Time trends of period prevalence rates of patients with inhaled long-acting beta-2-agonists-containing prescriptions: a European comparative database study.

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Marietta Rottenkolber

Full Text Available Inhaled, long-acting beta-2-adrenoceptor agonists (LABA have well-established roles in asthma and/or COPD treatment. Drug utilisation patterns for LABA have been described, but few studies have directly compared LABA use in different countries. We aimed to compare the prevalence of LABA-containing prescriptions in five European countries using a standardised methodology.A common study protocol was applied to seven European healthcare record databases (Denmark, Germany, Spain, the Netherlands (2, and the UK (2 to calculate crude and age- and sex-standardised annual period prevalence rates (PPRs of LABA-containing prescriptions from 2002-2009. Annual PPRs were stratified by sex, age, and indication (asthma, COPD, asthma and COPD.From 2002-2009, age- and sex-standardised PPRs of patients with LABA-containing medications increased in all databases (58.2%-185.1%. Highest PPRs were found in men ≥ 80 years old and women 70-79 years old. Regarding the three indications, the highest age- and sex-standardised PPRs in all databases were found in patients with "asthma and COPD" but with large inter-country variation. In those with asthma or COPD, lower PPRs and smaller inter-country variations were found. For all three indications, PPRs for LABA-containing prescriptions increased with age.Using a standardised protocol that allowed direct inter-country comparisons, we found highest rates of LABA-containing prescriptions in elderly patients and distinct differences in the increased utilisation of LABA-containing prescriptions within the study period throughout the five European countries.

Long-acting β2-agonists in asthma

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Jacobson, Glenn A; Raidal, Sharanne; Hostrup, Morten

2018-01-01

Long-acting β2-agonists (LABAs) such as formoterol and salmeterol are used for prolonged bronchodilatation in asthma, usually in combination with inhaled corticosteroids (ICSs). Unexplained paradoxical asthma exacerbations and deaths have been associated with LABAs, particularly when used without...... and effects on BHR, particularly that (S)-enantiomers of β2-agonists may be deleterious to asthma control. LABAs display enantioselective pharmacokinetics and pharmacodynamics. Biological plausibility of the deleterious effects of β2-agonists (S)-enantiomers is provided by in vitro and in vivo studies from...... mechanism in rapid asthma deaths. More effort should therefore be applied to investigating potential enantiospecific effects of LABAs on safety, specifically bronchoprotection. Safety studies directly assessing the effects of LABA (S)-enantiomers on BHR are long overdue....

Association of blood eosinophils and plasma periostin with FEV1 response after 3-month inhaled corticosteroid and long-acting beta2-agonist treatment in stable COPD patients.

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Park, Hye Yun; Lee, Hyun; Koh, Won-Jung; Kim, Seonwoo; Jeong, Ina; Koo, Hyeon-Kyoung; Kim, Tae-Hyung; Kim, Jin Woo; Kim, Woo Jin; Oh, Yeon-Mok; Sin, Don D; Lim, Seong Yong; Lee, Sang-Do

2016-01-01

COPD patients with increased airway eosinophilic inflammation show a favorable response to inhaled corticosteroids (ICS) in combination with a long-acting bronchodilator. Recent studies have demonstrated a significant correlation of sputum eosinophilia with blood eosinophils and periostin. We investigated whether high blood eosinophils and plasma periostin were associated with an improvement in forced expiratory volume in 1 second (FEV1) after 3-month treatment with ICS/long-acting beta2-agonist (LABA) in stable COPD patients. Blood eosinophils and plasma periostin levels were measured in 130 stable COPD subjects selected from the Korean Obstructive Lung Disease cohort. Subjects began a 3-month ICS/LABA treatment after washout period. High blood eosinophils (>260/µL, adjusted odds ratio =3.52, P=0.009) and high plasma periostin (>23 ng/mL, adjusted odds ratio =3.52, P=0.013) were significantly associated with FEV1 responders (>12% and 200 mL increase in FEV1 from baseline after treatment). Moreover, the addition of high blood eosinophils to age, baseline positive bronchodilator response, and FEV1 eosinophils and high plasma periostin were associated with improved lung function after 3-month ICS/LABA treatment. In particular, high blood eosinophils, in combination with age and baseline lung function parameters, might be a possible biomarker for identification of COPD patients with favorable FEV1 improvement in response to ICS/LABA treatment.

Pharmacogenetics of the β2-Adrenergic Receptor Gene

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Ortega, Victor E.; Hawkins, Gregory A.; Peters, Stephen P.; Bleecker, Eugene R.

2009-01-01

Asthma is a complex genetic disease with multiple genetic and environmental determinants contributing to the observed variability in response to common anti-asthma therapies. Asthma pharmacogenetic research has focused on multiple candidate genes including the β2-adrenergic receptor gene (ADRβ2) and its effect on individual responses to beta agonist therapy. At present, knowledge about the effects of ADRβ2 variation on therapeutic responses is evolving and should not alter current Asthma Guideline approaches consisting of the use of short acting beta agonists for as-needed symptom based therapy and the use of a regular long-acting beta agonist in combination with inhaled corticosteroid therapy for optimal control of asthma symptoms in those asthmatics who are not controlled on inhaled corticosteroid alone. This approach is based upon studies showing a consistent pharmacogenetic response to regular use of short acting beta agonists (SABA) and less consistent findings in studies evaluating long acting beta agonist (LABA). While emerging pharmacogenetic studies are provocative and should lead to functional approaches, conflicting data with responses to LABA therapy may be caused by factors that include small sample sizes of study populations and differences in experimental design that may limit the conclusions that may be drawn from these clinical trials at the present time. PMID:17996583

Inhaled Beta Agonist Bronchodilator Does Not Affect Trans-diaphragmatic Pressure Gradient but Decreases Lower Esophageal Sphincter Retention Pressure in Patients with Chronic Obstructive Pulmonary Disease (COPD) and Gastroesophageal Reflux Disease (GERD).

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Del Grande, Leonardo M; Herbella, Fernando A M; Bigatao, Amilcar M; Jardim, Jose R; Patti, Marco G

2016-10-01

Chronic obstructive pulmonary disease (COPD) patients have a high incidence of gastroesophageal reflux disease (GERD) whose pathophysiology seems to be linked to an increased trans-diaphragmatic pressure gradient and not to a defective esophagogastric barrier. Inhaled beta agonist bronchodilators are a common therapy used by patients with COPD. This drug knowingly not only leads to a decrease in the lower esophageal sphincter (LES) resting pressure, favoring GERD, but also may improve ventilatory parameters, therefore preventing GERD. This study aims to evaluate the effect of inhaled beta agonist bronchodilators on the trans-diaphragmatic pressure gradient and the esophagogastric barrier. We studied 21 patients (mean age 67 years, 57 % males) with COPD and GERD. All patients underwent high-resolution manometry and esophageal pH monitoring. Abdominal and thoracic pressure, trans-diaphragmatic pressure gradient (abdominal-thoracic pressure), and the LES retention pressure (LES basal pressure-transdiaphragmatic gradient) were measured before and 5 min after inhaling beta agonist bronchodilators. The administration of inhaled beta agonist bronchodilators leads to the following: (a) a simultaneous increase in abdominal and thoracic pressure not affecting the trans-diaphragmatic pressure gradient and (b) a decrease in the LES resting pressure with a reduction of the LES retention pressure. In conclusion, inhaled beta agonist bronchodilators not only increase the thoracic pressure but also lead to an increased abdominal pressure favoring GERD by affecting the esophagogastric barrier.

Effects of inspiratory resistance, inhaled beta-agonists and histamine on canine tracheal blood flow

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Kelly, W.T.; Baile, E.M.; Brancatisano, A.; Pare, P.D.; Engel, L.A.

1992-01-01

Tracheobronchial blood flow is potentially important in asthma as it could either influence the clearance of mediators form the airways, thus affecting the duration and severity of bronchoispasm, or enhance oedema formation with a resultant increase in airflow obstruction. In anaesthetized dogs, spontaneously breathing via a tracheostomy, we investigated the effects of three interventions which are relevant to acute asthma attacks and could potentially influence blood flow and its distribution to the mucosa and remaining tissues of the trachea: 1) increased negative intrathoracic pressure swings (-25±1 cmH 2 O) induced by an inspiratory resistance; 2) variable inhaled doses of a beta-adrenoceptor-agonist (terbutaline); and 3) aerosolized histamine sufficient to produce a threefold increase in pulmonary resistance. Microspheres labelled with different radioisotopes were used to measure blood flow. Resistive breathing did not influence tracheobronchial blood flow. Following a large dose of terbutaline, mucosal blood flow (Qmb) increased by 50%. After inhaled histamine, Qmb reached 265% of the baseline value. We conclude that, whereas increased negative pressure swings do not influence tracheobronchial blood flow or its distribution, inhalation of aerosolized terbutaline, corresponding to a conventionally nebulized dose, increases mucosal blood flow. Our results also confirm that inhaled histamine, in a dose sufficient to produce moderate bronchoconstriction, increases tracheal mucosal blood flow in the area of deposition. (au)

Effects of inspiratory resistance, inhaled beta-agonists and histamine on canine tracheal blood flow

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Kelly, W.T.; Baile, E.M.; Brancatisano, A.; Pare, P.D.; Engel, L.A. (Dept. of Respiratory Medicine, Westmead Hospital, Westmead, NSW (Australia))

1992-01-01

Tracheobronchial blood flow is potentially important in asthma as it could either influence the clearance of mediators form the airways, thus affecting the duration and severity of bronchoispasm, or enhance oedema formation with a resultant increase in airflow obstruction. In anaesthetized dogs, spontaneously breathing via a tracheostomy, we investigated the effects of three interventions which are relevant to acute asthma attacks and could potentially influence blood flow and its distribution to the mucosa and remaining tissues of the trachea: (1) increased negative intrathoracic pressure swings (-25[+-]1 cmH[sub 2]O) induced by an inspiratory resistance; (2) variable inhaled doses of a beta-adrenoceptor-agonist (terbutaline); and (3) aerosolized histamine sufficient to produce a threefold increase in pulmonary resistance. Microspheres labelled with different radioisotopes were used to measure blood flow. Resistive breathing did not influence tracheobronchial blood flow. Following a large dose of terbutaline, mucosal blood flow (Qmb) increased by 50%. After inhaled histamine, Qmb reached 265% of the baseline value. We conclude that, whereas increased negative pressure swings do not influence tracheobronchial blood flow or its distribution, inhalation of aerosolized terbutaline, corresponding to a conventionally nebulized dose, increases mucosal blood flow. Our results also confirm that inhaled histamine, in a dose sufficient to produce moderate bronchoconstriction, increases tracheal mucosal blood flow in the area of deposition. (au).

Combination therapy of inhaled steroids and long-acting beta2-agonists in asthma–COPD overlap syndrome

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Lee SY

2016-11-01

Full Text Available Suh-Young Lee,1,* Hye Yun Park,2,* Eun Kyung Kim,3 Seong Yong Lim,4 Chin Kook Rhee,5 Yong Il Hwang,6 Yeon-Mok Oh,7 Sang Do Lee,7 Yong Bum Park1 On behalf of the KOLD Study Group 1Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 3Department of Internal Medicine, Bundang CHA Medical Center, CHA University College of Medicine, Seongnam, 4Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 5Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 6Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical School, Gyeonggido, 7Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Ulsan, Republic of Korea *These authors contributed equally to this work Background: The efficacy of inhaled corticosteroids (ICSs/long-acting beta2-agonist (LABA treatment in patients with asthma–chronic obstructive pulmonary disease (COPD overlap syndrome (ACOS compared to patients with COPD alone has rarely been examined. This study aimed to evaluate the clinical efficacy for the improvement of lung function after ICS/LABA treatment in patients with ACOS compared to COPD alone patients. Methods: Patients with stable COPD were selected from the Korean Obstructive Lung Disease (KOLD cohort. Subjects began a 3-month ICS/LABA treatment after a washout period. ACOS was defined when the patients had 1 a personal history of asthma, irrespective of age, and wheezing in the last 12 months in a self-reported survey

The use of electronic alerts in primary care computer systems to identify the excessive prescription of short-acting beta2-agonists for people with asthma: a systematic review.

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McKibben, Shauna; De Simoni, Anna; Bush, Andy; Thomas, Mike; Griffiths, Chris

2018-04-16

Computers are increasingly used to improve prescribing decisions in the management of long-term conditions however the effects on asthma prescribing remain unclear. We aimed to synthesise the evidence for the use of computerised alerts that identify excessive prescribing of short-acting beta 2 -agonists (SABAs) to improve asthma management for people with asthma. MEDLINE, CINAHL, Embase, Cochrane and Scopus databases (1990-2016) were searched for randomised controlled trials using electronic alerts to identify excessive prescribing of SABAs for people with asthma in primary care. Inclusion eligibility, quality appraisal (Cochrane risk of bias tool) and data extraction were performed by two independent reviewers. Findings were synthesised narratively. A total of 2035 articles were screened and four trials were eligible. Three studies had low risk of bias: one reported a positive effect on our primary outcome of interest, excessive SABA prescribing; another reported positive effects on the ratio of inhaled corticosteroid (ICS)-SABA prescribing, and asthma control; a third reported no effect on outcomes of interest. One study at high risk of bias reported a reduction in exacerbations and primary care consultations. There is some evidence that electronic alerts reduce excessive prescribing of SABAs, when delivered as part of a multicomponent intervention in an integrated health care system. However due to the variation in health care systems, intervention design and outcomes measured, further research is required to establish optimal design of alerting and intervening systems.

Effect of inhaled formoterol and budesonide on exacerbations of asthma

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Pauwels, RA; Lofdahl, CG; Postma, DS; Tattersfield, AE; OByrne, P; Barnes, PJ; Ullman, A

1997-01-01

Background The role of long-acting, inhaled beta(2)-agonists in treating asthma is uncertain. In a double-blind study, we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide. Methods After a four-week run-in period of treatment

Genome-Wide Association Study of Short-Acting beta(2)-Agonists A Novel Genome-Wide Significant Locus on Chromosome 2 near ASB3

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Israel, Elliot; Lasky-Su, Jessica; Markezich, Amy; Damask, Amy; Szefler, Stanley J.; Schuemann, Brooke; Klanderman, Barbara; Sylvia, Jody; Kazani, Shamsah; Wu, Rongling; Martinez, Fernando; Boushey, Homer A.; Chinchilli, Vernon M.; Mauger, Dave; Weiss, Scott T.; Tantisira, Kelan G.; de Zeeuw, Dick; Navis, Gerjan J.

2015-01-01

Rationale: [beta(2)-Agonists are the most common form of treatment of asthma, but there is significant variability in response to these medications. A significant proportion of this responsiveness may be heritable. Objectives: To investigate whether a genome-wide association study (GWAS) could

Patient considerations in the treatment of COPD: focus on the new combination inhaler umeclidinium/vilanterol

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Albertson TE

2015-02-01

Full Text Available Timothy E Albertson,1–3 Richart Harper,1,2 Susan Murin,1,2 Christian Sandrock1 1Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA; 2Department of Medicine, Veterans Administration Northern California Health Care System, Mather, CA, USA; 3Department of Emergency Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA Abstract: Medication adherence among patients with chronic diseases, such as COPD, may be suboptimal, and many factors contribute to this poor adherence. One major factor is the frequency of medication dosing. Once-daily dosing has been shown to be an important variable in medication adherence in chronic diseases, such as COPD. New inhalers that only require once-daily dosing are becoming more widely available. Combination once-daily inhalers that combine any two of the following three agents are now available: 1 a long-acting muscarinic antagonist; 2 a long acting beta2 agonist; and 3 an inhaled corticosteroid. A new once-daily inhaler with both a long-acting muscarinic antagonist, umeclidinium bromide, and a long acting beta2 agonist, vilanterol trifenatate, is now available worldwide for COPD treatment. It provides COPD patients convenience, efficacy, and a very favorable adverse-effects profile. Additional once-daily combination inhalers are available or will soon be available for COPD patients worldwide. The use of once-daily combination inhalers will likely become the standard maintenance management approach in the treatment of COPD because they improve medication adherence. Keywords: medication adherence, long-acting beta2 agonist, long-acting muscarinic antagonist, inhaled corticosteroid, chronic obstructive pulmonary disease

Sports doping: Emerging designer and therapeutic B2-agonists

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Fragkaki, A.G.; Georgakopoulos, C.; Sterk, S.S.; Nielen, M.W.F.

2013-01-01

Beta2-adrenergic agonists, or ß2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of ß2-agonists is prohibited in sports by the World Anti-Doping

Effect of beta2-adrenoceptor agonists and other cAMP-elevating agents on inflammatory gene expression in human ASM cells: a role for protein kinase A.

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Kaur, Manminder; Holden, Neil S; Wilson, Sylvia M; Sukkar, Maria B; Chung, Kian Fan; Barnes, Peter J; Newton, Robert; Giembycz, Mark A

2008-09-01

In diseases such as asthma, airway smooth muscle (ASM) cells play a synthetic role by secreting inflammatory mediators such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, or IL-8 and by expressing surface adhesion molecules, including ICAM-1. In the present study, PGE(2), forskolin, and short-acting (salbutamol) and long-acting (salmeterol and formoterol) beta(2)-adrenoceptor agonists reduced the expression of ICAM-1 and the release of GM-CSF evoked by IL-1beta in ASM cells. IL-1beta-induced IL-8 release was also repressed by PGE(2) and forskolin, whereas the beta(2)-adrenoceptor agonists were ineffective. In each case, repression of these inflammatory indexes was prevented by adenoviral overexpression of PKIalpha, a highly selective PKA inhibitor. These data indicate a PKA-dependent mechanism of repression and suggest that agents that elevate intracellular cAMP, and thereby activate PKA, may have a widespread anti-inflammatory effect in ASM cells. Since ICAM-1 and GM-CSF are highly NF-kappaB-dependent genes, we used an adenoviral-delivered NF-kappaB-dependent luciferase reporter to examine the effects of forskolin and the beta(2)-adrenoceptor agonists on NF-kappaB activation. There was no effect on luciferase activity measured in the presence of forskolin or beta(2)-adrenoceptor agonists. This finding is consistent with the observation that IL-1beta-induced expression of IL-6, a known NF-kappaB-dependent gene in ASM, was also unaffected by beta(2)-adrenoceptor agonists, forskolin, PGE(2), 8-bromo-cAMP, or rolipram. Collectively, these results indicate that repression of IL-1beta-induced ICAM-1 expression and GM-CSF release by cAMP-elevating agents, including beta(2)-adrenoceptor agonists, may not occur through a generic effect on NF-kappaB.

Impact of multiple-dose versus single-dose inhaler devices on COPD patients’ persistence with long-acting β2-agonists: a dispensing database analysis

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van Boven, Job FM; van Raaij, Joost J; van der Galiën, Ruben; Postma, Maarten J; van der Molen, Thys; Dekhuijzen, PN Richard; Vegter, Stefan

2014-01-01

Background: With a growing availability of different devices and types of medication, additional evidence is required to assist clinicians in prescribing the optimal medication in relation to chronic obstructive pulmonary disease (COPD) patients’ persistence with long-acting β2-agonists (LABAs). Aims: To assess the impact of the type of inhaler device (multiple-dose versus single-dose inhalers) on 1-year persistence and switching patterns with LABAs. Methods: A retrospective observational cohort study was performed comparing a cohort of patients initiating multiple-dose inhalers and a cohort initiating single-dose inhalers. The study population consisted of long-acting bronchodilator naive COPD patients, initiating inhalation therapy with mono-LABAs (formoterol, indacaterol or salmeterol). Analyses were performed using pharmacy dispensing data from 1994 to 2012, obtained from the IADB.nl database. Study outcomes were 1-year persistence and switching patterns. Results were adjusted for initial prescriber, initial medication, dosing regimen and relevant comorbidities. Results: In all, 575 patients initiating LABAs were included in the final study cohort. Among them, 475 (83%) initiated a multiple-dose inhaler and 100 (17%) a single-dose inhaler. Further, 269 (47%) initiated formoterol, 9 (2%) indacaterol and 297 (52%) salmeterol. There was no significant difference in persistence between users of multiple-dose or single-dose inhalers (hazard ratio: 0.98, 95% confidence interval: 0.76–1.26, P=0.99). Over 80% re-started or switched medication. Conclusions: There seems no impact of inhaler device (multiple-dose versus single-dose inhalers) on COPD patients’ persistence with LABAs. Over 80% of patients who initially seemed to discontinue LABAs, re-started their initial medication or switched inhalers or medication within 1 year. PMID:25274453

Olodaterol Oral Inhalation

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... in a class of medications called long-acting beta-agonists (LABAs). It works by relaxing and opening ... the inhaler upright with the yellow cap closed. Turn the clear base in the direction of the ...

Comparative efficacy of inhaled corticosteroid and long-acting beta agonist combinations in preventing COPD exacerbations: a Bayesian network meta-analysis.

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Oba, Yuji; Lone, Nazir A

2014-01-01

A combination therapy with inhaled corticosteroid (ICS) and a long-acting beta agonist (LABA) is recommended in severe chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations. Currently, there are five ICS/LABA combination products available on the market. The purpose of this study was to systematically review the efficacy of various ICS/LABA combinations with a network meta-analysis. Several databases and manufacturer's websites were searched for relevant clinical trials. Randomized control trials, at least 12 weeks duration, comparing an ICS/LABA combination with active control or placebo were included. Moderate and severe exacerbations were chosen as the outcome assessment criteria. The primary analyses were conducted with a Bayesian Markov chain Monte Carlo method. Most of the ICS/LABA combinations reduced moderate-to-severe exacerbations as compared with placebo and LABA, but none of them reduced severe exacerbations. However, many studies excluded patients receiving long-term oxygen therapy. Moderate-dose ICS was as effective as high-dose ICS in reducing exacerbations when combined with LABA. ICS/LABA combinations had a class effect with regard to the prevention of COPD exacerbations. Moderate-dose ICS/LABA combination therapy would be sufficient for COPD patients when indicated. The efficacy of ICS/LABA combination therapy appeared modest and had no impact in reducing severe exacerbations. Further studies are needed to evaluate the efficacy of ICS/LABA combination therapy in severely affected COPD patients requiring long-term oxygen therapy.

Evaluation of partial beta-adrenoceptor agonist activity.

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Lipworth, B J; Grove, A

1997-01-01

A partial beta-adrenoceptor (beta-AR) agonist will exhibit opposite agonist and antagonist activity depending on the prevailing degree of adrenergic tone or the presence of a beta-AR agonist with higher intrinsic activity. In vivo partial beta-AR agonist activity will be evident at rest with low endogenous adrenergic tone, as for example with chronotropicity (beta 1/beta 2), inotropicity (beta 1) or peripheral vasodilatation and finger tremor (beta 2). beta-AR blocking drugs which have partial agonist activity may exhibit a better therapeutic profile when used for hypertension because of maintained cardiac output without increased systemic vascular resistance, along with an improved lipid profile. In the presence of raised endogenous adrenergic tone such as exercise or an exogenous full agonist, beta-AR subtype antagonist activity will become evident in terms of effects on exercise induced heart rate (beta 1) and potassium (beta 2) responses. Reduction of exercise heart rate will occur to a lesser degree in the case of a beta-adrenoceptor blocker with partial beta 1-AR agonist activity compared with a beta-adrenoceptor blocker devoid of partial agonist activity. This may result in reduced therapeutic efficacy in the treatment of angina on effort when using beta-AR blocking drugs with partial beta 1-AR agonist activity. Effects on exercise hyperkalaemia are determined by the balance between beta 2-AR partial agonist activity and endogenous adrenergic activity. For predominantly beta 2-AR agonist such as salmeterol and salbutamol, potentiation of exercise hyperkalaemia occurs. For predominantly beta 2-AR antagonists such as carteolol, either potentiation or attenuation of exercise hyperkalaemia occurs at low and high doses respectively. beta 2-AR partial agonist activity may also be expressed as antagonism in the presence of an exogenous full agonist, as for example attenuation of fenoterol induced responses by salmeterol. Studies are required to investigate whether

Comparative efficacy of inhaled ciclesonide, budesonide, and fluticasone in mild to moderately persistent bronchial asthma

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Tamoghna Maiti; Syed Mohammed Naser; Amrita Panda; Sekhar Mandal; Sonai Mandal; Tanmoy Gangopadhyay; Parvin Banu

2014-01-01

Background: Bronchodilators and glucocorticoids have been proven to be very effective and safe in asthma treatment, which recommend the use of steroids and beta2-agonist (long or short acting) as the first line of treatment in of asthma. This study was aimed to compare the efficacy of three different inhaled corticosteroids ciclesonide, budesonide, and fluticasone in bronchial asthma. Methods: A total of 30 patients with mild to moderately persistent bronchial asthma was selected as per th...

The Beta-2-Adrenoreceptor Agonists, Formoterol and Indacaterol, but Not Salbutamol, Effectively Suppress the Reactivity of Human Neutrophils In Vitro

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Ronald Anderson

2014-01-01

Full Text Available The clinical relevance of the anti-inflammatory properties of beta-2 agonists remains contentious possibly due to differences in their molecular structures and agonist activities. The current study has compared the effects of 3 different categories of β2-agonists, namely, salbutamol (short-acting, formoterol (long-acting and indacaterol (ultra-long-acting, at concentrations of 1–1000 nM, with human blood neutrophils in vitro. Neutrophils were activated with either N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP, 1 µM or platelet-activating factor (PAF, 200 nM in the absence and presence of the β2-agonists followed by measurement of the generation of reactive oxygen species and leukotriene B4, release of elastase, and expression of the β2-integrin, CR3, using a combination of chemiluminescence, ELISA, colorimetric, and flow cytometric procedures respectively. These were correlated with alterations in the concentrations of intracellular cyclic-AMP and cytosolic Ca2+. At the concentrations tested, formoterol and indacaterol caused equivalent, significant (P<0.05 at 1–10 nM dose-related inhibition of all of the pro-inflammatory activities tested, while salbutamol was much less effective (P<0.05 at 100 nM and higher. Suppression of neutrophil reactivity was accompanied by elevations in intracellular cAMP and accelerated clearance of Ca2+ from the cytosol of activated neutrophils. These findings demonstrate that β2-agonists vary with respect to their suppressive effects on activated neutrophils.

Long-acting muscarinic antagonist (LAMA) plus long-acting beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD).

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Horita, Nobuyuki; Goto, Atsushi; Shibata, Yuji; Ota, Erika; Nakashima, Kentaro; Nagai, Kenjiro; Kaneko, Takeshi

2017-02-10

Three classes of inhaler medications are used to manage chronic obstructive pulmonary disease (COPD): long-acting beta-agonists (LABA), long-acting muscarinic antagonists (LAMA), and inhaled corticosteroids (ICS). When two classes of medications are required, LAMA plus LABA (LAMA+LABA) and LABA plus ICS (LABA+ICS) are often selected because these combinations can be administered via a single medication device. The previous Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidance recommended LABA+ICS as the first-line treatment for managing stable COPD in high-risk people of categories C and D. However, the updated GOLD 2017 guidance recommends LAMA+LABA over LABA+ICS. To compare the benefits and harms of LAMA+LABA versus LABA+ICS for treatment of people with stable COPD. We performed an electronic search of the Cochrane Airways Group Specialised Register (2 February 2016), ClinicalTrials.gov (4 June 2016), and the World Health Organization Clinical Trials Search Portal (4 June 2016), followed by a handsearch (5 June 2016). Two review authors screened and scrutinised the selected articles. We included individual randomised controlled trials, parallel-group trials, and cross-over trials comparing LAMA+LABA and LABA+ICS for stable COPD. The minimum accepted trial duration was one month and trials should have been conducted in an outpatient setting. Two review authors independently extracted data and evaluated risk of bias. We resolved any discrepancies through discussion. We analysed dichotomous data as odds ratios (OR), and continuous data as mean differences (MD), with 95% confidence interval (CI) using Review Manager 5. Exacerbations were measured by counting the number of people experiencing one or more exacerbation. We included 11 studies comprising 9839 participants in our quantitative analysis. Most studies included people with moderate to severe COPD, without recent exacerbations. One pharmaceutical sponsored trial that included only people with

Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy.

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Bouyssou, Thierry; Hoenke, Christoph; Rudolf, Klaus; Lustenberger, Philipp; Pestel, Sabine; Sieger, Peter; Lotz, Ralf; Heine, Claudia; Büttner, Frank H; Schnapp, Andreas; Konetzki, Ingo

2010-02-15

Compound 4p was identified from a series of 6-hydroxy-4H-benzo[1,4]oxazin-3-ones as potent agonist of the human beta2-adrenoceptor with a high beta1/beta2-selectivity. A complete reversal of acetylcholine-induced bronchoconstriction which lasted over the whole study period of 5h was demonstrated for 4p in a guinea pig in vivo model without any signs of cardiovascular effects up to 10-fold above the first dose reaching 100% bronchoprotection. The enantiomerically pure (R)-form of 4p exerted a bronchodilatory efficacy over 24 h in dogs and guinea pigs in the absence of systemic pharmacodynamic effects. Formoterol which was tested as comparator in the same in vivo models of acetylcholine-induced bronchoconstriction did not retain efficacy after 24 h. In summary, the preclinical profile of compound (R)-4p (olodaterol, also known as BI 1744 CL) suggests a potential for once-daily dosing in man accompanied with an improved safety profile. Copyright 2010 Elsevier Ltd. All rights reserved.

Sports doping: emerging designer and therapeutic β2-agonists.

Science.gov (United States)

Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

2013-10-21

Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future. © 2013.

Acute systemic effects of inhaled salbutamol in asthmatic subjects expressing common homozygous beta2-adrenoceptor haplotypes at positions 16 and 27.

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Lee, Daniel K C; Bates, Caroline E; Lipworth, Brian J

2004-01-01

The relationship between beta2-adrenoceptor polymorphisms at positions 16 and 27, and the acute systemic beta2-adrenoceptor effects of inhaled salbutamol is unclear. We therefore elected to evaluate the influence of common homozygous beta2-adrenoceptor haplotypes on the acute systemic beta2-adrenoceptor effects following inhaled salbutamol in asthmatic subjects. An initial database search of 531 asthmatic subjects identified the two commonest homozygous haplotypes at positions 16 and 27 to be Arg16-Gln27 (12%) and Gly16-Glu27 (19%). After a 1-week washout period where all beta2-adrenoceptor agonists were withdrawn, 16 Caucasian subjects (Arg16-Gln27: n = 8 and Gly16-Glu27: n = 8) were given a single dose of inhaled salbutamol (1200 microg), followed by serial blood sampling for serum potassium, along with measurements of diastolic blood pressure and heart rate, at 5-min intervals for 20 min. The two groups were well matched for age, sex, FEV1, and inhaled corticosteroid dose. Baseline values for serum potassium, diastolic blood pressure and heart rate were not significantly different comparing Arg16-Gln27 vs Gly16-Glu27. The mean +/- SEM maximum serum potassium change from baseline over 20 min was significantly greater (P = 0.04) for Arg16-Gln27: -0.37 +/- 0.05 mmol l(-1) vs Gly16-Glu27: -0.23 +/- 0.04 mmol l(-1); 95% CI for difference: -0.01 to -0.28 mmol l(-1). The maximum diastolic blood pressure change from baseline over 20 min was significantly greater (P = 0.0008) for Arg16-Gln27: -13 +/- 1 mmHg vs Gly16-Glu27: -4 +/- 2 mmHg; 95% CI for difference: -5, 14 mmHg. There was no significant difference comparing the maximum heart rate change from baseline for Arg16-Gln27: 10 +/- 3 beats min(-1) vs Gly16-Glu27: 10 +/- 3 beats min(-1). Caucasian asthmatic subjects with the Arg16-Gln27 haplotype exhibited a greater systemic response to inhaled salbutamol, compared with those with the Gly16-Glu27 haplotype. The attenuated beta2-adrenoceptor response in the Gly16-Glu27

Enantioselective disposition of (R)-salmeterol and (S)-salmeterol in urine following inhaled dosing and application to doping control

DEFF Research Database (Denmark)

Jacobson, Glenn A; Hostrup, Morten; Narkowicz, Christian K

2017-01-01

Salmeterol (USAN, INN, BAN) is a long-acting beta2-adrenoceptor agonist (LABA) widely used in the treatment of airways disease. Although salmeterol is permitted via inhalation by athletes and supratherapeutic dosing may enhance performance, no urine threshold has been established by the World Anti...

Effect of Transdermal Tulobuterol Added to Inhaled Corticosteroids in Asthma Patients

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Gen Tamura

2005-01-01

Methods: A randomized, double-blind, double-dummy, parallel-group, multicenter trial was conducted. Male and female patients with a diagnosis of asthma requiring inhaled short-acting β2-agonists despite treatment with inhaled corticosteroids took tulobuterol tape (1 mg or 2 mg and corresponding placebo tapes for 4 weeks. Results: Mean morning peak expiratory flows (PEF in the 1 and 2 mg/day groups were significantly increased from the baseline value by 23.8 and 35.9 L/min at week 4, respectively. The increase in mean morning PEF in the 2 mg/day group was significantly higher than that in the 1 mg/day group. The mean evening PEF was significantly increased in both treatment groups compared with baseline values. Although the increase in mean evening PEF in the 2 mg/day group was greater than that in the 1 mg/day group, the difference between groups was statistically significant only at week 1. The safety profiles of the two treatments were similar. Conclusions: In patients with persistent asthma who require inhaled short-acting β2-agonists while receiving inhaled corticosteroids, transdermal tulobuterol significantly improved PEF in a dose-dependent manner, i.e., greater effect with 2 mg than with 1 mg per day.

Beta-Adrenergic Receptors and Mechanisms in Asthma: The New Long-Acting Beta-Agonists

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Robert G Townley

1996-01-01

Full Text Available The objective is to review β-adrenergic receptors and mechanisms in the immediate and late bronchial reaction in asthma and the new long-acting β-agonist. This will be discussed in light of the controversy of the potential adverse effect of regular use of long-acting β-agonists. We studied the effect of formoterol on the late asthmatic response (LAR and airway inflammation in guinea-pigs. Formoterol suppressed the LAR, antigen-induced airway inflammation and hyperresponsiveness, although isoproterenol failed to inhibit these parameters. β-Adrenergic hyporesponsiveness, and cholinergic and a- adrenergic hyperresponsiveness have been implicated in the pathogenesis of asthma. A decrease in β-adrenoreceptor function can result either from exogenously administered β-agonist or from exposure to allergens resulting in a late bronchial reaction. There is increasing evidence that eosinophils, macrophages, and lymphocytes which are of primary importance in the late bronchial reaction are also modulated by β2- adrenoreceptors. In functional studies of guinea-pig or human isolated trachea and lung parenchyma, PAF and certain cytokines significantly reduced the potency of isoproterenol to reverse methacholine- or histamine-induced contraction. The effect of glucocorticoids on pulmonary β-adrenergic receptors and responses suggests an important role for glucocorticoids to increase β-adrenergic receptors and responsiveness.

Beta-agonists and animal welfare

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The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

Interaction between corticosteroid and beta-agonist drugs. Biochemical and cardiovascular effects in normal subjects.

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Taylor, D R; Wilkins, G T; Herbison, G P; Flannery, E M

1992-08-01

The aim of this study was to investigate whether the administration of prednisone potentiates any of the acute biochemical and cardiovascular effects of high-dose inhaled beta-agonist drugs. These agents are known to cause dose-related changes in plasma potassium and glucose, as well as ECG changes in heart rate, corrected QT interval (QTc), T wave, and U wave. On theoretical grounds, the concomitant use of systemic corticosteroids might enhance these actions. Twenty-four healthy subjects were randomized to receive one of three treatments: salbutamol 5 mg or fenoterol 5 mg or normal saline solution. Each drug was administered twice, 30 min apart by nebulizer, and the procedure was repeated after each subject had received prednisone 30 mg daily for one week. Plasma potassium and glucose levels were measured, and ECGs were obtained after each treatment, together with 12-h Holter monitoring for arrhythmias. Changes in plasma potassium and glucose following nebulized beta-agonist were significantly greater after treatment with prednisone. Baseline potassium level fell from 3.75 mmol/L (95 percent CI 3.61, 3.89) to 3.50 mmol/L (95 percent CI 3.36, 3.64), and thereafter all values were significantly lower at each time point (p = 0.003). The lowest mean plasma potassium was obtained 90 min after fenoterol administration with prednisone pretreatment: 2.78 mmol/L (95 percent CI 2.44, 3.13). Increases in heart rate and QTc interval following both beta-agonist drugs were significant, but T-wave amplitude reductions did not reach significance. Prednisone treatment did not significantly alter the cardiovascular responses. Supraventricular and ventricular ectopic activity was related to beta-agonist use, but no potentiating effect was noted following steroid treatment. We conclude that the acute biochemical effects of beta-agonist administration are augmented by prior treatment with prednisone, but this is not the case for ECG effects. However, the degree of hypokalemia noted as

Association of MicroRNA-196a2 Variant with Response to Short-Acting β2-Agonist in COPD: An Egyptian Pilot Study

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Fawzy, Manal S.; Hussein, Mohammad H.; Abdelaziz, Eman Z.; Yamany, Hussain A.; Ismail, Hussein M.; Toraih, Eman A.

2016-01-01

Chronic obstructive pulmonary disease (COPD) is a multifactorial chronic respiratory disease, characterized by an obstructive pattern. Understanding the genetic predisposition of COPD is essential to develop personalized treatment regimens. MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs that modulate the expression levels of specific proteins based on sequence complementarity with their target mRNA molecules. Emerging evidences demonstrated the potential use of miRNAs as a disease biomarker. This pilot study aimed to investigate the association of the MIR-196a2 rs11614913 (C/T) polymorphism with COPD susceptibility, the clinical outcome and bronchodilator response to short-acting β2-agonist. Genotyping of rs11614913 polymorphism was determined in 108 COPD male patients and 116 unrelated controls using real-time polymerase chain reaction technology. In silico target prediction and network core analysis were performed. COPD patients did not show significant differences in the genotype distribution (p = 0.415) and allele frequencies (p = 0.306) of the studied miRNA when compared with controls. There were also no associations with GOLD stage, dyspnea grade, disease exacerbations, COPD assessment test for estimating impact on health status score, or the frequency of intensive care unit admission. However, COPD patients with CC genotype corresponded to the smallest bronchodilator response after Salbutamol inhalation, the heterozygotes (CT) had an intermediate response, while those with the TT genotype showed the highest response (p < 0.001). In conclusion MIR-196a2 rs11614913 polymorphism is associated with the bronchodilator response of COPD in our sample of the Egyptian population, generating hypothesis of the potential use of MIR-196a2 variant as a pharmacogenetic marker for COPD. PMID:27043015

Bronchodilator treatment of stable COPD: long-acting anticholinergics

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W. Vincken

2005-09-01

Full Text Available Since airflow obstruction in chronic obstructive pulmonary disease (COPD is to some extent reversible, bronchodilators play an important role in the maintenance treatment of COPD the more they reduce hyperinflation and, as a result, improve dyspnoea and exercise capacity. Since parasympathetic activity is the dominant reversible component of airflow obstruction in COPD, inhaled short-acting anticholinergic agents (SAAC, in particular ipratropium, became an efficient and safe first-line treatment, especially when combined with a short-acting beta2-adrenergic receptor agonist. Even better results were obtained when combining the SAAC ipratropium to a long-acting beta2-adrenergic receptor agonist (LABA, once they became available. Recently, tiotropium bromide, the first of a new class of selective and long-acting anticholinergic agents was introduced for once-daily maintenance treatment of COPD patients. Several large long-term randomised clinical trials comparing tiotropium to placebo as well as to the SAAC ipratropium and the LABA salmeterol, have confirmed the long-acting and superior bronchodilator effect of tiotropium without any evidence of drug tolerance developing. These studies also have clearly demonstrated that tiotropium positively affects several other important health outcomes, such as dyspnoea sensation, exercise capacity, utilisation of rescue bronchodilators, health-related quality of life, COPD exacerbations and hospitalisations because of exacerbations. The improvement in these real-life outcomes appears related to the reduction in both static and dynamic hyperinflation. In all these studies, tiotropium was well tolerated and safe; the only relevant side-effect encountered being dry mouth, usually mild and often transitory. Finally, it has been shown that the combination of tiotropium with a LABA affords superior bronchodilatation than both agents alone, indicating that both classes of long-acting bronchodilators should be

Which inhaled corticosteroid and long-acting β-agonist combination is better in patients with moderate-to-severe asthma, a dry powder inhaler or a pressurized metered-dose inhaler?

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Muraki, Masato; Gose, Kyuya; Hanada, Soichiro; Sawaguchi, Hirochiyo; Tohda, Yuji

2017-11-01

Two main types of devices are used to facilitate the administration of inhaled corticosteroid (ICS) and long-acting β-agonist (LABA) in combination, dry powder inhalers (DPIs) and pressurized metered-dose inhalers (pMDIs). There are few reports comparing the effects of the two devices, and it is unknown which should be recommended for asthma patients with given sets of characteristics. In the current study, the beneficial effects and side effects associated with DPIs and pMDIs were compared, and the question of which device should be recommended for asthma patients was investigated. A prospective, randomized, crossover, comparative study in adult outpatients with asthma was conducted using salmeterol/fluticasone propionate combination (SFC) 50 μg/250 μg, one inhalation of Adoair ® 250 Diskus ® twice daily or two inhalations of Adoair ® 125 Aerosol twice daily, for 8 weeks. Questionnaires, exhaled nitric oxide (FeNO) tests and pulmonary function tests were administered after the use of each device for 8 weeks, and the results derived from each device were compared. Sixty-eight subjects were included in the final analysis. There were no significant differences between quality-of-life scores, FeNO, spirometry test results and forced oscillation results. With regard to patient preferences, 57.4% preferred the Adoair ® Aerosol and 35.3% preferred the Adoair ® Diskus ® , as determined via the comparative evaluation questionnaire. Although DPI prescription accounts for the predominant market share of combined ICS/LABA in Japan, patients preferred a pMDI device to a DPI device. Compared to DPIs, pMDIs may be the preferential choice for patients with asthma.

Effect of β2-adrenergic receptor gene (ADRB2 3′ untranslated region polymorphisms on inhaled corticosteroid/long-acting β2-adrenergic agonist response

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Ambrose Helen J

2012-05-01

Full Text Available Abstract Background Evidence suggests that variation in the length of the poly-C repeat in the 3′ untranslated region (3′UTR of the β2-adrenergic receptor gene (ADRB2 may contribute to interindividual variation in β-agonist response. However, methodology in previous studies limited the assessment of the effect of sequence variation in the context of poly-C repeat length. The objectives of this study were to design a novel genotyping method to fully characterize sequence variation in the ADRB2 3′UTR poly-C repeat in asthma patients treated with inhaled corticosteroid and long-acting β2-adrenergic agonist (ICS/LABA combination therapy, and to analyze the effect of the poly-C repeat polymorphism on clinical response. Methods In 2,250 asthma patients randomized to treatment with budesonide/formoterol or fluticasone/salmeterol in a six-month study (AstraZeneca study code: SD-039-0735, sequence diversity in the ADRB2 poly-C repeat region was determined using a novel sequencing-based genotyping method. The relationship between the poly-C repeat polymorphism and the incidence of severe asthma exacerbations, and changes in pulmonary function and asthma symptoms from baseline to the average during the treatment period, were analyzed. Results Poly-C repeat genotypes were assigned in 97% (2,192/2,250 of patients. Of the 13 different poly-C repeat alleles identified, six alleles occurred at a frequency of >5% in one or more population in this study. The repeat length of these six common alleles ranged from 10 to 14 nucleotides. Twelve poly-C repeat genotypes were observed at a frequency of >1%. No evidence of an association between poly-C repeat genotype and the incidence of severe asthma exacerbations was observed. Patients’ pulmonary function measurements improved and asthma symptoms declined when treated with ICS/LABA combination therapy regardless of poly-C repeat genotype. Conclusions The extensive sequence diversity present in the poly

Comparison Review of Short-Acting and Long-Acting Glucagon-like Peptide-1 Receptor Agonists.

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Uccellatore, Annachiara; Genovese, Stefano; Dicembrini, Ilaria; Mannucci, Edoardo; Ceriello, Antonio

2015-09-01

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) are useful tools for treating type 2 diabetes mellitus. In their recent position statement, the American Diabetes Association and European Association for the Study of Diabetes recommend GLP1-RAs as add-on to metformin when therapeutic goals are not achieved with monotherapy, particularly for patients who wish to avoid weight gain or hypoglycemia. GLP1-RAs differ substantially in their duration of action, frequency of administration and clinical profile. Members of this class approved for clinical use include exenatide twice-daily, exenatide once-weekly, liraglutide and lixisenatide once-daily. Recently, two new once-weekly GLP1-RAs have been approved: dulaglutide and albiglutide. This article summarizes properties of short- and long-acting GLP-1 analogs, and provides useful information to help choose the most appropriate compound for individual patients.

The protective effect of a beta 2 agonist against excessive airway narrowing in response to bronchoconstrictor stimuli in asthma and chronic obstructive lung disease.

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Bel, E. H.; Zwinderman, A. H.; Timmers, M. C.; Dijkman, J. H.; Sterk, P. J.

1991-01-01

Beta 2 agonists reduce airway hypersensitivity to bronchoconstrictor stimuli acutely in patients with asthma and chronic obstructive lung disease. To determine whether these drugs also protect against excessive airway narrowing, the effect of inhaled salbutamol on the position and shape of the dose-response curves for histamine or methacholine was investigated in 12 patients with asthma and 11 with chronic obstructive lung disease. After pretreatment with salbutamol (200 or 400 micrograms) or placebo in a double blind manner dose-response curves for inhaled histamine and methacholine were obtained by a standard method on six days in random order. Airway sensitivity was defined as the concentration of histamine or methacholine causing a 20% fall in FEV1 (PC20). A maximal response plateau on the log dose-response curve was considered to be present if two or more data points for FEV1 fell within a 5% response range. In the absence of a plateau, the test was continued until a predetermined level of severe bronchoconstriction was reached. Salbutamol caused an acute increase in FEV1 (mean increase 11.5% predicted in asthma, 7.2% in chronic obstructive lung disease), and increase in PC20 (mean 15 fold in asthma, fivefold in chronic obstructive lung disease), and an increase in the slope of the dose-response curves in both groups. In subjects in whom a plateau of FEV1 response could be measured salbutamol did not change the level of the plateau. In subjects without a plateau salbutamol did not lead to the development of a plateau, despite achieving a median FEV1 of 44% predicted in asthma and 39% in chronic obstructive lung disease. These results show that, although beta 2 agonists acutely reduce the airway response to a given strength of bronchoconstrictor stimulus, they do not protect against excessive airflow obstruction if there is exposure to relatively strong stimuli. This, together with the steepening of the dose-response curve, could be a disadvantage of beta 2

Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.

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Maruyama, Tatsuya; Onda, Kenichi; Hayakawa, Masahiko; Matsui, Tetsuo; Takasu, Toshiyuki; Ohta, Mitsuaki

2009-06-01

In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.

Association of blood eosinophils and plasma periostin with FEV1 response after 3-month inhaled corticosteroid and long-acting beta2-agonist treatment in stable COPD patients

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Park HY

2015-12-01

with an improvement in forced expiratory volume in 1 second (FEV1 after 3-month treatment with ICS/long-acting beta2-agonist (LABA in stable COPD patients. Patients and methods: Blood eosinophils and plasma periostin levels were measured in 130 stable COPD subjects selected from the Korean Obstructive Lung Disease cohort. Subjects began a 3-month ICS/LABA treatment after washout period. Results: High blood eosinophils (>260/µL, adjusted odds ratio =3.52, P=0.009 and high plasma periostin (>23 ng/mL, adjusted odds ratio =3.52, P=0.013 were significantly associated with FEV1 responders (>12% and 200 mL increase in FEV1 from baseline after treatment. Moreover, the addition of high blood eosinophils to age, baseline positive bronchodilator response, and FEV1 <50% of the predicted value significantly increased the area under the curve for prediction of FEV1 responders (from 0.700 to 0.771; P=0.045. Conclusion: High blood eosinophils and high plasma periostin were associated with improved lung function after 3-month ICS/LABA treatment. In particular, high blood eosinophils, in combination with age and baseline lung function parameters, might be a possible biomarker for identification of COPD patients with favorable FEV1 improvement in response to ICS/LABA treatment. Keywords: eosinophils, periostin, COPD

Using long-acting beta2-agonists safely: What will be the impact of the US Food and Drug Administration's panel recommendations?

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Smart, Brian A

2009-01-01

The US Food and Drug Administration (FDA) has launched an investigation into the safety of long-acting beta(2)-agonists (LABAs). While the impact of this investigation is yet to be seen, clinicians should be circumspect in the use of these agents and prescribe them according to the recommendations of current asthma guidelines, informing patients and their caretakers about potential risks. As clinical trials attempt to address the question of whether LABAs are safe for use in pediatric and adult populations, current data provide no clear answers. A special hearing of the FDA's Pulmonary-Allergy Drugs Advisory Committee, Drug Safety and Risk Management Advisory Committee, and Pediatric Advisory Committee attempted to seek consensus on the matter as it reviewed the results of controlled clinical trials and conducted a benefit:risk assessment of LABAs to make recommendations on their safety.

Super agonist actions of clothianidin and related compounds on the SAD beta 2 nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes.

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Ihara, Makoto; Matsuda, Kazuhiko; Shimomura, Masaru; Sattelle, David B; Komai, Koichiro

2004-03-01

To compare the actions of clothianidin, a neonicotinoid acting on insect nicotinic acetylcholine receptors, and related compounds with that of imidacloprid, the compounds were tested on the Drosophila SAD-chicken beta2 nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. The maximum response of the SAD beta 2 nicotinic receptor to clothianidin was larger than that observed for acetylcholine. Ring breakage of the imidazolidine ring of imidacloprid resulting in the generation of a guanidine group was critical for this super agonist action.

Potential of beta-adrenergic agonists for increasing protein deposition in ruminants in developing countries

International Nuclear Information System (INIS)

Berschauer, F.

1989-01-01

Various substituted phenylethanolamines, acting on the sympathetic nervous system, have been shown to increase protein retention (via decreased proteolysis) and reduce fat deposition (via increased lipolysis and reduced lipogenesis) in ruminants and monogastrics. Research with finishing lambs in developed countries show various beta-adrenergic agonists to improve growth rate (by 18%), feed conversion (by 12%) and carcass quality (28% increase in area of longissimus dorsi and 33% reduction in subcutaneous fat). Similar effects of beta-agonists on carcass composition of well fed cattle have been reported. The effects of beta-agonists on livestock in developing countries of the tropics have not yet been investigated, but their effects in increasing metabolic rate suggest that treated ruminants would be more vulnerable to hot environments. Beta-agonists appear to improve nitrogen retention to a greater extent in breeds with a lower potential for muscle growth. In view of this, they might be particularly effective in improving nitrogen retention in tropical breeds which have a low growth potential. This aspect, together with the response of undernourished animals in the developing countries, needs investigation. Beta-adrenergic agonists are not yet registered for use in animal production, but product licenses for some of them are expected to be granted soon. (author). 31 refs, 1 fig., 12 tabs

Role of beta-adrenoceptors in memory consolidation: beta3-adrenoceptors act on glucose uptake and beta2-adrenoceptors on glycogenolysis.

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Gibbs, Marie E; Hutchinson, Dana S; Summers, Roger J

2008-09-01

Noradrenaline, acting via beta(2)- and beta(3)-adrenoceptors (AR), enhances memory formation in single trial-discriminated avoidance learning in day-old chicks by mechanisms involving changes in metabolism of glucose and/or glycogen. Earlier studies of memory consolidation in chicks implicated beta(3)- rather than beta(2)-ARs in enhancement of memory consolidation by glucose, but did not elucidate whether stimulation of glucose uptake or of glycolysis was responsible. This study examines the role of glucose transport in memory formation using central injection of the nonselective facilitative glucose transporter (GLUT) inhibitor cytochalasin B, the endothelial/astrocytic GLUT-1 inhibitor phloretin and the Na(+)/energy-dependent endothelial glucose transporter (SGLT) inhibitor phlorizin. Cytochalasin B inhibited memory when injected into the mesopallium (avian cortex) either close to or between 25 and 45 min after training, whereas phloretin and phlorizin only inhibited memory at 30 min. This suggested that astrocytic/endothelial (GLUT-1) transport is critical at the time of consolidation, whereas a different transporter, probably the neuronal glucose transporter (GLUT-3), is important at the time of training. Inhibition of glucose transport by cytochalasin B, phloretin, or phlorizin also interfered with beta(3)-AR-mediated memory enhancement 20 min posttraining, whereas inhibition of glycogenolysis interfered with beta(2)-AR agonist enhancement of memory. We conclude that in astrocytes (1) activities of both GLUT-1 and SGLT are essential for memory consolidation 30 min posttraining; (2) neuronal GLUT-3 is essential at the time of training; and (3) beta(2)- and beta(3)-ARs consolidate memory by different mechanisms; beta(3)-ARs stimulate central glucose transport, whereas beta(2)-ARs stimulate central glycogenolysis.

Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents

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Fabbri Leonardo M

2010-10-01

Full Text Available Abstract Chronic obstructive pulmonary disease (COPD is characterized by progressive airflow limitation and debilitating symptoms. For patients with moderate-to-severe COPD, long-acting bronchodilators are the mainstay of therapy; as symptoms progress, guidelines recommend combining bronchodilators from different classes to improve efficacy. Inhaled long-acting β2-agonists (LABAs have been licensed for the treatment of COPD since the late 1990s and include formoterol and salmeterol. They improve lung function, symptoms of breathlessness and exercise limitation, health-related quality of life, and may reduce the rate of exacerbations, although not all patients achieve clinically meaningful improvements in symptoms or health related quality of life. In addition, LABAs have an acceptable safety profile, and are not associated with an increased risk of respiratory mortality, although adverse effects such as palpitations and tremor may limit the dose that can be tolerated. Formoterol and salmeterol have 12-hour durations of action; however, sustained bronchodilation is desirable in COPD. A LABA with a 24-hour duration of action could provide improvements in efficacy, compared with twice-daily LABAs, and the once-daily dosing regimen could help improve compliance. It is also desirable that a new LABA should demonstrate fast onset of action, and a safety profile at least comparable to existing LABAs. A number of novel LABAs with once-daily profiles are in development which may be judged against these criteria. Indacaterol, a LABA with a 24-hour duration of bronchodilation and fast onset of action, is the most advanced of these. Preliminary results from large clinical trials suggest indacaterol improves lung function compared with placebo and other long-acting bronchodilators. Other LABAs with a 24-hour duration of bronchodilation include carmoterol, vilanterol trifenatate and oldaterol, with early results indicating potential for once-daily dosing in

Beta2- and beta3-adrenoceptors activate glucose uptake in chick astrocytes by distinct mechanisms: a mechanism for memory enhancement?

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Hutchinson, Dana S; Summers, Roger J; Gibbs, Marie E

2007-11-01

Isoprenaline, acting at beta-adrenoceptors (ARs), enhances memory formation in single trial discriminated avoidance learning in day-old chicks by mechanisms involving alterations in glucose and glycogen metabolism. Earlier studies of memory consolidation in chicks indicated that beta3-ARs enhanced memory by increasing glucose uptake, whereas beta2-ARs enhance memory by increasing glycogenolysis. This study examines the ability of beta-ARs to increase glucose uptake in chick forebrain astrocytes. The beta-AR agonist isoprenaline increased glucose uptake in a concentration-dependent manner, as did insulin. Glucose uptake was increased by the beta2-AR agonist zinterol and the beta3-AR agonist CL316243, but not by the beta1-AR agonist RO363. In chick astrocytes, reverse transcription-polymerase chain reaction studies showed that beta1-, beta2-, and beta3-AR mRNA were present, whereas radioligand-binding studies showed the presence of only beta2- and beta3-ARs. beta-AR or insulin-mediated glucose uptake was inhibited by phosphatidylinositol-3 kinase and protein kinase C inhibitors, suggesting a possible interaction between the beta-AR and insulin pathways. However beta2- and beta3-ARs increase glucose uptake by two different mechanisms: beta2-ARs via a Gs-cAMP-protein kinase A-dependent pathway, while beta3-ARs via interactions with Gi. These results indicate that activation of beta2- and beta3-ARs causes glucose uptake in chick astrocytes by distinct mechanisms, which may be relevant for memory enhancement.

Pirbuterol Acetate Oral Inhalation

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... Pirbuterol is in a class of medications called beta-agonist bronchodilators. It works by relaxing and opening ... cleaning. Once a week, remove the mouthpiece cover, turn the inhaler upside down and wipe the mouthpiece ...

Are beta2-agonists responsible for increased mortality in heart failure?

LENUS (Irish Health Repository)

Bermingham, Margaret

2012-02-01

AIMS: Previous large-scale, retrospective studies have shown increased mortality in heart failure (HF) patients using beta2-agonists (B2As). We further examined the relationship between B2A use and mortality in a well-characterized population by adjusting for natriuretic peptide levels as a measure of HF severity. METHODS AND RESULTS: This was a retrospective cohort study of patients attending an HF Disease Management Programme with mean follow-up of 2.9 +\\/- 2.4 years. Chart review confirmed B2A use, dose and duration of use, and documented pulmonary function evaluation. The primary endpoint was the effect of B2A use compared with no B2A use on mortality using unadjusted and adjusted Kaplan-Meier survival curves. Data were available for 1294 patients (age 70.6 +\\/- 11.5 years) of whom 64% were male and 22.2% were taking B2As. beta2-Agonist users were older, more likely to be male, to have smoked, to have chronic obstructive pulmonary disease (COPD) and asthma, and less likely to take beta-blockers. Multivariable associates of mortality included: B-type natriuretic peptide (BNP), coronary artery disease, age, and beta-blocker use. Unadjusted mortality rates for B2A users were found to be significantly higher than non-B2A users [hazard ratio (HR) 1.304, 95% confidence interval (CI) 1.030-1.652, P= 0.028]. However, when adjusted for age, sex, medication, co-morbidity, smoking, COPD, and BNP differences, overall mortality rates were similar [HR 1.043, 95% CI (0.771-1.412), P= 0.783]. CONCLUSION: Unlike previous reports, this retrospective evaluation of B2A therapy in HF patients shows no relationship with long-term mortality when adjusted for population differences including BNP. Large, prospective studies are required to define the risk\\/benefit ratio of B2As in patients with heart failure.

Thyroid Storm with Heart Failure Treated with a Short-acting Beta-adrenoreceptor Blocker, Landiolol Hydrochloride.

Science.gov (United States)

Yamashita, Yugo; Iguchi, Moritake; Nakatani, Rieko; Usui, Takeshi; Takagi, Daisuke; Hamatani, Yasuhiro; Unoki, Takashi; Ishii, Mitsuru; Ogawa, Hisashi; Masunaga, Nobutoyo; Abe, Mitsuru; Akao, Masaharu

2015-01-01

Beta-adrenoreceptor blockers are essential in controlling the peripheral actions of thyroid hormones and a rapid heart rate in patients with thyroid storm, although they should be used with great caution when there is the potential for heart failure. A 67-year-old woman was diagnosed as having thyroid storm in addition to marked tachycardia with atrial fibrillation and heart failure associated with a reduced left ventricular function. The administration of an oral beta blocker, bisoprolol fumarate, induced hypotension and was not tolerable for the patient, whereas landiolol hydrochloride, a short-acting intravenous beta-adrenoreceptor blocker with high cardioselectivity and a short elimination half-life, was useful for controlling the patient's tachycardia and heart failure without causing hemodynamic deterioration.

[Study of personal best value of peak expiratory flow in patients with asthma--comparison of the highest value of daily PEF under good control and the highest value of daily PEF obtained after using repeated inhaled beta2-agonist during high-dose inhaled steroid treatment].

Science.gov (United States)

Watanabe, Naoto; Makino, Sohei; Kihara, Norio; Fukuda, Takeshi

2008-12-01

In the guideline for asthma management, it is important to find the personal best value of peak expiratory flow (best PEF). Recently, we have substituted the highest value of PEF in daily life under good control (daily highest PEF) for the best PEF. In the present study, we considered whether the daily highest PEF could be used as the best PEF or not. Subjects were 30 asthmatics who were well controlled but whose baseline PEF values were less than 80 percent of predicted values. We compared the daily highest PEF and the highest of PEF obtained after repeated inhaled beta2-agonist (salbutamol MDI every 20 minutes three times). All subjects then received 1600 microg/day of beclomethasone dipropionate (BDP) for 4 to 8 weeks. We studied the effect of high-dose inhaled steroid treatment on each PEF value and compared the daily highest PEF and the highest PEF obtained after using repeated salbutamol MDI during high dose inhaled steroid therapy on the examination day again. The baseline PEF, daily highest PEF and the highest PEF obtained after salbutamol MDI were significantly less than the each values obtained after high-dose BDP. The best PEF value of them was the value obtained after repeated salbutamol MDI during high dose BDP. We suggest that the daily highest PEF under good control is not a substitute for best PEF because it changes according to the degree of improvement of airway inflammation. We recommend that a course of high dose inhaled steroid is effective in finding the best value of PEF for each individual with moderate asthma.

Towards better treatment outcomes in childhood asthma

NARCIS (Netherlands)

Koster, E.S.

2011-01-01

Standard treatment for peadiatric asthmatics is based on regular use of inhaled corticosteroids (ICS) combined with short-acting beta-agonists (SABA). Despite the effectiveness of this standard treatment strategy in most patients, there is large variability in treatment response. Many factors can

In patients with severe uncontrolled asthma, does knowledge of adherence and inhaler technique using electronic monitoring improve clinical decision making? A protocol for a randomised controlled trial.

LENUS (Irish Health Repository)

Mokoka, Matshediso C

2017-06-15

Many patients with asthma remain poorly controlled despite the use of inhaled corticosteroids and long-acting beta agonists. Poor control may arise from inadequate adherence, incorrect inhaler technique or because the condition is refractory. Without having an objective assessment of adherence, clinicians may inadvertently add extra medication instead of addressing adherence. This study aims to assess if incorporating objectively recorded adherence from the Inhaler Compliance Assessment (INCA) device and lung function into clinical decision making provides more cost-effective prescribing and improves outcomes.

The US Food and Drug Administration’s drug safety recommendations and long-acting beta2-agonist dispensing pattern changes in adult asthma patients: 2003–2012

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Zhou EH

2017-03-01

Full Text Available Esther H Zhou,1 Sally Seymour,2 Margie R Goulding,1 Elizabeth M Kang,1 Jacqueline M Major,1 Solomon Iyasu1 1Division of Epidemiology, Office of Surveillance and Epidemiology, 2Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA Background: Emerging safety issues associated with long-acting beta2-agonist (LABA have led to multiple regulatory activities by the US Food and Drug Administration (FDA since 2003, including Drug Safety Communications (DSCs in 2010. These DSCs had three specific recommendations for the safe use of LABA products in adult asthma treatment. Methods: We examined the initiation of LABA-containing products for adult asthma treatment using an intermittent time series approach in a claims database from 2003 to 2012. We assessed the alignment of dispensing patterns with the following 2010 FDA recommendations: 1 contraindicated use of single-ingredient (SI-LABA without an asthma controller medication (ACM; 2 a LABA should only be used when asthma is not adequately controlled on inhaled corticosteroids (ICSs or ACM; and 3 step-down asthma therapy (e.g., discontinue LABA when asthma control is achieved. Results: There were 477,922 adults (18–64 years old dispensed a new LABA during 2003–2012. Among LABA initiators, patients who initiated an SI-LABA and who did “not” have an ACM dispensed on the same date decreased from >9% in 2003 (the initial labeling change to <2% post 2010 DSCs (p-value <0.0001 in the segmented regression model. The proportion of asthma patients dispensed an ICS in 6 months prior to initiating LABA treatment did not increase. The proportion of patients with longer than 4 months of continuous treatment did not decrease over the study period. Conclusion: Although the decrease in SI-LABA initiation is consistent with FDA’s recommendations, low ICS dispensing before initiating a LABA and LABA continuation practices require further efforts

Arginase 1 and arginase 2 variations associate with asthma, asthma severity and beta(2) agonist and steroid response

NARCIS (Netherlands)

Vonk, Judith M.; Postma, Dirkje S.; Maarsingh, Harm; Bruinenberg, Marcel; Koppelman, Gerard H.; Meurs, Herman

Rationale Arginase probably plays an important role in asthma development, severity and progression. Polymorphisms in arginase 1 and arginase 2 genes have been associated with childhood asthma and FEV1 reversibility to beta(2) agonists. Objectives We investigated the association between arginase 1

Inhaled Steroids: First Line Treatment of Adult Asthma

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André Cartier

1995-01-01

Full Text Available Corticosteroids are the most potent inhaled anti-inflammatory drugs for asthma treatment. This paper reviews the clinical evidence supporting the early use of inhaled steroids in asthma as a first line treatment. Inhaled steroids can probably alter the course of asthma, especially in mild asthmatics. Once they have been shown to improve control of asthma and even if the need for beta2-agonists is virtually nil, their use should be continued at low doses (ie, equivalent to 400 to 500 μg of budesonide or beclomethasone for at least one year before attempting to reduce the dosage.

Conversion of agonist site to metal-ion chelator site in the beta(2)-adrenergic receptor

DEFF Research Database (Denmark)

Elling, C E; Thirstrup, K; Holst, Birgitte

1999-01-01

Previously metal-ion sites have been used as structural and functional probes in seven transmembrane receptors (7TM), but as yet all the engineered sites have been inactivating. Based on presumed agonist interaction points in transmembrane III (TM-III) and -VII of the beta(2)-adrenergic receptor,...... as generic, pharmacologic tools to switch 7TM receptors with engineered metal-ion sites on or off at will.......Previously metal-ion sites have been used as structural and functional probes in seven transmembrane receptors (7TM), but as yet all the engineered sites have been inactivating. Based on presumed agonist interaction points in transmembrane III (TM-III) and -VII of the beta(2)-adrenergic receptor......, in this paper we construct an activating metal-ion site between the amine-binding Asp-113 in TM-III-or a His residue introduced at this position-and a Cys residue substituted for Asn-312 in TM-VII. No increase in constitutive activity was observed in the mutant receptors. Signal transduction was activated...

Effect of formoterol, a long-acting β2-adrenergic agonist, on muscle strength and power output, metabolism and fatigue during maximal sprinting in men

DEFF Research Database (Denmark)

Kalsen, Anders; Hostrup, Morten; Backer, Vibeke

2016-01-01

The aim was to investigate the effect of the long-acting β2-adrenergic agonist formoterol on muscle strength and power output, muscle metabolism and phosphorylation of CaMKII Thr(287) and FXYD1 during maximal sprinting. In a double-blind crossover study, thirteen males (VO2max: 45.0±0.2 (mean±SE) m......L min(-1) kg(-1)) performed a 30-s cycle ergometer sprint after inhalation of either 54 µg formoterol (FOR) or placebo (PLA). Before and after the sprint, muscle biopsies were collected from vastus lateralis and maximal voluntary contraction (MVC) and contractile properties of quadriceps were measured...

COPD - control drugs

Science.gov (United States)

Chronic obstructive pulmonary disease - control drugs; Bronchodilators - COPD - control drugs; Beta agonist inhaler - COPD - control drugs; Anticholinergic inhaler - COPD - control drugs; Long-acting inhaler - COPD - control drugs; ...

Optimal treatment sequence in COPD: Can a consensus be found?

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J. Ferreira

2016-01-01

Full Text Available There is currently no consensus on the treatment sequence in chronic obstructive pulmonary disease (COPD, although it is recognized that early diagnosis is of paramount importance to start treatment in the early stages of the disease. Although it is fairly consensual that initial treatment should be with an inhaled short-acting beta agonist, a short-acting muscarinic antagonist, a long-acting beta-agonist or a long-acting muscarinic antagonist. As the disease progresses, several therapeutic options are available, and which to choose at each disease stage remains controversial. When and in which patients to use dual bronchodilation? When to use inhaled corticosteroids? And triple therapy? Are the existing non-inhaled therapies, such as mucolytic agents, antibiotics, phosphodiesterase-4 inhibitors, methylxanthines and immunostimulating agents, useful? If so, which patients would benefit? Should co-morbitities be taken into account when choosing COPD therapy for a patient?This paper reviews current guidelines and available evidence and proposes a therapeutic scheme for COPD patients. We also propose a treatment algorithm in the hope that it will help physicians to decide the best approach for their patients. The authors conclude that, at present, a full consensus on optimal treatment sequence in COPD cannot be found, mainly due to disease heterogeneity and lack of biomarkers to guide treatment. For the time being, and although some therapeutic approaches are consensual, treatment of COPD should be patient-oriented. Keywords: COPD, Treatment sequence, SABA, SAMA, LABA, LAMA, ICS, Triple therapy, Non-inhaled therapies

Toxicity studies of inhaled beta-emitting radionuclides - Status report

Energy Technology Data Exchange (ETDEWEB)

Hahn, F F; Boeker, B B; Gillett, N A; Griffith, W C; Lundgren, D L; McClellan, R O; Muggenburg, B A; Snipes, M B

1988-12-01

The effects of beta-emitting radionuclides inhaled in either a relatively soluble form ({sup 90}SrCl{sub 2}, {sup 144}CeCl{sub 3}, {sup 91}yl{sub 3}, or {sup 137}CsCl) or in a relatively insoluble form ({sup 90}Y, {sup 91}Y, {sup 144}Ce or {sup 90}Sr in fused aluminosilicate particles [FAP]) have been studied in laboratory animals. The results showed that the total beta dose and the dose-rate pattern can modify both the neoplastic and non-neoplastic effects of inhaled beta-emitting radionuclides. In addition, the solubility and chemical characteristics of the radionuclides influence which organs are affected. Effects are seen primarily in organs where the radionuclide is ultimately accumulated, e.g., lung, bone, liver, or tracheobronchial lymph nodes. In addition, effects may be seen in organs where there is little accumulation, but where the radiation dose may still be high, e.g., nasal epithelium and heart. Studies of inhaled {sup 144}Ce-FAP in four different species showed that, compared to mice and dogs, lung tumor risk factors are very low for Syrian hamsters and high for rats. Studies of mice, Syrian hamsters, rats, and dogs repeatedly exposed to aerosols of {sup 144}Ce-FAP showed that lung tumor incidence correlates better with cumulative dose to the lung than with dose rate. Most of the studies in this program are nearing completion and full analyses are in progress. (author)

Monitoring of PAEMs and beta-agonists in urine for a small group of experimental subjects and PAEs and beta-agonists in drinking water consumed by the same subjects.

Science.gov (United States)

Liou, Saou-Hsing; Yang, Gordon C C; Wang, Chih-Lung; Chiu, Yu-Han

2014-07-30

This 5-month study contains two parts: (1) to monitor the concentrations of 11 phthalate esters metabolites (PAEMs) and two beta-agonists in human urine samples collected from a small group of consented participants including 16 females and five males; and (2) to analyze the residues of phthalate esters (PAEs) and beta-agonists in various categories of drinking water consumed by the same group of subjects. Each category of human urine and drinking water had 183 samples of its own. The analytical results showed that nine PAEMs were detected in human urine and eight PAEs were detected in drinking water samples. It was found that average concentrations of PAEMs increased as the age increased, but no significant difference between sexes. Further, using the principal component analysis, the loadings of age effect were found to be two times greater than that of gender effect in terms of four DEHP metabolites. Regarding beta-agonists of concern (i.e., ractopamine and salbutamol), they were neither detected in human urine nor drinking water samples in this study. Copyright © 2014 Elsevier B.V. All rights reserved.

[Rapid determination of illicit beta2-agonist additives in health foods and traditional Chinese patent medicines with DCBI-MS/MS method].

Science.gov (United States)

Hou, Yu-Lan; Wu, Shuang; Wang, Hua; Zhao, Yong; Liao, Peng; Tian, Qing-Qing; Sun, Wen-Jian; Chen, Bo

2013-01-01

A novel rapid method for detection of the illicit beta2-agonist additives in health foods and traditional Chinese patent medicines was developed with the desorption corona beam ionization mass spectrometry (DCBI-MS) technique. The DCBI conditions including temperature and sample volume were optimized according to the resulting mass spectra intensity. Matrix effect on 9 beta2-agonists additives was not significant in the proposed rapid determination procedure. All of the 9 target molecules were detected within 1 min. Quantification was achieved based on the typical fragment ion in MS2 spectra of each analyte. The method showed good linear coefficients in the range of 1-100 mg x L(-1) for all analytes. The relative deviation values were between 14.29% and 25.13%. Ten claimed antitussive and antiasthmatic health foods and traditional Chinese patent medicines from local pharmacies were analyzed. All of them were negative with the proposed DCBI-MS method. Without tedious sample pretreatments, the developed DCBI-MS is simple, rapid and sensitive for rapid qualification and semi-quantification of the illicit beta2-agonist additives in health foods and traditional Chinese patent medicines.

Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γ Agonists

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Martin B. Oleksiewicz

2008-01-01

Full Text Available Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ agonists have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARα is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology. Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.

Effect of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function.

Science.gov (United States)

Takasu, Toshiyuki; Ukai, Masashi; Sato, Shuichi; Matsui, Tetsuo; Nagase, Itsuro; Maruyama, Tatsuya; Sasamata, Masao; Miyata, Keiji; Uchida, Hisashi; Yamaguchi, Osamu

2007-05-01

We evaluated the pharmacological characteristics of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]-ethyl} acetanilide (YM178). YM178 increased cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing human beta3-adrenoceptor (AR). The half-maximal effective concentration (EC50) value was 22.4 nM. EC50 values of YM178 for human beta1- and beta2-ARs were 10,000 nM or more, respectively. The ratio of intrinsic activities of YM178 versus maximal response induced by isoproterenol (nonselective beta-AR agonist) was 0.8 for human beta3-ARs, 0.1 for human beta1-ARs, and 0.1 for human beta2-ARs. The relaxant effects of YM178 were evaluated in rats and humans bladder strips precontracted with carbachol (CCh) and compared with those of isoproterenol and 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP-12177A) (beta3-AR agonist). EC50 values of YM178 and isoproterenol in rat bladder strips precontracted with 10(-6) M CCh were 5.1 and 1.4 microM, respectively, whereas those in human bladder strips precontracted with 10(-7) M CCh were 0.78 and 0.28 microM, respectively. In in vivo study, YM178 at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. These findings suggest the suitability of YM178 as a therapeutic drug for the treatment of symptoms of overactive bladder such as urinary frequency, urgency, and urge incontinence.

A European multicentre survey of impulse control behaviours in Parkinson's disease patients treated with short- and long-acting dopamine agonists.

Science.gov (United States)

Rizos, A; Sauerbier, A; Antonini, A; Weintraub, D; Martinez-Martin, P; Kessel, B; Henriksen, T; Falup-Pecurariu, C; Silverdale, M; Durner, G; Røkenes Karlsen, K; Grilo, M; Odin, P; Chaudhuri, K Ray

2016-08-01

Impulse control disorders (ICDs) in Parkinson's disease (PD) are associated primarily with dopamine agonist (DA) use. Comparative surveys of clinical occurrence of impulse control behaviours on longer acting/transdermal DA therapy across age ranges are lacking. The aim of this study was to assess the occurrence of ICDs in PD patients across several European centres treated with short- or long-acting [ropinirole (ROP); pramipexole (PPX)] and transdermal [rotigotine skin patch (RTG)] DAs, based on clinical survey as part of routine clinical care. A survey based on medical records and clinical interviews of patients initiating or initiated on DA treatment (both short- and long-acting, and transdermal) across a broad range of disease stages and age groups was performed. Four hundred and twenty-five cases were included [mean age 68.3 years (range 37-90), mean duration of disease 7.5 years (range 0-37)]. ICD frequencies (as assessed by clinical interview) were significantly lower with RTG (4.9%; P controlling for possible confounding factors. © 2016 EAN.

The treatment of bronchial obstruction by beta/sub 2/-agonist and anti-cholinergic aerosol. Advantages of associating the two types of substance

Energy Technology Data Exchange (ETDEWEB)

Minette, A.; Marcq, M.

1980-01-01

The authors review the basic aspects of bronchodilatory treatment using beta/sub 2/-agonist and atropinic aerosols; present the results of a review of literature on the subject of the toxicity of various vector gases used in aerosols of this type; discuss the problems associated with the deposition disparity of aerosols in normal and pathological lungs; present and discuss the results of the prevalence of positive responses to atropine methyl-nitrate and to beta-agonist given in aerosol form to a group of subjects with reversible bronchial obstruction; discuss the advantages of oxitropium bromide, an atropic substance which has recently been discovered and which is apparently more interesting than ipratropium bromide, against the background of the ventilatory effects as observed for these 2 substances on 19 patients suffering from reversible bronchial obstruction; and discuss the advantages of associating atropinic and beta/sub 2/-agonist substances in the same aerosol on the bass of the effects of a recently-developed preparation which combines fenoterol and ipratropium bromide. 57 refs.

Relief of dyspnoea by beta(2)-agonists after methacholine-induced bronchoconstriction

NARCIS (Netherlands)

van der Woude, HJ; Postma, DS; Politiek, MJ; Winter, TH; Aalbers, R

Virtually all asthma patients use bronchodilators. Formoterol and salbutamol have a rapid onset of bronchodilating effect, whereas salmeterol acts slower. We studied the onset of improvement of dyspnoea sensation after inhalation with these bronchodilators and placebo to reverse a

Magnitude of a conformational change in the glycine receptor beta1-beta2 loop is correlated with agonist efficacy

DEFF Research Database (Denmark)

Pless, Stephan Alexander; Lynch, Joseph W

2009-01-01

associated with the closed-flip transition in the alpha1-glycine receptor. We employed voltage-clamp fluorometry to compare ligand-binding domain conformational changes induced by the following agonists, listed from highest to lowest affinity and efficacy: glycine > beta-alanine > taurine. Voltage...

The use of multiple respiratory inhalers requiring different inhalation techniques has an adverse effect on COPD outcomes

Directory of Open Access Journals (Sweden)

Bosnic-Anticevich S

2016-12-01

incidence rate ratio (IRR comparing the rate of exacerbations between study cohorts. A secondary outcome compared average daily use of short-acting beta agonist (SABA. Results: The final study sample contained 8,225 patients in each cohort (mean age 67 [SD, 10], 57% males, 37% current smokers. Patients in the similar-devices cohort had a lower rate of exacerbations compared with those in the mixed-devices cohort (adjusted IRR 0.82, 95% confidence interval [CI] 0.80–0.84 and were less likely to be in a higher-dose SABA group (adjusted proportional odds ratio 0.54, 95% CI 0.51–0.57. Conclusion: COPD patients who were prescribed one or more additional inhaler devices requiring similar inhalation techniques to their previous device(s showed better outcomes than those who were prescribed devices requiring different techniques. Keywords: chronic obstructive pulmonary disease, inhalation technique, exacerbations, inhaler devices, observational, matched cohort

Long acting β2 agonists for stable chronic obstructive pulmonary disease with poor reversibility: a systematic review of randomised controlled trials

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Mensinkai Shaila

2004-08-01

Full Text Available Abstract Background The long acting β2-agonists, salmeterol and formoterol, have been recommended, by some, as first line treatment of stable chronic obstructive pulmonary disease (COPD. We reviewed evidence of efficacy and safety when compared with placebo or anticholinergic agents in patients with poorly reversible COPD. Methods After searching MEDLINE, EMBASE, HealthSTAR, BIOSIS Previews, PASCAL, ToxFile, SciSearch, the Cochrane Library, and PubMed, as well as Web sites, selected journals, reference lists, and contacting drug manufacturers, two reviewers independently screened reports of randomised controlled trials of parallel or crossover design lasting four weeks or longer and including patients with a forced expiratory volume in one second (FEV1 ≤ 75% of predicted, a ratio of FEV1 to forced vital capacity (FVC ≤ 88% of predicted, and Results Twelve trials satisfied our inclusion criteria; eight were high quality (Jadad score >2 and four were low quality (≤ 2. The adequacy of allocation concealment was unclear in all of them. We did not perform a meta-analysis due to differences in trial design and how outcomes were reported. Two trials comparing salmeterol with ipratropium did not detect differences; one trial comparing formoterol and ipratropium described greater improvement with formoterol in morning PEFR (15.3 versus 7.1 l/min, p = 0.040. Of twelve trials comparing long acting β2 agonists with placebo, six reported no improvement in exercise capacity, eleven reported improvements in FEV1 lung function (one reported no improvement, six reported less rescue inhaler usage (one reported no difference and five reported improved dyspnea scores (two reported no improvement. Differences in quality of life were detected in one salmeterol trial ; however, two salmeterol, and one formoterol trial reported no differences. Adverse effects of interest were not reported. Conclusion In terms of clinical outcomes and safety, we could not find

Effects of Inhaled Fenoterol and Positive End-Expiratory Pressure on the Respiratory Mechanics of Patients with Chronic Obstructive Pulmonary Disease

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Claude Guerin

2005-01-01

Full Text Available BACKGROUND: During acute ventilatory failure in patients with chronic obstructive pulmonary disease (COPD, applying external positive end-expiratory pressure (PEEPe will reopen small airways and, thus, may enhance peripheral deposition as well as the physiological effects of inhaled beta-2 agonists.

β2 agonists in athletes. An ergogenic aid? = β2 agonistas en deportistas. ¿Una ayuda ergogénica?

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Ospina Uribe, Carlos Fernando

2013-01-01

Full Text Available Asthma is a chronic disorder of the airways with bronchial hyperresponsiveness and bronchoconstriction. Exercise can trigger asthma symptoms; this condition is known as exerciseinduced bronchospasm (EIB. Asthma is common in Olympic athletes who therefore use β2 agonists to prevent and treat its episodes. These drugs are preferably supplied by inhalation. In sports, the use of β2 agonists is restricted by anti-doping regulation, arguing that these drugs have the potential to improve physical performance, which can result in a competitive advantage. β2 agonists are prohibited by the WADA (World Anti-Doping Agency, except salbutamol (maximum dose: 1.600 μg over 24 hours and salmeterol. Oral administration of salbutamol can induce ergogenic effects in athletes. It has been documented that when given orally β2 agonists can improve performance in endurance disciplines, increase muscle strength and improve anaerobic power. However, according to scientific evidence, inhaled β2 agonists do not have a relevant performance-enhancing effect in nonasthmatic athletes.

Recruitment of beta-arrestin2 to the dopamine D2 receptor: insights into anti-psychotic and anti-parkinsonian drug receptor signaling

DEFF Research Database (Denmark)

Klewe, Ib V; Nielsen, Søren M; Tarpø, Louise

2008-01-01

, SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating beta-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine...

Interaction with beta-arrestin determines the difference in internalization behavor between beta1- and beta2-adrenergic receptors.

Science.gov (United States)

Shiina, T; Kawasaki, A; Nagao, T; Kurose, H

2000-09-15

The beta(1)-adrenergic receptor (beta(1)AR) shows the resistance to agonist-induced internalization. As beta-arrestin is important for internalization, we examine the interaction of beta-arrestin with beta(1)AR with three different methods: intracellular trafficking of beta-arrestin, binding of in vitro translated beta-arrestin to intracellular domains of beta(1)- and beta(2)ARs, and inhibition of betaAR-stimulated adenylyl cyclase activities by beta-arrestin. The green fluorescent protein-tagged beta-arrestin 2 translocates to and stays at the plasma membrane by beta(2)AR stimulation. Although green fluorescent protein-tagged beta-arrestin 2 also translocates to the plasma membrane, it returns to the cytoplasm 10-30 min after beta(1)AR stimulation. The binding of in vitro translated beta-arrestin 1 and beta-arrestin 2 to the third intracellular loop and the carboxyl tail of beta(1)AR is lower than that of beta(2)AR. The fusion protein of beta-arrestin 1 with glutathione S-transferase inhibits the beta(1)- and beta(2)AR-stimulated adenylyl cyclase activities, although inhibition of the beta(1)AR-stimulated activity requires a higher concentration of the fusion protein than that of the beta(2)AR-stimulated activity. These results suggest that weak interaction of beta(1)AR with beta-arrestins explains the resistance to agonist-induced internalization. This is further supported by the finding that beta-arrestin can induce internalization of beta(1)AR when beta-arrestin 1 does not dissociate from beta(1)AR by fusing to the carboxyl tail of beta(1)AR.

Effect of RareGenetic Variants in the β2 Adrenergic Receptor Geneon the Risk for Exacerbations and Symptom Control During Long-Acting Beta Agonist Treatment in a Multi-Ethnic Asthma Population

Science.gov (United States)

Ortega, Victor E.; Hawkins, Gregory A.; Moore, Wendy C.; Hastie, Annette T.; Ampleford, Elizabeth J.; Busse, William W.; Castro, Mario; Chardon, Domingo; Erzurum, Serpil C.; Israel, Elliot; Montealegre, Federico; Wenzel, Sally E.; Peters, Stephen P.; Meyers, Deborah A.; Bleecker, Eugene R.

2014-01-01

Background Severe adverse life-threatening events associated with long-acting beta agonists (LABA) use have caused the FDA to review LABA safety which has resulted in a boxed warning and a mandatory LABA safety study in 46,800 asthmatics. Identification of an at-risk, susceptible subpopulation using predictive biomarkers is critical in understanding LABA safety. The β2-adrenergic receptor gene (ADRB2) contains a common, nonsynonymous single nucleotide polymorphism, Gly16Arg, that is unlikely to account for rare, life-threatening events. We hypothesize that rare ADRB2 variants with strong effects modulate therapeutic responses to long-acting beta agonist (LABA) therapy and contribute to rare, severe adverse events. Methods ADRB2 was sequenced in 197 African Americans, 191 non-Hispanic Whites, and 73 Puerto Ricans. Sequencing identified six rare variants which were genotyped in 1,165 asthmatics (total=1,626). The primary hypothesis was that severe asthma exacerbations requiring hospitalization were associated with rare ADRB2 variants. Replication was performed in 659 non-Hispanic White asthma subjects. Findings Asthmatics receiving LABA with a rare variant had increased asthma-related hospitalizations (meta-analysis for all ethnic groups: p=2·83 × 10−4), specifically LABA-treated non-Hispanic Whites with the rare Ile164 allele (only rare variant in Whites, OR4·48, 95% CI 1·40–14·0, p=0·01) and African Americans with a 25 base-pair promoter polynucleotide insertion (OR 13·43, 95% CI 2·02–265·4, p=0·006). The subset of non-Hispanic Whites and African Americans receiving LABAs with these rare variants had increased exacerbations requiring urgent outpatient healthcare visits (non-Hispanic Whites with or without the rare Ile164 allele: 2·6 visits versus 1·1 visits, p=8·4 × 10−7 and African Americans with or without the rare insertion: 3·7 visits versus 2·4 visits, 0·01), and more frequently were treated with chronic systemic corticosteroids (OR4�

Xamoterol, a new selective beta-1-adrenoceptor partial agonist, in the treatment of postural hypotension

DEFF Research Database (Denmark)

Mehlsen, J; Trap-Jensen, J

1986-01-01

Three patients severely disabled from postural hypotension were treated with xamoterol, a selective beta-1-adrenoceptor antagonist with a high degree of partial agonist activity. Oral treatment (200 mg b.i.d.) was chosen on the basis of the effects of acute intravenous administration of xamoterol...... and pindolol, a non-selective beta-adrenoceptor antagonist with partial agonist activity. In these patients pindolol had a predominantly antagonist effect, whereas xamoterol had a predominantly agonist effect after intravenous administration. Oral treatment was carried out with placebo control in a single......, supine). During the placebo period (2 weeks) heart rate decreased to pretreatment levels and mean blood pressure was reduced by only 14 mmHg. The patients reported substantial improvement in their condition during active medication. Xamoterol seems to be a useful alternative in the treatment of postural...

Fluticasone-formoterol: a systematic review of its potential role in the treatment of asthma

Directory of Open Access Journals (Sweden)

Prosser TR

2015-06-01

Full Text Available Theresa R Prosser, Suzanne G Bollmeier St Louis College of Pharmacy, St Louis, MO, USA Background: The purpose of this systematic review is to summarize and evaluate the available published data regarding the efficacy and safety of a combination product containing fluticasone propionate/formoterol (FP-F in order to establish its potential role compared with other inhaled combination corticosteroid/long-acting beta2 receptor agonists for the maintenance treatment of asthma.Methods: A PubMed and EMBASE search was conducted using the terms “fluticasone propionate”, “formoterol fumarate”, “Flutiform®”, and “asthma” in July 2014 to identify trials using this combination specifically for the treatment of asthma. Additional information was gathered from references cited in the identified publications, the package insert, and the ClinicalTrials.gov registry. All randomized controlled clinical trials for humans in asthma were evaluated for inclusion. Data from animal trials, clinical trials for chronic obstructive pulmonary disease, and non-English sources were excluded.Results: Seven short-term safety and efficacy trials of FP-F compared with its individual components and two comparison trials of FP-F versus other combination products were identified. Generally, the incidence of drug-related adverse events was low and consistent with previously reported drug class-related adverse events (ie, pharyngitis, dysphonia, and headache. The combination of FP-F was shown to be noninferior to fluticasone propionate/salmeterol for improving predose forced expiratory volume at one second (FEV1 and 2 hours post dose FEV1. FP-F was also noninferior to budesonide/formoterol in improving predose FEV1. Other clinical endpoints, including various symptom scores, asthma control, quality of life, and subjects’ assessment of the medications were not significantly different.Conclusion: Poor asthma control is common. The data from short-term studies

Montelukast use-a 19-year nationwide drug utilisation study

DEFF Research Database (Denmark)

Henriksen, Daniel Pilsgaard; Davidsen, Jesper Rømhild; Laursen, Christian B

2017-01-01

PURPOSE: Montelukast is a leukotriene receptor antagonist used in asthma and rhinitis treatment. Despite being marketed nearly two decades ago, little is known about its utilisation pattern. METHODS: Using the Danish National Prescription Registry, we identified subjects filling a montelukast...... montelukast initiators, 60% filled at least one prescription of short-acting beta-2-agonists (SABA) up to a year prior to montelukast initiation, and 49% filled a prescription of inhaled corticosteroids (ICS). Only 0.8% (n = 1148) of all individuals initiated montelukast without a redeemed prescription...... of short- or long-term inhalation therapy, systemic antihistamines, or nasal topical anti-allergic treatment. CONCLUSIONS: The usage of montelukast has increased over threefold since its market entry in 1998, mainly driven by an increased number of prevalent users. The majority of individuals who initiated...

Efficacy and safety of the CRTh2 antagonist AZD1981 as add-on therapy to inhaled corticosteroids and long-acting β2-agonists in patients with atopic asthma

Directory of Open Access Journals (Sweden)

Bateman ED

2018-05-01

Full Text Available Eric D Bateman,1 Christopher O’Brien,2 Paul Rugman,2 Sally Luke,2 Stefan Ivanov,2 Mohib Uddin2,3 1Department of Medicine, University of Cape Town, Cape Town, 7700, South Africa; 2Research and Development, 3Respiratory, Inflammation, and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, SE-431 83, Sweden Objectives: To evaluate the efficacy and safety of AZD1981, a potent, specific antagonist of the CRTh2 receptor, as add-on therapy to inhaled corticosteroids (ICS and long-acting β2-agonists (LABA, in patients with persistent asthma with an allergic component.Patients and methods: In this placebo-controlled, parallel-group Phase IIb study, patients with persistent atopic asthma on ICS and LABA were randomized to receive 12 weeks of treatment with placebo or AZD1981 (80 mg daily, 200 mg daily, and 10 mg, 40 mg, 100 mg, or 400 mg twice daily [BID]. The primary end point was the mean change from baseline in predose, prebronchodilator forced expiratory volume in 1 second (FEV1 averaged over weeks 2, 4, 8, and 12 in the AZD1981-treatment group vs the placebo group. Secondary end points included other measures of lung function, symptoms, and asthma control, as well as standard measures of safety.Results: In total, 1,140 patients (99.7% received study treatment. There were improvements in the primary end point across all treatment groups over 12 weeks of treatment. However, the improvement for the highest AZD1981 dose (400 mg BID vs placebo was not statistically significant (0.02 L, P=0.58, preventing interpretation of statistical testing for the lower doses. AZD1981 was well tolerated, and the incidence of adverse events was comparable across placebo and treatment groups.Conclusion: In patients with allergic asthma receiving ICS and LABA therapy, the addition of AZD1981 at doses up to 400 mg BID failed to produce a clinically relevant improvement in lung function or any other measured end point, but appeared to have an acceptable safety

Endogenous PKI gamma limits the duration of the anti-apoptotic effects of PTH and beta-adrenergic agonists in osteoblasts.

Science.gov (United States)

Chen, Xin; Song, In-Hwan; Dennis, James E; Greenfield, Edward M

2007-05-01

PKI gamma knockdown substantially extended the anti-apoptotic effects of PTH and beta-adrenergic agonists, whereas PKI gamma overexpression decreased these effects. Therefore, inhibition of PKI gamma activity may provide a useful co-therapy in combination with intermittent PTH or beta-adrenergic agonists for bone loss in conditions such as osteoporosis. PTH has both catabolic and anabolic effects on bone, which are primarily caused by cAMP/protein kinase A (PKA) signaling and regulation of gene expression. We previously showed that protein kinase inhibitor-gamma (PKI gamma) is required for efficient termination of cAMP/PKA signaling and gene expression after stimulation with PTH or beta-adrenergic agonists. Inhibition of osteoblast apoptosis is thought to be an important, but transient, mechanism partly responsible for the anabolic effects of intermittent PTH. Therefore, we hypothesized that endogenous PKI gamma also terminates the anti-apoptotic effect of PTH. PKI gamma knockdown by antisense transfection or siRNA was used to examine the ability of endogenous PKI gamma to modulate the anti-apoptotic effects of PTH and beta-adrenergic agonists in ROS 17/2.8 cells. Knockdown of PKI gamma substantially extended the anti-apoptotic effects of PTH, whether apoptosis was induced by etoposide or dexamethasone. In contrast, overexpression of PKI gamma decreased the anti-apoptotic effect of PTH pretreatment. This study is also the first demonstration that beta-adrenergic agonists mimic the anti-apoptotic effects of PTH in osteoblasts. Moreover, PKI gamma knockdown also substantially extended this anti-apoptotic effect of beta-adrenergic agonists. Taken together, these results show that endogenous PKI gamma limits the duration of the anti-apoptotic effects of cAMP/PKA signaling in osteoblasts. Because significant individual variability exists in the anabolic responses to PTH therapy in current clinical treatment of osteoporosis, inhibition of PKI gamma activity may provide a

[Predictive factors associated with severity of asthma exacerbations].

Science.gov (United States)

Atiş, Sibel; Kaplan, Eylem Sercan; Ozge, Cengiz; Bayindir, Suzan

2008-01-01

Several factors have been accused for asthma exacerbations, however, very few studies have evaluated whether different factors predict severity of asthma exacerbation. We aimed to determine the predictive factors for severity of asthma exacerbation. Retrospective analysis of data on 93 patients visited our emergency-department because of asthma exacerbation was reviewed. Hospitalization in intensive care unit and/or intubation because of asthma was accepted as the criteria for severe exacerbation. Logistic regression analysis estimated the strength of association of each variable, potentially related to severe asthmatic exacerbation, with severe/very severe as compared to mild/moderate asthmatic exacerbation. Independent variables included in the analysis were age, sex, smoking history, inhaler steroid using, compliance with medication, chronic asthma severity, presence of additional atopic diseases, prick test positivity, provocative factors, number of short-acting beta(2)-agonist using, number of visits to emergency department for asthma over one year period, previous severe exacerbation, pulmonary functions, and blood eosinophil count. 20 were severe/very severe and 73 mild/moderate asthmatic exacerbation. Frequent using of short-acting beta(2)-agonist (OR= 1.5, 95% CI= 1.08-5.3, p= 0.003), noncompliance with medication (OR= 3.6, 95% CI= 1.3-9.9, p= 0.013), previous severe asthmatic exacerbation (OR= 3.8, 95% CI= 1.48-10.01, p= 0.005) and recent admission to hospital (OR= 2.9, 95% CI= 1.07-8.09, p= 0.037) were found to be predictive factors for severe asthmatic exacerbation. Different predictive factors, in particular frequent using of short-acting beta(2)-agonist and noncompliance with medication may be associated with severe asthma exacerbations compared to milder exacerbations. This suggests different mechanisms are responsible for severity of asthma exacerbation.

Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications.

Science.gov (United States)

Noh, Hyunjin; Yu, Mi Ra; Kim, Hyun Joo; Lee, Ji Hye; Park, Byoung-Won; Wu, I-Hsien; Matsumoto, Motonobu; King, George L

2017-07-01

Macrophage activation is increased in diabetes and correlated with the onset and progression of vascular complications. To identify drugs that could inhibit macrophage activation, we developed a cell-based assay and screened a 1,040 compound library for anti-inflammatory effects. Beta2-adrenergic receptor (β2AR) agonists were identified as the most potent inhibitors of phorbol myristate acetate-induced tumor necrosis factor-α production in rat bone marrow macrophages. In peripheral blood mononuclear cells isolated from streptozotocin-induced diabetic rats, β2AR agonists inhibited diabetes-induced tumor necrosis factor-α production, which was prevented by co-treatment with a selective β2AR blocker. To clarify the underlying mechanisms, THP-1 cells and bone marrow macrophages were exposed to high glucose. High glucose reduced β-arrestin2, a negative regulator of NF-κB activation, and its interaction with IκBα. This subsequently enhanced phosphorylation of IκBα and activation of NF-κB. The β2AR agonists enhanced β-arrestin2 and its interaction with IκBα, leading to downregulation of NF-κB. A siRNA specific for β-arrestin2 reversed β2AR agonist-mediated inhibition of NF-κB activation and inflammatory cytokine production. Treatment of Zucker diabetic fatty rats with a β2AR agonist for 12 weeks attenuated monocyte activation as well as pro-inflammatory and pro-fibrotic responses in the kidneys and heart. Thus, β2AR agonists might have protective effects against diabetic renal and cardiovascular complications. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Common ADRB2 haplotypes derived from 26 polymorphic sites direct beta2-adrenergic receptor expression and regulation phenotypes.

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Alfredo Panebra

2010-07-01

Full Text Available The beta2-adrenergic receptor (beta2AR is expressed on numerous cell-types including airway smooth muscle cells and cardiomyocytes. Drugs (agonists or antagonists acting at these receptors for treatment of asthma, chronic obstructive pulmonary disease, and heart failure show substantial interindividual variability in response. The ADRB2 gene is polymorphic in noncoding and coding regions, but virtually all ADRB2 association studies have utilized the two common nonsynonymous coding SNPs, often reaching discrepant conclusions.We constructed the 8 common ADRB2 haplotypes derived from 26 polymorphisms in the promoter, 5'UTR, coding, and 3'UTR of the intronless ADRB2 gene. These were cloned into an expression construct lacking a vector-based promoter, so that beta2AR expression was driven by its promoter, and steady state expression could be modified by polymorphisms throughout ADRB2 within a haplotype. "Whole-gene" transfections were performed with COS-7 cells and revealed 4 haplotypes with increased cell surface beta2AR protein expression compared to the others. Agonist-promoted downregulation of beta2AR protein expression was also haplotype-dependent, and was found to be increased for 2 haplotypes. A phylogenetic tree of the haplotypes was derived and annotated by cellular phenotypes, revealing a pattern potentially driven by expression.Thus for obstructive lung disease, the initial bronchodilator response from intermittent administration of beta-agonist may be influenced by certain beta2AR haplotypes (expression phenotypes, while other haplotypes may influence tachyphylaxis during the response to chronic therapy (downregulation phenotypes. An ideal clinical outcome of high expression and less downregulation was found for two haplotypes. Haplotypes may also affect heart failure antagonist therapy, where beta2AR increase inotropy and are anti-apoptotic. The haplotype-specific expression and regulation phenotypes found in this transfection

Clinical pharmacokinetics of AZD3199, an inhaled ultra-long-acting β2-adrenoreceptor agonist (uLABA

Directory of Open Access Journals (Sweden)

Bjermer L

2015-02-01

Full Text Available Leif Bjermer,1 Piotr Kuna,2 Carin Jorup,3 Thomas Bengtsson,4 Johan Rosenborg4 1Department of Respiratory Medicine and Allergology, University Hospital, Lund, Sweden; 2Department of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Lodz, Lodz, Poland; 3AstraZeneca R&D, Mölndal, Sweden; 4StatMind, Lund, Sweden Objective: The clinical pharmacokinetics of AZD3199, an ultra-long-acting β2-agonist, were investigated in healthy volunteers and patients with asthma or chronic obstructive pulmonary disease (COPD. Materials and methods: Five studies are presented: one single ascending dose study in healthy Caucasian males; two multiple ascending dose studies in healthy males, one in Caucasians and one in Japanese; a Phase IIA asthma study; and a Phase IIB COPD study. Subjects received AZD3199 via a Spira nebulizer (Turbuhaler; equivalent delivered doses 5–3200 µg or Turbuhaler (single delivered doses of 120–1920 µg or repeated delivered once-daily doses 240–1,680 µg. AZD3199 pharmacokinetics were assessed using total plasma concentration and urinary excretion, and tolerability using adverse events, clinical laboratory tests, and physical examinations. Results: AZD3199 appeared rapidly in the systemic circulation following single and multiple dosing in healthy volunteers and patients (maximum plasma concentration within 30 minutes, with dose-proportional time-independent pharmacokinetics. Plasma exposure to unmetabolized drug was similar in healthy volunteers and patients with asthma, but relatively lower in patients with COPD. Estimated terminal half-life was up to 142 hours in healthy Caucasian males. AZD3199 was well tolerated and showed no or at most mild systemic effects. Conclusion: AZD3199 plasma exposure in healthy volunteers and patients suggested linear pharmacokinetics and a long half-life. Systemic availability was similar in healthy subjects and patients with asthma, but was lower in patients

Quantitative protein and fat metabolism in bull calves treated with beta-adrenergic agonist

DEFF Research Database (Denmark)

Chwalibog, André; Jensen, K; Thorbek, G

1996-01-01

Protein and energy utilization and quantitative retention of protein, fat and energy was investigated with 12 Red Danish bulls during two subsequent 6 weeks trials (Sections A and B) at a mean live weight of 195 and 335 kg respectively. Treatments were control (Group 1) and beta-agonist (L-644...... matter, metabolizable energy and digestible protein was of the same magnitude for all groups. The beta-agonist had no significant effect on protein digestibility and metabolizability of energy, but daily live weight gain was significantly higher in the treated bulls. The utilization of digested protein...

Short-acting glucagon-like peptide-1 receptor agonists as add-on to insulin therapy in type 1 diabetes

DEFF Research Database (Denmark)

Albèr, Anders; Brønden, Andreas; Knop, Filip K

2017-01-01

emptying in patients with type 1 diabetes, which could translate into effective lowering of postprandial glucose excursions; however, these observations regarding short-acting GLP-1RAs are all derived from small open-label trials and should thus be interpreted with caution. In the present paper we review......A large proportion of patients with type 1 diabetes do not reach their glycaemic target of glycated hemoglobin (HbA1c) type 1 diabetes are overweight and obese. Treatment of type 1 diabetes is based on insulin therapy......, which is associated with well-described and unfortunate adverse effects such as hypoglycaemia and increased body weight. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are the focus of increasing interest as a possible adjunctive treatment to insulin in type 1 diabetes because...

An analysis of the utilisation and expenditure of medicines dispensed for the management of severe asthma.

LENUS (Irish Health Repository)

McGowan, B

2009-03-01

There are approximately 6,300 people in Ireland with a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) and with a fast growing elderly population the incidence of COPD is likely to increase. This study examines the prescribing patterns of medicines dispensed for the management Asthma\\/COPD in patients over the age of 35 years using the HSE-Primary Care Reimbursement Services (PCRS) prescribing databases. The HSE-PCRS pharmacy claims data, which covers all those over 70 years of age and means tested for those less than 70 years, was analysed for the years 2005\\/2006. Approximately 26,548 (17.9%) of patients who were prescribed a respiratory drug received inhaled short-acting beta2 agonists in combination with a regular standard-dose inhaled corticosteroid. A further 5,044 (3.4%) were also prescribed a regular inhaled long-acting beta2 agonist (salmeterol or formoterol). A total of 2506 patients (6.2%) on combination therapy were co-prescribed four different anti-asthmatic treatments inclusive of oral prednisolone. A small proportion of the patients prescribed a respiratory drug were co-prescribed nicotine replacement therapy (n = 5177, 3.5%). In total there were 9,728 (6.2%) patients prescribed a mucolytic drug in combination with a respiratory drug and the rate of co-prescribing with antibiotics was 22%. COPD is a debilitating disease that is primarily caused by smoking and is therefore largely preventable. The HSE-PCRS pharmacy claims data is a valuable tool for helping to assess the burden of this disease in the Irish context.

A designated centre for people with disabilities operated by St Aidan's Day Care Centre Limited, Wexford

LENUS (Irish Health Repository)

McGowan, B

2009-03-01

There are approximately 6,300 people in Ireland with a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) and with a fast growing elderly population the incidence of COPD is likely to increase. This study examines the prescribing patterns of medicines dispensed for the management Asthma\\/COPD in patients over the age of 35 years using the HSE-Primary Care Reimbursement Services (PCRS) prescribing databases. The HSE-PCRS pharmacy claims data, which covers all those over 70 years of age and means tested for those less than 70 years, was analysed for the years 2005\\/2006. Approximately 26,548 (17.9%) of patients who were prescribed a respiratory drug received inhaled short-acting beta2 agonists in combination with a regular standard-dose inhaled corticosteroid. A further 5,044 (3.4%) were also prescribed a regular inhaled long-acting beta2 agonist (salmeterol or formoterol). A total of 2506 patients (6.2%) on combination therapy were co-prescribed four different anti-asthmatic treatments inclusive of oral prednisolone. A small proportion of the patients prescribed a respiratory drug were co-prescribed nicotine replacement therapy (n = 5177, 3.5%). In total there were 9,728 (6.2%) patients prescribed a mucolytic drug in combination with a respiratory drug and the rate of co-prescribing with antibiotics was 22%. COPD is a debilitating disease that is primarily caused by smoking and is therefore largely preventable. The HSE-PCRS pharmacy claims data is a valuable tool for helping to assess the burden of this disease in the Irish context.

