DOCSLIB.ORG

A Brief Historical Overview of the Antimalarials Chloroquine And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Iowa State University Capstones, Theses and Creative Components Dissertations Spring 2021 A brief historical overview of the antimalarials chloroquine and artemisinin: An investigation into their mechanisms of action and discussion on the predicament of antimalarial drug resistance Ekaterina Ellyce San Pedro Follow this and additional works at: https://lib.dr.iastate.edu/creativecomponents Part of the Chemicals and Drugs Commons Recommended Citation San Pedro, Ekaterina Ellyce, "A brief historical overview of the antimalarials chloroquine and artemisinin: An investigation into their mechanisms of action and discussion on the predicament of antimalarial drug resistance" (2021). Creative Components. 800. https://lib.dr.iastate.edu/creativecomponents/800 This Creative Component is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Creative Components by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. San Pedro 1 A Brief Historical Overview of the Antimalarials Chloroquine and Artemisinin: An Investigation into their Mechanisms of Action and Discussion on The Predicament of Antimalarial drug resistance By Ellyce San Pedro Abstract: Malaria is a problem that has affected humanity for millenia. As a result, two important antimalarial drugs, chloroquine and artemisinin, have been developed to combat Malaria. However, problems with antimalarial resistance have emerged. The following review discusses the history of Malaria and the synthesis of chloroquine and artemisinin. It discusses both drugs’ mechanisms of action and Plasmodium modes of resistance. It also further discusses the widespread predicament of antimalarial drug resistance, which is being combated by artemisinin-based combination therapy. Lastly, a case study is discussed concerning the reintroduction of chloroquine in areas where it has previously failed due to resistance. Introduction: Malaria or in Italian, “Mal ‘aria’” (Hempelmann & Krafts, 2013) has plagued humanity for millenia. From the ancient Egyptians in 1550 B.C. (Fagan, 2000) to the present day, historical records detail a deadly disease that results in symptoms such as shaking, fever, fatigue and death (CDC 2021). In the present day, Malaria has persisted, resulting in around 409,000 deaths in 2019 alone (CDC 2021). Prior to the modern day, Malaria’s origins were considered mysterious and miasmic in nature. But with the help of modern technology, great clinical advancements San Pedro 2 have been made in decreasing its potency. In particular, the antimalarial drugs chloroquine and artemisinin are today’s front-line defense against this dangerous disease. Parasite Life Cycle: Malaria is caused by a protozoan parasite. Malaria can be commonly contracted from four specific sporozoan species: P. malariae, P. falciparum, P. vivax and P. ovale (Fagan, 2000). The most common malarial infections are derived from the P. falciparum and P. vivax species (Fagan, 2000). The following parasite cycle can be used to generally describe the life cycles of the above listed parasites. The parasite life cycle requires a human host and a mosquito host (CDC 2021). The cycle begins when an infected female mosquito partakes in a human blood meal, which allows the entry of sporozoites into the skin (CDC 2021). The sporozoite then moves into the circulation (CDC 2021). Sporozoites are ambulatory parasites derived from a female anopheline mosquito that infects humans and targets human hepatocytes (WHO 2015). After sporozoite entry, a sporozoite infection of liver cells occurs. Sporozoites are obligate intracellular parasites that develop within the host cell during the vertebrate stage of the life cycle. The sporozoites then mature into schizonts (WHO 2015). Schizonts are mature malarial parasites that reside in the host’s liver cells where they undergo nuclear division (WHO 2015). Upon their maturation, the schizonts burst and release merozoites (CDC 2021). Merozoites are parasites that are released into the bloodstream when a liver cell bursts (WHO 2015). Upon formation, the merozoites proceed to invade erythrocytes. It is also important to note, that as the parasite grows within the erythrocyte, it must digest the host cell’s hemoglobin to acquire amino acids to support its metabolism and also to create more space in the host cell to San Pedro 3 grow. The sporogonic cycle or the sexual reproduction portion of the parasite life cycle occurs when the parasites multiply within the mosquito (CDC 2021). This occurs when parasite gametes are ingested by a mosquito in another blood meal. During the sporogonic cycle, the male microgametes fuse with female macrogametes to produce a zygote (CDC 