Drug associations as alternative and complementary therapy for neglected tropical diseases

Ferraz, Leslie Raphael de Moura; Silva, Laysa Creusa Paes Barreto Barros; Souza, Myla Lôbo de; Alves, Larissa Pereira; Sales, Victor de Albuquerque Wanderley; Barbosa, Ilka do Nascimento Gomes; Andrade, Mateus Chaves de; Santos, Widson Michael dos; Rolim, Larissa Araújo; Rolim-Neto, Pedro José

doi:10.1016/j.actatropica.2021.106210

Cited by 9 publications

(3 citation statements)

References 199 publications

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“…One alternative to avoid the damage caused by DETC is using new technologies, and a promising alternative is the use of polymeric nanoparticles. Several studies already demonstrate the importance and benefits of nanosystems when applied to the treatment of parasitic diseases, reducing the cellular damage caused by some compounds, increasing the efficacy of drugs, and improving their bioavailability [ 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Validation of Antiparasitic Activity of PLA-Nanoparticles of Sodium Diethyldithiocarbamate against Trypanosoma cruzi

et al. 2022

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Trypanosoma cruzi is a protozoan parasite responsible for Chagas disease, which affects millions around the world and is not treatable in its chronic stage. Sodium diethyldithiocarbamate is a compound belonging to the carbamate class and, in a previous study, demonstrated high efficacy against T. cruzi, showing itself to be a promising compound for the treatment of Chagas disease. This study investigates the encapsulation of sodium diethyldithiocarbamate by poly-lactic acid in nanoparticles, a system of biodegradable nanoparticles that is capable of reducing the toxicity caused by free DETC against cells and maintaining the antiparasitic activity. The nanosystem PLA-DETC was fabricated using nanoprecipitation, and its physical characterization was measured via DLS, SEM, and AFM, demonstrating a small size around 168 nm and a zeta potential of around −19 mv. Furthermore, the toxicity was determined by MTT reduction against three cell lines (VERO, 3T3, and RAW), and when compared to free DETC, we observed a reduction in cell mortality, demonstrating the importance of DETC nanoencapsulation. In addition, the nanoparticles were stained with FITC and put in contact with cells for 24 h, followed by confirmation of whether the nanosystem was inside the cells. Lastly, the antiparasitic activity against different strains of T. cruzi in trypomastigote forms was determined by resazurin reduction and ROS production, which demonstrated high efficacy towards T. cruzi equal to that of free DETC.

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Section: Introductionmentioning

confidence: 99%

In Vitro Validation of Antiparasitic Activity of PLA-Nanoparticles of Sodium Diethyldithiocarbamate against Trypanosoma cruzi

et al. 2022

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“…Besides targeting distinct and/or complementary mechanisms of action, which minimizes the chances of parasite drug resistance, drug combination may reach higher efficacy and lower incidence of adverse and side effects. In addition, lower doses also reduce the costs associated with research and development of new entities or separate production processes (Ferraz et al ., 2022 ). In fact, different combos have been successfully reported in clinical trials (Azim et al ., 2021 ) as well as in experimental models such as the milteforan TM plus paromomycin in L. infantum infection (Hendrickx et al ., 2017 ).…”

Section: Discussionmentioning

confidence: 99%

N⁶-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model

Present,

Girão,

Lin

et al. 2024

Parasitology

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Leishmania is a trypanosomatid parasite that causes skin lesions in its cutaneous form. Current therapies rely on old and expensive drugs, against which the parasites have acquired considerable resistance. Trypanosomatids are unable to synthesize purines relying on salvaging from the host, and nucleoside analogues have emerged as attractive antiparasitic drug candidates. 4-Methyl-7-β-D-ribofuranosyl-7H-pyrrolo[2,3-d]pyrimidine (CL5564), an analogue of tubercidin in which the amine has been replaced by a methyl group, demonstrates activity against Trypanosoma cruzi and Leishmania infantum. Herein, we investigated its in vitro and in vivo activity against L. amazonensis. CL5564 was 6.5-fold (P = 0.0002) more potent than milteforan™ (ML) against intracellular forms in peritoneal mouse macrophages, and highly selective, while combination with ML gave an additive effect. These results stimulated us to study the activity of CL5564 in mouse model of cutaneous Leishmania infection. BALB/c female and male mice infected by L. amazonensis treated with CL5564 (10 mg kg−1, intralesional route for five days) presented a >93% reduction of paw lesion size likely ML given orally at 40 mg kg−1, while the combination (10 + 40 mg kg−1 of CL5564 and ML, respectively) caused >96% reduction. The qPCR confirmed the suppression of parasite load, but only the combination approach reached 66% of parasitological cure. These results support additional studies with nucleoside derivatives.

