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Biomedical subjects

Henry Milgrom

Publications and source records attributed to Henry Milgrom.

At least 19 recordsLinked to original sources

Childhood asthma: breakthroughs and challenges.

As we move forward, our goal is to control and eliminate asthma and other allergic disorders. This may come through broadly applied manipulation of environmental, dietary, and infectious risk factors, possibly during the perinatal period. Or we may learn to identify genetically susceptible children and to intervene with individualized genotype-specific treatment before the onset of disease. Maybe we'll learn how to block the mechanisms that give rise to chronic inflammation, or how to subdue Th2 activation. However, as the Swedish proverb says--Don't throw away the old bucket until you know whether the new one holds water. To continue using the old bucket, we have to fix the leaks. One approach to reducing asthma disparities is through traditional disease prevention stages. Primary prevention targets asthma incidence; secondary prevention mitigates established disease and involves disease detection, management, and control; and tertiary prevention is the reduction of complications caused by severe disease. Once causative factors at each level of disease prevention are understood, this knowledge can be translated into clinical practice and public health policy. We need reliable diagnostic criteria to provide correct treatment for infants and toddlers. This will require longitudinal cohort studies supported by assessment of pulmonary function and inflammatory markers. We must find ways to convince more physicians to embrace controller therapy for more severe disease, and to identify the patients with less severe disease who also require ongoing controller therapy. We need to close the gap between what we know and what we do in practice. We need to link basic research to healthcare delivery, and to gain acceptance and support from the intended recipients of new interventions. We need better strategies for improving adherence. We need accountability, foresight, and imagination.

Adrenergic beta-Agonists↗

Effect of formoterol fumarate treatment on exercise-induced bronchoconstriction in children.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is common, particularly in children. OBJECTIVES: To compare the protective effect of single doses of formoterol fumarate via Aerolizer with placebo and albuterol in children with EIB. METHODS: In this randomized, double-blind, double-dummy, crossover trial, 23 children (aged 4-11 years) received formoterol, 12 or 24 microg; albuterol, 180 microg; or placebo at 4 separate visits. Protection against EIB was evaluated as the maximum percentage decrease in forced expiratory volume in 1 second (FEV1) from the preexercise value after exercise challenge tests (6-minute treadmill) conducted 15 minutes and 4, 8, and 12 hours after administration of the dose. RESULTS: The maximum percentage decrease in FEV1 after the 4-hour exercise test (primary efficacy variable) was significantly less for formoterol, 12 and 24 microg, vs placebo (P < .001 for both) or albuterol (P = .016 and .010, respectively); albuterol was not significantly different from placebo. Formoterol, 12 and 24 microg, differed from placebo at 8 hours (P = .002 and .001, respectively), with a smaller difference between albuterol and placebo (P = .045). Rescue medication use and a high dropout rate may have biased treatment differences at later time points. Protection against EIB (<20% maximum decrease in FEV1) across all time points was observed for 17 (77%) of 22 and 17 (74%) of 23 children with formoterol, 12 and 24 microg, respectively, compared with 8 (35%) of 23 with albuterol and 6 (27%) of 22 with placebo. CONCLUSIONS: Single doses of formoterol, 12 or 24 microg, are effective in protecting against EIB in children, affording a statistically significantly greater protective effect than placebo or albuterol.

Administration, Inhalation↗

Effects of treatment with mometasone furoate dry powder inhaler in children with persistent asthma.

BACKGROUND: Mometasone furoate dry powder inhaler (DPI) has been shown to effectively treat asthma in children. OBJECTIVE: To evaluate the efficacy and safety of 2 dosing regimens of mometasone furoate DPI in the treatment of mild-to-moderate persistent asthma in children previously using inhaled corticosteroids (ICSs). METHODS: A 12-week, multicenter, double-blind, parallel-group, placebo-controlled study evaluated 2 dosing regimens of mometasone furoate DPI (100 microg every evening and 100 microg twice daily) in 296 children 4 to 11 years old with asthma previously using ICSs. The primary efficacy variable was the change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline to end point. Secondary efficacy variables included absolute FEV1, forced expiratory flow between 25% and 75% forced vital capacity, morning and evening peak expiratory flow, asthma symptom scores, albuterol use, nocturnal awakenings, response to therapy, and health-related quality of life. RESULTS: Mean changes from baseline at end point in predicted FEV1 were 4.73 and 5.52 percentage points for mometasone furoate DPI, 100 microg every evening and 100 microg twice daily, respectively, the difference of which was not significant, and -1.77 percentage points for placebo (P < or = .002). Significant improvements in secondary efficacy variables were also observed for both mometasone furoate DPI treatments over placebo. Both mometasone furoate DPI doses were well tolerated, and no significant differences were noted among the 3 treatment groups in adverse event reporting. CONCLUSIONS: Both mometasone furoate DPI doses were well tolerated and significantly improved lung function, maintained effective asthma control, and improved quality of life in children with asthma.

