Evidence of off-label inhalation therapy on pediatric asthma practice in Japan.

BACKGROUND: In Japan, many asthma inhalers do not have formal approval for use in the pediatric population because of the lack of domestic data. In real-world settings, however, numerous off-label medications are prescribed. Currently, the nature of off-label prescriptions of asthma inhalers on pediatric patients in Japan remains unclear. METHODS: Using public open-source national medical claims data, we investigated the real-world descriptive epidemiology of off-label prescriptions for asthma inhalers for pediatric patients. We obtained the number of off-label prescriptions of formulations for patients aged 0-14 years from anonymously summarized prescription data for a 7-year period starting from April 2014. The actual prescription numbers and their chronology over time were then analyzed. RESULTS: In 2019, 143,439 asthma inhalers were used off label in children and adolescents. Overall, 96.1% were inhaled corticosteroids (ICSs) or long-acting beta stimulants (LABAs), and 3.9% were high-dose ICS. Of ICSs and LABAs, 18.8% were off-label prescriptions. The total number of off-label ICS/LABA prescriptions and their percentage relative to the overall formulations gradually decreased but a notable disparity was observed among inhaler types. CONCLUSIONS: There was a surprisingly large number of off-label prescriptions of asthma inhalers in the pediatric population in Japan. The proper use of ICSs/LABAs and expansion of insurance coverage should be advocated to reduce off-label use.

Recent advances in the treatment of childhood asthma: a clinical pharmacology perspective.

INTRODUCTION: Childhood asthma is a complex heterogenous inflammatory disease that can pose a large burden on patients and their caregivers. There is a strong need to adapt asthma treatment to the individual patient taking into account underlying inflammatory profiles, moving from a 'one size fits all' approach toward a much-needed personalized approach. AREAS COVERED: This review article aims to provide an overview of recent advances in the management and treatment of pediatric asthma, including novel insights on the molecular heterogeneity of childhood asthma, the emergence of biologicals to treat severe asthma, and innovative e-health and home monitoring techniques to make asthma management more convenient and accessible. EXPERT OPINION: Molecular technologies have provided new treatment leads. E-health and home monitoring technologies have helped to gain more insights into disease dynamics and improve adherence to treatment while bringing health care to the patient. However, uncontrolled childhood asthma is still a major unmet clinical need and precision-medicine approaches are still scarce in clinical practice. Advanced omics methods may help researchers or clinicians to more accurately phenotype and treat subtypes of childhood asthma and gain more insight into the complexity of the disease.

Utilization Patterns and Trends in the Use of Medications for Asthma in a Cohort of Colombian Patients.

Purpose: Asthma affects approximately 358 million people worldwide. This study aimed to determine the trend for the use of medications intended to treat asthma in a group of patients affiliated with the Colombian health system. Patients and Methods: This was a retrospective study on prescription patterns of medications used to treat asthma in patients over 5 years of age between 2017 and 2019. Sociodemographic variables, medications used and combinations, the persistence of use, and prescribing physicians were considered. Data were obtained from a drug-dispensing database from Colombia. Results: A total of 10,706 people diagnosed with asthma were identified, including predominantly females (56.8%), with a mean age of 32.2 ± 26.1 years. At the beginning of the follow-up, 53.2% of patients aged 5-11 years were receiving monotherapy, with a mean of 1.5 ± 0.6 drugs/patient, especially inhaled corticosteroids (ICSs; 55.9%) and short-acting ß-agonists (SABAs; 55.6%). Moreover, in patients older than 12 years, 53.5% were treated with monotherapy, with a mean of 1.6 ± 0.7 drugs/patient, 45.9% of whom were on SABAs, while 37.1% were on ICSs. Between 63.0% and 83.6% of patients were treated by a general practitioner. 12.5% of patients (n = 495) received triple therapy (ICS/LABA + LAMA [long-acting antimuscarinic]), particularly fluticasone/salmeterol + tiotropium. Conclusion: The identification of treatment patterns will allow physicians and decision makers to implement strategies in order to promote adherence to treatment and improve asthma medication use.

Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling.

BACKGROUND: Remodeling of the extracellular matrix (ECM) is a hallmark of heart failure (HF). Our previous analysis of the secretome of murine cardiac fibroblasts returned ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) as one of the most abundant proteases. ADAMTS5 cleaves chondroitin sulfate proteoglycans such as versican. The contribution of ADAMTS5 and its substrate versican to HF is unknown. METHODS: Versican remodeling was assessed in mice lacking the catalytic domain of ADAMTS5 (Adamts5ΔCat). Proteomics was applied to study ECM remodeling in left ventricular samples from patients with HF, with a particular focus on the effects of common medications used for the treatment of HF. RESULTS: Versican and versikine, an ADAMTS-specific versican cleavage product, accumulated in patients with ischemic HF. Versikine was also elevated in a porcine model of cardiac ischemia/reperfusion injury and in murine hearts after angiotensin II infusion. In Adamts5ΔCat mice, angiotensin II infusion resulted in an aggravated versican build-up and hyaluronic acid disarrangement, accompanied by reduced levels of integrin ß1, filamin A, and connexin 43. Echocardiographic assessment of Adamts5ΔCat mice revealed a reduced ejection fraction and an impaired global longitudinal strain on angiotensin II infusion. Cardiac hypertrophy and collagen deposition were similar to littermate controls. In a proteomics analysis of a larger cohort of cardiac explants from patients with ischemic HF (n=65), the use of ß-blockers was associated with a reduction in ECM deposition, with versican being among the most pronounced changes. Subsequent experiments in cardiac fibroblasts confirmed that ß1-adrenergic receptor stimulation increased versican expression. Despite similar clinical characteristics, patients with HF treated with ß-blockers had a distinct cardiac ECM profile. CONCLUSIONS: Our results in animal models and patients suggest that ADAMTS proteases are critical for versican degradation in the heart and that versican accumulation is associated with impaired cardiac function. A comprehensive characterization of the cardiac ECM in patients with ischemic HF revealed that ß-blockers may have a previously unrecognized beneficial effect on cardiac chondroitin sulfate proteoglycan content.

[Chronic obstructive pulmonary disease: the right treatment for the right patient]. / Chronisch-obstruktive Lungenerkrankung 2021 ­ die richtige Therapie für den richtigen Patienten.

In recent years, large treatment studies have been published in the field of chronic obstructive pulmonary disease (COPD) and were supplemented by several post-hoc analyses in 2020. The new evidence was incorporated into the 2021 update of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report. This article describes the updated fundamentals of and recommendations for the treatment of COPD. Indications for inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA), and/or long-acting beta-mimetics (LABA) will be addressed. The treatment of COPD is contrasted with that of bronchial asthma. The impact of a concomitant asthma component on the treatment strategy for COPD is also discussed. In addition, the article focuses on triple therapy with LAMA, LABA, and ICS, for which the evidence and indications are described. Bronchodilation remains the foundation of COPD therapy. For patients with clustered exacerbations, triple therapy with LAMA + LABA + ICS confers a mortality benefit. Further analysis or studies are needed to clarify whether this effect is more pronounced for specific subgroups.

Effectiveness of Spacer Devices on Preventing Undesirable Cardiovascular Effects of Inhaled Salbutamol.

