆菌目(Lactobacillales),更优选乳杆菌科(Lactobacillaceae),还更优选乳杆菌属(Lactobacillus)的细菌,最优选乳酸杆菌(Bacillus acidi lactici)。
在一个实施方案中,所述药物包括片剂优选双层片、咀嚼片、口腔崩解片,口含片,糖衣丸,乳剂,混悬剂,溶液剂,颗粒剂,滴丸剂,微丸优选肠溶微丸或缓释微丸,冻干粉针剂,注射剂,软胶囊或胶囊。
在一个实施方案中,所述药物中包含1mg至20mg单位剂量的艾普拉唑或其药学上可接受的盐,优选地,所述单位剂量可以为1mg、1.5mg、2mg、2.5mg、3mg、3.5mg、4mg、4.5mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg或20mg。
在一个实施方案中,在对个体给予所述药物时,艾普拉唑或其药学上可接受的盐的剂量为1-40mg/天,优选2.5-20mg/天,更优选约5-10mg/天,最优选约5mg/天或10mg/天。用药时间视需要而定,至少为一周、两周,或者1个月,最长可能因需要而终身给药。
在一个实施方案中,所述抑酸剂是富马酸伏诺拉生。
在本发明的又一方面,本发明提供了艾普拉唑或其药学上可接受的盐用于调节个体中血清胃泌素水平的用途,优选调节由于使用抑酸剂导致的血清胃泌素水平升高的用途。优选地,所述抑酸剂是富马酸伏诺拉生。优选地,所述调节包括降低血清胃泌素水平,或将由于使用抑酸剂导致的血清胃泌素水平升高回调至正常水平。
在本发明的再一方面,本发明还提供了一种试剂盒,其包含单独或与另外的活性成分组合的艾普拉唑或其药学上可接受的盐并且说明书中标明艾普拉唑或其药学上可接受的盐被用于降低肠道中拟杆菌门细菌数量并且增加厚壁菌门
细菌数量,和/或用于对肺炎球菌敏感的个体,和/或用于降低血清胃泌素水平,优选将由于使用抑酸剂导致的血清胃泌素水平升高回调至正常水平。优选地,所述抑酸剂是富马酸伏诺拉生。优选地,所述调节包括降低血清胃泌素水平,或将由于使用抑酸剂导致的血清胃泌素水平升高回调至正常水平。
在本发明的一个方面,本发明提供了用于调节个体中血清胃泌素水平的方法,优选调节由于使用抑酸剂导致的血清胃泌素水平升高的方法,所述方法包括向有此需要的个体给予艾普拉唑或其药学上可接受的盐。优选地,所述抑酸剂是富马酸伏诺拉生。优选地,所述调节包括降低血清胃泌素水平,或将由于使用抑酸剂导致的血清胃泌素水平升高回调至正常水平。
在本发明的一个方面,本发明提供了艾普拉唑或其药学上可接受的盐,其用于调节个体中血清胃泌素水平的用途,优选调节由于使用抑酸剂导致的血清胃泌素水平升高的用途。优选地,所述抑酸剂是富马酸伏诺拉生。优选地,所述调节包括降低血清胃泌素水平,或将由于使用抑酸剂导致的血清胃泌素水平升高回调至正常水平。
本发明的有益效果
本发明人发现,不同于其它质子泵抑制剂或抑酸剂如富马酸伏诺拉生,艾普拉唑或其药学上可接受的盐在使用期间能够调节肠道菌群中的拟杆菌门和厚壁菌门的细菌丰度,因而对有需求调节二者的个体具有重要的意义。此外,本发明人还出人意料地发现,相对于抑酸药物富马酸伏诺拉生,艾普拉唑或其药学上可接受的盐对个体中的胃肠道菌群影响更小,由此降低了患者在进行抑酸相关治疗时出现肺部感染,尤其是肺炎的风险,因而有望用于替代富马酸伏诺拉生的使用,从而降低不得不长期使用抑酸剂或质子泵抑制剂的群体罹患肺部疾病的风险,也有利于对于幽门螺旋杆菌的治疗,更适合需要长期用药的个体,如胃食管反流症患者。相对于抑酸药物富马酸伏诺拉生,艾普拉唑或其药学上可接受的盐对个体的血清胃泌素水平影响更小,由此降低了血清胃泌素增高带来的有关疾病的风险,因而有望用于替代富马酸伏诺拉生的使用,从而降低不得不长期使用抑酸剂或质子泵抑制剂的群体罹患胃炎、胃溃疡等疾病、萎缩性胃炎、胃泌素瘤的风险;另外,肠道微生态的改善有助于消化功能的增强。
