Therapy of Mycobacterium avium complex infections in beige mice with streptomycin encapsulated in sterically stabilized liposomes

Mycobacterium avium complex (MAC) causes serious opportunistic infections in AIDS patients. Previous studies with MAC-infected beige mice have indicated that weekly administration of liposome-encapsulated streptomycin can reduce significantly the CFU in the liver and spleen. We examined whether streptomycin encapsulated in recently developed sterically stabilized liposomes with prolonged circulation times would have a therapeutic effect in this animal model. Two liposome types with prolonged circulation (polyethyleneglycol-distearoylphosphatidylethanolamine [PEG-DSPE]- distearoylphosphatidylcholine [DSPC]-cholesterol [chol] or phosphatidylinositol [PI]-DSPC-chol) and conventional liposomes (phosphatidylglycerol [PG]-phosphatidylcholine [PC]-chol) encapsulating streptomycin and administered twice weekly were bactericidal to MAC strain 101 in the spleen when the level of infection after treatment was compared with the level of infection before treatment. PI-DSPC-chol and PG-PC-chol liposomes encapsulating streptomycin were bactericidal in the liver. Although PG-PC-chol or PEG-DSPE-DSPE-chol liposomes encapsulating streptomycin were not bactericidal in the lungs, they reduced the level of MAC infection by more than 3 orders of magnitude compared with the level of MAC infection in untreated controls

Treatment of intracellular Mycobacterium avium complex infection by free and liposome-encapsulated sparfloxacin

Mycobacterium avium-M. intracellulare complex (MAC) is the most frequent cause of opportunistic bacterial infection in patients with AIDS. Previous studies have indicated that liposome-encapsulated aminoglycosides are highly effective in treating MAC infections in mice. We investigated whether the fluoroquinolone sparfloxacin is effective in treating MAC infection in the murine macrophage-like cell line J774. Sparfloxacin was encapsulated in the membrane phase of multilamellar liposomes composed of phosphatidylglycerol-phosphatidylcholine-cholesterol (1:1:1 molar ratio). MAC-infected macrophages were treated for either 24 h or 4 days with free or liposome-encapsulated sparfloxacin. Treatment with free or liposome- encapsulated sparfloxacin (6 μg/ml) for 24 h resulted in the reduction of the growth index to 25 and 30% of that of untreated controls, respectively. When cultures were treated for 4 days, free sparfloxacin reduced the growth index to 6% of that of the untreated control, while liposome-encapsulated sparfloxacin reduced it to 8% of that of the control

Enhanced effect of liposome-encapsulated amikacin on Mycobacterium avium-M. intracellulare complex infection in beige mice

We examined the therapeutic effects of free and liposome-encapsulated amikacin on Mycobacterium avium-M. intracellulare complex infection by using the beige-mouse model of the disease. In the first series of studies, intravenous administration of four weekly doses of 5 mg of amikacin per kg encapsulated in large (approximately 0.4-μm diameter), unilamellar liposomes arrested the growth of M. avium-M. intracellulare complex organisms in the liver, as measured by CFU counts. M. avium-M. intracellulare complex levels in untreated animals and in those treated with the same dose of free amikacin increased by several orders of magnitude over 8 weeks. Liposome-encapsulated amikacin was also effective against M. avium-M. intracellulare complex organisms in the spleens and kidneys, reducing the CFU counts by about 1,000-fold compared with those of both untreated controls and free-drug-treated mice. In the lungs, a slight reduction in CFU was observed in the liposome-encapsulated-amikacin-treated group, but only at the 8-week point. Neither free nor liposome-encapsulated amikacin reduced the colony counts in the lymph nodes compared with those of control animals. Reductions in CFU in all organs greater than those caused by the liposome preparation could be achieved by intramuscular administration of free amikacin, but only at a 10-fold-higher dose given 6 days a week for 8 weeks. In the second series of studies, we investigated the effects of (i) doubling the dose of liposome-encapsulated amikacin and (ii) increasing the size of the liposomes and prolonging the treatment to five injections. Administration of 10 mg of amikacin per kg in liposomes 2 to 3 μm in diameter was more effective in the liver than 5 or 10 mg of amikacin per kg in liposomes 0.2 μm in diameter. A slight reduction in the CFU levels in the lungs was observed with the higher dose, irrespective of liposome size. Our results indicate that liposome-based delivery of amikacin enhances its anti-M. avium-M. intracellulare complex activity, particularly in the liver, spleen, and kidney, and may therefore improve the therapy of this disease

Therapy of Mycobacterium avium complex infections in beige mice with streptomycin encapsulated in sterically stabilized liposomes

Mycobacterium avium complex (MAC) causes serious opportunistic infections in AIDS patients. Previous studies with MAC-infected beige mice have indicated that weekly administration of liposome-encapsulated streptomycin can reduce significantly the CFU in the liver and spleen. We examined whether streptomycin encapsulated in recently developed sterically stabilized liposomes with prolonged circulation times would have a therapeutic effect in this animal model. Two liposome types with prolonged circulation (polyethyleneglycol-distearoylphosphatidylethanolamine [PEG-DSPE]- distearoylphosphatidylcholine [DSPC]-cholesterol [chol] or phosphatidylinositol [PI]-DSPC-chol) and conventional liposomes (phosphatidylglycerol [PG]-phosphatidylcholine [PC]-chol) encapsulating streptomycin and administered twice weekly were bactericidal to MAC strain 101 in the spleen when the level of infection after treatment was compared with the level of infection before treatment. PI-DSPC-chol and PG-PC-chol liposomes encapsulating streptomycin were bactericidal in the liver. Although PG-PC-chol or PEG-DSPE-DSPE-chol liposomes encapsulating streptomycin were not bactericidal in the lungs, they reduced the level of MAC infection by more than 3 orders of magnitude compared with the level of MAC infection in untreated controls