Background: Currently, there are no regulatory guidelines indicating spacer devices/valved holding chamber (VHC) should be used routinely during pulmonary function tests, and few studies evaluated if spacer devices reduce beta-agonist bronchodilators' side effects. Methods: A prospective study compared salbutamol's cardiovascular effects and bronchodilation response during spirometry tests with and without a spacer device/VHC. Heart rate (HR), the corrected QT interval (QTc), and systolic and diastolic blood pressure were measured 10 minutes after the first spirometry test, before the drug administration, and 20 minutes after inhalation in both groups. Spirometric parameters (forced expiratory volume in the first second [FEV1], forced vital capacity [FVC], and FEV1/FVC) were also measured for both groups. Results: HR and QTc increase were significantly higher in the pressurized meter dose inhalers alone group versus the VHC group [mean SD] [73.1 ± 10 bpm to 74.3 + 10 bpm, p = 0.021] and [median (25%-75% interquartile range)] [389 ms (381-404) to 398 ms (387-407), p = 0.045] vs. [mean SD] [75.4 ± 9 to 73.8 + 8 bpm, p = 0.4] and [median (25%-75% interquartile range)] [388 ms (347-408) to 385 ms (366-408), p = 0.35], respectively. FEV1 variation before and after salbutamol were similar between both groups. Discussion: Although VHC significantly reduces HR and QTc variation when using beta-agonist bronchodilators in healthy patients, no clinical repercussions of this variation were found in this study, since no event of tachycardia or pathological QTc was recorded. Conclusion: VHC has a diminished clinical impact for healthy patients when considering cardiovascular effects and spirometric parameters. Beta-agonist bronchodilators may be administrated despite the use of spacer devices in patients without known cardiovascular diseases. Its significance for other populations still needs to be determined.

Asthma, long-term asthma control medication and tooth wear in American adolescents and young adults.

OBJECTIVE: This study explored the associations of asthma and long-term asthma control medication with tooth wear among American adolescents and young adults. METHODS: Data from 2186 participants of the National Health and Nutrition Examination Survey (NHANES) were used. Asthma and prescribed long-term medication were collected through questionnaires. The number of surfaces with tooth wear was determined during clinical examinations. Associations were tested in Hurdle regression models adjusting for confounders. RESULTS: The prevalence of tooth wear was 58%, with an average of 6.1 (SD: 4.0) surfaces affected among those with the condition. The prevalence of asthma was 10.3%, with 2.9% of participants using long-term medication for asthma control. In the adjusted regression model, asthma was not associated with tooth wear. However, long-term control medication was associated with greater odds of having tooth wear (odds ratio: 3.33; 95%CI: 1.24-8.97), but it was not associated with the number of surfaces with tooth wear among those with the condition (rate ratio: 1.01; 95% CI: 0.58-1.75). CONCLUSION: This cross-sectional analysis of national data shows that taking long-term asthma medication was positively associated with having tooth wear.

Severe hypokalemia secondary to abuse of ß-adrenergic agonists in a pediatric patient: Case report / Hipocalemia grave secundária a abuso de agonistas ß-adrenérgicos em paciente pediátrico: relato de caso

ABSTRACT This study reports a case of a 13-year-old male with a 3-year history of severe and intermittent hypokalemia episodes of unknown origin, requiring admission to the intensive care unit (ICU) for long QT syndrome (LQTS), finally diagnosed of redistributive hypokalemia secondary to the abuse of β-adrenergic agonists in the context of a probable factitious disorder.

RESUMO O presente estudo relata o caso de um jovem de 13 anos de idade com histórico, há três anos, de episódios de hipocalemia grave intermitente de origem desconhecida, internado em unidade de terapia intensiva (UTI) por síndrome do QT longo (SQTL). O paciente foi diagnosticado com hipocalemia por redistribuição secundária ao abuso de agonistas β-adrenérgicos, em contexto de provável transtorno factício.

Conduta terapêutica em pacientes com doença pulmonar obstrutiva crônica: monoterapia ou terapia cominada? / Therapy for chronic obstructive pulmonary disease patients: monotherapy or combination therapy?