图1显示了在艾普拉唑(左)和富马酸伏诺拉生(右)给药后第4天,受试者粪便中菌群差异的NMDS分析;
图2显示了在艾普拉唑(左)和富马酸伏诺拉生(右)给药后第7天,受试者粪便中菌群差异的NMDS分析;
图3显示了在艾普拉唑(左)和富马酸伏诺拉生(右)给药后第4天,受试者粪便中菌群差异的Anosim分析;
图4显示了在艾普拉唑(左)和富马酸伏诺拉生(右)给药后第7天,受试者粪便中菌群差异的Anosim分析;
图5显示了在艾普拉唑给药后第7天,受试者粪便中门级菌群Metastaststis分析,其中针对每个研究的图表中左侧为A组,右侧为E组;
图6显示了在富马酸伏诺拉生给药后第7天,受试者粪便中门级菌群Metastaststis分析,其中针对每个研究的图表中左侧为B组,右侧为F组;
图7显示了艾普拉唑给药后第7天,受试者粪便中种级菌群Metastaststis分析,其中图表中左侧为A组,右侧为E组;
图8显示了在富马酸伏诺拉生给药后第7天,受试者粪便中种级菌群Metastaststis分析,其中针对每个研究的图表中左侧为B组,右侧为F组。
除非另外指明,否则本文所有科技术语具有的含义与所属技术领域的技术人员通常理解的含义相同。除非另外指明,否则本文中以全文或部分引用的所有专利和非专利文献或以其他方式公开的材料均通过引用方式并入本文。
实施例
下文将结合具体实施例对本发明的制备方法做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明的内容所实现的技术方案均涵盖在本发明旨在保护的范围内。
除非另外指明,否则下述实施例中所使用的实验方法均为本领域常规方法;下述实施例中所使用的试剂、原料、仪器、设备等,均可从商业途径获得。
实施例1 艾普拉唑与富马酸伏诺拉生对胃肠道菌群的影响
本试验的目的在于观察并比较艾普拉唑肠溶片与富马酸伏诺拉生片连续服药对胃肠道菌群的影响
试验用药物
艾普拉唑肠溶片(商品名:):规格:5mg;由丽珠集团生产;在遮光,密封,阴凉(不超过20℃)处保存;
富马酸伏诺拉生片(商品名:):规格:20mg,批号:11848733,有效期:2022年12月,日本武田制药公司生产,在30℃以下密闭保存。
受试者和给药方案
受试者总计为12名,第一批为4名,第二批为8名,分两批进行,每组受试者按计划给药。
研究开始后受试者被禁止随意出入观察室、禁止自带饮食、吸烟、饮酒、剧烈活动等。
受试者在给药前至少空腹10小时,在每周期给药当天早晨空腹用约240mL水口服试验用药品,给药前1小时至开始给药后2小时禁饮(服用时引用的约240mL水除外)。服药后4小时内您需要保持上身直立状态(必要的活动除外)。第一周期给药前1天,每周期给药第1天、第7天及第8天胃pH监测日白天需保持上身直立状态(必要的活动除外)。
每周期给药第1天、第7天给药后4小时后进食午餐、10小时后进食晚餐;其他给药日给药后1h进食早餐、给药后4小时后进食午餐、10小时后进食晚餐,每个周期给药当天的进食时间应大致相同。
研究期间,所有受试者在给药结束后48小时内均不能离开I期观察室。急救室需配备急救设备和急救药物。由培训过的医师和护士负责照料受试者。
第一批为4例受试者,采用随机、开放、多剂量、两制剂、两序列试验设计。平均分为第一组和第二组,第一组每天服用艾普拉唑肠溶片1片,规格:5mg;
第二组每天服用富马酸伏诺拉生片1片,规格:20mg。第二批为8例受试者,平均分为第三组和第四组,第三组每天服用艾普拉唑肠溶片2片,规格:5mg;第四组每天服用富马酸伏诺拉生片1片,规格:20mg。
样品(粪便)采集
