Methods for preventing or treating Helicobacter pylori (H. pylori) infection

Abstract

The present disclosure provides methods, drug combinations, and kits for treating, ameliorating, reversing, and / or preventing Helicobacter pylori (H. pylori) infection in a subject in need thereof.

Description

[Background technology]

[0001] Helicobacter pylori (H. pylori) is a major causative pathogen of chronic gastritis, peptic ulcer disease, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. It was classified as a Class I carcinogen by the World Health Organization's International Agency for Research on Cancer (WHO / IARC) in 1994. Globally, over half of adults are infected with H. pylori. The majority of H. pylori-infected individuals have chronic gastritis, approximately 10% develop peptic ulcer disease, and 1–3% develop gastric cancer. The prevalence of H. pylori infection in the adult population in China is 40–60%. According to the WHO / IARC 2014 World Cancer Report, the number of newly reported cases of gastric cancer in China in 2012 was 405,600, accounting for 42.6% of the total number of new cases worldwide, and approximately 325,400 people died from gastric cancer in China in 2012. Numerous clinical studies have shown that eradicating Helicobacter pylori can effectively prevent the recurrence of peptic ulcers and the occurrence of gastric cancer.

[0002] There are many problems associated with current treatments for Helicobacter pylori eradication. Due to the emergence and development of drug resistance, the eradication rate of standard triple therapy (clarithromycin, amoxicillin, and proton pump inhibitors) has declined from 90% in the early days to 50-70% today. In China, the problem of drug resistance is even more serious, with high resistance rates for the three most widely used antimicrobial drugs for eradicating Helicobacter pylori (metronidazole 40-70%, clarithromycin 20-50%, and levofloxacin 20-50%). To improve eradication rates, an expert consensus report published in China in 2016 recommended the use of bismuth quadruple therapy as first-line treatment in China. A recent large-scale clinical trial in China showed that the eradication rate with bismuth quadruple therapy was only 72.9%.

[0003] Therefore, there is an urgent need to develop new therapies for eradicating Helicobacter pylori, especially those that can address the problem of drug resistance. Summary of the Invention

[0004] The present disclosure provides new methods and products (e.g., drug combinations and / or kits) for treating, ameliorating, reversing, and / or preventing Helicobacter pylori (H. pylori) infection. The methods and products of the disclosure are highly effective in eradicating H. pylori, including drug-resistant H. pylori.

[0005] In one aspect, the present disclosure provides a method for treating, ameliorating, reversing, and / or preventing Helicobacter pylori (H. pylori) infection in a subject in need thereof, comprising administering to the subject an effective amount of compound I, 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin or a pharmaceutically acceptable salt thereof, and an effective amount of an acid blocker.

[0006] In some embodiments, compound I has formula 1 [ka] is a compound of

[0007] In some embodiments, compound I is 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S.

[0008] In some embodiments, compound I has formula 2 [ka] is a compound of

[0009] In some embodiments, Compound I is administered to a subject at a dose of about 400 mg to about 600 mg twice daily (BID) or three times daily (TID).

[0010] In some embodiments, Compound I is administered to a subject for 7 to 14 consecutive days.

[0011] In some embodiments, each time Compound I is administered to a subject after a meal.

[0012] In some embodiments, Compound I is administered in one or more dosage units, each dosage unit containing from about 100 mg to about 400 mg of Compound I.

[0013] In some embodiments, Compound I is administered as a capsule or tablet.

[0014] In some embodiments, the acid blocker is a proton pump inhibitor (PPI).

[0015] In some embodiments, the acid blocker is administered to a subject at a dose of about 10 mg to about 40 mg twice daily (BID) or three times daily (TID).

[0016] In some embodiments, the acid blocker is administered to the subject for at least 7-14 consecutive days.

[0017] In some embodiments, the acid blocker is administered as an enteric coated tablet.

[0018] In some embodiments, each enteric-coated tablet contains from about 10 mg to about 20 mg of an acid blocker.

[0019] In some embodiments, the acid blocker is selected from the group consisting of rabeprazole sodium, esomeprazole magnesium, omeprazole, lansoprazole, pantoprazole sodium, and ilaprazole.

[0020] In some embodiments, an acid blocker is administered to a subject along with Compound I.

[0021] In some embodiments, the method further comprises administering to the subject an effective amount of an additional antibiotic.

[0022] In some embodiments, the additional antibiotic is selected from the group consisting of rifabutin, clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, and furazolidone.

[0023] In some embodiments, the additional antibiotic is administered to the subject at a dose of about 100 mg to about 1000 mg twice daily (BID) or three times daily (TID).

[0024] In some embodiments, the additional antibiotic is administered to the subject for 7 to 14 consecutive days.

[0025] In some embodiments, the additional antibiotic is administered to the subject after a meal.

[0026] In some embodiments, the additional antibiotic is administered as a capsule or tablet, hi some embodiments, each capsule or tablet contains from about 100 mg to about 500 mg of the additional antibiotic.

[0027] In some embodiments, the additional antibiotic is amoxicillin.

[0028] In some embodiments, an additional antibiotic is administered to the subject along with Compound I and an acid blocker.

[0029] In some embodiments, the Helicobacter pylori is resistant to one or more antibiotics selected from the group consisting of clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, furazolidone, and rifabutin.

[0030] In some embodiments, the Helicobacter pylori is resistant to rifabutin and / or metronidazole.

[0031] In another aspect, the present disclosure provides a drug combination, comprising an effective amount of compound I 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin or a pharmaceutically acceptable salt thereof, and an effective amount of an acid blocker.

[0032] In some embodiments of the drug combination, Compound I is represented by Formula 1 [ka] is a compound of

[0033] In some embodiments of the drug combination, Compound I is 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S.

[0034] In some embodiments of the drug combination, Compound I is represented by Formula 2 [ka] is a compound of

[0035] In some embodiments of the drug combination, Compound I is included in an amount suitable for administration at a dose of about 400 mg to about 600 mg twice daily (BID) or three times daily (TID).

[0036] In some embodiments of the drug combination, Compound I is included in an amount suitable for administration for 7 to 14 consecutive days.

[0037] In some embodiments of the pharmaceutical combination, Compound I is contained in the form of a capsule or tablet. In some embodiments of the pharmaceutical combination, each capsule or tablet contains about 100 mg to about 400 mg of Compound I.

[0038] In some embodiments of the drug combination, the acid blocker is a proton pump inhibitor (PPI).

[0039] In some embodiments of the drug combination, the acid blocker is included in an amount suitable for administration at a dose of about 10 mg to about 40 mg twice daily (BID) or three times daily (TID).

[0040] In some embodiments of the drug combination, the acid blocker is included in an amount suitable for administration for at least 7 to 14 consecutive days.

[0041] In some embodiments of the drug combination, the acid blocker is included in the form of an enteric-coated tablet.

[0042] In some embodiments of the drug combination, each enteric-coated tablet contains from about 10 mg to about 20 mg of an acid blocker.

[0043] In some embodiments of the drug combination, the acid blocker is selected from the group consisting of rabeprazole sodium, esomeprazole magnesium, omeprazole, lansoprazole, pantoprazole sodium, and ilaprazole.

[0044] In some embodiments, the drug combination further comprises an effective amount of an additional antibiotic.

[0045] In some embodiments of the drug combination, the additional antibiotic is selected from the group consisting of rifabutin, clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, and furazolidone.

[0046] In some embodiments of the drug combination, the additional antibiotic is included in an amount suitable for administration at a dose of about 100 mg to about 1000 mg twice daily (BID) or three times daily (TID).

[0047] In some embodiments of the drug combination, the additional antibiotic is included in an amount suitable for administration for 7 to 14 consecutive days.

[0048] In some embodiments of the drug combination, the additional antibiotic is included in the form of a capsule or tablet, hi some embodiments, each capsule or tablet contains from about 100 mg to about 500 mg of the additional antibiotic.

[0049] In some embodiments of the drug combination, the additional antibiotic is amoxicillin.

[0050] In another aspect, the present disclosure provides a kit comprising a drug combination of the present disclosure.

