Posts filed under ‘Antiparasitarios’

Abordaje terapéutico actual de la malaria grave importada

Revista Española de Quimioterapia Septiembre 2016 V.29 Supl.1

EMMANUELE VENANZI, ROGELIO LÓPEZ-VÉLEZ

PDF

http://www.seq.es/seq/0214-3429/29/sup1/15venanzi.pdf

 

Resistencia a los antimaláricos

EMMANUELE VENANZI, ROGELIO LÓPEZ-VÉLEZ

PDF

http://www.seq.es/seq/0214-3429/29/sup1/16venanzi.pdf

 

April 9, 2017 at 12:44 pm

A New Development in Trypanosoma cruzi Detection

Journal of Clinical Microbiology March 2017 V.55 N.3 P.690-692

Herbert B. Tanowitz and Louis M. Weiss

Department of Pathology, Division of Tropical Medicine and Parasitology, and Department of Medicine, Division of Infectious Disease, Albert Einstein College of Medicine, Bronx, New York, USA

Chagas disease is caused by the parasite Trypanosoma cruzi and is an important cause of morbidity and mortality in areas of Latin America where Chagas disease is endemic and among infected individuals who have migrated to nonendemic areas of North America and Europe.

There are many diagnostic tests that are employed in the serological diagnosis of this infection. In this issue of the Journal of Clinical Microbiology, Bautista-López et al. provide characterization of excretory vesicles (EVs) from Vero cells infected with T. cruzi and provide data on the EVs produced by trypomastigotes and amastigotes (N. L. Bautista-López et al., J Clin Microbiol 55:744–758, 2017, https://doi.org/10.1128/JCM.01649-16).

Their proteomic study defines potential targets to evaluate for improved diagnostic tests, effects on host cell biology that contribute to the pathogenesis of infection, and vaccine candidates. If any of the EV-associated proteins identified were to be correlated to cure of infection, this would be a major advance….

PDF

http://jcm.asm.org/content/55/3/690.full.pdf+html

February 24, 2017 at 8:01 am

Safety, tolerability, and efficacy of repeated doses of dihydroartemisinin-piperaquine for prevention and treatment of malaria: a systematic review and meta-analysis

Lancet Infectious Diseases February 2017 V.17 N.2 P.184–193

Julie Gutman, MD,  Stephanie Kovacs, PhD, Prof Grant Dorsey, MD, Prof Andy Stergachis, PhD, Prof Feiko O ter Kuile, MD

Background

Intermittent preventive treatment (IPT) for malaria is used in infants, children, adults, and pregnant women. Dihydroartemisinin-piperaquine (DP) is an effective, well tolerated artemisinin-based combination therapy. The long half-life of piperaquine makes it attractive for IPT. We conducted a systematic review and meta-analysis to establish the efficacy and safety of repeated treatment with DP.

Methods

Following PRISMA guidelines, we searched multiple databases on Sept 1, 2016, with the terms: “human” AND “dihydroartemisinin-piperaquine” OR “DHA-PPQ”. Studies were eligible if they were randomised controlled trials (RCTs) or prospective cohort studies involving repeat exposures to standard 3-day courses of DP for either seasonal malaria chemoprevention, mass drug administration, or treatment of clinical malaria, conducted at any time and in any geographic location. Random-effects meta-analysis was used to generate pooled incidence rate ratios and relative risks, or risk differences.

Findings

11 studies were included: two repeat treatment studies (one in children younger than 5 years and one in pregnant women), and nine IPT trials (five in children younger than 5 years, one in schoolchildren, one in adults, two in pregnant women). Comparator interventions included placebo, artemether-lumefantrine, sulfadoxine-pyrimethamine (SP), SP+amodiaquine, SP+piperaquine, SP+chloroquine, and co-trimoxazole. Of 14 628 participants, 3935 received multiple DP courses (2–18). Monthly IPT-DP was associated with an 84% reduction in the incidence of malaria parasitaemia measured by microscopy compared with placebo. Monthly IPT-DP was associated with fewer serious adverse events than placebo, daily co-trimoxazole, or monthly SP. Among 56 IPT-DP recipients (26 children, 30 pregnant women) with cardiac parameters, all QTc intervals were within normal limits, with no significant increase in QTc prolongation with increasing courses of DP.

