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Leukotrienes: Function and Activity

Cysteinyl leukotrienes (CysLT C4, D4, E4) are released from mast cells along with histamine in response to acute inflammatory mediators. Eosinophils are major producers of cysteinyl leukotrienes in allergy – Mast cells are fixed cells located in the skin, nose, eyes, airway, and gut. Eosinophils are attracted into tissues affected by allergic inflammation associated with edema, vasodilation, pain/itching, heat, and evolution of disease chronicity/severity. Unlike histamines, CysLT levels are elevated acutely (initial phase) and remain elevated for several hours following an allergen challenge (late-phase reaction). Elevated urinary CysLT levels are measurable in asthma, rhinitis, and atopic dermatitis. Elevated CysLT levels are measurable in tears (allergic conjunctivitis) and nasal secretions (rhinitis). 

Why Block the Action of Leukotrienes?

Leukotrienes are:

 

  • Potent mediators of acute inflammation

  • Released by mast cells along with histamine, and later by eosinophils

  • Acted longer than histamine on both acute and late-phase allergic reactions 

  • A bridge to chronic inflammation

  • Not blocked by corticosteroids

Advantages vs. Standard-of-Care?

  • A safe non-steroidal treatment option 

  • Work days faster than corticosteroids

  • Can be used for prevention prior to exposure

  • Appropriate for treatment after exposure

  • Well-suited for use with children

Leukotriene Receptor Antagonists (LTRAs)

Originally approved for the treatment of asthma, Leukotriene Receptor Antagonists (LTRAs) block the action of the cysteinyl leukotrienes on the CysLT1 receptors, thus reducing constriction of the airways, buildup of mucus in the lungs, and inflammation of the breathing passages.

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LTRAs are medications that function as a leukotriene-related enzyme inhibitor (arachidonate 5-lipoxygenase) or leukotriene receptor antagonist (cysteinyl leukotriene receptors) and can be viewed as antihistamines that work faster, better, and longer.  The targets of LTRAs are those tissues that are directly exposed to irritants, which contain a specific cell type, mast cells. They are, as would be expected, found in skin, esophagus and stomach, nose, conjunctivae, and airway. 

 

Leukotrienes C4, D4, and E4 are released from mast cells together with histamine in response to acute inflammatory mediators, from ragweed to cat dander to cigarette smoke, virtually anything that commonly causes a rash, sneezing, or itching. Consequently, LTRAs opposes the function of inflammatory mediators produced by the immune system that promotes bronchoconstriction, inflammation, microvascular permeability, and mucus secretion in many allergic conditions. 

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Why Topical Zafirlukast?

Zafirlukast (Accolate) is an approved oral leukotriene receptor antagonist (LTRA) approved for the maintenance treatment of asthma, often used in conjunction with an inhaled steroid and/or long-acting bronchodilator. It was the first LTRA to be marketed in the US and is now approved in over 60 countries. The product is commercially available only in tablet form, dosed twice daily. The other major leukotriene receptor antagonist is montelukast (Singulair).

 

Unlike other members of the class, Zafirlukast has already been successfully formulated for topical use and shown safety and efficacy at 1/100 of the usual oral daily dosage while generating no (unmeasurably low) systemic blood levels. ACCOLADE is following up on this original work and has undertaken, together with established formulation companies, to re-purpose and develop topical products for uses in atopic inflammatory conditions, using proprietary formulations, devices (where appropriate).

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  • Zafirlukast is a potent FDA approved anti-leukotriene

  • Drug product is only available as an oral tablet 

  • It is particularly suitable for targeted topical development and use for allergic conditions

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