Relative systemic availability of budesonide in patients with asthma after inhalation from two dry powder inhalers

ABSTRACT

Background: To improve dosing consistency and product features, budesonide inhalation powder delivered via a dry powder inhaler (DPI) (DPI?A^* 200?μg) was redesigned to include lactose, a newly shaped mouthpiece, and a new dose indicator (DPI?B^*). Budesonide DPI?B is available in two strengths (90?μg, 180?μg).

Objective: To compare the relative rate and extent of the systemic availability of budesonide inhaled via DPI?A and DPI?B and test for systemic absorption bio­equivalence.

Methods: Adults (n?=37) with asthma as defined by the American Thoracic Society were randomized in an open-label, crossover, single-center, single-dose study to budesonide DPI?A 200?μg × 4 inhalations, budesonide DPI?B 180?μg × 4 inhalations, or budesonide DPI?B 90?μg × 8 inhalations, on 3 days, each separated by a washout period of?≥?5 days. Plasma samples were collected immediately before and up to 12?h after dosing. Primary pharmacokinetic variables were area under the drug plasma concentration–time curve from 0 to infinity (AUC_0–∞) and maximum plasma concentration (C_max); plasma concentration at 12?h (C_12h) and time to maximum plasma concentration (T_max) were secondary variables. Treatments were considered bioequivalent if the 90% confidence intervals (CIs) for their AUC_0–∞ and C_max ratios fell between 80 and 125%. Adverse events were collected.

Results: The 90% CIs for the ratios of AUC_0–∞ and C_max for budesonide DPI?A 200?μg and DPI?B 180?μg and for both budesonide DPI?B strengths fell between 80% and 125% (AUC_0–∞: budesonide DPI?B 180?μg × 4/DPI?A 200?μg × 4: 96.3% [90 % CI: 90.9, 102.1]; budesonide DPI?B 180?μg × 4/DPI?B 90?μg × 8: 92.2% [90 % CI: 87.0, 97.7]; C_max: (budesonide DPI?B 180?μg × 4/DPI?A 200?μg × 4: 100.4% [95 % CI: 92.1, 109.4]; budesonide DPI?B 180?μg × 4/DPI?B 90?μg × 8: 94.4% [90 % CI: 86.6, 102.9]). No differences in C_12h and T_max were found between treatments. All treatments were well tolerated.

Conclusions: Budesonide DPI?A 200?μg and DPI?B 180?μg have systemic absorption bioequivalence, and DPI?B 90?μg and 180?μg are dose-strength equivalent when administered at the same dose. These results may not be generalized to all patients with asthma, as this analysis included only patients with mild-to-moderate asthma aged?≥?19 years.     

The effect of budesonide and formoterol in one pressurized metered-dose inhaler on patient-reported outcomes in adults with mild-to-moderate persistent asthma

ABSTRACT

Objective: To determine the effects of budesonide and formoterol administered via one pressurized metered-dose inhaler (budesonide/formoterol pMDI) on patient-reported outcomes (PROs) and to determine the contributions of budesonide and formoterol to those effects in adults with asthma.

Research design and methods: A 12-week, random­ized, double-blind, double-dummy, placebo-controlled, multicenter study was conducted in 480 patients aged ≥?12 years with mild-to-moderate persistent asthma. After a 2-week run-in period during which current asthma therapy was discontinued, patients were randomized to receive two inhalations twice daily of budesonide/formo­terol pMDI 80/4.5?μg (160/9?μg), budesonide pMDI 80?μg (160?μg), formoterol via dry powder inhaler (DPI) 4.5?μg (9?μg), or placebo.

Main outcome measures: Analyses included a subpopulation of 405 patients aged ≥?18 years. PROs included the standardized Asthma Quality of Life Questionnaire (AQLQ(S)), the Medical Outcomes Study (MOS) Sleep Scale, the Patient Satisfaction with Asthma Medication (PSAM) questionnaire, and asthma control variables (recorded via electronic diaries), such as asthma symptoms, rescue medication use, and nighttime awakenings due to asthma. Patient and physician global assessments were collected at the end of the study.

Results: Patients aged ≥?18 years receiving budesonide/formoterol pMDI reported significantly greater improvements from baseline in AQLQ overall and domain scores, MOS Sleep Scale domain scores, and asthma control variables than patients receiving placebo (?p ≤ 0.033). Improvements from baseline in AQLQ(S) overall and domain scores, daily asthma symptoms scores, percentage of symptom-free days, percentage of rescue medication-free days, and percentage of asthma control days were significantly greater in patients receiving budesonide/formoterol pMDI versus formoterol DPI (?p ≤ 0.042). Patients receiving budesonide/formoterol pMDI reported significantly greater PSAM scores than did patients in all other treatment arms (?p ≤ 0.004). Study limitations may include the fact that the formoterol-alone arm used a different device and formulation than the other active arms as well as the absence of a treatment arm with budesonide and formoterol administered concomit­antly in separate inhalers. In addition, these results may not be generalized to all patients with asthma, as this analysis included only patients aged ≥?18 years.

