naphthoquinones and Leishmaniasis--Cutaneous

Leishmaniasis affects millions of people worldwide, and available treatments have severe limitations. Natural and derivative products are significant sources of innovative therapeutic agents. Naphthoquinones are natural or synthetic chemical compounds with broad biological activity. This systematic review aimed to evaluate the potential anti-Leishmania activity of bioactive compounds derived from naphthoquinones in animal models. Conducted in accordance with PRISMA guidelines, two blocks of MeSH terms were assembled: group I, Leishmania OR Leishmaniasis; group II, Atovaquone OR Lapachol OR Beta lapachone OR Naphthoquinones. The search was performed on PubMed, Web of Science, SCOPUS, EMBASE, and Lilacs databases. Twenty-four articles were retrieved and submitted for quality assessment using the SYRCLE critical appraisal tool. The in vivo anti-Leishmania potential of naphthoquinones was evaluated in visceral and cutaneous leishmaniasis using several measurement parameters. Analyzed compounds varied in structure, association with reference drugs, and encapsulation using a drug delivery system. The study design, including treatment protocol, differed between studies. The findings of the studies in this systematic review indicate the anti-Leishmania potential of naphthoquinones in vivo, with different treatment regimens directed against different Leishmania species. The employed drug delivery systems improve the results concerning selectivity, distribution, and required therapeutic dose. The immunomodulatory action was shown to be beneficial to the host, favoring an adequate immune response against infection by Leishmania parasites since it favored Th

Topics: Animals; Animals, Laboratory; Antiprotozoal Agents; Humans; Leishmania; Leishmaniasis, Cutaneous; Naphthoquinones

The parenteral administration of pentavalent antimonials for the treatment of all forms of leishmaniasis, including cutaneous leishamniasis (CL), has several limitations. Therapy is long, requiring repeated doses and the adverse reactions are frequent. Topical treatment is an attractive alternative for CL, offering significant advantages over systemic therapy: fewer adverse effects, ease of administration, and lower costs.. This review covers, from 1984 to the present, the progress achieved for the development of topical treatment for CL, using different drugs such as paromomycin (PA), imiquimod, amphotericin B (AmB), miltefosine, and buparvaquone. PA is the most commonly studied drug, followed by AmB and Imiquimod. These drugs were incorporated in conventional dosage forms or loaded in lipid nanocarries, which have been used mainly for improved skin delivery and antileishmanial activity.. Developing an effective topical treatment for CL using these antileishmanial drugs still remains a great challenge. Insights into the most promising delivery strategies to improve treatment of CL with PA and AmB using conventional dosage forms, lipid nanocarriers, and combined therapy are presented and discussed. The results obtained with combined therapy and alternative delivery systems are promising perspectives for improving topical treatment of CL.

Topics: Administration, Cutaneous; Aminoquinolines; Amphotericin B; Animals; Antiprotozoal Agents; Drug Delivery Systems; Humans; Imiquimod; Leishmaniasis, Cutaneous; Naphthoquinones; Paromomycin; Phosphorylcholine; Skin Absorption

Leishmaniasis is caused by several protozoan species of Leishmania, and being endemically present in 98 countries around the world, it is also a severe public-health problem. The available antileishmanial drugs are toxic and yet present risks of recurrent infection. Efforts to find new, effective, and safe oral agents for the treatment of leishmaniasis are continuing throughout the world. This work aimed to evaluate the antileishmania activity of cordiaquinone E (CORe), isolated from the roots of Cordia polycephala (Lam.) I. M. Johnston. Cytotoxicity, and possible mechanisms of action against promastigote and amastigote forms of Leishmania amazonensis were examined. CORe was effective in inhibiting promastigote (IC

Topics: Animals; Apoptosis; Cytokines; Dose-Response Relationship, Drug; HL-60 Cells; Host-Parasite Interactions; Humans; Leishmania mexicana; Leishmaniasis, Cutaneous; Macrophages; Mice; Naphthoquinones; Nitric Oxide; RAW 264.7 Cells; Reactive Oxygen Species; Trypanocidal Agents

