Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are responsible for efficacy against liver and sexual transmission stages of Plasmodium falciparum . The antimalarial activity of PQ against liver stages depends on host CYP2D6 status, whilst OH-PQm display direct, CYP2D6-independent, activity. PQ requires hepatic metabolism to exert activity against gametocyte stages. OH-PQm exert modest antimalarial efficacy against parasite gametocytes; however, potency is enhanced ca.1000 fold in the presence of cytochrome P450 NADPH:oxidoreductase (CPR) from the liver and bone marrow. Enhancement of OH-PQm efficacy is due to the direct reduction of quinoneimine metabolites by CPR with the concomitant and excessive generation of H 2 O 2 , leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles.

SignificanceFilarial nematode infections, caused by Wuchereria bancrofti, Brugia malayi (elephantiasis), and Onchocerca volvulus (river blindness) infect 150 million of the world’s poorest populations and cause profound disability. Standard treatments require repetitive, long-term, mass drug administrations and have failed to interrupted transmission in certain sub-Saharan African regions. A drug cure using doxycycline, which targets the essential filarial endosymbiont Wolbachia, is clinically effective but programmatically challenging to implement due to long treatment durations and contraindications. Here we provide proof-of-concept of a radical improvement of targeting Wolbachia via identification of drug synergy between the anthelmintic albendazole and antibiotics. This synergy enables the shortening of treatment duration of macrofilaricidal anti-Wolbachia based treatments from 4 wk to 7 d with registered drugs ready for clinical testing.

Implementation of this guideline for arterial blood gas measurement increases efficiency of test utilization without prolonging mechanical ventilation or affecting outcome.

Cannabinoids are reported to have actions through peroxisome proliferator-activated receptors (PPARs), which led us to investigate PPAR agonists for activity at the cannabinoid receptors. Radio-ligand binding and functional assays were conducted using human recombinant cannabinoid type 1 (CB 1 ) or cannabinoid type 2 (CB 2 ) receptors, as well as the guinea pig isolated ileum, using the full agonist CP55940 as a positive control. The PPAR-a agonist fenofibrate exhibited submicromolar affinity for both receptors (pK i CB 1 , 6.3 6 0.1; CB 2 , 7.7 6 0.1). Functionally, fenofibrate acted as an agonist at the CB 2 receptor (pEC 50 , 7.7 6 0.1) and a partial agonist at the CB 1 receptor, although with a decrease in functional response at higher concentrations, producing bell-shaped concentration-response curves. High concentrations of fenofibrate were able to increase the dissociation rate constant for [ 3 H]-CP55940 at the CB 1 receptor, (k fast without: 1.2 6 0.2/min; with: 3.8 6 0.1 3 10 22 /min) and decrease the maximal response to CP55940 (R max , 86 6 2%), which is consistent with a negative allosteric modulator. Fenofibrate also reduced electrically induced contractions in isolated guinea pig ileum via CB 1 receptors (pEC 50 , 6.0 6 0.4). Fenofibrate is thus identified as an example of a new class of cannabinoid receptor ligand and allosteric modulator, with the potential to interact therapeutically with cannabinoid receptors in addition to its primary PPAR target.-Priestley, R. S., Nickolls, S. A., Alexander, S. P. H., Kendall, D. A. A potential role for cannabinoid receptors in the therapeutic action of fenofibrate.

Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria.

A series of 2-pyrazolyl quinolones has been designed and synthesized in 5−7 steps to optimize for both in vitro antimalarial potency and various in vitro drug metabolism and pharmacokinetics (DMPK) features. The most potent compounds display no cross-resistance with multidrug resistant parasite strains (W2) compared to drug sensitive strains (3D7), with IC 50 (concentration of drug required to achieve half maximal growth suppression) values in the range of 15−33 nM. Furthermore, members of the series retain moderate activity against the atovaquone-resistant parasite isolate (TM90C2B). The described 2-pyrazoyl series displays improved DMPK properties, including improved aqueous solubility compared to previously reported quinolone series and acceptable safety margin through in vitro cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Q i site of the parasite bc 1 complex, which is supported by crystallographic studies of bovine cytochrome bc 1 complex.

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