The role of antileukotrienes in the treatment of asthma.

OBJECTIVE: This article reviews the literature on the role of antileukotrienes (anti-LTs), specifically montelukast, zafirlukast, and zileuton, in the treatment of asthma. DATA SOURCES: Relevant and appropriate controlled clinical studies were used. Only literature in the English language was reviewed. STUDY SELECTION: Material was taken from academic/scholarly journals, appropriate reviews, and published abstracts. RESULTS: In guidelines established by the National Asthma Education and Prevention Program and the National Heart, Lung, and Blood Institute, a stepwise approach to asthma management is recommended, with recommendations varying depending on degree of disease severity. The anti-LTs, the newest class of drugs for the treatment of asthma, play a circumscribed role in the guidelines as they were only recently available when the latest guidelines were published. Subsequently, however, extensive clinical experience with the anti-LTs has been amassed. Multiple clinical studies have demonstrated that the anti-LTs improve pulmonary function and quality of life, and reduce asthma symptoms, asthma exacerbations, and use of beta2-agonists and oral steroids. The anti-LTs may be particularly useful in asthma patients with aspirin sensitivity or concomitant allergic rhinitis, as well as in pediatric patients. These agents have additive effects with inhaled corticosteroids and may permit a reduction in inhaled corticosteroid dosages. CONCLUSIONS: The anti-LTs have several features that are likey to promote adherence to treatment and are generally well tolerated. The available clinical data suggest that anti-LTs should be considered as a therapeutic option or as additive therapy in patients with mild to severe asthma.

Effect of age on response to zafirlukast in patients with asthma in the Accolate Clinical Experience and Pharmacoepidemiology Trial (ACCEPT).

BACKGROUND: The Accolate Clinical Experience and Pharmacoepidemiology Trial (ACCEPT), evaluated zafirlukast in a wide spectrum of patients from a variety of clinical practices. OBJECTIVE: To determine the effect of age on the response to zafirlukast 20 mg twice daily in 3759 patients with mild, moderate, or severe asthma. METHODS: Patients received open-label administration of zafirlukast 20 mg twice daily (bid) for 4 weeks. Pulmonary function was measured twice daily, and overall asthma symptom scores, number of nighttime awakenings, severity of morning asthma symptoms, and beta2-agonist use were recorded daily. Trial results were analyzed to compare the efficacy of zafirlukast in 263 adolescent (12 to 17 years old), 2602 adult (18 to 65 years old), and 321 elderly (66 years old and older) patients (the evaluable population). RESULTS: After 4 weeks of zafirlukast therapy, improvements in pulmonary function decreased with age and were significant for all measures in adolescents and adults and for morning peak expiratory flow in elderly patients. Improvements in symptom response were statistically significant across age groups. Reduction in beta2-agonist rescue was similar in adolescents and adults but significantly less in elderly patients. CONCLUSIONS: Zafirlukast is an effective treatment for asthma in all patients, regardless of age. In elderly patients, improvement in asthma symptoms rather than pulmonary function may represent a primary marker for efficacy with zafirlukast.

Dose-proportional pharmacokinetics of budesonide inhaled via Turbuhaler.

