In vitro interaction between paromomycin sulphate and four drugs with leishmanicidal activity against three New World Leishmania species

Morais-Teixeira, Eliane de; Gallupo, Mariana Kolos; Rodrigues, Lucas Fonseca; Romanha, Álvaro J.; Rabello, Ana

doi:10.1093/jac/dkt318

Cited by 39 publications

(31 citation statements)

References 20 publications

(12 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Benaim et al (47) demonstrated the specific antiparasitic effects of amiodarone and the synergistic effects of combinations with posaconazole against Trypanosoma cruzi, in vitro and in vivo; similar effects were more recently reported for Leishmania mexicana and miltefosine (48). There is a growing recognition of the relevance of combination therapies to address several limitations of currently available antiLeishmania drugs, including toxicity as well as natural and acquired drug resistance (1,3,(49)(50)(51)(52). Indeed, several studies have reported the superior efficacies of combination therapies against leishmaniasis, and some of them demonstrated the synergic effects of combinations of amphotericin B with other available drugs, such as miltefosine, paromomycin, meglumine antimoniate, or azythromycin (49)(50)(51)(52).…”

Section: Discussionmentioning

confidence: 75%

“…There is a growing recognition of the relevance of combination therapies to address several limitations of currently available antiLeishmania drugs, including toxicity as well as natural and acquired drug resistance (1,3,(49)(50)(51)(52). Indeed, several studies have reported the superior efficacies of combination therapies against leishmaniasis, and some of them demonstrated the synergic effects of combinations of amphotericin B with other available drugs, such as miltefosine, paromomycin, meglumine antimoniate, or azythromycin (49)(50)(51)(52). The remarkable in vitro antiproliferative synergism against both proliferative stages of L. amazonensis of combinations of ITZ and POSA with E5700 observed in this work, and its correlate with the effects of the drugs on promastigote free sterol composition, confirms the notion that drugs acting at sequential steps of a metabolic pathway should have synergistic effects (25).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis

Macedo-Silva

Visbal

Urbina

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

e Leishmaniases comprise a spectrum of diseases caused by protozoan parasites of the Leishmania genus. Treatments available have limited safety and efficacy, high costs, and difficult administration. Thus, there is an urgent need for safer and more-effective therapies. Most trypanosomatids have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. In previous studies, we showed that Leishmania amazonensis is highly susceptible to aryl-quinuclidines, such as E5700, which inhibit squalene synthase, and to the azoles itraconazole (ITZ) and posaconazole (POSA), which inhibit C-14␣-demethylase. Herein, we investigated the antiproliferative, ultrastructural, and biochemical effects of combinations of E5700 with ITZ and POSA against L. amazonensis. Potent synergistic antiproliferative effects were observed against promastigotes, with fractional inhibitory concentration (FIC) ratios of 0.0525 and 0.0162 for combinations of E5700 plus ITZ and of E5700 plus POSA, respectively. Against intracellular amastigotes, FIC values were 0.175 and 0.1125 for combinations of E5700 plus ITZ and E5700 plus POSA, respectively. Marked alterations of the ultrastructure of promastigotes treated with the combinations were observed, in particular mitochondrial swelling, which was consistent with a reduction of the mitochondrial transmembrane potential, and an increase in the production of reactive oxygen species. We also observed the presence of vacuoles similar to autophagosomes in close association with mitochondria and an increase in the number of lipid bodies. Both growth arrest and ultrastructural/biochemical alterations were strictly associated with the depletion of the 14-desmethyl endogenous sterol pool. These results suggest the possibility of a novel combination therapy for the treatment of leishmaniasis.

show abstract

Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis

Macedo-Silva

Visbal

Urbina

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Recently, it was reported that the association of AMB and allicin, a natural product present in plants of the family Alliaceae, was synergistic for Leishmania infantum and L. donovani (43). It has also been demonstrated that AMB has a synergistic effect when used in association with paromomycin against L. amazonensis, Leishmania braziliensis, and L. infantum in vitro (44). This effect demonstrates the potential for developing drug associations that are effective against microorganisms, particularly when using AMB.…”

Section: Discussionmentioning

confidence: 83%

Resveratrol Is Active against Leishmania amazonensis: In Vitro Effect of Its Association with Amphotericin B

Ferreira

Soares

Nascimento

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Resveratrol is a polyphenol found in black grapes and red wine and has many biological activities. In this study, we evaluated the effect of resveratrol alone and in association with amphotericin B (AMB) against Leishmania amazonensis. Our results demonstrate that resveratrol possesses both antipromastigote and antiamastigote effects, with 50% inhibitory concentrations (IC 50 s) of 27 and 42 M, respectively. The association of resveratrol with AMB showed synergy for L. amazonensis amastigotes, as demonstrated by the mean sums of fractional inhibitory index concentration (mean ⌺FIC) of 0.483, although for promastigotes, this association was indifferent. Treatment with resveratrol increased the percentage of promastigotes in the sub-G 0 /G 1 phase of the cell cycle, reduced the mitochondrial potential, and showed an elevated choline peak and CH 2 -to-CH 3 ratio in the nuclear magnetic resonance (NMR) spectroscopy analysis; all these features indicate parasite death. Resveratrol also decreased the activity of the enzyme arginase in uninfected and infected macrophages with and without stimulation with interleukin-4 (IL-4), also implicating arginase inhibition in parasite death. The anti-Leishmania effect of resveratrol and its potential synergistic association with AMB indicate that these compounds should be subjected to further studies of drug association therapy in vivo.

show abstract

“…Moreover, AmpB shows effective antileishmanial activity against different Leishmania spp. species that have clinical relevance in the Americas, such as L. infantum, L. braziliensis and L. amazonensis (28) . However, the clinical use of AmpB has been limited due to its high toxicity, which can cause such clinical symptoms in patients as nephrotoxicity, cardiac alterations, hemolysis and liver damage, as well as nausea and fever (29) (30) .…”

Section: Amphotericin B and Its Delivery Systems For The Treatment Ofmentioning

confidence: 99%

New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment

Chávez-Fumagalli

Ribeiro

Castilho

et al. 2015

Rev. Soc. Bras. Med. Trop.

View full text Add to dashboard Cite

Leishmaniasis is one of the six major tropical diseases targeted by the World Health Organization. It is a life-threatening disease of medical, social and economic importance in endemic areas. No vaccine is yet available for human use, and chemotherapy presents several problems. Pentavalent antimonials have been the drugs of choice to treat the disease for more than six decades; however, they exhibit high toxicity and are not indicated for children, for pregnant or breastfeeding women or for chronically ill patients. Amphotericin B (AmpB) is a second-line drug, and although it has been increasingly used to treat visceral leishmaniasis (VL), its clinical use has been hampered due to its high toxicity. This review focuses on the development and in vivo usage of new delivery systems for AmpB that aim to decrease its toxicity without altering its therapeutic efficacy. These new formulations, when adjusted with regard to their production costs, may be considered new drug delivery systems that promise to improve the treatment of leishmaniasis, by reducing the side effects and the number of doses while permitting a satisfactory cost-benefit rati

show abstract

In vitro interaction between paromomycin sulphate and four drugs with leishmanicidal activity against three New World Leishmania species

Abstract: This work provides a preclinical dataset that supports future studies on multidrug treatment schedules against New World leishmaniasis.

Cited by 39 publications

References 20 publications

Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis

Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis

Resveratrol Is Active against Leishmania amazonensis: In Vitro Effect of Its Association with Amphotericin B

New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment

Contact Info

Product

Resources

About