SciCombinator

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Concept: Antimalarial drug

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Tafenoquine is a new prophylactic antimalarial drug. The current analysis presents an integrated safety assessment of the Tafenoquine Anticipated Clinical Regimen (Tafenoquine ACR) from 5 clinical trials, including 1 conducted in deployed military personnel and 4 in non-deployed residents, which also incorporated placebo and mefloquine comparator groups.

Concepts: Pharmacology, Clinical trial, Malaria, Quinine, Antimalarial drug, Malaria prophylaxis, Mefloquine, Antimalarial agents

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We report the detection and analysis of a suspected counterfeit sample of the anti-malarial medicine Metakelfin through developing Nitrogen-14 Nuclear Quadrupole Resonance (14N NQR) spectroscopy at a quantitative level. The sensitivity of quadrupolar parameters to the solid-state chemical environment of the molecule enables development of a technique capable of discrimination between the same pharmaceutical preparations made by different manufacturers. The 14N NQR signal returned by a tablet (or tablets) from a Metakelfin batch suspected to be counterfeit was compared with that acquired from a tablet(s) from a known-to-be-genuine batch from the same named manufacturer. Metakelfin contains two active pharmaceutical ingredients, sulfalene and pyrimethamine and NQR analysis revealed spectral differences for the sulfalene component indicative of differences in the processing history of the two batches. Furthermore, the NQR analysis provided quantitative information that the suspected counterfeit tablets contained only 43  3 % as much sulfalene as the genuine Metakelfin tablets. Conversely, conventional non-destructive analysis by FT-Raman and FT-NIR spectroscopies only achieved differentiation between batches, but no ascription. HPLC-UV analysis of the suspect tablets revealed a sulfalene content of 42  2 % of the labelled claim. The degree of agreement shows the promise of NQR as a means of the non-destructive identification and content-indicating first-stage analysis of counterfeit pharmaceuticals.

Concepts: Pharmacology, Medicine, Nuclear magnetic resonance, Pharmaceutical drug, Antimalarial drug, Active ingredient, Nuclear quadrupole resonance, Authentication

28

KEY MESSAGE : Rooting of Artemisia annua increases trichome size on leaves and helps drive the final steps of the biosynthesis of the sesquiterpene antimalarial drug, artemisinin. Artemisia annua produces the antimalarial drug, artemisinin (AN), which is synthesized and stored in glandular trichomes (GLTs). In vitro-grown A. annua shoots produce more AN when they form roots. This may be a function not of the roots, but rather media components such as the phytohormones, α-naphthaleneacetic acid (NAA) and 6-benzylaminopurine (BAP), or salts and sucrose used to maintain either rooted or unrooted shoot cultures. We investigated how three main media components altered artemisinic metabolite production, pathway gene transcripts, and GLT formation in both mature and developing leaves in rooted and unrooted cultures. Although transcript levels of AN biosynthetic genes were not altered, AN levels were significantly different, and there were major differences in both artemisinic metabolite levels and trichomes in mature versus developing leaves. For example, NAA induced higher AN production in rooted shoots, but only in mature leaves. In developing leaves, BAP increased GLT density on the leaf surface. When both phytohormones were present, GLTs were larger on young developing leaves, but smaller on mature leaves. Furthermore, although other media components increased GLT density, their size decreased on young leaves, but there was no effect on mature leaves. Roots also appeared to drive conversion of artemisinic precursors towards end products. These results suggest that, while the presence of roots affects AN and trichome production, phytohormones and other media constituents used for in vitro culture of A. annua also exert an influence.

Concepts: Gene, Amino acid, Artemisinin, Leaf, Plant morphology, Antimalarial drug, Artemisia annua, Trichome

27

Resistance by Plasmodium falciparum to almost all clinically used antimalarial drugs requires the development of new classes of antimalarials. 6-Iodouridine (15), a novel and potent inhibitor of orotidine-5'-monophosphate decarboxylase (ODCase), exhibited efficacy in a mouse model infected by P. chabaudi chabaudi. Compound 15 exhibited promising antimalarial activity against P. falciparum, including drug-resistant isolates, and no rapid drug-resistant populations of the parasite were observed when challenged with 15. Uridine provided options to overcome any toxicity in the host but still suppressing the parasite load when treated with 15. In drug combination studies, compound 15 showed good efficacy in vivo with artemisinin and azithromycin. The propionyl ester of 15 exhibited superior antimalarial efficacy. Antimalarial activities of 15, its prodrugs and potential for combination therapy are discussed in the context of novel strategies.