Differential effects of free and liposome encapsulated amikacin on the survival of Mycobacterium avium complex in mouse peritoneal macrophages

Liposome-encapsulated amikacin shows significantly greater inhibitory activity against the survival of Mycobacterium avium complex inside mouse peritoneal macrophages than the free drug. Similar results were obtained whether the drug was added simultaneously with, 48 h prior to, or 48 h after the addition of mycobacteria to the macrophages. These observations support the hypothesis that the in vivo intravenous delivery of liposome-encapsulated amikacin results in the localization of the antibiotic in phagosomes containing mycobacteria inside resident macrophages of the liver and spleen. © 1990

Efficacy of liposomal budesonide in experimental asthma

Background: Inhaled corticosteroids, such as budesonide, attenuate the inflammatory response in asthma. However, patient noncompliance and side effects of available inhaled corticosteroids limit their use. Liposomes are currently used in medicine to deliver a variety of drugs. Objective: The objective of our study was to determine whether weekly therapy with budesonide encapsulated in sterically stabilized (stealth) liposomes would be comparable to daily budesonide therapy in reducing allergic inflammation. Methods: Ovalbumin-sensitized C57/Black 6 mice received aerosolized (1) budesonide encapsulated in stealth or conventional liposomes, administered weekly, (2) budesonide (without liposomes), administered either daily or weekly, or (3) empty stealth liposomes, administered weekly. All treatment groups were compared with sensitized untreated or unsensitized mice. Histopathologic examination of the lung tissues and measurements of eosinophil peroxidase activity, peripheral blood eosinophil counts, and total serum IgE levels were done weekly for 4 weeks. Results: Weekly therapy with budesonide encapsulated in stealth liposomes was as effective as daily budesonide therapy in decreasing lung inflammation and lowering eosinophil peroxidase activity, peripheral blood eosinophils, and total serum IgE levels. In none of the other groups was there a significant decrease in the inflammatory parameters evaluated. Conclusion: We conclude that weekly therapy with budesonide encapsulated in stealth liposomes is as effective as daily budesonide in reducing markers of lung inflammation in experimental asthma. This novel strategy offers an effective alternative to standard daily budesonide therapy in asthma and has the potential to reduce toxicity and improve compliance

Chemotherapeutic potential of free and liposome encapsulated streptomycin against experimental mycobacterium avium complex infections in beige mice

We investigated in two experiments the chemotherapeutic role of streptomycin on the progression of Mycobacterium avium complex (MAC) disease in beige mice. In the first experiment, streptomycin 100 mg/kg given intramuscularly (im) five days a week for four weeks caused a significant reduction of the colony forming unit (cfu) counts of MAC from spleen, lungs and liver. In the same experiment, streptomycin, given in an encapsulated form in multilamellar liposomes at 15 mg/kg in two intravenous (iv) injections caused greater reduction of cfu in the three tissues. In the second experiment, the effect of free streptomycin at 150 mg/kg given im five days a week for eight weeks was compared with 15 mg/kg of streptomycin encapsulated in unilamellar liposomes given iv in four injections (one day and at three weekly intervals) with no further treatment within the eight weeks. Similar results as in the first experiment were obtained. In both experiments, liposome encapsulation resulted in several-fold increase in the chemotherapeutic efficacy when the data was expressed as reduction of cfu counts per unit dose of the drug. © 1991, by The British Society for Antimicrobial Chemotherapy

Liposome-mediated therapy of human immunodeficiency virus type-1 and mycobacterium infections

We review our recent work on the use of liposomes for the delivery of antiviral agents to human immunodeficiency virus type-1 (HIV-1) infected cells, and antimycobactcrial drugs to cells harboring Mycobacterium avium complex or Mycobacterium tuberculosis. Soluble CD4 has been used to target liposomes to HIV-1-infected cells. Antisense oligodeoxynucleotides have been effectively delivered into HIV-1-infected macrophages using pH-sensitive liposomes. pH-sensitive liposomes with serum stability are being developed as in vivo delivery vehicles. Liposomes encapsulating an HIV-1 protease inhibitor were more effective in inhibiting virus production in infected macrophages than the free drug. Anionic liposomes were found to inhibit HIV-1 infectivity, while cationic liposomes had a differential toxicity for HIV-1-infected macrophages. Lipophilic sulfated cyclodextrins have been synthesized as novel antiviral agents. Liposome-encapsulated ciprofloxacin treatment reduced the number of viable M. avium in macrophages more than the free antibiotic. Liposome-encapsulated paromomycin and sparfloxacin were effective against M. tuberculosis inside macrophages, including multi-drug-resistant strains. Streptomycin encapsulated in liposomes and delivered intravenously or subcutaneously reduced the number of viable M. tuberculosis in infected mice and prevented mortality. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted