Publications by authors named "Eileen Ryan"

55 Publications

Vaccine-induced immune thrombotic thrombocytopenia (VITT) - a novel clinico-pathological entity with heterogeneous clinical presentations.

Br J Haematol 2021 Jun 22. Epub 2021 Jun 22.

National Coagulation Centre, St. James's Hospital, Dublin, Ireland.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a novel entity that emerged in March 2021 following reports of unusual thrombosis after ChAdOx1 nCoV-19, (AstraZeneca) vaccination. Following the recognition of this syndrome, multiple consensus guidelines have been released to risk stratify patients presenting with possible symptoms after ChAdOx1 nCoV-19 vaccination. All guidelines rapidly identify VITT in patients with the complete triad of thrombocytopenia, thrombosis and elevated D-dimers after ChAdOx1 nCoV-19 vaccination. However, with earlier recognition of the associated symptoms, the clinical manifestations are likely to be more heterogeneous and represent an evolving spectrum of disease. In this setting, current guidelines may lack the sensitivity to detect early cases of VITT and risk missed or delayed diagnoses. The broad clinical phenotype and challenges associated with diagnosis of VITT are highlighted in our present case series of four patients with confirmed VITT. Dependent on the guidance used, each patient could have been classified as a low probability of VITT at presentation. The present study highlights the issues associated with the recognition of VITT, the limitations of current guidance and the need for heightened clinical vigilance as our understanding of the pathophysiology of this novel condition evolves.
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http://dx.doi.org/10.1111/bjh.17613DOI Listing
June 2021

Posttransplant Lymphoproliferative Disorder After Solid Organ Transplant: A Heterogeneous, Aggressive Disorder.

Clin Lymphoma Myeloma Leuk 2021 May 24. Epub 2021 May 24.

Department of Haematology, St Vincent's University Hospital, Elm Park, Dublin, Ireland.

Posttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplant. We identified 40 patients diagnosed with PTLD between 2009 and 2020 and analyzed their presentation, treatment strategies, and outcomes. Median age at diagnosis was 52.5 years (range 21.3 to 79). Median duration of immunosuppression was 95 months (range 4 to 292). Diffuse large B cell lymphoma (n = 16, 40%) and Burkitt lymphoma (n = 6, 15%) were the most common histological subtypes. First-line therapy varied. The median number of treatment lines was 1 (range 0 to 4). Sixteen patients (40%) achieved complete response after first-line therapy. Nineteen patients (47.5%) relapsed or progressed and received salvage therapy; 45% were alive at the end of the study period (median survival 52 months; range 1 to 266; 95% confidence interval 0 to 104). Causes of death included lymphoma-related (45.5%), therapy-related (27.3%), and other (27.3%). Five (22.7%) died within 3 months of diagnosis. Pearson's r test identified disease stage (P = .045) and proliferation index (P = .005) as negative predictors of response to frontline therapy. Bone marrow involvement (P = .033) and increased age (P = .018) were significant predictors of survival. Early mortality and poor response to frontline therapy are common, outlining the need for improved treatment strategies.
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http://dx.doi.org/10.1016/j.clml.2021.05.009DOI Listing
May 2021

Physician wellbeing - what do physicians want?

Authors:
Eileen P Ryan

J Osteopath Med 2021 May 31;121(7):607-609. Epub 2021 May 31.

Department of Psychiatry and Behavioral Health, The Ohio State University Wexner Medical Center, 1670 Upham Drive, Suite 130, Columbus, OH 43210-1250, USA.

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http://dx.doi.org/10.1515/jom-2021-0144DOI Listing
May 2021

Cytokine and lipid metabolome effects of low-dose acetylsalicylic acid in critically ill patients with systemic inflammation: a pilot, feasibility, multicentre, randomised, placebo-controlled trial.

Crit Care Resusc 2020 Sep;22(3):227-236

Department of Intensive Care, Austin Hospital, Melbourne, Vic, Australia.

Objective: The systemic inflammatory response syndrome (SIRS) is a dysregulated response that contributes to critical illness. Adjunctive acetylsalicylic acid (ASA) treatment may offer beneficial effects by increasing the synthesis of specialised proresolving mediators (a subset of polyunsaturated fatty acid-derived lipid mediators).

Design: Pilot, feasibility, multicentre, double-blind, randomised, placebo-controlled trial.

Setting: Four interdisciplinary intensive care units (ICUs) in Australia.

Participants: Critically ill patients with SIRS.

Interventions: ASA 100 mg 12-hourly or placebo, administered within 24 hours of ICU admission and continued until ICU day 7, discharge or death, whichever came first.

Main Outcome Measures: Interleukin-6 (IL-6) serum concentration at 48 hours after randomisation and, in a prespecified subgroup of patients, serum lipid mediator concentrations measured by mass spectrometry.

Results: The trial was discontinued in December 2017 due to slow recruitment and after the inclusion of 48 patients. Compared with placebo, ASA did not decrease IL-6 serum concentration at 48 hours. In the 32 patients with analysis of lipid mediators, low-dose ASA increased the concentration of 15-hydroxyeicosatetraenoic acid, a proresolving precursor of lipoxin A4, and reduced the concentration of the proinflammatory cytochrome P-dependent mediators 17-HETE (hydroxyeicosatetraenoic acid), 18-HETE and 20-HETE. In the eicosapentaenoic acid pathway, ASA significantly increased the concentration of the anti-inflammatory mediators 17,18-DiHETE (dihydroxyeicosatetraenoic acid) and 14,15-DiHETE.

Conclusions: In ICU patients with SIRS, low-dose ASA did not significantly alter serum IL-6 concentrations, but it did affect plasma concentrations of certain lipid mediators. The ability to measure lipid mediators in clinical samples and to monitor the effect of ASA on their levels unlocks a potential area of biological investigation in critical care.

Trial Registration: Australian New Zealand Clinical Trials Registry (ACTRN 12614001165673).
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September 2020

Structure-Activity Relationship of Antischistosomal Ozonide Carboxylic Acids.

J Med Chem 2020 04 19;63(7):3723-3736. Epub 2020 Mar 19.

College of Pharmacy, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska 986125, United States.

Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 () and OZ165 (). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with -substituted carboxymethoxy and -benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182039PMC
April 2020

An in vitro toolbox to accelerate anti-malarial drug discovery and development.

Malar J 2020 Jan 2;19(1). Epub 2020 Jan 2.

Medicines for Malaria Venture, PO Box 1826, 20 Route de Pré-Bois, CH-1215, Geneva 15, Switzerland.

Background: Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles.

Methods: Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC-MS/MS.

Results: Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds.

Conclusions: This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug-drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.
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http://dx.doi.org/10.1186/s12936-019-3075-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941357PMC
January 2020

Philadelphia chromosome-positive acute lymphoblastic leukemia with an e14a3 BCR-ABL1 fusion: The role of molecular monitoring.

Hematol Oncol Stem Cell Ther 2020 Sep 28;13(3):166-167. Epub 2019 May 28.

Department of Haematology, St. James's Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1016/j.hemonc.2019.04.001DOI Listing
September 2020

Structural and Biochemical Insights into the Function and Evolution of Sulfoquinovosidases.

ACS Cent Sci 2018 Sep 5;4(9):1266-1273. Epub 2018 Sep 5.

School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.

An estimated 10 billion tonnes of sulfoquinovose (SQ) are produced and degraded each year. Prokaryotic sulfoglycolytic pathways catabolize sulfoquinovose (SQ) liberated from plant sulfolipid, or its delipidated form α-d-sulfoquinovosyl glycerol (SQGro), through the action of a sulfoquinovosidase (SQase), but little is known about the capacity of SQ glycosides to support growth. Structural studies of the first reported SQase ( YihQ) have identified three conserved residues that are essential for substrate recognition, but crossover mutations exploring active-site residues of predicted SQases from other organisms have yielded inactive mutants casting doubt on bioinformatic functional assignment. Here, we show that SQGro can support the growth of on par with d-glucose, and that the SQase prefers the naturally occurring diastereomer of SQGro. A predicted, but divergent, SQase from proved to have highly specific activity toward SQ glycosides, and structural, mutagenic, and bioinformatic analyses revealed the molecular coevolution of catalytically important amino acid pairs directly involved in substrate recognition, as well as structurally important pairs distal to the active site. Understanding the defining features of SQases empowers bioinformatic approaches for mapping sulfur metabolism in diverse microbial communities and sheds light on this poorly understood arm of the biosulfur cycle.
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http://dx.doi.org/10.1021/acscentsci.8b00453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161063PMC
September 2018

Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria.

Bioorg Med Chem 2018 07 17;26(11):2996-3005. Epub 2018 May 17.

Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom.

A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.
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http://dx.doi.org/10.1016/j.bmc.2018.05.006DOI Listing
July 2018

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.

Nat Commun 2017 05 24;8:15159. Epub 2017 May 24.

Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.
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http://dx.doi.org/10.1038/ncomms15159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458052PMC
May 2017

Detailed Structural Characterization of Sphingolipids via 193 nm Ultraviolet Photodissociation and Ultra High Resolution Tandem Mass Spectrometry.

J Am Soc Mass Spectrom 2017 07 28;28(7):1406-1419. Epub 2017 Apr 28.

