Artemisinin resistance in Plasmodium falciparum: A process linked to dormancy?

Artemisinin (ART) based combination therapy (ACT) is used as the first line treatment of uncomplicated falciparum malaria in over 100 countries and is the cornerstone of malaria control and elimination programs in these areas. However, despite the high potency and rapid parasite killing action of ART derivatives there is a high rate of recrudescence associated with ART monotherapy and recrudescence is not uncommon even when ACT is used. Compounding this problem are reports that some parasites in Cambodia, a known foci of drug resistance, have decreased in vivo sensitivity to ART. This raises serious concerns for the development of ART resistance in the field even though no major phenotypic and genotypic changes have yet been identified in these parasites. In this article we review available data on the characteristics of ART, its effects on Plasmodium falciparum parasites and present a hypothesis to explain the high rate of recrudescence associated with this potent class of drugs and the current enigma surrounding ART resistance.

[1]  Y. Wu,et al.  How Chinese scientists discovered qinghaosu (artemisinin) and developed its derivatives? What are the future perspectives? , 1998, Medecine tropicale : revue du Corps de sante colonial.

[2]  L. Miller,et al.  Plasmodium falciparum malaria. Ultrastructure of parasitized erythrocytes in cardiac vessels. , 1971, The American journal of tropical medicine and hygiene.

[3]  O. Farges,et al.  Ex vivo perfusion of human spleens maintains clearing and processing functions. , 2006, Blood.

[4]  P. Olliaro,et al.  Artemisinin derivatives for treating uncomplicated malaria. , 1999, The Cochrane database of systematic reviews.

[5]  Dennis E. Kyle,et al.  Effects of Artesunate on Parasite Recrudescence and Dormancy in the Rodent Malaria Model Plasmodium vinckei , 2011, PloS one.

[6]  J. Cumming,et al.  Antimalarial activity of artemisinin (qinghaosu) and related trioxanes: mechanism(s) of action. , 1997, Advances in pharmacology.

[7]  G. Bàlint,et al.  Artemisinin and its derivatives: an important new class of antimalarial agents. , 2001, Pharmacology & therapeutics.

[8]  T. Q. Binh,et al.  Artemisinin for treatment of uncomplicated falciparum malaria: is there a place for monotherapy? , 2001, The American journal of tropical medicine and hygiene.

[9]  M. Gatton,et al.  Artemisinin-induced parasite dormancy: a plausible mechanism for treatment failure , 2011, Malaria Journal.

[10]  N. White,et al.  Preventing antimalarial drug resistance through combinations. , 1998, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[11]  S. Krishna,et al.  Artemisinins: activities and actions. , 2004, Microbes and infection.

[12]  S. Meshnick,et al.  Recrudescence in artesunate-treated patients with falciparum malaria is dependent on parasite burden not on parasite factors. , 2003, The American journal of tropical medicine and hygiene.

[13]  B. Metchock,et al.  Childhood mortality during and after hospitalization in western Kenya: effect of malaria treatment regimens. , 1996, The American journal of tropical medicine and hygiene.

[14]  T. K. Dien,et al.  Clinical Pharmacology and Therapeutic Potential of Artemisinin and its Derivatives in the Treatment of Malaria , 1996, Drugs.

[15]  C J Hull,et al.  Pharmacokinetics and pharmacodynamics. , 1979, British journal of anaesthesia.

[16]  W. Wernsdorfer,et al.  Isolated malaria outbreak in Somalia: role of chloroquine-resistant Plasmodium falciparum demonstrated in Balcad epidemic. , 1990, The Journal of tropical medicine and hygiene.

[17]  Bruce Russell,et al.  Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription , 2011, BMC Genomics.

[18]  X. Su,et al.  Increased Tolerance to Artemisinin in Plasmodium falciparum Is Mediated by a Quiescence Mechanism , 2010, Antimicrobial Agents and Chemotherapy.

