Troleandomycin as an oral corticosteroid steroid sparing agent in stable asthma.

BACKGROUND: Patients with chronic severe asthma are often dependent on the long term prescription of oral corticosteroids. The use of steroids is associated with serious side effects. Physicians treating such patients continue to search for alternative therapies that reduce the need for chronic dosing with oral steroids. troleandomycin is a compound that is established as an effective antibiotic but may also have non antibacterial actions that may be useful in the treatment of asthma. OBJECTIVES: The objective of this review was to assess the effects of adding troleandomycin to oral steroids in the treatment of chronic steroid dependent asthmatics. SEARCH STRATEGY: The Cochrane Airways Group trials register and reference lists of identified articles were searched. SELECTION CRITERIA: Randomised trials looking at the addition of troleandomycin compared to placebo in adult steroid dependent asthmatics. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data extraction was carried out by two reviewers independently. Study authors were contacted for missing information. MAIN RESULTS: Three trials fulfilled the criteria for inclusion in the review and a total of 112 patients were recruited into these studies. Data from 90 patients were analysed. There was no treatment effect for troleandomycin in terms of steroid dose reduction (SMD -0.29, 95% CI -0.75, 0.17). For measures of lung function a meta-analysis of data derived from two of the included studies showed no benefits for added troleandomycin (SMD 0.06 95% CI -0.8, 0.9). REVIEWER'S CONCLUSIONS: There is insufficient evidence to support the use of troleandomycin in the treatment of steroid dependent asthma.

Potential role of macrolides in the treatment of asthma.

A body of evidence highlights the fact that macrolides may not only enhance the host defence system through increased cytokine synthesis by host cells but also exhibit anti-inflammatory activity by including anti-inflammatory cytokines. Several authors have stressed the possibility that macrolides are useful in the treatment of asthma because of their antimicrobial activity rather than any anti-inflammatory action. However, the mechanism of action of macrolides in improving asthma and reducing airway responsiveness is speculated not to be due to their antibiotic properties, especially when these agents are active in noninfectious asthma. The steroid-sparing effect of macrolide antibiotics has been postulated to contribute to their beneficial actions in the treatment of asthma. Nevertheless, a number of studies have shown that macrolides antibiotics have an anti-inflammatory effect which is independent of their antibiotic action or any influence on corticosteroid metabolism. Macrolides may be useful in the treatment of patients with steroid-dependent asthma, probably because they inhibit eosinophilic inflammation. It has also been suggested that the effect of macrolides on bronchial hyperresponsiveness is mediated by their inhibitory action on superoxide production and chemotaxis of polymorphonuclear neutrophils and the mixed lymphocyte reaction. In any case, it is clear that the mechanism of action of macrolides in asthmatic syndrome is not unequivocal. Only well-designed and -conducted clinical studies are capable of assessing the efficacy and safety of immunosuppressive macrolides in the treatment of asthma.

Alternative treatments in the patient with intractable asthma.

Various medications have been suggested as alternative therapy for oral corticosteroids in the treatment of asthma, due to the known adverse effects of oral corticosteroids. Examples of such medications include methotrexate, gold, cyclosporin A, hydroxychloroquine, and dapsone, all of which have a significant side-effect profile. Intravenous gammaglobulin therapy used as an immuno-modulator has little if any side-effects, but it is very costly. The antileukotrienes represent a safe class of medications that may be of particular benefit to certain subgroups of asthmatic patients. Antileukotrienes have become commercially available in other countries.

Use of terfenadine and contraindicated drugs.

OBJECTIVE: To assess changes in concurrent use of products containing terfenadine and contraindicated macrolide antibiotics (erythromycin, clarithromycin, troleandomycin) and imidazole antifungals (ketoconazole, itraconazole) following reports of serious drug-drug interactions and changes in product labeling. DESIGN: Retrospective review of computerized pharmacy claims. SETTING: A large health insurer in New England. PATIENTS: Health plan members with 1 or more paid pharmacy claims for products containing terfenadine between January 1990 and June 1994. MAIN OUTCOME MEASURES: Among persons with paid claims for terfenadine in any given month, percentage with a prescription for any contraindicated drug that alternatively was dispensed on the same day as ("same-day dispensing") or had therapy days that overlapped those of ("overlapping use") a prescription for terfenadine. RESULTS: Concurrent use of terfenadine and contraindicated drugs declined over the study period. The rate of same-day dispensing declined by 84% from an average of 2.5 per 100 persons receiving terfenadine in 1990 to 0.4 per 100 persons during the first 6 months of 1994, while the rate of overlapping use declined by 57% (from 5.4 to 2.3 per 100 persons). Most cases involved erythromycin. CONCLUSIONS: Despite substantial declines following reports of serious drug-drug interactions and changes in product labeling, concurrent use of terfenadine and contraindicated macrolide antibiotics and imidazole antifungals continues to occur.

Immunosuppressive therapy for asthma.

