DOCSLIB.ORG

TITLE 1 What to Expect and When: Benznidazole Toxicity in Chronic Chagas Disease 2 Treatment 3 4 AUTHORS: Aldasoro E,1,2* Posada

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
TITLE 1 What to Expect and When: Benznidazole Toxicity in Chronic Chagas Disease 2 Treatment 3 4 AUTHORS: Aldasoro E,1,2* Posada 1 TITLE 2 What to expect and when: Benznidazole toxicity in chronic Chagas Disease 3 treatment 4 5 AUTHORS: Aldasoro E,1,2* Posada E, 1,2 Requena-Mendez A, 1,2 Calvo-Cano A, 1,2 6 Serret N,1 Casellas A,2 Sanz S,2 Soy D,3,4 Pinazo MJ,1,2 Gascon J1,2 7 8 1International Health Service, Hospital Clinic Barcelona, Barcelona, Spain 9 2ISGlobal, Barcelona Center for International Health Research (CRESIB), Barcelona, 10 Spain 11 3Pharmacy Service, Hospital Clinic Barcelona, Barcelona, Spain 12 4Institut de Investigació Biomèdica Agustí Pi i Sunyer (IDIBAPS), University of 13 Barcelona, Barcelona, Spain 14 15 RUNNING TITLE: Benznidazole toxicity in chronic Chagas Disease 16 17 CORRESPONDING AUTHOR: Dr Edelweiss Aldasoro 18 o Email: [email protected] 19 o Address: ISGlobal, Barcelona Institute for Global Health, Carrer 20 Roselló 132, 4-2, 08036 Barcelona 21 o Telephone: 0034932274135 22 23 SYNOPSIS 24 Background: Benznidazole is one of the two most effective antiparasitic drugs for 25 Chagas Disease treatment. However, the knowledge about its toxicity profile is 26 mostly based on post-marketing observational studies. 27 28 Objectives: Our study combines data from two prospective clinical trials designed 29 to control safety for the drug newly produced by ELEA Laboratories (Abarax®). 30 31 Methods: Eligible participants were selected by consecutive sampling strategy in 32 CINEBENZ and BIOMARCHA study between 2013 and 2016 (EUDRACT 2011- 33 002900-34, 2012-002645-38; and clinicaltrials.gov NCT01755403, NCT01755377, 34 respectively). Enrolled subjects received treatment with benznidazole 35 5mg/kg/day orally in two divided doses for eight weeks and were followed-up 36 fortnightly. 37 38 Results: We observed 305 adverse reactions among 85 out of 99 participants 39 (85.9%). Each patient had a median of three adverse reactions, 89.5% were mild 40 and the median duration was 12 days. Most adverse reactions appeared in the first 41 month of treatment except arthritis and peripheral neuropathy. 26 patients did not 42 complete treatment: two were withdrawn, one for ectopic pregnancy and one for 43 epilepsy relapse due to cysticercosis; two were lost to follow-up and 22 due to 44 adverse reactions, two of them severe. We observed some unexpected adverse 45 reactions that have not been described previously such as psychiatric symptoms, 46 erectile dysfunction, menstrual cycle alterations or lung infiltration. 47 48 Conclusions: There is a very high frequency of adverse reactions to benznidazole. 49 Most adverse reactions are mild but the treatment burden is significant and 50 unexpected reactions are not rare. Severe reactions are uncommon but they can be 51 life threatening. Further studies are necessary to optimise treatment. 52 53 54 INTRODUCTION 55 Chagas Disease is a chronic anthropo-zoonotic disease caused by the protozoan 56 Trypanosoma cruzi and it is most frequently transmitted through a vectorial route. 57 However, it is also a major public health problem in endemic and non-endemic 58 countries given its transmissibility from mother to child or through blood products 59 and organ transplants. Outbreaks with oral transmission have been also 60 described.1-3 It is estimated that 6-7 million people could be infected worldwide 61 and 20-30% of them could develop a potentially life-threating cardiac condition.1 62 63 The treatment in acute cases is very effective whereas in chronic disease the 64 effectiveness has been highly debated.4-6 There is a general understanding that 65 parasitic persistence increases the risk of cardiac lesions in chronically infected 66 patients and therefore parasite eradication may be necessary in the early stages of 67 the disease.7 On the other hand, the advanced cardiac stage is irreversible and 68 treatment of this stage is futile. The BENEFIT trial supported this concept 69 considering that it did not show significant morbidity or mortality reduction with 70 antiparasitic treatment in advanced cardiac stage.5,8-9 However, this study did not 71 provide answers about the long-term effectiveness of the antiparasitic approach in 72 early stages of the chronic disease. In the latest years the evidence from 73 observational studies has supported treating