New evidence of H1-receptor independent COX-2 inhibition by fexofenadine HCl in vitro.

BACKGROUND/AIMS: Fexofenadine HCl (FEX) has previously been shown to have anti-inflammatory properties in relieving nasal congestion in allergic rhinitis. The objective of this study was to further elucidate the mechanism of action behind the anti-inflammatory properties of FEX in addition to its H(1)-receptor antagonism. METHODS: The effects of two antihistamines, FEX and loratadine (LOR), were investigated on cyclooxygenase (COX)-1 and -2 enzymes in vitro. FEX (10(-9)-10(-3) mol/l) and LOR (10(-9)-10(-4) mol/l) were incubated with arachidonic acid in a COX screening assay with either ovine COX-1 or COX-2 or human COX-2. COX-2 enzyme inhibitory activity for the antihistamines was compared with the known selective COX-2 inhibitor DuP-679. RESULTS: High concentrations of FEX (10(-3) mol/l) significantly inhibited arachidonic acid-mediated ovine COX-1 activity, but low concentrations had no effect. Low concentrations of FEX (10(-8) mol/l) inhibited ovine COX-2 activity, and this inhibition decreased with increasing concentrations. The inhibition of COX-2 activity by FEX was similar to that seen with the selective COX-2 inhibitor, DuP-679. Conversely, LOR inhibited COX-1 activity at low concentrations (10(-8) mol/l), but had little inhibitory effect on COX-1 at high concentrations. LOR (10(-5) mol/l) markedly stimulated COX-2 activity. CONCLUSION: FEX showed selective arachidonic acid-mediated COX-2 inhibitory enzyme activity, which differed markedly from the COX inhibitory enzyme activity of LOR. This selective COX-2 inhibitor activity by FEX may contribute to its anti-inflammatory properties in relieving nasal congestion in allergic rhinitis.

Differential effects of fexofenadine on arachidonic acid metabolism in cultured human monocytes.

The relief of nasal congestion with the antihistamine fexofenadine in seasonal allergic rhinitis is thought to be due to its additional anti-inflammatory properties. The objective of this study was to evaluate the in vitro effects of fexofenadine on stimulated arachidonic acid metabolism. Human monocytes, isolated from blood and donated by 5 healthy volunteers, were either incubated for 20 h with 10 microg/ml lipopolysaccharide, with and without fexofenadine (10(-8)-10(-3) mol/l, n = 8-19), or were incubated for 20 h, with and without fexofenadine, and then stimulated with 0.5 mg/ml zymosan for 2 h. Leukotriene B4 (LTB4), LTC4, LTD4 and LTE4, prostaglandin E2 (PGE2) and F2alpha (PGF2alpha) production was determined by enzyme immunoassay. Zymosan-stimulated production of LTC4, LTD4 and LTE4 was significantly inhibited by clinically relevant concentrations of fexofenadine HCl: 10(-7) mol/l (22% inhibition vs. control, p = 0.008) and 10(-6) mol/l (24% inhibition vs. control, p = 0.020). Higher concentrations of fexofenadine (10(-4) and 10(-3) mol/l) inhibited LTB(4) generation. Lipopolysaccharide-stimulated production of PGE2 was significantly inhibited by fexofenadine HCl 10(-6) mol/l (26% inhibition, p = 0.035) and 10(-5) mol/l (40% inhibition, p = 0.001). Higher concentrations of fexofenadine HCl (10(-4) and 10(-3) mol/l) significantly inhibited PGF2alpha production by 50% (p = 0.026) and 63% (p = 0.001), respectively. Fexofenadine, at both clinically relevant and higher concentrations, inhibits LTC4, LTD4, LTE4 and PGE2 in cultured human monocytes. These additional anti-inflammatory properties may underlie the relief of nasal congestion observed in clinical studies.