Over the last four or five years, there have been some serious attempts to look for alternatives to corticosteroids in the management of severe bronchial asthma. Rheumatologists and dermatologists long ago recognized the importance of replacing corticosteroids with other agents. Some agents such as methotrexate are now clearly established through multiple double-blind trials as being appropriate substitutes for corticosteroids, whereas other agents which have been investigated, such as cyclosporin, are very promising. Finally, a third group of agents, including troleandomycin (TAO), have been found to be totally inappropriate as possible substitutes for corticosteroids.

Troleandomycin in the treatment of difficult asthma.

BACKGROUND: For difficult asthma, treatment is aimed at improving airway obstruction and minimizing adverse effects of systemic corticosteroids. The combination of troleandomycin (TAO) with methylprednisolone (MP) reportedly has a beneficial steroid-sparing effect on difficult asthma. METHODS: To test the steroid-sparing effect of TAO, 14 subjects with severe corticosteroid-dependent asthma were studied before and during treatment with MP and TAO. RESULTS: Treatment with MP and TAO resulted in a clear reduction in respiratory symptoms, asthmatic attacks, corticosteroid and hospitalization requirements, improvement in pulmonary function tests, and a remarkable decrease in peak expiratory flow rate circadian variability when compared with the period before TAO treatment (with corticosteroids). Treatment with MP and TAO was fairly well tolerated. Only a reduction (-5.2%, p < 0.01) in bone mineral content and an increase in plasma glucose levels (from 81.7 to 94.3 mg/dl, p < 0.05) were found, in comparison with pre-TAO values. One subject discontinued MP-TAO treatment because of a mild but persistent increase in serum alanine aminotransferase. In an evaluation of the clinical and pulmonary function test results, eight of the 14 subjects were responders and six were nonresponders. During follow-up three subjects discontinued TAO and consequently had an asthmatic attack after 4, 7, or 15 days, respectively. CONCLUSIONS: This study confirms that treatment with MP and TAO has a beneficial effect in a subgroup of severely steroid-dependent asthma patients.

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.

Unconventional approaches to drug therapy in severe asthma.

Asthma is now considered as an inflammatory disease. A subset of severe asthmatic patients requires large doses of daily systemic steroids to achieve some control of the inflammation of the airways. To minimize the daily absorption of glucocorticoids, a number of medicaments have been studied for the last three decades. Methotrexate, dapsone, hydroxychloroquine, ciclosporine A, gold salts, intravenous gammaglobulins, ketotifen, triacetyloleandomycin, all demonstrated some positive effects in a small number of studies. However, our impression is that most "steroid-sparing" medications are either poorly effective in large series and/or have intolerable side effects in these chronically ill patients; many are very expensive. A revised, adjusted therapeutic strategy, using currently recommended anti-asthmatic drugs, making a major use of inhaled topical corticosteroids, should limit the number of "cortico-dependent" asthmatic patients.

A double-blind study of troleandomycin and methylprednisolone in asthmatic subjects who require daily corticosteroids.

A group of 75 subjects with asthma requiring daily corticosteroids for control were enrolled in a 2-yr, double-blind, placebo-controlled study of the use of troleandomycin combined with methylprednisolone, compared with methylprednisolone alone, for the management of their asthma. The primary outcome variables were determination of the lowest stable methylprednisolone dose and assessment of corticosteroid side effects. Methylprednisolone dose was adjusted to maintain optimal control of asthma symptoms. A total of 30 patients receiving TAO and 27 patients receiving placebo completed 1 yr; 17 on TAO and 8 on placebo completed 2 yr of double-blind participation. Control of asthma was equivalent in both groups. The vast majority of patients in both groups achieved alternate-day dosing (29 of 30 on TAO and 23 of 27 on placebo in the first year). The lowest stable doses of methylprednisolone achieved were 10.4 mg/day (placebo) versus 6.3 mg/day (TAO) in the 1-yr group (p = 0.03). However, the baseline dose was also significantly higher in the placebo group (22.8 versus 17.6 mg/day in the TAO group). Therefore, the reductions in methylprednisolone dose were not significantly different between treatment groups. Differences were observed between the two treatment groups in serum IgG, fasting blood sugar, serum cholesterol, and progression of osteoporosis. In each instance the more unfavorable response occurred in those subjects receiving TAO. We conclude that the addition of TAO to methylprednisolone was not accompanied by a reduction in corticosteroid side effects compared with treatment with methylprednisolone alone. Furthermore, no evidence was found for a subset of "TAO responders."(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of urinary 6-beta-cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity.

The production of 14CO2 in the breath from an intravenous dose of [14C-N-methyl]-erythromycin (the erythromycin breath test [ERMBT]) and the measurement of the ratio of 6-beta-cortisol to free cortisol (6-beta-F/FF) in the urine have each been proposed as means of measuring hepatic P450IIIA catalytic activity in patients. We found that there was a significant correlation between the results of each test (r = 0.59, p less than 0.001) in 47 patients who were without liver disease and who were not taking medications believed to influence P450IIIA catalytic activity. In the 24 of these patients who were subsequently treated with the P450IIIA substrate cyclosporine, the ERMBT result was highly correlated with the mean trough cyclosporine blood level observed; however, there was no correlation between urinary 6-beta-F/FF and the cyclosporine blood levels. In a separate study of a patient during the anhepatic phase of liver transplantation surgery, the ERMBT result decreased by greater than 85%, whereas urinary 6-beta-F/FF decreased by just 50%. We conclude that the ERMBT and urinary 6-beta-F/FF do not always provide similar information about P450IIIA catalytic activity in patients, possibly because of extrahepatic production of 6-beta-F. Of the two tests, the ERMBT appears to provide the most relevant information for cyclosporine administration.

