Pull me - push you? The disparate financing mechanisms of drug research in global health.

BACKGROUND: There is an inconsistency in the way pharmaceutical research is financed. While pull mechanisms are predominantly used to incentivize later-stage pharmaceutical research for products with demand in the Global North, so-called neglected diseases are chiefly financed by push funding. This discrepancy has so far been ignored in the academic debate, and any compelling explanation for why we draw the line between push and pull at poor people is lacking. MAIN BODY: Clinical development of new pharmaceuticals is chiefly financed by free market pull mechanisms. Even in cases where markets fail to deliver adequate incentives, demand enhancement mechanisms are used to replicate pull funding artificially, for example, with subscription models for antibiotics. Push funding in clinical research is almost always used when the poverty of patients means that markets fail to create sufficient demand. The general question of whether push or pull generally is the more efficient way to conduct pharmaceutical research arises. CONCLUSIONS: If the state is efficient in directing limited budgets for pharmaceutical research, push funding should be expanded to global diseases. If private industry is the more efficient actor, there would be enormous value in experimenting more aggressively with different approaches to enhance market demand artificially for neglected diseases.

Vaccines for neglected, emerging and re-emerging diseases.

Efforts to produce vaccines against SARS and MERS were prematurely halted since their scope was perceived to be geographically restricted and they were subsequently categorized as neglected diseases. However, when a similar virus spread globally triggering the COVID-19 pandemic, we were harshly reminded that several other neglected diseases might also be waiting for the perfect opportunity to become mainstream. As climate change drives urbanization, natural selection of pathogens and their intermediate vectors and reservoirs, the risk of neglected diseases emerging within a larger susceptible pool becomes an even greater threat. Availability of a vaccine for COVID-19 is widely considered the only way to end this pandemic. Similarly, vaccines are also seen as the best tools available to control the spread of neglected (sometimes referred to as emerging or re-emerging) diseases, until the water, hygiene and sanitation infrastructure is improved in areas of their prevalence. Vaccine production is usually cost and labour intensive and thus minimal funding is directed towards controlling and eliminating neglected diseases (NDs). A customised but sustainable approach is needed to develop and deploy vaccines against NDs. While safety, efficacy and public trust are the three main success pillars for most vaccines, affordability is vital when formulating vaccines for neglected diseases.

Development and evaluation of the in vitro schistosomicidal activity of solid dispersions based on 2-(-5-bromo-1-H-indole-3-yl-methylene)-N-(naphthalene-1-ylhydrazine-carbothiamide.

Among all the neglected diseases, schistosomiasis is considered the second most important parasitic infection after malaria. Praziquantel is the most widely used drug for this disease, but its exclusive use may result in the development of drug-resistant schistosomiasis. To increase the control of the disease, new drugs have been developed as alternative treatments, among them 2-(-5-bromo-1-h-indole-3-yl-methylene)-N-(naphthalene-1-ylhydrazine-carbothiamide (LQIT/LT-50), which showed promising schistosomicidal activity in nonclinical studies. However, LQIT/LT-50 presents low solubility in water, resulting in reduced bioavailability. To overcome this solubility problem, the present study aimed to develop LQIT/LT-50 solid dispersions for the treatment of schistosomiasis. Solid dispersions were prepared through the solvent method using Soluplus©, polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP K-30) as hydrophilic carriers. The formulations with the best results in the compatibility tests, aqueous solubility and preliminary stability studies have undergone solubility tests and physicochemical characterizations by Fourier-transform infrared spectroscopy (FTIR), x-ray diffractometry (XRD), exploratory differential calorimetry (DSC), thermogravimetry (TG) and Raman spectroscopy. Finally, the schistosomicidal activity was evaluated in vitro. The phycochemical analyzes showed that when using PVP K-30, there was an interaction between the PVP K-30 and LQIT/LT-50, proving the successful development of the solid dispersion. Furthermore, an increase in the solubility of the new system was observed (LQIT/LT-50:PVP K-30) in addition to the improvement in the in vitro shistosomidal activity at 1:4 (w/w) molar ratio (i.e., 20% drug loading) when compared to LQIT/LT-50 alone. The development of the LQIT/LT-50:PVP K-30 1:4 solid dispersion is encouraging for the future development of new pharmaceutical solid formulations, aiming the schistosomicidal treatment.

