Effectiveness of the local or oral delivery of the novel naphthopterocarpanquinone LQB-118 against cutaneous leishmaniasis

Cunha-Júnior, Edézio Ferreira; Pacienza-Lima, Wallace; Ribeiro, Grazielle Alves; Netto, Chaquip D.; Canto‐Cavalheiro, Marilene M.; Silva, Alcides José Monteiro da; Costa, Paulo R. R.; Rossi-Bergmann, Bartira; Torres-Santos, Eduardo Caio

doi:10.1093/jac/dkr158

Cited by 36 publications

(29 citation statements)

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“…The pterocarpanquinone LQB-118, the lead compound from this class, has antiprotozoal and anti-leukemic cell line activities, even in cells with an multidrug resistance phenotype (8)(9)(10). We have also demonstrated that LQB-118 is effective in treating experimental cutaneous leishmaniasis via oral delivery (11,12), and the death of Leishmania amazonensis parasites involved oxidative stress with hallmarks of apoptosis (13). These results suggest that LQB-118 is a promising lead compound and should be further investigated.…”

mentioning

confidence: 69%

“…In previous studies, we determined the in vitro activity of LQB-118 against promastigotes and intracellular amastigotes of L. amazonensis and its effectiveness in controlling lesions of murine cutaneous leishmaniasis by intraperitoneal, subcutaneous, and oral routes. Furthermore, none of the main serological liver and renal toxicity markers (ALT/AST and creatinine, respectively) were altered after 82 days of LQB-118 oral treatment (11). We also have contributed in the understanding of the cell death mechanism that is induced by LQB-118.…”

Section: Discussionmentioning

confidence: 99%

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Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

Cunha-Júnior

Martins

Canto‐Cavalheiro

et al. 2016

Antimicrob Agents Chemother

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e Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is the second major cause of death by parasites, after malaria. The arsenal of drugs against leishmaniasis is small, and each has a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. Our group has focused on studying new drug candidates as alternatives to current treatments. The pterocarpanquinone LQB-118 was designed and synthesized based on molecular hybridization, and it exhibited antiprotozoal and antileukemic cell line activities. Our previous work demonstrated that LQB-118 was an effective treatment for experimental cutaneous leishmaniasis. In this study, we observed that treatment with 10 mg/kg of body weight/day LQB-118 orally inhibited the development of hepatosplenomegaly with a 99% reduction in parasite load. An in vivo toxicological analysis showed no change in the clinical, biochemical, or hematological parameters. Histologically, all of the analyzed organs were normal, with the exception of the liver, where focal points of necrosis with leukocytic infiltration were observed at treatment doses 5 times higher than the therapeutic dose; however, these changes were not accompanied by an increase in transaminases. Our findings indicate that LQB-118 is effective at treating different clinical forms of leishmaniasis and presents no relevant signs of toxicity at therapeutic doses; thus, this framework is demonstrated suitable for developing promising drug candidates for the oral treatment of leishmaniasis.

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confidence: 69%

Section: Discussionmentioning

confidence: 99%

Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

Cunha-Júnior

Martins

Canto‐Cavalheiro

et al. 2016

Antimicrob Agents Chemother

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“…The parasite load was determined 32 days post-infection using a quantitative limiting dilution assay, as previously described [29]. The infected ears were excised, weighed and minced in Schneider's medium with 20% fetal calf serum.…”

Section: Methodsmentioning

confidence: 99%

The Effect of (-)-Epigallocatechin 3-O - Gallate In Vitro and In Vivo in Leishmania braziliensis: Involvement of Reactive Oxygen Species as a Mechanism of Action

