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Tetracycline-containing Chitosan Microspheres for Local Treatment of Helicobacter pylori Infection

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Abstract

Helicobacter pylori infection is currently known to be the cause of at least 75% of all peptic ulcers. Although triple therapy protocols used at present in the clinics have resulted in significant benefits to the patients, the ultimate 100% eradication efficiency has never been achieved. In addition, the development of multidrug resistance to standard anti-microbial therapy can seriously hinder effective management of the disease. A rational approach to treat H. pylori, which localizes predominantly in the antral region of the stomach, is necessary for complete eradication of the infection. In this article, I review the summary of our work over the last several years on development of stomach-specific anti-H. pylori therapy using bioadhesive chitosan microspheres. To determine the gastric residence and local tetracycline concentrations as a function of time, tetracycline-containing chitosan microspheres were formulated and evaluated using the fasted Mongolian gerbil model. The H. pylori-infected gerbil model was used to evaluate the efficacy of the tetracycline-containing chitosan microsphere formulation. These preliminary results show great promise for this delivery strategy in the treatment of localized gastro-intestinal tract infections. Drug carrier systems can be engineered with the appropriate therapeutic agent(s) for efficient delivery to the target site and provide better control over localized infectious diseases. This strategy will ultimately lead to favorable clinical outcomes with less potential for resistance development.

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References

  • Bell G.D., Powell K., Burridge S.M., Pallecaros A., Jones P.H., Gant P.W., Harrison G., Trowell J.E. (1992). Experience with “triple” anti Helicobacter pylori eradication therapy: side effects and the importance of testing the pre-treatment bacterial isolate for metronidazole resistance. Aliment. Pharmacol. Ther. 6:427–435

    Article  CAS  Google Scholar 

  • Bingel S.A. (1995). Pathologic findings in an aging Mongolian gerbil (Meriones unguiculatus) colony. Lab. Anim. Sci. 45:597–600

    CAS  Google Scholar 

  • Blaser M.J. (1987). Gastric Campylobacter-like organisms, gastritis and peptic ulcer disease. Gastroenterology 93:371–383

    CAS  Google Scholar 

  • Blaser M.J. (1990). Helicobacter pylori and the pathogenesis of gastroduodenal inflammation. J. Infect. Dis. 161:626–633

    CAS  Google Scholar 

  • Chandy T., Sharma C.P. (1990). Chitosan – as a biomaterial. Biomat. Art. Cells. Art. Org. 18:1–24

    CAS  Google Scholar 

  • Claesson P.M., Ninham B.W. (1992). pH-dependent interactions between adsorbed chitosan layers. Langmuir 8:1406–1412

    Article  CAS  Google Scholar 

  • Domard A., Cartier N. (1992). Glucosamine oligomers: IV. Solid state-crystallization and sustained dissolution. Int. J. Biol. Macromol. 14:100–106

    Article  CAS  Google Scholar 

  • Dore M.P., Sepulveda A.R., Mura I., Realdi G., Osato M.S., Graham D.Y. (1997). Explanation for variability of omeprazole amoxicillin therapy? Tolerance of H. pylori to amoxicillin. Gastroenterology 112:A105

    Google Scholar 

  • Eaton K.A., Morgan D.R., Krakowka S. (1994). Campylobacter pylori virulence factors in gnotobiotic piglets. Infect. Immun. 57:1119–1125

    Google Scholar 

  • Forman D., Newell D.G., Fullerton F., Yarnell J.W., Stacey A.R., Wald N., Sitas F. (1991). Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. Br. Med. J. 302:1302–1305

    Article  CAS  Google Scholar 

  • H. pylori and peptic ulcer disease. 2003. URL http://www.cdc.gov/ulcer/md.htm#fda. (10/10/2003)

  • Hazell S.L., Lee A., Brady L. (1986). Campylobacter pyloridis and gastritis: association with intracellular spaces and adaptation to an environment of mucus as important factors in colonization of the gastric epithelium. J. Infect. Dis. 153:658–663

    CAS  Google Scholar 

  • Hejazi R. and Amiji M. 2001. Chitosan-based delivery systems: physicochemical properties and pharmaceutical applications. In: Dumitriu S. (ed.), Polymeric Biomaterials. Second Edition, Revised and Expanded. Marcel Dekker, Inc., New York, NY, Chapter 10, pp. 213–238

  • Hejazi R., Amiji M. (2002). Stomach-specific anti-H. pylori therapy. I: preparation and characterization of tetracycline-loaded chitosan microspheres. Int. J. Pharm. 235(1–2):87–94

    Article  CAS  Google Scholar 

  • Hejazi R., Amiji M. (2003a). Chitosan-based gastrointestinal delivery systems. J. Control. Release 89:151–165

    Article  CAS  Google Scholar 

  • Hejazi R., Amiji M. (2003b). Stomach-specific anti-H. pylori therapy. II: gastric residence studies of tetracycline-loaded chitosan microspheres in gerbils. Pharm. Dev. Technol. 8:253–262

