bedoradrine and Asthma

In severe asthma attacks or in severe chronic obstructive pulmonary disease (COPD) exacerbations, inhaled short-acting bronchodilators, such as salbutamol (albuterol), terbutaline or ipratropium, often have a limited effectiveness due to significantly impaired ventilation. For these reasons, the use of a systemic bronchodilator medication might be more appropriate as therapeutic options. However, such formulations, especially salbutamol, are usually, and unfortunately, associated with a high risk of cardiovascular events. For this reason, they are only seldom used, especially in the case of paediatric populations.. This drug evaluation paper reviews the potential therapeutic agent bedoradrine, an ultraselective β2 agonist, which is currently under development for treating exacerbated asthma and COPD. The article includes a review of both in vitro and in vivo studies as well as a review of the pharmacokinetics, efficacy, safety and tolerability.. The intravenous use of bedoradrine has demonstrated promising preliminary efficacy in existing clinical trials for exacerbated asthma. However, the efficacy of bedoradrine is still uncertain in exacerbated COPD. Further clinical studies should assess the efficacy and safety of bedoradrine as an add-on therapy to usual standardised approach and exacerbation-related variables should be used as outcome measures.

Topics: Acetamides; Adrenergic beta-2 Receptor Agonists; Animals; Asthma; Bronchodilator Agents; Child; Humans; Naphthalenes; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index

Inhaled beta-agonist therapy is central to the management of acute asthma. This review evaluates the benefit of an additional use of intravenous beta(2)-agonist agents.. To determine the benefit of adding intravenous (IV) beta(2)-agonists to inhaled beta(2)-agonist therapy for acute asthma treated in the emergency department.. Randomised controlled trials (RCTs) were identified using the Cochrane Airways Group Register which is a compilation of systematic searches of MEDLINE, EMBASE, CINAHL, and CENTRAL as well as handsearching of 20 respiratory journals. Bibliographies from included studies and known reviews were also searched. Primary authors and content experts were contacted to identify eligible studies. The search was performed in September 2012.. Only RCTs were considered for inclusion. Studies were included if patients presented to the emergency department with acute asthma and were treated with IV beta(2)-agonists with inhaled beta(2)-agonist therapy and existing standard treatments versus inhaled beta(2)-agonists and existing standard treatments.. Two review authors independently extracted data and confirmed their findings with corresponding authors of trials. We obtained missing data from authors or calculated from data present in the papers. We used fixed-effect model for odds ratios (OR) and for mean differences (MD) we used both fixed-effect and random-effects models and reported 95% confidence intervals (CI).. From 109 potentially relevant studies only three (104 patients) met our inclusion criteria: Bogie 2007 (46 children), Browne 1997 (29 children) and Nowak 2010 (29 adults). Bogie 2007 investigated the addition of intravenous terbutaline to high dose nebulised albuterol in children with acute severe asthma, requiring intensive care unit (ICU) admission. Browne 1997 investigated the benefit of adding intravenous salbutamol to inhaled salbutamol in children with acute severe asthma in the emergency department. Nowak 2010 investigated addition of IV bedoradrine to standard care (nebulised albuterol, ipratropium and oral corticosteroids) among adults, and was reported as a conference abstract only.There was no significant advantage (OR 0.29; 95%CI 0.06 to 1.38, one trial, 29 adults) for adding IV bedoradrine to standard care (nebulised albuterol, ipratropium and oral corticosteroids) with regard to hospitalisation rates.Various outcome indicators for the length of stay were reported among the trials. Browne 1997 reported a significantly shorter recovery time (in terms of cessation of 30 minute salbutamol) for children in the IV salbutamol with inhaled salbutamol group (four hours) versus the 11.1 hours for the inhaled salbutamol group (P = 0.03). Time to cessation of hourly nebuliser was also significantly shorter (P = 0.02) for the IV plus inhaled salbutamol group (11.5 hours versus 21.2 hours), and they were ready for emergency patient discharge on average 9.7 hours earlier than the inhaled salbutamol group (P < 0.05). In a paediatric ICU study Bogie 2007 reported no significant advantage in length of paediatric ICU admission (hours) for adding IV terbutaline to nebulised albuterol (MD -12.95, 95% CI: -38.74, 12.84).Browne 1997 reported there were only six out of 14 children with a pulmonary index score above six in the IV plus inhaled salbutamol group at two hours compared with 14 of the 15 in the inhaled salbutamol group (P = 0.02)In Browne 1997 there was a higher proportion of tremor in the IV plus inhaled salbutamol group than in the inhaled salbutamol group (P < 0.02). Nowak 2010 did not report any statistically significant adverse effects associated with adding IV bedoradrine to standard care (nebulised albuterol, ipratropium and oral corticosteroids). Troponin levels were elevated in three children in the IV terbutaline + nebulised albuterol group at 12 and 24 hours in Bogie 2007. There is very limited evidence from one study (Browne 1997) to support the use of IV beta(2)-agonists in children with severe acute asthma with respect to shorter recovery time, and similarly there is limited evidence (again from one study Browne 1997) suggesting benefit with regard to pulmonary index scores; however this advantage needs to be considered carefully in relation to the increased side effects associated with IV beta(2)-agonists. We identified no significant benefits for adults with severe acute asthma. Until more, adequately powered, high quality clinical trials in this area are conducted it is not possible to form a robust evaluation of the addition of IV beta(2)-agonists in children or adults with severe acute asthma.

