Inhibition Profiles of Picumast and Ketotifen on the in vitro Release of Prostanoids, Slow-Reacting Substance of Anaphylaxis, Histamine and Enzyme from Human Leukocytes and Rat Alveolar Macrophages
The inhibitory potency of the antiallergic compounds picumast (PIC; Boehringer Mannheim) and ketotifen (K; Sandoz) on the release of 3 preformed and 3 newly generated inflammatory mediators was estimated as an indicator for their antiallergic activity. Peripheral human leukocytes (HL) or rat alveolar macrophages (RAM) were stimulated by opsonized zymosan (C3-Z) and/or anti-IgE antibody, following preincuba-tion times with PIC and K. SRS-A was measured with the help of a guinea pig ileum bioassay, PGE2 and TxB2 by RI A (NEN), histamine (H) by an automated fluorimetric procedure, tryptic proteinase (P) by a colorimetric test employing Tos-Gly-Pro-Arg-pNA (Chromozym TH; Boehringer Mannheim) as chromogenic substrate and β-glucuronidase (β-G) by a colorimetric test (Sigma). PIC (IC30: 2 × 10––5 mol/l) was 100 times more potent than K as inhibitor of the anti-IgE-induced release of H and P and also 5 times more potent as inhibitor of SRS-A-formation/release in/from HL. In contrast, on RAM, K (IC30: 7 × 10––6 mol/l) had a 3 times greater potency as inhibitor of the C3-Z-induced SRS-A formation and suppressed PGE2 release (4 × 10––5–2 × 10––4 mol/l), whereas PIC (2 × 10––5 mol/l) potentiated PGE2 release remarkably. TxB2 release from RAM was inhibited nearly equipotently by PIC and K. β-G release was strongly potentiated by K (≥8 × 10––6 mol/l), but weakly inhibited by PIC (2 × 10––5 mol/l). PIC (≥4 × 10––5 mol/l) also increased the β-G release and in the same manner the anti-IgE- or C3-Z-induced release of other ‘preformed’ mediators like H and P from HL. The antiallergic potency of PIC in vivo could include a more pronounced stabilizing effect on different inflammatory cell types in comparison to K, for in our experiments in vitro, the release of pro-allergic/-inflammatory mediators was suppressed more effectively whereas the formation of anti-inflammatory PGE2 was potentiated by PIC, but inhibited by K.