[0051] In some embodiments, the kit further comprises instructions for applying the methods of the present disclosure.

[0052] In another aspect, the present disclosure provides use of an effective amount of compound I 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin or a pharmaceutically acceptable salt thereof and an effective amount of an acid blocker in the manufacture of a medicament for treating, ameliorating, reversing and / or preventing Helicobacter pylori (H. pylori) infection in a subject in need thereof.

[0053] In another aspect, the present disclosure provides use of a drug combination of the present disclosure or a kit of the present disclosure in the manufacture of a medicament for treating, ameliorating, reversing and / or preventing Helicobacter pylori (H. pylori) infection in a subject in need thereof.

[0054] In some embodiments, the Helicobacter pylori is resistant to one or more antibiotics selected from the group consisting of clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, furazolidone, and rifabutin.

[0055] In some embodiments, the Helicobacter pylori is resistant to rifabutin and / or metronidazole.

[0056] In another aspect, the present disclosure provides a drug combination of the present disclosure or a kit of the present disclosure for use in treating, ameliorating, reversing, and / or preventing Helicobacter pylori (H. pylori) infection in a subject in need thereof. In some embodiments, the Helicobacter pylori is resistant to one or more antibiotics selected from the group consisting of clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, furazolidone, and rifabutin. In some embodiments, the Helicobacter pylori is resistant to rifabutin and / or metronidazole.

[0057]

[0013] Further aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modification in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

[0058] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0059] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also referred to herein as "FIG.", "Fig." and "FIG."). [Brief explanation of the drawings]

[0060] [Figure 1] FIG. 1 shows a comparison of dissolution profiles of different dosage forms and strengths. [Figure 2] FIG. 1 shows a comparison of dissolution profiles of different dosage forms and strengths. [Figure 3] FIG. 1 shows a comparison of dissolution profiles of different dosage forms and strengths. DETAILED DESCRIPTION OF THE INVENTION

[0061] While various embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be used.

[0062] As used herein, the terms "antibiotic," "antimicrobial compound," and "antibiotic agent" are used interchangeably and generally refer to compounds or compositions that reduce the viability of or inhibit the growth or reproduction of microorganisms. "Inhibiting growth or reproduction" means increasing the developmental cycle time by at least twofold, e.g., at least 10-fold, at least 100-fold, or indefinitely, as in total cell death. Antibiotics can be naturally occurring, semi-synthetic, or fully synthetic agents that inhibit the growth of microorganisms (i.e., bacteria, fungi, viruses, parasites, and microbial spores), thereby preventing their development and microbial or pathogenic action. Antibiotic agents can be selected from the group consisting of small organic or inorganic molecules; sugars; oligosaccharides; polysaccharides; biological macromolecules, such as peptides, proteins, and peptide analogs and derivatives; peptidomimetics; antibodies and antigen-binding fragments thereof; nucleic acids; nucleic acid analogs and derivatives; glycogen or other sugars; immunogens; antigens; extracts made from biological materials such as bacteria, plants, fungi, or animal cells; animal tissue; naturally occurring or synthetic compositions; and any combination thereof. As used herein, "antibiotics" is intended to encompass antibacterial or antimicrobial agents, antifungal agents, antiprotozoal agents, antiviral agents and mixtures thereof.

[0063] As used herein, the term "acid blocker" generally refers to an agent that can reduce the amount, secretion and / or effects of acid (eg, gastric acid) in a subject.

[0064] As used herein, the term "drug combination" generally refers to a pharmaceutical product (e.g., a prescription drug) that contains two or more active ingredients. The two or more active ingredients may be contained in a single composition, a single package, separate, distinct compositions, or separate packages.

[0065] As used herein, the term "effective amount" generally refers to the amount necessary to produce a desired result, such as preventing, reducing, reversing, or alleviating the symptoms of a disease or disorder. Sometimes, the desired result can include enhancing the bioavailability of another drug or compound. Sometimes, the desired result can include favorable treatment of a disease state or condition. The term "effective" encompasses both the amount or concentration of one or more active agents described herein and the duration consistent with producing the intended effect.

[0066] As used herein, the term "Helicobacter pylori (H. pylori) infection" generally refers to the presence of abnormal levels or activity of H. pylori. A subject can be classified as having an H. pylori infection if whole H. pylori organisms, H. pylori genes, H. pylori proteins, H. pylori protein activity (e.g., urease activity), or human antibodies specific for H. pylori proteins or lipids are detected in the subject's tissues (tissue biopsy, blood, stool, saliva, etc.).

[0067] As used herein, the term "kit" generally refers to a collection or combination of materials, compositions, and / or items (such as tools, containers, or devices). A kit may also include instructions for using the kit. Different components of the kit may be packaged and provided separately.

[0068] As used herein, the term "pharmaceutically acceptable salt" generally refers to a salt of a compound that does not cause significant irritation to a subject to which it is administered and that does not abolish the biological activity and properties of the compound.

[0069] As used herein, the term "proton pump inhibitor" or "PPI" generally refers to an agent that can block, inhibit, or reduce the activity of the hydrogen-potassium adenosine triphosphatase enzyme (H,K-ATPase) system in a subject (e.g., on the luminal surface), thereby preventing or inhibiting acid secretion in the subject.

[0070] As used herein, the term "resistance" or "drug resistance" generally refers to the decreased effectiveness of a medication, such as an antimicrobial or antibiotic, in preventing or treating a disease or disorder. When an organism is resistant to more than one drug, it may be characterized as multidrug resistant.

[0071] As used herein, the term "subject" includes living organisms in which a disease or disorder can occur. The term "subject" includes animals (e.g., mammals (e.g., cats, dogs, horses, pigs, cows, goats, sheep, rodents (e.g., mice or rats), rabbits, squirrels, bears, primates (e.g., chimpanzees, monkeys, gorillas, and humans)), and birds (e.g., chickens, ducks, Peking ducks, geese), and transgenic species thereof. In some cases, the subject is a human or non-human primate (e.g., chimpanzees, monkeys, macaques, gorillas). In some cases, the subject is a human.

[0072] As used herein, unless expressly stated or clear from the context, the term "about" is understood to be within a normal range of variation, e.g., within two standard deviations of the mean, which may be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value.

[0073] Unless otherwise specified, "a," "an," "the," and "at least one" are used interchangeably and refer to one or more than one.

[0074] In the present disclosure, the term "comprise" also encompasses "is," "has," and "consist of." For example, "a composition comprising X and Y" can be understood to include compositions that include at least X and Y. This should also be understood to disclose compositions that include only X and Y (i.e., compositions consisting of X and Y).

[0075] In one aspect, the present disclosure provides a method for treating, ameliorating, reversing, and / or preventing Helicobacter pylori (H. pylori) infection in a subject in need thereof, comprising administering to the subject an effective amount of compound I, 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin or a pharmaceutically acceptable salt thereof, and an effective amount of an acid blocker.

[0076] In another aspect, the present disclosure provides a drug combination, comprising an effective amount of compound I 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin or a pharmaceutically acceptable salt thereof, and an effective amount of an acid blocker.

[0077] In another aspect, the present disclosure provides a kit comprising a drug combination of the present disclosure.

[0078] In another aspect, the present disclosure provides use of an effective amount of compound I 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin or a pharmaceutically acceptable salt thereof and an effective amount of an acid blocker in the manufacture of a medicament for treating, ameliorating, reversing and / or preventing Helicobacter pylori (H. pylori) infection in a subject in need thereof.

[0079] In another aspect, the present disclosure provides use of a drug combination or kit of the present disclosure in the manufacture of a medicament for treating, ameliorating, reversing and / or preventing Helicobacter pylori (H. pylori) infection in a subject in need thereof.

[0080] In some cases, the methods of the present disclosure further comprise administering to the subject an effective amount of an additional antibiotic.

[0081] In some cases, the drug combination of the present disclosure further comprises an effective amount of an additional antibiotic.