AIMS: The present pharmacokinetic study was undertaken to determine the dose proportionality of three different doses of budesonide-400 microg, 800 microg or 1600 microg administered twice daily by a dry-powder inhaler (Turbuhaler ) in adult patients with mild asthma. METHODS: A total of 38 patients received budesonide by inhalation, 13 received 400 microg twice daily, 12 received 800 microg twice daily and 13 received 1600 microg twice daily. Mean FEV1 at inclusion was 3.4, 4.0 and 3.9 l min-1 in the three groups, respectively. Blood samples were taken after a single dose, and after 3 weeks of daily treatment, for pharmacokinetic evaluation. Plasma concentrations of budesonide were determined by liquid chromatography plus mass spectrometry. RESULTS: Eleven evaluable patients remained in each dose group. Mean time to peak budesonide plasma concentration (tmax ) was short (0.28-0.40 h) and did not differ between treatment groups. Budesonide concentrations declined rapidly thereafter, indicating efficient pulmonary absorption and rapid elimination with a half-life of approximately 3 h. Cmax was 1. 4(2.0) nmol l-1 (single (repeated) doses), 2.6(3.6) nmol l-1 and 5. 4(6.4) nmol l-1 after 400, 800 and 1600 microg twice daily, respectively. The corresponding results for the area under the plasma concentration vs time curve (AUC) were 271(325), 490(628) and 915(1096) nmol l-1 min. Ninety percent confidence intervals for pairwise dose-normalized Cmax and AUC comparisons between groups were large but contained unity in all cases, thus indicating dose-proportional pharmacokinetics. Regression on analysis supported these findings. Mean AUC after repeated doses (AUC(0,12 h,RD)) was on average 23% higher than the mean AUC after single doses (AUC(0, infinity,SD)(P=0.04) with no significant differences between doses, indicating slight accumulation following bid dosing. CONCLUSIONS: In this relatively small study, budesonide inhaled via Turbuhaler appeared to have dose-proportional pharmacokinetics, both within and above the clinically recommended dose range for asthmatic patients.

Zafirlukast in clinical practice: results of the Accolate Clinical Experience and Pharmacoepidemiology Trial (ACCEPT) in patients with asthma.

BACKGROUND: Zafirlukast is an oral leukotriene receptor antagonist used in the treatment of patients with mild to moderate asthma. To investigate its effects in a clinical practice setting, we evaluated zafirlukast in a heterogeneous group of patients who had asthma of different degrees of severity and who were receiving concomitant asthma medications. METHODS: A total of 3759 patients were enrolled at 924 sites. Patients received zafirlukast 20 mg twice a day for 4 weeks. Pulmonary function was measured twice a day, and overall asthma symptom scores, number of nighttime awakenings, severity of morning asthma symptoms, and beta2-agonist use were recorded daily. RESULTS: In the efficacy analysis (3207 evaluable patients), all parameters showed statistically significant improvement that continued throughout the 4 weeks of the trial. A total of 71% of patients had improved pulmonary function and 72% had improved asthma symptoms. Improvement was consistent regardless of asthma severity category and regardless of concomitant asthma medication category. More than 70% of both physicians and patients indicated there was clinical improvement in pulmonary measures as well as in asthma symptoms. Common adverse events reported were headache (3.7%), nausea (1.4%), pharyngitis (1.4%), and sinusitis (1.1%). CONCLUSIONS: Zafirlukast 20 mg twice a day is well tolerated and improves pulmonary function and asthma symptoms, regardless of asthma severity category and regardless of concomitant asthma medication category.

A retrospective study of epinephrine administration for anaphylaxis: how many doses are needed?

The precise amount of epinephrine needed to reverse severe symptomatology due to an anaphylactic reaction is unknown. We tried to determine how frequently more than one injection of epinephrine is required to treat an anaphylactic reaction. A retrospective review of patient charts with anaphylactic reactions requiring epinephrine, in response to inhalant allergen and hymenoptera venom immunotherapy as well as live hymenoptera stings, examined type of reaction; number, doses, and timing of epinephrine administered; and ancillary treatment. A total of 105 anaphylactic reaction events of varying severity (Ring's classification) were recorded (54--Grade I, 29--Grade II, 18--Grade III, 0--Grade IV, 4--unknown). The median epinephrine dose administered was 0.3 cc (range 0.1 to 0.8 cc, 1:1000). The timing of the first epinephrine injection was < or = 5 minutes in 27, 6-10 minutes in 13, 11-30 minutes in 16, < or = 30 minutes in 32, 31-60 minutes in 12, and > 60 minutes in five epinephrine treated patients. Overall, 38 patients (35.5%; CI95, 26.4-44.6%) required > 1 epinephrine injection. Of these, 11 experienced Grade I (11/54-20.3%; CI95, 9.6-31.0%), 12--Grade II (12/29-41.5%, CI95, 23.5-59.3%), and 13--Grade III (13/18-72.2%, CI95, 51.5-92.9%); reactivity was unknown in 2 patients. Forty-four patients also received an antihistamine, 10 received corticosteroids, and 30 received both medications and/or other ancillary therapy. A significant number of patients (> 35%) with anaphylactic reactions received greater than one epinephrine dose to manage events for the three classes of severity. Patients at risk for anaphylaxis and their caregivers need to recognize that more than one dose of epinephrine may be required for treatment of anaphylaxis.

