Levalbuterol compared with racemic albuterol in the treatment of acute asthma: results of a pilot study

This was a prospective, open-label, nonrandomized pilot study to evaluate efficacy and tolerability of levalbuterol (LEV) in acute asthma. Asthmatics (forced expiratory volume in 1 second [FEV1], 20-55% predicted) were sequentially enrolled into cohorts of 12 to 14 and received 0.63, 1.25, 2.5, 3.75, or 5.0 mg LEV or 2.5 or 5.0 mg racemic albuterol (RAC) every 20 minutes x 3. After the first dose, FEV1 changes were 56% (0.6 L) for 1.25 mg LEV and 6% (0.07 L) and 14% (0.21 L) for 2.5 and 5 mg RAC respectively. After three doses, FEV1 changes were 74% (0.9 L), 39% (0.5 L), and 37% (0.6 L) for 1.25 mg, LEV 2.5 mg, RAC and 0.63 mg LEV respectively. LEV doses greater than 1.25 mg did not further improve bronchodilation. Baseline plasma (S)-albuterol levels were negatively correlated with baseline FEV1 (R = - 0.3, P = .004) and percent change in FEV1 (R = -0.3, P = .006). LEV at a dose of 1.25 mg produced effective bronchodilation that was greater than both RAC doses. The negative correlation between (S)-albuterol levels and FEV1 could suggest a deleterious effect of (S)-albuterol. Larger comparative studies are warranted.     

Comparison of nebulized magnesium sulfate plus albuterol to nebulized albuterol plus saline in children with acute exacerbations of mild to moderate asthma

A prospective, randomized, double blinded study was conducted to determine whether a combination of nebulized magnesium sulfate and albuterol as a single dose adds any benefit in management of children with mild to moderate asthma when compared to nebulized albuterol with saline. The difference in FEV1 was significant at 10 and 20 min after a single dose of the combined treatment with magnesium and albuterol when compared with the albuterol and saline group (1.41 L +/- 0.53 vs. 1.13 L +/- 0.34, respectively, p = 0.03). The addition of magnesium to albuterol seems to provide short-term benefits in children with acute exacerbations of mild to moderate asthma.     

Comparison of racemic albuterol and levalbuterol in the treatment of acute asthma in the ED

BACKGROUND: Acute asthma is often treated with racemic albuterol, a 1:1 mixture of (R)-albuterol and (S)-albuterol. Levalbuterol is the single-isomer agent comprised (R)-albuterol, an active bronchodilator, without any effects of (S)-albuterol. OBJECTIVE: To compare emergency department (ED) admission rates of patients presenting with acute asthma who were treated with either racemic albuterol or levalbuterol. SETTING: Suburban community teaching hospital. DESIGN: Retrospective observational case review. METHODS: Emergency department patients presenting with acute asthma at 2 different sites were reviewed over 9- and 3-month consecutive periods. Outcome measures included ED hospital admission rate, length of stay, arrival acuity, and treatment costs. Patients were excluded if younger than 1 year or if no treatment of acute asthma was rendered. RESULTS: Of the initial 736 consecutive cases, significantly fewer admissions (4.7% vs 15.1%, respectively; P = .0016) were observed in the levalbuterol vs racemic albuterol group. Of the subsequent 186 consecutive cases, significantly fewer admissions were also observed (13.8% vs 28.9%, respectively; P = .021) in the levalbuterol vs racemic albuterol group. Treatment costs were lower with levalbuterol mainly because of a decrease in hospital admissions. CONCLUSION: Levalbuterol treatment in the ED for patients with acute asthma resulted in higher patient discharge rates and may be a cost-effective alternative to racemic albuterol.     

沙丁胺醇联合布地奈德雾化吸入治疗老年支气管哮喘急性发作的疗效

【目的】观察雾化吸入沙丁胺醇、布地奈德治疗老年轻、中度支气管哮喘急性发作期的临床疗效。[方法]60例急性发作期支气管哮喘患者随机分为观察组（30例）和对照组（30例）。观察组每天雾化吸入沙丁胺醇、布地奈德雾化混悬液。对照组仅予沙丁胺醇雾化吸入,治疗4d后观察吸入前后,临床症状、体征及肺功能的变化。【结果】观察组肺功能FEV1、PEFR、FEV1／FVC分别为（2．54±0．75）L、（4．36±0．34）、（56．96±2．42）较对照组（2．13±0．64）L、（3．67±0．32）、（28．82±1．94）明显改善,差异有显著性（P〈0．05）。两组显效率分别为86．68％、60．00％,差异有显著性（P〈0．05）。而总有效率两组分别为93．33％、83．33％,差异无显著性（P〉0．05）。【结论】沙丁胺醇联合布地奈德雾化吸入能快速缓解老年患者哮喘急性发作时的症状,控制病情,可作为治疗老年支气管哮喘急性发作的主要方法。     

Twelve-week, randomized, placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in adolescents and adults with asthma

