Kazuko Matsuda

Albuterol Administration Is Commonly Associated With Increases in Serum Lactate in Patients With Asthma Treated for Acute Exacerbation of Asthma

BACKGROUND Controversy exists around the incidence and cause of hyperlactatemia during asthma exacerbations. We evaluated the incidence, potential causes, and adverse events of hyperlactatemia in patients with acute asthma exacerbation. METHODS This study was a subanalysis of subjects receiving placebo from a prospective, randomized trial evaluating an IV b -adrenergic agonist in acute asthma exacerbation. Plasma albuterol, serum lactate, and bicarbonate concentrations were measured at baseline and 1.25 h, and dyspnea score and spirometry were measured at baseline and hourly for 3 h. All subjects had a therapeutic trial comprising 5 to 15 mg nebulized albuterol, 0.5 to 1 mg nebulized ipratropium, and at least 50 mg oral prednisone or its equivalent prior to initiation of the study. Following randomization, subjects were treated with continued albuterol and IV magnesium at the discretion of their treating physician. Subjects were followed to hospital admission or discharge with follow-up at 24 h and 1 week. RESULTS One hundred seventy-fi ve subjects were enrolled in the parent trial, with 84 in the placebo group. Sixty-fi ve had complete data. Mean SD albuterol administration prior to baseline was 12.3 5.3 mg. Mean baseline lactate was 18.5 8.4 mg/dL vs 26.5 11.8 mg/dL at 1.25 h ( P , .001). Forty-fi ve subjects (69.2%) had hyperlactatemia. Mean baseline bicarbonate level was 22.6 2.9 mEq/L vs 21.9 4.0 mEq/L at 1.25 h ( P 5 .11). Plasma albuterol concentration correlated with lactate concentration ( b 5 0.45, P , .001) and maintained a significant association after adjusting for asthma severity ( b 5 0.41, P 5 .001). Hyperlactatemia did not increase the risk of hospitalization or relapse ( P 5 .26) or was associated with lower FEV 1 % predicted at 3 h ( P 5 .54). CONCLUSIONS Plasma albuterol was significantly correlated with serum lactate concentration after adjusting for asthma severity. Hyperlactatemia was not associated with poorer pulmonary function as measured by 3-h FEV 1 % predicted or increased hospitalization or relapse at 1 week.

Development of a real-time quantitative PCR assay for detection of a stable genomic region of BK virus

BackgroundBK virus infections can have clinically significant consequences in immunocompromised individuals. Detection and monitoring of active BK virus infections in certain situations is recommended and therefore PCR assays for detection of BK virus have been developed. The performance of current BK PCR detection assays is limited by the existence of viral polymorphisms, unknown at the time of assay development, resulting in inconsistent detection of BK virus. The objective of this study was to identify a stable region of the BK viral genome for detection by PCR that would be minimally affected by polymorphisms as more sequence data for BK virus becomes available.ResultsEmploying a combination of techniques, including amino acid and DNA sequence alignment and interspecies analysis, a conserved, stable PCR target region of the BK viral genomic region was identified within the VP2 gene. A real-time quantitative PCR assay was then developed that is specific for BK virus, has an analytical sensitivity of 15 copies/reaction (450 copies/ml) and is highly reproducible (CV ≤ 5.0%).ConclusionIdentifying stable PCR target regions when limited DNA sequence data is available may be possible by combining multiple analysis techniques to elucidate potential functional constraints on genomic regions. Applying this approach to the development of a real-time quantitative PCR assay for BK virus resulted in an accurate method with potential clinical applications and advantages over existing BK assays.

Bacterial Identification by 16S rRNA Gene PCR-Hybridization as a Supplement to Negative Culture Results

ABSTRACT PCR-hybridization was compared to culture methods for evaluating suspected blood infections. A total of 231 clinical samples from blood culture bottles that were flagged positive by the BacT/Alert system or were negative 1 week after inoculation were tested. When the PCR-hybridization and culture method results were compared, the positive and negative concordance rates were 99.2% (122/123) and 89.5% (94/105), respectively. Of the negative blood cultures, 10.5% (11/105) were positive by PCR-hybridization. Supplemental testing of negative blood cultures may identify bacterial pathogens that are undetectable by culture methods.

Evaluation of Bedoradrine Sulfate (MN-221), a Novel, Highly Selective Beta2-Adrenergic Receptor Agonist for the Treatment of Asthma via Intravenous Infusion

Background. 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. Objectives. 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. Methods. 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 (FEV1) and PK parameters were additionally monitored. The study was reviewed and approved by the Institutional Review Board at each site. Results. 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. Conclusions. 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

Efficacy of a new intravenous β2-adrenergic agonist (bedoradrine, MN-221) for patients with an acute exacerbation of asthma.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS Intravenous bedoradrine, in addition to standard therapy, did not significantly increase %FEV1 at 3 h, but it was associated with significantly improved dyspnea scores. TRIAL REGISTRATION Clinicaltrials.gov; study name: MN-221-CL-007, registration number: NCT00838591; www.clinical trials.gov.