Β2-adrenoreceptor Agonist Research Articles

Prenatal exposure to β2-adrenoreceptor agonists and the risk of autism spectrum disorders in offspring.

We aimed to examine the risk of autism spectrum disorders (ASDs) in the offspring who were exposed to maternal use of β2-adrenoreceptor agonist (β2AA) during pregnancy. This is a population-based cohort study including all live singleton births in Denmark from 1 January 1997 to 31 December 2008. Children born to mothers who used β2AA during pregnancy were categorized as exposed, and all other children were included in the unexposed group. Cases of ASDs were identified from the Danish Psychiatric Central Register and the Danish Patient Register. Incidence rate ratio (IRR) and 95% confidence interval were estimated by Poisson regression models. Among 751888 children in the cohort, 9098 (1.21%) received a diagnosis of ASDs. We observed an increased risk of ASDs in the exposed children (IRR=1.28, 1.11-1.47), especially for those who were exposed during the second trimester period (IRR=1.38, 1.14-1.67). However, when extending the exposure time window to 1year prior to pregnancy, we observed a similar association in children born to women who received β2AA treatment during pregnancy (IRR=1.33, 1.11-1.59) to that in children born to women who received β2AA treatment 1year prior to pregnancy (IRR=1.35, 1.17-1.56). Our finding suggested that children born to women who used β2AA during pregnancy have an increased risk of ASDs in later life, which is more likely due to underlying maternal diseases rather than the exposure to β2AA itself. However, further study, which would better differentiate the effects between indication and medicine, is needed to corroborate the finding. Copyright © 2017 John Wiley & Sons, Ltd.

Fluticasone furoate/vilanterol dry-powder inhaler in asthma: a guide to its use in the EU

Fluticasone furoate/vilanterol [Relvar®, Revinty® (EU); Breo® (USA)], a fixed-dose combination of an inhaled corticosteroid (ICS) and a long-acting β2-adrenoreceptor agonist (LABA), is delivered via Ellipta®, a dry powder inhaler and is administered once daily. EU approval of the combination for the treatment of asthma in adults and adolescents, for whom ICS/LABA therapy is appropriate, was based on the findings of phase 3 trials in patients (aged ≥12 years) whose asthma was uncontrolled by ICS and/or ICS/LABA therapy. Once-daily fluticasone furoate/vilanterol improved pulmonary function in these studies, being as effective as twice-daily fluticasone propionate/salmeterol and more effective than twice-daily fluticasone propionate. In addition, fluticasone furoate/vilanterol reduced the risk of severe asthma exacerbations, and improved asthma control and measures of asthma-related quality of life. It is generally well tolerated and, due to the low systemic exposure to fluticasone furoate and vilanterol when administered via inhalation, does not appear to be associated with clinically relevant systemic effects. With the added convenience of once-daily administration (which has the potential to improve treatment adherence in some patients), fluticasone furoate/vilanterol is a useful addition to the other fixed ICS/LABA combinations currently available for asthma, all of which require twice-daily administration.

IP-10 in occupational asthma: review of the literature and case-control study.

T-helper (Th)2 cytokines are thought to mediate most of the allergic inflammatory responses associated with atopic asthma. But the Th1-related chemokine, interferon (IFN)-γ-induced protein 10 (IP-10)/chemokine (C-X-C motif) ligand (CXCL)10, was the predominant chemokine measured during human allergic pulmonary late-phase reaction. Viral infection and allergens can exacerbate asthma by inducing the accumulation of these chemokines and inflammatory cells in the airway. Short-acting β2-adrenoreceptor agonists, budesonide and formoterol (all important relievers in asthma exacerbation), such as vitamin D3, vitamin C, have been shown to inhibit airway cells inflammatory responses by modulating these chemokines. Furthemore it has been suggested that Th1-related IP-10 and monokine induced by IFN-γ (MIG)/CXCL9 may be useful inflammatory markers of asthma exacerbation. In this study we have evaluated serum levels of the Th1-related CXC chemokine IP-10, in 8 patients with occupational asthma (OA) during exacerbation due to occupational exposure, and after 2-3 months, when patients were in stable conditions, in comparison with 8 age and gender matched healthy subjects. A significant increase in the serum levels of IP-10 were found in OA patients with an acute exacerbation in contrast to healthy controls (p<0.01), and in comparison with same OA patients after 2-3 months, when they were without any respiratory symptoms or disorders. These results suggest that the Th1-related CXC chemokines IP-10 is an useful inflammatory marker of OA exacerbation. However, other studies in larger number of patients are needed.