Abdominal Pain↗

Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a double-blind, randomized, placebo- and active-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of levalbuterol metered dose inhaler (MDI) in children aged 4-11 years (n = 173). RESEARCH DESIGN AND METHODS: Multicenter, randomized, double-blind 28-day study of QID levalbuterol 90 microg, racemic albuterol 180 mug, and placebo (2:1:1 ratio). Serial spirometry was performed on Days 0, 14, and 28. The primary endpoint was the double-blind average peak percent (%) change in FEV(1) from visit pre-dose; the primary comparison was with placebo. Secondary endpoints included the area under the FEV(1) percent change from pre-dose curve and peak % predicted FEV(1). Safety endpoints included adverse events, laboratory tests, rescue medication use, and electrocardiograms. RESULTS: Levalbuterol significantly improved the least square mean peak percent change in FEV(1) compared with placebo (levalbuterol 25.6% +/- 1.3% [p < 0.001]; racemic albuterol 21.8% +/- 1.8% [p = ns]; placebo 16.8% +/- 1.9%). Results for levalbuterol were similar for the other spirometry endpoints (p < 0.05 vs. placebo). No levalbuterol-treated patients had a peak percent change in FEV(1) < 10% (compared with 15.8% of racemic albuterol-treated patients and 30.3% of placebo-treated patients). The incidence of adverse events was 43.4% for levalbuterol, 56.4% for racemic albuterol, and 51.4% for placebo. The rate of discontinuation was 1.3% for levalbuterol, 2.6% for racemic albuterol, and 8.6% for placebo. The rate of asthma attacks (10.5%, 12.8%, 14.3%, respectively) was similar among treatments. Levalbuterol and racemic albuterol both reduced rescue medication use (p < 0.01 vs. placebo) and produced changes in ventricular heart rate and QT(c-F) that were similar to placebo. CONCLUSIONS: In this study, levalbuterol administered via MDI significantly improved airway function in comparison with placebo in asthmatic children aged 4-11 years with a safety profile that was similar to placebo.

Administration, Inhalation↗

Levosalbutamol in the treatment of asthma.

With the exception of levosalbutamol, all of the beta2-agonists that are currently in use are racemic mixtures that are composed in equal amounts of (R)- and (S)-enantiomers. Clinical and mechanistic studies have demonstrated that (R)-salbutamol alone provides the beta2-agonist activity that is needed for the relief of bronchoconstriction, as well as the beta2-adrenergically mediated side effects. (S)-Salbutamol, on the other hand, has minimal binding affinity for the beta2-receptor, indicating that its effects are likely to be mediated through another site. Furthermore, there is evidence that (S)-salbutamol opposes the desirable effects of (R)-salbutamol in the racemic mixture and contributes to the development of characteristic features of asthma, such as airway obstruction, bronchial hyperresponsiveness and airway inflammation. Evidence from clinical studies shows delayed recovery from exacerbation of asthma by patients who are exposed to high concentrations of (S)-salbutamol.

Adolescent↗

Ethical considerations in research involving children.

Ethical concerns and medical advances unique to children and adolescents make pediatric research an evolving endeavor. The child's changing physiology from infancy to maturity requires understanding of the benefits and risks of medical therapies currently available, but often not tested in children, as well as the risks and benefits of inclusion of children in clinical research. Recent mandates from the US Food and Drug Administration (FDA) require that drugs be tested for safety and efficacy in children. Growing concern for the prevalence of chronic disorders and increasing understanding of distinct phenotypes of these disorders points to a likely need for unique interventions matched to specific phenotypes. All contribute to the increasing complexity of ethical considerations in pediatric research.

Adolescent↗

Asthma and activities of daily living.

