AU3400699A - Improved method for eradication of Helicobacter Pylori - Google Patents

Description

WO 99/56749 1 PCT/AU99/00321 Improved Method for Eradication of Helicobacter Pylori Technical Field This invention relates to pharmaceutical compositions and therapeutic methods for the treatment and/or prevention of recurrence of gastrointestinal disorders 5 associated with infection by Helicobacter pylori (H. pylori). Background Helicobacter pylori has been found to cause chronic histological gastritis and peptic ulcer disease, such as gastric and duodenal ulcer. It also appears to cause a condition called non-ulcer dyspepsia where Helicobacter pylori causes inflammation in lo the stomach which is histologically associated with indigestion and epigastric pain. Helicobacter pylori is also thought to have a role in the causation of stomach cancer and its eradication may be instrumental in causing cure of ulcer disease, a reversal of a proportion of patients with non-ulcer dyspepsia, and prevention of gastric cancer development in those who may be predisposed to it. 15 Until recent times, H. pylori has been found to be difficult to eradicate using known chemotherapeutic agents. Although many antibiotics can suppress H. pylori growth in vivo the mucosal concentration appears to be inadequate and penetration of the usual gastric mucus layer is poor. Furthermore, there is frequently more than one infecting agent within the mucosa and hence, sensitivities of the various bacteria may 20 vary within one patient and within one region of the mucosa. The development of adequate in vivo eradication methods for chronic H. pylori infection has therefore been difficult. Furthermore, single antibiotics are almost never adequate for use and double antibiotic combinations have also resulted in poor eradication rates. A further major looming problem progressively affecting current eradication therapies is the rapid 25 development of clarithromycin resistance worldwide. The proportion of H. pylori infections which are resistant to clarithromycin is increasing by from 2-5% per year. Resistance is developing faster in the countries where clarithromycin is being used frequently; in particular, USA and Europe. Hence, new methods for eradication of H. pylori are urgently required. In addition, salvage therapies for patients who have failed 30 first time therapy are also unavailable and such treatments are becoming in demand as more and more patients undergo therapy and fail initial eradication attempts. It is therefore an object of the present invention to provide a novel pharmaceutical composition for the treatment and/or prevention of recurrence of gastrointestinal disorders associated with H. pylori. 35 It is a further object of the invention to provide methods for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient.

WO 99/56749 2 PCT/AU99/00321 Disclosure of the Invention The present inventor has found that the use of a novel combination antibiotic therapy not only results in high initial eradication rates of H. pylori but also can be used as a salvage therapy. There is a large volume of literature describing numerous 5 and varying combinations of antimicrobial agents for H. pylori eradication, to a large extent due to the fact that it is difficult to predict clinically which combination might work and which will be unsuccessful. Indeed, persons skilled in the art cannot - from in vitro studies or from their previous experience - simply predict the success or failure of a particular regime. 10 Rifampicin is an antimycobacterial antibiotic used in the treatment of tuberculosis. Recently, its semi-synthetic derivative, an ansamycin called rifabutin which is currently indicated for the treatment of tuberculosis or Mycobacterium avium complex infection, has been described as having in vitro activity against Helicobacter pylori when tested in culture. In the present invention combinations containing an 15 ansamycin have been found to be clinically effective in eradicating H. pylori. In a first embodiment, the present invention provides a pharmaceutical composition for the treatment of gastrointestinal disorders associated with H. pylori infection including a first antibiotic which is an ansamycin, and at least a second antibiotic or antimicrobial agent, together with at least one pharmaceutically acceptable 20 carrier, diluent, adjuvant or excipient. In a second embodiment, the invention provides a method for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient requiring said treatment and/or prevention, which method comprises administering to said patient sequentially or simultaneously a therapeutically effective 25 amount of a first antibiotic which is an ansamycin and a therapeutically effective amount of at least a second antibiotic or antimicrobial agent. Typically, a method of treatment in accordance with the invention results in the eradication of H. pylori from the patient who is treated. In a third embodiment, the invention further provides the use of a therapeutically 30 effective amount of a first antibiotic which is an ansamycin and a therapeutically effective amount of at least a second antibiotic or antimicrobial agent for the manufacture of a medicament for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient. In a fourth embodiment, the invention still further provides a therapeutically 35 effective amount of a first antibiotic which is an ansamycin and a therapeutically effective amount of at least a second antibiotic or antimicrobial agent when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient.