第一批和第二批受试者均在给药前1天及给药后第4天、第7天清晨采集受试者粪便进行肠道微生物群(菌群)检测。
将粪便采集在一次性集便器中,用一次性粪便采集管中的无菌勺从粪便样品中部取样,挖取2勺(3-5g)分别放入标记好的样品管和备份管中,勺子应垂直放入,并尽快转移至低温保温壶中保存待测。
试验结果
1.1相对丰度分析
在每个周期分析给药后第4天和给药后第7天的粪便菌群,以相对丰度的方式分析所采集的受试者粪便样品中的各种类细菌含量,结果汇总如下表3-7所示:
表3受试者粪便样品中乳酸杆菌相对丰度分析
表4受试者粪便样品中大肠杆菌相对丰度分析
表5受试者粪便样品中双歧杆菌相对丰度分析
表6受试者粪便样品中肠球菌属相对丰度分析
表7受试者粪便样品中拟杆菌纲相对丰度分析
1.2受试者粪便样品中各菌群统计学分析
现在参照附图,对NMDS差异分析和Anosim差异分析进行阐述说明。
参见图1和图2,通过NMDS差异分析可以看出,富马酸伏诺拉生组的受试者粪便样品中显示在给药第4天和给药第7天的肠道菌群与基线均有差异,而艾普拉唑组无明显的差异,说明艾普拉唑对肠道菌群的微生态影响小或无影响。参见图3和图4,通过进一步Anosim差异分析发现富马酸伏诺拉生的肠道菌群在基线、给药第4天、给药第7天均有显著差异,因此相比于艾普拉唑,富马酸伏诺拉生对肠道微生态影响大。
通过采用Metastats检验分析(参见图5~7)发现艾普拉唑给药后拟杆菌门减少,厚壁菌门增加;伏诺拉生给药后拟杆菌门减少,变形菌门、链球菌、嗜血杆菌增加,结果汇总如下表8所示。
表8:Metastats检验分析结果
由此可见,在艾普拉唑使用4天后,菌的变化较小,而伏诺拉生的菌的变化
较大,变形菌门、嗜血杆菌、链球菌的有害菌群均有显著的增加;艾普拉唑在给药一个周期之后,导致受试者中拟杆菌门细菌数量降低而同时厚壁菌门细菌的数量增加,由此对有需求调节二者的个体具有重要的意义。另外,艾普拉唑在服药后基本上不会导致其它细菌的菌群受到过度影响,即不会导致菌群失衡从而诱发相关疾病,因此安全性明显高于伏诺拉生,由此降低了患者在进行抑酸相关治疗时出现肺部感染,尤其是肺炎的风险,也有利于对于幽门螺旋杆菌的治疗,更适合需要长期用药的个体,如胃食管反流症患者。鉴于个体中的菌群在未受到干扰的情况下处于平衡状态,而无论是使用艾普拉唑还是伏诺拉生之后,均导致胃内pH升高,一般首先会诱发菌群失衡。然而,从上表3至7中第4天与第7天的对比可以看出,与伏诺拉生相比,艾普拉唑能够更快地使个体中的菌群回归正常水平。
1.3胃液菌群统计分析
胃液采集
第一批和第二批受试者均在给药前1天及第2天给药前、第7天给药前抽取胃液,用20mL注射器抽取12mL胃液,放置于样品管后,转移至低温保温壶中保存待测。
对胃液中的菌群进行对比分析,依照统计学结果对给药前后,细菌的丰度产生显著性差异的菌群进行分类和分级,汇总统计的试验结果如下表9中所示。
表9第2、7天给药前与给药前1天胃液菌群丰度有显著性差异的菌群数目
从上表9可以看出,对比第2天给药前和第7天给药前的胃液菌群,可以发现
在第7天给药前,伏诺拉生组丰度发生显著性差异的菌群数目远高于艾普拉唑组,第2天给药前两组差异不明显。
1.4受试者胃液中菌群的NMDS分析、LEfSe分析
NMDS分析显示相对于艾普拉唑组,伏诺拉生组给药第7天后菌群有显著差异。进一步LEfSe判别分析表明,艾普给药7天后双歧杆菌、大肠杆菌、克雷伯杆菌减少;伏诺拉生组双歧杆菌、大肠杆菌、克雷伯杆菌、肠球菌、分枝杆菌、乳酸杆菌、沙门氏菌减少。
1.5血清胃泌素水平分析
血清胃泌素样本的采集
给药第1天给药前及给药后第4天、第8天清晨抽取受试者空腹静脉血5mL进行血清胃泌素浓度检测。