Concepts: Pharmacology, Malaria, Plasmodium falciparum, Plasmodium, Plasmodium vivax, Quinine, Artemisinin, Antimalarial drug

26

Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated whether long-lasting artemisinin pressure selects a novel multidrug-tolerance profile. Although 50% inhibitory concentrations for 10 antimalarial drugs tested were unchanged, drug-tolerant parasites showed higher recrudescence rates for endoperoxides, quinolones, and an antifolate, including partner drugs of recommended combination therapies, but remained susceptible to atovaquone. Moreover, the age range of intraerythrocytic stages able to resist artemisinin was extended to older ring forms and trophozoites. Multidrug tolerance results from drug-induced quiescence, which enables parasites to survive exposure to unrelated antimalarial drugs that inhibit a variety of metabolic pathways. This novel resistance pattern should be urgently monitored in the field because this pattern is not detected by current assays and represents a major threat to antimalarial drug policy.

Concepts: Malaria, Plasmodium falciparum, Plasmodium, Quinine, Apicomplexa, Artemisinin, Antimalarial drug, Antimalarial agents

26

The dihydroartemisinin-piperaquine combination is an antimalarial agent newly available in Europe. It is an artemisinin-combined therapy (ACT) that has been used for more than 10 years in malaria-endemic areas and is recommended since 2010 by the WHO as a first-line treatment of uncomplicated Plasmodium falciparum malaria. In Europe, it has recently been authorized for the treatment of uncomplicated P. falciparum malaria in adults, children, and infants aged 6 months or older and weighing at least 5 kg. Its efficacy is similar to the combination of artemether and lumefantrine, and the regimen is easier. The tolerability profile is nearly the same as the other ACTs. Prolongation of the QT interval appears to be greater than with the artemether-lumefantrine combination in the first 48 hours of treatment, although no clinical consequences have been described. This side effect requires the use of electrocardiographic monitoring in some patients. A risk management plan has been set up by the manufacturer.

Concepts: Malaria, Plasmodium falciparum, Plasmodium, Quinine, Artemisinin, Antimalarial drug, Antimalarial agents, Lumefantrine

25

Recent studies suggest a role for autophagy in the secretion of IL-1 cytokines regulating the development of inflammatory diseases. The antimalarial drug and autophagy/lysosome inhibitor chloroquine (CHQ) is considered as potential trigger of drug-induced or drug-aggravated psoriasis, in which Th17 cells sustain a persistent inflammation. In this study, we investigated the effect of CHQ on human monocyte-derived Langerhans-like cells (MoLC) and dendritic cells (MoDC) in response to IL-1β. The presence of CHQ reduced IL-12p70 release in both subsets, but surprisingly increased IL-6 production in MoDC and IL-23 in MoLC. Importantly, CHQ-treated MoLC promoted IL-17A secretion by CD4(+) T cells and elevated RORC mRNA levels, whereas IFN-γ release was reduced. The dysregulation of IL-12 family cytokines in MoLC and MoDC occurred at the transcriptional level. Similar effects were obtained with other late autophagy inhibitors, whereas PI3K inhibitor 3-methyladenine failed to increase IL-23 secretion. The modulated cytokine release was dependent on IL-1 cytokine activation and abrogated by a specific IL-1R antagonist. CHQ elevated expression of TNFR-associated factor 6, a common intermediate in IL-1R and TLR-dependent signaling. Accordingly, treatment with Pam3CSK4 and CHQ enhanced IL-23 release in MoLC and MoDC. CHQ inhibited autophagic flux, confirmed by increased LC3-II and p62 expression, and activated ERK, p38, and JNK MAPK, but only inhibition of p38 abrogated IL-23 release by MoLC. Thus, our findings indicate that CHQ modulates cytokine release in a p38-dependent manner, suggesting an essential role of Langerhans cells and dendritic cells in CHQ-provoked psoriasis, possibly by promoting Th17 immunity.

Concepts: Inflammation, Gene expression, Interleukin 1, Interleukin 17, Interleukin, Enzyme inhibitor, Inhibitor, Antimalarial drug

19

Antimalarial drugs have thus far been derived mainly from two sources - natural products and synthetic ‘drug-like’ compounds. We hypothesized that antimalarial agents with novel mechanisms of action might be discovered using a diverse collection of synthetic compounds having three-dimensional features reminiscent of natural products and underrepresented in typical screening collections. We identified such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. The bicylic azetidines display single low-dose cure with activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to cure and prevent transmission of the disease as well as protect populations at risk, all in a single oral exposure, and highlight the strength of diversity-oriented synthesis to reveal promising therapeutic targets.

Concepts: Antimalarial drug

18

Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented.

Concepts: Malaria, Southeast Asia, Chemistry, Fiction, Chemical compound, Philippines, Artemisinin, Antimalarial drug

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Inappropriate treatment of malaria is widely reported particularly in areas where there is poor access to health facilities and self-treatment of fevers with anti-malarial drugs bought in shops is the most common form of care-seeking. The main objective of the study was to examine the impact of introducing rapid diagnostic tests for malaria (mRDTs) in registered drug shops in Uganda, with the aim to increase appropriate treatment of malaria with artemisinin-based combination therapy (ACT) in patients seeking treatment for fever in drug shops.

Concepts: Malaria, Illness, Drug addiction, Artemisinin, Fever, Dengue fever, Antimalarial drug, Plasmodium malariae