most of the chronic patients with the 74 available antiparasitic drugs.10-11 75 76 At the moment, the most effective drugs to treat Chagas disease are benznidazole 77 and nifurtimox. Both drugs have shown poor tolerance, significant adverse 78 reactions (ARs) and high treatment suspension rates. They were registered and 79 used in clinical practice since their launch in the 1970s with little understanding of 80 their mechanism of action and toxicity. Early comprehensive preclinical 81 toxicological investigation were conducted for nifurtimox whereas no equivalent 82 information has been available for benznidazole.12 Given that no pre-marketing 83 safety studies were performed for, most of the available knowledge on human 84 safety has been built up based on post-marketing retrospective observational 85 studies. Very few studies have been designed to offer a systematic post-marketing 86 surveillance, which could explain the variability in side effect reports between 87 different groups in addition to race or genetics differences. 88 89 Expert’s forums have discussed about the possibility of different safety profiles 90 depending on the drug manufacturer. This question was raised mostly when Elea 91 laboratories took responsibility of producing after a dramatic period of 2 years of 92 lack of benznidazole stock worldwide between 2011 and 2013.13 There were some 93 concerns that the drug produced by the Brazilian state-owned laboratory LAFEPE 94 and Elea Laboratories from Argentina may have a different toxicity profile, even if 95 some retrospective studies did not observe any significant differences in treatment 96 withdrawals.14 97 98 The aim of this study is to offer a systematic evaluation of safety in a prospective 99 study about the drug manufactured by Elea Laboratories in chronically infected 100 adults. 101 102 103 PATIENTS AND METHODS 104 Study design 105 From 2013 to 2016 we conducted two prospective, open-label and single centre 106 clinical trials in the International Health Department at Hospital Clinic of 107 Barcelona. CINEBENZ was designed to study the population pharmacokinetics of 108 benznidazole and BIOMARCHA monitored cardiac biomarkers before and after 109 treatment (EUDRACT 2011-002900-34 and 2012-002645-38, and clinicaltrials.gov 110 NCT01755403 and NCT01755377 registration numbers respectively). The 111 protocols were approved by the Ethics Committee of the Hospital Clinic of 112 Barcelona and AEMPS (the Spanish Agency of Medicines and Medical Devices), 113 they were conducted in accordance with the Declaration of Helsinki and national 114 and institutional standards. Before inclusion in the study, all patients provided 115 written informed consent. Both studies had the same treatment and follow-up 116 protocol during treatment and the ARs of both studies were analysed together. 117 118 Eligible subjects met the inclusion criteria of being at least 18 years old, diagnosed 119 by two different positive Trypanosoma cruzi serologic tests, not to have received 120 treatment before and not to have advanced cardiac disease. Exclusion criteria were 121 hypersensitivity to benznidazole, difficulties to follow-up, immunodeficiency, 122 hepatic or renal impairment, cardiac disease of other origin, pregnancy or 123 lactation. Enrolled subject received treatment with benznidazole 5 mg/kg/day 124 orally with or without food in two divided doses for eight weeks, with a maximum 125 of 400mg/day (Abarax®, Elea Laboratory, Argentina). 126 127 We selected all subjects attending health facilities meeting the inclusion and 128 exclusion criteria with consecutive sampling strategy. Patients were followed-up 129 fortnightly with clinical review and blood test. The clinical review consisted of an 130 open interview plus an exhaustive structured questioning, a physical examination 131 and vital sign measurements. Patients had a contact telephone number available 132 24h and they could be seen ad-hoc in the clinic if needed. As per site protocol at the 133 time, no food restriction was applied but commitment to avoid alcohol during 134 treatment was required. 135 136 Data management and Statistical analysis 137 Data collection and management were performed using OpenClinica open source 138 software, version 2.0.3.1. (Copyright© OpenClinica LLC and collaborators, 139 Waltham, MA, USA, www.OpenClinica.com). Data were described using frequencies 140 for discrete variables and median (IQR) for continuous variables. ARs incidence 141 rates and confidence intervals based on Poisson distribution were estimated. 