Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Antimalarials are widely used in African and Southeast Asian countries, where they are combined with other drugs for the treatment of concurrent ailments. The potential for P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) between antimalarials and P-gp substrates was examined using a Caco-2 cell-based model. Selected antimalarials were initially screened for their interaction with P-gp based on the inhibition of rhodamine-123 (Rho-123) transport in Caco-2 cells. Verapamil (100 mM) and quinidine (1 mM) were used as positive inhibition controls. Lumefantrine, amodiaquin, and artesunate all showed blockade of Rho-123 transport. Subsequently, the inhibitory effect of these antimalarials on the bi-directional passage of digoxin (DIG) was examined. All of the drugs decreased basal-toapical (B-A) P-gp-mediated DIG transport at concentrations of 100 mM and 1 mM. These concentrations may reflect therapeutic doses for amodiaquin and artesunate. Therefore, clinically relevant DDIs may occur between certain antimalarials and P-gp substrates in general

Rapid testing for malaria in settings where microscopy is available and peripheral clinics where only presumptive treatment is available: a randomised controlled trial in Ghana.

OBJECTIVE: To test in West Africa the impact of rapid diagnostic tests on the prescription of antimalarials and antibiotics both where microscopy is used for the diagnosis of malaria and in clinical (peripheral) settings that rely on clinical diagnosis. DESIGN: Randomised, controlled, open label clinical trial. SETTING: Four clinics in the rural Dangme West district of southern Ghana, one in which microscopy is used for diagnosis of malaria ("microscopy setting") and three where microscopy is not available and diagnosis of malaria is made on the basis of clinical symptoms ("clinical setting"). PARTICIPANTS: Patients with suspected malaria. Interventions Patients were randomly assigned to either a rapid diagnostic test or the current diagnostic method at the clinic (microscopy or clinical diagnosis). A blood sample for a research microscopy slide was taken for all patients. MAIN OUTCOME MEASURES: The primary outcome was the prescription of antimalarials to patients of any age whose double read research slide was negative for malaria. The major secondary outcomes were the correct prescription of antimalarials, the impact of test results on antibiotic prescription, and the correct prescription of antimalarials in children under 5 years. RESULTS: Of the 9236 patients screened, 3452 were randomised in the clinical setting and 3811 in the microscopy setting. Follow-up to 28 days was 97.6% (7088/7263). In the microscopy setting, 722 (51.6%) of the 1400 patients with negative research slides in the rapid diagnostic test arm were treated for malaria compared with 764 (55.0%) of the 1389 patients in the microscopy arm (adjusted odds ratio 0.87, 95% CI 0.71 to 1.1; P=0.16). In the clinical setting, 578 (53.9%) of the 1072 patients in the rapid diagnostic test arm with negative research slides were treated for malaria compared with 982 (90.1%) of the 1090 patients with negative slides in the clinical diagnosis arm (odds ratio 0.12, 95% CI 0.04 to 0.38; P=0.001). The use of rapid diagnostic tests led to better targeting of antimalarials and antibiotics in the clinical but not the microscopy setting, in both children and adults. There were no deaths in children under 5 years at 28 days follow-up in either arm. CONCLUSION: Where microscopy already exists, introducing rapid diagnostic tests had limited impact on prescriber behaviour. In settings where microscopy was not available, however, using rapid diagnostic tests led to a significant reduction in the overprescription of antimalarials, without any evidence of clinical harm, and to better targeting of antibiotics. Trial registration ClinicalTrials.gov NCT00493922

Mode of action and choice of antimalarial drugs for intermittent preventive treatment in infants.

Intermittent preventive treatment in infants (IPTi) is an effective and safe malaria control strategy. However, it remains unclear what antimalarials should be used to replace sulfadoxine-pyrimethamine (SP) when and where SP is no longer an effective drug for IPTi. Work recently conducted in Tanzania, combined with the findings of previous studies, indicates that IPTi is essentially intermittent chemoprophylaxis; consequently, long-acting antimalarials that provide a long period of post-treatment prophylaxis will be the most effective alternative to SP. However, because of concerns about development of drug resistance, new combinations of long-acting drugs are urgently needed

Evaluation of In-Hospital Management for Febrile Illness\ud in Northern Tanzania before and after 2010 World Health\ud Organization Guidelines for the Treatment of Malaria

