DOCSLIB.ORG

Malaria Chemoprevention with Monthly Dihydroartemisinin

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Malaria Chemoprevention with Monthly Dihydroartemisinin Kwambai et al. Trials (2018) 19:610 https://doi.org/10.1186/s13063-018-2972-1 STUDY PROTOCOL Open Access Malaria chemoprevention with monthly dihydroartemisinin-piperaquine for the post-discharge management of severe anaemia in children aged less than 5 years in Uganda and Kenya: study protocol for a multi-centre, two-arm, randomised, placebo-controlled, superiority trial Titus K. Kwambai1,2,3* , Aggrey Dhabangi4, Richard Idro4, Robert Opoka4, Simon Kariuki1, Aaron M. Samuels5, Meghna Desai5, Michael Boele van Hensbroek6, Chandy C. John7, Bjarne Robberstad8, Duolao Wang3, Kamija Phiri9 and Feiko O. ter Kuile1,3 Abstract Background: Children hospitalised with severe anaemia in malaria endemic areas in Africa are at high risk of readmission or death within 6 months post-discharge. Currently, no strategy specifically addresses this period. In Malawi, 3 months of post-discharge malaria chemoprevention (PMC) with monthly treatment courses of artemether- lumefantrine given at discharge and at 1 and 2 months prevented 30% of all-cause readmissions by 6 months post- discharge. Another efficacy trial is needed before a policy of malaria chemoprevention can be considered for the post- discharge management of severe anaemia in children under 5 years of age living in malaria endemic areas. Objective: We aim to determine if 3 months of PMC with monthly 3-day treatment courses of dihydroartemisinin- piperaquine is safe and superior to a single 3-day treatment course with artemether-lumefantrine provided as part of standard in-hospital care in reducing all-cause readmissions and deaths (composite primary endpoint) by 6 months in the post-discharge management of children less than 5 years of age admitted with severe anaemia of any or undetermined cause. (Continued on next page) * Correspondence: [email protected] 1Kenya Medical Research Institute (KEMRI), Centre for Global Health Research (CGHR), PO Box 1578, Kisumu 40100, Kenya 2Kisumu County Department of Health, Kenya Ministry of Health, Kisumu, Kenya Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kwambai et al. Trials (2018) 19:610 Page 2 of 12 (Continued from previous page) Methods/design: This is a multi-centre, two-arm, placebo-controlled, individually randomised trial in children under 5 years of age recently discharged following management for severe anaemia. Children in both arms will receive standard in-hospital care for severe anaemia and a 3-day course of artemether-lumefantrine at discharge. At 2 weeks after discharge, surviving children will be randomised to receive either 3-day courses of dihydroartemisinin-piperaquine at 2, 6 and 10 weeks or an identical placebo and followed for 26 weeks through passive case detection. The trial will be conducted in hospitals in malaria endemic areas in Kenya and Uganda. The study is designed to detect a 25% reduction in the incidence of all-cause readmissions or death (composite primary outcome) from 1152 to 864 per 1000 child years (power 80%, α = 0.05) and requires 520 children per arm (1040 total children). Results: Participant recruitment started in May 2016 and is ongoing. Trial registration: ClinicalTrials.gov, NCT02671175. Registered on 28 January 2016. Keywords: Malaria, Severe anaemia, Chemoprevention, Post-discharge, Readmission, Mortality, Dihydroartemisinin-piperaquine, Protocol, Cost-effectiveness Background malaria infections after discharge. These infections Severe anaemia, defined as haemoglobin (Hb) concentra- negate the initial rise in haemoglobin achieved by blood tion level below 5.0 g/dL or haematocrit below 15.0% transfusion, resulting in delayed haematological recov- [1], is a major public health problem in low and ery and potential rebound of severe anaemia and middle-income countries. Severe anaemia is associated death in some children [10, 15–17]. Furthermore, de- with approximately one third of hospital admissions layed haemolytic anaemia occurring 1 to 3 weeks among febrile children in sub-Saharan Africa, contribut- after artesunate treatment of falciparum malaria has ing substantially to paediatric morbidity and mortality, been reported in non-immune travellers [18, 19], al- especially in malaria endemic areas [2, 3]. Children though more recent studies show this to be rare in under 5 years of age are most vulnerable to the African children [20]. long-term effects of severe anaemia, including decreased Malaria control strategies in endemic and epidemic- cognitive performance and mental and motor develop- prone areas include intermittent preventive therapy ment [4]. Rates of in-hospital mortality due to severe an- (IPT). IPT is the administration of a full treatment aemia ranging from 4 to 12% have been reported in course using long-acting antimalarials at pre-defined different epidemiological settings [5–7]. In addition, time