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Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model.
Antimicrob Agents Chemother. 2007 Aug; 51(8):2830-6.AA

Abstract

Capreomycin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB), but it is limited therapeutically by its severe side effects. The objectives of the present studies were (i) to design low-density porous capreomycin sulfate particles for efficient pulmonary delivery to improve local and systemic drug bioavailability and capacity to reduce the bacillary load in the lungs in a manner similar to that achieved with intramuscular injections; (ii) to determine pharmacokinetic parameters after pulmonary administration of these capreomycin particles; and (iii) to evaluate the efficacy of these particles in treating animals in a small-aerosol-inoculum guinea pig model of TB. Capreomycin particles were manufactured by spray drying and characterized in terms of size and drug content. Pharmacokinetic parameters were determined by noncompartmental methods with healthy guinea pigs after administration of capreomycin particles by insufflation. The efficacy of the particles was evaluated by histopathological analysis and in terms of wet organ weight and bacterial burden in TB-infected animals. Lungs of animals receiving a 14.5-mg/kg dose of capreomycin particles showed significantly lower wet weights and smaller bacterial burdens than those of animals receiving any other treatment. These results were supported by histopathological analysis. The feasibility of inhaling capreomycin in a novel powder form, with the ultimate objective of the treatment of MDR-TB, is demonstrated by pharmacokinetic and pharmacodynamic studies with guinea pigs. If applied to humans with MDR-TB, such a therapeutic approach might simplify drug delivery by eliminating injections and might reduce adverse effects through lowering the dose.

Authors+Show Affiliations

University of North Carolina, Chapel Hill, NC 27599-7360, 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 availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17517845

Citation

Garcia-Contreras, L, et al. "Inhaled Large Porous Particles of Capreomycin for Treatment of Tuberculosis in a Guinea Pig Model." Antimicrobial Agents and Chemotherapy, vol. 51, no. 8, 2007, pp. 2830-6.
Garcia-Contreras L, Fiegel J, Telko MJ, et al. Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model. Antimicrob Agents Chemother. 2007;51(8):2830-6.
Garcia-Contreras, L., Fiegel, J., Telko, M. J., Elbert, K., Hawi, A., Thomas, M., VerBerkmoes, J., Germishuizen, W. A., Fourie, P. B., Hickey, A. J., & Edwards, D. (2007). Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model. Antimicrobial Agents and Chemotherapy, 51(8), 2830-6.
Garcia-Contreras L, et al. Inhaled Large Porous Particles of Capreomycin for Treatment of Tuberculosis in a Guinea Pig Model. Antimicrob Agents Chemother. 2007;51(8):2830-6. PubMed PMID: 17517845.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model. AU - Garcia-Contreras,L, AU - Fiegel,J, AU - Telko,M J, AU - Elbert,K, AU - Hawi,A, AU - Thomas,M, AU - VerBerkmoes,J, AU - Germishuizen,W A, AU - Fourie,P B, AU - Hickey,A J, AU - Edwards,D, Y1 - 2007/05/21/ PY - 2007/5/23/pubmed PY - 2007/10/20/medline PY - 2007/5/23/entrez SP - 2830 EP - 6 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 51 IS - 8 N2 - Capreomycin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB), but it is limited therapeutically by its severe side effects. The objectives of the present studies were (i) to design low-density porous capreomycin sulfate particles for efficient pulmonary delivery to improve local and systemic drug bioavailability and capacity to reduce the bacillary load in the lungs in a manner similar to that achieved with intramuscular injections; (ii) to determine pharmacokinetic parameters after pulmonary administration of these capreomycin particles; and (iii) to evaluate the efficacy of these particles in treating animals in a small-aerosol-inoculum guinea pig model of TB. Capreomycin particles were manufactured by spray drying and characterized in terms of size and drug content. Pharmacokinetic parameters were determined by noncompartmental methods with healthy guinea pigs after administration of capreomycin particles by insufflation. The efficacy of the particles was evaluated by histopathological analysis and in terms of wet organ weight and bacterial burden in TB-infected animals. Lungs of animals receiving a 14.5-mg/kg dose of capreomycin particles showed significantly lower wet weights and smaller bacterial burdens than those of animals receiving any other treatment. These results were supported by histopathological analysis. The feasibility of inhaling capreomycin in a novel powder form, with the ultimate objective of the treatment of MDR-TB, is demonstrated by pharmacokinetic and pharmacodynamic studies with guinea pigs. If applied to humans with MDR-TB, such a therapeutic approach might simplify drug delivery by eliminating injections and might reduce adverse effects through lowering the dose. SN - 0066-4804 UR - https://www.unboundmedicine.com/medline/citation/17517845/Inhaled_large_porous_particles_of_capreomycin_for_treatment_of_tuberculosis_in_a_guinea_pig_model_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=17517845 DB - PRIME DP - Unbound Medicine ER -