Skip to main content
SpringerLink
Log in

Pharmacodynamics of Antimalarial Agents

  • Protocol
  • First Online:
Antibiotic Pharmacodynamics

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

  • 1590 Accesses

Abstract

Antimalarials were among the first, and today are among the most widely used, anti-infective agents. The fundamental pharmacodynamic endpoint for antimalarials is quite simple: elimination of this eukaryotic protozoal pathogen from its host; numerous surrogates for this have been developed. Antimalarial therapy is confounded by several key factors including the coexistence of multiple pharmacologically distinct Plasmodium life cycle forms in the human host; limited resources for discovery, development, and deployment of new drugs; and a high requirement for safety due to the enormous patient population and use for chemoprophylaxis of healthy travelers. Further, for any particular drug, myriad influences impact the pharmacological endpoint, including rapidity of the onset of action, potency, ‘static vs. ‘cidal activity, susceptibility to parasite resistance, immune status of the host, and the suitability of prevailing pharmacokinetics. Classic and recently described pharmacodynamic endpoints in preclinical models are presented, as are new insights into the pharmacokinetic drivers of antimalarial pharmacodynamics. The efficacy and safety of existing drugs are surveyed, and some novel experimental agents are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Fairhurst RM, Wellems TE (2010) Plasmodium species (Malaria). In: Mandell GL, Bennett JE, Donlin R (eds) Mandel, Douglas and Bennett’s principles and practice of infectious diseases, vol 2, Churchill. Livingstone, Philadelphia, PA, pp 3437–3462

    Chapter  Google Scholar 

  2. White NJ, Pukrittayakamee S, Hien TT et al (2014) Malaria. Lancet 383(9918):723–735. doi:10.1016/S0140-6736(13)60024-0

    Article  PubMed  Google Scholar 

  3. Shapiro TA, Goldberg DE (2006) Chemotherapy of protozoal infections: malaria. In: Brunton LL, Lazo JS, Parker KL (eds) Goodman and Gilman’s the pharmacological basis of therapeutics, 11th edn. McGraw-Hill, New York, pp 1021–1047

    Google Scholar 

  4. Gardner MJ, Hall N, Fung E et al (2002) Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419(6906):498–511. doi:10.1038/nature01097

    Article  CAS  PubMed  Google Scholar 

  5. Trager W, Jensen JB (1976) Human malaria parasites in continuous culture. Science 193(4254):673–675

    Article  CAS  PubMed  Google Scholar 

  6. Dahl EL, Rosenthal PJ (2008) Apicoplast translation, transcription and genome replication: targets for antimalarial antibiotics. Trends Parasitol 24(6):279–284. doi:10.1016/j.pt.2008.03.007

    Article  CAS  PubMed  Google Scholar 

  7. Francis SE, Sullivan DJ Jr, Goldberg DE (1997) Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. Annu Rev Microbiol 51:97–123. doi:10.1146/annurev.micro.51.1.97

    Article  CAS  PubMed  Google Scholar 

  8. Painter HJ, Morrisey JM, Mather MW et al (2007) Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum. Nature 446(7131):88–91. doi:10.1038/nature05572

    Article  CAS  PubMed  Google Scholar 

  9. Gamo FJ, Sanz LM, Vidal J et al (2010) Thousands of chemical starting points for antimalarial lead identification. Nature 465(7296):305–310. doi:10.1038/nature09107

    Article  CAS  PubMed  Google Scholar 

  10. Guiguemde WA, Shelat AA, Bouck D et al (2010) Chemical genetics of Plasmodium falciparum. Nature 465(7296):311–315. doi:10.1038/nature09099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rottmann M, McNamara C, Yeung BK et al (2010) Spiroindolones, a potent compound class for the treatment of malaria. Science 329(5996):1175–1180. doi:10.1126/science.1193225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McGhee RB (1988) Major animal models in malaria research: avian. In: Wernsdorfer WH, McGregor I (eds) Malaria: principles and practice of malariology, vol 2. Churchill Livingstone, Edinburgh, pp 1545–1567

    Google Scholar 

  13. Cox FEG (1988) Major animal models in malaria research: rodent. In: Wernsdorfer WH, McGregor I (eds) Malaria: principles and practice of malariology, vol 2. Churchill Livingstone, Edinburgh, pp 1503–1543

    Google Scholar 

  14. Fidock DA, Rosenthal PJ, Croft SL et al (2004) Antimalarial drug discovery: efficacy models for compound screening. Nat Rev Drug Discov 3(6):509–520. doi:10.1038/nrd1416