WO 99/56749 3 PCT/AU99/00321 Typically in the embodiments of the invention the ansamycin is selected from the group consisting of rifamycin, rifaximin, rifampicin, rifabutin and pharmaceutically acceptable salts thereof. More typically, the ansamycin is rifampicin or rifabutin. Preferably, the ansamycin is rifabutin. 5 The pharmaceutical composition of the invention includes, in addition to the an ansamycin, one or more other antibiotics or antimicrobial agents. Typically, where the patient to whom the pharmaceutical composition is to be administered has previously not been treated for H. pylori infection, the pharmaceutical composition of the invention includes an ansamycin, typically rifabutin, and just one other antibiotic or 10 antimicrobial agent. In other cases, the pharmaceutical composition typically includes an ansamycin, typically rifabutin, and two different antibiotics or antimicrobial agents. In severe cases, or in cases where a resistant strain of H. pylori is encountered, three, four or even more antibiotics may be included together with the ansamycin. Similarly, in the method of the second embodiment and in the third and fourth 15 embodiments of the invention an ansamycin and a single other antibiotic or antimicrobial agent may be used, but more typically an ansamycin and two different other antibiotics or antimicrobial agents, or three, four or more, may be used. In the method of the second embodiment, the active agents, namely the ansamycin and the one or more other antibiotics or antimicrobial agents, may be administered 20 simultaneously or sequentially, in any order. The pharmaceutical composition of the first embodiment may further include a proton pump inhibitor (PPI). Similarly, a method of the second embodiment may further include the administration of a proton pump inhibitor. The inclusion of a PPI can help to enhance the eradication rate of H. pylori and can improve the patient's 25 symptoms, since patients are often dyspeptic at the beginning of the treatment. The administration of the PPI in the method of the second embodiment may be separate from the administration of the ansamycin and other antibiotic(s) or antimicrobial agent(s), or the PPI may be co-administered with the ansamycin and/or one or more other antibiotics or antimicrobial agents. Suitable PPIs include omeprazole, 30 pantoprazole, lansoprazole and rabeprazole. Similarly, the invention also provides the use of a therapeutically effective amount of an ansamycin, a therapeutically effective amount of at least one other antibiotic or antimicrobial agent, and a therapeutically effective amount of a proton pump inhibitor for the manufacture of a medicament for the treatment and/or prevention of recurrence 35 of a gastrointestinal disorder associated with H. pylori in a patient. The invention further provides a therapeutically effective amount of an ansamycin, a therapeutically effective amount of at least one other antibiotic or antimicrobial agent and a therapeutically effective amount of a proton pump inhibitor WO 99/56749 4 PCT/AU99/00321 when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient. The antibiotic(s) or antimicrobial agent(s) included in the pharmaceutical composition, method or use of the invention may be selected from the penicillins, 5 bismuth compounds, tetracyclines, nitroimidazoles, quinolones, lincosamides, macrolides and cephalosporins. Examples of the penicillins include penicillin G, penicillin V, pheneticillin, propicillin, methicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, nafcillin, ampicillin, amoxycillin, bacampicillin, hetacillin, metampicillin, pivampicillin, talampicillin, carbenicillin, carfecillin, carindacillin, 10 sulbenicillin, ticarcillin, azlocillin, mezlocillin, piperacillin, apalcillin, temocillin, mecillinam and pivmecillinam. Examples of bismuth compounds include bismuth subcitrate, bismuth aluminate, bismuth oxide, bismuth salicylate, bismuth sugballate, bismuth tannate, bismuth phosphate, bismuth tribromphenate, bismuth subcarbonate, bismuth subnitrate, and mixtures thereof. Examples of the tetracyclines including 15 tetracycline hydrochloride, oxytetracycline, doxycycline, methacycline, chlortetracycline, demeclocycline and minocycline. Examples of nitroimidazoles include metronidazole, tinidazole, nimorazole, ornidazole and orthanidazole. Examples of quinolones include ciprofloxacin, norfloxacin, enoxacin, lomefloxacin, pefloxacin, amifloxacin, fleroxacin, levofloxacin, nadifloxacin, rufloxacin, sparfloxacin, 20 tosufloxacin and ofloxacin. Examples of lincosamides include lincomycin and clindamycin. Examples of macrolides include erythromycin, spiramycin, oleandomycin, triacetyloleandomycin, clarithromycin, roxithromycin, josamycin, kitsamycin, midecamycin, miocamycin, rokitamycin, dirithromycin,, rosarimycin, flurithromycin and azithromycin. Examples of cephalosporins include cephalexin, 25 pivcephalexin, cephalothin, cephazolin, cefroxadine, cefadroxil, cefatrizine, cefaclor, cefprozil, cephradine, and second as well as third generation cephalosporins such as cephamandole, cefuroxime, cefuroxime axetil, cefonicid, ceforanide, cefotiam, cefotaxime, cefmenoxime, cefodizime, ceftizoxime, cefiximine, cefdinir, cefetamet pivoxil, cefpodoxime proxetil, ceftibuten, ceftazidime, ceftoperazone, cefpiramide, 30 cefsoludin, cefepime, cefpirome and ceftriaxone, and related compounds such as oxycephalosporins including latamoxef, and cephamycins such as cefoxitin, cefmetazole, cefotetan, cefbuperazone and cefminox. Typically, in one form of the invention rifabutin is used in combination with a penicillin as a first antibiotic, and a bismuth compound, as a second antimicrobial 35 agent. An alternative second antimicrobial agent in this form of the invention is a tetracycline. In one preferred embodiment of the invention, in previously untreated patients rifabutin can be used solely with clarithromycin, or rifabutin can be used in a triple therapy format with clarithromycin and a PPI such as pantoprazole. These all can be WO 99/56749 5 PCT/AU99/00321 given in twice daily dosage or up to five times daily for more resistant strains. In the treatment of highly resistant strains where salvage therapy is required, three, four or even more of the antibiotics or antimicrobial agents exemplified above can be combined with rifabutin to affect a cure of Helicobacter pylori infection. 