Pulmonary Target Delivery of Polymyxin B for Enhanced Efficacy

dc.contributor.advisorTam, Vincent H.
dc.contributor.committeeMemberChow, Diana Shu-Lian
dc.contributor.committeeMemberHu, Ming
dc.contributor.committeeMemberBond, Richard A.
dc.contributor.committeeMemberLi, Chun
dc.creatorHe, Jie 1981-
dc.date.accessioned2018-03-14T17:26:23Z
dc.date.available2018-03-14T17:26:23Z
dc.date.createdDecember 2012
dc.date.issued2012-12
dc.date.submittedDecember 2012
dc.date.updated2018-03-14T17:26:23Z
dc.description.abstractObjective: Polymyxin B is increasingly used as the last resort for multidrug resistant (MDR) Gram-negative bacterial infections. Limited by high polarity of the drug and poor penetration into the pulmonary epithelial lining fluid (ELF), polymyxin B does not distribute well to the lung tissues to achieve an effective concentration. In this study, polymyxin B liposomes were developed as well as the pharmacokinetics, exposure in the ELF and efficacy of a polymyxin B liposomal formulation were investigated. Methods: A rapid, sensitive and robust UPLC-MS/MS method had been developed for the quantification of four major polymyxin B components (PB1, PB2, PB3 and ile-PB1) in various biological matrices. Polymyxin B liposomes were developed and characterized. Two groups of 24 Swiss Webster mice were intravenously administrated polymyxin B liposomes, and aqueous solution, respectively, at approximately 3 mg/kg. Serial serum, ELF and kidney samples were collected for up to 6 hours to quantify major polymyxin B components. Treatment efficacy of the liposomal formulation was evaluated by two clinically relevant endpoints, bacterial burden in lung tissues at 24 h and survival, respectively. Results: The validated method was used to characterize the pharmacokinetics (serum, ELF and kidneys) of polymyxin B in mice. The limited exposure of polymyxin B in ELF observed was consistent with the less favorable efficacy of polymyxin B reported for the treatment of pulmonary infections. Compared with aqueous solution, the liposomal formulation was shown to have a slower total clearance. The AUC ratio in the ELF between liposome and aqueous solution group ranged from 5.0 to 7.0 for various major polymyxin B components. In the efficacy study, a significantly lower bacterial burden was seen in the liposomal group (3.8 ± 0.7 vs. 7.9 ± 0.8 Log10 CFU/g in solution group), which subsequently prolonged survival of infected animals. Conclusions: Treatment with a polymyxin B liposomal formulation yielded higher penetration into pulmonary ELF, which resulted in superior efficacy.
dc.description.departmentPharmacological and Pharmaceutical Sciences, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://hdl.handle.net/10657/2970
dc.language.isoeng
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectPolymyxin B
dc.subjectLiposomes
dc.subjectLipids
dc.subjectLC-MS/MS
dc.subjectPharmacokinetics
dc.subjectEpithelial lining fluid
dc.subjectEfficacy
dc.titlePulmonary Target Delivery of Polymyxin B for Enhanced Efficacy
dc.type.dcmiText
dc.type.genreThesis
thesis.degree.collegeCollege of Pharmacy
thesis.degree.departmentPharmacological and Pharmaceutical Sciences, Department of
thesis.degree.disciplinePharmaceutical Sciences
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.namePharmaceutics

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