Effect of fluticasone propionate aqueous nasal spray versus oral prednisone on the hypothalamic-pituitary-adrenal axis.

BACKGROUND: Fluticasone propionate is a glucocorticoid with negligible oral bioavailability and very low intranasal bioavailability that is used as an intranasal spray for the treatment of rhinitis. OBJECTIVE: The purpose of this study was to evaluate the hypothalamic-pituitary-adrenal (HPA)axis effects of fluticasone propionate aqueous nasal spray (FP ANS) compared with oral prednisone and placebo by using a 6-hour cosyntropin infusion test. METHODS: In a 4-week, randomized, double-blind, double-dummy, placebo-controlled parallel-group study, 105 adult patients with allergic rhinitis were randomly assigned to receive FP ANS 200 microg once daily, FP ANS 400 microg twice daily, oral prednisone 7.5 mg once daily, oral prednisone 15 mg once daily, or placebo. HPA-axis function was assessed at the screening visit and after 4 weeks of treatment by measuring morning plasma cortisol concentrations and poststimulation concentrations of plasma and urinary cortisol. RESULTS: There was no evidence of altered HPA-axis response to cosyntropin by the end of treatment with FP ANS 200 microg once daily or FP ANS 400 microg twice daily when compared with placebo. In contrast, 4 weeks of treatment with oral prednisone 7.5 or 15 mg once daily was associated with significant (p < 0.05 vs placebo) reduction in HPA-axis function, as evidenced by lower plasma cortisol concentrations (area under the plasma concentration-time curve and peak concentrations) after cosyntropin stimulation and reduced mean 24-hour urinary cortisol excretion. FP ANS 400 microg twice daily and both prednisone regimens were associated with a significant (p < 0.05 vs placebo) reduction in mean morning plasma cortisol concentrations. CONCLUSION: These results indicate that a 4-week course of FP ANS at four times the recommended dose does not suppress adrenal function in response to a 6-hour cosyntropin stimulation test.

Comparative clinical study of inhaled beclomethasone dipropionate and triamcinolone acetonide in persistent asthma.

UNLABELLED: At this time, no placebo-controlled studies in the clinical literature compare the efficacy and safety of the most widely prescribed oral inhaled corticosteroids when dosed at their recommended daily doses. This study compared the efficacy and safety of beclomethasone dipropionate (BDP) 336 microg/day administered by metered dose inhaler (MDI) alone, and triamcinolone acetonide (TA) 800 microg/day by MDI with a built-in tube extender in adults with persistent asthma. METHODS: This 56-day, randomized, double-blind, double-dummy, placebo-controlled, multicenter trial was conducted in 328 adults with mild to moderately severe asthma (FEV1 50% to 90% of predicted while maintained on inhaled corticosteroids). Patients were seen at a baseline visit and on study days 28 and 56. Efficacy variables included pulmonary function tests, physician and patient assessments of asthma condition, and use of rescue medication. RESULTS: Statistically significant improvements from baseline in most efficacy measures were demonstrated for both active treatments versus placebo, and with the following exception were the same between active treatments: mean increase in FEV1 in the beclomethasone dipropionate group was statistically significantly greater than in the triamcinolone acetonide group on day 28. Throughout the study, BDP was statistically superior to TA with respect to mean change from baseline in total asthma symptom scores and for 3 of 8 weeks in reducing the mean average weekly use of rescue albuterol (the two active treatments were comparable for this variable at all other time points). Beclomethasone dipropionate and TA were comparable in safety. CONCLUSION: In adult patients with mild to moderately severe persistent asthma, treatment with BDP consistently conferred greater improvement from baseline in mean FEV1 than TA. This difference achieved statistical significance after 28 days of therapy but was not maintained to endpoint. Decreases in overall asthma symptom scores and in the use of rescue albuterol were statistically significantly greater for the BDP group compared with the TA group. Based on these findings, we conclude that BDP is at least as effective as TA in the treatment of persistent asthma in adults, and judged by some measures, may be superior.