BACKGROUND: The addition of the long-acting beta(2)-adrenergic agonist formoterol to low- to moderate-dose budesonide has shown clinical efficacy in patients with persistent asthma. Combination therapy with budesonide/formoterol in 1 pressurized metered-dose inhaler (pMDI) has been found to have greater efficacy than its monocomponents in patients with moderate to severe persistent asthma, but it has not been assessed in patients with mild to moderate persistent asthma. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of budesonide and formoterol delivered via 1 pMDI (budesonide/formoterol pMDI), budesonide pMDI, formoterol dry powder inhaler (DPI), and placebo. METHODS: This 12-week, multicenter, double-blind, randomized, placebo-controlled, double-dummy study was conducted at 56 centers across the United States. Patients aged > or =12 years with mild to moderate persistent asthma treated with inhaled corticosteroids (ICSs) for > or =4 weeks before screening and who had a forced expiratory volume in 1 second (FEV(1)) of > or =60% to < or =90% of predicted normal at screening were eligible. After 2 weeks (current asthma therapy discontinued), patients received twice-daily budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations (160/9 microg), budesonide pMDI 80 microg x 2 inhalations (160 microg), formoterol DPI 4.5 microg x 2 inhalations (9 microg), or placebo. The coprimary efficacy variables were changes from baseline in morning predose FEV(1) and 12-hour mean FEV(1) (from serial spirometry) after administration of the morning dose of study medication. Tolerability was assessed based on adverse events (AEs); routine laboratory assessments; electrocardiography; 24-hour Holter monitor assessments; and physical examinations, including vital signs (eg, systolic and diastolic blood pressure and heart rate). AEs were recorded manually by the patient in paper notebooks and reviewed at each clinic visit by the investigator and during a final follow-up phone call. RESULTS: A total of 480 patients were randomized (299 females, 181 males; mean age, 36 years; mean FEV(1), 2.4 L; budesonide/formoterol pMDI, 123 patients; budesonide pMDI, 121; formoterol DPI, 114; placebo, 122). At end of treatment, the mean increases from baseline in predose FEV(1) were greater with budesonide/formoterol pMDI versus budesonide pMDI, formoterol DPI, and placebo (0.37 vs 0.23, 0.17, and 0.03 L, respectively; all, P<0.005). 0.005). After administration of the first dose and at weeks 2 and 12, mean increases in 12-hour mean FEV(1) were significantly greater with budesonide/formoterol pMDI (0.41, 0.47, and 0.50 L, respectively) versus budesonide pMDI (0.17, 0.30, and 0.32 L) and placebo (0.15, 0.12, and 0.12 L) (all, P < 0.001). Fewer patients receiving budesonide/formoterol pMDI met criteria for (18.7%; P < 0.001) or withdrew because of (7.3%; P < or = 0.010) worsening asthma versus formoterol DPI (42.1% and 18.4%, respectively) and placebo (56.6% and 32.8%); results were similar between budesonide pMDI (21.5% and 6.6%, respectively) and budesonide/formoterol pMDI. Three patients experienced serious AEs; none was considered related to study medication. The proportions of withdrawals due to worsening asthma were not significantly different between the budesonide/formoterol pMDI and budesonide pMDI groups. CONCLUSIONS: In this population of adults and adolescents with mild to moderate persistent asthma previously treated with ICSs, twice-daily budesonide/formoterol pMDI was associated with significantly increased pulmonary function versus its monocomponents. All study drugs were generally well tolerated.     

哮喘和慢性阻塞性肺疾病重叠综合征患者血清维生素D水平改变及其临床意义

目的哮喘和慢性阻塞性肺疾病重叠综合征(ACOS)患者血清维生素D水平改变及其临床意义研究。方法连续性收录22例哮喘患者、32例COPD患者和26例ACOS患者,综合分析比较三组患者肺功能情况和血清维生素D水平差异。结果哮喘组和ACOS组患者吸入支气管舒张剂后FEV1改善值明显高于COPD组(P0.05)。COPD组和ACOS组患者FEV1%pred水平均明显低于哮喘组(P0.05)。COPD患者血清25(OH)D3水平明显低于哮喘组和ACOS组患者,而哮喘组明显高于ACOS组(P0.05)。三组患者血清维生素D水平均与吸烟指数呈负相关(哮喘组:r=-0.582,P=0.029;COPD组:r=-0.601,P=0.022;ACOS:r=-0.687,P=0.015)。而ACOS组患者可见血清维生素D水平与FEV1改善值(r=0.620,P=0.032)和FEV1%pred(r=0.489,P=0.037)呈正相关。血清维生素D水平用以诊断ACOS的AUC为0.643,95%CI为0.523-0.678。结论 ACOS患者中血清维生素D水平低于哮喘患者,而高于COPD患者,且与肺功能具有一定的相关性。     

Efficacy and tolerability of salmeterol/fluticasone propionate versus montelukast in childhood asthma: A prospective, randomized, double-blind, double-dummy, parallel-group study