5 One preferred combination for use in the pharmaceutical compositions, methods and other embodiments of the present invention in patients who do not harbour resistant H. pylori is a combination of rifabutin, clarithromycin and pantoprazole. Another preferred combination is a combination of rifabutin, amoxycillin and a PPI such as omeprazole, pantoprazole or lansoprazole. A further preferred combination is a 10 combination of rifabutin, tetracycline and pantoprazole. These combinations can be given for between three and 21 days to affect a cure. In a further combination rifabutin can be combined with bismuth subcitrate, amoxycillin, and a PPI such as pantoprazole or omeprazole. This combination has the added advantage that the dosage of each agent can be reduced, compared to clinically 15is standard doses (with a reduction in the possibility of side effects as well as a reduction in cost) and the duration of treatment shortened, for example to 7 days. Pharmaceutical compositions of the invention include one or more pharmaceutically acceptable excipients, adjuvants, diluents or carriers which are generally known in the art. 20 Pharmaceutical compositions of the invention or for administration in a method of the invention may be prepared by means known in the art for the preparation of pharmaceutical compositions including blending, grinding, homogenising, suspending, dissolving, emulsifying, dispersing and where appropriate, mixing of the active agents together with one or more excipients, diluents, carriers and adjuvants. 25 For oral administration, the pharmaceutical composition may be in the form of tablets, lozenges, pills, troches, capsules, elixirs, powders, including lyophilised powders, solutions, granules, suspensions, emulsions, syrups and tinctures. Slow release, or delayed-release, forms may also be prepared, for example in the form of coated particles, multi-layer tablets or microgranules. 30 Solid forms for oral administration may contain pharmaceutically acceptable binders, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents. Suitable binders include gum acacia, gelatin, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, 35 aspartame or saccharine. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable WO 99/56749 6 PCT/AU99/00321 coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, 5 stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate. Liquid forms for oral administration may contain, in addition to the active agents, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, o10 ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof. Suspensions for oral administration may further include dispersing agents and/or suspending agents. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, poly-vinyl-pyrrolidone, sodium 15 alginate or cetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, stearate or -laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like. Emulsions for oral administration may further include one or more emulsifying 20 agents. Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as gum acacia or gum tragacanth. Dosages of the ansamycin and the other antibiotic(s) or antimicrobial agent(s) in the methods of the invention are in accordance with their generally known and safe dosage ranges. For example, dosages for the antimicrobial agents are well known to 25 medical practitioners, as are suitable dosages for rifabutin when it is administered for the treatment of tuberculosis or Mycobacterium avium complex infection. Thus, for example the typical daily dosage of rifabutin in a method of the invention is in the range of about 50mg to about 2000mg, more typically about 450mg . For tetracycline the typical daily dosage is in the range of from about 50mg to about 4000mg, more 30 typically about 1500mg; for amoxycillin, the typical daily dosage is in the range of from about 100mg to about 5000mg, more typically about 1500mg; for bismuth the typical daily dosage is in the range of from about 50mg to about 2000mg, more typically about 300mg; and for pantoprazole the typical daily dosage is in the range of from about 20mg to about 500mg, more typically about 120mg. 35 The agents may be administered once per day or more frequently, in divided doses. For example, rifabutin can be administered from twice daily up to five times daily. Treatment is typically continued until eradication of the H. pylori infection has been completed. Usually, the treatment is continued for from three days to 14 days, but can continue for up to 28 days. Dosages may be varied during the course of WO 99/56749 7 PCT/AU99/00321 treatment, depending on the attending physician's assessment of the progress of the patient, or they may be maintained substantially the same throughout the treatment. In addition, for resistant strains the patient can be pretreated with known immunising agents for Helicobacter pylori and then treated with any selected 5 combination of the rifabutin-containing combination therapies of the present invention. EXAMPLES Example 1 The Table presents the results of testing carried out on a number of patients using the epsilon test ("E-test", AB Biodisc) which show that in all cases where there was 10 infection by H. pylori which was resistant to one or both of metronidazole and clarithromycin, the infection was sensitive to rifabutin administration. The E-test is used as a graded antibiotic sensitivity detecting strip for examining resistance of H.pylori. Example 2 15 A male patient, 37 years old, who had been unsuccessfully treated previously for H. pylori infection using a combination of clarithromycin, amoxycillin and omeprazole was treated by administration of 4 times daily doses of rifabutin, pantoprazole and tetracycline in amounts of 600mg, 160mg and 2000mg per day respectively. After a period of 8 days on this treatment, the H. pylori infection in the patient had been 20 eradicated.