intervals irrespective of a patient’s malaria status to these reports indicate a high post-discharge mortality clear existing infections and to provide prolonged and morbidity, especially in the first 3 to 6 months. Lon- prophylaxis against new infections [21]. The World gitudinal follow-up of children aged less than 5 years ad- Health Organization (WHO) recommends IPT as a mal- mitted with severe anaemia in Malawi showed that 8.2% aria control strategy in malaria endemic areas for preg- died by 6 months post-discharge and 5.9% were readmit- nant women (IPTp) [22, 23], infants (IPTi) [24] and for ted with severe anaemia, compared to those without se- children in areas with seasonal malaria transmission vere anaemia, among whom 1.6% died and 0.5% were (‘seasonal malaria chemoprevention’, or SMC) [25]. Cur- readmitted [8, 9]. Similar high rates of post-discharge rently, no control strategy specifically addresses the mortality (10% by 8 weeks) were observed in malaria en- high-risk post-discharge period for children previously demic areas of western Kenya [10] and in Uganda, where treated for severe anaemia in malaria endemic areas. In 12% died or were readmitted within 6 months [11]. Malawi, 3 months of malaria chemoprevention with Standard in-hospital treatment of severe anaemia in three full treatment courses of artemether-lumefantrine, many countries in sub-Saharan Africa consists of a blood given in-hospital to children under 5 years of age admit- transfusion and parenteral artesunate for severe malaria ted with severe malarial anaemia, and at 1 and 2 months [12]. For severe malarial anaemia, this is completed with post-discharge, prevented 31% of deaths or readmissions a 3-day course of artemisinin-based combination therapy by 6 months post-discharge, and 30% of all-cause read- (ACT), usually artemether-lumefantrine. Children are missions [17]. These results are consistent with earlier often discharged with a short course of iron and folate, findings from The Gambia which showed that, in chil- typically with no further scheduled follow-up. Haemato- dren with severe anaemia, chemoprevention targeted logical recovery from malaria-associated anaemia takes during the malaria transmission season halved the rate at least 6 weeks [13, 14]. However, many children in of clinical malaria and reduced all-cause hospital re- these areas experience episodes of new or recrudescent admission by 78% in one trial and recurrence of severe Kwambai et al. Trials (2018) 19:610 Page 3 of 12 anaemia by 78% in another [26, 27]. These data indicate cost-effectiveness of PMC-DP compared to the current that malaria chemoprevention in the post-discharge standard of care. period may provide substantial health benefits. We are conducting an efficacy trial in Kenya and Design considerations Uganda to determine the efficacy and safety of 3 months Rationale for choice of DP for PMC of malaria chemoprevention post-discharge as a poten- Optimal antimalarial prophylaxis with maximum com- tially cost-effective strategy to reduce all-cause readmis- pliance would be provided by a regimen that is long act- sions and deaths in children admitted with severe ing so that administration is not required more anaemia. We hypothesise that, by creating a prophylactic frequently than monthly. Sulphadoxine, mefloquine and time-window post-transfusion for malaria, more time is DP have sufficiently long half-lives to be considered [28]. assured for bone marrow recovery, resulting in a more However, there is high-level resistance to sulphadoxine sustained haematological recovery post-discharge. in many parts of east and southern Africa, precluding its We refer to this strategy as post-discharge malaria che- use for this purpose in these malaria endemic areas [29]. moprevention (PMC) to illustrate the similarities with Both amodiaquine [30] and mefloquine are poorly toler- SMC rather than with IPT in pregnancy as it aims to pro- ated, which is an important consideration when provid- vide complete, rather than intermittent prophylaxis. ing drugs for malaria prevention to recipients with few or no symptoms
Load more

Recommended publications
  • Eurartesim, INN-Piperaquine & INN-Artenimol
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Eurartesim 160 mg/20 mg film-coated tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 160 mg piperaquine tetraphosphate (as the tetrahydrate; PQP) and 20 mg artenimol. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). White oblong biconvex film-coated tablet (dimension 11.5x5.5mm / thickness 4.4mm) with a break-line and marked on one side with the letters “S” and “T”. The tablet can be divided into equal doses. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Eurartesim is indicated for the treatment of uncomplicated Plasmodium falciparum malaria in adults, adolescents, children and infants 6 months and over and weighing 5 kg or more. Consideration should be given to official guidance on the appropriate use of antimalarial medicinal products, including information on the prevalence of resistance to artenimol/piperaquine in the geographical region where the infection was acquired (see section 4.4). 