[0082] Compound I Compound I of the present disclosure is represented by formula 1 [ka] In some cases, compound I is (9S,12E,14S,15R,16S,17R,18R,19R,20S,21S,22E,24Z)-16-(acetyloxy)-6,18,20-trihydroxy-14-methoxy(methyoxy)-7,9,15,17,19,21,25-heptamethyl-1'-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]spiro[9,4-(epoxypentadeca[1,11,13]trienimino)-2H-furo[2',3':7,8]naphtha[1,2-d]imidazole-2,4'-piperidine]-5,10,26(3H,9H)-trione.

[0083] In some embodiments, compound I is 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin.

[0084] In some embodiments, Compound I has a CAS number of 1001314-13-1.

[0085] In some embodiments, compound I has formula 2 [ka] It has the following structure.

[0086] In some embodiments, compound I has formula 3 [ka] (* is a chiral center).

[0087] Compound I may be administered to a subject at a dose of about 400 mg to about 600 mg twice daily (BID) or three times daily (TID). In some embodiments, Compound I is administered to a subject at a dose of about 400 mg to about 600 mg twice daily (e.g., about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg). In some embodiments, Compound I is administered to a subject at a dose of about 400 mg to about 600 mg three times daily (e.g., about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg).

[0088] Compound I can be administered to a subject for 7 to 14 consecutive days. For example, Compound I can be administered to a subject for 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days.

[0089] For example, Compound I may be administered to a subject at a dose of about 400 mg to about 600 mg twice daily for 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days (e.g., about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg).

[0090] For example, Compound I may be administered to a subject at a dose of about 400 mg to about 600 mg (e.g., about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg) three times daily for 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days.

[0091] In some embodiments, Compound I is administered to a subject at a dose of about 400 mg twice daily for 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days.

[0092] In some embodiments, Compound I is administered to a subject at a dose of about 600 mg twice daily for 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days.

[0093] In some embodiments, Compound I is administered to a subject at a dose of about 400 mg three times daily for 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days.

[0094] In some embodiments, Compound I is administered to a subject at a dose of about 600 mg three times daily for 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days.

[0095] Compound I can be administered to a subject before, with, or after a meal. In some embodiments, Compound I is administered to a subject after each meal.

[0096] Compound I can be administered to a subject in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) dosage units. Each dosage unit can contain from about 10 mg to about 600 mg (e.g., about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, The compound I may comprise about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg.

[0097] The dosage unit may be a capsule or a tablet. For example, the dosage unit may be a capsule containing about 10 mg to about 600 mg (e.g., about 100 mg to about 400 mg, e.g., 100 mg, 200 mg, 300 mg, or 400 mg) of Compound I. For example, the dosage unit may be a tablet containing about 10 mg to about 600 mg (e.g., about 100 mg to about 400 mg, e.g., 100 mg, 200 mg, 300 mg, or 400 mg) of Compound I.

[0098] Acid Blocker The acid blocker may be a proton pump inhibitor (PPI). For example, the acid blocker may be selected from the group consisting of rabeprazole sodium, esomeprazole magnesium, omeprazole, lansoprazole, pantoprazole sodium, and ilaprazole.

[0099] The acid blocker can be administered to a subject at a dose of about 10 mg to about 40 mg (eg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg).

[0100] Acid blockers can be administered to a subject twice daily (BID) or three times daily (TID).

[0101] For example, an acid blocker (eg, a PPI, such as sodium rabeprazole) can be administered to a subject twice daily at a dose of about 10 mg to about 40 mg (eg, about 20 mg) per administration.

[0102] For example, an acid blocker (eg, a PPI, such as sodium rabeprazole) can be administered to a subject at a dose of about 10 mg to about 40 mg (eg, about 20 mg) three times a day.

[0103] For example, the acid blocker can be administered to the subject for at least 7 to 14 consecutive days (e.g., at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, or at least 14 days).

[0104] In some embodiments, an acid blocker (e.g., a PPI, e.g., rabeprazole sodium) is administered to a subject at a dose of about 10 mg to about 40 mg (e.g., about 20 mg) twice daily for at least 7 to 14 consecutive days (e.g., at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, or at least 14 days).

[0105] In some embodiments, an acid blocker (e.g., a PPI, e.g., rabeprazole sodium) is administered to a subject at a dose of about 10 mg to about 40 mg (e.g., about 20 mg) three times daily for at least 7 to 14 consecutive days (e.g., at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, or at least 14 days).

[0106] The acid blocker can be administered to a subject in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) dosage units, each of which can contain about 10 mg to about 50 mg (e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of the acid blocker.

[0107] The dosage unit may be a capsule or a tablet. For example, the dosage unit may be a capsule containing about 10 mg to about 50 mg (e.g., about 10 mg to about 40 mg, e.g., 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg) of the acid blocker (e.g., a PPI, e.g., rabeprazole sodium). For example, the dosage unit may be a tablet (e.g., an enteric-coated tablet) containing about 10 mg to about 50 mg (e.g., about 10 mg to about 40 mg, e.g., 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg) of the acid blocker (e.g., a PPI, e.g., rabeprazole sodium).

[0108] The acid blocker (e.g., a PPI, e.g., rabeprazole sodium) can be administered before, together with, or after administration of Compound I. In some embodiments, the acid blocker (e.g., a PPI, e.g., rabeprazole sodium) is administered to the subject together with Compound I.

[0109] Each time, the acid blocker (eg, a PPI, eg, rabeprazole sodium) can be administered before, with, or after a meal (eg, breakfast, lunch, and / or dinner).

[0110] additional antibiotics According to any aspect of the present disclosure, the additional antibiotic may be selected from the group consisting of rifabutin, clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, and furazolidone.

[0111] In some embodiments, the additional antibiotic comprises two or more drugs selected from rifabutin, clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, and furazolidone. For example, the additional antibiotic may comprise an effective amount of amoxicillin and an effective amount of clarithromycin. For example, the additional antibiotic may comprise an effective amount of amoxicillin and an effective amount of levofloxacin. For example, the additional antibiotic may comprise an effective amount of amoxicillin and an effective amount of furazolidone. For example, the additional antibiotic may comprise an effective amount of tetracycline and an effective amount of metronidazole. For example, the additional antibiotic may comprise an effective amount of tetracycline and an effective amount of furazolidone. For example, the additional antibiotic may comprise an effective amount of amoxicillin and an effective amount of metronidazole. For example, the additional antibiotic may comprise an effective amount of amoxicillin and an effective amount of tetracycline.

[0112] The additional antibiotic may be administered to the subject at a dose of about 100 mg to about 1000 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg) (each separately or in combination). The additional antibiotic may be administered to the subject once daily, twice daily (BID), three times daily (TID), or four times daily.

[0113] For example, the additional antibiotic may include amoxicillin. The amoxicillin may be included or administered in an effective amount or dose. An effective amount of amoxicillin may be about 100 mg to about 1000 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). The amoxicillin may be administered to a subject twice daily (BID) or three times daily (TID). In some embodiments, the amoxicillin is administered to a subject at a dose of about 1000 mg twice or three times daily. In some embodiments, amoxicillin is administered to the subject at a dose of about 1000 mg per dose, administered to the subject twice daily.

[0114] In some cases, the additional antibiotic may include rifabutin. Rifabutin may be included or administered in an effective amount or dose. An effective amount of rifabutin may be about 100 mg to about 1000 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). Rifabutin may be administered to a subject once daily, twice daily (BID), or three times daily (TID). In some embodiments, rifabutin is administered to a subject at a dose of about 100 mg to about 300 mg once, twice, or three times daily. In some embodiments, rifabutin is administered to a subject at a dose of about 150 mg twice daily. In some embodiments, rifabutin is administered to a subject at a dose of about 300 mg once daily.

[0115] For example, the additional antibiotic may include clarithromycin. Clarithromycin may be included or administered in an effective amount or dose. An effective amount of clarithromycin may be about 100 mg to about 1000 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). Clarithromycin may be administered to a subject twice daily (BID) or three times daily (TID). In some embodiments, clarithromycin is administered to a subject at a dose of about 500 mg per dose, administered to a subject twice or three times daily. In some embodiments, clarithromycin is administered to a subject at a dose of about 500 mg twice daily.