142 Multilevel Poisson regression models were employed to assess fortnightly 143 incidence rate ratio (IRR) of ARs.15 To assess the existence of a time trend of the 144 IRR of ARs, the same models were performed using day instead of fortnight. 145 Following clinical criteria, all models were adjusted by sex and age. The 146 significance level was set at 0.05. The analysis was carried out using Stata 147 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: 148 StataCorp LP). 149 150 151 RESULTS 152 Out of 100 eligible patients, 99 received treatment with BNZ and one patient 153 declined to participate. Baseline demographic and clinical characteristics can be 154 seen in Table 1. In the cohort, 97 patients (98.0%) were Bolivian, 73.7% were 155 women and the median age was 36 (IQR 9). Regarding to Chagas Disease form, six 156 had a mild heart disease and the rest did not have any evidence of organic disease. 157 Out of 99 participants, 26 patients (26.3%) did not complete treatment: 22 due to 158 ARs; two were lost to follow-up; two had withdrawals criteria with severe 159 consequences, one for pregnancy and one for epilepsy relapse. (Table 2) 160 161 Eighty-five patients out of 99 (85.9%) had 305 ARs.
Load more

Recommended publications
  • Biopharmaceutical Optimization in Neglected Diseases for Paediatric Patients by Applying the Provisional Paediatric Biopharmaceu
    Gonzalez-Alvarez Isabel (Orcid ID: 0000-0002-1685-142X) i. Title (including PI’s name) “Biopharmaceutical Optimization in neglected diseases for paediatric patients by applying the provisional paediatric Biopharmaceutical Classification System” Principal investigator: Gordon L. Amidon Author for correspondence: [email protected] ii. Short running title of less than 40 characters Paediatric Biopharmaceutical Optimization in Neglected Diseases iii. The full names of all authors Jose Manuel del Moral Sanchez (delMoral-Sanchez JM) Isabel Gonzalez Alvarez (Gonzalez-Alvarez I) Aaron Cerda Revert (Cerda-Revert A) Marta Gonzalez Alvarez (Gonzalez-Alvarez M) Andres Navarro Ruiz (Navarro A) Gordon L. Amidon (Amidon GL) Marival Bermejo Sanz (Bermejo M) This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcp.13650 This article is protected by copyright. All rights reserved. iv. The authors’ institutional affiliations (ie where the work was carried out, with a footnote for an author’s present address if different from where the work was carried out) Jose Manuel del Moral Sanchez (delMoral-Sanchez JM) 1Institute of Molecular and Cellular Biology of Miguel Hernandez University. Avda de la Universidad s/n, 03202 Elche (Alicante) Spain 2Department of Pharmacokinetics and Pharmaceutical Technology,
    [Show full text]
  • Insights of Antiparasitic Activity of Sodium Diethyldithiocarbamate Against Different Strains of Trypanosoma Cruzi
    www.nature.com/scientificreports OPEN Insights of antiparasitic activity of sodium diethyldithiocarbamate against diferent strains of Trypanosoma cruzi Johny Wysllas de Freitas Oliveira1,2, Tafarel Melo Torres3, Cláudia Jassica Gonçalves Moreno1,2,4, Bruno Amorim‑Carmo2, Igor Zumba Damasceno5, Ana Katarina Menezes Cruz Soares6, Jeferson da Silva Barbosa7, Hugo Alexandre Oliveira Rocha2,6 & Marcelo Sousa Silva1,2,4,8* Chagas disease is caused by Trypanosoma cruzi and afects thousands of people. Drugs currently used in therapy are toxic and have therapeutic limitations. In addition, the genetic diversity of T. cruzi represents an important variable and challenge in treatment. Sodium diethyldithiocarbamate (DETC) is a compound with pharmacological versatility acting as metal chelators and ROS generation. Thus, the objective was to characterize the antiparasitic action of DETC against diferent strains and forms of T. cruzi and their mechanism. The diferent strains of T. cruzi were grown in LIT medium. To evaluate the antiparasitic activity of DETC, epimastigote and trypomastigote forms of T. cruzi were used by resazurin reduction methods and by counting. Diferent response patterns were obtained between the strains and an IC50 of DETC ranging from 9.44 ± 3,181 to 60.49 ± 7.62 µM. Cell cytotoxicity against 3T3 and RAW cell lines and evaluated by MTT, demonstrated that DETC in high concentration (2222.00 µM) presents low toxicity. Yet, DETC causes mitochondrial damage in T. cruzi, as well as disruption in parasite membrane. DETC has antiparasitic activity against diferent genotypes and forms of T. cruzi, therefore, representing a promising molecule as a drug for the treatment of Chagas disease.
