ABSTRACT. Background. The greatest prevalence of asthma is in preschool children; however, the clinical utility of asthma therapy for this age group is limited by a narrow therapeutic index, long-term tolerability, and frequency and/or difficulty of administration. Inhaled corticosteroids and inhaled cromolyn are the most commonly prescribed controller therapies for young children with persistent asthma, although very young patients may have difficulty using inhalers, and dose delivery can be variable. Moreover, reduced compliance with inhaled therapy relative to orally administered therapy has been reported. One potential advantage of montelukast is the ease of administering a once-daily chewable tablet; additionally, no tachyphylaxis or change in the safety profile has been evidenced after up to 140 and 80 weeks of montelukast therapy in adults and pediatric patients aged 6 to 14 years, respectively.To our knowledge, this represents the first large, multicenter study to address the effects of a leukotriene receptor antagonist in children younger than 5 years of age with persistent asthma, as well as one of the few asthma studies that incorporated end points validated for use in preschool children.Objective. Our primary objective was to determine the safety profile of montelukast, an oral leukotriene receptor antagonist, in preschool children with persistent asthma. Secondarily, the effect of montelukast on exploratory measures of asthma control was also studied.Design and Statistical Analysis. We conducted a double-blind, multicenter, multinational study at 93 centers worldwide: including 56 in the United States, and 21 in countries in Africa, Australia, Europe, North America, and South America. In this study, we randomly assigned 689 patients (aged 2-5 years) to 12 weeks of treatment with placebo (228 patients) or 4 mg of montelukast as a chewable tablet (461 patients) after a 2-week placebo baseline period. Patients had a history of physician-diagnosed asthma requiring use of -agonist and a predefined level of daytime asthma symptoms. Caregivers answered questions twice daily on a validated, asthmaspecific diary card and, at specified times during the study, completed a validated asthma-specific quality-oflife questionnaire. Physicians and caregivers completed a global evaluation of asthma control at the end of the study.Efficacy end points included: daytime and overnight asthma symptoms, daily use of -agonist, days without asthma, frequency of asthma attacks, number of patients discontinued because of asthma, need for rescue medication, physician and caregiver global evaluations of change, asthma-specific caregiver quality of life, and peripheral blood eosinophil counts. Although exploratory, the efficacy end points were predefined and their analyses were written in a data analysis plan before study unblinding. At screening and at study completion, a complete physical examination was performed. Routine laboratory tests were drawn at screening and weeks 6 and 12, and submitted to a central laboratory for a...
IMPORTANCEThe US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. OBJECTIVE To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018.INTERVENTIONS Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm 2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. MAIN OUTCOMES AND MEASURESThe primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. RESULTS Among 24 participants randomized (mean age, 35.5 [SD, 10.5] years; 12 [50%] women; 14 [58%] black or African American), 23 (96%) completed the trial. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash (1 participant with each sunscreen).
Sarcoidosis is an enigmatic disease with extremely variable manifestations in pattern, severity and course. Since Longcope and Freiman's descriptive monograph in 1952 (50) summarizing the clinical findings of the first half of this century, new dimensions of assessing the disease and treatment have been added. The impact of corticosteroids is central. The present review extends the studies to the second half of this century. Earlier diagnosis is facilitated and treatment often reverses many of the disease manifestations and improves the quality and extent of life for the patient. The management issues and guidelines outlined in this paper for both intrathoracic and extrathoracic disease are based on several longitudinal studies of the sarcoidosis patients summarized here, and 50 years of clinical experience by the senior author (CJJ) at Johns Hopkins Hospital, a tertiary referral center with an active Sarcoid Clinic. Case reports are presented in the appendix. It is clear that corticosteroids are the most effective therapeutic agent for sarcoidosis, usually with impressive and prompt response. This represents the dramatic difference in this disease after 1950. No more specific or effective immunosuppressive or antiinflammatory agents have been identified. Undesirable side effects are minimal if excessive doses are avoided. The effectiveness of "steroid-sparing agents" such as methotrexate is uncertain. Although irreversible tissue damage from the disease may limit the effectiveness of treatment, benefits of corticosteroids greatly exceed the negative side effects. Since spontaneous remissions without treatment do occur, a period of observation of 2 years are more is warranted if the patient is relatively asymptomatic. Gradual radiographic progression for 2 or more years, even without major symptoms or reduction in pulmonary function, indicates the need for a trial of corticosteroid treatment, especially in white patients where symptoms may lag behind the radiographic changes. Relapses as treatment is withdrawn are frequent, especially in African-American patients, who tend to have more severe and more prolonged disease than white patients. A minimum of 1 year of treatment is recommended unless no improvement is noted after 3 months. Continued low-dose prednisone at daily doses of 10-15 mg is helpful in preventing relapses and further progression of disease. Periodic attempts at tapering are justified. Repeated relapses may indicate the need for life-long treatment. When irreversible changes are present, especially in the presence of chronic fibrotic disease, changing goals of treatment to provide optimal supportive care may represent better management than having unrealistic expectations from increased corticosteroid dosage or the addition of other potentially toxic immunosuppressive agents. Many agents related to sarcoidosis require further research. The most important question facing sarcoid researchers today is etiology. It is difficult to design specific therapy when the fundamental causes and disease mechani...
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