Efficacy and safety of oral tolvaptan in patients undergoing hemodialysis: a Phase 2, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Loop diuretics are used to manage fluid retention in patients with end-stage kidney disease undergoing hemodialysis (HD). This randomized, double-blind, placebo-controlled, Phase 2 trial evaluated the efficacy and safety of tolvaptan, a vasopressin V2 receptor antagonist, in Japanese HD patients. METHODS: A total of 124 patients (24-h urine volume ≥500 mL) on thrice-weekly HD were randomized to receive oral tolvaptan 15 mg/day (n = 40), tolvaptan 30 mg/day (n = 40) or placebo (n = 44) for 24 weeks. Efficacy endpoints were change from baseline in 24-h urine volume, total fluid removal by HD per week and interdialytic weight gain (IDWG). Safety was assessed via the incidence of treatment-emergent adverse events (TEAEs). RESULTS: At treatment end, the difference (95% confidence interval) from the placebo group in the mean change from baseline in 24-h urine volume was significant in the tolvaptan 15 mg {429.1 mL [95% confidence interval (CI) 231.0, 627.2]; P < 0.0001} and 30 mg [371.6 mL (95% CI 144.1, 599.2); P = 0.0017] groups. The mean changes from baseline in total fluid removal by HD and IDWG were not significantly different in the tolvaptan groups versus the placebo group. Although the proportion of patients with TEAEs was lower in the placebo group (77.3%) than in the tolvaptan groups (92.3%), tolvaptan was safe and well-tolerated during the study period. CONCLUSIONS: Tolvaptan significantly sustained diuretic action for 24 weeks in HD patients but did not reduce total fluid removal by HD per week and IDWG to the same extent.

The post hoc analysis comparing the severity grades of chemoradiotherapy-induced oral mucositis scored between the central and local assessors in a multicenter, randomized controlled trial of rebamipide for head and neck cancer.

BACKGROUND: In the treatment of head and neck cancer, severity of chemoradiotherapy-induced oral mucositis has been recognized as one of the key factors affecting the outcomes of the anticancer therapies. Therefore, the development of treatments mitigating oral mucositis would be of clinical significance, although the adequate assessment procedure for efficacy evaluation remains to be established. We conducted this post hoc study to assess the effect of objective evaluation of the severity grade on the outcomes of the clinical trial. METHODS: In the original trial with rebamipide liquids (0, 2, and 4%) for chemoradiotherapy-induced oral mucositis, the investigators in local sites and independent central review separately determined the severity grades in accordance with Common Terminology Criteria of Adverse Events version 3.0 based on the Assessment Sheet scored by the investigators. The discordance in severity grades between the investigators and central review was analyzed on cross table. RESULTS: The analysis revealed the discordance rate over the trial was 34%. While the incidences of severe oral mucositis in the placebo, rebamipide 2%, and 4% groups evaluated by the central review were 39%, 29%, and 25%, respectively, the respective values in the investigator's evaluation were 32%, 39%, and 44%. CONCLUSION: In the clinical trial for the treatment of oral mucositis, it was strongly suggested that objective evaluation with a consistent scale would be required.

Tetomilast attenuates elastase-induced pulmonary emphysema through inhibition of oxidative stress in rabbits.

Tetomilast was originally identified as a potent inhibitor of superoxide production in human neutrophils, and is of interest because it may relieve oxidative stress related to chronic obstructive pulmonary disease (COPD). Our objective was to determine whether tetomilast effectively protects against the development of porcine pancreatic elastase (PPE)-induced emphysema in rabbits. Rabbits were divided into three groups (sham n=19, PPE n=19, PPE/Tetomilast n=18). The rabbits were once daily orally administered vehicle solution or tetomilast 5 d/week for 4 weeks before the PPE instillation. We compared pulmonary function, inflammatory cell infiltration, oxidative stress, and the incidences of apoptosis among the three groups. Tetomilast suppressed PPE-induced increases in the incidence of apoptosis and the production of 8-hydroxy-deoxyguanosine (8-OHdG) in lung tissues. PPE-instilled rabbits treated with tetomilast showed significantly less mean linear intercept and significantly better pulmonary function than rabbits administered PPE alone. Tetomilast may inhibit the development of emphysema by attenuating pulmonary inflammation and apoptosis caused by PPE-induced oxidative stress.

Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL-10-deficient mice.