In 2010, the World Health Organization (WHO) published updated guidelines emphasizing and expanding recommendations for a parasitological confirmation of malaria before treating with antimalarials. This study aimed to assess differences in historic (2007–2008) (cohort 1) and recent (2011–2012) (cohort 2) hospital cohorts in the diagnosis and treatment of febrile illness in a low malaria prevalence area of northern Tanzania. We analyzed data from two prospective cohort studies that enrolled febrile adolescents and adults aged $13 years. All patients received quality-controlled aerobic blood cultures and malaria smears. We compared patients’ discharge diagnoses, treatments, and outcomes to assess changes in the treatment of malaria and bacterial infections. In total, 595 febrile inpatients were enrolled from two referral hospitals in Moshi, Tanzania. Laboratory-confirmed malaria was detected in 13 (3.2%) of 402 patients in cohort 1 and 1 (0.5%) of 193 patients in cohort 2 (p = 0.041). Antimalarials were prescribed to 201 (51.7%) of 389 smear-negative patients in cohort 1 and 97 (50.5%) of 192 smearnegative patients in cohort 2 (p = 0.794). Bacteremia was diagnosed from standard blood culture in 58 (14.5%) of 401 patients in cohort 1 compared to 18 (9.5%) of 190 patients in cohort 2 (p = 0.091). In cohort 1, 40 (69.0%) of 58 patients with a positive blood culture received antibacterials compared to 16 (88.9%) of 18 patients in cohort 2 (p = 0.094). In cohort 1, 43 (10.8%) of the 399 patients with known outcomes died during hospitalization compared with 12 (6.2%) deaths among 193 patients in cohort 2 (p = 0.073). In a setting of low malaria transmission, a high proportion of smear-negative patients were diagnosed with malaria and treated with antimalarials despite updated WHO guidelines on malaria treatment. Improved laboratory diagnostics for non-malaria febrile illness might help to curb this practice.\u

Synthesis and Antileishmanial Activity of 1,2,4,5-Tetraoxanes against Leishmania donovani

A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC50 values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC50 value of 2.52 ± 0.65 µm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.This research was funded by Fundação para a Ciência e a Tecnologia (FCT), and FEDER/COMPETE 2020-UE, through projects UID/Multi/04326/2019 (Centre of Marine Sciences-CCMAR) and PTDC/MAR-BIO/4132/2014.info:eu-repo/semantics/publishedVersio

Community Case Management of Fever Due to Malaria and Pneumonia in Children Under Five in Zambia: A Cluster Randomized Controlled Trial

In a cluster randomized trial, Kojo Yeboah-Antwi and colleagues find that integrated management of malaria and pneumonia in children under five by community health workers is both feasible and effective. BACKGROUND. Pneumonia and malaria, two of the leading causes of morbidity and mortality among children under five in Zambia, often have overlapping clinical manifestations. Zambia is piloting the use of artemether-lumefantrine (AL) by community health workers (CHWs) to treat uncomplicated malaria. Valid concerns about potential overuse of AL could be addressed by the use of malaria rapid diagnostics employed at the community level. Currently, CHWs in Zambia evaluate and treat children with suspected malaria in rural areas, but they refer children with suspected pneumonia to the nearest health facility. This study was designed to assess the effectiveness and feasibility of using CHWs to manage nonsevere pneumonia and uncomplicated malaria with the aid of rapid diagnostic tests (RDTs). METHODS AND FINDINGS. Community health posts staffed by CHWs were matched and randomly allocated to intervention and control arms. Children between the ages of 6 months and 5 years were managed according to the study protocol, as follows. Intervention CHWs performed RDTs, treated test-positive children with AL, and treated those with nonsevere pneumonia (increased respiratory rate) with amoxicillin. Control CHWs did not perform RDTs, treated all febrile children with AL, and referred those with signs of pneumonia to the health facility, as per Ministry of Health policy. The primary outcomes were the use of AL in children with fever and early and appropriate treatment with antibiotics for nonsevere pneumonia. A total of 3,125 children with fever and/or difficult/fast breathing were managed over a 12-month period. In the intervention arm, 27.5% (265/963) of children with fever received AL compared to 99.1% (2066/2084) of control children (risk ratio 0.23, 95% confidence interval 0.14–0.38). For children classified with nonsevere pneumonia, 68.2% (247/362) in the intervention arm and 13.3% (22/203) in the control arm received early and appropriate treatment (risk ratio 5.32, 95% confidence interval 2.19–8.94). There were two deaths in the intervention and one in the control arm. CONCLUSIONS. The potential for CHWs to use RDTs, AL, and amoxicillin to manage both malaria and pneumonia at the community level is promising and might reduce overuse of AL, as well as provide early and appropriate treatment to children with nonsevere pneumonia.United States Agency for International Development (GHSA-00-00020-00) with Boston University; President's Malaria Initiativ

