DOCSLIB.ORG

In Silico and in Vitro Comparative Activity of Green Tea Components Against Leishmania Infantum

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
In Silico and in Vitro Comparative Activity of Green Tea Components Against Leishmania Infantum Journal of Global Antimicrobial Resistance 18 (2019) 187–194 Contents lists available at ScienceDirect Journal of Global Antimicrobial Resistance journal homepage: www.elsevier.com/locate/jgar In silico and in vitro comparative activity of green tea components against Leishmania infantum a b,h, a Shahram Khademvatan , Kaveh Eskandari *, Khosrow Hazrati-Tappeh , c,d, e,f g,f a,f Fakher Rahim **, Masoud Foroutan , Elham Yousefi , Negar Asadi a Department of Medical Parasitology and Mycology and Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran b Social Determinants of Health Research Center, Urmia University of Medical Sciences, Urmia, Iran c Research Center of Thalassemia & Hemoglobinopathy, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran d Clinical Research Development Unit, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran e Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran f Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran g Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran h Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran A R T I C L E I N F O A B S T R A C T Article history: Objectives: Green tea contains a predominant set of polyphenolic compounds with biological activities. Received 19 November 2018 The aim of this study was to investigate the antileishmanial activities of the main components of green Received in revised form 17 January 2019 tea, including catechin, (À)-epicatechin, epicatechin gallate (ECG) and (À)-epigallocatechin 3-O-gallate Accepted 12 February 2019 (EGCG), against Leishmania infantum promastigotes. Available online 20 February 2019 Methods: Green tea ligands and the control drug pentamidine were docked using AutoDock 4.3 software into the active sites of trypanothione synthetase and arginase, which were modelled using homology Keywords: modelling programs. The colorimetric MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bioinformatics bromide] assay was used to measure L. infantum promastigotes at different concentrations of green In silico tea compounds in a concentration- and time-dependent manner. Results were expressed as 50% and 90% In vitro Green tea inhibitory concentrations (IC50 and IC90, respectively). Leishmania infantum Results: In silico and in vitro assays showed that all of the green tea compounds have antileishmanial activity. EGCG and ECG were the most active compounds against L. infantum promastigotes, with IC50 values of 27.7 mM and 75 mM and IC90 values of 88.4 mM and 188.7 mM, respectively. Pentamidine displayed greater growth inhibition than all of the other tested compounds in a concentration- and time- dependent manner. Conclusion: In this study, in silico and docking results were in accordance with the in vitro activity of the compounds. Moreover, EGCG and ECG showed reasonable levels of selectivity for Leishmania. © 2019 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved. 1. Introduction infectious disease remains a serious health problem with ever- increasing cases around the world, especially in most develop- Leishmaniasis is a neglected tropical and subtropical disease ing countries [1]. Leishmaniasis has been reported in 98 resulting in a variety of clinical manifestations in humans, countries and approximately 350 million people are at risk of ranging from severe tegumentary forms (cutaneous, mucocuta- the infection, with 20 million people infected worldwide. The neous and diffuse cutaneous) to the fatal visceral form. This estimated incidence of the disease per annum is 2 million cases, of which 1.5 million are categorised as disfiguring cutaneous leishmaniasis and 0.5 million are the life-threatening visceral leishmaniasis [1]. * Corresponding author. Diverse clinical manifestations caused by the genus Leishmania ** Corresponding author at: Research Center of Thalassemia & Hemoglobinopathy, are highly dependent on the host’s immune condition, the parasite Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, species as well as interactions between host immune factors and Iran. parasite components [2]. Chemotherapy