ASM-024, a piperazinium compound, promotes the in vitro relaxation of β2-adrenoreceptor desensitized tracheas.

Science.gov (United States)

Israël-Assayag, Evelyne; Beaulieu, Marie-Josée; Cormier, Yvon

2015-01-01

Inhaled β2-adrenoreceptor agonists are widely used in asthma and chronic obstructive pulmonary disease (COPD) for bronchoconstriction relief. β2-Adrenoreceptor agonists relax airway smooth muscle cells via cyclic adenosine monophosphate (cAMP) mediated pathways. However, prolonged stimulation induces functional desensitization of the β2-adrenoreceptors (β2-AR), potentially leading to reduced clinical efficacy with chronic or prolonged administration. ASM-024, a small synthetic molecule in clinical stage development, has shown activity at the level of nicotinic receptors and possibly at the muscarinic level and presents anti-inflammatory and bronchodilator properties. Aerosolized ASM-024 reduces airway resistance in mice and promotes in-vitro relaxation of tracheal and bronchial preparations from animal and human tissues. ASM-024 increased in vitro relaxation response to maximally effective concentration of short-acting beta-2 agonists in dog and human bronchi. Although the precise mechanisms by which ASM-024 promotes airway smooth muscle (ASM) relaxation remain unclear, we hypothesized that ASM-024 will attenuate and/or abrogate agonist-induced contraction and remain effective despite β2-AR tachyphylaxis. β2-AR tachyphylaxis was induced with salbutamol, salmeterol and formoterol on guinea pig tracheas. The addition of ASM-024 relaxed concentration-dependently intact or β2-AR desensitized tracheal rings precontracted with methacholine. ASM-024 did not induce any elevation of intracellular cAMP in isolated smooth muscle cells; moreover, blockade of the cAMP pathway with an adenylate cyclase inhibitor had no significant effect on ASM-024-induced guinea pig trachea relaxation. Collectively, these findings show that ASM-024 elicits relaxation of β2-AR desensitized tracheal preparations and suggest that ASM-024 mediates smooth muscle relaxation through a different target and signaling pathway than β2-adrenergic receptor agonists. These findings suggest ASM-024

The relative effectiveness of inhaled alpha- and beta-emitting radionuclides in producing lung cancer

International Nuclear Information System (INIS)

Boecker, B.B.; Hahn, F.F.; Muggenburg, B.A.; Guilmetter, R.A.; Griffith, W.C.; McClellan, R.O.

1988-01-01

Proper assessment of a long-term human health risks associated with inhaled radionuclides requires knowledge of dose to critical cells and tissues and relationships between dose and effect for different biological end points. Results from epidemiological studies of exposed human populations provided important information for such assessments. However, because the types of exposures are limited, these results need to be supplemented with more detailed information on dosimetry and biological effects available through studies in laboratory animals and in vitro systems. To provide health risk information for inhaled fission product and actinide aerosols, life-span studies are being conducted using beagle dogs and other species at the Lovelace Inhalation Toxicology Research Institute (ITRI). Results of two life-span studies in dogs involving inhalation of the beta emitter 91 Y in fused aluminosilicate particles or the alpha emitter 239 PuO 2 are reported here

Remote monitoring of inhaled bronchodilator use and weekly feedback about asthma management: an open-group, short-term pilot study of the impact on asthma control.

Directory of Open Access Journals (Sweden)

David Van Sickle

Full Text Available OBJECTIVE: Adequate symptom control is a problem for many people with asthma. We asked whether weekly email reports on monitored use of inhaled, short-acting bronchodilators might improve scores on composite asthma-control measures. METHODS: Through an investigational electronic medication sensor attached to each participant's inhaler, we monitored 4 months' use of inhaled, short-acting bronchodilators. Participants completed surveys, including the Asthma Control Test(TM (ACT, to assess asthma control at entry and monthly thereafter. After the first month, participants received weekly email reports for 3 months. The reports summarized inhaled bronchodilator use during the preceding week and provided suggestions derived from National Asthma Education and Prevention Program (NAEPP guidelines. Paired t-tests and random-effects mixed models were implemented to assess changes in primary asthma endpoints. RESULTS: Thirty individuals participated in the 4-month study; 29 provided complete asthma control information. Mean age was 36.8 years (range: 19-74 years; 52% of respondents were female. Mean ACT scores were 17.6 (Standard Deviation [SD]  = 3.35 at entry and 18.4 (SD = 3.60 at completion of the first month. No significant difference appeared between ACT values at entry and completion of the first month (p = 0.66; however, after participants began receiving email reports and online information about their inhaler use, mean ACT scores increased 1.40 points (95% CI: 0.61, 2.18 for each subsequent study month. Significant decreases occurred in 2-week histories of daytime symptoms (β = -1.35, 95% CI: -2.65, -0.04 and nighttime symptoms (β = -0.84, 95% CI: -1.25, -0.44; no significant change in activity limitation (β = -0.21, 95% CI: -0.69, 0.26 was observed. Participants reported increased awareness and understanding of asthma patterns, level of control, bronchodilator use (timing, location and triggers, and improved

The Canadian Optimal Therapy of COPD Trial: Design, Organization and Patient Recruitment

Directory of Open Access Journals (Sweden)

Shawn D Aaron

2004-01-01

Full Text Available BACKGROUND: There are no published studies that have assessed whether adding long-acting beta 2-agonist bronchodilators and/or inhaled steroids to chronic therapy with tiotropium would provide additional clinical benefit to patients with moderate to severe chronic obstructive pulmonary disease (COPD.

Inhaled β-agonist therapy and respiratory muscle fatigue as under-recognised causes of lactic acidosis.

Science.gov (United States)

Lau, Emily; Mazer, Jeffrey; Carino, Gerardo

2013-10-14

A 49-year-old man with chronic obstructive pulmonary disease (COPD) presented with significant tachypnoea, fevers, productive cough and increased work of breathing for the previous 4 days. Laboratory data showed elevated lactate of 3.2 mEq/L. Continuous inhaled ipratropium and albuterol nebuliser treatments were administered. Lactate levels increased to 5.5 and 3.9 mEq/L, at 6 and 12 h, respectively. No infectious source was found and the lactic acidosis cleared as the patient improved. The lactic acidosis was determined to be secondary to respiratory muscle fatigue and inhaled β-agonist therapy, two under-recognised causes of lactic acidosis in patients presenting with respiratory distress. Lactic acidosis is commonly used as a clinical marker for sepsis and shock, but in the absence of tissue hypoperfusion and severe hypoxia, alternative aetiologies for elevated levels should be sought to avoid unnecessary and potentially harmful medical interventions.

Spotlight on fluticasone furoate/vilanterol trifenatate for the once-daily treatment of asthma: design, development and place in therapy

Directory of Open Access Journals (Sweden)

Albertson TE

2016-12-01

Full Text Available Timothy E Albertson,1–3 Samuel W Bullick,1,3 Michael Schivo,1 Mark E Sutter2,3 1Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, 2Department of Emergency Medicine, School of Medicine, UC Davis, Sacramento, 3Department of Medicine, Veterans Administration Northern California Health Care System, Mather, CA, USA Abstract: The use of inhaled corticosteroids (ICSs plays a key role in the treatment of asthmatic patients, and international guidelines have designated ICSs as an early maintenance therapy in controlling asthma symptoms. When asthmatic patients remain symptomatic on ICSs, one common option is to add a long-acting beta2 agonist (LABA to the maintenance treatment. Fixed combination inhalers that contain both an ICS and a LABA have been popular for both chronic obstructive pulmonary disease (COPD and asthma. Historically, these inhalers have been dosed twice daily. However, currently, there is a once-daily combination therapy with the ICS fluticasone furoate (FF and the LABA vilanterol trifenatate (VI with indications for use in both COPD and asthma. This dry powder inhaler (DPI comes in two doses of FF (100 or 200 µg both combined with VI (25 µg. This article reviews the clinical trial data for FF, VI and FF/VI combination inhalers and documents the efficacy and safety of once-daily inhaled maintenance therapy by DPI in asthmatic patients. Keywords: fluticasone furoate/vilanterol trifenatate, asthma, long-acting beta2 agonist, inhaled corticosteroid, combined inhaler, persistent asthma, dry powder inhaler  

Asthma quality of life during 1 year of treatment with budesonide with or without formoterol

NARCIS (Netherlands)

Juniper, EF; Svensson, K; O'Byrne, PM; Barnes, PJ; Bauer, CA; Lofdahl, CGA; Postma, DS; Pauwels, RA; Tattersfield, AE; Ullman, A

1999-01-01

The Formoterol and Corticosteroids Establishing Therapy (FACET) study has provided the first opportunity to examine the long-term effects of inhaled steroids and long-acting beta(2)-agonists on asthma-specific quality of life. The objectives of the present study were to: evaluate the effects of

Effects of formoterol (Oxis (R) Turbuhaler (R)) and ipratropium on exercise capacity in patients with COPD

NARCIS (Netherlands)

Liesker, JJW; Van de Velde, [No Value; Meysman, M; Vincken, W; Wollmer, P; Hansson, L; Kerstjens, HAM; Qvint, U; Pauwels, RA

Although long-acting inhaled beta(2)-agonists improve various outcome measures in COPD, no double-blind study has yet shown a significant effect of these drugs on exercise capacity. In a randomized, double-blind, placebo-controlled, crossover study, patients received formoterol (4.5,9, or 18 mug

Data-mining of medication records to improve asthma management.

Science.gov (United States)

Bereznicki, Bonnie J; Peterson, Gregory M; Jackson, Shane L; Walters, E Haydn; Fitzmaurice, Kimbra D; Gee, Peter R

2008-07-07

To use community pharmacy medication records to identify patients whose asthma may not be well managed and then implement and evaluate a multidisciplinary educational intervention to improve asthma management. We used a multisite controlled study design. Forty-two pharmacies throughout Tasmania ran a software application that "data-mined" medication records, generating a list of patients who had received three or more canisters of inhaled short-acting beta(2)-agonists in the preceding 6 months. The patients identified were allocated to an intervention or control group. Pre-intervention data were collected for the period May to November 2006 and post-intervention data for the period December 2006 to May 2007. Intervention patients were contacted by the community pharmacist via mail, and were sent educational material and a letter encouraging them to see their general practitioner for an asthma management review. Pharmacists were blinded to the control patients' identities until the end of the post-intervention period. Dispensing ratio of preventer medication (inhaled corticosteroids [ICSs]) to reliever medication (inhaled short-acting beta(2)-agonists). Thirty-five pharmacies completed the study, providing 702 intervention and 849 control patients. The intervention resulted in a threefold increase in the preventer-to-reliever ratio in the intervention group compared with the control group (P < 0.01) and a higher proportion of patients in the intervention group using ICS therapy than in the control group (P < 0.01). Community pharmacy medication records can be effectively used to identify patients with suboptimal asthma management, who can then be referred to their GP for review. The intervention should be trialled on a national scale to determine the effects on clinical, social, emotional and economic outcomes for people in the Australian community, with a longer follow-up to determine sustainability of the improvements noted.

Beta-blockers and statins in the context of asthma

Directory of Open Access Journals (Sweden)

Joanna Pawlak

2009-12-01

Full Text Available Asthma is a disease with a complex pathogenesis and differentiated clinical picture with airway inflammation in its background. Many cells and cell-released substances are engaged in the course of the disease. The basic treatment strategy in asthma is based on chronic administration of inhaled glucocorticosteroids (with a strong anti-inflammatory effect and beta2-adrenoreceptor agonists (bronchodilatory effect. Much attention has been recently paid to the effects of other medicines on mechanisms important in the pathogenesis of asthma, including beta-blockers and statins. Many researchers have suggested a potentially useful role of some beta-blockers in chronic asthma therapy, particularly considering their effect on the pharmacodynamics of beta receptors in the bronchi. Moreover, statins, due to their anti-inflammatory and immunomodulatory effects, can also be useful in the management of asthma.

Interpretation of positive results of a methacholine inhalation challenge and 1 week of inhaled bronchodilator use in diagnosing and treating cough-variant asthma.

Science.gov (United States)

Irwin, R S; French, C T; Smyrnios, N A; Curley, F J

1997-09-22

In diagnosing cough due to asthma, methacholine chloride inhalation challenge (MIC) interpreted in a traditional fashion has been shown to have positive predictive values from 60% to 82%. To determine whether any features of positive results of an MIC or the results of a 1-week trial of inhaled beta-agonist therapy were helpful in predicting when the cough was due to asthma. The study design was a prospective, randomized, double-blind, placebo-controlled, crossover format performed in adult, nonsmoking subjects, who were referred for diagnosis and treatment of chronic cough. The subjects had no other respiratory complaints or medical conditions for which they were taking medications, the results of baseline spirometry and chest roentgenograms were normal, and the results of MIC were positive. After obtaining baseline data, including MICs on 2 separate days, objective cough counting, and self-assessment of cough severity using a visual analog scale, subjects were randomized to receive 2 inhalations (1.3 mg) of metaproterenol sulfate or placebo by metered dose inhaler attached to a spacer device every 4 hours while awake. At 1 week, data identical to baseline were collected, and subjects received the other metered dose inhaler for 7 days. At 1 week, data identical to baseline were collected. After completion of the protocol, subjects were followed up in the clinic to observe the final response of the cough to specific therapy. Based on the disappearance of the cough with specific therapy, the cough was due to asthma in 9 of 15 subjects and nonasthma in 6 of 15 subjects. Baseline data were similar between groups. With respect to MICs, there were no significant differences between groups in the cumulative dose of methacholine that provoked a 20% decrease in forced expiratory volume in 1 second from the postsaline baseline value (PD20 values), slopes of dose-response curves, and maximal-response plateaus. Cough severity significantly improved after 1 week of

PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes.

Science.gov (United States)

Wang, Hong-Mei; Zhao, Yan-Xin; Zhang, Shi; Liu, Gui-Dong; Kang, Wen-Yan; Tang, Hui-Dong; Ding, Jian-Qing; Chen, Sheng-Di

2010-01-01

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Accumulating data indicate that astrocytes play an important role in the neuroinflammation related to the pathogenesis of AD. It has been shown that microglia and astrocytes are activated in AD brain and amyloid-beta (Abeta) can increase the expression of cyclooxygenase 2 (COX-2), interleukin-1, and interleukin-6. Suppressing the inflammatory response caused by activated astrocytes may help to inhibit the development of AD. Curcumin is a major constituent of the yellow curry spice turmeric and proved to be a potential anti-inflammatory drug in arthritis and colitis. There is a low age-adjusted prevalence of AD in India, a country where turmeric powder is commonly used as a culinary compound. Curcumin has been shown to suppress activated astroglia in amyloid-beta protein precursor transgenic mice. The real mechanism by which curcumin inhibits activated astroglia is poorly understood. Here we report that the expression of COX-2 and glial fibrillary acidic protein were enhanced and that of peroxisome proliferator-activated receptor gamma (PPARgamma) was decreased in Abeta(25-35)-treated astrocytes. In line with these results, nuclear factor-kappaB translocation was increased in the presence of Abeta. All these can be reversed by the pretreatment of curcumin. Furthermore, GW9662, a PPARgamma antagonist, can abolish the anti-inflammatory effect of curcumin. These results show that curcumin might act as a PPARgamma agonist to inhibit the inflammation in Abeta-treated astrocytes.

The putative imidazoline receptor agonist, harmane, promotes intracellular calcium mobilisation in pancreatic beta-cells.

Science.gov (United States)

Squires, Paul E; Hills, Claire E; Rogers, Gareth J; Garland, Patrick; Farley, Sophia R; Morgan, Noel G

2004-10-06

beta-Carbolines (including harmane and pinoline) stimulate insulin secretion by a mechanism that may involve interaction with imidazoline I(3)-receptors but which also appears to be mediated by actions that are additional to imidazoline receptor agonism. Using the MIN6 beta-cell line, we now show that both the imidazoline I(3)-receptor agonist, efaroxan, and the beta-carboline, harmane, directly elevate cytosolic Ca(2+) and increase insulin secretion but that these responses display different characteristics. In the case of efaroxan, the increase in cytosolic Ca(2+) was readily reversible, whereas, with harmane, the effect persisted beyond removal of the agonist and resulted in the development of a repetitive train of Ca(2+)-oscillations whose frequency, but not amplitude, was concentration-dependent. Initiation of the Ca(2+)-oscillations by harmane was independent of extracellular calcium but was sensitive to both dantrolene and high levels (20 mM) of caffeine, suggesting the involvement of ryanodine receptor-gated Ca(2+)-release. The expression of ryanodine receptor-1 and ryanodine receptor-2 mRNA in MIN6 cells was confirmed using reverse transcription-polymerase chain reaction (RT-PCR) and, since low concentrations of caffeine (1 mM) or thimerosal (10 microM) stimulated increases in [Ca(2+)](i), we conclude that ryanodine receptors are functional in these cells. Furthermore, the increase in insulin secretion induced by harmane was attenuated by dantrolene, consistent with the involvement of ryanodine receptors in mediating this response. By contrast, the smaller insulin secretory response to efaroxan was unaffected by dantrolene. Harmane-evoked changes in cytosolic Ca(2+) were maintained by nifedipine-sensitive Ca(2+)-influx, suggesting the involvement of L-type voltage-gated Ca(2+)-channels. Taken together, these data imply that harmane may interact with ryanodine receptors to generate sustained Ca(2+)-oscillations in pancreatic beta-cells and that this effect

Detection and identification of "new" beta-agonists in black-market preparations

NARCIS (Netherlands)

van Ginkel LA; Stephany RW; van Rossum HJ; Visser T; den Engelsman T; de Jong APJM; Jacquemijns M; Zomer G

1992-01-01

In several "black-market" used for growth promotion preparations new compounds were found belonging to the group of N-phenylethanolamines with structures very similar to compounds known to be used for veal calf and cattle production, the so called beta-agonists. The two most important

Differential effects of beta-adrenoceptor partial agonists in patients with postural hypotension

DEFF Research Database (Denmark)

Mehlsen, J; Stadeager, C; Trap-Jensen, J

1993-01-01

patients with postural hypotension of different aetiologies. Blood pressure, heart rate and stroke volume were measured in the supine and head-up tilted positions. Left ventricular ejection fraction (LVEF) was measured in the supine position, and vascular resistance, left ventricular volume, and left.......min-1 and LVEF from 0.57 to 0.52, and reduced mean arterial blood pressure from 103 mm Hg to 93 mm Hg. Xamoterol showed beta-adrenoceptor agonistic effects in the supine position through increments in heart rate from 72 to 90 beats.min-1 and LVEF from 0.58 to 0.66, and raised mean arterial blood...... pressure from 108 to 123 mm Hg. It is concluded that the degree of agonist activity of a beta-adrenergic agent is of importance if it is given to a patient with postural hypotension....

Oxidation of nutrients in bull calves treated with beta-adrenergic agonists

DEFF Research Database (Denmark)

Chwalibog, André; Jensen, K; Thorbek, G

1996-01-01

Oxidation of protein (OXP), carbohydrate (OXCHO) and fat (OXF) was investigated with 12 growing bulls treated with beta-agonist (L-644, 969) during two 6 weeks trials (Section A and B) at a mean live weight of 195 and 335 kg. Heat production and nutrient oxidation was calculated from gas exchange...

Profile of a fixed-dose combination of tiotropium/olodaterol and its potential in the treatment of COPD

Directory of Open Access Journals (Sweden)

Muruganandan S

2015-06-01

Full Text Available Sanjeevan Muruganandan,1 Lata Jayaram2,3 1Department of Respiratory and Sleep Medicine, Austin Health, 2Department of Respiratory and Sleep Medicine, Western Health, 3University of Melbourne, Melbourne, Victoria, Australia Abstract: Chronic obstructive pulmonary disease (COPD is a progressive, debilitating disorder that results in frequent exacerbations and impacts quality of life. It represents a growing burden of health care cost, both from societal and economic perspectives. Short- and long-acting bronchodilators remain the mainstay of therapy in COPD patients. New fixed-dose combination inhalers with novel pharmacological combinations of long-acting β2-agonists and muscarinic antagonists and delivered once-daily through a variety of devices are currently being developed and licensed for the treatment of COPD. There is mounting research suggesting that combining a fixed dose of a β2-agonist and a muscarinic antagonist achieves better bronchodilation and clinical outcomes compared with either agent alone. These once-daily dosing inhalers are anticipated to impact favorably on patient preference and compliance. This review examines the fixed-dose combination of tiotropium bromide and olodaterol delivered by a Respimat® Soft Mist™ inhaler at doses of 2.5/5 µg and 5/5 µg in moderate-to-very-severe COPD, and its potential role in COPD compared with other long-acting β2-agonist with long-acting muscarinic antagonist combinations and delivery devices. Keywords: fixed-dose combination inhalers, olodaterol, tiotropium bromide, COPD treatment, long-acting β2-agonists, long-acting muscarinic antagonist

Comparison Review of Short-Acting and Long-Acting Glucagon-like Peptide-1 Receptor Agonists

OpenAIRE

Uccellatore, Annachiara; Genovese, Stefano; Dicembrini, Ilaria; Mannucci, Edoardo; Ceriello, Antonio

2015-01-01

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) are useful tools for treating type 2 diabetes mellitus. In their recent position statement, the American Diabetes Association and European Association for the Study of Diabetes recommend GLP1-RAs as add-on to metformin when therapeutic goals are not achieved with monotherapy, particularly for patients who wish to avoid weight gain or hypoglycemia. GLP1-RAs differ substantially in their duration of action, frequency of administratio...

Assessing the association between omalizumab and arteriothrombotic events through spontaneous adverse event reporting.

Science.gov (United States)

Ali, Ayad K; Hartzema, Abraham G

2012-01-01

Omalizumab is a monoclonal antibody, indicated for the treatment of severe allergic asthma. In Europe, there have been concerns about the cardiovascular safety of omalizumab. The objective of this study was to analyze the association between omalizumab and arterial thrombotic events in a spontaneous adverse drug reaction reporting database in the US. Reports of arterial thrombotic events submitted to the US Food and Drug Administration's Adverse Event Reporting System (AERS) between 2004 and 2011 were retrieved and analyzed by the reporting odds ratio data mining algorithm. The reporting odds ratio of arterial thrombotic events for omalizumab was compared with specific asthma medications and all drugs in the AERS. Values ≥2 were considered significant safety signals. The Medical Dictionary for Regulatory Activities Preferred Terms were used to identify arterial thrombotic events (eg, stroke, myocardial infarction). In total, 293,783 reports of arterial thrombotic events were retrieved (about 2% of all adverse drug reaction reports), corresponding to 2274 asthma drug-arterial thrombotic events pairs (omalizumab, 222; inhaled corticosteroids [ICS], 131; long-acting beta-agonists [LABA], 102; single-device combination ICS-LABA, 506; inhaled short-acting beta-agonists [SABA], 475; oral SABA, 6; inhaled antimuscarinics [AMC], 477; single-device combination AMC-SABA, 127; xanthines, 50; leukotriene modifiers, 174; and mast cell stabilizers, 4). Reporting odds ratio and 95% confidence interval values for omalizumab compared with other asthma drugs and all drugs in AERS were 2.75 (2.39-316) and 1.09 (0.95-1.24), respectively. Omalizumab ranked second after ICS in the risk of arterial thrombotic events, followed by AMC, AMC-SABA, and ICS-LABA. Omalizumab is associated with higher than expected reporting of arterial thrombotic events in asthmatic patients. This hypothesis needs further testing in robust epidemiological studies.

In vitro desensitization of beta-adrenoceptors in guinea pig trachea: interactions between beta-adrenoceptor agonists and influence of adenosine and other drugs.

Science.gov (United States)

Matran, R; Naline, E; Advenier, C; Duroux, P

1989-01-01

The aim of this study was to investigate quantitatively the action of and the interaction between beta-adrenergic receptor agonists in desensitizing guinea pig isolated trachea. It was also to evaluate the influence of substances whose effects on desensitization are either disputed (theophylline, indomethacin, ketotifen, hydrocortisone) or unknown (nicardipine, Bay K 8644, fenspiride, adenosine). Tracheal strips were contracted with histamine (5 x 10(-5) M) or acetylcholine (5.10(-5) M) and concentration-response (C/R) curves for various beta-adrenoceptor agonists were determined before and after incubation (20 min to 4 h) with the same beta-adrenoceptor agonist (autodesensitization), with other beta-adrenoceptor agonists (cross-desensitization), or with a beta-adrenoceptor agonist and another substance. Our results show that the autodesensitization induced by isoprenaline is concentration dependent and that concentration dependence is more pronounced with salbutamol and fenoterol than with isoprenaline and adrenaline with respect to autodesensitization: shifts (log unit) of the C/R curves were 0.59 +/- 0.06 (N = 5) for salbutamol (10(-5) M), 0.78 +/- 0.09 (N = 5) for fenoterol (10(-6) M), 0.30 +/- 0.04 (N = 9) for isoprenaline (10(-5) M), and 0.33 +/- 0.05 (N = 5) for adrenaline (10(-5) M). Our studies of cross-desensitization (desensitization to isoprenaline, adrenaline, salbutamol, and fenoterol induced by incubation with isoprenaline 10(-5) M) showed a significantly greater shift in the C/R curves for fenoterol (0.56 +/- 0.08, N = 5) and salbutamol (0.62 +/- 0.05, N = 5) than for adrenaline (0.35 +/- 0.07, N = 5) and isoprenaline itself (0.30 +/- 0.05, N = 9). Of the substances we studied, none modified the desensitization induced by isoprenaline except hydrocortisone and adenosine. Hydrocortisone (10(-8) M) reduced it significantly, although to a negligible extent. Adenosine (3 x 10(-4) M) did not shift the C/R curve to isoprenaline by itself, but incubation

Leukotriene modifiers in pediatric asthma management

DEFF Research Database (Denmark)

Bisgaard, H

2001-01-01

-acting beta-agonists as complementary treatment to inhaled corticosteroids in pediatric asthma management because they provide bronchodilation and bronchoprotection without development of tolerance, and complement the antiinflammatory activity unchecked by steroids. In addition, the Cys-LTRA montelukast has...

Short-term effect of winter air pollution on respiratory health of asthmatic children in Paris.

Science.gov (United States)

Segala, C; Fauroux, B; Just, J; Pascual, L; Grimfeld, A; Neukirch, F

1998-03-01

There is controversy as to whether low levels of air pollution affect the symptoms and lung function in asthma. We addressed this by examining the short-term effects of winter air pollution on childhood asthma in Paris. We performed a 6 month follow-up of 84 medically diagnosed asthmatic children classified into two groups of severity. The outcomes included incidence and prevalence of asthma attacks, symptoms and use of supplementary beta2-agonists, peak expiratory flow (PEF) value and its variability. The statistical analysis controlled the lack of independence between daily health outcomes, trends and meteorology. Air pollution was associated with an increase in reports and duration of asthma attacks and asthma-like symptoms in mild asthmatic children. The strongest association was the risk of asthma attack for an increase of 50 microg x m(-3) of sulphur dioxide (SO2) on the same day (odds ratio (OR)=2.86). Maximum reduction in morning peak expiratory flow (PEF) (5%) and maximum increase in PEF variability (2%) were observed at a lag of 3 days for an increase of 50 microg x m(-3) of SO2 in the subgroup of mild asthmatics receiving no regular inhaled medication. In moderate asthmatic children, the duration of supplementary beta2-agonist use was strongly associated with air pollution. The general pattern of our results provides evidence of the effect of the low levels of air pollution encountered in Western Europe on symptoms and lung function in childhood asthma.

Long acting β2-agonist and corticosteroid restore airway glandular cell function altered by bacterial supernatant

Directory of Open Access Journals (Sweden)

Nawrocki-Raby Béatrice

2010-01-01

Full Text Available Abstract Background Staphylococcus aureus releases virulence factors (VF that may impair the innate protective functions of airway cells. The aim of this study was to determine whether a long-acting β2 adrenergic receptor agonist (salmeterol hydroxynaphthoate, Sal combined with a corticosteroid (fluticasone propionate, FP was able to regulate ion content and cytokine expression by airway glandular cells after exposure to S. aureus supernatant. Methods A human airway glandular cell line was incubated with S. aureus supernatant for 1 h and then treated with the combination Sal/FP for 4 h. The expression of actin and CFTR proteins was analyzed by immunofluorescence. Videomicroscopy was used to evaluate chloride secretion and X-ray microanalysis to measure the intracellular ion and water content. The pro-inflammatory cytokine expression was assessed by RT-PCR and ELISA. Results When the cells were incubated with S. aureus supernatant and then with Sal/FP, the cellular localisation of CFTR was apical compared to the cytoplasmic localisation in cells incubated with S. aureus supernatant alone. The incubation of airway epithelial cells with S. aureus supernatant reduced by 66% the chloride efflux that was fully restored by Sal/FP treatment. We also observed that Sal/FP treatment induced the restoration of ion (Cl and S and water content within the intracellular secretory granules of airway glandular cells and reduced the bacterial supernatant-dependent increase of pro-inflammatory cytokines IL8 and TNFα. Conclusions Our results demonstrate that treatment with the combination of a corticosteroid and a long-acting β2 adrenergic receptor agonist after bacterial infection restores the airway glandular cell function. Abnormal mucus induced by defective ion transport during pulmonary infection could benefit from treatment with a combination of β2 adrenergic receptor agonist and glucocorticoid.

Risk of Pneumonia with Inhaled Corticosteroid versus Long-Acting Bronchodilator Regimens in Chronic Obstructive Pulmonary Disease: A New-User Cohort Study

Science.gov (United States)

DiSantostefano, Rachael L.; Sampson, Tim; Le, Hoa Van; Hinds, David; Davis, Kourtney J.; Bakerly, Nawar Diar

2014-01-01

Introduction Observational studies using case-control designs have showed an increased risk of pneumonia associated with inhaled corticosteroid (ICS)-containing medications in patients with chronic obstructive pulmonary disease (COPD). New-user observational cohort designs may minimize biases associated with previous case-control designs. Objective To estimate the association between ICS and pneumonia among new users of ICS relative to inhaled long-acting bronchodilator (LABD) monotherapy. Methods Pneumonia events in COPD patients ≥45 years old were compared among new users of ICS medications (n = 11,555; ICS, ICS/long-acting β2-agonist [LABA] combination) and inhaled LABD monotherapies (n = 6,492; LABA, long-acting muscarinic antagonists) using Cox proportional hazards models, with propensity scores to adjust for confounding. Setting: United Kingdom electronic medical records with linked hospitalization and mortality data (2002–2010). New users were censored at earliest of: pneumonia event, death, changing/discontinuing treatment, or end of follow-up. Outcomes: severe pneumonia (primary) and any pneumonia (secondary). Results Following adjustment, new use of ICS-containing medications was associated with an increased risk of pneumonia hospitalization (n = 322 events; HR = 1.55, 95% CI: 1.14, 2.10) and any pneumonia (n = 702 events; HR = 1.49, 95% CI: 1.22, 1.83). Crude incidence rates of any pneumonia were 48.7 and 30.9 per 1000 person years among the ICS-containing and LABD cohorts, respectively. Excess risk of pneumonia with ICS was reduced when requiring ≥1 month or ≥ 6 months of new use. There was an apparent dose-related effect, with greater risk at higher daily doses of ICS. There was evidence of channeling bias, with more severe patients prescribed ICS, for which the analysis may not have completely adjusted. Conclusions The results of this new-user cohort study are consistent with published findings; ICS were associated

BLOOD EOSINOPHIL NUMBERS AND ACTIVITY DURING 24 HOURS - EFFECTS OF TREATMENT WITH BUDESONIDE AND BAMBUTEROL

NARCIS (Netherlands)

WEMPE, JB; TAMMELING, EP; KOETER, GH; HAKANSSON, L; VENGE, P; POSTMA, DS

1992-01-01

The effects of the inhaled corticosteroid budesonide and the oral long-acting beta-agonist bambuterol on circadian variation of blood eosinophil numbers, serum levels of eosinophil cationic protein (ECP), serum eosinophil chemotactic activity (ECA), and serum neutrophil chemotactic activity (NCA)

Cost-effectiveness of budesonide/formoterol for maintenance and reliever asthma therapy in Denmark--cost-effectiveness analysis based on five randomised controlled trials

DEFF Research Database (Denmark)

Wickstrøm, Jannie; Dam, Nanna; Malmberg, Irena

2009-01-01

Budesonide/formoterol maintenance and reliever therapy (Symbicort SMART) is an effective asthma-management regime where patients use budesonide/formoterol both as maintenance treatment and as additional doses as needed to improve overall asthma control by reducing symptoms and exacerbations....... The aim of this study was to determine the cost-effectiveness of the Symbicort SMART regime in Denmark vs higher dose inhaled corticosteroid (ICS) plus reliever medication, similar dose inhaled corticosteroid/long-acting beta(2)-agonist (ICS/LABA) combination therapy plus reliever medication or higher...

Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial

DEFF Research Database (Denmark)

Troosters, T; Celli, B; Lystig, T

2010-01-01

-term Impacts on Function with Tiotropium (UPLIFT) was conducted. Analysis focused on the effect of tiotropium versus matching placebo in the 810 (13.5%) COPD patients not on other maintenance treatment (long-acting beta-agonists, inhaled corticosteroids, theophyllines or anticholinergics) at randomisation...

A European multicentre survey of impulse control behaviours in Parkinson's disease patients treated with short- and long-acting dopamine agonists

DEFF Research Database (Denmark)

Rizos, A; Sauerbier, A; Antonini, A

2016-01-01

BACKGROUND AND PURPOSE: Impulse control disorders (ICDs) in Parkinson's disease (PD) are associated primarily with dopamine agonist (DA) use. Comparative surveys of clinical occurrence of impulse control behaviours on longer acting/transdermal DA therapy across age ranges are lacking. The aim...... release PPX (PPX-IR) (19.0%; P controlling...

Safety and efficacy of the prostaglandin D2 receptor antagonist AMG 853 in asthmatic patients.

Science.gov (United States)

Busse, William W; Wenzel, Sally E; Meltzer, Eli O; Kerwin, Edward M; Liu, Mark C; Zhang, Nan; Chon, Yun; Budelsky, Alison L; Lin, Joseph; Lin, Shao-Lee

2013-02-01

The D-prostanoid receptor and the chemoattractant receptor homologous molecule expressed on T(H)2 cells (CRTH2) are implicated in asthma pathogenesis. AMG 853 is a potent, selective, orally bioavailable, small-molecule dual antagonist of human D-prostanoid and CRTH2. We sought to determine the efficacy and safety of AMG 853 compared with placebo in patients with inadequately controlled asthma. Adults with moderate-to-severe asthma were randomized to placebo; 5, 25, or 100 mg of oral AMG 853 twice daily; or 200 mg of AMG 853 once daily for 12 weeks. All patients continued their inhaled corticosteroids. Long-acting β-agonists were not allowed during the treatment period. Allowed concomitant medications included short-acting β-agonists and a systemic corticosteroid burst for asthma exacerbation. The primary end point was change in total Asthma Control Questionnaire score from baseline to week 12. Secondary and exploratory end points included FEV(1), symptom scores, rescue short-acting β-agonist use, and exacerbations. Among treated patients, no effect over placebo (n = 79) was observed in mean changes in Asthma Control Questionnaire scores at 12 weeks (placebo, -0.492; range for AMG 853 groups [n = 317], -0.444 to -0.555). No significant differences between the active and placebo groups were observed for secondary end points. The most commonly reported adverse events were asthma, upper respiratory tract infection, and headache; 9 patients experienced serious adverse events, all of which were deemed unrelated to study treatment by the investigator. AMG 853 as an add-on to inhaled corticosteroid therapy demonstrated no associated risks but was not effective at improving asthma symptoms or lung function in patients with inadequately controlled moderate-to-severe asthma. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Asthma prescribing practices of government and private doctors in Malaysia--a nationwide questionnaire survey.

Science.gov (United States)

Loh, Li-Cher; Wong, Pel-Se

2005-03-01

A self-answered, anonymously completed questionnaire survey was performed between June 2002 and May 2003 where doctors from government and private sectors in Malaysia were invited to participate by post or during medical meetings. One hundred and sixteen government doctors and 110 private doctors provided satisfactorily completed questionnaires (effective respondent rate: 30.1%). The most preferred medications for 'first-line', 'second-line' and 'third-line' treatment were for government doctors: inhaled short-acting beta2-agonist (SABA) (98%), inhaled corticosteroids (CS) (75%), and leukotriene antagonist (52%); and for private doctors: oral SABA (81%), inhaled CS (68%), and oral CS (58%). The first choice inhaler device for most government and private doctors were metered dose inhalers, with cost and personal preferences (for private doctors), and technical ability (for government doctors) as the key considerations when deciding on the choice of device. This benchmark data on the asthma prescribing practices of a healthcare delivery system fully dichotomized into government and private sector, provides evidence for practice differences affected by the nature of the healthcare system, and might have implications on healthcare systems of other countries that share similarities with that of Malaysia.

Agonist-induced desensitization of adenylyl cyclase in Y1 adrenocortical tumor cells

International Nuclear Information System (INIS)

Olson, M.F.; Tsao, J.; Pon, D.J.; Schimmer, B.P.

1991-01-01

Y1 adrenocortical tumor cells (Y1DS) and Y1 mutants resistant to ACTH-induced desensitization of adenylyl cyclase (Y1DR) were transfected with a gene encoding the mouse beta 2-adrenergic receptor (beta 2-AR). Transfectants expressed beta 2-ARs that were able to stimulate adenylyl cyclase activity and steroid biosynthesis. These transfectants were used to explore the basis for the DR mutation in Y1 cells. The authors demonstrate that beta-adrenergic agonists desensitize the adenylyl cyclase system in transfected Y1DS cells whereas transfected Y1DR cells are resistant to desensitization by beta-adrenergic agonists. The fate of the beta 2-ARs during desensitization was evaluated by photoaffinity labelling with [125I]iodocyanopindolol diazerine. Desensitization of Y1DS transfectants was accompanied by a modest loss in receptor density that was insufficient to account for the complete loss of responsiveness to beta-adrenergic agonists. The extent of receptor loss induced by beta-adrenergic agonists in Y1DR transfectants exceeded that in the Y1DS transfectants indicating that the mutation which protects Y1DR cells from agonist-induced desensitization is prior to receptor down-regulation in the desensitization pathway. From these results we infer that ACTH and isoproterenol desensitize adenylyl cyclase by a common pathway and that receptor loss is not a major component of the desensitization process in these cells

β(2)-Agonists and Physical Performance: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

NARCIS (Netherlands)

Pluim, Babette M.; de Hon, Olivier; Staal, J. Bart; Limpens, Jacqueline; Kuipers, Harm; Overbeek, Shelley E.; Zwinderman, Aeilko H.; Scholten, Rob J. P. M.

2011-01-01

Inhaled β(2)-agonists are commonly used as bronchodilators in the treatment of asthma. Their use in athletes, however, is restricted by anti-doping regulations. Controversies remain as to whether healthy elite athletes who use bronchodilators may gain a competitive advantage. The aim of this

Is the 'blue' colour convention for inhaled reliever medications important? A UK-based survey of healthcare professionals and patients with airways disease.

Science.gov (United States)

Fletcher, Monica; Scullion, Jane; White, John; Thompson, Bronwen; Capstick, Toby

2016-11-03

In many countries, short-acting β 2 -agonist inhalers have traditionally been coloured blue. This inhaled therapy has also conventionally been known as a 'reliever' by patients and healthcare professionals (HCPs), in comparison with 'preventer' medications (inhaled steroids). With the rapidly changing market in inhaled therapy for COPD and asthma and growing numbers of devices, there has been some concern that the erosion of traditional colour conventions is leading to patients (and HCPs) becoming confused about the role of different therapies. In order to assess whether there was concern over the perceived changing colour conventions, the UK Inhaler Group carried out a large online survey of patients and HCPs. The aim was to determine how patients and HCPS identify and describe inhaled drugs, and how this might impact on use of medicines and safety. The results of the survey highlighted the importance of the term 'blue inhaler' for patients with only 11.3% never referring to the colour when referring to their inhaler. For HCPs, 95% felt colour conventions were important when referring to reliever medication. In addition, HCPs appear to refer to inhalers mainly by colour when talking to patients. Our conclusions were that the concept of a 'blue inhaler' remains important to patients and healthcare professionals. These results add to the debate about the need to formalise the colour coding of inhaled therapies, in particular using the colour blue for inhalers for rapid relief of symptoms, as this convention may be an important measure and contributor to patient safety. Our survey should provide impetus for all interested parties to discuss and agree a formal industry-wide approach to colour coding of inhaled therapies for the benefit of patients and carers and HCPs.

Characterization of a Ca2+ response to both UTP and ATP at human P2Y11 receptors: evidence for agonist-specific signaling.

Science.gov (United States)

White, Pamela J; Webb, Tania E; Boarder, Michael R

2003-06-01

Previous reports on heterologously-expressed human P2Y11 receptors have indicated that ATP, but not UTP, is an agonist stimulating both phosphoinositidase C and adenylyl cyclase. Consistent with these findings, we report that in 1321N1 cells expressing human P2Y11 receptors, UTP stimulation did not lead to accumulation of inositol(poly)phosphates under conditions in which ATP gave a robust, concentration-dependent effect. Unexpectedly, however, both UTP and ATP stimulated increases in cytosolic Ca2+ concentration ([Ca2+]c), with both nucleotides achieving similar EC50 and maximal responses. The responses to maximally effective concentrations of ATP and UTP were not additive. The [Ca2+]c increase in response to UTP was less dependent on extracellular Ca2+ than was the response to ATP. AR-C67085 (2-propylthio-beta,gamma-difluoromethylene-d-ATP, a P2Y11-selective agonist), adenosine 5'-O-(3-thiotriphosphate), and benzoyl ATP were all full agonists with potencies similar to those of ATP and UTP. In desensitization experiments, exposure to ATP resulted in loss of the UTP response; this response was more sensitive to desensitization than that of ATP. Pertussis toxin pretreatment attenuated the response to UTP but left the ATP response unaffected. The presence of 2-aminoethyl diphenylborate differentially affected the responses of ATP and UTP. No mRNA transcripts for P2Y2 or P2Y4 were detectable in the P2Y11-expressing cells. We conclude that UTP is a Ca2+-mobilizing agonist at P2Y11 receptors and that ATP and UTP acting at the same receptor recruit distinct signaling pathways. This example of agonist-specific signaling is discussed in terms of agonist trafficking and differential signal strength.

Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?

DEFF Research Database (Denmark)

Schwartz, Thue W; Holst, Birgitte

2007-01-01

Many small-molecule agonists also display allosteric properties. Such ago-allosteric modulators act as co-agonists, providing additive efficacy--instead of partial antagonism--and they can affect--and often improve--the potency of the endogenous agonist. Surprisingly, the apparent binding sites...... different binding modes. In another, dimeric, receptor scenario, the endogenous agonist binds to one protomer while the ago-allosteric modulator binds to the other, 'allosteric' protomer. It is suggested that testing for ago-allosteric properties should be an integral part of the agonist drug discovery...... process because a compound that acts with--rather than against--the endogenous agonist could be an optimal agonist drug....

A designated centre for people with disabilities operated by St Catherine's Association Limited, Wicklow

LENUS (Irish Health Repository)

Mokoka, Matshediso C

2017-06-15

Many patients with asthma remain poorly controlled despite the use of inhaled corticosteroids and long-acting beta agonists. Poor control may arise from inadequate adherence, incorrect inhaler technique or because the condition is refractory. Without having an objective assessment of adherence, clinicians may inadvertently add extra medication instead of addressing adherence. This study aims to assess if incorporating objectively recorded adherence from the Inhaler Compliance Assessment (INCA) device and lung function into clinical decision making provides more cost-effective prescribing and improves outcomes.

St John's House, 202 Merrion Road, Dublin 4.

LENUS (Irish Health Repository)

Mokoka, Matshediso C

2017-06-15

Many patients with asthma remain poorly controlled despite the use of inhaled corticosteroids and long-acting beta agonists. Poor control may arise from inadequate adherence, incorrect inhaler technique or because the condition is refractory. Without having an objective assessment of adherence, clinicians may inadvertently add extra medication instead of addressing adherence. This study aims to assess if incorporating objectively recorded adherence from the Inhaler Compliance Assessment (INCA) device and lung function into clinical decision making provides more cost-effective prescribing and improves outcomes.

The efficacy and safety of triple inhaled treatment in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis using Bayesian methods

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Kwak MS

2015-11-01

Full Text Available Min-Sun Kwak,1 Eunyoung Kim,2 Eun Jin Jang,3 Hyun Jung Kim,4 Chang-Hoon Lee5 1Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea; 2Department of Statistics, Kyungpook National University, Daegu, Republic of Korea; 3Department of Information Statistics, Andong National University, Andong, Republic of Korea; 4Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; 5Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea Purpose: Although tiotropium (TIO and inhaled corticosteroid (ICS/long-acting β-agonists are frequently prescribed together, the efficacy of “triple therapy” has not been scientifically demonstrated. We conducted a systematic review and meta-analysis using Bayesian methods to compare triple therapy and TIO monotherapy.Methods: We searched the MEDLINE, EMBASE, and Cochrane Library databases for randomized controlled trials comparing the efficacy and safety of triple therapy and TIO monotherapy in patients with chronic obstructive pulmonary disease (COPD. We conducted a meta-analysis to compare the effectiveness and safety of triple therapy and TIO monotherapy using Bayesian random effects models.Results: Seven trials were included, and the risk of bias in the majority of the studies was acceptable. There were no statistically significant differences in the incidence of death and acute exacerbation of disease in the triple therapy and TIO monotherapy groups. Triple therapy improved the prebronchodilator forced expiratory volume in 1 second (mean difference [MD], 63.68 mL; 95% credible interval [CrI], 45.29–82.73, and patients receiving triple therapy showed more improvement in St George Respiratory Questionnaire scores (MD, -3.11 points; 95% Cr

The pharmacological rationale for combining muscarinic receptor antagonists and beta-adrenoceptor agonists in the treatment of airway and bladder disease

NARCIS (Netherlands)

Dale, Philippa R.; Cernecka, Hana; Schmidt, Martina; Dowling, Mark R.; Charlton, Steven J.; Pieper, Michael P.; Michel, Martin C.

Muscarinic receptor antagonists and beta-adrenoceptor agonists are used in the treatment of obstructive airway disease and overactive bladder syndrome. Here we review the pharmacological rationale for their combination. Muscarinic receptors and beta-adrenoceptors are physiological antagonists for

Treatment of exercise-induced asthma, respiratory and allergic disorders in sports and the relationship to doping: Part II of the report from the Joint Task Force of European Respiratory Society (ERS) and European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA(2)LEN.

Science.gov (United States)

Carlsen, K H; Anderson, S D; Bjermer, L; Bonini, S; Brusasco, V; Canonica, W; Cummiskey, J; Delgado, L; Del Giacco, S R; Drobnic, F; Haahtela, T; Larsson, K; Palange, P; Popov, T; van Cauwenberge, P

2008-05-01

The aims of part II is to review the current recommended treatment of exercise-induced asthma (EIA), respiratory and allergic disorders in sports, to review the evidence on possible improvement of performance in sports by asthma drugs and to make recommendations for their treatment. The literature cited with respect to the treatment of exercise induced asthma in athletes (and in asthma patients) is mainly based upon the systematic review given by Larsson et al. (Larsson K, Carlsen KH, Bonini S. Anti-asthmatic drugs: treatment of athletes and exercise-induced bronchoconstriction. In: Carlsen KH, Delgado L, Del Giacco S, editors. Diagnosis, prevention and treatment of exercise-related asthma, respiratory and allergic disorders in sports. Sheffield, UK: European Respiratory Journals Ltd, 2005:73-88) during the work of the Task Force. To assess the evidence of the literature regarding use of beta(2)-agonists related to athletic performance, the Task Force searched Medline for relevant papers up to November 2006 using the present search words: asthma, bronchial responsiveness, exercise-induced bronchoconstriction, athletes, sports, performance and beta(2)-agonists. Evidence level and grades of recommendation were assessed according to Sign criteria. Treatment recommendations for EIA and bronchial hyper-responsiveness in athletes are set forth with special reference to controller and reliever medications. Evidence for lack of improvement of exercise performance by inhaled beta(2)-agonists in healthy athletes serves as a basis for permitting their use. There is a lack of evidence of treatment effects of asthma drugs on EIA and bronchial hyper-responsiveness in athletes whereas extensive documentation exists in treatment of EIA in patients with asthma. The documentation on lack of improvement on performance by common asthma drugs as inhaled beta(2)-agonists with relationship to sports in healthy individuals is of high evidence, level (1+). Exercise induced asthma should be

An interspecies comparison of the biological effects of an inhaled, relatively insoluble beta emitter

International Nuclear Information System (INIS)

Griffith, W.C.; Lundgren, D.L.; Hahn, F.F.; Boecker, B.B.; McClellan, R.O.

1986-01-01

Mice, rats, Syrian hamsters, and beagle dogs were exposed by inhalation to graded levels of 144 Ce in relatively insoluble forms to demonstrate species similarities and differences regarding patterns of deposition, fate, dosimetry, and dose-response relationships. All animals were serially evaluated to determine lung burdens, held for life-span observation, necropsied at death, and examined histopathologically to characterize the lesions present and to determine the cause of death. The primary malignant lung tumors observed in rodents were predominantly squamous-cell carcinomas and adenocarcinomas, whereas those in dogs at earlier times were primarily hemangiosarcomas and those in dogs that died at later times were pulmonary carcinomas. The relationship between the incidence of lung cancer and absorbed beta dose to the lung differed among species. The results of modeling these data provide a better understanding of how the choice of species can influence the outcome of a life-span study. The data are used to estimate the risk of lung cancer in man from an inhaled beta-emitting radionuclide. 26 refs., 5 figs., 6 tabs

Asthma and Adherence to Inhaled Corticosteroids

DEFF Research Database (Denmark)

Bårnes, Camilla Boslev; Ulrik, Charlotte Suppli

2015-01-01

Inhaled corticosteroids (ICS) are the cornerstone of maintenance asthma therapy. However, in spite of this, adherence to ICS remains low. The aim of this systematic literature review was to provide an overview of the current knowledge of adherence to ICS, effects of poor adherence, and means...... was found to be between 22 and 63%, with improvement up to and after an exacerbation. Poor adherence was associated with youth, being African-American, having mild asthma, ... prescribed fixed-combination therapy (ICS and long-acting β2 agonists). Good adherence was associated with higher FEV1, a lower percentage of eosinophils in sputum, reduction in hospitalizations, less use of oral corticosteroids, and lower mortality rate. Overall, 24% of exacerbations and 60% of asthma...

Once-daily long-acting beta-agonists for chronic obstructive pulmonary disease: an indirect comparison of olodaterol and indacaterol

Directory of Open Access Journals (Sweden)

Roskell NS

2014-07-01

Full Text Available Neil S Roskell,1 Antonio Anzueto,2 Alan Hamilton,3 Bernd Disse,4 Karin Becker5 1Statistics, Bresmed Health Solutions Ltd, Sheffield, UK; 2School of Medicine, University of Texas Health Science Center, San Antonio, TX, USA; 3Medical Department, Boehringer Ingelheim (Canada Ltd, Burlington, ON, Canada; 4Medical Department, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany; 5Global Health Economics and Outcomes Research, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany Purpose: In the absence of head-to-head clinical trials comparing the once-daily, long-acting beta2-agonists olodaterol and indacaterol for the treatment of chronic obstructive pulmonary disease (COPD, an indirect treatment comparison by systematic review and synthesis of the available clinical evidence was conducted. Methods: A systematic literature review of randomized, controlled clinical trials in patients with COPD was performed to evaluate the efficacy and safety of olodaterol and indacaterol. Network meta-analysis and adjusted indirect comparison methods were employed to evaluate treatment efficacy, using outcomes based on trough forced expiratory volume in 1 second (FEV1, Transition Dyspnea Index, St George’s Respiratory Questionnaire total score and response, rescue medication use, and proportion of patients with exacerbations. Results: Eighteen trials were identified for meta-analysis (eight, olodaterol; ten, indacaterol. Olodaterol trials included patients of all severities, whilst indacaterol trials excluded patients with very severe COPD. Concomitant maintenance bronchodilator use was allowed in most olodaterol trials, but not in indacaterol trials. When similarly designed trials/data were analyzed for change from baseline in trough FEV1 (liters, the following mean differences (95% confidence interval were observed: trials excluding concomitant bronchodilator: indacaterol 75 mcg versus olodaterol 5 mcg, –0.005 (–0.077 to 0.067, and indacaterol 150 mcg

Assessing the association between omalizumab and arteriothrombotic events through spontaneous adverse event reporting

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Ali AK

2012-05-01

Full Text Available Ayad K Ali, Abraham G HartzemaDepartment of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USABackground: Omalizumab is a monoclonal antibody, indicated for the treatment of severe allergic asthma. In Europe, there have been concerns about the cardiovascular safety of omalizumab. The objective of this study was to analyze the association between omalizumab and arterial thrombotic events in a spontaneous adverse drug reaction reporting database in the US.Methods and materials: Reports of arterial thrombotic events submitted to the US Food and Drug Administration's Adverse Event Reporting System (AERS between 2004 and 2011 were retrieved and analyzed by the reporting odds ratio data mining algorithm. The reporting odds ratio of arterial thrombotic events for omalizumab was compared with specific asthma medications and all drugs in the AERS. Values ≥2 were considered significant safety signals. The Medical Dictionary for Regulatory Activities Preferred Terms were used to identify arterial thrombotic events (eg, stroke, myocardial infarction.Results: In total, 293,783 reports of arterial thrombotic events were retrieved (about 2% of all adverse drug reaction reports, corresponding to 2274 asthma drug-arterial thrombotic events pairs (omalizumab, 222; inhaled corticosteroids [ICS], 131; long-acting beta-agonists [LABA], 102; single-device combination ICS-LABA, 506; inhaled short-acting beta-agonists [SABA], 475; oral SABA, 6; inhaled antimuscarinics [AMC], 477; single-device combination AMC-SABA, 127; xanthines, 50; leukotriene modifiers, 174; and mast cell stabilizers, 4. Reporting odds ratio and 95% confidence interval values for omalizumab compared with other asthma drugs and all drugs in AERS were 2.75 (2.39–316 and 1.09 (0.95–1.24, respectively. Omalizumab ranked second after ICS in the risk of arterial thrombotic events, followed by AMC, AMC-SABA, and ICS-LABA.Conclusion: Omalizumab is

The effect of various opiate receptor agonists on the seizure threshold in the rat. Is dynorphin an endogenous anticonvulsant?

