Evaluation of the utilization patterns of leukotriene modifiers in a large managed care health plan.

Chitre M.

Excellus Health Plan, Inc., 344 South Warren St., Syracuse, NY 13202, USA. paul.lakomski flrx.com

OBJECTIVE: To assess the utilization of leukotriene modifiers (LM) relative to national guidelines and to investigate possible emergency room utilization differences for LMs as monotherapy versus inhaled corticosteroid (ICS) monotherapy or combination ICS and LM therapy. METHODS: The utilization of leukotriene modifiers (montelukast sodium, zafirlukast, and zileuton), concurrent inhaled steroids (beclomethasone, budesonide, flunisolide, fluticasone, and triamcinolone), beta-agonists (albuterol, bitolterol, formoterol, isoetharine, levalbuterol, metaproterenol, pirbuterol, salmeterol, and terbutaline) and low-sedating antihistamines ([LSAs] cetirizine, desloratadine, fexofenadine, and loratadine) were assessed from the drug claims database of a large health insurer for dates of service for the 12-month period from September 1, 2001, through August 31, 2002. New-start LM patients were identified as having no previous LM drug claim within a 180-day look-back period from the first date of fill for the LM. Claims were stratified into age cohorts of.under 16 years. and.16 years and older. Emergency room (ER) claims for patients utilizing LMs, ICSs, and patients on both LM and ICS were retrieved for analysis from the medical claims database for the same 12-month study period. RESULTS: More than 89% of new LM starts had no history of an ICS in the claims database. Overall, 61% of all (new and existing) LM patients did not have a claim for an ICS in their drug claims profile during the study period. An estimated 25% of LM utilization was not for asthma. No differences in ER utilization were found between ICS users and LM users; however, the ER utilization rate (0.090 ER visits per patient per year) was lower with combination therapy compared with monotherapy with ICS (0.110 ER visits per patient per year, P = 0.001) or LM (0.119 emergency room visits per patient per year, P<0.001). CONCLUSIONS: The majority of LM use in this health plan was initial monotherapy, contrary to national treatment guidelines for asthma. At the time of the study, the apparent off-label use of LM for allergic rhinitis was significant for this health plan.

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Comparison of montelukast versus budesonide in the treatment of exercise-induced bronchoconstriction.

Gonzalez-Quintela A.

Allergy Unit, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain. mearturo uscmail.usc.es

BACKGROUND: Previous studies in which leukotriene-receptor antagonist and corticosteroids were used have suggested a possible role for these anti-inflammatory drugs in the prevention of exercise-induced bronchoconstriction, but no direct comparisons have been made. OBJECTIVE: A crossover study was undertaken to compare the ability of both montelukast and budesonide to protect patients from exercise-induced bronchoconstriction. METHODS: A total of 20 patients (median age, 17 years; range, 8 to 36 years), who had clinical exercise-induced bronchoconstriction for 1 year and decreased FEV1 of at least 20% after exercise on two occasions, were enrolled in this study. To compare the therapies in each patient, we administered, consecutively, 10 mg of montelukast once daily at bedtime for 3 days and, later, 400 microg of budesonide twice daily for 15 days, or vice versa, with a 15-day intervening washout period during which no patient received treatment. Exercise challenges were performed at baseline (no therapy) and after each treatment. The percentage of FEV1 declines at 2, 7, and 12 minutes after exercise and the area under the curve (summarizing the extent and modification of FEV1 decreases relative to time) were measured and compared. RESULTS: Both budesonide and montelukast significantly reduced the decrease in FEV1 (area under the curve) after exercise with respect to the baseline condition of no therapy (P = 0.0001). Overall, budesonide offered better protection (area under the curve) than did montelukast (P = 0.01), particularly in the short-term evaluation (2 minutes after exercise; P = 0.003); however, considerable individual variations in the responses to both budesonide and montelukast were observed. The degree of protection against decreases in FEV1 ranged from 0% to almost 100% for both treatments. In 16 of 20 patients, budesonide therapy offered better protection than did montelukast, and in the other 4 patients, montelukast showed better protection than did budesonide. No side effects of either montelukast or budesonide were detected during the study. CONCLUSIONS: Treatment with budesonide or montelukast prevents exercise-induced bronchoconstriction. Because substantial variation in the response may be present among patients, both drugs should be tested in each patient before long-term therapy is chosen.

