Epigallocathechin-O-3-Gallate Inhibits Trypanothione Reductase of Leishmania Infantum, Causing Alterations in Redox Balance And
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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. -
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. -
Diverse Biosynthetic Pathways and Protective Functions Against Environmental Stress of Antioxidants in Microalgae
plants Review Diverse Biosynthetic Pathways and Protective Functions against Environmental Stress of Antioxidants in Microalgae Shun Tamaki 1,* , Keiichi Mochida 1,2,3,4 and Kengo Suzuki 1,5 1 Microalgae Production Control Technology Laboratory, RIKEN Baton Zone Program, Yokohama 230-0045, Japan; [email protected] (K.M.); [email protected] (K.S.) 2 RIKEN Center for Sustainable Resource Science, Yokohama 230-0045, Japan 3 Kihara Institute for Biological Research, Yokohama City University, Yokohama 230-0045, Japan 4 School of Information and Data Sciences, Nagasaki University, Nagasaki 852-8521, Japan 5 euglena Co., Ltd., Tokyo 108-0014, Japan * Correspondence: [email protected]; Tel.: +81-45-503-9576 Abstract: Eukaryotic microalgae have been classified into several biological divisions and have evo- lutionarily acquired diverse morphologies, metabolisms, and life cycles. They are naturally exposed to environmental stresses that cause oxidative damage due to reactive oxygen species accumulation. To cope with environmental stresses, microalgae contain various antioxidants, including carotenoids, ascorbate (AsA), and glutathione (GSH). Carotenoids are hydrophobic pigments required for light harvesting, photoprotection, and phototaxis. AsA constitutes the AsA-GSH cycle together with GSH and is responsible for photooxidative stress defense. GSH contributes not only to ROS scavenging, but also to heavy metal detoxification and thiol-based redox regulation. The evolutionary diversity of microalgae influences the composition and biosynthetic pathways of these antioxidants. For example, α-carotene and its derivatives are specific to Chlorophyta, whereas diadinoxanthin and fucoxanthin are found in Heterokontophyta, Haptophyta, and Dinophyta. It has been suggested that Citation: Tamaki, S.; Mochida, K.; Suzuki, K. Diverse Biosynthetic AsA is biosynthesized via the plant pathway in Chlorophyta and Rhodophyta and via the Euglena Pathways and Protective Functions pathway in Euglenophyta, Heterokontophyta, and Haptophyta. -
Development of Drug Resistance in Trypanosoma Brucei Rhodesiense and Trypanosoma Brucei Gambiense
411-419 13/9/08 11:56 Page 411 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 22: 411-419, 2008 411 Development of drug resistance in Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Treatment of human African trypanosomiasis with natural products (Review) STEFANIE GEHRIG1 and THOMAS EFFERTH2 1Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 364, 2German Cancer Research Center, Pharmaceutical Biology (C015), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Received April 10, 2008; Accepted June 12, 2008 DOI: 10.3892/ijmm_00000037 Abstract. Human African trypanosomiasis is an infectious Contents disease which has resulted in the deaths of thousands of people in Sub-Saharan Africa. Two subspecies of the 1. Introduction protozoan parasite Trypanosoma brucei are the causative 2. Disease and clinical manifestation agents of the infection, whereby T. b. gambiense leads to 3. Standard chemotherapy chronic development of the disease and T. b. rhodesiense 4. Development of resistance establishes an acute form, which is fatal within months or 5. Screening of natural products even weeks. Current chemotherapy treatment is complex, 6. Conclusion since special drugs have to be used for the different development stages of the disease, as well as for the parasite concerned. Melarsoprol is the only approved drug for 1. Introduction effectively treating both subspecies of human African trypanosomiasis in its advanced stage, however, the drug's Human African typanosomiasis is a vector-born parasitic potency is constrained due to an unacceptable side effect: disease demonstrating a major public health problem for encephalopathy, which develops in one out of every 20 people in the Sub-Saharan region. -
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. -
A Tryparedoxin-Coupled Biosensor Reveals a Mitochondrial Trypanothione Metabolism in Trypanosomes
1 A tryparedoxin-coupled biosensor reveals a mitochondrial trypanothione 2 metabolism in trypanosomes 3 Samantha Ebersoll1, Marta Bogacz1, Lina M. Günter1, Tobias P. Dick2, R. Luise 4 Krauth-Siegel1* 5 1 6 Biochemie-Zentrum der Universität Heidelberg, Heidelberg, Germany; 2Division of Redox 7 Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, 8 Germany 9 10 11 *For correspondence: [email protected] 12 13 14 15 Competing interests: 16 The authors declare that no competing interests exist. 1 17 Abstract Trypanosomes have a trypanothione redox metabolism that provides the reducing 18 equivalents for numerous essential processes, most being mediated by tryparedoxin (Tpx). 19 While the biosynthesis and reduction of trypanothione are cytosolic, the molecular basis of 20 the thiol redox homeostasis in the single mitochondrion of these parasites has remained 21 largely unknown. Here we expressed Tpx-roGFP2, roGFP2-hGrx1 or roGFP2 in either the 22 cytosol or mitochondrion of Trypanosoma brucei. We show that the novel Tpx-roGFP2 is a 23 superior probe for the trypanothione redox couple and that the mitochondrial matrix harbors a 24 trypanothione system. Inhibition of trypanothione biosynthesis by the anti-trypanosomal drug 25 Eflornithine impairs the ability of the cytosol and mitochondrion to cope with exogenous 26 oxidative stresses, indicating a direct link between both thiol systems. Tpx depletion abolishes 27 the cytosolic, but only partially affects the mitochondrial sensor response to H2O2. This 28 strongly suggests that the mitochondrion harbors some Tpx and, another, as yet unidentified, 29 oxidoreductase. 30 31 Introduction 32 Trypanosomatids are the causative agents of African sleeping sickness (Trypanosoma brucei 33 gambiense and T. -
Trypanosomatid Hydrogen Peroxidase Metabolism
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Volume 221, number 2, 427-431 FEB 05098 September 1987 Trypanosomatid hydrogen peroxidase metabolism P.G. Penketh, W.P.K. Kennedy*, C.L. Patton and A.C. Sartorelli MacArthur Center for Parasitology and Tropical Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA and * Wolfson Molecular Biology Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London WCLE 7HT, England Received 7 July 1987 The rate of whole cell HZ02 metabolism in several salivarian and stercorarian trypanosomes and Leishrnania species was measured. These cells metabolized Hz02 at rates between 2.3 and 48.2 nmol/lO* cells per min depending upon the species employed. Hz02 metabolism was largely insensitive to NaN3, implying that typi- cal catalase and peroxidase haemoproteins are not important in Hz02 metabolism. The metabolism of H202, however, was almost completely inhibited by N-ethylmaleimide. In representative species, Hz02 metabolism was shown to occur through a trypanothione-dependent mechanism. Hydrogen peroxide; Trypanothione; Macrophage; (Trypanosoma, Leishmania) 1. INTRODUCTION been reported that L. donovani possesses a surface-membrane acid phosphatase which reduces Many trypanosomatids have been reported to the magnitude of the oxidative burst of lack or to be extremely deficient in enzyme systems neutrophils, inferring a pathophysiological role for necessary for the removal of Hz02 (i.e. catalase, this enzyme [5]. However, defense mechanisms glutathione peroxidase) [l-5]. Defense against endogenously generated Hz02 and the mechanisms against H202, however, appear to be possibly diminished quantity of Hz02 produced a ubiquitous requirement of most aerobic cells [6]. -
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. -
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. -
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. -
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 -
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.