Critical Therapeutics Inc's Zyflo (zileuton tablets)

Asthma is a chronic respiratory diseasecaused by inflammation and narrowingof the airways. In 2002, approximately30 million people had beendiagnosed with asthma in their lifetime.¹ Although asthma affects moremales during childhood years, it is predominantlydiagnosed in females afterage 40.¹

Typical symptoms of asthma includewheezing, shortness of breath, andcough. The goals of treatment includeimproving respiratory function andquality of life, as well as reducing exacerbations,emergency visits, hospitalizations,and mortality. In September2005, Critical Therapeutics Inc receivedFDA approval for Zyflo (zileuton tablets)as alternative therapy for the preventionand chronic treatment of asthmain patients 12 years of age and older.²

Pharmacology

Zileuton is a specific 5-lipoxygenaseinhibitor that leads to the inhibition ofleukotriene formation.³ The enzyme 5-lipoxygenase is responsible for the activationof leukotriene synthesis fromarachidonic acid. Leukotrienes are mediatorsfor inflammatory conditions andare most often associated with asthma.They are responsible for bronchoconstriction,inflammation, edema, andmucus secretion.^4-6

Clinical Trials

A multicenter, double-blind, parallelgroup,placebo-controlled trial evaluatedthe long-term efficacy and safety ofzileuton. Approximately 400 patientswith mild-to-moderate asthma were randomizedto receive zileuton 400 mg qid,600 mg qid, or placebo. Sustained improvementin lung function was seenover a 6-month period with zileuton. Theresults demonstrated significantlygreater increases in patients' forcedexpiratory volume in 1 second (FEV₁)from baseline in both zileuton groups(P<.05) except at day 64. The zileuton 600-mg qid group demonstrated decreases incorticosteroid rescues and in daytime andnocturnal symptoms, as well as improvementin morning peak expiratory flow rate(P <.05).⁵

In a 12-month, parallel-group, multicenter,open-label study, investigatorsassessed the efficacy of zileuton inapproximately 3000 patients with a historyof chronic asthma. The patientswere randomized to receive either zileuton600 mg qid plus usual asthma care orusual asthma care alone. The findingsdemonstrated that patients treated withzileuton required fewer rescues withsteroids (P<.001), as well as fewer hospitalizationsand emergency care visits(P<.05). The patients also experiencedsignificant improvement in their FEV₁(P<.048).⁶

Safety

The most common adverse reactionsinclude abdominal pain, dyspepsia, nausea,and alanine transaminase (ALT) elevations.² Because zileuton is metabolizedvia the cytochrome P-450 system, itshould not be given to patients withactive liver disease or to those who haveALT elevations 3 or more times the upperlimit of normal.

Concurrent use of zileuton withethanol may increase central nervoussystem depression. Zileuton is in pregnancycategory C, and its excretion inbreast milk is unknown.³

Outlook

Zyflo appears to be safe and effectivein reducing asthmatic exacerbations andimproving respiratory function. Patientswith long-term zileuton therapy shouldbe monitored for ALT elevations. Zileutonis available in 600-mg tablets. The recommendeddaily adult dose is 600 mg qidfor the treatment of chronic asthma.³

Dr. Soo is a senior research pharmacistwith the Investigational DrugService at Brigham and Women'sHospital, Boston, Mass. Ms. Hoach isa sixth-year PharmD candidate fromNortheastern University, currently onclinical clerkship in theInvestigational Drug Service atBrigham and Women's Hospital.

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