    Article  CAS  PubMed  Google Scholar 

  15. Craig AG, Grau GE, Janse C et al (2012) The role of animal models for research on severe malaria. PLoS Pathog 8(2):e1002401. doi:10.1371/journal.ppat.1002401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Angulo-Barturen I, Jimenez-Diaz MB, Mulet T et al (2008) A murine model of falciparum-malaria by in vivo selection of competent strains in non-myelodepleted mice engrafted with human erythrocytes. PLoS One 3(5):e2252. doi:10.1371/journal.pone.0002252

    Article  PubMed  PubMed Central  Google Scholar 

  17. Collins WE (1988) Major animal models in malaria research: simian. In: Wernsdorfer WH, McGregor I (eds) Malaria: principles and practice of malariology, vol 2. Churchill Livingstone, Edinburgh, pp 1473–1501

    Google Scholar 

  18. Cox-Singh J (2012) Zoonotic malaria: Plasmodium knowlesi, an emerging pathogen. Curr Opin Infect Dis 25(5):530–536. doi:10.1097/QCO.0b013e3283558780

    Article  PubMed  Google Scholar 

  19. Bruce-Chwatt LJ (1967) Clinical trials of anti-malarial drugs. Trans R Soc Trop Med Hyg 61(3):412–426

    Article  Google Scholar 

  20. Shapiro TA, Ranasinha CD, Kumar N et al (1999) Prophylactic activity of atovaquone against Plasmodium falciparum in humans. Am J Trop Med Hyg 60(5):831–836

    CAS  PubMed  Google Scholar 

  21. Seder RA, Chang LJ, Enama ME et al (2013) Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science 341(6152):1359–1365. doi:10.1126/science.1241800

    Article  CAS  PubMed  Google Scholar 

  22. Desjardins RE, Canfield CJ, Haynes JD et al (1979) Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother 16(6):710–718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bennett TN, Paguio M, Gligorijevic B et al (2004) Novel, rapid, and inexpensive cell-based quantification of antimalarial drug efficacy. Antimicrob Agents Chemother 48(5):1807–1810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Karl S, Wong RP, St Pierre TG et al (2009) A comparative study of a flow-cytometry-based assessment of in vitro Plasmodium falciparum drug sensitivity. Malar J 8:294. doi:10.1186/1475-2875-8-294

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sanz LM, Crespo B, De-Cozar C et al (2012) P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action. PLoS One 7(2):e30949. doi:10.1371/journal.pone.0030949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Young RD, Rathod PK (1993) Clonal viability measurements on Plasmodium falciparum to assess in vitro schizonticidal activity of leupeptin, chloroquine, and 5-fluoroorotate. Antimicrob Agents Chemother 37(5):1102–1107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Paguio MF, Bogle KL, Roepe PD (2011) Plasmodium falciparum resistance to cytocidal versus cytostatic effects of chloroquine. Mol Biochem Parasitol 178(1–2):1–6. doi:10.1016/j.molbiopara.2011.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Painter HJ, Morrisey JM, Vaidya AB (2010) Mitochondrial electron transport inhibition and viability of intraerythrocytic Plasmodium falciparum. Antimicrob Agents Chemother 54(12):5281–5287. doi:10.1128/AAC.00937-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Le Manach C, Scheurer C, Sax S et al (2013) Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum. Malar J 12:424. doi:10.1186/1475-2875-12-424

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bakshi RP, Nenortas E, Tripathi AK et al (2013) Model system to define pharmacokinetic requirements for antimalarial drug efficacy. Sci Transl Med 5(205):205ra135. doi:10.1126/scitranslmed.3006684

    Article  PubMed  Google Scholar 

  31. Barrette A, Ringwald P (2010) Global report on antimalarial drug efficacy and drug resistance: 2000–2010. World Health Organization, Switzerland

    Google Scholar 

  32. Zhao X, Xu C, Domagala J et al (1997) DNA topoisomerase targets of the fluoroquinolones: a strategy for avoiding bacterial resistance. Proc Natl Acad Sci U S A 94(25):13991–13996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hitchings GH (1969) A quarter century of chemotherapy. JAMA 209(9):1339–1340

    Article  CAS  PubMed  Google Scholar 

  34. Richards WHG (1966) Antimalarial activity of sulphonamides and a sulphone, singly and in combination with pyrimethamine, against drug resistant and normal strains of laboratory plasmodia. Nature 212(5069):1494–1495