4.2 Posology and method of administration Posology Eurartesim should be administered over three consecutive days for a total of three doses taken at the same time each day. 2 Dosing should be based on body weight as shown in the table below. Body weight Daily dose (mg) Tablet strength and number of tablets per dose (kg) PQP Artenimol 5 to <7 80 10 ½ x 160 mg / 20 mg tablet 7 to <13 160 20 1 x 160 mg / 20 mg tablet 13 to <24 320 40 1 x 320 mg / 40 mg tablet 24 to <36 640 80 2 x 320 mg / 40 mg tablets 36 to <75 960 120 3 x 320 mg / 40 mg tablets > 75* 1,280 160 4 x 320 mg / 40 mg tablets * see section 5.1 If a patient vomits within 30 minutes of taking Eurartesim, the whole dose should be re-administered; if a patient vomits within 30-60 minutes, half the dose should be re-administered.
    [Show full text]
  • Pharmacological and Cardiovascular Perspectives on the Treatment of COVID-19 with Chloroquine Derivatives
    www.nature.com/aps REVIEW ARTICLE Pharmacological and cardiovascular perspectives on the treatment of COVID-19 with chloroquine derivatives Xiao-lei Zhang1, Zhuo-ming Li1, Jian-tao Ye1, Jing Lu1, Lingyu Linda Ye2, Chun-xiang Zhang3, Pei-qing Liu1 and Dayue D Duan2 The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and an ongoing severe pandemic. Curative drugs specific for COVID-19 are currently lacking. Chloroquine phosphate and its derivative hydroxychloroquine, which have been used in the treatment and prevention of malaria and autoimmune diseases for decades, were found to inhibit SARS-CoV-2 infection with high potency in vitro and have shown clinical and virologic benefits in COVID-19 patients. Therefore, chloroquine phosphate was first used in the treatment of COVID-19 in China. Later, under a limited emergency- use authorization from the FDA, hydroxychloroquine in combination with azithromycin was used to treat COVID-19 patients in the USA, although the mechanisms of the anti-COVID-19 effects remain unclear. Preliminary outcomes from clinical trials in several countries have generated controversial results. The desperation to control the pandemic overrode the concerns regarding the serious adverse effects of chloroquine derivatives and combination drugs, including lethal arrhythmias and cardiomyopathy. The risks of these treatments have become more complex as a result of findings that COVID-19 is actually a multisystem disease. While respiratory symptoms are the major clinical manifestations, cardiovascular abnormalities, including arrhythmias, myocarditis, heart failure, and ischemic stroke, have been reported in a significant number of COVID-19 patients. Patients with preexisting cardiovascular conditions (hypertension, arrhythmias, etc.) are at increased risk of severe COVID-19 and death.
    [Show full text]
  • Plasmodium Falciparum Clinical Isolates: in Vitro Genotypic and Phenotypic Characterization Nonlawat Boonyalai1* , Brian A
    Boonyalai et al. Malar J (2020) 19:269 https://doi.org/10.1186/s12936-020-03339-w Malaria Journal RESEARCH Open Access Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: in vitro genotypic and phenotypic characterization Nonlawat Boonyalai1* , Brian A. Vesely1, Chatchadaporn Thamnurak1, Chantida Praditpol1, Watcharintorn Fagnark1, Kirakarn Kirativanich1, Piyaporn Saingam1, Chaiyaporn Chaisatit1, Paphavee Lertsethtakarn1, Panita Gosi1, Worachet Kuntawunginn1, Pattaraporn Vanachayangkul1, Michele D. Spring1, Mark M. Fukuda1, Chanthap Lon1, Philip L. Smith2, Norman C. Waters1, David L. Saunders3 and Mariusz Wojnarski1 Abstract Background: High rates of dihydroartemisinin–piperaquine (DHA–PPQ) treatment failures have been documented for uncomplicated Plasmodium falciparum in Cambodia. The genetic markers plasmepsin 2 (pfpm2), exonuclease (pfexo) and chloroquine resistance transporter (pfcrt) genes are associated with PPQ resistance and are used for moni- toring the prevalence of drug resistance and guiding malaria drug treatment policy. Methods: To examine the relative contribution of each marker to PPQ resistance, in vitro culture and the PPQ survival assay were performed on seventeen P. falciparum isolates from northern Cambodia, and the presence of E415G-Exo and pfcrt mutations (T93S, H97Y, F145I, I218F, M343L, C350R, and G353V) as well as pfpm2 copy number polymor- phisms were determined. Parasites were then cloned by limiting dilution and the cloned parasites were tested for drug susceptibility. Isobolographic analysis of several drug combinations for standard clones and newly cloned P. falciparum Cambodian isolates was also determined. Results: The characterization of culture-adapted isolates revealed that the presence of novel pfcrt mutations (T93S, H97Y, F145I, and I218F) with E415G-Exo mutation can confer PPQ-resistance, in the absence of pfpm2 amplifcation.