Conclusions: Patients receiving treatment with budesonide/for­moterol pMDI experienced significantly greater improvements from baseline in asthma-related quality of life, quality of sleep, and asthma control and greater satisfaction with treatment than patients receiving placebo. The combination of budesonide and formoterol in one pMDI is beneficial in improving how a patient feels and functions as a result of treatment.     

Efficacy and safety of budesonide and formoterol in one pressurised metered-dose inhaler in adults and adolescents with moderate to severe asthma: a randomised clinical trial

BACKGROUND: Inhaled corticosteroids (ICSs) are the preferred maintenance therapy for adults and children with mild, moderate and severe persistent asthma, with the addition of a long-acting beta(2)-adrenoceptor agonist to ICS therapy recommended for patients with moderate or severe persistent asthma. The efficacy and safety of the combination of budesonide and formoterol delivered via dry powder inhaler (DPI) is well documented. OBJECTIVE: To compare the efficacy and safety of budesonide/formoterol pressurised metered-dose inhaler (budesonide/formoterol pMDI; Symbicort pMDI, AstraZeneca LP, Wilmington, DE, USA) with budesonide pMDI (Pulmicort pMDI, Astra [corrected] Zeneca, Lund, Sweden), formoterol DPI (Oxis Turbuhaler, AstraZeneca, Lund, Sweden), budesonide plus formoterol in separate inhalers (budesonide pMDI + formoterol DPI) and placebo. STUDY DESIGN: This was a 12-week randomised, double-blind, double-dummy, placebo-controlled study. SETTING: This multicentre study was conducted in the respiratory specialty clinical practice setting. PATIENTS: The study included 596 patients > or =12 years of age with moderate to severe persistent asthma previously receiving ICSs. INTERVENTIONS: After 2 weeks on budesonide pMDI 80 microg x two inhalations (160 microg) twice daily, patients received budesonide/formoterol pMDI 160 microg/4.5 microg x two inhalations (320 microg/9 microg); budesonide pMDI 160 microg x two inhalations (320 microg) + formoterol DPI 4.5 microg x two inhalations (9 microg); budesonide pMDI 160 microg x two inhalations (320 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); or placebo twice daily. MAIN OUTCOME MEASURES: There were two prespecified primary efficacy variables: mean change from baseline in morning predose forced expiratory volume in 1 second (FEV(1)), obtained approximately 12 hours after the most recent administration of study medication at home and immediately before the next administration of study medication at the clinic; and mean change from baseline in 12-hour FEV(1), assessed as the average change in FEV(1) from serial spirometry over the 12-hour period after administration of the morning dose of study medication at the clinic. RESULTS: Mean changes from baseline in morning predose FEV(1) at end of treatment were greater (p < or = 0.049) with budesonide/formoterol pMDI (0.19L) versus budesonide pMDI (0.10L), formoterol DPI (-0.12L) and placebo (-0.17L). Mean changes from baseline in 12-hour FEV(1) were greater (p < or = 0.001) with budesonide/formoterol pMDI after 1 day (0.37L), 2 weeks (0.34L) and at end of treatment (0.37L) versus budesonide pMDI (0.11, 0.15 and 0.15L) and placebo (0.09, -0.03 and -0.03L), and after 2 weeks and at end of treatment versus formoterol DPI (0.19 and 0.17L). Fewer (p < or = 0.025) patients receiving budesonide/formoterol pMDI versus monoproducts or placebo met worsening asthma criteria. Results were similar in the budesonide/formoterol pMDI group and the budesonide pMDI + formoterol DPI group on all measures. All treatments were well tolerated with similar safety profiles. CONCLUSIONS: In this population, twice-daily budesonide/formoterol pMDI provides asthma control significantly greater than the monocomponents or placebo and comparable with budesonide pMDI + formoterol DPI. Safety profiles were similar for all treatments.     

Efficacy and safety of single therapeutic and supratherapeutic doses of indacaterol versus salmeterol and salbutamol in patients with asthma

ABSTRACT

Objective: This study compared the bronchodilator efficacy and safety of indacaterol with placebo, salbutamol and salmeterol, in patients with persistent asthma, at single therapeutic and supratherapeutic doses.

Research design and methods: This was a randomised, open-label crossover study in adult subjects with asthma (forced expiratory volume in 1 second [FEV₁] ≥?60% predicted). In part A, patients (n = 20) received single doses of indacaterol 200?µg, salbutamol 200?µg, salmeterol 50?µg and placebo. In part B, patients (n = 19) received single doses of indacaterol 1000?µg, salbutamol 1000?µg, salmeterol 250?µg and placebo.

Main outcomes measures; Results: For the primary endpoint, FEV₁ area under the effect curve during 0–24?h, indacaterol 200?µg was statistically superior to placebo and salbutamol. Indacaterol 200?µg FEV₁ was higher than placebo (5?min to 24?h), salbutamol 200?µg (4–24?h), and salmeterol 50?µg (5 and 15?min and 22 and 24?h). Few adverse events were reported; all were mild or moderate in severity. Initial changes were observed in glucose, potassium, heart rate and QTc interval, but all values remained within normal ranges. Values matched placebo levels after a shorter time for indacaterol 1000?µg than for salmeterol 250?µg.

