Dictionary of Allergies .. Cysteinyl leukotrienes

Cysteinyl leukotrienes

Cysteinyl-LTs were demonstrated to be the chemical constituents of the slow reacting substance of anaphylaxis, already known since 1940 as a mixture of unidentified chemical mediators released in response to various stimuli, including anaphylactic reactions, and characterized by slow, but potent, long-acting contracting activity on smooth muscle cells.The antigen-induced release of cysteinyl LTs might play an important role in the early-phase increase of nasal vascular permeability. Our knowledge of the role played  by cysteinyl LTs as mediators of rhinitis is insufficient, and there are only a few studies on the effects of LTRAs and LT synthesis inhibitors in allergic rhinitis and in nasal polyposis. 

Leukotrienes are lipid inflammatory mediators that play an important role in the pathophysiology of many allergic inflammatory disorders and are implicated in asthma, COPD, arthritis, cardiovascular disease and cancer Cysteinyl leukotrienes are important mediators of asthmatic responses.

They are the most potent bronchoconstrictors known; their release is triggered by exposure to inhaled allergens after exercise and after aspirin ingestion by subjects with aspirin-sensitive asthma. The cysteinyl leukotrienes promote inflammatory cell migration into the airways, as well as bone marrow eosinophilopoiesis after allergen inhalation [3]. Leukotriene synthesis requires 5-lipoxygenase activating protein (FLAP), which acts as a scaffolding protein for the assembly of other enzymes involved in the leukotriene synthetic pathway occurring at the nuclear envelope of leukocytes. By blocking the formation of both leukotriene B4 and the cysteinyl leukotrienes (ie, LTC4 , LTD4 and LTE4), FLAP inhibitors act as broad-spectrum leukotriene-modifier drugs that may have a wide range of therapeutic applications.

FLAP inhibitors such as MK-886, MK-0591 and veliflapon (BAY-X-1005, DG-031) demonstrated promise in clinical trials with patients with inflammatory diseases in the mid 1990 s, but, unlike the 'lukast' class of cysteinyl-leukotriene receptor antagonists, these compounds were not brought to market. The elucidation of the 3D structure of FLAP has enabled novel compound development, and several FLAP inhibitors including 2190914 (AM-103) and GSK-2190915 (both under development by GlaxoSmithKline plc) have entered phase II trials for the treatment of inflammatory disease, including asthma [2].

Leukotriene inhibitors are effective at attenuating asthmatic responses to all of these stimuli and are also effective at treating persistent asthma. These drugs are a viable alternative to low-dose inhaled corticosteroid (ICS) treatment but should be reserved for patients who cannot or will not use ICSs, often because of concerns about potential side effects of ICS treatment, which limits their use, particularly in children. Leukotriene receptor antagonists are also alternatives to long-acting inhaled beta(2)-agonists as add-on therapy to ICSs, but their efficacy together with ICSs is less than that of ICS/long-acting inhaled beta(2)-agonist combinations. Leukotriene receptor antagonists have an excellent safety profile [3].

References

Mygind N, et al: Leukotrienes, leukotriene receptor antagonists, and rhinitis. Allergy 2000: 55:421-424.

2. Sampson AP. FLAP inhibitors for the treatment of inflammatory diseases. Curr Opin Investig Drugs. 2009 Nov;10(11):1163-72.

3. O'Byrne PM, Gauvreau GM, Murphy DM. Efficacy of leukotriene receptor antagonists and synthesis inhibitors in asthma. J Allergy Clin Immunol. 2009 Sep;124(3):397-403. Epub 2009 Jul 16.