    Article  CAS  PubMed  Google Scholar 

  35. Greenberg J, Boyd BL, Josephson ES (1948) Synergistic effect of chlorguanide and sulfadiazine against Plasmodium gallinaceum in the chick. J Pharmacol Exp Ther 94(1):60–64

    CAS  PubMed  Google Scholar 

  36. Vaidya A (2001) Atovaquone-proguanil combination. In: Rosenthal PJ (ed) Antimalarial chemotherapy. Humana Press Inc., Totowa, NJ, pp 203–218

    Chapter  Google Scholar 

  37. Hastings IM, Hodel EM (2014) Pharmacological considerations in the design of anti-malarial drug combination therapies—is matching half-lives enough? Malar J 13(1):62. doi:10.1186/1475-2875-13-62

    Article  PubMed  PubMed Central  Google Scholar 

  38. White NJ (2013) Pharmacokinetic and pharmacodynamic considerations in antimalarial dose optimization. Antimicrob Agents Chemother 57(12):5792–5807. doi:10.1128/AAC.00287-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lazarus A (1922) Paul Ehrlich, vol 2. Rikola, Wien

    Book  Google Scholar 

  40. Lipkin IJ, Ramsden W (1918) Nephelometric estimation of quinine in blood and urine. Br Med J 1(2994):560–561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Craig WA (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26(1):1–10, quiz 11–12

    Article  CAS  PubMed  Google Scholar 

  42. Drusano GL (2004) Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol 2(4):289–300. doi:10.1038/nrmicro862

    Article  CAS  PubMed  Google Scholar 

  43. Coatney GR (1963) Pitfalls in a discovery: the chronicle of chloroquine. Am J Trop Med Hyg 12:121–128

    CAS  PubMed  Google Scholar 

  44. Sullivan DJ Jr, Gluzman IY, Russell DG et al (1996) On the molecular mechanism of chloroquine’s antimalarial action. Proc Natl Acad Sci U S A 93(21):11865–11870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Klayman DL (1985) Qinghaosu (artemisinin): an antimalarial drug from China. Science 228(4703):1049–1055

    Article  CAS  PubMed  Google Scholar 

  46. Alonso PA, Djimde A, Magill A et al (2011) A research agenda for malaria eradication: drugs. PLoS Med 8(1):e1000402. doi:10.1371/journal.pmed.1000402

    Article  Google Scholar 

  47. Fidock DA, Nomura T, Talley AK et al (2000) Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 6(4):861–871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sullivan DJ Jr, Matile H, Ridley RG et al (1998) A common mechanism for blockade of heme polymerization by antimalarial quinolines. J Biol Chem 273(47):31103–31107

    Article  CAS  PubMed  Google Scholar 

  49. Nomura T, Carlton JM, Baird JK et al (2001) Evidence for different mechanisms of chloroquine resistance in 2 Plasmodium species that cause human malaria. J Infect Dis 183(11):1653–1661. doi:10.1086/320707

    Article  CAS  PubMed  Google Scholar 

  50. Krishna S, White NJ (1996) Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications. Clin Pharmacokinet 30(4):263–299

    Article  CAS  PubMed  Google Scholar 

  51. Taylor WR, White NJ (2004) Antimalarial drug toxicity: a review. Drug Saf 27(1):25–61

    Article  CAS  PubMed  Google Scholar 

  52. Amaravadi RK, Lippincott-Schwartz J, Yin XM et al (2011) Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 17(4):654–666. doi:10.1158/1078-0432.CCR-10-2634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Meyer KC, Decker C, Baughman R (2010) Toxicity and monitoring of immunosuppressive therapy used in systemic autoimmune diseases. Clin Chest Med 31(3):565–588. doi:10.1016/j.ccm.2010.05.006

    Article  PubMed  Google Scholar 

  54. Achan J, Talisuna AO, Erhart A et al (2011) Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J 10:144. doi:10.1186/1475-2875-10-144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Warrell DA (1989) Treatment of severe malaria. J R Soc Med 82(Suppl 17):44–50, discussion 50–51

    PubMed  PubMed Central  Google Scholar 

  56. Foley M, Tilley L (1998) Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents. Pharmacol Ther 79(1):55–87

    Article  CAS  PubMed  Google Scholar 

  57. Osdene TS, Russell PB, Rane L (1967) 2,4,7-Triamino-6-ortho-substituted Arylpteridines. A new series of potent antimalarial agents. J Med Chem 10(3):431–434. doi:10.1021/jm00315a031

    Article  CAS  PubMed  Google Scholar 

  58. Trenholme CM, Williams RL, Desjardins RE et al (1975) Mefloquine (WR 142,490) in the treatment of human malaria. Science 190(4216):792–794

    Article  CAS  PubMed  Google Scholar 

  59. Price RN, Uhlemann AC, Brockman A et al (2004) Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364(9432):438–447. doi:10.1016/S0140-6736(04)16767-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Karbwang J, White NJ (1990) Clinical pharmacokinetics of mefloquine. Clin Pharmacokinet 19(4):264–279. doi:10.2165/00003088-199019040-00002

    Article  CAS  PubMed  Google Scholar 

  61. Rieckmann KH (1971) Determination of the drug sensitivity of Plasmodium falciparum. JAMA 217(5):573–578

    Article  CAS  PubMed  Google Scholar 

  62. Davis TM, Hung TY, Sim IK et al (2005) Piperaquine: a resurgent antimalarial drug. Drugs 65(1):75–87

    Article  CAS  PubMed  Google Scholar 

  63. White NJ, van Vugt M, Ezzet F (1999) Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet 37(2):105–125

    Article  CAS  PubMed  Google Scholar 

  64. Arnold J, Alving AS, Hockwald RS et al (1955) The antimalarial action of primaquine against the blood and tissue stages of falciparum malaria (Panama, P-F-6 strain). J Lab Clin Med 46(3):391–397

    CAS  PubMed  Google Scholar 

  65. Hill DR, Baird JK, Parise ME et al (2006) Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I. Am J Trop Med Hyg 75(3):402–415

    CAS  PubMed  Google Scholar 

  66. Beutler E (1959) The hemolytic effect of primaquine and related compounds: a review. Blood 14(2):103–139

    CAS  PubMed  Google Scholar 

  67. Alving AS, Carson PE, Flanagan CL et al (1956) Enzymatic deficiency in primaquine-sensitive erythrocytes. Science 124(3220):484–485

    CAS  PubMed  Google Scholar 

  68. Posner GH, Park SB, Gonzalez L et al (1996) Evidence for the importance of high-valent Fe=O and of a diketone in the molecular mechanism of action of antimalarial trioxane analogs of artemisinin. J Am Chem Soc 118:3537–3538

    Article  CAS  Google Scholar 

  69. Newton PN, Barnes KI, Smith PJ et al (2006) The pharmacokinetics of intravenous artesunate in adults with severe falciparum malaria. Eur J Clin Pharmacol 62(12):1003–1009. doi:10.1007/s00228-006-0203-2

    Article  CAS  PubMed  Google Scholar 

  70. Benakis A, Paris M, Loutan L et al (1997) Pharmacokinetics of artemisinin and artesunate after oral administration in healthy volunteers. Am J Trop Med Hyg 56(1):17–23

    CAS  PubMed  Google Scholar 

  71. Hassan Alin M, Ashton M, Kihamia CM et al (1996) Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients. Trans R Soc Trop Med Hyg 90(1):61–65

    Article  CAS  PubMed  Google Scholar 

  72. Klonis N, Xie SC, McCaw JM et al (2013) Altered temporal response of malaria parasites determines differential sensitivity to artemisinin. Proc Natl Acad Sci U S A 110(13):5157–5162. doi:10.1073/pnas.1217452110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Moehrle JJ, Duparc S, Siethoff C et al (2013) First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials. Br J Clin Pharmacol 75(2):524–537. doi:10.1111/j.1365-2125.2012.04368.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Dondorp AM, Yeung S, White L et al (2010) Artemisinin resistance: current status and scenarios for containment. Nat Rev Microbiol 8(4):272–280. doi:10.1038/nrmicro2331

    CAS  PubMed  Google Scholar 

  75. Anderson TJ, Nair S, Nkhoma S et al (2010) High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia. J Infect Dis 201(9):1326–1330. doi:10.1086/651562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Takala-Harrison S, Clark TG, Jacob CG et al (2013) Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia. Proc Natl Acad Sci U S A 110(1):240–245. doi:10.1073/pnas.1211205110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ariey F, Witkowski B, Amaratunga C et al (2014) A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505(7481):50–55. doi:10.1038/nature12876

    Article  PubMed  Google Scholar 

  78. Hudson AT (1993) Atovaquone—a novel broad-spectrum anti-infective drug. Parasitol Today 9(2):66–68

    Article  CAS  PubMed  Google Scholar 

  79. Desta Z, Zhao X, Shin JG et al (2002) Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 41(12):913–958. doi:10.2165/00003088-200241120-00002

    Article  CAS  PubMed  Google Scholar 

  80. Ferone R, Burchall JJ, Hitchings GH (1969) Plasmodium berghei dihydrofolate reductase. Isolation, properties, and inhibition by antifolates. Mol Pharmacol 5(1):49–59

    CAS  PubMed  Google Scholar 

  81. Watkins WM, Sixsmith DG, Chulay JD (1984) The activity of proguanil and its metabolites, cycloguanil and p-chlorophenylbiguanide, against Plasmodium falciparum in vitro. Ann Trop Med Parasitol 78(3):273–278

    CAS  PubMed  Google Scholar 

  82. Foote SJ, Galatis D, Cowman AF (1990) Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proc Natl Acad Sci U S A 87(8):3014–3017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Srivastava IK, Vaidya AB (1999) A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother 43(6):1334–1339

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Peterson DS, Walliker D, Wellems TE (1988) Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proc Natl Acad Sci U S A 85(23):9114–9118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Triglia T, Menting JG, Wilson C et al (1997) Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum. Proc Natl Acad Sci U S A 94(25):13944–13949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang P, Read M, Sims PF et al (1997) Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization. Mol Microbiol 23(5):979–986

    Article  CAS  PubMed  Google Scholar 

  87. Dahl EL, Shock JL, Shenai BR et al (2006) Tetracyclines specifically target the apicoplast of the malaria parasite Plasmodium falciparum. Antimicrob Agents Chemother 50(9):3124–3131. doi:10.1128/AAC.00394-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Clendenning WE (1965) Complications of tetracycline therapy. Arch Dermatol 91:628–632

    Article  CAS  PubMed  Google Scholar 

  89. Burrows JN, Burlot E, Campo B et al (2014) Antimalarial drug discovery—the path towards eradication. Parasitology 141(1):128–139. doi:10.1017/S0031182013000826

    Article  PubMed  PubMed Central  Google Scholar 

  90. Flannery EL, Chatterjee AK, Winzeler EA (2013) Antimalarial drug discovery—approaches and progress towards new medicines. Nat Rev Microbiol 11(12):849–862. doi:10.1038/nrmicro3138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Coteron JM, Marco M, Esquivias J et al (2011) Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J Med Chem 54(15):5540–5561. doi:10.1021/jm200592f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Spillman NJ, Allen RJ, McNamara CW et al (2013) Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host Microbe 13(2):227–237. doi:10.1016/j.chom.2012.12.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. McNamara CW, Lee MC, Lim CS et al (2013) Targeting Plasmodium PI(4)K to eliminate malaria. Nature 504(7479):248–253. doi:10.1038/nature12782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Vennerstrom JL, Arbe-Barnes S, Brun R et al (2004) Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 430(7002):900–904. doi:10.1038/nature02779

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs. David Sullivan and Kartiki Desai for their careful reading of the manuscript and thoughtful comments; Dr. Elizabeth Nenortas for proofing chemical structures; and Rachel Shapiro Grasmick for drawing the malaria life cycle. This project was supported by the Johns Hopkins Malaria Research Institute, the Bloomberg Family Foundation, and by NIH grants R01AI095453 and R01AI111962.

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology, and Malaria Research Institute, The Johns Hopkins University School of Medicine, 303 Hunterian Building, 725 North Wolfe Street, Baltimore, MD, 21205, USA

    Rahul P. Bakshi & Theresa A. Shapiro

Authors
  1. Rahul P. Bakshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Theresa A. Shapiro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theresa A. Shapiro .

Editor information

Editors and Affiliations

  1. College of Pharmacolgy,Univ of Minnesota, Dept of Experimental and Clinical Pharma, Minneapolis, Minnesota, USA

    John C. Rotschafer

  2. Division of Infectious Diseases, University of Wisconsin, Madison, Wisconsin, USA

    David R. Andes

  3. College of Pharmacy and Medicine, University of Illinois, Chicago, Illinois, USA

    Keith A. Rodvold

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this protocol

Cite this protocol

Bakshi, R.P., Shapiro, T.A. (2016). Pharmacodynamics of Antimalarial Agents. In: Rotschafer, J., Andes, D., Rodvold, K. (eds) Antibiotic Pharmacodynamics. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3323-5_17

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-3323-5_17

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3321-1

  • Online ISBN: 978-1-4939-3323-5

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation