Shirley Murphy

Improving Pediatric Dosing Through Pediatric Initiatives: What We Have Learned

OBJECTIVE. The goal was to review the impact of pediatric drug studies, as measured by the improvement in pediatric dosing and other pertinent information captured in the drug labeling. METHODS. We reviewed the pediatric studies for 108 products submitted (July 1998 through October 2005) in response to a Food and Drug Administration written request for pediatric studies, and the subsequent labeling changes. We analyzed the dosing modifications and focused on drug clearance as an important parameter influencing pediatric dosing. RESULTS. The first 108 drugs with new or revised pediatric labeling changes had dosing changes or pharmacokinetic information (n = 23), new safety information (n = 34), information concerning lack of efficacy (n = 19), new pediatric formulations (n = 12), and extended age limits (n = 77). A product might have had ≥1 labeling change. We selected specific examples (n = 16) that illustrate significant differences in pediatric pharmacokinetics. CONCLUSIONS. Critical changes in drug labeling for pediatric patients illustrate that unique pediatric dosing often is necessary, reflecting growth and maturational stages of pediatric patients. These changes provide evidence that pediatric dosing should not be determined by simply applying weight-based calculations to the adult dose. Drug clearance is highly variable in the pediatric population and is not readily predictable on the basis of adult information.

Secretory leukocyte protease inhibitor and lung inflammation in developing bronchopulmonary dysplasia

OBJECTIVE To investigate secretory leukocyte protease inhibitor (SLPI) concentrations in tracheal lavage fluids of neonates with an endotracheal tube in place during the first month of life, and to evaluate the relationship of SLPI to neutrophil counts and elastase activity in patients in whom bronchopulmonary dysplasia (BPD) developed versus those in whom it did not. DESIGN A prospective, inception cohort study. SETTING University childrens hospital neonatal intensive care unit. PATIENTS Fifty-three neonates who weighed < 2000 gm at birth, and who had an endotracheal tube in place, were enrolled. Forth-one patients survived to 28 days; BPD developed in 24 but not in 17 patients. MAIN OUTCOME MEASURES Tracheal lavage was performed on days 1, 2, 4, 7, 14, 21, and 28, and analyzed for neutrophils, elastase activity, and SLPI. Results were evaluated longitudinally for 28 days, and were compared between BPD and no-BPD groups during the first week. RESULTS SLPI concentrations increased significantly for all patients during the study period. During the first week, SLPI concentrations were similar between BPD and no-BPD groups; neutrophil counts and elastase activity were higher in the BPD group. CONCLUSIONS Patients in whom BPD ultimately developed had early evidence of increased pulmonary inflammation and a significantly less favorable protease-antiprotease balance. If elastase-induced injury contributes to the development of BPD, early therapy with recombinant SLPI might be beneficial by increasing the antielastase capacity of epithelial lining fluid.

The natural history of asthma

Our understanding of the natural history of asthma is improving through the establishment of a more precise definition of asthma linked with information from large-scale longitudinal studies. Risk factors for the development of childhood asthma including sex, atopic status, genetic and familial factors, respiratory infections, and outdoor and indoor pollution are now more clearly understood. New information on the relation of viral wheezing episodes in infancy to later childhood asthma is evolving. We now know that children who start wheezing early in life and continue to wheeze at age 6 years are more likely to have a maternal history of asthma, elevated serum IgE levels, and normal lung function in the first year of life. However, at age 6 years they have both elevated serum IgE levels and diminished lung function. Approximately 50% of adults who report having had childhood asthma no longer have symptoms. Airway responsiveness in childhood tends to predict airway responsiveness in adulthood and to be greater in asthmatics with persistent symptoms. Studies of the natural history of asthma support the hypothesis that early therapeutic intervention in mild disease may lead to an improved clinical outcome. Adults exposed to specific occupational environments are at additional risk for the development of asthma. As we learn more about the natural history of asthma, we will have a better understanding of the effect of early diagnosis, environmental control, and therapy on the outcome of the disease.

