Observational study of the effects of using montelukast vs fluticasone in patients matched at baseline.

Weiss KB.

Merck & Co Inc, West Point, Pennsylvania 19486-0004, USA. felicia_ramey merck.com

BACKGROUND: The relative effectiveness of inhaled corticosteroids and leukotriene receptor antagonists in asthma therapy continues to be the subject of clinical studies. Recent studies have examined the impact of these therapies using a retrospective design. Retrospective studies require special attention to nonrandom assignment of participants to treatment groups and, consequently, to the need to appropriately account for baseline differences. OBJECTIVE: To examine the relative effectiveness of montelukast sodium vs fluticasone propionate as controller monotherapy in patients with asthma. METHODS: A retrospective cohort analysis of claims data from 6,160 individuals continuously enrolled in 1 of 20 US managed care plans. Patients using fluticasone were matched to those treated with montelukast using propensity scores and age (2-55 years). Health care use was determined for the 12-month periods before and after the initial controller prescription. Outcomes included asthma-related hospitalizations and emergency department visits, along with use of oral corticosteroids and short-acting beta-agonists. Logistic regression analyses were also performed. RESULTS: Overall, controller therapy significantly reduced the odds of postindex asthma-related hospitalizations (odds ratio, 0.56; 95% confidence interval, 0.38-0.79); no significant difference was observed with asthma-related emergency department visits (odds ratio, 0.89; 95% confidence interval, 0.76-1.04). Differences in the relative effect in the montelukast and fluticasone groups were not observed. Similarly, increases in the postindex rate of short-acting beta-agonist use and increases in oral corticosteroid use for both montelukast and fluticasone patients were noted. CONCLUSIONS: Similar outcomes were observed in montelukast and fluticasone users in this matched cohort analysis.

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Pharmacological profile of CR3465, a new leukotriene CysLT1 receptor antagonist with broad anti-inflammatory activity.

Makovec F.

Rotta Research Laboratorium S.p.A., Pharmacology and Toxicology Department, Via Valosa di Sopra 7/9-20052 Monza (MI), Italy. Flora.Ferrari rotta.com

CR3465 (L-Tyrosine, N-[(2-quinolinyl)carbonyl]-O-(7-fluoro-2-quinolinylmethyl) sodium salt) is a potent antagonist of [3H]leukotriene D4 ([3H]LTD4) binding to guinea pig lung preparations, its Ki (4.7+/-0.7 nM) being comparable with that of montelukast (5.6+/-0.6 nM). In tracheal strips from standard or ovalbumin-sensitized guinea pigs, CR3465 caused parallel rightward shifts in the concentration-response curves obtained with either LTD4 or antigen (pA(2), 8.74 and 8.15). Intravenous (i.v.) administration of the agent both antagonized (ED50, 9.9+/-1.9 microg/kg) and reverted LTD4 -induced bronchoconstriction of anesthetized guinea pigs. CR3465 reduced inflammatory infiltrates in the bronchoalveolar lavage fluid after antigen challenge of sensitized animals, and proved also active in inhibiting phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) activities exhibited by human platelets and neutrophils (IC50, 2.01+/-0.07 and 4.7+/-0.5 microM). In line with properties shown by phosphodiesterase inhibitors, CR3465 reduced the contractile response of guinea pig airways to histamine and decreased N-formyl-Met-Leu-Phe (fMLP)-induced degranulation of human neutrophils (IC50, 13.8 microM). Oral administration (20 mg/kg) of the compound in rats produced a significant (37%) ex vivo inhibition of tumor necrosis factor-alpha (TNF-alpha) release from lipopolysaccharide-stimulated whole blood. Pharmacokinetic data in the rat demonstrated approximately 100% bioavailability of the agent. We conclude that CR3465 represents a potent leukotriene CysLT1 receptor antagonist with enhanced effects, being also useful for counteracting spasmogenic and inflammatory stimuli other than those elicited by cysteinyl-leukotrienes (Cys-LTs).

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Preventive therapy for asthmatic children under Florida Medicaid: changes during the 1990s.

David C.

