It is possible to use a smaller number of subjects in thorough QT studies in Japan than in Europe and the US utilizing moxifloxacin as a positive control. There were no detectable effects of favipiravir on the QT/QTc interval.

Background: Little is currently known about the immunopathogenesis of dengue virus infection. However, the complex interaction of host immune responses during dengue virus infection has important implications on the clinical outcome of patients. The role of Th genes during dengue virus infection is poorly defined.Methods: In this project, we determine which genes are differentially regulated in dengue type 2 virus-infected cell lines (HepG2 -hepatocytes, K562 -myelogenous leukaemia cell line and Jurkat -T cells). We used real-time PCR to profile the expression of 84 genes related to the three classes of helper T cells: Th1, Th2 and Th3. This array includes cytokine and chemokine genes representative of Th1, Th2 and Th3 cells, transcriptional factors that regulate the expression of these cytokines as well as genes involved in the antimicrobial humoral response.Results: The susceptibilities of the three cell lines to dengue type 2 virus were evident by detection of viral antigen and virus growth curve. Majority of the Th genes that are differentially regulated in all the three cell lines infected with dengue virus. However, Jurkat and K562 cells showed more common regulation as compared to HepG2 cells probably because both of them are leukocytes. Among the differentially regulated genes, TLR6 was significantly regulated in both dengue type 2 virus-infected K562 cells and Jurkat cells. Semi-quantitative PCR and Western detection were performed to confirm the up-regulation of TLR6. High level of IL-6 expression was also detected from K562 cells and Jurkat cells.Conclusion: K562 and Jurkat cells are permissive to dengue type 2 virus infection. TLR 6 is up-regulated which in turn leads to upregulation of IL-6 during dengue virus infection. This may have implications in the immunopathogenesis of dengue virus biology.

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.

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