using pentavalent anti- E-mail addresses: [email protected] (K. Eskandari), 1 fi [email protected] (F. Rahim). monials such as Glucantime as the rst-line therapy and https://doi.org/10.1016/j.jgar.2019.02.008 2213-7165/© 2019 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved. 188 S. Khademvatan et al. / Journal of Global Antimicrobial Resistance 18 (2019) 187–194 pentamidine, amphotericin B and miltefosine as second-line drugs anticancer effects, apoptosis induction and antiproliferative have limitations such as toxicity, resistance, parenteral activity against Trypanosoma and Leishmania parasites have been administration, variable efficacy and long administration sched- studied in many investigations [20–23]. In a previous study, Feily ules [3]. Therefore, there is an immediate requirement for new et al. suggested that the ethanolic extract of green tea (in different available, safe and affordable compounds for the treatment of concentrations) has significant leishmanicidal activity against leishmaniasis [4,5]. Leishmania major promastigotes [24]. In another work, dos Reis In silico screening, structure–activity relationship analysis, et al. showed the inhibition of Leishmania amazonensis and rat bioinformatics, and in vitro or in vivo biological evaluation are ARGs by green tea, EGCG, catechin and EC [25]. considered as valuable pharmacological tools for neglected The aim of this study was to investigate the in vitro diseases such as leishmaniasis. Knowledge of the tertiary antileishmanial activities of green tea crude extract and its main structure of a protein used as the drug target together with components, including catechin, EC, epicatechin gallate (ECG) and computational methods can lead to the identification of potential EGCG, against Leishmania infantum promastigotes in comparison drug binding sites. Moreover, an identified binding site can be with the control drug pentamidine. In addition, a docking used to characterise physicochemical properties and binding simulation of the interaction between inhibitors and the structural ligands on the target protein. Thus, using various methods for models of ARG-L and TS was performed using AutoDock tools in identification of ligand binding sites in proteins, especially recent order to visualise the profile of interaction with the catalytic site of methods for ligand binding site so-called computer-aided drug the enzyme. design, can contribute to finding effective and relatively safe drugs [4–7]. Target specification is one of the main steps in the 2. Materials and methods process of drug development. Moreover, the biological properties of a protein depend on its physical interaction with other 2.1. Reagents molecules, therefore the ability to make high-affinity and selective interactions with a drug or other biologically important All of the tested compounds, catechin, EC, ECG, EGCG, fetal molecules depends on the formation of a set of bonds and bovine serum (FBS), RPMI 1640 medium, penicillin, streptomycin, interactions. Theoretically, during specification and exploitation MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro- of a drug target, characteristic features of selected targets need to mide] and dimethyl sulfoxide (DMSO) were purchased from be unique to pathogens and significantly different from their host Sigma-Aldrich (St Louis, MO). All the aforementioned compounds homologue or absent in the host [8,9]. Phylogenetically, as well as the reference drug pentamidine were refrigerated at 4 C trypanosomatids branch out relative to the higher eukaryotes and were diluted in phosphate-buffered saline (PBS) (pH 7.2) at the and their cellular organisation differs from mammalian cells. time of incubation. Accordingly, it is possible to detect a number of targets that are specific to these pathogens [10]. 