Serum Eosinophil Cationic Protein Is a Useful Marker for Assessing the Efficacy of Inhaled Corticosteroid Therapy in Children with Bronchial Asthma.

Bronchial asthma (BA) is a chronic inflammatory disorder of airways for which the effective therapies include inhaled corticosteroids (ICS) and short-acting β2-adrenoreceptor agonist (SABA). Serum eosinophil cationic protein (ECP) has been reported to reflect the degree of airway inflammation. We, therefore, explored the implication of serum ECP in assessing the efficacy of ICS therapy in BA children. Our prospective randomized control study enrolled 126 BA children and 78 healthy children (the control group). The BA patients were randomly assigned as two groups; 59 children were treated with ICS, twice a day, for three months and 67 patients received SABA inhalation only if necessary. After the 3-month therapy, the serum levels of ECP, endothelin-1, and nitric oxide and the eosinophil percentage (EOS%) in induced sputum were significantly lower in the ICS group, compared with the SABA group, but were still higher than the control group (all P < 0.05). The forced expiratory volume (FEV1%pred) and forced vital capacity (FEV1/FVC) were improved to the levels of the control group after therapy. Pearson correlation analysis presented that higher serum ECP levels were associated with higher EOS% in serum and with lower pulmonary function indices (FEVl%pred and FEV1/FVC). Importantly, the ICS group exhibited higher quality of life scores and lower symptom scores compared with the SABA group (all P < 0.05). ROC results revealed the diagnostic efficiency of serum ECP levels on the efficacy of ICS. In conclusion, measuring serum ECP levels is helpful for assessing the efficacy of ICS therapy in BA children.

Inhalation of a Short-Acting β2-Adrenoreceptor Agonist Induces a Hypercoagulable State in Healthy Subjects.

BackgroundCatecholamine infusion elicits an increase in clotting factors and this increase has been attributed to stimulation of β2-adrenorecptors (β2AR). Accordingly, we tested the hypothesis that inhalation of a short-acting selective β2AR agonist can induce a procoagulant state in healthy individuals.MethodsWe recruited 23 healthy volunteers (nine females; mean age: 26±0.8 years; body mass index: 24.7±0.5 kg/m2) and randomly allocated them into two groups, the β2AR arm (seventeen subjects) and the saline arm (six subjects). Hemodynamics, plasma norepinephrine concentration, and procoagulant, anticoagulant, and fibrinolytic profiles of each participant were determined using specific assays before and after inhalation of either 2 mL nebulized normal saline or a mixture of 1 mL saline and 1 mL of salbutamol (5 mg salbutamol sulfate), a selective β2AR agonist, which were delivered by a nebulizer over ten minutes.ResultsSaline inhalation had no effect on the procoagulant, anticoagulant and fibrinolytic profiles of the six healthy volunteer in the study's saline arm. Salbutamol inhalation caused (a) a significant increase in the activity or levels of the procoagulant factors; FVIII increased by 11±3% (p = 0.04), von Willebrand factor increased by 7±1% (p = 0.03), and (b) a significant decrease in the activated partial prothrombin time from 27.4±0.4 seconds to 25.5 ±0.5 seconds (p<0.001) in the 17 volunteers in the study's β2AR arm. D-dimer and prothrombin fragments F1+2 were elevated by 200 ±90% and 505.0 ±300.0%, respectively. In addition, the activity of the anticoagulant protein C pathway (demonstrated by the protein C Global assay) decreased from 1.0±0.08 to 0.82±0.06 (p<0.001). Although plasma levels of tissue plasminogen activator decreased, all other indices of the fibrinolytic system did not change following salbutamol inhalation.ConclusionWe found that a single inhalation of salbutamol, a short-acting β2AR agonist, activates the clotting system without affecting the fibrinolytic system. This induction of a procoagulant state in healthy subjects warrants further investigation in patients treated with these agents.

Formoterol decreases muscle wasting as well as inflammation in the rat model of rheumatoid arthritis.