Management of paediatric soil-transmitted helminthiasis in a non-endemic area: experience in a reference international health unit.

Soil-transmitted helminth (STH) infections inflict disability worldwide, especially in the poorest communities. Current therapeutic options against STHs show limited efficacy, particularly against Trichuris trichiura. The empirical management of patients coming from high-prevalence areas has been suggested for non-endemic areas. This study aimed to describe the management of STH infections in a non-endemic setting using an individualised approach. We performed a retrospective, descriptive study of all patients up to 16 years of age with STH infections attended at an international health unit in a non-endemic area (2014-2018), including all T. trichiura, Necator americanus, Ancylostoma duodenale, and Ascaris lumbricoides infections diagnosed using a formol-ether concentration technique and direct visualisation. Patients were treated according to current international guidelines. Sixty-one stool samples from 48 patients testing positive for STHs were collected, with 96% (46/48) reporting a previous long-term stay in endemic areas. Cure rates with 3-day benzimidazole regimens were 72% for T. trichiura, 40% for hookworms, and 83% for A. lumbricoides. The results were not influenced by any reinfection risk due to the study being performed in a non-endemic area. Patients coming from STH-endemic areas should be evaluated with appropriate diagnostic tools and followed up until cure control results. Cure rates in our cohort were moderate to low, similar to those published in studies in endemic areas. The efficacy of current treatment options is insufficient to recommend a specific empirical approach in high-income countries' healthcare systems.

Prevalence of trachoma in indigenous and non-indigenous areas, Northeastern Brazil, 2019-2021.

Objective: To estimate the prevalence of trachoma in indigenous and non-indigenous populations in selected areas of the state of Maranhão, in northeastern Brazil. Methods: This was a population-based survey with probabilistic sampling. For the diagnosis of trachoma, external ocular examination was performed using head magnifying loupes, at 2.5X magnification. The prevalence of trachomatous inflammation - follicular (TF) in children aged 1-9 years and the prevalence of trachomatous trichiasis (TT) in the population aged ≥15 years were estimated. Relative frequencies of sociodemographic and environmental characteristics were obtained. Results: The study included 7 971 individuals, 3 429 from non-indigenous populations and 4 542 from indigenous populations. The prevalence of TF in non-indigenous and indigenous populations was 0.1% and 2.9%, respectively, and the prevalence of TT among indigenous populations was 0.1%. Conclusions: The prevalence of TF and TT in the two evaluation units in the state of Maranhão were within the limits recommended for the elimination of trachoma as a public health problem. However, the prevalence of TF was higher in the indigenous evaluation unit, indicating a greater vulnerability of this population to the disease. The prevalence of TF of below 5.0% implies a reduction in transmission, which may have resulted from improved socioeconomic conditions and/or the implementation of the World Health Organization SAFE strategy.

Potential for Emergence of Foodborne Trematodiases Transmitted by an Introduced Snail (Melanoides tuberculata) in California and Elsewhere in the United States.

We document that 3 human-infectious trematodes and their introduced first intermediate host snail (Melanoides tuberculata) are widespread throughout southern California. We surveyed 41 fishing localities, 19 of which harbored snails infected with zoonotic trematodes. Two of the parasites, Haplorchis pumilio and Centrocestus formosanus, are fishborne intestinal trematodes recognized as being important human pathogens in other areas of the world; the third, Philophthalmus gralli, can infect the human eye. An additional 5 species detected infecting M. tuberculata are likely of little direct threat to people; however, they may be recently introduced to the Americas, highlighting the risk that additional pathogenic trematodes transmitted by the snail in its native range could be introduced to the United States. The current, possible human-infection risk in California clarifies the need to consider the introduced snail and its parasites from a public health perspective anywhere in the United States the snail has been introduced.