    [Show full text]
  • A Screening-Based Approach to Circumvent Tumor Microenvironment
    JBXXXX10.1177/1087057113501081Journal of Biomolecular ScreeningSingh et al. 501081research-article2013 Original Research Journal of Biomolecular Screening 2014, Vol 19(1) 158 –167 A Screening-Based Approach to © 2013 Society for Laboratory Automation and Screening DOI: 10.1177/1087057113501081 Circumvent Tumor Microenvironment- jbx.sagepub.com Driven Intrinsic Resistance to BCR-ABL+ Inhibitors in Ph+ Acute Lymphoblastic Leukemia Harpreet Singh1,2, Anang A. Shelat3, Amandeep Singh4, Nidal Boulos1, Richard T. Williams1,2*, and R. Kiplin Guy2,3 Abstract Signaling by the BCR-ABL fusion kinase drives Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myelogenous leukemia (CML). Despite their clinical activity in many patients with CML, the BCR-ABL kinase inhibitors (BCR-ABL-KIs) imatinib, dasatinib, and nilotinib provide only transient leukemia reduction in patients with Ph+ ALL. While host-derived growth factors in the leukemia microenvironment have been invoked to explain this drug resistance, their relative contribution remains uncertain. Using genetically defined murine Ph+ ALL cells, we identified interleukin 7 (IL-7) as the dominant host factor that attenuates response to BCR-ABL-KIs. To identify potential combination drugs that could overcome this IL-7–dependent BCR-ABL-KI–resistant phenotype, we screened a small-molecule library including Food and Drug Administration–approved drugs. Among the validated hits, the well-tolerated antimalarial drug dihydroartemisinin (DHA) displayed potent activity in vitro and modest in vivo monotherapy activity against engineered murine BCR-ABL-KI–resistant Ph+ ALL. Strikingly, cotreatment with DHA and dasatinib in vivo strongly reduced primary leukemia burden and improved long-term survival in a murine model that faithfully captures the BCR-ABL-KI–resistant phenotype of human Ph+ ALL.
