Eficacia terapéutica de diferentes regímenes de administración de la anfotericina B liposomal en un modelo animal experimental de aspergilosis pulmonar invasora
In recent years, great advances have been produced in the treatment of invasive pulmonary aspergillosis. However, current treatment recommendations still show suboptimal rates of success underlining the need for better therapies. A possible new strategy adressed to increase therapeutic success might be based on new ways to administer currently available antifungals.
Liposomal amphotericin B has a therapeutic window wider than amphotericin deoxycholate as it has a rate of adverse effects lower than the conventional formulation. This work explores the efficacy of new ways of administration of liposomal amphotericin B addressed to increase its concentration at the primary focus of infection, the pulmonary tissue. With this purpose, an experimental model of invasive pulmonary aspergillosis in steroid-immunosuppressed rats was used. Survival, pulmonary weight (as indirect marker of tissue damage), and fungal load (colony forming units and chitin quantification) were used as endpoints to evaluate the efficacy of treatments.
In a first set of experiments, differences between 1 mg/kg/day of amphotericin B deoxycholate (d-AmB) and scalated does of liposomal amphotericin B (L-AmB; dose range: 3, 5, and 10 mg/kg/day) given intravenously were evaluated. All treatment regimens improved the survival of animals as compared to untreated controls, but only rats treated with the highest dose of L-AmB also achieved a significant reduction of pulmonary weight and fungal load as compared to controls, d-AmB or L-AmB 3 mg/kg.
The second set of experiments was intended to assess the efficacy of the administration of high loading doses of L-AmB (10 mg/kg for 3 or 4 days) discontinuated or followed by lower maintenance doses (3 mg/kg/day until the end of the treatment). Strategies based on the infusion of high loading doses resulted in a significant improvement of survival and reduced pulmonary weight as compared to the untreated control group. Groups that received low maintenance doses, also showed a significant reduction of lung weight compared to d-AmB. A trend to a reduction of the fungal load was seen in groups that received loading doses but this reduction reached statistical significance as compared to controls in the group treated with 10 mg/kg 4 days plus 3 mg/kg/day until completion of the treatment period.
In a third set of experiments, the efficacy of aerosolized delivery of d-AmB and L-Amb, and the effectiveness of the coadministration of intravenous and nebulized L-AmB were studied. Aerosolized administration prolonged significantly the survival and reduced the pulmonary weight of animals as compared to untreated controls and intravenous d-AmB. They also reduced the fungal load, but the reduction, in terms of chitin content, was significant as compared to controls only in animals receiving nebulized L-AmB alone or associated to intravenous L-AmB. Combined intravenous plus nebulized administration of L-AmB did not performed better than aerosolized L-Amb alone.
From the global of this work, the following conclusions can be drawn: (1) the animal model of invasive pulmonary aspergillosis in steroid-immunosuppressed rats is useful in studies of therapeutic efficacy. (2) Liposomal amphotericin B displays a dose-efficacy relationship. (3) Administration of high loading doses is a valid strategy for the treatment of invasive pulmonary aspergillosis although the duration of the initial loadinf treatment cannot be inferred from this work. (4) Administration of nebulized amphotericin B, particularly L-AmB, can be useful for the treatment of invasive pulmonary aspergillosis. (5) Coadministration of intravenous plus nebulized amphotericin B seems a wise approach to the treatment of invasive pulmonary aspergillosis given that it is difficult to discard the possibility of a extrapulmonary dissemination in humans.
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Advisor:Pahissa i Berga, Albert; Gavaldà i Santapau, Joan
School:Universitat Autónoma de Barcelona
Source Type:Master's Thesis
Keywords:417 departament de medicina
Date of Publication:11/28/2007