Tamoxifen and meglumine antimoniate combined therapy in cutaneous leishmaniasis patients: a randomised trial

Machado, Paulo Roberto Lima; Ribeiro, Camila Sampaio; França‐Costa, Jaqueline; Dourado, Mayra; Trinconi, Cristiana T.; Yokoyama-Yasunaka, Jenicer K.U.; Malta‐Santos, Hayna; Borges, Valéria M.; Carvalho, Edgar M.; Uliana, Sílvia Reni Bortolin

doi:10.1111/tmi.13119

Cited by 25 publications

(23 citation statements)

References 20 publications

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“…Four studies evaluated the combination with each of the following intervention/drugs: allopurinol, 23‐26 imiquimod 27‐30 and pentoxifylline 31‐34 . Three studies investigated the trichloroacetic acid 50% (TCA), 35‐37 and the remaining eleven trials evaluated other additional interventions comprising tamoxifen, 38 cimetidine, 39 omeprazole, 40 ketoconazole, 41 terbinafine, 42 paromomycin, 43 granulocyte macrophage colony‐stimulating factor, 44 interferon gamma, 45 honey, 46 dressing 47 and herbal extract 48 . The trials were conducted in endemic CL areas: fifteen studies in Iran, four in Brazil, three in Colombia and Peru and the following countries conducted one study: Guatemala, Syria, Yemen, Pakistan, Afghanistan and U.A.E.…”

Section: Resultsmentioning

confidence: 99%

Evidence supporting the enhanced efficacy of pentavalent antimonials with adjuvant therapy for cutaneous leishmaniasis: a systematic review and meta‐analysis

Husein‐ElAhmed

Gieler

Steinhoff

2020

Acad Dermatol Venereol

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Cutaneous leishmaniasis (CL) is one of the major neglected disease worldwide. Although many drugs have been used, the pentavalent antimonials (PA) remain as the first-line choice despite their toxicity and limited efficacy. The combination of two drugs has risen as a potential alternative to increase the cure rate while lowering the side-effects caused by pentavalent antimonials (PA). The objective of this study was to critically review and appraise the potential synergism of the adjuvant therapies of PA with other drugs/interventions previously used in the literature. We carried out a search of literature from PubMed, MEDLINE, Embase, Cochrane and clinicaltrials.gov. Articles that described a two-arm or threearm design in which one of the arms consisted in a combination of a drug/intervention with intralesional or systemic PA were selected. The primary outcome was proportion of complete clearance of the lesions defined as complete re-epithelization and/or negative direct smear. Our literature search identified 554 references. Thirty-one records with a total sample size of 2668 participants met the eligibility criteria. The studies investigated the association of PA with the following: cryotherapy (five studies), allopurinol, imiquimod, pentoxifylline (four studies each), trichloroacetic acid 50% (three studies) and other additional interventions (eleven studies). Overall, the combined therapy of PA with a supplementary intervention was superior to PA monotherapy (RR: 1.23 95% CI: 1.11-1.35, I 2 = 64%). In association with PA, the comparator-specific stratified analysis showed that cryotherapy (RR: 1.50 95% CI: 1.25-1.81, I 2 = 57%) and allopurinol (RR: 1.70 95% CI: 1.37-2.12, I 2 = 28%) were superior to PA in monotherapy. On the contrary, the combined therapy with imiquimod (RR: 1.08 95% CI: 0.88-1.32, I 2 = 40%) and pentoxifylline (RR: 1.14 95% CI: 0.94-1.40, I 2 = 41%) revealed a non-significant result. The application of TCA along with PA did not show significant differences in the clearance rate, although it was close to it (RR: 1.31 95% CI: 0.99-1.73, I 2 = 84%). The present work represents an attempt to find new and reliable treatment modalities to enhance the efficacy based on the adjuvant therapy of pre-existing drugs/interventions with PA. According to our results, the combination of allopurinol-PA is the most effective adjuvant therapy. The application of cryotherapy and TCA stand as useful and encouraging supplementary interventions. The combination of imiquimod-PA and pentoxifylline adds no additional benefit. The results of this work may be helpful in devising and modifying the current guidelines for CL which face major remaining evidence gaps. Triple therapies consisting in cryotherapy-PA-TCA or allopurinol-PA-cryotherapy or allopurinol-PA-TCA can represent promising treatments yet to be confirmed in future trials.

