Efficacy and tolerability of a new formulation of artesunate-mefloquine for the treatment of uncomplicated malaria in adult in Senegal: open randomized trial

BACKGROUND: Prompt treatment of malaria attacks with arteminisin-based combination therapy (ACT) is an essential tool for malaria control. A new co-blister tablet of artesunate-mefloquine (AM) with 25 mg/kg mefloquine has been developed for the management of uncomplicated malaria attacks. This non-inferiority randomized trial, was conducted to evaluate the efficacy and safety of the new formulation of AM in comparison to artemether-lumefantrine (AL) for the treatment of acute uncomplicated Plasmodium falciparum malaria in adults in Senegal. METHODS: The study was carried out from September to December 2010 in two health centres in Senegal. The study end points included (i) PCR corrected adequate clinical and parasitological response (ACPR) at day 28, (ii) ACPR at days 42 and 63, (iii) parasites and fever clearance time, (iv) incidence of adverse events and patients biological profile at day 7 using the WHO 2003 protocol for anti-malarial drug evaluation. RESULTS: Overall, 310 patients were randomized to receive either AM (n = 157) or AL (n = 153). PCR corrected ACPR at day 28 was at 95.5% in the AM arm while that in the AL arm was at 96.7% (p = 0.83). Therapeutic efficacy was at 98.5% in the AM arm versus 98.2% in the AL group at day 42 (p = 1). At day 63, ACPR in the AM and AL arms was at 98.2% and 97.7%, respectively (p = 0.32). The two treatments were well tolerated with similar biological profile at day 7. However, dizziness was more frequent in the AM arm. CONCLUSION: Artesunate-mefloquine (25 mg/Kg mefloquine) is efficacious and well-tolerated for the treatment of uncomplicated P. falciparum malaria in adult patients

The association between malaria parasitaemia, erythrocyte polymorphisms, malnutrition and anaemia in children less than 10 years in Senegal:a case control study

BACKGROUND: Malaria and anaemia (Haemoglobin <11 g/dl) remain frequent in tropical regions and are closely associated. Although anaemia aetiologies are known to be multi-factorial, most studies in malaria endemic areas have been confined to analysis of possible associations between anaemia and individual factors such as malaria. A case control study involving children aged from 1 to 10 years was conducted to assess some assumed contributors to anaemia in the area of Bonconto Health post in Senegal. METHODS: Study participants were randomly selected from a list of children who participated in a survey in December 2010. Children aged from 1 to 10 years with haemoglobin level below 11 g/dl represented cases (anaemic children). Control participants were eligible if of same age group and their haemoglobin level was >= 11 g/dl. For each participant, a physical examination was done and anthropometric data collected prior to a biological assessment which included: malaria parasitaemia infection, intestinal worm carriage, G6PD deficiency, sickle cell disorders, and alpha-talassaemia. RESULTS: Three hundred and fifty two children < 10 years of age were enrolled (176 case and 176 controls). In a logistic regression analysis, anaemia was significantly associated with malaria parasitaemia (aOR=5.23, 95%CI[1.1-28.48]), sickle cell disorders (aOR=2.89, 95%CI[1,32-6.34]), alpha-thalassemia (aOR=1.82, 95%CI[1.2-3.35]), stunting (aOR=3.37, 95%CI[1.93-5.88], age ranged from 2 to 4 years (aOR=0.13, 95%CI[0.05-0.31]) and age > 5 years (aOR=0.03, 95%CI[0.01-0.08]). Stratified by age group, anaemia was significantly associated with stunting in children less than 5 years (aOR=3.1 95%CI[1.4 – 6.8]), with, sickle cell disorders (aOR=3.5 95%CI [1.4 – 9.0]), alpha-thalassemia (or=2.4 95%CI[1.1–5.3]) and stunting (aOR=3.6 95%CI [1.6–8.2]) for children above 5 years. No association was found between G6PD deficiency, intestinal worm carriage and children’s gender. CONCLUSION: Malaria parasitaemia, stunting and haemoglobin genetic disorders represented the major causes of anaemia among study participants. Anaemia control in this area could be achieved by developing integrated interventions targeting both malaria and malnutrition

Safety and Efficacy of Adding a Single Low Dose of Primaquine to the Treatment of Adult Patients With Plasmodium falciparum Malaria in Senegal, to Reduce Gametocyte Carriage: A Randomized Controlled Trial.

