Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

Scalable Similarity Search for Molecular Descriptors

Similarity search over chemical compound databases is a fundamental task in the discovery and design of novel drug-like molecules. Such databases often encode molecules as non-negative integer vectors, called molecular descriptors, which represent rich information on various molecular properties. While there exist efficient indexing structures for searching databases of binary vectors, solutions for more general integer vectors are in their infancy. In this paper we present a time- and space- efficient index for the problem that we call the succinct intervals-splitting tree algorithm for molecular descriptors (SITAd). Our approach extends efficient methods for binary-vector databases, and uses ideas from succinct data structures. Our experiments, on a large database of over 40 million compounds, show SITAd significantly outperforms alternative approaches in practice.Comment: To be appeared in the Proceedings of SISAP'1

Co-Crystalline Solid Solution Affords a High-Soluble and Fast-Absorbing Form of Praziquantel

Praziquantel (PZQ) is a chiral class-II drug, and it is used as a racemate for the treatment of schistosomiasis. The knowledge of several cocrystals with dicarboxylic acids has prompted the realization of solid solutions of PZQ with both enantiomers of malic acid and tartaric acid. Here, the solid form landscape of such a six-component system has been investigated. In the process, two new cocrystals were structural-characterized and three non-stoichiometric, mixed crystal forms identified and isolated. Thermal and solubility analysis indicates a fourfold solubility advantage for the newly prepared solid solutions over the pure drug. In addition, a pharmacokinetic study was conducted in rats, which involved innovative mini-capsules for the oral administration of the solid samples. The available data indicate that the faster dissolution rate of the solid solutions translates in faster absorption of the drug and helps maintain a constant steady-state concentration

Observations Derived From the Characterization of Monolithic Fuel Plates Irradiated as Part of the RERTR-6 Experiment

Evaluation of the PIE results of the monolithic plates that were irradiated as part of the RERTR-6 experiment has continued. Specifically, comparisons have been made between the microstructures of the fuel plates before and after irradiation. Using the results from the rigorous characterization that was performed on the as-fabricated plates using scanning electron microscopy, it is possible to improve understanding of how monolithic fuel plates perform when they are irradiated. This paper will discuss the changes that occur, if any, in the microstructure of a monolithic fuel plate that is fabricated using techniques like what were employed for fabricating RERTR-6 fuel plates. In addition, the performance of fuel/cladding interaction layers that were present in the fuel plates due to the fabrication process will be discussed, particularly in the context of swelling of these layers and how these layers exhibit different behaviors depending on whether the fuel alloy in the fuel plate is U-7Mo or U-10Mo

A Six-Planet System Around the Star HD 34445

We present a new precision radial velocity dataset that reveals a multi-planet system orbiting the G0V star HD 34445. Our 18-year span consists of 333 precision radial velocity observations, 56 of which were previously published, and 277 which are new data from Keck Observatory, Magellan at Las Campanas Observatory, and the Automated Planet Finder at Lick Observatory. These data indicate the presence of six planet candidates in Keplerian motion about the host star with periods of 1057, 215, 118, 49, 677, and 5700 days, and minimum masses of 0.63, 0.17, 0.1, 0.05, 0.12 and 0.38 Jupiter masses respectively. The HD 34445 planetary system, with its high degree of multiplicity, its long orbital periods, and its induced stellar radial velocity half-amplitudes in the range $2 \,{\rm m\, s^{-1}} \lesssim K \lesssim 5\,{\rm m\, s^{-1}}$ is fundamentally unlike either our own solar system (in which only Jupiter and Saturn induce significant reflex velocities for the Sun), or the Kepler multiple-transiting systems (which tend to have much more compact orbital configurations)Comment: 10 pages, 11 figure

US RERTR FUEL DEVELOPMENT POST IRRADIATION EXAMINATION RESULTS

Post irradiation examinations of irradiated RERTR plate type fuel at the Idaho National Laboratory have led to in depth characterization of fuel behavior and performance. Both destructive and non-destructive examination capabilities at the Hot Fuels Examination Facility (HFEF) as well as recent results obtained are discussed herein. New equipment as well as more advanced techniques are also being developed to further advance the investigation into the performance of the high density U-Mo fuel