Effects of budesonide by means of the Turbuhaler on the hypothalmic-pituitary-adrenal axis in asthmatic subjects: a dose-response study.

BACKGROUND: As a general phenomenon, corticosteroids may suppress the activity in the hypothalamic-pituitary-adrenal (HPA) axis. The adrenal stimulation test is a commonly used method to assess the relative risk of exogenous corticosteroids to induce systemic side effects. OBJECTIVES: This clinical trial was performed to assess the effects of budesonide on the HPA axis (at 800, 1600, or 3200 microg/day, given as a twice daily regimen, administered by means of the Turbuhaler) in adult patients with mild, non-steroid-dependent asthma. METHODS: Sixty-four asthmatic patients received budesonide or placebo by inhalation or 10 mg/day oral prednisone once daily as a positive control in a double-blind, double-dummy, randomized, placebo-controlled, parallel-group, multicenter study. Plasma cortisol concentration was measured to assess the effect on the HPA axis before and during a 6-hour infusion of synthetic adrenocorticotropic hormone (ACTH), cosyntropin. RESULTS: After 6 weeks of treatment, plasma cortisol concentrations after adrenal stimulation by cosyntropin infusion had fallen by 4% in the placebo group; by 13%, 11%, and 27% in the budesonide groups (800, 1600, and 3200 microg/day, respectively); and by 35% in the prednisone group. The decrease was significant only in the 3200 microg/day budesonide (p = 0.03) and prednisone (p = 0.005) groups. Over the same time period, decreases in basal plasma cortisol concentrations were 1% in the placebo group; 19%, 19%, and 34% in the three budesonide groups; and 37% in the prednisone group. Only in the prednisone group was the decrease significant (p = 0.03 vs placebo). CONCLUSIONS: In this study budesonide inhaled by means of the Turbuhaler, at doses recommended for clinical use (800 or 1600 microg/day), did not produce any statistically significant suppression of the HPA axis compared with placebo.

Tri-Nasal triamcinolone acetonide nasal spray 200 and 400 micrograms qd versus placebo and Nasacort triamcinolone acetonide nasal aerosol 440 micrograms qd in patients suffering from seasonal allergic rhinitis during the grass season.

Tri-Nasal Nasal Spray is an investigational solution of triamcinolone acetonide (TAA) currently being evaluated as a treatment for allergic rhinitis. The safety and efficacy of 200 and 400 micrograms once daily doses of Tri-Nasal Nasal Spray, an active control (440 micrograms once daily of Nasacort Nasal aerosol), and Tri-Nasal Nasal Spray placebo were compared over a 2-week treatment period in a double-blind (the Nasacort treatment was not blinded), parallel design trial. A total of 377 adult patients in 13 centers were enrolled during the grass pollen season. The primary efficacy variable was the weekly average of the SSI (Symptom Severity Index), the sum of daily nasal congestion, rhinorrhea, and sneezing severity scores from the patient diary. A total of 355 patients completed the study. All active treatments were significantly more effective than placebo in relieving nasal symptoms at each treatment week. The 400 micrograms Tri-Nasal Nasal Spray and Nasacort treatments had a rapid onset of action, demonstrating significant improvement in the SSI versus placebo by the second day of treatment. Results for the individual nasal symptoms and other secondary efficacy measures paralleled those of the primary efficacy variables. Tri-Nasal Nasal Spray and Nasacort were comparable in safety, and in treating the nonocular symptoms of seasonal allergic rhinitis.

Ipratropium bromide nasal spray 0.03% provides additional relief from rhinorrhea when combined with terfenadine in perennial rhinitis patients; a randomized, double-blind, active-controlled trial.