Adjuvant-induced arthritis is an experimental model of rheumatoid arthritis that is associated with body weight loss and muscle wasting. β2-adrenergic receptor agonists are powerful anabolic agents that trigger skeletal muscle hypertrophy and have been proposed as a promising treatment for muscle wasting in human patients. The aim of this work was to determine whether formoterol, a selective β2-adrenoreceptor agonist, is able to ameliorate muscle wasting in arthritic rats. Arthritis was induced in male Wistar rats by intradermal injection of Freund's adjuvant. Control and arthritic rats were injected daily with 50 μg/kg sc formoterol or saline for 12 days. Body weight change, food intake, and arthritis index were analyzed. After euthanasia, in the gastrocnemius mRNA was analyzed by PCR, and proteins were analyzed by Western blotting. Arthritis decreased gastrocnemius weight, cross-sectional area, and myofiber size, whereas formoterol increased those variables in both arthritic and control rats. Formoterol decreased the external signs of arthritis as well as NF-κB(p65) activation, TNFα, and COX-2 levels in the gastrocnemius of arthritic and control rats. Those effects of formoterol were associated with a decreased expression of myostatin, atrogin-1, and MuRF1 and in LC3b lipidation. Arthritis increased the expression of MyoD, myogenin, IGF-I, and IGFBP-3 and -5 in the gastrocnemius. In control and in arthritic rats, treatment with formoterol increased Akt phosphorylation and myogenin levels, whereas it decreased IGFBP-3 expression in the gastrocnemius. These data suggest that formoterol has an anti-inflammatory effect and decreases muscle wasting in arthritic rats through increasing Akt activity and myogenin and decreasing myostatin, the p-NF-κB(p65)/TNF pathway, and IGFBP-3.

Tiotropium/Olodaterol: A Review in COPD.

Tiotropium/olodaterol (Stiolto™ Respimat®, Spiolto™ Respimat®) is a fixed-dose combination of the long-acting antimuscarinic agent tiotropium bromide (hereafter referred to as tiotropium) and the long-acting β2-adrenoreceptor agonist olodaterol delivered via the Respimat® Soft Mist™ inhaler. It is indicated for the maintenance treatment of airflow obstruction in adults with COPD. Several randomized, phase III studies of 6-52 weeks' duration evaluated the efficacy of once-daily tiotropium/olodaterol in patients with GOLD stage 2-3 or 2-4 COPD. Tiotropium/olodaterol maintenance therapy improved lung function to a greater extent than the individual components or placebo and provided clinically meaningful improvements in health-related quality of life and dyspnoea in 12- and 52-week studies. Tiotropium/olodaterol consistently improved 24-h lung function in 6-week studies, providing greater benefits than the monotherapies, placebo or twice-daily fixed-dose fluticasone propionate/salmeterol. Inspiratory capacity and exercise endurance were also improved with tiotropium/olodaterol following 6 or 12 weeks' treatment. The tolerability profile of tiotropium/olodaterol in the phase III studies was generally similar to that of the component monotherapies. The most common adverse events and serious adverse events during 52 weeks' therapy were respiratory in nature, with COPD exacerbation, unsurprisingly, reported most frequently with tiotropium/olodaterol and component monotherapies. Although additional data assessing the effect of tiotropium/olodaterol on exacerbations and comparative studies with other recommended therapies are needed to definitively position tiotropium/olodaterol, current evidence indicates that tiotropium/olodaterol is a useful treatment option for patients with COPD.

β2-Adrenoreceptor Agonist Inhalation During Ex Vivo Lung Perfusion Attenuates Lung Injury

Attenuation of ischemia reperfusion injury (IRI) is important in lung transplantation. Our group previously reported that β2-adrenoreceptor agonist inhalation during the period before procurement successfully attenuated IRI in donated lungs after cardiac death. We therefore hypothesized that β2-adrenoreceptor agonist inhalation during exvivo lung perfusion (EVLP) after procurement might also have a protective effect. Cardiac-dead beagles were left at room temperature for 210 minutes, and all lungs were subsequently procured and subjected to EVLP for 240 minutes. The beagles were allocated to 2 groups: the β2 group (receiving an aerosolized β2-adrenoreceptor agonist 20 minutes after initiation of EVLP; n= 7) and the control group (receiving an aerosolized control solvent at the same time point; n= 6). Physiologic data, including lung function, were evaluated during EVLP. The β2 group showed significantly lower peak airway pressure and pulmonary artery pressure than the control group. Dynamic pulmonary compliance was higher, pulmonary vascular resistance (PVR) was lower, and the wet-to-dry lung weight ratio was lower in the β2group than in the control group. Cyclic adenosine monophosphate (cAMP) and total adenosine nucleotide (TAN) levels in lung tissue after EVLP were higher in the β2 group than in the control group. The β2 group also showed more cystic fibrosis transmembrane conductance regulator (CFTR) gene expression. After procurement, β2-adrenoreceptor agonist inhalation during EVLP attenuates lung injury in a canine model of organ donation after cardiac death.