We report that 3 human-infecting trematodes and their introduced intermediate host snail are widespread in southern California freshwater fishing localities. Eating undercooked or underfrozen fish is the way people get infected by 2 of the parasite species, which are recognized as important human pathogens in other areas of the world. We also found 5 non­human-infectious trematodes carried by the snail that may be cointroduced, highlighting the possibility that other dangerous pathogens transmitted by the snail where it is native could arrive later or already be present in the United States. The common presence of the human-infecting fishborne trematodes at fishing localities, the widespread popularity of eating uncooked fish (eg, as sashimi, sushi, poke, or ceviche), and the potential for additional human-infecting trematodes to also be introduced, all justify consideration of the introduced snail and its parasites from a public health perspective in California and other areas in the United States where the parasites or the host snail have already been reported.

Rapid Serologic Test for Diagnosis of Yaws in Patients with Suspicious Skin Ulcers.

The Chembio DPP (Dual Path Platform) Syphilis Screen & Confirm kit (https://chembio.com) is a rapid serologic test that can be used to diagnose yaws. We evaluated its capacity to detect patients with ulcers that tested PCR positive for Treponema pallidum subsp. pertenue. DPP detected 84% of ulcers that were positive by PCR.

Neuroimmunology of rabies: New insights into an ancient disease.

Rabies is an ancient neuroinvasive viral (genus Lyssavirus, family Rhabdoviridae) disease affecting approximately 59,000 people worldwide. The central nervous system (CNS) is targeted, and rabies has a case fatality rate of almost 100% in humans and animals. Rabies is entirely preventable through proper vaccination, and thus, the highest incidence is typically observed in developing countries, mainly in Africa and Asia. However, there are still cases in European countries and the United States. Recently, demographic, increasing income levels, and the coronavirus disease 2019 (COVID-19) pandemic have caused a massive raising in the animal population, enhancing the need for preventive measures (e.g., vaccination, surveillance, and animal control programs), postexposure prophylaxis, and a better understanding of rabies pathophysiology to identify therapeutic targets, since there is no effective treatment after the onset of clinical manifestations. Here, we review the neuroimmune biology and mechanisms of rabies. Its pathogenesis involves a complex and poorly understood modulation of immune and brain functions associated with metabolic, synaptic, and neuronal impairments, resulting in fatal outcomes without significant histopathological lesions in the CNS. In this context, the neuroimmunological and neurochemical aspects of excitatory/inhibitory signaling (e.g., GABA/glutamate crosstalk) are likely related to the clinical manifestations of rabies infection. Uncovering new links between immunopathological mechanisms and neurochemical imbalance will be essential to identify novel potential therapeutic targets to reduce rabies morbidity and mortality.

Development of solid dispersions based on 3- (2,6-difluorobenzyl) -5- (5-bromo-1H-indol-3-ylmethylene) thiazolidine-2,4-dione for schistosomicidal treatment.

Schistosomiasis is an endemic disease in Brazil. It is important to broaden the treatment options to control and containment of the disease. Thiazolidine derivatives appear as important alternatives to treatment. In vitro studies have demonstrated excellent schistosomiasis activity for LPSF/GQ-238. The molecule, however, has poorly water-soluble. This study focused on increasing the aqueous solubility of LPSF/GQ-238 by obtaining solid dispersions. Were prepared by the solvent techniques, using Soluplus®, Polyethylene glycol (PEG), and Polyvinylpyrrolidone (PVP-K30) as carriers. Solubility tests, Scanning Electron Microscopy (SEM), X-ray Diffraction (XRD), Exploratory Differential Calorimetry (DSC), and Raman Spectroscopy characterized these new intermediate products. The solubility tests showed that the higher the proportion of polymer used in the preparation of the dispersion, the greater the solubility presented. The observation of the morphology by SEM analysis, elucidated, that the new chemical entity (NCE) has a characteristic crystalline structure. The folding of this structure by the polymer was observed in all analyzed dispersions, thus demonstrating the amorphous state of the product. The scales observed in the structures of the dispersions demonstrate the successive wrinkles that occurred. The greater the proportion of the polymer, the greater the number of folds that occurred, which may explain the greater solubility observed in these preparations. The X-ray diffraction profile of the NCE reveals the presence of intense peaks, presenting a crystalline pattern. The polymer, on the other hand, shows amorphous nature, evidenced by the absence of peaks. All the analyzed dispersions did not present the characteristic peaks of the NCE, evidencing the amorphous behavior of the products. The thermal degradation profile of the NCE presents a characteristic crystalline structure endothermic peak. This peak was not observed in any of the obtained dispersions, evidencing the obtaining of a new solid state. Raman spectroscopy showed that peaks in the range 200-400 (cm-1) by NCE were lost when compared to all analyzed dispersions, showing a slight change in the structure of the molecule when dispersed, probably due to the formation of hydrogen bonds with the polymer. The in vitro study showed a significant improvement in the activity of the NCE against the adult worm and to the schistosomulae. It was possible to observe that the obtained solid dispersions were physicochemically and biologically viable for schistosomicidal treatment due to the increase of solubility of the molecule.