[0116] For example, the additional antibiotic may include metronidazole. Metronidazole may be included or administered in an effective amount or dose. An effective amount of metronidazole may be about 100 mg to about 1000 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). Metronidazole may be administered to a subject three or four times daily. In some embodiments, metronidazole is administered to a subject at a dose of about 400 mg three times daily. In some embodiments, metronidazole is administered to a subject at a dose of about 400 mg administered to the subject four times daily.

[0117] For example, the additional antibiotic may include levofloxacin. Levofloxacin may be included or administered in an effective amount or dose. An effective amount of levofloxacin may be about 100 mg to about 1000 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). Levofloxacin may be administered to a subject once daily or twice daily. In some embodiments, levofloxacin is administered to a subject at a dose of about 500 mg once daily. In some embodiments, levofloxacin is administered to a subject at a dose of about 200 mg twice daily.

[0118] For example, the additional antibiotic may include furazolidone. Furazolidone may be included or administered in an effective amount or dose. An effective amount of furazolidone may be about 100 mg to about 1000 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). Furazolidone may be administered to a subject once or twice daily. In some embodiments, furazolidone is administered to a subject at a dose of about 100 mg twice daily.

[0119] For example, the additional antibiotic may include tetracycline. The tetracycline may be included or administered in an effective amount or dose. An effective amount of tetracycline may be about 100 mg to about 1000 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg). The tetracycline may be administered to the subject three or four times daily. In some embodiments, the tetracycline is administered to the subject at a dose of about 500 mg three times daily. In some embodiments, the tetracycline is administered to the subject at a dose of about 500 mg per dose, administered to the subject four times per day.

[0120] The additional antibiotic may be administered to the subject for 7 to 14 consecutive days (e.g., 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days).

[0121] In some embodiments, the additional antibiotic is or comprises amoxicillin and is administered to the subject at a dose of about 1000 mg per dose, administered two or three times daily, for 7 to 14 consecutive days.

[0122] The additional antibiotic may be administered to the subject before, with, or after a meal. In some embodiments, the additional antibiotic is administered to the subject after each meal (e.g., breakfast, lunch, or dinner).

[0123] The additional antibiotic may be administered to a subject in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) dosage units, each of which may contain about 100 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg) of the additional antibiotic (e.g., amoxicillin).

[0124] The dosage unit may be a capsule or a tablet. For example, the dosage unit may be a capsule containing about 100 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg) of the additional antibiotic (e.g., amoxicillin). For example, the dosage unit may be a tablet containing about 100 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg) of the additional antibiotic (e.g., amoxicillin).

[0125] The additional antibiotic (e.g., amoxicillin) may be administered before, along with, or after administration of Compound I. In some embodiments, the additional antibiotic (e.g., amoxicillin) is administered to the subject along with Compound I.

[0126] The additional antibiotic (e.g., amoxicillin) may be administered before, together with, or after administration of the acid blocker (e.g., a PPI, e.g., rabeprazole sodium). In some embodiments, the additional antibiotic (e.g., amoxicillin) is administered to the subject together with the acid blocker (e.g., a PPI, e.g., rabeprazole sodium).

[0127] The additional antibiotic (e.g., amoxicillin) may be administered before, together with, or after administration of Compound I and an acid blocker (e.g., a PPI, e.g., rabeprazole sodium). In some embodiments, the additional antibiotic (e.g., amoxicillin) is administered to the subject together with Compound I and an acid blocker (e.g., a PPI, e.g., rabeprazole sodium).

[0128] Helicobacter pylori (H. pylori) infection In any aspect of the present disclosure, the Helicobacter pylori infection may be associated with or caused by one or more drug-resistant strains of Helicobacter pylori.

[0129] In some cases, drug-resistant Helicobacter pylori may be resistant to antibiotics, such as one or more antibiotics selected from the group consisting of clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, furazolidone, and rifabutin.

[0130] In some embodiments, the drug-resistant Helicobacter pylori is resistant to rifabutin. In some embodiments, the drug-resistant Helicobacter pylori is resistant to metronidazole. In some embodiments, the drug-resistant Helicobacter pylori is resistant to rifabutin and metronidazole.

[0131] Drug Combinations and Kits The present disclosure also provides drug combinations and / or kits.

[0132] The drug combination or kit may further include instructions for applying or practicing the methods of the present disclosure.

[0133] A drug combination may be a pharmaceutical product that is marketed as a whole. In some cases, a drug combination includes one or more separate products or components that are intended to function or be used together.

[0134] The drug combinations or kits of the present disclosure may be used to treat, ameliorate, reverse and / or prevent Helicobacter pylori (H. pylori) infection in a subject in need thereof.

[0135] In some cases, the drug combination or kit of the present disclosure may include one or more separately packaged daily dose drug combination units. Each daily dose unit contains a drug combination intended to be administered to a subject during one day. Each daily dose unit may contain one, two, three, or four single-dose drug combination sets (or single-administration drug combination sets). For example, a daily dose unit may include a morning drug combination set and an evening drug combination set, where the morning drug combination set may include all drugs administered after breakfast, and the evening drug combination set may include all drugs administered after dinner.

[0136] In some embodiments, a single-dose drug combination set comprises about 400 mg to about 600 mg of Compound I of the present disclosure or a pharmaceutically acceptable salt thereof, and about 10 mg to about 40 mg of an acid blocker of the present disclosure (e.g., a PPI, e.g., rabeprazole sodium).

[0137] In some embodiments, the drug combination or kit includes 7 to 14 separately packaged daily dose drug combination units.

[0138] In some embodiments, each of the single-dose drug combination sets also contains about 100 mg to about 1000 mg of an additional antibiotic of the present disclosure (eg, amoxicillin).

[0139] In some embodiments, each single-dose drug combination set contains 4 to 6 capsules of Compound I of the present disclosure, each capsule containing about 100 mg of Compound I or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, each of the single-dose drug combination sets includes one tablet (e.g., an enteric-coated tablet) of an acid blocker (e.g., a PPI, e.g., rabeprazole sodium) of the present disclosure, each tablet containing about 20 mg of the acid blocker.

[0141] In some embodiments, each single-dose drug combination set includes two capsules of an additional antibiotic (eg, amoxicillin), each capsule containing about 500 mg of the additional antibiotic.

[0142] In some embodiments, each single-dose drug combination set includes four capsules of an additional antibiotic (eg, amoxicillin), each capsule containing about 250 mg of the additional antibiotic.

[0143] example The following examples are given to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, such as pl, picoliter; s or sec, seconds; min, minutes; h or hr, hours; aa, amino acids; nt, nucleotides; im, intramuscular; ip, intraperitoneal; sc, subcutaneous; rt, room temperature; etc.

[0144] Example 1: Combination therapy to eradicate H. pylori infection Forty asymptomatic, healthy subjects who tested positive for Helicobacter pylori infection were enrolled in the study. The 40 subjects were randomly assigned to four groups in a 1:1:1:1 ratio.

[0145] Subjects in each group were administered a different treatment according to the following schedule: Group A: Compound I capsules 200 mg / dose (2 capsules, 100 mg / capsule), twice daily (BID); rabeprazole sodium enteric-coated tablets 20 mg / dose (1 tablet, 20 mg / tablet), twice daily (BID) Group B: Compound I capsules 400 mg / dose (4 capsules, 100 mg / capsule), twice daily (BID); rabeprazole sodium enteric-coated tablets 20 mg / dose (1 tablet, 20 mg / tablet), twice daily (BID) Group C: Compound I capsules 600 mg / dose (6 capsules, 100 mg / capsule), twice daily (BID); rabeprazole sodium enteric-coated tablets 20 mg / dose (1 tablet, 20 mg / tablet), twice daily (BID) Group D: Compound I capsules 400 mg / dose (4 capsules, 100 mg / capsule), twice daily (BID); rabeprazole sodium enteric-coated tablets 20 mg / dose (1 tablet, 20 mg / tablet), twice daily (BID); amoxicillin capsules 1 g / dose (4 capsules, 0.25 g / capsule), twice daily (BID)

[0146] All subjects were admitted to the clinical research center one day before dosing (Day D-1), randomly assigned to their respective groups, and completed safety and baseline evaluations. From Days 1 through 14, subjects received their respective treatments / drugs orally within 30 minutes after breakfast and dinner. On Day 15, subjects received their final dose orally within 30 minutes after breakfast. Each subject received a total of 29 doses during the study. All subjects were discharged after completing safety and tolerability assessments on Day 17 and returned to the clinical research center for follow-up urea breath tests (UBTs) between Days 44 and 50 to evaluate the efficacy of Helicobacter pylori eradication.

