Artemisinin-Based Drugs Target the Plasmodium falciparum Heme Detoxification Pathway.

Artemisinin (ART)-based antimalarial drugs are believed to exert lethal effects on malarial parasites by alkylating a variety of intracellular molecular targets. Recent work with live parasites has shown that one of the alkylated targets is free heme within the parasite digestive vacuole, which is liberated upon hemoglobin catabolism by the intraerythrocytic parasite, and that reduced levels of heme alkylation occur in artemisinin-resistant parasites. One implication of heme alkylation is that these drugs may inhibit parasite detoxification of free heme via inhibition of heme-to-hemozoin crystallization; however, previous reports that have investigated this hypothesis present conflicting data. By controlling reducing conditions and, hence, the availability of ferrous versus ferric forms of free heme, we modify a previously reported hemozoin inhibition assay to quantify the ability of ART-based drugs to target the heme detoxification pathway under reduced versus oxidizing conditions. Contrary to some previous reports, we find that artemisinins are potent inhibitors of hemozoin crystallization, with effective half-maximal concentrations approximately an order of magnitude lower than those for most quinoline-based antimalarial drugs. We also examine hemozoin and in vitro parasite growth inhibition for drug pairs found in the most commonly used ART-based combination therapies (ACTs). All ACTs examined inhibit hemozoin crystallization in an additive fashion, and all but one inhibit parasite growth in an additive fashion.

Artemisinin-Based Antimalarial Drug Therapy: Molecular Pharmacology and Evolving Resistance.

The molecular pharmacology of artemisinin (ART)-based antimalarial drugs is incompletely understood. Clinically, these drugs are used in combination with longer lasting partner drugs in several different artemisinin combination therapies (ACTs). ACTs are currently the standard of care against Plasmodium falciparum malaria across much of the world. A harbinger of emerging artemisinin resistance (ARTR), known as the delayed clearance phenotype (DCP), has been well documented in South East Asia (SEA) and is beginning to affect the efficacy of some ACTs. Though several genetic mutations have been associated with ARTR/DCP, a molecular mechanism remains elusive. This paper summarizes our current understanding of ART molecular pharmacology and hypotheses for ARTR/DCP.

Artesunate Activation by Heme in an Aqueous Medium.

The reaction between the antimalarial drug artesunate (ATS) and ferriprotoporphyrin_(IX) (FPIX) in the presence of glutathione (GSH) has been monitored by nuclear magnetic resonance (NMR) spectroscopy. By following the disappearance of resonances of protons near the endoperoxide group in ATS, the rate at which the drug is activated can be directly measured. In an aqueous medium, the rate of ATS activation is limited by the rate of reduction of the FPIX Fe(III) center by GSH. The reaction is observed to slow dramatically in the presence of other heme binding antimalarial drugs. These findings explain the long observed antagonism between artemisinin derivatives and quinoline-based drugs. This discovery suggests that combination therapy that involves artemisinin or any of its derivatives and a quinoline-based drug may be compromised.

Dihydroartemisinin-Ferriprotoporphyrin IX Adduct Abundance in Plasmodium falciparum Malarial Parasites and the Relationship to Emerging Artemisinin Resistance.

Previously (Heller, L. E., and Roepe, P. D. Quantification of Free Ferriprotoporphyrin IX Heme and Hemozoin for Artemisinin Sensitive versus Delayed Clearance Phenotype Plasmodium falciparum Malarial Parasites. Biochemistry, DOI: 10.1021/acs.biochem.8b00959, preceding paper in this issue), we quantified free ferriprotoporphyrin IX (FPIX) heme abundance for control versus delayed clearance phenotype (DCP) intraerythrocytic Plasmodium falciparum malarial parasites. Because artemisinin drugs are activated by free FPIX, these data predict that the abundance of long-hypothesized toxic artemisinin drug-FPIX covalent adducts might differ for control versus DCP parasites. If so, this would have important repercussions for understanding the mechanism of the DCP, also known as emerging artemisinin resistance. To test these predictions, we studied in vitro formation of FPIX-dihydroartemisinin (DHA) adducts and then for the first time quantified the abundance of FPIX-DHA adducts formed within live P. falciparum versus the stage of intraerythrocytic development. Using matched isogenic parasite strains, we quantified the adduct for DCP versus control parasite strains and found that mutant PfK13 mediates lower adduct abundance for DCP parasites. The results suggest improved models for the molecular pharmacology of artemisinin-based antimalarial drugs and the molecular mechanism of the DCP.

Quantification of Free Ferriprotoporphyrin IX Heme and Hemozoin for Artemisinin Sensitive versus Delayed Clearance Phenotype Plasmodium falciparum Malarial Parasites.

We use Plasmodium falciparum culture synchronization, optimized heme and hemozoin extraction protocols, and mass spectrometry to quantify the abundance of free ferriprotoporphyrin IX (FPIX) heme and crystallized FPIX (hemozoin; Hz) for various growth stages of intraerythrocytic P. falciparum malarial parasites. Because of altered cell cycle kinetics for delayed clearance phenotype (DCP) parasites relative to that of the control, we test whether FPIX and Hz abundances differ for DCP and control parasites.

Interventions to reach underscreened populations: a narrative review for planning cancer screening initiatives.

OBJECTIVES: This review was conducted to support knowledge translation (KT) and implementation of interventions to increase participation in organized cancer screening programs in the province of Ontario, Canada. METHODS: A rigorously designed literature search yielded over 900 references which were then subjected to exclusion criteria. The remainder was organized according to type of intervention, based on the categories applied in two authoritative systematic reviews and an analysis of the level of evidence. Emerging themes in the literature were then identified to provide a bridge between high-level evidence and on-the-ground practice. RESULTS: We identify three promising types of KT interventions: community-based health education; lay or peer health education; and targeted or tailored interventions. Each is summarized with illustrative examples and a summary of key themes and considerations. CONCLUSIONS: The authors conclude with a summary the types and a decision tool designed to help KT and implementation teams select interventions which could be adapted to their own context.

Self-assembly of isomeric monofunctionalized thiophenes.

Controlling the self-assembly of thiophene-containing molecules and polymers requires a strong fundamental understanding of the relationship between molecular features and structure-directing forces. Here, the effects of ring-substitution position on the two-dimensional self-assembly of monosubstituted thiophenes at the phenyloctane/HOPG interface are studied using scanning tunneling microscopy (STM). The influence of π···π-stacking, hydrogen-bonding, and alkyl-chain interactions are explored computationally. Alteration of the amide attachment point from the 2- to the 3-position induces transformation from head-to-tail packing to head-to-head packing. This may be attributed to canceling of lateral dipoles.

eToolkits:improving pain management.

A collaboration of the Centre for Global eHealth Innovation of the University Health Network, the International Union against Cancer (UICC) eUICC initiative, Purdue Pharma and Mundipharma with partners in Latin America and leaders in the management and study of pain worldwide is described. This project evaluates methods of sharing and adapting pain management approaches in models of the diffusion of innovation to bridge the 'know-do' gap in the management of pain and will provide information on the costs, limitations and benefits of efforts to adapt the resources for use in a variety of cultural, geographic and linguistic contexts.