School of Chemistry, University of Melbourne, Parkville, Victoria, 3010, Australia.

Sphingolipids serve not only as components of cellular membranes but also as bioactive mediators of numerous cellular functions. As the biological activities of these lipids are dependent on their structures, and due to the limitations of conventional ion activation methods employed during tandem mass spectrometry (MS/MS), there is a recognized need for the development of improved structure-specific methods for their comprehensive identification and characterization. Here, positive-ionization mode 193 nm ultraviolet photodissociation (UVPD)-MS/MS has been implemented for the detailed structural characterization of lipid species from a range of sphingolipid classes introduced to the mass spectrometer via electrospray ionization as their lithiated or protonated adducts. These include sphingosine d18:1(4E), dihydrosphingosine (sphinganine) d18:0, sphingadiene d18:2(4E,11Z), the isomeric sphingolipids ceramide d18:1(4E)/18:0 and dihydroceramide d18:0/18:1(9Z), ceramide-1-phosphate d18:1(4Z)/16:0, sphingomyelin d18:1(4E)/18:1(9Z) the glycosphingolipids galactosyl ceramide d18:1(4E)/24:1(15Z) and lactosyl ceramide d18:1(4E)/24:0, and several endogenous lipids present within a porcine brain total lipid extract. In addition to the product ions formed by higher energy collision dissociation (HCD), UVPD is shown to yield a series of novel structurally diagnostic product ions resulting from cleavage of both sphingosine carbon-carbon and acyl chain carbon-carbon double bonds for direct localization of site(s) of unsaturation, as well as via diagnostic cleavages of the sphingosine backbone and N-C amide bond linkages. With activation timescales and dissociation efficiencies similar to those found in conventional MS/MS strategies, this approach is therefore a promising new tool in the arsenal of ion activation techniques toward providing complete structural elucidation in automated, high-throughput lipid analysis workflows. Graphical Abstract ᅟ.
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http://dx.doi.org/10.1007/s13361-017-1668-1DOI Listing
July 2017

Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439).

J Med Chem 2017 04 18;60(7):2654-2668. Epub 2017 Jan 18.

College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.

Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pK and lower log D values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01586DOI Listing
April 2017

Novel inhibitors of Plasmodium falciparum based on 2,5-disubstituted furans.

Eur J Med Chem 2017 Jan 11;126:929-936. Epub 2016 Dec 11.

Instituto de Química, Universidade Estadual de Campinas, Barão Geraldo, PO Box 6154, Campinas, SP 13084-971, Brazil. Electronic address:

Phenotypic HTS campaigns with a blood stage malaria assay have been used to discover novel chemotypes for malaria treatment with potential alternative mechanisms of action compared to existing agents. N-(5-(3-Chloro-4-fluorophenyl)furan-2-yl)-N,N-dimethylpropane-1,3-diamine, 1 was identified as a modest inhibitor of P. falciparum NF54 (IC = 875 nM) with an apparent long plasma half-life after high dose oral administration to mice, although the compound later showed poor metabolic stability in liver microsomes through ring- and side chain-oxidation and N-dealkylation. We describe here the synthesis of derivatives of 1, exploring the influence of substitution patterns around the aromatic ring, variations on the alkyl chain and modifications in the core heterocycle, in order to probe potency and metabolic stability, where 4k showed a long half-life in rats.
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http://dx.doi.org/10.1016/j.ejmech.2016.12.024DOI Listing
January 2017

Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles.

ACS Cent Sci 2016 Oct 14;2(10):687-701. Epub 2016 Sep 14.

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , 160 College Street, Toronto, Ontario M5S 3E1, Canada.

The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.
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http://dx.doi.org/10.1021/acscentsci.6b00086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084075PMC
October 2016

Chemical Derivatization and Ultrahigh Resolution and Accurate Mass Spectrometry Strategies for "Shotgun" Lipidome Analysis.

Acc Chem Res 2016 09 30;49(9):1596-604. Epub 2016 Aug 30.

School of Chemistry, The University of Melbourne , Parkville, Victoria 3010, Australia.