Objetivo: Comparar a dupla terapia broncodilatadora com glicopirrônio mais indacaterol à monoterapia com glicopirrônio em pacientes portadores de doença pulmonar obstrutiva crônica. Métodos: Estudo clínico prospectivo, unicêntrico, controlado, cruzado, randomizado e duplo-cego realizado com 14 pacientes com diagnóstico de doença pulmonar obstrutiva crônica grau II. Os participantes receberam cada um dos tratamentos durante 30 dias. Antes de cada terapia, realizou-se período de wash-out por 7 dias, com broncodilador de curta ação. Antes e após cada intervenção, os pacientes passaram por exame de espirometria e responderam ao questionário COPD Assessment Test. Resultados: Observou-se melhora na função pulmonar medida por meio do volume expiratório forçado no primeiro segundo de 19mL (±36) para a monoterapia e 87mL (±33) para a terapia dupla. O ganho foi de 67mL (p=0,042) da associação dos medicamentos em relação ao glicopirrônio isolado. A melhora na qualidade de vida, medida a partir das pontuações do questionário, foi de 4,7 (±8,9) pontos para a monoterapia e 5,2 (±11) pontos para a dupla terapia (p=0,08). Conclusão: Ambos os tratamentos demonstram melhora na função pulmonar dos pacientes.

Objective: To compare dual bronchodilator therapy (Glycopyrronium with Indacaterol) versus Glycopyrronium monotherapy in patients with chronic obstructive pulmonary disease. Methods: This was a prospective, unicentric, controlled, crossover, randomized, and double-blind clinical trial with 14 patients diagnosed with grade II chronic obstructive pulmonary disease. The participants received each treatment during the period of 30 days. Before each therapy, a 7-day wash-out period with a short-acting bronchodilator was instituted. Before and after each intervention, the patients underwent spirometry and answered the COPD Assessment Test questionnaire. Results: An improvement in pulmonary function measured by forced expiratory volume during the first second of 19mL (±36) for monotherapy, and 87mL (±33) for dual therapy was observed. The gain was of 67mL (p=0.042) in the association of the drugs in relation to Glycopyrronium alone. The mean improvement in quality of life measured from the questionnaire scores was 4.7 (±8.9) points for monotherapy and 5.2 (± 11) points for dual therapy (p=0.08). Conclusion: Both treatments show improvement in the patients' pulmonary function.

Use of a Remote Inhaler Monitoring Device to Measure Change in Inhaler Use with Chronic Obstructive Pulmonary Disease Exacerbations.

BACKGROUND: Remote inhaler monitoring is an emerging technology that enables the healthcare team to monitor the time and location of a patient's inhaler use. We assessed the feasibility of remote inhaler monitoring for chronic obstructive pulmonary disease (COPD) patients and the pattern of albuterol inhaler use associated with COPD exacerbations. METHODS: Thirty-five participants with COPD used an electronic inhaler sensor for 12 weeks which recorded the date and time of each albuterol actuation. Self-reported COPD exacerbations and healthcare utilization were assessed monthly. We used generalized estimating equations with a logit link to compare the odds of an exacerbation day to a nonexacerbation day by the frequency of daily albuterol use. RESULTS: Average daily albuterol use on nonexacerbation days varied greatly between patients, ranging from 1.5 to 17.5 puffs. There were 48 exacerbation events observed in 29 participants during the study period, of which 16 were moderate-to-severe exacerbations. During the moderate-to-severe exacerbation days, the median value in average daily albuterol use increased by 14.1% (interquartile range: 2.7%-56.9%) compared to average nonexacerbation days. A 100% increase in inhaler use was associated with increased odds of a moderate-to severe exacerbation (odds ratio 1.54; 95% CI: 1.21-1.97). Approximately 74% of participants reported satisfaction with the sensor. CONCLUSIONS: The electronic inhaler sensor was well received in older patients with COPD over a 12-week period. Increased albuterol use captured by the device was associated with self-reported episodes of moderate-to-severe exacerbations.