Conclusions: In this single-dose, open-label study, indacaterol 200?µg provided effective 24‐h bronchodilation, with a longer duration than salmeterol 50?µg and a good overall safety profile. The sustained bronchodilation of indacaterol 1000?µg was not associated with sustained systemic adverse effects.     

Mometasone furoate dry powder inhaler: a once-daily inhaled corticosteroid for the treatment of persistent asthma

ABSTRACT

Background: Mometasone furoate (MF), a potent synthetic inhaled corticosteroid (ICS) with a high affinity for the glucocorticoid receptor, is approved for use in the treatment of asthma.

Scope: Publications reviewed in this article were identified via searches of MEDLINE and EMBASE databases using the terms ‘mometasone furoate AND pharmacology’ and ‘mometasone furoate AND asthma AND clinical trial’. Data from abstracts presented at respiratory society meetings, and relevant background information, are also reviewed.

Findings: In clinical studies, MF, administered by dry powder inhaler (MF-DPI), was effective in treating all severities of persistent asthma, improving pulmonary function, reducing asthma symptoms, and reducing or eliminating the need for oral corticosteroids. Once-daily dosing of MF-DPI was effective in patients with mild or moderate persistent asthma previously taking twice-daily regimens of inhaled corticosteroids (ICSs), and in patients taking only inhaled β₂?agonists for symptom relief. Once-daily dosing in the evening with MF-DPI 200?µg conferred a greater benefit than morning dosing with MF-DPI 200?µg. Patients with severe asthma who were dependent on oral corticosteroids (OCSs) and high doses of ICSs were able to achieve greater asthma control and reduce or even eliminate OCSs when switched to MF-DPI. In trials of up to 1 year in duration, MF-DPI was well tolerated, with the majority of adverse events considered mild or moderate in intensity. MF had low systemic bioavailability and no clinically significant hypothalamic–pituitary–adrenal-axis suppression at therapeutic doses. The DPI device is a multiple-dose inhaler with a counter containing agglomerates of MF and lactose. Patients of all severities of persistent asthma were able to generate and maintain airflow profiles necessary to provide a uniform and accurate dose.

Limitations: Only one study evaluated both morning and evening administration of once-daily doses, and one of the comparative clinical trials was an open-label study.

Conclusion: Once-daily administration of MF-DPI 200–400?µg in patients with mild to moderate persistent asthma effectively improved lung function and asthma control. In patients with severe persistent asthma dependent on oral corticosteroids, treatment with MF-DPI 400?µg BID permitted substantial reduction of oral corticosteroid use. All MF-DPI treatments were well tolerated and had minimal systemic effects.     

Efficacy and safety of mometasone furoate administered once-daily in the evening in patients with persistent asthma dependent on inhaled corticosteroids

ABSTRACT

Background: Once-daily dosing with an inhaled corticosteroid (ICS) may simplify asthma management and improve patient compliance. Since asthma is frequently worse at night, evening dosing appears to be a more obvious choice to accommodate the chronobiology of asthma than morning dosing.

Objective: The primary study objective was to compare the efficacy and safety of mometasone furoate (MF) dry powder inhaler (MF-DPI) 400 µg qd PM (one 400 g inhalation) with placebo for the treatment of asthma in patients previously dependent on twice a day (bid, bis in die) ICS therapy. We also compared different regimens of MF-DPI with each other and with placebo.

Methods: This 12-week, multicenter, double-blind, placebo-controlled study evaluated lung function and asthma symptoms in 400 subjects with persistent asthma randomized to MF-DPI 200 µg qd (once a day, quaque die) PM, 400 µg qd PM as one inhalation from a 400 µg device, 400 µg qd PM as two inhalations from a 200 µg device, 200 µg twice daily (bid), or placebo. Evening doses were to be taken in the late afternoon or early evening, preferably before dinner time.

Results: Mean changes from baseline at endpoint in FEV₁ (forced expiratory volume in 1 s) were similar for MF-DPI 400 µg qd PM (one inhalation; 0.41 L), MF-DPI 400 g qd PM (2 inhalations; 0.49 L), MF-DPI 200 µg qd PM (0.41 L), and MF-DPI 200 µg bid (0.51 L); and all were significantly improved compared with placebo (0.16 L; p < 0.001). Secondary efficacy variables, including nocturnal awakenings and use of rescue albuterol, were also significantly improved with MF-DPI treatment compared with placebo. All treatments were generally safe and well tolerated, with adverse events of mild to moderate severity.

