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.

Background: 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. Methods: 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. Results: 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 50 = 3.31 μM). Conclusions: Results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.

BackgroundPre-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 efficacy and safety of PrEP with hydroxychloroquine against placebo in healthcare workers at high risk of SARS-CoV-2 infection during an epidemic period.MethodsWe 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 400mg of hydroxychloroquine daily the first four consecutive days and subsequently, 400mg weekly during the study period. Participants in the control group followed the same treatment schedule with placebo tablets. Results52.8% of participants were in the hydroxychloroquine arm and 47.2% in the placebo arm. Both groups showed similar proportion of participants experiencing at least one adverse event (AE) (p=0.548). No serious AE were reported. Almost all AE (96.4%) were mild. Only mild gastrointestinal symptoms were significantly higher in the hydroxychloroquine arm compared to the placebo arm (28.3% vs 16.9%, p=0.044). Given the national epidemic incidence decay, only one participant in each group was COVID-19 diagnosed. Consequently, our study design deemed underpowered to evaluate any benefit regarding PrEP efficacy.ConclusionsFirst month follow-up analysis displayed that PrEP with hydroxychloroquine at low doses is safe.Trial registrationThis trial was registered at clinicaltrials.gov (NCT04331834) on April 2nd 2020.

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C hagas disease, caused by Trypanosoma cruzi parasite, is one of the most prevalent parasitic infections in Latin America and is responsible for millions of clinical cases. However, mainly because of migratory movements, the epidemiology of Chagas disease has changed in recent decades; cases have increased substantially in North America, Europe, and Asia, where it is not endemic (1). Thus, raising awareness of this debilitating or deadly neglected tropical disease and promoting the creation of global strategies for its accurate diagnosis, treatment, and control are of paramount importance. Detection of T. cruzi-specific antibodies in serologic assays is the current standard technique

Background 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. Methods 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. Results 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). Conclusions 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. Trial registration ClinicalTrials.govNCT04331834. Registered on April 2, 2020.

Chagas disease is caused by infection with the parasite Trypanosoma cruzi, which might lead to a chronic disease state and drive to irreversible damage to the heart and/or digestive tract tissues. Endemic in 21 countries in the Americas, it is the neglected disease with a highest burden in the region. Current estimates point at ~6 million people infected, of which ~30% will progress onto the symptomatic tissue disruptive stage. There is no vaccine but there are two anti-parasitic drugs available: benznidazole and nifurtimox. However, their efficacy is variable at the chronic symptomatic stage and both have frequent adverse effects.Since there are no prognosis markers, drugs should be administered to all T. cruzi-infected individuals in the indeterminate and early symptomatic stages. Nowadays, there are no testsof-cure either, which greatly undermines patients´ follow-up and the search of safer and more efficacious drugs. Therefore, the identification and validation of biomarkers of disease progression and/or treatment response on which to develop tests of prognosis and/or cure is a major research priority. Both parasite-and host-derived markers have been investigated. In the present manuscript we present an updated outlook of the latter.

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.