BACKGROUND: Asthma control remains suboptimal in adults and children worldwide. Inhaled salmeterol/fluticasone propionate combination (SFC) and oral montelukast (MON) are 2 treatments available for childhood asthma. OBJECTIVE: This study, the PEdiatric Asthma Control Evaluation (PEACE), investigated the efficacy and tolerability of SFC compared with MON for the control of persistent asthma in children. METHODS: Children with asthma (forced expiratory volume in 1 second [FEV(1)] 55%-80% predicted; reversibility >or=12%) aged 6 to 14 years who were receiving only short-acting beta(2)-agonists entered a 2-week run-in period. Symptomatic patients (rescue use or symptoms during 4 of the last 7 days) were randomized to double-blind, double-dummy treatment with SFC 50/100 microg BID via multidose dry powder inhaler or MON 5-mg tablet QD for 12 weeks. The primary end point was change from baseline in morning peak expiratory flow (PEF). Efficacy assessments included lung function, asthma symptoms, rescue medication use, and asthma control. Tolerability was assessed by recording the number and type of adverse events (AEs) and the number of asthma exacerbations. RESULTS: Of 607 patients screened, 548 were randomized to treatment. The SFC group contained 281 patients and the MON group included 267. Demographic characteristics and baseline data were similar for both groups (mean age, 9.3 years for both groups; mean [SD] FEV(1), 1.49 [0.43] L in the SFC group and 1.48 [0.43] L in the MON group). There were more males in the MON group (179 [67%]) than in the SFC group (156 [56%]). The adjusted mean (SE) changes from baseline in morning PEF were 45.88 (2.82) L/min with SFC and 28.7 (2.86) L/min with MON (treatment difference, 17.16 L/min; 95% CI, 9.23-25.08; P < 0.001). Compared with MON, the SFC group had significantly more asthma symptom-free days (odds ratio [OR], 1.74; 95% CI, 1.07-2.82; P = 0.025), more rescue-free days (OR, 3.24; 95% CI, 2.09-5.02; P < 0.001), and more asthma-controlled weeks (difference in treatment medians over weeks 1-12, 16.77%; 95% CI, 8.3-16.77; P < 0.001). Both treatments were well tolerated, with a similar number of patients reporting AEs (SFC group, 155/281 [55%]; MON group, 153/267 [57%]); the most common AE in both groups was headache (SFC group, 66 [23%]; MON group, 72 [27%]). The mean exacerbation rates over 12 weeks (post hoc analysis) were 0.12 in the SFC group and 0.30 in the MON group (SFC/MON ratio, 0.40; 95% CI, 0.29-0.57; P < 0.001). CONCLUSIONS: In these children with uncontrolled asthma previously on short-acting beta(2)-agonist monotherapy (% predicted FEV(1) <80%, frequent asthma symptoms and rescue medication use), treatment with SFC was significantly more effective in improving morning PEF and other measures of asthma control and in decreasing exacerbation rates (in a post hoc analysis) than treatment with MON. The 2 drugs were both well tolerated, with similar numbers and types of AEs reported.     

Effect of terfenadine and ipratropium bromide on ultrasonically nebulized distilled water-induced asthma

Inhalation of ultrasonically nebulized distilled water was used to evaluate non-specific bronchial reactivity and to investigate nonimmunologically mediated asthma. Release of histamine and other mediators from mast cells and stimulation of lung irritant receptors are mechanisms that may be involved in nebulized distilled water-induced bronchoconstriction. To investigate the contribution of these mechanisms the effect of terfenadine and ipratropium bromide on the bronchial response to this stimulus was assessed. A total of 30 asthmatics (mean 28.7 years) were submitted on three different days to distilled water challenge with or without prior treatment with oral terfenadine or inhaled aerosolized ipratropium bromide. The decrease in forced expiratory volume in 1 s induced by the same dose of distilled water was significantly (P less than 0.001) reduced from 35.6 +/- 15.8% to 19.5 +/- 16% with terfenadine and to 23.9 +/- 19.7% with ipratropium bromide. The results suggest that histamine release and reflex bronchoconstriction are mechanisms involved in asthma induced by ultrasonically nebulized distilled water.     

Comparison of nebulized epinephrine and terbutaline in patients with acute severe asthma: a controlled trial

PURPOSE: To compare the efficacy and tolerability of nebulized adrenaline and terbutaline in acute severe asthma. METHODS: Design: Prospective pilot randomized double-blind cross-over trial. Setting: Emergency department of a university hospital. Patients: Thirty-eight patients admitted with severe acute asthma. Each patient received adrenaline (3 mg) and terbutaline (5 mg) nebulizations over 20 min in randomized order. Additional treatment comprised methylprednisolone, intravenous hydration, and oxygen. The efficacy and tolerability of the two drugs were evaluated at the end of each nebulization as well as potential synergistic effects. RESULTS: Eighteen patients received adrenaline first, and 20 received terbutaline first. Peak expiratory flow (PEF) improved significantly in both groups after the first nebulization (from 157 L/min +/- 111 L/min to 199 L/min +/- 134 L/min with adrenaline, P <.01; and from 142 L/min +/- 65 L/min to 193 L/min +/- 181 L/min with terbutaline, P <.01). Both drugs induced a significant decrease in respiratory frequency. The improvement in PaO2 was only significant with terbutaline. Respiratory frequency, PEF and PaO2 were not improved by the second nebulization. No adverse effects were observed. CONCLUSIONS: Adrenaline nebulization was as effective and as well tolerated as terbutaline in acute severe asthma. No synergistic effect between terbutaline and adrenaline was observed.     