Topics: Acetamides; Acute Disease; Administration, Inhalation; Administration, Intravenous; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Albuterol; Anti-Asthmatic Agents; Asthma; Child; Drug Therapy, Combination; Emergencies; Humans; Ipratropium; Naphthalenes; Randomized Controlled Trials as Topic; Terbutaline

Many patients with acute exacerbation of asthma are non-responders to inhaled β-adrenergic agonists. The goal of this study was to evaluate the safety and efficacy of intravenous bedoradrine (MN-221), a highly selective β2-adrenergic agonist, as adjunct to standard therapy in the management of patients with acute exacerbation of asthma who did not respond to standard therapy.. Patients (N = 167) received standard therapy and were randomized to either bedoradrine (1200 μg) or placebo. Safety and efficacy parameters were monitored hourly for 3 h, followed by a 24-h follow-up visit and an 8-day follow-up phone call. Change in %FEV1 from baseline to Hour 3 was the primary outcome. Secondary outcome measures included change in %FEV1 at 1 and 2 h, change in dyspnea score at 1, 2, and 3 h, treatment failure rate, defined as a combination of hospitalization on the index visit or return to the emergency department within 1 week, and safety monitoring.. There was no significant difference in %FEV1 at 3 h between the 2 groups. The dyspnea scores were significantly improved for patients treated with bedoradrine compared to placebo (AUC0-2 hP < 0.005, AUC0-3 hP < 0.05). The safety profile for those treated with bedoradrine was consistent with the known mechanism of action of β-adrenergic agonists, and included both cardiovascular and metabolic effects.. Intravenous bedoradrine, in addition to standard therapy, did not significantly increase %FEV1 at 3 h, but it was associated with significantly improved dyspnea scores.. Clinicaltrials.gov; study name: MN-221-CL-007, registration number: NCT00838591; www.clinical trials.gov.

Topics: Acetamides; Acute Disease; Administration, Inhalation; Administration, Intravenous; Adrenergic beta-2 Receptor Agonists; Adult; Asthma; Bronchodilator Agents; Double-Blind Method; Dyspnea; Female; Glucocorticoids; Humans; Ipratropium; Male; Middle Aged; Naphthalenes; Prednisone; Prospective Studies; Spirometry; Treatment Outcome

The number of hospitalizations or deaths due to asthma, most of which result from acute exacerbations of asthma, has remained the same for the past 20 years. MN-221 (bedoradrine sulfate) is a novel, highly selective beta2- (β2-) adrenergic agonist administered via intravenous (IV) infusion in development for the treatment for acute exacerbation of asthma.. Trial MN-221-CL-004 assessed the safety profile and preliminary efficacy of MN-221 in escalating doses in patients with stable mild-to-moderate asthma. Study MN-221-CL-005 assessed the safety profile and preliminary efficacy of MN-221 in patients with stable moderate-to-severe asthma when given as a fixed dose over 1- or 2- hr infusion.. Two randomized, placebo-controlled clinical trials (n = 40) were performed to evaluate the pharmacokinetic (PK) and clinical effects of a novel, highly selective β2-agonist, MN-221, via IV infusion. Safety evaluations included vital signs, adverse events (AEs), clinical laboratory parameters, and electrocardiogram results. Efficacy evaluation included measurement of forced expiratory volume in 1 second (FEV) a₁nd PK parameters were additionally monitored. The study was reviewed and approved by the Institutional Review Board at each site.. Adverse effects were mild or moderate and there were no serious AEs or deaths during the studies. The most frequently reported AEs were tremor, hypokalemia, and headache. There were no consistent dose-dependent effects of MN-221 on any safety parameters, with the exception of heart rate, which was not considered to be clinically significant and did not require any treatment. Moderate hypokalemia occurred once in one subject in the MN-221-CL-004 study and twice in one subject in the MN-221-CL-005 study and were transient and returned to normal range following single oral potassium chloride treatments. PK assessments indicated a linear response in MN-221 plasma concentrations for the doses evaluated. Dose escalation results showed that mean changes in FEV₁ from pre-infusion were significantly greater than placebo and an overall dose response was statistically significant (p < .0001). Post-infusion FEV1 improvements appeared to plateau at the 30 μg/min dose level despite a higher peak plasma concentration at 60 μg/min. Dose-rate escalation results demonstrated greater mean increases in change in FEV₁ compared to the placebo group with the largest increase associated with the higher MN-221 dose rate and peak plasma concentration.. The safety profile of MN-221 and evidence of dose- and plasma-concentration-related bronchodilation supports further clinical development and suggests the potential for clinical benefit without increased clinical risk, particularly for patients where inhaled or nebulized therapy is not adequate or possible. Trial registry name and registration number:Name: MN-221-CL-005Number: NCT00679263.

Topics: Acetamides; Adolescent; Adrenergic beta-2 Receptor Agonists; Adult; Area Under Curve; Asthma; Bronchodilator Agents; Dose-Response Relationship, Drug; Electrocardiography; Female; Forced Expiratory Volume; Humans; Infusions, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Naphthalenes; Young Adult