Alan K. Kamada

Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma

BACKGROUND Troleandomycin (TAO), a macrolide antibiotic, was studied as an alternative treatment in 18 children with severe, steroid-requiring asthma. METHODS In this investigation three treatment arms were used in randomized, double-blind, parallel fashion: combination TAO and methylprednisolone (MPn), combination TAO and prednisone, and MPn alone. RESULTS All groups tolerated a considerable reduction in glucocorticoid dose over the 12 weeks of the study: 80% +/- 6% for TAO-MPn, 55% +/- 8% for TAO-prednisone, and 44% +/- 14% for MPn alone. These reductions are all statistically significant (p < 0.05) within groups, and the differences between groups were statistically significant between the TAO-MPn and MPn alone groups. The concentration of methacholine required to induce a 20% decrease in forced expiratory volume in 1 second and pulmonary function were not significantly improved in any treatment group. Safety parameters including blood chemistry and hematology, adrenal function assessment; bone densitometry, and muscle strength testing, were not altered significantly. Two patients who received TAO had elevated liver enzyme levels; one required discontinuation of TAO and one experienced spontaneous resolution without intervention. Lack of statistically significant changes in the efficacy parameters were likely a result of small sample size and effects of the glucocorticoid dose taper. CONCLUSIONS TAO is safe and may be a reasonable treatment alternative in a limited trial for patients who are unable to tolerate tapering of their glucocorticoid dosage. Therapy should be guided by the goal of treatment, that is, glucocorticoid dose reduction or improvement of pulmonary function with appropriate monitoring of pulmonary function and adverse effects.

Zileuton: The First 5-Lipoxygenase Inhibitor for the Treatment of Asthma

OBJECTIVE: To introduce and review zileuton, an orally active 5-lipoxygenase inhibitor that represents the first of a new class of medications to be used in the treatment of asthma. DATA SOURCES: A MEDLINE search (from 1966 to December 1995) was performed to identify pertinent English-language literature. STUDY SELECTION: Basic science studies on the pharmacokinetics of zileuton, its pathophysiologic effects on asthma, and clinical efficacy trials were reviewed. DATA EXTRACTION: Clinical trials were emphasized. Studies from ex vivo or animal models of pharmacologic and pharmacodynamic effects were considered for review where no in vivo human data were available. DATA SYNTHESIS: Zileuton has shown the ability to attenuate induced bronchospasm, produce some degree of bronchodilation, and provide antiinflammatory or steroid-sparing effects with both single doses (800 mg) and chronic treatment (400 and 600 mg qid). Zileuton has been studied in patients requiring daily inhaled beta-adrenergic agonist treatment; however, data from pediatric populations and comparisons with other asthma medications are limited at this time. Adverse effects include dyspepsia and elevated liver enzymes (incidence ∼3%). One case of jaundice has been reported among the more than 5000 patients treated with zileuton. There is also some concern for drug interactions with hepatically cleared medications, such as theophylline. CONCLUSIONS: Zileuton represents the first drug of a new treatment category for asthma, the 5-lipoxygenase inhibitors. Some people with asthma may receive considerable benefit, but as it is an entirely new drug entity, zileutons final place in the hierarchy of asthma medications remains to be determined.

Glucocorticoids and growth in asthmatic children.

The effects of asthma and oral and inhaled glucocorticoid therapy on growth in children are reviewed. Previous reports have shown that asthma itself may delay the onset of puberty, an effect which may masquerade as growth suppression. Oral glucocorticoids appear to impair growth; however, lower doses and alternate‐day therapy may have less risk of this effect. While a controversial topic, inhaled glucocorticoids in lower doses appear to be associated with a small risk of adverse effects on growth. Minimal data are available for higher doses. Knemometry, a relatively new technique used for measuring small changes in growth, has detected short‐term effects with both oral and inhaled glucocorticoids therapy. However, a number of limitations are associated with short‐term growth studies. Clinicians should be aware of the potential for growth impairment with glucocorticoid therapy so adequate monitoring can be undertaken and appropriate intervention introduced when deemed necessary.

