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VLA-1 (very late antigen-1) is implicated in recruitment, retention and activation of leukocytes and its blockade has been referred as a potential target of new drug discovery to address unmet medical needs in inflammatory disease area. In the present study, we investigate the effects of an anti-murine CD49a (integrin α subunit of VLA-1) monoclonal antibody (Ha31/8) on various experimental models of inflammatory diseases in mice. Pretreatment with Ha31/8 at an intraperitoneal dose of 250 μg significantly (P

気管支喘息の基本となる病態が気道の慢性炎症であることから，吸入ステロイド薬を中心とした抗炎症療法の導入は喘息症状のコントロールを可能にし，喘息患者のquality of lifeを飛躍的に向上させた．その一方で，分子レベルでの病態への理解が深まり，特に気道炎症の発症・進展に関わる過程と関連する各種因子の解明が進むことで，より安全で効果的な治療薬の創製に向けた研究開発が試みられている．本稿では，気道炎症の制御を作用メカニズムとした新規喘息治療薬に焦点をあて，その概略を紹介する．

We have developed novel orally active quinazoline analogues as inhibitors of AP-1 and NF-κB mediated transcriptional activation. Among the derivatives prepared, 1-[2-(2-thienyl)quinazolin-4-ylamino]-3-methyl-3-pyrroline-2,5-dione ( 10 ) showed significant activity in an adjuvant-induced arthritis rat model by reducing the swelling by 65% in the non-injected foot. The synthesis, structure–activity relationship, and in vivo activity are described.

This study demonstrated the decrease of bone mineral density (BMD) in the type II collagen (CII)-induced arthritis (CIA) model in rats and the relationship between BMD and paw edema and the effect of dexamethasone-21-phosphate (DEX). The paw swelling occurred on Day 10 and reached its peak on Day 18 after CII injection. BMD in the CII-injected group is lower than that in the control group. BMD in the proximal and distal regions of the femur largely decreased in comparison with that of the middle region. The oral administration of DEX (0.1 mg/kg) inhibited the swelling and decrease of BMD in all three regions of the femur.

This study demonstrates that systemic and local decreases in bone mineral density (BMD) occurred with Freund's complete adjuvant injection in the rat right footpad using dual energy X-ray absorptiometry. The rats were assigned to either adjuvant-treated or non-treated control groups composed of eight animals each. There was significant decrease in BMD in the adjuvant group compared to the control group at the distal region of femur or proximal region of tibia on Day 7 post-adjuvant injection (P < 0.05). On the other hand, the femur or tibia of the noninjected side showed a smaller and delayed decrease in BMD than did the injected side. These decreases in BMD were seen in not only the trabecular but also the cortical bone. In addition, the vertebrae also showed delayed but significant decrease (P < 0.05) in BMD on Day 21.

Cyclosporine A and steroids are effective against rheumatoid arthritis and also known as substrates of P-glycoprotein (P-gp). We investigated the effect of arthritis on the hepatic and intestinal P-gp activity in rats, and substantiated the expression level of the hepatic P-gp. Doxorubicin was used as a P-gp substrate. Cumulative biliary excretion and intestinal exsorption of doxorubicin following intravenous administration were compared between adjuvant arthritis (AA) and normal rats. Intestinal P-gp activity was also investigated by intestinal everted sac method, and hepatic P-gp was detected by FITC-labeled antibody and visualized using a confocal laser microscope system. Biliary clearance of doxorubicin in AA rats was significantly decreased from that in normal rats. The expression level of the hepatic P-gp in AA rats was very low compared to normal rats, indicating down-regulation. Intestinal exsorption clearance was not different between AA and normal rats. Permeability of doxorubicin across intestinal everted sac was comparable between AA and normal rats, corresponding to in vivo study. In AA rats, hepatic P-gp activity was decreased due to the reduction of expression level, but intestinal P-gp activity was not changed. Different regulation systems may be involved in liver and intestine.

Some enediyne antitumor antibiotics induce site-selective cleavages for yeast tRNA(Phe) with three-dimensional structure. Of special interest is the fact that tRNA(Phe) is specifically cleaved at the anticodon arm regions by C-1027 and esperamicin A1 in the presence of Mg2+ ions. Although neocarzinostatin strongly breaks tRNA(Phe) at 5'-GPu steps in the absence of magnesium ions, its cleavage ability is completely lost in the presence of 100 microM Mg2+ ions. Dynemicin A, which favors an intercalative binding, causes no strand scissions for the RNA with secondary and tertiary structures. This cutting of tRNA(Phe) may reveal that RNA as well as DNA constitutes a therapeutically relevant target for certain enediyne antitumor antibiotics.

The transcription factor NF-kappa B plays a significant role in inflammatory diseases. In this study we have investigated the expression of activated NF-kappa B p65 subunit in the rat adjuvant arthritis model in a 28-day time-course experiment using immunohistochemistry. The expression of p65 was detected in the synovial lining layer and around the blood vessels in the inflamed synovium as early as Day 3 post-adjuvant injection. The cells that expressed p65 in the synovial lining were thought to be macrophage-like synoviocytes. The expression was stronger in the injected hindpaw than that in the noninjected hindpaw. Dexamethasone treatment at 1 mg/kg p.o. (Days 0-20) suppressed both the hindpaw edema and increase in p65 expression. Withdrawal of the treatment caused increases in both p65 expression and paw volume. Together these suggest that activated NF-kappa B was specifically expressed in the arthritic synovium and may play a significant role in the development of arthritis.