Leishmaniasis is a neglected disease presenting cutaneous, mucosal and visceral forms and affecting an estimated 12 million mostly low-income people. Treatment of cutaneous leishmaniasis (CL) is recommended to expedite healing, reduce risk of scarring, prevent parasite dissemination to other mucocutaneous (common with New World species) or visceral forms and reduce the chance of relapse, but remains an unmet need. Available treatments are painful, prolonged (>20 days) and require hospitalisation, which increases the cost of therapy. Here we present the development of optimised topical self-nanoemulsifying drug delivery systems (SNEDDS) loaded with buparvaquone (BPQ, a hydroxynapthoquinone from the open Malaria Box) for the treatment of CL from New World species. The administration of topical BPQ-SNEDDS gels for 7 days resulted in a reduction of parasite load of 99.989 ± 0.019% similar to the decrease achieved with intralesionally administered Glucantime® (99.873 ± 0.204%) in a L. amazonensis BALB/c model. In vivo efficacy was supported by ex vivo permeability and in vivo tape stripping studies. BPQ-SNEDDS and their hydrogels demonstrated linear flux across non-infected CD-1 mouse skin ex vivo of 182.4 ± 63.0 μg cm

Topics: Animals; Antiprotozoal Agents; Hydrogels; Leishmaniasis, Cutaneous; Mice; Mice, Inbred BALB C; Naphthoquinones

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Disease Models, Animal; Female; Flow Cytometry; Hep G2 Cells; Humans; Inhibitory Concentration 50; Leishmania infantum; Leishmania mexicana; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Liver; Mice; Mice, Inbred BALB C; Naphthoquinones; Parasite Load; Plant Extracts; Random Allocation; RAW 264.7 Cells; Skin; Spleen; Tabebuia

Leishmania (Leishmania) amazonensis is a protozoan that causes infections with a broad spectrum of clinical manifestations. The currently available chemotherapeutic treatments present many problems, such as several adverse side effects and the development of resistant strains. Natural compounds have been investigated as potential antileishmanial agents, and the effects of epoxy-α-lapachone on L. (L.) amazonensis were analyzed in the present study. This compound was able to cause measurable effects on promastigote and amastigote forms of the parasite, affecting plasma membrane organization and leading to death after 3 h of exposure. This compound also had an effect in experimentally infected BALB/c mice, causing reductions in paw lesions 6 weeks after treatment with 0.44 mM epoxy-α-lapachone (mean lesion area, 24.9 ± 2.0 mm(2)), compared to untreated animals (mean lesion area, 30.8 ± 2.6 mm(2)) or animals treated with Glucantime (mean lesion area, 28.3 ± 1.5 mm(2)). In addition, the effects of this compound on the serine proteinase activities of the parasite were evaluated. Serine proteinase-enriched fractions were extracted from both promastigotes and amastigotes and were shown to act on specific serine proteinase substrates and to be sensitive to classic serine proteinase inhibitors (phenylmethylsulfonyl fluoride, aprotinin, and antipain). These fractions were also affected by epoxy-α-lapachone. Furthermore, in silico simulations indicated that epoxy-α-lapachone can bind to oligopeptidase B (OPB) of L. (L.) amazonensis, a serine proteinase, in a manner similar to that of antipain, interacting with an S1 binding site. This evidence suggests that OPB may be a potential target for epoxy-α-lapachone and, as such, may be related to the compound's effects on the parasite.

Topics: Animals; Antipain; Antiprotozoal Agents; Computer Simulation; Leishmania mexicana; Leishmaniasis, Cutaneous; Mice; Mice, Inbred BALB C; Naphthoquinones; Protein Binding; Serine Endopeptidases; Serine Proteinase Inhibitors

In this study, in vitro anti-leishmanial activity of buparvaquone was evaluated against promastigotes and intracellular amastigotes of Pakistani Leishmania tropica isolate KWH23 in relation to the current standard chemotherapy for leishmaniasis (sodium stibogluconate, sodium stibogluconate, amphotericin B and miltefosine). For buparvaquone, mean % inhibition in intracellular amastigotes at four different concentrations (1.35 µM, 0.51 µM, 0.17 µM and 0.057 µM) was 78%, 44%, 20% and 14% respectively, whereas, against promastigotes it was 89%, 77%, 45% and 35% respectively. IC50 values calculated to estimate the anti-leishmanial activity of buparvaquone against intra-cellular amastigotes and promastigotes was 0.53 µM (95% C.I. = 0.32-0.89) and 0.15 µM (95% C.I. = 0.01-1.84) respectively. Amphotericin B was the most potent in-vitro drug tested, with an IC50 of 0.075 µM (95% C.I. = 0.006-0.907) against promastigotes, and 0.065 µM (95% C.I. = 0.048-0.089) against intra-cellular amastigotes. Amphotericin B was more cytotoxic against THP1 cells, with an IC50 of 0.15 µM (95% C.I. = 0.01-0.95) and an apparent in-vitro therapeutic index of 2.0, than was buparvaquone, with an IC50 of 12.03 µM (95% C.I. = 5.36-26.96) against THP1 cells and a therapeutic index of 80.2. The study proposes that buparvaquone may be further investigated as a candidate drug for treatment of cutaneous leishmaniasis.