Genetic and genomic approaches for the discovery of parasite genes involved in antimalarial drug resistance

The biggest threat to the war on malaria is the continued evolution of drug resistance by the parasite. Resistance to almost all currently available antimalarials now exists in Plasmodium falciparum which causes the most suffering among all human malaria parasites. Monitoring of antimalarial efficacy and the development and subsequent spread of resistance has become an important part in the treatment and control of malaria. With recent reports of reduced efficacy of artemisinin, the current recommended treatment for uncomplicated malaria, there is urgent need for better methods to recognize and monitor drug resistance for effective treatment. Molecular markers have become a welcome addition to complement the more laborious and costly in vitro and in vivo methods that have traditionally been used to monitor drug resistance. However, there are currently no molecular markers for resistance to some antimalarials. This review highlights the role of the various genetic and genomic approaches that have been used in identifying the molecular markers that underlie drug resistance in P. falciparum. These approaches include; candidate genes, genetic linkage and genome-wide association studies. We discuss the requirements and limitations of each approach and use various examples to illustrate their contributions in identifying genomic regions of the parasite associated with antimalarial drug responses

Reduction of transmission from malaria patients by artemisinin combination therapies: a pooled analysis of six randomized trials.

BACKGROUND: Artemisinin combination therapies (ACT), which are increasingly being introduced for treatment of Plasmodium falciparum malaria, are more effective against sexual stage parasites (gametocytes) than previous first-line antimalarials and therefore have the potential to reduce parasite transmission. The size of this effect is estimated in symptomatic P. falciparum infections. METHODS: Data on 3,174 patients were pooled from six antimalarial trials conducted in The Gambia and Kenya. Multivariable regression was used to investigate the role of ACT versus non-artemisinin antimalarial treatment, treatment failure, presence of pre-treatment gametocytes and submicroscopic gametocytaemia on transmission to mosquitoes and the area under the curve (AUC) of gametocyte density during the 28 days of follow up. RESULTS: ACT treatment was associated with a significant reduction in the probability of being gametocytaemic on the day of transmission experiments (OR 0.20 95% CI 0.16-0.26), transmission to mosquitoes by slide-positive gametocyte carriers (OR mosquito infection 0.49 95% CI 0.33-0.73) and AUC of gametocyte density (ratio of means 0.35 95% CI 0.31-0.41). Parasitological treatment failure did not account for the difference between ACT and non-artemisinin impact. The presence of slide-positive gametocytaemia prior to treatment significantly reduced ACT impact on gametocytaemia (p < 0.001). Taking account of submicroscopic gametocytaemia reduced estimates of ACT impact in a high transmission setting in Kenya, but not in a lower transmission setting in the Gambia. CONCLUSION: Treatment with ACT significantly reduces infectiousness of individual patients with uncomplicated falciparum malaria compared to previous first line treatments. Rapid treatment of cases before gametocytaemia is well developed may enhance the impact of ACT on transmission

Costing Artemisinin-based Combination Therapy for Malaria in Tanzania

Malaria continues to be a major contributor to the burden of disease in Tanzania, with a prevalence of 33.39 percent nationally. As antimalarial resistance to sulfadoxine-pyrimethamine in Tanzania continues to grow, the government is in the process of changing its national policy regarding first-line treatment for uncomplicated malaria to an artemisinin-based combination therapy (ART). ACT, a new type of antimalarial drug combination, has proved to be effective at treating malaria and reducing malaria transmission. The PHRplus project, on behalf of the Roll Back Malaria \ud Partnership in conjunction with the World Bank, undertook a costing study to estimate the five-year financing needs and identify financing gaps for procurement of three possible ACT combinations, Coartem®, artesunate amodiaquine (ART AQ), and ArtecomTM. The Global Fund to Fight AIDS, Tuberculosis and Malaria award for malaria during the fourth round of proposals will cover the majority of the first year of public sector ACT implementation if Coartem® (with a financing gap of US$1.4 million) is chosen, or the bulk of public sector implementation for the full five-year period under ART AQ or Artecom. ACT funding must be secured for the medium- to long-term future. Financing for the purchase of ACTs is likely to come from the Global Fund, the World Bank, and the various other partner agencies