Selting Kim, Waldrep J Clifford, Reinero Carol, Branson Keith, Gustafson Daniel, Kim Dae Young, Henry Carolyn, Owen Nellie, Madsen Richard, Dhand Rajiv
Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri 65211, USA.
J Aerosol Med Pulm Drug Deliv. 2008 Sep;21(3):255-68. doi: 10.1089/jamp.2008.0684.
Delivery of drugs by airway can minimize systemic toxicity and maximize local drug concentrations. Most cancers metastasize to the lungs. Our purpose was to determine platinum concentrations in the lung after targeted delivery of cisplatin (CDDP) with an intracorporeal nebulizing catheter (INC), and to determine the safety of escalating doses of inhaled CDDP. In anesthetized and mechanically ventilated healthy dogs, the INC (AeroProbe) was introduced via flexible bronchoscope into the right caudal lung lobe (RCLL) and CDDP (10 mg/m2) administered. Tissue and serum platinum concentrations were compared to those after an equivalent intravenous dose of CDDP (n = 3 dogs/group). In three additional dogs, pharmacokinetics were performed after inhaled and intravenous CDDP. Increasing dosages of inhaled CDDP (10, 15, 20, and 30 mg/m2) were then administered every 2 weeks. Dogs were sacrificed for postmortem examination at week 10. One additional dog was treated with a single dose of 30 mg/m2 and sacrificed 2 weeks later. Immediately following a single inhaled dose, mean CDDP levels were 44 times greater in the RCLL than in most other tissues and 15.6 times lower in the serum compared to intravenous dosing. Pharmacokinetic comparison showed that the AUC0-24h was similar (p = 0.72), but maximum serum concentration was fivefold lower after inhalation than intravenous delivery (p = 0.02). Escalating doses of inhaled CDDP (cumulative 75 mg/m2) produced no significant clinical or hematological effects, but there was radiographic and histologic evidence of severe pneumonitis with mild to moderate fibrosis confined to the RCLL. Radiographic and histologic changes were similar in the single, high-dose dog. Targeted inhaled CDDP achieved high concentrations in the treated lobe, with lower peak serum levels than after intravenous administration. Escalating doses of inhaled CDDP produced focal pneumonitis and fibrosis in the treated lung lobe with minimal clinical and hematologic effects. Targeted inhaled chemotherapy could be a promising method of treatment for primary and secondary lung tumors.
通过气道给药可将全身毒性降至最低，并使局部药物浓度最大化。大多数癌症会转移至肺部。我们的目的是确定使用体内雾化导管（INC）靶向递送顺铂（CDDP）后肺内的铂浓度，并确定递增剂量吸入性CDDP的安全性。在麻醉并机械通气的健康犬中，通过柔性支气管镜将INC（AeroProbe）插入右尾叶肺（RCLL）并给予CDDP（10 mg/m²）。将组织和血清中的铂浓度与静脉给予等量CDDP后的浓度进行比较（每组n = 3只犬）。在另外三只犬中，在吸入和静脉给予CDDP后进行药代动力学研究。然后每2周递增吸入性CDDP的剂量（10、15、20和30 mg/m²）。在第10周处死犬进行尸检。另外一只犬接受单次30 mg/m²的剂量治疗，并在2周后处死。单次吸入剂量后立即检测，RCLL中的平均CDDP水平比大多数其他组织高44倍，血清中的水平比静脉给药低15.6倍。药代动力学比较显示，AUC0 - 24h相似（p = 0.72），但吸入后血清最大浓度比静脉给药低五倍（p = 0.02）。递增剂量的吸入性CDDP（累积75 mg/m²）未产生明显的临床或血液学影响，但有影像学和组织学证据表明局限于RCLL的严重肺炎伴轻度至中度纤维化。单次高剂量犬的影像学和组织学变化相似。靶向吸入性CDDP在治疗的肺叶中达到高浓度，血清峰值水平低于静脉给药后。递增剂量的吸入性CDDP在治疗的肺叶中产生局灶性肺炎和纤维化，临床和血液学影响最小。靶向吸入化疗可能是治疗原发性和继发性肺肿瘤的一种有前景的方法。