    [Show full text]
  • Nitroaromatic Antibiotics As Nitrogen Oxide Sources
    Review biomolecules Nitroaromatic Antibiotics as Nitrogen Oxide Sources Review Allison M. Rice, Yueming Long and S. Bruce King * Nitroaromatic Antibiotics as Nitrogen Oxide Sources Department of Chemistry and Biochemistry, Wake Forest University, Winston-Salem, NC 27101, USA; Allison M. Rice , Yueming [email protected] and S. Bruce (A.M.R.); King [email protected] * (Y.L.) * Correspondence: [email protected]; Tel.: +1-336-702-1954 Department of Chemistry and Biochemistry, Wake Forest University, Winston-Salem, NC 27101, USA; [email protected]: Nitroaromatic (A.M.R.); [email protected] antibiotics (Y.L.) show activity against anaerobic bacteria and parasites, finding * Correspondence: [email protected]; Tel.: +1-336-702-1954 use in the treatment of Heliobacter pylori infections, tuberculosis, trichomoniasis, human African trypanosomiasis, Chagas disease and leishmaniasis. Despite this activity and a clear need for the Abstract: Nitroaromatic antibiotics show activity against anaerobic bacteria and parasites, finding usedevelopment in the treatment of new of Heliobacter treatments pylori forinfections, these conditio tuberculosis,ns, the trichomoniasis, associated toxicity human Africanand lack of clear trypanosomiasis,mechanisms of action Chagas have disease limited and their leishmaniasis. therapeutic Despite development. this activity Nitroaro and a clearmatic need antibiotics for require thereductive development bioactivation of new treatments for activity for theseand this conditions, reductive the associatedmetabolism toxicity can convert
    [Show full text]
  • Solid Dispersions As a Technological Strategy to Improve the Bio-Performance of Antiparasitic Drugs with Limited Solubility †
    Proceedings Solid Dispersions as a Technological Strategy to Improve the Bio-Performance of Antiparasitic Drugs with Limited Solubility † Santiago N. Campos, Alicia G. Cid, Analía I. Romero, Mercedes Villegas, Cintia A. Briones Nieva, Elio E. Gonzo and José M. Bermúdez * INIQUI (Instituto de Investigaciones para la Industria Química), UNSa (Universidad Nacional de Salta), CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Salta 4400, Argentina; [email protected] (S.N.C.); [email protected] (A.G.C.); [email protected] (A.I.R.); [email protected] (M.V.); [email protected] (C.A.B.N.); [email protected] (E.E.G.) * Correspondence: [email protected]; Tel.: +54-387-425-5410 † Presented at the 1st International Electronic Conference on Pharmaceutics, 1–15 December 2020; Available online: https://iecp2020.sciforum.net/. Abstract: Albendazole (ABZ) and benznidazole (BZL) are drugs with low solubility used in parasitic infections treatment. In this research, solid dispersion (SD) technology was used to enhance ABZ and BZL performance by increasing their dissolution rate and solubility. SDs were prepared by the fusion method, employing Poloxamer 407 (P407) as carrier to disperse 32 of BZL or 50% w/w of ABZ. Furthermore, physical mixtures (PM) of P407 and either ABZ or BZL were also prepared, and then SDs and PMs were characterized. Dissolution tests of SDs, PMs and commercial formulations (CF) of ABZ and BZL were carried out and dissolution profiles were analyzed with the lumped mathe- matical model, which allowed parameters of pharmaceutical relevance to be obtained. The results indicated that ABZ SD presented an initial dissolution rate (IDR) 21-fold and 11-fold faster than PM Citation: Campos, S.N.; Cid, A.G.; and CF, respectively, while the IDR of BZL SD was 2.5-fold and 4.5-fold faster than PM and CF, Romero, A.I.; Villegas, M.; Briones respectively.
