Characterization of bencycloquidium bromide, a novel muscarinic M-3 receptor antagonist in guinea pig airways

Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
European journal of pharmacology (Impact Factor: 2.53). 03/2011; 655(1-3):74-82. DOI: 10.1016/j.ejphar.2011.01.017
Source: PubMed


In this study we have investigated the antagonist affinity, efficacy and duration of action of bencycloquidium bromide (BCQB), a selective muscarinic M(3) receptor antagonist, as a possible clinical bronchodilator for the treatment of chronic obstructive pulmonary disease (COPD) and asthma. In competition studies, BCQB showed high affinity toward the M(3) receptor in Chinese hamster ovary (CHO) cells (M(3) pKi=8.21, M(2) pKi=7.21, and M(1) pKi=7.86); pA(2)=8.85, 8.71 and 8.57 in methacholine-induced contraction of trachea, ileum and urinary bladder, 8.19 in methacholine-induced bradycardia of right atrium in vitro, respectively. In function studies, duration of inhibition of carbachol-induced tonic contraction, BCQB and ipratropium had a very similar onset and offset of action, but onset faster and offset slower than that of tiotropium. After treatment with intratracheally instilled or the inhalation route, BCQB protects against methacholine or antigen-induced bronchoconstriction in a dose-dependent manner in the normal and sensitized guinea pigs in vivo. BCQB and ipratropium-induced inhibitory activity was short lasting, as it declined quickly when compared to tiotropium. These results suggest that BCQB bind muscarinic M(3) receptors with high affinity. On this basis we speculate that a putative BCQB-based therapy for COPD might require more than once-a-day administration to be as effective as the currently employed once-daily therapy with tiotropium. Nevertheless, Inhalable M(3)-selective compounds may spare M(2)-cardiac receptors and reduce the risks of cardiovascular events associated with the long-term treatment of these agents.

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    • "Many studies have shown that intranasal BCQB has good efficacy in the treatment of rhinitis especially rhinorrhea in preclinical studies.[6–10] Additionally, BCQB displayed a better safety profile than IB due to its high selectivity for the M1 and M3 receptors over the M2 receptor.[11,12] As a result, M2 cardiac receptors are spared thereby reducing the risks of cardiovascular adverse events.[13] "
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    ABSTRACT: Bencycloquidium bromide (BCQB) is a novel, potent and selective muscarinic M1/M3 receptor antagonist under development for the treatment of rhinorrhea in rhinitis. The pharmacokinetics and safety of BCQB in animals have been established in preclinical studies. However, no clinical pharmacokinetic data are available for BCQB in humans. The aim of this first-in-human study was to evaluate the pharmacokinetics, safety and tolerability of BCQB following single and multiple intranasal doses in healthy Chinese subjects. The clinical trial was comprised of the following four studies: (i) an open-label, single-dose escalation study to evaluate the safety and tolerability in healthy subjects after intranasal doses of BCQB ranging from 45 to 450 μg (total of six doses); (ii) an open-label, multiple-dose escalation study to assess the safety and tolerability in healthy subjects after intranasal administration with 120 and 150 μg doses of BCQB (360 and 450 μg/day) administered three times daily for 15 days; (iii) a randomized, open-label and parallel-group design to evaluate the single-dose pharmacokinetics of BCQB after intranasal dosing (45, 90, and 180 μg); and (iv) ten subjects received 120 μg of BCQB by intranasal administration, three times daily for 5 days with a final single dose on day 7 to assess its multiple-dose pharmacokinetics. Safety and tolerability of BCQB were evaluated by monitoring adverse events (AEs), ECG recordings, vital signs and clinical laboratory parameters. The pharmacokinetic parameters for BCQB were calculated by software using non-compartmental methods. All AEs were mild, of limited duration and no more frequent at higher doses. There was no serious adverse event, death or withdrawal. No clinically significant change was noted in clinical laboratory parameters, cardiac parameters or vital signs. Following single intranasal dosing, BCQB was rapidly absorbed with a median time to maximum concentration (t(max)) of 8 minutes for 45, 90, and 180 μg dose groups; the plasma concentration of BCQB decreased in a biphasic manner with the mean half-life (t(½)) of 8.5 hours; the maximum concentration (C(max)) and area under the plasma concentration-time curve (AUC) of BCQB increased linearly across the examined dose range of 45-180 μg. During the multiple dosing, the steady state was achieved within 3 days of 120 μg three times daily dosing of BCQB. A slightly greater AUC was observed after 5 days of multiple dosing, with the mean accumulation ratio of 1.26; however, the half-life was unchanged. BCQB was safe and well tolerated in healthy Chinese subjects when administered intranasally with single and multiple doses across the doses studied. The mean C(max) and AUC increased proportionally to the studied doses, and the steady state was achieved within 3 days after three times daily dosing. A slight accumulation of BCQB following multiple dosing was observed. The pharmacokinetics, safety and tolerability profiles of BCQB pose it as a good candidate for further development in the treatment of rhinorrhea in rhinitis.
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    ABSTRACT: Parasympathetic nerves control the symptoms and inflammation of allergic diseases primarily by signaling through peripheral muscarinic receptors. Parasympathetic signaling targets classic effector tissues such as airway smooth muscle and secretory glands and mediates acute symptoms of allergic disease such as airway narrowing and increased mucus secretion. In addition, parasympathetic signaling modulates inflammatory cells and non-neuronal resident cell types such as fibroblasts and smooth muscle contributing to chronic allergic inflammation and tissue remodeling. Importantly, muscarinic antagonists are experiencing a rebirth for the treatment of asthma and may be useful for treating other allergic diseases.
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    ABSTRACT: Background/Aims: Ipratropium bromide, an anticholinergic agent widely used in obstructive lung disease, has previously been shown to trigger suicidal death of nucleated cells or apoptosis. Despite their lack of mitochondria and nuclei, key organelles in the execution of apoptosis, erythrocytes may similarly undergo suicidal cell death, which is characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine-exposure at the cell surface. Triggers of eryptosis include increase of cytosolic Ca(2+)-activity ([Ca(2+)](i)). The present study explored whether ipratropium bromide triggers eryptosis. Methods: [Ca Ca(2+)](i) was estimated utilizing Fluo3 fluorescence, cell volume from forward scatter, phosphatidylserine-exposure from annexin-V-binding, and hemolysis from hemoglobin release. Results: A 48 h exposure to ipratropium bromide (1 nM) significantly increased [Ca(2+)](i), decreased forward scatter and increased annexin-V-binding. Ipratropium bromide treatment was followed by slight but significant increase of hemolysis. Removal of extracellular Ca(2+) or inhibition of Ca(2+) permeable cation channels with amiloride (1 mM) virtually abolished cell membrane scrambling. Ca(2+) ionophore ionomycin (1 µM, 30 min) increased the percentage of phosphatidylserine exposing erythrocytes to similarly high levels in the absence and presence of ipratropium bromide (1 nM). Conclusions: Ipratropium bromide triggers suicidal erythrocyte death or eryptosis, an effect mainly due to stimulation of Ca(2+)-entry.
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