2.2. Template selection and homology modelling Trypanothione synthetase (TS) and arginase (ARG) are unique and essential enzymes for Leishmania parasite survival and can The protein sequences of TS and ARG of L. infantum and several serve as drug targets [11]. Synthesis of trypanothione [bis other kinetoplastid families were retrieved by protein Basic Local (glutathionyl)spermidine] is catalysed by TS and trypanothione Alignment Search Tool (BLAST) in GenBank from the National reductase in the polyamine (PA) synthesis pathway and protects Center for biotechnology information (NCBI) and Los Alamos trypanosomatids against oxidative stress by promoting the National Laboratory websites [26]. Multiple sequence alignment removal of reactive oxygen species, reactive nitrogen species was conducted using ClustalW v.1.8 to locate the regions of and other reactive species produced by the host’s defence system interest. Three-dimensional (3D) structural models of TS and ARG [12]. PAs play a significant role in differentiation, proliferation and were created using Swiss-Model and Geno3D software and cellular redox mechanisms in Leishmania [13]. Thus, enzymes of the models were validated using a set of structural the
Load more

Recommended publications
  • Miltefosine Combined with Intralesional Pentamidine for Leishmania Braziliensis Cutaneous Leishmaniasis in Bolivia
    Am. J. Trop. Med. Hyg., 99(5), 2018, pp. 1153–1155 doi:10.4269/ajtmh.18-0183 Copyright © 2018 by The American Society of Tropical Medicine and Hygiene Miltefosine Combined with Intralesional Pentamidine for Leishmania braziliensis Cutaneous Leishmaniasis in Bolivia Jaime Soto,1* Paula Soto,1 Andrea Ajata,2 Daniela Rivero,3 Carmelo Luque,2 Carlos Tintaya,2 and Jonathan Berman4 1FUNDERMA (Fundacion ´ Nacional de Dermatolog´ıa), Santa Cruz, Bolivia; 2Servicio Departamental de Salud, Departamento de La Paz, La Paz, Bolivia; 3Hospital Dermatologico ´ de Jorochito, Santa Cruz, Bolivia; 4AB Foundation, North Bethesda, Maryland Abstract. Bolivian cutaneous leishmaniasis due to Leishmania braziliensis was treated with the combination of mil- tefosine (150 mg/day for 28 days) plus intralesional pentamidine (120 μg/mm2 lesion area on days 1, 3, and 5). Ninety-two per cent of 50 patients cured. Comparison to historic controls at our site suggests that the efficacy of the two drugs was additive. Adverse effects and cost were also additive. This combination may be attractive when a prime consideration is efficacy (e.g., in rescue therapy), avoidance of parenteral therapy, or the desire to treat locally and also provide systemic protection against parasite dissemination. INTRODUCTION METHODS AND PATIENTS Cutaneous leishmaniasis (CL) in the New World gener- Study design and treatments. This was an open-label ally presents as a papule that enlarges and ulcerates over evaluation of one intervention: standard treatment with oral 1–3 months and then self-cures, but the predominant spe- miltefosine in combination with intralesional treatment with cies at our site in Bolivia, Leishmania (Viannia) braziliensis pentamidine.
    [Show full text]
  • 204684Orig1s000
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 204684Orig1s000 OFFICE DIRECTOR MEMO Deputy Office Director Decisional Memo Page 2 of 17 NDA 204,684 Miltefosine Capsules 1. Introduction Leishmania organisms are intracellular protozoan parasites that are transmitted to a mammalian host by the bite of the female phlebotomine sandfly. The main clinical syndromes are visceral leishmaniasis (VL), cutaneous leishmaniasis (CL), and mucosal leishmaniasis (ML). VL is the result of systemic infection and is progressive over months or years. Clinical manifestations include fever, hepatomegaly, splenomegaly, and bone marrow involvement with pancytopenia. VL is fatal if untreated. Liposomal amphotericin B (AmBisome®) was FDA approved in 1997 for the treatment of VL. CL usually presents as one or more skin ulcers at the site of the sandfly bite. In most cases, the ulcer spontaneously resolves within several months, leaving a scar. The goals of therapy are to accelerate healing, decrease morbidity and decrease the risk of relapse, local dissemination, or mucosal dissemination. There are no FDA approved drugs for the treatment of CL. Rarely, CL disseminates from the skin to the naso-oropharyngeal mucosa, resulting in ML. ML can also develop some time after CL spontaneous ulcer healing. The risk of ML is thought to be highest with CL caused by the subgenus Viannia. ML is characterized in the medical literature as progressive with destruction of nasal and pharyngeal structures, and death may occur due to complicating aspiration pneumonia. There are no FDA approved drugs for the treatment of ML. Paladin Therapeutics submitted NDA 204, 684 seeking approval of miltefosine for the treatment of VL caused by L.