    Article  CAS  Google Scholar 

  • Hejazi R., Amiji M. (2004). Stomach-specific anti-H. pylori therapy. III: effect of chitosan microsphere crosslinking on the gastric residence and local tetracycline concentrations in fasted gerbils. Int. J. Pharm. 272(1–2):99–108

    Article  CAS  Google Scholar 

  • Hirano S., Seino H., Akiyama Y., Nonaka I. (1990). Chitosan: a biocompatible material for oral and intravenous administrations. In: Gebelein C.G., Dunn R.L. (eds), Progress in Biomedical Polymers. Plenum Press, New York NY, pp. 283–290

    Google Scholar 

  • Hoppe-Seiler F. (1994). Chitin and chitosan. Ber. Deutsch Chem. Ges. 27:3329–3331

    Google Scholar 

  • Hunt R.H. (1995). Helicobacter pylori eradication: a critical appraisal and current concerns. Scand. J. Gastroenterol. 30:73–76

    Google Scholar 

  • Ikeno T., Ota H., Sugiyama A., Ishida K., Katsuyama T., Genta R.M., Kawasaki S. (1999). Helicobacter pylori-induced chronic active gastritis, intestinal metaplasia, and gastric ulcer in Mongolian gerbils. Am. J. Pathol. 154:951–960

    CAS  Google Scholar 

  • Ito M., Ban A., Ishihara M. (2000). Anti-ulcer effects of chitin and chitosan, healthy foods, in rats. Jpn. J. Pharmacol. 82:218–225

    Article  CAS  Google Scholar 

  • Knapczk J., Krowczynski L., Pawlik B., Liber Z. (1984). Pharmaceutical dosage forms with chitosan. In: Skjak-Braek G., Anthonsen T., Sandford P. (eds), Chitin and Chitosan: Sources, Chemistry, Biochemistry, Physical Properties and Applications. Elsevier Applied Science, London, UK, pp. 665–669

    Google Scholar 

  • Lee A. (1999). Animal models of Helicobacter infection. Mol. Med. Today 5:500–501

    Article  CAS  Google Scholar 

  • Lehr C.M., Bouwstra J.A., Schacht E., Junginger H.E. (1992). In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int. J. Pharm. 78:43–48

    Article  CAS  Google Scholar 

  • Levy S.B. (1992). The Antibiotic Paradox: How Miracle Drugs are Destroying the Miracle. Plenum Press Inc., New York, NY

    Google Scholar 

  • Malfertheiner P. (1993). Compliance, adverse events, and antibiotic resistance in Helicobacter pylori treatment. Scand. J. Gastroenterol. 28:34–37

    Google Scholar 

  • Marshall B.J. (1983). Unidentified curved bacilli in gastric epithelium in active chronic gastritis. Lancet 1:1273–1275

    Google Scholar 

  • Marshall B.J., Warren J.R. (1984). Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1:1311–1315

    Article  CAS  Google Scholar 

  • Matsumoto S., Washizuka Y., Matsumoto Y., Tawara S., Ikeda F., Yokota Y., Karita M. (1997). Induction of ulceration and severe gastritis in Mongolian gerbil by Helicobacter pylori infection. J. Med. Microbiol. 46:391–397

    Article  CAS  Google Scholar 

  • Megraud F. 1994. Helicobacter pylori resistance to antibiotics. In: Hunt R.H. and Tytgat Guido N.J. (eds), Helicobacter pylori: Basic Mechanisms to Clinical Cure. Kluwer Academic Publishers, Dordrecht, The Netherlands, pp. 570–583

  • Mergaud F., Trimoulet P., Lamouliatte H., Boyanova L. (1991). Bactericidal effect of amoxicillin on Helicobacter pylori in an in vitro model using epithelial cells. Antimicrob. Agents Chemother. 35:869–872

    Google Scholar 

  • Miyazaki S., Nakayama A., Oda M., Takada M., Attwood D. (1994). Chitosan and sodium alginate based bioadhesive tablets for intraoral drug delivery. Biol. Pharm. Bull. 17:745–747

    CAS  Google Scholar 

  • NIH Consensus Conference (1994). Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in peptic ulcer disease. JAMA 272:65–69

    Article  Google Scholar 

  • Nomura A.M., Stemmermann G.N., Chyou P.H., Kato I., Perez-Perez G.I., Blaser M.J. (1991). Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N. Engl. J. Med. 325:1132–1136

    Article  CAS  Google Scholar 

  • Parsonnet J., Friedman G.D., Vandersteen D.P., Chang Y., Vogelman J.H., Orentreich N., Sibley R.K. (1991). Helicobacter pylori infection and the risk of gastric carcinoma. N. Engl. J. Med. 325:1127–1131

    Article  CAS  Google Scholar 

  • Patel V.R., Amiji M.M. (1996a). pH-sensitive swelling and drug release properties of chitosan-poly(ethylene oxide) semi-interpenetrating polymer network. In: Ottenbrite R., Huang S., Park K. (eds), Hydrogels and Biodegradable Polymers for Bioapplications Volume 627. American Chemical Society Syposium Publication, Washington, DC, pp. 209–220

