Inhalable particles containing isoniazid and rifabutin as adjunct therapy for safe, efficacious and relapse-free cure of experimental animal tuberculosis in one month

被引：13

作者：

Singh, Amit K. ^{[1
,2
]}

Verma, Rahul K. ^{[1
,4
]}

Mukker, Jatinder Kaur ^{[1
,5
]}

Yadav, Awadh B. ^{[1
,6
]}

Muttil, Pavan ^{[1
,7
]}

Sharma, Rolee ^{[1
,8
]}

Mohan, Mradul ^{[1
,9
]}

Agrawal, Atul K. ^{[1
,10
]}

Gupta, Anuradha ^{[1
,11
]}

Dwivedi, Anil K. ^{[1
]}

Gupta, Pushpa ^{[2
]}

Gupta, Umesh D. ^{[2
]}

Mani, Uthirappan ^{[3
]}

Chaudhari, Bhushan P. ^{[3
]}

Murthy, Ramesh C. ^{[3
]}

Sharma, Sharad ^{[1
]}

Bhadauria, Smrati ^{[1
]}

Singh, Sarika ^{[1
]}

Rath, Srikanta Kumar ^{[1
]}

Misra, Amit ^{[1
]}

机构：

[1] CSIR, Cent Drug Res Inst, Lucknow 226031, Uttar Pradesh, India

[2] Natl JALMA Inst Leprosy & Other Mycobacterial Dis, Agra 282001, Uttar Pradesh, India

[3] CSIR, Indian Inst Toxicol Res, Lucknow 226001, Uttar Pradesh, India

[4] Inst Nano Sci & Technol, Mohali 160062, India

[5] Takeda Dev Ctr Amer Inc, Cambridge, MA 02139 USA

[6] Univ Allahabad, Allahabad 211002, Uttar Pradesh, India

[7] Univ New Mexico, Dept Pharmaceut Sci, Albuquerque, NM 87106 USA

[8] Integral Univ, Dept Biotechnol, Kursi Rd, Lucknow 226026, Uttar Pradesh, India

[9] ICMR Natl Inst Malaria Res, New Delhi 110077, India

[10] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA

[11] Sungkyunkwan Univ, Biomacromol Lab, Gyeonggi Do 16419, South Korea

来源：

TUBERCULOSIS | 2021年 / 128卷

关键词：

Adjunct therapy; Pulmonary drug delivery; Preclinical efficacy; Preclinical safety/tolerability; DRUG-DELIVERY SYSTEM; MYCOBACTERIUM-TUBERCULOSIS; DRY POWDER; PULMONARY DELIVERY; ALVEOLAR MACROPHAGES; PARTIAL BIODISTRIBUTION; MICROPARTICLES; PHARMACOKINETICS; MICROSPHERES; INHALATION;

D O I：

10.1016/j.tube.2021.102081

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

We investigated the preclinical efficacy and safety/tolerability of biodegradable polymeric particles containing isoniazid (INH) and rifabutin (RFB) dry powder for inhalation (DPI) as an adjunct to oral first-line therapy. Mice and guinea pigs infected with Mycobacterium tuberculosis H37Rv (Mtb) were treated with similar to 80 and similar to 300 mu g of the DPI, respectively, for 3-4 weeks starting 3, 10, and 30 days post-infection. Adjunct combination therapy eliminated culturable Mtb from the lungs and spleens of all but one of 52 animals that received the DPI. Relapse-free cure was not achieved in one mouse that received DPI + oral, human-equivalent doses (HED) of four drugs used in the Directly Observed Treatment, Short Course (DOTS), starting 30 days post-infection. Oral doses (20 mg/Kg/day, each) of INH + RFB reduced Mtb burden from similar to 10(6) to similar to 10(3) colony-forming units. Combining half the oral dose with DPI prevented relapse of infection four weeks after stopping the treatment. The DPI was safe in rodents, guinea pigs, and monkeys at 1, 10, and 100 mu g/day doses over 90 days. In conclusion, we show the efficacy and safety/tolerability of the DPI as an adjunct to oral chemotherapy in three different animal models of TB.

引用

页数：10