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Section: Resultsmentioning

confidence: 99%

Evidence supporting the enhanced efficacy of pentavalent antimonials with adjuvant therapy for cutaneous leishmaniasis: a systematic review and meta‐analysis

Husein‐ElAhmed

Gieler

Steinhoff

2020

Acad Dermatol Venereol

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“…Although our study is exploratory, our data suggest that the molecular players involved in the necroptosis pathway might be useful as a target in alternative treatments in combination of immunomodulatory drugs with drugs currently used for human leishmaniasis disease. Many clinical trials studies in endemic area for leishmaniasis have pointed out the benefits of combination treatment using multiple drugs ( Machado et al, 2010 , 2018 ; Brito et al, 2014 ). In addition, RIPK3 inhibitors have not been used in clinical trials addressing inflammatory diseases, including leishmaniasis.…”

Section: Resultsmentioning

confidence: 99%

Leishmania braziliensis Subverts Necroptosis by Modulating RIPK3 Expression

et al. 2018

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Leishmania braziliensis infection causes skin ulcers, typically found in localized cutaneous leishmaniasis (LCL). This tissue pathology associates with different modalities of cell necrosis, which are subverted by the parasite as a survival strategy. Herein we examined the participation of necroptosis, a specific form of programmed necrosis, in LCL lesions and found reduced RIPK3 and PGAM5 gene expression compared to normal skin. Assays using infected macrophages demonstrated that the parasite deactivates both RIPK3 and MLKL expression and that these molecules are important to control the intracellular L. braziliensis replication. Thus, LCL-related necroptosis may be targeted to control infection and disease immunopathology.

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“…Considering that there is no LV chemotherapy available by oral route in Brazil and considering the global resistance to oral miltefosine in various parts of the world, the present study investigated the effect of oral TMX-NC on parasite burden and on the histopathological characteristics in L. infantum -infected mice and hamsters. Indicated for treatment or prevention of human breast cancer, TMX is used continuously for 5–10 years with daily doses of 10–40 mg/day and shows a good safety profile [ 57 ]. In the literature, doses administered for the experimental treatment of breast tumors in mice range from 45 to 400 mg/kg/day [ 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our histopathological analysis of the liver and spleen showed that our formulation was able to reduce alterations in these organs. Therefore, the highest doses tested orally in our experimental models of visceral leishmaniasis in mice and hamsters, when transposed to human doses, will be within the range already studied clinically, which was already found not to induce significant adverse effects in patients [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Repositioning of Tamoxifen in Surface-Modified Nanocapsules as a Promising Oral Treatment for Visceral Leishmaniasis

et al. 2021

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Standards of care for human visceral leishmaniasis (VL) are based on drugs used parenterally, and oral treatment options are urgently needed. In the present study, a repurposing strategy was used associating tamoxifen (TMX) with polyethylene glycol-block-polylactide nanocapsules (NC) and its anti-leishmanial efficacy was reported in vivo. Stable surface modified-NC (5 mg/mL of TMX) exhibited 200 nm in size, +42 mV of zeta potential, and 98% encapsulation efficiency. Atomic force microscopy evidenced core-shell-NC. Treatment with TMX-NC reduced parasite-DNA quantified in liver and spleen compared to free-TMX; and provided a similar reduction of parasite burden compared with meglumine antimoniate in mice and hamster models. Image-guided biodistribution showed accumulation of NC in liver and spleen after 30 min post-administration. TMX-NC reduced the number of liver granulomas and restored the aspect of capsules and trabeculae in the spleen of infected animals. TMX-NC was tested for the first time against VL models, indicating a promising formulation for oral treatment.

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Tamoxifen and meglumine antimoniate combined therapy in cutaneous leishmaniasis patients: a randomised trial

Abstract: In the doses and schemes used in this study, co-administration of oral tamoxifen and Sb resulted in higher cure rates in comparison with the standard scheme of treatment, although not to statistically significant levels.

Cited by 25 publications

References 20 publications

Evidence supporting the enhanced efficacy of pentavalent antimonials with adjuvant therapy for cutaneous leishmaniasis: a systematic review and meta‐analysis

Evidence supporting the enhanced efficacy of pentavalent antimonials with adjuvant therapy for cutaneous leishmaniasis: a systematic review and meta‐analysis

Leishmania braziliensis Subverts Necroptosis by Modulating RIPK3 Expression

Repositioning of Tamoxifen in Surface-Modified Nanocapsules as a Promising Oral Treatment for Visceral Leishmaniasis

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