2021). These zygotes will eventually mature into oocytes that will become sporozoites (CDC 2021). These sporozoites will be released from the mosquito’s salivary glands (CDC 2021). This continues the parasite’s life cycle as the mosquito continues taking blood meals. Past Explanations for Malaria: In the past, many explanations have been attributed to the cause of Malaria. Malaria was first attributed to miasma. Miasma was thought to be a dangerous cloud of particles that caused diseases (Hempelmann & Krafts, 2013). This led to the coinage of the Italian phrase “mal’aria”, indicating bad air (Hempelmann & Krafts, 2013). The idea of a malarial parasite was not introduced until microscopic staining techniques were able to detect the presence of the parasites in blood (Hempelmann & Krafts, 2013). Dr. Ronald Ross, a British army surgeon, was the first individual to prove that mosquitoes transmitted Malaria (Hempelmann & Krafts, 2013). In 1897, Ross obtained mosquitoes and gave them blood that had crescent-shaped cells (Murray, 1923). After feeding, Ross saw that there were pigmented crystals in the stomach wall (Murray 1923). Ross realized that mosquitoes do not normally produce the pigment known as hemozoin and he deduced that this pigment could be related to Malaria (Murray, 1923). Prior to this in 1880, Dr. Alphonse Laveragen discovered that Malaria was caused by a protozoan parasite (Nye, 2002). This discovery occurred when Dr. San Pedro 4 Laveragen, a military surgeon, visualized the malarial parasite through the use of blood smears (Nye, 2002). Past Treatments/Drugs Used to Treat Malaria: Antimalarial drugs have had a colorful history. Alternatives to quinine (the derivative for chloroquine), have included methylene blue dye, Prontosil and Atabrine (Lowe, 2020). Unfortunately, these drugs were not highly effective. They have also had the unfortunate side effect of turning patients into a whole spectrum of colors (Lowe, 2020). Methylene blue gave patients a blue tint. Prontosil turned patients into a permanent shade of red (Lowe, 2020). Atabrine gave individuals a yellow hue, while also causing depression, psychosis, seizures, and other problems (Lowe, 2020). In terms of today’s antimalarial treatments, the CDC states that common drugs that are used to treat Malaria include: atovaquone/Proguanil, and chloroquine (CDC 2021). However, chloroquine and artemisinin remain as the two frontline drugs that are most commonly used to combat the effects of Malaria. Chloroquine - A History: Chloroquine was discovered in 1934 by Johnann Hans Andersag (Lowe, 2020) from cinchona trees that are located in South America. Chloroquine is a weak base drug and it belongs to the family of 4-aminoquinolines (Coban, 2020). Quinolone was extracted in 1820 by researchers Pelletier and Caventou (Lowe, 2020). Quinine was synthesized in 1944 (Lowe, 2020). Unlike its predecessors, chloroquine possesses strong antimalarial activity and does not change the appearance of a patient's skin tones (Lowe, 2020). San Pedro 5 Chloroquine Mechanism of Action: Chloroquine's mechanism of action is still not fully understood. However, there are several suppositions that may explain how chloroquine functions in infected erythrocytes. An early theory for chloroquine’s mechanism of action focused on chloroquine’s ability to bind DNA and RNA (Coban, 2020). It was previously thought that chloroquine would bind to the host cell’s DNA and RNA through hydrogen bonds and electrostatic forces (Coban, 2020). However, DNA-chloroquine interactions required an excessively high concentration of chloroquine to occur (Coban, 2020). This amount was much higher than needed to eliminate parasites, therefore making it unlikely that this supposition was true (Coban, 2020). The second and more substantial mechanism of action relies on chloroquine’s interactions with free-heme in the infected erythrocyte. Chloroquine weakens the malarial parasite by reducing its ability to synthesize hemozoin, a substance that is significant to Plasmodium survival (Pilat et al, 2020). In the absence of antimalarial drugs, the malarial parasite performs hemoglobin degradation using proteases such as plasmepsins and falcipains (Coban, 2020). Plasmepsins and falcipains are a part of Plasmodium-specific families of aspartic proteases and cysteine proteases. These proteases catabolize hemoglobin to release peptides and nutrients that the parasite requires to survive (Wicht et al, 2020). However, it has also been shown that many of these amino acids are returned to the serum. Thus, hemoglobin degradation is also surmised to create space in the infected erythrocyte for parasite growth (Krugliak et al, 2002). San Pedro
Recommended publications
  • Malaria in the Prehistoric Caribbean : the Hunt for Hemozoin