[19]  W. Peters,et al.  The prevention of antimalarial drug resistance. , 1990, Pharmacology & therapeutics.

[20]  R. Vishwakarma,et al.  Artemisinin (qinghaosu)--a new gametocytocidal drug for malaria. , 1989, Chemotherapy.

[21]  E. Lagarde,et al.  Impact of chloroquine resistance on malaria mortality. , 1998, Comptes rendus de l'Academie des sciences. Serie III, Sciences de la vie.

[22]  A. Björkman Malaria associated anaemia, drug resistance and antimalarial combination therapy. , 2002, International journal for parasitology.

[23]  D. Warhurst,et al.  Qinghaosu resistance in rodent malaria. , 1986, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[24]  D. Kyle,et al.  Phenotypic and Genotypic Analysis of In Vitro-Selected Artemisinin-Resistant Progeny of Plasmodium falciparum , 2011, Antimicrobial Agents and Chemotherapy.

[25]  D. Kyle,et al.  Pharmacokinetics and pharmacodynamics of qinghaosu derivatives: how do they impact on the choice of drug and the dosage regimens? , 1998, Medecine tropicale : revue du Corps de sante colonial.

[26]  J. Inselburg Induction and isolation of artemisinine-resistant mutants of Plasmodium falciparum. , 1985, The American journal of tropical medicine and hygiene.

[27]  A. Björkman,et al.  Repetitive dosing of artemisinin and quinine against Plasmodium falciparum in vitro: a simulation of the in vivo pharmacokinetics. , 1997, Acta tropica.

[28]  S. Meshnick Artemisinin antimalarials: mechanisms of action and resistance. , 1998, Medecine tropicale : revue du Corps de sante colonial.

[29]  J. Dame,et al.  The Plasmodium falciparum Translationally Controlled Tumor Protein Homolog and Its Reaction with the Antimalarial Drug Artemisinin* , 1998, The Journal of Biological Chemistry.

[30]  K. Silamut,et al.  Artemisinin resistance in Plasmodium falciparum malaria. , 2009, The New England journal of medicine.

[31]  C. Drakeley,et al.  Artesunate reduces but does not prevent posttreatment transmission of Plasmodium falciparum to Anopheles gambiae. , 2001, The Journal of infectious diseases.

[32]  M. Gatton,et al.  Phenotypic Changes in Artemisinin-Resistant Plasmodium falciparum Lines In Vitro: Evidence for Decreased Sensitivity to Dormancy and Growth Inhibition , 2011, Antimicrobial Agents and Chemotherapy.

[33]  S. Nakazawa,et al.  Plasmodium falciparum: recrudescence of parasites in culture. , 1995, Experimental parasitology.

[34]  O. Cars,et al.  Studies of the killing kinetics of benzylpenicillin, cefuroxime, azithromycin, and sparfloxacin on bacteria in the postantibiotic phase , 1997, Antimicrobial agents and chemotherapy.

[35]  M. Gatton,et al.  Artemisinin‐induced dormancy in plasmodium falciparum: duration, recovery rates, and implications in treatment failure. , 2010, The Journal of infectious diseases.

[36]  Weltgesundheitsorganisation World malaria report , 2005 .

[37]  N. White,et al.  Assessment of the pharmacodynamic properties of antimalarial drugs in vivo , 1997, Antimicrobial agents and chemotherapy.

[38]  Angus Cameron,et al.  A single amino acid residue can determine the sensitivity of SERCAs to artemisinins , 2005, Nature Structural &Molecular Biology.

[39]  D. Kyle,et al.  Open randomized trial of oral artemether alone and a sequential combination with mefloquine for acute uncomplicated falciparum malaria. , 1997, The American journal of tropical medicine and hygiene.

[40]  W. Stein,et al.  Genetic Predisposition Favors the Acquisition of Stable Artemisinin Resistance in Malaria Parasites , 2010, Antimicrobial Agents and Chemotherapy.