Introduction: More information is needed about the safety of low-dose primaquine in populations where G6PD deficiency is common. Methods: Adults with Plasmodium falciparum malaria were randomized to receive 1 of 3 artemisinin combination therapies (ACTs) with or without primaquine (0.25 mg/kg). Glucose-6-phosphate dehydrogenase (G6PD) status was determined using a rapid test. Patients were followed for 28 days to record hemoglobin concentration, adverse events, and gametocyte carriage. The primary end point was the change in Hb at day 7. Results: In sum, 274 patients were randomized, 139 received an ACT alone, and 135 received an ACT + primaquine. The mean reduction in Hb at day 7 was similar in each group, a difference in the ACT + PQ versus the ACT alone group of -0.04 g/dL (95% confidence interval [CI] -0.23, 0.31), but the effect of primaquine differed according to G6PD status. In G6PD-deficient patients the drop in Hb was 0.63 g/dL (95% CI 0.03, 1.24) greater in those who received primaquine than in those who received an ACT alone. In G6PD-normal patients, the reduction in Hb was 0.22 g/dL (95% CI -0.08, 0.52) less in those who received primaquine (interaction P = .01). One G6PD normal patient who received primaquine developed moderately severe anaemia (Hb < 8 g/dL). Dark urine was more frequent in patients who received primaquine. Primaquine was associated with a 73% (95% CI 24-90) reduction in gametocyte carriage (P = .013). Conclusion: Primaquine substantially reduced gametocyte carriage. However, the fall in Hb concentration at day 7 was greater in G6PD-deficient patients who received primaquine than in those who did not and one patient who received primaquine developed moderately severe anemia. Clinical Trial registration: PACTR201411000937373 (www.pactr.org)

Pilot feasibility study of an emergency paediatric kit for intra-rectal quinine administration used by the personnel of community-based health care units in Senegal

<p>Abstract</p> <p>Background</p> <p>Quinine injection is the reference treatment for malaria when oral administration is impossible. Quinine can also be administered by the intra-rectal route and, over the last ten years, a series of studies have been conducted in children to determine the ideal dose and dilution in the African situation. The aim of the present study was to evaluate the feasibility and usefulness of a kit for an immediate administration of quinine alkaloids (Quinimax^®) by community health workers, prior to transfer of the child to a more sophisticated health care establishment.</p> <p>Methods</p> <p>A prospective, open, descriptive community intervention study conducted in northern Senegal at six village Health Units in children fewer than ten years of age with non-per-os malaria. Controls were given the routine care prior to transfer to a Health Center, and cases were in addition administered Quinimax^®(20 mg/ml) via the intra-rectal route before transfer. Patients were followed through complete cure and parasitological tests were carried out on Days 0, 3 and 7.</p> <p>Results</p> <p>134 patients (79 cases/55 controls) were recruited between November 2003 and May 2004 or October and November 2004. The two groups were comparable at inclusion. In the case group, oral drugs could be administered after a mean of <it>16.8 hours </it>versus <it>33.6 hours </it>in the control group. Time-to cure was shorter in cases than in controls. Complete parasite clearance was obtained in all patients by Day 7. The kit was well accepted by all concerned and more than 80% of community health workers judged the kit easy to use.</p> <p>Conclusion</p> <p>The emergency paediatric kit is a useful tool in the management of malaria in children who cannot be treated orally. It is feasible and easy to use for health workers in community-based Health Units where, according to the WHO, nearly 80% of malarial morbidity and mortality occurs.</p

Impact of combining intermittent preventive treatment with home management of malaria in children less than 10 years in a rural area of Senegal: a cluster randomized trial