    Malaria in the Prehistoric Caribbean : the Hunt for Hemozoin

    University of Louisville ThinkIR: The University of Louisville's Institutional Repository Electronic Theses and Dissertations 5-2018 Malaria in the prehistoric Caribbean : the hunt for hemozoin. Mallory D. Cox University of Louisville Follow this and additional works at: https://ir.library.louisville.edu/etd Part of the Archaeological Anthropology Commons Recommended Citation Cox, Mallory D., "Malaria in the prehistoric Caribbean : the hunt for hemozoin." (2018). Electronic Theses and Dissertations. Paper 2926. https://doi.org/10.18297/etd/2926 This Master's Thesis is brought to you for free and open access by ThinkIR: The University of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The University of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. MALARIA IN THE PREHISTORIC CARIBBEAN: THE HUNT FOR HEMOZOIN By Mallory D. Cox B.A., University of Louisville, 2015 A Thesis Submitted to the Faculty of the College of Arts and Sciences of the University of Louisville in Partial Fulfillment of the Requirements for the Degree of Master of Arts in Anthropology Department of Anthropology University of Louisville Louisville, Kentucky May 2018 MALARIA IN THE PREHISTORIC CARIBBEAN: THE HUNT FOR HEMOZOIN By Mallory D. Cox B.A., University of Louisville, 2015 A Thesis Approved on April 23, 2018 By the following Thesis Committee: _______________________________________________ Dr. Anna Browne Ribeiro _______________________________________________ Philip J. DiBlasi _______________________________________________ Dr. Sabrina Agarwal ii ACKNOWLEDGMENTS I have been very fortunate to receive guidance, support, and scholarship from many different individuals along this exciting journey into academia.
  • An Iron-Carboxylate Bond Links the Heme Units of Malaria Pigment (Plasmodium/Hemoglobin/Hemozoin/Extended X-Ray Absorption Fine Structure) ANDREW F

    An Iron-Carboxylate Bond Links the Heme Units of Malaria Pigment (Plasmodium/Hemoglobin/Hemozoin/Extended X-Ray Absorption Fine Structure) ANDREW F

    Proc. Nati. Acad. Sci. USA Vol. 88, pp. 325-329, January 1991 Biochemistry An iron-carboxylate bond links the heme units of malaria pigment (Plasmodium/hemoglobin/hemozoin/extended x-ray absorption fine structure) ANDREW F. G. SLATER*t, WILLIAM J. SWIGGARD*, BRIAN R. ORTONf, WILLIAM D. FLITTER§, DANIEL E. GOLDBERG*, ANTHONY CERAMI*, AND GRAEME B. HENDERSON*¶ *Laboratory of Medical Biochemistry, The Rockefeller University, New York, NY 10021-6399; and tDepartment of Physics, and §Department of Biology and Biochemistry, Brunel University, Uxbridge, United Kingdom Communicated by Maclyn McCarty, October 15, 1990 (receivedfor review August 17, 1990) ABSTRACT The intraerythrocytic malaria parasite uses the purified pigment are shown to be identical to those of hemoglobin as a major nutrient source. Digestion of hemoglo- hemozoin in situ. Using chemical synthesis and IR, ESR, and bin releases heme, which the parasite converts into an insoluble x-ray absorption spectroscopy we demonstrate that hemo- microcrystalline material called hemozoin or malaria pigment. zoin consists of heme moieties linked by a bond between the We have purified hemozoin from the human malaria organism ferric ion of one heme and a carboxylate side-group oxygen Plasmodium falkiparum and have used infrared spectroscopy, of another. This linkage allows the heme units released by x-ray absorption spectroscopy, and chemical synthesis to de- hemoglobin breakdown to aggregate into an ordered insolu- termine its structure. The molecule consists of an unusual ble product and represents a novel way for the parasite to polymer of hemes linked between the central ferric ion of one avoid the toxicity associated with soluble hematin. heme and a carboxylate side-group oxygen of another.
  • Plasmodium Falciparum Merozoite Surface Protein 1 Blocks the Proinflammatory Protein S100P