[0147] Subjects' blood samples were collected and analyzed according to the following schedule: Day 1: Within 30 minutes after breakfast, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, and 12 hours after breakfast (before the second dose on Day 1); Days 3, 5, 7, 9, 11, 13, and 14: within 30 minutes after breakfast; Day 15: Within 30 minutes after breakfast, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours (Day 16) and 48 hours (Day 17) after breakfast.

[0148] Whole blood was collected at 4 mL per tube using an anticoagulant-containing vacuum collection tube, and the plasma was centrifuged. The plasma samples were divided into two portions and stored in a refrigerator at −80°C. One portion was used for pharmacokinetic analysis, and the other portion was used as a backup.

[0149] The amounts of Compound I, rabeprazole sodium and / or amoxicillin in plasma were determined by LC-MS / MS.

[0150] The linear range of detection was as follows: Compound I: Lower limit of quantitation (LLOQ): 1.00ng / mL; Upper limit of quantification (ULOQ): 1,000ng / mL Rabeprazole sodium: LLOQ: 2.00 ng / mL; ULOQ: 1,000 ng / mL Amoxicillin: LLOQ: 40.0 ng / mL; ULOQ: 20,000 ng / mL.

[0151] Pharmacokinetic evaluation Plasma drug concentrations of various groups at different time points were determined, including arithmetic mean, standard deviation, minimum, median, maximum, geometric mean, coefficient of variation, and geometric coefficient of variation.

[0152] Pharmacokinetic parameters calculated from the first and last administration, including arithmetic mean, standard deviation, minimum, median, maximum, geometric mean, coefficient of variation, geometric coefficient of variation, etc., were descriptively analyzed according to the various study groups. Additionally, the cumulative index AUC 0-tau,ss (D15) / AUC 0-tau (D1) was calculated. Mean and individual drug-time curves were plotted linearly and semi-logarithmically. Analysis of variance or non-parametric tests were performed on pharmacokinetic parameters between study groups.

[0153] 1) Pharmacokinetic characteristics of Compound I and its metabolites in combination therapy In groups A, B, C and D, Compound I capsules were administered at doses of 200 mg BID, 400 mg BID, 600 mg BID and 400 mg BID, respectively.

[0154] Compound I capsules combined with enteric-coated rabeprazole sodium tablets in each group (Groups A, B, and C): After the first administration on Day 1, the main pharmacokinetic parameters of Compound I (C max , AUC 0-tau , AUC 0-∞ ) increased with increasing dose of Compound I; the plasma concentration of Compound I in each group tended to reach a steady state from the third day of continuous administration; after the last administration on the 15th day, the main pharmacokinetic parameter of Compound I (C max,ss , C min,ss , C avg,ss , AUC 0-∞,ss , AUC 0-tau,ss , AUC 0-last,ss ) increased with increasing dose of Compound I, whereas R ac was decreased, with only slight accumulation. Comparing Group B and Group D (i.e., administered the same dose of Compound I), no significant differences were observed in the main pharmacokinetic parameters, as shown in Table 1.

[0155] It can be seen that no significant differences were observed for the combination therapy (after combining with rabeprazole sodium and / or amoxicillin) compared to the PK (pharmacokinetic) parameters of Compound I for 14 days of continuous administration.

[0156] [Table 1-1] [Table 1-2]

[0157] 2) Pharmacokinetic characteristics of rabeprazole in combination therapy In the combination therapy in groups A, B, C, and D, enteric-coated rabeprazole sodium tablets were administered at a dose of 20 mg BID.

[0158] Compound I capsules combined with enteric-coated rabeprazole sodium tablets in each dose group (Group A, Group B, Group C): After the first dose on Day 1, the main pharmacokinetic parameters of rabeprazole (C) were measured with increasing doses of Compound I in the combination therapy. max , AUC 0-tau , AUC 0-∞ The plasma concentration of rabeprazole in each group showed a tendency to reach a steady state from the third day of continuous administration. After the last administration on the 15th day, the C of rabeprazole increased with increasing dose of Compound I in the combination therapy. max,ss increased first and then decreased, and no significant changes were observed for other major pharmacokinetic parameters, and there was no significant accumulation.

[0159] These results suggest that the combination with Compound I may slightly affect the peak concentration of rabeprazole after 14 days of continuous administration.Comparing the results of Groups B and D, it was found that amoxicillin had no significant effect on the main pharmacokinetic parameters of rabeprazole after the first dose on Day 1 and the last dose on Day 15.

[0160] 3) Pharmacokinetic characteristics of amoxicillin in combination therapy In group D, there were no significant differences in the pharmacokinetic parameters of amoxicillin after the last dose on day 15 compared with the first dose on day 1, and only mild accumulation was observed, with plasma concentrations tending to steady state from day 3 of continuous administration.

[0161] In summary, the main pharmacokinetic parameters of Compound I increased with increasing dose of Compound I. After 14 days of continuous administration, rabeprazole and amoxicillin had no significant effect on the pharmacokinetic profile of Compound I.

[0162] Safety evaluation Safety tolerability assessments include evaluation of adverse events (AEs), serious adverse events (SAEs), drug-related AEs, and AEs leading to withdrawal.

[0163] The number and incidence of all adverse events were summarized according to each study group, systemic organ class, and preferred term.

[0164] The list describes the incidence of adverse events in each study group (occurring in each study group alone, in group 2, or in group 3) according to the CTCA 5.0 assessment.

[0165] The list describes the number and incidence of adverse events in each study group according to severity and drug relevance for the study, by system organ class and preferred term.

[0166] For each study group, the mean, standard deviation, median, minimum and maximum values ​​of vital signs (blood pressure, respiration, pulse and temperature) and laboratory indicators before and after drug administration were calculated, and paired t-test or non-parametric test was used for pre- and post-comparison, as appropriate.

[0167] SAEs and unexpected serious adverse reactions (SUSARs) were listed separately.

[0168] A total of 41 participants were enrolled, 40 completed the study, and all 40 participants who completed the study were included in the safety analysis population. Fifty-seven TEAE episodes occurred in 27 subjects, for an incidence rate of 67.5%, of which 25 patients had 53 TEAEs related to the disclosed combination therapy, for a total incidence rate of 62.5% (Table 2). Most drug-related adverse events were grade 1, with 7 grade 2 cases in 6 subjects and only 1 subject experiencing grade 3 severity (hypertriglyceridemia). With the exception of one case of grade 2 rash due to administration of the disclosed combination therapy, the remaining drug-related AEs were uninterventionally resolved completely. There were no grade 3 or higher adverse events throughout the study, no adverse events leading to discontinuation of the combination therapy, no adverse reactions leading to participant withdrawal from the study, no SAEs, and no AEs leading to death.

[0169] [Table 2]

[0170] Incidence of 15% or greater of common adverse events associated with combination therapy: Group A: elevated serum creatinine (30%), hyperglycemia (20%); Group B: elevated hemobilirubin (20%), hyperglycemia (20%); Group C: none; Group D: Elevated alanine aminotransferase (20%), elevated aspartate aminotransferase (20%), hypertriglyceridemia (20%), hyperuricemia (20%), rash (20%), papules (20%).

[0171] No significant dose-related effects were observed in groups A, B, or C, and no significant differences were observed between groups B and D (which used the same dose of Compound I).

