Blot F, Tavakoli R, Sellam S, Epardeau B, Faurisson F, Bernard N, Becquemin M H, Frachon I, Stern M, Pocidalo J J
Department of Pneumology, CMC Foch, Suresnes, France.
J Heart Lung Transplant. 1995 Nov-Dec;14(6 Pt 1):1162-72.
With regard to limiting the systemic effects of cyclosporine A and obtaining better control of acute pulmonary allograft rejection, local immunosuppressive therapy with aerosolized cyclosporine A seems of interest. Given the in situ immunologic mechanisms of acute rejection, as well as the anatomic structure of the lung, this therapy is feasible as previously described by others. The aim of our study is to determine the pharmacokinetic parameters of nebulized cyclosporine A and the best modalities of administration.
In a pharmacokinetic study, the cyclosporine A was given either by intramuscular injection (10 mg/kg) or by aerosol at 10 and 25 mg/kg doses; 70 rats were killed at 25 and 50 minutes and 2, 4, 6, 8, 12, 24, or 48 hours after cyclosporine A administration. Cyclosporine A levels were measured in whole blood and in the lung. The areas under the concentration time curves were determined. Twenty-four lung transplantations were then performed. The rats were killed on postoperative day 9. Acute rejection was scored on a scale of 0 to 4, and cyclosporine A trough levels were measured in the lung and in the blood.
With a jet nebulizer, the mass median aerodynamic diameter was 2.5 microns, with a standard geometric deviation of 2.3. In blood, the area under the concentration curve was greater for intramuscular (80.6 ng.hr/ml) than for aerosol administrations at 10 (15.1 ng.hr/ml) and 25 mg/kg (41.0 ng.hr/ml) doses. In the lungs, the area under the concentration curve was greater for the aerosol route at 25 mg/kg doses (588 ng.hr/mg) than for the low-dose (200 ng.hr/mg) or intramuscular administration (200 ng.hr/mg). The lung targeting index of cyclosporine A (ratio area under the concentration curve-lungs/area under the concentration curve-blood) was greater for both aerosol administrations than for the intramuscular route. In the study of the prevention of acute rejection, rats without immunosuppression (n = 6), rats receiving daily doses of cyclosporine A intramuscularly (10 mg/kg), and rats with aerosolized cyclosporine A daily (10 and 25 mg/kg/day) showed mean grades of acute rejection of, respectively, 4, 2.03 +/- 0.27, 2.33 +/- 0.52, and 2.17 +/- 0.46. The deposition of nebulized cyclosporine A was lower in transplanted than in native lung.
Nebulized cyclosporine A allows better pulmonary concentration than intramuscular administration, and results in lower systemic levels. Prevention of acute rejection is as good with aerosolized cyclosporine A as with intramuscular cyclosporine A. This first pharmacokinetic study of nebulized cyclosporine A could lead to clinical applications.
关于限制环孢素A的全身效应并更好地控制急性肺移植排斥反应，雾化吸入环孢素A的局部免疫抑制治疗似乎具有吸引力。鉴于急性排斥反应的原位免疫机制以及肺的解剖结构，这种治疗方法如前人所述是可行的。我们研究的目的是确定雾化吸入环孢素A的药代动力学参数以及最佳给药方式。
在一项药代动力学研究中，环孢素A通过肌肉注射（10mg/kg）或雾化吸入给予，剂量分别为10mg/kg和25mg/kg；在给予环孢素A后25分钟和50分钟以及2、4、6、8、12、24或48小时处死70只大鼠。测定全血和肺中的环孢素A水平。确定浓度-时间曲线下的面积。然后进行了24次肺移植。术后第9天处死大鼠。急性排斥反应按0至4分进行评分，并测定肺和血液中环孢素A的谷浓度。
使用喷射雾化器时，质量中值空气动力学直径为2.5微米，标准几何标准差为2.3。在血液中，肌肉注射（80.6ng·hr/ml）的浓度曲线下面积大于10mg/kg（15.1ng·hr/ml）和25mg/kg（41.0ng·hr/ml）剂量雾化吸入给药。在肺中，25mg/kg剂量雾化吸入给药的浓度曲线下面积（588ng·hr/mg）大于低剂量（200ng·hr/mg）或肌肉注射给药（200ng·hr/mg）。两种雾化吸入给药方式的环孢素A肺靶向指数（浓度曲线下面积-肺/浓度曲线下面积-血液之比）均高于肌肉注射途径。在预防急性排斥反应的研究中，未接受免疫抑制的大鼠（n = 6）、每日肌肉注射环孢素A（10mg/kg）的大鼠以及每日雾化吸入环孢素A（10mg/kg和25mg/kg/天）的大鼠急性排斥反应的平均分级分别为4、2.03±0.27、2.33±0.52和2.17±0.46。雾化吸入的环孢素A在移植肺中的沉积低于天然肺。
雾化吸入环孢素A比肌肉注射能使肺内浓度更高，且全身水平更低。雾化吸入环孢素A预防急性排斥反应的效果与肌肉注射环孢素A一样好。这项关于雾化吸入环孢素A的首次药代动力学研究可能会带来临床应用。