表10第二批受试者血清胃泌素水平
在给药第8天,10mg艾普拉唑肠溶片与20mg富马酸伏诺拉生片血清胃泌素浓度差异具有统计学意义。
上文对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
- 艾普拉唑或其药学上可接受的盐在制备用于在个体中调节菌群,优选肠道菌群的药物中的应用。
- 根据权利要求1所述的应用,其中所述调节菌群是调节肠道拟杆菌门细菌和厚壁菌门细菌丰度;优选地,所述拟杆菌门细菌包括拟杆菌纲(Bacteroidia),优选拟杆菌目(Bacteroidales),更优选拟杆菌科(Bacteroidaceae),还更优选拟杆菌属(Bacteroides)的细菌;优选地,所述厚壁菌门细菌优选包括芽孢杆菌纲(Bacilli),优选乳杆菌目(Lactobacillales),更优选乳杆菌科(Lactobacillaceae),还更优选乳杆菌属(Lactobacillus)的细菌,最优选乳酸杆菌(Bacillus acidi lactici)。
- 根据权利要求1或2所述的应用,其中所述调节菌群是指在个体中减少肠道拟杆菌门细菌并且增加肠道厚壁菌门细菌。
- 根据权利要求1至3任一项所述的应用,其中,所述个体由于使用了不同于艾普拉唑或其药学上可接受的盐的质子泵抑制剂或抑酸剂而导致胃肠道菌群失调;优选地,所述失调包括肠道中拟杆菌门细菌和厚壁菌门细菌丰度失调。更优选地,肠道中拟杆菌门细菌和厚壁菌门细菌丰度失调是相对于健康个体而言肠道中拟杆菌门细菌增加和肠道中厚壁菌门细菌减少。
- 根据权利要求1至4任一项所述的应用,其中,所述抑酸剂是富马酸伏诺拉生。
- 根据权利要求1至5任一项所述的应用,其中,所述个体由于使用了不同于艾普拉唑或其药学上可接受的盐的质子泵抑制剂或抑酸剂而存在肺部感染的风险或患有肺部感染;更优选地,所述肺部感染是肺炎球菌感染。
- 根据权利要求1至5任一项所述的应用,其中,艾普拉唑的药学上可接受的盐选自艾普拉唑钠、艾普拉唑镁、艾普拉唑锌、艾普拉唑钾、艾普拉唑锂或艾普拉唑钙。
- 根据权利要求1至5任一项所述的应用,其中,所述个体患有下述胃肠道疾病:胃灼热、炎性肠病、克罗恩病、过敏性肠综合征、溃疡性结肠炎、消化性溃疡、应激性溃疡、出血性消化性溃疡、十二指肠溃疡及十二指肠溃疡复发、与非甾体抗炎药(NSAID)相关的胃溃疡、成人活动性良性胃溃疡、感染性肠炎、结肠炎、胃酸过多症、消化不良、胃轻瘫、佐林格-埃利森综合征、胃食管返流疾病(GERD)、幽门螺旋杆菌相关的疾病、糜烂性食管炎、短肠综合征,或者任何以上疾病的组合。
- 艾普拉唑或其药学上可接受的盐用于调节个体中血清胃泌素水平的用途,优选调节由于使用抑酸剂导致的血清胃泌素水平升高的用途;优选地,所述抑酸剂是富马酸伏诺拉生;优选地,所述调节包括降低血清胃泌素水平,或将由于使用抑酸剂导致的血清胃泌素水平升高回调至正常水平。
- 一种试剂盒,其包含单独的或与另外的活性成分组合的艾普拉唑或其药学上可接受的盐并且说明书中标明其被用于降低肠道中拟杆菌门细菌数量并且增加厚壁菌门细菌数量,和/或用于对肺炎球菌敏感的个体,和/或用于降低血清胃泌素水平,优选将由于使用抑酸剂导致的血清胃泌素水平升高回调至正常水平。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070082929A1 (en) * | 2005-10-06 | 2007-04-12 | Gant Thomas G | Inhibitors of the gastric H+, K+-atpase with enhanced therapeutic properties |
