Asthma zileuton

In 10 patients with asthma, zileuton treatment for 2 weeks significantly increased thromboxane B2 concentrations and spontaneous platelet aggregation (5). These results suggest that zileuton may be associated with an increased risk of thrombosis. 

Zafirlukast and zileuton are used in the prophylaxis and treatment of chronic asthma in adults and children older than 12 years. Montelukast is used in the prophylaxis and treatment of chronic asthma in adults and in children older than 2 years. 

These dru are contraindicated in patients with a known hypersensitivity to the dragp. Montelukast, zaflrlukast, and zileuton are not used in the reversal of bronchospasm in acute asthma attacks. Zileuton is con-... 

Leukotriene modifiers either inhibit 5-lipoxygenase (zileuton) or competitively antagonize the effects of leukotriene D4 (montelukast and zafirlukast). These agents improve FEV, and decrease asthma symptoms, rescue drug use, and exacerbations due to asthma. Although these agents offer the convenience of oral therapy for asthma, they are significantly less effective than low doses of inhaled corticosteroids.2,33... 

This hypothesis was investigated in a retrospective analysis of the response to an ALOX5 inhibitor, ABT-761, which is clinically similar to zileuton. In 221 patients with asthma who received either high-dose ABT-761 (n= 114) or placebo (n= 107] treatment, approximately 6% of asthmatic patients had no wild-type allele... 

A 40-year-old male with a diagnosis of moderate to severe asthma is placed on zileuton. What is the mechanism of action of zileuton ... 

LTB4 is a potent bronchoconstrictor, as are several other leukotrienes. A 5-lip-oxygenase inhibitor, Zileuton, is approved for therapy of asthma (though it is not much used for this purpose) as is a leukotriene blocker, montelukast, marketed as Singulair. Singulair is widely used by asthmatics as a preventive for asthma attacks. Certain corticosteroids are employed for the same purpose. Neither montelukast nor the steroids are effective in terminating an established asthmatic attack. Beta agonists are employed for that purpose (see chapter 17). 

The recommended dosage of zileuton for the symptomatic treatment of patients with asthma is 600 mg 4 times/day for a total daily dose of 2400 mg. For ease of administration, zileuton may be taken with meals and at bedtime. 

Zileuton inhibits leukotriene-dependent smooth muscle contractions. Pretreatment with zileuton attenuated bronchoconstriction caused by cold air challenge in patients with asthma. 

Montelukast, zafirlukast, and zileuton are indicated for the prophylaxis and chronic treatment of asthma. They should not be used to treat acute asthmatic episodes. All three agents are administered orally. 

Zileuton (8.81) is an inhibitor of 5-lipoxygenase montelukast (8.82) and zafirlukast (8.83) are inhibitors of the leukotriene LTD4 receptor. All of these agents have demonstrated efficacy in the treatment of asthma, a common chronic inflammatory disease of the airways. 

Although they remain less effective than inhaled corticosteroids, a 5-LOX inhibitor (zileuton) and selective antagonists of the CysLTl receptor for leukotrienes (zafirlukast, montelukast, and pranlukast see Chapter 20) are used clinically in mild to moderate asthma. Growing evidence for a role of the leukotrienes in cardiovascular disease has expanded the potential clinical applications of leukotriene modifiers. Conflicting data have been reported in animal studies depending on the disease model used and the molecular target (5-LOX versus FLAP). Human genetic studies have demonstrated a link between cardiovascular disease and polymorphisms in the leukotriene biosynthetic enzymes, in particular FLAP, in some populations. 

Of these agents, zileuton is the least prescribed because of reports of occasional liver toxicity. The receptor antagonists appear to have little toxicity. Reports of Churg-Strauss syndrome (a systemic vasculitis accompanied by worsening asthma, pulmonary infiltrates, and eosinophilia) appear to have been coincidental, with the syndrome unmasked by the reduction in prednisone dosage made possible by the addition of zafirlukast or montelukast. Of these two, montelukast is the most prescribed, probably because it can be taken without regard to meals and because of the convenience of once-daily treatment. 

Theophylline [the OFF i lin] is a bronchodilator that relieves airflow obstruction in chronic asthma, and decreases the symptoms of the chronic disease. Previously the main-stay of asthma therapy, theophylline has been largely replaced with (3-agonists and corticosteroids. Theophylline is well absorbed by the gastrointestinal tract, and several sustained-release preparations are available. The drug has a narrow therapeutic window, and an overdose of the drug may cause seizures or potentially fatal arrhythmias. Further, theophylline interacts adversely with many drugs. See pp. 450-451 for a description of newly approved drugs, zileuton, zafirlukast, and montelukast. 

New asthma drugs act by blocking the synthesis of leukotriene C4 from arachidonic acid. For example, zileuton (trade name Zyflo) inhibits the enzyme (called a lipoxygenase) needed for the first step of this process. By blocking the synthesis of leukotriene C4, a compound responsible for the disease, zileuton treats the cause of asthma, not just its symptoms. 

Generic name zileuton Trade name Zyflo anti-asthma drug... 

Arachidonic acid is also metabolised by lipoxygenase to straight-chain hydroperoxy acids and then to leukotrienes which cause increased vascular permeability, vasoconstriction, bronchoconstriction, as well as chemotactic activity for leucocytes (whence their name). Inhibitors of lipoxygenase, e.g. zileuton, and leukotriene receptor antagonists, e.g. montelukast, zafirlukast, have found a place in the therapy of asthma (see p. 559). 

Dube LM, Swanson LJ, Awni W. Zileuton, a leukotriene synthesis inhibitor in the management of chronic asthma. Clinical pharmacokinetics and safety. Chn Rev AUergy Immunol 1999 17(1-2) 213-21. 

Taskapan MO. Zileuton and atopic dermatitis. Ann AUergy Asthma Immunol 2001 87(2) 162-3. 

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