Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications.

Intranasal corticosteroids (INSs) are effective treatments for allergic rhinitis, rhinosinusitis, and nasal polyposis. In recent years, increased understanding of corticosteroid and glucocorticoid receptor pharmacology has enabled the development of molecules designed specifically to achieve potent, localized activity with minimal risk of systemic exposure. Pharmacologic potency studies using affinity and other assessments have produced similar rank orders of potency, with the most potent being mometasone furoate, fluticasone propionate, and its modification, fluticasone furoate. The furoate and propionate ester side chains render these agents highly lipophilic, which may facilitate their absorption through nasal mucosa and uptake across phospholipid cell membranes. These compounds demonstrate negligible systemic absorption. Systemic absorption rates are higher among the older corticosteroids (flunisolide, beclomethasone dipropionate, triamcinolone acetonide, and budesonide), which have bioavailabilities in the range of 34-49%. Studies, including 1-year studies with mometasone furoate, fluticasone propionate, and budesonide that evaluated potential systemic effects of INSs in children have generally found no adverse effects on hypothalamic-pituitary-adrenal axis function or growth. Clinical data suggest no significant differences in efficacy between the INSs. Theoretically, newer agents with lower systemic availability may be preferable, and may come closer to the pharmacokinetic/pharmacologic criteria for the ideal therapeutic choice.

Nasal allergies and beyond: a clinical review of the pharmacology, efficacy, and safety of mometasone furoate.

Mometasone furoate nasal spray (MFNS; Nasonex, Schering-Plough Corporation, Kenilworth, NJ, USA) is an effective and well-tolerated intranasal corticosteroid approved for the prophylactic treatment of seasonal allergic rhinitis, and the treatment of perennial allergic rhinitis. MFNS is a potent molecule with a rapid onset of action and excellent safety and efficacy profiles. Having recently received approval for the treatment of nasal polyposis, data indicate that MFNS may also be effective in rhinosinusitis.

Montelukast improves symptoms of seasonal allergic rhinitis over a 4-week treatment period.

BACKGROUND: Proinflammatory mediators such as the cysteinyl leukotrienes are important in the pathophysiology of allergic rhinitis. This study evaluated the efficacy and tolerability of montelukast, a cysteinyl leukotriene receptor antagonist, given once daily in the morning for treatment of seasonal (fall) allergic rhinitis for 4 weeks. METHODS: This was a randomized, double-blind trial with a placebo run-in and a 4-week treatment period. Patients (n = 1079) with a history of allergic rhinitis and a positive skin test to seasonal pollen allergens were assigned to placebo, montelukast 10 mg, or loratadine 10 mg. Symptoms were assessed with a daily diary. RESULTS: Montelukast was more effective than placebo in improving scores for the primary endpoint of daytime nasal symptoms (P = 0.003) and the secondary endpoints of night-time, composite, and daytime eye symptoms, patient's and physician's global evaluations of allergic rhinitis, and rhinoconjunctivitis quality-of-life (P

Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinical trial.

BACKGROUND: Nasal challenge studies have suggested histamine and cysteinyl leukotrienes are important proinflammatory mediators in allergic rhinitis. This study was designed to determine the efficacy of montelukast, a cysteinyl leukotriene receptor antagonist, administered alone or concomitantly with loratadine, an H(1)-receptor antagonist, in seasonal allergic rhinitis. OBJECTIVE: The purpose of this study was to determine the effect of concomitant use of montelukast and loratadine in the treatment of seasonal allergic rhinitis. METHODS: In this multicenter (N = 12) double-blind, randomized, parallel-group, placebo-controlled 2-week trial, 460 men and women, aged 15 to 75 years, with spring seasonal allergic rhinitis were randomly allocated to receive 1 of the following 5 treatments: montelukast 10 or 20 mg, loratadine 10 mg, montelukast 10 mg with loratadine 10 mg, or placebo, once daily in the evening. The primary end point was daytime nasal symptoms score (average of congestion, rhinorrhea, itching, and sneezing). Other end points were eye symptoms, nighttime symptoms, individual daytime nasal symptoms, global evaluations (patient's and physician's), and rhinoconjunctivitis quality-of-life scores. RESULTS: Concomitant montelukast with loratadine improved the primary end point significantly (P <.001) compared with placebo and each agent alone. Compared with placebo, montelukast with loratadine also significantly improved eye symptoms, nighttime symptoms, individual daytime nasal symptoms, global evaluations, and quality of life. Montelukast alone and loratadine alone caused modest improvements in rhinitis end points. All treatments were similarly well tolerated. CONCLUSIONS: Concomitant montelukast with loratadine provided effective treatment for seasonal allergic rhinitis and associated eye symptoms with a safety profile comparable with placebo.

