Comparative Study of the Effects of Cefodizime and HBW 538 in Potentiating the Production of Reactive Oxygen Species by Human Polymorphonuclear Leukocytes

Q4 · MEDICINE

Article

Author: Sugiyama, H. ; Ohyatsu, I. ; Miyashita, H. ; Goldstein, E. ; Ono, Y. ; Tokumura, Y. ; Nishiya, H. ; Kunii, O. ; Aoki, M. ; Miyashita, T.

The immunomodulatory activity of cefodizime (CDZM), an aminothiazolylcephalosporin, was compared to that of HBW 538, a derivative of the CDZM side chain at position 3 (the mercaptothiazolyl group) in respect to the production of reactive oxygen species (ROS) by human whole blood and polymorphonuclear leukocytes (PMN) in vitro. Ten-fold diluted whole blood and PMN from healthy individuals were incubated with CDZM or HBW 538 alone at the concentrations of 1, 10, or 100 micrograms/ml, or CDZM or HBW 538 at 100 micrograms/ml in combination with tumor necrosis factor-alpha (TNF-alpha) at 100 U/ml or lipopolysaccharide (LPS) at 1 microgram/ml. The production of ROS was measured by a chemiluminescence (CL) assay in which luminol was added to a mixture and after which the PMN or whole blood were stimulated with nonopsonized zymosan or phorbol myristate acetate. The following results were obtained: (1) The CL responses of whole blood and PMN were slightly but not significantly enhanced by CDZM at 100 micrograms/ml, whereas both CL responses were significantly enhanced by exposure to HBW 538 at 10 and 100 micrograms/ml. (2) The enhanced PMN CL response which followed priming with TNF-alpha or LPS was not augmented by CDZM but was significantly augmented by HBW 538. These results indicate that the ability of the HBW 538 molecule to enhance the production of ROS by stimulated PMN and to act agonistically with TNF-alpha or LPS is abrogated when HBW 538 is part of the CDZM molecule.(ABSTRACT TRUNCATED AT 250 WORDS)

01 Jan 1991·Drugs under experimental and clinical research

Immunophenotypization of cells involved in local immune response and serum antibodies in cephalosporin-treated mice.

Article

Author: Schrinner, E ; Broketa, G ; Mazuran, R ; Tomasić, J

The in vivo potency of cefodizime (HR 221), tiprotimod (a new synthetic thiazole derivative of HR 221, HBW 538) and cefotaxime to modulate the initiation of immune response in the draining lymph node (LN) after subcutaneous injection of SRBC was evaluated. The timing and sequence of events in the regional LN was investigated by immunophenotypization of node cells with monoclonal antibodies, and the systemic reaction was estimated as primary antibody response to SRBC. From the results it is possible to conclude that: (1) subcutaneous administration of a small dose (2.5-3.0 mg/kg) of cephalosporins, together with antigen, enhanced primary antibody production and persistence; (2) the increase in serum antibodies was preceded by a change in percentage of L3T4+ cells within the regional (popliteal) lymph node. In comparison to antigen alone, cephalosporins (during early immune response) increased the percentage of L3T4+ cells; (3) LN cellularity was strongly enhanced by cephalosporins; (4) cefotaxime influenced the kinetics of the cellularity and the L3T4/Lyt-2 index differently than cefodizime and HBW 538. HBW 538 had either a similar or stronger effect than cefodizime, as judged by the adjuvant effect on antibody production and the appearance of L3T4+ cells during the immunizing period.

01 Oct 1989·Arzneimittel-Forschung

Immunomodulation by the new synthetic thiazole derivative tiprotimod. 3rd communication: influence on host resistance to microorganisms, tumors and on experimental immune disorders.

Article

Author: Dürckheimer, W ; Hänel, H ; Schorlemmer, H U ; Dickneite, G ; Sedlacek, H H

To evaluate the influence of [2-(3-carboxy-1-probylthio)-4-methyl-1,3-thiazole]acetic acid (tiprotimod, HBW 538) on the host defense mechanisms, a number of experimental studies in different animal models were performed. The prophylactic treatment of NMRI mice with tiprotimod significantly prolonged the mean survival time of the animals after intravenous infection with Candida albicans 200/175 and increased the resistance to the fungal infection to 180% in comparison to controls. In vitro the drug showed no direct fungistatic or fungicidal activity. In an experimental model of persistent systemic candidiasis Balb/c mice infected intravenously with Candida albicans were treated with the immunomodulator tiprotimod after the fungal colonization of kidney was manifested (3 days post infection). The treatment of the mice after the infection resulted in a reduction of the infectious load and the abscess formation in kidney as well as in a decrease of numbers of yeasts in the urine. In the syngeneic B16 melanoma tumor model tiprotimod significantly prolonged the medium survival time and reduced the number of visuable metastases in the lungs even when applied after resection of the primary tumor graft. Tiprotimod also beneficially influenced the course of the disease in two murine graft-vs-host models (hemolytic anemia and immune complex glomerulonephritis) which lead to a B cell mediated autoimmune disease with fatal outcome. The application of the drug in the induction phase mitigated the development of the diseases and prevented animals from dying.(ABSTRACT TRUNCATED AT 250 WORDS)

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