    [Show full text]
  • Downloaded and Saved in PDB Format
    bioRxiv preprint doi: https://doi.org/10.1101/833145; this version posted November 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Full title: Efficacy of Lumefantrine against piperaquine resistant Plasmodium berghei parasites is 2 selectively restored by probenecid, verapamil, and cyproheptadine through ferredoxin NADP+- 3 reductase and cysteine desulfurase 4 5 Short title: Mechanisms of Lumefantrine resistance and reversal in Plasmodium berghei ANKA 6 7 Authors: Fagdéba David Bara1,2,3, Loise Ndung’u1, Noah Machuki Onchieku1, Beatrice Irungu2, 8 Simplice Damintoti Karou3, Francis Kimani4, Damaris Matoke-Muhia4, Peter Mwitari2, Gabriel 9 Magoma1,5, Alexis Nzila6, Daniel Kiboi5* 10 11 Affiliations: 1Department of Molecular Biology and Biotechnology, Pan African University 12 Institute for Basic Sciences, Technology and Innovation (PAUSTI), Nairobi, Kenya. 2Centre for 13 Traditional Medicine and Drug Research, Kenya Medical Research Institute, Nairobi, Kenya. 14 3School of Food and Biology Technology, Universite du Lome, Lome, Togo. 4Centre for 15 Biotechnology Research and Development, Kenya Medical Research Institute, Nairobi, Kenya. 16 5Department of Biochemistry, Jomo Kenyatta University of Agriculture and Technology 17 (JKUAT), Nairobi, Kenya. 6Department of Life Sciences, King Fahd University of Petroleum and 18 Minerals, Dharam, Saudi Arabia. 19 20 Corresponding author: [email protected] ; [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/833145; this version posted November 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Treatment Failure Due to the Potential Under-Dosing of Dihydroartemisinin-Piperaquine in a Patient with Plasmodium Falciparum Uncomplicated Malaria
    INFECT DIS TROP MED 2019; 5: E525 Treatment failure due to the potential under-dosing of dihydroartemisinin-piperaquine in a patient with Plasmodium falciparum uncomplicated malaria I. De Benedetto1, F. Gobbi2, S. Audagnotto1, C. Piubelli2, E. Razzaboni3, R. Bertucci1, G. Di Perri1, A. Calcagno1 1Department of Medical Sciences, Unit of Infectious Diseases, University of Torino, Amedeo di Savoia Hospital, Torino, Italy 2Department of Infectious–Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Verona, Italy 3Unit of Infectious Diseases, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy ABSTRACT: — Background: Dihydroartemisinin/piperaquine (DHA-PPQ) 40/320 mg is approved for the treatment of Plasmodium falciparum uncomplicated malaria. Different recommendations are provided by WHO guidelines and drug data sheet about dosing in overweight patients. We report here a treatment failure likely caused by sub-optimal dosing of dihydroartemisinin-piperaquine in a case of uncomplicated P. fal- ciparum malaria in a returning traveler from Burkina Faso. INTRODUCTION kg). They, therefore, provided an updated dosing body weight dosing schedule in their 2015 guidelines for Dihydroartemisinin/piperaquine (DHA-PPQ) 40/320 malaria treatment that provides for a dose of 200/1600 mg tablet formulation is approved for the treatment mg (5 tablets) in individuals > 80 kg1. of Plasmodium falciparum uncomplicated malaria in adults and children > 6 months and > 5 kg of body weight. Following WHO guidelines, the daily
    [Show full text]
  • Ehealth DSI [Ehdsi V2.2.2-OR] Ehealth DSI – Master Value Set
    MTC eHealth DSI [eHDSI v2.2.2-OR] eHealth DSI – Master Value Set Catalogue Responsible : eHDSI Solution Provider PublishDate : Wed Nov 08 16:16:10 CET 2017 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 1 of 490 MTC Table of Contents epSOSActiveIngredient 4 epSOSAdministrativeGender 148 epSOSAdverseEventType 149 epSOSAllergenNoDrugs 150 epSOSBloodGroup 155 epSOSBloodPressure 156 epSOSCodeNoMedication 157 epSOSCodeProb 158 epSOSConfidentiality 159 epSOSCountry 160 epSOSDisplayLabel 167 epSOSDocumentCode 170 epSOSDoseForm 171 epSOSHealthcareProfessionalRoles 184 epSOSIllnessesandDisorders 186 epSOSLanguage 448 epSOSMedicalDevices 458 epSOSNullFavor 461 epSOSPackage 462 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 2 of 490 MTC epSOSPersonalRelationship 464 epSOSPregnancyInformation 466 epSOSProcedures 467 epSOSReactionAllergy 470 epSOSResolutionOutcome 472 epSOSRoleClass 473 epSOSRouteofAdministration 474 epSOSSections 477 epSOSSeverity 478 epSOSSocialHistory 479 epSOSStatusCode 480 epSOSSubstitutionCode 481 epSOSTelecomAddress 482 epSOSTimingEvent 483 epSOSUnits 484 epSOSUnknownInformation 487 epSOSVaccine 488 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 3 of 490 MTC epSOSActiveIngredient epSOSActiveIngredient Value Set ID 1.3.6.1.4.1.12559.11.10.1.3.1.42.24 TRANSLATIONS Code System ID Code System Version Concept Code Description (FSN) 2.16.840.1.113883.6.73 2017-01 A ALIMENTARY TRACT AND METABOLISM 2.16.840.1.113883.6.73 2017-01
    [Show full text]
  • Eurartesim (Piperaquine Tetraphosphate