Long-acting muscarinic antagonists vs. long-acting β 2 agonists in COPD exacerbations: a systematic review and meta-analysis / Antagonistas muscarínicos de longa duração vs. β 2 -agonistas de longa duração em exacerbações da DPOC: revisão sistemática e meta-análise

ABSTRACT Objective: To determine whether long-acting muscarinic antagonists (LAMAs) provide superior therapeutic effects over long-acting β2 agonists (LABAs) for preventing COPD exacerbations. Methods: This was a systematic review and meta-analysis of randomized clinical trials involving patients with stable, moderate to severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease criteria, treated with a LAMA (i.e., tiotropium bromide, aclidinium, or glycopyrronium), followed for at least 12 weeks and compared with controls using a LABA in isolation or in combination with a corticosteroid. Results: A total of 2,622 studies were analyzed for possible inclusion on the basis of their title and abstract; 9 studies (17,120 participants) were included in the analysis. In comparison with LABAs, LAMAs led to a greater decrease in the exacerbation rate ratio (relative risk [RR] = 0.88; 95% CI: 0.84-0.93]; a lower proportion of patients who experienced at least one exacerbation (RR = 0.90; 95% CI: 0.87-0.94; p < 0.00001); a lower risk of exacerbation-related hospitalizations (RR = 0.78; 95% CI: 0.69-0.87; p < 0.0001); and a lower number of serious adverse events (RR = 0.81; 95% CI: 0.67-0.96; p = 0.0002). The overall quality of evidence was moderate for all outcomes. Conclusions: The major findings of this systematic review and meta-analysis were that LAMAs significantly reduced the exacerbation rate (exacerbation episodes/year), as well as the number of exacerbation episodes, of hospitalizations, and of serious adverse events.

RESUMO Objetivo: Determinar se long-acting muscarinic antagonists (LAMAs, antagonistas muscarínicos de longa duração) são superiores a long-acting β2 agonists (LABAs, β2-agonistas de longa duração) na prevenção de exacerbações da DPOC. Métodos: Revisão sistemática e meta-análise de ensaios clínicos controlados aleatórios com pacientes com DPOC estável, de moderada a grave, conforme os critérios da Global Initiative for Chronic Obstructive Lung Disease, tratados com LAMA (brometo de tiotrópio, aclidínio ou glicopirrônio), acompanhados durante pelo menos 12 semanas e comparados a controles que usaram LABA isoladamente ou com um corticosteroide. Resultados: Foram analisados 2.622 estudos para possível inclusão com base em seu título e resumo; 9 estudos (17.120 participantes) foram incluídos na análise. Em comparação com LABAs, LAMAs resultaram em maior diminuição da razão da taxa de exacerbações [risco relativo (RR) = 0,88; IC95%: 0,84-0,93]; menor proporção de pacientes que apresentaram pelo menos uma exacerbação (RR = 0,90; IC95%: 0,87-0,94; p < 0,00001); menor risco de hospitalizações em virtude de exacerbação da doença (RR = 0,78; IC95%: 0,69-0,87; p < 0,0001) e menor número de eventos adversos sérios (RR = 0,81; IC95%: 0,67-0,96; p = 0,0002). A qualidade geral das evidências foi moderada para todos os desfechos. Conclusões: O principal achado desta revisão sistemática e meta-análise foi que LAMAs reduziram significativamente a taxa de exacerbações (episódios de exacerbação/ano), os episódios de exacerbação, as hospitalizações e os eventos adversos sérios.

Function and dysfunction of human sinoatrial node.