BACKGROUND: Tetomilast (OPC-6535) was originally developed as a compound inhibiting superoxide production in neutrophils. Although its mechanism of action is not completely understood, phosphodiesterase type 4 inhibitory function has been postulated. The therapeutic effect of PDE4 inhibitors has been reported for chronic inflammatory disorders such as chronic obstructive pulmonary diseases. In this study we aimed to examine whether tetomilast could be a novel drug for inflammatory bowel diseases by further clarifying its antiinflammatory effects. METHODS: Cytokines from human peripheral blood mononuclear cells were measured by enzyme-linked immunosorbent assay (ELISA) and Cytokine Beads Array. The transcripts were quantified by reverse-transcriptase polymerase chain reaction (RT-PCR). Phosphorylation of transcription factors was examined by phosflow. To examine its in vivo effect, a once-daily oral dose of tetomilast was tested in murine IL-10(-/-) chronic colitis. RESULTS: Tetomilast suppressed TNF-alpha and IL-12 but not IL-10 production from lipopolysaccharide (LPS)-stimulated human monocytes. It suppressed TNF-alpha, IFN-gamma, and IL-10 from CD4 lymphocytes. Tetomilast suppressed cytokine production at the transcriptional level but did not alter phosphorylation of p65, ERK, p38, and STAT3. HT-89, a protein kinase A inhibitor, did not abolish the effect of tetomilast, suggesting that it was independent from the classical cAMP/PKA pathway. IL-10 was not essential to the inhibitory effect of tetomilast on TNF-alpha and IL-12. Tetomilast ameliorated IL-10(-/-) chronic colitis with reduced clinical symptoms, serum amyloid A, and histological scores with decreased TNF-alpha mRNA expression. CONCLUSIONS: Tetomilast exerts its antiinflammatory effects on human monocytes and CD4 cells. Combined with in vivo data these findings support the feasibility of tetomilast as a novel drug for inflammatory bowel diseases.

Rebamipide enema is effective for treatment of experimental dextran sulfate sodium induced colitis in rats.

We investigated therapeutic efficacy of rebamipide using dextran sulfate sodium (DSS) induced colitis model in rats. Three percent DSS solution was given to rats for 9 days. After that, we evaluated the drug efficacy on colitis sustained with continuous drinking of 1% DSS. Twice-daily treatment with 0.3% or 1% rebamipide for 14 days significantly ameliorated the stool abnormality in the colitis model, preferentially suppressed hematochezia. The colonic mucosal lesion, determined by Alcian blue staining on day 24, was significantly reduced by rebamipide enema in a dose-dependent manner. Either rebamipide or 5-aminosalycilic acid (5-ASA) enema treated once daily significantly ameliorated colitis. The minimum effective dose of rebamipide was 0.3% in once-daily treatment, and that of 5-ASA was 10%. In a mechanistic study, the epithelial cell sheet formation of the T84 colon cancer cell was measured as an increase in generation of trans-epithelial electrical resistance in vitro. Rebamipide accelerated the increase, while 5-ASA conversely suppressed it. These results suggest that rebamipide enema is effective for treatment of experimental ulcerative colitis (UC).

Effects of OPC-6535 on lipopolysaccharide-induced acute liver injury in the rat: involvement of superoxide and tumor necrosis factor-alpha from hepatic macrophages.

BACKGROUND: The objective of this study was to investigate the effects of OPC-6535 on Propionibacterium acnes-primed and lipopolysaccharide-induced liver injury in the rat. METHODS: P. acnes was administered intravenously to the rat at 16 mg/kg 7 days before the experiments. In liver perfusion experiments, lipopolysaccharide was mixed in perfusion buffer at 2.5 microg/mL. The chemiluminescence method and histochemical reduction of nitro blue tetrazolium were used for detecting superoxide. Release of cytokines into the perfusate was examined. In in vivo experiments, lipopolysaccharide was administered intravenously to the rat at 200 microg/kg. Concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and cytokines were determined in the plasma, and myeloperoxidase activity was measured in the liver tissue. OPC-6535 was given intravenously at 1 mg/kg 30 minutes before lipopolysaccharide challenge, and was then, in perfusion experiments, added to the buffer at 10 micromol/L. RESULTS: In perfusion experiments, P. acnes and lipopolysaccharide caused dramatic production of superoxide, tumor necrosis factor-alpha (TNF-alpha) and growth-related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1). Superoxide was mainly from hepatic macrophages. Treatment with OPC-6535 suppressed superoxide and TNF-alpha but did not affect GRO/CINC-1. In in vivo experiments, P. acnes and lipopolysaccharide increased the level of TNF-alpha, GRO/CINC-1, AST and ALT in the plasma, and myeloperoxidase activity in the liver. OPC-6535 reduced TNF-alpha, AST, and ALT, but did not affect GRO/CINC-1 or myeloperoxidase. CONCLUSION: Attenuation of liver injury by OPC-6535 is believed to be due to its inhibitory effects on superoxide and TNF-alpha production by hepatic macrophages in P. acnes- and lipopolysaccharide-treated rats.