Chagas disease, caused by the protozoa parasite Trypanosoma cruzi, is a neglected tropical disease and a major public health problem affecting more than 6 million people worldwide. Many challenges ...remain in the quest to control Chagas disease: the diagnosis presents several limitations and the two available treatments cause several side effects, presenting limited efficacy during the chronic phase of the disease. In addition, there are no preventive vaccines or biomarkers of therapeutic response or disease outcome. Trypomastigote form and T. cruzi-infected cells release extracellular vesicles (EVs), which are involved in cell-to-cell communication and can modulate the host immune response. Importantly, EVs have been described as promising tools for the development of new therapeutic strategies, such as vaccines, and for the discovery of new biomarkers. Here, we review and discuss the role of EVs secreted during T. cruzi infection and their immunomodulatory properties. Finally, we briefly describe their potential for biomarker discovery and future perspectives as vaccine development tools for Chagas Disease.
Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected disease that affects ~7 million people worldwide. Development of new drugs to treat the infection remains a priority since ...those currently available have frequent side effects and limited efficacy at the chronic stage. Natural products provide a pool of diversity structures to lead the chemical synthesis of novel molecules for this purpose. Herein we analyzed the anti-T. cruzi activity of nine alkaloids derived from plants of the family Amaryllidaceae.
The activity of each alkaloid was assessed by means of an anti-T. cruzi phenotypic assay. We further evaluated the compounds that inhibited parasite growth on two distinct cytotoxicity assays to discard those that were toxic to host cells and assure parasite selectivity.
We identified a single compound (hippeastrine) that was selectively active against the parasite yielding selectivity indexes of 12.7 and 35.2 against Vero and HepG2 cells, respectively. Moreover, it showed specific activity against the amastigote stage (IC
= 3.31 μM).
Results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.
Chagas disease is caused by the protozoan parasite
and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have ...variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease.
modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-
activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC
= 0.27 μmol L
) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind
Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic
infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages.
Chagas disease is emerging in countries to which it is not endemic. Biomarkers for earlier therapeutic response assessment in patients with chronic Chagas disease are needed. We profiled ...plasma-derived extracellular vesicles from a heart transplant patient with chronic Chagas disease and showed the potential of this approach for discovering such biomarkers.
Introduction: Chagas disease, caused by infection with the parasite Trypanosoma cruzi, represents a huge public health problem in the Americas, where millions of people are affected. Despite the ...availability of two drugs against the infection (benznidazole and nifurtimox), multiple factors impede their effective usage: (1) gaps in patient and healthcare provider awareness; (2) lack of access to diagnosis; (3) drug toxicity and absence of treatment algorithms to address adverse effects; (4) failures in drug supply and distribution; and (5) inconsistent drug efficacy against the symptomatic chronic stage.
Areas covered: We review new approaches and technologies to enhance access to diagnosis and treatment to reduce the disease burden. We also provide an updated picture of recently published and ongoing anti-T. cruzi drug clinical trials. Although there has been progress improving the research and development (R&D) landscape, it is unclear whether any new treatments will emerge soon. Literature search methodologies included multiple queries to public databases and the use of own-built libraries.
Expert opinion: Besides R&D, there is a major need to continue awareness and advocacy efforts by patient associations, local and national governments, and international agencies. Overall, health systems strengthening is essential to ensure vector control commitments, as well as patient access to diagnosis and treatment.
Abstract
Background
Chagas disease is a neglected zoonosis caused by the parasite
Trypanosoma cruzi
. It affects over six million people, mostly in Latin America. Drugs available to treat
T. cruzi
...infection have associated toxicity and questionable efficacy at the chronic stage. Hence, the discovery of more effective and safer drugs is an unmet medical need. For this, natural products represent a pool of unique chemical diversity that can serve as excellent templates for the synthesis of active molecules.
Methods
A collection of 79 extracts of Amaryllidaceae plants were screened against
T. cruzi
. Active extracts against the parasite were progressed through two cell toxicity assays based on Vero and HepG2 cells to determine their selectivity profile and discard those toxic to host cells. Anti-
T. cruzi
-specific extracts were further qualified by an anti-amastigote stage assay.
Results
Two extracts, respectively from
Crinum erubescens
and
Rhodophiala andicola
, were identified as highly active and specific against
T. cruzi
and its mammalian replicative form.
Conclusions
The results retrieved in this study encourage further exploration of the chemical content of these extracts in search of new anti-
T. cruzi
drug development starting points.