    Plasmodium Falciparum Merozoite Surface Protein 1 Blocks the Proinflammatory Protein S100P

    Plasmodium falciparum merozoite surface protein 1 blocks the proinflammatory protein S100P Michael Waisberga,1, Gustavo C. Cerqueirab, Stephanie B. Yagera, Ivo M. B. Francischettic,JinghuaLua, Nidhi Geraa, Prakash Srinivasanc, Kazutoyo Miurac, Balazs Radad, Jan Lukszoe, Kent D. Barbiane, Thomas L. Letod, Stephen F. Porcellae, David L. Narumf, Najib El-Sayedb, Louis H. Miller c,1, and Susan K. Piercea aLaboratory of Immunogenetics, dLaboratory of Host Defenses, cLaboratory of Malaria and Vector Research, eResearch Technologies Branch, and fLaboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and bMaryland Pathogen Research Institute, University of Maryland, College Park, MD 20742 Contributed by Louis H. Miller, February 15, 2012 (sent for review November 23, 2011) The malaria parasite, Plasmodium falciparum, and the human immune This complex interplay between the human host and P. falci- system have coevolved to ensure that the parasite is not eliminated parum presumably involves a myriad of molecular interactions and reinfection is not resisted. This relationship is likely mediated between the human immune system and the parasite that have through a myriad of host–parasite interactions, although surprisingly coevolved together. However, remarkably, to date the only few such interactions have been identified. Here we show that the 33- interactions that have been described are those between the P. falciparum kDa fragment of merozoite surface protein 1 (MSP133), parasite’s hemozoin (8) or hemozoin–DNA complexes (9) and an abundant protein that is shed during red blood cell invasion, binds the host’s toll-like receptor 9 (TLR9) or the NLRP3 inflamma- fl to the proin ammatory protein, S100P.
  • Antimalarials Inhibit Hematin Crystallization by Unique Drug

    Antimalarials Inhibit Hematin Crystallization by Unique Drug

    Antimalarials inhibit hematin crystallization by unique SEE COMMENTARY drug–surface site interactions Katy N. Olafsona, Tam Q. Nguyena, Jeffrey D. Rimera,b,1, and Peter G. Vekilova,b,1 aDepartment of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204-4004; and bDepartment of Chemistry, University of Houston, Houston, TX 77204-5003 Edited by Patricia M. Dove, Virginia Tech, Blacksburg, VA, and approved May 9, 2017 (received for review January 3, 2017) In malaria pathophysiology, divergent hypotheses on the inhibition assisted by a protein complex that catalyzes hematin dimerization of hematin crystallization posit that drugs act either by the (45). In a previous paper, we reconciled these seemingly opposite sequestration of soluble hematin or their interaction with crystal viewpoints by suggesting that β-hematin crystals grow from a thin surfaces. We use physiologically relevant, time-resolved in situ shroud of lipid that coats their surface (46), a mechanism that surface observations and show that quinoline antimalarials inhibit is qualitatively consistent with experimental observations (47). β-hematin crystal surfaces by three distinct modes of action: step Driven by the evidence favoring neutral lipids as a preferred en- pinning, kink blocking, and step bunch induction. Detailed experi- vironment for hematin crystallization in vivo (46), we use a sol- mental evidence of kink blocking validates classical theory and dem- vent comprising octanol saturated with citric buffer (CBSO) at onstrates that this mechanism is not the most effective inhibition pH 4.8 as a growth medium. pathway. Quinolines also form various complexes with soluble he- Recent observations of hematin crystallization from a bio- matin, but complexation is insufficient to suppress heme detoxifica- mimetic organic medium demonstrated that it strictly follows a tion and is a poor indicator of drug specificity.
  • Vector Control: a Cornerstone in the Malaria Elimination Campaign