[41]  M. Gatton,et al.  Deamplification of pfmdr1-Containing Amplicon on Chromosome 5 in Plasmodium falciparum Is Associated with Reduced Resistance to Artelinic Acid In Vitro , 2010, Antimicrobial Agents and Chemotherapy.

[42]  Richard J. Maude,et al.  Intrahost modeling of artemisinin resistance in Plasmodium falciparum , 2010, Proceedings of the National Academy of Sciences.

[43]  L. Dequan,et al.  Changes in susceptibility of Plasmodium falciparum to artesunate in vitro in Yunnan Province, China. , 2003 .

[44]  T. Maoka,et al.  Malaria Parasites Giving Rise to Recrudescence In Vitro , 2002, Antimicrobial Agents and Chemotherapy.

[45]  R. Price,et al.  Effects of artemisinin derivatives on malaria transmissibility , 1996, The Lancet.

[46]  R. Price,et al.  Multidrug-Resistant Plasmodium vivax Associated with Severe and Fatal Malaria: A Prospective Study in Papua, Indonesia , 2008, PLoS medicine.

[47]  Xavier C Ding,et al.  Plasmodium sensitivity to artemisinins: magic bullets hit elusive targets. , 2011, Trends in parasitology.

[48]  M. Hoshen,et al.  Mathematical modelling of the chemotherapy of Plasmodium falciparum malaria with artesunate: postulation of ‘dormancy’, a partial cytostatic effect of the drug, and its implication for treatment regimens , 2000, Parasitology.

[49]  Yang Hl,et al.  [Comparison of sensitivity of artesunate-sensitive and artesunate-resistant Plasmodium falciparum to chloroquine and amodiaquine]. , 1999 .

[50]  R. Price,et al.  Drug resistant falciparum malaria: clinical consequences and strategies for prevention. , 2001, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[51]  F. Nosten,et al.  Artemisinin-based combination treatment of falciparum malaria. , 2007, The American journal of tropical medicine and hygiene.

[52]  N. White,et al.  Delaying antimalarial drug resistance with combination chemotherapy. , 1999, Parassitologia.

[53]  P. Olliaro,et al.  Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review. , 2004, Journal of postgraduate medicine.

[54]  S. Meshnick,et al.  Treatment of malaria in Vietnam with oral artemisinin. , 1993, The American journal of tropical medicine and hygiene.

[55]  D. Fidock,et al.  Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites§ , 2007, Molecular microbiology.

[56]  A. C. Alves,et al.  Malaria Parasites Can Develop Stable Resistance to Artemisinin but Lack Mutations in Candidate Genes atp6 (Encoding the Sarcoplasmic and Endoplasmic Reticulum Ca2+ ATPase), tctp, mdr1, and cg10 , 2006, Antimicrobial Agents and Chemotherapy.

[57]  M. Fukuda,et al.  Evidence of artemisinin-resistant malaria in western Cambodia. , 2008, The New England journal of medicine.

[58]  S. Ward,et al.  Quinolines and artemisinin: chemistry, biology and history. , 2005, Current topics in microbiology and immunology.

[59]  N. White,et al.  In vivo removal of malaria parasites from red blood cells without their destruction in acute falciparum malaria. , 1997, Blood.

[60]  Nirbhay Kumar,et al.  Stage-specific gametocytocidal effect in vitro of the antimalaria drug qinghaosu onPlasmodium falciparum , 2004, Parasitology Research.

[61]  S. Meshnick,et al.  Artemisinin: mechanisms of action, resistance and toxicity. , 2002, International journal for parasitology.

[62]  J. Peters,et al.  Role of pfmdr1 Amplification and Expression in Induction of Resistance to Artemisinin Derivatives in Plasmodium falciparum , 2010, Antimicrobial Agents and Chemotherapy.

[63]  Debashish Das,et al.  High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia. , 2010, The Journal of infectious diseases.