Interpretation

Monthly DP appears well tolerated and effective for IPT. Additional data are needed in pregnancy and to further explore the cardiac safety with monthly dosing.

Funding

Bill & Melinda Gates Foundation and NIH.

FULL TEXT

http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(16)30378-4/fulltext?elsca1=etoc

PDF

http://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(16)30378-4.pdf

February 1, 2017 at 2:09 pm

A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype–genotype association study

Lancet Infectious Diseases February 2017 V.17 N.2 P.174–183

Benoit Witkowski, PhD†, Valentine Duru, MSc†, Nimol Khim, PhD, Leila S Ross, PhD, Benjamin Saintpierre, MSc, Johann Beghain, MSc, Sophy Chy, BS, Saorin Kim, BS, Sopheakvatey Ke, BS, Nimol Kloeung, BS, Rotha Eam, BS, Chanra Khean, BS, Malen Ken, BS, Kaknika Loch, BS, Anthony Bouillon, PhD, Anais Domergue, MSc, Laurence Ma, MSc, Christiane Bouchier, PhD, Rithea Leang, PhD, Rekol Huy, MD, Prof Grégory Nuel, PhD, Jean-Christophe Barale, PhD, Eric Legrand, PhD, Pascal Ringwald, MD, Prof David A Fidock, PhD, Odile Mercereau-Puijalon, PhD, Frédéric Ariey, PhD, Dr Didier Ménard, PhD

Background

Western Cambodia is the epicentre of Plasmodium falciparum multidrug resistance and is facing high rates of dihydroartemisinin–piperaquine treatment failures. Genetic tools to detect the multidrug-resistant parasites are needed. Artemisinin resistance can be tracked using the K13 molecular marker, but no marker exists for piperaquine resistance. We aimed to identify genetic markers of piperaquine resistance and study their association with dihydroartemisinin–piperaquine treatment failures.

Methods

We obtained blood samples from Cambodian patients infected with P falciparum and treated with dihydroartemisinin–piperaquine. Patients were followed up for 42 days during the years 2009–15. We established in-vitro and ex-vivo susceptibility profiles for a subset using piperaquine survival assays. We determined whole-genome sequences by Illumina paired-reads sequencing, copy number variations by qPCR, RNA concentrations by qRT-PCR, and protein concentrations by immunoblotting. Fisher’s exact and non-parametric Wilcoxon rank-sum tests were used to identify significant differences in single-nucleotide polymorphisms or copy number variants, respectively, for differential distribution between piperaquine-resistant and piperaquine-sensitive parasite lines.

Findings

Whole-genome exon sequence analysis of 31 culture-adapted parasite lines associated amplification of the plasmepsin 2–plasmepsin 3 gene cluster with in-vitro piperaquine resistance. Ex-vivo piperaquine survival assay profiles of 134 isolates correlated with plasmepsin 2 gene copy number. In 725 patients treated with dihydroartemisinin–piperaquine, multicopy plasmepsin 2 in the sample collected before treatment was associated with an adjusted hazard ratio (aHR) for treatment failure of 20·4 (95% CI 9·1–45·5, p<0·0001). Multicopy plasmepsin 2 predicted dihydroartemisinin–piperaquine failures with 0·94 (95% CI 0·88–0·98) sensitivity and 0·77 (0·74–0·81) specificity. Analysis of samples collected across the country from 2002 to 2015 showed that the geographical and temporal increase of the proportion of multicopy plasmepsin 2 parasites was highly correlated with increasing dihydroartemisinin–piperaquine treatment failure rates (r=0·89 [95% CI 0·77–0·95], p<0·0001, Spearman’s coefficient of rank correlation). Dihydroartemisinin–piperaquine efficacy at day 42 fell below 90% when the proportion of multicopy plasmepsin 2 parasites exceeded 22%.

