Methemoglobinemia and Adverse Events in Plasmodium vivax Malaria Patients Associated with High Doses of Primaquine Treatment

Jaime Carmona-Fonseca Grupo Salud y Comunidad and Grupo Malaria, Universidad de Antioquia, Medellín, Colombia

Search for other papers by Jaime Carmona-Fonseca in
Current site
Google Scholar
PubMed
Close
,
Gonzalo Álvarez Grupo Salud y Comunidad and Grupo Malaria, Universidad de Antioquia, Medellín, Colombia

Search for other papers by Gonzalo Álvarez in
Current site
Google Scholar
PubMed
Close
, and
Amanda Maestre Grupo Salud y Comunidad and Grupo Malaria, Universidad de Antioquia, Medellín, Colombia

Search for other papers by Amanda Maestre in
Current site
Google Scholar
PubMed
Close
Restricted access

Primaquine (PQ) is recommended to prevent relapses in patients with Plasmodium vivax malaria infection. However, treatment with PQ causes methemoglobinemia. In this study, we measured the methemoglobin (MetHB) levels in three groups of subjects who received PQ treatment at 0.58, 0.83, or 1.17 mg/kg/d. A total of 112 subjects were studied. MetHB levels were detected at ≥ 4% in 46–50% 1 day after PQ treatment in all three groups and 4–9% of subjects had MetHB levels ≥ 4% 15 days after treatment. Only subjects receiving the highest doses of PQ had mild and brief adverse events, and 17% of them were associated with treatment. We conclude that when PQ is administered under certain conditions (i.e., normal glucose-6-phosphate dehydrogenase activity, in non-pregnant subjects and with a light meal), daily doses as high as 1.17 mg/kg do not represent a serious risk of high MetHB levels to patients.

Author Notes

Reprint requests: Amanda Maestre, Universidad de Antioquia, Calle 62 # 52–59, Medellín, Colombia. E-mail: aemaestre@quimbaya.udea.edu.co.
  • 1

    van Heijst NP, Metahemoglobinemia. IPCSIntox databank. Available at: http://www.intox.org/databank/documents/treat/treats/trt40_s.htm. Accessed November 1, 2007.

    • PubMed
    • Export Citation
  • 2

    Hall AH, Kulig KW, Rumack BH, 1986. Drug- and chemical-induced methaemoglobinaemia. Clinical features and management. Med Toxicol 1 :253–260.

  • 3

    Toxicologia.net, Índice de tóxicos. 16. Metahemoglobinizantes. Available at: http://wzar.unizar.es/stc/toxicologianet/pages/x/x16/01.htm. Accessed November 1, 2007.

    • PubMed
    • Export Citation
  • 4

    Bradberry SM, 2003. Occupational methaemoglobinaemia. Mechanisms of production, features, diagnosis and management including the use of methylene blue. Toxicol Rev 22 :13–27.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Medline-plus, Información en salud para todos. Enciclopedia médica en español. U.S. National Library of Medicine; National Institutes of Health, Department of Health and Human Services. Available at: http://www.nlm.nih.gov/medlineplus/spanish/ency/article/000562.htm#Nombres%20alternativos. Accessed November 1, 2007.

    • PubMed
    • Export Citation
  • 6

    Coleman MD, Coleman NA, 1996. Drug-induced methaemoglobi-naemia. Treatment issues. Drug Saf 14 :394–405.

  • 7

    Fonseca D, Mateus H, Silva C, Contreras N, Restrepo C, 2005. Deficiencia de glucosa 6-fosfato deshidrogenasa. Aspectos gen-erales de la eritroenzimopatía más frecuente en el mundo. Acta Med Colomb 30–64 :59–64.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Clayman CB, Arnold J, Hochwald RS, Yount EH, Edgcomb JH, Alving AS, 1952. Toxicity of primaquine in caucasians. JAMA 149 :1563–1568.

  • 9

    Hockwald RS, Arnold J, Clayman CB, Alving MD, 1952. Toxicity of primaquine to negroes. J Am Med Assoc 149 :1568–1570.

  • 10

    Frank JE, 2005. Diagnosis and management of G6PD deficiency. Am Fam Physician 72 :1277–1282.

  • 11

    Luzzatto L, 2006. Glucose 6-phosphate dehydrogenase deficiency: from genotype to phenotype. Haematologica 91 :1303–1306.

  • 12

    Santana MS, Rocha MA, Arcanjo AR, Sardinha JF, Alecrim WD, Alecrim MD, 2007. Associação de metemoglobinemia e defi-ciência de glicose-6-fosfato desidrogenase em pacientes com malária tratados com primaquina. Rev Soc Bras Med Trop 40 :533–536.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Carmona-Fonseca J, Álvarez G, Blair S, 2006. Malaria por Plasmodium vivax: curación del ataque agudo con tres dosis diferentes de primaquina y dosis fija de cloroquina. Antioquia, Colombia, 2003–2004. Biomedica (Bogota) 26 :353–365.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Álvarez G, Piñeros JG, Tobón A, Ríos A, Maestre A, Blair S, Carmona-Fonseca J, 2006. Efficacy of three chloroquine–pri-maquine regimens for treatment of Plasmodium vivax malaria in Colombia. Am J Trop Med Hyg 75 :605–609.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Beutler E, Duparc S, the G6PD Deficiency Working Group, 2007. Glucose-6-phosphate dehydrogenase deficiency and antimalar-ial drug development. Am J Trop Med Hyg 77 :779–789.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Arnold J, Alving AS, Clayman CB, 1961. Induced primaquine resistance in vivax malaria. Trans R Soc Trop Med Hyg 55 :345–350.

  • 17

    Collins WE, Jeffery GM, 1996. Primaquine resistance in Plasmodium vivax. Am J Trop Med Hyg 55 :243–249.

  • 18

    Schwartz E, Regev-Yochay G, Kurnik D, 2000. Short report: a consideration of primaquine dose adjustment for radical cure of Plasmodium vivax malaria. Am J Trop Med Hyg 63 :393–395.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Signorini L, Matteelli A, Castelnuovo F, Castelli F, Oladeji O, Carosi G, 1996. Short report: primaquine-tolerant P. vivax in an Italian traveler from Guatemala. Am J Trop Med Hyg 55 :472–473.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Goller JL, Jolley D, Ringwald P, Biggs BA, 2007. Regional differences in the response of Plasmodium vivax malaria to pri-maquine as anti-relapse therapy. Am J Trop Med Hyg 76 :203–207.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Lalloo DG, Shingadia D, Pasvol G, Chiodini PL, Whitty CJ, Beeching NJ, Hill DR, Warrell DA, Bannister BA; HPA Advisory Committee on Malaria Prevention in UK Travellers, 2007. UK malaria treatment guidelines. J Infect 54 :111–121.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Lwanga SK, Lameshow S, 1991. Determinación del Tamaño Muestral en los Estudios Sanitarios. Ginebra: OMS.

    • PubMed
    • Export Citation
  • 23

    Carmona-Fonseca J, 2003. La malaria en Colombia, Antioquia y las zonas de Urabá y Bajo Cauca: panorama para interpretar la falla terapéutica antimalárica. Parte 1. Iatreia 16 :299–318.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Carmona-Fonseca J, 2004. La malaria en Colombia, Antioquia y las zonas de Urabá y Bajo Cauca: panorama para interpretar la falla terapéutica antimalárica. Parte 2. Iatreia 17 :34–53.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Beutler E, 1967. Glucose-6-phosphate dehydrogenase deficiency. Diagnosis, clinical and genetic implications. Am J Clin Pathol 47 :303–311.

  • 26

    World Health Organization W.H.O., 2000. Severe falciparum malaria. Trans R Soc Trop Med Hyg 94 :1–90.

  • 27

    Menéndez-Capote R, Díaz-Pérez L, Luzardo-Suárez C, 1997. Hemólisis y tratamiento con primaquina. Informe Preliminar. Rev Cubana Med Trop 49 :136–138.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Ude A, 1993. Manual de Toxicología. Medellín: Universidad de Antioquia.

  • 29

    Rodríguez-Fernández A, Del Pozo-Hessing C, 2005. Intoxicación por cianuro. Medisan 5 :103–107.

  • 30

    Fletcher KA, Evans DA, Gilles HM, Greaves J, Bunnag D, Harinasuta T, 1981. Studies on the pharmacokinetics of pri-maquine. Bull World Health Organ 59 :407–412.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Baird JK, Lacy MD, Basri H, Barcus MJ, Maguire JD, Bangs MJ, Gramzinski R, Sismadi P, Krisin, Ling J, Wiady I, Kusumaningsih M, Jones TR, Fryauff DJ, Hoffman SL; United States Naval MedicalResearchUnit2ClinicalTrialsTeam,2001.Randomized, parallel placebo-controlled trial of primaquine for malaria pro-phylaxis in Papua, Indonesia. Clin Infect Dis 33 :1990–1997.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Fryauff DJ, Baird JK, Basri H, Sumawinata I, Purnomo, Richie TL, Ohrt CK, Mouzin E, Church CJ, Richards AL, 1995. Randomised placebo-controlled trial of primaquine for prophylaxis of falci-parum and vivax malaria. Lancet 346 :1190–1193.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Soto J, Toledo J, Rodriquez M, Sanchez J, Herrera R, Padilla J, Berman J, 1998. Primaquine prophylaxis against malaria in nonimmune Colombian soldiers: efficacy and toxicity. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 129 :241–244.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Soto J, Toledo J, Rodriquez M, Sanchez J, Herrera R, Padilla J, Berman J, 1999. Double-blind, randomized, placebo-controlled assessment of chloroquine/primaquine prophylaxis for malaria in nonimmune Colombian soldiers. Clin Infect Dis 29 :199–201.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Weiss WR, Oloo AJ, Johnson A, Koech D, Hoffman SL, 1995. Daily primaquine is effective for prophylaxis against falciparum malaria in Kenya: comparison with mefloquine, doxycycline, and chloroquine plus proguanil. J Infect Dis 171 :1569–1575.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Clyde DF, McCarthy VC, 1977. Radical cure of Chesson strain vivax malaria in man by 7, not 14, days of treatment with pri-maquine. Am J Trop Med Hyg 26 :562–563.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Wilairatana P, Silachamroon U, Krudsood S, Singhasivanon P, Treeprasertsuk S, Bussaratid V, Phumratanaprapin W, Srivilirit S, Looareesuwan S, 1999. Efficacy of primaquine regimens for primaquine-resistant Plasmodium vivax malaria in Thailand. Am J Trop Med Hyg 61 :973–977.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Cohen RJ, Sachs JR, Wicker DJ, Conrad ME, 1968. Methemo-globinemia provoked by malarial chemoprophylaxis in Vietnam. N Engl J Med 279 :1127–1131.

Past two years Past Year Past 30 Days
Abstract Views 614 507 23
Full Text Views 336 6 0
PDF Downloads 135 8 0
 

 

 

 
 
Affiliate Membership Banner
 
 
Research for Health Information Banner
 
 
CLOCKSS
 
 
 
Society Publishers Coalition Banner
Save