Science.gov (United States)

Przewłocka, B; Stala, L; Lasoń, W; Przewłocki, R

1983-01-01

The effects of various opiate receptor agonists on the seizure threshold after an intravenous infusion of pentylenetetrazol were investigated in rats. The mu- and epsilon-receptor agonists, morphine (20-40 micrograms) and beta-endorphin (5-10 micrograms) show proconvulsant properties towards clonic and tonic seizures. The delta-receptor agonist (D-Ala2,D-Leu5-enkephalin, DADL 5-40 micrograms) and alpha-neoendorphin (20-40 micrograms) show pro- and anticonvulsant properties towards clonic and tonic seizures, respectively. Anticonvulsant properties of DADL are possibly due to its action on the spinal cord, since after the intrathecal injection this effect is still observed. Similarities between DADL and alpha-neoendorphin suggest that they may act through the same receptor. The kappa-receptor agonist dynorphin A (5-20 micrograms) and its degradation-resistant analogue D-Arg-dynorphin1-13 (10 micrograms) show significant anticonvulsant properties. Our present results suggest that the kappa-receptor agonist dynorphin may act physiologically as an endogenous anticonvulsant, in contrast to other opioid peptides.

ICI 182,780 has agonistic effects and synergizes with estradiol-17 beta in fish liver, but not in testis

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Power Deborah M

2006-12-01

Full Text Available Abstract Background ICI 182,780 (ICI belongs to a new class of antiestrogens developed to be pure estrogen antagonists and, in addition to its therapeutic use, it has been used to knock-out estrogen and estrogen receptor (ER actions in several mammalian species. In the present study, the effects and mechanism of action of ICI were investigated in the teleost fish, sea bream (Sparus auratus. Methods Three independent in vivo experiments were performed in which mature male tilapia (Oreochromis mossambicus or sea bream received intra-peritoneal implants containing estradiol-17 beta (E2, ICI or a combination of both compounds. The effects of E2 and ICI on plasma calcium levels were measured and hepatic and testicular gene expression of the three ER subtypes, ER alpha, ER beta a and ER beta b, and the estrogen-responsive genes, vitellogenin II and choriogenin L, were analyzed by semi-quantitative RT-PCR in sea bream. Results E2 treatment caused an increase in calcium levels in tilapia, while ICI alone had no noticeable effect, as expected. However, pretreatment with ICI synergistically potentiated the effect of E2 on plasma calcium in both species. ICI mimicked some E2 actions in gene expression in sea bream liver upregulating ER alpha, vitellogenin II and choriogenin L, although, unlike E2, it did not downregulate ER beta a and ER beta b. In contrast, no effects of E2 or ICI alone were detected in the expression of ERs in testis, while vitellogenin II and choriogenin L were upregulated by E2 but not ICI. Finally, pretreatment with ICI had a synergistic effect on the hepatic E2 down-regulation of ER beta b, but apparently blocked the ER alpha up-regulation by E2. Conclusion These results demonstrate that ICI has agonistic effects on several typical estrogenic responses in fish, but its actions are tissue-specific. The mechanisms for the ICI agonistic activity are still unknown; although the ICI induced up-regulation of ER alpha mRNA could be one of

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

DEFF Research Database (Denmark)

Maspero, Jorge; Guerra, Frances; Cuevas, Francisco

2008-01-01

BACKGROUND: Asthma control remains suboptimal in adults and children worldwide. Inhaled salmeterol/fluticasone propionate combination (SFC) and oral montelukast (MON) are 2 treatments available for childhood asthma. OBJECTIVE: This study, the PEdiatric Asthma Control Evaluation (PEACE......), investigated the efficacy and tolerability of SFC compared with MON for the control of persistent asthma in children. METHODS: Children with asthma (forced expiratory volume in 1 second [FEV(1)] 55%-80% predicted; reversibility >or=12%) aged 6 to 14 years who were receiving only short-acting beta(2)-agonists...... in morning peak expiratory flow (PEF). Efficacy assessments included lung function, asthma symptoms, rescue medication use, and asthma control. Tolerability was assessed by recording the number and type of adverse events (AEs) and the number of asthma exacerbations. RESULTS: Of 607 patients screened, 548...

The costo-uterine muscle of the rat contains a homogeneous population of beta-adrenoceptors.

Science.gov (United States)

Hartley, M. L.; Pennefather, J. N.

1985-01-01

The effects of two selective beta-adrenoceptor antagonists on the inhibitory responses to some sympathomimetic amines of electrically-stimulated preparations of costo-uterine muscle, taken from virgin rats, have been examined quantitatively. pA2 values for the antagonist, atenolol (beta 1-selective) and ICI 118,551 (beta 2-selective) were obtained using as agonists, fenoterol (beta 2-selective agonist) and noradrenaline (alpha- and beta-adrenoceptor agonist, beta 1-selective); and in addition, with ICI 118,551 only, isoprenaline (beta-agonist, non-selective) and adrenaline (alpha- and beta-adrenoceptor agonist, beta 2-selective). Catecholamine uptake mechanisms and alpha-adrenoceptors were not blocked in any of these experiments. Atenolol competitively antagonized the effects of fenoterol and noradrenaline to a similar extent, the pA2 values being 5.4 and 5.7, respectively. ICI 118,551 competitively antagonized the effects of fenoterol, isoprenaline, adrenaline and noradrenaline to a similar extent; pA2 values ranged from 8.7 with noradrenaline to 9.1 with isoprenaline. These results extend our previous observations which indicated that the adrenoceptors mediating inhibition of electrically-evoked contractions of costo-uterine muscle of the virgin rat are homogeneous and of the beta 2-subtype. The potency of the beta 1-selective agonist RO 363 in producing inhibition of electrically-evoked contractions of this tissue was also examined. RO 363 was 200 times less potent than isoprenaline but was a full agonist. This indicates that there is efficient coupling between beta 2-adrenoceptor activation and tissue response in this non-innervated preparation. PMID:2858239

Beta 2-adrenergic receptors on eosinophils. Binding and functional studies

International Nuclear Information System (INIS)

Yukawa, T.; Ukena, D.; Kroegel, C.; Chanez, P.; Dent, G.; Chung, K.F.; Barnes, P.J.

1990-01-01

We have studied the binding characteristics and functional effects of beta-adrenoceptors on human and guinea pig eosinophils. We determined the binding of the beta-antagonist radioligand [125I]pindolol (IPIN) to intact eosinophils obtained from the peritoneal cavity of guinea pigs and from blood of patients with eosinophilia. Specific binding was saturable, and Scatchard analysis showed a single binding site with a dissociation constant (Kd) of 24.6 pM and maximal number of binding sites (Bmax) of 7,166 per cell. ICI 118,551, a beta 2-selective antagonist, inhibited IPIN binding with a Ki value of 0.28 nM and was approximately 5,000-fold more effective than the beta 1-selective antagonist, atenolol. Isoproterenol increased cAMP levels about 5.5-fold above basal levels (EC50 = 25 microM); albuterol, a beta 2-agonist, behaved as a partial agonist with a maximal stimulation of 80%. Binding to human eosinophils gave similar results with a Kd of 25.3 pM and a Bmax corresponding to 4,333 sites per cell. Incubation of both human and guinea pig eosinophils with opsonized zymosan (2 mg/ml) or with phorbol myristate acetate (PMA) (10(-8) and 10(-6) M) resulted in superoxide anion generation and the release of eosinophil peroxidase; albuterol (10(-7) to 10(-5) M) had no inhibitory effect on the release of these products. Thus, eosinophils from patients with eosinophilia and from the peritoneal cavity of guinea pigs possess beta-receptors of the beta 2-subtype that are coupled to adenylate cyclase; however, these receptors do not modulate oxidative metabolism or degranulation. The possible therapeutic consequences of these observations to asthma are discussed

Effectiveness and safety of concurrent beta-blockers and inhaled bronchodilators in COPD with cardiovascular comorbidities

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Salvatore Corrao

2017-09-01

Full Text Available Chronic obstructive pulmonary disease (COPD is the most common chronic respiratory disease and its prevalence is increasing worldwide, in both industrialised and developing countries. Its prevalence is ∼5% in the general population and it is the fourth leading cause of death worldwide. COPD is strongly associated with cardiovascular diseases; in fact, ∼64% of people suffering from COPD are treated for a concomitant cardiovascular disease and approximately one in three COPD patients die as a consequence of cardiovascular diseases. Inhaled bronchodilators might have adverse cardiovascular effects, including ischaemic events and arrhythmias, and beta-blockers might adversely influence the respiratory symptoms and the response to bronchodilators. For these reasons, it is important to know the safety profiles and the possible interactions between these two classes of drug, in order to prescribe them with greater awareness. In this article, we review the literature about the epidemiology of COPD, its association with cardiovascular diseases, and the safety of concurrent use of inhaled bronchodilators and beta-blockers, as a tool for improving the approach to complex therapies in clinical practice.

Influence of radiation-dose pattern from inhaled beta--gamma-emitting radionuclides on canine peripheral lymphocytes

International Nuclear Information System (INIS)

Jones, R.K.; Boecker, B.B.; Pickrell, J.A.; Hobbs, C.H.; McClellan, R.O.

1976-01-01

As part of studies assess the biological hazards associated with inhaled radionuclides, periodic hematologic evaluations were performed on beagle dogs given a single nose-only exposure to aerosols of beta--gamma-emitting isotopes. The physical form and specific radionuclides selected produced radiation-dose patterns representative of those which might be encountered in the event of human accidental exposures. Dogs received graded lung burdens of either 90 Y, 91 Y, 144 Ce, or 90 Sr, each in fused clay. Differences in the effective half-lives of these radionuclides resulted in a spectrum of cumulative radiation doses to lung delivered at a variety of dose rates. Since the form in which the radionuclides were inhaled was relatively insoluble, the lung and intrathoracic tissues represented the primary recipient of the dose. Regardless of the effective half-life of radionuclide retention, a dose-related depression of peripheral lymphocytes was observed at various times after inhalation exposure. The time at which maximum depression and subsequent recovery occurred, however, was most directly related to the effective half-life of the radionuclide. Of special interest was the persistence of lymphopenia through 2 1 / 2 years after exposure to 144 Ce and 90 Sr in fused clay where, other than tracheobronchial lymph nodes, the lymphoid tissue received very little radiation dose. The possible mechanisms responsible for lymphocyte depression from these various radiation-dose patterns are discussed

Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study

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Myrseth Sven-Erik

2006-06-01

Full Text Available Abstract Background This study examined the attitudes and actions of 3415 physician-recruited adults aged ≥ 16 years with asthma in eleven countries who were prescribed regular maintenance therapy with inhaled corticosteroids or inhaled corticosteroids plus long-acting β2-agonists. Methods Structured interviews were conducted to assess medication use, asthma control, and patients' ability to recognise and self-manage worsening asthma. Results Despite being prescribed regular maintenance therapy, 74% of patients used short-acting β2-agonists daily and 51% were classified by the Asthma Control Questionnaire as having uncontrolled asthma. Even patients with well-controlled asthma reported an average of 6 worsenings/year. The mean period from the onset to the peak symptoms of a worsening was 5.1 days. Although most patients recognised the early signs of worsenings, the most common response was to increase short-acting β2-agonist use; inhaled corticosteroids were increased to a lesser extent at the peak of a worsening. Conclusion Previous studies of this nature have also reported considerable patient morbidity, but in those studies approximately three-quarters of patients were not receiving regular maintenance therapy and not all had a physician-confirmed diagnosis of asthma. This study shows that patients with asthma receiving regular maintenance therapy still have high levels of inadequately controlled asthma. The study also shows that patients recognise deteriorating asthma control and adjust their medication during episodes of worsening. However, they often adjust treatment in an inappropriate manner, which represents a window of missed opportunity.

Beta-adrenoceptor-agonist and insulin actions on glucose metabolism in rat skeletal muscle in different thyroid states.

OpenAIRE

Dimitriadis, G D; Richards, S J; Parry-Billings, M; Leighton, B; Newsholme, E A; Challiss, R A

1991-01-01

1. The actions of the beta-adrenoceptor agonist isoprenaline on glucose and glycogen metabolism, in the presence of various concentrations of insulin, were investigated in isolated soleus muscle preparations taken from eu-, hyper- and hypothyroid rats. 2. Hyperthyroidism, induced by 3,3',5-tri-iodo-D-thyronine (T3) administration for 5 days, increased the rate of lactate formation and suppressed the rate of glycogen synthesis in soleus muscle in response to isoprenaline, even in the presence ...

Chronic β2 -adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men

DEFF Research Database (Denmark)

Hostrup, Morten; Onslev, Johan; Jacobson, Glenn

2018-01-01

Although the effects of training have been studied for decades, data on muscle proteome signature remodelling induced by high intensity training in relation to functional changes in humans remains incomplete. Likewise, β2 -agonists are frequently used to counteract exercise......-induced bronchoconstriction, but the effects β2 -agonist treatment on muscle remodelling and adaptations to training are unknown. In a placebo-controlled parallel study, we randomized 21 trained men to four weeks of high intensity training with (HIT + β2 A) or without (HIT) daily inhalation of β2 -agonist (terbutaline, 4 mg...... (P ≤ 0.01) and exercise performance (11.6 vs. 6.1%, P ≤ 0.05) in HIT + β2 A compared to HIT. These findings indicate that daily β2 -agonist treatment attenuates the beneficial effects of high intensity training on exercise performance and oxidative capacity, and causes remodelling of muscle proteome...

Lixisenatide for the treatment of type 2 diabetes

DEFF Research Database (Denmark)

Petersen, A B; Knop, F K; Christensen, M

2013-01-01

Lixisenatide (trade name Lyxumia®), a short-acting glucagon-like peptide 1 receptor (GLP-1R) agonist, was approved for the treatment of type 2 diabetes by the European Medicines Agency in early 2013. In preclinical investigations, acceptable toxicity and carcinogenicity profiles were demonstrated...... in patients with type 2 diabetes, treatment with lixisenatide alone and in combination with insulin and various oral antidiabetics conferred significant reductions in HbA1c, fasting and postprandial plasma glucose. In direct comparison with the other GLP-1R agonists on the market (exenatide and liraglutide......, as well as pancreatic beta cell-preserving actions and favorable effects on glycemic control. Following subcutaneous administration in humans, lixisenatide displays linear pharmacokinetics and an absorption-dependent elimination half-life of 2-3 hours. In clinical trials of up to 1 year duration...

The Cytomegalovirus UL146 Gene Product vCXCL1 Targets Both CXCR1 and CXCR2 as an Agonist

DEFF Research Database (Denmark)

Luttichau, H.R.

2010-01-01

Large DNA viruses, such as herpesvirus and poxvirus, encode proteins that target and exploit the chemokine system of their host. UL146 and UL147 in the cytomegalovirus (CMV) genome encode the two CXC chemokines vCXCL1 and vCXCL2. In this study, vCXCL1 was probed against a panel of the 18 classified...... human chemokine receptors. In calcium mobilization assays vCXCL1 acted as an agonist on both CXCR1 and CXCR2 but did not activate or block any of the other 16 chemokine receptors. vCXCL1 was characterized and compared with CXCL1/GRO alpha, CXCL2/GRO beta, CXCL3/GRO gamma, CXCL5/ENA-78, CXCL6/GCP2, CXCL7...

Effect of inhaled terbutaline on substrate utilization and 300-kcal time trial performance

DEFF Research Database (Denmark)

Kalsen, Anders; Hostrup, Morten; Karlsson, Sebastian

2014-01-01

. There was no difference between PLA and TER in net muscle glycogen utilization and lactate accumulation during the time trial. IMTG did not change with treatment or exercise. PDH-E1α Ser(293) and Ser(300) phosphorylation were lower (P...In a randomized double-blind crossover design, we investigated the effect of the beta2-agonist terbutaline on endurance performance and substrate utilization in nine moderately trained males (maximum oxygen uptake (VO2max): 58.9±3.1 mL min(-1) kg(-1)). Subjects performed 60 min of submaximal...... exercise (65-70% of VO2max) immediately followed by a 300-kcal time trial with inhalation of either terbutaline (TER) or placebo (PLA). Pulmonary gas exchange was measured during the submaximal exercise and muscle biopsies were collected before and after the exercise bouts. Time trial performance...

The effects of beta 2-agonists and methylxanthines on neutrophil function in vitro.

Science.gov (United States)

Llewellyn-Jones, C G; Stockley, R A

1994-08-01

Therapeutic agents which affect polymorphonuclear neutrophil (PMN) functions have the potential to reduce or increase PMN activation and, hence, influence the progression of lung inflammation. We have assessed the effects of the beta 2-agonist, terbutaline, and the methylxanthine, aminophylline, on PMN functions in vitro at both therapeutic and higher concentrations. At therapeutic levels, both agents increased PMN chemotaxis to formyl-methionyl-leucyl-phenylalanine (FMLP) in a dose-dependent manner from a control value of 22.5 +/- 3.58 cells.field-1 to 26.1 +/- 4.73 cells.field-1 with 4 mg.l-1 terbutaline, and to 26.3 +/- 4.49 cells.field-1 with 20 mg.l-1 aminophylline. When the cells were preincubated with higher doses of the agents in separate experiments there was inhibition of chemotaxis from a control value of 31.1 +/- 2.06 cells.field-1 to 18.3 +/- 0.82 cells.field-1 at 160 mg.l-1 terbutaline, and to 16.1 +/- 0.77 cells.field-1 at 400 mg.l-1 aminophylline. A similar effect was seen when the PMNs were preincubated with terbutaline and aminophylline prior to assessment of superoxide anion generation, with stimulation of superoxide release at therapeutic levels of the drugs and inhibition at higher doses (19% increase from resting control cells at terbutaline 4 mg.l-1 and 53% reduction at 160 mg.l-1; 28% increase with aminophylline 20 mg.l-1 and 22% reduction at 400 mg.l-1). Both terbutaline and aminophylline had no effect on PMN degranulation, as assessed by the degradation of fibronectin.(ABSTRACT TRUNCATED AT 250 WORDS)

Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

Science.gov (United States)

Young, R. B.; Bridge, K. Y.

2003-01-01

Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate CAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of CAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of CAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

Chronic β2 -adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men.

Science.gov (United States)

Hostrup, Morten; Onslev, Johan; Jacobson, Glenn A; Wilson, Richard; Bangsbo, Jens

2018-01-15

While several studies have investigated the effects of exercise training in human skeletal muscle and the chronic effect of β 2 -agonist treatment in rodent muscle, their effects on muscle proteome signature with related functional measures in humans are still incompletely understood. Herein we show that daily β 2 -agonist treatment attenuates training-induced enhancements in exercise performance and maximal oxygen consumption, and alters muscle proteome signature and phenotype in trained young men. Daily β 2 -agonist treatment abolished several of the training-induced enhancements in muscle oxidative capacity and caused a repression of muscle metabolic pathways; furthermore, β 2 -agonist treatment induced a slow-to-fast twitch muscle phenotype transition. The present study indicates that chronic β 2 -agonist treatment confounds the positive effect of high intensity training on exercise performance and oxidative capacity, which is of interest for the large proportion of persons using inhaled β 2 -agonists on a daily basis, including athletes. Although the effects of training have been studied for decades, data on muscle proteome signature remodelling induced by high intensity training in relation to functional changes in humans remains incomplete. Likewise, β 2 -agonists are frequently used to counteract exercise-induced bronchoconstriction, but the effects β 2 -agonist treatment on muscle remodelling and adaptations to training are unknown. In a placebo-controlled parallel study, we randomly assigned 21 trained men to 4 weeks of high intensity training with (HIT+β 2 A) or without (HIT) daily inhalation of β 2 -agonist (terbutaline, 4 mg dose -1 ). Of 486 proteins identified by mass-spectrometry proteomics of muscle biopsies sampled before and after the intervention, 32 and 85 were changing (false discovery rate (FDR) ≤5%) with the intervention in HIT and HIT+β 2 A, respectively. Proteome signature changes were different in HIT and HIT+β 2 A (P�

PARTIAL AGONISTS, FULL AGONISTS, ANTAGONISTS - DILEMMAS OF DEFINITION

NARCIS (Netherlands)

HOYER, D; BODDEKE, HWGM

The absence of selective antagonists makes receptor characterization difficult, and largely dependent on the use of agonists. However, there has been considerable debate as to whether certain drugs acting at G protein-coupled receptors are better described as agonists, partial agonists or

Budesonide/formoterol maintenance and reliever therapy versus conventional best practice

DEFF Research Database (Denmark)

Demoly, Pascal; Louis, Renaud; Søes-Petersen, Ulrik

2009-01-01

Budesonide/formoterol maintenance and reliever therapy (Symbicort SMART) reduces asthma exacerbations and symptoms versus fixed-dose regimens plus short-acting beta(2)-agonists (SABA) in double-blind trials. Information is lacking regarding its effectiveness versus conventional best practice (CBP...

Methacholine PC20 In African Americans And Whites With Asthma With Homozygous Genotypes at ADRB2 Codon 16

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Blake, Kathryn; Cury, James D.; Hossain, Jobayer; Tantisira, Kelan; Wang, Jianwei; Mougey, Edward; Lima, John

2013-01-01

BACKGROUND African Americans have worse asthma outcomes compared to whites. Adrenoceptor beta 2, surface gene (ADRB2) Gly16Arg genotypes have been associated with β2-agonist bronchodilator response, asthma exacerbation rate, response to methacholine, and lung function decline but not specifically in African Americans. OBJECTIVE We sought to compare the provocative concentration of methacholine that causes a 20% fall in FEV1 (PC20) in African Americans and whites with asthma who were ADRB2 homozygous at codon16 (Arg16Arg or Gly16Gly). METHODS African Americans and whites whose parents and grandparents were of the same race, aged ≥ 10 years, with baseline FEV1 of ≥60% predicted, and no upper or lower respiratory tract infection within the previous 2 weeks meeting genotype criteria were enrolled. PC20 was measured after withholding short-acting and long-acting β2-agonists for 8 and 12 hours respectively, montelukast for 24 hours, ipratropium bromide and inhaled corticosteroids for 12 hours, and antihistamines for 72 hours. RESULTS 423 participants were screened and 88 had a positive challenge. Participants were 32yrs ± 19yrs (mean ± SD), 70% female, 51% White (vs. African American), 6% Hispanic. Similar numbers of participants were using inhaled corticosteroids by race and genotype. There were significant differences in log PC20 between race/genotype groups (p=0.012). African American Arg16Arg participants had a lower log PC20 than White Gly16Gly (p=0.009) and African American Gly16Gly (p=0.041) participants. Both race and genotype contributed significantly to the model (p=0.037 and p=0.014, respectively) but there was no interaction between race and genotype on log PC20. CONCLUSIONS AND CLINICAL RELEVANCE Airway hyperresponsiveness is influenced by race and the ADRB2 codon 16 polymorphism. African Americans with the Arg16Arg genotype have increased airway reactivity and may be at risk for worse asthma outcomes. Inclusion of genetic information as an

Magnetic moment of short lived {beta}-emitter {sup 24m}Al

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Nishimura, D., E-mail: daiki@vg.phys.sci.osaka-u.ac.jp; Komurasaki, J.; Matsuta, K.; Mihara, M.; Matsumiya, R. [Osaka University, Department of Physics (Japan); Momota, S. [Kochi University of Technology (Japan); Ohtsubo, T. [Niigata University, Department of Physics (Japan); Izumikawa, T. [Niigata University, RI Center (Japan); Hirano, H. [Niigata University, Department of Physics (Japan); Kitagawa, A.; Kanazawa, M.; Torikoshi, M.; Sato, S. [National Institute of Radiological Sciences (Japan); Fukuda, M.; Ishikawa, D. [Osaka University, Department of Physics (Japan); Minamisono, T. [Fukui University of Technology (Japan); Watanabe, R.; Kubo, T. [Niigata University, Department of Physics (Japan); Nojiri, Y. [Kochi University of Technology (Japan); Alonso, J. R. [Lawrence Berkeley Laboratory (United States)

2007-11-15

The magnetic moment of short lived {beta}-emitter {sup 24m}Al (426 keV, I{sup {pi}} = 1{sup +}, T{sub 1/2} = 131 ms) has been measured by means of {beta}-NMR technique, for the first time. From the {beta}-NMR spectrum, the magnetic moment was determined as |{mu}({sup 24m}Al)|=(2.99{+-}0.09){mu}{sub N}. Combined with the known magnetic moment of the mirror partner {sup 24m}Na, the expectation value of < S{sub z} > is obtained to be (0.08 {+-} 0.12). These values are reproduced well by the shell model calculation.

Respiratory medication used in COPD patients from seven Latin American countries: the LASSYC study.

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Casas, Alejandro; Montes de Oca, Maria; Menezes, Ana Mb; Wehrmeister, Fernando C; Lopez Varela, Maria Victorina; Mendoza, Laura; Ramírez, Larissa; Miravitlles, Marc

2018-01-01

Limited information is available regarding medication use in COPD patients from Latin America. This study evaluated the type of medication used and the adherence to different inhaled treatments in stable COPD patients from the Latin American region. This was an observational, cross-sectional, multinational, and multicenter study in COPD patients attended by specialist doctors from seven Latin American countries. Adherence to inhaled therapy was assessed using the Test of Adherence to Inhalers (TAI) questionnaire. The type of medication was assessed as: short-acting β-agonist (SABA) or short-acting muscarinic antagonist (SAMA) only, long-acting muscarinic antagonist (LAMA), long-acting β-agonist (LABA), LABA/LAMA, inhaled corticosteroid (ICS), ICS/LABA, ICS/LAMA/LABA, or other. In total, 795 patients were included (59.6% male), with a mean age of 69.5±8.7 years and post-bronchodilator FEV 1 of 50.0%±18.6%. The ICS/LAMA/LABA (32.9%) and ICS/LABA (27.7%) combinations were the most common medications used, followed by LABA/LAMA (11.3%), SABA or SAMA (7.9%), LABA (6.4%), LAMA (5.8%), and ICS (4.3%). The types of medication most commonly used in each Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2013 category were ICS/LABA (A: 32.7%; B: 19.8%; C: 25.7%; D: 28.2%) and ICS/LAMA/LABA (A: 17.3%; B: 30.2%; C: 33%; D: 41.1%). The use of long-acting bronchodilators showed the highest adherence (good or high adherence >50%) according to the TAI questionnaire. COPD management in specialist practice in Latin America does not follow the current guideline recommendations and there is an overuse of ICSs in patients with COPD from this region. Treatment regimens including the use of long-acting bronchodilators are associated with the highest adherence.

Inhalation of Budesonide/Formoterol Increases Diaphragm Muscle Contractility

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Chiyohiko Shindoh

2012-01-01

Conclusions: BUD/FORM inhalation has an inotropic effect on diaphragm muscle, protects diaphragm muscle deterioration after endotoxin injection, and inhibits NO production. Increments in muscle contractility with BUD/FORM inhalation are induced through a synergistic effect of an anti-inflammatory agent and 02-agonist.

Swimming pool exposure is associated with autonomic changes and increased airway reactivity to a beta-2 agonist in school aged children: A cross-sectional survey

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Paciência, Inês; Silva, Diana; Martins, Carla; Madureira, Joana; de Oliveira Fernandes, Eduardo; Padrão, Patrícia; Moreira, Pedro; Delgado, Luís; Moreira, André

2018-01-01

Background Endurance swimming exercises coupled to disinfection by-products exposure has been associated with increased airways dysfunction and neurogenic inflammation in elite swimmers. However, the impact of swimming pool exposure at a recreational level on autonomic activity has never been explored. Therefore, this study aimed to investigate how swimming pool attendance is influencing lung and autonomic function in school-aged children. Methods A total of 858 children enrolled a cross sectional survey. Spirometry and airway reversibility to beta-2 agonist, skin-prick-tests and exhaled nitric oxide measurements were performed. Pupillometry was used to evaluate autonomic nervous function. Children were classified as current swimmers (CS), past swimmers (PS) and non-swimmers (NS), according to the amount of swimming practice. Results Current swimmers group had significantly lower maximum and average pupil constriction velocities when compared to both PS and NS groups (3.8 and 5.1 vs 3.9 and 5.3 vs 4.0 and 5.4 mm/s, p = 0.03 and p = 0.01, respectively). Moreover, affinity to the beta-2 agonist and levels of exhaled nitric oxide were significantly higher in CS when compared to NS (70 vs 60 mL and 12 vs 10 ppb, pswimming practice, particularly in atopic individuals (β = 1.12, 1.40 and 1.31, respectively). After case-case analysis, it was possible to observe that results were not influenced by the inclusion of individuals with asthma. Conclusions Concluding, swimming pool attendance appears to be associated with autonomic changes and increased baseline airway smooth muscle constriction even in children without asthma. PMID:29529048

Budesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol

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Lombardi DM

2006-01-01

Full Text Available Abstract Background To compare the efficacy and safety of budesonide/formoterol (Symbicort® with formoterol (Oxis® in the treatment of patients with acute asthma who showed evidence of refractoriness to short-acting β2-agonist therapy. Methods In a 3 hour, randomized, double-blind study, a total of 115 patients with acute asthma (mean FEV1 40% of predicted normal and a refractory response to salbutamol (mean reversibility 2% of predicted normal after inhalation of 400 μg, were randomized to receive either budesonide/formoterol (320/9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 1280/36 μg] or formoterol (9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 36 μg]. The primary efficacy variable was the average FEV1 from the first intake of study medication to the measurement at 90 minutes. Secondary endpoints included changes in FEV1 at other timepoints and change in respiratory rate at 180 minutes. Treatment success, treatment failure and patient assessment of the effectiveness of the study medication were also measured. Results FEV1 increased after administration of the study medication in both treatment groups. No statistically significant difference between the treatment groups was apparent for the primary outcome variable, or for any of the other efficacy endpoints. There were no statistically significant between-group differences for treatment success, treatment failure or patient assessment of medication effectiveness. Both treatments were well tolerated. Conclusion Budesonide/formoterol and formoterol provided similarly rapid relief of acute bronchoconstriction in patients with asthma who showed evidence of refractoriness to a short-acting β2-agonist.

Cytokine-induced loss of glucocorticoid function: effect of kinase inhibitors, long-acting β(2-adrenoceptor [corrected] agonist and glucocorticoid receptor ligands.

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Christopher F Rider

Full Text Available Acting on the glucocorticoid receptor (NR3C1, glucocorticoids are widely used to treat inflammatory diseases. However, glucocorticoid resistance often leads to suboptimal asthma control. Since glucocorticoid-induced gene expression contributes to glucocorticoid activity, the aim of this study was to use a 2 × glucocorticoid response element (GRE reporter and glucocorticoid-induced gene expression to investigate approaches to combat cytokine-induced glucocorticoid resistance. Pre-treatment with tumor necrosis factor-α (TNF or interleukin-1β inhibited dexamethasone-induced mRNA expression of the putative anti-inflammatory genes RGS2 and TSC22D3, or just TSC22D3, in primary human airway epithelial and smooth muscle cells, respectively. Dexamethasone-induced DUSP1 mRNA was unaffected. In human bronchial epithelial BEAS-2B cells, dexamethasone-induced TSC22D3 and CDKN1C expression (at 6 h was reduced by TNF pre-treatment, whereas DUSP1 and RGS2 mRNAs were unaffected. TNF pre-treatment also reduced dexamethasone-dependent 2×GRE reporter activation. This was partially reversed by PS-1145 and c-jun N-terminal kinase (JNK inhibitor VIII, inhibitors of IKK2 and JNK, respectively. However, neither inhibitor affected TNF-dependent loss of dexamethasone-induced CDKN1C or TSC22D3 mRNA. Similarly, inhibitors of the extracellular signal-regulated kinase, p38, phosphoinositide 3-kinase or protein kinase C pathways failed to attenuate TNF-dependent repression of the 2×GRE reporter. Fluticasone furoate, fluticasone propionate and budesonide were full agonists relative to dexamethasone, while GSK9027, RU24858, des-ciclesonide and GW870086X were partial agonists on the 2×GRE reporter. TNF reduced reporter activity in proportion with agonist efficacy. Full and partial agonists showed various degrees of agonism on RGS2 and TSC22D3 expression, but were equally effective at inducing CDKN1C and DUSP1, and did not affect the repression of CDKN1C or TSC22D3

Preclinical evaluation of SMM-189, a cannabinoid receptor 2-specific inverse agonist.

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Presley, Chaela; Abidi, Ammaar; Suryawanshi, Satyendra; Mustafa, Suni; Meibohm, Bernd; Moore, Bob M

2015-08-01

Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune-related disease. Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury. We have previously reported the receptor affinity of 3',5'-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone (SMM-189) and the characterization of the beneficial effects of SMM-189 in the mouse model of mild traumatic brain injury. Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury.

Beta-2 receptor agonist exposure in the uterus associated with subsequent risk of childhood asthma.

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Ogawa, Kohei; Tanaka, Satomi; Limin, Yang; Arata, Naoko; Sago, Haruhiko; Yamamoto-Hanada, Kiwako; Narita, Masami; Ohya, Yukihiro

2017-12-01

Although the beta-2 receptor agonist (B2RA) is occasionally prescribed in the prenatal period for women with preterm labor, few studies have referred to the long-term effects of intrauterine exposure to B2RA on fetus. We examined the association between intrauterine exposure to B2RA and asthma in the offspring. We obtained data from a hospital-based birth cohort study conducted in Tokyo, Japan. The outcomes of interest were three indicators, consisting of current wheeze, current asthma, and ever asthma at 5 years of age, based on the International Study of Asthma and Allergies in Childhood questionnaire. Logistic regression analysis was used to evaluate the association between intrauterine B2RA exposure and outcomes. To evaluate dose-dependent risk, we categorized children into three groups according to both the cumulative dose and duration (days) and conducted trend analysis. Of 1158 children, 94 (8.1%) were exposed to B2RA in utero, and 191 (16.5%), 111 (9.6%), and 168 (14.5%) children experienced current wheeze, current asthma, and ever asthma, respectively. After adjusting for confounders, we found an increased risk of current asthma caused by B2RA exposure with an adjusted odds ratio of 2.04 (95% confidence interval: 1.02-4.05). Trend analysis showed that B2RA exposure in utero was associated with a dose-dependent increased risk of current asthma in terms of both cumulative dose and duration (P values for trend were .015 and .017, respectively). These results were similar to those for other outcome measures. Exposure to B2RA in utero could be a risk for childhood asthma. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Management of chronic asthma in adults in diverse regions of the world.

Science.gov (United States)

Lalloo, U G; McIvor, R A

2006-05-01

Asthma is a chronic inflammatory disease of the lungs associated with significant morbidity and mortality worldwide. Adoption of current treatment guidelines that propose inhaled corticosteroids (ICS) as the foundation for asthma treatment should control most patients with chronic asthma. Rapid-acting inhaled beta (beta) 2-agonists are best reserved for acute symptom relief. Long-acting beta-2-agonists in combination with ICS are the most effective asthma treatment currently available when asthma is not controlled on low-dose ICS alone; however, they are not universally available due to cost. Slow-release theophylline may be an alternative cost-effective add-on therapy to ICS in resource-poor areas, although its potential for toxicity has limited its use over the last decade. New targeted anti-inflammatory therapies lack the broad anti-inflammatory activity of ICS and are unaffordable in most settings. Implementation of guidelines for asthma care is an unresolved challenge, and major gaps in asthma care are consistent across the globe. Review of asthma management worldwide shows that control of the disease in relation to the Global Initiative for Asthma (GINA) goals of asthma treatment is not achieved in a large proportion of patients, despite the widespread availability of guidelines and even with access to effective treatment in resource-rich settings. Many resource-poor countries have the additional challenge of lack of access to basic asthma treatment such as ICS. The challenge is to provide global access to core asthma medications, particularly ICS, at affordable prices, to improve implementation of treatment guidelines and to encourage better health care provider and patient education.

Inhaled Beta2-agonist increases power output and glycolysis during sprinting in men

DEFF Research Database (Denmark)

Kalsen, Anders; Hostrup, Morten; Söderlund, Karin

2016-01-01

. Moreover, net rate of glycogenolysis (6.5±0.8 vs. 3.1±0.7 mmol glucosyl units kg dw s) and glycolysis (2.4±0.2 vs. 1.6±0.2 mmol glucosyl units kg dw s) were higher (P... and glycolysis in skeletal muscles. Furthermore, as terbutaline counteracted a reduction in ATP in type II fibers, terbutaline may postpone fatigue development in these fibers....

Association of asthma therapy and Churg-Strauss syndrome: an analysis of postmarketing surveillance data.

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DuMouchel, William; Smith, Eric T; Beasley, Richard; Nelson, Harold; Yang, Xionghu; Fram, David; Almenoff, June S

2004-07-01

Churg-Strauss syndrome (CSS), also known as allergic granulomatous angiitis (AGA), is a rare vasculitis that occurs in patients with bronchial asthma. The nature of the association of CSS with various asthma therapies is unclear. This study investigated the associations of different multidrug asthma therapy regimens and the reporting of AGA (the preferred code for CSS in the coding dictionary for the Adverse Event Reporting System [AERS]) by applying an iterative method of disproportionally analysis to th AERS database maintained by the US Food and Drug Administration. The public-release version of the AERS database was used to identify reports of AGA in patients receiving asthma therapy. Reporting of AGA was examined using iterative disproportionality methods in patients receiving > or =1 of the following drug classes: inhaled corticosteroid (ICS), leukotriene receptor antagonist (LTRA), short-acting beta(2)-agonist (SABA), or long-acting beta(2)-agonist (LABA). The Bayesian data-mining algorithm known as the multi-item gamma poisson shrinker was used to determine the relative reporting rates by calculation of the empirical Bayes geometric mean (EBGM) and its 90% CI (EB05 = lower limit and EB95 = upper limit) for each drug. Subset analyses were performed for each drug with different medication combinations to differentiate the relative reporting of AGA for each. A strong association was found between LTRA use and AGA (EBGM = 104.0, EB05 = 95.0, EB95 = 113.8) that persisted with all combinations of therapy studied. AGA was also associated with the ICS, SABA and LABA classes (EBGM values of 27.8, 14.6 and 40.4, respectively). However, the latter associations were mostly dependent on the presence of concurrent LTRA and, to a lesser extemt, oral corticosteroid therapy and became negligible (ie, EB05 < 2) for patients who were not receiving these concurrent treatments. Differences based on relative reporting were observed in the patterns of association of AGA with LTRA

Distinct Signaling Cascades Elicited by Different Formyl Peptide Receptor 2 (FPR2 Agonists

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Fabio Cattaneo

2013-04-01

Full Text Available The formyl peptide receptor 2 (FPR2 is a remarkably versatile transmembrane protein belonging to the G-protein coupled receptor (GPCR family. FPR2 is activated by an array of ligands, which include structurally unrelated lipids and peptide/proteins agonists, resulting in different intracellular responses in a ligand-specific fashion. In addition to the anti-inflammatory lipid, lipoxin A4, several other endogenous agonists also bind FPR2, including serum amyloid A, glucocorticoid-induced annexin 1, urokinase and its receptor, suggesting that the activation of FPR2 may result in potent pro- or anti-inflammatory responses. Other endogenous ligands, also present in biological samples, include resolvins, amyloidogenic proteins, such as beta amyloid (Aβ-42 and prion protein (Prp106–126, the neuroprotective peptide, humanin, antibacterial peptides, annexin 1-derived peptides, chemokine variants, the neuropeptides, vasoactive intestinal peptide (VIP and pituitary adenylate cyclase activating polypeptide (PACAP-27, and mitochondrial peptides. Upon activation, intracellular domains of FPR2 mediate signaling to G-proteins, which trigger several agonist-dependent signal transduction pathways, including activation of phospholipase C (PLC, protein kinase C (PKC isoforms, the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt pathway, the mitogen-activated protein kinase (MAPK pathway, p38MAPK, as well as the phosphorylation of cytosolic tyrosine kinases, tyrosine kinase receptor transactivation, phosphorylation and nuclear translocation of regulatory transcriptional factors, release of calcium and production of oxidants. FPR2 is an attractive therapeutic target, because of its involvement in a range of normal physiological processes and pathological diseases. Here, we review and discuss the most significant findings on the intracellular pathways and on the cross-communication between FPR2 and tyrosine kinase receptors triggered by different FPR2

Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors

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Rohde, Line Aagot Hede; Ahring, Philip Kiær; Jensen, Marianne Lerbech

2012-01-01

The a4ß2 subtype of the nicotinic acetylcholine receptor (nAChR) has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Still, a thorough understanding of structure-function relationships of a4ß2 agonists is lacking...

A novel natural Nrf2 activator with PPARγ-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia

Energy Technology Data Exchange (ETDEWEB)

Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying [Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan (China); Hsu, Ya-Wen [SunWay Biotechnology Company, Taipei, Taiwan (China); Pan, Tzu-Ming, E-mail: tmpan@ntu.edu.tw [Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan (China)

2013-11-01

Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-γ (PPARγ) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPARγ agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able to elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to D-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPARγ-agonist activity were confirmed by Nrf2 and PPARγ reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. - Highlights: • Monascin acts as a PPARgamma agonist. • Monascin activates Nrf2 and AMPK. • Monascin promotes MG metabolism into D-lactic acid. • Monascin attenuates inflammation and diabetes in vivo.

Stridor Post-Pneumonectomy - “The Post-pneumonectomy Syndrome”

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Manoj Waghmare

2017-04-01

Full Text Available We report a case of a 33 year old lady who presented to our department with complaints of breathlessness and stridor. On enquiry she gave history of right pneumonectomy for right main bronchus carcinoid 15 years ago. Chest X-ray as initial investigation showed homogenous opacity in right hemothorax with mediastinal shift to right. Computed tomography of thorax showed post-pneumonectomy status with left lower lobe bronchus compression between the aorta and main pulmonary artery with post obstructive overinflation of left lower lobe. Spirometry was suggestive of an obstructive abnormality. Diagnosis of post-pneumonectomy syndrome was made and patient was treated with inhaled corticosteroids and inhaled long acting beta2 agonist.

Single-inhaler combination therapy for maintenance and relief of asthma: a new strategy in disease management.

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Peters, Matthew

2009-01-01

When an adequate standard of asthma control is not achieved with maintenance treatment of inhaled corticosteroids, the addition of a long-acting beta(2)-adrenergic receptor agonist (LABA) bronchodilator is recommended. Using a combination product, salmeterol/fluticasone propionate (Seretide or Advair) or budesonide/formoterol (Symbicort) is preferred for convenience and avoids any risk that LABA might be used as monotherapy. As formoterol has a rapid onset of bronchodilator effect, the budesonide/formoterol combination can be used for both the maintenance and reliever components of asthma treatment (Symbicort SMART) and this is endorsed as an effective treatment by the Global Initiative for Asthma. The efficacy of this approach has been evaluated in a series of well conducted, controlled studies. Current control of asthma symptoms is improved or achieved with reduced total dose administration with Symbicort SMART compared with any reasonable alternate option. In every study, the risk of severe exacerbations was lower with Symbicort SMART than comparator treatment. Patients who benefit to the greatest extent are those with evidence of more severe asthma and greater exacerbation risk. When initiated in suitable patients in conjunction with appropriate education, Symbicort SMART is dominant in pharmacoeconomic terms. Symbicort SMART delivers improved asthma outcomes with lower treatment and social costs than any alternative.

Estrogen receptor beta-selective agonists stimulate calcium oscillations in human and mouse embryonic stem cell-derived neurons.

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Lili Zhang

2010-07-01

Full Text Available Estrogens are used extensively to treat hot flashes in menopausal women. Some of the beneficial effects of estrogens in hormone therapy on the brain might be due to nongenomic effects in neurons such as the rapid stimulation of calcium oscillations. Most studies have examined the nongenomic effects of estrogen receptors (ER in primary neurons or brain slices from the rodent brain. However, these cells can not be maintained continuously in culture because neurons are post-mitotic. Neurons derived from embryonic stem cells could be a potential continuous, cell-based model to study nongenomic actions of estrogens in neurons if they are responsive to estrogens after differentiation. In this study ER-subtype specific estrogens were used to examine the role of ERalpha and ERbeta on calcium oscillations in neurons derived from human (hES and mouse embryonic stem cells. Unlike the undifferentiated hES cells the differentiated cells expressed neuronal markers, ERbeta, but not ERalpha. The non-selective ER agonist 17beta-estradiol (E(2 rapidly increased [Ca2+]i oscillations and synchronizations within a few minutes. No change in calcium oscillations was observed with the selective ERalpha agonist 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyltrisphenol (PPT. In contrast, the selective ERbeta agonists, 2,3-bis(4-Hydroxyphenyl-propionitrile (DPN, MF101, and 2-(3-fluoro-4-hydroxyphenyl-7-vinyl-1,3 benzoxazol-5-ol (ERB-041; WAY-202041 stimulated calcium oscillations similar to E(2. The ERbeta agonists also increased calcium oscillations and phosphorylated PKC, AKT and ERK1/2 in neurons derived from mouse ES cells, which was inhibited by nifedipine demonstrating that ERbeta activates L-type voltage gated calcium channels to regulate neuronal activity. Our results demonstrate that ERbeta signaling regulates nongenomic pathways in neurons derived from ES cells, and suggest that these cells might be useful to study the nongenomic mechanisms of estrogenic compounds.

The alpha7 nicotinic acetylcholine receptor-selective antagonist, methyllycaconitine, partially protects against beta-amyloid1-42 toxicity in primary neuron-enriched cultures.

Science.gov (United States)

Martin, Shelley E; de Fiebre, Nancy Ellen C; de Fiebre, Christopher M

2004-10-01

Studies have suggested that the neuroprotective actions of alpha7 nicotinic agonists arise from activation of receptors and not from the extensive desensitization which rapidly follows activation. Here, we report that the alpha7-selective nicotinic antagonist, methyllycaconitine (MLA), protects against beta-amyloid-induced neurotoxicity; whereas the alpha4beta2-selective antagonist, dihydro-beta-erythroidine, does not. These findings suggest that neuroprotective actions of alpha7-acting agents arise from receptor inhibition/desensitization and that alpha7 antagonists may be useful neuroprotective agents.

Beta₂-adrenergic stimulation increases energy expenditure at rest, but not during submaximal exercise in active overweight men

DEFF Research Database (Denmark)

Onslev, Johan; Jacobson, Glenn A; Narkowicz, Christian K

2017-01-01

was related to plasma ln-rac-formoterol concentrations (r = 0.75, P = 0.005). CONCLUSION: Selective β2-adrenoceptor agonism effectively increases metabolic rate and fat oxidation in overweight individuals. The potential for weight loss induced by β2-agonists may be greater for R-enantiopure formulations.......PURPOSE: β2-Agonists have been proposed as weight-loss treatment, because they elevate energy expenditure. However, it is unknown what effect β2-agonists have on energy expenditure in overweight individuals. Furthermore, the influence of β2-agonist R- and S-enantiomer ratio for the increased energy...... expenditure is insufficiently explored. METHODS: Nineteen males were included in the study of which 14 completed. Subjects were 31.6 (±3.5) years [mean (±95% CI)] and had a fat percentage of 22.7 (±2.1)%. On separate days, subjects received either placebo or inhaled racemic (rac-) formoterol (2 × 27 µg...

Treatment of type 2 diabetes with glucagon-like peptide-1 receptor agonists

DEFF Research Database (Denmark)

Hansen, K B; Knop, F K; Holst, Jens Juul

2009-01-01

of hypoglycaemia with GLP-1 receptor agonists is low, the compounds have clinically relevant effects on body weight, and data are suggesting beneficial effects on cardiovascular risk factors. Exenatide was released in 2005 for the treatment of type 2 diabetes and liraglutide is expected to be approved by the Food......The incretin system is an area of great interest for the development of new therapies for the management of type 2 diabetes. Existing antidiabetic drugs are often insufficient at getting patients to glycaemic goals. Furthermore, current treatment modalities are not able to prevent the continued...... ongoing decline in pancreatic beta-cell function and, lastly, they have a number of side effects including hypoglycaemia and weight gain. Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of pharmacological agents, which improve glucose homeostasis in a multifaceted way. Their effects...

Analysis of agonist dissociation constants as assessed by functional antagonism in guinea pig left atria

International Nuclear Information System (INIS)

Molenaar, P.; Malta, E.

1986-01-01

In electrically driven guinea pig left atria, positive inotropic responses to (-)-isoprenaline and the selective beta 1-adrenoceptor agonist RO363 were obtained in the absence and in the presence of the functional antagonists adenosine, carbachol, gallopamil, nifedipine, and Ro 03-7894. Each of the functional antagonists reduced the maximum response to both agonists and produced nonparallel rightward shifts in the cumulative concentration effect curves. For both agonists, dissociation constants (KA) were calculated using the equation described by Furchgott (1966) for irreversible antagonism. For RO363, which is a partial agonist with high agonist activity, the equations outlined for functional interaction by Mackay (1981) were also employed to calculate KA values. The KA values obtained by each method were compared with the dissociation constants (KD) for the two agonists determined from their ability to displace the radioligand (-)-[ 125 I]iodocyanopindolol from beta 1-adrenoceptors in guinea pig left atrial membrane preparations. The estimates of KA varied substantially from KD values. The KD values were taken as more accurate estimates of the true values for the dissociation constants because a high degree of correlation exists between pKD and pD2 values for a number of other beta-adrenoceptor agonists that behave as partial agonists and between pKD and pKB values for a number of beta-adrenoceptor antagonists. Thus, it appears that there are serious limitations in the current theory for using functional antagonism as a means of obtaining agonist dissociation constants

Trends in the use of antiasthmatic medications in Morocco (1999-2010).

Science.gov (United States)

Ghanname, Imane; Ahid, Samir; Berrada, Ghizlane; Belaiche, Abdelmjid; Hassar, Mohamed; Cherrah, Yahya

2013-12-01

Asthma is a big public health problem in Morocco. The drug therapy existing in Morocco is currently insufficient because of the low purchasing power and the low health insurance coverage available to the average citizen in Morocco. In this study we evaluated the consumption of antiasthmatics in Morocco during the period 1999-2010, the classes of used drugs and the generics' market share. We used sales data from the Moroccan subsidiaries of the IMS Health "Intercontinental Marketing Service". The consumption volume was converted to Defined Daily Doses (DDDs). During 1999-2010, antiasthmatics's consumption increased from 3.91 to 14.47 DDD per 1000 inhabitants per day. In 2010, the association Beta-2-mimetic-Glucocorticosteroids were the most consumed (8.53 DDD/1000 Inhabitants/day) followed by the short-acting inhaled Beta-2-mimetic (4 DDD/1000 Inhabitants/day) and inhaled Glucocorticosteroids alone accounted for 1.13 DDD/1000 Inhabitants/day. The largest consumption share in volume was held by the short-acting inhaled Beta-2-mimetic (42%) followed by the combination Beta-2-mimetic-Glucocorticosteroids (38%). Between 1999 and 2010, the market for generic antiasthmatics increased from 1.84 to 2.18 DDD/1000 Inhabitants/day. The ratio of the monthly average cost of treatment to the minimum wage in Morocco decreased from 10.8% in 1999 to 7.11% in 2010. Antiasthmatics' consumption in Morocco has undergone significant changes between 1999 and 2010. However, the availability of these drugs expressed as the Average Monthly Expenditure/Guaranteed Minimum Wage ratio improved. Despite this, the use of antiasmathics in Morocco remains low.

Anti-IgE: lessons from clinical trials in patients with severe allergic asthma symptomatic despite optimised therapy

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R. Buhl

2007-09-01

Full Text Available The efficacy of omalizumab has been extensively investigated in clinical trials in patients with severe persistent allergic (pre-treatment total immunoglobulin E 30–700 IU·mL–1 asthma including the Investigation of Omalizumab in Severe Asthma Treatment (INNOVATE study, which enrolled patients with inadequately controlled severe persistent allergic asthma despite receiving high-dose inhaled corticosteroid in combination with a long-acting beta2-agonist, and also additional controller medication if required. In the INNOVATE study, add-on omalizumab significantly reduced clinically significant exacerbation rates by 26% (0.68 versus 0.91, severe exacerbation rates by 50% (0.24 versus 0.48 and emergency visit rates by 44% (0.24 versus 0.43 and significantly improved asthma-related quality of life (QoL compared with placebo. In a pooled analysis of data from seven studies, add-on omalizumab significantly reduced asthma exacerbation rates by 38% (0.91 versus 1.47 and total emergency visits by 47% (0.332 versus 0.623. In addition, omalizumab significantly improved QoL versus current asthma therapy in a pooled analysis of data from six studies. Omalizumab has demonstrated a good safety and tolerability profile in completed phase-I, -II and -III studies involving >7,500 patients with asthma, rhinitis or related conditions. Omalizumab represents a major advance for the treatment of severe persistent allergic asthma that is inadequately controlled despite treatment with inhaled corticosteroids and a long-acting beta2-agonist.

