1997 - SK&F 106615
1: Immunopharmacology. 1997 Aug;37(1):53-61. Related Articles, Links
Selective immunomodulatory activity of SK&F 106615, a macrophage-targeting antiarthritic compound, on antibody and cellular responses in rats and mice.
Badger AM, Newman-Tarr TM, Satterfield JL.
Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA.
The azaspiranes are novel immunomodulators which are effective in a variety of animal models of autoimmune disease and transplantation.
The compounds appear to target macrophages and alter their functional activity. One of these compounds, SK&F 106615 (N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine++ + dihydrochloride), is now in phase II clinical trials for rheumatoid arthritis.
As many drugs/compounds effective in autoimmune disease and transplantation are overtly immunosuppressive, we designed studies to show that SK&F 106615 has selective immunomodulatory effects and that it does not perform in a manner characteristic of classical immunosuppressive agents on immune function.
SK&F 106615 inhibited mouse and rat spleen cell and rat peripheral blood mononuclear cell proliferation in vitro with an IC50 of 500 nM.
In vivo, treatment of C57BL/6 mice (15 mg/kg/day, i.p.) or rats (20 mg/kg/day, p.o.) for 2 weeks had no effects on specific antibody synthesis to ovalbumin (OVA) compared to rapamycin (RAP) which completely suppressed the antibody response.
Compared to cyclosporin A (CsA), FK 506 and RAP which suppressed the antibody (plaque forming) response to particulate (sheep red blood cells) antigen in a dose responsive manner, SK&F 106615 administered at a dose of 50 mg/kg was inactive.
There was an inhibition of the proliferative response of lymph node cells from treated mice and rats to mitogen and antigen in ex vivo assays. SK&F 106615, but not RAP, induced cells in the spleens of mice that could inhibit normal spleen cell proliferation in a co-culture assay.
Thus, a selective immunomodulatory effect can be shown for SK&F 106615 in the absence of generalized immunosuppression.
PMID: 9285244 [PubMed - indexed for MEDLINE]
ncbi.nlm.nih.gov |