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Effects of glucocorticoid and cysteinyl leukotriene 1 receptor antagonist on CD(34+) hematopoietic cells in bone marrow of asthmatic mice.

Lei S.

Department of Respiratory Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China. fuyulirose hotmail.com

BACKGROUND: Corticosteroids remain the most effective therapy available for asthma. They have widespread effects on asthmatic airway inflammation. However, little is known about the effects of corticosteroids on the production of bone marrow inflammatory cells in asthma. This study observed the effects of glucocorticoid and cysteinyl leukotriene 1 receptor antagonist on CD34+ hematopoietic cells, so as to explore the possible effectiveness of a bone marrow-targeted anti-inflammatory strategy. METHODS: Balb/c mice were sensitized and challenged with ovalbumin (OVA) to establish an asthmatic model. For two consecutive weeks, asthmatic mice were challenged with OVA while being given either prednisone, montelukast, prednisone plus montelukast, or sterile saline solution. The mice were killed 24 hours after the last challenge with OVA, and bronchoalveolar lavage fluid (BALF), peripheral blood, and bone marrow were collected. Eosinophils in peripheral blood and BALF, and nucleated cells in BALF, peripheral blood, and bone marrow were counted. The percentages of CD34+ cells, CD4+ T lymphocytes and CD8+ T lymphocytes among nucleated cells in peripheral blood and bone marrow were counted by flow cytometry. Immunocytochemistry and in situ hybridization were employed to detect expression of CD34 and interleukin (IL)-5Ralpha mRNA (CD34+ IL-5Ralpha mRNA+ cells) among bone marrow hematopoietic cells. RESULTS: Compared with the sterile saline solution group, the number of eosinophils in BALF and peripheral blood, CD34+ cells in peripheral blood and bone marrow, and CD34+ IL-5Ralpha mRNA+ cells in bone marrow of mice from the prednisone and prednisone plus montelukast groups were significantly lower (P < 0.01). The number of eosinophils in BALF from the montelukast group was also significantly lower (P < 0.05). CONCLUSIONS: The results suggest that, in this asthmatic mouse model, prednisone probably inhibits proliferation, differentiation, and migration of CD34+ cells in bone marrow, blocks eosinophilopoiesis in bone marrow, and interferes with eosinophil migration into peripheral blood and subsequent recruitment in the airway. In addition, montelukast may suppress eosinophil infiltration into the lungs of asthmatic mice. However, a significant inhibitory effect of montelukast on the proliferation and migration of CD34+ cells and a cooperating effect with prednisone on bone marrow of asthmatic mice were not observed.

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[The effects of anti-inflammatory and anti-asthmatic agents on CD34+ hematopoietic cells in bone marrow of asthmatic mice]

[Article in Chinese]

Deng YL.

Department of Respiratory Medicine, West China Hospital Sichuan University, Chengdu 610041, China.