Role for cysteinyl leukotriene receptor antagonist therapy in asthma and their potential role in allergic rhinitis based on the concept of "one linked airway disease".

OBJECTIVE: This review focuses on the shared pathophysiology of asthma and allergic rhinitis. The similarities illustrate the "one linked airway disease" concept, a unifying theory of these upper and lower airway inflammatory disorders. Since leukotrienes are mediators in both conditions, studies have been performed to assess the potential therapeutic role of cysteinyl leukotriene antagonists. The purpose of this paper is to provide an overview of the accumulating data concerning these agents in treating asthma and allergic rhinitis. DATA SOURCES: Relevant publications obtained from a literature review. STUDY SELECTION: Relevant publications on the topics of leukotrienes, leukotriene receptor antagonists, asthma, and allergic rhinitis were critically evaluated. RESULTS AND CONCLUSIONS: Studies to date have documented the efficacy of cysteinyl leukotriene receptor antagonists for asthma. The pathophysiology of allergic rhinitis and its similarities to asthma suggest that these agents could play a significant therapeutic role in managing this upper airway disorder. Because the leukotriene antagonists are oral agents, they may be valuable in treating not only either condition but also both at the same time when they coexist. They appear to be beneficial when prescribed as the initial medicine and when used in conjunction with other therapies.

Involuntary smoking and asthma.

Involuntary smoking is the third leading preventable cause of death, and among children it causes lower respiratory infections, middle ear disease, sudden infant death syndrome, and asthma. Half the world's children may be exposed to environmental tobacco smoke (ETS), exacerbating symptoms in 20% of children with asthma. Recent studies have reinforced previous conclusions that ETS exposure causes onset of childhood asthma and exacerbation of symptoms throughout life. The exact mechanisms by which this is accomplished are still unclear, as are the relative contributions of prenatal versus postnatal exposure. However, favorable health outcomes can be attained with reduced exposure. Among the few studies of ETS exposure reduction interventions, low-intensity advice methods appeared ineffective, and counseling parent smokers appeared successful. Direct counseling of school-aged children to avoid ETS has yet to be tested. Community norms may need to shift further in favor of protecting children and others from ETS before minimal interventions can be successful. This will require combined and ongoing efforts of the medical and public health establishments, in concert with legislation mandating tobacco-free public places and with ETS-related media campaigns.

Impact of cetirizine on the burden of allergic rhinitis.

OBJECTIVE: The goals of this article include the reporting of the epidemiology, economic and medical impact of allergic rhinitis. In addition, the pharmacology and clinical profile of the therapeutic agent cetirizine are reviewed. DATA SOURCES: A detailed literature search was conducted. References are limited to the English language and human subjects and tissues. Studies considered relevant and important over the past 20 years are highlighted. STUDY SELECTION: Prevalence and morbidity data were chosen from more recent assessments. Because cetirizine is a relatively new compound, studies from the past several years from peer-reviewed journals have been emphasized. RESULTS: Allergic rhinitis affects between 15% and 25% of the US general population. It shares common pathophysiologic mechanisms with conjunctivitis and asthma and predisposes to nasal infections, otitis media, sinusitis, nasal polyposis, and orthodontic malocclusions. Direct medical care costs amount to up to 3 billion dollars every year. In addition, the quality of life of affected individuals is substantially compromised. Cetirizine is a potent H1-receptor antagonist and has anti-inflammatory properties. It does not interact with concomitantly administered medications, has no cardiac adverse effects, and does not appear to be associated with teratogenicity. Impairment of CNS function is comparable to other low-sedating antihistamines at the recommended dose of 10 mg daily for adults. Its clinical efficacy for allergic respiratory diseases has been established in numerous trials. CONCLUSIONS: Allergic rhinitis causes considerable suffering. Cetirizine, with a fine risk-benefit ratio, can be a most valuable therapeutic option.

The pharmacological basis for the treatment of perennial allergic rhinitis and non-allergic rhinitis with topical corticosteroids.