Nemours Children's Clinic, Jacksonville, Florida 32207, USA. cdavid nemours.org

BACKGROUND: In response to the increasing prevalence and severity of asthma in this country, the National Institutes of Health in 1991 published an expert consensus report Guidelines for the Diagnosis and Management of Asthma. An important aspect of the report included the recommendation that children with moderate asthma may benefit from daily treatment with anti-inflammatory drugs such as inhaled corticosteroids and cromolyn. OBJECTIVES: The objective of this article is to examine changes in prescribing of daily anti-inflammatory drugs for children covered by Florida Medicaid during two 2-year periods, the first just after publication of the Guidelines and the second 7 years later; and to estimate adherence to treatment by children who received one of them. DESIGN: The study groups for each of the two 2-year periods included only children 2 to 18 years old who had medical or institutional claims to Medicaid for asthma and who were continuously covered during the period. From outpatient claims files, a record was assembled for each child containing the number of prescriptions in each category of asthma drugs during each interval. For each child who had received a prescription for any daily preventative drug, the number of such prescriptions and the time after the first were used to calculate availability of medication. RESULTS: The proportion of children receiving at least one prescription for a preventive drug rose from 26.9 per cent of children in 1990-1992 to 52.6 per cent in 1997-1998. African-American children were less likely to receive a preventive in the earlier period, but the difference narrowed by 1997. Assuming that one refill provided a month's supply of drug, the percentage of children who had enough drug dispensed to treat for more than half of the time following the initial prescription rose from 6.1 to 11.2 per cent. For children with the highest use of beta-agonist (11 or more prescriptions over 2 years), the percentage rose from 25.3 to 35.8; in those with 5 or more courses of a systemic steroid, the proportion rose from 36.6 to 40.2. During the second interval, adherence to use of oral montelukast was no better than to inhaled daily medications. CONCLUSION: In the 7 years after the publication of the NIH Guidelines, asthmatic children covered by Florida Medicaid had an approximate doubling in the proportion who received a prescription for a daily anti-inflammatory drug. However, during both intervals the adherence to treatment once prescribed remained low even among those with the severest asthma. Effective strategies to improve adherence will be needed before these drugs can realize their potential.

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Montelukast: new preparation. No current use in asthma.

.

(1) Montelukast, an antiasthmatic drug belonging to the leukotriene antagonist family, has two indications in France: as adjunctive treatment for mild to moderate chronic asthma when regular inhaled steroid therapy and short-acting inhaled beta 2 stimulants "on demand" are inadequate; and in the prevention of effort-induced asthma. (2) The clinical file on montelukast contains no methodologically acceptable comparisons with reference treatments. (3) Several placebo-controlled trials have shown the efficacy of montelukast, with an improvement in clinical scores and respiratory function tests in chronic asthma; and prevention of effort-induced asthma. (4) In chronic asthma montelukast has not been compared with oral or inhaled long-acting beta 2 stimulants, or with sustained-release theophylline in patients inadequately controlled by steroid therapy. (5) In effort-induced asthma, only two trials have compared montelukast to salmeterol. On the basis of preliminary results the authors concluded that montelukast was superior in both studies. (6) Clinical trials showed no clear difference in the frequency of side effects in patients on montelukast and those on a placebo. However, montelukast may possibly be associated with the Churg and Strauss syndrome in rare cases. (7) Montelukast is an expensive drug.

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Treatment of chronic cough in children with montelukast,a leukotriene receptor antagonist.

Zapalka M.

Department of Pediatrics, University Hospital and Palacky University, Olomouc, Czech Republic. koprivaf risc.upol.cz

Twenty-two children (13 boys and 9 girls) with chronic cough were treated with the leukotriene receptor antagonist montelukast (Singulair tbl. 5 mg) administered once daily for four weeks. In 14 children (68%), the cough ceased during the third week of treatment. Children responding to montelukast were found to have higher blood levels of eosinophil cationic protein (S-ECP) in the pretreatment blood sample than children with no response (responders 14.88+/-2.651 microg/l versus nonresponders 6.62+/-0.948 microg/l; p<0.01). Blood S-ECP levels remained higher also in the post-treatment blood sample in responders (10.55+/-1.631 microg/l) compared to nonresponders (6.13+/-0.937 microg/l; p<0.05). The difference is statistically significant. There were also differences in absolute eosinophil blood count and IgE blood levels between the two groups in the pretreatment blood sample. Using 24-hour pH-metry, two children not responding to therapy were subsequently diagnosed to have gastroesophageal reflux. Judging from the results, one might deduct that patients with chronic cough who have increased levels of serum ECP and absolute eosinophil blood counts are likely to benefit from treatment with montelukast.

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