The stress hormone norepinephrine increases migration of prostate cancer cells in vitro and in vivo.

The metastatic process is the most serious cause of cancer death. Norepinephrine, secreted in chronic stress conditions, stimulates the motility of breast and colon cells through β-adrenergic receptor. On these bases, we examined its possible role in metastasis formation and development invitro and in vivo. Treatments with norepinephrine (β2-adrenoreceptor agonist) in mice xenografted with human DU145 prostate cancer cells increased the metastatic potential of these cells. Specifically, we showed that treatment of mice with norepinephrine induced a significant increase of the migratory activity of cancer cells in a concentration-dependent manner and that this process was blocked by propanolol (β-adrenergic antagonist). Mice treated with norepinephrine, displayed an increased number of metastatic foci of DU145 cells in inguinal lymph nodes and also showed an increased expression of MMP2 and MMP9 in tumor samples compared to controls. Moreover, we demonstrated that propanolol induced in norepinephrine treated DU145 cells a E-cadherin finger-like membrane protrusions driven by vimentin remodeling. Altogether these data suggest that β2-AR plays an important role in prostate cancer metastasis formation and that the treatment with antagonist propanolol, could represents an interesting tool to control this process in cells overexpressing β2AR.

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

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 could potentially provide clinical benefit when used adjunctively with inhaled β2-adrenoreceptor agonists in those patients exhibiting a reduced response to their chronic use.

An Efficient and Practical Synthesis of Salmeterol

Salmeterol (Serevent® 9) is a potent, long-acting β2-adrenoreceptor agonist used as a bronchodilator for the prevention of bronchospasm in patients with asthma and chronic obstructive pulmonary dis...

Bronchodilating drugs for chronic obstructive pulmonary disease: current status and future trends.

Inhaled bronchodilators, including long-acting muscarinic receptor antagonists (LAMA) and long-acting β2-adrenoreceptor agonists (LABA), are the mainstay of pharmacological treatment of stable chronic obstructive pulmonary disease (COPD). Among approved LAMA, tiotropium bromide, glycopyrronium bromide, and umeclidinium bromide are administered once daily, whereas aclidinium bromide is administered every 12 h. New LAMA are under development for COPD. Among the approved LABA, indacaterol has a 24 h duration of action, whereas salmeterol and formoterol require twice-daily administration. New once-daily LABA, including vilanterol, olodaterol, milveterol, carmoterol, and abediterol, are in development. LAMA/LABA fixed dose combinations (FDCs) provide the convenience of two bronchodilators with different mechanism of action in a single inhaler. Indacaterol/glycopyrronium, umeclidinium/vilanterol, and olodaterol/tiotropium FDCs have been approved or are under approval and are likely to become a standard pharmacological strategy for COPD. Inhaled dual-pharmacology compounds, combining muscarinic antagonism and β2-agonism (MABA) in a single molecule, potentially provide additive or synergistic bronchodilation over either inhaled antimuscarinic or β2-agonist monotherapy.

Fluticasone furoate/vilanterol: a review of its use in patients with asthma.

