Patil-Gadhe Arpana A, Kyadarkunte Abhay Y, Pereira Michael, Jejurikar Gauri, Patole Milind S, Risbud Arun, Pokharkar Varsha B
Department of Pharmaceutics, Bharati Vidyapeeth University, Poona College of Pharmacy, Erandwane, Pune, India ; National Centre for Cell Sciences, University of Pune Campus, Ganeshkhind, Pune, India.
Department of Microbiology, National Aids Research Centre, Bhosari, Pune, Maharashtra, India.
Toxicol Int. 2014 Sep-Dec;21(3):275-82. doi: 10.4103/0971-6580.155361.
Oral therapy for pulmonary tuberculosis (TB) treatment suffers from the limitation of hepatic metabolism leading insufficient concentration of antitubercular (anti-TB) drugs in alveolar macrophage which harbors Mycobacterium tuberculosis (MTB). Targeted aerosol delivery of antituberculous drug to lung is efficient for treating local lung TB infection.
The present study was aimed to evaluate rifapentine (RPT) loaded proliposomal dry powder for inhalation (RLDPI) for anti-TBactivity and cytotoxicity in vitro. In vivo toxicity study was also undertaken in Wistar rats to determine safe concentration of RLDPI for administration.
Anti-TB activity of developed RLDPI was assessed using drug susceptibility testing (DST) on Mycobacteria growth indicator tube (MGIT) method. In vitro cytotoxicity was performed in A549 cell lines and IC50 values were used to compare the cytotoxicity of formulation with pure RPT. In vivo repeated dose toxicity study was undertaken using Wistar rats at three different doses for 28-days by intratracheal insufflations method.
The results of DST study revealed sensitivity of tubercle bacteria to RLDPI at concentration equivalent to 10 μg/mL of RPT. This study confirmed anti-TB potential of RPT in spray-dried RLDPI, though the spray drying method is reported to reduce activity of drugs. Cytotoxicity study in A549 cells demonstrated that RPT when encapsulated in liposomes as RLDPI was safe to cells as compared to pure RPT. In vivo toxicity study revealed that RPT in the form of RLDPI was safe at 1 and 5 mg/kg dose. However, mortality was seen at higher dose (10 mg/kg), possibly because of liver and kidney damage.
Thus, these studies demonstrated safety of RLDPI for the treatment of pulmonary TB.
肺结核（TB）的口服治疗受肝脏代谢的限制，导致抗结核药物在携带结核分枝杆菌（MTB）的肺泡巨噬细胞中的浓度不足。将抗结核药物靶向气溶胶递送至肺部对治疗局部肺结核感染有效。
本研究旨在评估载有利福喷汀（RPT）的脂质体干粉吸入剂（RLDPI）的体外抗结核活性和细胞毒性。还对Wistar大鼠进行了体内毒性研究，以确定RLDPI给药的安全浓度。
使用分枝杆菌生长指示管（MGIT）法进行药物敏感性试验（DST），评估所制备的RLDPI的抗结核活性。在A549细胞系中进行体外细胞毒性试验，并使用IC50值比较制剂与纯RPT的细胞毒性。通过气管内注入法，对Wistar大鼠以三种不同剂量进行为期28天的体内重复剂量毒性研究。
DST研究结果显示，结核杆菌对浓度相当于10μg/mL RPT的RLDPI敏感。本研究证实了喷雾干燥的RLDPI中RPT的抗结核潜力，尽管据报道喷雾干燥法会降低药物活性。A549细胞的细胞毒性研究表明，与纯RPT相比，当RPT以RLDPI形式包封在脂质体中时对细胞是安全的。体内毒性研究表明，1和5mg/kg剂量的RLDPI形式的RPT是安全的。然而，在较高剂量（10mg/kg）时出现了死亡，可能是由于肝和肾损伤。
因此，这些研究证明了RLDPI治疗肺结核的安全性。
