Abstract
The promotion of the concept of cytoprotection has fostered hopes that the use of co-prescribed mucosal protective agents would revolutionize the prevention of NSAID-induced ulcers and supply the basis for novel ulcer therapy. Prostaglandins do not, however, accelerate ulcer healing when applied at doses that exert an unequivocal cytoprotective activity. Attempts have therefore been made in recent years to create new less-toxic NSAIDs, such as combined lipoxygenase/cyclo-oxygenase inhibitors, NSAIDs coupled to an NO donor and so-called COX-2 inhibitors. All these preparations do in fact exert a diminished gastrointestinal toxicity. There is however increasing evidence accumulating from studies performed in and outside our laboratories that in chromic ulcer models their increased gastrointestinal tolerance is not necessarily reflected by non-interference with ulcer healing. It is thus mandatory to distinguish between cytoprotective and healing properties of drugs interfering with the cyclo-oxygenase pathway.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Halter F, Hurlimann S, Inauen W. Pathophysiology and clinical relevance of Helcobacter pylori. Yale J Biol Med. 1992;65:625–38.
Hawkey CJ. Non-steroidal anti-inflammatory drugs and peptic ulcers. Br Med J. 1990;300:278–84.
Peura DA, Graham DY. Helicobacter pylori: consensus reached: peptic ulcer is on the way to becoming an historic disease (editorial). Am J Gastroenterol. 1994;89:1137–9.
Armstrong HP, Blower AL. Non-steroidal anti-inflammatory drugs and life-threatening complications of peptic ulceration. Gut. 1987;28:527–532.
Somerville K, Faulkner G, Langman M. Non-steroidal anti-inflammatory drugs and bleeding peptic ulcer. Lancet. 1986;1:462–4.
Halter, F, Weber B, Huber T, Eigenmann, F, Frey MP, Ruchti C. Diaphragm disease of the ascending colon. Association with sustained-release diclofenac. J. Clin. Gastroenterol. 1993;16:74–80.
Inauen W, Wyss PA, Kayser S et al. Influence of prostaglandins, omeprazole, and indomethacin on healing of experimental gastric ulcers in the rat. Gastroenterology. 1988;95:636–41.
Wang JY, Yamasaki S, Takeuchi K, Okabe S. Delayed healing of acetic acid-induced gastric ulcers in rats by indomethacin. Gastroenterology. 1989;96:393–402.
Robert A, Nezamis JE, Lancaster C, Hanchar AJ. Cytoprotection by prostaglandins in rats. Prevention of gastric necrosis produced by alcohol, HCVL, NaOH, hypertonic NACl, and thermal injury. Gastroenterology. 1979;77:433–43.
Hirose H, Takeuchi K, Okabe S. Effect of indomethacin on gastric mucosal blood flow around acetic acid induced gastric ulcers in rats. Gastroenterology. 1991;100:1259–65.
Graham DY, Agrawal NM, Roth SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lancet. 1988;2:1277–80.
Schmassmann A, Tarnawski A, Peskar BM, Varga L, Flogerzi B, Halter F. Sequential assessment of gastric ulcer healing in rats: reversal of indomethacin-induced effects by omeprazole. Am J Physiol. 1994;268:G276–85.
Levi S, Goodlad RA, Lee CY et al. Inhibitory effect of non-steroidal anti-inflammatory drugs on mucosal cell proliferation associated with gastric ulcer healing. Lancet. 1990;336:840–3.
Ogihara Y, Okabe S. Mechanism by which indomethacin delays gastric ulcer healing in the rat: Inhibited contraction of the ulcer base. Jpn J Pharmacol. 1993;61:123–31.
Graham DY, Smith JL, Spjut HJ, Torres E. Gastric adaptation studies in humans during continuous aspirin administration. Gastroenterology. 1988;95:327–33.
Hawkey CJ, Walt RP. Prostaglandins for peptic ulcer. A promise unfulfilled. Lancet. 1986;2:1084–7.
Dorta G, Nicolet D, Vouillamoz D, Margalith D, Blum Al, Armstrong D. Effects of misoprostol on healing and prevention of biopsy-induced gastroduodenal lesions occuring during the administration of diclofenac in volunteers. Aliment Pharmacol Ther 1996;10:563–9.
Walan A, Bader JP, Classen M et al. Effect of omeprazole and ranitidine on ulcer healing and relapse rates in patients with benign gastric ulcer. N Engl J Med 1989;320:69–75.