    [Show full text]
  • Natural Products That Target the Arginase in Leishmania Parasites Hold Therapeutic Promise
    microorganisms Review Natural Products That Target the Arginase in Leishmania Parasites Hold Therapeutic Promise Nicola S. Carter, Brendan D. Stamper , Fawzy Elbarbry , Vince Nguyen, Samuel Lopez, Yumena Kawasaki , Reyhaneh Poormohamadian and Sigrid C. Roberts * School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; cartern@pacificu.edu (N.S.C.); stamperb@pacificu.edu (B.D.S.); fawzy.elbarbry@pacificu.edu (F.E.); nguy6477@pacificu.edu (V.N.); lope3056@pacificu.edu (S.L.); kawa4755@pacificu.edu (Y.K.); poor1405@pacificu.edu (R.P.) * Correspondence: sroberts@pacificu.edu; Tel.: +1-503-352-7289 Abstract: Parasites of the genus Leishmania cause a variety of devastating and often fatal diseases in humans worldwide. Because a vaccine is not available and the currently small number of existing drugs are less than ideal due to lack of specificity and emerging drug resistance, the need for new therapeutic strategies is urgent. Natural products and their derivatives are being used and explored as therapeutics and interest in developing such products as antileishmanials is high. The enzyme arginase, the first enzyme of the polyamine biosynthetic pathway in Leishmania, has emerged as a potential therapeutic target. The flavonols quercetin and fisetin, green tea flavanols such as catechin (C), epicatechin (EC), epicatechin gallate (ECG), and epigallocatechin-3-gallate (EGCG), and cinnamic acid derivates such as caffeic acid inhibit the leishmanial enzyme and modulate the host’s immune response toward parasite defense while showing little toxicity to the host. Quercetin, EGCG, gallic acid, caffeic acid, and rosmarinic acid have proven to be effective against Leishmania Citation: Carter, N.S.; Stamper, B.D.; in rodent infectivity studies.
    [Show full text]
  • The Epidemiology and Clinical Features of Balamuthia Mandrillaris Disease in the United States, 1974 – 2016
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Clin Infect Manuscript Author Dis. Author manuscript; Manuscript Author available in PMC 2020 August 28. Published in final edited form as: Clin Infect Dis. 2019 May 17; 68(11): 1815–1822. doi:10.1093/cid/ciy813. The Epidemiology and Clinical Features of Balamuthia mandrillaris Disease in the United States, 1974 – 2016 Jennifer R. Cope1, Janet Landa1,2, Hannah Nethercut1,3, Sarah A. Collier1, Carol Glaser4, Melanie Moser5, Raghuveer Puttagunta1, Jonathan S. Yoder1, Ibne K. Ali1, Sharon L. Roy6 1Waterborne Disease Prevention Branch, Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA 2James A. Ferguson Emerging Infectious Diseases Fellowship Program, Baltimore, MD, USA 3Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA 4Kaiser Permanente, San Francisco, CA, USA 5Office of Financial Resources, Centers for Disease Control and Prevention Atlanta, GA, USA 6Parasitic Diseases Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA Abstract Background—Balamuthia mandrillaris is a free-living ameba that causes rare, nearly always fatal disease in humans and animals worldwide. B. mandrillaris has been isolated from soil, dust, and water. Initial entry of Balamuthia into the body is likely via the skin or lungs. To date, only individual case reports and small case series have been published. Methods—The Centers for Disease Control and Prevention (CDC) maintains a free-living ameba (FLA) registry and laboratory. To be entered into the registry, a Balamuthia case must be laboratory-confirmed.