Fluticasone furoate/vilanterol (Relvar(®)) is a once-daily, fixed combination of an inhaled corticosteroid (ICS) and a long-acting β2-adrenoreceptor agonist (LABA), delivered via a dry powder inhaler (Ellipta(®)). It is approved for the treatment of asthma in the EU and Japan, and is the first once-daily ICS/LABA to be available for this indication. Fluticasone furoate is an enhanced-affinity glucocorticoid receptor agonist, with potent anti-inflammatory activity. Vilanterol produces rapid and prolonged bronchodilation. In phase III trials in adolescents and adults with various levels of asthma uncontrolled on ICS and/or ICS/LABA, fluticasone furoate/vilanterol 100/25 or 200/25µg once daily (approved dosages in the EU) significantly improved pulmonary function compared with placebo or equivalent dosages of fluticasone furoate alone (in some trials) or fluticasone propionate. In similar trials, fluticasone furoate/vilanterol 100/25µg once daily was as effective as fluticasone propionate/salmeterol 250/50µg twice daily in improving pulmonary function and significantly reduced the risk of severe asthma exacerbation relative to fluticasone furoate alone. In clinical trials, fluticasone furoate/vilanterol was generally well tolerated with fewer than 15% of patients experiencing treatment-related adverse events, the most common of which were oral/oropharyngeal candidiasis, dysphonia, extrasystoles and cough. The tolerability profile of fluticasone furoate/vilanterol was generally similar to that of fluticasone propionate/salmeterol. Thus, fluticasone furoate/vilanterol is an effective and generally well tolerated ICS/LABA option for the treatment of uncontrolled asthma.

Terbutaline and Associated Risks for Neurodevelopmental Disorders

Preterm labor often leads to a preterm birth and has been shown to be the most important determinant of risk for perinatal morbidity and mortality. While medication management has been utilized by physicians to delay preterm labor, the results these medications achieve remain inconsistent, in addition to increasing the risk to the developing fetus. Terbutaline has been among the most commonly used β2-adrenoreceptor (β2AR) agonists in the management of preterm labor. The research suggests that tocolytic terbutaline therapy carries a significant risk for the mother and the child, which can be magnified by extended exposure, sex of the fetus, and administration during critical fetal developmental periods. This paper highlights the research on terbutaline in treatment of preterm labor, along with the possible associated cognitive deficits in adolescents who were treated with terbutaline in utero. Two case summaries are presented to illustrate the potential deficits in clinical presentations of adolescents with history of intrauterine exposure to terbutaline. Publicizing the association between terbutaline and these deficits can not only assist obstetricians and expectant mothers in making a more informed choice in the treatment of preterm labor but also provide neuropsychologists and pediatricians with information helpful in understanding the etiology of these impairments.

Aquaporin 1 and 5 Expression Evoked by the β2 Adrenoreceptor Agonist Terbutaline and Lipopolysaccharide in Mice and in the Human Monocytic Cell Line THP-1 Is Differentially Regulated

Aquaporin 1 (AQP1) and AQP5 expression may impact on key mechanisms in sepsis. However, it is unclear whether these AQPs are expressed to an equal extent or regulated differentially. Accordingly, we investigated the time-dependent expression of AQP1 and AQP5 following stimulation with lipopolysaccharide (LPS) in cultured human THP-1 cells and in the lungs of mice injected with LPS. Furthermore, we tested the hypothesis that the β2 adrenoreceptor agonist terbutaline or its downstream effector cyclic adenosine monophosphate (cAMP) mitigates LPS-evoked changes of AQP expression. THP-1 cells were stimulated with either LPS (1 μg/mL; serotype O127:B8), 8-Br-cAMP (1 mM), or both, and RNA and protein were extracted at baseline and after 2, 6, and 24 h. C57BL/6 mice that received LPS (20 mg/kg i.p.), terbutaline (2.5 mg/kg), or both were killed 8 h later, and lungs were excised for RNA extraction and lung wet weight determination. Real-time polymerase chain reaction and Western blot analysis show that LPS increased AQP1 (3 h, P < 0.0001) but not AQP5 mRNA and protein expression in THP-1 cells. cAMP increased AQP1 (6 h, P < 0.0001) but not AQP5 mRNA and protein expression. Incubation with both substances accelerated the increase in AQP1 (2 h, P = 0.001) expression, whereas AQP5 expression decreased after 2 h but increased after 24 h (P = 0.0148). In mice lungs, LPS decreased AQP1 (P = 0.0082) but not AQP5 mRNA expression and increased lung wet weight. Terbutaline increased AQP1 mRNA expression twice (P = 0.0005) but not AQP5 mRNA expression. Terbutaline did neither abolish the LPS-induced decrease in AQP1 and AQP5 expression nor increase lung weight. Thus, AQP1 and AQP5 expression is differentially regulated following exposure to LPS, the β2 adrenoreceptor agonist terbutaline, and cAMP. Furthermore, neither terbutaline nor cAMP mitigated the LPS-evoked change of AQP1 and AQP5 expression.

