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Behavior of Plasmodium falciparum against first-line regimens for malaria: evaluation of in vitro sensitivity and dormancy mechanism of artemisinin combination therapies

Grant number: 13/19588-8
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2014
Effective date (End): October 31, 2016
Field of knowledge:Health Sciences - Collective Health
Principal Investigator:Silvia Maria Fátima Di Santi
Grantee:Rosa Del Carmen Miluska Vargas Rodriguez
Home Institution: Superintendência de Controle de Endemias (SUCEN). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Approximately 3.3 billion people live at risk of contracting malaria worldwide, with 219 million cases and 660,000 deaths in 2010. In 2011 were notified 267,000 cases of the disease in Brazil. Plasmodium falciparum requires prompt and effective treatment, due to its ability to evolve to severe cases and death. Artemisinin derivatives can reach high plasma levels quickly, reducing significantly the number of asexual stage parasites. The artemisinin combination therapy (ACT) is based on a derivative of artemisinin associated with a slow-acting and prolonged antimalarial drug, thus increasing the efficacy of treatment and reducing the potential for development of resistance. The first-line treatments used in Brazil in uncomplicated P. falciparum are the combinations of artemether-lumefantrine (Coartem) and artesunate-mefloquine (Farmanguinhos). The regimen of second choice is the combination of quinine-doxycycline. A parasite is considered resistant when it is able to survive and multiply in their asexual blood stage, despite the administration and absorption of a suitable chemotherapeutic regimen. Today, there are some evidences of decreased efficacy to treatment with artemisinin and its derivatives in isolates of P. falciparum from Thailand and Cambodia. Single nucleotide polymorphisms (SNPs) in several genes have shown to affect the response of the parasite to different antimalarials. A phenomenon that requires further study is the mechanism of dormancy in P. falciparum proposed as a mechanism of tolerance to artemisinin. According to this, the parasites are able to tolerate the action of artemisinin by blocking its maturation temporarily, similar to what occurs with some bacteria. Resistance of P. falciparum to antimalarial drugs remains a challenge to control programs. The adoption of ACTs as first-line treatment for non-severe P. falciparum, requires monitoring studies to detect decreased sensitivity of this parasite to artemisinin derivatives and drugs used in association, as mefloquine and lumefantrine. This study proposes the in vitro determination of the phenotypic profile of the response of P. falciparum to artesunate and mefloquine, since this ACT is used in non-endemic region in Brazil. For the first time in Brazil, it proposes to assess the in vitro response to lumefantrine, used in combination with artemether in our endemic area. Also unprecedent is the evaluation of the mechanism of dormancy in Brazilian isolates of P. falciparum to ACTs adopted in the country.