A Randomized, Comparative, Multicentric Clinical Trial to Assess the Efficacy and Safety of Zileuton Extended-Release Tablets With Montelukast Sodium Tablets in Patients Suffering From Chronic Persistent Asthma

Abstract

Leukotriene (LT) modifiers are anti-inflammatory drugs that are useful as an add-on therapy with first-line asthma-controller medications. This group includes LT synthesis inhibitors (eg, Zileuton) and receptor antagonists (eg, Montelukast), whose direct comparative clinical data are not available. This study was conducted to assess the comparative efficacy and safety of orally administered Zileuton extended-release (ER) with Montelukast sodium in patients suffering from chronic persistent asthma. Patients of 18-65 years of age with mild to moderate chronic stable asthma were randomized to treatment with Zileuton ER 2400 mg/d or Montelukast 10 mg/d for 12 weeks. Peak expiratory flow rate (PEFR) and asthma symptoms (cough, wheeze, chest tightness, and shortness of breath each on a 4-point scale) were assessed on monthly scheduled out-patient visits. Safety assessments by clinical and laboratory parameters were carried out during the course of the study. Among 210 patients eligible for efficacy assessment, PEFR improved by 64.8 ± 52.8 (95% confidence interval: 54.8-74.7) L/min with Zileuton ER (n = 109) and 40.6 ± 47.5 (31.3-49.9) L/min with Montelukast (n = 101; P < 0.001), whereas percent improvements were 27.0% (22.6%-31.5%) versus 18.4% (14.1%-22.7%), respectively (P = 0.006). Zileuton ER lead to ≥12% PEFR improvements in 74 of 109 [67.9% (59.1%-76.7%)] patients, whereas the same was noted in 52 of 101 [51.5% (41.7%-61.2%)] patients receiving Montelukast (P = 0.015). The reduction in the mean overall symptom intensity score was also significantly better with Zileuton ER [-5.0 ± 2.1 (4.6-5.4) versus -4.2 ± 2.3 (3.8-4.7)] (P = 0.018); however, the same was not observed for the decline in the individual symptom scores. A lesser but not significantly different adverse event rate was reported in the Zileuton ER group than the Montelukast group with the commonest events being headache and gastrointestinal effects in both the groups. Thus, Zileuton ER seems to be more efficacious than Montelukast and well tolerated for the treatment of mild to moderate chronic persistent asthma in adult patient population. Further studies can elucidate the comparative treatment benefits of these LT modifiers in asthma management.

Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway

“…The potential of blocking this pathway in the treatment of conditions of chronic inflammation is highlighted by the use of zileuton to improve pulmonary function in children and adults with mild-to-severe asthma [38,39]. Cysteinyl leukotriene receptor 1 and 2 (i.e., CysLT-R1 and CysLT-R2) antagonists such as montelukast and zafirlukast [40,41] are also available in some countries, however zileuton is the only Food and Drug Administration (FDA) approved anti-leukotriene inhibitor.…”

Cysteinyl Leukotrienes in Eosinophil Biology: Functional Roles and Therapeutic Perspectives in Eosinophilic Disorders

“…Clinical trials evaluating zafirlukast, montelukast, and pranlukast have shown a decrease of eosinophil count in blood and airways of asthmatic patients (60, 61). However, other studies (62, 63) suggest that the development of dual CysLT1/2R antagonists might bring additional advantages to the asthma treatment over the current used CysLT1R blockers. In fact, patients with chronic persistent asthma presented superior improvement in lung function when treated with a cysLT synthesis inhibitor compared to a CysLT1R antagonist (62).…”

“…However, other studies (62, 63) suggest that the development of dual CysLT1/2R antagonists might bring additional advantages to the asthma treatment over the current used CysLT1R blockers. In fact, patients with chronic persistent asthma presented superior improvement in lung function when treated with a cysLT synthesis inhibitor compared to a CysLT1R antagonist (62). However, recently, a clinical study with a dual CysLT1/2R blocker, the compound ONO-6950, in non-smoking subjects with mild allergic asthma, showed no additional benefits of this therapeutic strategy to the treatment of asthma (64).…”

Regulation of inflammation by lipid mediators in oral diseases

“…For instance, treatment with the BLT1 antagonists BIIL284, CP105696, and U-75302 reduces atherosclerosis (Ketelhuth et al, 2015), insulin resistance (Li et al, 2015), and chronic obstructive pulmonary disease (COPD) (Dong et al, 2016), respectively. Finally, a 5-LOX inhibitor, zileuton, which inhibits the synthesis of both LTB 4 and Cys-LT, has been approved for the treatment of chronic asthma (Kubavat et al, 2013) and is being investigated as a treatment for colon polyps (Gounaris et al, 2015), sickle-cell disease (Quarmyne et al, 2013), and stroke (Costa Silva et al, 2015).…”