Why are tapeworm carriers so difficult to find? A methodological proposal for their search and recovery.

Neurocysticercosis, caused by the larval stage of Taenia solium, is a life-threatening condition and the most severe form of the disease. Yet, despite being a required link in the parasite life cycle, tapeworm carriers are rarely reported. This study is aimed to find and evaluate T. solium carriers, describing some characteristics of these patients and the treatment. Taeniasis cases were searched for in various Mexican states from 1983 to 2016. Previous informed consent, tapeworm-carrier patients were administered with niclosamide and a saline purge. Parasite specimens were recovered and identified, both morphologically and by PCR. From 117 treated patients, Taenia sp. specimens were obtained from 46 subjects (47.8%). From these, complete parasites were recovered from 42 (90.5%), and only detached proglottids from 4 patients. Cases were more frequent in Morelos, Chiapas, and Guerrero. More than one adult cestode was recovered from 4 patients (9.5%). To improve treatment efficacy and adherence, the drug was administered in late afternoon, resulting a high recovery yield of complete parasites (90.5%). The success rate of deworming campaigns in areas of Mexico and the world that are endemic for Taenia sp. could be improved by administering the treatment at times that do not interfere with the patients' daily activities, and national health authorities could apply this simple strategy to help eradication efforts in endemic areas. The detection of carriers will only be possible through the coordinated efforts of public and private health services, a better education of the general population to improve self-detection, and adequate, personalized diagnostic procedures for suspect cases.

Diagnostic pathways of Chagas disease in Spain: a qualitative study.

BACKGROUND: Due to the mobility of the population in recent years and the spread of Chagas disease (CD) to non-endemic regions, early diagnosis and treatment of CD has become increasingly relevant in non-endemic countries. In order for screening to be effective, health system accessibility must be taken into consideration. This study uses Tanahashi's Health Service Coverage model to gain a deeper understanding of the main diagnostic pathways for Chagas disease in a non-endemic country and the barriers and bottlenecks present in each pathway. METHODS: This study used a qualitative design with a phenomenological approach. Twenty-one interviews, two focus group sessions, and two triangular group sessions were conducted between 2015 and 2018 with 37 Bolivian men and women diagnosed with CD in Madrid, Spain. A topic guide was designed to ensure that the interviewers obtained the data concerning knowledge of CD (transmission, symptoms, and treatment), attitudes towards CD, and health behaviour (practices in relation to CD). All interviews, focus groups and triangular groups were recorded and transcribed. A thematic, inductive analysis based on Grounded Theory was performed by two researchers. RESULTS: Three main pathways to CD diagnosis were identified: 1) pregnancy or blood/organ donation, with no bottlenecks in effective coverage; 2) an individual actively seeking CD testing, with bottlenecks relating to administrative, physical, and time-related accessibility, and effectiveness based on the healthcare professional's knowledge of CD; 3) an individual not actively seeking CD testing, who expresses psychological discomfort or embarrassment about visiting a physician, with a low perception of risk, afraid of stigma, and testing positive, and with little confidence in physicians' knowledge of CD. CONCLUSIONS: Existing bottlenecks in the three main diagnostic pathways for CD are less prevalent during pregnancy and blood donation, but are more prevalent in individuals who do not voluntarily seek serological testing for CD. Future screening protocols will need to take these bottlenecks into consideration to achieve effective coverage.