    [Show full text]
  • Epigallocathechin-O-3-Gallate Inhibits Trypanothione Reductase of Leishmania Infantum, Causing Alterations in Redox Balance And
    ORIGINAL RESEARCH published: 25 March 2021 doi: 10.3389/fcimb.2021.640561 Epigallocathechin-O-3-Gallate Inhibits Trypanothione Reductase of Leishmania infantum, Causing Alterations in Redox Balance and Edited by: Leading to Parasite Death Brice Rotureau, Institut Pasteur, France Job D. F. Inacio 1, Myslene S. Fonseca 1, Gabriel Limaverde-Sousa 2, Ana M. Tomas 3,4, Reviewed by: Helena Castro 3 and Elmo E. Almeida-Amaral 1* Wanderley De Souza, Federal University of Rio de Janeiro, 1 Laborato´ rio de Bioqu´ımica de Tripanosomatideos, Instituto Oswaldo Cruz (IOC), Fundac¸ão Oswaldo Cruz – FIOCRUZ, Brazil Rio de Janeiro, Brazil, 2 Laborato´ rio de Esquistossomose Experimental, Instituto Osvaldo Cruz, Fundac¸ão Oswaldo Cruz – Andrea Ilari, FIOCRUZ, Rio de Janeiro, Brazil, 3 i3S—Instituto de Investigac¸ão e Inovac¸ão em Sau´ de, Universidade do Porto, Porto, Italian National Research Portugal, 4 ICBAS—Instituto de Cieˆ ncias Biome´ dicas Abel Salazar, Universidade do Porto, Porto, Portugal Council, Italy Marina Gramiccia, ISS, Italy Leishmania infantum is a protozoan parasite that causes a vector borne infectious disease *Correspondence: in humans known as visceral leishmaniasis (VL). This pathology, also caused by L. Elmo E. Almeida-Amaral donovani, presently impacts the health of 500,000 people worldwide, and is treated elmo@ioc.fiocruz.br with outdated anti-parasitic drugs that suffer from poor treatment regimens, severe side Specialty section: effects, high cost and/or emergence of resistant parasites. In previous works we have This article was submitted to disclosed the anti-Leishmania activity of (-)-Epigallocatechin 3-O-gallate (EGCG), a Parasite and Host, flavonoid compound present in green tea leaves.
    [Show full text]
  • Treatment of Visceral Leishmaniasis with Intravenous Pentamidine And
    International Journal of Infectious Diseases 14 (2010) e522–e525 Contents lists available at ScienceDirect International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid Case Report Treatment of visceral leishmaniasis with intravenous pentamidine and oral fluconazole in an HIV-positive patient with chronic renal failure — a case report and brief review of the literature Jan Rybniker a, Valentin Goede a, Jessica Mertens b, Monika Ortmann c, Wolfgang Kulas d, Matthias Kochanek a, Thomas Benzing e, Jose´ R. Arribas f, Gerd Fa¨tkenheuer a,* a 1st Department of Internal Medicine, University of Cologne, 50924 Cologne, Germany b Department of Gastroenterology, University of Cologne, Cologne, Germany c Institute of Pathology, University of Cologne, Cologne, Germany d Nephrologisches Zentrum Mettmann, Mettmann, Germany e Department of Medicine and Centre for Molecular Medicine, University of Cologne, Cologne, Germany f Enfermedades Infecciosas, Hospital Universitario La Paz, Madrid, Spain ARTICLE INFO SUMMARY Article history: We report the case of an HIV-positive patient with visceral leishmaniasis and several relapses after Received 3 March 2009 treatment with the two first-line anti-leishmanial drugs, liposomal amphotericin B and miltefosine. End- Accepted 4 June 2009 stage renal failure occurred in 2007 when the patient was on long-term treatment with miltefosine. A Corresponding Editor: William Cameron, relapse of leishmaniasis in 2008 was successfully treated with a novel combination regimen of Ottawa, Canada intravenous pentamidine and oral fluconazole. Secondary prophylaxis with fluconazole monotherapy did not prevent parasitological relapse of leishmaniasis. Keywords: ß 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Visceral leishmaniasis HIV Fluconazole Pentamidine Miltefosine Renal failure 1.
