A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology.
SDZ ASM 981, a novel ascomycin macrolactam derivative, has high anti-inflammatory activity in animal models of allergic contact dermatitis and shows clinical efficacy in atopic dermatitis, allergic contact dermatitis and psoriasis, after topical application. Here we report on the in vitro activities of this promising new drug. SDZ ASM 981 inhibits the proliferation of human T cells after antigen-specific or non-specific stimulation. It downregulates the production of Th1 [interleukin (IL)-2, interferon-gamma] and Th2 (IL-4, IL-10) type cytokines after antigen-specific stimulation of a human T-helper cell clone isolated from the skin of an atopic dermatitis patient. SDZ ASM 981 inhibits the phorbol myristate acetate/phytohaemagglutinin-stimulated transcription of a reporter gene coupled to the human IL-2 promoter in the human T-cell line Jurkat and the IgE/antigen-mediated transcription of a reporter gene coupled to the human tumour necrosis factor (TNF)-alpha promoter in the murine mast-cell line CPII. It does not, however, affect the human TNF-alpha promoter controlled transcription of a reporter gene in a murine dendritic cell line (DC18 RGA) after stimulation via the FcgammaRIII receptor. SDZ ASM 981 also prevents the release of preformed pro-inflammatory mediators from mast cells, as shown in the murine cell line CPII after stimulation with IgE/antigen. In summary, these results demonstrate that SDZ ASM 981 is a specific inhibitor of the production of pro-inflammatory cytokines from T cells and mast cells in vitro.
Grassberger
M
M
Novartis Research Institute, Brunner Strasse 59, A-1235 Vienna, Austria. grassberger@pharma.novartis.com
Baumruker
T
T
Enz
A
A
Hiestand
P
P
Hultsch
T
T
Kalthoff
F
F
Schuler
W
W
Schulz
M
M
Werner
F J
FJ
Winiski
A
A
Wolff
B
B
Zenke
G
G
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003879:Dermatologic Agents / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D020104:Immunophilins / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D012871:Skin Diseases / Q000188:drug therapy* / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000473:pathology; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D022021:Tacrolimus Binding Proteins
D016207:Cytokines; D003879:Dermatologic Agents; C117268:pimecrolimus; D019703:Calcineurin; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D016559:Tacrolimus