US20100113524A1 (en) * | 2006-09-19 | 2010-05-06 | Garst Michael E | Prodrugs of proton pump inhibitors including the (1h-pyrrol-1-yl)-1h-benzimidazole moiety |
CN102973940A (zh) * | 2011-09-02 | 2013-03-20 | 丽珠医药集团股份有限公司 | 一种用于抑制或杀灭幽门螺旋杆菌的药物组合物及其用途 |
CN104857017A (zh) * | 2015-05-14 | 2015-08-26 | 邓学峰 | 一种艾普拉唑的药物组合物 |
CN107174662A (zh) * | 2017-05-23 | 2017-09-19 | 珠海赛隆药业股份有限公司 | 质子泵抑制剂和胃粘膜保护剂组成的复合物及其用途 |
-
2022
- 2022-03-04 CN CN202210211033.5A patent/CN116726011A/zh active Pending
-
2023
- 2023-03-03 WO PCT/CN2023/079657 patent/WO2023165619A1/zh unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070082929A1 (en) * | 2005-10-06 | 2007-04-12 | Gant Thomas G | Inhibitors of the gastric H+, K+-atpase with enhanced therapeutic properties |
US20100113524A1 (en) * | 2006-09-19 | 2010-05-06 | Garst Michael E | Prodrugs of proton pump inhibitors including the (1h-pyrrol-1-yl)-1h-benzimidazole moiety |
CN102973940A (zh) * | 2011-09-02 | 2013-03-20 | 丽珠医药集团股份有限公司 | 一种用于抑制或杀灭幽门螺旋杆菌的药物组合物及其用途 |
CN104857017A (zh) * | 2015-05-14 | 2015-08-26 | 邓学峰 | 一种艾普拉唑的药物组合物 |
CN107174662A (zh) * | 2017-05-23 | 2017-09-19 | 珠海赛隆药业股份有限公司 | 质子泵抑制剂和胃粘膜保护剂组成的复合物及其用途 |
Non-Patent Citations (1)
Title |
---|
DAWEI WU, YANG YUSHUANG, CUI QINGZHI: "Clinical Research of Ilaprazole Sequential in treatment of Peptic Ulcer and the Effects on Serum Gastrin and Gastrin Gene Expression ", HEBEI-YIXUE = HEBEI MEDICINE, XX, CN, vol. 24, no. 5, 31 May 2018 (2018-05-31), CN , pages 791 - 794, XP093088877, ISSN: 1006-6233, DOI: 10.3969/j.issn.1006-6233.2018.05.023 * |
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