JPC-2997, a New Aminomethylphenol with High In Vitro and In Vivo Antimalarial Activities against Blood Stages of Plasmodium

4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-phenol (JPC-2997) is a new aminomethylphenol compound that is highly active in vitro against the chloroquine-sensitive D6, the chloroquine-resistant W2, and the multidrug-resistant TM90-C2B Plasmodium falciparum lines, with 50% inhibitory concentrations (IC_50s) ranging from 7 nM to 34 nM. JPC-2997 is >2,500 times less cytotoxic (IC₅₀s > 35 μM) to human (HepG2 and HEK293) and rodent (BHK) cell lines than the D6 parasite line. In comparison to the chemically related WR-194,965, a drug that had advanced to clinical studies, JPC-2997 was 2-fold more active in vitro against P. falciparum lines and 3-fold less cytotoxic. The compound possesses potent in vivo suppression activity against Plasmodium berghei, with a 50% effective dose (ED₅₀) of 0.5 mg/kg of body weight/day following oral dosing in the Peters 4-day test. The radical curative dose of JPC-2997 was remarkably low, at a total dose of 24 mg/kg, using the modified Thompson test. JPC-2997 was effective in curing three Aotus monkeys infected with a chloroquine- and pyrimethamine-resistant strain of Plasmodium vivax at a dose of 20 mg/kg daily for 3 days. At the doses administered, JPC-2997 appeared to be well tolerated in mice and monkeys. Preliminary studies of JPC-2997 in mice show linear pharmacokinetics over the range 2.5 to 40 mg/kg, a low clearance of 0.22 liters/h/kg, a volume of distribution of 15.6 liters/kg, and an elimination half-life of 49.8 h. The high in vivo potency data and lengthy elimination half-life of JPC-2997 suggest that it is worthy of further preclinical assessment as a partner drug.     

Fibroblast growth factor 2 decreases bleomycin‐induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation

Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin‐induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double‐transgenic (DTG) mice with doxycycline‐inducible overexpression of human FGF2 (SPC‐rtTA;TRE‐hFGF2) or single‐transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild‐type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline‐induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFβ1‐induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad‐dependent gene expression, FGF2 inhibited TGFβ1‐induced stress fiber formation and serum response factor‐dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin‐induced pulmonary fibrosis in vivo and reverses TGFβ1‐induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Pharmacokinetics and pharmacodynamics of vecuronium administered by bolus and infusion during halothane or balanced anesthesia

Vecuronium was administered to two patient groups as a single intravenous dose, 60 micrograms/kg, combined with an infusion, 1 microgram/min/kg. Anesthesia was maintained for the first group with a halothane-nitrous oxide technique; the second group received fentanyl-barbiturate-tranquilizer-nitrous oxide. As the infusion ended, plasma vecuronium concentrations were 0.34 (+/- 0.10) microgram/ml for the halothane group and 0.32 (+/- 0.07) microgram/ml for the fentanyl group, associated with 93% (+/- 8) and 88% (+/- 10) twitch depression, respectively. Vecuronium plasma concentration-time data were combined with the simultaneous intensities of neuromuscular blockade to model the kinetic-dynamic values for each patient. For the halothane group the steady-state volume was 0.21 (+/- 0.04) L/kg, the clearance was 2.9 (+/- 0.1) ml/min/kg, and the elimination half-life was 100 (+/- 36) minutes; for the fentanyl group these were 0.20 (+/- 0.08) L/kg, 3.2 (+/- 0.1) ml/min/kg, and 84 (+/- 43) minutes, respectively. Plasma concentrations associated with 50% blockade averaged 0.2 microgram/ml for both groups. Neither the pharmacokinetics nor the pharmacodynamics of vecuronium in humans differed between these two patient groups.     

A comprehensive severity score for the morbidly adherent placenta: combining ultrasound and magnetic resonance imaging

Background

Ultrasound (US) is the first-line imaging modality to assess the morbidly adherent placenta, but sensitivity and specificity are lacking.

Objective

This investigation aims to improve diagnostic accuracy with a comprehensive score using clinical history, US, and magnetic resonance imaging (MRI).

Materials and methods

We conducted a retrospective cohort study of pregnant women who received both transvaginal US and MRI with suspicion for morbidly adherent placenta between 2009 and 2016. US was scored with the following metrics: (i) previa, (ii) hypervascularity, (iii) loss of retroplacental clear space and (iv) lacunae. MRI was evaluated for (i) intraparenchymal vessels, (ii) abnormally dilated vessels, (iii) fibrin deposition, (iv) placental bulge and (v) bladder dome irregularity. Bayesian analysis was used to estimate the probability of morbidly adherent placenta for a given score. Diagnostic testing parameters were calculated.

Results

Among the 41 women with concerning imaging, histologically identified disease was confirmed in 16. The probability of morbidly adherent placenta increased with the score. At the highest US score, the probability of disease was 63.7%. With the highest MRI score, the probability of adherent placentation was 90.5%. Combining the US and MRI findings had a sensitivity of 56% and a specificity of 92%.

Conclusion

A combined scoring system using MRI and US may accurately identify patients at risk for morbidity associated with morbidly adherent placenta.