Steroid-refractory severe ulcerative colitis responding to cyclosporine and long-term follow-up.

We report a case of steroid-refractory ulcerative colitis, treated with cyclosporine, in a 38-year-old woman with a 13-year history of ulcerative colitis. No remission was achieved with treatments that included intravenous hyperalimentation, sulfasalazine, and intensive parenteral prednisolone therapy for 4 weeks. Intravenous infusion of cyclosporine was performed because the patient refused to undergo surgery. Her condition improved dramatically and colectomy was avoided. She has been maintained on oral cyclosporine and azathioprine since steroids were discontinued, and she has remained in clinical and endoscopic remission for 2 years. The side effects were not significant, but mild paresthesia in both hands and mild hypertension, which was controlled by anti-hypertensives. Cyclosporine seems to be an effective treatment for patients with steroid-refractory severe active ulcerative colitis in whom colectomy seems inevitable. We believe further clinical trials of the treatment are warranted.

Malignant transformation of Nakamura type IV gastric polyp with CA 19-9 production.

In a 68-year-old Japanese man, a gastric polyp 24mm in diameter with a stalk 15 mm in diameter was diagnosed as well differentiated adenocarcinoma and treated by endoscopic polypectomy. Histologically, most of the resected tissue was adenoma, and atypical cells were papillarily proliferating to form adenocarcinoma in adenoma, a Nakamura type IV gastric polyp. Infiltration of carcinoma was limited to within the mucosal layer. Immunohistochemical study with anti-CA19-9 antibody revealed positive staining in carcinoma cells. Serum CA19-9 level, which showed slight elevation, returned to the normal range 1 month after the polypectomy. The proliferating cell nuclear antigen (PCNA) labeling index and DNA ploidy pattern were analyzed in the resected tissue. The PCNA labeling index was 30% in carcinoma, 17% in adenoma, and 0.1% in the normal tissue. The DNA ploidy pattern was diploid in adenoma and aneuploid in adenocarcinoma. These findings suggest that gastric adenoma, as well as colonic adenoma, may have the potential for malignant transformation.

Phosphoramidon, an inhibitor of endothelin-converting enzyme, prevents indomethacin-induced gastric mucosal damage in rats.

Endothelin-1 (ET-1) is produced from inactive precursor big ET-1 by endothelin-converting enzyme-1 (ECE-1), a membrane-bound metalloprotease, structurally similar to another metalloprotease, neutral endopeptidase 24.11 (NEP). Although both phosphoramidon and thiorphan are metalloprotease inhibitors, the ECE activity is inhibited by phosphoramidon but not by thiorphan, a specific inhibitor of NEP. Therefore, to investigate whether an ECE inhibitor can prevent indomethacin-induced gastric mucosal damage in rats, we compared the effects between the two metalloprotease inhibitors on both gastric mucosal integrity and the levels of ET-1 and big ET-1 in gastric tissue. Phosphoramidon significantly decreased ET-1 levels, causing a concomitant big ET-1 increase and dose-dependently attenuated indomethacin-induced gastric mucosal damage. By contrast, thiorphan neither changed the ratio of ET-1/big ET-1 nor attenuated the damage. In conclusion, the prevention of gastric mucosal damage by an ECE inhibitor indicates that endogenous ET-1 may play an important role in the pathogenesis of indomethacin-induced gastric mucosal damage.

Gastric mucosal injury induced by local ischemia-reperfusion in rats. Role of endogenous endothelin-1 and free radical.

We investigated the role of an endogenous vasoconstrictor peptide endothelin-1 (ET-1) and free radicals in local gastric ischemia-reperfusion injury in rats. Local gastric ischemia was induced by clamping the left gastric artery for 15 min and reperfusion was done for 10-30 min in the presence of 150 mM exogenous HCl intragastrically. Local gastric ischemia and reperfusion resulted in significant macroscopic and microscopic gastric mucosal damage together with elevation of gastric tissue ET-1 concentration. Gastric tissue ET-1 was found to increase after 15 min of ischemia alone and also with 30 min of reperfusion. A novel nonpeptide endothelin receptor antagonist, bosentan, or a combination of radical scavengers (superoxide dismutase, catalase, and deferoxamine) both attenuated gastric mucosal injury. However, the greater protection observed with bosentan than with radical scavengers might reflect a preferential role of endothelin-1 in this type of injury.

Bosentan, a novel synthetic mixed-type endothelin receptor antagonist, attenuates acute gastric mucosal lesions induced by indomethacin and HCl in the rat: role of endogenous endothelin-1.

Endothelin-1 has been reported to be responsible for gastric mucosal damage in various experimental models. We evaluated the role of endogenous endothelin-1 in the pathogenesis of gastric mucosal damage induced by indomethacin and HCl in the rat. Rats were given indomethacin (25 mg/kg) subcutaneously, and 15 min later, 0.2N HCl intragastrically. Gastric mucosal damage, gastric endogenous endothelin-1, and gastric mucosal hemodynamics were measured. The effects of bosentan, a mixed endothelin receptor antagonist, on gastric mucosal integrity and hemodynamics were assessed. Gastric endogenous endothelin-1 was significantly elevated at 20 min, gastric mucosal blood flow began to decrease significantly at 25 min, and gastric damage occupied 52.2% of the total glandular mucosa at 135 min after injection of indomethacin. Intragastric pretreatment with bosentan (5, 10, 30, and 60 mg/kg) significantly attenuated gastric damage, to 26.1%, 7.7%, 3.6%, and 1.6%, respectively, of the total glandular mucosa. Bosentan (60 mg/kg) prevented the initial decrease of blood flow and, even at 135 min, improved blood flow and hemoglobin oxygen saturation significantly. We suggest that indomethacin-induced endogenous endothelin-1 diminishes gastric mucosal blood flow and tissue oxygenation and ultimately causes gastric damage. Endogenous endothelin-1 may play an important role in the pathogenesis of the acute gastric mucosal lesions induced by indomethacin and HCl.

Phosphoramidon, an endothelin converting enzyme inhibitor attenuates local gastric ischemia-reperfusion injury in rats.

Recently increased production of endothelin-1 has been implicated in the pathogenesis of gastric ischemia-reperfusion injury. We have investigated the effects of endothelin converting enzyme inhibition on local gastric ischemia-reperfusion injury in rats by using two metalloprotease inhibitors, phosphoramidon and thiorphan. In presence of exogenous 0.15M HCI intragastrically, local ischemia was induced by the clamping of left gastric artery for 15 min and reperfusion was done for 30 min. In separate group of rats, phosphoramidon (10-60 mg/kg) or thiorphan (60 mg/kg) were given as i.v. bolus injection immediately before the induction of ischemia. Phosphoramidon dose dependently attenuated the macroscopic and microscopic mucosal injuries while thiorphan did not. These results indicate that phosphoramidon-sensitive endothelin converting enzyme activity is highly present in stomach and phosphoramidon, by inhibiting the conversion of big endothelin-1 to endothelin-1 attenuated the gastric mucosal damage in this model.