[0172] During the study, particular attention was paid to the following adverse events that were expected to be correlated with the study combination treatment:

[0173] (1) A total of nine cases of elevated serum creatinine occurred, including four in group A, one in group B, two in group C, and two in group D, with an incidence rate of 15%. Decreased renal creatinine clearance occurred in four cases, including two in group A, one in group C, and one in group D, with an incidence rate of 7.5%. Of these, subjects in group A had decreased renal creatinine clearance and elevated serum creatinine. All adverse events of elevated serum creatinine and decreased renal creatinine clearance in this study were grade 1 level, were essentially transient, and no treatment measures were taken during the study, leading to complete recovery. No dose-dose correlation was observed.

[0174] (2) A total of 7 cases of transaminase elevation occurred, of which 1 case in group A had elevated alanine aminotransferase, 1 case in group C and 2 cases in group D had elevated alanine aminotransferase accompanied by elevated aspartate aminotransferase. The AEs started on day 6 or day 8, but started later in group C (day 12). All were grade 1 in severity and were essentially transient. No treatment measures were taken during the study, and all recovered completely.

[0175] (3) A total of 10 cases of skin abnormalities occurred. Of these, 8 cases of skin abnormalities were drug-related and manifested by rash, papules, and itching. One case in Group A had a rash. In Group B, one case had itching and one case had a rash. In Group D, one case had itching, papules, and a rash; one case had a large area of ​​rash and developed grade 2 symptoms that improved after antihistamine treatment; and one case had papules. In Group B, one case had grade 2 eczema / lichen, which was determined to be unrelated to the concomitant therapy in this study.

[0176] According to the CTC AE 5.0 evaluation, 46 cases of grade 1 adverse events occurred and 10 cases of grade 2 adverse events occurred. Of the drug-related AEs, 45 cases were grade 1 and 6 cases were grade 2 (1 case of leukopenia, 3 cases of neutropenia, 1 case of hypertriglyceridemia, and 1 case of rash). Three cases of grade 3 AEs occurred in Group B (1 case of hypertriglyceridemia). No AEs above grade 3 occurred. AEs were generally transient and did not require specific treatment. In fact, only one case of grade 2 rash was treated with combination therapy; the remaining drug-related AEs did not require intervention and have completely resolved.

[0177] Unanticipated Adverse Reactions: A total of 7 cases (15.0%) of unexpected adverse reactions occurred during the study, including 6 cases (12.5%) of hyperglycemia and 1 case of itchy eyelid, all of which were determined to be related to the combination therapy of the present disclosure, were Grade 1 in severity, and all resolved without treatment.

[0178] The results show that the combination therapy of the present disclosure had a good safety and tolerability profile after 14 consecutive days of administration in asymptomatic healthy individuals who were positive for Helicobacter pylori infection.

[0179] Efficacy evaluation The initial analysis of eradication efficacy was based on the entire data set, defined as all subjects who were randomly selected and received at least one dose of the study combination therapy.

[0180] The eradication efficacy in each study group was evaluated by UBT tests (negative or positive) performed at baseline, 8 days after drug administration, 16 days after drug administration, and at follow-up visits 44 to 50 days. Descriptive analysis was performed using frequencies (percentages), and between-group comparisons were performed using Fisher's exact test. To aid in analysis, UBT values ​​were listed as the mean, standard deviation, median, minimum, maximum, and deviation from baseline.

[0181] After 14 consecutive days of administration of the combination therapy of the present disclosure, and through the follow-up period (days 44 to 50), the rate of negative UBT results increased with increasing doses of Compound I combined with enteric-coated rabeprazole sodium tablets (i.e., groups A, B, and C). As can be seen from Table 3, the H. pylori eradication rate was as high as 80% in group D.

[0182] [Table 3]

[0183] It is understood that the combination therapy of the present disclosure can be used to successfully eradicate H. pylori infection.

[0184] Example 2: Combination therapy to eradicate H. pylori infection In this example, 80 subjects who tested positive for Helicobacter pylori infection were enrolled in the study. The 80 subjects were randomly assigned to five groups in a 2:2:1:1:2 ratio, including four treatment groups and one control group, with the dosing regimen shown in Table 4.

[0185] [Table 4] All subjects were admitted to the clinical center one day prior to dosing (D-1), completed safety and baseline examinations, and were randomly assigned to one of the groups.

[0186] Study schedule for Groups A, B, C and Control (14 consecutive days of administration): Subjects received daily combination therapy according to their respective group dosing regimens from Days 1 through 14, with the final dose administered on the morning of Day 15. Pharmacokinetic blood samples were collected at scheduled time points throughout the study for safety tolerability assessments and 14All subjects were discharged from the hospital after completing safety tolerability assessments and PK blood sampling on Day 17 (Day 17) and returned to the study site for follow-up visits on Days 44-50 (Days 44-50). Follow-up for adverse events and laboratory abnormalities continued until subjects fully recovered or returned to baseline levels or a stable condition. 14 A C UBT test was performed to evaluate the efficacy of eradicating Helicobacter pylori (H. pylori).

[0187] Study schedule for Group D (7 consecutive days of administration): Subjects received combination therapy daily according to their respective group dosing regimens on days 1 through 7, with the final dose administered on the morning of day 8. Pharmacokinetic blood samples were collected at scheduled time points throughout the study for safety tolerability assessments and 14 All subjects were discharged after completing safety tolerability assessments and PK blood sampling on Day 10 (Day 10) and returned to the study site for follow-up visits on Days 37-43 (Days 37-43). Follow-up for adverse events and laboratory abnormalities continued until subjects fully recovered or returned to baseline levels or a stable condition. 14 A C UBT test was performed to evaluate the efficacy of eradicating Helicobacter pylori (H. pylori).

[0188] The dosing regimen was as follows: Group A, Group B and Control: The combination therapy was administered orally twice daily, within 30 minutes after breakfast and dinner, for 14 consecutive days. The final dose was administered on day 15, within 30 minutes after breakfast. Each subject received a total of 29 doses. Groups C and D: Three doses were administered daily, with two doses spaced approximately 8 hours apart.

[0189] In Group C, the combination therapy was administered for 14 consecutive days, with the final dose administered after breakfast on Day 15. Each subject received a total of 43 doses.

[0190] In Group D, the combination therapy was administered for 7 consecutive days. The final dose was administered after breakfast on Day 8. Each subject received a total of 22 doses.

[0191] Specific dosing and regimens are shown in Table 5.

[0192] [Table 5]

[0193] Pharmacokinetic evaluation PK collection time: Blood samples for PK analysis were collected at the following time points: 1) Regarding Group A, Group B and the control group: Day 1: Within 30 minutes before administration, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, and 12 hours after administration (before the second dose of that day); Days 3, 5, 7, 9, 11, 13, and 14: Within 30 minutes prior to administration: Day 15: Within 30 minutes before administration, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours (Day 16), and 48 hours (Day 17) after administration. 2) Regarding Group C: Day 1: Within 30 minutes before administration, and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, and 8 hours after administration (before the second dose of that day); Days 3, 5, 7, 9, 11, 13, and 14: Within 30 minutes prior to administration: Day 15: Within 30 minutes before administration, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours (Day 16), and 48 hours (Day 17) after administration. 3) Group D: Day 1: Within 30 minutes before administration, and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, and 8 hours after administration (before the second dose of that day); Days 3, 5, and 7: Within 30 minutes prior to administration: Day 8: Within 30 minutes before administration, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours (Day 9), and 48 hours (Day 10) after administration.

[0194] PK Blood Sample Processing: Whole blood was collected at 4 mL per tube using an anticoagulant-containing vacuum collection tube, and the plasma was centrifuged. The plasma samples were divided into two portions and stored in a refrigerator at −80°C. One portion was used for pharmacokinetic analysis, and the other portion was used as a backup.

[0195] For the first dose, PK analysis will evaluate at least the following parameters: T max , C max , t 1 / 2 , AUC 0-∞ , AUC 0-tau , V d / F and CL / F.

[0196] For groups A, B and the control, the two doses were separated by 12 hours. For groups C and D, the two doses were separated by 8 hours.

[0197] For the last dose, PK analysis will be performed to assess at least the following parameters: T max,ss , C max,ss , C min,ss , C avg,ss , t 1 / 2,ss , AUC 0-∞,ss , AUC 0-last,ss , AUC 0-tau,ss , V d / Fss, CL / Fss, DF(=100x(C max,s- C min,ss ) / Cavg,ss )) and R ac (A, B, C and control groups: AUC on day 15) 0-tau,ss / AUC on day 1 0-tau Group D: AUC on day 8 0-tau,ss / AUC on day 1 0-tau ) was included.

