Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, Cathays Park Campus, Cardiff, Wales, UK.
Eur J Pharmacol. 2010 Sep 1;641(2-3):213-9. doi: 10.1016/j.ejphar.2010.05.025. Epub 2010 Jun 8.
Inhaled corticosteroids are regularly co-administered with beta(2)-adrenoceptor agonists. This study evaluates in conscious guinea-pigs the bronchodilator effect, alone or combined with salbutamol, of TPI 1020, a novel anti-inflammatory corticosteroid and nitric oxide (NO) donor derived from budesonide. Guinea-pigs received inhaled histamine (3 mM) and specific airway conductance (sG(aw)) measured. Responses to histamine were measured before and on the next day 15 min after a 15 min inhalation of vehicle, salbutamol, TPI 1020, budesonide, the NO-donor, S-nitroso-N-acetylpenicillamine (SNAP), or combinations of these drugs. Salbutamol and TPI 1020 caused concentration-dependent bronchodilatation measured as inhibition of histamine-induced bronchoconstriction. TPI 1020-induced bronchodilatation was blocked by the guanylyl cyclise inhibitor, ODQ, indicating cGMP-dependence through released NO. While salbutamol at 80 microM did not exert significant bronchodilatation, significant inhibitions were observed when co-administered with TPI 1020, 0.11 and 0.33 mM. The combined effects of TPI 1020 and salbutamol lasted significantly longer than either drug alone. Inhaled budesonide was a weak bronchodilator and when co-administered with salbutamol there was enhanced bronchodilatation. Addition of the NO-donor, SNAP (0.1 mM), to the budesonide/salbutamol combination, also improved the inhibition of histamine-induced bronchoconstriction. This study has shown that TPI 1020 potentiates the bronchodilator activity of salbutamol, and their combination lasted longer than either drug administered individually. Both the corticosteroid and NO-releasing activities of TPI 1020 appear to be required for the potentiation of salbutamol. Combination of TPI 1020 with a beta(2)-adrenoceptor agonist may therefore be useful against acute bronchoconstriction episodes in asthma, and may offer an opportunity for reducing doses of inhaled beta(2)-adrenoceptor agonists.
在清醒的豚鼠中，评估了吸入性皮质类固醇与β2-肾上腺素受体激动剂（如沙丁胺醇）联合应用时的支气管扩张作用。本研究使用了一种新型抗炎皮质类固醇 TPI 1020，它是一种来源于布地奈德的一氧化氮（NO）供体，评估了其在豚鼠中的支气管扩张作用，单独应用或与沙丁胺醇联合应用。豚鼠吸入组胺（3mM）并测量特定气道传导率（sG（aw））。在吸入 15 分钟载体、沙丁胺醇、TPI 1020、布地奈德、NO 供体 S-亚硝基-N-乙酰青霉胺（SNAP）或这些药物联合应用后 15 分钟，测量组胺反应。沙丁胺醇和 TPI 1020 引起的支气管扩张作用呈浓度依赖性，表现为对组胺诱导的支气管收缩的抑制作用。TPI 1020 引起的支气管扩张作用被鸟苷酸环化酶抑制剂 ODQ 阻断，表明通过释放的 NO 依赖 cGMP。虽然 80μM 的沙丁胺醇没有显著的支气管扩张作用，但当与 TPI 1020 联合应用时，观察到 0.11 和 0.33mM 时出现显著抑制。TPI 1020 和沙丁胺醇的联合作用持续时间明显长于单独应用任何一种药物。吸入布地奈德是一种弱支气管扩张剂，与沙丁胺醇联合应用时可增强支气管扩张作用。向布地奈德/沙丁胺醇联合用药中加入一氧化氮供体 SNAP（0.1mM）也可改善对组胺诱导的支气管收缩的抑制作用。本研究表明，TPI 1020 增强了沙丁胺醇的支气管扩张作用，其联合作用持续时间长于单独应用任何一种药物。TPI 1020 的皮质激素和释放 NO 的活性似乎都是增强沙丁胺醇作用所必需的。因此，TPI 1020 与β2-肾上腺素受体激动剂联合应用可能对抗哮喘急性支气管痉挛发作有用，并可能为减少吸入β2-肾上腺素受体激动剂的剂量提供机会。