Pharmacogenetics of asthma

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Lima, John J.; Blake, Kathryn V.; Tantisira, Kelan G.; Weiss, Scott T.

2009-01-01

Purpose of review Patient response to the asthma drug classes, bronchodilators, inhaled corticosteroids and leukotriene modifiers, are characterized by a large degree of heterogeneity, which is attributable in part to genetic variation. Herein, we review and update the pharmacogenetics and pharmaogenomics of common asthma drugs. Recent findings Early studies suggest that bronchodilator reversibility and asthma worsening in patients on continuous short-acting and long-acting β-agonists are related to the Gly16Arg genotype for the ADRB2. More recent studies including genome-wide association studies implicate variants in other genes contribute to bronchodilator response heterogeneity and fail to replicate asthma worsening associated with continuous β-agonist use. Genetic determinants of the safety of long-acting β-agonist require further study. Variants in CRHR1, TBX21, and FCER2 contribute to variability in response for lung function, airways responsiveness, and exacerbations in patients taking inhaled corticosteroids. Variants in ALOX5, LTA4H, LTC4S, ABCC1, CYSLTR2, and SLCO2B1 contribute to variability in response to leukotriene modifiers. Summary Identification of novel variants that contribute to response heterogeneity supports future studies of single nucleotide polymorphism discovery and include gene expression and genome-wide association studies. Statistical models that predict the genomics of response to asthma drugs will complement single nucleotide polymorphism discovery in moving toward personalized medicine. PMID:19077707

Comparison of efficacy combination of inhaled phormoterol / budesonide turbuhaler vs. combination of nebulized salbutamol / ipratropium bromide on moderate asthma acute exacerbation in Persahabatan Hospital

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Zulkarnain Barasila

2006-03-01

Full Text Available The aim of this study was to compare efficacy combination of phormoterol/budesonide turbuhaler vs. salbutamol/ipratropium bromide nebulization. Main therapy for acute asthma is inhaled short acting β2-agonist. Asthma patients are using two drugs, controller and reliever. Recently there is device-containing combination of long-acting β2-agonist with rapid onset and corticosteroid. This combination can act as reliever and controller. An opened randomized clinical trial of 76 patients between the ages of 12 and 60 years presenting to Persahabatan Hospital with asthma score between 8-12 participated in this study. After initial evaluation, patients were divided into two groups. Thirty-eight patients were administered combination of formoterol/budesonide 4.5/160 µg via turbuhaler (T-group every 20 minutes, total of three doses, and another 38 of salbutamol/ipratropium bromide 2.5/0.25 mg via nebulizer (N-group also with the same manner. There were no statistical difference in sex, mean age, high, weight, initial PEFR, and asthma score between two groups. The significant increased of PEFR and decreased of asthma score were observed in both groups. However, there were no significant difference of PEFR and asthma score between the two groups within every time-interval. Adverse events were mild including hoarseness, tremor and palpitation. Of T-group, 1 subject was suffered from 3 adverse events simultaneously (hoarseness, tremor and palpitation, 5 subjects were only tremor. Of N-group, all 6 subjects were only suffered from tremor. A combination of formoterol/budesonide turbuhaler and a combination of nebulized salbutamol/ipratropium bromide are clinically equivalent for treatment moderate acute asthma. However, nebulized salbutamol/ipratropium bromide had less adverse effects. (Med J Indones 2006; 15:34-42Keywords: phormoterol, budesonide, salbutamol, ipratropium bromide, acute asthma

Modulation of short-term social memory in rats by adenosine A1 and A(2A) receptors.

Science.gov (United States)

Prediger, Rui D S; Takahashi, Reinaldo N

2005-03-16

The recognition of an unfamiliar juvenile rat by an adult rat has been shown to imply short-term memory processes. The present study was designed to examine the role of adenosine receptors in the short-term social memory of rats using the social recognition paradigm. Adenosine (5.0-10.0 mg/kg), the selective adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 0.025-0.05 mg/kg) and the selective adenosine A(2A) receptor agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine (DPMA, 1.0-5.0 mg/kg), given by i.p. route 30 min before the test, disrupted the juvenile recognition ability of adult rats. This negative effect of adenosine (5.0 mg/kg, i.p.) on social memory was prevented by pretreatment with the non-selective adenosine receptor antagonist caffeine (10.0 mg/kg, i.p.), the adenosine A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1.0 mg/kg, i.p.) and the adenosine A(2A) antagonist 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, 1.0 mg/kg, i.p.). Furthermore, acute administration of caffeine (10.0-30.0 mg/kg, i.p.), DPCPX (1.0-3.0 mg/kg, i.p.) or ZM241385 (0.5-1.0 mg/kg, i.p.) improved the short-term social memory in a specific manner. These results indicate that adenosine modulates the short-term social memory in rats by acting on both A1 and A(2A) receptors, with adenosine receptor agonists and antagonists, respectively, disrupting and enhancing the social memory.

Beta3 adrenoceptors substitute the role of M(2) muscarinic receptor in coping with cold stress in the heart: evidence from M(2)KO mice.

Science.gov (United States)

Benes, Jan; Novakova, Martina; Rotkova, Jana; Farar, Vladimir; Kvetnansky, Richard; Riljak, Vladimir; Myslivecek, Jaromir

2012-07-01

We investigated the role of beta3-adrenoceptors (AR) in cold stress (1 or 7 days in cold) in animals lacking main cardioinhibitive receptors-M2 muscarinic receptors (M(2)KO). There was no change in receptor number in the right ventricles. In the left ventricles, there was decrease in binding to all cardiostimulative receptors (beta1-, and beta2-AR) and increase in cardiodepressive receptors (beta3-AR) in unstressed KO in comparison to WT. The cold stress in WT animals resulted in decrease in binding to beta1- and beta2-AR (to 37%/35% after 1 day in cold and to 27%/28% after 7 days in cold) while beta3-AR were increased (to 216% of control) when 7 days cold was applied. MR were reduced to 46% and 58%, respectively. Gene expression of M2 MR in WT was not changed due to stress, while M3 was changed. The reaction of beta1- and beta2-AR (binding) to cold was similar in KO and WT animals, and beta3-AR in stressed KO animals did not change. Adenylyl cyclase activity was affected by beta3-agonist CL316243 in cold stressed WT animals but CL316243 had almost no effects on adenylyl cyclase activity in stressed KO. Nitric oxide activity (NOS) was not affected by BRL37344 (beta3-agonist) both in WT and KO animals. Similarly, the stress had no effects on NOS activity in WT animals and in KO animals. We conclude that the function of M2 MR is substituted by beta3-AR and that these effects are mediated via adenylyl cyclase rather than NOS.

Varenicline: a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist approved for smoking cessation.

Science.gov (United States)

Lam, Sum; Patel, Priti N

2007-01-01

Tobacco smoking remains a significant health problem in the United States. It has been associated with staggering morbidity and mortality, specifically due to malignancies and cardiovascular disease. Smoking cessation can be difficult and frequently requires pharmacologic interventions in addition to nonpharmacologic measures. Previously available agents are nicotine replacement products and bupropion, which increased quit rates by about 2-fold compared with placebo. Varenicline is the first drug in a new class known as the selective alpha4beta2 nicotinic receptor partial agonists. In several randomized, double-blind, 52-week clinical trials involving healthy chronic smokers, varenicline demonstrated superiority to placebo and bupropion in terms of efficacy measures. Additionally, it improved tobacco withdrawal symptoms and reinforcing effects of smoking in relapsed patients. Patients should start therapy in combination with tobacco cessation counseling 1 week before quit date and continue the regimen for 12 weeks. The dose of varenicline should be titrated to minimize nausea. The recommended dosage is 0.5 mg once daily (QD) on days 1-3; titrate to 0.5 mg twice daily (BID) on days 4-7; and 1 mg BID starting on day 8. An additional 12-week maintenance therapy may be considered for those who achieve abstinence. The most common side effects are nausea (30%), insomnia (18%), headache (15%), abnormal dreams (13%), constipation (8%), and abdominal pain (7%). Overall, varenicline is a breakthrough in the management of tobacco addiction and has demonstrated good efficacy in motivated quitters. It also provides an option for smokers who cannot tolerate other pharmacologic interventions.

Inhaled hyaluronic acid microparticles extended pulmonary retention and suppressed systemic exposure of a short-acting bronchodilator

DEFF Research Database (Denmark)

Li, Ying; Han, Meihua; Liu, Tingting

2017-01-01

The aim of this study was to investigate the feasibility of using hyaluronic acid (HA), a biomucoadhesive carbohydrate polymer to prolong the pulmonary retention and reduce the systemic exposure of inhaled medicine. Salbutamol sulphate (SAS), a model bronchodilator, was co-spray dried with HA...... to spray-dried plain SAS powders, the SAS-loaded HA microparticles possessed enhanced biomucoadhesive property in vitro and had much longer pulmonary retention and reduced systemic exposure in vivo. By incorporation, the pulmonary retention time of SAS was prolonged from 2h to 8h while the maximum...

Combinations of long acting β2 agonists to tiotropium: A randomized, double-blind, placebo-controlled, active-drug controlled, parallel design academic clinical trial in moderate COPD male patients

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Mohammed Imran

2015-01-01

Conclusions: Study shows that tiotropium alone once a day is the evidence based and rationale pharmacotherapy in moderate COPD. There is no advantage or statistical significance of adding long acting β2 agonists (LABA such as formoterol to tiotropium either for 12 h (once daily or 24 h (twice daily.

Treatment of allergic asthma: Modulation of Th2 cells and their responses

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Erb Klaus J

2011-08-01

Full Text Available Abstract Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral, leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.

Ciclesonide Oral Inhalation

Science.gov (United States)

... use ciclesonide inhalation.Ciclesonide inhalation helps to prevent asthma attacks (sudden episodes of shortness of breath, wheezing, and coughing) but will not stop an asthma attack that has already started. Do not use ciclesonide ...

Flunisolide Oral Inhalation

Science.gov (United States)

... use flunisolide inhalation.Flunisolide inhalation helps to prevent asthma attacks (sudden episodes of shortness of breath, wheezing, and coughing) but will not stop an asthma attack that has already started. Do not use flunisolide ...

Comparing clinical efficacy of Symbicort versus Pulmicort in reducing asthma symptom and improving its control

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Mohammad Emami

2014-01-01

Full Text Available Background: Recently, higher efficacy of the combination of long-acting beta2-adrenoceptor agonist and inhaled corticosteroids on controlling asthma symptoms has been hypothesized. This study aimed to examine the clinical effects of the combination of Budesonide with formoterol (Symbicort and Budesonide (Pulmicort alone in persistent asthma. Materials and Methods: In a randomized double-blinded clinical trial, 76 patients with definite diagnosis of moderate-to-severe asthma were randomized to receive Pulmicort 180 mcg/inhalation two puffs twice daily, or receive Symbicort 80/4.5 mg/inhalation two puffs twice daily, or receive Symbicort 160/4.5 mg/inhalation two puffs twice daily for 3 months. All participants were initially evaluated by spirometry for assessing respiratory parameters and also the level of asthma control was assessed by Asthma Control Test (ACT. Results: More significant improvement in spirometry parameters, including forced expiratory volume in 1 second (FEV1, forced vital capacity (FVC, FEV1/FVC ratio, as well as in peak expiratory flow (PEF in both groups of Symbicort with the regimens 80/4.5 mg/inhalation or 160/4.5 mg/inhalation 2 puffs twice daily compared with Pulmicort group, ACT score was significantly improved in Symbicort group with the regimens 160/4.5 mg/inhalation compared with both Symbicort groups with lower dosage and Pulmicort group . Response to treatment in PEF parameter and also in ACT level was significantly more in those who received Symbicort with the regimens 160/4.5 mg/inhalation compared with other two interventional groups adjusted for gender and age. Conclusion: Symbicort with the regimens 160/4.5 mg/inhalation has higher efficacy in reducing asthma symptom and improving its control compared with low doses of this drug and with Pulmicort.

Asthma

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Kim Harold

2011-11-01

Full Text Available Abstract Asthma is the most common respiratory disorder in Canada. Despite significant improvement in the diagnosis and management of this disorder, the majority of Canadians with asthma remain poorly controlled. In most patients, however, control can be achieved through the use of avoidance measures and appropriate pharmacological interventions. Inhaled corticosteroids (ICSs represent the standard of care for the majority of patients. Combination ICS/long-acting beta2-agonists (LABA inhalers are preferred for most adults who fail to achieve control with ICS therapy. Allergen-specific immunotherapy represents a potentially disease-modifying therapy for many patients with asthma, but should only be prescribed by physicians with appropriate training in allergy. Regular monitoring of asthma control, adherence to therapy and inhaler technique are also essential components of asthma management. This article provides a review of current literature and guidelines for the appropriate diagnosis and management of asthma.

Acidity of unstimulated saliva and dental plaque in asthmatics, treated with inhaled corticosteroids and long-acting sympathicomimetics.

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Emilia Karova

2012-07-01

Full Text Available The number of asthmatics is continuously increasing all over the world. The aim of the study is to study the effect of different combinations of inhaled corticosteroids and long-acting sympathicomimetics on salivary and plaque pH in asthmatics with mild persistent asthma. The effect of different quantities of lactose, as gustatory corrector in the inhalers, is traced out.Thirty patients of both sexes, from 20 to 55 years old participated in the study. Salivary and plaque pH values are traced out in 30 minutes period after drug inhalation, at 6-months interval. It is found out that inhaled drugs cause significant decrease of initial salivary pH values, the lowest ones reported on first and fifth minute after the inhalation. The average salivary pH levels on the 30th minute remain significantly lower than initial ones.Most considerable changes in pH values are registered for patients treated with Fluticasone propionate and Salmeterol.

Low Use and Adherence to Maintenance Medication in Chronic Obstructive Pulmonary Disease in the General Population

DEFF Research Database (Denmark)

Ingebrigtsen, Truls S; Marott, Jacob L; Nordestgaard, Børge G

2015-01-01

OBJECTIVE: We tested the hypothesis that use of and adherence to maintenance medication is low among individuals in the general population who have chronic obstructive pulmonary disease (COPD) , even in cases of severe and very severe COPD. DESIGN AND PARTICIPANTS: We identified 5,812 individuals...... with COPD from the Copenhagen General Population Study, and classified them according to the Global Initiative for Obstructive Lung Disease (GOLD) airflow limitation grades 1-4. Dispensing of fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists, long-acting anti...... for COPD in the general population was associated with the severity of COPD as defined by GOLD, but even in severe and very severe COPD, use and adherence was low....

Long-acting reversible contraceptive acceptability and unintended pregnancy among women presenting for short-acting methods: a randomized patient preference trial.

Science.gov (United States)

Hubacher, David; Spector, Hannah; Monteith, Charles; Chen, Pai-Lien; Hart, Catherine

2017-02-01

Measures of contraceptive effectiveness combine technology and user-related factors. Observational studies show higher effectiveness of long-acting reversible contraception compared with short-acting reversible contraception. Women who choose long-acting reversible contraception may differ in key ways from women who choose short-acting reversible contraception, and it may be these differences that are responsible for the high effectiveness of long-acting reversible contraception. Wider use of long-acting reversible contraception is recommended, but scientific evidence of acceptability and successful use is lacking in a population that typically opts for short-acting methods. The objective of the study was to reduce bias in measuring contraceptive effectiveness and better isolate the independent role that long-acting reversible contraception has in preventing unintended pregnancy relative to short-acting reversible contraception. We conducted a partially randomized patient preference trial and recruited women aged 18-29 years who were seeking a short-acting method (pills or injectable). Participants who agreed to randomization were assigned to 1 of 2 categories: long-acting reversible contraception or short-acting reversible contraception. Women who declined randomization but agreed to follow-up in the observational cohort chose their preferred method. Under randomization, participants chose a specific method in the category and received it for free, whereas participants in the preference cohort paid for the contraception in their usual fashion. Participants were followed up prospectively to measure primary outcomes of method continuation and unintended pregnancy at 12 months. Kaplan-Meier techniques were used to estimate method continuation probabilities. Intent-to-treat principles were applied after method initiation for comparing incidence of unintended pregnancy. We also measured acceptability in terms of level of happiness with the products. Of the 916

Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD

DEFF Research Database (Denmark)

Wedzicha, Jadwiga A; Banerji, Donald; Chapman, Kenneth R

2016-01-01

BACKGROUND: Most guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the first-choice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role...... of treatment with a LABA-LAMA regimen in these patients is unclear. METHODS: We conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either...... the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily. The primary outcome was the annual rate of all COPD exacerbations. RESULTS: A total of 1680 patients were assigned...

Reduced beta-adrenergic receptor activation decreases G-protein expression and beta-adrenergic receptor kinase activity in porcine heart.

OpenAIRE

Ping, P; Gelzer-Bell, R; Roth, D A; Kiel, D; Insel, P A; Hammond, H K

1995-01-01

To determine whether beta-adrenergic receptor agonist activation influences guanosine 5'-triphosphate-binding protein (G-protein) expression and beta-adrenergic receptor kinase activity in the heart, we examined the effects of chronic beta 1-adrenergic receptor antagonist treatment (bisoprolol, 0.2 mg/kg per d i.v., 35 d) on components of the myocardial beta-adrenergic receptor-G-protein-adenylyl cyclase pathway in porcine myocardium. Three novel alterations in cardiac adrenergic signaling as...

Comparative study of budesonide as a nebulized suspension vs pressurized metered-dose inhaler in adult asthmatics

DEFF Research Database (Denmark)

Bisgaard, H; Nikander, K; Munch, E

1998-01-01

The study objective was to compare the effect of budesonide administered as a nebulized suspension as compared to a spray with a spacer in adult asthmatics. In a double-blind, double-dummy crossover study, 26 adult patients with moderately severe unstable asthma were randomized to three 4-week...... treatment periods with budesonide 0.8 mg b.i.d. administered by a pressurized metered-dose inhaler (pMDI) with spacer (Nebuhaler) and budesonide 1 mg and 4 mg b.i.d. administered by a Pari Inhalier Boy jet nebulizer. The nebulizer was activated only during inspiration. The total mass output was similar from...... the two devices but their fraction of small particles differed by a factor of 2 in favour of pMDI. Effect was evaluated from daily home measurements of peak expiratory flow (PEF), need of beta 2-agonist and symptom scores. Plasma cortisol and budesonide levels were measured in a subgroup of 10 patients...

Rapid agonist-induced loss of sup 125 I-. beta. -endorphin opioid receptor sites in NG108-15, but not SK-N-SH neuroblastoma cells

Energy Technology Data Exchange (ETDEWEB)

Cone, R.I.; Lameh, J.; Sadee, W. (Univ. of California, San Francisco (United States))

1991-01-01

The authors have measured {mu} and {delta} opioid receptor sites on intact SK-N-SH and NG108-15 neuroblastoma cells, respectively, in culture. Use of {sup 125}I-{beta}-endorphin ({beta}E) as a tracer, together with {beta}E(6-31) to block high-affinity non-opioid binding in both cell lines, permitted the measurement of cell surface {mu} and {delta} opioid receptor sites. Labeling was at {delta} sites in NG108-15 cells and predominantly at {mu} sites in SK-N-SH cells. Pretreatment with the {mu} and {delta} agonist, DADLE, caused a rapid loss of cell surface {delta} receptor sites in NG108-15 cells, but failed to reduce significantly {mu} receptor density in SK-N-SH cells.

An investigation into the receptor-regulating effects of the acute administration of opioid agonists and an antagonist on beta adrenergic receptors in the rat cerebral cortex

International Nuclear Information System (INIS)

Roper, I.

1987-01-01

Past and current research indicated that biochemical deviations which might be involved in the etiology and pathophysiology of depression, included abnormalities or imbalances in the noradrenergic, serotonergic, hormonal and possibly in the endogenous opioid, dopaminergic, histaminergic, cholinergic and trace amine systems. In order to investigate a possible link between the noradrenergic system and opioids, it was decided to test the acute effects of opioid administration on cortical beta adrenoceptor numbers and affinity. As these receptors have been most consistently downregulated by antidepressant treatment, they may be involved in the mechanism of antidepressant action of these agents. It was decided to investigate beta adrenoceptor-regulatory effects of opioid treatment. Naloxone was tested alone, with a view to suppressing any possible endogenous opioid influences upon beta receptor status and revealing an effect which would possibly be the opposite of that brought about by the administration of opioid agonists. Naloxone was administered together with morphine to demonstrate that any beta receptor up- or downregulation which might be measured, had indeed been opioid-receptor mediated. It was found that the acute administration of four different mu opioid agonists, naloxone and naloxone plus morphine, did not cause any statistically significant alterations in cortical beta adrenergic receptor numbers or affinity in the rat. A radioactive ligand, the beta adrenoceptor-labelling compound referred to as DHA (L-dihydroalprenolol HCI) was used in this study

The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells

International Nuclear Information System (INIS)

Chuu, Chih-pin; Chen, Rou-Yu; Hiipakka, Richard A.; Kokontis, John M.; Warner, Karen V.; Xiang, Jialing; Liao, Shutsung

2007-01-01

T0901317 is a potent non-steroidal synthetic liver X receptor (LXR) agonist. T0901317 blocked androgenic stimulation of the proliferation of androgen-dependent LNCaP 104-S cells and androgenic suppression of the proliferation of androgen-independent LNCaP 104-R2 cells, inhibited the transcriptional activation of an androgen-dependent reporter gene by androgen, and suppressed gene and protein expression of prostate specific antigen (PSA), a target gene of androgen receptor (AR) without affecting gene and protein expression of AR. T0901317 also inhibited binding of a radiolabeled androgen to AR, but inhibition was much weaker compared to the effect of the antiandrogens, bicalutamide and hydroxyflutamide. The LXR agonist T0901317, therefore, acts as an antiandrogen in human prostate cancer cells

Characterization of beta-adrenergic receptors in synaptic membranes from rat cerebral cortex and cerebellum

International Nuclear Information System (INIS)

Lautens, L.

1986-01-01

Beta-adrenergic receptor ligand binding sites have been characterized in synaptic membranes from rat cerebral cortex and cerebellum using radioligand binding techniques. The equilibrium and kinetic properties of binding were assessed. The binding sites were non-interacting and exhibited two states of agonist binding which were sensitive to guanyl nucleotide. Synaptic membranes from cerebral cortex contained an equal number of beta 1 - and beta 2 -receptors; membranes from cerebellum possessed more beta 2 -than beta 1 -receptors. Photoaffinity labeling experiments revealed two different beta-adrenergic receptor polypeptides, R 1 and R 2 (and possibly a third, R 3 ) in synaptic membranes. The ratios of incorporation of photoaffinity label into R 1 : 2 were approximately 1:1 (cerebral cortex) and 5:1 (cerebellum). Photoaffinity labeling of R 1 and R 2 was inhibited equally well by both agonist and antagonist in synaptic membranes from cerebellum; whereas agonist was a less potent inhibitor in membranes from cerebral cortex. Both subtypes of beta-adrenergic receptors exhibited the same apparent molecular weight in synaptic membranes from cerebral cortex. The beta-adrenergic receptors in synaptic membranes from cerebral cortex and cerebellum were glycoproteins which exhibited the same apparent molecular weight after exposure to endoglycosidase F. The partial proteolytic digest maps of photoaffinity labeled beta-adrenergic receptors from rat cerebral cortex, cerebellum, lung and heart were compared

Alterations in vasodilator-stimulated phosphoprotein (VASP) phosphorylation: associations with asthmatic phenotype, airway inflammation and β2-agonist use

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Hastie, Annette T; Wu, Min; Foster, Gayle C; Hawkins, Gregory A; Batra, Vikas; Rybinski, Katherine A; Cirelli, Rosemary; Zangrilli, James G; Peters, Stephen P

2006-01-01

Background Vasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP via cAMP and cGMP dependent protein kinases releases this "brake" on cell motility. Thus, phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation. Two hypotheses were examined: (1) injury from segmental allergen challenge increases VASP phosphorylation in airway epithelium in asthmatic but not nonasthmatic normal subjects, (2) regular in vivo β2-agonist use increases VASP phosphorylation in asthmatic epithelium, altering cell adhesion. Methods Bronchial epithelium was obtained from asthmatic and non-asthmatic normal subjects before and after segmental allergen challenge, and after regularly inhaled albuterol, in three separate protocols. VASP phosphorylation was examined in Western blots of epithelial samples. DNA was obtained for β2-adrenergic receptor haplotype determination. Results Although VASP phosphorylation increased, it was not significantly greater after allergen challenge in asthmatics or normals. However, VASP phosphorylation in epithelium of nonasthmatic normal subjects was double that observed in asthmatic subjects, both at baseline and after challenge. Regularly inhaled albuterol significantly increased VASP phosphorylation in asthmatic subjects in both unchallenged and antigen challenged lung segment epithelium. There was also a significant increase in epithelial cells in the bronchoalveolar lavage of the unchallenged lung segment after regular inhalation of albuterol but not of placebo. The haplotypes of the β2-adrenergic receptor did not appear to associate with increased or decreased phosphorylation of VASP. Conclusion Decreased VASP phosphorylation was observed in epithelial cells of asthmatics compared to nonasthmatic normals, despite response to β-agonist. The decreased

Alterations in vasodilator-stimulated phosphoprotein (VASP phosphorylation: associations with asthmatic phenotype, airway inflammation and β2-agonist use

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Cirelli Rosemary

2006-02-01

Full Text Available Abstract Background Vasodilator-stimulated phosphoprotein (VASP mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP via cAMP and cGMP dependent protein kinases releases this "brake" on cell motility. Thus, phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation. Two hypotheses were examined: (1 injury from segmental allergen challenge increases VASP phosphorylation in airway epithelium in asthmatic but not nonasthmatic normal subjects, (2 regular in vivo β2-agonist use increases VASP phosphorylation in asthmatic epithelium, altering cell adhesion. Methods Bronchial epithelium was obtained from asthmatic and non-asthmatic normal subjects before and after segmental allergen challenge, and after regularly inhaled albuterol, in three separate protocols. VASP phosphorylation was examined in Western blots of epithelial samples. DNA was obtained for β2-adrenergic receptor haplotype determination. Results Although VASP phosphorylation increased, it was not significantly greater after allergen challenge in asthmatics or normals. However, VASP phosphorylation in epithelium of nonasthmatic normal subjects was double that observed in asthmatic subjects, both at baseline and after challenge. Regularly inhaled albuterol significantly increased VASP phosphorylation in asthmatic subjects in both unchallenged and antigen challenged lung segment epithelium. There was also a significant increase in epithelial cells in the bronchoalveolar lavage of the unchallenged lung segment after regular inhalation of albuterol but not of placebo. The haplotypes of the β2-adrenergic receptor did not appear to associate with increased or decreased phosphorylation of VASP. Conclusion Decreased VASP phosphorylation was observed in epithelial cells of asthmatics compared to nonasthmatic normals, despite response to β-agonist

Cardiovascular morbidity and the use of inhaled bronchodilators

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Christine Macie

2008-03-01

Full Text Available Christine Macie, Kate Wooldrage, Jure Manfreda, Nicholas AnthonisenDepartment of Medicine, University of Manitoba, Winnipeg, Manitoba, CanadaAbstract: We used the Manitoba Health database to examine the relationship between use of inhaled respiratory drugs in people with chronic obstructive respiratory diseases and cardiovascular hospitalizations from 1996 through 2000. The drugs examined were beta agonists [BA], ipratropium bromide IB, and inhaled steroids (ICS. End points were first hospitalizations for supraventricular tachycardia, myocardial infarction, heart failure or stroke. A nested case control analysis was employed comparing people with and without cardiovascular events. Cases and controls were matched for gender and age, and conditional logistic regression was used in multivariate analysis considering other respiratory drugs, respiratory diagnosis and visit frequency, non-respiratory, non-cardiac comorbidities, and receipt of drugs for cardiovascular disease. In univariate analyses, BA, IB and ICS were all associated with hospitalizations for cardiovascular disease, but in multivariate analyses ICS did not increase risk while both BA and IB did. There were interactions between respiratory and cardiac drugs receipt in that bronchodilator associated risks were higher in people not taking cardiac drugs; this was especially true for stroke. There were strong interactions with specific cardiac drugs; for example, both BA and IB substantially increased the risk of supraventricular tachycardia in patients not anti-arryhthmic agents, but not in the presence of such agents. We conclude that bronchodilator therapy for chronic obstructive diseases is associated with increased cardiovascular risk, especially in patients without previous cardiovascular diagnoses, and that this is unlikely due to the severity of the respiratory disease, since risk was not increased with ICS.Keywords: bronchodilator therapy, inhaled corticosteroids, nested case

Efeito do salbutamol liberado através de inalador de pó seco sobre o broncoespasmo induzido por metacolina Effects of salbutamol delivered by dry-powder inhaler on methacholine-induced bronchoconstriction

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Adalberto Sperb Rubin

2004-06-01

Full Text Available INTRODUÇÃO: Os beta2-agonistas de curta duração sob a forma de nebulímetro pressurizado são os fármacos utilizados rotineiramente na reversão do broncoespasmo induzido pela metacolina. A administração desses fármacos na forma de pó seco, liberados por inaladores de pó seco pode ser uma alternativa eficaz. OBJETIVO: Avaliar a efetividade e rapidez de ação do salbutamol liberado através de inalador de pó seco pulvinal (Butovent® na reversão do broncoespasmo induzido por metacolina, comparando-o com o salbutamol liberado por nebulímetro pressurizado. MÉTODO: Foram avaliados prospectivamente 60 pacientes sucessivos com broncoespasmo induzido por metacolina, cuja queda do volume expiratório forçado no primeiro segundo (VEF1 foi de, no mínimo, 20%. Foram randomizados 30 pacientes para receber 200 mcg de salbutamol liberado por nebulímetro pressurizado e 30 pacientes para receber 200 mcg de salbutamol através de inalador de pó seco (pulvinal, na etapa final do teste de broncoprovocação, com o objetivo de reverter o broncoespasmo induzido pela metacolina. Foram avaliados os VEF1 obtidos 1 minuto e 5 minutos após a administração do broncodilatador. RESULTADOS: Os grupos foram pareados por sexo, idade, peso, altura, dose provocativa causadora de queda de 20% no VEF1 (primeiro grupo: 1,3 mg ; segundo grupo: 1,19 mg; p = 0,79 e VEF1 pós-metacolina (primeiro grupo: 2,03 l; segundo grupo: 1,99 l; p = 0,87, sem diferença significativa entre eles. O incremento médio do VEF1 foi de 16,2% (1 minuto e 22,2% (5 minutos no primeiro grupo e de 17% (1 minuto e 23,6% (5 minutos no segundo grupo, não havendo diferença estatística entre eles (p = 0,8. CONCLUSÕES: Os beta2-agonistas administrados através de inalador de pó seco (pulvinal apresentam a mesma eficácia broncodilatadora e rapidez de ação que no tradicional método por nebulímetro pressurizado.BACKGROUND: Short-acting beta2 agonists delivered by metered-dose inhaler

Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach.

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Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kunz, Christina; Formella, Stephan; Kloft, Charlotte

2016-03-01

Olodaterol, a novel β2-adrenergic receptor agonist, is a long-acting, once-daily inhaled bronchodilator approved for the treatment of chronic obstructive pulmonary disease. The aim of the present study was to describe the plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers by population pharmacokinetic modelling and thereby to infer its pulmonary fate. Plasma and urine data after intravenous administration (0.5-25 μg) and oral inhalation (2.5-70 μg via the Respimat® inhaler) were available from a total of 148 healthy volunteers (single and multiple dosing). A stepwise model building approach was applied, using population pharmacokinetic modelling. Systemic disposition parameters were fixed to estimates obtained from intravenous data when modelling data after inhalation. A pharmacokinetic model, including three depot compartments with associated parallel first-order absorption processes (pulmonary model) on top of a four-compartment body model (systemic disposition model), was found to describe the data the best. The dose reaching the lung (pulmonary bioavailable fraction) was estimated to be 49.4% [95% confidence interval (CI) 46.1, 52.7%] of the dose released from the device. A large proportion of the pulmonary bioavailable fraction [70.1% (95% CI 66.8, 73.3%)] was absorbed with a half-life of 21.8 h (95% CI 19.7, 24.4 h). The plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers were adequately described. The key finding was that a high proportion of the pulmonary bioavailable fraction had an extended pulmonary residence time. This finding was not expected based on the physicochemical properties of olodaterol. © 2015 The British Pharmacological Society.

Human fat cell alpha-2 adrenoceptors. I. Functional exploration and pharmacological definition with selected alpha-2 agonists and antagonists

International Nuclear Information System (INIS)

Galitzky, J.; Mauriege, P.; Berlan, M.; Lafontan, M.

1989-01-01

This study was undertaken to investigate more fully the pharmacological characteristics of the human fat cell alpha-2 adrenoceptor. Biological assays were performed on intact isolated fat cells while radioligand binding studies were carried out with [ 3 H]yohimbine in membranes. These pharmacological studies brought: (1) a critical definition of the limits of the experimental conditions required for the exploration of alpha-2 adrenergic responsiveness on human fat cells and membranes; (2) an improvement in the pharmacological definition of the human fat cell postsynaptic alpha-2 adrenoceptor. Among alpha-2 agonists, UK-14,304 was the most potent and the relative order of potency was: UK-14,304 greater than p-aminoclonidine greater than clonidine = B-HT 920 greater than rilmenidine. For alpha-2 antagonists, the potency order was: yohimbine greater than idazoxan greater than SK ampersand F-86,466 much greater than benextramine; (3) a description of the impact of benextramine (irreversible alpha-1/alpha-2 antagonist) on human fat cell alpha-2 adrenergic receptors and on human fat cell function; the drug inactivates the alpha-2 adrenergic receptors with a minor impact on beta adrenergic receptors and without noticeable alterations of fat cell function as assessed by preservation of beta adrenergic and Al-adenosine receptor-mediated lipolytic responses; and (4) a definition of the relationship existing between alpha-2 adrenergic receptor occupancy, inhibition of adenylate cyclase activity and antilipolysis with full and partial agonists. The existence of a receptor reserve must be taken into account when evaluating alpha-2 adrenergic receptor distribution and regulation of human fat cells

R-134a (1,1,1,2-Tetrafluoroethane) Inhalation Induced Reactive Airways Dysfunction Syndrome.

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Doshi, Viral; Kham, Nang; Kulkarni, Shreedhar; Kapitan, Kent; Henkle, Joseph; White, Peter

2016-01-01

R-134a (1,1,1,2-tetrafluoroethane) is widely used as a refrigerant and as an aerosol propellant. Inhalation of R-134a can lead to asphyxia, transient confusion, and cardiac arrhythmias. We report a case of reactive airways dysfunction syndrome secondary to R-134a inhalation. A 60-year-old nonsmoking man without a history of lung disease was exposed to an air conditioner refrigerant spill while performing repairs beneath a school bus. Afterward, he experienced worsening shortness of breath with minimal exertion, a productive cough, and wheezing. He was also hypoxic. He was admitted to the hospital for further evaluation. Spirometry showed airflow obstruction with an FEV1 1.97 L (45% predicted). His respiratory status improved with bronchodilators and oral steroids. A repeat spirometry 2 weeks later showed improvement with an FEV1 2.5 L (60% predicted). Six months after the incident, his symptoms had improved, but he was still having shortness of breath on exertion and occasional cough.

Acidity of unstimulated saliva and dental plaque in asthmatics, treated with inhaled corticosteroids and long-acting sympathicomimetics.

OpenAIRE

Emilia Karova; George Christoff

2012-01-01

The number of asthmatics is continuously increasing all over the world. The aim of the study is to study the effect of different combinations of inhaled corticosteroids and long-acting sympathicomimetics on salivary and plaque pH in asthmatics with mild persistent asthma. The effect of different quantities of lactose, as gustatory corrector in the inhalers, is traced out.Thirty patients of both sexes, from 20 to 55 years old participated in the study. Salivary and plaque pH values are traced ...

The relative potency of inverse opioid agonists and a neutral opioid antagonist in precipitated withdrawal and antagonism of analgesia and toxicity.

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Sirohi, Sunil; Dighe, Shveta V; Madia, Priyanka A; Yoburn, Byron C

2009-08-01

Opioid antagonists can be classified as inverse agonists and neutral antagonists. In the opioid-dependent state, neutral antagonists are significantly less potent in precipitating withdrawal than inverse agonists. Consequently, neutral opioid antagonists may offer advantages over inverse agonists in the management of opioid overdose. In this study, the relative potency of three opioid antagonists to block opioid analgesia and toxicity and precipitate withdrawal was examined. First, the potency of two opioid inverse agonists (naltrexone and naloxone) and a neutral antagonist (6beta-naltrexol) to antagonize fentanyl-induced analgesia and lethality was determined. The order of potency to block analgesia was naltrexone > naloxone > 6beta-naltrexol (17, 4, 1), which was similar to that to block lethality (13, 2, 1). Next, the antagonists were compared using withdrawal jumping in fentanyl-dependent mice. The order of potency to precipitate withdrawal jumping was naltrexone > naloxone 6beta-naltrexol (1107, 415, 1). The relative potencies to precipitate withdrawal for the inverse agonists compared with the neutral antagonist were dramatically different from that for antagonism of analgesia and lethality. Finally, the effect of 6beta-naltrexol pretreatment on naloxone-precipitated jumping was determined in morphine and fentanyl-dependent mice. 6beta-Naltrexol pretreatment decreased naloxone precipitated withdrawal, indicating that 6beta-naltrexol is a neutral antagonist. These data demonstrate that inverse agonists and neutral antagonists have generally comparable potencies to block opioid analgesia and lethality, whereas the neutral opioid antagonist is substantially less potent in precipitating opioid withdrawal. These results support suggestions that neutral antagonists may have advantages over inverse agonists in the management of opioid overdose.

Can the anti-inflammatory activities of β2-agonists be harnessed in the clinical setting?

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Theron AJ

2013-11-01

Full Text Available Annette J Theron,1,2 Helen C Steel,1 Gregory R Tintinger,1 Charles Feldman,3 Ronald Anderson1 1Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, 2Tshwane Academic Division of the National Health Laboratory Service, Pretoria, 3Division of Pulmonology, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa Abstract: Beta2-adrenoreceptor agonists (β2-agonists are primarily bronchodilators, targeting airway smooth muscle and providing critical symptomatic relief in conditions such as bronchial asthma and chronic obstructive pulmonary disease. These agents also possess broad-spectrum, secondary, anti-inflammatory properties. These are mediated largely, though not exclusively, via interactions with adenylyl cyclase-coupled β2-adrenoreceptors on a range of immune and inflammatory cells involved in the immunopathogenesis of acute and chronic inflammatory disorders of the airways. The clinical relevance of the anti-inflammatory actions of β2-agonists, although often effective in the experimental setting, remains contentious. The primary objectives of the current review are: firstly, to assess the mechanisms, both molecular and cell-associated, that may limit the anti-inflammatory efficacy of β2-agonists; secondly, to evaluate pharmacological strategies, several of which are recent and innovative, that may overcome these limitations. These are preceded by a consideration of the various types of β2-agonists, their clinical applications, and spectrum of anti-inflammatory activities, particularly those involving adenosine 3',5'-cyclic adenosine monophosphate-activated protein kinase-mediated clearance of cytosolic calcium, and altered gene expression in immune and inflammatory cells. Keywords: adenylyl cyclase, corticosteroids, cyclic AMP, muscarinic

The changes in beta-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac beta3-adrenoceptors.

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Arioglu, E; Guner, S; Ozakca, I; Altan, V M; Ozcelikay, A T

2010-02-01

Thyroid hormone deficiency has been reported to decrease expression and function of both beta(1)- and beta(2)-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of beta(3)-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on beta(1)- and beta(2)-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to beta-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of beta-adrenoceptors, Gialpha, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and -dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a beta(3)-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac beta(2)- and beta(3)-adrenoceptor, Gialpha(2), Gialpha(3), GRK3, and eNOS mRNA expressions. However, beta(1)-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of beta(3)-adrenoceptors as well as the signalling pathway components mediated through beta(3)-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.

How Do Dual Long-acting Bronchodilators Prevent Exacerbations of Chronic Obstructive Pulmonary Disease?

DEFF Research Database (Denmark)

Beeh, Kai M; Burgel, Pierre-Regis; Franssen, Frits M E

2017-01-01

that combinations of long-acting β2-adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) provide greater reductions in exacerbation frequency than either their monocomponents or LABA/inhaled corticosteroids (LABA/ICS) combinations in patients at low and high risk for these events....... In this review, small groups of experts critically evaluated mechanisms potentially responsible for the increased benefit of LABA/LAMA combinations over single LABDs or LABA/ICS in decreasing exacerbation. These included effects on lung hyperinflation and mechanical stress, inflammation, excessive mucus...... production with impaired mucociliary clearance, and symptom severity. The data assembled and analyzed by each group were reviewed by all authors and combined into this manuscript. Available clinical results support the possibility that effects of LABA/LAMA combinations on hyperinflation, mucociliary...

LHCb: $2\\beta_s$ measurement at LHCb

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Conti, G

2009-01-01

A measurement of $2\\beta_s$, the phase of the $B_s-\\bar{B_s}$ oscillation amplitude with respect to that of the ${\\rm b} \\rightarrow {\\rm c^{+}}{\\rm W^{-}}$ tree decay amplitude, is one of the key goals of the LHCb experiment with first data. In the Standard Model (SM), $2\\beta_s$ is predicted to be $0.0360^{+0.0020}_{-0.0016} \\rm rad$. The current constraints from the Tevatron are: $2\\beta_{s}\\in[0.32 ; 2.82]$ at 68$\\%$CL from the CDF experiment and $2\\beta_{s}=0.57^{+0.24}_{-0.30}$ from the D$\\oslash$ experiment. Although the statistical uncertainties are large, these results hint at the possible contribution of New Physics in the $B_s-\\bar{B_s}$ box diagram. After one year of data taking at LHCb at an average luminosity of $\\mathcal{L}\\sim2\\cdot10^{32}\\rm cm^{-2} \\rm s^{-1}$ (integrated luminosity $\\mathcal{L}_{\\rm int}\\sim 2 \\rm fb^{-1}$), the expected statistical uncertainty on the measurement is $\\sigma(2\\beta_s)\\simeq 0.03$. This uncertainty is similar to the $2\\beta_s$ value predicted by the SM.

Functional human antibody CDR fusions as long-acting therapeutic endocrine agonists.

Science.gov (United States)

Liu, Tao; Zhang, Yong; Liu, Yan; Wang, Ying; Jia, Haiqun; Kang, Mingchao; Luo, Xiaozhou; Caballero, Dawna; Gonzalez, Jose; Sherwood, Lance; Nunez, Vanessa; Wang, Danling; Woods, Ashley; Schultz, Peter G; Wang, Feng

2015-02-03

On the basis of the 3D structure of a bovine antibody with a well-folded, ultralong complementarity-determining region (CDR), we have developed a versatile approach for generating human or humanized antibody agonists with excellent pharmacological properties. Using human growth hormone (hGH) and human leptin (hLeptin) as model proteins, we have demonstrated that functional human antibody CDR fusions can be efficiently engineered by grafting the native hormones into different CDRs of the humanized antibody Herceptin. The resulting Herceptin CDR fusion proteins were expressed in good yields in mammalian cells and retain comparable in vitro biological activity to the native hormones. Pharmacological studies in rodents indicated a 20- to 100-fold increase in plasma circulating half-life for these antibody agonists and significantly extended in vivo activities in the GH-deficient rat model and leptin-deficient obese mouse model for the hGH and hLeptin antibody fusions, respectively. These results illustrate the utility of antibody CDR fusions as a general and versatile strategy for generating long-acting protein therapeutics.

Structure-activity relationships of the unique and potent agouti-related protein (AGRP)-melanocortin chimeric Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH2 peptide template.

Science.gov (United States)

Wilczynski, Andrzej; Wilson, Krista R; Scott, Joseph W; Edison, Arthur S; Haskell-Luevano, Carrie

2005-04-21

The melanocortin receptor system consists of endogenous agonists, antagonists, G-protein coupled receptors, and auxiliary proteins that are involved in the regulation of complex physiological functions such as energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. Herein, we report the structure-activity relationship (SAR) of a new chimeric hAGRP-melanocortin agonist peptide template Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) that was characterized using amino acids previously reported in other melanocortin agonist templates. Twenty peptides were examined in this study, and six peptides were selected for (1)H NMR and computer-assisted molecular modeling structural analysis. The most notable results include the identification that modification of the chimeric template at the His position with Pro and Phe resulted in ligands that were nM mouse melanocortin-3 receptor (mMC3R) antagonists and nM mouse melanocortin-4 receptor (mMC4R) agonists. The peptides Tyr-c[beta-Asp-His-DPhe-Ala-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) and Tyr-c[beta-Asp-His-DNal(1')-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) resulted in 730- and 560-fold, respectively, mMC4R versus mMC3R selective agonists that also possessed nM agonist potency at the mMC1R and mMC5R. Structural studies identified a reverse turn occurring in the His-DPhe-Arg-Trp domain, with subtle differences observed that may account for the differences in melanocortin receptor pharmacology. Specifically, a gamma-turn secondary structure involving the DPhe(4) in the central position of the Tyr-c[beta-Asp-Phe-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) peptide may differentiate the mixed mMC3R antagonist and mMC4R agonist pharmacology.

Influence of Natural Lung Surfactant Inhalations on Clinical Symptoms and Pulmonary Function Parameters in Patients with Bronchial Asthma. Communication 1

Directory of Open Access Journals (Sweden)

O.V. Stepanova

2016-12-01

Full Text Available Background: Damage to lung surfactant (LS enabling the lung local immunity may contribute to the development of bronchial inflammation in patients with bronchial asthma. Methods and Results: A 40-day course of 16 LS (Surfactant-BL inhalations at the dose of 25mg was added to inhaled corticosteroids (ICS and short/long-acting bronchodilators or combined inhalers in 14 patients with bronchial asthma. After 7 inhalations, patients demonstrated a significant decrease in shortness of breath and bronchospasm attacks, double reduction of ICS dose (p=0.01, and improvement of pulmonary function. Forced vital capacity (FVC increases during treatment in a linear fashion (y=62.9+5.60•x; p<0.05, reaching the normal level (80% after 9 inhalations (Day 15. Forced expiratory volume (FEV1 increases in a linear fashion (y=50.7+4.15•x; p<0.05 without reaching the normal level (80% after 16 inhalations (Day 41. The FEV1/FVC ratio does not change significantly in the time period between Day 1 to Day 15. By Day 41 the value decreases significantly to 67.4±4.66% (p<0.05. The peak expiratory flow (PEF parameter increases in a linear fashion (y=53.9+5.00•x; p<0.01 from 57.7±6.33% to 76.2±9.33% of the predicted value. Conclusion: LS inhalations improve the condition of patients with BA, allow ICS dose reduction by 2 times, and improve pulmonary function parameters.

Selective adenosine A2A receptor agonists and antagonists protect against spinal cord injury through peripheral and central effects

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Esposito Emanuela

2011-04-01

Full Text Available Abstract Background Permanent functional deficits following spinal cord injury (SCI arise both from mechanical injury and from secondary tissue reactions involving inflammation. Enhanced release of adenosine and glutamate soon after SCI represents a component in the sequelae that may be responsible for resulting functional deficits. The role of adenosine A2A receptor in central ischemia/trauma is still to be elucidated. In our previous studies we have demonstrated that the adenosine A2A receptor-selective agonist CGS21680, systemically administered after SCI, protects from tissue damage, locomotor dysfunction and different inflammatory readouts. In this work we studied the effect of the adenosine A2A receptor antagonist SCH58261, systemically administered after SCI, on the same parameters. We investigated the hypothesis that the main action mechanism of agonists and antagonists is at peripheral or central sites. Methods Spinal trauma was induced by extradural compression of SC exposed via a four-level T5-T8 laminectomy in mouse. Three drug-dosing protocols were utilized: a short-term systemic administration by intraperitoneal injection, a chronic administration via osmotic minipump, and direct injection into the spinal cord. Results SCH58261, systemically administered (0.01 mg/kg intraperitoneal. 1, 6 and 10 hours after SCI, reduced demyelination and levels of TNF-α, Fas-L, PAR, Bax expression and activation of JNK mitogen-activated protein kinase (MAPK 24 hours after SCI. Chronic SCH58261 administration, by mini-osmotic pump delivery for 10 days, improved the neurological deficit up to 10 days after SCI. Adenosine A2A receptors are physiologically expressed in the spinal cord by astrocytes, microglia and oligodendrocytes. Soon after SCI (24 hours, these receptors showed enhanced expression in neurons. Both the A2A agonist and antagonist, administered intraperitoneally, reduced expression of the A2A receptor, ruling out the possibility that the

[The add-on effect of omalizumab on patients with uncontrolled bronchial asthma].

Science.gov (United States)

Minami, Yoshinori; Endo, Satoshi; Okumur, Shunsuke; Sasaki, Takaaki; Yamamoto, Yasushi; Ogasa, Toshiyuki; Osanai, Shinobu; Ohsaki, Yoshinobu

2011-11-01

A high-dose administration of inhaled corticosteroid is effective in the majority of patients with bronchial asthma, but is often difficult to attain sufficient control in certain subsets of patients. Omalizumab has recently emerged as a promising drug for bronchial asthma. To assess its add-on effect we administered omalizumab to patients with uncontrolled atopic asthma for more than 16 weeks and gave them questionnaires. The study population comprised 9 patients with frequent asthmatic symptoms despite the administration of high-dose inhaled corticosteroid and other disease controllers. We scored disease control using the Asthma Health Questionnaire-33-Japan and the Asthma Control Test, and evaluated the frequencies of short-acting beta2-agonist use for rescue and drip infusion of theophyllines and/or systemic steroids in a retrospective fashion. Asthmatic scores were significantly improved after 16 weeks of omalizumab therapy. The frequencies of reliever use and drip infusion were also decreased. These trends were present even in patients in whom no aeroallergen-specific IgE antibodies were detected. No statistically significant side effects were observed. Our study confirmed the add-on effect of omalizumab based on evaluation by simple questionnaires. Further studies are needed to clarify whether omalizumab therapy is suitable for patients without specific IgE antibodies.

The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo.

Science.gov (United States)

Xie, Zhongcong; Culley, Deborah J; Dong, Yuanlin; Zhang, Guohua; Zhang, Bin; Moir, Robert D; Frosch, Matthew P; Crosby, Gregory; Tanzi, Rudolph E

2008-12-01

An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease-associated amyloid beta-protein (Abeta) in cultured cells. However, the in vivo relevance has not been addressed. We therefore set out to determine effects of isoflurane on caspase activation and levels of beta-site amyloid precursor protein-cleaving enzyme (BACE) and Abeta in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction. Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and Abeta up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the Abeta aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo. Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane may promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation.

Developmental changes of beta-adrenergic receptor-linked adenylate cyclase of rat liver

International Nuclear Information System (INIS)

Katz, M.S.; Boland, S.R.; Schmidt, S.J.

1985-01-01

beta-Adrenergic agonist-sensitive adenylate cyclase activity and binding of the beta-adrenergic antagonist(-)-[ 125 I]iodopindolol were studied in rat liver during development of male Fischer 344 rats ages 6-60 days. In liver homogenates maximum adenylate cyclase response to beta-adrenergic agonist (10(-5) M isoproterenol or epinephrine) decreased by 73% (P less than 0.01) between 6 and 60 days, with most of the decrease (56%; P less than 0.01) occurring by 20 days. beta-adrenergic receptor density (Bmax) showed a corresponding decrease of 66% (P less than 0.01) by 20 days without subsequent change. Binding characteristics of stereospecificity, pharmacological specificity, saturability with time, and reversibility were unchanged with age. GTP-, fluoride-, forskolin-, and Mn2+-stimulated adenylate cyclase activities also decreased during development, suggesting a decrease of activity of the catalytic component and/or guanine nucleotide regulatory component of adenylate cyclase. These results indicate that the developmental decrease of beta-adrenergic agonist-sensitive adenylate cyclase activity may result from decreased numbers of beta-adrenergic receptors. Developmental alterations of nonreceptor components of the enzyme may also contribute to changes of catecholamine-sensitive adenylate cyclase

Novel GLP-1 fusion chimera as potent long acting GLP-1 receptor agonist.

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Qinghua Wang

2010-09-01

Full Text Available GLP-1 has a variety of anti-diabetic effects. However, native GLP-1 is not suitable for therapy of diabetes due to its short half-life (t1/2168 h. Intraperitoneal glucose tolerance test (IPGTT in mice showed that GLP-1/hIgG2 significantly decreased glucose excursion. Furthermore, IPGTT performed on mice one week after a single drug-injection also displayed significantly reduced glucose excursion, indicating that GLP-1/hIgG2 fusion protein has long-lasting effects on the modulation of glucose homeostasis. GLP-1/hIgG2 was found to be effective in reducing the incidence of diabetes in multiple-low-dose streptozotocin-induced type 1 diabetes in mice. Together, the long-lasting bioactive GLP-1/hIgG2 retains native GLP-1 activities and thus may serve as a potent GLP-1 receptor agonist.