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Cell Line, Tumor; Child; Humans; Inhibitory Concentration 50; Leishmania tropica; Leishmaniasis, Cutaneous; Macrophages; Male; Meglumine; Meglumine Antimoniate; Naphthoquinones; Organometallic Compounds; Pakistan; Parasitic Sensitivity Tests

Patients affected by cutaneous leishmaniasis need a topical treatment which cures lesions without leaving scars. Lesions are produced not only by the parasite but also by an uncontrolled and persistent inflammatory immune response. In this study, we proposed the loading of β-lapachone (β-LP) in lecithin-chitosan nanoparticles (NP) for targeting the drug to the dermis, where infected macrophages reside, and promote wound healing. Although the loading of β-LP in NP did not influence the drug antileishmanial activity it was critical to achieve important drug accumulation in the dermis and permeation through the skin. When topically applied in Leishmania major infected BALB/c mice, β-LP NP achieved no parasite reduction but they stopped the lesion progression. Immuno-histopathological assays in CL lesions and quantitative mRNA studies in draining lymph nodes confirmed that β-LP exhibited anti-inflammatory activity leading to the down-regulation of IL-1β and COX-2 expression and a decrease of neutrophils infiltrate.. Cutaneous leishmaniasis often leaves patients with unsightly scars due to the body's inflammatory response to the infection. The authors in this paper described topical treatment using β-lapachone (β- LP) loaded in lecithin-chitosan nanoparticles (NP) in an animal model. Results confirmed the reduction of inflammatory response without affecting the parasite killing efficacy. These findings would pave way for further clinical testing in the near future.

Topics: Administration, Topical; Animals; Antiparasitic Agents; Chitosan; Drug Carriers; Drug Delivery Systems; Lecithins; Leishmania major; Leishmaniasis, Cutaneous; Mice, Inbred BALB C; Nanoparticles; Naphthoquinones; Skin

Previous results demonstrate that the hybrid synthetic pterocarpanquinone LQB-118 presents antileishmanial activity against Leishmania amazonensis in a mouse model. The aim of the present study was to use a hamster model to investigate whether LQB-118 presents antileishmanial activity against Leishmania (Viannia) braziliensis, which is the major Leishmania species related to American tegumentary leishmaniasis. The in vitro antileishmanial activity of LQB-118 on L. braziliensis was tested on the promastigote and intracellular amastigote forms. The cell death induced by LQB-118 in the L. braziliensis promastigotes was analyzed using an annexin V-FITC/PI kit, the oxidative stress was evaluated by 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) and the ATP content by luminescence. In situ labeling of DNA fragments by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was used to investigate apoptosis in the intracellular amastigotes. L. braziliensis-infected hamsters were treated from the seventh day of infection with LQB-118 administered intralesionally (26 µg/kg/day, three times a week) or orally (4,3 mg/kg/day, five times a week) for eight weeks. LQB-118 was active against the L. braziliensis promastigotes and intracellular amastigotes, producing IC50 (50% inhibitory concentration) values of 3,4±0,1 and 7,5±0,8 µM, respectively. LQB-118 induced promastigote phosphatidylserine externalization accompanied by increased reactive oxygen species production and ATP depletion. Intracellular amastigote DNA fragmentation was also observed, without affecting the viability of macrophages. The treatment of L. braziliensis-infected hamsters with LQB-118, either orally or intralesionally, was effective in the control of lesion size, parasite load and increase intradermal reaction to parasite antigen. Taken together, these results show that the antileishmanial effect of LQB-118 extends to L. braziliensis in the hamster model, involves the induction of parasite apoptosis and shows promising therapeutic option by oral or local routes in leishmaniasis.

Topics: Animals; Antiprotozoal Agents; Apoptosis; Cricetinae; Female; Leishmania braziliensis; Leishmaniasis, Cutaneous; Macrophages; Membrane Potential, Mitochondrial; Mesocricetus; Naphthoquinones; Phosphatidylserines; Pterocarpans

This paper describes the antileishmanial properties of LQB-118, a new compound designed by molecular hybridization, orally active in Leishmania amazonensis-infected BALB/c mice.. In vitro antileishmanial activity was determined in L. amazonensis-infected macrophages. For in vivo studies, LQB-118 was administered intralesionally (15 μg/kg/day, five times a week), intraperitoneally (4.5 mg/kg/day, five times a week) or orally (4.5 mg/kg/day, five times a week) to L. amazonensis-infected BALB/c mice throughout experiments lasting 85 or 105 days. At the end of the experiments, serum levels of alanine aminotransferase, aspartate aminotransferase and creatinine were measured as toxicological parameters.. LQB-118 was active against intracellular amastigotes of L. amazonensis [50% inhibitory concentration (IC(50)) 1.4 μM] and significantly less so against macrophages (IC(50) 18.5 μM). LQB-118 administered intralesionally, intraperitoneally or orally was found to control both lesion and parasite growth in L. amazonensis-infected BALB/c mice, without altering serological markers of toxicity.. 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.

