Characterization of bencycloquidium bromide, a novel muscarinic M3 receptor antagonist in guinea pig airways

Jiang, Jun; Cao, Rui; Deng, Wan-Ding; Jin, Fangming; Dong, Xiaopeng; Zhu, Yuchuan; Chen, Xiaoping; Xie, Yicheng; Bao, Meng-Jing; Li, Fenfen; Xie, Qiang-min

doi:10.1016/j.ejphar.2011.01.017

“…However, no statistical significance (p > 0.05) in t ½ was found among the studied dose groups. The duration of action of 50% of BCQB (t ½ , off-set) in classical bioassays was approximately 3 hours, [11] which was shorter than the terminal t ½ of BCQB in plasma. It may be due to the fact that the terminal t ½ in plasma is reflective of the rate of drug elimination from the body but not reflective of the duration of drug action.…”

Section: Discussionmentioning

confidence: 99%

“…BCQB is under development not only for the treatment of rhinorrhea in rhinitis but also for the therapy of COPD. [7,11] The aerosol with quantitative inhalation of bencycloquidium bromide [27] is under development. The objective of this FIH study was to assess the pharmacokinetics, safety and tolerability after single and multiple intranasal doses of BCQB in healthy Chinese subjects.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9][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] Preclinical toxicity studies also showed no apparent change in the ECG or heart rate in dogs [13] and rats.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics, Safety and Tolerability of Bencycloquidium Bromide, a Novel Selective Muscarinic M1/M3 Receptor Antagonist, After Single and Multiple Intranasal Doses in Healthy Chinese Subjects

Sun

¹

,

Ding

²

,

Wang

³

et al. 2012

View full text Add to dashboard Cite

Background: 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. Objective: 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. Methods: 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 mg (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 mg doses of BCQB (360 and 450 mg/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 mg); and (iv) ten subjects received 120 mg 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

show abstract

“…[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] Preclinical toxicity studies also showed no apparent change in the ECG or heart rate in dogs[13] and rats.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, Safety and Tolerability of Bencycloquidium Bromide, a Novel Selective Muscarinic M1/M3 Receptor Antagonist, After Single and Multiple Intranasal Doses in Healthy Chinese Subjects

Sun

¹

,

Ding

²

,

Wang

³

et al. 2012

View full text Add to dashboard Cite

Background: 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.Objective: 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.Methods: 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 mg (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 mg 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 noncompartmental methods.Results: 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 (tmax) of 8 minutes for 45, 90, and 180 mg dose groups; the plasma concentration of BCQB decreased in a biphasic manner with the mean half-life (t1/2) of 8.5 hours; the maximum concentration (Cmax) 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.Conclusion: BCQB was safe and well tolerated in healthy Chinese subjects when administered intranasally with single and multiple doses across the doses studied. The mean Cmax 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 deve...

show abstract

“…Ipratropium bromide, a nonselective antagonist of the muscarinic receptors located on airway smooth muscle [1], is widely used to counteract rhinorrhea of common cold [2], asthma and chronic obstructive pulmonary disease (COPD) [3][4][5][6][7] as well as prevention of the Arthus reaction [8]. When applied locally, the drug is well tolerated [2].…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Suicidal Erythrocyte Death by Ipratropium Bromide

Shaik

¹

,

Alhourani²,

Bosc³

et al. 2012

Cell Physiol Biochem

View full text Add to dashboard Cite

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 Ca²⁺-activity ([Ca²⁺]_i). The present study explored whether ipratropium bromide triggers eryptosis. Methods: [Ca Ca²⁺]_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 [Ca²⁺]_i, decreased forward scatter and increased annexin-V-binding. Ipratropium bromide treatment was followed by slight but significant increase of hemolysis. Removal of extracellular Ca²⁺ or inhibition of Ca²⁺ permeable cation channels with amiloride (1 mM) virtually abolished cell membrane scrambling. Ca²⁺ 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 Ca²⁺-entry.

show abstract

Characterization of bencycloquidium bromide, a novel muscarinic M3 receptor antagonist in guinea pig airways

Cited by 19 publications

References 40 publications

Pharmacokinetics, Safety and Tolerability of Bencycloquidium Bromide, a Novel Selective Muscarinic M1/M3 Receptor Antagonist, After Single and Multiple Intranasal Doses in Healthy Chinese Subjects

Pharmacokinetics, Safety and Tolerability of Bencycloquidium Bromide, a Novel Selective Muscarinic M1/M3 Receptor Antagonist, After Single and Multiple Intranasal Doses in Healthy Chinese Subjects

Pharmacokinetics, Safety and Tolerability of Bencycloquidium Bromide, a Novel Selective Muscarinic M1/M3 Receptor Antagonist, After Single and Multiple Intranasal Doses in Healthy Chinese Subjects

Stimulation of Suicidal Erythrocyte Death by Ipratropium Bromide

Contact Info

Product

Resources

About