Conclusions: Once-daily evening dosing of MF-DPI at doses of 400 and 200 µg restored lung function and improved nocturnal and daytime symptom control in subjects with asthma previously dependent on bid ICS therapy. Comparable effectiveness of a total daily dose of 400 µg was demonstrated between once daily in the evening and twice-daily administration. The results also confirm the effectiveness of MF-DPI 200 µg qd PM, the lowest dose studied.     

Clinical comparability between the CFC and HFA budesonide pressurised metered-dose inhalers in paediatric patients with asthma: a randomised controlled trial

ABSTRACT

Objective: To evaluate the efficacy and tolerability of a novel hydrofluoroalkane (HFA) pressurised metered dose inhaler (pMDI) formulation of budesonide (Pulmicort) versus the conventional chlorofluorocarbon (CFC) pMDI formulation in paediatric patients with asthma.

Methods: This was a Phase III, multicentre, 12‐week, double-blind, randomised, parallel-group study involving children (6–12 years of age) with mild to moderate asthma. Patients received either budesonide HFA pMDI or budesonide CFC pMDI 200?µg twice daily, with or without a spacer (NebuChamber/Nebunette*). Primary efficacy endpoint: mean percentage change in forced expiratory volume in 1 second (FEV₁) from baseline to week 12. Secondary efficacy endpoints included changes in FEV₁ per cent of predicted normal, forced vital capacity, morning and evening peak expiratory flow rate, asthma symptoms and use of rescue medication.

Results: A total of 159 patients received treatment (HFA 77, CFC 82). For mean percentage change in FEV₁ from baseline to week 12, the difference between the treatments (CFC pMDI – HFA pMDI) was –3.1% (95% confidence interval [CI] –8.0% to 1.8%) for the full analysis set and was not affected by spacer use. The upper CI was < 10% (the predefined non-inferiority margin), so non-inferiority was demonstrated. Improvements in the secondary efficacy endpoints with both budesonide formulations were not significantly different. In both groups there were similar numbers of adverse events and no evidence of oral candidiasis at week 12.

Conclusions: Treatment with budesonide HFA pMDI is effective and well tolerated in children with asthma and is clinically comparable to budesonide CFC pMDI.     

The effect of adjustable dosing with budesonide/formoterol on health-related quality of life and asthma control compared with fixed dosing

SUMMARY

Background: Budesonide/formoterol in a single inhaler is an effective therapy for asthma. We investigated whether adjustable maintenance dosing with budesonide/formoterol could maintain health-related quality of life (HRQL) and asthma control.

Patients/methods: Asthma patients (n = 4025) received budesonide/formoterol (Symbicort* 160/4.5?µg) 2 inhalations twice daily (bid) for 4?weeks during run-in of this open, multicentre study. Patients were randomised to adjustable dosing (budesonide/formoterol 1 inhalation bid; stepping up to 2 or 4 inhalations bid for 1?week if asthma worsened) or fixed dosing (budesonide/formoterol 2 inhalations bid), for 12?weeks. Change in HRQL (standardised Asthma Quality of Life Questionnaire, AQLQ[S], score) during randomised treatment was the primary efficacy variable. Secondary variables included asthma control (peak expiratory flow [PEF], symptom-severity score, nocturnal awakenings, reliever-medication use) and study-medication intake.

Results: Clinically significant (≥ 0.5) improvements in AQLQ(S) score (mean 0.73), morning and evening PEF (mean 42.5 and 24.8?L/min, respectively), and symptom-severity score (mean 0.36) were achieved during run-in. The improvements were maintained in both groups although, overall, adjustable-dosing patients took fewer daily inhalations of budesonide/formoterol than fixed-dosing patients (mean 2.63 versus 3.82, p < 0.001).

Conclusion: Adjustable maintenance dosing with budesonide/formoterol maintains HRQL and asthma control as effectively as fixed dosing and is associated with a reduced drug load overall.     

Pharmacokinetics of budesonide and formoterol administered via 1 pressurized metered-dose inhaler in patients with asthma and COPD

In 3 open-label studies, the systemic bioavailability of budesonide and formoterol administered via pressurized metered-dose inhaler (pMDI) or dry powder inhaler (DPI) formulations was evaluated in asthma (24 children, 55 adults) or chronic obstructive pulmonary disease (COPD; n = 26) patients. Treatments were administered at doses high enough to estimate pharmacokinetic parameters reliably. Two of the studies included an experimental budesonide pMDI formulation. In study 1 (asthma, adults), budesonide area under the curve (AUC) was 32% and 31% lower and maximal budesonide concentration (C(max)) 45% and 56% lower after budesonide/formoterol pMDI and budesonide pMDI versus budesonide DPI. Formoterol AUC and C(max) were 13% and 39% lower after budesonide/formoterol pMDI versus formoterol DPI. In study 2 (asthma, children), budesonide AUC and C(max) were 27% and 41% lower after budesonide/formoterol pMDI versus budesonide DPI + formoterol DPI. In study 3 (COPD/asthma, adults), budesonide AUC and C(max) were similar and formoterol AUC and C(max) 18% and 22% greater after budesonide/formoterol pMDI versus budesonide pMDI + formoterol DPI (COPD). Budesonide and formoterol AUC were 12% and 15% higher in COPD versus asthma patients. In conclusion, systemic exposure generally is similar or lower with budesonide/formoterol pMDI versus combination therapy via separate DPIs or monotherapy and comparable between asthma and COPD patients.     