The provider's ability to judge the severity of a patient's illness is a vital part of the care of chronic disorders. In the treatment of asthma, it should extend beyond the objectively quantifiable measures of obstruction or inflammation. "Interference with activities of daily living" is a highly subjective assessment that may not allow quantitative comparisons, but it matters to the patient. Interventions aimed at lessening the burden of asthma on the daily life of the patient and his or her family may hold the key to improvement in a broader range of outcome measures.

Activities of Daily Living↗

Comparison of the effects of fluticasone propionate aqueous nasal spray and loratadine on daytime alertness and performance in children with seasonal allergic rhinitis.

BACKGROUND: Concern has been directed at the relative sedating properties of lipophilic and lipophobic antihistamines, but few studies have sought to determine the comparative benefit of seasonal allergic rhinitis (SAR) treatments in controlling symptoms and consequently improving alertness. OBJECTIVE: To compare the relative contributions of fluticasone propionate aqueous nasal spray and loratadine in enhancing daytime performance in 8- to 17-year-old children. METHODS: All participants had a documented history of SAR, positive response to a skin prick (wheal 3-mm greater than negative control or equal to the positive control) for seasonal aeroallergens, and clinically identifiable symptoms at the time of randomization. Following confirmation during baseline of current SAR symptoms, participants were randomized to 1 of the 2 treatments and returned 2 weeks later for evaluation of symptom control, quality of life, attention, reaction time, and memory. RESULTS: Children in the fluticasone propionate aqueous nasal spray group but not the loratadine group demonstrated improvement in nasal symptoms, nasal quality of life score, and composite verbal memory. No differences were identified on any scores from the Conners Continuous Performance Test. CONCLUSIONS: Treatments that most effectively control SAR symptoms are also likely to provide the greatest benefit to children whose daytime functioning, including their capacity to learn at school, is compromised by their illness.

Administration, Intranasal↗

Measuring adherence with the Doser CT in children with asthma.

Non-adherence with prescribed asthma treatment causes compromised treatment effectiveness, including greater morbidity, mortality, and health care utilization costs. As a result, there is an increasing interest in measuring patient adherence behaviors. Electronic monitoring devices offer a promising method for assessing patient adherence behavior patterns. The reliability of the Doser Clinical Trials (CT) (Meditrack Products, Hudson, MA), an inexpensive, pressure-actuated device that monitors metered-dose inhaler (MDI) usage, was evaluated in a field study of outpatient pediatric asthmatics. Canister weight and various Doser CT measures of patient medication use were compared to determine the reliability and usefulness of the device. Doser CTs were dispensed to 16 research subjects for use on corticosteroid MDIs over a period of several months. One Doser CT per month was dispensed to each subject. Doser CTs were collected at 30-60 day intervals, with a total of 61 months of Doser CT data obtained across the subjects. MDI canister weights were monitored for a subset of 6 subjects. Usable Doser CT data were summarized and average adherence estimates were computed. Adherence estimates differed from one another and the adherence estimate, as measured by canister weight, was significantly higher than each Doser CT estimate. However, overall, the Doser CT showed adequate reliability as evidenced by high correlations among the Doser CT estimates of adherence and the existing gold standard of canister weight. The Doser CT is likely to be useful for monitoring MDI use in clinical care and research, potentially providing greater accuracy than the standard of canister weight.

Administration, Inhalation↗

Anti-IgE therapy in allergic disease.

PURPOSE OF REVIEW: Recombinant monoclonal humanized anti-IgE has put forward a fundamentally new concept for the control of allergic disorders. This review will present recent data from clinical studies with anti-IgE in asthma, allergic rhinitis, and food allergy and will examine the place of anti-IgE among current therapeutic options for the treatment of asthma. RECENT FINDINGS: Therapy with anti-IgE depresses circulating free IgE to the limits of detection, inhibits early- and late-phase responses to allergens, suppresses inflammation and improves the control of allergic diseases. In moderate to severe asthma it results in fewer exacerbations and a lower requirement for both corticosteroids and beta-agonists. IgE appears to be an important regulator of high-affinity Fc receptors (FcepsilonRI) and, in the mouse, to enhance mast cell survival and activation. IgE receptors have been found on diverse inflammatory cells. Anti-IgE reduces the expression of FcepsilonRI on inflammatory cells. Current work has documented a marked decrease in tissue eosinophils, lymphocytes, and interleukin-4-positive cells by anti-IgE treatment and has provided insight into the mechanisms underlying improved control of asthma. SUMMARY: Clinical studies with anti-IgE have promoted and will continue to advance the understanding of IgE-mediated disease mechanisms. They have documented its efficacy in the treatment of allergic diseases, but much remains to be learned about the most effective clinical strategies and the selection of patients for therapy.