Sinoatrial node (SAN) automaticity is jointly regulated by a voltage (cyclic activation and deactivation of membrane ion channels) and Ca(2+) clocks (rhythmic spontaneous sarcoplasmic reticulum Ca(2+) release). Using optical mapping in Langendorff-perfused canine right atrium, we previously demonstrated that the ß-adrenergic stimulation pushes the leading pacemaker to the superior SAN, which has the fastest activation rate and the most robust late diastolic intracellular calcium (Cai) elevation. Dysfunction of the superior SAN is commonly observed in animal models of heart failure and atrial fibrillation (AF), which are known to be associated with abnormal SAN automaticity. Using the 3D electroanatomic mapping techniques, we demonstrated that superior SAN served as the earliest atrial activation site (EAS) during sympathetic stimulation in healthy humans. In contrast, unresponsiveness of superior SAN to sympathetic stimulation was a characteristic finding in patients with AF and SAN dysfunction, and the 3D electroanatomic mapping technique had better diagnostic sensitivity than corrected SAN recovery time testing. However, both tests have significant limitations in detecting patients with symptomatic sick sinus syndrome. Recently, we reported that the location of the EAS can be predicted by the amplitudes of P-wave in the inferior leads. The inferior P-wave amplitudes can also be used to assess the superior SAN responsiveness to sympathetic stimulation. Inverted or isoelectric P-waves at baseline that fail to normalize during isoproterenol infusion suggest SAN dysfunction. P-wave morphology analyses may be helpful in determining the SAN function in patients at risk of symptomatic sick sinus syndrome.

A randomized controlled study of the efficacy of tamsulosin monotherapy and its combination with mirabegron for overactive bladder induced by benign prostatic obstruction.

PURPOSE: We evaluated the efficacy and safety of add-on treatment with a ß3-adrenoceptor agonist (mirabegron) for overactive bladder symptoms remaining after α1-blocker (tamsulosin) treatment in men with benign prostatic obstruction. MATERIALS AND METHODS: Patients with benign prostatic obstruction with urinary urgency at least once per week and a total OABSS of 3 or more points after 8 or more weeks of treatment with tamsulosin were enrolled in the study. They were randomly allocated to receive 0.2 mg tamsulosin daily or 0.2 mg tamsulosin and 50 mg mirabegron daily for 8 weeks. The primary end point was change in total OABSS. Safety assessments included change in post-void residual urine volume and adverse events. RESULTS: From January 2012 through September 2013 a total of 94 patients were randomized. Of these patients 76 completed the protocol treatment. In the full analysis set the change in total OABSS during the treatment period was significantly greater in the combination group than in the monotherapy group (-2.21 vs -0.87, p=0.012). The changes in scores for urinary urgency, daytime frequency, International Prostate Symptom Score storage symptom subscore and quality of life index at 8 weeks were significantly greater in the combination group. The change in post-void residual urine volume was significantly greater in the combination group. Although 6 patients experienced adverse events in the combination group, urinary retention was observed in only 1 patient. CONCLUSIONS: Combined tamsulosin and mirabegron treatment is effective and safe for patients with benign prostatic obstruction who have overactive bladder symptoms after tamsulosin monotherapy.

Function and Dysfunction of Human Sinoatrial Node

Sinoatrial node (SAN) automaticity is jointly regulated by a voltage (cyclic activation and deactivation of membrane ion channels) and Ca2+ clocks (rhythmic spontaneous sarcoplasmic reticulum Ca2+ release). Using optical mapping in Langendorff-perfused canine right atrium, we previously demonstrated that the beta-adrenergic stimulation pushes the leading pacemaker to the superior SAN, which has the fastest activation rate and the most robust late diastolic intracellular calcium (Cai) elevation. Dysfunction of the superior SAN is commonly observed in animal models of heart failure and atrial fibrillation (AF), which are known to be associated with abnormal SAN automaticity. Using the 3D electroanatomic mapping techniques, we demonstrated that superior SAN served as the earliest atrial activation site (EAS) during sympathetic stimulation in healthy humans. In contrast, unresponsiveness of superior SAN to sympathetic stimulation was a characteristic finding in patients with AF and SAN dysfunction, and the 3D electroanatomic mapping technique had better diagnostic sensitivity than corrected SAN recovery time testing. However, both tests have significant limitations in detecting patients with symptomatic sick sinus syndrome. Recently, we reported that the location of the EAS can be predicted by the amplitudes of P-wave in the inferior leads. The inferior P-wave amplitudes can also be used to assess the superior SAN responsiveness to sympathetic stimulation. Inverted or isoelectric P-waves at baseline that fail to normalize during isoproterenol infusion suggest SAN dysfunction. P-wave morphology analyses may be helpful in determining the SAN function in patients at risk of symptomatic sick sinus syndrome.