Wang JY, Nagai H, Okabe S. Effect of omeprazole on delayed healing of acetic acid-induced gastric ulcers in rats. Jpn J Pharmacol. 1990;54:82–5.
Sirko SP, Schindler R, Doyle MJ, Weisman SM, Dinarello CA. Transcription, translation and secretion of interleukin 1 and tumor necrosis factor: effects of tebufelone, a dual cyclooxygenase/5-lipoxygenase inhibitor. Eur J Immunol. 1991;21:243–50.
Halter F, Rainsford KD, Sirko SS, Schmassmann A. NSAID-induced mucosal injury: analysis of gastric toxicity of new generation NSAIDs: ulcerogenicity compared with ulcer healing. Yale J Biol Med. (in press).
Wallace JL, Reuter B, Cicala C, McKnight W, Grisham MB, Cirino G. Novel nonsteroidal anti-inflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology. 1994;107:173–9.
Elliott SN, McKnight W, Cirino G, Wallace, JL. A nitri oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats. Gastroenterology. 1995;109:524–30.
Elliott SN, McKnight W, Cirino G, Wallace JL. A nitric oxide-releasing nonsteroidal anti-inflammatory drugs. Agents Actions. 1995;46:121–9.
Benoni G, Terzi M, Adami A, Grigolini L, Del Soldato P, Cuzzolin L. Plasma concentrations and pharmacokinetic parameters of nitrofenac using a simple and sensitive HPLC method. J Pharm Sci. 1995;84:93–5.
Wallace JL, Reuter B, Cicala C, McKnight W, Grisham M, Cirino G. A diclofenac derivative without ulcerogenic properties. Eur J Pharmacol. 1994;25:249–55.
Conforti A, Donini M, Brocco G, DelSoldato P, Benoni G, Cuzzolin L. Acute anti-inflammatory activity and gastrointestinal tolerability of diclofenac and nitrofenac. Agents Actions. 1993;40:176–80.
Reuter BK, Cirino G, Wallace JL. Markedly reduced intestinal toxicity of a diclofenac derivative. Life Sci 1994;55:1–8.
Cuzzolin, L, Conforti A, Donini M, Adami A, Del Soldato P, Benoni G. Effects on intestinal microflora, gastrointestinal tolerability and antiinflammatory efficacy of diclofenac and nitrofenac in adjuvant arthritic rats. Pharmacol Res. 1994;29:89–97.
Roth GJ, Siok CJ, Ozols J. Structural characteristics of prostaglandin synthase from sheep vesicular gland. J Biol Chem. 1980;255:1301–4.
Williams CS, Dubois RN: Prostaglandin endoperoxide synthase: Why two isoforms? Am J Physiol. 1996;270:G393-G400.
Boyce S, Chan CC, Gordon R et al. L-745,337: A selective inhibitor of cyclo-oxygenase-2 elicits antinociception but not gastric ulceration in rats. Neuropharmacology. 33;1994;1609–11.
Chan CC, Boyce, S, Brideau C et al. Pharmacology of a selective oxygenase-2 inhibitor, L-745, 337: A novel nonsteroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach. J Pharmacol Exp Ther. 1995;274:1531–7.
Schmassmann A, Tarnawski A, Peskar BM, Varga L, Flogerzi B, Halter F. Influence of acid and angiogenesis on kinetics of gastric ulcer healing in rats: interaction with indomethacin. Am J Physiol. 1995;268:G276–85.
Schmassmann A, Netzer P, Flogerzi B, Halter F. Role of cyclooxygenase-1 and-2 in gastric ulcer healing in rats. Gastroenterology. 1997;112A:283.
Tarnawski A, Wahlstrom K, Gergely H, Sarfeh IJ. Expression of cyclooxygenase-1 and-2 (COX-1 and COX-2) in normal gastric mucosa. Effect of antacid (hydrotalcit) treatment. Gastroenterology. 1996;110:A275.
Mizuno H, Sakamoto C, Matusda K et al. Induction of cyclooxygenase-2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology. 1997;112:387–97.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Halter, F., Peskar, B., Rainsford, K.D. et al. Cytoprotection and healing: Two unequal brethren. Inflammopharmacol 5, 407–414 (1997). https://doi.org/10.1007/s10787-997-0036-3
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10787-997-0036-3