Anti-inflammatory drugs in the treatment of allergic disease.

The treatment of asthma is undergoing significant change with an emphasis on anti-inflammatory therapy. While glucocorticoids are the most potent anti-inflammatory agent, certain patients fail to respond. These patients may be candidates for alternative anti-inflammatory therapy, such as troleandomycin, methotrexate, gold, hydroxychloroquine, or dapsone. In addition, the application of immunomodulator therapy, such as intravenous gamma globulin or cyclosporine, may be useful.

Effect of low-dose troleandomycin on theophylline clearance: implications for therapeutic drug monitoring.

Troleandomycin (TAO) is an alternative agent used in the treatment of severe, steroid-requiring asthma. Its mechanism of action, once thought to be inhibition of theophylline clearance, remains unclear. Twenty-four-hour theophylline profiles were obtained in 11 children with severe asthma prior to and after 2 and 12 weeks of low-dose TAO therapy. Theophylline dosages were adjusted by blinded investigators to maintain serum theophylline concentrations (STCs) between 10 and 20 micrograms/ml. Dosages were decreased from 877 +/- 60 mg/day (mean +/- SEM) before TAO to 811 +/- 56 mg/day (NS) after 2 weeks and 764 +/- 56 mg/day (p less than 0.05) after 12 weeks. Because of the dosage adjustments, STCs did not increase significantly. Theophylline clearance was reduced from 65.7 +/- 9.8 ml/kg/hour at baseline to 50.2 +/- 4.1 ml/kg/hour (p less than 0.05) after 2 weeks and 50.1 +/- 6.2 ml/kg/hour (p less than 0.05) after 12 weeks of TAO therapy. We conclude that TAO can significantly reduce theophylline clearance, resulting in increased STCs if dosages are not titrated. We recommend an empiric 25% reduction of daily theophylline dose with the initiation of TAO. We also recommend monitoring STCs 4 hours after the morning dose (with twice-daily dosing of sustained-release products) after 3, 7, 14, and 30 days of TAO therapy, then periodically as indicated.

Brief report: therapeutic manipulations in severe nocturnal asthma. A nonconventional approach in a severe high-risk asthmatic.

A patient with severe nocturnal asthma of multifactorial pathogenesis with high-risk features leading to several episodes of nocturnal respiratory arrests is described. Despite aggressive conventional therapy with bronchodilators and glucocorticoid agents, the patient had progressive worsening within the year prior to admission. After a nonconventional approach consisting of: high-dose inhaled steroids, afternoon dose of prednisone, addition of troleandomycin therapy, high-dose inhaled ipratropium at bedtime, maximizing serum theophylline concentrations in the early morning, and nasal CPAP through the night; the patient's pulmonary functions were optimized with minimal or no reduction in morning FEV1, and decreased airways hyperresponsiveness to methacholine.

Use of TAO without methylprednisolone in the treatment of severe asthma.

The antimicrobial agent troleandomycin (TAO) has been shown to be effective in reducing corticosteroid requirements in patients with corticosteroid-dependent asthma. To our knowledge, the efficacy of TAO without concomitant use of corticosteroids has never been documented. We report the case of a 12-year-old patient with corticosteroid-dependent asthma who has remained asymptomatic and without any evidence of pulmonary deterioration during treatment with TAO without concomitant use of corticosteroids.

Use of troleandomycin as a steroid-sparing agent in both asthma and chronic obstructive pulmonary disease.

Troleandomycin has been reported to be useful for reducing the steroid requirement of patients with asthma. The purpose of this study was to evaluate the usefulness of troleandomycin in treating patients with steroid-dependent asthma as well as in patients with steroid-dependent chronic obstructive pulmonary disease (COPD). Twelve patients with obstructive airway disease were studied; 6 patients had a diagnosis of asthma, and 6 patients had COPD. All had failed previous attempts to reduce their dosage of steroids. Among the patients with asthma, it was possible to taper methylprednisolone dosage from 29.3 +/- 21.8 mg to 11.1 +/- 7.4 11.1 mg (P less than .05). In the group with COPD there was also a significant decrease in steroid dosage--from 22.6 +/- 12.2 to 6.0 +/- 4.5 mg. These changes were not associated with a decline in spirometric values; nor was improvement secondary to improved theophylline levels, as demonstrated by a significant decrease in serum theophylline levels from 12.4 +/- 3.6 mg/dL baseline to 8.5 +/- 2.8 mg/dL (P less than .001) after maximal steroid tapering. We conclude that troleandomycin is effective in reducing the steroid dosage in patients with COPD or asthma.