    [Show full text]
  • Redalyc.In Vitro Activity of 2-Pyridinecarboxylic Acid Against Trypanosomes of the Subgenus Schizotrypanum Isolated from The
    Acta Scientiarum. Biological Sciences ISSN: 1679-9283 [email protected] Universidade Estadual de Maringá Brasil Ceridóreo Corrêa, Paulo Roberto; da Silveira Pinto, Artur; Divina de Fátima Silva, Grácia; Vieira Filho, Sidney Augusto; Pains Duarte, Lucienir; Yamada-Ogatta, Sueli Fumie In vitro activity of 2-pyridinecarboxylic acid against trypanosomes of the subgenus Schizotrypanum isolated from the bat Phyllostomus hastatus Acta Scientiarum. Biological Sciences, vol. 33, núm. 4, 2011, pp. 437-443 Universidade Estadual de Maringá .png, Brasil Available in: http://www.redalyc.org/articulo.oa?id=187121352009 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative DOI: 10.4025/actascibiolsci.v33i4.6482 In vitro activity of 2-pyridinecarboxylic acid against trypanosomes of the subgenus Schizotrypanum isolated from the bat Phyllostomus hastatus Paulo Roberto Ceridóreo Corrêa1, Artur da Silveira Pinto2, Grácia Divina de Fátima Silva3, Sidney Augusto Vieira Filho4, Lucienir Pains Duarte3 and Sueli Fumie Yamada-Ogatta1* 1Departamento de Microbiologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid, BR-445, 86051-990, Londrina, Paraná, Brazil. 2Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. 3Núcleo de Estudos de Plantas Medicinais, Departamento de Química , Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. 4Departamento de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil. *Author for correspondence. E-mail: [email protected] ABSTRACT.
    [Show full text]
  • Treatment with Suboptimal Dose of Benznidazole Mitigates Immune Response Molecular Pathways in Mice with Chronic Chagas Cardiomyopathy
    ORIGINAL RESEARCH published: 14 July 2021 doi: 10.3389/fcimb.2021.692655 Treatment With Suboptimal Dose of Benznidazole Mitigates Immune Response Molecular Pathways in Mice With Chronic Chagas Cardiomyopathy Priscila Silva Grijo´ Farani 1,2, Khodeza Begum 3, Glaucia Vilar-Pereira 2, Isabela Resende Pereira 2, Igor C. Almeida 3, Sourav Roy 3, Joseli Lannes-Vieira 2 and Otacilio Cruz Moreira 1* 1 Real Time PCR Platform RPT09A, Laboratory of Molecular Biology and Endemic Diseases, Oswaldo Cruz Institute, Edited by: Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, 2 Laboratory of Biology of the Interactions, Oswaldo Cruz Institute, Giovane R. Sousa, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, 3 Department of Biological Sciences, Border Biomedical Research Center, Harvard Medical School, University of Texas at El Paso, El Paso, TX, United States United States Reviewed by: Chronic Chagas cardiomyopathy (CCC) is the most frequent and severe form of Chagas Ana Rosa Pe´ rez, Consejo Nacional de Investigaciones disease, a neglected tropical illness caused by the protozoan Trypanosoma cruzi, and the Cient´ıficas y Te´ cnicas (CONICET), main cause of morbimortality from cardiovascular problems in endemic areas. Although Argentina efforts have been made to understand the signaling pathways and molecular mechanisms Michael Lewis, University of London, underlying CCC, the immunological signaling pathways regulated by the etiological United Kingdom treatment with benznidazole (Bz) has not been reported. In experimental CCC, Bz *Correspondence: combined with the hemorheological and immunoregulatory agent pentoxifylline (PTX) Otacilio Cruz Moreira fi otacilio@ioc.fiocruz.br has bene cial effects on CCC. To explore the molecular mechanisms of Bz or Bz+PTX therapeutic strategies, C57BL/6 mice chronically infected with the T.
