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

Tgf-Β1 Expression Is Reduced In Hydrocephalic H-Tx Rat Brain

Transforming growth factor-β1 (TGF-β1) is a cytokine with diverse biological effects. Overexpression of TGF-β1 in mice has been shown to induce progressive hydrocephalus. We have used a quantitative RT-PCR method to analyze the TGF-β1 expression in the brains of H-Tx rat, a model of congenital hydrocephalus. Our studies have shown that rather than increased expression, the 3- and 10-day hydrocephalic H-Tx rats have significantly lower TGF-β1 levels than their normal siblings (p \u3c0.01). This difference became insignificant in the 21-day group. Besides, both hydrocephalic and normal H-Tx rats have significantly lower TGF-β1 levels in all three age groups of 3-, 10- and 21-days than SD control rats (p \u3c0.01 in all three groups) although the difference tends to become less significant with development. We also tested the expression of another cytokine, the epidermal growth factor, and observed a similar reduction. This suggests that the TGF- β1 expression change is not unique to the development of hydrocephalus in this rat model. Our hypothesis is that the TGF-β1 expression decrease in the H-Tx rat is not the cause of the disease. Rather it might be the result of feedback inhibition by increase in the expression of the gene it regulates, including an extracellular matrix component. Effort is currently being made to test this hypothesis

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