Assessment of FDA-approved drugs against Strongyloides ratti in vitro and in vivo to identify potentially active drugs against strongyloidiasis

BACKGROUND: Infections with Strongyloides stercoralis belong to the most neglected helminth diseases, and research and development (R&D) efforts on novel drugs are inadequate. METHODS: A commercially available library containing 1600 FDA-approved drugs was tested in vitro against Strongyloides ratti larvae (L3) at 100 microM. Hits (activity > 70%) were then evaluated against S. ratti adult worms at 10 microM. Morantel, prasterone, and levamisole were tested in the S. ratti rat model using dosages of 1-100 mg/kg. RESULTS: Seventy-one of the 1600 compounds tested against S. ratti L3 revealed activity above 70%. Of 64 compounds which progressed into the adult screen, seven compounds achieved death of all worms (benzethonium chloride, cetylpyridinium chloride, Gentian violet, methylbenzethonium chloride, morantel citrate, ivermectin, coumaphos), and another eight compounds had activity > 70%. Excluding topical and toxic compounds, three drugs progressed into in vivo studies. Prasterone lacked activity in vivo, while treatment with 100 mg/kg morantel and levamisole cured all rats. The highest in vivo activity was observed with levamisole, yielding a median effective dose (ED50) of 1.1 mg/kg. CONCLUSIONS: Using a drug repurposing approach, our study identified levamisole as a potential backup drug for strongyloidiasis. Levamisole should be evaluated in exploratory clinical trials

Structural Control of Metamaterial Oscillator Strength and Electric Field Enhancement at Terahertz Frequencies

The design of artificial nonlinear materials requires control over the internal resonant charge densities and local electric field distributions. We present a MM design with a structurally controllable oscillator strength and local electric field enhancement at terahertz frequencies. The MM consists of a split ring resonator (SRR) array stacked above an array of nonresonant closed conducting rings. An in-plane, lateral shift of a half unit cell between the SRR and closed ring arrays results in a decrease of the MM oscillator strength by a factor of 4 and a 40% change in the amplitude of the resonant electric field enhancement in the SRR capacitive gap. We use terahertz time-domain spectroscopy and numerical simulations to confirm our results and we propose a qualitative inductive coupling model to explain the observed electromagnetic reponse.Comment: 11 pages, 5 figure

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

Decoupling Crossover in Asymmetric Broadside Coupled Split Ring Resonators at Terahertz Frequencies

We investigate the electromagnetic response of asymmetric broadside coupled split ring resonators (ABC-SRRs) as a function of the relative in-plane displacement between the two component SRRs. The asymmetry is defined as the difference in the capacitive gap widths (\Delta g) between the two resonators comprising a coupled unit. We characterize the response of ABC-SRRs both numerically and experimentally via terahertz time-domain spectroscopy. As with symmetric BC-SRRs (\Delta g=0 \mu m), a large redshift in the LC resonance is observed with increasing displacement, resulting from changes in the capacitive and inductive coupling. However, for ABC-SRRs, in-plane shifting between the two resonators by more than 0.375Lo (Lo=SRR sidelength) results in a transition to a response with two resonant modes, associated with decoupling in the ABC-SRRs. For increasing \Delta g, the decoupling transition begins at the same relative shift (0.375Lo), though with an increase in the oscillator strength of the new mode. This strongly contrasts with symmetric BC-SRRs which present only one resonance for shifts up to 0.75Lo. Since all BC-SRRs are effectively asymmetric when placed on a substrate, an understanding of ABC-SRR behavior is essential for a complete understanding of BC-SRR based metamaterials

Validation of machine learning models to detect amyloid pathologies across institutions.

Semi-quantitative scoring schemes like the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) are the most commonly used method in Alzheimer's disease (AD) neuropathology practice. Computational approaches based on machine learning have recently generated quantitative scores for whole slide images (WSIs) that are highly correlated with human derived semi-quantitative scores, such as those of CERAD, for Alzheimer's disease pathology. However, the robustness of such models have yet to be tested in different cohorts. To validate previously published machine learning algorithms using convolutional neural networks (CNNs) and determine if pathological heterogeneity may alter algorithm derived measures, 40 cases from the Goizueta Emory Alzheimer's Disease Center brain bank displaying an array of pathological diagnoses (including AD with and without Lewy body disease (LBD), and / or TDP-43-positive inclusions) and levels of Aβ pathologies were evaluated. Furthermore, to provide deeper phenotyping, amyloid burden in gray matter vs whole tissue were compared, and quantitative CNN scores for both correlated significantly to CERAD-like scores. Quantitative scores also show clear stratification based on AD pathologies with or without additional diagnoses (including LBD and TDP-43 inclusions) vs cases with no significant neurodegeneration (control cases) as well as NIA Reagan scoring criteria. Specifically, the concomitant diagnosis group of AD + TDP-43 showed significantly greater CNN-score for cored plaques than the AD group. Finally, we report that whole tissue computational scores correlate better with CERAD-like categories than focusing on computational scores from a field of view with densest pathology, which is the standard of practice in neuropathological assessment per CERAD guidelines. Together these findings validate and expand CNN models to be robust to cohort variations and provide additional proof-of-concept for future studies to incorporate machine learning algorithms into neuropathological practice