Medical treatment of perennial rhinitis is aimed at providing symptomatic relief of individual symptoms. Multiple agents are administered when no single agent provides complete relief. Studies assessing the benefit/risk of combined therapy are important, especially for newly available agents such as ipratropium bromide nasal spray, a topical anticholinergic agent approved for the treatment of rhinorrhea in allergic and nonallergic perennial rhinitis. The objective was to determine whether the combined use of ipratropium bromide nasal spray 0.03% (42 mcg per nostril) administered three times daily with a nonsedating antihistamine (terfenadine, 60 mg administered twice daily) is safe and provides greater clinical benefit than use of the placebo nasal spray plus terfenadine. Our method was a multicenter, 6-week, double-blind, randomized, active-controlled, crossover trial of 205 patients with perennial rhinitis (114 allergic and 91 nonallergic), 18 to 75 years of age, who had clinically significant rhinorrhea. After a 1-week run-in period, patients were treated for 2 weeks with one of the two treatment regimens, followed by a 1-week washout period, and then were treated for another 2 weeks with the other treatment regimen. Daily diary symptoms scores of rhinorrhea, congestion, and sneezing were obtained, as well as biweekly patient and physician global assessments of treatment effectiveness of each of the nasal symptoms. Ipratropium bromide nasal spray plus terfenadine was more effective than vehicle plus terfenadine in reducing the average severity (38% versus 28%) and duration (46% versus 30%) of rhinorrhea during the 2 weeks of treatment from baseline (p < 0.05). The advantage of ipratropium bromide nasal spray plus terfenadine was evident by the second day of treatment and continued throughout the 2-week treatment period. Of patients who responded more to one treatment than another, 69% responded to ipratropium bromide nasal spray plus terfenadine, compared to 31% to vehicle plus terfenadine (p < 0.05). Both physicians and patients rated control of rhinorrhea and sneezing by ipratropium bromide nasal spray plus terfenadine as superior to vehicle plus terfenadine (p < 0.05). The symptom of congestion was controlled equally well by both treatments. Combined active therapy was well tolerated with no increase in adverse events over that seen previously with ipratropium bromide nasal spray alone. The combination of ipratropium bromide nasal spray with terfenadine is more effective than vehicle plus terfenadine for the treatment of rhinorrhea, and does not result in a potentiation of adverse drug reactions.

Limited coronal CT: an alternative screening examination for sinonasal inflammatory disease.

Coronal CT is the definitive procedure for radiologic evaluation of sinonasal inflammatory disease, yet many clinicians rely on the less expensive plain film sinus series. We designed a limited four slice coronal CT and prospectively compared it with conventional coronal CT and plain film sinus series in 25 patients to determine whether a limited CT examination is a suitable alternative to these other radiologic procedures in screening for sinonasal inflammatory disease. The presence, amount, and location of mucous membrane disease, opacification, air fluid levels, retention cysts, erosions, and anomalies were recorded for each technique. The limited CT agreed with the complete CT in 82% of the 200 sinus compartments reviewed. Localized disease, usually mucosal thickening of 3 mm or less and missed on the limited CT, but detected on the complete CT, accounted for 22 of 36 errors of interpretation. Underestimation of mucosal disease, usually 2 mm or less, accounted for eight errors and misinterpretation of partial volume effect for three errors. Using complete CT a s the established standard, plain film missed 37 instances of disease detected on the limited CT; 73% involved an error of mucosal thickening 4 mm or greater. A limited coronal CT of the paranasal sinuses offers a potentially lower cost alternative to complete CT in screening for sinonasal inflammatory disease. It is more accurate than plain film series. Localized disease and osteomeatal disease is underestimated with the current protocol, and so a limited CT should not be used for evaluating potential cancer patients or for surgical planning.

Common variable immunodeficiency in a renal transplant patient with severe recurrent bacterial infection: a case report and review of the literature.

The second reported case of common variable immunodeficiency (acquired agammaglobulinemia) after renal transplantation is presented. Agammaglobulinemia presumably resulted from long-standing immunosuppression. This case and our review of the literature indicate that agammaglobulinemia is a rare event after transplantation but can be treated successfully with intravenous immunoglobulin. Additionally, hypogammaglobulinemia occurs frequently after transplantation and should be monitored and treated in appropriate clinical situations. The treatment of our patient with intravenous immunoglobulin also suggests that patients with common variable immunodeficiency can undergo renal transplantation.