Adolescent↗

Exhaled nitric oxide in children with asthma receiving Xolair (omalizumab), a monoclonal anti-immunoglobulin E antibody.

OBJECTIVE: To evaluate the effect of a humanized monoclonal antibody to immunoglobulin E, omalizumab (Xolair, Novartis Pharmaceuticals, East Hanover, NJ; Genentech Inc, South San Francisco, CA), on airway inflammation in asthma, as indicated by the fractional concentration of exhaled nitric oxide (FE(NO)), a noninvasive marker of airway inflammation. Xolair was approved recently by the US Food and Drug Administration for moderate-to-severe allergic asthma in adolescents and adults. STUDY DESIGN: As an addendum at 2 sites to a randomized, multicenter double-blind, placebo-controlled trial, FE(NO) was assessed in children with allergic asthma over 1 year. There were 3 consecutive study periods: 1) stable dosing of inhaled beclomethasone dipropionate (BDP) when the dose was optimized (period of 16 weeks); 2) inhaled steroid-reduction phase (period of 12 weeks), during which BDP was tapered if subjects remained stable; and 3) open-label extension phase, during which subjects receiving placebo were switched to active omalizumab (period of 24 weeks). The primary outcome was area under the FE(NO) versus time curve (AUC) for adjusted FE(NO), defined as the ratio of FE(NO) at each time point compared with the value at baseline. RESULTS: Twenty-nine subjects participated and were randomized to omalizumab (n = 18) and placebo (n = 11) treatment groups in a 2:1 ratio dictated by the main study. There was a significant difference for age, resulting in a difference in absolute forced expiratory volume in 1 second but no difference in asthma severity based on the forced expiratory volume in 1 second percentage predicted. Baseline BDP dose was comparable between groups, as were baseline values of mean FE(NO) (active: 38.6 +/- 25.6 ppb; placebo: 52.7 +/- 52.9 ppb). The degree of BDP dose reduction during the steroid-reduction and open-label phases was equivalent between the omalizumab and placebo-treated groups; subjects in the omalizumab- and placebo-treated groups had reduced their BDP dose by an average of 51% and 60%, respectively, at the end of the steroid-reduction phase and by 68% and 94%, respectively, by the end of the open-label period. In the active and placebo groups, 44% and 27% and 75% and 73% of subjects had stopped use of inhaled corticosteroids at the end of the steroid-reduction and open-label phases, respectively. There was no significant difference between the active and placebo groups during the steroid-stable phase for AUC of adjusted nitric oxide (1.31 +/- 1.511 vs 1.45 +/- 0.736). However, during the steroid-reduction phase, the variability of adjusted FE(NO) in the placebo-treated group was greater than that of the omalizumab-treated group at most visits, with a significant difference between groups for AUC of adjusted nitric oxide (0.88 +/- 0.69 vs 1.65 +/- 1.06). FE(NO) fell from 82.1 +/- 55.6 ppm at the end of the steroid-reduction phase to 33.3 +/- 21.6 ppb at the end of the open-label period in the placebo group who were placed on active omalizumab. This decrease occurred while the mean dose of BDP remained very low. Analysis of FE(NO) over 52 weeks of omalizumab treatment in the active group demonstrated that there was a significant reduction from baseline to the end of the open-label period (41.9 +/- 29.0 to 18.0 +/- 21.8 ppb) despite a high degree of steroid reduction. CONCLUSION: In this preliminary study based on FE(NO), a noninvasive marker of airway inflammation, treatment with omalizumab may inhibit airway inflammation during steroid reduction in children with allergic asthma. The degree of inhibition of FE(NO) was similar to that seen for inhaled corticosteroids alone, suggesting an antiinflammatory action for this novel therapeutic agent in asthma. This is in keeping with recent evidence that omalizumab inhibits eosinophilic inflammation in induced sputum and endobronchial tissue.

Anti-Asthmatic Agents↗

Managing outpatient asthma exacerbations.

