Oral Leukotriene Inhibitor (MK-886) Blocks Allergen-induced Airway Responses

Abstract

To elucidate the role of leukotrienes (LT) in allergic asthma in humans the effect of MK-886, an LT biosynthesis inhibitor, was evaluated on antigen-induced early (EAR) and late (LAR) asthmatic reactions and bronchial responsiveness to histamine. Eight atopic men participated in a two-part, double-blind, placebo-controlled, crossover trial. MK-886 was administered in two oral doses of 500 mg and 250 mg, 1 h before and 2 h after allergen inhalation, respectively. Biochemical effects of MK-886 were evaluated by the inhibition of urinary LTE4 excretion and calcium ionophore-stimulated LTB4 biosynthesis in whole blood ex vivo. MK-886 significantly inhibited the EAR by 58.4% (AUC0-3 h) and the LAR by 43.6% (AUC3-7 h) when compared with placebo (p < 0.01). There was no difference in PC20 histamine 30 h post allergen challenge between MK-886 and placebo (0.33 and 0.27 doubling doses, p > 0.1). MK-886 inhibited calcium ionophore-stimulated LTB4 production in whole blood (54.2 +/- 25.6%) for up to 6 h post allergen challenge. LTE4 excretion in urine was inhibited by 51.5% during the EAR by as much as 80% during the LAR. This indicates that LT play a role in allergen-induced asthmatic reactions in humans in vivo and that LT synthesis inhibitors such as MK-886 should be further explored for the treatment of asthma.

IL-17 Promotes p38 MAPK-Dependent Endothelial Activation Enhancing Neutrophil Recruitment to Sites of Inflammation

“…2) and by the activation of 5-LO through its phosphorylation by the p38 MAPK-activated protein kinase MAPKAP-K2 (39). Interestingly, FLAP inhibitors have demonstrated benefits in allergic asthma clinical trials (29), whereas naturally occurring mutations in the promoter of region of 5-LO may be associated with asthma (40).…”

“…1). Moreover, an inhibitor of 5-LO, MK886 (29), attenuated the IL-17-conditioned LMVEC medium-driven neutrophil migration when added to LMVECs prior to their stimulation with IL-17 (Fig. 2G).…”

Pharmacological Characterization of 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic Acid (AM103), a Novel Selective 5-Lipoxygenase-Activating Protein Inhibitor That Reduces Acute and Chronic Inflammation

“…For example, the 5-LO inhibitor, zileuton, showed progressive improvement on respiratory measures and decreased asthma symptoms over a 4-week period (Israel et al, 1993). In addition, MK-886 and MK-591, two distinct FLAP inhibitors, prevented LT production and inhibited early and late-phase response to allergen challenge (Friedman et al, 1993;Diamant et al, 1995). MK-0591 has also shown efficacy in chronic asthma studies (Young, 1999).…”

“…In addition, a number of CysLT 1 -receptor antagonists, including montelukast, are approved for treatment of asthma and allergic rhinitis. Three FLAP inhibitors have been evaluated in human clinical trials, including MK-866 (Friedman et al, 1993), MK-591 (Diamant et al, 1995), and BAYX-1005 (Hamilton et al, 1997), and all showed efficacy against the early and late phases of allergen-induced lung-volume decline. Although none of these FLAP inhibitors is marketed, MK-591 was efficacious in chronic asthma (Young, 1999).…”

Asthma and leukotrienes: antileukotrienes as novel anti‐asthmatic drugs

“…Among drugs which inhibit leukotriene biosynthesis, the FLAP antagonists MK-886 [94], MK-591 [171] and BAY ϫ 1005 [95] have been documented to be potent inhibitors of leukotriene formation when given to humans in vivo [171][172][173]. The 5-lipoxygenase inhibitor, zileuton (Table 1), is now registered in the US for the treatment of asthma.…”