High-dose systemic glucocorticoid therapy in the treatment of severe asthma: A case of resistance and patterns of response

At some frequent interval, perhaps once a month, REFERENCES these would be reported to a central data collection 1. Yunginger JW. Sweeney KG. Stumer WQ. ct ,jl. Fatal i’ood center. Of course it would be ideal if each patient induced anaphylaxis. JAMA 1988;260: 1450-2 could be evaluated to determine if a food (and which 2. Sampson HA. Mendelson L, Rosen JP. Patal and trear-fatal food food) was actually responsible for the symptoms, but anaphylaxis reactions in children. N Engl J 2lcd 1992327:

Coexistence of glucocorticoid receptor and pharmacokinetic abnormalities: Factors that contribute to a poor response to treatment with glucocorticoids in children with asthma

Rapid glucocorticoid clearance and abnormal glucocorticoid receptor binding have been described as factors that contribute to an inadequate response to treatment with glucocorticoids in patients with asthma. We report the coexistence of these abnormalities in children with severe asthma who respond poorly to systemic glucocorticoid therapy.

Therapeutic Controversies in the Treatment of Asthma

OBJECTIVE: To introduce readers to the current controversial topics in the area of asthma therapy. Background is provided such that clinicians are aware of these issues and can make rational decisions. DATA SOURCES: Pertinent articles were individually identified and reviewed from each journal. STUDY SELECTION: Relevant studies, determined by topic and other specific criteria, e.g., testing methodology, were included. DATA SYNTHESIS: Further investigation is required in the areas discussed. Systemic effects, specifically growth suppression (in children), adrenal suppression, and osteoporosis, have been demonstrated with high-dose inhaled glucocorticoids; however, the clinical relevance of such intravenous glucocorticoid formulations via nebulizer have not been demonstrated. Likewise, data on the equivalence of the inhaled glucocorticoids, with regard to efficacy and potential systemic effects, and the differences between metered-dose inhalers and dry powder inhalers, with regard to aerosol characteristics and drug delivery, are unclear. Theophylline, when used with inhaled β-adrenergic agonists and systemic glucocorticoids for the treatment of acute asthma, as not been shown to provide clear benefit and may result in increased adverse effects. The use of regular (vs. “as needed” or prn) inhaled β-adrenergic agonists, although shown in two studies to be detrimental to the control of asthma and result in an increased risk of death or near death caused by asthma, has not been conclusively demonstrated to be harmful. CONCLUSIONS: Monitoring for adverse effects and the use of techniques to minimize systemic absorption (spacers and mouth rinsing) are recommended when high-dose inhaled glucocorticoid therapy is used. Intranasal and intravenous glucocorticoid products are not recommended for administration via nebulizer because of safety concerns. Until further data are available, inhaled glucocorticoids are thought to be equivalent on a μg-per-μg basis rather than an actuation-per-actuation basis. Theophylline is no longer recommended for treatment of acute exacerbations in nonhospitalized patients not already receiving the medication, and the link between deterioration of asthma control (and the risk for death) and regular inhaled beta-adrenergic agonists appears weak.

The safety of inhaled corticosteroid therapy in children.

Although discussed for many years, systemic adverse effects from inhaled corticosteroid therapy remains a complicated and controversial topic. It is by now well-known that inhaled corticosteroids may affect growth, bone, and adrenal function, yet the clinical relevance and the risks for such adverse effects are poorly defined. Earlier intervention, use of higher doses, differing potency claims, and new inhalers also affect the potential for systemic effects following inhaled administration. Until further research better characterizes these risks and identifies appropriate monitoring, caution in the use of this highly effective therapy is advised.

Pathogenesis of Asthma: Therapeutic Implications

The current knowledge of asthma, specifically an appreciation of the contributing mechanisms leading to its development as well as its clinical features, has increased vastly in recent years. A better understanding of asthmas inflammatory nature has resulted in wider use of antiinflammatory agents. Specific effects of available antiasthma medications have been better elucidated, thereby helping to focus the development of newer drugs and improve the use of currently available therapeutic agents. The purpose of this article is to further understanding of asthma by providing the pathologic and physiologic basis of this disease. This is vitally important information as it is shaping the directions of the therapeutic approach to asthma care.

Salmeterol: Its Place in Asthma Management

SALMETEROLXINAFOATE (Serevent, Allen and Hanburys) is an inhaled beta-adrenergic agonist approved for mainte-nance asthma therapy in adults and children older than 12 years of age. The recommended dose is two inhalations (42 μg) twice daily. Its adverse effect profile is similar to that of albuterol; however, salmeterol has a prolonged, 12-hour duration of action. It may also have activity as an antiinflammatory agent, which may be beneficial in the treatment of asthma; however, the clinical relevance of these potential effects remains to be elucidated. As a new therapeutic agent for the treatment of asthma, its place in the hierarchy of asthma therapies is currently undefined and a number ofquestions may arise regarding its use.