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Dry powder PA-824 aerosols for treatment of tuberculosis in guinea pigs.
Antimicrob Agents Chemother. 2010 Apr; 54(4):1436-42.AA

Abstract

Novel treatments for multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB), or latent TB are needed urgently. Recently, we reported the formulation and characterization of the nitroimidazo-oxazine PA-824 for efficient aerosol delivery as dry powder porous particles and the subsequent disposition in guinea pigs after pulmonary administration. The objective of the present study was to evaluate the effects of these PA-824 therapeutic aerosols on the extent of TB infection in the low-inoculum aerosol infection guinea pig model. Four weeks after infection by the pulmonary route, animals received daily treatment for 4 weeks of either a high or a low dose of PA-824 dry powder aerosol. Animals received PA-824 cyclodextrin/lecithin suspensions orally as positive controls, and those receiving placebo particles or no treatment were negative controls. The lungs and spleens of animals receiving the high dose of inhaled PA-824 particles exhibited a lower degree of inflammation (indicated by wet tissue weights), bacterial burden, and tissue damage (indicated by histopathology) than those of untreated or placebo animals. Treatment with oral PA-824 cyclodextrin/lecithin suspension resulted in a more significant reduction in the bacterial burden of lungs and spleen, consistent with a dose that was larger than inhaled doses (eight times the inhaled low dose and four times the inhaled high dose). However, histopathological analysis revealed that the extent of tissue damage was comparable in groups receiving the oral or either inhaled dose. The present studies indicate the potential use of PA-824 dry powder aerosols in the treatment of TB.

Authors+Show Affiliations

University of North Carolina School of Pharmacy, Chapel Hill, North Carolina 27599, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20086154

Citation

Garcia-Contreras, Lucila, et al. "Dry Powder PA-824 Aerosols for Treatment of Tuberculosis in Guinea Pigs." Antimicrobial Agents and Chemotherapy, vol. 54, no. 4, 2010, pp. 1436-42.
Garcia-Contreras L, Sung JC, Muttil P, et al. Dry powder PA-824 aerosols for treatment of tuberculosis in guinea pigs. Antimicrob Agents Chemother. 2010;54(4):1436-42.
Garcia-Contreras, L., Sung, J. C., Muttil, P., Padilla, D., Telko, M., Verberkmoes, J. L., Elbert, K. J., Hickey, A. J., & Edwards, D. A. (2010). Dry powder PA-824 aerosols for treatment of tuberculosis in guinea pigs. Antimicrobial Agents and Chemotherapy, 54(4), 1436-42. https://doi.org/10.1128/AAC.01471-09
Garcia-Contreras L, et al. Dry Powder PA-824 Aerosols for Treatment of Tuberculosis in Guinea Pigs. Antimicrob Agents Chemother. 2010;54(4):1436-42. PubMed PMID: 20086154.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dry powder PA-824 aerosols for treatment of tuberculosis in guinea pigs. AU - Garcia-Contreras,Lucila, AU - Sung,Jean C, AU - Muttil,Pavan, AU - Padilla,Danielle, AU - Telko,Martin, AU - Verberkmoes,Jarod L, AU - Elbert,Katharina J, AU - Hickey,Anthony J, AU - Edwards,David A, Y1 - 2010/01/19/ PY - 2010/1/21/entrez PY - 2010/1/21/pubmed PY - 2010/6/30/medline SP - 1436 EP - 42 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 54 IS - 4 N2 - Novel treatments for multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB), or latent TB are needed urgently. Recently, we reported the formulation and characterization of the nitroimidazo-oxazine PA-824 for efficient aerosol delivery as dry powder porous particles and the subsequent disposition in guinea pigs after pulmonary administration. The objective of the present study was to evaluate the effects of these PA-824 therapeutic aerosols on the extent of TB infection in the low-inoculum aerosol infection guinea pig model. Four weeks after infection by the pulmonary route, animals received daily treatment for 4 weeks of either a high or a low dose of PA-824 dry powder aerosol. Animals received PA-824 cyclodextrin/lecithin suspensions orally as positive controls, and those receiving placebo particles or no treatment were negative controls. The lungs and spleens of animals receiving the high dose of inhaled PA-824 particles exhibited a lower degree of inflammation (indicated by wet tissue weights), bacterial burden, and tissue damage (indicated by histopathology) than those of untreated or placebo animals. Treatment with oral PA-824 cyclodextrin/lecithin suspension resulted in a more significant reduction in the bacterial burden of lungs and spleen, consistent with a dose that was larger than inhaled doses (eight times the inhaled low dose and four times the inhaled high dose). However, histopathological analysis revealed that the extent of tissue damage was comparable in groups receiving the oral or either inhaled dose. The present studies indicate the potential use of PA-824 dry powder aerosols in the treatment of TB. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/20086154/Dry_powder_PA_824_aerosols_for_treatment_of_tuberculosis_in_guinea_pigs_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=20086154 DB - PRIME DP - Unbound Medicine ER -