Medicamentos contra malária e Resistência Silde inicial Discente: Leonardo Hiroyuki Santos Momo Docente: Carsten Wrenger e Gerhard Wunderlich Fevereiro 2012

Malária Problema de saúde pública >90 países 300 – 500 milhões de novos casos reportados 90 % -> África Background Malaria is a public health problem in more than 90 countries. Each year, between 300 and 500 million new cases are reported worldwide [1]. According to the Roll Back Malaria Campaign of the World Health Organization (WHO), 90 percent of the more than one million deaths worldwide caused by malaria every year take place in Africa, and malaria constitutes 10 percent of the continent's overall disease burden

Breve histórico 1914 – Início de campanha para erradicação da malária Dicloro-Difenil-Tricloroetano 1969 – Fim deste estágio The opening of the panama canal in 1914 initiated an era in which efforts to control malaria were aimed at the anopheline mosquito. The World Health Organization’s Global Malaria Eradication Campaign in the 1950s and 1960s marked the apex of these efforts. The use of dichlorodiphenyltrichloroethane (DDT) rid vast areas of endemic malaria virtually everywhere except in sub- Saharan Africa. The eradication strategy was abandoned in 1969, because it came to be considered logistically, socially, and politically impractical, especially given public concern about the effects of DDT on the environment. It took two decades and a global resurgence of malaria before a new strategy emerged, one that was focused on treatment rather than prevention. 1 This treatment strategy is currently being debated, and its efficacy is unproved. 2,3 Both the broad collapse

Fonte: artigo “Effectiveness of Antimalarial Drugs”

Malária Tratamento e prevenção de casos fatais existe se a condição é diagnosticada rapidamente. -Demora na busca de terapia -Uso incorreto de drogas anti-malária -Resistência do parasita às drogas Treatment and prevention of malaria deaths exist if the condition is promptly diagnosed, treated and/or referred. Delay in seeking therapy, misuse of anti-malarial drugs, and resistance of malaria parasites to existing drugs frustrate measures to effectively manage the disease in Africa

Medicamentos Cloroquina sulfadoxina-pirimetamina 1-2% custo médio de outros medicamentos Both drugs are antifolates; they inhibit the production of enzymes involved in the synthesis of folic acid within the parasites. Either drug by itself is only moderately effective in treating malaria, because the parasite Plasmodium falciparum may be able to use exogenous folic acid, i.e. folic acid which is present in the parasite's environment, while in combination, the two substances have a synergistic effect which outbalances that ability. The combination is considered to be more effective in treating malaria caused by Plasmodium falciparum than that caused by Plasmodium vivax, for whichchloroquine is considered more effective, though in the absence of a species-specific diagnosis the sulfadoxine-pyrimethamine combination may be indicated Due to side effects, however, it is no longer recommended as a routine preventative,but only to treat serious malaria infections or to prevent them in areas where other drugs may not work

Fonte: artigo “Effectiveness of Antimalarial Drugs”

Fonte: artigo “Effectiveness of Antimalarial Drugs”

Sobre os medicamentos A maioria dos medicamentos foca no ciclo sanguíneo da doença -Cultura em sangue -Fase sintomática Alguns novos medicamentos focam no estágio assintomático do fígado Almost all of these efforts have focused on the cyclic blood stage of the disease, partly because the parasites can be easily maintained in culture through addition of human red blood cells to the growth medium, and partly because blood stage infection causes malaria’s characteristic symptoms. However, the asymptomatic liver stage, which the parasite goes through only once in its life history, presents the best opportunity for developing drugs that both hit new targets and also could be used in highly desirable eradication campaigns. Recent research, especially on the frequency of differentially expressed genes in blood and liver stage parasites, supports the feasibility of discovering stage-specific drugs.

Resistência -resistência inata espécie-específico -resistência inata sorovar-específico -resistência adquirida

Fonte: artigo “Effectiveness of Antimalarial Drugs”

Resistência:Cloroquina Início em 1943 – Substância adquirida de alemães na 2ª GM Aumento de resistência de 11x Resistência generalizada cloroquina

Resistência: Sulfadoxina-pirimetamina Age inibindo a produção de enzimas envolvidas na síntese de ácido fólico Devido aos efeitos colaterais, é mais recomendado em casos mais severos de malária. This combination acts synergistically against folate synthesis, inhibiting dihydropteroate synthase and dihydrofolate reductase. sulfadoxina pirimetamina

A quinina é fluorescente Resistência:Quinina Jesuítas no Peru foram os primeiros a utilizar a quinina Agem inibindo a biocristalização de hemozoínas quinina A quinina é fluorescente

Artemisinina Um dos medicamentos mais recomendados para o tratamento de malária Dihidroartemisina Atualmente sem consenso sobre seu mecanismo Artemisia annua All artemisinins used today are prodrugs of the biologically active metabolite dihydroartemisinin, which is active during the stage when the parasite is located inside red blood cells. Although there is no consensus regarding the mechanism through which artemisinin derivatives kill the parasites [38], several lines of evidence indicate that artemisinins exert their antimalarial action by perturbing redox homeostasis in malaria parasites. When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin within its digestive vacuole, a process that generates oxidative stress[39]. In one theory the iron of the heme directly reduces the peroxide bond in artemisinin, generating high-valent iron-oxo species and resulting in a cascade of reactions that produce reactive oxygen radicalswhich damages the parasite and lead to its death[40]. A more recently described alternative is that artemisinins disrupt cellular redox cycling[41]. Numerous studies have investigated the type of damage oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasites by artemisinin.[42] These observations were supported by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin and inhibition of hemozoinformation by malaria parasites. Electron microscopic evidence linking artemisinin action to the parasite's digestive vacuole has been obtained showing that the digestive vacuole membrane suffers damage soon after parasites are exposed to artemisinin.[43] This would also be consistent with data showing that the digestive vacuole is already established by the mid-ring stage of the parasite's blood cycle,[44] a stage that is sensitive to artemisinins but not other antimalarials. A commonly cited theory that the parasite's SERCA pump (PfATP6)[45] is a key target of artemisinins has been questioned[46]. Artemisinins do not inhibit this protein when it is expressed in yeast[47][48] and transfection studies show no significant effect of PfATP6 genotype on artemisinin phenotype[49]. Although a single field study identified a mutation in PfATP6 that was associated with resistance to artemether,[50] this mutation has not achieved a meaningful prevalence in any location, and the phenotypic association is not replicated elsewhere.[51] There is no role for PfSERCA in the artemisinin resistance that appears to be emerging in Cambodia[31][32]. A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated the drug acts on the electron transport chain, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane[52]. artemisinina

Referências bibliográficas Artigos relacionados: “Anti-malaria drug blocks proteotoxic stress response:Anti-cancer implications” “The Limits and Intensity of Plasmodium falciparum Transmission: Implications for Malaria Control and Elimination Worldwide” “Effectiveness of Antimalarial Drugs” “Self-reported use of anti-malarial drugs and health facility management of malaria in Ghana” “A Research Agenda for Malaria Eradication: Drugs”

Fonte:artigo “The Next Opportunity in Anti-Malaria Drug Discovery: The Liver Stage”- Emily R. Derbyshire