Selecting GLP-1 agonists in the management of type 2 diabetes: differential pharmacology and therapeutic benefits of liraglutide and exenatide

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Jonathan Pinkney

2010-08-01

Full Text Available Jonathan Pinkney1, Thomas Fox1, Lakshminarayan Ranganath21Department of Diabetes and Endocrinology, Peninsula College of Medicine and Dentistry, Plymouth, United Kingdom; 2Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Liverpool, United KingdomAbstract: Failure of secretion of the incretin hormone glucagon-like peptide-1 (GLP-1 plays a prominent role in type 2 diabetes, and restoration of GLP-1 action is an important therapeutic objective. Although the short duration of action of GLP-1 renders it unsuited to therapeutic use, 2 long-acting GLP-1 receptor agonists, exenatide and liraglutide, represent a significant advance in treatment. In controlled trials, both produce short-term glucose-lowering effects, with the reduction in hemoglobin A1c of up to 1.3%. These responses are often superior to those observed with additional oral agents. However, unlike sulfonylureas, thiazolidinediones, or insulin, all of which lead to significant weight gain, GLP-1 receptor agonists uniquely result in long-term weight loss of around 5 kg, and higher doses may enhance this further. Reduction in blood pressure of 2–7 mm Hg also has been observed. Both drugs produce transient mild gastrointestinal side effects; although mild hypoglycemia can occur, this is usually in combination with other hypoglycemic therapies. However, serious hypoglycemia and acute pancreatitis are rare. The once-daily dosage of liraglutide makes it more convenient than twice-daily dosage of prandial exenatide, and a superior glucose-lowering effect was observed in the only head-to-head comparison reported so far. Besides cost, these considerations currently favor liraglutide over exenatide. Further studies are needed to confirm long-term safety, and most importantly, that short-term benefits translate into long-term reductions of diabetes-related cardiovascular events and other complications.Keywords: diabetes, weight loss, glycemic control

Protection against inhaled oxidants through scavenging of oxidized lipids by macrophage receptors MARCO and SR-AI/II

DEFF Research Database (Denmark)

Dahl, Morten; Bauer, Alison K; Arredouani, Mohamed

2007-01-01

Alveolar macrophages (AMs) express the class A scavenger receptors (SRAs) macrophage receptor with collagenous structure (MARCO) and scavenger receptor AI/II (SRA-I/II), which recognize oxidized lipids and provide innate defense against inhaled pathogens and particles. Increased MARCO expression...... in lungs of ozone-resistant mice suggested an additional role protecting against inhaled oxidants. After ozone exposure, MARCO-/- mice showed greater lung injury than did MARCO+/+ mice. Ozone is known to generate oxidized, proinflammatory lipids in lung lining fluid, such as 5beta,6beta......-epoxycholesterol (beta-epoxide) and 1-palmitoyl-2-(9'-oxo-nonanoyl)-glycerophosphocholine (PON-GPC). Intratracheal instillation of either lipid caused substantial neutrophil influx in MARCO-/- mice, but had no effect in MARCO+/+ mice. Normal AMs showed greater uptake in vitro of beta-epoxide compared with MARCO-/- AMs...

Electrochemical sensor based on a carbon nanotube-modified imprinted sol–gel for selective and sensitive determination of β2-agonists

International Nuclear Information System (INIS)

Xu, Wei; Liu, Ping; Guo, Chunhui; Dong, Chao; Zhang, Xiuhua; Wang, Shengfu

2013-01-01

We describe a molecularly imprinted electrochemical sensor for selective and sensitive determination of β2-agonists. It is making use of a combination of single-wall carbon nanotubes (SWNTs) with a molecularly imprinted sol–gel. The SWNTs were introduced in order to enhance electron transport and sensitivity. The imprinted sol–gel film with its specific binding sites acts as a selective recognition element and as a preconcentrator for β 2 -agonists. The morphology of the imprinted film was characterized by scanning electron microscopy. The optimized sensor displays high sensitivity and excellent selectivity for the β 2 -agonists as shown for their determination in human serum samples. (author)

Small-molecule AT2 receptor agonists

DEFF Research Database (Denmark)

Hallberg, Mathias; Sumners, Colin; Steckelings, U Muscha

2018-01-01

The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist...... with the highest affinity for the AT2R reported to date (Ki = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8......, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also...

State of the Art Compendium: Canadian Thoracic Society Recommendations for Management of Chronic Obstructive Pulmonary Disease

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Denis E O’Donnell

2004-01-01

Full Text Available Chronic obstructive pulmonary disease (COPD is a common cause of disability and death in Canada. Moreover, morbidity and mortality from COPD continue to rise, and the economic burden is enormous. The main goal of the Canadian Thoracic Society’s evidence-based guidelines is to optimize early diagnosis, prevention and management of COPD in Canada. The main message of the guidelines is that COPD is a preventable and treatable disease. Targeted spirometry is strongly recommended to expedite early diagnosis in smokers and former smokers who develop respiratory symptoms, and who are at risk for COPD. Smoking cessation remains the single most effective intervention to reduce the risk of COPD and to slow its progression. Education, especially self-management plans, are key interventions in COPD. Therapy should be escalated on an individual basis in accordance with the increasing severity of symptoms and disability. Long-acting anticholinergics and beta-2-agonist inhalers should be prescribed for patients who remain symptomatic despite short-acting bronchodilator therapy. Inhaled steroids should not be used as first line therapy in COPD, but have a role in preventing exacerbations in patients with more advanced disease who suffer recurrent exacerbations. Acute exacerbations of COPD cause significant morbidity and mortality and should be treated promptly with bronchodilators and a short course of oral steroids; antibiotics should be prescribed for purulent exacerbations. Patients with advanced COPD and respiratory failure require a comprehensive management plan that incorporates structured end-of-life care. Management strategies, consisting of combined modern pharmacotherapy and nonpharmacotherapeutic interventions (eg, pulmonary rehabilitation and exercise training can effectively improve symptoms, activity levels and quality of life, even in patients with severe COPD.

State of the Art Compendium: Canadian Thoracic Society recommendations for the management of chronic obstructive pulmonary disease.

Science.gov (United States)

O'Donnell, Denis E; Aaron, Shawn; Bourbeau, Jean; Hernandez, Paul; Marciniuk, Darcy; Balter, Meyer; Ford, Gordon; Gervais, Andre; Goldstein, Roger; Hodder, Rick; Maltais, Francois; Road, Jeremy; McKay, Valoree; Schenkel, Jennifer; Ariel, Annon; Day, Anna; Lacasse, Yves; Levy, Robert; Lien, Dale; Miller, John; Rocker, Graeme; Sinuff, Tasmin; Stewart, Paula; Voduc, Nha; Abboud, Raja; Ariel, Amnon; Becklake, Margo; Borycki, Elizabeth; Brooks, Dina; Bryan, Shirley; Calcutt, Luanne; Chapman, Ken; Choudry, Nozhat; Couet, Alan; Coyle, Steven; Craig, Arthur; Crawford, Ian; Dean, Mervyn; Grossman, Ronald; Haffner, Jan; Heyland, Daren; Hogg, Donna; Holroyde, Martin; Kaplan, Alan; Kayser, John; Lein, Dale; Lowry, Josiah; McDonald, Les; MacFarlane, Alan; McIvor, Andrew; Rea, John; Reid, Darlene; Rouleau, Michel; Samis, Lorelei; Sin, Don; Vandemheen, Katherine; Wedzicha, J A; Weiss, Karl

2004-01-01

Chronic obstructive pulmonary disease (COPD) is a common cause of disability and death in Canada. Moreover, morbidity and mortality from COPD continue to rise, and the economic burden is enormous. The main goal of the Canadian Thoracic Society's evidence-based guidelines is to optimize early diagnosis, prevention and management of COPD in Canada. The main message of the guidelines is that COPD is a preventable and treatable disease. Targeted spirometry is strongly recommended to expedite early diagnosis in smokers and former smokers who develop respiratory symptoms, and who are at risk for COPD. Smoking cessation remains the single most effective intervention to reduce the risk of COPD and to slow its progression. Education, especially self-management plans, are key interventions in COPD. Therapy should be escalated on an individual basis in accordance with the increasing severity of symptoms and disability. Long-acting anticholinergics and beta-2-agonist inhalers should be prescribed for patients who remain symptomatic despite short-acting bronchodilator therapy. Inhaled steroids should not be used as first line therapy in COPD, but have a role in preventing exacerbations in patients with more advanced disease who suffer recurrent exacerbations. Acute exacerbations of COPD cause significant morbidity and mortality and should be treated promptly with bronchodilators and a short course of oral steroids; antibiotics should be prescribed for purulent exacerbations. Patients with advanced COPD and respiratory failure require a comprehensive management plan that incorporates structured end-of-life care. Management strategies, consisting of combined modern pharmacotherapy and nonpharmacotherapeutic interventions (eg, pulmonary rehabilitation and exercise training) can effectively improve symptoms, activity levels and quality of life, even in patients with severe COPD.

Bronchial thermoplasty: a novel treatment for severe asthma requiring monitored anesthesia care.

Science.gov (United States)

Lee, Jamille A; Rowen, David W; Rose, David D

2011-12-01

Dexmedetomidine used in monitored anesthesia care produces a safe and effective technique well documented in research. We report the successful use of dexmedetomidine for sedation during bronchial thermoplasty, a new treatment for patients with severe persistent asthma refractory to inhaled corticosteroids and long-term beta-2 agonists.

Efficacy and safety of the long-acting β2-agonist olodaterol over 4 weeks in Japanese patients with chronic obstructive pulmonary disease

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Ichinose M

2015-08-01

Full Text Available Masakazu Ichinose,1 Ayako Takizawa,2 Toshiyasu Izumoto,2 Yusuke Tadayasu,2 Alan L Hamilton,3 Christina Kunz,4 Yoshinosuke Fukuchi51Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan; 3Boehringer Ingelheim, Burlington, Ontario, Canada; 4Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; 5Juntendo University School of Medicine, Tokyo, JapanBackground: Olodaterol is a novel long-acting β2-agonist with proven ≥24-hour duration of action in preclinical and clinical studies.Objective: This randomized, double-blind, placebo-controlled, parallel-group study evaluated the dose response of once-daily (QD olodaterol based on bronchodilator efficacy, safety, and pharmacokinetics over 4 weeks in Japanese patients with chronic obstructive pulmonary disease (COPD.Methods: All eligible patients were randomized to receive 2 µg, 5 µg, or 10 µg of olodaterol or placebo for 4 weeks via the Respimat® Soft Mist™ inhaler. The primary end point was the change from baseline in trough forced expiratory volume in 1 second (FEV1 after 4 weeks of olodaterol treatment. Secondary end points included trough FEV1 after 1 week and 2 weeks of treatment, FEV1 area under the curve from 0 hour to 3 hours (AUC0–3, peak FEV1 from 0 hour to 3 hours (peak FEV1, and corresponding forced vital capacity (FVC responses. Rescue medication use, COPD symptoms, physician global evaluation, pharmacokinetics, and safety were also assessed.Results: A total of 328 patients with COPD were randomized to receive treatment. All olodaterol doses assessed in the study showed statistically significant increases in trough FEV1 compared to placebo at Day 29 (P<0.0001. Mean increases in peak FEV1 and FEV1 AUC0–3 compared to placebo were also significant (P<0.0001. A clear dose–response relationship was observed across all treatment groups. FVC responses (trough

Respiratory medication used in COPD patients from seven Latin American countries: the LASSYC study

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Casas A

2018-05-01

Full Text Available Alejandro Casas,1 Maria Montes de Oca,2 Ana MB Menezes,3 Fernando C Wehrmeister,3 Maria Victorina Lopez Varela,4 Laura Mendoza,5 Larissa Ramírez,6 Marc Miravitlles7 On behalf of the LASSYC team 1Fundación Neumológica Colombiana, Universidad del Rosario, Bogotá, Colombia; 2Universidad Central de Venezuela, Caracas, Venezuela; 3Federal University of Pelotas, Pelotas, Brazil; 4Universidad de la República, Montevideo, Uruguay; 5Hospital Clínico Universidad de Chile, Santiago de Chile, Chile; 6AstraZeneca, San José, Costa Rica; 7Department of Pneumology, Hospital Universitari Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES, Barcelona, Spain Background: Limited information is available regarding medication use in COPD patients from Latin America. This study evaluated the type of medication used and the adherence to different inhaled treatments in stable COPD patients from the Latin American region.Methods: This was an observational, cross-sectional, multinational, and multicenter study in COPD patients attended by specialist doctors from seven Latin American countries. Adherence to inhaled therapy was assessed using the Test of Adherence to Inhalers (TAI questionnaire. The type of medication was assessed as: short-acting β-agonist (SABA or short-acting muscarinic antagonist (SAMA only, long-acting muscarinic antagonist (LAMA, long-acting β-agonist (LABA, LABA/LAMA, inhaled corticosteroid (ICS, ICS/LABA, ICS/LAMA/LABA, or other.Results: In total, 795 patients were included (59.6% male, with a mean age of 69.5±8.7 years and post-bronchodilator FEV1 of 50.0%±18.6%. The ICS/LAMA/LABA (32.9% and ICS/LABA (27.7% combinations were the most common medications used, followed by LABA/LAMA (11.3%, SABA or SAMA (7.9%, LABA (6.4%, LAMA (5.8%, and ICS (4.3%. The types of medication most commonly used in each Global Initiative for Chronic Obstructive Lung Disease (GOLD 2013 category were ICS/LABA (A: 32.7%; B: 19.8%; C: 25.7%; D: 28.2% and

Effect of adrenaline and alpha-agonists on net rate of liquid absorption from the pleural space of rabbits.

Science.gov (United States)

Zocchi, L; Raffaini, A; Agostoni, E

1997-05-01

Indirect evidence supporting a solute-coupled liquid absorption from the pleural space of rabbits has recently been provided; moreover, the beta 2-adrenoceptor agonist terbutaline has been found to increase this absorption. In this study the effect of adrenaline and alpha-adrenoceptor agonists on net rate of liquid absorption (Jnet) from albumin Ringer hydrothoraces of various sizes has been determined in anaesthetized rabbits. In hydrothoraces with adrenaline (5 x 10(-6) M) the relationship between Jnet and volume of liquid injected was displaced upwards by 0.09 ml h-1 relative to that in control hydrothoraces (P liquid absorption, since beta-agonists inhibit lymphatic activity while, at relatively high concentrations, they may increase active transport. Conversely, the strong stimulation of lymphatic alpha-receptors that should occur with adrenaline after beta-blockade may fail to increase lymphatic drainage, because it has been shown that the increase in contraction frequency of lymphatics may be balanced by the decrease in their stroke volume. Arterial blood pressure during the hydrothoraces with adrenaline was unchanged. In hydrothoraces with the alpha 2-agonist clonidine (5 x 10(-6) M; a less potent agent than adrenaline) the slope of the relationship between Jnet and volume injected increased by 26% (P liquid load. In hydrothoraces with the alpha 1-agonist phenylephrine (5 x 10(-6) or 10(-7) M) Jnet was simlar to control values.

Where current pharmacological therapies fall short in COPD: symptom control is not enough

Directory of Open Access Journals (Sweden)

N. Roche

2007-09-01

Full Text Available Chronic obstructive pulmonary disease (COPD is a common and progressive condition that is currently the fourth leading cause of death worldwide. There is now a large body of evidence indicating that both pulmonary and systemic inflammation are present in patients with stable COPD and may underlie both respiratory symptoms and common comorbidities of this disease. Smoking cessation and long-term oxygen therapy have been shown to change the course of COPD and recent results obtained with the combination of fluticasone and salmeterol have indicated that it could decrease mortality and slow the decline in lung function in patients with this disease. However, some pharmacological treatments can significantly improve dyspnoea, exercise tolerance, limitations in activity, rate of exacerbations and quality of life (e.g. long-acting bronchodilators and inhaled corticosteroids combined with a long-acting beta2-agonist. The ability of these agents to modify the rate of disease progression remains to be firmly established in large-scale, long-term trials. The concept of disease modification itself in COPD may need to be revisited and more precisely defined in terms of markers and clinical outcomes, including extrarespiratory manifestations: agents that durably affect symptoms, activities, exacerbations and quality of life should probably be considered as disease modifiers. It is also reasonable to suggest that early diagnosis and treatment of patients with COPD might be the first and potentially most important disease-modifying intervention. There is clearly a need for new therapies that directly target the specific inflammatory processes underlying chronic obstructive pulmonary disease and its pulmonary and extrapulmonary manifestations.

Switching patients from other inhaled corticosteroid devices to the Easyhaler®: historical, matched-cohort study of real-life asthma patients

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Price D

2014-04-01

Full Text Available David Price,1,2 Vicky Thomas,2 Julie von Ziegenweidt,2 Shuna Gould,2 Catherine Hutton,2 Christine King2 1Academic Centre of Primary Care, University of Aberdeen, Aberdeen, UK; 2Research in Real Life, Oakington, Cambridge, UK Purpose: To investigate the clinical and cost effectiveness of switching real-life asthma patients from other types of inhalers to the Easyhaler® (EH for the administration of inhaled corticosteroids (ICS. Patients and methods: Historical, matched-cohort study of 1,958 asthma patients (children and adults treated in UK primary-care practices, using data obtained from the Optimum Patient Care Research Database and Clinical Practice Research Datalink. Other inhalers (OH included pressurized metered-dose inhalers, breath-actuated inhalers, and dry-powder inhalers, delivering beclomethasone, budesonide, fluticasone, or ciclesonide. Patients remaining on OH unchanged (same drug, dosage, and device; n=979 were matched 1:1 with those switched to the EH (beclomethasone or budesonide at the same or lower ICS dosage (n=979, based on age, sex, year of index patient review/switch, most recent ICS drug, dosage, and device, and the number of severe exacerbations and average daily short-acting β2 agonist (SABA dosage in the preceding year. Clinical outcomes and health care costs were compared between groups for 12 months before and after the switch. Co-primary clinical outcomes were: 1 risk domain asthma control (RDAC – no asthma-related hospitalization, acute oral steroid use, or lower respiratory tract infection (LRTI; 2 exacerbation rate (American Thoracic Society [ATS] definition – where exacerbation is asthma-related hospitalization or acute oral steroid use; 3 exacerbation rate (clinical definition – where exacerbation is ATS exacerbation or LRTI; and 4 overall asthma control (OAC – RDAC plus average salbutamol-equivalent SABA dosage ≤200 μg/day. Non-inferiority (at least equivalence of EH was tested against OH for the

Cerebral blood flow measurement using stable xenon CT with very short inhalation times

Energy Technology Data Exchange (ETDEWEB)

Touho, Hajime; Karasawa, Jun; Shishido, Hisashi; Yamada, Keisuke; Shibamoto, Keiji [Osaka Neurological Inst., Toyonaka (Japan)

1991-02-01

A noninvasive, simplified method using inhalation of stable xenon (Xe{sup s}) and computed tomographic (CT) scanning to estimate regional cerebral blood flow (rCBF) and regional partition coefficient (r{lambda}) is described. Twenty-four patients with cerebrovascular occlusive disease and six volunteer controls inhaled 30% Xe{sup s} and 70% oxygen for 180 seconds and exhaled for 144 seconds during serial CT scanning without denitrogenation. The end-tidal Xe{sup s} concentration was continuously monitored with a thermoconductivity analyzer to determine the build-up range (A value) and build-up rate constant (K value) for arteries with the curve fitting method. The time-CT number (Hounsfield unit) curve for cerebral tissue during the Xe{sup s} washin and washout phases was used to calculate r{lambda} and rCBF using least squares curve fitting analysis. The resultant r{lambda} and rCBF map demonstrated a reliable distribution between the gray and white matter, and infarcted areas. rCBF was high in gray matter, low in white matter, and much lower in infarcted areas than in white matter. r{lambda} was high in white matter, low in gray matter, and much lower in infarcted areas. Xe{sup s} CT-CBF studies with very short inhalation of 180 seconds is a clinically useful method for evaluation of rCBF in patients with cerebrovascular diseases. (author).

Failure of gamma-aminobutyrate acid-beta agonist baclofen to improve balance, gait, and postural control after vestibular schwannoma resection.

Science.gov (United States)

De Valck, Claudia F J; Vereeck, Luc; Wuyts, Floris L; Van de Heyning, Paul H

2009-04-01

Incomplete postural control often occurs after vestibular schwannoma (VS) surgery. Customized vestibular rehabilitation in man improves and speeds up this process. Animal experiments have shown an improved and faster vestibular compensation after administration of the gamma-aminobutyrate acid (GABA)-beta agonist baclofen. To examine whether medical treatment with baclofen provides an improvement of the compensation process after VS surgery. A time-series study with historical control. Tertiary referral center. Thirteen patients who underwent VS resection were included and compared with a matched group of patients. In addition to an individualized vestibular rehabilitation protocol, the study group received medical treatment with 30 mg baclofen (a GABA-beta agonist) daily during the first 6 weeks after surgery. Clinical gait and balance tests (Romberg maneuver, standing on foam, tandem Romberg, single-leg stance, Timed Up & Go test, tandem gait, Dynamic Gait Index) and Dizziness Handicap Inventory. Follow-up until 24 weeks after surgery. When examining the postoperative test results, the group treated with baclofen did not perform better when compared with the matched (historical control) group. Repeated-measures analysis of variance revealed no significant group effect, but a significant time effect for almost all balance tests during the acute recovery period was found. An interaction effect between time and intervention was seen concerning single-leg stance and Dizziness Handicap Inventory scores for the acute recovery period. Medical therapy with baclofen did not seem to be beneficial in the process of central vestibular compensation.

Synthesis and biodistribution of [C-11]procaterol, a beta(2)-adrenoceptor agonist for positron emission tomography

NARCIS (Netherlands)

Visser, TJ; van der Wouden, EA; van Waarde, A; Doze, P; Elsinga, PH; Vaalburg, W

The potent, subtype-selective radioligand (+/-)-erythro-5-(1-hydroxy-2-[C-11]isopropyl-aminobutyl)-8-hydroxy-carbostyril ([C-11]procaterol) was synthesized and evaluated for visualization of pulmonary beta(2)-adrenoceptors with positron emission tomography (PET). Procaterol was labelled by reductive

A case of lactic acidosis complicating assessment and management of asthma

Directory of Open Access Journals (Sweden)

Veenith Tonny V

2008-04-01

Full Text Available Abstract Introduction Lactic acidosis often occurs in severely unwell patients presenting to Accident and Emergency. It is commonly associated with either hypoxia or decreased tissue perfusion secondary due to cardiovascular collapse or sepsis. Case presentation We present a case of severe lactic acidosis in the presence of normal tissue perfusion and oxygenation in a 31-year-old patient with poorly-controlled asthma. Acidosis promptly reversed on discontinuation of inhaled beta-agonists. Conclusion Lactic acidosis secondary to inhaled beta-agonist administration may be a common scenario which can be misinterpreted very easily and can confuse the clinical picture. Further studies will be needed to establish the exact aetiology of this lactic acid production.

Pharmacokinetics and safety of olodaterol administered with the Respimat Soft Mist inhaler in subjects with impaired hepatic or renal function

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Kunz C

2016-03-01

Full Text Available Christina Kunz,1 Doreen Luedtke,1 Anna Unseld,2 Alan Hamilton,3 Atef Halabi,4 Martina Wein,5 Stephan Formella6 1Translational Medicine and Clinical Pharmacology, 2Global Biometrics and Clinical Applications, Boehringer Ingelheim Pharma GmbH and Co KG, Biberach, Germany; 3Boehringer Ingelheim, Burlington, ON, Canada; 4CRS Clinical Research Services Kiel GmbH, Kiel, 5Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH and Co KG, Biberach, 6Medicine Coordination, Boehringer Ingelheim Pharma GmbH and Co KG, Ingelheim, Germany Purpose: In two trials, the influences of hepatic and renal impairment on the pharmacokinetics of olodaterol, a novel long-acting inhaled β2-agonist for treatment of COPD, were investigated.Subjects and methods: The first trial included eight subjects with mild hepatic function impairment (Child–Pugh A, eight subjects with moderate impairment (Child–Pugh B, and 16 matched healthy subjects with normal hepatic function. The second trial included eight subjects with severe renal impairment (creatinine clearance <30 mL·min-1 and 14 matched healthy subjects with normal renal function. Subjects received single doses of 20 or 30 µg olodaterol administered with the Respimat Soft Mist inhaler.Results: Olodaterol was well tolerated in all subjects. The geometric mean ratios and 90% confidence intervals of dose-normalized area under the plasma concentration-time curve from time zero to 4 hours (AUC0–4 for subjects with mild and moderate hepatic impairment compared to healthy subjects were 97% (75%–125% and 105% (79%–140%, respectively. Corresponding values for dose-normalized maximum concentration (Cmax were 112% (84%–151% (mild impairment and 99% (73%–135% (moderate impairment. The geometric mean ratio (90% confidence interval of AUC0–4 for subjects with severe renal impairment compared to healthy subjects was 135% (94%–195%, and for Cmax was 137% (84%–222%. There was no significant relationship

Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β2-Adrenoceptor Agonists in Airway Smooth Muscle

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Kentaro Fukunaga

2016-09-01

Full Text Available Long-acting muscarinic antagonists (LAMAs and short-acting β2-adrenoceptor agonists (SABAs play important roles in remedy for COPD. To propel a translational research for development of bronchodilator therapy, synergistic effects between SABAs with LAMAs were examined focused on Ca2+ signaling using simultaneous records of isometric tension and F340/F380 in fura-2-loaded tracheal smooth muscle. Glycopyrronium (3 nM, a LAMA, modestly reduced methacholine (1 μM-induced contraction. When procaterol, salbutamol and SABAs were applied in the presence of glycopyrronium, relaxant effects of these SABAs are markedly enhanced, and percent inhibition of tension was much greater than the sum of those for each agent and those expected from the BI theory. In contrast, percent inhibition of F340/F380 was not greater than those values. Bisindolylmaleimide, an inhibitor of protein kinase C (PKC, significantly increased the relaxant effect of LAMA without reducing F340/F380. Iberiotoxin, an inhibitor of large-conductance Ca2+-activated K+ (KCa channels, significantly suppressed the effects of these combined agents with reducing F340/F380. In conclusion, combination of SABAs with LAMAs synergistically enhances inhibition of muscarinic contraction via decreasing both Ca2+ sensitization mediated by PKC and Ca2+ dynamics mediated by KCa channels. PKC and KCa channels may be molecular targets for cross talk between β2-adrenoceptors and muscarinic receptors.

Interferon-Beta in Pediatric Multiple Sclerosis Patients: Safety in Short-Term Prescription

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Amir Hadi Maghzi

2012-02-01

Full Text Available Introduction: None of the approved immunomodulatory drugs in adults Multiple Sclerosis (MS patients have been officially approved for the pediatric patients and are currently used off-label in this population. Objectives: In this study, we evaluated the effectiveness and tolerability of intramuscular interferon beta1-a (Avonex® and subcutaneously injected interferon beta1-b (Betaferon® in children with definite relapsing-remitting MS (RRMS. Thirteen patients aged younger than 16, who were recently diagnosed with definite RRMS according to the McDonalds criteria, were enrolled in this study. Six patients were treated with Avonex® 30 μg, intramuscularly every week, and seven patients were treated with Betaferon® 250 μg, subcutaneously every other day. All patients were treated with adult doses; initially interferon-beta was prescribed with half dose, and it was increased to full adult dose steadily. Results: Eleven girls and two boys, mean (SD age of 14.7 (1.9 years, were studied. Following nine months of using interferon-beta, nine patients (69.2% had no relapses and the remaining four, experienced only one relapse. The mean EDSS score was decreased significantly after the study period. Conclusion: The present study provides reasonable data for the use of interferon-beta in Pediatric MS due to lack of short-term complications and safety. Studies with larger sample size and longer follow up duration are required to shed light on the long term impact of the interferon-beta therapy in children.

Comparative efficacy of indacaterol in chronic obstructive pulmonary disease

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Ribeiro M

2012-03-01

Full Text Available Marcos Ribeiro, Kenneth R ChapmanAsthma and Airway Centre, University Health Network, Toronto Western Hospital, University of Toronto, Toronto, ON, CanadaAbstract: Long-acting bronchodilators have been shown to improve multiple clinical outcomes in chronic obstructive pulmonary disease (COPD including lung function, symptoms, dyspnea, quality of life, and exacerbations. Indacaterol is a novel, inhaled, long-acting β2-agonist providing 24-hour bronchodilation with once-daily dosing. It is currently approved for the maintenance treatment of COPD to be administered as 150 or 300 µg once-daily doses as licensed in many countries and 75 µg as licensed in the US by means of a single-dose dry powder inhaler. The data from clinical development support a favorable safety and tolerability profile within the β2-agonist drug class, with no relevant issues identified. Current evidence indicates that indacaterol is suitable for use as first-line monotherapy in COPD patients with moderate disease (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II and beyond that do not require an inhaled corticosteroid (ICS as per GOLD guidelines, or in combination with an ICS in severe or very severe patients with repeated exacerbations. Data from trials with the novel once-daily β2-agonist, indacaterol, indicate superior bronchodilation and clinical efficacy over twice-daily long-acting β2-agonists and at least equipotent bronchodilation as once-daily tiotropium. Bronchodilators are central in the symptomatic management of COPD. It is likely that once-daily dosing of a bronchodilator would be a significant convenience and probably a compliance-enhancing advantage, leading to improved overall clinical outcomes in patients with COPD.Keywords: indacaterol, onset of action, chronic obstructive pulmonary disease, bronchodilators, once-daily, long-acting β2-agonists

Severe chronic bronchiolitis as the presenting feature of primary Sjögren's syndrome.

Science.gov (United States)

Borie, Raphael; Schneider, Sophie; Debray, Marie-Pierre; Adle-Biasssette, Homa; Danel, Claire; Bergeron, Anne; Mariette, Xavier; Aubier, Michel; Papo, Thomas; Crestani, Bruno

2011-01-01

Sjögren's syndrome is a frequent auto-immune disorder with a pulmonary location in almost 10% of the patients. Although bronchial involvement is very common, most patients only complain of cough and this involvement rarely results in severe symptoms or chronic respiratory failure are rarely observed. We describe here 5 patients with severe chronic bronchiolitis revealing primary Sjögren's syndrome. The lung involvement resulted in chronic bronchorrhea, recurrent sinusitis, diffuse bronchiolar nodules with bronchiectasis on the CT scan, and a severe obstructive airway pattern on lung function tests. Improvement was obtained in 4 patients with combination of inhaled corticosteroids, inhaled long acting beta-agonists, and a low dose of erythromycin. Copyright © 2010 Elsevier Ltd. All rights reserved.

Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes

DEFF Research Database (Denmark)

Lund, Asger; Knop, Filip K; Vilsbøll, Tina

2014-01-01

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone, secreted in response to ingestion of nutrients, and has important effects on several of the pathophysiological features of type 2 diabetes (T2D). The effects include potentiation of insulin secretion, suppression of glucagon secretion...... effects. This review gives an overview of the clinical data on GLP-1R agonists that have been compared in head-to-head studies and focuses on relevant differences between the compounds. Highlighting these similarities and differences could be beneficial for physicians in choosing the best treatment......, slowing of gastric emptying and suppression of appetite. In circulation, GLP-1 has a half-life of approximately 2min due to rapid degradation by the enzyme dipeptidyl peptidase 4 (DPP-4). Because of this short half-life GLP-1 receptor (GLP-1R) agonists, resistant to degradation by DPP-4 have been...

Relation between the 2{nu}{beta}{beta} and 0{nu}{beta}{beta} nuclear matrix elements

Energy Technology Data Exchange (ETDEWEB)

Vogel, Petr [Kellogg Radiation Laboratory, Caltech, Pasadena, CA 91125 (United States); Simkovic, Fedor [Department of Nuclear Physics and Biophysics, Comenius University, Mlynska dolina F1, SK-84248 Bratislava (Slovakia)

2011-12-16

A formal relation between the GT part of the nuclear matrix elements M{sub GT}{sup 0{nu}} of 0{nu}{beta}{beta} decay and the closure matrix elements M{sub cl}{sup 2{nu}} of 2{nu}{beta}{beta} decay is established. This relation is based on the integral representation of these quantities in terms of their dependence on the distance r between the two nucleons undergoing transformation. We also discuss the difficulties in determining the correct values of the closure 2{nu}{beta}{beta} decay matrix elements.

Molecular cloning and characterization of a human beta-Gal-3'-sulfotransferase that acts on both type 1 and type 2 (Gal beta 1-3/1-4GlcNAc-R) oligosaccharides.

Science.gov (United States)

Honke, K; Tsuda, M; Koyota, S; Wada, Y; Iida-Tanaka, N; Ishizuka, I; Nakayama, J; Taniguchi, N

2001-01-05

A novel sulfotransferase gene (designated GP3ST) was identified on human chromosome 2q37.3 based on its similarity to the cerebroside 3'-sulfotransferase (CST) cDNA (Honke, K., Tsuda, M., Hirahara, Y., Ishii, A., Makita, A., and Wada, Y. (1997) J. Biol. Chem. 272, 4864-4868). A full-length cDNA was obtained by reverse transcription-polymerase chain reaction and 5'- and 3'-rapid amplification of cDNA ends analyses of human colon mRNA. The isolated cDNA clone predicts that the protein is a type II transmembrane protein composed of 398 amino acid residues. The amino acid sequence indicates 33% identity to the human CST sequence. A recombinant protein that is expressed in COS-1 cells showed no CST activity, but did show sulfotransferase activities toward oligosaccharides containing nonreducing beta-galactosides such as N-acetyllactosamine, lactose, lacto-N-tetraose (Lc4), lacto-N-neotetraose (nLc4), and Gal beta 1-3GalNAc alpha-benzyl (O-glycan core 1 oligosaccharide). To characterize the cloned sulfotransferase, a sulfotransferase assay method was developed that uses pyridylaminated (PA) Lc4 and nLc4 as enzyme substrates. The enzyme product using PA-Lc4 as an acceptor was identified as HSO(3)-3Gal beta 1-3GlcNAc beta 1-3Gal beta 1- 4Glc-PA by two-dimensional (1)H NMR. Kinetics studies suggested that GP3ST is able to act on both type 1 (Gal beta 1-3GlcNAc-R) and type 2 (Gal beta 1-4GlcNAc-R) chains with a similar efficiency. In situ hybridization demonstrated that the GP3ST gene is expressed in epithelial cells lining the lower to middle layer of the crypts in colonic mucosa, hepatocytes surrounding the central vein of the liver, extravillous cytotrophoblasts in the basal plate and septum of the placenta, renal tubules of the kidney, and neuronal cells of the cerebral cortex. The results of this study indicate the existence of a novel beta-Gal-3'-sulfotransferase gene family.

Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis.

Science.gov (United States)

Vallée, Alexandre; Vallée, Jean-Noël; Guillevin, Rémy; Lecarpentier, Yves

2018-05-01

Multiple sclerosis (MS) is marked by neuroinflammation and demyelination with loss of oligodendrocytes in the central nervous system. The immune response is regulated by WNT/beta-catenin pathway in MS. Activated NF-kappaB, a major effector of neuroinflammation, and upregulated canonical WNT/beta-catenin pathway positively regulate each other. Demyelinating events present an upregulation of WNT/beta-catenin pathway, whereas proper myelinating phases show a downregulation of WNT/beta-catenin pathway essential for the promotion of oligodendrocytes precursors cells proliferation and differentiation. The activation of WNT/beta-catenin pathway results in differentiation failure and impairment in remyelination. However, PI3K/Akt pathway and TCF7L2, two downstream targets of WNT/beta-catenin pathway, are upregulated and promote proper remyelination. The interactions of these signaling pathways remain unclear. PPAR gamma activation can inhibit NF-kappaB, and can also downregulate the WNT/beta-catenin pathway. PPAR gamma and canonical WNT/beta-catenin pathway act in an opposite manner. PPAR gamma agonists appear as a promising treatment for the inhibition of demyelination and the promotion of proper remyelination through the control of both NF-kappaB activity and canonical WNT/beta-catenin pathway.

Development and validation of an UHPLC-MS/MS method for β2-agonists quantification in human urine and application to clinical samples.

Science.gov (United States)

Bozzolino, Cristina; Leporati, Marta; Gani, Federica; Ferrero, Cinzia; Vincenti, Marco

2018-02-20

A fast analytical method for the simultaneous detection of 24 β 2 -agonists in human urine was developed and validated. The method covers the therapeutic drugs most commonly administered, but also potentially abused β 2 -agonists. The procedure is based on enzymatic deconjugation with β-glucuronidase followed by SPE clean up using mixed-phase cartridges with both ion-exchange and lipophilic properties. Instrumental analysis conducted by UHPLC-MS/MS allowed high peak resolution and rapid chromatographic separation, with reduced time and costs. The method was fully validated according ISO 17025:2005 principles. The following parameters were determined for each analyte: specificity, selectivity, linearity, limit of detection, limit of quantification, precision, accuracy, matrix effect, recovery and carry-over. The method was tested on real samples obtained from patients subjected to clinical treatment under chronic or acute therapy with either formoterol, indacaterol, salbutamol, or salmeterol. The drugs were administered using pressurized metered dose inhalers. All β 2 -agonists administered to the patients were detected in the real samples. The method proved adequate to accurately measure the concentration of these analytes in the real samples. The observed analytical data are discussed with reference to the administered dose and the duration of the therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Conformational variability of the glycine receptor M2 domain in response to activation by different agonists

DEFF Research Database (Denmark)

Pless, Stephan Alexander; Dibas, Mohammed I; Lester, Henry A

2007-01-01

change. Although taurine and beta-alanine were weak partial agonists at the alpha1R19'C glycine receptor, they induced large fluorescence changes. Propofol, which drastically enhanced these currents, did not induce a glycine-like blue shift in the spectral emission peak. The inhibitors strychnine...... and picrotoxin elicited fluorescence and current changes as expected for a competitive antagonist and an open channel blocker, respectively. Glycine and taurine (or beta-alanine) also produced an increase and a decrease, respectively, in the fluorescence of a label attached to the nearby L22'C residue. Thus...

Is the human nasal cavity at risk from inhaled radionuclides?

International Nuclear Information System (INIS)

Boecker, B.B.; Hahn, F.F.; Cuddihy, R.G.; Snipes, M.B.; McClellan, R.O.

1986-01-01

In a series of three life-span studies in which beagle dogs inhaled relatively soluble forms of beta-emitting radionuclides, a number of cancers of the nasal cavity have arisen at long times after the inhalation exposure. No such cancers were observed in the control dogs. Data obtained in other studies involving serial sacrifice of dogs that received these radionuclides in similar forms have shown that high local concentrations of the radionuclides can persist in nasal turbinates for long periods of time, depending on the physical half-life of the radionuclide inhaled. Several nasal carcinomas have also been observed in dogs injected with 137 CsCl in which the relative concentrations of beta activity in the turbinate region were not as pronounced as in the above studies. Similar risks of sinonasal cancer were calculated for dogs in each of these studies regardless of differences in radionuclide, dosimetry, and route of administration. Since sinonasal cancers have occurred in people exposed to alpha-emitting radionuclides, it is reasonable to assume this could occur with beta emitters as well. Radiation protection guidelines should account for the sinonasal region being at risk. 23 refs., 1 fig., 6 tabs

beta. -endorphin modulation of mitogen-stimulated calcium uptake by rat thymocytes

Energy Technology Data Exchange (ETDEWEB)

Hemmick, L.M.; Bidlack, J.M.

1987-10-19

Lymphocytes stimulated by mitogens or antigens exhibit an enhanced calcium uptake early in the proliferation or activation response. Modulation of this calcium uptake results in alterations of proliferation and immunocompetence. ..beta..-endorphin and other opioids affect several parameters of lymphocyte competence. Limited data are available concerning the mechanism(s) of these effects. This study examines whether a possible opioid mechanism is the modification of the early calcium influx into stimulated lymphocytes. The time course of both concanavalin A (Con A) and phytohemagglutinin (PHA)-stimulated /sup 45/Ca/sup 2 +/ uptake into thymocytes was characterized to determine the optimal time for testing the effects of opioids. BETA-Endorphin 1-31 significantly enhanced Con A-stimulated /sup 45/Ca/sup 2 +/ uptake into rat thymocytes. This peptide had no significant effect on PHA-simulated /sup 45/Ca/sup 2 +/ uptake or on basal thymocyte /sup 45/Ca/sup 2 +/ flux. The ..beta../sub h/-endorphin stimulatory effect was titratable in the range of 0.1 nM to 10 ..mu..M. Naloxone did not reverse the enhancement. Met-enkephalinamide and other opioid agonists did not duplicate the stimulatory effect. Thus, the ..beta../sub h/-endorphin 1-31 enhancement of Con A-stimulated /sup 45/Ca/sup 2 +/ uptake by rat thymocytes does not operate via classical opioid receptor mechanisms. ..beta../sub h/-endorphin 1-31 appears to be acting on a subset of T cells that are responsive to Con A but not to PHA. 30 references, 4 figures, 1 table.

Mortality in COPD patients discharged from hospital: the role of treatment and co-morbidity

Directory of Open Access Journals (Sweden)

Nieminen Markku M

2006-08-01

Full Text Available Abstract Background The aim of this study was to analyse mortality and associated risk factors, with special emphasis on health status, medications and co-morbidity, in patients with chronic obstructive pulmonary disease (COPD that had been hospitalized for acute exacerbation. Methods This prospective study included 416 patients from each of the five Nordic countries that were followed for 24 months. The St. George's Respiratory Questionnaire (SGRQ was administered. Information on treatment and co-morbidity was obtained. Results During the follow-up 122 (29.3% of the 416 patients died. Patients with diabetes had an increased mortality rate [HR = 2.25 (1.28–3.95]. Other risk factors were advanced age, low FEV1 and lower health status. Patients treated with inhaled corticosteroids and/or long-acting beta-2-agonists had a lower risk of death than patients using neither of these types of treatment. Conclusion Mortality was high after COPD admission, with older age, decreased lung function, lower health status and diabetes the most important risk factors. Treatment with inhaled corticosteroids and long-acting bronchodilators may be associated with lower mortality in patients with COPD.

Human myometrial adrenergic receptors: identification of the beta-adrenergic receptor by [3H]dihydroalprenolol binding

International Nuclear Information System (INIS)

Hayashida, D.N.; Leung, R.; Goldfien, A.; Roberts, J.M.

1982-01-01

The radioactive beta-adrenergic antagonist [ 3 H] dihydroalprenolol (DHA) binds to particulate preparations of human myometrium in a manner compatible with binding to the beta-adrenergic receptor. The binding of DHA is rapid (attaining equilibrium in 12 minutes), readily reversible (half time = 16 minutes), high affinity (K/sub D/ = 0.50 nM), low capacity (Bmax = 70 fmoles/mg of protein), and stereoselective ([-]-propranolol is 100 times as potent as [+] -propranolol in inhibiting DHA binding). Adrenergic agonists competed for DHA binding sites in a manner compatible with beta-adrenergic interactions and mirrored β 2 pharmacologic potencies: isoproterenol > epinephrine >> norepinephrine. Studies in which zinterol, a β 2 -adrenergic agonist, competed for DHA binding sites in human myometrial particulate indicated that at least 87% of the beta-adrenergic receptors present are β 2 -adrenergic receptors. Binding of DHA to human myometrial beta-adrenergic receptors provides a tool which may be used in the examination of gonadal hormonal modification of adrenergic response in human uterus as well as in the analysis of beta-adrenergic agents as potentially useful tocolytic agents

Mometasone furoate in the management of asthma: a review

Directory of Open Access Journals (Sweden)

Ricardo A Tan

2008-09-01

Full Text Available Ricardo A Tan1, Jonathan Corren21California Allergy and Asthma Medical Group, Los Angeles, CA; 2Allergy Research Foundation, Los Angeles, CA, USAAbstract: Inhaled corticosteroids (ICS have proven to be the most effective and essential therapy for the treatment of bronchial asthma. The 2007 National Asthma Education and Prevention Program guidelines recommend ICS as preferred therapy for patients with mild to severe persistent asthma. Mometasone furoate (MF is a relatively new ICS agent with high affinity for the glucocorticoid receptor. It is approved in the US for maintenance treatment of asthma for patients 4 years of age and older. It has been shown to be well tolerated with no significant adverse side effects observed in clinical trials and post-marketing surveillance. The efficacy of mometasone furoate has been established in large, well-designed studies. In patients with persistent asthma previously treated either with short-acting beta-agonists alone or twice-daily maintenance therapy with ICS, once-daily MF has been shown to be superior to placebo in improving lung function, symptom control, and quality of life; and has shown comparable efficacy compared with budesonide, beclomethasone, and fluticasone. Twice-daily dosing with MF has been demonstrated to successfully allow for reduction or elimination of oral corticosteroids in severe asthmatics.Keywords: inhaled steroids, mometasone furoate, once-daily dosing, asthma, stepwise approach

Incidence of bone cancer in beagles after inhalation of 90SrCl2 or 238PuO2: Implications for estimation of risk to humans

International Nuclear Information System (INIS)

Mewhinney, J.A.; Griffith, W.C.; Hahn, F.F.; Snipes, M.B.; Boecker, B.B.; McClellan, R.O.

1986-01-01

Among the life-span studies conducted with beagle dogs, bone cancer has been in two studies the predominant effect at death. These studies involved dogs that inhaled 90 SrCl 2 , which is very soluble in body fluids; and dogs that inhaled 238 PuO 2 , which is initially insoluble but eventually becomes fragmented and more soluble. Both radionuclides were deposited in the skeleton after dissolution in the lung and absorption into the bloodstream. All dogs in the 90 Sr study are dead, and all living dogs in the 238 Pu study are at least 7 years postexposure. Results from these two studies were compared to determine the relative biological effectiveness (RBE) of chronic beta and alpha radiation delivered from these two radionuclides. These data also were used to estimate the risk of bone cancer in man by using comparisons with data from the 90 Sr-, 239 Pu-, and 226 Ra-injected dogs at the University of Utah and data on humans who ingested 226 Ra or were injected with 224 Ra. Such comparisons provided a link between studies in laboratory animals and the available human data. In this way risks of bone cancer in humans from inhaled plutonium or strontium were estimated, even though currently no human cases of bone cancer are known to have resulted from the inhalation of either of these radionuclides. 15 refs., 7 figs., 7 tabs

Control del asma en pacientes que acuden a consulta de atención primaria en España (estudio ACTIS

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Eduardo Calvo

2017-12-01

. Participants: Asthma patients attending physicians office to collect repeat prescriptions for continuous treatment (Group A, or due to symptoms worsening (Group B. Main measurements: Socio-demographic characteristics (age, gender, education, smoking history, physician's assessment of asthma severity, current treatment for asthma, co-morbidities, healthcare-related resources utilization (primary care or emergency visits, hospitalizations, labour or school absenteeism, ACT score and treatment adherence. Results: 376 patients from group A and 262 from group B were included, 59% female, mean age 45 years, 21% smokers and time since asthma diagnosis 8.9 years. 87% were on short acting beta-2 agonists, 62% long acting beta-2 agonists with inhaled corticosteroids and 13.8% regular inhaled corticosteroids. Poor asthma control was observed in 75.6% from group B and 23.8% from group A; only 5.3% from group A showed total asthma control (ACT = 25. Poorer asthma control was significantly associated with longer disease duration and higher use of resources. Conclusions: Prevalence of poor asthma control among patients attending due to symptoms worsening continues to be very high even in patients who come to renew their prescription. Poor asthma control is associated to high use of resources and high impact on burden of disease. Palabras clave: Asma, Asthma Control Test, Atención primaria, Control del asma, Keywords: Asthma, Asthma Control Test, Primary care, Asthma control

Identification of factors involved in medication compliance: incorrect inhaler technique of asthma treatment leads to poor compliance

Directory of Open Access Journals (Sweden)

Darbà J

2016-02-01

Full Text Available Josep Darbà,1 Gabriela Ramírez,2 Antoni Sicras,3 Laura García-Bujalance,4 Saku Torvinen,5 Rainel Sánchez-de la Rosa6 1Department of Economics, Universitat de Barcelona, 2BCN Health Economics & Outcomes Research S.L., 3Department of Planning, Badalona Serveis Assistencials S.A., Barcelona, 4Market Access Department, Teva Pharmaceutical, Madrid, Spain; 5Market Access Department, Teva Pharmaceuticals Europe BV, Amsterdam, the Netherlands; 6Medical Department, Teva Pharmaceutical, Madrid, Spain Objective: To identify the impact of delivery device of inhaled corticosteroids and long-acting β2-agonist (ICS/LABA on asthma medication compliance, and investigate other factors associated with compliance. Materials and methods: We conducted a retrospective and multicenter study based on a review of medical registries of asthmatic patients treated with ICS/LABA combinations (n=2,213 whose medical devices were either dry powder inhalers (DPIs, such as Accuhaler®, Turbuhaler®, and NEXThaler® or pressurized metered-dose inhalers (pMDI. Medication compliance included persistence outcomes through 18 months and medication possession ratios. Data on potential confounders of treatment compliance such as asthma exacerbations, comorbidities, demographic characteristics, and health care resource utilization were also explored. Results: The probability of asthma medication compliance in case of DPIs was lower compared to pMDIs, which suggests that inhaler devices influence inhalation therapies. There were additional confounding factors that were considered as explanatory variables of compliance. A worse measure of airflow obstruction (forced expiration volume in 1 second, comorbidities and general practitioner (GP consultations more than once per month decreased the probability of compliance. Within comorbidities, alcoholism was positively associated with compliance. Patients of 29–39, 40–50, and 51–61 age groups or suffering from more than two

Dimers of beta 2-glycoprotein I mimic the in vitro effects of beta 2-glycoprotein I-anti-beta 2-glycoprotein I antibody complexes

NARCIS (Netherlands)

Lutters, B. C.; Meijers, J. C.; Derksen, R. H.; Arnout, J.; de Groot, P. G.

2001-01-01

Anti-beta(2)-glycoprotein I antibodies are thought to cause lupus anticoagulant activity by forming bivalent complexes with beta(2)-glycoprotein I (beta(2)GPI). To test this hypothesis, chimeric fusion proteins were constructed of the dimerization domain (apple 4) of factor XI and beta(2)GPI. Both a

Positioning new pharmacotherapies for COPD

Directory of Open Access Journals (Sweden)

Barjaktarevic IZ

2015-07-01

Full Text Available Igor Z Barjaktarevic,1 Anthony F Arredondo,1 Christopher B Cooper1,2 1Department of Medicine, 2Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA Abstract: COPD imposes considerable worldwide burden in terms of morbidity and mortality. In recognition of this, there is now extensive focus on early diagnosis, secondary prevention, and optimizing medical management of the disease. While established guidelines recognize different grades of disease severity and offer a structured basis for disease management based on symptoms and risk, it is becoming increasingly evident that COPD is a condition characterized by many phenotypes and its control in a single patient may require clinicians to have access to a broader spectrum of pharmacotherapies. This review summarizes recent developments in COPD management and compares established pharmacotherapy with new and emerging pharmacotherapies including long-acting muscarinic antagonists, long-acting β-2 sympathomimetic agonists, and fixed-dose combinations of long-acting muscarinic antagonists and long-acting β-2 sympathomimetic agonists as well as inhaled cortiocosteroids, phosphodiesterase inhibitors, and targeted anti-inflammatory drugs. We also review the available oral medications and new agents with novel mechanisms of action in early stages of development. With several new pharmacological agents intended for the management of COPD, it is our goal to familiarize potential prescribers with evidence relating to the efficacy and safety of new medications and to suggest circumstances in which these therapies could be most useful. Keywords: COPD phenotypes, once-daily inhalers, fixed-combination inhalers, long-acting muscarinic antagonist, LAMA, long-acting β-2 sympathomimetic agonist, LABA

Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors

International Nuclear Information System (INIS)

Rajasekaran, Maheswari; Brents, Lisa K.; Franks, Lirit N.; Moran, Jeffery H.; Prather, Paul L.

2013-01-01

K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB 1 Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB 2 Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB 2 Rs (hCB 2 Rs). The affinity of cannabinoids for hCB 2 Rs was determined by competition binding studies employing CHO-hCB 2 membranes. Intrinsic activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB 2 cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB 2 Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB 2 Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and Δ 9 -tetrahydrocannabinol (Δ 9 -THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB 2 R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB 2 Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB 2 Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB 1 and CB 2 Rs. - Highlights: • JWH-018 and JWH-073 are synthetic cannabinoids present in abused K2

A computational psychiatry approach identifies how alpha-2a noradrenergic agonist guanfacine affects feature-based reinforcement learning in the macaque

NARCIS (Netherlands)

Hassani, S.A.; Oemisch, M.; Balcarras, M.; Westendorff, S.; Ardid, S.; van der Meer, M.A.; Tiesinga, P.H.E.; Womelsdorf, T.

