Gavaldà Amadeu, Ramos Israel, Carcasona Carla, Calama Elena, Otal Raquel, Montero José Luis, Sentellas Sonia, Aparici Monica, Vilella Dolors, Alberti Joan, Beleta Jorge, Miralpeix Montserrat
Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Pulm Pharmacol Ther. 2014 Aug;28(2):114-21. doi: 10.1016/j.pupt.2014.05.005. Epub 2014 Jun 10.
This study characterised the in vitro and in vivo profiles of two novel long-acting muscarinic antagonists, aclidinium bromide and glycopyrronium bromide, using tiotropium bromide and ipratropium bromide as comparators. All four antagonists had high affinity for the five muscarinic receptor sub-types (M1-M5); aclidinium had comparable affinity to tiotropium but higher affinity than glycopyrronium and ipratropium for all receptors. Glycopyrronium dissociated faster from recombinant M3 receptors than aclidinium and tiotropium but more slowly than ipratropium; all four compounds dissociated more rapidly from M2 receptors than from M3 receptors. In vitro, aclidinium, glycopyrronium and tiotropium had a long duration of action at native M3 receptors (>8 h versus 42 min for ipratropium). In vivo, all compounds were equi-potent at reversing acetylcholine-induced bronchoconstriction. Aclidinium, glycopyrronium and ipratropium had a faster onset of bronchodilator action than tiotropium. Aclidinium had a longer duration of action than glycopyronnium (time to 50% recovery of effect [t½ offset] = 29 h and 13 h, respectively); these compare with a t½ offset of 64 h and 8 h for tiotropium and ipratropium, respectively. Aclidinium was less potent than glycopyrronium and tiotropium at inhibiting salivation in conscious rats (dose required to produce half-maximal effect [ED50] = 38, 0.74 and 0.88 μg/kg, respectively) and was more rapidly hydrolysed in rat, guinea pig and human plasma compared with glycopyrronium or tiotropium. These results indicate that while aclidinium and glycopyrronium are both potent antagonists at muscarinic receptors with similar kinetic selectivity for M3 receptors versus M2, aclidinium has a longer dissociation half-life at M3 receptors and a longer duration of bronchodilator action in vivo than glycopyrronium. The rapid plasma hydrolysis of aclidinium, coupled to its kinetic selectivity, may confer a reduced propensity for systemic anticholinergic side effects with aclidinium versus glycopyrronium and tiotropium.
本研究以噻托溴铵和异丙托溴铵作为对照，对两种新型长效毒蕈碱拮抗剂——阿地溴铵和格隆溴铵的体外和体内特性进行了表征。所有这四种拮抗剂对五种毒蕈碱受体亚型（M1 - M5）均具有高亲和力；阿地溴铵对所有受体的亲和力与噻托溴铵相当，但高于格隆溴铵和异丙托溴铵。格隆溴铵从重组M3受体上解离的速度比阿地溴铵和噻托溴铵快，但比异丙托溴铵慢；所有四种化合物从M2受体上的解离速度均比从M3受体上快。在体外，阿地溴铵、格隆溴铵和噻托溴铵对天然M3受体的作用持续时间较长（阿地溴铵和格隆溴铵>8小时，而异丙托溴铵为42分钟）。在体内，所有化合物在逆转乙酰胆碱诱导的支气管收缩方面效力相当。阿地溴铵、格隆溴铵和异丙托溴铵的支气管扩张作用起效比噻托溴铵快。阿地溴铵的作用持续时间比格隆溴铵长（效应恢复到50%的时间[t½偏移]分别为29小时和13小时）；与之相比，噻托溴铵和异丙托溴铵的t½偏移分别为64小时和8小时。在清醒大鼠中，阿地溴铵抑制唾液分泌的效力低于格隆溴铵和噻托溴铵（产生半数最大效应所需剂量[ED50]分别为38、0.74和0.88μg/kg），并且与格隆溴铵或噻托溴铵相比，在大鼠、豚鼠和人血浆中水解速度更快。这些结果表明，虽然阿地溴铵和格隆溴铵在毒蕈碱受体上均为强效拮抗剂，对M3受体与M2受体具有相似的动力学选择性，但阿地溴铵在M3受体上的解离半衰期更长，在体内的支气管扩张作用持续时间比格隆溴铵长。阿地溴铵在血浆中快速水解，再加上其动力学选择性，可能使阿地溴铵相较于格隆溴铵和噻托溴铵产生全身抗胆碱能副作用的倾向降低。