Graphic abstract
Chagas disease (CD) and tuberculosis (TB) are important health problems in Bolivia. Current treatments for both infections require a long period of time, and adverse drug reactions (ADRs) are ...frequent. This study aims to strengthen the Bolivian pharmacovigilance system, focusing on CD and TB. A situation analysis of pharmacovigilance in the Department of Cochabamba was performed. The use of a new local case report form (CRF) was implemented, together with the CRF established by the Unidad de Medicamentos y Tecnología en Salud (UNIMED), in several healthcare centers. Training and follow-up on drug safety monitoring and ADR reporting was provided to all health professionals involved in CD and TB treatment. A comparative analysis of the reported ADRs using the CRF provided by UNIMED, the new CRF proposal, and medical records, was also performed. Our results showed that out of all patients starting treatment for CD, 37.9% suffered ADRs according to the medical records, and 25.3% of them were classified as moderate/severe (MS). Only 47.4% of MS ADRs were reported to UNIMED. Regarding TB treatment, 9.9% of all patients suffered ADRs, 44% of them were classified as MS, and 75% of MS ADRs were reported to UNIMED. These findings show that the reinforcement of the Bolivian pharmacovigilance system is an ambitious project that should involve a long-term perspective and the engagement of national health workers and other stakeholders at all levels. Continuity and perseverance are essential to achieve a solid ADR reporting system, improving patient safety, drug efficacy and adherence to treatment.
Chagas disease has the highest prevalence of any parasitic disease in the Americas, affecting 6-7 million people. Conventional diagnosis requires a well-equipped laboratory with experienced ...personnel. The development of new diagnostic tools that are easy to use and adapted to the reality of affected populations and health systems is still a significant challenge. The main objective of this study was to measure
infection status using saliva samples of infected subjects. Blood and saliva samples from 20
-seropositive individuals and 10 controls were tested for
infection using two different commercial serological tests. We have shown that detection of
infection is possible using saliva samples, supporting the potential use of saliva to diagnose Chagas disease in humans. This method could provide a simple, low-cost but effective tool for the diagnosis of
infection. Its noninvasive nature makes it particularly well suited for endemic areas.
Pre-exposure prophylaxis (PrEP) is a promising strategy to break COVID-19 transmission. Although hydroxychloroquine was evaluated for treatment and post-exposure prophylaxis, it is not evaluated for ...COVID-19 PrEP yet. The aim of this study was to evaluate the efficacy and safety of PrEP with hydroxychloroquine against placebo in healthcare workers at high risk of SARS-CoV-2 infection during an epidemic period.
We conducted a double-blind placebo-controlled randomized clinical trial in three hospitals in Barcelona, Spain. From 350 adult healthcare workers screened, we included 269 participants with no active or past SARS-CoV-2 infection (determined by a negative nasopharyngeal SARS-CoV-2 PCR and a negative serology against SARS-CoV-2). Participants allocated in the intervention arm (PrEP) received 400 mg of hydroxychloroquine daily for the first four consecutive days and subsequently, 400 mg weekly during the study period. Participants in the control group followed the same treatment schedule with placebo tablets.
52.8% (142/269) of participants were in the hydroxychloroquine arm and 47.2% (127/269) in the placebo arm. Given the national epidemic incidence decay, only one participant in each group was diagnosed with COVID-19. The trial was stopped due to futility and our study design was deemed underpowered to evaluate any benefit regarding PrEP efficacy. Both groups showed a similar proportion of participants experiencing at least one adverse event (AE) (p=0.548). No serious AEs were reported. Almost all AEs (96.4%, 106/110) were mild. Only mild gastrointestinal symptoms were significantly higher in the hydroxychloroquine arm compared to the placebo arm (27.4% (39/142) vs 15.7% (20/127), p=0.041).
Although the efficacy of PrEP with hydroxychloroquine for preventing COVID-19 could not be evaluated, our study showed that PrEP with hydroxychloroquine at low doses is safe.
ClinicalTrials.gov NCT04331834 . Registered on April 2, 2020.
Malaria and Chagas disease, caused by Plasmodium spp. and Trypanosoma cruzi parasites, remain important global health problems. Available treatments for those diseases present several limitations, ...such as lack of efficacy, toxic side effects, and drug resistance. Thus, new drugs are urgently needed. The discovery of new drugs may be benefited by considering the significant biological differences between hosts and parasites. One of the most striking differences is found in the purine metabolism, because most of the parasites are incapable of de novo purine biosynthesis. Herein, we have analyzed the in vitro anti-P. falciparum and anti-T. cruzi activity of a collection of 81 purine derivatives and pyrimidine analogs. We firstly used a primary screening at three fixed concentrations (100, 10, and 1 µM) and progressed those compounds that kept the growth of the parasites < 30% at 100 µM to dose–response assays. Then, we performed two different cytotoxicity assays on Vero cells and human HepG2 cells. Finally, compounds specifically active against T. cruzi were tested against intracellular amastigote forms. Purines 33 (IC50 = 19.19 µM) and 76 (IC50 = 18.27 µM) were the most potent against P. falciparum. On the other hand, 6D (IC50 = 3.78 µM) and 34 (IC50 = 4.24 µM) were identified as hit purines against T. cruzi amastigotes. Moreover, an in silico docking study revealed that P. falciparum and T. cruzi hypoxanthine guanine phosphoribosyltransferase enzymes could be the potential targets of those compounds. Our study identified two novel, purine-based chemotypes that could be further optimized to generate potent and diversified anti-parasitic drugs against both parasites.
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