The currently available respiratory topical corticosteroids are all effective at reducing the nasal symptoms of itch, sneezing, rhinorrhoea and obstruction associated with allergic rhinitis. The mechanism of action of corticosteroids is related to their anti-inflammatory activities. They have been documented to prevent fluid exudation and reduce the number of circulating inflammatory cells, including lymphocytes, mast cells, basophils, eosinophils, macrophages, and neutrophils. This occurs through multiple mechanisms, e.g. eosinophil infiltration is suppressed by preventing cytokine production, reducing local mechanisms of tissue infiltration, and decreasing eosinophil survival. Furthermore, corticosteroids also reduce preformed and newly-generated mediators (e.g. histamine, tryptase, prostanoids, leukotrienes), and inhibit production of cytokines and chemokines by inflammatory cells (e.g. IL-1 through IL-6, IL-8, RANTES, TNF-alpha, IFN-gamma and GM-CSF). The currently available corticosteroids differ pharmacologically. Fluticasone propionate appears to have the greatest affinity for the glucocorticoid receptor, and binds more quickly and dissociates more slowly from the receptor compared with other corticosteroids, suggesting a more prolonged duration of action. Its increased specificity for respiratory tissue may lead to greater potency with less potential for systemic adverse effects. Fluticasone propionate has been compared with other corticosteroids in animal models for relative topical and systemic potency, and according to these data, it has the most favourable risk-benefit ratio.

The accuracy of environmental tobacco smoke exposure measures among asthmatic children.

This study determined the reliability and validity of parent-reported measures of environmental tobacco smoke (ETS) exposure among 91 asthmatic children. Test-retest reliability assessments were conducted for environmental, biological and parent-reported measures of ETS exposure. All measures except a urine cotinine assay resulted in satisfactory levels of reliability. The parent-reported measures of ETS exposure were compared to the environmental filter measure of nicotine as well as submitted to a construct validity test. Parent-reported home exposure to ETS proved moderately and significantly correlated to the filter measure. Approximately 80% of all hypothetical constructs agreed with the observed relationships for convergent, divergent and discriminant validity. It was concluded that middle class Caucasian parents' reports of their asthmatic child's residential ETS exposure are reliable and valid. These parent-reported measures should be valuable tools for epidemiological investigations and for clinical programs designed to reduce asthmatic children's residential exposure to ETS.

Prevalence, economic, and medical impact of tobacco smoking.

OBJECTIVE: The goal of this review is to report the epidemiology and risks associated with tobacco smoking. It also suggests reasons and measures to achieve a smoke-free society. DATA SOURCES: References are limited to the English language and human subjects. All are publications from either the United States or the United Kingdom and extend back to the past 50 years. Sources include computerized databases and bibliographies of recent articles and books. STUDY SELECTION: Papers were selected on the basis of their timeliness, credibility of their data, explanation of important findings, extrapolation of clinical data from large patient populations, and clarification of controversial issues. Approximately 60% of the articles initially reviewed are included in the bibliography. RESULTS: Tobacco smoking continues to affect the lives of millions of Americans. The risks of cardiovascular diseases, cancer, and respiratory diseases are significantly increased in both the smoker and in those exposed to environmental tobacco smoke. CONCLUSIONS: Understanding the consequences of tobacco smoking is necessary to effectively mobilize the appropriate political, social, and medical resources to combat this most important health issue.

Reduction of environmental tobacco smoke exposure among asthmatic children: a controlled trial.

STUDY OBJECTIVE: This randomized clinical trial tested a behavioral medicine program designed to reduce asthmatic children's exposure to environmental tobacco smoke (ETS) in the home. DESIGN: Families were randomly assigned to an experimental preventive medicine counseling group, a monitoring control group, or a usual treatment control group. Families were measured six times over 1 year. PARTICIPANTS: Ninety-one families were recruited from four allergy clinics. INTERVENTION: The experimental group received a 6-month series of counseling sessions designed to decrease ETS exposure. This group also monitored smoking, exposure, and children's asthma symptoms. The monitoring group did not receive counseling and the usual treatment control group received outcome measures only. MEASUREMENTS AND RESULTS: Parents reported the daily number of cigarettes children were exposed to during the week preceding interviews. A nicotine air monitor and construct validity analysis confirmed the validity of exposure reports. Exposure to the parent's cigarettes in the home decreased for all groups. The experimental group attained a 79 percent decrease in children's ETS exposure, compared with 42 percent for the monitoring control and 34 percent for the usual treatment control group. Repeated-measures analysis of variance resulted in a significant (F([10,350] = 1.92, p < 0.05) group by time effect. At the final 12-month visit, the experimental/counseling group sustained a 51% decrease in children's exposure to cigarettes in the home from all smokers, while the monitoring control group showed an 18% decrease and the usual treatment control group a 15% decrease from pre-intervention [corrected]. CONCLUSION: A behavioral medicine program was successful in reducing exposure to ETS in the home for these asthmatic children.

