Leukotriene pathway inhibitors

Like the other eicosanoids, the leukotrienes are also involved in inflammatory diseases. Accordingly, leukotriene pathway inhibitors are emerging as important agents. Two fundamental approaches to the design of leukotriene pathway inhibitors have been pursued ... 

This chapter presents the basic pharmacology of the methylxanthines, cromolyn, leukotriene pathway inhibitors, and monoclonal anti-IgE antibody—agents whose medical use is almost exclusively for pulmonary disease. The other classes of drugs previously... 

Although there are data on the variability of the treatment response for each of these classes of agents, there are no systematic studies on the reasons for variance in the treatment response to steroids or theophylline. Therefore, this chapter will focus on the specific pharmacogenomics of /1-agonists and inhibitors of the cysteinyl-leukotriene pathway [18, 30] and on general considerations related to pharmacogenomic mechanisms. 

SMP-114 (licofelone) is a drug candidate for rheumatoid arthritis, currently in Phase II clinical trials (Figure 8.57). It inhibits all three of the major enzymes involved in the arachidonic acid pathway (5-LOX, COX-1, and COX-2), thereby preventing production of both leukotrienes and prostaglandins. This mode of action could therefore lead to a better tolerability than that of conventional cyclooxygenase (COX-1 and COX-2) inhibitors because of the shunt of arachidonic acid metabolism toward the production of proinflammatory leukotrienes, via 5-lipoxygenase (LOX). 

Arachidonic acid released from membrane phospholipids or other sources is metabolized by the LO pathway to the smooth muscle contractile and vasoactive leukotrienes (LT), LTC4, and LTD4, as well as to the potent chemoattractant LTB4. These molecules are intimately involved in inflammation, asthma, and allergy, as well as in other multiple physiological and pathological processes. For example, cirsiliol (3, 4, 5-trihydroxy-6,7-dimethoxyflavone) proved to be a potent inhibitor of 5-LO (IC50, 0.1 pM) derived from basophilic leukemia cells and peritoneal polymorphonuclear leukocytes. 

Most people tolerate aspirin well, but not patients with asthma, of whom there is a subgroup in whom aspirin precipitates asthmatic attacks (61,62). This is a distinct clinical syndrome, called aspirin-induced asthma, which affects about 10% of adults with asthma (63). Aspirin-induced asthma is usually accompanied by naso-ocular symptoms and can be triggered not only by aspirin, but by several NSAIDs, a fact that makes immunological cross-reactivity most unlikely. The propensity of an NSAID to precipitate an attack of asthma is probably related to inhibition of COX (63). There is evidence that potent inhibitors of COX-1 (such as ibuprofen, indometacin, and naproxen) are more likely to precipitate bronchoconstriction than NSAIDs that inhibit COX-2 preferentially (such as meloxicam and nime-sulide) (64,65). A widely accepted hjrpothesis is that in patients with asthma and aspirin intolerance, NSAJD-induced COX inhibition results in increased products from the 5-lipoxygenase pathway, the leukotrienes, which are both potent bronchoconstrictors and also inducers of... 

The mechanism by which cyclooxygenase inhibition produces bronchospasm in susceptible individuals is unknown. Arachidonic acid metabolism through the 5-lipoxygenase pathway may lead to the excess production of leukotrienes C4 and D4. Leukotrienes C4, D4, and E4 produce bronchospasm and promote histamine release from mast cells, whereas the administration of leukotriene receptor antagonists and 5-lipoxygenase inhibitors ablate the pulmonary and nonpuhnonary responses to aspirin in aspirin-sensitive asthmatics. The precise mechanism by which augmented leukotriene production occurs is unknown, and available hypotheses do not explain why only a small number of asthmatic patients react to aspirin and NSAIDs. 

Figure VI-1-3 presents the pathways for the synthesis of PGe, PGE]( PGE2, PGF2a, IX Aj, and the i leukotrienes from the membrane phospholipids. It also shows the sites of action of the corticosteroids, i NSAIDS, COX 2 inhibitors, zileuton and zafirlukast, and other "-lukasts."...

The major eicosanoids are products of 0)-6 essential fatty acids, and the essentiality of this group of fatty acids relates primarily to their functions as eicosanoids. Both the prostanoids and the leukotrienes (LTs) were discovered as vasoactive substances active on reproductive and pulmonary smooth muscle, respectively. The structures of the more stable prostanoids were determined in the late 1950s and early 1960s by workers at the Karolinksa Institute in Sweden and Unilever Laboratories in the Netherlands. The LTs were known initially as slow-reacting substances of anaphylaxis. Their structures were determined in the early 1980s. The details of the pathways and the enzymes and receptors for these pathways were characterized over the last 35 years. Because eicosanoid overproduction is associated with a number of pathologies, potent enzyme inhibitors and receptor antagonists have been developed that are widely used therapeutically. 

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