    ® Eurartesim (piperaquine tetraphosphate/ dihydroartemisinin ) Guide for Healthcare Professionals (Physician Leaflet) REVISED EDITION 2016 This guide is intended to provide you with information regarding the safe use of Eurartesim and to support you in providing information and counseling to your patients. Guide for Healthcare Professionals – Final English version, dated 05 August 2016 Pag.2 About Eurartesim Eurartesim tablets contain two active antimalarial ingredients: dihydroartemisinin (DHA) and piperaquine tetraphosphate (PQP). The formulation meets WHO recommendations, which advise combination treatment for Plasmodium falciparum malaria to reduce the risk of resistance development, with artemisinin-based preparations regarded as the ‘policy standard’. Eurartesim is effective against Plasmodium falciparum malaria in adults and children. Data are available from large clinical trials that involved over 2600 patients in Africa and Asia, of whom over 1000 were children under 5 years of age. The studies were designed to compare the safety and efficacy of Eurartesim with the established artemisinin combination therapies artemether/lumefantrine (in Africa) and artesunate/mefloquine (in Asia). Eurartesim was shown to be at least as effective as the comparator agents and well tolerated, overall. The DHA component of Eurartesim reaches high concentrations within the parasitised erythrocytes and shows rapid schizontocidal activity by means of free-radical damage to parasite membrane systems. The exact mechanism of action of the PQP component is unknown, but is thought to mirror that of chloroquine, a close structural analogue. PQP has shown good activity against chloroquine- resistant Plasmodium strains in vitro and has a long half-life (20–22 days) resulting in a sustained antimalarial effect. This medicinal product is subject to additional monitoring.
    [Show full text]
  • Medical Review(S) Review of Request for Priority Review
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-268 MEDICAL REVIEW(S) REVIEW OF REQUEST FOR PRIORITY REVIEW To: Edward Cox, MD, MPH Director, Office of Antimicrobial Products Through: Renata Albrecht, M.D Director, DSPTP, OAP From: Joette M. Meyer, Pharm.D. Acting Medical Team Leader, DSPTP, OAP NDA: 22-268 Submission Date: 6/27/08 Date Review Completed 7/25/08 Product: Coartem (artemether/lumefantrine) Sponsor: Novartis Pharmaceuticals Corporation East Hanover, NJ Proposed Indication: Treatment of malaria in patients of 5kg body weight and above with acute, uncomplicated infections due to Plasmodium falciparum or mixed infections including P. falciparum Proposed Dosing Regimen: A standard 3-day treatment schedule with a total of 6 doses is recommended and dosed based on bodyweight: 5 kg to < 15 kg: One tablet as an initial dose, 1 tablet again after 8 hours and then 1 tablet twice daily (morning and evening) for the following two days 15 kg to < 25 kg bodyweight: Two tablets as an initial dose, 2 tablets again after 8 hours and then 2 tablets twice daily (morning and evening) for the following two days 25 kg to < 35 kg bodyweight: Three tablets as an initial dose, 3 tablets again after 8 hours and then 3 tablets twice daily (morning and evening) for the following two days 35 kg bodyweight and above: Four tablets as a single initial dose, 4 tablets again after 8 hours and then 4 tablets twice daily (morning and evening) for the following two days Abbreviations A artemether ACT artemisinin-based combination therapy AL artemether-lumefantrine
    [Show full text]
  • Current Antimalarial Therapies and Advances in the Development of Semi-Synthetic Artemisinin Derivatives
    Anais da Academia Brasileira de Ciências (2018) 90(1 Suppl. 2): 1251-1271 (Annals of the Brazilian Academy of Sciences) Printed version ISSN 0001-3765 / Online version ISSN 1678-2690 http://dx.doi.org/10.1590/0001-3765201820170830 www.scielo.br/aabc | www.fb.com/aabcjournal Current Antimalarial Therapies and Advances in the Development of Semi-Synthetic Artemisinin Derivatives LUIZ C.S. PINHEIRO1, LÍVIA M. FEITOSA1,2, FLÁVIA F. DA SILVEIRA1,2 and NUBIA BOECHAT1 1Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos Farmanguinhos, Fiocruz, Departamento de Síntese de Fármacos, Rua Sizenando Nabuco, 100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil 2Universidade Federal do Rio de Janeiro, Programa de Pós-Graduação em Química, Avenida Athos da Silveira Ramos, 149, Cidade Universitária, 21941-909 Rio de Janeiro, RJ, Brazil Manuscript received on October 17, 2017; accepted for publication on December 18, 2017 ABSTRACT According to the World Health Organization, malaria remains one of the biggest public health problems in the world. The development of resistance is a current concern, mainly because the number of safe drugs for this disease is limited. Artemisinin-based combination therapy is recommended by the World Health Organization to prevent or delay the onset of resistance. Thus, the need to obtain new drugs makes artemisinin the most widely used scaffold to obtain synthetic compounds. This review describes the drugs based on artemisinin and its derivatives, including hybrid derivatives and dimers, trimers and tetramers that contain an endoperoxide bridge. This class of compounds is of extreme importance for the discovery of new drugs to treat malaria. Key words: malaria, Plasmodium falciparum, artemisinin, hybrid.