    [Show full text]
  • Chagas Disease Discovery (1909 – 2009)
    Presented by DNDi at ASTMH 2009 Drugs for Neglected Diseases Iniciative & Universidade Federal de Ouro Preto, Brazil Combination of Benznidazole and Nifurtimox plus Posaconazole enhances activity against Trypanosoma cruzi in experimental Chagas disease Maria Terezinha Bahia, André Talvani, Shing Chang, Isabela Ribeiro Neglected populations Future New Chemical Entities ‐ Target Product Profile Old drugs with new Chemotherapy strategies Specific anti‐ T. cruzi treatment Improvements in Case Management –Heart Disease Present (2009) Vector control/eradication programmes Description of main clinical manifestations Trypanosoma cruzi identification Past (1909) Chagas disease discovery (1909 – 2009) 1 Presented by DNDi at ASTMH 2009 Evaluating combination treatment… Combination with registered compounds (Benznidazole/Nifurtimox) Aims: (i) improvement of efficacy (ii) improvement of safety and tolerability (iii) reduction of the dose and duration of the therapeutic regimen (iv) Potential impact on resistance development to each individual compounds from the combinations Starting point: Evaluation of combination therapy Nifurtimox/Benznidazole + Azole compounds « Reduction in time, costs and risks » Current available drugs • Benznidazole and Nifurtimox: nitroheterocyclic drugs • Parasiticidal activity: conversion of reactive intermediates within the parasite that generate superoxide, which causes oxidative damage to components of the parasite • Compounds activated within the parasite, probably by a Type 1 Mitochondrial Nitroreductase enzyme Wilkinson et al. PNAS 2008; 105:5022‐7 Paulino et al. Mini Rev Med Chem. 2005 2 Presented by DNDi at ASTMH 2009 Trypanosoma cruzi Ergosterol Biosynthesis Pathway Azole class of compounds: Posaconazole, Ravuconazole E.G. Hankins et al. / Molecular & Biochemical Parasitology 144 (2005) 68–75 Combination of nitroheterocyclic compounds Benznidazole and Nifurtimox plus Posaconazole Swiss mice inoculated with 5.0 x 103 blood trypomastigotes of T.
    [Show full text]
  • Nicotinamide Mononucleotide Adenylyltransferase of Trypanosoma Cruzi (Tcnmnat): a Cytosol Protein Target for Serine Kinases
    670 Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 111(11): 670-675, November 2016 Nicotinamide mononucleotide adenylyltransferase of Trypanosoma cruzi (TcNMNAT): a cytosol protein target for serine kinases Diana Milena Sánchez-Lancheros1, Luis Fernando Ospina-Giraldo2, María Helena Ramírez-Hernández1/+ 1Universidad Nacional de Colombia, Departamento de Biología, Bogotá, Colombia 2Universidad Nacional de Colombia, Departamento de Farmacia, Bogotá, Colombia Nicotinamide/nicotinate adenine dinucleotide (NAD+/NaAD) performs essential functions in cell metabolism and energy production due to its redox properties. The nicotinamide/nicotinate mononucleotide adenylyltransferase (NMNAT, EC 2.7.7.1/18) enzyme catalyses the key step in the biosynthesis of NAD+. Previously, the enzyme NMNAT was identified in Trypanosoma cruzi (TcNMNAT), a pathogenic agent with epidemiological importance in Latin America. To continue with the functional characterisation of this enzyme, its subcellular location and its possible post-translational modifications were examined in this study. For this, polyclonal antibodies were generated in mice, with soluble and denatured recombinant protein being used to detect the parasite’s NMNAT. Immunodetection assays were performed on whole extracts of T. cruzi, and an approximation of its intracellular location was deter- mined using confocal microscopy on wild and transgenic parasites, which revealed the cytosol distribution patterns. This localisation occurs according to the needs of the dinucleotides that exist in this compartment. Additionally, a bioinformatics study was performed as a first approach to establish the post-translational modifications of the enzyme. Possible phosphorylation events were experimentally analysed by western blot, highlighting TcNMNAT as a potential target for serine kinases. Key words: Trypanosoma cruzi - NAD+ biosynthesis - NMNAT - polyclonal antibodies - subcellular location - post-transcriptional modifications Trypanosoma cruzi is the protozoan parasite that several biosynthesis pathways is no surprise.
