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      Challenges of drug-resistant malaria Translated title: Défis du paludisme résistant

      review-article
      1 , 2 , * , 1
      Parasite
      EDP Sciences
      Malaria, Drug Resistance, Nanotechnology, RNAi, Stem cell, Peptides

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          Abstract

          Over the past six decades, the drug resistance of Plasmodium falciparum has become an issue of utmost concern. Despite the remarkable progress that has been made in recent years in reducing the mortality rate to about 30% with the scaling-up of vector control, introduction of artemisinin-based combination therapies and other malaria control strategies, the confirmation of artemisinin resistance on the Cambodia–Thailand border threatened all the previous success. This review addresses the global scenario of antimalarial resistance and factors associated with it, with the main emphasis on futuristic approaches like nanotechnology and stem cell therapy that may impede resistant malaria, along with novel medications which are preparing to enter the global antimalarial market. These novel studies are likely to escalate over the coming years and will hopefully help to reduce the burden of malaria.

          Translated abstract

          Au cours des six dernières décennies, la résistance aux médicaments de Plasmodium falciparum est devenue une question extrêmement préoccupante. Malgré des progrès remarquables accomplis ces dernières années pour réduire le taux de mortalité à environ 30 %, avec l’intensification de la lutte antivectorielle, l’introduction des thérapies combinées basées sur l’artémisinine et d’autres stratégies de lutte contre le paludisme, la confirmation de la résistance à l’artémisinine sur la frontière Cambodge-Thaïlande a menacé tous les succès précédents. Cette synthèse porte sur le scénario global de diverses résistances antipaludiques et les facteurs qui y sont associés, en soulignant les approches futuristes comme la nanotechnologie et la thérapie par les cellules souches, qui peuvent entraver le paludisme résistant, et les nouveaux médicaments qui vont bientôt entrer sur le marché antipaludéen mondial. Ces nouvelles études vont s’intensifier au cours des prochaines années et, nous l’espérons, contribuer à réduire la charge du paludisme.

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          Most cited references97

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          A molecular marker for chloroquine-resistant falciparum malaria.

          Chloroquine-resistant Plasmodium falciparum malaria is a major health problem, particularly in sub-Saharan Africa. Chloroquine resistance has been associated in vitro with point mutations in two genes, pfcrt and pfmdr 1, which encode the P. falciparum digestive-vacuole transmembrane proteins PfCRT and Pgh1, respectively. To assess the value of these mutations as markers for clinical chloroquine resistance, we measured the association between the mutations and the response to chloroquine treatment in patients with uncomplicated falciparum malaria in Mali. The frequencies of the mutations in patients before and after treatment were compared for evidence of selection of resistance factors as a result of exposure to chloroquine. The pfcrt mutation resulting in the substitution of threonine (T76) for lysine at position 76 was present in all 60 samples from patients with chloroquine-resistant infections (those that persisted or recurred after treatment), as compared with a base-line prevalence of 41 percent in samples obtained before treatment from 116 randomly selected patients (P<0.001), indicating absolute selection for this mutation. The pfmdr 1 mutation resulting in the substitution of tyrosine for asparagine at position 86 was also selected for, since it was present in 48 of 56 post-treatment samples from patients with chloroquine-resistant infections (86 percent), as compared with a base-line prevalence of 50 percent in 115 samples obtained before treatment (P<0.001). The presence of pfcrt T76 was more strongly associated with the development of chloroquine resistance (odds ratio, 18.8; 95 percent confidence interval, 6.5 to 58.3) than was the presence of pfmdr 1 Y86 (odds ratio, 3.2; 95 percent confidence interval, 1.5 to 6.8) or the presence of both mutations (odds ratio, 9.8; 95 percent confidence interval, 4.4 to 22.1). This study shows an association between the pfcrt T76 mutation in P. falciparum and the development of chloroquine resistance during the treatment of malaria. This mutation can be used as a marker in surveillance for chloroquine-resistant falciparum malaria.
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            A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants.

            The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).
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              Intercontinental spread of pyrimethamine-resistant malaria.

              Here we present molecular evidence demonstrating that malaria parasites bearing high-level pyrimethamine resistance originally arrived in Africa from southeast Asia. The resistance alleles carried by these migrants are now spreading across Africa at an alarming rate, signaling the end of affordable malaria treatment and presenting sub-Saharan Africa with a public health crisis.
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                Author and article information

                Journal
                Parasite
                Parasite
                parasite
                Parasite
                EDP Sciences
                1252-607X
                1776-1042
                2014
                18 November 2014
                : 21
                : ( publisher-idID: parasite/2014/01 )
                : 61
                Affiliations
                [1 ] Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research Chandigarh 160012 India
                [2 ] Department of Pharmacology, Postgraduate Institute of Medical Education and Research Chandigarh 160012 India
                Author notes
                [* ]Corresponding author: drbikashus@ 123456yahoo.com
                Article
                parasite140070 10.1051/parasite/2014059
                10.1051/parasite/2014059
                4234044
                25402734
                971f280b-7f62-4846-8315-a73e8f8f4f8e
                © S. Sinha et al., published by EDP Sciences, 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 06 July 2014
                : 23 October 2014
                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 142, Pages: 15
                Categories
                Review Article

                malaria,drug resistance,nanotechnology,rnai,stem cell,peptides
                malaria, drug resistance, nanotechnology, rnai, stem cell, peptides

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