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Tiotropium bromide (Spiriva, BA679BR, Boehringer Ingelheim) is a novel inhaled, long-acting anticholinergic bronchodilator that is employed as a once-daily maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). Like ipratropium bromide, tiotropium bromide is a quaternary ammonium derivative that binds to muscarinic receptors. However, although tiotropium binds with high affinity to muscarinic receptors of M1-, M2- and M3-subtypes, it dissociates very slowly from M1- and M3-receptors but more rapidly from M2-receptors, thereby giving it a unique kinetic selectivity. To date, the short-acting anticholinergic agents ipratropium and oxitropium bromide have been extensively employed as bronchodilator therapy for patients with COPD. Indeed, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy emphasises the role of bronchodilators in symptomatic management of all stages of COPD. It is encouraging that tiotropium given once daily from a dry powder inhaler at 18 g has been shown to cause greater improvement in lung function and reduction in symptoms than ipratropium bromide given four times daily. Furthermore, clinical studies over a 1-year period have demonstrated that tiotropium has impressive and maintained effects on lung function, symptoms and health-related quality of life, and may also reduce exacerbations. In a recent large scale comparative study over 6 months, tiotropium has been shown to cause superior bronchodilation and symptomatic improvement when compared to twice daily salmeterol in COPD. The only significant reported adverse event is dry mouth, which is found in approximately 10%-15% of subjects, but this is reversible and rarely causes discontinuation of therapy. Based on these promising features, it is likely that tiotropium used alone or in combination with other bronchodilators will emerge as first-line maintenance treatment for patients with airway obstruction due to COPD.
Drug eluting stents for the treatment of small vessel coronary artery disease have traditionally yielded inferior clinical outcomes compared to the use of DES in large vessels. The benefit of the second-generation Resolute zotarolimus-eluting stent (R-ZES) in small vessels was examined.Two-year clinical outcomes from five combined R-ZES studies were compared between patients with small (reference vessel diameter [RVD] ≤2.5 mm; n = 1,956) and large (RVD >2.5 mm; n = 3174) vessels.Despite a higher incidence of comorbidities in the small vessel group, there was no significant difference in target lesion failure (TLF) (10.1% vs. 8.7%; P = 0.54) at 2 years. When the subgroup of patients with diabetes was examined (n = 1,553) there was no significant difference in 2-year TLF in small compared to large vessels (11.2% vs. 11.1%; P = 0.17). Similarly, within the small vessel cohort, no significant difference was seen regarding TLF at 2 years between people with and without diabetes (11.2% vs 9.6%; P = 0.28).When used for the treatment of small vessels, the R-ZES appears to provide acceptable clinical results at 2 years when compared to its performance in large vessels.
We present Stratospheric Observatory For Infrared Astronomy (SOFIA) + Atacama Large Millimeter/submillimeter Array (ALMA) continuum and spectral-line polarization data on the massive molecular cloud BYF 73, revealing important details about the magnetic field morphology, gas structures, and energetics in this unusual massive star formation laboratory. The 154 mu m HAWC+ polarization map finds a highly organized magnetic field in the densest, inner 0.55 x 0.40 pc portion of the cloud, compared to an unremarkable morphology in the cloud's outer layers. The 3 mm continuum ALMA polarization data reveal several more structures in the inner domain, including a parsec-long, similar to 500 M (circle dot) "Streamer" around the central massive protostellar object MIR 2, with magnetic fields mostly parallel to the east-west Streamer but oriented north-south across MIR 2. The magnetic field orientation changes from mostly parallel to the column density structures to mostly perpendicular, at thresholds N (crit) = 6.6 x 10(26) m(-2), n (crit) = 2.5 x 10(11) m(-3), and B (crit) = 42 +/- 7 nT. ALMA also mapped Goldreich-Kylafis polarization in (CO)-C-12 across the cloud, which traces, in both total intensity and polarized flux, a powerful bipolar outflow from MIR 2 that interacts strongly with the Streamer. The magnetic field is also strongly aligned along the outflow direction; energetically, it may dominate the outflow near MIR 2, comprising rare evidence for a magnetocentrifugal origin to such outflows. A portion of the Streamer may be in Keplerian rotation around MIR 2, implying a gravitating mass 1350 +/- 50 M (circle dot) for the protostar+disk+envelope; alternatively, these kinematics can be explained by gas in free-fall toward a 950 +/- 35 M (circle dot) object. The high accretion rate onto MIR 2 apparently occurs through the Streamer/disk, and could account for similar to 33% of MIR 2's total luminosity via gravitational energy release.
We have investigated the effects of bradykinin (Bk) antagonists on Bk-induced airway microvascular leakage and bronchoconstriction in mechanically ventilated guinea pigs by simultaneous measuring extravasation of Evans blue dye and airway opening pressure (Pao). Bradykinin (1 microgram/kg intravenously) significantly increased leakage of dye in trachea, main bronchi, and intrapulmonary airways, and increased Pao, indicating airway narrowing. The selective Bk B2 antagonist D-Arg-[Hyp3-Thi5,8-D-Phe7]-Bk (NPC 349; 400 micrograms/kg intravenously) did not alter basal leakage, but when given 2 min before Bk, significantly inhibited the Bk-induced plasma extravasation by 99.8% in the trachea (p less than 0.05), by 75.9% in main bronchi (p less than 0.05), by 83.5% in proximal intrapulmonary airways (p less than 0.05), and by 91.5% in distal intrapulmonary airways (p less than 0.05). NPC 349 also reduced the increase in Pao induced by Bk by 73.5% (p less than 0.05) without affecting the basal Pao. However, NPC 349 had no inhibitory effect on Bk-induced leak or bronchoconstriction when given 30 min before Bk. By contrast, the B1 antagonist des Arg9-Leu8-Bk (500 micrograms/kg intraveneously) had no effect on the Bk-increased plasma extravasation and Pao. We conclude that Bk increases airway plasma leakage and bronchoconstriction via activation of B2 receptors.