Annotation of GC-MS Data of Antimicrobial Constituents in the Antarctic Seaweed Phaeurus antarcticus by Molecular Networking.

Phaeurus antarcticus is a member of the Desmarestiaceae family endemic to the Antarctic Peninsula. Reports addressing its chemical composition and biological activities are scarce. Herein, bioactive non-polar compounds of P. antarcticus against pathogenic bacteria, Leishmania amazonensis and Neospora caninum parasites were targeted through GC-MS Molecular Networking and multivariate analysis (OPLS-DA). The effects on horseradish peroxidase (HRP) were also evaluated. P. antarcticus exhibited selective bacteriostatic and bactericidal activities against Staphylococcus aureus with MIC and MBC values from 6.25-100 µg mL-1 . Fractions HX-FC and HX-FD were the most active against L. amazonensis with EC50 ranging from 18.5-62.3 µg mL-1 . Additionally, fractions HX-FC and HX-FD showed potent inhibition of N. caninum at EC50 values of 2.8 and 6.3 µg mL-1 , respectively. All fractions inhibited HRP activity, indicating possible interactions with Heme proteins. It was possible to annotate compounds from tree mains clusters, containing terpenoids, steroids, fatty acids, and alcohols by correlating the spectral data of the GC-MS analysis with Molecular Networking and the OPLS-DA results.

[Synthesis of evidence and recommendations: guideline for the treatment of leishmaniasis in the Region of the AmericasSíntese de evidências e recomendações: diretrizes para o tratamento das leishmanioses na Região das Américas]. / Síntesis de evidencia y recomendaciones: directrices para el tratamiento de las leishmaniasis en la Región de las Américas.

Introduction: Leishmaniasis continues to be a neglected infectious disease of great importance, mainly affecting the poorest people with the least access to health services. In the Americas, it is a public health problem due to its magnitude, wide geographical distribution, and levels of morbidity and mortality. Objective: Summarize the recommendations included in Guideline for the Treatment of Leishmaniasis in the Region of the Americas, published by the Pan American Health Organization/World Health Organization, in order to provide adequate management of patients diagnosed with leishmaniasis, reduce clinical complications and deaths caused by drug toxicity, reduce the lethality of visceral leishmaniasis, and address key aspects of implementation of the guidelines. Methods: The guideline and its recommendations were summarized and a systematic search was carried out in PubMed, Lilacs, Health Systems Evidence, Epistemonikos, and gray literature for other studies conducted in the Region of the Americas, in order to identify barriers, facilitators, and implementation strategies. Results: Recommendations are presented, addressing the pharmacological treatment of patients diagnosed with cutaneous, mucosal, and visceral leishmaniasis in the Americas, as well as case management and secondary prophylaxis in patients coinfected with visceral leishmaniasis and HIV, and patients with other diseases that cause immunosuppression. Conclusions: The recommendations aim to provide the government entities and health professionals that care for leishmaniasis patients in the Americas with knowledge on management of the disease. Barriers are discussed (related to human resources, knowledge of guidelines, inputs, costs, access, and patient access), as well as facilitators and strategies to support implementation.