[0198] Safety evaluation The safety of the treatment was assessed according to the CTC AE 5.0 assessment.

[0199] All subjects were observed for adverse events (AEs) occurring during the study, and their clinical characteristics, severity, time of onset, time of completion, treatment measures, and outcome were recorded to determine the correlation between AEs and the combination therapy of the present disclosure.

[0200] Safety tolerability assessment mainly includes adverse events (AEs), physical examination, vital signs (blood pressure, pulse, respiration and temperature), laboratory tests (blood routine, urine routine, blood biochemistry, coagulation function) and ECG etc.

[0201] Efficacy evaluation Groups A, B, C and Control: Subjects were enrolled in the screening period (D-14 to D-2), baseline period (D-1), day 8 (D8), day 16 (D16), and days 44 to 50 (D44 to D50). 14 The subjects were fasted before breakfast and the effect of eradicating Helicobacter pylori (H. pylori) in each group was determined by UBT test. Group D: Subjects were enrolled in the screening period (D-14 to D-2), baseline period (D-1), day 8 (D8), and days 37 to 43 (D37 to D43). 14 The subjects were fasted before breakfast and the effect of eradicating Helicobacter pylori (H. pylori) in each group was determined by UBT test.

[0202] statistical analysis Dataset definition: Full Analysis Set (FAS): refers to all randomized subjects who received at least one dose of the disclosed combination therapy; Modified intention-to-treat population (mITT): 28-34 days after last dose 14 C refers to all randomized subjects who underwent UBT testing; Per-protocol population (PP): randomized and treated with >80% (including 80%) of the total amount of drug expected to be used in the study, 28-34 days after the last dose 14 C refers to participants tested for UBT who did not experience any significant protocol violations; Safety Analysis Set (SS): refers to subjects who participated in the study and received at least one dose of the disclosed combination therapy; Pharmacokinetic Concentration Analysis Dataset (PKCS): refers to all enrolled subjects who received the disclosed combination therapy and had at least one PK concentration observation; Pharmacokinetic Parameter Analysis Data Set (PKPS): Refers to all enrolled subjects who received a combination therapy of the present disclosure and had at least one observed PK parameter data point.

[0203] Demographic analysis: Demographic analysis was based on the Full Analysis Set (FAS). Descriptive statistical analysis of all demographics (age, sex, weight, height, BMI, ethnicity, etc.) and baseline characteristics based on the last available data measurement prior to administration of the disclosed combination therapy.

[0204] Evaluation of Helicobacter pylori eradication effect: The sterilization effect analysis was carried out in four groups: Group A, Group B, Group C, and the control group. 14 C UBT test (negative or positive) at baseline, day 8, day 16, and follow-up days 44-50, as well as the three groups in group D 14The full analysis set (FAS) was used to compare the C UBT test results (negative or positive) at baseline, on day 8, and at follow-up on days 37-43. Intergroup comparison analyses were primarily based on comparisons between the treatment and control groups, and between treatment groups. The Helicobacter pylori eradication rate was 28-34 days after the last dose. 14 C is defined as the proportion of subjects with a negative UBT test result. At the same time, the Helicobacter pylori eradication rate was calculated for each group for the mITT analysis population and the PP analysis population, and a sensitivity analysis was performed.

[0205] Safety analysis: Safety tolerability assessment analysis was primarily based on descriptive statistical summaries. AEs, treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), drug-related AEs, and AEs leading to withdrawal from the study were pooled.

[0206] The list summarizes the number, frequency and incidence of all adverse events by different groups, systemic organ classes and preferred terms.

[0207] The list describes the number and incidence of adverse events at all levels in each group according to the different groups and according to the CTCAE classification.

[0208] The list describes the number and incidence of adverse events in each group, by system organ class and preferred term, according to severity and relationship to concomitant therapy.

[0209] The list describes the number and incidence of common adverse events in each group by system organ class and preferred term.

[0210] Different groups will describe laboratory test results that were normal before the study but abnormal after treatment.

[0211] The mean, standard deviation, median, minimum and maximum values ​​of vital signs (blood pressure, respiration, pulse and temperature) and laboratory indexes before and after administration according to different groups were calculated, and paired t-test or non-parametric test was used for pre- and post-comparison, as appropriate.

[0212] SAEs and unexpected serious adverse reactions (SUSARs) were listed separately.

[0213] Pharmacokinetic analysis: Plasma concentration data were estimated and analyzed for non-AV model pharmacokinetic parameters using Phoenix WinNolin software, PK concentration data were analyzed using PKCS data, and major pharmacokinetic parameters were calculated using PKPS data. Subjects with severe deviations from the study protocol were excluded from the pharmacokinetic analysis.

[0214] The results of the main pharmacokinetic parameters were summarized by sample size, arithmetic mean, standard deviation, coefficient of variation, median, minimum, maximum, and geometric mean and geometric coefficient of variation by different groups. The main pharmacokinetic parameters included T max , C max , t 1 / 2 , AUC 0-∞ , AUC 0-tau PK parameters for the first dose, such as Vd / F, CL / F; T max,ss , C max,ss , C min,ss , C avg,ss , t 1 / 2,ss , AUC 0-last,ss , AUC 0-tau,ss , AUC 0-∞,ss , V / F ss , CL / F ss PK parameters for the last dose including , Rac, DF, etc. are included.

[0215] Example 3: Comparison of different dosage forms Dissolution profiles were compared using Compound I tablets (batch number: T01-22012, strength: 400 mg) and Compound I capsules (batch number: CT-22C077, strength: 100 mg). Four capsules were simultaneously placed in a sink basket and the same dissolution cup to ensure the total dose of the tablets was the same (all 400 mg). Each vehicle was tested in triplicate for each dosage form, and the comparative dissolution data for the capsules and tablets are shown in the table below.

[0216] [Table 6]

[0217] [Table 7]

[0218] [Table 8]

[0219] From the above data, it can be seen that in conjunction with the clinical use of Compound I (fed conditions in combination with a proton pump inhibitor) and its characteristics of rapid release in the stomach and absorption in the intestine, it was primarily tested using dissolution media that mimic the drug's dissolution and release in vivo, such as pH 4.5 buffer and FeSSGF gastric (fed conditions) buffer pH 5.0.

[0220] The results show that the dissolution of Compound I in both media was low due to the low solubility of the drug substance, so the method was optimized by adding 0.5% surfactant Tween-80 in pH 4.5 media to improve the dissolution, and the dissolution trends of both dosage forms in these two media were basically similar.

[0221] Due to the large tablet weight of this product, there was accumulation of the insoluble excipient microcrystalline cellulose during the dissolution process. Therefore, the dissolution speed was increased from 50 rpm to 75 rpm. The results showed that the dissolution trend under these conditions was similar to that in the pH 4.5 buffer solution (for both 300 mg and 400 mg tablets), and the dissolution rate of the capsules was slightly faster than that of the tablets only after 15 minutes.

[0222] The results are shown in Figures 1 to 3. It can be seen that the dissolution profiles of the different dosage forms are similar.

[0223] While exemplary embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. The present invention is not intended to be limited by the specific examples provided herein. While the present invention has been described with reference to the foregoing specification, the description and illustration of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it should be understood that all aspects of the present invention are not limited to the specific depictions, configurations, or relative proportions set forth herein, which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the present disclosure. Therefore, it is contemplated that the present invention shall also cover any such alternatives, modifications, variations, or equivalents. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. 1. A method of treating, ameliorating, reversing and / or preventing Helicobacter pylori (H. pylori) infection in a subject in need thereof, comprising:

10. A method comprising administering to the subject an effective amount of compound I 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin or a pharmaceutically acceptable salt thereof, and an effective amount of an acid blocker.