    Google Scholar 

  • Patel V.R., Amiji M.M. (1996b). Preparation and characterization of freeze-dried chitosan-poly(ethylene oxide) hydrogels for site-specific antibiotic delivery in the stomach. Pharm. Res. 13:588–593

    Article  CAS  Google Scholar 

  • Patel V.R., Amiji M.M. (1996c). pH-sensitive swelling and drug release properties of chitosan-poly(ethylene oxide) semi-interpenetrating polymer network. In: Ottenbrite R., Huang S., Park K. (eds), Hydrogels and Biodegradable Polymers for Bioapplications Volume 627. American Chemical Society Symposium Series Publication. American Chemical Society, Washington, DC, pp 209–220

    Google Scholar 

  • Peterson W.L., Graham D.Y., Marshall B., Blaser M.J., Genta R.M., Klein P.D., Stratton C.W., Drnec J., Prokocimer P., Siepman N. (1993). Clarithromycin as monotherapy for eradication of Helicobacter pylori: a randomized, double-blind trial. Am. J. Gastroenterol. 88:1860–1864

    CAS  Google Scholar 

  • Qaqish R.B., Amiji M.M. (1999). Synthesis of fluorescent chitosan derivative and its application for the study of chitosan–mucin interactions. Carbohyd. Polym. 38:99–107

    Article  CAS  Google Scholar 

  • Reddy R., Osato M., Gutierrez O., Kim J.G., Graham D.Y. (1996). Metronidazole resistance is high in Korea and Columbia and appears to be rapidly increasing in the US. Gastroenterology 10:A236

    Google Scholar 

  • Rha C.K., Rodriguez-Sanchez D., Kienzle-Sterzer C. (1984). Novel applications of chitosan. In: Colwell R.R., Pariser E.R., Sinskey A.J. (eds), Biotechnology of Marine Polysaccharides. Hemisphere Publishing, Washington, DC, pp. 284–311

    Google Scholar 

  • Roberts G.A.F. (1992). Solubility and solution behaviour of chitin and chitosan. In: Roberts G.A.F. (ed.), Chitin Chemistry. MacMillan Press, Houndmills, pp. 274–329

    Google Scholar 

  • Roberts G.A.F. (1992). Structure of chitin and chitosan. In: Roberts G.A.F. (ed.), Chitin Chemistry. MacMillan Press, Houndmills, pp. 1–53

    Google Scholar 

  • Talley N.J., Zinsmeister A.R., Weaver A., DiMagno E.P., Carpenter H.A., Perez-Perez G.I., Blaser M.J. (1991). Gastric adenocarcinoma and Helicobacter pylori infection. J. Natl. Cancer Inst. 83:1734–1739

    CAS  Google Scholar 

  • The United States Pharmacopeia/National Formulary. 1990. Volume XXII. The United States Pharmacopeial Convention, Inc. Rockville, MD, 1788 pp

  • Tytgat G.N.J., Noach L., Rauws E.A.J. (1991). Helicobacter pylori. Scand. J. Gastroenterol. 26:1–8

    Google Scholar 

  • Vasquez A., Valdez Y., Gilman R.H., McDonald J.J., Westblom T.U., Berg D., Mayta H., Gutierrez V. (1996). Metronidazole and clarithromycin resistance in Helicobacter pylori determined by measuring MICs of antimicrobial agents in color indicator egg yolk agar in a miniwell format. J. Clin. Microbiol. 34:1232–1234

    CAS  Google Scholar 

  • Worthington J.M., Fulghum R.S. (1988). Cecal and fecal bacterial flora of the Mongolian gerbil and the chinchilla. Appl. Environ. Microbiol. 54:1210–1215

    CAS  Google Scholar 

  • Yalpana M., Pantaleone D. (1994). An examination of the unusual susceptibilities of aminoglycans to enzymatic hydrolysis. Carbohyd. Res. 256:159–175

    Article  CAS  Google Scholar 

  • Yao K.D., Peng T. (1994). Swelling kinetics and release characteristics of crosslinked chitosan:polyether polymer network (semi-IPN) hydrogels. J. Polym. Sci., Part A: Polym. Chem. 32:1213–1223

    Article  CAS  Google Scholar 

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Acknowledgements

This work was partially supported by the National Institutes of Health SBIR Phase I subcontract funding from EOS Pharmaceuticals (Woburn, MA) and by Northeastern University through the Research and Scholarship Development Grant. The author is deeply appreciative of the collaborations with Dr David Cave when he was the Chief of Gastroenterology at Saint Elizabeth’s Medical Center in Boston (currently at University of Massachusetts Medical Center, Worcester, MA) and Dr Masae Tatematsu and his co-workers at the Aichi Cancer Center in Nagoya, Japan. In addition, many graduate students in the author’s laboratory have been involved in these studies and their participation is gratefully acknowledged.

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  1. Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, 110 Mugar Life Sciences Building, Boston, MA, 02115, USA

    Mansoor M. Amiji

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Amiji, M.M. Tetracycline-containing Chitosan Microspheres for Local Treatment of Helicobacter pylori Infection. Cellulose 14, 3–14 (2007). https://doi.org/10.1007/s10570-006-9070-3

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