picibanil and Myocarditis

The effects of combination therapy with the immunomodulators OK432 (derived from the Su strain of Streptococcus pyogenes A3; 1 unit corresponds to 0.1 mg of dried streptococci dissolved in 0.1 ml of saline) and human recombinant interferon-alpha A/D (IFN) on cardiac atrial natriuretic peptide (ANP) gene expression and myocardial hypertrophy were examined in a murine model of viral myocarditis with congestive heart failure. Therapy was started 24 h after inoculation with encephalomyocarditis virus and was continued for 14 days. The plasma ANP concentration in untreated infected mice was significantly (P < .01) increased on day 10 (115 +/- 48 pg/ml) and day 30 (43 +/- 22 pg/ml) after inoculation relative to that in uninfected controls (5 +/- 4 pg/ml), whereas plasma ANP levels in treated mice were significantly (P < .01) reduced on day 10 (14 +/- 13 pg/ml) and day 30 (11 +/- 9 pg/ml) in comparison with untreated infected mice. The atrial and ventricular ANP messenger RNA (mRNA) concentrations in untreated mice showed increases of approximately 1.4- and 29.3-fold, respectively, on day 10 and increases of 1.8- and 34-fold, respectively, on day 30 compared with the concentration in uninfected controls. Combined OK432 and IFN significantly (P < .01) reduced the increase in ANP mRNA concentration in ventricles to 6.0- and 6.7-fold on days 10 and 30, respectively. Neither OK432 nor IFN monotherapy reduced the ANP mRNA concentrations in atria and ventricles compared with those in untreated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Cardiovirus Infections; Encephalomyocarditis virus; Female; Gene Expression Regulation; Humans; Interferon Type I; Interferon-alpha; Mice; Mice, Inbred C3H; Myocarditis; Picibanil; Recombinant Fusion Proteins; Recombinant Proteins; RNA, Messenger

OK432 (preparation derived from the Su strain of Streptococcus pyogenes A3; Picibanil, CAS 39325-01-4) is an immunomodulator. The treatment of mice with OK432 enhances their resistance to encephalomyocarditis virus (EMCV) along with a concomitant increase of interferon (IFN) titer and natural killer (NK) cell activity. To ascertain whether IFN or NK cell activity may play a crucial role in the mechanism of resistance, we compared these strains: EMCV resistant C57BL mice, C3H mice with myocarditis and DBA/2 mice with both myocarditis and diabetes mellitus. Although IFN production in all three kinds of mice was significantly increased on day 3 after inoculation, NK cell activity in EMCV resistant C57BL mice was significantly lower than that in C3H and DBA/2 mice. The lower antiviral resistance of mice treated with both OK432 and anti-interferon antibody (aIFN) was accompanied by a reduction of serum IFN titer, irrespective of the reduction in NK cell activity. Decreased activation of NK cells by anti-asialo GM1 monoclonal antibody (aNK) of OK432-treated mice also resulted in higher viral titers. However, these titers of both OK432 and aNK-treated mice were significantly lower than those of both OK432 and aIFN-treated mice. The degree of elevation of viral titer showed the following trend: OK432 and a IFN-treated mice > OK432 and aNK-treated mice >> OK432-treated mice. Moreover, histological changes of the heart in OK432 and aIFN-treated mice were significantly (p < 0.05) more severe than that in OK432 and aNK-treated and that in OK432-treated infected mice 7 days after inoculation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adjuvants, Immunologic; Animals; Antibodies; Diabetes Mellitus, Experimental; Encephalomyocarditis virus; Enterovirus Infections; Interferons; Killer Cells, Natural; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Myocarditis; Myocardium; Picibanil; Streptococcus pyogenes

We investigated the effects of OK432, recombinant human interferon alpha A/D (rIFN alpha A/D) and a combination of these drugs on murine acute myocarditis due to encephalomyocarditis virus. Mice were administered 1 KE of OK432 and 10(4)U/g of rIFN alpha A/D starting 24 hr after viral inoculation for 14 days. The survival rate of mice having the combination therapy was significantly higher than that of untreated mice on day 21 (15 of 20 vs. 6 of 20, P less than .001), whereas the viral titer in the heart, the heart weight/body weight ratio and the scores for myocardial inflammation and necrosis were significantly lower. On the other hand, therapy with OK432 or rIFN alpha A/D individually improved neither the survival rate nor the extent of myocardial damage. The natural killer cell activity in the combination therapy mice on day 3 after infection was significantly increased in comparison with untreated mice (46.2 +/- 5.5 vs. 37.7 +/- 2.8%, P less than .01), and the cytotoxicity of peritoneal macrophages was increased (45.0 vs. 26.7%). Thus, the combination therapy of OK432 and rIFN alpha A/D was more effective than the therapy with OK432 alone or rIFN alpha A/D alone against acute viral myocarditis when the treatment was started early after infection, and the stimulation of host immunologic response by OK432 may be important for this combination therapy.

Topics: Animals; Body Weight; Cytotoxicity, Immunologic; Drug Therapy, Combination; Encephalomyocarditis virus; Female; Heart; Interferon Type I; Killer Cells, Natural; Macrophages; Mice; Mice, Inbred C3H; Myocarditis; Myocardium; Necrosis; Picibanil; Recombinant Proteins

OK432, one of the immunomodulators used for cancer treatment in Japan was examined for its effects on murine myocarditis due to encephalomyocarditis (EMC) virus. The survival rate of mice administered with 1 KE of OK432 intraperitoneally every other day starting 2 days before viral inoculation was significantly higher than that of the control mice administered virus alone on days 10-21 (16/20 vs. 4/20, p less than 0.001), and the viral titer in the heart, the heart weight/body weight ratio, and the scores for myocardial inflammation and necrosis were significantly lower. The natural killer (NK) cell activity and interferon (IFN) titer on day 1 after infection were increased in comparison with the control group (NK cell activity: 51.1 vs. 37.9%, p less than 0.05. IFN: 1205 vs 512 U/ml), and the cytotoxicity of peritoneal macrophages was increased (50.6 vs. 29.1%). Thus, OK432 given before viral inoculation significantly improved survival and reduced both the viral titer in the heart and myocardial damage in this experimental model of acute EMC viral myocarditis. Accordingly, the stimulation of the host immunologic response by OK432 may be important for elimination of virus of the heart.

Topics: Animals; Cytotoxicity, Immunologic; Encephalomyocarditis virus; Female; In Vitro Techniques; Interferons; Killer Cells, Natural; Mice; Mice, Inbred C3H; Myocarditis; Organ Size; Picibanil