Increased Risk of Sudden Cardiac Arrest in Obstructive Pulmonary Disease: A Case-Control Study

BackgroundWe aimed to determine whether (1) patients with obstructive pulmonary disease (OPD) have an increased risk of sudden cardiac arrest (SCA) due to ventricular tachycardia or fibrillation (VT/VF), and (2) the SCA risk is mediated by cardiovascular risk-profile and/or respiratory drug use.MethodsA community-based case-control study was performed, with 1310 cases of SCA of the ARREST study and 5793 age, sex and SCA-date matched non-SCA controls from the PHARMO database. Only incident SCA cases, age older than 40 years, that resulted from unequivocal cardiac causes with electrocardiographic documentation of VT/VF were included. Conditional logistic regression analysis was used to assess the association between SCA and OPD. Pre-specified subgroup analyses were performed regarding age, sex, cardiovascular risk-profile, disease severity, and current use of respiratory drugs.ResultsA higher risk of SCA was observed in patients with OPD (n = 190 cases [15%], 622 controls [11%]) than in those without OPD (OR adjusted for cardiovascular risk-profile 1.4 [1.2–1.6]). In OPD patients with a high cardiovascular risk-profile (OR 3.5 [2.7–4.4]) a higher risk of SCA was observed than in those with a low cardiovascular risk-profile (OR 1.3 [0.9–1.9]) The observed SCA risk was highest among OPD patients who received short-acting β2-adrenoreceptor agonists (SABA) or anticholinergics (AC) at the time of SCA (SABA OR: 3.9 [1.7–8.8], AC OR: 2.7 [1.5–4.8] compared to those without OPD).ConclusionsOPD is associated with an increased observed risk of SCA. The most increased risk was observed in patients with a high cardiovascular risk-profile, and in those who received SABA and, possibly, those who received AC at the time of SCA.

Characterizing Systemic Exposure of Inhaled Drugs: Application to the Long-Acting β2-Agonist PF-00610355

PF-00610355 is an orally inhaled long-acting β2-adrenoreceptor agonist that is being developed for the once-daily treatment of chronic obstructive pulmonary disease (COPD). The pharmacological effect is exerted in the lungs. However, systemic exposure of PF-00610355 is expected to be responsible for certain drug-related adverse effects. This analysis characterizes PF-00610355 using an integrated analysis of systemic exposure, across trials and patient populations. A total of 6,107 samples of PF-00610355 plasma concentration, collected in 264 subjects from eight studies in healthy volunteers, asthma, and COPD patients, were analyzed using non-linear mixed-effects models. Model-based mean (95 % CI) exposure profiles for a range of PF-00610355 doses in COPD patients were simulated. PF-00610355 exposure profiles were described by a three-compartment disposition model with first-order absorption through a transit compartment. Patient status, inhalation device, and demographic factors were found to influence systemic drug exposure. Relative fine particle dose had a minor effect, whereas no effect of baseline lung function on the systemic exposure was found. An implicit method to address pharmacokinetic variability between occasions of drug intake yielded similar results as the established explicit method, yet in a much more efficient way. The estimated systemic pre-dose and maximum PF-00610355 plasma concentration was 23 and 38 % in COPD patients compared to healthy volunteers, respectively. The analysis illustrated the value of an integrated pharmacokinetic analysis to address specific challenges in the clinical development of long-/ultra-long-acting β2-agonists and inhaled compounds in general, both in relation to selecting a safe starting dose in patients, but also in understanding exposure and systemic safety information across different patient populations and different inhalation devices/formulations.