Reduction of secondary smoke exposure in asthmatic children: parent counseling.

Epidemiological evidence shows that children's exposure to secondhand tobacco smoke increases their risk of respiratory illness. This study evaluated five families and their asthmatic children (aged 5-14 years) in an outpatient counseling program for reducing the children's exposure to passive smoking. Intervention included biweekly counseling/instructions for parents to limit their children's tobacco exposure. A multiple-baseline, quasiexperimental design was used for self-reported measures of the children's smoke exposure and the parent's smoking frequency. Counseling was associated with smoke exposure reduction of 40-80% from baseline for each of 5 children, with most improvements sustained during follow-up. This study provides support for the development of tobacco exposure prevention programs for children with pulmonary disease.

Intranasal fluocortin butyl in patients with perennial rhinitis: a 12-month efficacy and safety study including nasal biopsy.

Fluocortin butyl (FCB) is a recently developed topical intranasal corticosteroid that is inhaled as a powder and has been demonstrated to be well tolerated and to improve symptoms and signs of perennial rhinitis in previous short-term studies. This multicenter, open-label study evaluated the efficacy and safety of FCB during a 12-month treatment period in patients with perennial rhinitis. Treatment was initiated with one inhalation of FCB in each nostril three times a day (total dosage, 3 mg/day). In subsequent months, one third of the patients was maintained at the dosage of 3 mg/day, one third at a lower dosage of 2 mg/day, and the remaining one third of the patients at a larger dosage of 4 to 8 mg/day. Of 109 patients enrolled in the study, 90 patients (82.6%) completed all 12 months of treatment. Symptom and sign scores decreased significantly (p less than 0.001) at the 2-month evaluation compared to scores at baseline, and the improvement was maintained throughout the 12-month study period. After 12 months, greater than 80% of the patients had substantial control of symptoms. Specimens of nasal biopsies, performed at the beginning and end of treatment, revealed a decrease in eosinophils and other cellular infiltrates, a slight tendency of an increase in mast cell counts, and a trend toward normalization of the nasal mucosa. There were few adverse effects. Mean plasma cortisol levels were normal before and after corticotropin stimulation at baseline and after 12 months of FCB therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Vocal cord dysfunction in a child with asthma.

Vocal cord dysfunction is uncommon in children. We present the case of a 12-year-old boy with a history of mild, intermittent asthma from 7 to 10 years of age. Subsequently, severe, rapid-onset attacks of respiratory distress occurred with increasing frequency. After a life-threatening attack of airway obstruction with 3 minutes of apnea, he was hospitalized for diagnostic studies. Although pulmonary function tests were normal, laryngoscopy under general anesthesia revealed extremely severe vocal cord spasm induced by minimal contact of the laryngoscope. It required intravenous lidocaine and muscle relaxant to reverse. Spasm was not demonstrable one week later on repeat laryngoscopy and bronchoscopy. No structural abnormalities were seen. There was considerable family stress exacerbated by anxiety about the patient's illness. Parents were told that the condition was different from asthma and probably functional in origin. There have been no further episodes, possibly due to counseling and education in relaxation techniques as well as oral pharmacotherapy for asthma with avoidance of inhaled medications.

A simplified screening test for the diagnosis of allergy.

The Quidel allergy screen is a relatively rapid (less than 2 hours) multiallergen dipstick method for detecting specific immunoglobin E antibodies in serum. It was developed to answer the need of primary physician nonspecialists in allergy for a convenient in-office screening test for diagnosing allergy. The new test was evaluated against the benchmark diagnostic skin tests and the radioallergosorbent serologic tests for sensitivity, specificity, accuracy, and technical feasibility in an office setting. It was found that while the Quidel allergy screen lacks the specificity of the standard tests, its overall sensitivity, as defined by the percentage of patients with positive skin reactions who also tested positive with the Quidel screen (68%), its ease of use, and its rapidity warrant its consideration as a screening tool for confirming a possible case of allergy.