    [Show full text]
  • Front-Line Glioblastoma Chemotherapeutic Temozolomide Is Toxic
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of East Anglia digital repository 1 Front-line glioblastoma chemotherapeutic temozolomide is toxic 2 to Trypanosoma brucei and potently enhances melarsoprol and 3 eflornithine 4 5 Dietmar Steverding *, Stuart A. Rushworth 6 7 Bob Champion Research & Education Building, Norwich Medical School, University of East 8 Anglia, Norwich, NR4 7UQ, UK 9 10 11 12 __________ 13 * Tel: +44-1603-591291; fax: +44-1603-591750. 14 E-mail address: [email protected] 15 1 16 A B S T R A C T 17 18 Sleeping sickness is an infectious disease that is caused by the protozoan parasite 19 Trypanosoma brucei. The second stage of the disease is characterised by the parasites 20 entering the brain. It is therefore important that sleeping sickness therapies are able to cross 21 the blood-brain barrier. At present, only three medications for chemotherapy of the second 22 stage of the disease are available. As these trypanocides have serious side effects and are 23 difficult to administer, new and safe anti-trypanosomal brain-penetrating drugs are needed. 24 For these reasons, the anti-glioblastoma drug temozolomide was tested in vitro for activity 25 against bloodstream forms of T. brucei. The concentration of the drug required to reduce the 26 growth rate of the parasites by 50% was 29.1 μM and to kill all trypanosomes was 125 μM. 27 Importantly, temozolomide did not affect the growth of human HL-60 cells up to a 28 concentration of 300 μM.
    [Show full text]
  • Piperaquine Antimalarial Product Across Intestinal Membranes Sunday O
    DOI: 10.21276/sjmps Saudi Journal of Medical and Pharmaceutical Sciences ISSN 2413-4929 (Print) Scholars Middle East Publishers ISSN 2413-4910 (Online) Dubai, United Arab Emirates Website: http://scholarsmepub.com/ Original Research Article Effect of Metronidazole on Piperaquine Permeability from Dihydroartemisinin- Piperaquine Antimalarial Product across Intestinal Membranes Sunday O. Awofisayo*1, Emem Umoh1, Chioma N. Igwe1, Peter D. Ojobor2 1Department of Clinical Pharmacy and Biopharmacy, Faculty of Pharmacy, University of Uyo, Nigeria 2Central Research Laboratory, University of Lagos, Nigeria *Corresponding Author: Sunday O. Awofisayo Email: [email protected] Abstract: The effects of metronidazole (MN) on intestinal absorption properties are less investigated. This work aimed at assessing the effect of MN on piperaquine (PQ) permeability from dihydroartemisinin-piperaquine (DP) co-formulated antimalarial product, across intestinal epithelial membrane. Excised intestinal tissues from New Zealand male albino rabbits (n=2) were loaded with DP equivalent to PQ (100 mg/mL) and MN (100 mg/mL), according to animals’ body weight. Tissues were submerged in tyrode solution (TS) in an organ bath (100 mL). DP alone was similarly loaded in duodenum and ileum as control C1 and C2, respectively. Sampling (5 mL) of TS was taken at 0, 0.5, 1, 2, 4 and 6 h post immersion. Analysis of samples was performed using high pressure liquid chromatographic (HPLC) system with Zorbact Eclipse XDB column C8 (150 x 4.6 mm, 4.6 µm), mobile phase containing acetonitrile: 10 mM ammonium acetate (70:30, % v/v). The UV wavelength of detection and flow rate were 220 nm and 0.7 mL/min, respectively.
    [Show full text]