Argatroban more effectively inhibits the thrombin activity in synovial fluid than naturally occurring thrombin inhibitors.

The purpose of this study was to clarify the precise effect of argatroban on the inhibition of cytokine secretion induced by thrombin on synovial cells. The efficiency of thrombin inactivation by thrombin inhibitors was evaluated in human synovial fluids (SFs). In SFs from 13 osteoarthritis (OA) and 11 rheumatoid arthritis (RA) patients, thrombin, Factor Xa (FXa), plasmin activity, IL-6, MMP-3, VEGF, and D-dimer concentrations were measured. Tissue factor (TF) activity or IL-6, MMP-3, and VEGF secretion of human synovial cells with or without thrombin and argatroban were measured. The efficiency of thrombin inactivation in SFs was compared for thrombin inhibitors: argatroban, antithrombin III (ATIII), or heparin cofactor II (HCII). In SFs, thrombin, FXa, plasmin, D-dimer, IL-6, and MMP-3 were significantly higher in RA than in OA. In synovial cell experiments, TNF-alpha and thrombin enhanced TF activity on the cell surface, and IL-6, MMP-3, and VEGF secretion were enhanced by thrombin. Increased TF activity, and IL-6, MMP-3, and VEGF secretion induced by thrombin were inhibited by argatroban. In SFs, argatroban inactivated thrombin more effectively than ATIII or HCII. Since thrombin plays an important role in the disease activity of OA and RA, it is a potential therapeutic molecular target. Argatroban was the most effective anticoagulant to inhibit thrombin activity in SF. Intra-articular injection is ideal administration because it can deliver high dose of argatroban without high risk of systematic complication.

Anti-androgenic activity of Myricae Cortex--isolation of active constituents from bark of Myrica rubra.

The aqueous ethanol extract of Myricae Cortex (bark of Myrica rubra Sieb. et Zucc., Myricaceae) showed in vitro testosterone 5alpha-reductase inhibitory activity and in vivo anti-androgenic activity using growth of flank organ in castrated Syrian hamsters and/or hair regrowth after shaving in testosterone-treated C57Black/6CrSlc mice. Three constituents, myricanone, myricanol, and myricetin were identified as the main active principles.

[Successful treatment of interstitial pneumonia with lipo-PGE1 and pentoxifylline in a patient with dermatomyositis].

Interstitial pneumonia complicated with dermatomyositis sometimes shows a resistance to high dose steroid therapy and a fatal course particularly in patients without showing the elevation of creatine kinase. We experienced a 48 year old woman who developed heliotrope rash, Gottron's sign, multiple cutaneous ulcers, and dyspnea on exertion. These symptoms were resistant to low dose steroid therapy. Serum levels of creatine kinase were normal. Anti-nuclear antibodies and anti-Jo-1 antibody were negative. High resolution CT scan of the chest showed areas of multiple air space consolidation and subpleural linear shadows. Lung biopsy performed under video-assist thoracosurgery revealed diffuse alveolitis with scattered lymphoid folicules and mild accumulation of macrophages in the alveolar spaces. There were no honey-combing. These features were compatible with "non-specific interstitial penumonia" proposed by Katzenstein, 1995. The patient was treated with 10 micrograms lipo-PGE1, PGE1 incorporated in lipid microspheres, and 300 mg pentoxifylline, which resulted in a dramatic improvement of both interstitial pneumonia and cutaneous ulcers. The present case suggested a novel strategy for the treatment of interstitial pneumonia.

Metabolism of 3,7-dioxo-5 beta-cholanoic acid in the biliary fistula rodents and rabbits.

Intestinal absorption and metabolism of 3,7-dioxo-5 beta-cholanoic acid, were studied in the bile fistula rats, hamsters, guinea-pigs and rabbits. The influence of dose (1 and 100 mg/kg) on the absorption and the metabolism was also estimated. The dioxo bile acid was absorbed efficiently from the intestine and quickly excreted into bile in these animals. Large dose did not retard the absorption rate and showed a significant choleretic effect for a few hours. Species differences were observed in the metabolism of this compound. In hamsters and guinea-pigs, most of the metabolites in the bile were conjugated with either taurine or glycine. The proportion of bile acids amidated with glycine was greater with the large dose. In rats, the biliary metabolites were conjugated with taurine, but not with glycine, whereas in rabbits, glycine conjugates were the only recovered metabolites. Unconjugated metabolites were also detected in the bile of the rodents, and the proportion of them rose to 17-29% after the administration of 100 mg/kg quantities. A small part of unchanged 3,7-dioxo-5 beta-cholanoic acid was excreted into the bile as both the conjugated and unconjugated forms in these animals. The greater part of this compound administered was metabolized to 7-ketolithocholic acid, chenodeoxycholic acid and ursodeoxycholic acid. In hamsters and guinea-pigs, chenodeoxycholic acid was a greater metabolite of this compound than ursodeoxycholic acid, while in rats and rabbits, the amount of ursodeoxycholic acid exceeded that of chenodeoxycholic acid. In rats, the resulting dihydroxy bile acids were further metabolized to alpha- and beta-muricholic acids.