Introdução: As leishmanioses continuam sendo doenças infecciosas negligenciadas de grande importância, uma vez que afetam principalmente as pessoas mais pobres e com menos acesso aos serviços de saúde. Na Região das Américas, constituem um problema de saúde pública devido à sua magnitude, ampla distribuição geográfica e morbimortalidade. Objetivo: Sintetizar as recomendações contidas nas Diretrizes para o tratamento das leishmanioses na Região das Américas, publicadas pela Organização Pan-Americana da Saúde/Organização Mundial da Saúde, a fim de proporcionar o manejo adequado dos pacientes diagnosticados com leishmaniose; reduzir as complicações clínicas e as mortes causadas pela toxicidade dos medicamentos, bem como a letalidade da leishmaniose visceral; e abordar os principais aspectos da sua implementação. Métodos: Realizou-se uma síntese das diretrizes e suas recomendações. Além disso, foi feita uma busca sistemática nas bases de dados PubMed, Lilacs, Health Systems Evidence e Epistemonikos, e na literatura cinzenta de outros estudos desenvolvidos na Região das Américas, a fim de identificar barreiras, facilitadores e estratégias de implementação. Resultados: Apresentam-se recomendações que abordam o tratamento farmacológico de pacientes diagnosticados com leishmaniose cutânea, mucosa e visceral nas Américas, bem como para o manejo e a profilaxia secundária em pacientes coinfectados com leishmaniose visceral e HIV e pacientes com outras doenças que causam imunossupressão. Conclusões: As recomendações buscam fornecer conhecimento sobre o manejo das leishmanioses para entidades governamentais e profissionais de saúde das Américas que atendem pacientes com a doença. Apresentam-se barreiras relacionadas aos recursos humanos, conhecimento das diretrizes, insumos, custo, acesso e barreiras dos pacientes, bem como facilitadores e estratégias de apoio à implementação.

[Mortality from neglected tropical ciseases in Brazil in the 21st Century: Analysis of spatial and temporal trends and associated factorsMortalidad por enfermedades tropicales desatendidas en Brasil en el siglo XXI: análisis de tendencias espaciales y temporales y factores asociados]. / Mortalidade por doenças tropicais negligenciadas no Brasil no século XXI: análise de tendências espaciais e temporais e fatores associados.

Objective: To analyze the spatial-temporal distribution and factors associated with mortality from neglected tropical diseases (NTDs) in Brazil from 2000 to 2019. Method: We performed an ecological study to analyze NTD-related deaths recorded in the Ministry of Health Mortality Information System (SIM). For the temporal analysis, the joinpoint method was used. Spatial dependence was analyzed using global Moran and local Getis-Ord Gi* indices. Four non-spatial and spatial regression models were used to identify factors associated with mortality. Results: The mean mortality rate from NTDs in Brazil during the study period was 3.32 deaths per 100 000 inhabitants, with the highest rate (8.68 deaths per 100 000 inhabitants) recorded in the Midwest. The most prevalent causes of death were Chagas disease (n = 94 781; 74.9%) and schistosomiasis (n = 10 271; 8.1%). There was a 1.24% reduction (95%CI = -1.6; -0.9; P < 0.001) in NTD-related mortality in Brazil per year. A high/high spatial distribution pattern and hotspots were observed in municipalities in the states of Goiás, Minas Gerais, Bahia, Tocantins, and Piauí. The indicators "population in households with density > 2 people per bedroom" (ß = -0.07; P = 0.00) and "municipal human development index" (ß = -3.36; P = 0.08) were negatively associated with the outcome, while the "index of social vulnerability" (ß = 2.74; P = 0.05) was positively associated with the outcome. Conclusion: Lower human development and higher social vulnerability are associated with higher mortality from NTDs, which should guide NTD prevention and control efforts.

Objetivo: Analizar la distribución espacial y temporal de la mortalidad por enfermedades tropicales desatendidas en Brasil en el período 2000-2019 y los factores asociados a ella. Método: Estudio ecológico centrado en el análisis de las muertes por enfermedades tropicales desatendidas registradas en el Sistema de Información sobre Mortalidad. Para el análisis temporal se utilizó el método de regresión de puntos de inflexión (joinpoint). La dependencia espacial se analizó mediante los índices de Moran global y local y Gi* de Getis-Ord. Se utilizaron cuatro modelos de regresión espacial y no espacial para detectar los factores relacionados con la mortalidad. Resultados: La tasa media de mortalidad por enfermedades tropicales desatendidas en Brasil fue de 3,32 muertes por 100 000 habitantes en el periodo del estudio, y la tasa más alta observada (8,68 muertes por 100 000 habitantes) fue la del Centro Oeste. Las causas de muerte más prevalentes fueron la enfermedad de Chagas (n = 94.781; 74,9%) y la esquistosomiasis (n = 10.271; 8,1%). Se registró una disminución de 1,24% (IC del 95% = -1,6; -0,9; p < 0,001) anual de la mortalidad por enfermedades tropicales desatendidas en el país. Se observó un patrón de distribución espacial alto/alto, con puntos calientes en municipios de los estados de Bahía, Goiás, Minas Gerais, Piauí y Tocantins. Los indicadores "población en hogares con densidad > 2 habitantes por dormitorio" (ß = -0,07; P = 0,00) e "índice de desarrollo humano municipal" (ß = -3,36; P = 0,08) mostraron una asociación negativa con el resultado, mientras que el indicador "índice de vulnerabilidad social" (ß = 2,74; P = 0,05) arrojó una asociación positiva. Conclusiones: Cuanto menor es el grado de desarrollo humano y mayor la vulnerabilidad social, mayor es la mortalidad por enfermedades tropicales desatendidas, lo que debe orientar las medidas correspondientes de prevención y control.