Frequency-tunable metamaterials using broadside-coupled split ring resonators

We present frequency tunable metamaterial designs at terahertz (THz) frequencies using broadside-coupled split ring resonator (BC-SRR) arrays. Frequency tuning, arising from changes in near field coupling, is obtained by in-plane horizontal or vertical displacements of the two SRR layers. For electrical excitation, the resonance frequency continuously redshifts as a function of displacement. The maximum frequency shift occurs for displacement of half a unit cell, with vertical displacement resulting in a shift of 663 GHz (51% of f0) and horizontal displacement yielding a shift of 270 GHz (20% of f0). We also discuss the significant differences in tuning that arise for electrical excitation in comparison to magnetic excitation of BC-SRRs

Preservice Elementary Teachers’ Beliefs about the Role of Definition in the Learning of Mathematics

Answering a call to emphasize the act of defining over the learning of definitions, we have shifted the content of a geometry course for preservice elementary teachers (PSETs) away from comparing and applying pre-written classification structures to classroom episodes centered on authoring definitions for special quadrilaterals. PSETs complete activities using geometry software, and collaboratively create definitions for specific quadrilaterals. In order to fully understand the potential of this curricular shift, we asked preservice elementary mathematics teachers’ to share their perceptions of the process of writing mathematical definitions. Data from participant reflections were analyzed for themes related to mathematical definition and the act of defining. The framework that resulted from iterative discussions by the researchers examined beliefs about the nature of definition and mathematical empathy (Araki, 2015). Findings also suggest that beliefs about authority and positioning students as authors of mathematics are associated with mathematical empathy. Experiences related to the process of defining enabled PSETs to see far greater subjectivity in the discipline of mathematics and to consider, perhaps for the first time, that they, too, were both able and deserving of becoming authors of mathematical ideas

Design, synthesis and evaluation of praziquantel analogues and new molecular hybrids as potential antimalarial and anti-schistosomal agents

Malaria and schistosomiasis are two of the neglected tropical diseases that persistently wreak havoc worldwide. Although many antimalarial drugs such as chloroquine are readily available, the emergence of drug resistance necessitates the development of new therapies to combat this disease. Conversely, Praziquantel (PZQ) remains the sole effective drug against schistosomiasis, but its extensive use raises concerns about the potential for drug resistance to develop. In this project, the concept of molecular hybridization was used as a strategy to design the synthesis of new molecular hybrids with potential antimalarial and antischistosomal activity. A total of seventeen molecular hybrids and two PZQ analogues were prepared by coupling 6-alkylpraziquanamines with cinnamic acids and cyclohexane carboxylic acid, respectively. The synthesised compounds were evaluated for their antimalarial and antischistosomal activity; while all of the above compounds were inactive against Plasmodium falciparum (IC(50) > 6 µM), many were active against schistosomiasis with four particular compounds exhibiting up to 100% activity against newly transformed schistosomula and adult worms at 50 µM. Compared to PZQ, the reference drug, the activity of which is 91.7% at 1 µM, one particular molecular hybrid, compound 32, which bears a para-isopropyl group on the cinnamic acid moiety, exhibited a notable activity at 10 µM (78.2% activity). This compound has emerged as the front runner candidate that might, after further optimization, hold promise as a potential lead compound in the fight against schistosomiasis

Characterization of the population pharmacokinetics of moxidectin in adults infected with strongyloides stercoralis: support for a fixed-dose treatment regimen

BACKGROUND: Moxidectin has recently attracted attention as a novel candidate for the treatment of helminth infections, including Strongyloides stercoralis. This study aims to characterize the population pharmacokinetics (PPK) of moxidectin in S. stercoralis-infected adults using a pharmacometric approach, and to perform model-based simulations to explore different drug dosing strategies. METHODS: A PPK study embedded in a dose-escalation phase IIa trial was conducted in NamBak, Laos. Eight micro blood samples were collected from each of 96 S. stercoralis-infected adults following a moxidectin dose-ranging study, from 2 to 12 mg. A PPK model was developed using nonlinear mixed-effects modeling, and dosing strategies were explored using simulations in S. stercoralis-infected subjects with varying age and body weight (n = 5000 per dosing strategy). RESULTS: A two-compartment model including delayed absorption with lag-time best described the available PK data. Allometric scaling was applied to account for the influence of body weight. High clearance was found in the infected adults (4.47 L/h [95% confidence interval 3.63-5.39] for a 70 kg individual) compared with that previously reported for healthy adults. Model-based simulations indicated similar variability in mean ± standard deviation area under the curve from time zero to infinity of 1907 ± 1552 and 2175 ± 1670 ng × h/mL in the 60-70 kg weight group, after 8 mg fixed- or weight-based dosing, respectively. CONCLUSION: We describe the first PPK model for moxidectin in adults with S. stercoralis infection. Equivalent exposures after fixed-dose and weight-dependent dosing strategies support the use of a simple fixed-dose approach, particularly in large-scale treatment programs. TRIAL REGISTRATION: Registered at ClinicalTrials.gov (NCT04056325)