Once-daily sitagliptin,a dipeptidyl peptidase-4 inhibitor,for the treatment of patients with type 2 diabetes

ABSTRACT

Objective: Sitagliptin, an oral, potent, and selective dipeptidyl peptidase-4 (DPP?4) inhibitor was evaluated as once-daily monotherapy in a 12-week randomized, double-blind, placebo-controlled, parallel group, dose-ranging study. Additionally, the glycemic response to sitagliptin 100?mg daily was evaluated as a once-daily (100?mg once-daily) or twice-daily (50?mg twice-daily) dosing regimen.

Research design and methods: In a multinational, double-blind, randomized, placebo-controlled, parallel-group, dose-range finding study, 555 patients, 23–74 years of age, with HbA_1c of 6.5–10.0% were randomized to one of five treatment groups: placebo, sitagliptin 25, 50 or 100?mg once-daily, or sitagliptin 50?mg twice-daily for 12 weeks. The efficacy analysis was based on the all-patients-treated population using an ANCOVA model.

Results: Mean baseline HbA_1c ranged from 7.6 to 7.8% across treatment groups, with 29% of all patients with values ≤?7%. After 12 weeks, treatment with all doses of sitagliptin significantly (?p < 0.05) reduced HbA_1c by –0.39 to –0.56% and fasting plasma glucose by –11.0 to –17.2?mg/dLrelative to placebo, with the greatest reduction observed in the 100-mg once-daily group. Mean daily glucose was significantly (?p < 0.05) reduced by –14.0 to –22.6?mg/dL with all doses of sitagliptin relative to placebo. HOMA?β was significantly (?p < 0.05) increased by 11.3–15.2 with all sitagliptin doses relative to placebo. QUICKI and HOMA?IR were not significantly changed with sitagliptin treatment. There were no significant differences observed between the sitagliptin 100?mg once-daily and 50?mg twice-daily groups for any parameter. For sitagliptin, the incidence of adverse events of hypoglycemia was low, with one event in each of the 25- and 50-mg once-daily and 50-mg twice-daily treatment groups and two events in the 100?mg once-daily treatment group. There was no mean change in body weight with sitagliptin relative to placebo. Study duration may be a limitation because the extent of the glycemic response and the safety and tolerability may not have been fully elucidated in this 12-week study.

Conclusion: Sitagliptin monotherapy improved indices of glycemic control compared to placebo and was generally well-tolerated in patients with type 2 diabetes. The glycemic response to treatment with sitagliptin 100?mg/day was similar between the sitagliptin 100-mg once-daily and 50-mg twice-daily dose regimens.     

Maintenance plus reliever budesonide/formoterol compared with a higher maintenance dose of budesonide/formoterol plus formoterol as reliever in asthma:an efficacy and cost-effectiveness study

ABSTRACT

Objective: To evaluate efficacy and costeffectiveness of budesonide/formoterol (Symbicort) maintenance (one dose once or twice daily) plus additional doses as needed (Symbicort Maintenance And Reliever Therapy, SMART) compared with a higher fixed dose of budesonide/ formoterol with formoterol as needed in patients with persistent asthma.

Study design and methods: 6‐month, open, randomised study of 465 patients either not well controlled on an inhaled corticosteroid (ICS), or well controlled on a combination of ICS and a long-acting β₂‐agonist (LABA). Treatments: budesonide/formoterol 160/4.5?µg, one inhalation, once or twice daily maintenance plus additional doses as-needed (1 × SMART or 2 × SMART), or budesonide/formoterol 160/4.5?µg two inhalations twice daily plus formoterol 4.5?µg as needed (2 × 2 FIX + F). Children 6–11 years old used an 80/4.5?µg dose strength. Primary variables of efficacy were the changes in the Asthma Control Questionnaire (ACQ₅) and morning peak expiratory flow (PEF).

Results: Mean age of patients 40 years (range 6–82 years); 53% female. No differences between the groups were found in ACQ₅ scores or asthma exacerbation rates. Morning PEF was higher in the 2 × 2 FIX + F group vs. the 1 × SMART and 2 × SMART groups (differences 13?L/min and 9?L/min, respectively; p < 0.002). The 1 × SMART group showed a significant decrease in asthma controlled days compared with the two other groups. No difference was seen between the 2 × SMART group and the 2 × 2 FIX + F group. Treatment costs were significantly lower in the SMART groups compared with the 2 × 2 FIX + F group.

Conclusion: Compared with the 2 × 2 FIX + F treatment the use of budesonide/formoterol was 30–40% lower in the SMART groups while maintaining equal ACQ₅ scores. Daily asthma control improved equally with 2 × SMART compared to 2 × 2 FIX + F with a reduction in asthma medication cost. The one dose once daily maintenance treatment (1 × SMART) resulted in a low level of treatment failure (exacerbations) but led to more days with symptoms. Therefore, a daily dose of two inhalations seems to be the lowest appropriate dose in patients with moderate persistent asthma.     