Calcium handling in porcine coronary endothelial cells by gastrin-17

In porcine coronary artery endothelial cells (PCAEC), gastrin-17 has recently been found to increase nitric oxide (NO) production by the endothelial NO synthase (eNOS) isoform through cholecystokinin 1/2 (CCK1/2) receptors and the involvement of protein kinase A (PKA), PKC and the β2-adrenoreceptor-related pathway. As eNOS is the Ca(2)(+)-dependent isoform of the enzyme, we aimed to examine the effects of gastrin-17 on Ca(2)(+) movements. Thus, experiments were performed in Fura-2-acetoxymethyl-ester-loaded PCAEC, where changes of cytosolic Ca(2)(+) ([Ca(2)(+)]c) caused by gastrin-17 were analysed and compared with those of CCK receptors and β2-adrenoreceptors agonists/antagonists. In addition, some experiments were performed by stimulating cells with gastrin-17 in the presence or absence of cAMP/PKA activator/inhibitor and of phospholipase C (PLC) and Ca(2)(+)-calmodulin dependent protein kinase II (CaMKII) blockers. The results have shown that gastrin-17 can promote a transient increase in [Ca(2)(+)]c mainly originating from an intracellular pool sensitive to thapsigargin and from the extracellular space. In addition, the response of cells to gastrin-17 was increased by the adenylyl cyclase activator and the β2-adrenoreceptor agonists and affected mainly by the CCK2 receptor agonists/antagonists. Moreover, the effects of gastrin-17 were prevented by β2-adrenoreceptors and CaMKII blockers and the adenylyl cyclase/PKA and PLC inhibitors. Finally, in PCAEC cultured in Na(+)-free medium or loaded with the plasma membrane Ca(2)(+) pump inhibitor, the gastrin-17-evoked Ca(2)(+) transient was long lasting. In conclusion, this study shows that gastrin-17 affected intracellular Ca(2)(+) homeostasis in PCAEC by both promoting a discharge of an intracellular pool and by interfering with the operation of store-dependent channels through mainly CCK2 receptors and PKA/PLC- and CaMKII-related signalling downstream of β2-adrenoreceptor stimulation.

Effect of an Agonist of β2 Adrenoreceptors on Inhibition in the Rat Hippocampal CA1 Area Induced by Activation of GABAB Receptors

In experiments on rat brain slices using extracellular recording, we studied the effects of an agonist of β2 adrenoreceptors, metaproterenol (MPT), on reactions of pyramidal neurons of the hippocampal CA1 area induced by activation of GABAB receptors. Isolated application of an agonist of GABAB receptors, baclofen (10 μM), resulted in intense inhibition (by 50% or more during the 1st min of action) of orthodromic field discharges (OFDs) in the pyramidal layer of the above-mentioned area of the hippocampus; the discharges were evoked by electrical stimulation of Schaffer collaterals. On the 3rd to 4th min, OFDs were suppressed nearly completely. After washing out from baclofen, the parameters of the evoked responses never completely restored to the initial level. In all cases, simultaneous application of 150 μM MPT and 10 μM baclofen prevented full manifestation of the inhibitory effect of the latter agent on OFDs of pyramidal neurons. The amplitude of evoked responses decreased, but the relative intensity of inhibition under these conditions during 2-min-long application was significantly lower than that upon isolated action of baclofen. The recovery of the amplitude of evoked responses in the course of washing out under conditions of parallel action of MPT was more rapid and, in some cases, complete. Therefore, our experiments showed that GABAB-ergic inhibitory transmission in the rat hippocampal CA1 area in vitro can be suppressed significantly by the β2 adrenoreceptor agonist.

Advances in drug delivery: is triple therapy the future for the treatment of chronic obstructive pulmonary disease?

Introduction: Current therapies for chronic obstructive pulmonary disease (COPD) focus on the improvement of clinical symptoms via the use of bronchodilators: β2-adrenoreceptor agonists and muscarinic (M3) acetycholine receptor antagonists. The combination of inhaled corticosteroids (ICSs) and long-acting β2 agonists (LABAs), or LABAs and anticholinergics has become an efficient alternative to single therapies. These combinations consist of a LABA and an ICS together with an anticholinergic, such as ipratropium or tiotropium.Areas covered: This review summarizes the latest thinking and findings on the usefulness of triple therapy in the treatment and management of COPD. Drawing on commercial, clinical, scientific and intellectual property data and publications, it aims to provide an overview to understand the efficacy and need for COPD triple therapy. The reader will gain an in-depth view of the triple therapy approach in managing COPD, existing molecules in the market or in development as well as new chemical entities. Clinical evidence in support of triple therapy, formulations and products are also discussed.Expert opinion: There is limited documented clinical evidence for the use of triple therapy in COPD, reflected in the lack of commercial activity in the field. The future for the management of COPD may lie with triple therapy, but may equally rest on a better understanding of the disease and subsequent development of new chemical entities, such as dimer molecules, longer-acting β-agonists and antimuscarinics.