2. The compound I is of formula 1 【Chemical 1】 The method of claim 1, wherein the compound is

3. The method of claim 1 or 2, wherein compound I is 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S.

4. The compound I is of formula 2 【Chemistry 2】 4. The method of claim 1, wherein the compound is

5. 5. The method of any one of claims 1 to 4, wherein Compound I is administered to the subject at a dose of about 400 mg to about 600 mg twice daily (BID) or three times daily (TID).

6. 6. The method of any one of claims 1 to 5, wherein compound I is administered to the subject for 7 to 14 consecutive days.

7. 7. The method of any one of claims 1 to 6, wherein each time, compound I is administered to the subject after a meal.

8. 8. The method of any one of claims 1 to 7, wherein Compound I is administered in one or more dosage units, each dosage unit containing from about 100 mg to about 400 mg of Compound I.

9. 9. The method of any one of claims 1 to 8, wherein Compound I is administered as a capsule or tablet.

10. 10. The method of any one of claims 1 to 9, wherein the acid blocker is a proton pump inhibitor (PPI).

11. 11. The method of any one of claims 1 to 10, wherein the acid blocker is administered to the subject at a dose of about 10 mg to about 40 mg twice daily (BID) or three times daily (TID).

12. 12. The method of any one of claims 1 to 11, wherein the acid blocker is administered to the subject for at least 7 to 14 consecutive days.

13. 13. The method of any one of claims 1 to 12, wherein the acid blocker is administered as an enteric-coated tablet.

14. 14. The method of claim 13, wherein each of the enteric-coated tablets contains from about 10 mg to about 20 mg of the acid blocker.

15. 15. The method of any one of claims 1 to 14, wherein the acid blocker is selected from the group consisting of rabeprazole sodium, esomeprazole magnesium, omeprazole, lansoprazole, pantoprazole sodium, and ilaprazole.

16. 16. The method of any one of claims 1 to 15, wherein the acid blocker is administered to the subject together with Compound I.

17. 17. The method of any one of claims 1 to 16, further comprising administering to the subject an effective amount of an additional antibiotic.

18. 18. The method of claim 17, wherein the additional antibiotic is selected from the group consisting of rifabutin, clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, and furazolidone.

19. 19. The method of claim 17 or 18, wherein the additional antibiotic is administered to the subject at a dose of about 100 mg to about 1000 mg twice daily (BID) or three times daily (TID).

20. 20. The method of any one of claims 17 to 19, wherein the additional antibiotic is administered to the subject for 7 to 14 consecutive days.

21. 21. The method of any one of claims 17 to 20, wherein each time the additional antibiotic is administered to the subject after a meal.

22. 22. The method of any one of claims 17 to 21, wherein the additional antibiotic is administered as a capsule or tablet.

23. 23. The method of claim 22, wherein each capsule or tablet contains from about 100 mg to about 500 mg of the additional antibiotic.

24. 24. The method of any one of claims 17 to 23, wherein the additional antibiotic is amoxicillin.

25. 25. The method of any one of claims 17 to 24, wherein the additional antibiotic is administered to the subject together with Compound I and the acid blocker.

26. 26. The method of any one of claims 1 to 25, wherein the Helicobacter pylori is resistant to one or more antibiotics selected from the group consisting of clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, furazolidone, and rifabutin.

27. 27. The method of claim 26, wherein the Helicobacter pylori is resistant to rifabutin and / or metronidazole.

28. A drug combination comprising an effective amount of compound I 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin or a pharmaceutically acceptable salt thereof and an effective amount of an acid blocker.

29. The compound I is of formula 1 【Chemistry 3】 29. The pharmaceutical combination of claim 28, wherein the compound is

30. 30. The pharmaceutical combination of claim 28 or 29, wherein said compound I is 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S.

31. The compound I is of formula 2 【Chemistry 4】 31. The pharmaceutical combination of any one of claims 28 to 30, wherein the compound is

32. 32. The pharmaceutical combination of any one of claims 28 to 31, wherein Compound I is included in an amount suitable for administration at a dose of about 400 mg to about 600 mg twice daily (BID) or three times daily (TID).

33. 33. The pharmaceutical combination of any one of claims 28 to 32, wherein Compound I is contained in an amount suitable for administration for 7 to 14 consecutive days.

34. 34. The pharmaceutical combination of any one of claims 28 to 33, wherein Compound I is contained in the form of a capsule or tablet.

35. 35. The pharmaceutical combination of claim 34, wherein each capsule or tablet contains from about 100 mg to about 400 mg of Compound I.

36. 36. The pharmaceutical combination of any one of claims 28 to 35, wherein the acid blocker is a proton pump inhibitor (PPI).

37. 37. The pharmaceutical combination of any one of claims 28-36, wherein the acid blocker is included in an amount suitable for administration at a dose of about 10 mg to about 40 mg twice daily (BID) or three times daily (TID).

38. 38. The pharmaceutical combination of any one of claims 28 to 37, wherein the acid blocker is included in an amount suitable for administration for at least 7 to 14 consecutive days.

39. 39. The pharmaceutical combination of any one of claims 28 to 38, wherein the acid blocker is in the form of an enteric coated tablet.

40. 40. The pharmaceutical combination of claim 39, wherein each enteric coated tablet contains from about 10 mg to about 20 mg of said acid blocker.

41. 41. The pharmaceutical combination of any one of claims 28 to 40, wherein the acid blocker is selected from the group consisting of rabeprazole sodium, esomeprazole magnesium, omeprazole, lansoprazole, pantoprazole sodium and ilaprazole.

42. 42. The pharmaceutical combination of any one of claims 28 to 41, further comprising an effective amount of an additional antibiotic.

43. 43. The pharmaceutical combination of claim 42, wherein the additional antibiotic is selected from the group consisting of rifabutin, clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, and furazolidone.

44. 44. The pharmaceutical combination of claim 42 or 43, wherein the additional antibiotic is included in an amount suitable for administration at a dose of about 100 mg to about 1000 mg twice daily (BID) or three times daily (TID).

45. 45. The pharmaceutical combination of any one of claims 42 to 44, wherein the additional antibiotic is included in an amount suitable for administration for 7 to 14 consecutive days.

46. 46. ​​The pharmaceutical combination of any one of claims 42 to 45, wherein the additional antibiotic is contained in the form of a capsule or tablet.

47. 47. The pharmaceutical combination of claim 46, wherein each said capsule or tablet contains from about 100 mg to about 500 mg of said additional antibiotic.

48. 48. The pharmaceutical combination of any one of claims 42 to 47, wherein the additional antibiotic is amoxicillin.

49. 49. A kit comprising the pharmaceutical combination of any one of claims 28 to 48.

50. 50. The kit of claim 49, further comprising instructions for applying the method of any one of claims 1 to 27.

51. 1. Use of an effective amount of compound I 4-deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin or a pharmaceutically acceptable salt thereof, and an effective amount of an acid blocker in the manufacture of a medicament for treating, ameliorating, reversing and / or preventing Helicobacter pylori (H. pylori) infection in a subject in need thereof.

52. Use of a pharmaceutical combination according to any one of claims 28 to 48 or a kit according to claim 49 or 50 in the manufacture of a medicament for treating, ameliorating, reversing and / or preventing Helicobacter pylori (H. pylori) infection in a subject in need thereof.

53. 53. The use of claim 51 or 52, wherein the Helicobacter pylori is resistant to one or more antibiotics selected from the group consisting of clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, furazolidone, and rifabutin.

54. 54. The use of claim 53, wherein the Helicobacter pylori is resistant to rifabutin and / or metronidazole.

55. 51. A pharmaceutical combination according to any one of claims 28 to 48 or a kit according to claim 49 or 50 for use in the treatment, amelioration, reversal and / or prevention of Helicobacter pylori (H. pylori) infection in a subject in need thereof.

56. 56. The drug combination or kit for use of claim 55, wherein the Helicobacter pylori is resistant to one or more antibiotics selected from the group consisting of clarithromycin, amoxicillin, metronidazole, levofloxacin, tetracycline, furazolidone, and rifabutin.

57. 57. A drug combination or kit for use according to claim 55 or 56, wherein the Helicobacter pylori is resistant to rifabutin and / or metronidazole.

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