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“…And, from a practical perspective, when compared to the co-administration of drugs, the fixed-dose combination is more convenient, mainly considering the case of mass drug administration. Due to these advantages, fixed-dose combinations are routinely used in developing countries for the treatment of infectious diseases such as HIV or tuberculosis and are recommended as an alternative therapy for neglected tropical diseases ( Ferraz et al, 2022 ). In the event of STH, it is well established that the poor efficacy of benzimidazoles against T. trichiura and S. stercolaris is significantly improved by the co-administration of ivermectin ( Matamoros et al, 2021 ; Knopp et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Characterization and Comparative Bioavailability of an Innovative Orodispersible Fixed-Dose Combination of Ivermectin and Albendazole: A Single Dose, Open Label, Sequence Randomized, Crossover Clinical Trial in Healthy Volunteers

Algorta¹,

Krolewiecki

Pinto³

et al. 2022

Front. Pharmacol.

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Soil-transmitted helminths are intestinal worm diseases transmitted through the soil. Available treatments are albendazole and/or ivermectin. The co-administration of existing drugs is an appropriate strategy. A fixed-dose combination adds practical advantages mainly considering mass drug administration. The aim is to characterize pharmacokinetics and to evaluate the comparative bioavailability of an innovative fixed-dose combination of ivermectin/albendazole 18/400 mg compared with the marketed references. Seventy-eight healthy volunteers were included in this laboratory-blinded, randomized, three-treatment, three-period crossover study. Each subject received a single dose of ivermectin/albendazole 18/400 mg (1 tablet); ivermectin 3 mg (6 tablets); and albendazole 400 mg (1 tablet). Serial blood samples for the pharmacokinetic analysis were obtained pre-dose and up to 72 h post-dose. Plasma concentrations of ivermectin H2B1a, ivermectin H2B1b, albendazole, and albendazole sulfoxide were analyzed by LC-MS/MS. Pharmacokinetic parameters were estimated by a non-compartmental analysis and bioavailability compared through a bioequivalence analysis. Safety and tolerability were assessed throughout the study. Main pharmacokinetic parameters of the fixed combination were estimated for both, ivermectin [Cmax (mean, confidence interval): 86.40 (30.42–39.23) ng/ml; AUC0-72 (mean, CI): 1,040 (530–1,678) ng·h/mL; tmax (median, min., and max.); 4.50 (2.50–5.50)] and albendazole [Cmax (mean, CI): 22.27 (1.89–111.78) ng/ml; AUC0-72 (mean, CI): 94.65 (11.65–507.78) ng·h/mL; tmax (median, min., and max.): 2.50 (1.00–12.00) h]. The 90% confidence interval of the geometric mean ratios demonstrated the bioequivalence in the case of ivermectin (Cmax: 110.68%–120.49%; AUC0-72: 110.46%–119.60%) but not in the case of albendazole (Cmax: 53.10%–70.34%; AUC0-72: 61.13%–76.54%). The pharmacokinetic profile of a new fixed-dose combination of ivermectin and albendazole was characterized. The bioequivalence versus the reference ivermectin was demonstrated, though bioequivalence versus albendazole was not shown. The three medications analyzed were well tolerated. The results allow the advancement to the next phase of the clinical program to demonstrate efficacy and safety in patients affected by soil-transmitted helminths.Clinical Trial Registration:https://www.clinicaltrialsregister.eu/ctr-search/search/, identifier Nr. 2020-003438-19

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Drug associations as alternative and complementary therapy for neglected tropical diseases

Cited by 9 publications

References 199 publications

In Vitro Validation of Antiparasitic Activity of PLA-Nanoparticles of Sodium Diethyldithiocarbamate against Trypanosoma cruzi

In Vitro Validation of Antiparasitic Activity of PLA-Nanoparticles of Sodium Diethyldithiocarbamate against Trypanosoma cruzi

N⁶-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model

Pharmacokinetic Characterization and Comparative Bioavailability of an Innovative Orodispersible Fixed-Dose Combination of Ivermectin and Albendazole: A Single Dose, Open Label, Sequence Randomized, Crossover Clinical Trial in Healthy Volunteers

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Drug associations as alternative and complementary therapy for neglected tropical diseases

Cited by 9 publications

References 199 publications

In Vitro Validation of Antiparasitic Activity of PLA-Nanoparticles of Sodium Diethyldithiocarbamate against Trypanosoma cruzi

In Vitro Validation of Antiparasitic Activity of PLA-Nanoparticles of Sodium Diethyldithiocarbamate against Trypanosoma cruzi

N6-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model

Pharmacokinetic Characterization and Comparative Bioavailability of an Innovative Orodispersible Fixed-Dose Combination of Ivermectin and Albendazole: A Single Dose, Open Label, Sequence Randomized, Crossover Clinical Trial in Healthy Volunteers

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N⁶-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model