Suppression of adjuvant arthritis of rats by a novel matrix metalloproteinase-inhibitor.

BAY 12-9566 (4-[4-(chlorophenyl)phenyl]-4-oxo-2S-(phenylthiomethyl) butanoic acid) is a newly developed, synthetic matrix metalloproteinase (MMP) inhibitor (MMPI) that selectively inhibits MMP-2, MMP-3 and MMP-9 isozymes. We study the effect of BAY 12-9566 on inflammation and cartilage destruction in adjuvant-induced arthritis (AA) in rats. Rats were injected with adjuvant and treated for 21 days with vehicle, Indomethacin or BAY 12-9566. AA was assessed: by measuring arthritic index, paw volume, urinary pyridinoline (Pyr) and deoxypyridinoline (Dpyr); by examining joint inflammation; and by microscopic morphometry of articular cartilages. Oral treatment of rats for 22 days with 50 mg kg(-1) body weight/d BAY 12-9566 showed decreased AA as determined by improvement in body weight gain (P<0.01), arthritic index (P<0.05) and swelling of paws contralateral to the adjuvant injection site (P<0.05). Neutrophil infiltration and collagen degradation were also significantly lower (P<0.01) in this treatment group. Cartilage destruction was successfully suppressed (P<0.01) in rats treated with either 50 mg kg(-1) body weight/d BAY 12-9566 or 1 mg kg(-1) body weight/d Indomethacin. These results indicate that BAY 12-9566 successfully suppressed inflammation and cartilage destruction in rats with AA. Moreover, these results also suggested that MMP-2, MMP-3 and MMP-9 are involved in arthritic diseases such as rheumatoid arthritis.

[Successful adjuvant therapy of M-CSF with chemotherapy of two cases of chemotherapy resistant acute promyelocytic leukemia].

We demonstrate two conventional chemotherapy-resistant cases of acute promyelocytic leukemia (APL) who were successfully treated with macrophage-colony stimulating factor (M-CSF). Case no 1 was a 40-year-old woman who was made diagnosis of APL on June, 1992, and treated repeatedly with a conventional chemotherapy, BHAC-DMP regimen, resulting in complete remission on October, 1992. After a couple of years, she had relapse with marked growth of APL cells in bone marrow. She was treated with BHAC-AMP and modified B-triple V but could not obtain remission. Case no 2 was a 36-year-old-man with APL who was treated with BHAC-DMP and BHAC-AMP and modified B-triple V therapy. These three conventional chemotherapy regimen were not effective for him. Eight million units of human native M-CSF was administered intravenously for 14 days after the last BHAC-AMP therapy in case no 1, and for 5 days after the last modified B-triple V therapy in case no 2. After the therapy, APL cells in peripheral blood or bone marrow of both patients disappeared completely and normal hemopoietic cells increased, obtaining in complete remission in both cases. These successful cases treated with M-CSF combining chemotherapy may suggest a new therapeutic strategy for APL in addition to all-trans retinoic acid.