Topics: Administration, Oral; Administration, Topical; Alanine Transaminase; Animals; Antiprotozoal Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Creatinine; Disease Models, Animal; Inhibitory Concentration 50; Leishmania mexicana; Leishmaniasis, Cutaneous; Liver; Mice; Mice, Inbred BALB C; Naphthoquinones; Pterocarpans; Rodent Diseases; Serum; Treatment Outcome

As the part of a study to develop buparvaquone (BPQ) formulations for the treatment of cutaneous leishmaniasis, the topical delivery of BPQ and one of its prodrugs from a range of formulations was evaluated. In previous studies, BPQ and its prodrugs were shown to be potent antileishmanials in-vitro, with ED50 values in the nanomolar range. 3-Phosphono-oxymethyl-buparvaquone (3-POM-BPQ) was the most potent antileishmanial and was chosen, together with the parent drug, for further investigation. The ability of the parent and prodrug formulations to cross human and murine skin was tested in-vitro using the Franz diffusion cells. Formulations intended for topical application containing either BPQ or 3-POM-BPQ were developed using excipients that were either acceptable for topical use (GRAS or FDA inactive ingredients) or currently going through the regulatory process. BPQ was shown to penetrate both human epidermal membranes and full thickness BALB/c skin from a range of formulations (gels, emulsions). Similarly, 3-POM-BPQ penetrated full-thickness BALB/c skin from several gel formulations. In-vitro binding studies showed that BPQ bound melanin in a dose-dependent manner and preferably bound to delipidized skin over untreated BALB/c skin (on a weight to weight basis). The results confirm that BPQ and its prodrug 3-POM-BPQ can penetrate the skin from several formulations, making them potentially interesting candidates for further investigation of topical formulations using in-vivo models of cutaneous leishmaniasis.

Topics: Administration, Cutaneous; Animals; Antiprotozoal Agents; Chemistry, Pharmaceutical; Ethanol; Female; Humans; In Vitro Techniques; Leishmaniasis, Cutaneous; Melanins; Mice; Mice, Inbred BALB C; Myristates; Naphthoquinones; Organophosphates; Polyethylene Glycols; Prodrugs; Propylene Glycol; Skin; Skin Absorption

The efficacy of different formulations of the naphthoquinone buparvaquone and two phosphate prodrugs in in vivo models of both visceral and cutaneous leishmaniasis is described.. Several topical formulations of buparvaquone containing acceptable excipients were tested in vivo against Leishmania major cutaneous lesions in BALB/c mice. In vivo studies against Leishmania donovani investigated whether the prodrugs had improved efficacy when compared with buparvaquone.. Both a hydrous gel and water-in-oil emulsion of buparvaquone significantly reduced cutaneous parasite burden (P < 0.05, 22 days post-infection) and lesion size, compared with the untreated control (P < 0.0001, 16 days post-infection). The prodrug 3-phosphonooxymethyl-buparvaquone was formulated into an anhydrous gel and this also significantly reduced parasite burden and lesion size (P < 0.0001, 16 days post-infection). Histology confirmed this efficacy. In the visceral model, both prodrugs were significantly more effective at reducing liver parasite burden than the parent drug, buparvaquone. Buparvaquone-3-phosphate was shown to be the most effective antileishmanial (P = 0.0003, 50 mg buparvaquone molar equivalent/kg/day five times), reducing the liver parasite burden by approximately 34% when compared with the untreated control.. The introduction of a topical formulation, such as buparvaquone (or its prodrug), would be a significant advance for the treatment of simple cutaneous lesions. In particular, the avoidance of the parenteral antimonials would greatly increase patient compliance and reduce treatment costs.