OBJECTIVE: To observe the effects of glucocorticoids and cysteinyl leukotrienes 1 receptor antagonist on CD(34)(+) hematopoietic cells, and to study the rationality of a bone marrow-targeting anti-inflammatory strategy. METHODS: Twenty-four BALB/c mice were sensitized and challenged by 1% ovalbumin (OVA) to establish the asthmatic model. Asthmatic mice were challenged by 1% OVA and divided into 4 groups: fed by sterile saline (group A), prednisone (group B), montelukast (group C) and prednisone plus montelukast (group D) respectively for two consecutive weeks. The mice were killed at 24 h after the last challenge, then bronchoalveolar lavage fluid (BALF), peripheral blood and bone marrow were prepared. Eosinophils in peripheral blood and BALF, nucleate cells in BALF, peripheral blood and bone marrow were counted. The percentage of CD(34)(+) cells, CD(4)(+), CD(8)(+) T lymphocyte to nucleate cells in peripheral blood and bone marrow were counted by flow cytometry. Immunocytochemistry and in situ hybridization were employed to detect the hematopoietic cells expression of CD(34)(+) and IL-5Ralpha mRNA in bone marrow (CD(34)(+) IL-5Ralpha mRNA(+) cells). RESULTS: The number of EOS in BALF and peripheral blood and the number of CD(34)(+) cells in peripheral blood and bone marrow in group A were [(18.3 +/- 1.3) x 10(5)/L], [(2.5 +/- 0.4) x 10(8)/L], [(9.6 +/- 5.1) x 10(7)/L] and [(7.7 +/- 3.2) x 10(7)/femur] respectively, compared with the corresponding indices in group B [(4.6 +/- 1.7) x 10(5)/L, (1.5 +/- 0.3) x 10(8)/L, (3.9 +/- 2.1) x 10(7)/L, (3.3 +/- 1.8) x 10(7)/femur] and group D [(3.7 +/- 1.4) x 10(5)/L, (1.7 +/- 0.3) x 10(8)/L, (4.1 +/- 1.8) x 10(7)/L, (2.2 +/- 0.7) x 10(7)/femur]; the differences all were significant (all P < 0.01). The number of bone marrow CD(34)(+) IL-5Ralpha mRNA(+) in group B and D were (23 +/- 7)% and (21 +/- 4)%, as compared with the corresponding index in group A [(37 +/- 4)%], the differences were significant (P < 0.01); the number of eosinophils in BALF in group C was (12.2 +/- 1.1) x 10(5)/L, as compared with the corresponding index in group A [(18.3 +/- 1.3) x 10(5)/L], the difference was significant (P < 0.05). CONCLUSIONS: Prednisone probably inhibits the proliferation, differentiation and emigration of CD(34)(+) cells in the bone marrow of asthmatic mice, and inhibits eosinophilopoiesis in bone marrow, eosinophil migration into peripheral blood and recruitment to the airways. Montelukast may suppress eosinophil infiltrating into lungs of asthmatic mice, but it does not inhibit the proliferation and emigration of CD(34)(+) cells and does not show apparent synergistic effect with prednisone.

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Effect of montelukast, a cysteinyl receptor antagonist, on myofibroblasts in interstitial lung disease.

Greif J.

Department of Pulmonary and Allergic Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv University, 6 Weizman Street, Tel Aviv 64239, Israel. fireman tasmc.health.gov.il

Montelukast, a potent cysteinyl receptor antagonist, may be an antifibrotic therapeutic agent for lung fibrosis. Seven sarcoidosis patients and 10 with unusual interstitial pneumonia underwent conventional bronchoalveolar lavage, from which myofibroblasts were recovered. Myofibroblast proliferation was assayed, alpha smooth muscle actin levels were measured, TGFbeta mRNA RT-PCR transcripts were semiquantitated, and secretion was evaluated in myofibroblast supernatants. Montelukast at 10(-8) M concentration had a suppressive effect on cell proliferation (31 +/- 18%), which was significantly enhanced by LTD4 10(-8) M. No differences were found between sarcoidosis (31.28 +/- 15.9%) and unusual interstitial pneumonia (30.56 +/- 24.3%) lines. Fetal calf serum (20%) produced an enhancing effect (29.8 +/- 21.6%) in all lines. Myofibroblasts recovered from sarcoidosis patients showed lower alpha-smooth muscle actin contents than unusual interstitial pneumonia lines (0.09 +/- 0.02 vs. 0.34 +/- 0.16, p =0.039, respectively). Montelukast suppressed alpha-actin in short-term cultures in sarcoidosis myofibroblasts and in long-term unusual interstitial pneumonia myofibroblasts. Montelukast at 10(-6) M concentratin decreased the TGFbeta-induced alpha-actin expression in all lines tested. Montelukast decreased mRNA expression of TGFbeta. Montelukast may be a therapeutic agent in pathological conditions involving fibrotic and remodeling processes.

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