Psychotropic agents. II. Synthesis and psychotropic activity of conformationally restricted butyrophenone analogs.
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Biomedical subjects
Publications and source records attributed to M Kitagawa.
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Prophylactic effect of repeated intravenous administrations of oil-attached BCG cell-wall skeleton (BCG-CWS) on the induction of tumor by 7,12-dimethylbenz[a]anthracene (DMBA) was investigated in various strains of mice. The subcutaneous injection of DMBA emulsified in oil induced squamous cell carcinoma in almost all of the strains of mice. Treatment of C57BL/6, BALB/c, and ddO strains with BCG-CWS with appropriate route and timing resulted in the retardation of DMBA-induced tumor development manifested by a prolonged latent period of tumor outgrowth. In contrast, the same BCG-CWS treatment of C3H/He and BTK mice was incapable in preventing such DMBA-induced carcinogenesis. Thus, the treatment with BCG-CWS was effective for preventing the DMBA-induced carcinogenesis in certain strains of mice, but the effectiveness varied depending on the strain. The implication of such a strain variationof the BCG-CWS effect on the prophylaxis of chemical carcinogenesis was discussed in the context of differences in the magnitude of immunopotentiation of the host by BCG-CWS.
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Of 52 serum samples from infertile women tested against isolated porcine oocytes by immunofluorescence, 8 produced intense reactions in zonae pellucidae, while only one of 52 sera from control subjects showed the reaction. Autoantibodies to the zona may be present in these women.
Specific anti-testosterone antiserum was obtained from mice of the strain C57B1/6. Testosterone 3(O-carboxymethyl)oxime-keyhole limpet hemocyanin conjugate was administered to male and female mice of the strains C57B1/6 (H-2b), DBA/2 (H-2d), (C57B1/6 x DBA/2)F1, (H-2b/d), and AKR (H-2k). Antisera obtained from male and female C57B1/6 mice were more specific for testosterone than those from the other strains, and the cross-reaction with 5alpha-dihydrotestosterone was 25.0 and 29.2%, respectively. The titer of antiserum from C57B1/6 mice was the highest and that of antiserum from DBA/2 mice was the lowest. On the other hand, the titer of antiserum from the female was higher than that of antiserum from the male in each strain. These results indicate that the mouse strain and sex differences are important factors for antibody formation from challenged antigen.
6,11-Dhydro-11-oxodibenz[b,e]oxepins and some related compounds have been synthesized and evaluated for antiinflammatory effect according to the carrageenan paw edema method in rats. The structure-activity relationships have been discussed among acetic acid, carboxylic acid, alcohol, and tetrazole derivatives of dibenzoxepins and acetic acid derivatives of thienobenzoxepins and of the corresponding thiepins. The 3-isopropyl alcohol 9 and 11-deoxo-3-propionic acid (49) were more active than indomethacin but not as active as the title compound (i.e., 43). Carboxylic acids, tetrazoles, esters, amides, and ketones were less active than the corresponding acetic acids. Three compounds (31, 33, and 34) were evaluated for ulcerogenicity and lethality but none surpassed 6,11-dihydro-11-oxodibenz[b,e]oxepin-3-acetic acid (41) in therapeutic ratio.
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Helper and suppressor T-cell activities were detected simultaneously in the spleen cells of mice immunized with para-azobenzoate (PAB)-mouse gammaglobulin (MGG). Dinitrophenyl (DNP)-specific B cells were raised by immunization with DNP-keyhole limpet hemocyanin (KLH) and used as the indicator B-cell population. The helper and suppressor T-cell activities were determined after adoptively transferring spleen cells from PAB-MGG- primed donors and DNP-KLH-primed donors into X-irradiated recipients. Stimulation of these recipients with DNP-MGG-PAB detected helper T-cell activity, which was measured in terms of increased anti-DNP antibody responses of DNP-KLH-primed cells over these responses in the presence of unprimed cells. On the other hand, when DNP-KLH-primed cells were stimulated with DNP-KLH-PAB in the presence of PAB-MGG-primed cells, anti-DNP antibody responses were substantially lower than in unprimed normal cells. This suppressor cell population was (a) hapten-reactive, (b) present in B-cell-depleted spleen cells, (c) Thy-1 positive, (d) detectable earlier than the helper T-cell activities after priming (e) more radiosensitive than helper cells, and (f) found in the spleen but not the lymph nodes in contrast to helper T cells. These data indicate that these suppressor T cells are distinct from the helper T cells. PAB-reactive T cells clearly suppressed the antibody response by inhibiting KLH-reactive helper T-cell functions. The hapten-reactive T-lymphocyte system described here should be useful for analyzing and manipulating the immune response and for studying regulatory interactions of helper and suppressor T cells in the induction of antibody responses.
An experimental condition was established in vivo for selectively eliminating hapten-reactive suppressor T-cell activity generated in mice primed with a para-azobenzoate (PAB)-mouse gamma globulin (MGG)-conjugate and treated with PAB-nonimmunogenic copolymer of D-amino acids (D- glutamic acid and D-lysine; D-GL). The elimination of suppressor T-cell activity with PAB-D-GL treatment from the mixed populations of hapten- reactive suppressor and helper T cells substantially increased apparent helper T-cell activity. Moreover, the inhibition of PAB-reactive suppressor T-cell generation by the pretreatment with PAB-D-GL before the PAB-MGG-priming increased the development of PAB-reactive helper T-cell activity. The analysis of hapten-specificity of helper T cells revealed that the reactivity of helper cells developed in the absence of suppressor T cells was more specific for primed PAB-determinants and their cross-reactivities to structurally related determinants such as meta-azobenzoate (MAB) significantly decreased, as compared with the helper T-cell population developed in the presence of suppressor T lymphocytes. In addition, those helper T cells generated in the absence of suppressor T cells were highly susceptible to tolerogenesis by PAB-D- GL. Similarly, the elimination of suppressor T lymphocytes also enhanced helper T-cell activity in a polyclonal fashion in the T-T cell interactions between benzylpenicilloyl (BPO)-reactive T cells and PAB- reactive T cells after immunization of mice with BPO-MGG-PAB. Thus inhibition of BPO-reactive suppressor T-cell development by the BPO-v-GL- pretreatment resulted in augmented generation of PAB-reactive helper T cells with higher susceptibility of tolerogenesis to PAB-D-GL. Thus, these results support the notion that suppressor T cells eventually suppress helper T-cell activity and indicate that the function of suppressor T cells related to helper T-cell development is to inhibit the increase in the specificity and apparent affinity of helper T cells in the primary immune response. The hapten-reactive suppressor and helper T lymphocytes are considered as a model system of T cells that regulate the immune response, and the potential applicability of this system to manipulating various T cell-mediated immune responses is discussed in this context.
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