Wolzt Michael, de la Peña Amparo, Berclaz Pierre-Yves, Tibaldi Fabián S, Gates Jeffrey R, Muchmore Douglas B
Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, Austria A-1090.
Diabetes Care. 2008 Apr;31(4):735-40. doi: 10.2337/dc07-0873. Epub 2008 Jan 11.
This study evaluated pharmacokinetic and glucodynamic responses to AIR inhaled insulin relative to subcutaneous insulin lispro, safety, pulmonary function, and effects of salbutamol coadministration.
Healthy, mildly asthmatic, and moderately asthmatic subjects (n = 13/group, aged 19-58 years, nonsmoking, and nondiabetic) completed this phase I, open-label, randomized, crossover euglycemic clamp study. Subjects received 12 units equivalent AIR insulin or 12 units subcutaneous insulin lispro or salbutamol plus AIR insulin (moderate asthma group only) before the clamp.
AIR insulin exposure was reduced 34 and 41% (both P < 0.01) in asthmatic subjects (area under the curve(0-t'), 24.0 and 21.1 nmol x min x l(-1) in mild and moderate asthma subjects, respectively) compared with healthy subjects (35.2 nmol x min x l(-1)), respectively. Glucodynamic (G) effects were similar in healthy and mildly asthmatic subjects (G(tot) = 38.7 and 23.4 g, respectively; P = 0.16) and were reduced in moderately asthmatic subjects (G(tot) = 10.7 g). Salbutamol pretreatment (moderately asthmatic subjects) improved bioavailability. AIR insulin had no discernable effect on pulmonary function. AIR insulin adverse events (cough, headache, and dizziness) were mild to moderate in intensity and have been previously reported or are typical of studies involving glucose clamp procedures.
This study suggests that pulmonary disease severity and asthma treatment status influence the metabolic effect of AIR insulin in individuals with asthma but do not affect AIR insulin pulmonary safety or tolerability. In view of the potential interactions between diabetes treatment and pulmonary status, it is prudent to await the results of ongoing clinical trials in diabetic patients with comorbid lung disease before considering the use of inhaled insulin in such patients.
本研究评估了吸入式胰岛素（AIR）相对于皮下注射赖脯胰岛素的药代动力学和糖动力学反应、安全性、肺功能以及沙丁胺醇联合给药的影响。
健康、轻度哮喘和中度哮喘受试者（每组n = 13，年龄19 - 58岁，不吸烟且非糖尿病患者）完成了这项I期开放标签随机交叉正常血糖钳夹研究。在钳夹前，受试者接受12单位等效的AIR胰岛素或12单位皮下注射赖脯胰岛素或沙丁胺醇加AIR胰岛素（仅中度哮喘组）。
与健康受试者（曲线下面积（0 - t'）为35.2 nmol·min·L⁻¹）相比，哮喘受试者中AIR胰岛素暴露量分别降低了34%和41%（均P < 0.01）（轻度和中度哮喘受试者的曲线下面积分别为24.0和21.1 nmol·min·L⁻¹）。健康和轻度哮喘受试者的糖动力学（G）效应相似（G总量分别为38.7和23.4 g；P = 0.16），而中度哮喘受试者的G效应降低（G总量 = 10.7 g）。沙丁胺醇预处理（中度哮喘受试者）提高了生物利用度。AIR胰岛素对肺功能无明显影响。AIR胰岛素不良事件（咳嗽、头痛和头晕）强度为轻至中度，此前已有报道或为涉及葡萄糖钳夹程序研究中的典型情况。
本研究表明，肺部疾病严重程度和哮喘治疗状态会影响哮喘患者中AIR胰岛素的代谢效应，但不影响AIR胰岛素的肺部安全性或耐受性。鉴于糖尿病治疗与肺部状态之间可能存在相互作用，在考虑在此类患者中使用吸入式胰岛素之前，谨慎等待正在进行的糖尿病合并肺部疾病患者临床试验结果是明智的。