2017-01-01

Noradrenaline is believed to support cognitive flexibility through the alpha 2A noradrenergic receptor (a2A-NAR) acting in prefrontal cortex. Enhanced flexibility has been inferred from improved working memory with the a2A-NA agonist Guanfacine. But it has been unclear whether Guanfacine improves

Enhancement of the response to purinergic agonists in P2Y1 transfected 1321N1 cells by antagonists suramin and PPADS.

Science.gov (United States)

Brown, C A; Charlton, S J; Boarder, M R

1997-03-01

1. We have previously shown that both suramin and pyridoxal-phosphate-6-azophenyl-2',4' disulphonic acid (PPADS) act as antagonists at transfected P2Y1 receptors. Here we show that under certain experimental conditions these two P2 antagonists can enhance the response to agonists acting at these receptors. 2. The expression of either P2Y1 or P2Y2 receptors in 1321N1 human astrocytoma cells results, on a change of medium, in an elevation of basal (no added agonist) accumulation of [3H]-inositol(poly)phosphates([3H]-InsPx) compared to cells not expressing these receptors. This elevation is much greater in P2Y1 transfectants than in P2Y, transfectants. 3. Both PPADS and suramin reduced this basal level of [3H]-InsPx accumulation in the P2Y1 expressing cells. 4. When a protocol was used which required changing the culture medium, antagonists were added at a concentration which reduced the basal accumulation by about 50%, there was a significant stimulation in response to increasing concentrations of 2-methylthioadenosine 5'-triphosphate (2MeSATP), in the absence of antagonists there was no significant effect of the agonist. 5. However, when 2MeSATP was added in the absence of a change of medium and with no antagonist present, there was a several fold increase in [3H]-InsPx accumulation. These results show that a release of endogenous agonist activity (possibly ATP/ADP) from the P2Y1 expressing cells can create conditions in which a response to an agonist such as 2MeSATP can only be seen in the presence of a competitive antagonist.

Pharmacological, neurochemical, and behavioral profile of JB-788, a new 5-HT1A agonist.

Science.gov (United States)

Picard, M; Morisset, S; Cloix, J F; Bizot, J C; Guerin, M; Beneteau, V; Guillaumet, G; Hevor, T K

2010-09-01

A novel pyridine derivative, 8-{4-[(6-methoxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-ylmethyl)-amino]-butyl}-8-aza-spiro[4.5]decane-7,9-dione hydrochloride, termed JB-788, was designed to selectively target 5-HT(1A) receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT(1A) receptor expressed in human embryonic kidney 293 (HEK-293) cells with a K(i) value of 0.8 nM. Its binding affinity is in the same range as that observed for the (+/-)8-OH-DPAT, a reference 5HT(1A) agonist compound. Notably, JB-788 only bound weakly to 5-HT(1B) or 5-HT(2A) receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, alpha(2), beta(1) and beta(2) adrenergic receptors, or dopaminergic D(1) receptors. JB-788 was found to display substantial binding affinity for dopaminergic D(2) receptors and, to a lesser extend to alpha(1) adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT(1A), thus acting as a potent 5-HT(1A) receptor agonist (E(max.) 75%, EC(50) 3.5 nM). JB-788 did not exhibit any D(2) receptor agonism but progressively inhibited the effects of quinpirole, a D(2) receptor agonist, in the cAMP accumulation test with a K(i) value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area

Fluticasone furoate and vilanterol inhalation powder for the treatment of chronic obstructive pulmonary disease.

Science.gov (United States)

Matera, Maria Gabriella; Capuano, Annalisa; Cazzola, Mario

2015-02-01

Fluticasone furoate/vilanterol (FF/VI) is a novel inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) fixed dose combination that, by simplifying the dosing schedule, allows, for the first time in a member of the ICS/LABA class, a shift from twice-daily to once-daily treatment. FF/VI is delivered via a novel, single-step activation, multi-dose dry powder inhaler for oral inhalation, Ellipta. Regrettably, there are no head-to-head trials that have shown superiority in the safety or efficacy of FF versus other ICSs, but evidence shows that VI has a quicker onset of effect versus salmeterol. However, the clinical utility of this effect in a maintenance medication is still questionable. Furthermore, benefits of FF/VI over twice-daily ICS/LABA comparator have not been shown yet and, in addition, its adverse event profile is generally consistent with the known class effects of an ICS/LABA fixed dose combination. In particular, there is an increase in the risk of pneumonia among patients treated with FF/VI relative to VI, mainly among those who benefit most from FF/VI. Nevertheless, the interesting pharmacological profiles of both FF and VI, the possibility that FF/VI can be administered once-daily, and the attractive characteristics of Ellipta are important features that could help FF/VI to be a successful combination in the treatment of chronic obstructive pulmonary disease.

Characterization of a series of anabaseine-derived compounds reveals that the 3-(4)-dimethylaminocinnamylidine derivative is a selective agonist at neuronal nicotinic alpha 7/125I-alpha-bungarotoxin receptor subtypes.

Science.gov (United States)

de Fiebre, C M; Meyer, E M; Henry, J C; Muraskin, S I; Kem, W R; Papke, R L

1995-01-01

Investigation of the naturally occurring, nicotinic agonist anabaseine and novel derivatives has shown that these compounds have cytoprotective and memory-enhancing effects. The hypothesis that these arise at least in part through actions on brain nicotinic receptors was evaluated by examining the ability of these compounds to displace the binding of nicotinic ligands and to affect the function of the alpha 4 beta 2 and alpha 7 receptor subtypes expressed in Xenopus oocytes. The derivative 3-(4)-dimethylaminocinnamylidine anabaseine (DMAC) was found to be a selective alpha 7 receptor agonist; it was more potent than nicotine, acetylcholine, anabaseine, and other derivatives at activating the alpha 7 receptor subtype, while displaying little agonist activity at alpha 4 beta 2 and other receptor subtypes. Compared with anabaseine and the other derivatives, DMAC was the most potent at displacing 125I-alpha-bungarotoxin binding (putative alpha 7) and the least potent at displacing [3H]cytisine binding (putative alpha 4 beta 2) to brain membranes. Independently of agonist activities, all of the novel compounds displayed secondary inhibitory activity at both receptor subtypes. At the alpha 4 beta 2 receptor subtype, inhibition by the 3-(2,4)-dimethoxybenzylidene derivative was enhanced by coapplication of acetylcholine, suggesting a noncompetitive form of inhibition. Anabaseine and nicotine prolonged the time course of activation of alpha 4 beta 2 receptors, compared with acetylcholine, suggesting sequential channel-blocking activity. As selective agonists, anabaseine derivatives such as DMAC may be useful for elucidating the function of alpha 7 nicotinic receptors, including their potential role(s) in the cytoprotective and memory-enhancing effects of nicotinic agents.

Cromolyn Oral Inhalation

Science.gov (United States)

... your doctor.Cromolyn oral inhalation helps to prevent asthma attacks (sudden episodes of shortness of breath, wheezing, and coughing) but will not stop an asthma attack that has already started. Your doctor will prescribe ...

Expression of inwardly rectifying potassium channels (GIRKs) and beta-adrenergic regulation of breast cancer cell lines

International Nuclear Information System (INIS)

Plummer, Howard K III; Yu, Qiang; Cakir, Yavuz; Schuller, Hildegard M

2004-01-01

Previous research has indicated that at various organ sites there is a subset of adenocarcinomas that is regulated by beta-adrenergic and arachidonic acid-mediated signal transduction pathways. We wished to determine if this regulation exists in breast adenocarcinomas. Expression of mRNA that encodes a G-protein coupled inwardly rectifying potassium channel (GIRK1) has been shown in tissue samples from approximately 40% of primary human breast cancers. Previously, GIRK channels have been associated with beta-adrenergic signaling. Breast cancer cell lines were screened for GIRK channels by RT-PCR. Cell cultures of breast cancer cells were treated with beta-adrenergic agonists and antagonists, and changes in gene expression were determined by both relative competitive and real time PCR. Potassium flux was determined by flow cytometry and cell signaling was determined by western blotting. Breast cancer cell lines MCF-7, MDA-MB-361 MDA-MB 453, and ZR-75-1 expressed mRNA for the GIRK1 channel, while MDA-MB-468 and MDA-MB-435S did not. GIRK4 was expressed in all six breast cancer cell lines, and GIRK2 was expressed in all but ZR-75-1 and MDA-MB-435. Exposure of MDA-MB-453 cells for 6 days to the beta-blocker propranolol (1 μM) increased the GIRK1 mRNA levels and decreased beta 2 -adrenergic mRNA levels, while treatment for 30 minutes daily for 7 days had no effect. Exposure to a beta-adrenergic agonist and antagonist for 24 hours had no effect on gene expression. The beta adrenergic agonist, formoterol hemifumarate, led to increases in K + flux into MDA-MB-453 cells, and this increase was inhibited by the GIRK channel inhibitor clozapine. The tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a high affinity agonist for beta-adrenergic receptors stimulated activation of Erk 1/2 in MDA-MB-453 cells. Our data suggests β-adrenergic receptors and GIRK channels may play a role in breast cancer

Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28.

Science.gov (United States)

Hulshof, Janneke W; Vischer, Henry F; Verheij, Mark H P; Fratantoni, Silvina A; Smit, Martine J; de Esch, Iwan J P; Leurs, Rob

2006-11-01

G-protein coupled receptors encoded by viruses represent an unexplored class of potential drug targets. In this study, we describe the synthesis and pharmacological characterization of the first class of inverse agonists acting on the HCMV-encoded receptor US28. It is shown that replacement of the 4-hydroxy group of lead compound 1 with a methylamine group results in a significant 6-fold increase in affinity. Interestingly, increasing the rigidity of the spacer by the introduction of a double bond also leads to a significant increase in binding affinity compared to 1. These novel inverse agonists serve as valuable tools to elucidate the role of constitutive signaling in the pathogenesis of viral infection and may have therapeutic potential as leads for new antiviral drugs.

Abnormal temperature control after intoxication with short-acting barbiturates.

Science.gov (United States)

de Villota, E D; Mosquera, J M; Shubin, H; Weil, M H

1981-09-01

Changes in rectal and toe temperatures were measured in 16 patients who had been intoxicated with short-acting barbiturates. The lowest temperatures observed in the group of 16 patients averaged 35.5 +/- 2.0 degrees C. In 11 patients, the interval between intoxication and admission was documented. There was a significant correlation (r = 0.83) between the time of estimated intoxication and hypothermia. Patients who were admitted soon after the ingestion of the barbiturates had the lowest rectal temperatures. These observations indicate that hypothermia is a usual clinical sign in the initial period after intoxication with a short-acting barbiturate. Except for 2 patients, rectal temperature exceeded 38 degrees C during the interval of recovery with the maximum rectal temperature averaging 39.0 +/- 0.8 degrees C. Hyperthermia was not related to infection of the airways, lungs, urinary tract, or bloodstream. In 11 patients, pathogenic organisms were recovered from the airway and/or urine, but there was no difference in the highest rectal temperature in these patients (39.0 +/- 0.9 degrees C) when compared with 5 patients from whom no pathogenic organisms were recovered (39.2 +/- 0.7 degrees C). Accordingly, there was no evidence that hyperthermia was due to infection. The skin temperatures of the ventrum of the first toe were not typically decreased during hypothermia. To the contrary, increases in skin temperatures were often observed during hypothermia. These observations provide evidence of altered thermoregulation with increased surface heat loss accounting for the hypothermia in the early course and heat conservation with hyperthermia during the later course of intoxication by short-acting barbiturates.

Silencing p110{beta} prevents rapid depletion of nuclear pAkt

Energy Technology Data Exchange (ETDEWEB)

Ye, Zhi-wei; Ghalali, Aram; Hoegberg, Johan [Institute of Environmental Medicine, Karolinska Institutet, S-17177 Stockholm (Sweden); Stenius, Ulla, E-mail: ulla.stenius@ki.se [Institute of Environmental Medicine, Karolinska Institutet, S-17177 Stockholm (Sweden)

2011-12-02

Highlights: Black-Right-Pointing-Pointer p110{beta} was essential for the statin- and ATP-induced depletion of nuclear pAkt and an associated inhibition of growth. Black-Right-Pointing-Pointer p110{beta} knock-out inhibited statin-induced changes in binding between FKBP51, pAkt and PTEN. Black-Right-Pointing-Pointer Data supports the hypothesis that nuclear pAkt is important for anti-cancer effects of statins. -- Abstract: The p110{beta} subunit in the class IA PI3K family may act as an oncogene and is critical for prostate tumor development in PTEN knockout mice. We tested the possible involvement of p110{beta} in a recently described rapid depletion of phosphorylated Akt (pAkt) in the nucleus. Previous work showed that this down-regulation is induced by extracellular ATP or by statins and is mediated by the purinergic receptor P2X7. Here, we used p110{beta} knock out mouse embryonic fibroblasts (MEFs) and siRNA-treated cancer cells. We found that p110{beta} is essential for ATP- or statin-induced nuclear pAkt depletion in MEFs and in several cancer cell lines including prostate cancer cells. ATP, statin or the selective P2X7 agonist BzATP also inhibited cell growth, and this inhibition was not seen in p110{beta} knock out cells. We also found that p110{beta} was necessary for statin-induced changes in binding between FKBP51, pAkt and PTEN. Our data show that p110{beta} is essential for the ATP- and statin-induced effects and support a role of nuclear pAkt in cancer development. They also provide support for a chemopreventive effect of statins mediated by depletion of nuclear pAkt.

Long- and Short-Run Components of Factor Betas: Implications for Equity Pricing

DEFF Research Database (Denmark)

Asgharian, Hossein; Christiansen, Charlotte; Hou, Ai Jun

We suggest a bivariate component GARCH model that simultaneously obtains factor betas’ long- and short-run components. We apply this new model to industry portfolios using market, small-minus-big, and high-minus-low portfolios as risk factors and find that the cross-sectional average and dispersion...... of the betas’ short-run component increase in bad states of the economy. Our analysis of the risk premium highlights the importance of decomposing risk across horizons: The risk premium associated with the short-run market beta is significantly positive. This is robust to the portfolio-set choice....

Drug and cell type-specific regulation of genes with different classes of estrogen receptor beta-selective agonists.

Directory of Open Access Journals (Sweden)

Sreenivasan Paruthiyil

2009-07-01

Full Text Available Estrogens produce biological effects by interacting with two estrogen receptors, ERalpha and ERbeta. Drugs that selectively target ERalpha or ERbeta might be safer for conditions that have been traditionally treated with non-selective estrogens. Several synthetic and natural ERbeta-selective compounds have been identified. One class of ERbeta-selective agonists is represented by ERB-041 (WAY-202041 which binds to ERbeta much greater than ERalpha. A second class of ERbeta-selective agonists derived from plants include MF101, nyasol and liquiritigenin that bind similarly to both ERs, but only activate transcription with ERbeta. Diarylpropionitrile represents a third class of ERbeta-selective compounds because its selectivity is due to a combination of greater binding to ERbeta and transcriptional activity. However, it is unclear if these three classes of ERbeta-selective compounds produce similar biological activities. The goals of these studies were to determine the relative ERbeta selectivity and pattern of gene expression of these three classes of ERbeta-selective compounds compared to estradiol (E(2, which is a non-selective ER agonist. U2OS cells stably transfected with ERalpha or ERbeta were treated with E(2 or the ERbeta-selective compounds for 6 h. Microarray data demonstrated that ERB-041, MF101 and liquiritigenin were the most ERbeta-selective agonists compared to estradiol, followed by nyasol and then diarylpropionitrile. FRET analysis showed that all compounds induced a similar conformation of ERbeta, which is consistent with the finding that most genes regulated by the ERbeta-selective compounds were similar to each other and E(2. However, there were some classes of genes differentially regulated by the ERbeta agonists and E(2. Two ERbeta-selective compounds, MF101 and liquiritigenin had cell type-specific effects as they regulated different genes in HeLa, Caco-2 and Ishikawa cell lines expressing ERbeta. Our gene profiling studies

A novel nicotinic agonist facilitates induction of long-term potentiation in the rat hippocampus.

Science.gov (United States)

Hunter, B E; de Fiebre, C M; Papke, R L; Kem, W R; Meyer, E M

1994-02-28

Long-term potentiation (LTP) can be modulated by a number of neurotransmitter receptors including muscarinic and GABAergic receptor types. We have found that a novel nicotinic agonist, 2,4-dimethoxybenzylidene anabaseine (DMXB), facilitated the induction of LTP in the hippocampus in a dose-dependent and mecamylamine-sensitive manner. DMXB displaced high affinity nicotinic [125I]alpha-bungarotoxin and [3H]acetylcholine binding in rat brain. Xenopus oocyte studies demonstrated that DMXB has agonist activity at alpha 7 but not alpha 4/beta 2 nicotinic receptor subtypes. These results indicated that DMXB is a novel nicotinic agonist with apparent specificity for the alpha 7/alpha-bungarotoxin nicotinic receptor subtype and indicate that nicotinic receptor activation is capable of modulating the induction of long-term potentiation.

Effects of short-term isokinetic training with reciprocal knee extensors agonist and antagonist muscle actions : A controlled and randomized trial

NARCIS (Netherlands)

Cunha, Rafael; Carregaro, Rodrigo L.; Martorelli, André; Vieira, Amilton; Oliveira, Ana B.; Bottaro, Martim

Background: Previous studies have shown that preloading an antagonist muscle may increase the acute agonist neuromuscular performance. In addition, studies have suggested that very short-term resistance exercise (RE) programs may also be useful to increase strength and muscular performance.

The design and discovery of lixisenatide for the treatment of type 2 diabetes mellitus

DEFF Research Database (Denmark)

Christensen, Mikkel; Miossec, Patrick; Larsen, Bjarne Due

2014-01-01

INTRODUCTION: Lixisenatide is a once-daily short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) used in the treatment of type 2 diabetes mellitus (T2DM). It is used in combination with oral antidiabetics and/or basal insulin in patients inadequately controlled on these medicati......INTRODUCTION: Lixisenatide is a once-daily short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) used in the treatment of type 2 diabetes mellitus (T2DM). It is used in combination with oral antidiabetics and/or basal insulin in patients inadequately controlled...... with the other GLP-1RAs. The combination of two injectables, such as basal insulin to lower fasting plasma glucose and a GLP-1RA that curtails PPG excursions, is clinically valuable and could differentiate lixisenatide from other GLP-1RAs, especially from those continuously acting GLP-1RAs with little effect...

Air classifier technology (ACT) in dry powder inhalation. Part 1 : Introduction of a novel force distribution concept (FDC) explaining the performance of a basic air classifier on adhesive mixtures

NARCIS (Netherlands)

de Boer, A H; Hagedoorn, P; Gjaltema, D; Goede, J; Frijlink, H W

2003-01-01

Air classifier technology (ACT) is introduced as part of formulation integrated dry powder inhaler development (FIDPI) to optimise the de-agglomeration of inhalation powders. Carrier retention and de-agglomeration results obtained with a basic classifier concept are discussed. The theoretical

Hot beta particles in the lung: Results from dogs exposed to fission product radionuclides

Energy Technology Data Exchange (ETDEWEB)

Hahn, F.F.; Griffith, W.C.; Hobbs, C.H. [and others

1995-12-01

The Chernobyl nuclear reactor accident resulted in the release of uranium dioxide fuel and fission product radionuclides into the environment with the fallout of respirable, highly radioactive particles that have been termed {open_quotes}hot beta particles.{close_quotes} There is concern that these hot beta particles (containing an average of 150-20,000 Bq/particle), when inhaled and deposited in the lung, may present an extraordinary hazard for the induction of lung cancer. We reviewed data from a group of studies in dogs exposed to different quantities of beta-emitting radionuclides with varied physical half-lives to determine if those that inhaled hot beta particles were at unusual risk for lung cancer. This analysis indicates that the average dose to the lung is adequate to predict biologic effects of lung cancer for inhaled beta-emitting radionuclides in the range of 5-50 Gy to the lung and with particle activities in the range of 0.10-50 Bq/particle.

Dual aminergic regulation of central beta adrenoceptors. Effect of atypical antidepressants and 5-hydroxytryptophan

International Nuclear Information System (INIS)

Manier, D.H.; Gillespie, D.D.; Sulser, F.

1989-01-01

Nonlinear regression analysis of agonist competition binding curves reveals that the [ 3 H]-dihydroalprenolol-labeled receptor population with low affinity for isoproterenol is increased by p-chlorophenylalanine (PCPA) and this increase is abolished by 5-hydroxytryptophan (5-HTP) in vivo. Desipramine (DMI) decreased the beta adrenoceptor population with high agonist affinity to the same degree in PCPA-treated animals as in control animals, thus explaining the reported discrepancy between beta adrenoceptor number and responsiveness of the beta adrenoceptor-coupled adenylate cyclase system. Mianserin also selectively reduced the beta adrenoceptor population with high agonist affinity in membrane preparations of normal animals, whereas fluoxetine selectively abolished the upregulation of the low affinity sites in reserpinized animals and had no effect on either receptor population from brain of normal animals. The results emphasize the importance of nonlinear regression analysis of agonist competition binding for the interpretation of drug action and encourage the pursuit of the molecular neurobiology of the serotonin (5-HT)/norepinephrine (NE) link in brain

Dual aminergic regulation of central beta adrenoceptors. Effect of atypical antidepressants and 5-hydroxytryptophan

Energy Technology Data Exchange (ETDEWEB)

Manier, D.H.; Gillespie, D.D.; Sulser, F.

1989-06-01

Nonlinear regression analysis of agonist competition binding curves reveals that the (/sup 3/H)-dihydroalprenolol-labeled receptor population with low affinity for isoproterenol is increased by p-chlorophenylalanine (PCPA) and this increase is abolished by 5-hydroxytryptophan (5-HTP) in vivo. Desipramine (DMI) decreased the beta adrenoceptor population with high agonist affinity to the same degree in PCPA-treated animals as in control animals, thus explaining the reported discrepancy between beta adrenoceptor number and responsiveness of the beta adrenoceptor-coupled adenylate cyclase system. Mianserin also selectively reduced the beta adrenoceptor population with high agonist affinity in membrane preparations of normal animals, whereas fluoxetine selectively abolished the upregulation of the low affinity sites in reserpinized animals and had no effect on either receptor population from brain of normal animals. The results emphasize the importance of nonlinear regression analysis of agonist competition binding for the interpretation of drug action and encourage the pursuit of the molecular neurobiology of the serotonin (5-HT)/norepinephrine (NE) link in brain.

Chemoradioprotection of the rat parotid gland by the beta-sympathomimetic agonist, terbutaline

International Nuclear Information System (INIS)

Sinesi, M.S.

1981-01-01

The present study demonstrates the effectiveness of the beta-adrenergic stimulator known as terbutaline in providing increased radioresistance to the normal, (i.e. nonmalignant) rat parotid salivary gland. Radiation damage was assessed by gland weight and microscopic examination of saline-treated and terbutaline-treated groups during days 1 to 10 and at 60 days post-irradiation. Terbutaline-treated groups exhibited both a sparing of gland weight loss as well as better preservation of glandular microstructure at all periods examined post-irradiation. Radioprotection of human parotid glands would provide relief from the xerostomia and its severe sequelae which often follow radiotherapy to the head and neck region in cancer patients. Terbutaline, with its preferential affinity for the beta-2 adrenergic receptor may provide a therapeutic advantage without the cardiac effects which normally accompany less specific (beta-1 + beta-2) adrenergic stimulation. In addition to providing a model for clinical protection of the salivary glands, this demonstration of protection of the rat parotid may also serve as a model for investigation of the mechanisms of action of terbutaline and other radioprotective compounds

Seasonal occurrence of antibiotics and a beta agonist in an agriculturally-intensive watershed

International Nuclear Information System (INIS)

Jaimes-Correa, Juan C.; Snow, Daniel D.; Bartelt-Hunt, Shannon L.

2015-01-01

We evaluated the occurrence of 12 veterinary antibiotics and a beta agonist over spatial and temporal scales in Shell Creek, an intensively agricultural watershed in Nebraska, using Polar Organic Chemical Integrative Samplers (POCIS). Twelve pharmaceuticals were detected with concentrations ranging from 0.0003 ng/L to 68 ng/L. The antibiotics measured at the highest time-weighted average concentrations were lincomycin (68 ng/L) and monensin (49 ng/L), and both compounds were detected at increased concentrations in summer months. Analysis of variance indicates that mean concentrations of detected pharmaceuticals have no significant (p > 0.01) spatial variation. However, significant temporal differences (p < 0.01) were observed. This study demonstrates the utility of passive samplers such as POCIS for monitoring ambient levels of pharmaceuticals in surface waters. - Highlights: • Passive samplers were used to evaluate veterinary pharmaceuticals in an agricultural watershed. • Monensin and lincomycin were detected at the highest TWA concentrations. • Significantly higher concentrations were detected in summer months. • Pulses of antibiotics correspond with rainfall-runoff events. - The spatial and temporal differences in the occurrence of thirteen veterinary pharmaceuticals was evaluated in an intensively agricultural watershed

Pharmacokinetics of Short- and Long-acting Formulations of Oxytetracycline After Intramuscular Administration in Chickens.

Science.gov (United States)

Gberindyer, Aondover F; Okpeh, Ene R; Semaka, Asaaga A

2015-12-01

Both short- and long-acting formulations of oxytetracycline are commonly used in veterinary medicine to treat animals infected with gram-negative and gram-positive bacteria, rickettsiae, mycoplasma, and chlamydiae. To compare pharmacokinetics of short- and long-acting oxytetracycline in chickens, injectable formulations from the same pharmaceutical company were administered to healthy 6-week-old broiler chickens in accordance to the labeled instructions. Fourteen chickens were separated into 2 groups: chickens in group A (n = 7) were administered the short-acting formulation (10 mg/kg IM q24h) for 4 consecutive days, whereas those in group B (n = 7) were treated with a single dose (20 mg/kg IM) of the long-acting formulation. Blood samples were collected into heparinized tubes before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 24 hours after initial treatment. Thereafter, blood samples were taken every 24 hours up to 120 hours. Plasma concentrations of oxytetracycline were determined by competitive enzyme-linked immunoabsorbent assay, and pharmacokinetic parameters were obtained. Both formulations delivered therapeutic plasma concentrations of oxytetracycline for approximately 100% of their respective dosing intervals as recommended. However, considering the additional labor, patient stress, and mortalities associated with handling, in addition to rejection of the carcass due to tissue necrosis resulting from multiple injections, we recommend use of the long-acting instead of the short-acting injectable formulation in broiler chickens.

Impact of long-term treatment with inhaled corticosteroids and bronchodilators on lung function in a patient with post-infectious bronchiolitis obliterans.

Science.gov (United States)

Calabrese, Cecilia; Corcione, Nadia; Rea, Gaetano; Stefanelli, Francesco; Meoli, Ilernando; Vatrella, Alessandro

2016-01-01

Post-infectious bronchiolitis obliterans (PIBO) is a small airways disease characterized by fixed airflow limitation. Therefore, inhaled bronchodilators and corticosteroids are not recommended as maintenance therapy options. The management of PIBO currently consists only of close monitoring of affected patients, aimed at the prevention and early treatment of pulmonary infections. In recent years, there has been an increase in the incidence of PIBO in the pediatric population. Patients with PIBO are characterized by a progressive decline in lung function, accompanied by a decrease in overall functional capacity. Here, we report the case of a relatively young man diagnosed with PIBO and followed for three years. After short- and long-term therapy with an inhaled corticosteroid/long-acting 2 agonist combination, together with an inhaled long-acting antimuscarinic, the patient showed relevant improvement of airway obstruction that had been irreversible at the time of the bronchodilator test. The lung function of the patient worsened when he interrupted the triple inhaled therapy. In addition, a 3-week pulmonary rehabilitation program markedly improved his physical performance. RESUMO A bronquiolite obliterante pós-infecciosa (BOPI) é uma doença das pequenas vias aéreas caracterizada por limitação fixa do fluxo aéreo. Portanto, os broncodilatadores e os corticosteroides inalatórios não são recomendados como opções de terapia de manutenção. Atualmente, o manejo da BOPI consiste apenas de um acompanhamento rigoroso dos pacientes afetados, visando à prevenção e ao tratamento precoce de infecções pulmonares. A incidência de BOPI tem aumentado na população pediátrica nos últimos anos. Os pacientes com BOPI caracterizam-se por um declínio progressivo da função pulmonar, associado a uma diminuição da capacidade funcional global. Relatamos aqui o caso de um homem relativamente jovem diagnosticado com BOPI, acompanhado por três anos. Ap

Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

International Nuclear Information System (INIS)

Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya; Hirose, Takahisa; Kawamori, Ryuzo; Fujitani, Yoshio; Watada, Hirotaka

2009-01-01

Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

Energy Technology Data Exchange (ETDEWEB)

Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Hirose, Takahisa [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Kawamori, Ryuzo [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Center for Beta Cell Biology and Regeneration, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan); Fujitani, Yoshio, E-mail: fujitani@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Watada, Hirotaka, E-mail: hwatada@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan)

2009-12-18

Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors

Energy Technology Data Exchange (ETDEWEB)

Rajasekaran, Maheswari; Brents, Lisa K.; Franks, Lirit N. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Moran, Jeffery H. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Arkansas Department of Public Health, Public Health Laboratory, Little Rock, AR 72205 (United States); Prather, Paul L., E-mail: pratherpaull@uams.edu [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)

2013-06-01

K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB{sub 1}Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB{sub 2}Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB{sub 2}Rs (hCB{sub 2}Rs). The affinity of cannabinoids for hCB{sub 2}Rs was determined by competition binding studies employing CHO-hCB{sub 2} membranes. Intrinsic activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB{sub 2} cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB{sub 2}Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB{sub 2}Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and Δ{sup 9}-tetrahydrocannabinol (Δ{sup 9}-THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB{sub 2}R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB{sub 2}Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB{sub 2}Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB{sub 1} and CB{sub 2}Rs. - Highlights: • JWH-018

Intra-individual variability in the urine concentrations of inhaled salmeterol in male subjects with reference to doping analysis – impact of urine specific gravity correction

DEFF Research Database (Denmark)

Hostrup, Morten; Kalsen, Anders; Hemmersbach, Peter

2012-01-01

and a-hydroxysalmeterol during visits one and two were 12.6 and 21.8%, respectively. The intra-individual variability of salmeterol and a-hydroxysalmeterol in the urine concentrations were significantly higher when uncorrected for USG with 43.0 and 43.7% versus 20.4% (p...Since 2010, the World Anti-Doping Agency (WADA) has introduced urinary thresholds for some beta2-agonists. In doping analysis urine samples of beta2-agonists are not corrected for the Urine Specific Gravity (USG) by the WADA laboratories. Several studies have observed high differences in the urine...

ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell function

International Nuclear Information System (INIS)

Pi Jingbo; Zhang Qiang; Fu Jingqi; Woods, Courtney G.; Hou Yongyong; Corkey, Barbara E.; Collins, Sheila; Andersen, Melvin E.

2010-01-01

This review focuses on the emerging evidence that reactive oxygen species (ROS) derived from glucose metabolism, such as H 2 O 2 , act as metabolic signaling molecules for glucose-stimulated insulin secretion (GSIS) in pancreatic beta-cells. Particular emphasis is placed on the potential inhibitory role of endogenous antioxidants, which rise in response to oxidative stress, in glucose-triggered ROS and GSIS. We propose that cellular adaptive response to oxidative stress challenge, such as nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant induction, plays paradoxical roles in pancreatic beta-cell function. On the one hand, induction of antioxidant enzymes protects beta-cells from oxidative damage and possible cell death, thus minimizing oxidative damage-related impairment of insulin secretion. On the other hand, the induction of antioxidant enzymes by Nrf2 activation blunts glucose-triggered ROS signaling, thus resulting in reduced GSIS. These two premises are potentially relevant to impairment of beta-cells occurring in the late and early stage of Type 2 diabetes, respectively. In addition, we summarized our recent findings that persistent oxidative stress due to absence of uncoupling protein 2 activates cellular adaptive response which is associated with impaired pancreatic beta-cell function.

In vitro bioactivity of 17alpha-estradiol.

Science.gov (United States)

Sievernich, André; Wildt, Ludwig; Lichtenberg-Fraté, Hella

2004-12-01

A miniaturised short-term in vitro assay based on the activation of the human estrogen receptor alpha and genetically modified yeast (Saccharomyces cerevisiae) cells was performed to explore the capacity of this system to monitor the bioactivity of estrogenic compounds, particularly 17alpha- and 17beta-estradiol. Together with the human estrogen receptor (hER)-alpha plasmid, the reporter plasmid containing a yeast-optimised version of the green fluorescent protein (yEGFP) linked to three repeats of the cis-acting estrogen hormone-responsive element (ERE) were expressed in a strain being deleted in the pleiotropic drug resistance transporters Pdr5, Snq2 and Yor1, known to facilitate efflux of organic compounds including steroids and chemotherapeutics. Agonists that bind to hER in vitro trigger estrogen receptor-mediated transcriptional activation of the GFP reporter gene monitored by fluorescence emission at 535 nm. The sensitivity of the assay was tested with various 17alpha- and 17beta-estradiol concentrations, yielding a detection limit of 5 pg/ml (0.018 nM) for the agonist 17beta-E2 in solvent and in human charcoal-stripped serum using a S. cerevisiae pdr5, snq2 and yor1 mutant strain. For 17alpha-estradiol only, at approximately 1500 pg/ml a similar fluorescence response compared to 100 pg/ml 17beta-E2 was observed implicating a much weaker potency of this stereoisomer. The specificity of the system was tested by expression of a truncated hER lacking the ligand-binding domain E and by administration of the androgen, 4-androsten 3,17 dione. Both controls did not yield an increase in fluorescence emission. This fluorescence emission assay enables detection of estrogenic biological activity induced by direct agonists, such as 17beta-E2 at concentrations similar to those found in human sera or by estrogen-like chemicals.

Identification of novel selective V2 receptor non-peptide agonists.

Science.gov (United States)

Del Tredici, Andria L; Vanover, Kim E; Knapp, Anne E; Bertozzi, Sine M; Nash, Norman R; Burstein, Ethan S; Lameh, Jelveh; Currier, Erika A; Davis, Robert E; Brann, Mark R; Mohell, Nina; Olsson, Roger; Piu, Fabrice

2008-10-30

Peptides with agonist activity at the vasopressin V(2) receptor are used clinically to treat fluid homeostasis disorders such as polyuria and central diabetes insipidus. Of these peptides, the most commonly used is desmopressin, which displays poor bioavailability as well as potent activity at the V(1b) receptor, with possible stress-related adverse effects. Thus, there is a strong need for the development of small molecule chemistries with selective V(2) receptor agonist activity. Using the functional cell-based assay Receptor Selection and Amplification Technology (R-SAT((R))), a screening effort identified three small molecule chemotypes (AC-94544, AC-88324, and AC-110484) with selective agonist activity at the V(2) receptor. One of these compounds, AC-94544, displayed over 180-fold selectivity at the V(2) receptor compared to related vasopressin and oxytocin receptors and no activity at 28 other G protein-coupled receptors (GPCRs). All three compounds also showed partial agonist activity at the V(2) receptor in a cAMP accumulation assay. In addition, in a rat model of central diabetes insipidus, AC-94544 was able to significantly reduce urine output in a dose-dependent manner. Thus, AC-94544, AC-88324, and AC-110484 represent novel opportunities for the treatment of disorders associated with V(2) receptor agonist deficiency.

The synthesis of [[sup 2]H],[[sup 3]H], and [[sup 14]C]-labeled 8[beta]-[(methylthio)methyl]-6-propylergoline mesylate (pergolide mesylate), a potent, long-acting dopamine agonist

Energy Technology Data Exchange (ETDEWEB)

Wheeler, W.J.; Kau, D.L.K.; Bach, N.J. (Lilly (Eli) and Co., Indianapolis, IN (United States). Lilly Research Labs.)

1990-03-01

The [[sup 3]H]- and two[[sup 14]C]-isopomers of 8[beta]-[(methylthio)methyl]-6-propylergoline mesylate (pergolide mesylate) have been synthesized. The [[sup 3]H]-derivative was synthesized by the palladium catalyzed tritiation of the corresponding 6-allyl derivative. Reaction of 8[beta]-[(methylthio)methyl]-ergoline with 1-[[sup 14]C]-1-propyl bromide yielded pergolide labeled in the 6-propyl group. Alternatively, reaction of 8[beta]-mesyloxy-6-propylergoline with [[sup 14]C]-sodium cyanide, followed by base hydrolysis, yielded 8 [beta]-carboxy-6-propylergoline-[[sup 14]C], which was subsequently converted to pergolide mesylate radiolabeled in the 17-position via a four step sequence. (Author).

Effect of the α2 -receptor agonists medetomidine, detomidine, xylazine, and romifidine on the ketamine metabolism in equines assessed with enantioselective capillary electrophoresis.

Science.gov (United States)

Sandbaumhüter, Friederike A; Theurillat, Regula; Bettschart-Wolfensberger, Regula; Thormann, Wolfgang

2017-08-01

The combination of ketamine and an α 2 -receptor agonist is often used in veterinary medicine. Four different α 2 -receptor agonists, medetomidine, detomidine, xylazine, and romifidine, which differ in their chemical structure and thus in selectivity for the α 2 -receptor and in the sedative and analgesic potency, are typically employed during surgery of equines. Recovery following anesthesia with ketamine and an α 2 -receptor agonist is dependent on the α 2 -receptor agonist. This prompted us to investigate (i) the inhibition characteristics for the N-demethylation of ketamine to norketamine and (ii) the formation of the ketamine metabolites norketamine, 6-hydroxynorketamine (6HNK), and 5,6-dehydronorketamine (DHNK) in presence of the four α 2 -receptor agonists and equine liver microsomes. Samples were analyzed with enantioselective capillary electrophoresis using highly sulfated γ-cyclodextrin as chiral selector. All four α 2 -receptor agonists have an impact on the ketamine metabolism. Medetomidine was found to be the strongest inhibitor, followed by detomidine, whereas xylazine and romifidine showed almost no effect on the ketamine N-demethylation in the inhibition studies with a short-incubation period of the reaction mixture. After prolonged incubation, inhibition with xylazine and romifidine was also observed. The formation of 6HNK and DHNK is affected by all selected α 2 -receptor agonists. With medetomidine, levels of these metabolites are reduced compared to the case without an α 2 -receptor agonist. For detomidine, xylazine, and romifidine, the opposite was found. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Impact of different combinations of inhaled corticosteroids and long-acting sympathicomimetics on dental health of asthmatics.

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George Christoff

2012-07-01

Full Text Available The aim of the investigation is to study the effect of inhaled corticosteroids and long-acting sympathicomimetics on dental health in asthmatics. Thirty patients, from 20 to 55 years old, participate in the study. D-, M-, F- and DMFT indexes are determined in a 6 months period. All participants fill in a questionnaire. Asthmatics complain most frequently from oral dryness, take frequently sugar and soft drinks and visit irregularly dental practitioners. A significant increase in M-index is found out at the second visit. F-index increases considerably for patients treated with Beclometasone and Formoterol and D-index decreases significantly when treated with Budesonide and Formoterol. DMFT index increases considerably for all patients. Highest values of DMFT index are registered for patients treated with Fluticasone propionate and Salmeterol. Prolonged use of inhaled drugs with greater quantities of lactose leads to more impaired dental status in asthmatics and higher values of DMFT index.

Detection and pharmacokinetics of salmeterol in thoroughbred horses following inhaled administration.

Science.gov (United States)

Fenwick, S J; Hincks, P R; Scarth, J P; Wieder, M E; Hillyer, L L; Paine, S W

2017-10-01

Salmeterol is a man-made beta-2-adrenergic receptor agonist used to relieve bronchospasm associated with inflammatory airway disease in horses. Whilst judicious use is appropriate in horses in training, they cannot race with clinically effective concentrations of medications under the British Horseracing Authority's Rules of Racing. Salmeterol must therefore be withdrawn prior to race day and pharmacokinetic (PK) studies used to establish formal detection time advice. Salmeterol xinafoate (Serevent Evohaler ® ) was administered (0.1 mg twice daily for 4.5 days) via inhalation to six horses. Urine and blood samples were taken up to 103 h postadministration. Hydrolysed samples were extracted using solid phase extraction. A sensitive Ultra high performance tandem mass spectrometry (UPLC-MS/MS) method was developed, with a Lower limit of quantification (LLOQ) for salmeterol of 10 pg/mL in both matrices. The majority of salmeterol plasma concentrations, postlast administration, were below the method LLOQ and so unusable for PK analysis. Urine PK analysis suggested a half-life consistent with duration of pharmacological effect. Average estimated urine concentration at steady-state was obtained via PK modelling and used to estimate a urine concentration of 59 ± 34 pg/mL as a marker of effective lung concentration. From this, potential detection times were calculated using a range of safety factors. © 2017 John Wiley & Sons Ltd.

In utero Exposure to beta-2-Adrenergic Receptor Agonist Drugs and Risk for Autism Spectrum Disorders

DEFF Research Database (Denmark)

Gidaya, Nicole B.; Lee, Brian K.; Burstyn, Igor

2016-01-01

OBJECTIVES: The purpose of this study was to investigate associations between use of β-2-adrenergic receptor (B2AR) agonist drugs during pregnancy and risk for autism spectrum disorders (ASD). METHODS: A case-control study was conducted by using Denmark’s health and population registers. Among...... exposure during pregnancy, preconception, and by trimester. RESULTS: In total, 3.7% of cases and 2.9% of controls were exposed to B2ARs during pregnancy. Use of B2ARs during pregnancy was associated with increased risk of ASD, even after adjustment for maternal asthma and other covariates (OR: 1.3, 95% CI......: 1.1–1.5). The elevated risk was observed with use of B2AR during preconception (OR: 1.3, 95% CI: 1.0–1.6), first trimester (OR: 1.3, 95% CI: 1.1–1.5), second trimester (OR: 1.5, 95% CI: 1.1–1.7), and the third trimester (OR: 1.4, 95% CI: 1.1–1.7). There was some evidence that longer B2AR within-pregnancy...

Aerosol Characteristics of Admixture of Budesonide Inhalation Suspension with a Beta2-Agonist, Procaterol

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Toshiko Itazawa

2013-01-01

Conclusions: There is a possibility that admixture might influence of aerodynamic characteristics of procaterol, but not budesonide. In vivo data will be needed for the clinical implications of our findings.

Inhaled 239PuO2 in rats with pulmonary emphysema

International Nuclear Information System (INIS)

Lundgren, D.L.; Mauderly, J.L.; Hahn, F.F.

1984-01-01

The modifying effects of a pre-existing lung disease (emphysema) on the deposition, distribution, retention, and effects of inhaled 239 PuO 2 in the rat are being investigated. Preliminary observations indicated that the deposition and retention patterns for 239 Pu particles inhaled by rats with emphysema and control rats were similar, but the distribution of inhaled 239 Pu immediately after exposure was different. Respiratory function measured through one year after exposure to 239 Pu was consistent with emphysema and was not altered by the 239 Pu lung burden. Long-term observations are continuing. 4 references, 2 tables

The effect of inhaled corticosteroids on the development of emphysema in smokers assessed by annual computed tomography.

Science.gov (United States)

Shaker, Saher B; Dirksen, Asger; Ulrik, Charlotte S; Hestad, Marianne; Stavngaard, Trine; Laursen, Lars C; Maltbaek, Niels; Clementsen, Paul; Skjaerbaek, Nanna; Nielsen, Lars; Stoel, Berend; Skovgaard, Lene T; Tonnesen, Philip

2009-04-01

The objective was to evaluate the effect of inhaled corticosteroids on disease progression in smokers with moderate to severe chronic obstructive pulmonary disease (COPD), as assessed by annual computed tomography (CT) using lung density (LD) measurements. Two hundred and fifty-four current smokers with COPD were randomised to treatment with either an inhaled corticosteroids (ICS), budesonide 400 microg bid, or placebo. COPD was defined as FEV(1) < or = 70% pred, FEV(1)/FVC < or = 60% and no reversibility to beta(2)-agonists and oral corticosteroids. The patients were followed for 2-4 years with biannual spirometry and annual CT and comprehensive lung function tests (LFT). CT images were analysed using Pulmo-CMS software. LD was derived from a pixel-density histogram of the whole lung as the 15th percentile density (PD15) and the relative area of emphysema at a threshold of -910 Hounsfield units (RA-910), and both were volume-adjusted to predicted total lung capacity. At baseline, mean age was 64 years and 64 years; mean number of pack-years was 56 and 56; mean FEV(1) was 1.53 L (51% pred) and 1.53 L (53% pred); mean PD15 was 103 g/L and 104 g/L; and mean RA-910 was 14% and 13%, respectively, for the budesonide and placebo groups. The annual fall in PD15 was -1.12 g/L in the budesonide group and -1.81 g/L in the placebo group (p = 0.09); the annual increase in RA-910 was 0.4% in the budesonide group and 1.1% in the placebo group (p = 0.02). There was no difference in annual decline in FEV(1) between ICS (-54 mL) and placebo (-56 mL) (p = 0.89). Long-term budesonide inhalation shows a non-significant trend towards reducing the progression of emphysema as determined by the CT-derived 15th percentile lung density from annual CT scans in current smokers with moderate to severe COPD.

A systematic review of adverse drug events associated with administration of common asthma medications in children.

Directory of Open Access Journals (Sweden)

James S Leung

Full Text Available To systematically review the literature and determine frequencies of adverse drug events (ADE associated with pediatric asthma medications.Following PRISMA guidelines, we systematically searched six bibliographic databases between January 1991 and January 2017. Study eligibility, data extraction and quality assessment were independently completed and verified by two reviewers. We included randomized control trials (RCT, case-control, cohort, or quasi-experimental studies where the primary objective was identifying ADE in children 1 month- 18 years old exposed to commercial asthma medications. The primary outcome was ADE frequency.Our search identified 14,540 citations. 46 studies were included: 24 RCT, 15 cohort, 4 RCT pooled analyses, 1 case-control, 1 open-label trial and 1 quasi-experimental study. Studies examined the following drug classes: inhaled corticosteroids (ICS (n = 24, short-acting beta-agonists (n = 10, long-acting beta-agonists (LABA (n = 3, ICS + LABA (n = 3, Leukotriene Receptor Antagonists (n = 3 and others (n = 3. 29 studies occurred in North America, and 29 were industry funded. We report a detailed index of 406 ADE descriptions and frequencies organized by drug class. The majority of data focuses on ICS, with 174 ADE affecting 13 organ systems including adrenal and growth suppression. We observed serious ADE, although they were rare, with frequency ranging between 0.9-6% per drug. There were no confirmed deaths, except for 13 potential deaths in a LABA study including combined adult and pediatric participants. We identified substantial methodological concerns, particularly with identifying ADE and determining severity. No studies utilized available standardized causality, severity or preventability assessments.The majority of studies focus on ICS, with adrenal and growth suppression described. Serious ADE are relatively uncommon, with no confirmed pediatric deaths. We identify substantial methodological concerns

A Novel Dimeric Inhibitor Targeting Beta2GPI in Beta2GPI/Antibody Complexes Implicated in Antiphospholipid Syndrome

Energy Technology Data Exchange (ETDEWEB)

A Kolyada; C Lee; A De Biasio; N Beglova

2011-12-31

{beta}2GPI is a major antigen for autoantibodies associated with antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. Only the dimeric form of {beta}2GPI generated by anti-{beta}2GPI antibodies is pathologically important, in contrast to monomeric {beta}2GPI which is abundant in plasma. We created a dimeric inhibitor, A1-A1, to selectively target {beta}2GPI in {beta}2GPI/antibody complexes. To make this inhibitor, we isolated the first ligand-binding module from ApoER2 (A1) and connected two A1 modules with a flexible linker. A1-A1 interferes with two pathologically important interactions in APS, the binding of {beta}2GPI/antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of {beta}2GPI/antibody complexes to anionic phospholipids. We tested the inhibition of {beta}2GPI present in human serum, {beta}2GPI purified from human plasma and the individual domain V of {beta}2GPI. We demonstrated that when {beta}2GPI/antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of {beta}2GPI to cardiolipin, regardless of the source of {beta}2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of {beta}2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-{beta}2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric {beta}2GPI to cardiolipin. Our results suggest that the approach of using a dimeric inhibitor to block {beta}2GPI in the pathological multivalent {beta}2GPI/antibody complexes holds significant promise. The novel inhibitor A1-A1 may be a starting point in the development of an effective therapeutic for antiphospholipid syndrome.

Beta agonists in livestock feed: status, health concerns, and international trade.

Science.gov (United States)

Centner, T J; Alvey, J C; Stelzleni, A M

2014-09-01

Since the U.S. Food and Drug Administration approved ractopamine hydrochloride and zilpaterol hydrochloride in animal feeds, usage of those compounds has been a topic of worldwide debate. Ractopamine and zilpaterol are β-adrenergic agonists used as veterinary drugs to increase weight gain in certain animals raised for food. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) established maximum residue limits for ractopamine, which were adopted by the Codex Alimentarius Commission (Codex). No maximum residue limits for zilpaterol have been adopted by JECFA, and new reports of animal mobility issues confront the use of this feed additive. However, many countries disagree with the Codex standards and are restricting or banning meat products containing β agonists. The bans by major importers of U.S. meat products have prompted some to advocate that the United States use the World Trade Organization dispute settlement body. This paper looks at the developments to provide a fuller accounting of what the issues may mean to U.S. firms selling meat products containing residues of β agonists.

Basal testosterone concentrations after the application of a slow-release GnRH agonist implant are associated with a loss of response to buserelin, a short-term GnRH agonist, in the tom cat.

Science.gov (United States)

Goericke-Pesch, Sandra; Georgiev, Plamen; Fasulkov, Ivan; Vodenicharov, Angel; Wehrend, Axel

2013-07-01

Slow-release GnRH agonist implants are considered an effective, reversible alternative to surgical castration in male tom cats. Individual differences exist regarding the onset of efficacy and might be delayed in some animals. Single measurements of testosterone (T) might result in basal concentrations also in intact male cats. Consequently, GnRH stimulation tests are performed to measure T increase in intact animals and to differentiate castrated from intact male cats. In this study, five tom cats were treated with a 4.7-mg deslorelin implant and GnRH stimulation tests using buserelin were performed before treatment and at 4-week intervals afterward until Week 20. After the last test in Week 20 all animals were castrated. Four of five animals had basal T after 4 weeks and-in contrast to pretreatment-application of buserelin did not result in any further T increase. In one animal, T was low after implant insertion, but not basal; however, a GnRH stimulation test induced a slight increase of T in Week 8 and 16 only and no response in Weeks 4, 12, and 20. Testicular volume was significantly decreased and penile spines disappeared in all cats. Testicular histology showed mixed atrophy, but also fully elongated spermatids in three of five male cats making infertility questionable. Because of the loss of the stimulatory effect of short-term GnRH application (buserelin), it can be assumed that long-term GnRH agonists also act by some mechanisms of downregulation of pituitary GnRH receptors in the tom cat. Copyright © 2013 Elsevier Inc. All rights reserved.

