Chagas Disease and the London Declaration on Neglected Tropical Diseases

Fil: Tarleton, Rick L.. University of Georgia; Estados Unidos. Chagas Disease Foundation; Estados UnidosFil: Gurtler, Ricardo Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; ArgentinaFil: Urbina, Julio A.. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Ramsey, Janine. Instituto Nacional de Salud Pública; MéxicoFil: Viotti, Rodolfo Jorge. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; Argentin

Congenital Chagas’ disease transmission in the United States: Diagnosis in adulthood

Two brothers with congenitally-acquired Chagas’ disease (CD) diagnosed during adulthood are reported. The patients were born in the USA to a mother from Bolivia who on subsequent assessment was found to be serologically positive for Trypanosoma cruzi. Serologic screening of all pregnant women who migrated from countries with endemic CD is strongly recommended

Population pharmacokinetics of benznidazole in adult patients with Chagas disease

AIM: To build a population pharmacokinetic (PopPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. METHODS: Prospective, open-label, single-center clinical trial(EudraCT:2011-002900-34;CINEBENZclinicaltrials.govnumber:NCT01755403), approved by the local ethics committee. Patients received 2.5mg/kg/12h (Abarax(R), Elea Laboratory, Argentina) for 60 days. Plasma BZN samples were taken at several times along the study and analyzed by HPLC-UV. The PopPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion and residual variability were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate the BNZ concentration-time course profile for different dosage regimens. RESULTS: A total of 358 plasma BZN concentrations from 39 patients were included in the analysis. A one-compartment-PK-model characterized by clearance(CL/F) and apparent volume of distribution(V/F) with first order absorption(Ka) and elimination, adequately described the data (CL/F:1.73 L/h; V/F:89.6 L; Ka:1.15 h-1). No covariates were found to be significant for CL/F and V/F. Internal and external validation of the final model showed adequate results. Data from simulations revealed that a dose of 2.5mg/kg/12h might lead to overexposure in the most of the patients. A lower dose (2.5mg/kg/24h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3-6 mg/L. CONCLUSION: A population PK model for BNZ in adults with chronic Chagas disease has been developed. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24h would adequately keep BNZ trough plasma concentrations within the recommended target range concentrations for the majority of patients

Antiproliferative, Ultrastructural, and Physiological Effects of Amiodarone on Promastigote and Amastigote Forms of Leishmania amazonensis

Amiodarone (AMIO), the most frequently antiarrhythmic drug used for the symptomatic treatment of chronic Chagas' disease patients with cardiac compromise, has recently been shown to have also specific activity against fungi, Trypanosoma cruzi and Leishmania. In this work, we characterized the effects of AMIO on proliferation, mitochondrial physiology, and ultrastructure of Leishmania amazonensis promastigotes and intracellular amastigotes. The IC50 values were 4.21 and 0.46 μM against promastigotes and intracellular amastigotes, respectively, indicating high selectivity for the clinically relevant stage. We also found that treatment with AMIO leads to a collapse of the mitochondrial membrane potential (ΔΨm) and to an increase in the production of reactive oxygen species, in a dose-dependent manner. Fluorescence microscopy of cells labeled with JC-1, a marker for mitochondrial energization, and transmission electron microscopy confirmed severe alterations of the mitochondrion, including intense swelling and modification of its membranes. Other ultrastructural alterations included (1) presence of numerous lipid-storage bodies, (2) presence of large autophagosomes containing part of the cytoplasm and membrane profiles, sometimes in close association with the mitochondrion and endoplasmic reticulum, and (3) alterations in the chromatin condensation and plasma membrane integrity. Taken together, our results indicate that AMIO is a potent inhibitor of L. amazonensis growth, acting through irreversible alterations in the mitochondrial structure and function, which lead to cell death by necrosis, apoptosis and/or autophagy

Growth inhibition and ultrastructural alterations induced by Δ24(25)-sterol methyltransferase inhibitors in Candida spp. isolates, including non-albicans organisms