Effect of angiotensin II infusion with and without angiotensin II type 1 receptor blockade on nitric oxide metabolism and endothelin in human beings: a placebo-controlled study in healthy volunteers

BACKGROUND: Angiotensin II has been shown to induce the synthesis of endothelium-derived relaxing factor nitric oxide (NO) and endothelin in vitro. In human beings, to our knowledge, no data on NO release in response to angiotensin II and on the influence of angiotensin II type 1 receptor blockade have been published. METHODS: In a placebo-controlled study in nine healthy volunteers, angiotensin II was administered intravenously for 6 hours with and without pretreatment with valsartan, a specific angiotensin II type 1 receptor antagonist. NO (NO2 + NO3) and endothelin plasma concentrations, clearance values for inulin and paraaminohippuric acid and NO (NO2 + NO3) excretion in urine were determined. RESULTS: During angiotensin II infusion NO plasma concentrations remained unaltered compared with placebo after 3 hours: 6.66 +/- 5.49 versus 5.56 +/- 3.09 micromol/L (P = ns) but increased after 6 hours: 18.36 +/- 20.02 versus 7.13 +/- 3.87 micromol/L (P < .04). The same was noted after pretreatment with valsartan: 7.61 +/- 5.69 versus 5.56 +/- 3.09 micromol/L (P= ns) after 3 hours, and 21.70 +/- 11.51 versus 7.13 +/- 3.87 micromol/L (P = .02) after 6 hours. In urine fractional NO excretion decreased after angiotensin II infusion: 0.87 +/- 0.72 versus 0.95 +/- 0.71 (P = .5) during the first 3 hours, and 0.44 +/- 0.39 versus 0.78 +/- 0.43 (P = .01) during the following 3 hours. After valsartan pretreatment the decrease in fractional urinary NO excretion began earlier: 0.40 +/- 0.15 versus 0.95 +/- 0.71 (P = .04) during the first 3 hours, and 0.17 +/- 0.11 versus 0.78 +/- 0.43 (P = .01) during the following 3 hours. Endothelin plasma concentrations showed no difference after angiotensin II infusion with or without valsartan. CONCLUSIONS: Our observations demonstrate for the first time that angiotensin II increases NO plasma concentrations in human beings and that this response is not mediated by angiotensin II type 1 receptor. In spite of increased NO plasma levels, urinary NO excretion decreased. Endothelin plasma levels remained unchanged during angiotensin II infusion.     

Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial

OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate (a selective, long-acting beta(2)-adrenergic agonist that is the [R,R] isomer of formoterol) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease (COPD). METHODS: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial was conducted at 60 centers across the United States. Male and female patients aged >or=35 years with physician-diagnosed COPD received arformoterol (15 microg BID, 25 microg BID, or 50 microg QD via nebulizer), salmeterol (42 microg BID via metered dose inhaler), or placebo. Pulmonary function was assessed by spirometry; dyspnea, by the Transitional Dyspnea Index (TDI); and health status, by the St. George's Respiratory Questionnaire (SGRQ). Adverse events (AEs) were assessed by site personnel at all clinic visits (screening, first dose at week 0, and at weeks 3, 6, 9, 12, and follow-up). COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit. RESULTS: A total of 717 patients received study medication.The demographic composition of all treatment arms was similar. The mean age was 62.9 years, 58% were men, and mean baseline forced expiratory volume in 1 second (FEV(1)) was 1.2 L (41% predicted). Mean improvement in trough FEV(1) over 12 weeks was significantly greater with all 3 arformoterol doses (15 microg BID, +16.9%; 25 microg BID, +18.9%; 50 microg QD, +14.9%) and for salmeterol (+17.4%) relative to placebo (+6.0%; P < 0.001). There were significantly greater improvements in the mean percentage change in FEV(1) AUC(0-12h) from the predose value over 12 weeks (15 microg BID, 12.7%, 25 microg BID, 13.9%, 50 microg QD, 18.9%; salmeterol, 9.8%) versus placebo (2.7%; P 相似文献   

Ipratropium treatment of acute airways disease

OBJECTIVE: To examine the use of ipratropium bromide in adults with acute exacerbation of either asthma or chronic obstructive pulmonary disease (COPD) during admission and at discharge from 3 teaching hospitals. METHODS: An extensive range of clinical and demographic data was retrospectively extracted from the medical records of consecutive patients aged >/=12 years admitted to the medical wards of the hospitals during 1999-2001 with acute exacerbations of asthma or COPD, either as a primary diagnosis or as a major comorbidity. RESULTS: Data were gathered for 302 patients (97 with asthma, 205 with COPD). Almost 90% of all patients received ipratropium bromide during their hospital admission. The indication for using ipratropium bromide during hospitalization was considered appropriate in 84% of the asthma patients and 68% of the COPD patients. Over 20% of the patients with asthma had been using ipratropium bromide prior to the hospital admission, and almost one-third of the patients with asthma were discharged with ipratropium bromide, even though its role in chronic asthma is limited. More than 90% of the patients received nebulized drug therapy during their hospital stay, with 41% being prescribed nebulized therapy at discharge. This was often considered inappropriate, given that >50% of all patients had been using inhaler devices and nebulizers concurrently while hospitalized. CONCLUSIONS: In the majority of cases, ipratropium bromide had been used during hospitalization in accordance with guidelines for the management of acute exacerbations of asthma or COPD. However, there was also evidence of potentially inappropriate prolonged use of the agent in the community setting, particularly for asthma. Also of concern was the relatively high use of nebulized drug therapy when delivery via other means was appropriate.     