    [Show full text]
  • Lopinavir, an HIV-1 Peptidase Inhibitor, Induces Alteration on the Lipid Metabolism of Cambridge.Org/Par Leishmania Amazonensis Promastigotes
    Parasitology Lopinavir, an HIV-1 peptidase inhibitor, induces alteration on the lipid metabolism of cambridge.org/par Leishmania amazonensis promastigotes 1 2 3 Special Issue Research Karina M. Rebello , Valter V. Andrade-Neto , Aline A. Zuma , 3 4 Article Maria Cristina M. Motta , Claudia Regina B. Gomes , Marcus Vinícius N. de Souza4, Geórgia C. Atella5, Marta H. Branquinha6, ‡Both authors share senior authorship. André L. S. Santos6, Eduardo Caio Torres-Santos2,‡ and Claudia M. d’Avila-Levy1,‡ Cite this article: Rebello KM et al (2018). Lopinavir, an HIV-1 peptidase inhibitor, 1Laboratório de Estudos Integrados em Protozoologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz induces alteration on the lipid metabolism of (FIOCRUZ), Rio de Janeiro, Brazil; 2Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Leishmania amazonensis promastigotes. 3 145 – FIOCRUZ, Rio de Janeiro, Brazil; Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Parasitology , 1304 1310. https://doi.org/ 4 10.1017/S0031182018000823 Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil; Laboratório de Síntese de Fármacos, Farmanguinhos, FIOCRUZ, Rio de Janeiro, Brazil; 5Instituto de Bioquímica Médica, UFRJ, Rio de Received: 8 February 2018 Janeiro, Brazil and 6Laboratório de Investigação de Peptidases, Instituto de Microbiologia Paulo de Góes, UFRJ, Revised: 3 April 2018 Rio de Janeiro, Brazil Accepted: 5 April 2018 First published online: 28 May 2018 Key words: Abstract Aspartyl; chemotherapy; co-infection; The anti-leishmania effects of HIV peptidase inhibitors (PIs) have been widely reported; how- leishmaniasis; trypanosomatids ever, the biochemical target and mode of action are still a matter of controversy in Leishmania Author for correspondence: parasites.
    [Show full text]
  • Interactions with Protease Inhibitors Charts Revised February 2018
    www.hiv-druginteractions.org Interactions with Protease Inhibitors Charts revised February 2018. Full information available at www.hiv-druginteractions.org Page 1 of 4 Please note that if a drug is not listed it cannot automatically be assumed it is safe to coadminister. ATV Cobi DRV FPV IDV LPV RTV SQV TPV ATV Cobi DRV FPV IDV LPV RTV SQV TPV Anaesthetics & Muscle Relaxants Antibacterials (continued) Alcuronium Ertapenem Bupivacaine Erythromycin Cisatracurium Ethambutol Desflurane Ethionamide Dexmedetomidine Flucloxacillin Enflurane Gentamicin Ephedrine Imipenem/Cilastatin Halothane Isoniazid Isoflurane Kanamycin Ketamine Levofloxacin Linezolid Nitrous oxide Meropenem Propofol Metronidazole Rocuronium Moxifloxacin Sevoflurane Nitrofurantoin Sufentanil Ofloxacin Suxamethonium (succinylcholine) Para-aminosalicylic acid Tetracaine Penicillins Thiopental for distribution. for Pyrazinamide Tizanidine Rifabutin Vecuronium Rifampicin Analgesics Rifapentine Alfentanil Rifaximin Aspirin Spectinomycin Buprenorphine Streptomycin Celecoxib Sulfadiazine Codeine Telithromycin Tetracyclines
    [Show full text]
  • Clinical Trial Protocol
    Research Protocol - A randomized trial of AmBisome monotherapy and combination of AmBisome and miltefosine for the treatment of VL in HIV positive patients in Ethiopia followed by secondary VL prophylactic treatment with pentamidine Item Type Other Authors Hailu, Asrat; Diro, Ermias; Kolja, Stille; Ritmeijer, Koert; Yifru, Sisay; van Griensven, Johan; Zijlstra, Ed; Dorlo, Thomas Rights These materials can be used, adapted and copied as long as citation of the source is given including the direct URL to the material. This work is licensed under a Creative Commons Attribution 4.0 International License: http://creativecommons.org/licenses/by/4.0/ https:// i.creativecommons.org/l/by/4.0/88x31.png Download date 24/09/2021 17:38:21 Link to Item http://hdl.handle.net/10144/332058 CLINICAL TRIAL PROTOCOL A randomized trial of AmBisome® monotherapy and combination of AmBisome® and miltefosine for the treatment of VL in HIV positive patients in Ethiopia followed by secondary VL prophylactic treatment with pentamidine Name of product(s)/ Liposomal amphotericin B (AmBisome®) Project code Miltefosine (Impavido®) Drug Class Polyene, alkylphosphocholine Phase Phase III Indication HIV and VL co-infected patients Protocol Number HIV/VL 0511 Sponsor DNDi, Chemin Louis Dunant, 15, 1202 GENEVA, Switzerland Phone: +41 22 906 9230 Co-sponsor MSF Operational Centre Amsterdam Confidential Page 1 of 61 FINAL Version 2 dated 29th November 2012 Protocol number HIV/VL 0511 AmBisome®, Miltefosine 2nd Version Coordinating Principal Investigators Investigator/Principal Coordinating Investigator: Prof Asrat Hailu Investigator Gondar site investigator: Dr Ermias Diro Abdurafi site investigator: Dr. Stille Kolja , Médecins Sans Frontières (MSF) Co-investigators Dr Koert Ritmeijer, Médecins Sans Frontières, Amsterdam Dr Sisay Yifru, College of Health Sciences, Gondar University Dr Johan van Griensven, Institute of Tropical Medicine, Antwerp Prof Ed Zijlstra, DNDi Dr.