Effects of catecholamines on volemic replacement with saline solution and the impact on heart rate variability in rabbits subjected to hemorrhage. A study by spectral analysis

PURPOSE: To verify the effects of different catecholamines on volemic expansion and on the autonomic nervous system in rabbits that were subjected to hemorrhage. METHODS: Twenty four rabbits subjected to hemorrhage (with a 25% loss of blood volume) and were randomly divided into four experimental groups: 1) HEMO Group underwent replacement with their own blood in an equal volume; 2) SS Group underwent replacement with saline solution (SS) in a volume that corresponded to three times the removed blood volume; 3) ISP Group underwent replacement with SS and isoprenaline; 4) FNL Group underwent replacement with SS and phenylephrine. Spectral Analysis of the heart rate and heart rate variability were performed from the recorded data. Hematocrit was measured throughout the experiment. RESULTS: Replacement with SS and an α- or β-agonist did not produce differences in the intravascular retention compared to replacement with SS alone. An analysis of HRV showed that the FNL group maintained the LF/HF ratio better than ISP and SS. CONCLUSIONS: No difference in vascular retention when α- or β- agonists were added to SS during post-hemorrhagic recovery. The animals in the FNL group maintained the integrity of the autonomic response within normal physiological standards during hemorrhagic stress. .

S100A1 in human heart failure: lack of recovery following left ventricular assist device support.

BACKGROUND: We hypothesized that S100A1 is regulated during human hypertrophy and heart failure and that it may be implicated in remodeling after left ventricular assist device. S100A1 is decreased in animal and human heart failure, and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling. METHODS AND RESULTS: We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca(2+)ATPase, phospholamban, and ryanodine receptor proteins, as well as ß-adrenergic receptor density in nonfailing, hypertrophied (left ventricular hypertrophy), failing, and failing left ventricular assist device-supported hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, sarcoplasmic endoplasmic reticulum Ca(2+)ATPase and phospholamban were normal in left ventricular hypertrophy, but decreased in failing hearts, while ryanodine receptor was unchanged in either group. Baseline muscle contraction was not altered in left ventricular hypertrophy or failing hearts. ß-Adrenergic receptor and inotropic response were decreased in failing hearts. In failing left ventricular assist device-supported hearts, S100A1 and sarcoplasmic endoplasmic reticulum Ca(2+)ATPase showed no recovery, while phospholamban, ß-adrenergic receptor, and the inotropic response fully recovered. CONCLUSIONS: S100A1 and sarcoplasmic endoplasmic reticulum Ca(2+)ATPase, both key Ca(2+)-regulatory proteins, are decreased in human heart failure, and these changes are not reversed after left ventricular assist device. The clinical significance of these findings for cardiac recovery remains to be addressed.

Repeated use of albuterol inhaler as a potential cause of Takotsubo cardiomyopathy.

PATIENT: Female, 78 FINAL DIAGNOSIS: Takotsubo cardiomyopathy Symptoms: Chest discomfort, chest pain, dyspnea, short of breath Medication: - Clinical Procedure: - Specialty: Cardiology. OBJECTIVE: Unusual or unexpected effect of treatment. BACKGROUND: Takotsubo cardiomyopathy is an increasingly recognized cardiac condition that usually results from an acute stressor. Some medications are becoming recognized as possible stressors. Albuterol is widely used in general medicine. We report an unusual link between Takotsubo cardiomyopathy and albuterol. CASE REPORT: A 78-year-old woman presented to our emergency department for chest pain of 2-day duration. The patient had been taking albuterol inhaler therapy for worsening shortness of breath followed by chest pain. Her albuterol use was excessive. There were no other acute stressors. The electrocardiogram showed ST-elevations in the anterior and inferior leads. Emergent coronary angiography showed noncritical coronary artery disease and left ventriculography showed apical ballooning. CONCLUSIONS: When patients taking albuterol present with acute chest pain in the absence of other etiologies, beta-agonist-induced Takotsubo cardiomyopathy should be considered.