    Vector Control: a Cornerstone in the Malaria Elimination Campaign

    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REVIEW 10.1111/j.1469-0691.2011.03664.x Vector control: a cornerstone in the malaria elimination campaign K. Karunamoorthi1,2 1) Unit of Medical Entomology & Vector Control, Department of Environmental Health Science, College of Public Health and Medical Sciences, Jimma University, Jimma, Ethiopia and 2) Research & Development Centre, Bharathiar University, Coimbatore, Tamil Nadu, India Abstract Over many decades, malaria elimination has been considered to be one of the most ambitious goals of the international community. Vector control is a cornerstone in malaria control, owing to the lack of reliable vaccines, the emergence of drug resistance, and unaffordable potent antimalarials. In the recent past, a few countries have achieved malaria elimination by employing existing front-line vector control interventions and active case management. However, many challenges lie ahead on the long road to meaningful accom- plishment, and the following issues must therefore be adequately addressed in malaria-prone settings in order to achieve our target of 100% worldwide malaria elimination and eventual eradication: (i) consistent administration of integrated vector management; (ii) identifi- cation of innovative user and environment-friendly alternative technologies and delivery systems; (iii) exploration and development of novel and powerful contextual community-based interventions; and (iv) improvement of the efficiency and efficacy of existing interven- tions and their combinations, such as vector control, diagnosis, treatment, vaccines, biological control of vectors, environmental man- agement, and surveillance. I strongly believe that we are moving in the right direction, along with partnership-wide support, towards the enviable milestone of malaria elimination by employing vector control as a potential tool.
  • The History and Ethics of Malaria Eradication and Control Campaigns in Tropical Africa

    The History and Ethics of Malaria Eradication and Control Campaigns in Tropical Africa

    Malaria Redux: The History and Ethics of Malaria Eradication and Control Campaigns in Tropical Africa Center for Historical Research Ohio State University Spring 2012 Seminars: Epidemiology in World History Prof. J.L.A. Webb, Jr. Department of History Colby College DRAFT: NOT FOR CITATION 2 During the 1950s, colonial malariologists, in conjunction with experts from the World Health Organization (WHO), set up malaria eradication pilot projects across tropical Africa. They deployed new synthetic insecticides such as DLD, HCH, and DDT, and new antimalarials, such as chloroquine and pyrimethamine, in an effort to establish protocols for eradication. These efforts ‘protected’ some fourteen million Africans. Yet by the early 1960s, the experts concluded that malaria eradication was not feasible, and the pilot projects were disbanded. The projects had achieved extremely low levels of infection for years at a time, but the experts had to accept with regret that their interventions were unable to reduce malaria transmission to zero. The projects had high recurrent costs, and it was understood that they were financially unsustainable. The pilot projects were allowed to lapse. The malaria eradication pilot projects had reduced the rates of infection to levels so low that the ‘protected’ populations lost their acquired immunities to malaria during the years of the projects. In the immediate aftermath of the projects, the Africans were subject to severe malaria, which sometimes afflicted entire communities in epidemic form, until they regained their immunities. How Should We Understand the Ethics of the Early Eradication Efforts? The ethics of malaria control in the 1950s and 1960s seemed self-evident to the interventionists.
  • CRISPR-Based Innovative Genetic Tools for Control of Anopheles Gambiae Mosquitoes

