The liver is known as one of the main organisms in the human's body and the key place for excretion and metabolism, which plays various roles in synthetizing proteins, detoxification, and producing the biochemical compounds essential for digestion system. Liver diseases are considered as one of the major causes of morbidity and mortality in human in the world; furthermore, it seems that hepatotoxicity due to drugs is the most common cause of the death. The damaged structural integrity of the liver increases serum levels of transaminases (AST and ALT) and ALP because they are usually found in the cytoplasm and released into the circulation system during cellular damage (13).
Nephrotoxicity due to the drugs is usually associated with their accumulation in the renal cortex, their affinity to kidneys and kinetics of the drug trapping process (14). Aminoglycoside nephrotoxicity is functionally expressed by the reduced capacity of the urinary concentration, lysosomal enzymuria, reduced ammonium excretion, mild glycosuria, tubular proteinuria, and dropping glomerular filtration rate (GFR). About 8% to 26% of patients receiving aminoglycosides for more than 7 to 10 days developed a mild renal injury, which was nearly at all times reversible (14, 15). Gentamicin, which is a typical aminoglycoside antibiotic, is extensively used in the clinical practices. Nephrotoxicity induced by gentamicin is characterized by direct tubular necrosis, without morphological changes in glomerular structures (14).
The use of liposomes in the pharmaceutical industries caused a considerable improvement, particularly through controlling and increasing the drug level in the body and its side effects and the dosage reduction (16). In general, liposomal formulation compared with the normal formulation increases the penetration of drugs into the skin. Also, the drug-delivery systems would be more stable and targeted (9). The concentrations of phospholipid and the existence of polyunsaturated fatty acids in the liposomes are among the effective factors on the severity of the penetration of drugs into the skin. Liposomes not only can pass through subcutaneous tissue, but also they can enter the systemic blood stream. One of the reasons for the application of the liposome in topical medication formulation is that phospholipid existing in the structure of the liposomes can penetrate the lipid compounds of the skin and can be released on the inside of the subcutaneous tissue, and as a result of interaction with them and the combination of liposomal phospholipid with lipids contained in the membranous skin layers, the membrane fluidity of the skin is impaired, and skin defensive characteristics reduce.
Penetration of hydrophilic drugs into the skin is difficult, because the nature of the skin is lipophilic (9). Since the liposomes size in the liposomal formulation containing paromomycin sulfate is very fine, they may enter the bloodstream through the epidermis by passing the derma. These particles when enter the bloodstream are phagocytosed by Kupffer cells in the liver and splenic macrophage (12). Aminoglycosides cause proximal tubular injury and necrosis and renal dysfunction. About 10% of kidney problems are associated with the use of these drugs (15). Paromomycin like all aminoglycoside antibiotics inhibits the biosynthesis of proteins in the living organisms. Its antileishmanial activity was discovered in 1960. Also, its antileishmanial activity was reported in the clinical tests versus both forms of visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL).
In Jaafari et al. (12) in vivo study, results in BALB/c mice infected with L. major showed that using topical formulations containing paromomycin sulfate induced a significantly smaller size lesion and lower spleen parasite burden than the control groups and PMS cream. It is speculated that after topical application of PMS formulations, at least some of the vesicles, especially those with smaller than 100 nm, pass through subcutaneous tissue of intact skin and reach the bloodstream.
In this study, topical PMS liposomes prepared by the fusion method plus homogenization provided liposomes of submicron sizes. Analysis of the particle size distribution showed that the average size of LPMFs was less than 100 nm. To comment on the liver toxicity, tests for ALK, AST, ALT showed nanoliposome formulations containing paromomycin sulfate with 10% concentration in the group study had no significant difference in this enzyme compared with the control group and negative control groups during the three time periods, (10,20, and 30 days) and this indicates no drug hepatotoxicity in rats. On the contrary, increase in enzymes AST, ALK, and ALT particularly indicates liver toxicity. It can be concluded that nanoliposomal formulation of paromomycin sulfate after topical application and systemic absorption has no toxic effects on liver cells.
Also for assessing nephrotoxicity, evaluation of creatinine and BUN levels showed that liposomal formulation of paromomycin sulfate did not make significant changes in BUN and creatinine levels. BUN and creatinine serum are the most common lab indicators of renal function. BUN like creatinine is directly excreted by the kidneys. Renal normal function and normal serum creatinine levels should remain constant. Therefore, we can talk with more certainty about the effect of nanoliposomal formulations of paromomycin in kidney and liver of rats.
Furthermore, examination of histopathological effects on the liver and kidney are necessary. The pathological result of the liver showed that the negative control group compared with the control group in periods of 10, 20, and 30 days, had a normal structure. Positive control group during the periods of 10 and 20 days did not show changes in the liver compared with the control group and negative control groups. In 30-day period, in the positive group compared with the control and control negative groups, changes as cell swelling were observed, which were reversible and negligible. Histopathological results of the kidney showed that structure of negative control and positive control groups compared with control group had not changed in the periods of 10 and 20 days is normal. The group receiving nanoliposomal paromomycin sulfate in the 30-day period was compared with the control and negative control groups and mild tubular necrosis was seen in the kidney.
Considering that previous studies have approved the effectiveness of the formulation of nanoliposomal formulation containing paromomycin sulfate on leishmania as well as topical use of this formulation cured the wounds relatively and reduced the microbial load of the spleen due to the systemic absorption of part of the drug; therefore, the possibility existed that it causes toxicity. Accordingly, this study examined renal and hepatic toxicity caused by topical formulation of nanoliposomal formulation containing paromomycin. The results showed that the short-term use of nanoliposomal topical formulations containing paromomycin sulfate formulations for treatment of the CL has not created certain toxicity in kidney and liver, but its long-term use leads to mild renal tubular necrosis and reversible cell swelling in the liver. Therefore, it should be used with caution during long-term treatments.
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