Topics: Animals; Antiprotozoal Agents; Chemistry, Pharmaceutical; Female; Leishmania donovani; Leishmania major; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Liver; Mice; Mice, Inbred BALB C; Naphthoquinones; Prodrugs; Skin

Water-soluble phosphate prodrugs of buparvaquone (1), containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral drug delivery against cutaneous and visceral leishmaniasis. The successful prodrug synthesis involved a strong base; e.g., sodium hydride. Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethyl-buparvaquone (4b) prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent drug (

Topics: Administration, Oral; Administration, Topical; Alkaline Phosphatase; Animals; Antiprotozoal Agents; Cricetinae; Female; Humans; Hydrolysis; In Vitro Techniques; Leishmania; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Macrophages, Peritoneal; Mice; Naphthoquinones; Organophosphates; Permeability; Prodrugs; Skin; Solubility; Water

This study aims to evaluate the in vitro and in vivo leishmanicidal activity of lapachol, a naphthoquinone found in the seeds and heartwood of certain tropical plants, and to compare its efficacy with a reference drug, sodium stibogluconate (Pentostam(R)). These compounds (0.0125-4.0 mg/mL) were evaluated in vitro against intracellular amastigotes of Leishmania (Viannia) braziliensis (LVb), then tested in an animal model (hamster) to try to reproduce the leishmanicidal activity. In vitro, lapachol exhibited an anti-amastigote effect, whereas in vivo it did not prevent the development of LVb-induced lesions at an oral dose of 300 mg/kg/day for 42 days. Pentostam(R) demonstrated a significant anti-amastigote effect in vitro for LVb and apparent clinical cure in vivo (60 mg/kg/day). However, it could not completely eradicate parasites from the tissues of infected animals. The observation that lapachol exerts leishmanicidal activity in vitro without offering significant protection against LVb-infected lesions in hamsters suggests that lapachol in vivo might possibly inhibit the microbicidal functioning of macrophages. Alternatively, it might be transformed into an inactive metabolite(s) or neutralized, losing its leishmanicidal activity. It is also possible that an optimal and sustained plasma level of the drug could not be achieved at the dose used in this study.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cricetinae; Disease Models, Animal; Female; Leishmania braziliensis; Leishmaniasis, Cutaneous; Macrophages, Peritoneal; Male; Mesocricetus; Mice; Naphthoquinones; Plants, Medicinal

Plumbagin, 3,3'-biplumbagin and 8,8'-biplumbagin are naphthoquinones isolated by activity-directed fractionation from a Bolivian plant, Pera benensis, used in folk medicine as treatment of cutaneous leishmaniasis caused by Leishmania braziliensis. BALB/c mice were infected with L. mexicana or L. venezuelensis and treated 24 h after the parasitic infection with plumbagin (5 or 2.5 mg/kg/day), 3,3'-biplumbagin, 8,8'-biplumbagin (25 mg/kg/d) or Glucantime (200 mg/kg/d). Lesion development was the criteria employed to evaluate the inhibitory effect. The bis-naphthoquinones were less potent than Glucantime against L. amazonensis and L. venezuelensis. Plubagin and Glucantime delayed the development of L. amazonensis and L. venezuelensis. Assays of a single local treatment on foot-pad infection two weeks after the parasitic inoculation with L. amazonensis showed that 8,8'-biplumbagin (50 mg/kg/d) was as potent as Glucantime (400 mg/kg/d).

Topics: Animals; Antiprotozoal Agents; Disease Models, Animal; Female; Leishmaniasis, Cutaneous; Leishmaniasis, Mucocutaneous; Male; Meglumine; Meglumine Antimoniate; Mice; Mice, Inbred BALB C; Naphthoquinones; Organometallic Compounds; Plant Extracts

The stem barks of Pera benensis are employed by the Chimane Indians in the Bolivian Amazonia as treatment of cutaneous leishmaniasis caused by the protozoan Leishmania braziliensis. The chloroform extracts containing quinones were found active against the promastigote forms of Leishmania and the epimastigote forms of Trypanosoma cruzi at 10 micrograms ml-1. The activity guided fractionation of the extract by chromatography afforded active compounds. Their structures were elucidated, by spectral and chemical studies, as known naphthoquinones, plumbagin, 3,3'-biplumbagin, 8-8'-biplumbagin, and triterpene, lupeol. The activity in vitro of each compound was evaluated against 5 strains of Leishmania (promastigote), 6 strains of Trypanosoma cruzi (epimastigote) and the intracellular form (amastigote) of Leishmania amazonensis. The baseline drugs used were Glucantime and pentamidine (Leishmania spp.), nifurtimox and benznidazole (T. cruzi). Plumbagin was the most active compound in vitro. This study has demonstrated that Pera benensis, a medicinal plant used in folk medicine, is an efficient treatment of cutaneous leishmaniasis.

Topics: Animals; Bolivia; Chagas Disease; Leishmania; Leishmaniasis, Cutaneous; Medicine, Traditional; Mice; Naphthoquinones; Plants, Medicinal; Spectrophotometry, Ultraviolet; Trypanocidal Agents; Trypanosoma cruzi