Compatibility of arformoterol tartrate inhalation solution with three nebulized drugs

ABSTRACT

Objective: Arformoterol tartrate inhalation solution (15?μg/2?mL) is approved for the twice-daily, long-term maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary diseases (COPD). This study assessed the chemical and physical compatibility of arformoterol (15?μg/2?mL) with ipratropium bromide (0.5?mg/2.5?mL), acetylcysteine (800?mg/4?mL), and budesonide (0.25?mg/2?mL and 0.5?mg/2?mL).

Methods: Immediately (T₀) and 30?min (T₃₀) after preparation, the admixtures were tested by visual inspection, pH measurement, and HPLC assay of each active component.

Results: For all admixtures, no visible signs of change were observed. The pH of all admixtures at T₀ ranged from 4.82 to 6.40, which was within the range of individual drugs. For all admixtures, no unacceptable changes (less than 1% or 0.1 pH unit) in the pH values were observed within 30?min compared with the initial pH values in the admixtures, which met acceptance criteria of not more than (NMT) 10.0%. At both T₀ and T₃₀, the assay of each active component in all admixtures ranged from 98.3% to 101.4% compared to the assay in control samples, which met acceptance criteria of NMT 10.0%. In addition, no changes (less than 8%) in the assay of each active component at T₃₀ were observed compared to the initial assay values, which met acceptance criteria of NMT 10.0%. This study did not evaluate the clinical efficacy or safety of mixing arformoterol in patients. Nor did the study assess the aerosol characteristics of these admixtures or any potential changes in drug output.

Conclusion: The results demonstrated that arformoterol was chemically and physically compatible with commercially available nebulized formulations of ipratropium bromide, acetylcysteine, and budesonide.     

Budesonide/Formoterol pressurized metered-dose inhaler

*The corticosteroid budesonide and the long-acting [beta]2-adrenoceptor agonist formoterol have been combined into a single pressurized metered-dose inhaler (pMDI) for use in patients aged > or =12 years with asthma. *In well designed 12-week clinical trials in patients with mild to moderate or moderate to severe persistent asthma, lung function improved to a significantly greater extent with twice-daily budesonide/formoterol pMDI 160 [micro]g/9 [micro]g or 320 [micro]g/9 [micro]g than with placebo or the same nominal dosage of either of the components alone. *Budesonide/formoterol pMDI was also associated with improvements from baseline in patient-reported asthma control, asthma symptom and asthma-related quality of life outcomes that were significantly greater than those with placebo and, for many endpoints, monotherapy with the individual components. *In a 52-week safety study, treatment with twice-daily budesonide/formoterol pMDI 320 [micro]g/9 [micro]g was associated with rapid and durable improvements in lung function and asthma control that were significantly greater than those with twice-daily budesonide pMDI 640 [micro]g monotherapy. *Budesonide/formoterol pMDI was well tolerated in clinical trials. Its overall adverse event profile is consistent with the known tolerability profiles of long-acting [beta]2-adrenoceptor agonist and inhaled corticosteroid therapy, and is similar to that shown with placebo.     

The association between blood eosinophil count and benralizumab efficacy for patients with severe,uncontrolled asthma: subanalyses of the Phase III SIROCCO and CALIMA studies

Objective: Benralizumab, an anti-eosinophilic monoclonal antibody, in combination with high-dosage inhaled corticosteroids and long-acting β₂-agonists (ICS/LABA), significantly reduced asthma exacerbations, improved lung function, and reduced symptoms for patients with severe, uncontrolled asthma with blood eosinophil counts ≥300 cells/μL in the Phase III SIROCCO and CALIMA studies. To understand the efficacy and safety of benralizumab for patients with eosinophil-driven disease with blood eosinophil counts lower than 300 cells/μL, we evaluated the effect of applying an eosinophil cutoff of ≥150 cells/μL.

Methods: Adult patients with uncontrolled asthma despite high-dosage ICS/LABA?±?additional asthma controller(s) received subcutaneous benralizumab 30?mg every 8 weeks (Q8W; first three doses every 4 weeks) or placebo for 48 (SIROCCO) or 56 (CALIMA) weeks. Efficacy measures including annual exacerbation rate, prebronchodilator FEV₁, and total asthma symptom score were analyzed by baseline blood eosinophil counts ≥150 vs. <150 cells/μL.

Results: Benralizumab reduced asthma exacerbation rates by 42% in SIROCCO (rate ratio?=?0.58; 95% CI?=?0.46–0.74; p?n?=?325) and 36% in CALIMA (rate ratio?=?0.64; 95% CI?=?0.50–0.81; p?n?=?300) vs. placebo (n?=?306 for SIROCCO, n?=?315 for CALIMA) for patients with blood eosinophil counts ≥150 cells/μL. Benralizumab increased prebronchodilator FEV₁ (both studies, p?≤?0.002) and improved total asthma symptom score in SIROCCO (p?=?0.009) at end of treatment vs. placebo for patients with blood eosinophil counts ≥150 cells/μL. The overall adverse events frequency was similar between treatment groups and eosinophil count cohorts.