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Claims (40)

1. A pharmaceutical composition for the treatment of gastrointestinal disorders associated with H. pylori infection including a first antibiotic which is an ansamycin, and at least a second antibiotic or antimicrobial agent, together with at least 5 one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

2. A pharmaceutical composition according to claim 1, further including a proton pump inhibitor.

3. A pharmaceutical composition according to claim 1 or claim 2, including, in addition to said ansamycin, at least two antibiotics or antimicrobial agents. 10

4. A pharmaceutical composition according to claim 1 wherein the second antibiotic or antimicrobial agent is selected from the group consisting of penicillins, bismuth compounds, tetracyclines, nitroimidazoles, quinolones, lincosamides, macrolides and cephalosporins.

5. A pharmaceutical composition according to claim 2, wherein the 15 proton pump inhibitor is selected from omeprazole, pantoprazole, rabeprazole and lansoprazole.

6. A pharmaceutical composition according to claim 5, wherein the proton pump inhibitor is pantoprazole.

7. A pharmaceutical composition according to claim 6, wherein said 20 ansamycin is rifabutin, and said second antibiotic or antimicrobial agent is tetracycline.

8. A pharmaceutical composition according to claim 1, wherein said ansamycin is rifabutin.

9. A pharmaceutical composition according to claim 7, wherein said second antimicrobial agent is selected from clarithromycin, amoxycillin and 25 tetracycline.

10. A pharmaceutical composition according to claim 1 including rifabutin, a penicillin and a bismuth compound.

11. A method for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient requiring said treatment 30 and/or prevention, which method comprises administering to said patient sequentially or simultaneously a therapeutically effective amount of a first antibiotic which is an ansamycin and a therapeutically effective amount of at least a second antibiotic or antimicrobial agent.

12. A method according to claim 11, further including administering to 35 said patient a proton pump inhibitor.

13. A method according to claim 11 or claim 12, wherein, in addition to said ansamycin, at least two antibiotics or antimicrobial agents are administered.

14. A method according to claim 11 wherein said second antibiotic or antimicrobial agent is selected from the group consisting of penicillins, bismuth WO 99/56749 11 PCT/AU99/00321 compounds, tetracyclines, nitroimidazoles, quinolones, lincosamides, macrolides and cephalosporins.

15. A method according to claim 12, wherein said proton pump inhibitor is selected from omeprazole, pantoprazole, rabeprazole and lansoprazole. 5

16. A method according to claim 15, wherein said proton pump inhibitor is pantoprazole.

17. A method according to claim 16, wherein said ansamycin is rifabutin, and said second antibiotic or antimicrobial agent is tetracycline.

