[Histological study on healing of cryocautery-induced rat gastric ulcer treated with T-593].

The effect of T-593, a novel anti-ulcer agent, on the healing of cryocautery-induced rat gastric ulcer was investigated histologically in comparison with that of famotidine. Seven days after ulceration, T-593 (30 mg/kg) or famotidine (30 mg/kg) was orally administered twice daily for 8 weeks. Two, 4 and 8 weeks after the start of administration, the ulcer size was measured by a stereoscopic microscope, and the gastric mucosa was observed histologically. The thickness of the regenerated mucosa, the density and the arrangement of gastric glands, the degree of inflammatory-cell infiltration in the submucosal tissue and the number of microvessels in the submucosal tissue were quantified. In macroscopical evaluation, T-593 and famotidine significantly accelerated ulcer healing, and the time courses of the ulcer index were similar in both cases. In histological evaluation of healed ulcers, T-593 normalized the thickness of regenerated mucosa and reduced the degree of inflammatory-cell infiltration and the number of microvessels in the submucosal tissue, while famotidine had no effect. In conclusion, T-593 possesses accelerating effects not only on the restoration of regenerated mucosa but also on the maturation of submucosal tissue. Therefore, T-593 improves the quality of ulcer healing.

Implication of endogenous nitric oxide in gastric mucosal protective effect of T-593, a novel anti-ulcer agent, in rats.

The relationship of endogenous nitric oxide (NO) to the gastric mucosal protective effect of the novel anti-ulcer agent T-593, (+/-)-(E)-1-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-3-[2-[[[5-(methylamino) methyl-2-furyl]methyl]thio]ethyl]-2-(methylsulfonyl) guanidine, was investigated in rats. T-593 (3-30 mg/kg, p.o.) dose dependently prevented the formation of gastric mucosal lesions induced by oral administration of aspirin (200 mg/kg) in 0.15 N HCl (HCl-aspirin). Pretreatment with N(G)-nitro-L-arginine methylester (L-NAME), a selective inhibitor of NO synthase (NOS), attenuated the mucosal protective effect of T-593. This effect of L-NAME was antagonized by pretreatment with L-arginine, a substrate of NOS, but not with D-arginine. Activity of total NOS composed of inducible and constitutive NOS in the gastric mucosa was decreased by HCl-aspirin, and T-593 inhibited this decrease. On the other hand, HCl-aspirin and T-593 did not affect inducible NOS activity in the gastric mucosa. Furthermore, we confirmed that T-593 inhibits the decrease in gastric mucosal blood flow (GMBF) induced by HCl-aspirin, and this effect is completely inhibited by pretreatment with L-NAME. These results suggest that the mucosal protective effect of T-593 is partly mediated by endogenous NO via improvement of GMBF and that a possible mechanism for the effect of T-593 is the maintenance of constitutive NOS activity in gastric mucosa.

[Characteristics of T-593, a novel antiulcer agent, and each of its enantiomers on pharmacodynamics].

T-593 consists of two optical isomers, (-)-S and (+)-R. Our previous report showed that T-593 has biphasic effects, that is a long-lasting antisecretory action and an improving effect on gastric mucosal blood flow (GMBF). In this study, we compared the sole potency of each isomer on these bi-phasic effects. On the anti-secretory action investigated by the pylorus-ligation method, the (-)-S-isomer showed strong inhibition, while the (+)-R-isomer showed no effect, whereas the GMBF improvement was provided by the (+)-R-isomer. These results show the bi-phasic effects of racemic T-593 are separately derived from each isomer. The (-)-S-isomer strongly inhibited acute gastric mucosal lesion formation, with a potency comparable to T-593 itself, while the (+)-R-isomer showed less effect. Chronic gastric ulcer induced by acetic acid was, however, not healed by the sole treatment of each optical isomer, while racemic T-593 showed a significant effect. This result shows not only anti-secretion but also GMBF improvement is necessary to heal the chronic ulcer. This interesting property of T-593 is expected to raise the quality of ulcer healing (QOUH) and also may prevent ulcer recurrence.

[Effect of T-593 on gastric bleeding and lesions induced by indomethacin and water-immersion stress in rats: improving effect of T-593 on reduced gastric mucosal blood flow in rats].

The effect of T-593, a novel antiulcer agent, was investigated with respect to gastric bleeding and lesions induced by indomethacin (3 mg/kg, s.c.) and water (23 degrees C) immersion stress (IM-WIS) with perfusion of HCl (0.13N) into the rat stomach. It was found that the total amounts of gastric bleeding and lesions after IM-WIS with perfusion of HCl were more significantly decreased in T-593 (1 mg/kg, i.v., 0.1 mg/kg/hr, d.i.)- and secretion (15 CU/kg/hr, d.i.)-treated rats, respectively. On the other hand, famotidine (1 mg/kg, i.v.) did not affect gastric bleeding and lesions. The gastric mucosal blood flow (GMBF) reduction was induced by IM-WIS. T-593 (0.03-0.1 mg/kg/hr, d.i.) inhibited the GMBF reduction dose-dependently. The GMBF improvement by T-593 disappeared with pretreatment of L-NAME (2 mg/kg, s.c.) and was recovered by L-arginine (50 mg/kg, i.v.). This indicates that GMBF improvement by T-593 is dependent on EDRF (NO). This interesting property of T-593 is expected to contribute to the clinical promotion of ulcer healing.

[Influence of T-593 on the recurrence and relapse of cryocautery-induced gastric ulcer in rats: sequential observation with an endoscope and histological evaluation].

We investigated the influence of T-593, a novel anti-ulcer agent, on the recurrence and relapse of cryocautery-induced gastric ulcer in rats, in comparison with the action of famotidine and ranitidine. The drugs were administered from the 7th to the 119th day and then discontinued to the 190th day after induction of gastric ulcer. The healing, recurrence and relapse process of gastric ulcer was sequentially observed with an endoscope. In the control group, the reduction of ulcer index was observed until the 76th day after ulcer induction followed by aggravation, suggesting the recurrence and relapse occurred on cryocautery-induced gastric ulcer in rats. In the famotidine and ranitidine groups, the recurrence and relapse occurred after cessation of administration. The recurrence and/or relapse rate of T-593 was lower than those of other drugs. In the histological measurement, the grades of heterotopic regenerated gland and inflammatory cell infiltration of T-593 was lower than those of the control and other drugs in the ulcer area. From these results, it is concluded that T-593 induces ulcer healing with a lower recurrence and/or relapse rate of ulcers than other conventional H2-antagonists, and T-593 may thus be a useful anti-ulcer drug for clinical therapy.

[Mycoplasma pneumoniae pneumonia with diffuse nodular shadows and right hilar lymphadenopathy].

A 51-year-old man was admitted to our hospital because of fever, a productive cough, and dyspnea. His chest X-ray film revealed diffuse reticulonodular shadows and right hilar lymphadenopathy. A chest CT scan revealed thickened bronchial walls and diffuse centriacinar or centrilobular nodular shadows. Serologic testing provided conclusive evidence of Mycoplasma pneumoniae infection. The diffuse pattern and hilar lymphadenopathy on chest X-ray films are uncommon in this disease, and they caused some uncertainty regarding the correct diagnosis. M. pneumoniae attaches to cells of the respiratory tract and produces a locally acting cytotoxin. Immunologic mechanisms have been shown to play an important role in the pathogenesis of pneumonia. This case suggests that immunologic mechanisms are an important factor in diffuse lung lesions.