Effect of face mask design on inhaled mass of nebulized albuterol, using a pediatric breathing model

BACKGROUND: Aerosol face mask design and the distance at which the face mask is held from the face affect the delivery of nebulized medication to pediatric patients. OBJECTIVE: To measure the inhaled mass of nebulized albuterol with 3 types of pediatric face mask, at 3 different distances from the face, with a model of a spontaneously breathing infant. METHODS: We compared a standard pediatric face mask and 2 proprietary pediatric face masks (one shaped to resemble a dragon face, the other shaped to resemble a fish face). The albuterol was nebulized with a widely used jet nebulizer. Aerosol delivery with each type of mask was measured with the mask at 0 cm (ie, mask directly applied to the mannequin face), 1 cm, and 2 cm from the mannequin face. In each test the nebulizer was filled with a 3-mL unit dose of albuterol sulfate and powered by oxygen at 8 L/min, with a total nebulization time of 5 min. The mannequin face was connected to a lung simulator that simulated a spontaneously breathing infant. We measured inhaled mass by collecting the aerosol on a 2-way anesthesia filter that was attached to the back of the mannequin's oral opening via a 15-mm silicon adapter. We also measured residual drug left in the nebulizer, and estimated the drug lost to the atmosphere. RESULTS: The mean +/- SD inhaled percentage of the nominal dose values at 0 cm, 1 cm, and 2 cm, respectively, were 2.18 +/- 0.53%, 1.45 +/- 0.46%, and 0.92 +/- 0.51% with the standard mask; 2.65 +/- 0.55%, 1.7 +/- 0.38%, and 1.3 +/- 0.37% with the dragon mask; and 3.67 +/- 0.8%, 2.92 +/- 0.4%, and 2.26 +/- 0.56% with the fish mask. With all 3 masks there was a statistically significant difference (p < 0.001) in inhaled mass between the 0 cm and 2 cm distance. The fish mask had a significantly higher (p < 0.001) inhaled mass than the dragon mask or the standard mask, at all 3 distances. CONCLUSIONS: The inhaled mass of albuterol is significantly reduced when the mask is moved away from the face. The fish mask had significantly higher inhaled mass than the standard mask or the dragon mask, under the conditions we studied. Mask design may affect nebulized albuterol delivery to pediatric patients.     

Effectiveness and tolerability of zafirlukast for the treatment of asthma in children

OBJECTIVE: This study was undertaken to examine the dose-response relationship of zafirlukast (5 to 40 mg BID) and to assess the efficacy and tolerability of the 10-mg BID dose in school-aged children with mild to moderate asthma. BACKGROUND: The efficacy and tolerability of zafirlukast, an oral leukotriene-receptor antagonist, has been demonstrated in adolescents and adults aged > or = 12 years. METHODS: Data from 2 placebo-controlled, parallel-group, multicenter trials (trial 1, 4-week double-blind; trial 2, 6-week double-blind) were integrated. Children aged 5 to 11 years were randomly assigned to receive zafirlukast 5 mg BID (n = 99), 10 mg BID (n = 205), 20 mg BID (n = 105), 40 mg BID (n = 99), or placebo (n = 206). The primary outcome was change from baseline in forced expiratory volume in 1 second (FEV1) expressed as percent of predicted normal. Secondary outcomes were FEV1 (L), morning and evening peak expiratory flow, peak flow variability, short-acting beta2-agonist use, asthma episode score, and nights awakened by asthma. RESULTS: Mean baseline FEV1 was 76.5% of predicted. The greatest improvements were generally seen with zafirlukast 5 mg BID or 10 mg BID, with no additional clinically significant benefits seen at higher doses. The pooled data analysis showed that 10 mg BID compared with placebo significantly improved (P < 0.045) all efficacy outcomes except asthma-episode score and nights awakened with asthma. However, in the subset of children who had > or = 1 night awakened per week at baseline (zafirlukast 10 mg BID = 78; placebo = 86), 10 mg BID significantly reduced nights awakened (P = 0.009) (mean difference from placebo at end point = -0.81 night/wk). All zafirlukast doses were well tolerated and had tolerability profiles that were clinically indistinguishable from placebo. CONCLUSION: These results support the effectiveness and tolerability of the 10-mg BID dose of zafirlukast for the prophylaxis and chronic treatment of mild to moderate asthma in children.     

