Effect of iguratimod and other anti-rheumatic drugs on adenocarcinoma colon 26-induced cachexia in mice.

OBJECTIVE: To examine the effect of iguratimod (T-614) and other anti-rheumatic drugs on a mouse model of adenocarcinoma-induced cachexia. METHODS: Cachexia was induced in BALB/c mice by s.c. inoculation of colon 26/clone 20 cells (day 0). The drugs were administered p.o. daily from day 0 for 15 days for prophylactic experiments and from day 7 for 8 days for therapeutic experiments. Serum biochemical parameters and wasting of adipose tissue and muscle were evaluated as the nutritional condition in tumor-bearing mice at day 14. Interleukin-6 (IL-6) levels in serum and tumor tissue of those mice were also quantified. RESULTS: Administration of T-614 did not inhibit the tumor growth, but it resulted in attenuation of cachexia symptoms, such as the reduction in epididymal fat and gastrocnemius muscle, and the decrease of serum albumin. Furthermore, T-614 decreased the serum levels of IL-6, and reduced its gene expression in the tumor tissues. Exogenously administered IL-6 nullified the suppressive effect of T-614. Prednisolone prevented the weight loss and the wasting without inhibiting tumor growth. Methotrexate and indomethacin did not exert any preferable effects in a therapeutic dosing schedule. CONCLUSIONS: Our results demonstrate that T-614 exerts an anticachectic effect in tumor-bearing mice through the inhibition of IL-6 gene expression.

[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.