    CRISPR-Based Innovative Genetic Tools for Control of Anopheles Gambiae Mosquitoes

    CRISPR-based innovative genetic tools for control of Anopheles gambiae mosquitoes The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Smidler, Andrea. 2019. CRISPR-based innovative genetic tools for control of Anopheles gambiae mosquitoes. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:42029729 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA CRISPR-based innovative genetic tools for control of Anopheles gambiae mosquitoes A dissertation presented by Andrea L. Smidler to The Committee on Higher Degrees in Biological Sciences in Public Health in partial fulfillment of the requirements for the degree of Doctor of Philosophy In the subject of Biological Sciences in Public Health Harvard University Cambridge, Massachusetts April 2019 i © 2019 – Andrea Smidler All rights reserved ii Dissertation Advisor: Dr. Flaminia Catteruccia, Dr. George Church Andrea Smidler CRISPR-based innovative genetic tools for control of Anopheles gambiae mosquitoes ABSTRACT Malaria and other mosquito-borne diseases pose an immense burden on mankind. Since the turn of the century, control campaigns have relied on the use of insecticide-impregnated bed nets and indoor residual sprays to stop Anopheles mosquitoes from transmitting the malaria parasite. Although these are our best strategies to control the spread of disease, wild mosquito populations are developing resistance to insecticides at an alarming rate, making disease control increasingly challenging.
  • Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: a Phase 2A Controlled Human Malaria Parasite Infection and Immunogenicity Study Jason A

    Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: a Phase 2A Controlled Human Malaria Parasite Infection and Immunogenicity Study Jason A

    The Journal of Infectious Diseases MAJOR ARTICLE Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study Jason A. Regules,1,3,6 Susan B. Cicatelli,4 Jason W. Bennett,1,3,6 Kristopher M. Paolino,4 Patrick S. Twomey,2,3 James E. Moon,1,3 April K. Kathcart,1,3 Kevin D. Hauns,1,3 Jack L. Komisar,1,3 Aziz N. Qabar,1,3 Silas A. Davidson,5 Sheetij Dutta,1,3 Matthew E. Griffith,6 Charles D. Magee,6 Mariusz Wojnarski,2,3 Jeffrey R. Livezey,2,3 Adrian T. Kress,2,3 Paige E. Waterman,4 Erik Jongert,9 Ulrike Wille-Reece,7 Wayne Volkmuth,8 Daniel Emerling,8 William H. Robinson,8 Marc Lievens,9 Danielle Morelle,9 Cynthia K. Lee,7 Bebi Yassin-Rajkumar,7 Richard Weltzin,7 Joe Cohen,9 Robert M. Paris,3 Norman C. Waters,1,3 Ashley J. Birkett,9 David C. Kaslow,9 W. Ripley Ballou,9 Christian F. Ockenhouse,7 and Johan Vekemans9 1Malaria Vaccine Branch, 2Experimental Therapeutics Branch, 3Military Malaria Research Program, 4Clinical Trials Center, Translational Medicine Branch, 5Entomology Branch, Walter Reed Army Institute of Research, Silver Spring, and 6Uniformed Services University of the Health Sciences, Bethesda, Maryland; 7PATH Malaria Vaccine Initiative, Seattle, Washington; 8Atreca, Redwood City, California; and 9GSK Vaccines, Rixensart, Belgium Background. Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria Downloaded from parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses.
  • Staying the Course?

    Staying the Course?