Beta-Adrenergic Agonists for Acute, Severe Asthma

OBJECTIVE: To critically review the use of beta-adrenergic agonists in acute, severe asthma with particular focus on aerosol administration. DATA SOURCES: English language articles published since 1971 on the use of beta-agonists for acute asthma. Studies were identified from bibliographies of book chapters, review articles, and other research articles. STUDY SELECTION: All studies (21 total) comparing systemic with inhaled beta-agonists were reviewed, regardless of their design or outcome. Selected studies highlighting specific aspects of beta-agonist use in acute asthma such as beta-agonists versus other bronchodilators, aerosol delivery, and intravenous beta-agonists were also reviewed. DATA EXTRACTION: Performed subjectively by the authors with specific aspects of quality discussed within the body of the article. DATA SYNTHESIS: The beta-agonists provide superior bronchodilation in acute severe asthma compared with either the methylxanthines and/or anticholinergics. The majority of studies found aerosolized beta-agonists to be either as effective as or more effective than parenteral beta-agonists and to produce fewer adverse cardiovascular effects. Studies showing preference for parenteral therapy have either been of poor design or used low doses of an aerosolized beta-agonist. Based on studies of aerosol delivery, there is no advantage of jet nebulization over metered-dose inhalers; however, other aspects, including ease of administration, favor nebulization as the delivery method of choice. The articles recommending intravenous beta-agonists consist of a series of uncontrolled cases. CONCLUSIONS: Aerosolized selective beta2-agonists are the bronchodilator treatments of choice for acute, severe asthma. Attention to the details of dosing and delivery are required for optimal results. The final dose and dosing interval are determined by the patients response. Intravenous beta-agonists are hazardous and cannot be recommended.

Cromolyn Sodium: A Review of Mechanisms and Clinical Use in Asthma

The cellular and clinical pharmacology of cromolyn sodium are reviewed. Cromolyn sodium inhibits the release of mediators of inflammation, induced by specific antigens as well as nonspecific mechanisms, such as exercise, from mast cells. Cromolyn may also inhibit the activity of other cell types that produce inflammation. It is the only antiasthmatic that blocks both early and late asthmatic responses induced by allergen inhalation and exercise. Consequently, cromolyn therapy can block the increase in bronchial hyperreactivity induced by chronic allergen exposure. Cromolyn is effective for controlling the symptoms of mild to moderate chronic asthma in 60 to 70 percent of patients. In comparative studies, cromolyn has been as effective as theophylline for controlling symptoms of chronic asthma with fewer side effects, and may be particularly suited for asthmatic patients with learning or behavioral problems. The combination of theophylline and cromolyn is often more effective than either agent alone. Because of the convenience of administration, cromolyn is preferred over theophylline for exercise-induced asthma. Cromolyn may allow the corticosteroid dosage to be reduced in severe steroid-dependent asthmatics, but it is primarily indicated for the prophylaxis of mild to moderate disease. Adverse reactions to cromolyn are uncommon to rare. Cromolyn is now available in a Spinhaler, a metered-dose aerosol, and a nebulizer solution. If taken properly all preparations appear to be equally effective. Attention to proper inhalation technique and appropriate education of the patient is essential to ensure a good outcome with cromolyn.

GENE ENRICHMENT IN AN AMERICAN INDIAN POPULATION: AN EXCESS OF SEVERE COMBINED IMMUNODEFICIENCY DISEASE

A subgroup of Athabascan Indians in Arizona and New Mexico was found to have an unusually high incidence of severe combined immunodeficiency, probably due to founder effect. Closed genetic pressures have limited their histocompatibility-antigen heterogeneity, enabling 3 patients to be grafted, 2 of them across HLA-B locus barriers.