    [Show full text]
  • World Health Organization Model List of Essential Medicines, 21St List, 2019
    World Health Organizatio n Model List of Essential Medicines 21st List 2019 World Health Organizatio n Model List of Essential Medicines 21st List 2019 WHO/MVP/EMP/IAU/2019.06 © World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. World Health Organization Model List of Essential Medicines, 21st List, 2019. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris.
    [Show full text]
  • 204684Orig1s000
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 204684Orig1s000 MEDICAL REVIEW(S) Clinical Investigator Financial Disclosure Review Template Application Number: 204684 Submission Date(s): September 27, 2012 and April 19, 2013 Applicant: Paladin Therapeutics, Inc. Product: IMPAVIDO (miltefosine) Reviewer: Hala Shamsuddin, M.D. Date of Review: February 24, 2014 Covered Clinical Study (Name and/or Number): Study 3154 Study 3168 Study Z020a and b Study SOTO Study Z022 Dutch PK study Was a list of clinical investigators provided: Yes X No (Request list from applicant) Total number of investigators identified: Six (6) Number of investigators who are sponsor employees (including both full-time and part-time employees): None Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): Six (6) If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)): Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: None Significant payments of other sorts: None Proprietary interest in the product tested held by investigator: None Significant equity interest held by investigator in sponsor of covered study: None Is an attachment provided with details Yes X No (Request details from of the disclosable financial applicant) interests/arrangements: Is a description of the steps taken to Yes X No (Request information minimize potential bias provided: from applicant) Number of investigators with certification of due diligence (Form FDA 3454, box 3) None Is an attachment provided with the NA No (Request explanation Reference ID: 3464181 reason: from applicant) Discuss whether the applicant has adequately disclosed financial interests/arrangements with clinical investigators as recommended in the guidance for industry Financial Disclosure by Clinical Investigators.
    [Show full text]
  • Environmentally Classified Pharmaceuticals 2014-2015
    2014-2015 ENVIRONMENTALLY CLASSIFIED PHARMACEUTICALS Stockholm County Council Contents Reducing Residues from Pharmaceuticals in Nature is Part Reducing Residues from Pharmaceuticals of the Environmental Work of in Nature is Part of the Environmental Work of Stockholm County Council ..................1 Stockholm County Council Impact of Pharmaceuticals on Contributing to the reduction of environmental the Environment .........................................................................2 risks from pharmaceuticals is an important part How the Substances are Classified ......................2 of the environmental work of Stockholm County How to Read the Table .................................................4 Council. According to the Environmental Challenge Substances which are Exempt 2016, the Council´s 2012-2016 Environmental from Classification ............................................................6 Programme, the Council is mandated to i.a. do The Precautionary Principle ......................................6 preventive environmental health work. This invol- Tables A Alimentary Tract and Metabolism............................7 ves fostering healthy inhabitants in an environ- ment with clean air and water. To reduce the most B Blood and Blood-Forming Organs ............................9 environmentally hazardous remains of medicinal C Cardiovascular System .................................................10 products in the natural surroundings is therefore D Dermatologicals ............................................................13
    [Show full text]