Hiroshi Kosuzume

The immunomodulatory action of inosiplex in relation to its effects in experimental viral infections.

The effect of inosiplex (Isoprinosine) on viral replication, experimental viral infections and host immune functions has been examined. Inosiplex was found to have a broad spectrum of antiviral activity, inhibiting the RNA viruses, influenza (INFV) and parainfluenza (PIV), as well as the DNA viruses, herpes simplex (HSV) and vaccinia (VACV). However, the antiviral effects were modest when compared to amantadine and adenine arabinoside (ARA-A). Inosiplex in vivo caused a statistically significant increase in survival of treated animals (hamster, mice) infected with RNA or DNA viruses. This effect of inosiplex was apparent in animals which were previously immunosuppressed. Inosiplex, at optimal dose, conferred total protection in treated mice against secondary influenza infection. Since this was accompanied by statistically significant increases in serum anti-hemagglutinin and anti-neuraminidase titers, an effect of inosiplex on host defenses against secondary viral infection was implicated. This effect was further demonstrated by passive transfer of protection by splenocytes from inosiplex-treated donors to untreated recipients. Inosiplex was found to enhance the mitogen- (PHA-, ConA and MLC-) induced blastogenesis of lymphocytes from untreated mice. The LPS response was not affected. Inosiplex added in vitro caused a dose-dependent increase in the primary immune anti-SRBC response in vitro, as determined by direct and indirect PFC; there was also a dose-dependent effect on the secondary in vitro direct and indirect PFC responses. Inosiplex in vivo enhanced the primary immune response to SRBC, as determined by direct PFC assay; this was also the case for immunosuppressed mice. The drug enhanced delayed type hypersensitivity to picryl chloride in the mouse. Macrophage function was also enhanced by inosiplex, as was apparent from phagocytosis of SRBC. Gamma interferon production from murine lymphocytes was augmented by inosiplex in vitro. Treatment with inosiplex had no effect on natural killer cells or on antibody dependent cellular cytotoxicity. Thus, the pronounced effect of inosiplex on secondary viral infections may result through two different mechanisms: a direct antiviral effect and an elevation of multiple parameters of host immunity, which are usually compromised during viral infection. The latter mechanism may be the more important.

Effects of trapidil on thromboxane A2-induced aggregation of platelets, ischemic changes in heart and biosynthesis of thromboxane A2.

Trapidil inhibited the aggregation of rat platelets and the contraction of the isolated aortic strip of rabbit mainly caused by thromboxane A2, and the thromboxane A2 biosynthesis in rabbit platelets. The drug also reduced ischemic changes in ECG, the incidence of myocardial infarction, histopathological changes and a decrease in serum high density lipoprotein cholesterol, and inhibited an increase in plasma thromboxane B2 and a decrease in plasma 6-keto-prostaglandin F1 alpha content in the animals with an experimental ischemic heart injury caused by the injection of thromboxane A2 into the coronary artery. These findings suggest that trapidil is a new type of a therapeutic agent for ischemic heart disease which not only dilates the coronary artery but also inhibits the actions and biosynthesis of thromboxane A2 and may promote the biosynthesis of prostaglandin I2.

Structure of slow-reacting substance of anaphylaxis (SRS-A)

To elucidate the chemical structure of slow-reacting substance of anaphylaxis from rat (SRS-A rat), SRS-A rat were purified by the method of Orange with modification using DEAE-Sephadex A-25 chromatography. Ultraviolet absorption spectrum of purified SRS-A rat indicated the presence of conjugated triene. Arylsulfatase B degradation products and HCl degradation products were subjected to analysis by a gas chromatography and mass spectrometry and a thin layer chromatography. Products obtained by arylsulfatase b catalysis contained 5,6-dihydroxy-7,9,11,14-eicosatetraenoic acid. HCl degradation products showed the presence of glycine, glutamic acid and cysteic acid. Furthermore, the analysis of anhydrous hydrazine degradation products of SRS-A rat and of HCl hydrolyzed products of dinitrophenylated SRS-A rat revealed the presence of glycine at C-terminal and glutamine acid at N-terminal. The study of the substrate specificity of arylsulfatase B against various materials including SRS-A rat suggested the presence of sulfone in SRS-A rat. The molecular ion peak of SRS-A rat sodium salt was observed at m/e 680 in field desorption mass spectrum of SRS-A rat. On the basis of these data, we identified the structure of SRS-A rat as [gamma]glutamyl-4(5-hydroxy-7,9,11,14-eicosatetraenoic acid-6-yl)-4,4-dioxyocysteinyl] glycine.

The effects of pepsin on the natural progression of autoimmunity in glomerulonephritis in the NZB/W F1 mouse

The effects of pepsin on autoimmune glomerulonephritis of New Zealand Black and White F1 hybrid (NZB/W F1) mice were investigated. Intravenous pepsin significantly improved survival rate and suppressed progressive increase in urinary protein and histopathological changes in kidney. Increased serum levels of immune complexes, anti-DNA antibody and natural thymocytotoxic autoantibody were decreased and abnormalities in lymphocyte subsets were ameliorated by pepsin. Pepsin suppressed autoantibody production and enhanced antibody production against xenogeneic substance in these mice. The fact that pepsin ameliorates abnormalities in immune function may contribute to the preventive effects of pepsin against pathogenesis and progression of immune complex nephritis.