et al. 2014

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BackgroundLeishmaniasis is a parasitic disease associated with extensive mortality and morbidity. The treatment for leishmaniasis is currently based on pentavalent antimonials and amphotericin B; however, these drugs result in numerous adverse side effects. Natural compounds have been used as novel treatments for parasitic diseases. In this paper, we evaluated the effect of (-)-epigallocatechin 3-O-gallate (EGCG) on Leishmania braziliensis in vitro and in vivo and described the mechanism of EGCG action against L. braziliensis promastigotes and intracellular amastigotes.Methodology/Principal Finding In vitro activity and reactive oxygen species (ROS) measurements were determined during the promastigote and intracellular amastigote life stages. The effect of EGCG on mitochondrial membrane potential (ΔΨm) was assayed using JC-1, and intracellular ATP concentrations were measured using a luciferin-luciferase system. The in vivo experiments were performed in infected BALB/c mice orally treated with EGCG. EGCG reduced promastigote viability and the infection index in a time- and dose-dependent manner, with IC50 values of 278.8 µM and 3.4 µM, respectively, at 72 h and a selectivity index of 149.5. In addition, EGCG induced ROS production in the promastigote and intracellular amastigote, and the effects were reversed by polyethylene glycol (PEG)-catalase. Additionally, EGCG reduced ΔΨm, thereby decreasing intracellular ATP concentrations in promastigotes. Furthermore, EGCG treatment was also effective in vivo, demonstrating oral bioavailability and reduced parasitic loads without altering serological toxicity markers.Conclusions/SignificanceIn conclusion, our study demonstrates the leishmanicidal effects of EGCG against the two forms of L. braziliensis, the promastigote and amastigote. In addition, EGCG promotes ROS production as a part of its mechanism of action, resulting in decreased ΔΨm and reduced intracellular ATP concentrations. These actions ultimately culminate in parasite death. Furthermore, our data suggest that EGCG is orally effective in the treatment of L. braziliensis-infected BALB/c mice without altering serological toxicity markers.

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“…Mice were individually weighted during treatment with CH8, CH8/PLGA, PLGA, and meglumine antimoniate on days 9, 16, and 23 of infection to assess weight loss. Animals were killed on day 26 of infection, the sera were collected and assayed for AST, ALT, and creatinine as parameters of liver and kidney toxicity, using a colorimetric commercial kit (Doles, Brazil) adapted for microvolumes (47). The positive-control sera were taken from mice which received 200 l of 1% carbon tetrachloride (CCl 4 ) in soybean oil by the intraperitoneal route 3 days before serum collection (48).…”

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confidence: 99%

Depot Subcutaneous Injection with Chalcone CH8-Loaded Poly(Lactic-Co-Glycolic Acid) Microspheres as a Single-Dose Treatment of Cutaneous Leishmaniasis

Sousa-Batista

Pacienza-Lima

Arruda-Costa

et al. 2018

Antimicrob Agents Chemother

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Conventional chemotherapy of cutaneous leishmaniasis (CL) is based on multiple parenteral or intralesional injections with systemically toxic drugs. Aiming at a single-dose localized therapy, biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles loaded with 7.8% of an antileishmanial nitrochalcone named CH8 (CH8/PLGA) were constructed to promote sustained subcutaneous release. , murine macrophages avidly phagocytosed CH8/PLGA smaller than 6 μm without triggering oxidative mechanisms. Upon 48 h of incubation, both CH8 and CH8/PLGA were 40 times more toxic to intracellular than to macrophages. , BALB/c were given one or three subcutaneous injections in the infected ear with 1.2 mg/kg of CH8 in free or CH8/PLGA forms, whereas controls received three CH8-equivalent doses of naked PLGA microparticles or meglumine antimoniate (Glucantime; Sanofi-Aventis). Although a single injection with CH8/PLGA reduced the parasite loads by 91%, triple injections with free CH8 or CH8/PLGA caused 80 and 97% reductions, respectively, in relation to saline controls. Meglumine antimoniate treatment was the least effective (only 36% reduction) and the most toxic, as indicated by elevated alanine aminotransferase serum levels. Together, these findings show that CH8/PLGA microparticles can be effectively and safely used for single-dose treatment of CL.

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Effectiveness of the local or oral delivery of the novel naphthopterocarpanquinone LQB-118 against cutaneous leishmaniasis

Abstract: These results demonstrate that the molecular hybridization of a naphthoquinone core to pterocarpan yielded a novel antileishmanial compound that was locally and orally active in an experimental cutaneous leishmaniasis model.

Cited by 36 publications

References 10 publications

Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

The Effect of (-)-Epigallocatechin 3-O - Gallate In Vitro and In Vivo in Leishmania braziliensis: Involvement of Reactive Oxygen Species as a Mechanism of Action

Depot Subcutaneous Injection with Chalcone CH8-Loaded Poly(Lactic-Co-Glycolic Acid) Microspheres as a Single-Dose Treatment of Cutaneous Leishmaniasis

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