    FOR MORE INFORMATION: Staying the course? PATH Malaria Vaccine Initiative 455 Massachusetts Avenue NW MALARIA RESEARCH AND DEVELOPMENT Suite 1000 Washington, DC 20001 USA IN A TIME OF ECONOMIC UNCERTAINTY Phone: 202.822.0033 Fax: 202.457.1466 Email: [email protected] IC UNCERTAINTY IC M E OF ECONO OF E M ENT IN A TI A IN ENT M MALARIA RESEARCH AND DEVELOP AND RESEARCH MALARIA E? E? S STAYING THE THE COUR STAYING Staying the course? MALARIA RESEARCH AND DEVELOPMENT IN A TIME OF ECONOMIC UNCERTAINTY Copyright © 2011, Program for Appropriate Technology in Health (PATH). All rights reserved. The material in this document may be freely used for educational or noncommercial purposes, provided that the material is accompanied by an acknowledgment line. Photos: Anna Wang, MMV (cover, page 5, and page 43, bottom) and IVCC (page 32 and page 43, top). Illustration on page 11 by Lamont W. Harvey. Suggested citation: PATH. Staying the Course? Malaria Research and Development in a Time of Economic Uncertainty. Seattle: PATH; 2011. ISBN 978-0-9829522-0-7 ii Acknowledgements We extend our collective gratitude to the many people who gave their time and expertise during the course of this project. The staff at Policy Cures served as authors of the report, including Mary Moran, Javier Guzman, Lisette Abela-Oversteegen, Brenda Omune and Nick Chapman. The final report could not have been prepared without valuable input from the staff of the PATH Malaria Vaccine Initiative (MVI), in particular Theresa Raphael and Sally Ethelston. Information critical to the compilation of this report was obtained from the following organisations and individuals: MVI—Christian Loucq, Katya Spielberg and Ashley Birkett; Medicines for Malaria Venture—Julia Engelking, Matthew Doherty, Andrea Lucard, Jaya Banerji, Claude Oeuvray and Peter Potter-Lesage; Innovative Vector Control Consortium—Tom McLean and Robert Sloss; Foundation for Innovative New Diagnostics—Lakshmi Sundaram, Iveth Gonzalez, David Bell and Mark Perkins.
  • Oxidative Stress in Malaria

    Oxidative Stress in Malaria

    Int. J. Mol. Sci. 2012, 13, 16346-16372; doi:10.3390/ijms131216346 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review Oxidative Stress in Malaria Sandro Percário 1,*, Danilo R. Moreira 1, Bruno A. Q. Gomes 1, Michelli E. S. Ferreira 1, Ana Carolina M. Gonçalves 1, Paula S. O. C. Laurindo 1, Thyago C. Vilhena 1, Maria F. Dolabela 2 and Michael D. Green 3 1 Oxidative Stress Research Laboratory, Institute of Biological Sciences, Federal University of Para (LAPEO/ICB/UFPA) Av. Augusto Correa, 1, Guama, Belem, Para 66075-110, Brazil; E-Mails: [email protected] (D.R.M.); [email protected] (B.A.Q.G.); [email protected] (M.E.S.F.); [email protected] (A.C.M.G.); [email protected] (P.S.O.C.L.); [email protected] (T.C.V.) 2 Pharmacy Faculty, Institute of Health Sciences, Federal University of Para. Av. Augusto Correa, 1, Guama, Belem, Para 66075-110, Brazil; E-Mail: [email protected] 3 US Centers for Disease Control and Prevention, 1600 Clifton Road NE, mailstop G49, Atlanta, GA 30329, USA; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected] or [email protected]; Tel.: +55-91-8156-2289; Fax: +55-91-3201-7102. Received: 17 October 2012; in revised form: 8 November 2012 / Accepted: 23 November 2012 / Published: 3 December 2012 Abstract: Malaria is a significant public health problem in more than 100 countries and causes an estimated 200 million new infections every year.
  • Analyzing the Morphology of Hemozoin in Drug Resistant Plasmodium & Quantifying the Compartmental Kinetics of Hemozoin Durin

    Analyzing the Morphology of Hemozoin in Drug Resistant Plasmodium & Quantifying the Compartmental Kinetics of Hemozoin Durin

