Shun-Ichi Hata

N-Carboxyphenyl)-4-chloroanthranilic acid disodium salt: a novel anti-arthritic agent without anti-inflammatory and immunosuppressive activities

Adjuvant arthritis in rats is well known as a chronic model of inflammation and has usually been employed in the evaluation of anti-arthritic drugs (Winter, 1965). Cell-mediated immunity is considered to be important for the development of adjuvant arthritis (Eugui & Houssay, 1975; Pearson & Wood, 1959, 1964; Waksman, Pearson & Sharp, 1960; Waksman & Wennersten, 1963). It has been reported that anti-inflammatory and immunosuppressive agents possess prophylactic or therapeutic activity in adjuvant arthritis (Winter, 1965; Glenn, 1966; Winter & Nuss, 1966; Currey & Ziff, 1968; Perper, Alvarez & others, 1971 ; Walz, DiMartino & Misher, 1971 ; Martel, Klicius & Herr, 1974). In this article we describe a new type of anti-arthritic agent, N-(2-carboxyphenyl)-4-chloroanthranilic acid disodium salt (CCA), which inhibits adjuvant arthritis in rats, in spite of its lack of both anti-inflammatory and immunosuppressive activities. Male Sprague-Dawley rats (8 weeks old) were purchased from Clea Japan, Inc. Adjuvant arthritis was induced by intradermal injection of 0.5 mg of heat-killed Mycobacterium tuberculosis cells suspended in liquid paraffin into the tails of rats.

N-(2-Carboxyphenyl)-4-chloroanthranilic acid disodium salt: prevention of autoimmune kidney disease in NZB/NZW F1 hybrid mice

NZB x NZW F, hybrid (B/W) mice spontaneously develop antinucleic acid antibodies and immune complex glomerulonephritis which resembles human systemic lupus erythematosus (Helyer & Howie, 1963a; Larnbert & Dixon, 1968). Cell-mediated immunity is deficient with age in B/W mice, e.g. the spleen cells of old mice lack the ability to induce a graft-vs-host reaction (Gerber, Hardin & others, 1974), and to respond to mitogens (Leventhal & Talal, 1970). and the rejection process of these mice against skin allografts (Gelfand & Steinberg, 1973) and some tumors (Gazdar, Beitzel & Talal, 1971), is impaired. Evidence has accumulated suggesting that the deficiency of suppressor T-cell activity allows the formation of autoantibody and the development of autoimmune diseases in NZB and B/W mice (Allison, Denman & Barnes, 1971; Chused, Steinberg & Parker, 1973; Barthold, Kysela & Steinberg, 1974; Steinberg & Talal, 1975: Krakauer, Waldmann & Strober, 1976; Talal & Steinberg, 1976). In addition, neonatal thymectomy results in a high incidence of disorders in B/W mice (Helyer & Howie, 1963b). Gershwin & Steinberg (1975a) reported that biweekly injections of thymocytes from young NZB mice, which include suppressor T lymphocytes, inhibited the pathogenesis of autoimmune haemolytic anaemia in syngeneic mice. Very recently a similar prophylactic effect was observed in B/W mice treated with the soluble factor from suppressor T lymphocytes (Krakauer, Strober & others, 1977). Further, it has been reported that injections of concanavalin A (Gershwin & Steinberg, 1975b) or thymosin (Gershwin, Ahmed & others, 1974; Talal & Steinberg, 1976) depressed immunologic abnormality and delayed the onset of, or prevented development of, autoimmune diseases in NZB or B/W mice. From the above evidence, we considered that agents activating the T-cell function might prevent the appearance of autoantibody and the development of autoimmune desease in B/W mice.

Measuring Methods for Ultra-Low Light Intensity and Their Application to Extra-Weak Spontaneous Bioluminescence from Living Tissues

This paper reports experimental and theoretical studies and their comparisons on the sensitivity of photoelectric methods for detecting very weak optical signals based on the analog and digital techniques. The single photoelectron counting and the enhanced single photoelectron counting methods were found to be advantageous over the other methods with regard to both signal-to-noise ratio and effective range for optical input powers. Furthermore, the measurements of extra-weak spontaneous bioluminescence from living tissues such as tumors and livers of mice and rats were performed as a new application of the detection methods discussed and evaluated.

A novel antiarthritic agent, CCA (lobenzarit disodium), and the role of thymus-derived lymphocytes in the inhibition of rat adjuvant arthritis.

Lobenzarit disodium (CCA) has been reported to have an inhibitory effect on the development of adjuvant arthritis (AA) in rats. Earlier studies have suggested that the therapeutic effect of CCA might be based on its immunoregulatory activity, although the precise mechanisms of action are unclear. In this paper, possible involvement of thymus-derived lymphocytes in the suppression of AA was studied. It was found that CCA failed to inhibit the development of AA in rats whose T lymphocytes were depleted by the injection of rabbit antithymocyte serum (ATS), whereas the same schedule of treatment with CCA significantly suppressed AA developed in control rats which were injected with normal rabbit serum. In addition, adult thymectomy abrogated the antiarthritic effect of CCA. These data suggest the possibility that the therapeutic effect of CCA in AA might be mediated by ATS-sensitive, short-lived, thymus-derived lymphocytes.

The lipid-lowering profile in rodents AZ-1355, A New Dibenzoxazepine Derivative

The lipid-lowering profile of ethyl 10,11-dihydro-4-methoxydibenz[b,f]-(1,4)oxazepine-8-carboxylate (AZ-1355) has been evaluated using clofibrate as a reference compound. This compound is structurally unrelated to any other hypolipidemic agent. AZ-1355 was selected not only for its effect in reducing serum lipids, but also because it inhibits platelet aggregation in vivo and elevates the prostaglandin I2/thromboxane A2 ratio in vitro. It lowers serum total cholesterol in Triton-treated hyperlipidemic mice, and also lowers serum total cholesterol and triglyceride in dietary hyperlipidemic rats. In golden hamsters chosen for further evaluation, AZ-1355 reduced serum, liver and cardiac lipids, improved the beta/alpha-lipoprotein ratio and increased the HDL cholesterol. Thus, it is apparent that the lipid-lowering profile of AZ-1355 differs from that of clofibrate.

Effects of CCA (Disodium 4-chloro-2, 2'-iminodibenzoate) on the biological activities of both lymphocytes and macrophages were investigated

In the in vitro studies of murine lymphocytes, CCA showed a tendency to increase the viability of spleen cells and an activity to enhance the mitogenic responses of those cells by LPS, B-mitogen. Enhancing effects of CCA on T-mitogen-induced lymphocytes reaction have also been reported in other papers. These results were considered in connection with a phenomenon that CCA increased the RNA polymerase activity of nucleus from rat lymphnode cells. CCA also enhanced thein vivo mitogenic reaction by Con A. CCA was not mytogenic by itself.As for the activities of macrophages, CCA did not almost show any effects inin vitrostudies while it did in the carbon clearance test using both normal and tumor-bearing animals.