Pharmacokinetics, toxicity, and efficacy of liposomal capreomycin in disseminated Mycobacterium avium beige mouse model

Abstract

Capreomycin was incorporated into multilamellar vesicles of pure dipalmitoylphosphatidylcholine. The pharmacokinetics and nephrotoxicity of capreomycin in the free and liposomal forms were studied in normal mice. The efficacies of the two forms were evaluated by using the Mycobacterium avium complex beige mouse model. Approximately 107 viable M. avium cells were injected intravenously. Seven days later, treatment with either liposomal or free capreomycin at 60 or 120 mg/kg of body weight was administered daily for 5 days. Mice were sacrificed 5 days after the end of treatment, and the viable bacteria in liver, spleen, lungs, and blood were counted. After 5 days of treatment with dosages of 60 or 120 mg/kg/day, the level of blood urea nitrogen increased in the group treated with free capreomycin but not in the group treated with liposomal capreomycin. After intravenous injection of 120 mg/kg, liposomes enhanced the diffusion of capreomycin in the spleen, lungs, and kidneys and increased the half-life in serum. The 120-mg/kg dose of liposomal capreomycin significantly reduced the number of viable mycobacteria in the liver, spleen, and blood compared with those in the controls. Although these results are promising, further studies are needed to assess the efficacy of liposomal capreomycin for the treatment of M. avium complex infections.Since the appearance of the human immunodeficiency virus (HIV), the incidence of Mycobacterium avium complex (MAC) infections has increased considerably and has involved between 18 and 50% of HIV-infected patients (17,24,33). Treatment is difficult because of the weakened immune defense system of the host and the resistance of MAC strains to many classic antituberculous agents. Moreover, the phenotypes of resistance of these strains are very heterogeneous (25,26,49).Experimental infection models involving animal or human macrophage cultures and acute or chronic infections in the mouse have been developed to assess the activities of antiinfectious agents against MAC (32). Numerous studies have been performed either in vitro (25,28,36,49) or on macrophages (46) and in animal models (6,21,34,38,39) with classic or more recent antituberculous agents (ciprofloxacin, sparfloxacin, azithromycin, and clarithromycin) alone or in combi-

Unilamellar vesicles as potential capreomycin sulfate carriers: Preparation and physicochemical characterization

“…These results, confirmed by IR measurements, demonstrated that DSPC may represent a more suitable phospholipid carrier for this peptide than DPPC and HPC do. The proved effectiveness in mice, 7 the relative stability and homogeneity of these preparations (in particular, DSPC vesicles), and the CS activity against multidrug-resistant bacteria strains 9 make these formulations worthy of being tested, after appropriate modification if needed, for a possible aerosol application.…”

“…16 This noninvasiveness allows the improvement of patience compliance. Looking at this alternative therapeutic application and considering the remarkable in vivo results, 7 we investigated large unilamellar vesicles (LUVs) as potential CS carriers for possible peptide pulmonary delivery. In fact, LUVs may be more suitable for this particular application because, compared with MLVs, they are smaller and their size can be better controlled and homogenized.…”

“…In particular, it has been demonstrated that entrapment of CS in multilamellar vesicles (MLVs) reduced renal toxicity, enhanced peptide penetration into tissues, and increased CS activity in a beige mouse model of M avium complex infection. 7 Pulmonary administration of aerosolized liposomes represents a valid alternative route for topical drug delivery for lung infection treatments. [10][11][12][13][14] The advantages of such an administration route are (1) facilitated administration of sustained-release formulations to maintain therapeutic drug levels in the lungs, (2) aqueous compatibility, and (3) facilitated intracellular delivery, particularly to alveolar macrophages and lymphocytes.…”

Efforts Towards the Development of New Antitubercular Agents: Potential for Thiolactomycin Based Compounds

“…Capreomycin 12 also belongs to this class of antibiotic, which is given in combination with other antibiotics for treating tuberculosis ( Figure 3). Unfortunately, it exhibits adverse effects including nephrotoxicity and eighth cranial nerve toxicity (55).…”

Mouse Model for Efficacy Testing of Antituberculosis Agents via Intrapulmonary Delivery

“…INH, an orally administered drug, and the parenteral anti-TB drugs capreomycin and amikacin were chosen to validate the efficacy of intrapulmonary aerosol delivery versus that of standard routes of administration in mice experimentally infected with M. tuberculosis. All three drugs are currently used for human TB treatment and have been extensively studied in the murine model of TB infection used for drug testing (1,(5)(6)(7)(17)(18)(19). The purpose of this work is to obtain an in vivo proof of concept to demonstrate that when drugs are administered locally via intrapulmonary aerosol delivery to mice chronically infected with M. tuberculosis, they can have efficacy similar to that seen when drugs are administered by their standard route of administration (by injection or oral gavage), even when given at a lower dose and dosing frequency.…”