Disposition of instilled versus nebulized tobramycin and imipenem in ventilated intensive care unit (ICU) patients

BACKGROUND: Delivery of antibiotics to the lower respiratory tract could potentially achieve antimicrobial bronchial drug concentrations without toxicity. AIM: To assess bronchial and serum concentrations of imipenem or tobramycin obtained by nebulization or instillation in critically ill mechanically ventilated patients. METHODS: Prospective randomized open trial. Eighteen patients ventilated for more than 48 h were included. Two doses of imipenem/cilastatin (1000/500 mg) separated by 8 h, or two doses of tobramycin 200 mg separated by 12 h were randomly nebulized or instilled into the tracheal tube. Five bronchoaspirates (two bronchoscopic, three blind) and five blood samples were collected on a timed schedule after the second dose. Respiratory and serum samples were analysed by HPLC, and a subset of blood samples was also evaluated by enzyme-immunoassay. RESULTS: When instilled, imipenem/cilastatin obtained higher concentrations in respiratory secretions than when nebulized (P=0.022, 1 h after the last dose; P=0.029, 2 h after the last dose). Tobramycin showed equally high concentrations when nebulized or instilled. Instillation of tobramycin may result in significant accumulation in patients with renal failure. CONCLUSIONS: High bronchial concentrations of imipenem could only be achieved by instillation, whereas tobramycin seems suitable for both modes of administration. Instillation of these antibiotics is a safe procedure that achieves high drug concentrations in respiratory secretions.     

Efficacy and tolerability of fluticasone propionate/salmeterol administered twice daily via hydrofluoroalkane 134a metered-dose inhaler in adolescent and adult patients with persistent asthma: a randomized, double-blind, placebo-controlled, 12-week study

OBJECTIVE: This study compared the efficacy and tolerability of the combination of fluticasone propionate (FP) and salmeterol (SAL) delivered via a single hydrofluoroalkane (HFA) 134a metered-dose inhaler (MDI) with those of its 2 components alone delivered via a chlorofluorocarbon (CFC) MDI and placebo (PLA) delivered via HFA MDI in adolescent and adult patients with persistent asthma that was not controlled by medium doses (equivalent to FP 440-660 microg/d) of inhaled corticosteroids (ICSs). METHODS: This was a randomized, double-blind,placebo-controlled, parallel-group study consisting of a 2-week, single-blind, placebo run-in period followed by a 12-week, double-blind treatment period. Participants had to be > or =12 years of age and have a diagnosis of asthma requiring pharmacotherapy for at least 6 months before the study. Patients had to have used ICS therapy for > or =3 months before the study and at a consistent dose for the previous month. Lack of asthma control was defined as a forced expiratory volume in 1 second (FEV(1)) that was 40% to 85% of the predicted value. Patients could not enter the double-blind treatment period if they had 3 days when they required >12 puffs of rescue albuterol per day or >3 nighttime awakenings due to asthma that required treatment with albuterol during the 7 days before the randomization visit. Patients were randomized to receive one of the following treatments delivered via MDI twice daily for 12 weeks: FSC 220/42 microg HFA (2 inhalations of FSC 110/21 microg; 125 microg/21 microg ex-valve); FP 220 microg CFC (2 inhalations of FP 110 microg); SAL 42 microg CFC (2 inhalations of 21 microg); or 2 inhalations of PLA HFA. The primary efficacy end point for FSC versus FP was the mean area under the 12-hour serial FEV(1) curve relative to the prerandomization baseline (FEV(1) AUC(bl)). The primary efficacy end points for FSC versus SAL were the mean change from baseline in morning predose FEV(1) at end point and the probability of not being withdrawn from the study due to worsening asthma. Tolerability assessments included electrocardiograms, routine clinical laboratory tests, vital signs, oropharyngeal examinations, and physical examinations. Adverse events were assessed at each clinic visit. RESULTS: Thirty-two adolescent and 333 adult patients were randomly assigned to receive double-blind treatment. The treatment groups were comparable at baseline with respect to demographic characteristics (mean age, 38-41 years; white race, 78%-88%) and pulmonary function (mean percent predicted FEV(1), 68%-69%; mean asthma symptom score, 1.6 [scale 0-5]; and mean daily albuterol use, 3.1 puffs). After 12 weeks of treatment, the mean FEV(1) AUC(bl) was significantly greater in patients who received FSC compared with those who received FP, SAL, or PLA (7.0, 3.6, 5.3, and 1.4 L-h, respectively; all comparisons, P < or = 0.020). At end point, the mean change from baseline in morning predose FEV(1) for FSC was significantly greater than that for FP, SAL, and PLA (0.41, 0.19, 0.15, and -0.12 L; all comparisons, P < or = 0.001). During 12 weeks of treatment, 7% of patients receiving FSC were withdrawn due to worsening asthma, compared with 24% of patients receiving SAL and 54% of patients receiving PLA (P < 0.001); 11% of patients receiving FP were withdrawn due to worsening asthma. Treatment with FSC resulted in significant improvements in morning and evening peak expiratory flow compared with FP, SAL, and PLA (both, P < 0.001); need for rescue albuterol compared with FP and PLA (P < or =0.005); and asthma symptom scores compared with PLA (P < 0.001). The tolerability of FSC was similar to that of FP or SAL alone. The incidence of possibly drug-related adverse events was generally similar across treatment groups, and the most common (occurring in > or= 2% of patients) were headache (1%-4%), throat irritation (1%-2%), candidiasis of the mouth/throat (0%-2%), unspecified oropharyngeal plaques (0%-2%), and palpitations (0%-2%). CONCLUSIONS: In these adolescent and adult patients whose asthma was not controlled by medium doses of an ICS, FSC delivered via HFA 134a MDI (2 inhalations of 110/21-microg strength administered BID) was more effective in improving lung function than FP or SAL monotherapy or PLA. All treatments were well tolerated.     