Interpretation

Piperaquine resistance in Cambodia is strongly associated with amplification of plasmepsin 2–3, encoding haemoglobin-digesting proteases, regardless of the location. Multicopy plasmepsin 2 constitutes a surrogate molecular marker to track piperaquine resistance. A molecular toolkit combining plasmepsin 2 with K13 and mdr1 monitoring should provide timely information for antimalarial treatment and containment policies.

Funding

Institut Pasteur in Cambodia, Institut Pasteur Paris, National Institutes of Health, WHO, Agence Nationale de la Recherche, Investissement d’Avenir programme, Laboratoire d’Excellence Integrative “Biology of Emerging Infectious Diseases”.

FULL TEXT

http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(16)30415-7/fulltext?elsca1=etoc

PDF

http://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(16)30415-7.pdf

February 1, 2017 at 2:08 pm

Genetic markers associated with dihydroartemisinin–piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype–phenotype association study

Lancet Infectious Diseases February 2017 V.17 N.2 P.164–173

Dr Roberto Amato, PhD,  Pharath Lim, MD, Olivo Miotto, PhD, Chanaki Amaratunga, PhD, Dalin Dek, MSc, Richard D Pearson, PhD, Jacob Almagro-Garcia, MSc, Aaron T Neal, PhD, Sokunthea Sreng, Seila Suon, MD, Eleanor Drury, BSc[Hons], Dushyanth Jyothi, MPhil, Jim Stalker, MA, Dominic P Kwiatkowski, FRCP, Dr Rick M Fairhurst, MD

Background

As the prevalence of artemisinin-resistant Plasmodium falciparum malaria increases in the Greater Mekong subregion, emerging resistance to partner drugs in artemisinin combination therapies seriously threatens global efforts to treat and eliminate this disease. Molecular markers that predict failure of artemisinin combination therapy are urgently needed to monitor the spread of partner drug resistance, and to recommend alternative treatments in southeast Asia and beyond.

Methods

We did a genome-wide association study of 297 P falciparum isolates from Cambodia to investigate the relationship of 11 630 exonic single-nucleotide polymorphisms (SNPs) and 43 copy number variations (CNVs) with in-vitro piperaquine 50% inhibitory concentrations (IC50s), and tested whether these genetic variants are markers of treatment failure with dihydroartemisinin–piperaquine. We then did a survival analysis of 133 patients to determine whether candidate molecular markers predicted parasite recrudescence following dihydroartemisinin–piperaquine treatment.

Findings

Piperaquine IC50s increased significantly from 2011 to 2013 in three Cambodian provinces (2011 vs 2013 median IC50s: 20·0 nmol/L [IQR 13·7–29·0] vs 39·2 nmol/L [32·8–48·1] for Ratanakiri, 19·3 nmol/L [15·1–26·2] vs 66·2 nmol/L [49·9–83·0] for Preah Vihear, and 19·6 nmol/L [11·9–33·9] vs 81·1 nmol/L [61·3–113·1] for Pursat; all p≤10−3; Kruskal-Wallis test). Genome-wide analysis of SNPs identified a chromosome 13 region that associates with raised piperaquine IC50s. A non-synonymous SNP (encoding a Glu415Gly substitution) in this region, within a gene encoding an exonuclease, associates with parasite recrudescence following dihydroartemisinin–piperaquine treatment. Genome-wide analysis of CNVs revealed that a single copy of the mdr1 gene on chromosome 5 and a novel amplification of the plasmepsin 2 and plasmepsin 3 genes on chromosome 14 also associate with raised piperaquine IC50s. After adjusting for covariates, both exo-E415G and plasmepsin 2–3 markers significantly associate (p=3·0 × 10−8 and p=1·7 × 10−7, respectively) with decreased treatment efficacy (survival rates 0·38 [95% CI 0·25–0·51] and 0·41 [0·28–0·53], respectively).

