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Asthma and chronic obstructive pulmonary disease (COPD) are the most common diagnoses for adults and children with respiratory tract inflammation. Recently, a novel fixed dose combination consisting of Ipratropium and Fenoterol has been released for the management and control of the symptoms of such disorders. The current research has newly developed and optimized three smart, accurate, simple, cost-effective, and eco-friendly spectrophotometric methods that enabled the simultaneous determination of the drugs under study in their combined inhaler dosage form, without the need for any previous separation steps, using water as a green solvent. The strategy employed was based on calculating one or two factors as a numerical spectrum or constant, which provided the complete removal of any component in the mixture that might overlap and the mathematical filtration of the targeted analyte. The methods developed could be classified into two types of spectrophotometric windows. Window I; involved absorption spectrum in their original zero-order forms (°D), which included recently designed methods named induced concentration subtraction (ICS) and induced dual wavelength (IDW). While window III focused on the ratio spectrum as the induced amplitude modulation (IAM) method. The extremely low absorptivity and lack of distinct absorption maximum in the zero-order absorption spectrum of Ipratropium were two intrinsic challenges that were better overcome by the proposed spectrophotometric methods than by the conventionally used ones. According to ICH guidelines, the proposed methods were validated using unified regression over range 2.0–40.0 µg/mL in the ICS method, while the linearity ranges for the IDW and IAM methods were 5.0–40.0 µg/mL of Ipratropium and 2.0–40.0 µg/mL of Fenoterol. Moreover, the three proposed methods were effectively used to assay the co-formulated marketed inhaler and further expanded to confirm the delivered dose uniformity in compliance with the USP guidelines. Finally, the established methods were evaluated for their greenness and blueness, in comparison to the official and reported analysis methods, using advanced cutting edge software metrics. Furthermore, the suggested techniques adhered well to the white analytical chemistry postulates that were recently published.

In Thailand, nebulized ipratropium bromide/fenoterol, is commonly used in addition to salbutamol for severe asthma exacerbation. Recently, nebulized MgSO4 is indicated in GINA 2015 as an additive treatment for severe cases. However, there is limited data showed the efficacy of both drugs in childhood severe asthma. The purpose of this study to compare efficacy and safety of nebulized MgSO4 and ipratropium bromide/fenoterol in moderate to severe asthma attacks. In this a prospective, double-blind, randomized, controlled trial study, we enrolled thirty-three children, age ranged from 2 to 15 years old, with PRAM score ≥ 4 (moderate to severe asthma exacerbation) despite 3 doses of nebulized salbutamol. Each patient was randomized to receive either three doses of nebulized MgSO4 or nebulized ipratropium bromide/fenoterol every 30 minutes. The PRAM score was measured at 0, 30, 60, 90, 120 and 240 minutes after the treatment. The adverse event and admission days were also evaluated. Sixteen patients received nebulized MgSO4 and seventeen received nebulized ipratropium bromide/fenoterol. Almost patients were classified as having moderate asthmatic attack. There were no statistically significant difference between the two study groups in almost baseline characteristic, PRAM score at 0, 30, 60, 90, 120, 240 minutes. The hospital length of stay was also similar between two groups (p = 0.83). There were no serious events in both groups. Our double blind, randomized, controlled pilot study demonstrated non-inferior outcomes including clinical benefit and safety of nebulized MgSO4 and nebulized ipratropium bromide/fenoterol among Thai children with acute moderate asthmatic.

The authors describe a rapid method for the determination of 11 [beta].sub.2-agonists by exploiting the color changes and fluorescence intensity changes of copper nanoclusters coated with bovine serum albumin (BSA-CuNCs). On addition to a solution of the BSA-CuNCs, some [beta].sub.2-agonists (metaproterenol, terbutaline, dopamine hydrochloride, isoproterenol, fenoterol) cause color transitions to occur, while the others do not cause an effect. In addition, [beta].sub.2-agonists such as isoxsuprine, ritodrine, ractopamine, metaproterenol, terbutaline, dopamine, isoproterenol and fenoterol quench the fluorescence of the CuNCs (best measured at excitation/emission wavelengths of 325/410 nm), while the others do not quench. By combining the effects on color and fluorescence, one can differentiate the various types of agonists. The possible quenching mechanism is investigated. The strong decrease in fluorescence intensity upon addition of certain [beta].sub.2-agonists can also be used quantify the concentration of the [beta].sub.2-agonists.

Targeting exosome biogenesis and release may have potential clinical implications for cancer therapy. Herein, we have optimized a quantitative high throughput screen (qHTS) assay to identify compounds that modulate exosome biogenesis and/or release by aggressive prostate cancer (PCa) CD63-GFP-expressing C4-2B cells. A total of 4,580 compounds were screened from the LOPAC library (a collection of 1,280 pharmacologically active compounds) and the NPC library (NCGC collection of 3,300 compounds approved for clinical use). Twenty-two compounds were found to be either potent activators or inhibitors of intracellular GFP signal in the CD63-GFP-expressing C4-2B cells. The activity of lead compounds in modulating the secretion of exosomes was validated by a tunable resistive pulse sensing (TRPS) system (qNano-IZON) and flow cytometry. The mechanism of action of the lead compounds in modulating exosome biogenesis and/or secretion were delineated by immunoblot analysis of protein markers of the endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways. The lead compounds tipifarnib, neticonazole, climbazole, ketoconazole, and triademenol were validated as potent inhibitors and sitafloxacin, forskolin, SB218795, fenoterol, nitrefazole and pentetrazol as activators of exosome biogenesis and/or secretion in PC cells. Our findings implicate the potential utility of drug-repurposing as novel adjunct therapeutic strategies in advanced cancer.

Diabetic kidney disease is a major cause of end-stage kidney disease. Various metabolic, hemodynamic, inflammatory, and profibrotic factors secondary to diabetes mellitus result in complex intracellular signaling, which in turn is responsible for the functional and structural changes associated with diabetic kidney disease. The beneficial effects of β [sub.2]-adrenergic agonists on renal cells bearing β [sub.2]-adrenergic receptors in diabetic kidney disease models have been reported. This narrative review explains the various mechanisms by which β [sub.2]-adrenergic agonists can have potential beneficial effects on diabetic kidney disease and highlights various in vitro, animal and human studies which lend credence to this hypothesis. It also touches upon the challenges and future concerns regarding their use in patients with this condition.

Objective To compare the effectiveness of the oxytocin receptor antagonist atosiban with the beta mimetic fenoterol as uterine relaxants in women undergoing external cephalic version (ECV) for breech presentation.Design Multicentre, open label, randomised controlled trial.Setting Eight hospitals in the Netherlands, August 2009 to May 2014.Participants 830 women with a singleton fetus in breech presentation and a gestational age of more than 34 weeks were randomly allocated in a 1:1 ratio to either 6.75 mg atosiban (n=416) or 40 μg fenoterol (n=414) intravenously for uterine relaxation before ECV.Main outcome measures The primary outcome measures were a fetus in cephalic position 30 minutes after the procedure and cephalic presentation at delivery. Secondary outcome measures were mode of delivery, incidence of fetal and maternal complications, and drug related adverse events. All analyses were done on an intention-to-treat basis.Results Cephalic position 30 minutes after ECV occurred significantly less in the atosiban group than in the fenoterol group (34% v 40%, relative risk 0.73, 95% confidence interval 0.55 to 0.93). Presentation at birth was cephalic in 35% (n=139) of the atosiban group and 40% (n=166) of the fenoterol group (0.86, 0.72 to 1.03), and caesarean delivery was performed in 60% (n=240) of women in the atosiban group and 55% (n=218) in the fenoterol group (1.09, 0.96 to 1.20). No significant differences were found in neonatal outcomes or drug related adverse events.Conclusions In women undergoing ECV for breech presentation, uterine relaxation with fenoterol increases the rate of cephalic presentation 30 minutes after the procedure. No statistically significant difference was found for cephalic presentation at delivery.Trial registration Dutch Trial Register, NTR 1877.

Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled [[beta].sub.2]-adrenergic receptor ([[beta].sub.2]AR) agonists ([[beta].sub.2]-agonists) promote--with limited efficacy--bronchodilation in asthma. All[beta].sub.2]-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a [[beta].sub.2]AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of G-protein coupled receptor allosteric ligands, we investigated the impact of Cmpd-6 on [[beta].sub.2]AR-mediated bronchoprotection. Consistent with our findings using human [[beta].sub.2]ARs, Cmpd-6 allosterically potentiated [[beta].sub.2]-agonist binding to guinea pig [[beta].sub.2]ARs and downstream signaling of [[beta].sub.2]ARs. In contrast, Cmpd6 had no such effect on murine [[beta].sub.2]ARs, which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced [[BETA].SUB.2] agonist-mediated bronchoprotection against methacholine- induced bronchoconstriction in guinea pig lung slices, but--in line with the binding studies--not in mice. Moreover, Cmpd-6 robustly potentiated [[beta].sub.2] agonist-mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced [[beta].sub.2] agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of [[beta].sub.2]AR- selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases.