Conclusion: These results support the efficacy and safety of benralizumab for patients with severe asthma and blood eosinophil counts ≥150 cells/μL.     

Selenium and rutin alone or in combination do not have stronger protective effects than their separate effects against cadmium-induced renal damage

Context: Selenium (Se) and rutin (RUT) are antioxidants that protect against tissue damage.

Objective: In this study, the separate and combine protective effects of RUT and Se against cadmium (Cd)-induced renal damage were evaluated in rats.

Materials and methods: Wistar rats were treated by gavage to RUT (30?mg/kg) or Se (0.15?ppm) or Cd (200?ppm) in drinking water alone or in combination (30?mg/kg RUT?+0.15?ppm Se?+?200?ppm Cd). Corn oil was used as vehicle (2?mL/kg). After a 5-week treatment period, rat kidneys were removed for biochemical assays and histopathological examination. Se and Cd levels were evaluated by flame atomic absorption spectrophotometry.

Results: The malondialdehyde and glutathione levels as well as superoxide dismutase and catalase activities in the Cd-treated animals were increased compared with control values (0.056?±?0.0003 versus 0.011?±?0.0005?μmol/mg; 0.005?±?0.0006 versus 0.00085?±?0.0002?μg/mg; 1.62?±?0.09 versus 0.48?±?0.12 units/mg; 650?±?25 versus 361.89?±?31?μmol H₂O₂/mg, respectively). Cd treatment was also associated with decreased renal Se concentration (4.19?±?0.92 versus 7.73?±?0.7?μg/g dry weight), increased alkaline phosphatase (0.07?±?0.0015 versus 0.033?±?0.0019 unit/mg), acid phosphatase (0.029?±?0.0021 versus 0.015?±?0.0016 unit/mg), and lactate dehydrogenase (0.032?±?0.004 versus 0.014?±?0.0027 unit/mg) activities, respectively, and with evidence of severe renal damage. The combination of RUT and Se or their separate effects prevented the Cd-induced oxidative renal damage. However, their combine effects do not have stronger effects than their separate effect against Cd-induced renal damage.

Discussion and conclusion: RUT and Se function as potent antioxidant in the protection of renal damage induced by Cd.     

Concomitant inhaled corticosteroid resensitises cardiac β2-adrenoceptors in the presence of long-acting β2-agonist therapy

Objective: The aim of the present study was to evaluate the effects of concomitant inhaled corticosteroid therapy on the sensitivity of cardiac β₂-adrenoceptors in patients receiving regular long-acting β₂-agonists. Methods: Twelve healthy subjects (6 female), mean age 29 years, were randomised in a double-blind cross-over study to receive either inhaled placebo or inhaled budesonide 1.2 mg twice daily, each for 7 days, with a minimum of 7 days washout period between the two treatments. Patients also received concomitant treatment with inhaled eformoterol 24 μg twice daily during each of the 2 treatment periods. The patients attended the laboratory during both treatment periods at 0730 hours, when a dose-response curve for systemic β₂-adrenoceptor responses to inhaled salbutamol (0.8–3.2 mg) was constructed before and after completing 7 days of each treatment. Early morning (0800 hours) plasma cortisol was also evaluated as a marker of systemic glucocorticoid activity. Results: There was a significant fall in 0800 hours plasma cortisol induced by budesonide comparing pre- and post- values (407 vs 322 nmol · l⁻¹, but not with placebo. There were no differences in the response to salbutamol prior to treatment when comparing eformoterol with placebo versus eformoterol with budesonide. Comparing before and after within-treatment heart rate response, there was a significant reduction in peak salbutamol response with eformoterol and placebo, which was partially reversed by eformoterol and budesonide. For between-treatment comparisons after eformoterol treatment, the heart rate was significantly higher in the presence of budesonide in comparison with placebo for peak salbutamol response (change from baseline), i.e. 24.2 vs 34.7 beats · min⁻¹. There was, however, no significant difference in the peak delta potassium response to salbutamol after eformoterol treatment when comparing budesonide with placebo (−0.39 vs −0.48 mmol · l⁻¹). Conclusion: Concomitant therapy with inhaled budesonide resensitised the cardiac β₂-adrenoceptor response to salbutamol in subjects who were receiving regular twice-daily eformoterol. This may be of clinical relevance in terms of the propensity for systemic β₂-mediated adverse effects with repeated puffs of salbutamol, which might conceivably occur in the setting of acute asthma. Received: 28 October 1997 / Accepted in revised form: 11 March 1998     

A conscious rat model involving bradycardia and hypotension after oral administration: a toxicokinetical study of aconitine

1.?A model of aconitine-induced bradycardia and hypotension, which is similar to aconitine poisoning in humans, was constructed in conscious rats by oral administration.

