Toll-like receptor 4 signal transduction inhibitor, M62812, suppresses endothelial cell and leukocyte activation and prevents lethal septic shock in mice.

Sepsis occurs when microbes activate toll-like receptors (TLRs) stimulating widespread inflammation and activating coagulation cascades. TLR4 signal transduction has been recognized as a key pathway for lipopolysaccharide (LPS)-induced activation of various cells and an attractive target for treatment of sepsis. We found a new benzisothiazole derivative, M62812 that inhibits TLR4 signal transduction. This compound suppressed LPS-induced upregulation of inflammatory cytokines, adhesion molecules and procoagulant activity in human vascular endothelial cells and peripheral mononuclear cells. The half maximal inhibitory concentrations in these assays ranged from 1 to 3 microg/ml. Single intravenous administration of M62812 (10-20 mg/kg) protected mice from lethality and reduced inflammatory and coagulatory parameters in a murine d-galactosamine-sensitized endotoxin shock model. M62812 (20 mg/kg) also prevented mice from lethality in a murine cecal ligation and puncture model. These results suggest that inhibition of TLR4 signal transduction can suppress coagulation as well as inflammation during sepsis and may be clinically beneficial in sepsis treatment.

Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors V. A series of new derivatives containing a spiro[imidazo[1,2-a]pyrazine-2(3H),4'-piperidin]-5(1H)-one scaffold.

We have already reported unique compounds containing a N,O-spiro acetal structure as an orally active factor Xa (FXa) inhibitor. This time, we described a N,N-spiro acetal structure as an analogue of the N,O-spiro acetal structure for an orally active FXa inhibitor. The synthesis of these analogues could be achieved in a similar fashion to the N,O-spiro acetal synthesis. Consequently, FXa inhibitory activity was increased and more active compounds could be found (M58163: IC50 = 0.61 nM, M58169: IC50 = 0.58 nM). Additionally, the absolute configuration could be determined by X-ray crystallography analysis (M58169: (R)-config.).

A phase I study of bi-weekly combination therapy with S-1 and docetaxel for advanced or recurrent gastric cancer.

BACKGROUND: S-1 is a novel oral fluorouracil antitumor drug that contains a combination of 3 pharmacological agents: tegafur (FT), a 5-fluorouracil (5-FU) prodrug, 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits the activity of dihydropyrimidine dehydrogenase (DPD), and potassium oxonate (Oxo), which reduces the gastrointestinal toxicity of 5-FU. S-1 and docetaxel have both been identified as effective agents for the treatment of gastric cancer. However, little is known about the effects and/or adverse effects of a combination of these drugs in the treatment of gastric cancer. The aim of this phase I study was to determine the maximum-tolerated dose (MTD) and the recommended dose of docetaxel with a fixed dose of S-1 in patients with advanced or recurrent gastric cancer. PATIENTS AND METHODS: Patients with metastatic, recurrent, or unresectable gastric cancer received docetaxel at a starting dose of 25 mg/m2 by i.v. infusion over 1 h on days 1, 15 and 29, and S-1 at the full dose of 80 mg/m2 daily for 4 weeks of every 6 weeks. Nine patients were treated with increasing dosages of docetaxel as follows: (docetaxel/S-1, mg/m2): 25/80 (level 1), 30/80 (level 2) and 35/80 (level 3). All cases were assessable for drug safety and 7 were assessable for response. Colony-stimulating factor (CSF) was not used in this study. The adverse effects of treatment were analyzed according to NCI-CTC, version 2 and the response was assessed according to the Japanese Classification of Gastric Cancer, 13th Ed. RESULTS: The MTD was reached at the 35/80 mg/m2 dose-level in 3 out of 3 patients. These patients experienced some dose-limiting toxicity (DLT) or grade 3 anemia. The reported DLTs included diarrhea, stomatitis and general fatigue. Due to these results, 3 additional patients were not enrolled at this dose-level. No hematological or non-hematological adverse effects (more severe than grade 2) were observed in any of the level 1 or 2 patients. However, among the level 1 patients, 66.7% developed grade 2 leukocytopenia and 33.3% developed grade 2 neutropenia. Among the level 2 patients, 33.3% developed grade 2 appetite loss, diarrhea and general fatigue. Partial responses were achieved in 3 (42.9%) out of the 7 patients with evaluable lesions. These results indicated that the appropriate doses of the 2 drugs in combination therapy are 30 mg/m2 for docetaxel and 80 mg/m2 for S-1. CONCLUSION: The S-1/docetaxel drug combination showed a good safety profile, with diarrhea and general fatigue being common, but manageable, adverse reactions. Moreover, the responses observed in this study suggest that the drug combination shows a high degree of efficacy in patients with advanced and/or recurrent gastric cancer.

[Essential thrombocythemia associated with incomplete type intestinal Behçet disease during hydroxyurea treatment].

A 77-year-old man was diagnosed as having essential thrombocythemia in 1992. Treatment with hydroxyurea was started in 1997, which stabilized the platelet count. The patient then suffered from pharyngalgia and rhinitis with a high fever, immediately after which he developed tarry stools and anemia and was admitted to our hospital. The physical examination revealed splenomegaly, oral aphthous ulcers, genital ulcers and skin lesions on the lower limbs. His hematological and biochemical tests revealed anemia and increased level of C-reactive protein. He also had an HLA-B51 phenotype. The findings of gastro-intestinal and colon fiberoscopy showed a duodenal ulcer and multiple ulcers on ascending colon. He was thus diagnosed as having intestinal tract-type Behçet disease. After withdrawal of the hydroxyurea administration, the intestinal ulcers, oral aphthous ulcers and genital ulcers improved.