Bronchodilator Efficacy of Single Doses of Indacaterol in Japanese Patients with COPD: A Randomised, Double-Blind, Placebo-Controlled Trial

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Motokazu Kato

Full Text Available ABSTRACT: Background: Indacaterol is an investigational, novel, inhaled once-daily ultra-long-acting beta-2 agonist for the treatment of chronic obstructive pulmonary disease (COPD. This study evaluated the 24-h bronchodilatory efficacy and safety of indacaterol in Japanese patients with COPD. Methods: This Phase-II, randomised, placebo-controlled, crossover study comprised four double-blind, single-dose treatment periods (washout between periods: 14-28 days. Japanese patients aged 40-75 years with moderate-to-severe COPD were randomised to receive single doses of indacaterol (150, 300, or 600 μg or placebo via a single-dose dry-powder inhaler. Efficacy (primary endpoint: standardised FEV1AUC22-24h and safety were assessed for 24 h post-dose in each treatment period. Results: Of the 50 patients randomised (92% male; mean age, 67.2 years, 45 completed the study. Standardised FEV1AUC22-24h was significantly higher for all indacaterol doses as compared with placebo, with clinically relevant differences of 130, 160, and 170 mL for 150, 300, and 600 μg, respectively (P < 0.001. The improvement in FEV1 was seen as early as 5 min post-dose with indacaterol and sustained for 24 h (P < 0.001 vs placebo at all time points. All indacaterol doses were well tolerated and showed no clinically meaningful effect on pulse rate, blood pressure, QTc interval, and laboratory parameters when compared with placebo. Conclusions: In the Japanese COPD population studied, single doses of indacaterol (150, 300, and 600 μg provided sustained 24-h bronchodilation, with onset of action within 5 min post-dose. All doses were well tolerated. These results are consistent with data from Caucasian populations. KEY WORDS: beta2-agonists, bronchodilator, COPD, efficacy, indacaterol

Antimicrobial actions of the human epididymis 2 (HE2 protein isoforms, HE2alpha, HE2beta1 and HE2beta2

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French Frank S

2004-08-01

Full Text Available Abstract Background The HE2 gene encodes a group of isoforms with similarities to the antimicrobial beta-defensins. We demonstrated earlier that the antimicrobial activity of HE2 proteins and peptides is salt resistant and structure dependent and involves permeabilization of bacterial membranes. In this study, we further characterize the antimicrobial properties of HE2 peptides in terms of the structural changes induced in E. coli and the inhibition of macromolecular synthesis. Methods E. coli treated with 50 micro g/ml of HE2alpha, HE2beta1 or HE2beta2 peptides for 30 and 60 min were visualized using transmission and scanning electron microscopy to investigate the impact of these peptides on bacterial internal and external structure. The effects of HE2alpha, HE2beta1 and HE2beta2 on E. coli macromolecular synthesis was assayed by incubating the bacteria with 2, 10 and 25 micro g/ml of the individual peptides for 0–60 min and measuring the incorporation of the radioactive precursors [methyl-3H]thymidine, [5-3H]uridine and L-[4,5-3H(N]leucine into DNA, RNA and protein. Statistical analyses using Student's t-test were performed using Sigma Plot software. Values shown are Mean ± S.D. Results E. coli treated with HE2alpha, HE2beta1 and HE2beta2 peptides as visualized by transmission electron microscopy showed extensive damage characterized by membrane blebbing, thickening of the membrane, highly granulated cytoplasm and appearance of vacuoles in contrast to the smooth and continuous membrane structure of the untreated bacteria. Similarly, bacteria observed by scanning electron microscopy after treating with HE2alpha, HE2beta1 or HE2beta2 peptides exhibited membrane blebbing and wrinkling, leakage of cellular contents, especially at the dividing septa, and external accumulation of fibrous materials. In addition, HE2alpha, HE2beta1 and HE2beta2 peptides inhibited E. coli DNA, RNA and protein synthesis. Conclusions The morphological changes observed

Partial agonism through a zinc-Ion switch constructed between transmembrane domains III and VII in the tachykinin NK(1) receptor

DEFF Research Database (Denmark)

Holst, B; Elling, C E; Schwartz, T W

2000-01-01

switch located exactly one helical turn below the two previously identified interaction points for Substance P in, respectively, TM-III and -VII. The metal-ion chelator, phenantroline, which in the beta(2)-adrenergic receptor increased both the potency and the agonistic efficacy of Zn(2+) or Cu(2......Partly due to lack of detailed knowledge of the molecular recognition of ligands the structural basis for partial versus full agonism is not known. In the beta(2)-adrenergic receptor the agonist binding site has previously been structurally and functionally exchanged with an activating metal....... In contrast to the similarly mutated beta(2)-adrenergic receptor, signal transduction-i.e., inositol phosphate turnover-could be stimulated by both Zn(2+) and by the natural agonist, Substance P in the mutated NK(1) receptor. The metal-ion acted as a 25% partial agonist through binding to the bidentate zinc...

Suppression of the cough reflex by α2-adrenergic receptor agonists in the rabbit

Science.gov (United States)

Cinelli, Elenia; Bongianni, Fulvia; Pantaleo, Tito; Mutolo, Donatella

2013-01-01

The α2-adrenergic receptor agonist clonidine has been shown to inhibit citric acid-induced cough responses in guinea pigs when administered by aerosol, but not orally. In contrast, oral or inhaled clonidine had no effect on capsaicin-induced cough and reflex bronchoconstriction in humans. In addition, intravenous administration of clonidine has been shown to depress fentanyl-induced cough in humans. We investigated the effects of the α2-adrenergic receptor agonists, clonidine and tizanidine, on cough responses induced by mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. Drugs were microinjected (30–50 nL) into the caudal nucleus tractus solitarii (cNTS) and the caudal ventral respiratory group (cVRG) as well as administered intravenously in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections of clonidine into the cNTS or the cVRG reduced cough responses at 0.5 mmol/L and abolished the cough reflex at 5 mmol/L. Bilateral microinjections of 0.5 mmol/L tizanidine into the cNTS completely suppressed cough responses, whereas bilateral microinjections of 5 mmol/L into the cVRG only caused mild reductions in them. Depressant effects on the cough reflex of clonidine and tizanidine were completely reverted by microinjections of 10 mmol/L yohimbine. Intravenous administration of clonidine (80–120 μg/kg) or tizanidine (150–300 μg/kg) strongly reduced or completely suppressed cough responses. These effects were reverted by intravenous administration of yohimbine (300 μg/kg). The results demonstrate that activation of α2-adrenergic receptors in the rabbit exerts potent inhibitory effects on the central mechanism generating the cough motor pattern with a clear action at the level of the cNTS and the cVRG. PMID:24400133

Neutrophil beta-2 microglobulin: an inflammatory mediator

DEFF Research Database (Denmark)

Bjerrum, O W; Nissen, Mogens Holst; Borregaard, N

1990-01-01

Beta-2 microglobulin (beta 2m) constitutes the light invariant chain of HLA class I antigen, and is a constituent of mobilizable compartments of neutrophils. Two forms of beta 2m exist: native beta 2m and proteolytically modified beta 2m (Des-Lys58-beta 2m), which shows alpha mobility in crossed ...

Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH.

Science.gov (United States)

Rashid, Jahidur; Alobaida, Ahmad; Al-Hilal, Taslim A; Hammouda, Samia; McMurtry, Ivan F; Nozik-Grayck, Eva; Stenmark, Kurt R; Ahsan, Fakhrul

2018-06-28

Peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-γ agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% ± 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH. Copyright © 2018 Elsevier B.V. All rights reserved.

Effect of novel inhaler technique reminder labels on the retention of inhaler technique skills in asthma: a single-blind randomized controlled trial.

Science.gov (United States)

Basheti, Iman A; Obeidat, Nathir M; Reddel, Helen K

2017-02-09

Inhaler technique can be corrected with training, but skills drop off quickly without repeated training. The aim of our study was to explore the effect of novel inhaler technique labels on the retention of correct inhaler technique. In this single-blind randomized parallel-group active-controlled study, clinical pharmacists enrolled asthma patients using controller medication by Accuhaler [Diskus] or Turbuhaler. Inhaler technique was assessed using published checklists (score 0-9). Symptom control was assessed by asthma control test. Patients were randomized into active (ACCa; THa) and control (ACCc; THc) groups. All patients received a "Show-and-Tell" inhaler technique counseling service. Active patients also received inhaler labels highlighting their initial errors. Baseline data were available for 95 patients, 68% females, mean age 44.9 (SD 15.2) years. Mean inhaler scores were ACCa:5.3 ± 1.0; THa:4.7 ± 0.9, ACCc:5.5 ± 1.1; THc:4.2 ± 1.0. Asthma was poorly controlled (mean ACT scores ACCa:13.9 ± 4.3; THa:12.1 ± 3.9; ACCc:12.7 ± 3.3; THc:14.3 ± 3.7). After training, all patients had correct technique (score 9/9). After 3 months, there was significantly less decline in inhaler technique scores for active than control groups (mean difference: Accuhaler -1.04 (95% confidence interval -1.92, -0.16, P = 0.022); Turbuhaler -1.61 (-2.63, -0.59, P = 0.003). Symptom control improved significantly, with no significant difference between active and control patients, but active patients used less reliever medication (active 2.19 (SD 1.78) vs. control 3.42 (1.83) puffs/day, P = 0.002). After inhaler training, novel inhaler technique labels improve retention of correct inhaler technique skills with dry powder inhalers. Inhaler technique labels represent a simple, scalable intervention that has the potential to extend the benefit of inhaler training on asthma outcomes. REMINDER LABELS IMPROVE INHALER TECHNIQUE: Personalized

Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists.

Science.gov (United States)

Cheng, Jianjun; McCorvy, John D; Giguere, Patrick M; Zhu, Hu; Kenakin, Terry; Roth, Bryan L; Kozikowski, Alan P

2016-11-10

On the basis of the structural similarity of our previous 5-HT 2C agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT 2C agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT 2C agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.

Toxicity of inhaled 90Y in fused clay particles in beagle dogs. VI

International Nuclear Information System (INIS)

Hobbs, C.H.; Chiffelle, T.L.; Hahn, F.F.; Jones, R.K.; Mauderly, J.L.; McClellan, R.O.; Pickrell, J.A.

1974-01-01

Studies on the metabolism, dosimetry, and effects of inhaled 90 Y in fused clay in the Beagle dog are being continued to assess the consequences of inhalation of an energetic beta emitter that has a short effective half-life in the lung. A radiation dose pattern study in which 12 dogs were sacrificed in pairs at 0, 2, 4, 6, 8, and 12 days post-inhalation exposure has been completed. A longevity study in which 89 dogs have been exposed to 90 Y fused clay with initial lung burdens ranging from 80 to 5200 μCi/kg body weight and 12 control dogs were exposed to stable yttrium in fused clay is in progress. The 90 Y was retained in lung with a half-life similar to its physical half-life (64 hours) and with only small quantities translocated to tracheobronchial lymph nodes, skeleton, and liver. The infinite radiation doses to lung, tracheobronchial lymph nodes, skeleton, and liver for an initial lung burden of 100 μCi 90 Y/kg of body weight were estimated to be 1600, 170, 0.54, and 0.38 rads, respectively. Thirty-eight of 39 dogs with doses to lung from 9300 to 70,000 rads have died at 7.5 to 903 days post-exposure. The one surviving dog in this dose range has radiographic evidence of pulmonary fibrosis at 1316 days post-exposure. All the dogs that died had radiation pneumonitis. The dog that died at 903 days post-exposure with a dose to lung of 11,000 rads also had 2 small pulmonary adenomas. Fifty exposed dogs with doses to lung of 1300 to 7900 rads are surviving with no significant abnormalities at 1278 to 1834 days post-exposure and will be studied for the remainder of their lifespan. (U.S.)

Omalizumab: Clinical Use for the Management of Asthma

OpenAIRE

Thomson, Neil C.; Chaudhuri, Rekha

2012-01-01

Omalizumab, a humanized monoclonal antibody that binds circulating IgE antibody, is a treatment option for patients with moderate to severe allergic asthma whose asthma is poorly controlled with inhaled corticosteroids and inhaled long-acting β 2 agonist bronchodilators. This review considers the mechanism of action, pharmacokinetics, efficacy, safety and place in management of omalizumab in asthma and focuses particularly on key articles published over the last three years. Omalizumab reduce...

[Severe uncontrolled asthma in patients over 75 years old: Treatment with omalizumab].

Science.gov (United States)

Romand, P; Kelkel, E; Saint-Raymond, C; Glas, N; Caillaud, D; Devouassoux, G

2016-05-01

With an aging population and an increase in the prevalence of asthma, this disease is becoming more common in the elderly. Nevertheless, the management of severe asthma can be complex, due to an increased risk of uncontrolled disease in patients over 65 years old and partly to the inherent characteristics of old age: comorbidities, underestimation of the role of allergies, poor adherence, difficulties with inhalation devices, etc. We report two cases of women over 75 with severe persistent allergic asthma not controlled by high doses of inhaled corticosteroids and long-acting beta-2-agonists in whom treatment with omalizumab was initiated. Following treatment with omalizumab a decrease in the number and severity of exacerbations, improved asthma control and dose reduction or discontinuation of systemic corticosteroids were observed. The tolerance of omalizumab was good in both cases. Omalizumab is to be considered an effective and well-tolerated therapeutic option for elderly patients with inadequately controlled severe allergic asthma. Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.

COST–EFFECTIVENESS ANALYSIS OF THE MONTELUKAST APPLICATION IN CHILDREN WITH BRONCHIAL ASTHM IN THE CONDITIONS OF THE REPUBLIC OF BELARUS HEALTH CARE SYSTEM

Directory of Open Access Journals (Sweden)

I. N. Kozhanova

2012-01-01

Full Text Available The aim of this study was to estimate the montelukast cost-effectiveness in children with mild and moderate persistent asthma in Belarus. Patients and methods. A one-year decision tree model of asthma for a hypothetical cohort of 100 children with asthma and a lack of basic therapy or taking either montelukast or inhaled glucocorticosteroids has been constructed on the basis of the results of randomized clinical studies and local data. Results. In children older than 6 years of age the CER of fluticasone application was $1.45 per «day without asthma attacks, exacerbations, use of short-acting β2-receptor agonists» as compared to the montelukast CER — $2.62. In 2–6-year-old children the CER of montelukast application was $4.1, the budesonide inhalation suspension CER — $5.6, the CER of the lack of basis therapy — $6.9. Conclusion. The use of oral montelukast is considered to be cost-effective in 2–6-year-old children with mild and moderate persistent asthma as compared to the budesonide inhalation suspension or lack of basis therapy in the Republic of Belarus. Inhaled glucocorticosteroids is the priority medicine in children older than 6 years of age who are able to master the inhalation technique.

EFFECTS OF BUDESONIDE AND BAMBUTEROL ON CIRCADIAN VARIATION OF AIRWAY RESPONSIVENESS AND NOCTURNAL SYMPTOMS OF ASTHMA

NARCIS (Netherlands)

WEMPE, JB; TAMMELING, EP; POSTMA, DS; AUFFARTH, B; TEENGS, JP; KOETER, GH

Effects of the inhaled corticosteroid budesonide and the oral beta-agonist bambuterol on the nocturnal worsening of asthma were studied in patients with allergic asthma with a circadian peak expiratory flow variation greater-than-or-equal-to 15% (group 1, n = 8) and

A pulse synthesis of beta-FeSi sub 2 layers on silicon implanted with Fe sup + ions

CERN Document Server

Batalov, R I; Terukov, E I; Kudoyarova, V K; Weiser, G; Kuehne, H

2001-01-01

The synthesis of thin beta-FeSi sub 2 films was performed by means of the Fe sup + ion implantation into Si (100) and the following nanosecond pulsed ion treatment of implanted layer. Using the beta-FeSi sub 2 beta-FeSi sub 2 e X-ray diffraction it is shown that the pulsed ion treatment results in the generation of the mixture of two phases: FeSi and beta-FeSi sub 2 with stressed crystal lattices. The following short-time annealing leads to the total transformation of the FeSi phase into the beta-FeSi sub 2 one. The Raman scattering data prove the generation of the beta-FeSi sub 2 at the high degree of the silicon crystallinity. The experimental results of the optical absorption testify to the formation of beta-FeSi sub 2 layers and precipitates with the straight-band structure. The photoluminescence signal at lambda approx = 1.56 mu m observes up to 210 K

Betting Against Beta

DEFF Research Database (Denmark)

Frazzini, Andrea; Heje Pedersen, Lasse

We present a model with leverage and margin constraints that vary across investors and time. We find evidence consistent with each of the model’s five central predictions: (1) Since constrained investors bid up high-beta assets, high beta is associated with low alpha, as we find empirically for U...... of the BAB factor is low; (4) Increased funding liquidity risk compresses betas toward one; (5) More constrained investors hold riskier assets........S. equities, 20 international equity markets, Treasury bonds, corporate bonds, and futures; (2) A betting-against-beta (BAB) factor, which is long leveraged low beta assets and short high-beta assets, produces significant positive risk-adjusted returns; (3) When funding constraints tighten, the return...

Psychological insulin resistance in type 2 diabetes patients regarding oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin.

Science.gov (United States)

Petrak, Frank; Herpertz, Stephan; Stridde, Elmar; Pfützner, Andreas

2013-08-01

"Psychological insulin resistance" (PIR) is an obstacle to insulin treatment in type 2 diabetes, and patients' expectations regarding alternative ways of insulin delivery are poorly understood. PIR and beliefs regarding treatment alternatives were analyzed in patients with type 2 diabetes (n=532; mean glycated hemoglobin, 68±12 mmol/mol [8.34±1.5%]) comparing oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin. Questionnaires were used to assess barriers to insulin treatment (BIT), generic and diabetes-specific quality of life (Short Form 36 and Problem Areas in Diabetes, German version), diabetes knowledge, locus of control (Questionnaire for the Assessment of Diabetes-Specific Locus of Control, in German), coping styles (Freiburg Questionnaire of Illness Coping, 15-Items Short Form), self-esteem (Rosenberg Self-Esteem Scale, German version), and mental disorders (Patient Health Questionnaire, German version). Patients discussed treatment optimization options with a physician and were asked to make a choice about future diabetes therapy options in a two-step treatment choice scenario. Step 1 included oral antidiabetes drugs or subcutaneous insulin injection (SCI). Step 2 included an additional treatment alternative of inhaled insulin (INH). Subgroups were analyzed according to their treatment choice. Most patients perceived their own diabetes-related behavior as active, problem-focused, internally controlled, and oriented toward their doctors' recommendations, although their diabetes knowledge was limited. In Step 1, rejection of the recommended insulin was 82%, and in Step 2, it was 57%. Fear of hypoglycemia was the most important barrier to insulin treatment. Patients choosing INH (versus SCI) scored higher regarding fear of injection, expected hardship from insulin therapy, and BIT-Sumscore. The acceptance of insulin is very low in type 2 diabetes patients. The option to inhale insulin increases the acceptability for some but

Simulation of radon short lived decay daughters' inhalation using the lung compartmental model

International Nuclear Information System (INIS)

Tomulescu, Vlad C.

2002-01-01

Radon and its short-lived decay daughters are the main source of radiation on natural ways for population. The radon gas, released from soil, water or construction materials is producing by radioactive decay the following solid daughters: Po-218, Bi-214, Pb-214, and Po-214, which can attach to aerosols, and consequently penetrate the organism by inhalation. The human respiratory tract can be approximated by aid of a compartment model that takes into account the different anatomical structures exposed to contamination and irradiation, as well as the respective physiological processes. This model is associated to a mathematical equation system that describes the behavior of the radioactive material inside the body. The results represent the dose equivalent on different organs and tissues, as a function of subject and the activity performed in contaminating environment. (author)

Btk Inhibitor RN983 Delivered by Dry Powder Nose-only Aerosol Inhalation Inhibits Bronchoconstriction and Pulmonary Inflammation in the Ovalbumin Allergic Mouse Model of Asthma.

Science.gov (United States)

Phillips, Jonathan E; Renteria, Lorena; Burns, Lisa; Harris, Paul; Peng, Ruoqi; Bauer, Carla M T; Laine, Dramane; Stevenson, Christopher S

2016-06-01

In allergen-induced asthma, activated mast cells start the lung inflammatory process with degranulation, cytokine synthesis, and mediator release. Bruton's tyrosine kinase (Btk) activity is required for the mast cell activation during IgE-mediated secretion. This study characterized a novel inhaled Btk inhibitor RN983 in vitro and in ovalbumin allergic mouse models of the early (EAR) and late (LAR) asthmatic response. RN983 potently, selectively, and reversibly inhibited the Btk enzyme. RN983 displayed functional activities in human cell-based assays in multiple cell types, inhibiting IgG production in B-cells with an IC50 of 2.5 ± 0.7 nM and PGD2 production from mast cells with an IC50 of 8.3 ± 1.1 nM. RN983 displayed similar functional activities in the allergic mouse model of asthma when delivered as a dry powder aerosol by nose-only inhalation. RN983 was less potent at inhibiting bronchoconstriction (IC50(RN983) = 59 μg/kg) than the β-agonist salbutamol (IC50(salbutamol) = 15 μg/kg) in the mouse model of the EAR. RN983 was more potent at inhibiting the antigen induced increase in pulmonary inflammation (IC50(RN983) = <3 μg/kg) than the inhaled corticosteroid budesonide (IC50(budesonide) = 27 μg/kg) in the mouse model of the LAR. Inhalation of aerosolized RN983 may be effective as a stand-alone asthma therapy or used in combination with inhaled steroids and β-agonists in severe asthmatics due to its potent inhibition of mast cell activation.

COMPARTMENTALIZATION OF THE INFLAMMATORY RESPONSE TO INHALED GRAIN DUST

Science.gov (United States)

Interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and the secreted form of the IL-1 receptor antagonist (sIL-1RA) are involved in the inflammatory response to inhaled grain dust. Previously, we found considerable production of these cytokines in the lower...

Stimulation of phospholipase C in cultured microvascular endothelial cells from human frontal lobe by histamine, endothelin and purinoceptor agonists.

Science.gov (United States)

Purkiss, J. R.; West, D.; Wilkes, L. C.; Scott, C.; Yarrow, P.; Wilkinson, G. F.; Boarder, M. R.

1994-01-01

1. Cultures of endothelial cells derived from the microvasculature of human frontal lobe have been investigated for phospholipase C (PLC) responses to histamine, endothelins and purinoceptor agonists. 2. Using cells prelabelled with [3H]-inositol and measuring total [3H]-inositol (poly)phosphates, histamine acting at H1 receptors stimulated a substantial response with an EC50 of about 10 microM. 3. Endothelin-1 also gave a clear stimulation of phosphoinositide-specific phospholipase C. Both concentration-response curves and binding curves showed effective responses and binding in the rank order of endothelin-1 > sarafotoxin S6b > endothelin-3, suggesting an ETA receptor. 4. Assay of total [3H]-inositol (poly)phosphates showed no response to the purinoceptor agonists, 2-methylthioadenosine 5'-trisphosphate (2MeSATP), adenosine 5'-O-(3-thiotrisphosphate) (ATP gamma S) or beta,gamma-methylene ATP. Both ATP and UTP gave a small PLC response. 5. Similarly, when formation of [32P]-phosphatidic acid from cells prelabelled with 32Pi was used as an index of both PLC and phospholipase D, a small response to ATP and UTP was seen but there was no response to the other purinoceptor agonists tested. 6. Study by mass assay of stimulation by ATP of inositol (1,4,5) trisphosphate accumulation revealed a transient response in the first few seconds, a decline to basal, followed by a small sustained response. 7. These results show that human brain endothelial cells in culture are responsive to histamine and endothelins in a manner which may regulate brain capillary permeability. Purines exert a lesser influence. PMID:8032588

The interaction of beta 2-microglobulin (beta 2m) with mouse class I major histocompatibility antigens and its ability to support peptide binding. A comparison of human and mouse beta 2m

DEFF Research Database (Denmark)

Pedersen, L O; Stryhn, A; Holter, T L

1995-01-01

of class I molecules are involved in peptide binding, whereas most of class I molecules are involved in beta 2m binding. We propose that mouse beta 2m interacts with the minor peptide binding (i.e. the "empty") fraction with a lower affinity than human beta 2m does, whereas mouse and human beta 2m interact......The function of major histocompatibility complex (MHC) class I molecules is to sample peptides derived from intracellular proteins and to present these peptides to CD8+ cytotoxic T lymphocytes. In this paper, biochemical assays addressing MHC class I binding of both peptide and beta 2-microglobulin...... (beta 2m) have been used to examine the assembly of the trimolecular MHC class I/beta 2m/peptide complex. Recombinant human beta 2m and mouse beta 2ma have been generated to compare the binding of the two beta 2m to mouse class I. It is frequently assumed that human beta 2m binds to mouse class I heavy...

Asthma management in pregnancy: young female doctors knowledge and practice

International Nuclear Information System (INIS)

Younis, M.; Anwar, S.; Aneela, I.; Saeed, M.S.

2012-01-01

Background: Optimal asthma control in pregnant women is very much essential for the good health of both mother and the fetus. Maternal and fetal complications occur due to poor control of asthma. There are concerns that management of bronchial asthma in pregnant women should be optimal by the health professionals. Objective: The aim of the study was to evaluate the knowledge and practices of young female doctors about the bronchial asthma management in pregnancy. Study Design: Randomized evidence based. Study Setting: Punjab Public Service Commission (PPSC) interviews for women medical officers and female doctors working in different medical units and chest unit of Mayo Hospital a tertiary care hospital affiliated with King Edward Medical University, Lahore. Materials and Methods: A questionnaire based survey of knowledge and practices of one hundred and one female doctors in the management of bronchial asthma was made. Amongst these, 32 doctors were FCPS 1 in medicine and gynecology. Remaining 69 doctors were in the pipeline and they have completed one year house job in different specialties. The case scenario was Asthma management approach during pregnancy in a stable patient of moderate severity. Inclusion Criteria 1. All those female doctors who have completed one year house job. 2. Female doctors working in gynecology, medicine, surgery and allied specialties. Results: Overall 14 (13.6%) doctors (5 (35.7%) PGs and 9 (64.3%) Non PGs) have the standard prescription of inhaled corticosteroids with long acting inhaled B2 agonists and montelukast as controller medication and short acting inhaled B2 agonist as needed as reliever medication according to the standard guidelines. Conclusion: The majority of young female doctors had the suboptimal knowledge and practice of asthma management in pregnancy. We suggest initiating the training programs to optimize their knowledge and practices. (author)

Human beta 2 chain of laminin (formerly S chain): cDNA cloning, chromosomal localization, and expression in carcinomas

DEFF Research Database (Denmark)

Wewer, U M; Gerecke, D R; Durkin, M E

1994-01-01

or other known laminin genes. Immunostaining showed that the beta 2 chain is localized to the smooth muscle basement membranes of the arteries, while the homologous beta 1 chain is confined to the subendothelial basement membranes. The beta 2 chain was found in the basement membranes of ovarian carcinomas......Overlapping cDNA clones that encode the full-length human laminin beta 2 chain, formerly called the S chain, were isolated. The cDNA of 5680 nt contains a 5391-nt open reading frame encoding 1797 amino acids. At the amino terminus is a 32-amino-acid signal peptide that is followed by the mature...... beta 2 chain polypeptide of 1765 amino acids with a calculated molecular mass of 192,389 Da. The human beta 2 chain is predicted to have all of the seven structural domains typical of the beta chains of laminin, including the short cysteine-rich alpha region. The amino acid sequence of human beta 2...

Short and long-lasting behavioral consequences of agonistic encounters between male Drosophila melanogaster.

Science.gov (United States)

Trannoy, Séverine; Penn, Jill; Lucey, Kenia; Popovic, David; Kravitz, Edward A

2016-04-26

In many animal species, learning and memory have been found to play important roles in regulating intra- and interspecific behavioral interactions in varying environments. In such contexts, aggression is commonly used to obtain desired resources. Previous defeats or victories during aggressive interactions have been shown to influence the outcome of later contests, revealing loser and winner effects. In this study, we asked whether short- and/or long-term behavioral consequences accompany victories and defeats in dyadic pairings between male Drosophila melanogaster and how long those effects remain. The results demonstrated that single fights induced important behavioral changes in both combatants and resulted in the formation of short-term loser and winner effects. These decayed over several hours, with the duration depending on the level of familiarity of the opponents. Repeated defeats induced a long-lasting loser effect that was dependent on de novo protein synthesis, whereas repeated victories had no long-term behavioral consequences. This suggests that separate mechanisms govern the formation of loser and winner effects. These studies aim to lay a foundation for future investigations exploring the molecular mechanisms and circuitry underlying the nervous system changes induced by winning and losing bouts during agonistic encounters.

Decreased agonist sensitivity of human GABA(A) receptors by an amino acid variant, isoleucine to valine, in the alpha1 subunit.

Science.gov (United States)

Westh-Hansen, S E; Rasmussen, P B; Hastrup, S; Nabekura, J; Noguchi, K; Akaike, N; Witt, M R; Nielsen, M

1997-06-25

Recombinant human GABA(A) receptors were investigated in vitro by coexpression of cDNAs coding for alpha1, beta2, and gamma2 subunits in the baculovirus/Sf-9 insect cell system. We report that a single amino acid exchange (isoleucine 121 to valine 121) in the N-terminal, extracellular part of the alpha1 subunit induces a marked decrease in agonist GABA(A) receptor ligand sensitivity. The potency of muscimol and GABA to inhibit the binding of the GABA(A) receptor antagonist [3H]SR 95531 (2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium bromide) was higher in receptor complexes of alpha1(ile 121) beta2gamma2 than in those of alpha1(val 121) beta2gamma2 (IC50 values were 32-fold and 26-fold lower for muscimol and GABA, respectively). The apparent affinity of the GABA(A) receptor antagonist bicuculline methiodide to inhibit the binding of [3H]SR 95531 did not differ between the two receptor complex variants. Electrophysiological measurements of GABA induced whole-cell Cl- currents showed a ten-fold decrease in the GABA(A) receptor sensitivity of alpha1 (val 121) beta2gamma2 as compared to alpha1(ile 121) beta2gamma2 receptor complexes. Thus, a relatively small change in the primary structure of the alpha1 subunit leads to a decrease selective for GABA(A) receptor sensitivity to agonist ligands, since no changes were observed in a GABA(A) receptor antagonist affinity and benzodiazepine receptor binding.

Acute Inhalation Toxicity of T-2 Mycotoxin in the Rat and Guinea Pig

Science.gov (United States)

1990-01-01

2/kg body weight for the guinea pig . These data show that inhaled T-2 toxin is approximately 20 times more toxic to the rat (0.05 mg T-2/kg body wt...inhaled vs 1.0 mg T-2/kg body wt ip) and at least twice as toxic to the guinea pig (0.4 mg T-2/kg body wt inhaled vs 1-2 mg T-2/kg body wt ip) than ip...administered T-2 toxin. Histopathologic examination of major organs in both the rat and guinea pig after respiratory exposure to T-2 toxin indicated

Exercise-induced bronchospasm: implications for patients with or without asthma in primary care practice

Directory of Open Access Journals (Sweden)

Hayden ML

2011-11-01

Full Text Available Stuart W Stoloff1, Gene L Colice2, Mary Lou Hayden3, Timothy J Craig4, Nancy K Ostrom5, Nemr S Eid6, Jonathan P Parsons71University of Nevada School of Medicine, Reno, NV, 2Washington Hospital Center, Washington, DC, 3University of Virginia, Charlottesville, VA, 4Pennsylvania State University, Hershey, PA, 5Allergy and Asthma Medical Group and Research Center, San Diego, CA, 6University of Louisville, Louisville, KY, 7Ohio State University Asthma Center, Columbus, OH, USAAbstract: Exercise-induced bronchospasm (EIB can represent a substantial barrier to physical activity. We present the cases of two patients with EIB, one with asthma, and one without asthma, who were evaluated at our primary care practice. The first case was a 44-year-old man with a history of seasonal allergic rhinitis but no asthma, who reported difficulty breathing when playing tennis. The second case was a 45-year-old woman who presented with persistent, generally well-controlled asthma, who was now experiencing bouts of coughing and wheezing during exercise. In both cases, an exercise challenge was used to diagnose EIB, and patients were prescribed a short-acting beta agonist to be used immediately before initiating exercise. EIB is a frequently encountered problem among patients presenting to primary care specialists. Affected patients should be made aware of the importance of proactive treatment with a short-acting beta agonist before initiating any exercise.Keywords: asthma, compliance, exercise-induced bronchospasm

Prediction of selective estrogen receptor beta agonist using open data and machine learning approach.

Science.gov (United States)

Niu, Ai-Qin; Xie, Liang-Jun; Wang, Hui; Zhu, Bing; Wang, Sheng-Qi

2016-01-01

Estrogen receptors (ERs) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. ERs have been validated as important drug targets for the treatment of various diseases, including breast cancer, ovarian cancer, osteoporosis, and cardiovascular disease. ERs have two subtypes, ER-α and ER-β. Emerging data suggest that the development of subtype-selective ligands that specifically target ER-β could be a more optimal approach to elicit beneficial estrogen-like activities and reduce side effects. Herein, we focused on ER-β and developed its in silico quantitative structure-activity relationship models using machine learning (ML) methods. The chemical structures and ER-β bioactivity data were extracted from public chemogenomics databases. Four types of popular fingerprint generation methods including MACCS fingerprint, PubChem fingerprint, 2D atom pairs, and Chemistry Development Kit extended fingerprint were used as descriptors. Four ML methods including Naïve Bayesian classifier, k-nearest neighbor, random forest, and support vector machine were used to train the models. The range of classification accuracies was 77.10% to 88.34%, and the range of area under the ROC (receiver operating characteristic) curve values was 0.8151 to 0.9475, evaluated by the 5-fold cross-validation. Comparison analysis suggests that both the random forest and the support vector machine are superior for the classification of selective ER-β agonists. Chemistry Development Kit extended fingerprints and MACCS fingerprint performed better in structural representation between active and inactive agonists. These results demonstrate that combining the fingerprint and ML approaches leads to robust ER-β agonist prediction models, which are potentially applicable to the identification of selective ER-β agonists.

[Warning symptoms of asthma attack and asthma self-management: a national asthma control survey from China].

Science.gov (United States)

Lin, J T; Wang, W Q; Zhou, X; Wang, C Z; Huang, M; Cai, S X; Chen, P; Lin, Q C; Zhou, J Y; Gu, Y H; Yuan, Y D; Sun, D J; Yang, X H; Yang, L; Huo, J M; Chen, Z C; Jiang, P; Zhang, J; Ye, X W; Liu, H G; Tang, H P; Liu, R Y; Liu, C T; Zhang, W; Hu, C P; Chen, Y Q; Liu, X J; Dai, L M; Zhou, W; Huang, Y J; Xu, J Y

2017-08-08

Objective: To investigate warning symptoms of asthma attack and evaluate asthma self-management status of asthma patients in urban China. Methods: A multi-center, cross-sectional, questionnaire-based survey was carried out from 30 general hospitals dispersed in 30 provinces of mainland China (except for Tibet) during Oct 2015 to May 2016. Information of frequency and warning symptoms of asthma attack, the time from warning symptoms to asthma attack, the impact of asthma attack and asthma self-management were collected from asthma patients of outpatient department. Results: Altogether 3 875 asthmatic outpatients were recruited. 78.1% (3 026/3 875) of the patients reported restriction of exercise and daily activities during asthma exacerbation. 82.5% (3 160/3 829) of the patients had warning symptoms before asthma attack, the most common warning symptoms were cough, chest tightness and shortness of breath. The median time from warning symptoms to asthma attack was 2 h, the mean time was 90 h. Only 4.4% (167/3 829) of the patients had definite confidence to control asthma when symptoms deteriorated. 76.7% (2 937/3 828) of the patients used medications to control asthma when asthma symptoms deteriorated. Medication choice: inhaled corticosteroid (ICS) + formoterol 45.8% (1 776/3 875), short-acting beta-agonist (SABA) 23.9% (927/3 875). Conclusions: Most asthma patients have warning symptoms before asthma attack, the most common symptoms are cough, chest tightness and shortness of breath. The proportion of patients conducting effective asthma self-management remains low.

Agonistic effects of a monoclonal antibody specific for the interleukin-2 receptor

International Nuclear Information System (INIS)

Eardley, D.D.; Makrides, V.

1986-01-01

Interleukin-2 (IL-2) mediated immune responses can be blocked by monoclonal antibodies to the IL-2 receptor. The monoclonal antibody, M720, is defined as specific for the IL-2 receptor because it blocks 35 S-IL-2 binding to Con A blasts, reacts with lymphoblasts but not resting splenocytes, and inhibits IL-2 induced proliferation to mitogen, antigen, or allogeneic stimuli. Under appropriate culture conditions, the IL-2 receptor-specific antibody can act like IL-2 in that it will induce proliferation in T cells in the absence of additional antigen or mitogen. This agonistic effect is dependent on time, dose of antibody, and requires fetal calf serum (FCS) in the media. Because the FCS is not mitogenic by itself, the authors propose that the FCS components act as incomplete mitogen to induce appearance of IL-2 receptors but lack a factor which would push the majority of the cells into the S phase of the cell cycle. This factor is usually IL-2, but in the authors experiments, the IL-2 receptor-specific antibody can provide the same stimulus. These data indicate that factors like FCS can induce IL-2 receptors, but without additional IL-2 or receptor triggering, the cells will not proceed through the synthetic and proliferative phases of cell growth

Effect of interleukin 13 on bronchial hyperresponsiveness and the bronchoprotective effect of beta-adrenergic bronchodilators and corticosteroids.

Science.gov (United States)

Townley, Robert G; Gendapodi, Pradeep R; Qutna, Nidal; Evans, Joseph; Romero, Francisco A; Abel, Peter

2009-03-01

Fluticasone affects airway bronchial hyperresponsiveness (BHR) and enhances bronchodilation and bronchoprotection induced by beta-adrenergic agonists. Interleukin 13 (IL-13), however, induces BHR. To test the hypotheses that fluticasone inhibits BHR after either allergen sensitization or IL-13 administration and that fluticasone restores the bronchodilation and bronchoprotective effects of beta-agonists. The BHR to methacholine induced by IL-13 or ovalbumin was determined in BALB/c mice, and the provocation concentration of methacholine that caused an increase in enhanced pause in expiration of 200% (PC200) was calculated. We compared this response to methacholine in control mice with the response after treatment with IL-13 receptor alpha 2-IgGFc fusion protein (IL-13R alpha 2) (an IL-13 blocker), fluticasone, albuterol, salmeterol, fluticasone-albuterol, and fluticasone-salmeterol. IL-13R alpha 2 (PC200, 17.59) completely blocks the BHR-induced effects of IL-13 (PC200, 7.28; P < .005). After IL-13 therapy (PC200, 5.90; P < .005), 1 mg/mL of albuterol (PC200, 3.38; P = .33), fluticasone (PC200, 4.59; P = .40), or fluticasone plus 50 microg/mL of salmeterol (PC200, 5.59; P = .11) showed no significant bronchoprotection. In nonsensitized mice, fluticasone plus 0.25 microg/mL of salmeterol (PC200, 25.90; P < .005) showed significantly greater bronchoprotection than did salmeterol alone (PC200, 11.08; P = .26). Fluticasone plus 0.3 mg/mL of albuterol and fluticasone plus 1 mg/mL of albuterol were significantly more protective than was fluticasone or albuterol alone in ovalbumin-sensitized mice. The protective effects of fluticasone, beta-agonists, and fluticasone plus beta-agonists are significantly less in IL-13-treated mice than in nonsensitized or ovalbumin-sensitized mice.

Regional trends in the use of short-acting and long-acting contraception accessed through the private and public sectors.

Science.gov (United States)

Ugaz, Jorge I; Chatterji, Minki; Gribble, James N; Mitchell, Susan

2015-08-01

To examine trends in the source of modern contraception (public versus private sector); method choice (long-acting or permanent methods versus short-acting methods); and method and source combined. A retrospective analysis was conducted using data collected by national Demographic and Health Surveys and Reproductive Health Surveys during the period 1992-2012. The dataset included 18 low-income countries in Sub-Saharan Africa, 10 from Latin America and the Caribbean (LAC), and 8 from Asia. A substantial proportion-between 40% and 49%-of modern contraceptive users relied on the private sector in Asia and LAC in the last 20years, yet the proportion has been smaller in Sub-Saharan Africa, between 27% and 30%. Increased use of short-acting methods from both public and private sectors has driven the rise in contraceptive prevalence in Asia and LAC. Similarly, increased contraceptive prevalence in Sub-Saharan Africa reflected the increased use of short-acting methods obtained mainly through the public sector, with only limited use of long-acting or permanent methods through the private sector. The private sector has played a key role in the increase of modern CPR and the provision of modern contraceptives around the world, providing almost half of them in low-income countries. Yet, such increase was driven primarily by a more substantial role in the provision of short-acting methods than long acting and permanent methods. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.

Inhaler education for hospital-based pharmacists: how much is required?

Science.gov (United States)

Jackevicius, C A; Chapman, K R

1999-01-01

To compare the effectiveness of a more intensive educational intervention with a less intensive intervention on the ability of hospital pharmacists to be prepared to educate patients regarding inhaled device technique. Randomized controlled trial. Inhaler technique and knowledge were assessed pre-education, immediately after and three months after education by a research assistant blinded to the educational allocation. Tertiary hospital pharmacy department. Hospital-based pharmacists. A 1 h 'hands-on' session with feedback (more intense education, MIE) or written materials describing inhaler use (less intense education, LIE). The change in overall score from pre-education to early posteducation for MIE was greater than for LIE (mean [95% CI]) (2.64 [1.27 to 4.01] versus 1.26 [0.05 to 2.47], PMIE group than the LIE group, a difference that was not statistically significant (1.78 [0.82 to 2.74] versus 1. 22 [0.06 to 2.39], P=0.09). Scores in both groups were lower in the late posteducation period compared with the early posteducation period. Greater increases in total score in the immediate posteducation period were associated with a low baseline score and the MIE intervention. Individual coaching in inhaler technique produces greater improvement in inhaler knowledge among hospital pharmacists than provision of written materials. However, the advantage of the more intensive intervention was short-lived, with little advantage evident in three months.

Reducing Prescriptions of Long-acting Benzodiazepine Drugs in Denmark

DEFF Research Database (Denmark)

Eriksen, Sophie Isabel; Bjerrum, Lars

2015-01-01

Prolonged consumption of benzodiazepine drugs (BZD) and benzodiazepine receptor agonists (zolpidem, zaleplon, zopiclone; altogether Z drugs) is related to potential physiological and psychological dependence along with other adverse effects. This study aimed to analyse the prescribing of long...... to the prescription. The observed reduction in BZD use was correlated to the introduction of new national guidelines on prescription of addictive drugs, but this study was not designed to detect a causal relationship. The prescribing of long-acting BZD decreased considerably more than the prescribing of short......-acting BZD (half-life >10 hr), compared to short-acting BZD in Denmark during a 10-year period. Descriptive analysis of total sales data from the Danish Register of Medicinal Product Statistics, to individuals in the primary healthcare sector, of all BZD and Z-drugs in the period of 2003-2013. Prescription...

Berberine-induced pigment dispersion in Bufo melanostictus melanophores by stimulation of beta-2 adrenergic receptors.

Science.gov (United States)

Ali, Sharique A; Naaz, Ishrat; Choudhary, Ram Kumar

2014-02-01

Reduced production of melanin by decreased or the absence of melanocytes leads to various hypopigmentation disorders, and the development of melanogenetic agents for photoprotection and hypopigmentation disorders is one of the top priority areas of research. Hence, the present study was carried out to elucidate the ability of berberine, a principal active ingredient present in the roots of the herb Berberis vulgaris to stimulate pigment dispersion in the isolated skin melanophores of the toad Bufo melanostictus. In the present study, mean melanophore size index of the isolated skin melanophores of B. melanostictus was assayed after treating with various concentrations of berberine. A marked melanin dispersion response leading to skin darkening was observed in the isolated melanophores of toad in response to berberine, which was found to be mediated through beta-2 adrenergic receptors. The physiologically significant dose-related melanin dispersion effects of berberine per se were found to be completely abolished by propranolol, which is a specific beta-2 adrenergic receptor blocker. These per se melanin dispersal effects were also found to be markedly potentiated by isoprenaline, which is a specific beta-adrenoceptor agonist. The results indicate that berberine causes a tremendous, dose-dependent, physiologically significant pigment dispersing in the isolated skin melanophores of B. melanostictus.

Short-time beta grain growth kinetics for a conventional titanium alloy

International Nuclear Information System (INIS)

Semiatin, S.L.; Sukonnik, I.M.

1996-01-01

The kinetics of beta grain growth during short-time, supertransus heat treatment of Ti-5Al-4V were determined using a salt-pot technique. The finite-time, subtransus temperature transient during salt-pot heating was quantified through measurements of the heat transfer coefficient characterizing conduction across the salt-titanium interface and a simple heat conduction analysis which incorporated this heat transfer coefficient. Grain size versus time data adjusted to account for the subtransus temperature transient were successfully fit to the parabolic grain growth law d n - d 0 n = kt exp(-Q/RT) using an exponent n equal to 2.0. Comparison of the present results to rapid, continuous heat treatment data in the literature for a similar titanium alloy revealed a number of semi-quantitative similarities

Teaching inhaler use in chronic obstructive pulmonary disease patients.

Science.gov (United States)

Lareau, Suzanne C; Hodder, Richard

2012-02-01

To review barriers to the successful use of inhalers in patients with chronic obstructive pulmonary disease (COPD), and the role of the nurse practitioner (NP) in facilitating optimum inhaler use. Review of the national and international scientific literature. Pharmacologic treatment of COPD patients comprises mainly inhaled medications. Incorrect use of inhalers is very common in these individuals. Some of the consequences of poor inhaler technique include reduced therapeutic dosing, medication adherence, and disease stability, which can lead to increased morbidity, decreased quality of life, and a high burden on the healthcare system. Knowledgeable evaluation and frequent reassessment of inhaler use coupled with education of patients, caregivers, and healthcare professionals can significantly improve the benefits COPD patients derive from inhaled therapy. Patient education is vital for correct use of inhalers and to ensure the effectiveness of inhaled medications. The NP has a critical role in assessing potential barriers to successful learning by the patient and improving inhaler technique and medication management. The NP can also facilitate success with inhaled medications by providing up-to-date inhaler education for other healthcare team members, who may then act as patient educators. ©2011 The Author(s) Journal compilation ©2011 American Academy of Nurse Practitioners.

Complete reversal of muscle wasting in experimental cancer cachexia: Additive effects of activin type II receptor inhibition and β-2 agonist.

Science.gov (United States)

Toledo, Míriam; Busquets, Sílvia; Penna, Fabio; Zhou, Xiaolan; Marmonti, Enrica; Betancourt, Angelica; Massa, David; López-Soriano, Francisco J; Han, H Q; Argilés, Josep M

2016-04-15

Formoterol is a highly potent β2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the β2-agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer. © 2015 UICC.

Inhalant Dependence and its Medical Consequences

Directory of Open Access Journals (Sweden)

Mehmet Hamid Boztaş

2010-12-01

Full Text Available The term of inhalants is used for matters easily vapors. Inhalants are preferred for rapid, positive reinforcement and mild high effects. Products including inhalants are cheap, accessible, legal substances and are prevalently used in community. The prevalence of inhalant use in secondary schools in Turkey is about 5.1%. Inhalant substance dependence is generally observed within 14-15 age group. Age at first use could be as low as 5 to 6 years of age. Substance dependence is more probable in adults working in substance existing places. Inhalant usage is common in disadvantaged groups, children living in street, people with history of crimes, prison, depression, suicide, antisocial attitudes and conflict of family, history of abuse, violence and any other drug dependence and isolated populations. Inhalants are absorbed from lungs, after performing their quick and short effect metabolized by cytochrom P450 enzyme system except inhalant nitrites group which has a depressing effect like alcohol. In chronic use general atrophy, ventricular dilatation and wide sulcus were shown in cerebrum, cerebellum and pons by monitoring brain. Defects are mostly in periventricular, subcortical regions and in white matter. Demyelinization, hyperintensity, callosal slimming and wearing off in white and gray matter margins was also found. Ravages of brain shown by brain monitorisation are more and serious in inhalant dependence than in other dependences. It is important to decrease use of inhalants. Different approaches should be used for subcultures and groups in prevention. Prohibiting all the matters including inhalant is not practical as there are too many substances including inhalants. Etiquettes showing harmful materials can be used but this approach can also lead the children and adolescents recognize these substances easily.. Despite determintal effects of inhalant dependence, there are not yet sufficient number of studies conducted on prevention and

The severity of airways obstruction as a determinant of treatment response in COPD

DEFF Research Database (Denmark)

Calverley, Peter Ma; Pauwels, Romain A; Jones, Paul W

2006-01-01

Abstract: Guidelines recommend that patients with COPD are stratified arbitrarily by baseline severity (FEV1) to decide when to initiate combination treatment with a long-acting ß2-agonist and an inhaled corticosteroid. Assessment of baseline FEV1 as a continuous variable may provide a more relia...

Acute lung injury induces cardiovascular dysfunction

DEFF Research Database (Denmark)

Suda, Koichi; Tsuruta, Masashi; Eom, Jihyoun

2011-01-01

Acute lung injury (ALI) is associated with systemic inflammation and cardiovascular dysfunction. IL-6 is a biomarker of this systemic response and a predictor of cardiovascular events, but its possible causal role is uncertain. Inhaled corticosteroids and long-acting β2 agonists (ICS/LABA) down-r...

MELATONIN DAN MELATONIN RECEPTOR AGONIST SEBAGAI PENANGANAN INSOMNIA PRIMER KRONIS

Directory of Open Access Journals (Sweden)

Ni Luh Putu Ayu Maha Iswari

2013-04-01

Full Text Available Melatonin is a hormone that has an important role in the mechanism of sleep. Hypnotic effects of melatonin and melatonin receptor agonist are mediated via MT1 and MT2 receptors, especially in circadian rhythm pacemaker, suprachiasmatic nucleus, which is worked on the hypothalamic sleep switch. This mechanism is quite different with the GABAergic drugs such as benzodiazepine. Agonist melatonin triggers the initiation of sleep and normalize circadian rhythms so that makes it easier to maintain sleep. The main disadvantage of melatonin in helping sleep maintenance on primary insomnia is that the half life is very short. The solution to this problem is the use of prolonged-release melatonin and melatonin receptor agonist agents such as ramelteon. Melatoninergic agonist does not cause withdrawal effects, dependence, as well as cognitive and psychomotor disorders as often happens on the use of benzodiazepine.  

Triple therapy in COPD: new evidence with the extrafine fixed combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide

Directory of Open Access Journals (Sweden)

Singh D

2017-10-01

Full Text Available Dave Singh,1 Massimo Corradi,2 Monica Spinola,3 Alberto Papi,4 Omar S Usmani,5 Mario Scuri,3 Stefano Petruzzelli,3 Jørgen Vestbo1 1Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK; 2Department of Medicine and Surgery, University of Parma, Parma, Italy; 3Chiesi Farmaceutici SpA, Parma, Italy; 4Department of Medical Sciences, Research Centre on Asthma and COPD, University of Ferrara, Ferrara, Italy; 5National Heart and Lung Institute, Imperial College London, London, UK Abstract: The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs, long-acting beta2 agonists (LABAs, and long-acting muscarinic antagonists (LAMAs has become an option for maintenance treatment of COPD and as a “step-up” therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff/formoterol fumarate (6 µg/puff/glycopyrronium bromide (12.5 µg/puff has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients. Keywords: COPD, inhaled triple therapy, beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide

Role of short-acting nitroglycerin in the management of ischemic heart disease

Directory of Open Access Journals (Sweden)

Boden WE

2015-08-01

Full Text Available William E Boden,1–3 Santosh K Padala,1–3 Katherine P Cabral,4 Ivo R Buschmann,5 Mandeep S Sidhu1–31Department of Medicine, Division of Cardiology, Albany Medical College, 2Department of Medicine, Division of Cardiology, Albany Stratton Veterans Affairs Medical Center, 3Department of Medicine, Division of Cardiology, Albany Medical Center, 4Department of Pharmacy, Albany College Pharmacy and Health Sciences, Albany, NY, USA; 5Department of Angiology, Medical University of Brandenburg & Charité, Berlin, GermanyAbstract: Nitroglycerin is the oldest and most commonly prescribed short-acting anti-anginal agent; however, despite its long history of therapeutic usage, patient and health care provider education regarding the clinical benefits of the short-acting formulations in patients with angina remains under-appreciated. Nitrates predominantly induce vasodilation in large capacitance blood vessels, increase epicardial coronary arterial diameter and coronary collateral blood flow, and impair platelet aggregation. The potential for the prophylactic effect of short-acting nitrates remains an under-appreciated part of optimal medical therapy to reduce angina and decrease myocardial ischemia, thereby enhancing the quality of life. Short-acting nitroglycerin, administered either as a sublingual tablet or spray, can complement anti-anginal therapy as part of optimal medical therapy in patients with refractory and recurrent angina either with or without myocardial revascularization, and is most commonly used to provide rapid therapeutic relief of acute recurrent angina attacks. When administered prophylactically, both formulations increase angina-free walking time on treadmill testing, abolish or delay ST segment depression, and increase exercise tolerance. The sublingual spray formulation provides several clinical advantages compared to tablet formulations, including a lower incidence of headache and superiority to the sublingual tablet in terms of

Lifetime health risks from internally deposited beta-emitting radionuclides

International Nuclear Information System (INIS)

Boecker, B.B.; Griffith, W.C.; Hahn, F.F.; Nikula, K.J.; Lundgren, D.L.; Muggenburg, B.A.

1997-01-01

Much of our knowledge on the lifetime health risks resulting from internal depositions of beta- and gamma-emitting radionuclides has come from studies in laboratory animals conducted to provide information not available from human epidemiological studies. This paper is focused primarily on results of experiments in which laboratory animals (dogs and rodents) were exposed once, briefly, by inhalation or intravenous injection to an individual fission-product radionuclide and were studied for radionuclide metabolism, dosimetry, and lifetime health effects. The relative importance of many dose- and effect-modifying factors was studied. The main long-term biological effects were cancers in the organs and tissues receiving the highest doses. Results for three different patterns of irradiation (skeleton, lung, and whole-body) are presented. The risks of bone cancers produced by 90 Sr are compared with those from 238 Pu in dogs. Lung cancer risks for several beta emitters inhaled in a relatively insoluble form by dogs are compared with results for 144 CeO 2 inhaled by rats. Late-occurring biological effects from the relatively uniform whole-body irradiation from intravenously injected 137 Cs are also presented. In addition to radionuclide-specific results, cross-cutting analyses of these studies provide valuable information on broader issues such as dose protraction, relative biological effectiveness, threshold considerations, and inter-species comparisons including extrapolation to human exposure situations. (authors)

Reversion of methacholine induced bronchoconstriction with inhaled diazepam in patients with asthma

OpenAIRE

Miric, Mirjana; Ristic, Sinisa; Joksimovic, Bojan N; Medenica, Snezana; Racic, Maja; Ristic, Slavica; Joksimovic, Vedrana R; Skipina, Mirjana

2016-01-01

Background: Benzodiazepines have a direct bronchodilatory effect. Methacholine is a non-selective muscarinic receptor agonist causing bronchoconstriction. Aim: To examine the effects of inhaled benzodiazepines, modulating bronchoconstriction induced by methacholine in patients with asthma. Patients and Methods: Twelve patients with well controlled asthma were studied. On the first day, after determining the initial values of pulmonary function, a dose response curve was carried out with progr...