Agitated colloid is superior to saline and equivalent to levovist in enhancing tricuspid regurgitation Doppler envelope and in the opacification of right heart chambers: a quantitative, qualitative, and cost-effectiveness study.

BACKGROUND: Doppler spectrum of tricuspid regurgitation (TR) is used to noninvasively assess right ventricular (RV) pressure. With mild TR, the native (Nat) TR envelope may not allow accurate pressure evaluation. Proprietary contrast agents, such as Levovist (Lev) can be used to augment TR Doppler and opacify right-sided heart chambers, but they are expensive, and their efficacy has not been objectively evaluated in patients with difficult baseline studies or compared with less expensive saline (Sal) or colloid solutions, such as Gelofusine (Gel). METHODS: Twenty-five consecutive patients with poor quality Nat TR envelopes on transthoracic echocardiogram were reexamined after serial intravenous injection of 3 contrast agents (Sal, Gel, and Lev). Doppler signals for each agent recorded on video and digitally on optical disk were assessed for signal quality, estimated RV pressure, interobserver and intraobserver variation, and longevity of signal. Quality of right ventricular-right atrial (RV-RA) opacification was also determined for Sal and Gel. Of the 25 patients, 9 underwent percutaneous right-sided heart catheterization. We used the pressures obtained from the catheterization to independently evaluate the pressure estimates from echocardiography. RESULTS: All 3 contrast agents significantly improved the mean quality grade (grades 0-5) of TR envelopes (Nat 1.12, Sal 1.97, Gel 2.56, Lev 2.41, P <.001), decreased the number of uninterpretable envelopes (grade 0) (Nat 49%, Sal 12%, Gel 4%, Lev 12%, P <.0001 for comparison of each agent relative to Nat), and improved the correlation between echocardiographic and catheter-derived RV-RA pressure measurements (Nat r = 0.65, Sal r = 0.75, Gel r = 0.90, Lev r = 0.88). The persistence of enhanced Doppler signals of interpretable quality (> grade 1) was greater for Lev (15.8 seconds) and Gel (15 seconds) than Sal (7.6 seconds) (P =.002). Opacification of RV and RA, measured as mean luminosity score during 2-dimensional harmonic imaging, was significantly higher for Gel than Sal (92.84 +/- 31.2 vs 56.06 +/- 25.6, respectively; P =.0003). Sal, Gel and Lev, respectively, cost $0.10, $2.50, and $75.00 per study. CONCLUSION: Agitated colloid is a novel, effective, and inexpensive alternative to proprietary agents and saline for the assessment of pulmonary systolic pressure and right-sided heart opacification.     

Pharmacokinetic basis for the efficient and safe use of low-dose mycophenolate mofetil in combination with tacrolimus in kidney transplantation.

BACKGROUND: Mycophenolate mofetil (MMF) is an effective posttransplantation immunosuppressive agent used in combination with cyclosporin A (CsA) or tacrolimus (Tc). An increase in plasma mycophenolic acid (MPA) has been shown in patients receiving Tc-MMF combination therapy compared with CsA-MMF combination therapy at the same dose of MMF. The aim of this prospective study was to assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship for MPA in kidney transplant patients receiving low-dose MMF (500 mg twice a day) in combination with Tc. METHODS: Adult kidney transplant recipients (n = 51) were included. MPA-PK profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained within the first 2 weeks after transplantation, 3 months after grafting, and at every adverse clinical event [side effect or acute rejection (AR)]. All patients received Tc, MMF (500 mg twice a day), and steroids. RESULTS: Thirty patients (59%) had uneventful outcomes, and 21 patients had 33 episodes of MPA-related side effects; only 3 patients had AR. A total of 78 MPA-PK profiles were obtained. The following PK parameters were increased in the side-effects group compared with the non-side effects group: mean MPA c(min), 2.63 +/- 1.58 vs 1.75 +/- 0.82 mg/L (P = 0.016); mean c(30), 10.47 +/- 6.27 vs 7.66 +/- 8.95 mg/L (P = 0.009); mean c(60), 9.67 +/- 5.42 vs 5.83 +/- 2.6 mg/L (P = 0.0002); mean area under the MPA time-concentration curve from 0 to 12 h [MPA-AUC((0-12))], 48.38 +/- 18.5 vs 36.04 +/- 10.82 mg. h/L (P = 0.0006); mean dose-normalized MPA-AUC, 0.16 +/- 0.05 vs 0.12 +/- 0.04 (mg. h/L)/(mg/m(2)) (P = 0.0015). For the three AR patients, MPA concentrations obtained at the time of AR revealed MPA c(min) values of 1.86, 1.76, and 3.83 mg/L, respectively, and MPA-AUC((0-12)) values of 37.7, 24.9, and 104.9 mg. h/L. The threshold of toxicity was 3 mg/L (sensitivity, 38.7%; specificity, 91.5%) for c(min), 8.09 mg/L for maximum MPA concentration during the first hour (sensitivity, 77.8%; specificity, 67.4%), and 37.6 mg. h/L for MPA-AUC((0-12)) (sensitivity, 83.3%; specificity, 59.6%). CONCLUSIONS: These results demonstrate the relationship between plasma MPA concentrations and toxicity. High c(min), c(30), and c(60) values as well as AUC((0-12)) are associated with increased risk for side effects. These values may have an importance in a routine monitoring program.     

Pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin in patients with major thermal injuries

Adequate penetration of antibiotics into burn tissue and maintenance of effective serum levels are essential for the treatment of patients sustaining major thermal injuries. The pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin were determined in 12 critically ill patients with burn injuries. Mean age for the 12 patients was 45 +/- 17 (range 25-82 years), total body surface area burned (TBSAB) = 38 +/- 15% and Acute Physiology and Chronic Health Evaluation (APACHE) II score = 8 +/- 6. Patients received recommended doses of ciprofloxacin, 400 mg q12h iv, for three doses beginning 72 h post-burn. Serum concentrations were measured at t = 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 4.0 and 12.0 h after the first and third doses. Burn eschar biopsies were obtained after the third ciprofloxacin dose. Three of these 12 patients (25%) manifested later signs of clinical sepsis (TBSAB = 61 +/- 6% and APACHE II score = 11 +/- 3) and underwent a second infusion of three doses of intravenous ciprofloxacin, blood sampling and eschar biopsy. Serum and eschar concentrations were determined by high performance liquid chromatography. Serum ciprofloxacin concentrations were comparable to those of normal volunteers (C(max) = 4.0 +/- 1 mg/L and AUC = 11.4 +/- 2 mg.h/L) during the immediate post-burn period after dose 1 (C(max1) = 4.8 +/- 3 mg/L and AUC(0-12) = 12.5 +/- 7 mg. h/L) and dose 3 (C(max3) = 4.9 +/- 2 mg/L and AUC(24-36) = 17.5 +/- 11 mg.h/L). Mean burn eschar concentration during the 72 h post-burn was significantly lower than that found during clinical sepsis (18 +/- 17 compared with 41.3 +/- 54 microg/g; P < 0.05 by t test). Similar serum concentrations were achieved in patients with clinical sepsis (C(max1) = 4.2 +/- 0.2 mg/L and AUC(0-12) = 15.0 +/- 3 mg. h/L; C(max3) = 5.0 +/- 1 mg/L and AUC(24-36) = 22.8 +/- 9 mg.h/L). A positive correlation between burn eschar concentrations and C(max) (r = 0.71, r(2) = 0.51, P = 0.01) was found by linear regression analysis. A C(max)/MIC ratio > 10 (MIC = 0.5 mg/L) and an AUC/MIC ratio > 100 SIT(-1).h (serum inhibitory titre) (MIC = 0.125 mg/L) were achieved. High burn eschar concentrations and serum levels, similar to those found in normal volunteers, can be achieved after intravenous ciprofloxacin infusion in critically ill burns patients.     

Ionized magnesium levels and the ratio of ionized calcium to magnesium in asthma patients before and after treatment with magnesium

OBJECTIVE: Prior studies have been equivocal about the efficacy of magnesium therapy in acute asthma exacerbations. We hypothesize that pretreatment ionized magnesium (Mg(2+)) levels and/or the ratio of ionized calcium to ionized magnesium (Ca(2+)/Mg(2+)) may have been confounding variables in these previous studies. Here, we report on the incidence of abnormal divalent ion levels in our asthma population. MATERIAL AND METHODS: The study was designed as a randomized, double-blind, placebo-controlled trial of intravenous magnesium. Inclusion criteria were: age >18 years, percentage predicted forced expiratory volume (FEV(1)) <75 % after an initial beta-agonist. African-American patients (AA) at an urban university hospital were randomized to 2 g IV Mg or placebo. Mg(2+) and Ca(2+)/Mg(2+) levels were measured pre- and post-infusion. Data were reported as means+/-SD. Student's t-test and Fisher's exact test were used where appropriate (alpha = 0.05, two tailed). RESULTS: Fifty-five AA patients (mean age of 42.7 years+/-15.6 years, range 18-75 years) were studied. A significantly (p<0.05) lower level of Mg(2+) was found in asthma (AS) patients compared with that in the AA group, by 0.03 mmol/L (95 % CI, 0.007-0.053 mmol/L). The AS group had a mean increase in Ca(2+)/Mg(2+) ratios over the AA group, of 0.27 (95 % CI, 0.16-0.38); 100 % of patients with abnormal divalent ion levels were corrected with IV magnesium. CONCLUSIONS: We identified a subgroup of asthmatic patients with significant abnormalities in their divalent ion concentrations, which was corrected with IV magnesium.