Mutations in bone morphogenetic protein receptor type II (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (PAH). However, disease penetrance is only 20-30%, suggesting a requirement for additional triggers. Inflammation is emerging as a key disease-related factor in PAH, but to date there is no clear mechanism linking BMPR-II deficiency and inflammation. To establish a direct link between BMPR-II deficiency, a consequentially heightened inflammatory response, and development of PAH. We used pulmonary artery smooth muscle cells from Bmpr2(+/-) mice and patients with BMPR2 mutations and compared them with wild-type controls. For the in vivo model, we used mice heterozygous for a null allele in Bmpr2 (Bmpr2(+/-)) and wild-type littermates. Acute exposure to LPS increased lung and circulating IL-6 and KC (IL-8 analog) levels in Bmpr2(+/-) mice to a greater extent than in wild-type controls. Similarly, pulmonary artery smooth muscle cells from Bmpr2(+/-) mice and patients with BMPR2 mutations produced higher levels of IL-6 and KC/IL-8 after lipopolysaccharide stimulation compared with controls. BMPR-II deficiency in mouse and human pulmonary artery smooth muscle cells was associated with increased phospho-STAT3 and loss of extracellular superoxide dismutase. Chronic lipopolysaccharide administration caused pulmonary hypertension in Bmpr2(+/-) mice but not in wild-type littermates. Coadministration of tempol, a superoxide dismutase mimetic, ameliorated the exaggerated inflammatory response and prevented development of PAH. This study demonstrates that BMPR-II deficiency promotes an exaggerated inflammatory response in vitro and in vivo, which can instigate development of pulmonary hypertension.

PurposeDespite safety concerns, β2-sympathomimetics are still widely used as tocolytic agents. β-Blockers in turn are used to treat vasculo-proliferative diseases of the newborn such as retinopathy of prematurity (ROP), which may lead to visual impairment and blindness. The scope of this study was to investigate whether antenatal exposure to the β2-sympathomimetic fenoterol contributes to the development of ROP.MethodsFor this single-center retrospective case–control study of prospectively collected clinical data, all infants born before 32 weeks of gestation between 2001 and 2012 were included. The association of prenatal exposure to fenoterol and the development of ROP were analyzed by multivariate logistic regression.Resultsn = 1134 infants < 32 weeks of gestation were screened for eligibility, out of which n = 722 met the inclusion criteria. Exposure to fenoterol (n = 505) was not associated with a higher rate of ROP (OR 0.721, 95% CI 0.463–1.122). Further, duration of exposure (days) did not alter the incidence of ROP (OR 1.001, 95% CI 0.986–1.016). Frequency distribution of different ROP stages and the need for therapeutic intervention was also not affected by prenatal exposure to fenoterol. Risk factors for the development of ROP like low birth weight, low gestational age, prolonged respiratory support and multiple gestation were confirmed in our large study cohort.Conclusionβ2-Sympathomimetic tocolysis does not increase the rate of ROP in premature infants born < 32 weeks of gestation. Our results render fenoterol a safe tocolytic agent regarding neonatal ROP development.

An ultrasensitive paper based lateral flow assay is described for rapid and simultaneous fluorometric detection of several [beta]-agonists including clenbuterol and its chemical analogues (mabuterol, brombuterol, cimaterol, cimbuterol, bromchlorbuterol and banbuterol). A nonspecific monoclonal antibody (mAb) against clenbuterol and its analogues was prepared and employed in a competitive immunoassay where mAb conjugated to fluorescent nanoparticles and free [beta]-agonists compete for the binding sites. This enables rapid screening for the 7 [beta]-agonists in a single run that takes about 8 min. Detection limits for the seven [beta]-agonists are <50 pg g.sup.-1 of pork. Recoveries ranged from 69.5% to 102.4%, and relative standard deviations were ±15%. The assay was applied to the analysis of both using spiked and unspiked pork for [beta]-agonists, and the results compare well to those obtained by HPLC-MS.