    [Show full text]
  • Treatment of Adult Chronic Indeterminate Chagas Disease with Benznidazole and Three E1224 Dosing Regimens: a Proof-Of-Concept, Randomised, Placebo-Controlled Trial
    Articles Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial Faustino Torrico*, Joaquim Gascon*, Lourdes Ortiz, Cristina Alonso-Vega, María-Jesús Pinazo, Alejandro Schijman, Igor C Almeida, Fabiana Alves, Nathalie Strub-Wourgaft, Isabela Ribeiro, on behalf of the E1224 Study Group† Summary Background Chagas disease is a major neglected vector-borne disease. In this study, we investigated the safety and Lancet Infect Dis 2018 efficacy of three oral E1224 (a water-soluble ravuconazole prodrug) regimens and benznidazole versus placebo in Published Online adult chronic indeterminate Chagas disease. January 15, 2017 http://dx.doi.org/10.1016/ S1473-3099(17)30538-8 Method In this proof-of-concept, double-blind, randomised phase 2 clinical trial, we recruited adults (18–50 years) with See Online/Comment confirmed diagnosis of Trypanosoma cruzi infection from two outpatient units in Bolivia. Patients were randomised http://dx.doi.org/10.1016/ with a computer-generated randomisation list, which was stratified by centre and used a block size of ten. Patients S1473-3099(17)30535-2 were randomly assigned (1:1:1:1:1) to five oral treatment groups: high-dose E1224 (duration 8 weeks, total dose *Contributed equally 4000 mg), low-dose E1224 (8 weeks, 2000 mg), short-dose E1224 (4 weeks + 4 weeks placebo, 2400 mg), benznidazole †Members listed at the end of (60 days, 5 mg/kg per day), or placebo (8 weeks, E1224-matched tablets). Double-blinding was limited to the E1224 the paper and placebo arms, and assessors were masked to all treatment allocations.
    [Show full text]
  • Tapeworm Infection1.Qxd
    Page 1 of 2 TAPEWORM infection Drug Adult dosage Pediatric dosage — Adult (intestinal stage) Diphyllobothrium latum (fish), Taenia saginata (beef), Taenia solium (pork), Dipylidium caninum (dog) Drug of choice: Praziquantel1,2 5-10 mg/kg PO once 5-10 mg/kg PO once Alternative: Niclosamide3* 2 g PO once 50 mg/kg PO once Hymenolepis nana (dwarf tapeworm) Drug of choice: Praziquantel1,2 25 mg/kg PO once 25 mg/kg PO once Alternative: Nitazoxanide1,4 500 mg PO once/d or bid x 3d5 1-3yrs: 100 mg PO bid x 3d5 4-11yrs: 200 mg PO bid x 3d5 — Larval (tissue stage) Echinococcus granulosus (hydatid cyst) Drug of choice:6 Albendazole7 400 mg PO bid x 1-6mos 15 mg/kg/d (max. 800 mg) x 1-6mos Echinococcus multilocularis Treatment of choice: See footnote 8 Taenia solium (Cysticercosis) Treatment of choice: See footnote 9 Alternative: Albendazole7 400 mg PO bid x 8-30d; can be 15 mg/kg/d (max. 800 mg) PO in repeated as necessary 2 doses x 8-30d; can be repeated as necessary OR Praziquantel1,2 100 mg/kg/d PO in 3 doses x 100 mg/kg/d PO in 3 doses x 1 day then 50 mg/kg/d in 1 day then 50 mg/kg/d in 3 doses x 29 days 3 doses x 29 days * Availability problems. See table below. 1. Not FDA-approved for this indication. 2. Praziquantel should be taken with liquids during a meal. 3. Niclosamide must be chewed thoroughly before swallowing and washed down with water.
