Abstract:
:Toxicity and poor adherence to treatment that favors the generation of resistance in the Leishmania parasites highlight the need to develop better alternatives. Here, we evaluated the in vitro effectiveness of hydrazone derived from chromanes 2-(2,3-dihydro-4H-1-benzothiopyran-4-ylidene) hydrazide (TC1) and 2-(2,3-dihydro-4H-1-benzopyran-4-ylidene) hydrazide (TC2) and the mixture of triterpene saponin hederagenin-3-O-(3,4-O-diacetyl-ß-D-xylopyranosyl-(1à3)-a-L- rhamnopyranosyl-(1à2)-a-L-arabinofuranoside, hederagenin-3-O-(3,4-O-diacetyl-a-L- arabinopyranosyl-(1à3)-a-L-rhamnopyranosyl-(1à2)-a-L-arabinofuranoside and, hederagenin-3-O-(4-O-acetyl-ß-D-xylopyranosyl-(1à3)-a-L-rhamnopyranosyl-(1à2)-a-L-arabinofuranoside from Sapindus saponaria (SS) on L. braziliensis and L. pifanoi. Mixtures of TC1 or TC2 with saponin were formulated for topical application and the therapeutic effectiveness was evaluated in the model for cutaneous leishmaniasis (CL) in golden hamster. The mode of action of these compounds was tested on various parasite processes and ultrastructural parasite modifications. TC1, TC2 and SS showed moderate cytotoxicity when tested independently but toxicity was improved when tested in combination. The compounds were more active against intracellular Leishmania amastigotes. In vivo studies showed that combinations of TC1 or TC2 with SS in 1:1 ratio (w/w) cured 100% of hamsters with no signs associated with toxicity. The compounds did cause changes in the mitochondrial activity of the parasite with a decrease in ATP levels and depolarization of membrane potential and overproduction of reactive oxygen species; nevertheless, these effects were not related to alterations in membrane permeability. The phagolysosome ultrastructure was also affected impacting the survival of Leishmania but the function of the lysosome nor the pH inside the phagolysosome did not change. Lastly, there was a protease inhibition which was directly related to the decrease in the ability of Leishmania to infect and multiply inside the macrophage. The results suggest that the combination of TC1 and TC2 with SS in a 1:1 ratio is capable of curing CL in hamsters. This effect may be due to the ability of these compounds to affect parasite survival and the ability to infect new cells.
journal_name
Int J Parasitol Drugs Drug Resistauthors
Upegui Zapata YA,Echeverri F,Quiñones W,Torres F,Nacher M,Rivas LI,Meira CDS,Gedamu L,Escobar G,Archbold R,Vélez ID,Robledo SMdoi
10.1016/j.ijpddr.2020.06.004subject
Has Abstractpub_date
2020-08-01 00:00:00pages
94-106issn
2211-3207pii
S2211-3207(20)30017-8journal_volume
13pub_type
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journal_title:International journal for parasitology. Drugs and drug resistance
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journal_title:International journal for parasitology. Drugs and drug resistance
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journal_title:International journal for parasitology. Drugs and drug resistance
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journal_title:International journal for parasitology. Drugs and drug resistance
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journal_title:International journal for parasitology. Drugs and drug resistance
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journal_title:International journal for parasitology. Drugs and drug resistance
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journal_title:International journal for parasitology. Drugs and drug resistance
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journal_title:International journal for parasitology. Drugs and drug resistance
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journal_title:International journal for parasitology. Drugs and drug resistance
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abstract:OBJECTIVES:This study evaluated the implications of clinically acquired miltefosine resistance (MIL-R) by assessing virulence in mice and sand flies to reveal the potential of MIL-R strains to circulate. METHODS:Experimental infections with the MIL-R clinical Leishmania infantum isolate MHOM/FR/2005/LEM5159, having a ...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2020.04.004
更新日期:2020-08-01 00:00:00