title: Rifabutin encapsulated in liposomes exhibits increased therapeutic activity in a model of disseminated tuberculosis.
abstract: Tuberculosis (TB) is a leading cause of death amongst infectious diseases. The low permeation of antimycobacterial agents and their difficult access to infected macrophages necessitate long-term use of high drug doses. Liposomes preferentially accumulate in macrophages, increasing the efficacy of antibiotics against intracellular parasites. In the present work, several rifabutin (RFB) liposomal formulations were developed and characterised and their in vivo profile was compared with free RFB following intravenous administration. With the RFB liposomal formulations tested, higher concentrations of the antibiotic were achieved in liver, spleen and lungs 24h post administration compared with free RFB. The concentration of RFB in these organs was dependent on the rigidity of liposomal lipids. The liposomal RFB formulation prepared with dipalmitoyl phosphatidylcholine:dipalmitoyl phosphatidylglycerol (DPPC:DPPG) was the most effective and was selected for biological evaluation in a mouse model of disseminated TB. Compared with mice treated with free RFB, mice treated with the DPPC:DPPG RFB formulation exhibited lower bacterial loads in the spleen (5.53 log(10) vs. 5.18 log(10)) and liver (5.79 log(10) vs. 5.41 log(10)). In the lung, the level of pathology was lower in mice treated with encapsulated RFB. These results suggest that liposomal RFB is a promising approach for the treatment of extrapulmonary TB in human immunodeficiency virus co-infected patients.
authors.affiliation: Unidade Novas Formas de Agentes Bioactivos, Departamento de Biotecnologia, Instituto Nacional de Engenharia Tecnologia e Inovação, I.P., Estrada do Paço do Lumiar, 22, 1649-038 Lisboa, Portugal. Manuela.Gaspar@ineti.pt
authors.forename: M M
authors.initials: MM
authors.lastname: Gaspar
authors.forename: A
authors.initials: A
authors.lastname: Cruz
authors.forename: A F
authors.initials: AF
authors.lastname: Penha
authors.forename: J
authors.initials: J
authors.lastname: Reymão
authors.forename: A C
authors.initials: AC
authors.lastname: Sousa
authors.forename: C V
authors.initials: CV
authors.lastname: Eleutério
authors.forename: S A
authors.initials: SA
authors.lastname: Domingues
authors.forename: A G
authors.initials: AG
authors.lastname: Fraga
authors.forename: A Longatto
authors.initials: AL
authors.lastname: Filho
authors.forename: M E M
authors.initials: ME
authors.lastname: Cruz
authors.forename: J
authors.initials: J
authors.lastname: Pedrosa
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002626:Chemistry, Pharmaceutical; D008081:Liposomes; D008099:Liver / Q000737:chemistry / Q000382:microbiology; D008168:Lung / Q000737:chemistry / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D017828:Rifabutin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013154:Spleen / Q000737:chemistry / Q000382:microbiology; D013997:Time Factors; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D008081:Liposomes; D017828:Rifabutin