Triamcinolone acetonide Aqueous nasal spray in patients with seasonal ragweed allergic rhinitis: a placebo-controlled, double-blind study.

Because some patients may prefer aqueous nasal sprays and once-daily dosing for relief of seasonal allergic rhinitis symptoms, a new aqueous formulation of triamcinolone acetonide (TAA Aqueous) was developed. We conducted a randomized, placebo-controlled, double-blind study to compare the efficacy and safety of once-daily administration of 220 micrograms/d of TAA Aqueous for 1 week, followed by either 220 micrograms/d or 110 micrograms/d for an additional 2 weeks, with that of placebo in 429 patients with seasonal allergic rhinitis. Patients recorded the severity of symptoms (nasal stuffiness, discharge, sneezing, nasal index [the sum of the first three variables], nasal itching, and eye symptoms) on daily diary cards. Patients' and physicians' global evaluations of efficacy were made at the end of the 3-week study period. Both regimens of TAA Aqueous significantly improved symptoms compared with placebo at most time points. Patients demonstrated significant improvements in nasal symptoms as early as the first day of treatment (within 12 to 16 hours based on treatment in the morning and symptom assessment at bedtime). Although TAA Aqueous 220 micrograms/d provided numerically greater reductions in nasal symptoms compared with 110 micrograms/d, these differences in efficacy over the last 2 weeks were not statistically significant. The incidence of adverse effects with both TAA Aqueous regimens was low and comparable to that of placebo. In summary, during the first week of therapy, TAA Aqueous 220 micrograms/d significantly reduced nasal symptoms. During the last 2 weeks of therapy, the 110 micrograms/d regimen of TAA Aqueous was effective as continued therapy for most patients. Both the 110 micrograms/d and 220 micrograms/d regimens of TAA Aqueous provided significantly better relief of nasal symptoms than did placebo.

Systemic mastocytosis presenting as osteoporosis: a clinical and histomorphometric study.

Ten patients with systemic mastocytosis (SM) were evaluated for their metabolic bone disease (4 men and 6 women; mean +/- SD, 59 +/- 13 yr). All patients presented with generalized osteopenia and/or atraumatic vertebral compression fractures. Three patients had long-standing urticaria pigmentosa; in these, the diagnosis of cutaneous mastocytosis had been established by skin biopsy. One of the 3 and 2 of the other 7 individuals had symptoms suggestive of SM. Although six patients had previously undergone decalcified bone marrow trephine core biopsy (DBMB), findings were consistent with SM in only 2 of them. X-Ray survey revealed generalized osteopenia in all 10 patients and vertebral compression fractures in 9. No patient had sclerotic bone lesions. Histological findings of undecalcified transiliac crest biopsy (UTBB) specimens from 9 patients (5 patients underwent both DBMB and UTBB, 4 underwent only UTBB, and 1 had only DBMB) disclosed bone marrow that contained nodules characteristic of mast cell granulomas and numerous scattered oval- and spindle-shaped mast cells. The trabecular bone contained abundant newly synthesized bone matrix and a significant increase in osteoblastic, osteoclastic, and resorptive surfaces. Dynamic histomorphometric parameters revealed a significantly increased mineral apposition rate. Our study suggests that SM may be a more frequent cause of osteoporosis than previously recognized. Generalized osteopenia with compression fractures may be the only presentation of SM. Undecalcified bone biopsy is useful in the diagnosis of SM. Accelerated bone remodeling is a characteristic histomorphometric feature of SM with diffuse osteopenia.

Hypersensitivity reaction to desipramine.

Adverse reactions to the tricyclic antidepressant drugs imipramine and desipramine have been described and include eosinophilia, pulmonary infiltrates with eosinophilia, and elevated total serum IgE levels. The immunologic mechanism accounting for these adverse reactions has not been elucidated. This article describes a patient manifesting bronchospasm, profound eosinophilia, and elevated serum IgE levels after therapy with desipramine that resolved rapidly after withdrawal of the drug. Immunologic investigations failed to demonstrate specific IgE directed against a protein conjugate of desipramine but demonstrated the ability of desipramine to induce mast cell degranulation with direct intradermal skin challenges.