<p>Abstract</p> <p>Background</p> <p>Current malaria control strategies recommend (i) early case detection using rapid diagnostic tests (RDT) and treatment with artemisinin combination therapy (ACT), (ii) pre-referral rectal artesunate, (iii) intermittent preventive treatment and (iv) impregnated bed nets. However, these individual malaria control interventions provide only partial protection in most epidemiological situations. Therefore, there is a need to investigate the potential benefits of integrating several malaria interventions to reduce malaria prevalence and morbidity.</p> <p>Methods</p> <p>A randomized controlled trial was carried out to assess the impact of combining seasonal intermittent preventive treatment in children (IPTc) with home-based management of malaria (HMM) by community health workers (CHWs) in Senegal. Eight CHWs in eight villages covered by the Bonconto health post, (South Eastern part of Senegal) were trained to diagnose malaria using RDT, provide prompt treatment with artemether-lumefantrine for uncomplicated malaria cases and pre-referral rectal artesunate for complicated malaria occurring in children under 10 years. Four CHWs were randomized to also administer monthly IPTc as single dose of sulphadoxine-pyrimethamine (SP) plus three doses of amodiaquine (AQ) in the malaria transmission season, October and November 2010. Primary end point was incidence of single episode of malaria attacks over 8 weeks of follow up. Secondary end points included prevalence of malaria parasitaemia, and prevalence of anaemia at the end of the transmission season. Primary analysis was by intention to treat. The study protocol was approved by the Senegalese National Ethical Committee (approval 0027/MSP/DS/CNRS, 18/03/2010).</p> <p>Results</p> <p>A total of 1,000 children were enrolled. The incidence of malaria episodes was 7.1/100 child months at risk [95% CI (3.7-13.7)] in communities with IPTc + HMM compared to 35.6/100 child months at risk [95% CI (26.7-47.4)] in communities with only HMM (aOR = 0.20; 95% CI 0.09-0.41; <it>p </it>= 0.04). At the end of the transmission season, malaria parasitaemia prevalence was lower in communities with IPTc + HMM (2.05% versus 4.6% <it>p </it>= 0.03). Adjusted for age groups, sex, <it>Plasmodium falciparum </it>carriage and prevalence of malnutrition, IPTc + HMM showed a significant protective effect against anaemia (aOR = 0.59; 95% CI 0.42-0.82; <it>p </it>= 0.02).</p> <p>Conclusion</p> <p>Combining IPTc and HMM can provide significant additional benefit in preventing clinical episodes of malaria as well as anaemia among children in Senegal.</p

Multicentric assessment of the efficacy and tolerability of dihydroartemisinin-piperaquine compared to artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in sub-Saharan Africa

<p>Abstract</p> <p>Background</p> <p>The choice of appropriate artemisinin-based combination therapy depends on several factors (cost, efficacy, safety, reinfection rate and simplicity of administration). To assess whether the combination dihydroartemisinin-piperaquine (DP) could be an alternative to artemether-lumefantrine (AL), the efficacy and the tolerability of the two products for the treatment of uncomplicated falciparum malaria in sub-Saharan Africa have been compared.</p> <p>Methods</p> <p>A multicentric open randomized controlled clinical trial of three-day treatment of DP against AL for the treatment of two parallel groups of patients aged two years and above and suffering from uncomplicated falciparum malaria was carried out in Cameroon, Côte d'Ivoire and Senegal. Within each group, patients were randomly assigned supervised treatment. DP was given once a day for three days and AL twice a day for three days. Follow-up visits were performed on day 1 to 4 and on day 7, 14, 21, 28 to evaluate clinical and parasitological results. The primary endpoint was the recovery rate by day 28.</p> <p>Results</p> <p>Of 384 patients enrolled, 197 were assigned DP and 187 AL. The recovery rates adjusted by genotyping, 99.5% in the DP group and 98.9% in the AL group, were not statistically different (p = 0.538). No Early Therapeutic Failure (ETF) was observed. At day 28, two patients in the DP group and five in AL group had recurrent parasitaemia with <it>Plasmodium falciparum</it>. In the DP group, after PCR genotyping, one of the two recurrences was classified as a new infection and the other as recrudescence. In AL group, two recurrences were classified after correction by PCR as recrudescence. All cases of recrudescence were classified as Late Parasitological Failure (LPF). In each group, a rapid recovery from fever and parasitaemia was noticed. More than 90% of patients did no longer present fever or parasitaemia 48 hours after treatment. Both drugs were well tolerated. Indeed, no serious adverse events were reported during the follow-up period. Most of the adverse events which developed were moderate and did not result in the treatment being stopped in either treatment group.</p> <p>Conclusions</p> <p>Dihydroartemisinin-piperaquine was as effective and well-tolerated as artemether-lumefantrine in the treatment of uncomplicated falciparum malaria. In addition, dihydroartemisinin-piperaquine, a single daily dose, could be an advantage over artemether-lumefantrine in Africa because of better treatment observance.</p

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts