Amodiaquine failure associated with erythrocytic glutathione in Plasmodium falciparum malaria.
OBJECTIVE
To establish the relationship between production of glutathione and the therapeutic response to amodiaquine (AQ) monotherapy in Plasmodium falciparum non-complicated malaria patients.


METHODS
Therapeutic response to AQ was evaluated in 32 patients with falciparum malaria in two townships of Antioquia, Colombia, and followed-up for 28 days. For every patient, total glutathione and enzymatic activity (glutathione reductase, GR, and gamma-glutamylcysteine synthetase, gamma-GCS) were determined in parasitized erythrocytes, non-infected erythrocytes and free parasites, on the starting day (day zero, before ingestion of AQ) and on the day of failure (in case of occurrence).


RESULTS
There was found an AQ failure of 31.25%. Independent of the therapeutic response, on the starting day and on the day of failure, lower total glutathione concentration and higher GR activities in parasitized erythrocytes were found, compared with non-infected erythrocytes (p < 0.003). In addition, only on the day of failure, gamma-GCS activity of parasitized erythrocytes was higher, compared with that of healthy erythrocytes (p = 0.01). Parasitized and non-parasitized erythrocytes in therapeutic failure patients (TF) had higher total glutathione on the starting day compared with those of adequate clinical response (ACR) (p < 0.02). Parasitized erythrocytes of TF patients showed lower total glutathione on the failure day, compared with starting day (p = 0.017). No differences was seen in the GR and gamma-GCS activities by compartment, neither between the two therapeutic response groups nor between the two treatment days.


CONCLUSIONS
This study is a first approach to explaining P. falciparum therapeutic failure in humans through differences in glutathione metabolism in TF and ACR patients. These results suggest a role for glutathione in the therapeutic failure to antimalarials.
Zuluaga
Lina
L
Grupo Malaria, Universidad de Antioquia, Torre 1, Piso 6, Laboratorio 610, Sede de Investigación Universitaria (SIU), Universidad de Antioquia, Medellín, Colombia. linazulu83@yahoo.es <linazulu83@yahoo.es>
Pabón
Adriana
A
López
Carlos
C
Ochoa
Aleida
A
Blair
Silvia
S
D000293:Adolescent; D000328:Adult; D000655:Amodiaquine / Q000627:therapeutic use*; D000818:Animals; D002648:Child; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000469:parasitology; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000097:blood; D005978:Glutathione / Q000097:blood*; D005980:Glutathione Reductase / Q000097:blood; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood* / Q000188:drug therapy* / Q000201:enzymology / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification / Q000378:metabolism
D000655:Amodiaquine; D005980:Glutathione Reductase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione