Abstract
Plasmodium vivax is the most prevalent of the five species causing malaria in humans. The current available treatment for P. vivax malaria is limited and unsatisfactory due to at least two drawbacks: the undesirable side effects of primaquine (PQ) and drug resistance to chloroquine. Phenylalanine-alanine-PQ (Phe-Ala-PQ) is a PQ prodrug with a more favorable pharmacokinetic profile compared to PQ. The toxicity of this prodrug was evaluated in in vitro assays using a human hepatoma cell line (HepG2), a monkey kidney cell line (BGM), and human red blood cells deficient in the enzyme glucose-6-phosphate-dehydrogenase (G6PD). In addition, in vivo toxicity assays were performed with rats that received multiple doses of Phe-Ala-PQ to evaluate biochemical, hematological, and histopathological parameters. The activity was assessed by the inhibition of the sporogonic cycle using a chicken malaria parasite. Phe-Ala-PQ blocked malaria transmission in Aedes mosquitoes. When compared with PQ, it was less cytotoxic to BGM and HepG2 cells and caused less hemolysis of G6PD-deficient red blood cells at similar concentrations. The prodrug caused less alteration in the biochemical parameters than did PQ. Histopathological analysis of the liver and kidney did show differences between the control and Phe-Ala-PQ-treated groups, but they were not statistically significant. Taken together, the results highlight the prodrug as a novel lead compound candidate for the treatment of P. vivax malaria and as a blocker of malaria transmission.
Highlights
Malaria is a major human infectious disease that affects 500 million individuals each year [1]
The current drugs available are limited and unsatisfactory due to undesirable side effects, high cost and drug resistance (MDR) to antimalarials; in addition, most such blood schizonticides are not able to act against other parasite stages [4], and the combination of two or more drugs is used to reduce the risk of treatment failure [5]
Primaquine (PQ) is the only antimalarial active against gametocytes from all species of parasite, including chloroquineresistant P. falciparum and latent liver forms responsible for relapsing malaria caused by P. ovale and P. vivax
Summary
Malaria is a major human infectious disease that affects 500 million individuals each year [1]. Among the five parasite species that affect humans, Plasmodium falciparum is responsible for the most severe morbidities and worldwide number of deaths. The current drugs available are limited and unsatisfactory due to undesirable side effects, high cost and drug resistance (MDR) to antimalarials; in addition, most such blood schizonticides are not able to act against other parasite stages [4], and the combination of two or more drugs is used to reduce the risk of treatment failure [5]. Primaquine (PQ) is the only antimalarial active against gametocytes from all species of parasite, including chloroquineresistant P. falciparum and latent liver forms responsible for relapsing malaria caused by P. ovale and P. vivax. The exact mechanism how PQ eliminates the parasite hypnozoites and gametocytes is still unknown, but its proposed mode of action includes a) impairment of the parasite mitochondria interfering with the ubiquinone function in the respiratory chain and b) high production of intracellular reactive species increasing oxidative stress [7,8]
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