<p>Abstract</p> <p>Background</p> <p>Although <it>Candida </it>species are commensal microorganisms, they can cause many invasive fungal infections. In addition, antifungal resistance can contribute to failure of treatment.</p> <p>The purpose of this study was to evaluate the antifungal activity of inhibitors of Δ²⁴⁽²⁵⁾-sterol methyltransferase (24-SMTI), 20-piperidin-2-yl-5α-pregnan-3β-20(R)-diol (AZA), and 24(R,S),25-epiminolanosterol (EIL), against clinical isolates of <it>Candida </it>spp., analysing the ultrastructural changes.</p> <p>Results</p> <p>AZA and EIL were found to be potent growth inhibitors of <it>Candida </it>spp. isolates. The median MIC₅₀was 0.5 μg.ml^-1for AZA and 2 μg.ml^-1for EIL, and the MIC₉₀was 2 μg.ml^-1for both compounds. All strains used in this study were susceptible to amphotericin B; however, some isolates were fluconazole- and itraconazole-resistant. Most of the azole-resistant isolates were <it>Candida </it>non-<it>albicans </it>(CNA) species, but several of them, such as <it>C. guilliermondii, C. zeylanoides</it>, and <it>C. lipolytica</it>, were susceptible to 24-SMTI, indicating a lack of cross-resistance. Reference strain <it>C. krusei </it>(ATCC 6258, FLC-resistant) was consistently susceptible to AZA, although not to EIL. The fungicidal activity of 24-SMTI was particularly high against CNA isolates. Treatment with sub-inhibitory concentrations of AZA and EIL induced several ultrastructural alterations, including changes in the cell-wall shape and thickness, a pronounced disconnection between the cell wall and cytoplasm with an electron-lucent zone between them, mitochondrial swelling, and the presence of electron-dense vacuoles. Fluorescence microscopy analyses indicated an accumulation of lipid bodies and alterations in the cell cycle of the yeasts. The selectivity of 24-SMTI for fungal cells versus mammalian cells was assessed by the sulforhodamine B viability assay.</p> <p>Conclusion</p> <p>Taken together, these results suggest that inhibition of 24-SMT may be a novel approach to control <it>Candida </it>spp. infections, including those caused by azole-resistant strains.</p

Magic-angle spinning 31 P NMR spectroscopy of condensed phosphates in parasitic protozoa: visualizing the invisible

Abstract We report the results of a solid-state 31 P nuclear magnetic resonance (NMR) spectroscopic investigation of the acidocalcisome organelles from Trypanosoma brucei (bloodstream form), Trypanosoma cruzi and Leishmania major (insect forms). The spectra are characterized by a broad envelope of spinning sidebands having isotropic chemical shifts at V V0, 3 37 and 3 321 ppm. These resonances are assigned to orthophosphate, terminal (K K) phosphates of polyphosphates and bridging (L L) phosphates of polyphosphates, respectively. The average polyphosphate chain length is V V3.3 phosphates. Similar results were obtained with whole L. major promastigotes. 31 P NMR spectra of living L. major promastigotes recorded under conventional solution NMR conditions had spectral intensities reduced with respect to solution-state NMR spectra of acid extracts, consistent with the invisibility of the solid-state phosphates. These results show that all three parasites contain large stores of condensed phosphates which can be visualized by using magic-angle spinning NMR techniques. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies

New chemotherapy regimens and biomarkers for Chagas disease: The rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia.