    ANALYZING THE MORPHOLOGY OF HEMOZOIN IN DRUG RESISTANT PLASMODIUM & QUANTIFYING THE COMPARTMENTAL KINETICS OF HEMOZOIN DURING CLEARANCE OF INFECTION By Abeer A. Sayeed A thesis submitted to the Johns Hopkins University in conformity with the requirements for the degree of Master of Science Baltimore, Maryland April, 2019 ©2019 Abeer Sayeed All Rights Reserved ABSTRACT Malaria infection by Plasmodium parasites poses a significant public health burden globally. During the parasite’s erythrocytic life cycle stages, it produces hemozoin, an inert, crystalline by-product of hemoglobin degradation, to avoid oxidative stress. This process is essential for parasite survival and is therefore a target for antimalarials. In this thesis, we explore the effect of single nucleotide polymorphisms (SNPs) in drug resistant parasites on hemozoin morphology. We found that parasites with compressed trophozoite stages in a ring-stage artemisinin resistant strain (C580Y) harboring a Kelch-13 propeller mutation, produce significantly smaller sized hemozoin crystals than the isogenic susceptible strain (CamWT). Smaller sized hemozoin crystals were also observed in a chloroquine resistant strain (FCB) as compared to its isogenic chloroquine sensitive strain (106/1). We did not observe a significant difference in non- isogenic drug sensitive and resistant strains, suggesting that a SNP conferring resistance may be sufficient to alter hemozoin morphology. From these data we predict that parasites may alter their hemozoin nucleation processes as a stress response in order to overcome drug pressure. Current malarial diagnostics have their limitations and therefore need improvement. Hemozoin is being explored as a potential biomarker to be used in malaria diagnostics. Therefore, it is essential to understand the kinetics of hemozoin during infection and clearance in order to develop appropriate tools to detect malaria infection using hemozoin.
  • Interplay Between Plasmodium Falciparum Haemozoin and L-Arginine: Implication for Nitric Oxide Production

    Interplay Between Plasmodium Falciparum Haemozoin and L-Arginine: Implication for Nitric Oxide Production

    Corbett et al. Malar J (2018) 17:456 https://doi.org/10.1186/s12936-018-2602-0 Malaria Journal RESEARCH Open Access Interplay between Plasmodium falciparum haemozoin and L‑arginine: implication for nitric oxide production Yolanda Corbett1,2* , Sarah D’Alessandro1,3, Silvia Parapini1,3, Diletta Scaccabarozzi1, Parisa Kalantari4, Stefania Zava1, Flavio Giavarini1, Donatella Caruso1, Irma Colombo1, Timothy J. Egan5 and Nicoletta Basilico3 Abstract Background: Plasmodium falciparum haemozoin, a detoxifcation product of digested haemoglobin from infected erythrocytes, is released into the bloodstream upon schizont rupture and accumulates in leukocytes. High levels of haemozoin correlate with disease severity. Some studies have shown that concentrations of the substrate of inducible nitric oxide synthase (iNOS), L-arginine, as well as nitric oxide are low in patients infected with P. falciparum malaria. The present study investigates, in vitro, the role of P. falciparum haemozoin on nitric oxide production, iNOS expres- sion in macrophages, and the possible interaction between L-arginine and haemozoin. Methods: Plasmodium falciparum haemozoin was obtained from in vitro cultures through magnetic isolation. Phagocytosis of haemozoin by immortalized bone marrow derived macrophages was detected by confocal refection combined with fuorescence microscopy. Nitrite concentrations in the supernatants was evaluated by Griess assay as a standard indication of nitric oxide production, while iNOS expression was detected on cell extracts by western blotting. Detection of L-arginine in haemozoin-treated or untreated media was achieved by liquid chromatography– tandem mass spectrometry (LC–MS/MS). Results: Haemozoin synergizes in vitro with interferon-gamma to produce nitric oxide. However, when mouse macrophages were stimulated with haemozoin, a proportional increase of nitric oxide was observed up to 25 μM of haemozoin, followed by a decrease with doses up to 100 μM, when nitric oxide release was completely abrogated.