Interpretation

The exo-E415G SNP and plasmepsin 2–3 amplification are markers of piperaquine resistance and dihydroartemisinin–piperaquine failures in Cambodia, and can help monitor the spread of these phenotypes into other countries of the Greater Mekong subregion, and elucidate the mechanism of piperaquine resistance. Since plasmepsins are involved in the parasite’s haemoglobin-to-haemozoin conversion pathway, targeted by related antimalarials, plasmepsin 2–3 amplification probably mediates piperaquine resistance.

FULL TEXT

http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(16)30409-1/fulltext?elsca1=etoc

PDF

http://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(16)30409-1.pdf

February 1, 2017 at 2:06 pm

Dihydroartemisinin-piperaquine: if it works for control, can we use it for elimination?

Lancet Infectious Diseases February 2017 V.17 N.2 P.121–122

COMMENT

Quique Bassat

Historically, antimalarial drugs have been used at a population level in malaria-endemic areas with the objective of decreasing the burden, impact, and transmissibility of malaria. Continuous chemoprophylaxis, once experimented but never seriously considered a feasible wide-scale implementable strategy, has been superseded by the concept of intermittent treatment targeting different population groups, presenting many advantages, including non-interference with the acquisition of natural immunity against malaria. A fundamental premise for the use of any drug as part of population wide distribution efforts, besides its efficacy, is that the drug is sufficiently safe so as to not to risk endangering the healthy individuals that will be exposed to it. The artemisinin-derived combination dihydroartemisinin-piperaquine (DP), registered under the European Medicines Agency in 2011, would appear as an ideal candidate for the treatment of malaria, not only because of its high-demonstrated efficacy, but on account of its excellent tolerability and good safety profile, well reported in the literature. From a preventive point of view, the long half-life of the partner drug piperaquine conveys protection of 22 days for adult patients and around 20 days for paediatric patients, indicating a better post-treatment prophylactic effect than other combination therapies. In the Lancet Infectious Diseases, Julie Gutman and colleagues analyse the safety, tolerability, and efficacy of repeated doses of DP, for the treatment and prevention of malaria, with a particular focus on its use as intermittent preventive treatment (IPT). Their meta-analysis, looking at over 4000 patients exposed to repeated courses of DP, substantiates the high efficacy of this drug in terms of controlling malaria and all-cause hospital admission, and the good tolerability of repeated treatment schemes, with no evidence of arrhythmias secondary to the potential QT prolongation effect of cumulative doses of piperaquine after repeated doses. Although numbers are clearly insufficient to rule out this rare, life-threatening complication, and the small number of carefully ECG monitored patients calls for caution and further cardio safety studies, this analysis adds up to the growing body of evidence supporting the potential of this drug for IPT strategies. as an alternative to the currently recommended drugs. In areas where transmission remains high, it may be prudent to restrict ACTs for the treatment of cases, and not overexpose this drug family for prophylactic purposes…

FULL TEXT

http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(16)30459-5/fulltext?elsca1=etoc

PDF

http://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(16)30459-5.pdf

February 1, 2017 at 2:04 pm

New genetic marker for piperaquine resistance in Plasmodium falciparum

Lancet Infectious Diseases February 2017 V.17 N.2 P.119–121

COMMENT

Arjen M Dondorp

In the Greater Mekong subregion, Plasmodium falciparum resistance to artemisinins is increasingly compounded by concurrent resistance to partner drugs in combination therapies, which results in high treatment failure rates. Artemisinin combination therapies are first-line drugs for the treatment of falciparum malaria in all endemic countries; new antimalarials will probably not be marketed within this decade. Clinical drug efficacy studies are time and resource consuming and availability of molecular markers for drug resistance can facilitate near real-time monitoring, which is needed for guiding policy changes towards locally effective combination therapies in the Greater Mekong subregion. Markers are available for artemisinin resistance (Kelch13 mutations8) and mefloquine resistance (mdr1 amplification9). Markers for other artemisinin partner drugs used in the region, including lumefantrine, amodiaquine, and piperaquine, are less well defined….

FULL TEXT

http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(16)30414-5/fulltext?elsca1=etoc

PDF

http://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(16)30414-5.pdf

February 1, 2017 at 2:03 pm

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