Introduction Chagas disease (CD) affects ∼7 million people worldwide. Benznidazole (BZN) and nifurtimox (NFX) are the only approved drugs for CD chemotherapy. Although both drugs are highly effective in acute and paediatric infections, their efficacy in adults with chronic CD (CCD) is lower and variable. Moreover, the high incidence of adverse events (AEs) with both drugs has hampered their widespread use. Trials in CCD adults showed that quantitative PCR (qPCR) assays remain negative for 12 months after standard-of-care (SoC) BZN treatment in ∼80% patients. BZN pharmacokinetic data and the nonsynchronous nature of the proliferative mammal-dwelling parasite stage suggested that a lower BZN/NFX dosing frequency, combined with standard or extended treatment duration, might have the same or better efficacy than either drug SoC, with fewer AEs. Methods and analysis New ThErapies and Biomarkers for ChagaS infEctiOn (TESEO) is an open-label, randomised, prospective, phase-2 clinical trial, with six treatment arms (75 patients/arm, 450 patients). Primary objectives are to compare the safety and efficacy of two new proposed chemotherapy regimens of BZN and NFX in adults with CCD with the current SoC for BZN and NFX, evaluated by qPCR and biomarkers for 36 months posttreatment and correlated with CD conventional serology. Recruitment of patients was initiated on 18 December 2019 and on 20 May 2021, 450 patients (study goal) were randomised among the six treatment arms. The treatment phase was finalised on 18 August 2021. Secondary objectives include evaluation of population pharmacokinetics of both drugs in all treatment arms, the incidence of AEs, and parasite genotyping. Ethics and dissemination The TESEO study was approved by the National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), federal regulatory agency of the Plurinational State of Bolivia and the Ethics Committees of the participating institutions. The results will be disseminated via publications in peer-reviewed journals, conferences and reports to the NIH, FDA and participating institutions. Trial registration number NCT03981523.We are very grateful to Marcelo Abril, Fundación Mundo Sano, Buenos Aires, Argentina, and Dr. Sergio Sosa-Estani, DNDi, Rio de Janeiro, Brazil, for their continuous support during the elaboration and implementation of this trial; Dr. Martin Springsklee (Medical Affairs Anti-Infectives), Dr. Ulrich-Dietmar Madeja (Head, Neglected Tropical Disease Programmes), and Dr. Maria-Luisa Rodriguez (Global Project Leader) at Bayer AG, Berlin, Germany, and this company for the kind donation of the nifurtimox to be used in this study; Dr. Pedro Albajar Viñas, WHO, for the support to the study through the kind advancement of nifurtimox from the WHO stockpile; Ernesto Palma (Business Development and External Markets Manager) and Luis Ferrero (former ELEA’s Especial Business Manager), at Laboratorio ELEA Phoenix S.A., Buenos Aires, Argentina, and this company for the generous donation of the benznidazole to be used in the TESEO study. We also thank Dr. Soyoung Jeon (currently at the New Mexico State University) and Dr. Xiaogang Su, Dept. of Mathematical Sciences, Border Biomedical Research Center (BBRC), University of Texas at El Paso, for the statistical analyses performed during the TESEO project evaluation by NIH. We are very thankful to all the medical, supporting (nurses, social workers, and laboratory staff) and administrative personnel of the three Chagas Platforms in Bolivia for their technical assistance and dedication in the recruitment, treatment, and follow-up of the CCD patients in this study. We would also like to thank all the staff (postdoctoral fellows, technicians, and administrative personnel) and graduate and undergraduate students of the participating institutions involved in this clinical trial and part of the TESEO Study Group

2024 Recommendations for Validation of Noninvasive Arterial Pulse Wave Velocity Measurement Devices

BACKGROUND: Arterial stiffness, as measured by arterial pulse wave velocity (PWV), is an established biomarker for cardiovascular risk and target-organ damage in individuals with hypertension. With the emergence of new devices for assessing PWV, it has become evident that some of these devices yield results that display significant discrepancies compared with previous devices. This discrepancy underscores the importance of comprehensive validation procedures and the need for international recommendations. METHODS: A stepwise approach utilizing the modified Delphi technique, with the involvement of key scientific societies dedicated to arterial stiffness research worldwide, was adopted to formulate, through a multidisciplinary vision, a shared approach to the validation of noninvasive arterial PWV measurement devices. RESULTS: A set of recommendations has been developed, which aim to provide guidance to clinicians, researchers, and device manufacturers regarding the validation of new PWV measurement devices. The intention behind these recommendations is to ensure that the validation process can be conducted in a rigorous and consistent manner and to promote standardization and harmonization among PWV devices, thereby facilitating their widespread adoption in clinical practice. CONCLUSIONS: It is hoped that these recommendations will encourage both users and developers of PWV measurement devices to critically evaluate and validate their technologies, ultimately leading to improved consistency and comparability of results. This, in turn, will enhance the clinical utility of PWV as a valuable tool for assessing arterial stiffness and informing cardiovascular risk stratification and management in individuals with hypertension

Resurgence of Vaccine-Preventable Diseases in Venezuela as a Regional Public Health Threat in the Americas.

Venezuela's tumbling economy and authoritarian rule have precipitated an unprecedented humanitarian crisis. Hyperinflation rates now exceed 45,000%, and Venezuela's health system is in free fall. The country is experiencing a massive exodus of biomedical scientists and qualified healthcare professionals. Reemergence of arthropod-borne and vaccine-preventable diseases has sparked serious epidemics that also affect neighboring countries. In this article, we discuss the ongoing epidemics of measles and diphtheria in Venezuela and their disproportionate impact on indigenous populations. We also discuss the potential for reemergence of poliomyelitis and conclude that action to halt the spread of vaccine-preventable diseases within Venezuela is a matter of urgency for the country and the region. We further provide specific recommendations for addressing this crisis