Asthma is a chronic inflammatory disease that renders individuals prone to acute exacerbations. Several allergic and nonallergic triggers can incite an asthma exacerbation. The goals of managing an asthma exacerbation are prompt recognition, rapid reversal of airflow obstruction, prevention of relapses, and forestalling future episodes. A written asthma home-management plan is essential to minimize the severity of exacerbations. Short-acting b-agonists, oxygen, and corticosteroids are fundamental to early intervention in acute asthma exacerbation. Anticholinergics and magnesium sulfate can help nonresponders. Newer agents such as levalbuterol and long-acting b-agonists might be future additions to our armamentarium of drugs to treat acute exacerbations. Initiation or intensification of long-term controller therapy, treatment of co-morbid conditions, and avoidance of possible triggers along with prompt follow-up can help prevent relapses. Listening to patient preferences and concerns to enhance adherence and regular follow-up care can help prevent future episodes.

Acute Disease↗

Adherence intervention research: what have we learned and what do we do next?

Although there is general agreement from studies demonstrating that adherence to inhaled corticosteroid therapy is often inadequate to establish consistent control, relatively little concurrence exists in reports of interventions to correct the problem. Half of the studies reviewed found that the experimental intervention did not change adherence, and behavior change reported by patients was often not accompanied by changes in treatment success. Studies used a variety of methods that differed in quality with findings that were often contradictory. Key limitations in many studies included reliance on inadequate adherence measures, inclusion of convenience samples of well-motivated patients, and assessments of intervention outcomes artificially boosted by attrition of least adherent participants. Research is encouraged into innovative interventions that are brief, easily implemented, and can be tailored to individual patients and diverse clinical settings. Of particular importance is inclusion of hard-to-reach patients, including urban and rural poor and the use of valid measures of adherence at intervals sufficient to establish enduring benefit.

Administration, Inhalation↗

Sedation and performance impairment of diphenhydramine and second-generation antihistamines: a meta-analysis.

BACKGROUND: Antihistamines are among the most frequently used medications in the United States. Despite dramatically higher cost, second-generation antihistamines are replacing diphenhydramine because of the perception that they are not constrained by its sedating effects. OBJECTIVE: We sought to examine, through meta-analytic procedures, the collective evidence regarding the sedating and performance-impairing effects of diphenhydramine relative to placebo and second-generation antihistamines. METHODS: A search that began with the MEDLINE database was limited to those studies that included patients with atopic disease and control subjects, were blinded and randomized clinical trials, objectively examined alertness and psychomotor performance, reported means and variances, and were written in English. Information was systematically abstracted from the resulting 18 articles, and effect size was calculated. RESULTS: Diphenhydramine impaired performance relative to placebo control and second-generation antihistamines, including acrivastine, astemizole, cetirizine, fexofenadine, loratadine, and terfenadine. However, results were quite varied, the average sedating effect of diphenhydramine was modest, and in some instances results of tests of performance in the diphenhydramine group showed less sedation than in the control or second-generation antihistamine groups. A significant (P <.05) average effect size indicated a mild sedating effect caused by second-generation antihistamines in comparison with placebo. CONCLUSION: The absence of a consistent finding of diphenhydramine-induced sedation is surprising given that most studies have been designed to increase the probability of this outcome, including administering a 50-mg dose. On the basis of this meta-analysis of performance-impairment trials, a clear and consistent distinction between sedating and nonsedating antihistamines does not exist.

Diphenhydramine↗

Management of the acute exacerbation of asthma.

All patients with asthma are at risk of having asthma exacerbations characterized by worsening symptoms, airflow obstruction, and an increased requirement for rescue bronchodilators. The goals of managing an asthma exacerbation are prompt recognition and rapid reversal of airflow obstruction to avert relapses and future episodes. Short-acting beta-agonists, oxygen, and corticosteroids form the basis of management of acute asthma exacerbation, but a role is emerging for anticholinergics and newer agents such as levalbuterol and formoterol. Initiation or intensification of long-term controller therapy, treatment of comorbid conditions, avoidance of likely triggers, and timely follow-up care prevent setbacks. Acceptance of current treatment guidelines by physicians and adherence to the recommended clinical regimens by patients are essential for effective management of asthma. The physician should strive to establish a constructive relationship with the patient by addressing the patient's concerns, reaching agreement on the goals of therapy, and developing a written action plan for patient self-management.

Acute Disease↗