18. A method according to claim 11, wherein said ansamycin is rifabutin. 1o

19. A method according to claim 12, wherein the antimicrobial agent is selected from clarithromycin, amoxycillin and tetracycline.

20. A method according to claim 11 wherein rifabutin, a penicillin and a bismuth compound are administered to said patient.

21. Use of a therapeutically effective amount of a first antibiotic which is 15 an ansamycin and a therapeutically effective amount of at least a second antibiotic or antimicrobial agent for the manufacture of a medicament for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient.

22. Use according to claim 21 of a therapeutically effective amount of a 20 first antibiotic which is an ansamycin, a therapeutically effective amount of at least a second antibiotic or antimicrobial agent and a therapeutically effective amount of a proton pump inhibitor for the manufacture of a medicament for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient. 25

23. Use of therapeutically effective amounts of at least three antibiotics or antimicrobial agents for the manufacture of a medicament for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient, wherein one of said antibiotics or antimicrobial agents is an ansamycin.

24. Use according to claim 21 wherein said second antibiotic or 30 antimicrobial agent is selected from the group consisting of penicillins, bismuth compounds, tetracyclines, nitroimidazoles, quinolones, lincosamides, macrolides and cephalosporins.

25. Use according to claim 22, wherein said proton pump inhibitor is selected from omeprazole, pantoprazole, rabeprazole and lansoprazole. 35

26. Use according to claim 25, wherein said proton pump inhibitor is pantoprazole.

27. Use according to claim 26, wherein said ansamycin is rifabutin, and said second antibiotic or antimicrobial agent is tetracycline.

28. Use according to claim 21, wherein said ansamycin is rifabutin. WO 99/56749 12 PCT/AU99/00321

29. Use according to claim 22, wherein said second antimicrobial agent is selected from clarithromycin, amoxycillin and tetracycline.

30. Use according to claim 21 of rifabutin, a penicillin and a bismuth compound for the manufacture of a medicament for the treatment and/or prevention of s recurrence of a gastrointestinal disorder associated with H. pylori in a patient.

31. A therapeutically effective amount of a first antibiotic which is an ansamycin and a therapeutically effective amount of at least a second antibiotic or antimicrobial agent when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient. 10

32. A therapeutically effective amount of a first antibiotic which is an ansamycin and a therapeutically effective amount of at least a second antibiotic or antimicrobial agent and a therapeutically effective amount of a proton pump inhibitor when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient. 15is

33. Therapeutically effective amounts of at least three antibiotics or antimicrobial agents when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient, wherein one of said antibiotics or antimicrobial agents is an ansamycin.

34. A therapeutically effective amount of a first antibiotic which is an 20 ansamycin and a therapeutically effective amount of at least a second antibiotic or antimicrobial agent selected from the group consisting of penicillins, bismuth compounds, tetracyclines, nitroimidazoles, quinolones, lincosamides, macrolides and cephalosporins, when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient. 25

35. A therapeutically effective amount of a first antibiotic which is an ansamycin and a therapeutically effective amount of at least a second antibiotic or antimicrobial agent and a therapeutically effective amount of a proton pump inhibitor selected from omeprazole, pantoprazole, rabeprazole and lansoprazole, when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated 30 with H. pylori in a patient.

36. A therapeutically effective amount of a first antibiotic which is an ansamycin and a therapeutically effective amount of at least a second antibiotic or antimicrobial agent and a therapeutically effective amount of pantoprazole when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder 35 associated with H. pylori in a patient.

37. A therapeutically effective amount of rifabutin and a therapeutically effective amount of tetracycline and a therapeutically effective amount of pantoprazole when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient. WO 99/56749 13 PCT/AU99/00321

38. A therapeutically effective amount of a first antibiotic which is rifabutin and a therapeutically effective amount of at least a second antibiotic or antimicrobial agent when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient. 5

39. A therapeutically effective amount of a first antibiotic which is an ansamycin and a therapeutically effective amount of at least a second antibiotic or antimicrobial agent selected from clarithromycin, amoxycillin and tetracycline, and a therapeutically effective amount of a proton pump inhibitor when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori lo in a patient.

40. A therapeutically effective amount of rifabutin, a therapeutically effective amount of penicillin and a therapeutically effective amount of a bismuth compound when used for the treatment and/or prevention of recurrence of a gastrointestinal disorder associated with H. pylori in a patient.