Evaluation of an FDA approved library against laboratory models of human intestinal nematode infections

Treatment options for infections with soil-transmitted helminths (STH) - Ascaris lumbricoides, Trichuris trichiura and the two hookworm species, Ancylostoma duodenale and Necator americanus - are limited despite their considerable global health burden. The aim of the present study was to test the activity of an openly available FDA library against laboratory models of human intestinal nematode infections.; All 1,600 drugs were first screened against Ancylostoma ceylanicum third-stage larvae (L3). Active compounds were scrutinized and toxic compounds, drugs indicated solely for topical use, and already well-studied anthelmintics were excluded. The remaining hit compounds were tested in parallel against Trichuris muris first-stage larvae (L1), Heligmosomoides polygyrus third-stage larvae (L3), and adult stages of the three species in vitro. In vivo studies were performed in the H. polygyrus and T. muris mice models.; Fifty-four of the 1,600 compounds tested revealed an activity of > 60 % against A. ceylanicum L3 (hit rate of 3.4 %), following incubation at 200 μM for 72 h. Twelve compounds progressed into further screens. Adult A. ceylanicum were the least affected (1/12 compounds active at 50 μM), while eight of the 12 test compounds revealed activity against T. muris L1 (100 μM) and adults (50 μM), and H. polygyrus L3 (200 μM). Trichlorfon was the only compound active against all stages of A. ceylanicum, H. polygyrus and T. muris. In addition, trichlorfon achieved high worm burden reductions of 80.1 and 98.9 %, following a single oral dose of 200 mg/kg in the T. muris and H. polygyrus mouse model, respectively.; Drug screening on the larval stages of intestinal parasitic nematodes is feasible using small libraries and important given the empty drug discovery and development pipeline for STH infections. Differences and commonalities in drug activities across the different STH species and stages were confirmed. Hits identified might serve as a starting point for drug discovery for STH

Radioactivity Concentrations in Spa Waters - Dose Assessment

In this study 6 different spa water samples from Serbia, Hungary and Czech Republic were investigated in order to determine their radioactivity concentrations. These waters have been used on a large scale for medical and bathing purposes; for therapy, rehabilitation and recreation and also used for drinking, which is the most important. The obtained results showed that natural activity concentrations of alpha emitting radionuclides was within World Health Organization recommended levels and Serbian applicable regulations, but the gross beta activity exceed 1 Bq L-1 for some of the samples. Considering the fact that gross beta activity in four samples was higher than recommended levels, gamma spectrometric measurements were performed, in order to identify radionuclides which caused increase of the gross beta activity. It was found that K-40 was responsible for the elevated gross beta activity. Based on the obtained results the annual effective dose was calculated.3rd International Conference on Radiation and Applications in Various Fields of Research (RAD), Jun 08-12, 2015, Budva, Montenegr

Fifth European Dirofilaria and Angiostrongylus Days (FiEDAD) 2016

Peer reviewe

Activity profile of an FDA-approved compound library against Schistosoma mansoni

As plans to expand mass drug treatment campaigns to fight schistosomiasis form, worries about reliance on praziquantel as the sole available treatment motivate the investigation for novel antischistosomal compounds. Drug repurposing might be an inexpensive and effective source of novel antischistosomal leads.; 1600 FDA approved compounds were first assayed against Schistosoma mansoni schistosomula at a concentration of 10 µM. Active compounds identified from this screen were advanced to the adult worm screen at 33.33 µM, followed by hit characterization. Leads with complementary pharmacokinetic and toxicity profiles were then selected for in vivo studies.; The in vitro screen identified 121 and 36 compounds active against the schistosomula and adult stage, respectively. Further, in vitro characterization and comparison with already available pharmacokinetic and toxicity data identified 11 in vivo candidates. Doramectin (10 mg/kg) and clofazimine (400 mg/kg) were found to be active in vivo with worm burden reductions of 60.1% and 82.7%, respectively.; The work presented here expands the knowledge of antischistosomal properties of already approved compounds and underscores variations observed between target-based and phenotypic approaches and among laboratories. The two in vivo-active drugs identified in this study, doramectin and clofazimine are widely available and present as novel drug classes as starting points for further investigation

Performance analysis of MPPM FSO transmission over Gamma–Chi-square strong atmospheric turbulence

In this paper, performance analysis of free space optical (FSO) system operating in conditions of strong atmospheric turbulence over Gamma–Chi-square turbulence model, has been carried out. We have observed reception over multi-pulse pulse-position (MPPM) modulation format for the case of strong atmospheric turbulence conditions modeled with Gamma–Chi-square turbulence model and have compared it with turbulence modeling distributions such are: Gamma–Gamma distribution, K-distribution, negative exponential distribution, log–normal distribution. First, we have provided closed-form analytical expressions for average bit error rate (ABER) at the reception for each observed case and then based on them, we have obtained numerical and Monte Carlo simulation results in order to observe turbulence level impact on system performance

Compounds active on adult <i>S</i>. <i>mansoni</i> at a concentration of 33.33 μM at 24 hours.

<p>Activity was defined as scoring an average of ≤ 0.5 on the viability scale. The reason for exclusion is also listed and the data is based on compound material safety data sheets, FDA documents and previous publications.</p><p>Compounds active on adult <i>S</i>. <i>mansoni</i> at a concentration of 33.33 μM at 24 hours.</p

121 Hit compounds at NTS screening stage.

<p>Compounds were tested at a concentration of 10 μM and hits were defined as compounds for which the NTS scored ≤ 0.5 on our viability scale at 72 hours post-exposure.</p><p>*Indicates compound excluded due to toxicity concerns.</p><p>**Indicates compound that has already been well-characterized on <i>Schistosoma spp</i>. and hence was excluded.</p><p>121 Hit compounds at NTS screening stage.</p

Worm burden reductions of <i>S</i>.<i>mansoni-</i>infected mice treated with <i>in vitro-</i>hit FDA Pharmakon compounds.

<p>*Indicates that the 4^th mouse of this group died prematurely.</p><p>** WBR for clofazimine (200 mg/kg) was calculated based on worm burden of Control Batch 2.</p><p>Worm burden reductions of <i>S</i>.<i>mansoni-</i>infected mice treated with <i>in vitro-</i>hit FDA Pharmakon compounds.</p

IC₅₀ values of compounds selected for <i>in vivo</i> testing.

<p>IC₅₀ values of compounds selected for <i>in vivo</i> testing.</p

Venn diagrams representing overlaps between: (A) our NTS screen and that of Abdulla et al., (B) our NTS screen and <i>in silico</i> hits from Neves et al. and (C) NTS hits from Abdulla et al. and hits from Neves et al.

<p>The small dark circles within each large circle represent the number of compounds that were not present in the comparator’s library.</p