Effect of ibuprofen on monocyte activation by liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (CGP 19835A): can ibuprofen reduce fever and chills without compromising immune stimulation?
The purpose of this study was to determine the effects of ibuprofen on the ability of liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) to activate human blood monocytes in vitro. We undertook these experiments because the major toxic side-effects following L-MTP-PE infusion, fever and chills, could be prevented when ibuprofen was given orally immediately before L-MTP-PE infusion. It was therefore important to determine whether ibuprofen interfered with the macrophage-activation properties of L-MTP-PE. Peripheral blood monocytes were isolated from normal donors, then incubated with L-MTP-PE in the presence or absence of ibuprofen. The cytotoxic properties of the monocytes were assessed by a radioisotope-release assay against A375 cells. Ibuprofen at dose levels of 40 micrograms/ml suppressed the generation of the cytotoxic phenotype but did not interfere with the killing process once the cells were activated. Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) production, as well as the mRNA expression of these cytokines, was suppressed by 40 micrograms/ml ibuprofen. Since IL-1 and TNF play a crucial role in the cytotoxic function of monocytes, these findings may explain the mechanism by which ibuprofen inhibited the generation of the cytotoxic phenotype by L-MTP-PE. By contrast, ibuprofen dose levels up to 10 micrograms/ml had no effect on the generation of monocyte-mediated cytotoxicity by L-MTP-PE and no effect on the production, secretion, or mRNA expression of TNF and IL-1. Therefore, we concluded that if ibuprofen is to be used to control the side-effects of L-MTP-PE, blood levels of up to 10 micrograms/ml are desirable. In two of three patients, we determined that an oral dose of 200 mg given immediately before L-MTP-PE infusion could achieve these desired blood levels.
Fujimaki
W
W
Department of Cell Biology (HMB 173), University of Texas M. D. Anderson Cancer Center, Houston 77030.
Griffin
J R
JR
Kleinerman
E S
ES
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D003601:Cytotoxicity Tests, Immunologic; D004337:Drug Carriers; D005334:Fever / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D008081:Liposomes; D016260:Monocytes, Activated Killer / Q000187:drug effects*; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D000276:Adjuvants, Immunologic; D004337:Drug Carriers; D007375:Interleukin-1; D008081:Liposomes; D010714:Phosphatidylethanolamines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C037144:mifamurtide; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D007052:Ibuprofen