Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway.

The antidiabetic drug metformin can diminish apoptosis induced by oxidative stress in endothelial cells and prevent vascular dysfunction even in nondiabetic patients. Here we tested whether it has a beneficial effect in a rat model of gentamicin toxicity. Mitochondrial analysis, respiration intensity, levels of reactive oxygen species, permeability transition, and cytochrome c release were assessed 3 and 6 days after gentamicin administration. Metformin treatment fully blocked gentamicin-mediated acute renal failure. This was accompanied by a lower activity of N-acetyl-beta-D-glucosaminidase, together with a decrease of lipid peroxidation and increase of antioxidant systems. Metformin also protected the kidney from histological damage 6 days after gentamicin administration. These in vivo markers of kidney dysfunction and their correction by metformin were complemented by in vitro studies of mitochondrial function. We found that gentamicin treatment depleted respiratory components (cytochrome c, NADH), probably due to the opening of mitochondrial transition pores. These injuries, partly mediated by a rise in reactive oxygen species from the electron transfer chain, were significantly decreased by metformin. Thus, our study suggests that pleiotropic effects of metformin can lessen gentamicin nephrotoxicity and improve mitochondrial homeostasis.

Recent advances in delivery systems for anti-HIV1 therapy.

In the last years, different non-biological and biological carrier systems have been developed for anti-HIV1 therapy. Liposomes are excellent potential anti-HIV1 carriers that have been tested with drugs, antisense oligonucleotides, ribozymes and therapeutic genes. Nanoparticles and low-density lipoproteins (LDLs) are cell-specific transporters of drugs against macrophage-specific infections such as HIV1. Through a process of protein transduction, cell-permeable peptides of natural origin or designed artificially allow the delivery of drugs and genetic material inside the cell. Erythrocyte ghosts and bacterial ghosts are a promising delivery system for therapeutic peptides and HIV vaccines. Of interest are the advances made in the field of HIV gene therapy by the use of autologous haematopoietic stem cells and viral vectors for HIV vaccines. Although important milestones have been reached in the development of carrier systems for the treatment of HIV, especially in the field of gene therapy, further clinical trials are required so that the efficiency and safety of these new systems can be guaranteed in HIV patients.

Study of the factors influencing the encapsulation of zidovudine in rat erythrocytes.

Antiretroviral-loaded erythrocytes offer a promising therapy against HIV owing to their potential to deliver this kind of drugs to macrophages and reticulo-endothelial (RES) tissues. The aim of the present work was to develop and optimize a hypotonic dialysis method for the encapsulation of the antiretroviral Zidovudine (AZT) in rat erythrocytes. The influence of several factors in the encapsulation was also evaluated. Variables such as the initial AZT concentration, the dialysis time, and the dialysis bag/buffer volume ratio exhibited statistically significant differences in the encapsulation of the drug in erythrocytes. The amount of drug encapsulated was related to the different values of the variables by multiple linear regression. Osmotic fragility and haematological parameters were estimated as indicators of erythrocyte viability. No statistically significant differences in the osmotic fragility profiles of the control and carrier erythrocytes were observed, and this parameter was also independent of the dialysis concentration of AZT, the hypo-osmotic dialysis time, and the dialysis bag/buffer volume ratio. The in vitro release of AZT from carrier erythrocytes pointed to a fast leakage of the drug; however, around 30% of the drug remained encapsulated for a prolonged period of time. Pre-dialysis diamide treatment did not have a significant effect on the encapsulation and release of AZT in erythrocytes.

Increasing the selectivity of amikacin in rat peritoneal macrophages using carrier erythrocytes.

The selectivity of amikacin in macrophages in vitro and its biodistribution in peritoneal macrophages and other tissues were studied in rats using carrier erythrocytes. Amikacin-loaded erythrocytes were prepared using a hypotonic dialysis method. The in vitro uptake of amikacin by peritoneal macrophages was studied using cell monolayers. The in vivo uptake by macrophages and the tissue distribution of amikacin were studied in two groups of rats that received either amikacin in saline solution, or amikacin-loaded erythrocytes. Pharmacokinetic analyses were performed using model-independent methods. The administration of the antibiotic using carrier erythrocytes elicited a higher accumulation in macrophages, both in vitro and in vivo. The tissue pharmacokinetics of amikacin in vivo using carrier erythrocytes revealed an accumulation of the antibiotic in specific tissues such as the liver and spleen. Minor changes in the pharmacokinetics were observed in organs and tissues such as renal cortex and medulla. According to the partition coefficients obtained, the relative uptake of amikacin when carrier erythrocytes were used was: spleen>peritoneal macrophages>liver>lung>renal cortex>renal medulla. Loaded erythrocytes can be seen to be potentially useful for the delivery of aminoglycoside antibiotics in macrophages.

Delivery systems to increase the selectivity of antibiotics in phagocytic cells.

Many infectious diseases are caused by facultative organisms that are able to survive in phagocytic cells. The intracellular location of these microorganisms protects them from the host defence systems and from some antibiotics with poor penetration into phagocytic cells. One strategy used to improve the penetration of antibiotics into phagocytic cells is the use of carrier systems that deliver these drugs directly to the target cell. Delivery systems such as liposomes, micro/nanoparticles, lipid systems, conjugates, and biological carriers such as erythrocyte ghosts may contribute to increasing the therapeutic efficacy of antibiotics and antifungal agents in the treatment of infections caused by intracellular microorganisms. The main objective of this review is to analyze recent advances and current perspectives in the use of antibiotic delivery systems in the treatment of intracellular infections such as mycobacterial infections, brucellosis, salmonellosis, listeriosis, fungal infections, visceral leishmaniasis, and HIV.