SEM and TEM Characterization of As-Fabricated U-7Mo Disperson Fuel Plates

The starting microstructure of a dispersion fuel plate can have a dramatic impact on the overall performance of the plate during irradiation. To improve the understanding of the as-fabricated microstructures of dispersion fuel plates, SEM and TEM analysis have been performed on RERTR-9A archive fuel plates, which went through an additional hot isostatic procsssing (HIP) step during fabrication. The fuel plates had depleted U-7Mo fuel particles dispersed in either Al-2Si or 4043 Al alloy matrix. For the characterized samples, it was observed that a large fraction of the ?-phase U-7Mo alloy particles had decomposed during fabrication, and in areas near the fuel/matrix interface where the transformation products were present significant fuel/matrix interaction had occurred. Relatively thin Si-rich interaction layers were also observed around the U-7Mo particles. In the thick interaction layers, (U)(Al,Si)3 and U6Mo4Al43 were identified, and in the thin interaction layers U(Al,Si)3, U3Si3Al2, U3Si5, and USi1.88-type phases were observed. The U3Si3Al2 phase contained some Mo. Based on the results of this work, exposure of dispersion fuel plates to relatively high temperatures during fabrication impacts the overall microstructure, particularly the nature of the interaction layers around the fuel particles. The time and temperature of fabrication should be carefully controlled in order to produce the most uniform Si-rich layers around the U-7Mo particles

Efficacy and Safety of Artemether in the Treatment of Chronic Fascioliasis in Egypt: Exploratory Phase-2 Trials

Fasciola hepatica and F. gigantica are two liver flukes that parasitize herbivorous large size mammals (e.g., sheep and cattle), as well as humans. A single drug is available to treat infections with Fasciola flukes, namely, triclabendazole. Recently, laboratory studies and clinical trials in sheep and humans suffering from acute fascioliasis have shown that artesunate and artemether (drugs that are widely used against malaria) also show activity against fascioliasis. Hence, we were motivated to assess the efficacy and safety of oral artemether in patients with chronic Fasciola infections. The study was carried out in Egypt and artemether administered according to two different malaria treatment regimens. Cure rates observed with 6×80 mg and 3×200 mg artemether were 35% and 6%, respectively. In addition, high efficacy was observed when triclabendazole, the current drug of choice against human fascioliasis, was administered to patients remaining Fasciola positive following artemether treatment. Concluding, monotherapy with artemether does not represent an alternative to triclabendazole against fascioliasis, but its role in combination chemotherapy regimen remains to be investigated

Results of Recent Microstructural Characterization of Irradiated U-Mo Dispersion Fuels with Al Alloy Matrices that Contain Si

RERTR U-Mo dispersion fuel plates are being developed for application in research reactors throughout the world. As part of this development, reactor experiments are being conducted in the Advanced Test Reactor to determine the irradiation performance of different dispersion fuels that contain U-Mo alloys with different Mo contents and Al alloy matrices with different Si contents. Of particular interest is the performance of the dispersion fuels depending on the Si content of the Al alloy matrix, since the addition of Si is being looked to for improving the performance of these dispersion fuels. This paper will describe the results of recent microstructural examinations that have been performed using optical metallography and scanning electron microscopy on as-fabricated and as-irradiated dispersion fuels with different amounts of Si added to the Al matrix. Differences in the microstructural development during irradiation as a function of the Si content in the Al matrix will be discussed, and comments will be made about the development and stability of the fuel/matrix interaction layers that are commonly present in irradiated dispersion fuels

Microstructure Characterization of RERTR Fuel

A variety of phases have the potential to develop in the irradiated fuels for the reduced enrichment research test reactor (RERTR) program. To study the radiation stability of these potential phases, three depleted uranium alloys were cast. The phases of interest were identified including U(Si,Al)3, (U,Mo)(Si,Al)3, UMo2Al20, UAl4, and U6Mo4Al43. These alloys were irradiated with 2.6 MeV protons at 200ºC up to 3.0 dpa. The microstructure is characterized using SEM and TEM. Microstructural characterization for an archive dispersion fuel plate (U-7Mo fuel particles in Al-2%Si cladding) was also carried out. TEM sample preparation for the irradiated dispersion fuel has been developed