2.?Blood pressure (BP) and heart rate (HR) of Sprague-Dawley rats were measured using a volume pressure recording (VPR) system. The pharmacokinetics of toxic doses of aconitine and its metabolites were analyzed using UPLC-MS/MS.

3.?The HR was significantly decreased by 29% at 2?h after oral administration of 200?μg/kg aconitine. When the dose was increased to 400?μg/kg, systolic BP and diastolic BP were significantly decreased by 11% and 12% at 2?h after the administration, except when bradycardia occurred at 2?h and 4?h. The drug concentration-time curve showed a double-peak phenomenon in rats administered a 400?μg/kg dose. The AUC_0–12?h value in the 400?μg/kg group significantly increased 0.8-fold compared to the 200?μg/kg group. Moreover, a high plasma concentration of 16-O-demethyaconitine was found in the rats that received two toxic doses.

4.?In conclusion, bradycardia and hypotension are induced in conscious rats by a toxic dose of aconitine (400?μg/kg), and there was no significant difference in dose-normalized AUC_0–12?h values between oral administrations of 200?μg/kg and that of 400?μg/kg. However, the dose-normalized C_max and AUC_0–12?h values in 200?μg/kg and 400?μg/kg groups were significantly smaller than those in 100?μg/kg group. The metabolites of aconitine, 16-O-demethyaconitine, and benzoylaconitine may also contribute to the hypotensive response.     

Pharmacokinetics of budesonide and formoterol administered via a series of single-drug and combination inhalers: four open-label, randomized, crossover studies in healthy adults

Objective: To investigate the pharmacokinetics of budesonide and formoterol administered concomitantly in healthy adults. Methods: Three single-dose, open-label crossover studies (n=28 each) were conducted (Study I: budesonide pMDI, formoterol DPI, budesonide pMDI+formoterol DPI; Study II: budesonide/formoterol pMDI, budesonide pMDI+formoterol DPI; Study III: budesonide/formoterol pMDI [three budesonide formulation strengths; constant formoterol]). Study IV (n=28) assessed steady state pharmacokinetics (budesonide/formoterol pMDI [two/four inhalations twice daily, 5-day treatment; four inhalations, single-dose]). Results: Study I: no pharmacokinetic interactions were observed between budesonide and formoterol. Study II: AUC ratios were 97.9% (budesonide) and 82.2% (formoterol) (budesonide/formoterol pMDI versus budesonide pMDI+formoterol DPI). Study III: formoterol AUC was comparable across budesonide/formoterol pMDI formulation strengths; budesonide AUC increased with formulation strength in proportion to fine particle dose. Study IV: dose proportionality was demonstrated for budesonide (AUC ratio, 104.3%) and suggested for formoterol (AUC ratio, 117.6%) with budesonide/formoterol pMDI (steady state); budesonide and formoterol AUC was higher with repeated versus single-dose budesonide/formoterol pMDI (four inhalations). Conclusions: No pharmacokinetic interactions were observed between budesonide and formoterol. Budesonide dose variation in budesonide/formoterol pMDI did not affect formoterol exposure. Steady state budesonide/formoterol pMDI dose-doubling yielded proportional increases in budesonide and formoterol exposure. Copyright © 2008 John Wiley & Sons, Ltd.     

Budesonide/formoterol for the treatment of asthma

Budesonide/formoterol (Symbicort^®, AstraZeneca plc) is a novel treatment for asthma, combining an inhaled corticosteroid – budesonide, and a long-acting β₂-agonist – formoterol, in a single inhaler, the Turbuhaler^®. Randomised, clinical studies in patients with asthma have demonstrated that budesonide/formoterol is more effective than the inhaled corticosteroids, budes-onide and fluticasone alone, and at least as effective as both monocomponents in separate inhalers. Results from clinical studies suggest a synergistic effect when both drugs are administered via one inhaler, although the mechanisms for this are not fully understood. Budesonide/formoterol has a rapid onset of effect, apparent within 1 min of treatment, which is largely because of the properties of formoterol. Once- and twice-daily dosing with budesonide/formoterol are effective treatment options for patients with mild or moderate asthma. Studies have also shown that the beneficial safety profiles and dose relationships of both budesonide and formoterol allow dose adjustments of budesonide/formoterol in response to variations in the patient’s asthma. Findings from the budesonide/formoterol adjustable maintenance dosing programme, comparing fixed and adjustable, symptom-guided dosing regimens, demonstrate that patients achieve equally good asthma control with adjustable dosing (from one inhalation twice-daily to more than four inhalations twice-daily), but at a significantly lower overall drug load. Adverse events, mainly expected inhaled corticosteroid and long-acting β₂agonist class effects, have been few in number and mild in nature. In addition, there is growing evidence that budesonide/formoterol is also effective in patients with chronic obstructive pulmonary disease. The future for treatment with budesonide/formoterol may include as-needed administration in addition to maintenance therapy.