Assessment of acute bronchodilator effects from specific airway resistance changes in stable COPD patients.

BACKGROUND: In COPD patients, reversibility is currently evaluated from the changes of forced expiratory volume at 1s (ΔFEV1) and forced vital capacity (ΔFVC). By lowering peripheral airway smooth muscle tone, bronchodilators should decrease dynamic hyperinflation, gas trapping, and possibly dyspnea at rest. Hence, we hypothesize that specific airway resistance changes (ΔsRAW) should better characterize the acute response to bronchodilators. METHODS: On two days, 60 COPD patients underwent dyspnea evaluation (VAS score) and pulmonary function testing at baseline and one hour after placebo or 300µg indacaterol administration. RESULTS: Spirographic and ΔsRAW-based criteria identified as responders 24 and 45 patients, respectively. ΔsRAW correlated with changes of intrathoracic gas volume (ΔITGV) (r=0.61; p<0.001), residual volume (ΔRV) (r=0.60; p<0.001), ΔFVC (r=0.44; p=0.001), and ΔVAS (r=0.73; p<0.001), while ΔFEV1 correlated only with ΔFVC (r=0.34; p=0.008). Significant differences in terms of ΔITGV (p=0.002), ΔRV (p=0.023), and ΔVAS (p<0.001) occurred only if patients were stratified according to ΔsRAW. CONCLUSIONS: In assessing the acute functional effect of bronchodilators, ΔsRAW-based criterion is preferable to FEV1-FVC-based criteria, being more closely related to bronchodilator-induced improvements of lung mechanics and dyspnea at rest.

Clinical research of Salmeterol fluticasone propionate and Tiotropium bromide for improvement of pulmona-ry function in patients with chronic obstructive pulmonary disease and bronchial asthma / 中国基层医药

Objective To observe the improvement of Salmeterol fluticasone propionate and Tiotropium bromide for inhalation in the treatment of chronic obstructive pulmonary disease ( COPD ) with bronchial asthma patients.Methods 89 patients were randomly divided into the observation group with 46 cases and control group with 43 cases,both groups were given conventional therapy.The control group was given Salmeterol fluticasone propionate 50μg/500μg,twice a day;the observation group was given Tiotropium bromide 18μg, twice a day, based on the therapy of control group.The two groups were treated for 14 days,and then curative effect,score of SGRQ,pulmonary function and blood gas analysis index were evaluated, and adverse reactions were recorded.Results The total effective rate of treatment group was 86.1%,higher than that of the control group(68.6%) (Z=2.68,P<0.05);Compared with the control group after treatment,functional parameters[ FEV1 ( L) ,FEV1 (%) and FEV1/FVC(%) ] of the observation group increased significantly,and the observation group were all higher than that of the control group [(2.27 ±0.45) vs (1.92 ±0.36),(64.27 ±16.11) vs (53.64 ±15.55),(54.85 ±14.81) vs (45.33 ± 13.23)],the differences were all statistically significant(t=4.20,3.16,3.19,all P<0.05);PaO2 of the two groups patients were increased and PaCO2 were decreased,scores of SGRQ were decreased obviously,and the change of the observation group was obviously[(47.61 ±3.64) vs (49.34 ±4.23),(67.33 ±5.56) vs (63.66 ±5.21), (45.34 ±3.72) vs (50.65 ±4.16)],the difference was statistically significant(t =2.13,3.32,6.54,all P<0.05) .Conclusion Salmeterol fluticasone propionate and Tiotropium bromide for inhalation can improve lung func-tional parameters and respiratory conditions of the parents with COPD and bronchial asthma obviously, reduce the score of SGRQ,curative effect is distinct,worthy of clinical popularization and application.