Effects of half-sized secretory leukocyte protease inhibitor and Chinese traditional medicines, yokuinin and mao-bushi-saishin-to, on therapeutic efficacies of benzoxazinorifamycin KRM-1648 against Mycobacterium avium complex infection induced in mice

Abstract

We examined the effects of such drugs having anti-inflammatory activity as half-sized secretory leukocyte protease inhibitor (1/2 SLPI) and Chinese traditional medicines, Yokuinin (YOK) and Mao-Bushi-Saishin-To (MBST), on therapeutic efficacies of benzoxazinorifamycin KRM-1648 against Mycobacterium avium complex (MAC) infection induced in mice, since it is possible that these agents inhibit the increase in tissue levels of immunosuppressive cytokines due to MAC infection. First, Zymosan A-induced murine peritoneal macrophages treated with either 1/2 SLPI, YOK or MBST at 37 degrees C for 2 days were infected with M. avium N-444 and further cultivated in the medium with or without addition of 1/2 SLPI, YOK or MBST at 37 degrees C for up to 7 days. Treatment of macrophages with these drugs caused some decrease in the intracellular growth of the organisms. Secondly, we evaluated effects of 1/2 SLPI, YOK and MBST on the therapeutic efficacy of benzoxazinorifamycin KRM-1648 against M. avium infection induced in mice. When MAC-infected mice were given KRM-1648 (20 mg/kg) alone, or in combination with 1/2 SLPI (100 mg/kg), YOK (50 mg/kg), or MBST (50 mg/kg), by gavage, except for 1/2 SLPI which was given via i.p. route, once a week, from day 1 for up to 8 weeks after infection, these drugs did not affect the expression of therapeutic activity of KRM-1648. When MAC-infected mice were given KRM-1648 alone (once a week), or in combination with YOK (five times per week) or MBST (five times per week), MBST increased the expression of therapeutic activity of KRM-1648. These findings indicate that suppression of inflammatory reactions using MBST is capable to improve the therapeutic efficacy of KRM-1648 in MAC infection. Moreover, these results also mean that combined use of these drugs in MAC patients receiving KRM-1648 therapy may not cause any disadvantages to the therapeutic efficacy of KRM-1648.