title: Combination of midazolam and a cyclooxygenase-2 inhibitor inhibits lipopolysaccharide-induced interleukin-6 production in human peripheral blood mononuclear cells.
abstract: BACKGROUND
  Interleukin-6 (IL-6) plays an important role in immune and inflammatory responses. Midazolam has been reported to modulate IL-6 response. Cyclooxygenase (COX) inhibitors, which are used together with midazolam in some patients undergoing surgery, also modulate it. We hypothesized that their combination results in eliciting the synergistical effect on the IL-6 response.
  
  
  OBJECTIVE
  The aim of the present study was to evaluate the effect of the combination of midazolam and a COX inhibitor on IL-6 production.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and incubated with lipopolysaccharide (LPS), midazolam, and/or COX inhibitors, including indomethacin, SC-560, a COX-1 selective inhibitor, and NS-398, a COX-2 selective inhibitor. The supernatant concentrations of IL-6 and prostaglandins (PGs), including PGE2, PGF2α, PGD2, and 15-deoxy-Δ¹²,¹⁴-prostaglandin J2 (15dPGJ2) were measured.
  
  
  RESULTS
  Midazolam had no effect on IL-6 production in the cells incubated for 12 h, and any COX inhibitors also had no effect. However, the combination of midazolam and NS-398 significantly inhibited it. Midazolam raised the concentration of 15dPGJ2 in the supernatant of the cells, but not the concentration of other PGs. DISSCUSSION AND CONCLUSION: The results in the present study demonstrated that the combination of midazolam and a COX-2 inhibitor inhibited LPS-induced IL-6 production in human PBMCs even if each drug separately did not have any effect on it. The finding suggests that their combination is effective against excessive IL-6 production such as severe inflammatory response and that the effect of midazolam on IL-6 production is possibly elicited via 15dPGJ2.
authors.affiliation: Department of Dental Anesthesiology and Special Care Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. miyawaki@md.okayama-u.ac.jp
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyawaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kohjitani
authors.forename: Shigeru
authors.initials: S
authors.lastname: Maeda
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Higuchi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Arai
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Tomoyasu
authors.forename: Masahiko
authors.initials: M
authors.lastname: Shimada
mesh_terms: D000328:Adult; D014151:Anti-Anxiety Agents / Q000819:agonists / Q000494:pharmacology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008874:Midazolam / Q000819:agonists / Q000494:pharmacology*; D009578:Nitrobenzenes / Q000819:agonists / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000096:biosynthesis; D013449:Sulfonamides / Q000819:agonists / Q000494:pharmacology*
chemical_list: C477819:15-deoxyprostaglandin J2; D014151:Anti-Anxiety Agents; D052246:Cyclooxygenase 2 Inhibitors; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D008874:Midazolam; D015230:Prostaglandin D2