Intralobar pulmonary sequestration: A clinical and pathological spectrum

Pulmonary sequestration is a mass of abnormal pulmonary tissue that does not communicate with the tracheobronchial tree and is supplied by an anomalous systemic artery. Whereas extralobar sequestration is clearly congenital, intralobar sequestration, which frequently presents in older children with pathological findings showing acute and chronic inflammation, may have an acquired origin secondary to frequent infections. Several large autopsy series support an acquired etiology of intralobar sequestration. Four cases of intralobar sequestration are presented that demonstrate a spectrum of inflammatory change that support its congenital, rather than acquired origin. Case 1 was a newborn who presented with tachypnea and a right lower lobe density. Resection at 3 weeks of age showed no inflammation in the sequestration specimen. Case 2 presented as a newborn infant with congestive heart failure. Pulmonary sequestration was confirmed by arteriogram. Resection at 3 months of age showed chronic inflammation. Case 3 presented at 7 months of age with chronic pneumonia. The resected specimen demonstrated moderately severe acute and chronic inflammation. Case 4 presented as a 6 year old. The operative specimen showed extensive bronchiectatic changes with marked acute and chronic inflammation. These cases support the congenital origin of intralobar sequestration and suggest a temporal progression from no inflammation to severe acute and chronic inflammation.

Immune-complex-mediated glomerulonephritis and pulmonary hemorrhage simulating Goodpasture syndrome

Two female children whose clinical presentations and renal light-microscopic findings were consistent with Goodpasture syndrome are described. Immunopathologic studies demonstrated granular deposition of immunoglobulins and complement, suggesting that the renal disease was mediated by circulating immune complexes and not by anti-glomerular basement membrane antibody. Anti-GBM antibody was absent in both patients. These patients represent the first report in children of idiopathic nephritis due to immune complexes with associated pulmonary hemorrhage. The findings raise some doubt as to the accuracy of previous reports of Goodpasture syndrome in children, and also demonstrate the diagnostic and therapeutic importance of evaluation the renal immunopathology in the child with nephritis and pulmonary hemorrhage.

Corticosteroids for Acute, Severe Asthma

Corticosteroids have been used in the therapy of acute, severe asthma since the early 1950s. Numerous randomized, double-blind, placebo-controlled trials in adults and children have proven corticosteroids to be efficacious. Only the results from less rigorously designed trials have failed to show a beneficial effect. The onset of response, dose, and mode of administration have been relatively well defined; however, other aspects (i.e., duration of therapy, need to taper the dose, and risks of multiple short bursts) require further study. Early institution of corticosteroids in well-defined patient populations will decrease the need for hospitalizations. However, administration of corticosteroids to every patient presenting to the clinicians office or emergency room prior to aggressive bronchodilator therapy is unwarranted. All patients demonstrating an incomplete response or the inability to maintain a complete response following one to two hours of aggressive bronchodilator therapy should receive a course of corticosteroids. Courses as short as three to five days have proven efficacy in outpatients, whereas hospitalized patients usually are treated for seven to ten days. The duration of therapy depends on the individual rate of response.

Should Anticholinergics Be Used in Acute Severe Asthma

Anticholinergic drugs have been used in Western medicine for the treatment of asthma since the early 19th century. Studies evaluating drug efficacy in acute severe asthma over the last decade have renewed interest in the optimal use of anticholinergics in this condition. Unlike other bronchodilators (i.e., beta2-agonists and methylxanthines), the anticholinergics produce bronchodilation only by inhibiting cholinergic-mediated bronchospasm. Therefore, anticholinergic drugs are more dependent on the mechanism of bronchospasm than other bronchodilators. The 18 clinical trials of anticholinergics in acute severe asthma are critically reviewed for design and endpoint measurements. Anticholinergics alone produce a modest bronchodilation in acute severe asthma but are not as consistently effective as beta2-agonists. Anticholinergics consistently produce an added bronchodilation to aerosolized beta2-agonists in single- and multiple-dose studies. This bronchodilation appears to be greater in the more severely obstructed patients. This bronchodilation is generally modest (10–20 percent), has not yet been shown to produce greater overall outcome, and has not been evaluated against high-dose frequent administration of aerosolized beta2-agonists. Currently, only the quaternary amine derivatives are recommended for use in acute asthma. These agents should be reserved as second-line agents for acute severe asthma except possibly for those patients presenting with more severe obstruction (peak expiratory flow rate <35 percent of predicted).