    [Show full text]
  • Antichagasic and Trichomonacidal Activity of 1-Substituted 2-Benzyl-5-Nitroindazolin-3-Ones and 3-Alkoxy-2-Benzyl-5-Nitro-2H-Ind
    European Journal of Medicinal Chemistry 115 (2016) 295e310 Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech Research paper Antichagasic and trichomonacidal activity of 1-substituted 2-benzyl- 5-nitroindazolin-3-ones and 3-alkoxy-2-benzyl-5-nitro-2H- indazoles* Cristina Fonseca-Berzal a, b, Alexandra Ibanez-Escribano~ a, b, Felipe Reviriego a, c, Jose Cumella c, Paula Morales c, Nadine Jagerovic c, Juan Jose Nogal-Ruiz a, b, Jose Antonio Escario a, b, Patricia Bernardino da Silva d, Maria de Nazare C. Soeiro d, ** * Alicia Gomez-Barrio a, b, , Vicente J. Aran a, c, a Moncloa Campus of International Excellence (UCM-UPM & CSIC), Spain b Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramon y Cajal s/n, 28040, Madrid, Spain c Instituto de Química Medica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/Juan de la Cierva 3, 28006, Madrid, Spain d Laboratorio de Biologia Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365, 21040-900, Rio de Janeiro, Brazil article info abstract Article history: Two series of new 5-nitroindazole derivatives, 1-substituted 2-benzylindazolin-3-ones (6e29, series A) Received 23 November 2015 and 3-alkoxy-2-benzyl-2H-indazoles (30e37, series B), containing differently functionalized chains at Received in revised form position 1 and 3, respectively, have been synthesized starting from 2-benzyl-5-nitroindazolin-3-one 5, 26 February 2016 and evaluated against the protozoan parasites Trypanosoma cruzi and Trichomonas vaginalis, etiological Accepted 14 March 2016 agents of Chagas disease and trichomonosis, respectively.
    [Show full text]
  • Benznidazole
    Clinical Pharmacy Program Guidelines for Benznidazole Program Prior Authorization Medication Benznidazole tablets Markets in Scope Arizona, Calirofnria, Colorado, Hawaii, Maryland, Nevada, New Jersey, New York, New York EPP, Pennsylvania- CHIP, Rhode Island, South Carolina Issue Date 2/2018 Pharmacy and 3/2021 Therapeutics Approval Date Effective Date 6/2021 1. Background: Benznidazole, a nitroimidazole antimicrobial, is indicated in pediatric patients 2 to 12 years of age for the treatment of Chagas disease (American trypanosomiasis), caused by Trypanosoma cruzi. Antiparasitic treatment is indicated for all cases of acute or reactivated Chagas disease and for chronic Trypanosoma cruzi (T. cruzi) infection in children up to 18 years old. Congenital infections are considered acute disease. Treatment is strongly recommended for adults up to 50 years old with chronic infection who do not already have advanced Chagas cardiomyopathy. For adults older than 50 years with chronic T. cruzi infection, the decision to treat with antiparasitic drugs should be individualized, weighing the potential benefits and risks for the patient. Physicians should consider factors such as the patient’s age, clinical status, preference, and overall health.2 2. Coverage Criteria: A. Authorization 1. Benznidazole will be approved based on the following criteria: a. Diagnosis of Chagas disease (American trypanosomiasis) due to Trypanosoma cruzi Authorization will be issued for 60 days. 3. Additional Clinical Rules: Confidential and Proprietary, © 2021 UnitedHealthcare Services Inc. 1 • Notwithstanding Coverage Criteria, UnitedHealthcare may approve initial and re- authorization based solely on previous claim/medication history, diagnosis codes (ICD-10) and/or claim logic. Use of automated approval and re-approval processes varies by program and/or therapeutic class.
    [Show full text]