Integrated control of neglected tropical diseases in Brazil: document review of a national campaign in light of WHO recommendations.

Objective: To describe the results of a national campaign aimed at the integrated control of neglected tropical diseases in Brazil in light of the World Health Organization (WHO) official documentation related to the integration of strategies for the prevention, control, and elimination or eradication of neglected tropical diseases. Methods: A document review that included official WHO documents published between 2007 and 2020 and campaign results extracted from the official technical report produced by the Brazilian Ministry of Health. Results: The integrated control of neglected tropical diseases was gradually incorporated in the WHO documentation over time. Preventive chemotherapy through mass drug administration, intensified case management, and integrated vector management were extensively recommended as strategies for integrated control. The Brazilian campaign was carried out in four iterations between 2013 and 2017. Children aged 5 to 14 years enrolled in municipal public schools nationwide were targeted. In summary, a total of 1 074 and 73 522 new cases of leprosy and trachoma, respectively, were detected. Nearly 18 million doses of preventive chemotherapy for soil-transmitted helminthiasis were administered. More than 700 cases of schistosomiasis were diagnosed and treated. Conclusions: The integrated strategies implemented in Brazil throughout the campaign generated results aligned with the WHO recommendations for the control of neglected tropical diseases, especially those regarding mass drug administration, active case detection, and intensified case management. Therefore, the continuity of the campaign with adequate evaluation tools must be encouraged as a constant public health policy in the Brazilian government agenda.

From Benznidazole to New Drugs: Nanotechnology Contribution in Chagas Disease.

Chagas disease is a neglected tropical disease caused by the protozoan Trypanosoma cruzi. Benznidazole and nifurtimox are the two approved drugs for their treatment, but both drugs present side effects and efficacy problems, especially in the chronic phase of this disease. Therefore, new molecules have been tested with promising results aiming for strategic targeting action against T. cruzi. Several studies involve in vitro screening, but a considerable number of in vivo studies describe drug bioavailability increment, drug stability, toxicity assessment, and mainly the efficacy of new drugs and formulations. In this context, new drug delivery systems, such as nanotechnology systems, have been developed for these purposes. Some nanocarriers are able to interact with the immune system of the vertebrate host, modulating the immune response to the elimination of pathogenic microorganisms. In this overview of nanotechnology-based delivery strategies for established and new antichagasic agents, different strategies, and limitations of a wide class of nanocarriers are explored, as new perspectives in the treatment and monitoring of Chagas disease.

Piplartine-Inspired 3,4,5-Trimethoxycinnamates: Trypanocidal, Mechanism of Action, and In Silico Evaluation.

Chagas disease (CD) is one of the main neglected tropical diseases that promote relevant socioeconomic impacts in several countries. The therapeutic options for the treatment of CD are limited, and parasite resistance has been reported. Piplartine is a phenylpropanoid imide that has diverse biological activities, including trypanocidal action. Thus, the objective of the present work was to prepare a collection of thirteen esters analogous to piplartine (1-13) and evaluate their trypanocidal activity against Trypanosoma cruzi. Of the tested analogues, compound 11 ((E)-furan-2-ylmethyl 3-(3,4,5-trimethoxyphenyl)acrylate) showed good activity with IC50 values = 28.21 ± 5.34 µM and 47.02 ± 8.70 µM, against the epimastigote and trypomastigote forms, respectively. In addition, it showed a high rate of selectivity to the parasite. The trypanocidal mechanism of action occurs through the induction of oxidative stress and mitochondrial damage. In addition, scanning electron microscopy showed the formation of pores and leakage of cytoplasmic content. Molecular docking indicated that 11 probably produces a trypanocidal effect through a multi-target mechanism, including affinity with proteins CRK1, MPK13, GSK3B, AKR, UCE-1, and UCE-2, which are important for the survival of the parasite. Therefore, the results suggest chemical characteristics that can serve for the development of new trypanocidal prototypes for researching drugs against Chagas disease.

Recommendations for Screening and Diagnosis of Chagas Disease in the United States.

BACKGROUND: Chagas disease affects an estimated 326 000-347 000 people in the United States and is severely underdiagnosed. Lack of awareness and clarity regarding screening and diagnosis is a key barrier. This article provides straightforward recommendations, with the goal of simplifying identification and testing of people at risk for US healthcare providers. METHODS: A multidisciplinary working group of clinicians and researchers with expertise in Chagas disease agreed on 6 main questions, and developed recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, after reviewing the relevant literature on Chagas disease in the United States. RESULTS: Individuals who were born or resided for prolonged time periods in endemic countries of Mexico and Central and South America should be tested for Trypanosoma cruzi infection, and family members of people who test positive should be screened. Women of childbearing age with risk factors and infants born to seropositive mothers deserve special consideration due to the risk of vertical transmission. Diagnostic testing for chronic T. cruzi infection should be conducted using 2 distinct assays. CONCLUSIONS: Increasing provider-directed screening for T. cruzi infection is key to addressing this neglected public health challenge in the United States.

Lizards as Silent Hosts of Trypanosoma cruzi.

We assessed 4 lizard species in Chile for Trypanosoma cruzi, the causative agent of Chagas disease, and 1 species for its ability to transmit the protozoan to uninfected kissing bugs. All lizard species were infected, and the tested species was capable of transmitting the protozoan, highlighting their role as T. cruzi reservoirs.

Energy metabolism as a target for cyclobenzaprine: A drug candidate against Visceral Leishmaniasis.

Leishmaniases have a broad spectrum of clinical manifestations, ranging from a cutaneous to a progressive and fatal visceral disease. Chemotherapy is nowadays the almost exclusive way to fight the disease but limited by its scarce therapeutic arsenal, on its own compromised by adverse side effects and clinical resistance. Cyclobenzaprine (CBP), an FDA-approved oral muscle relaxant drug has previously demonstrated in vitro and in vivo activity against Leishmania sp., but its targets were not fully unveiled. This study aimed to define the role of energy metabolism as a target for the leishmanicidal mechanisms of CBP. Methodology to assess CBP leishmanicidal mechanism variation of intracellular ATP levels using living Leishmania transfected with a cytoplasmic luciferase. Induction of plasma membrane permeability by assessing depolarization with DiSBAC(2)3 and entrance of the vital dye SYTOX® Green. Mitochondrial depolarization by rhodamine 123 accumulation. Mapping target site within the respiratory chain by oxygen consumption rate. Reactive oxygen species (ROS) production using MitoSOX. Morphological changes by transmission electron microscopy. CBP caused on L. infantum promastigotes a decrease of intracellular ATP levels, with irreversible depolarization of plasma membrane, the collapse of the mitochondrial electrochemical potential, mild uncoupling of the respiratory chain, and ROS production, with ensuing intracellular Ca2+ imbalance and DNA fragmentation. Electron microscopy supported autophagic features but not a massive plasma membrane disruption. The severe and irreversible mitochondrial damage induced by CBP endorsed the bioenergetics metabolism as a relevant target within the lethal programme induced by CBP in Leishmania. This, together with the mild-side effects of this oral drug, endorses CBP as an appealing novel candidate as a leishmanicidal drug under a drug repurposing strategy.