Lipids play critical structural and functional roles in the regulation of cellular homeostasis, and it is increasingly recognized that the disruption of lipid metabolism or signaling or both is associated with the onset and progression of certain metabolically linked diseases. As a result, the field of lipidomics has emerged to comprehensively identify and structurally characterize the diverse range of lipid species within a sample of interest and to quantitatively monitor their abundances under different physiological or pathological conditions. Mass spectrometry (MS) has become a critical enabling platform technology for lipidomic researchers. However, the presence of isobaric (i.e., same nominal mass) and isomeric (i.e., same exact mass) lipids within complex lipid extracts means that MS-based identification and quantification of individual lipid species remains a significant analytical challenge. Ultrahigh resolution and accurate mass spectrometry (UHRAMS) offers a convenient solution to the isobaric mass overlap problem, while a range of chromatographic separation, differential extraction, intrasource separation and selective ionization methods, or tandem mass spectrometry (MS/MS) strategies may be used to address some types of isomeric mass lipid overlaps. Alternatively, chemical derivatization strategies represent a more recent approach for the separation of lipids within complex mixtures, including for isomeric lipids. In this Account, we highlight the key components of a lipidomics workflow developed in our laboratory, whereby certain lipid classes or subclasses, namely, aminophospholipids and O-alk-1'-enyl (i.e., plasmalogen) ether-containing lipids, are shifted in mass following sequential functional group selective chemical derivatization reactions prior to "shotgun" nano-ESI-UHRAMS analysis, "targeted" MS/MS, and automated database searching. This combined derivatization and UHRAMS approach resolves both isobaric mass lipids and certain categories of isomeric mass lipids within crude lipid extracts, with no requirement for extensive sample handling prior to analysis, with additional potential for enhanced ionization efficiencies, improved molecular level structural characterization, and multiplexed relative quantification. When integrated with a monophasic method for the simultaneous global extraction of both highly polar and nonpolar lipids, this workflow has been shown to enable the sum composition level identification and relative quantification of 500-600 individual lipid species across four lipid categories and from 36 lipid classes and subclasses, in only 1-2 min data acquisition time and with minimal sample consumption. Thus, while some analytical challenges remain to be addressed, shotgun lipidomics workflows encompassing chemical derivatization strategies have particular promise for the analysis of samples with limited availability that require rapid and unbiased assessment of global lipid metabolism.
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http://dx.doi.org/10.1021/acs.accounts.6b00030DOI Listing
September 2016

Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides.

J Med Chem 2016 11 19;59(21):9686-9720. Epub 2016 Sep 19.

School of Chemistry and Biochemistry, The University of Western Australia , 35 Stirling Highway, Crawley, Perth 6009, Western Australia, Australia.

The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00442DOI Listing
November 2016

Juvenile Sex Offenders.

Curr Psychiatry Rep 2016 Jul;18(7):67

Department of Psychiatry and Neurobehavioral Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.

Sexual offending by juveniles accounts for a sizable percentage of sexual offenses, especially against young children. In this article, recent research on female juvenile sex offenders (JSOs), risk factors for offending in juveniles, treatment, and the ways in which these youth may differ from general delinquents will be reviewed. Most JSOs do not go on to develop paraphilic disorders or to commit sex offenses during adulthood, and as a group, they are more similar to nonsexual offending juvenile delinquents than to adult sex offenders. Recent research has elucidated some differences between youth who commit sex offenses and general delinquents in the areas of atypical sexual interests, the use of pornography, and early sexual victimization during childhood.
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http://dx.doi.org/10.1007/s11920-016-0706-1DOI Listing
July 2016

Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity.

J Med Chem 2016 06 21;59(11):5416-31. Epub 2016 May 21.

Departments of Chemistry and Global Health, University of Washington , Seattle, Washington 98195, United States.

Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904246PMC
June 2016

Juvenile Sex Offenders.

Authors:
Eileen P Ryan

Child Adolesc Psychiatr Clin N Am 2016 Jan 16;25(1):81-97. Epub 2015 Oct 16.

Institute of Law, Psychiatry and Public Policy, University of Virginia School of Medicine, PO Box 800660, Charlottesville, VA 22903, USA. Electronic address:

Public policy has tended to treat juvenile sex offenders (JSOs) as adult sex offenders in waiting, despite research that contradicts this notion. Although as a group, JSOs are more similar to general delinquents than to adult sex offenders, atypical sexual interests and sexual victimization during childhood may be a pathway for sexual offending that differentiates some JSOs from their nonsexually delinquent peers. Developmental considerations must be considered in risk assessment evaluations of these youth. This article reviews theories of sexual offending in youth, risk factors for juvenile offending and reoffending, psychopathology in JSOs, risk assessment, and treatment.
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http://dx.doi.org/10.1016/j.chc.2015.08.010DOI Listing
January 2016

Evidence for the in vitro bioactivation of aminopyrazole derivatives: trapping reactive aminopyrazole intermediates using glutathione ethyl ester in human liver microsomes.

Chem Res Toxicol 2015 Sep 8;28(9):1747-52. Epub 2015 Sep 8.

Cancer Therapeutics CRC , 343 Royal Parade, Parkville, Victoria 3052 Australia.

Drug-induced toxicity is a leading cause of drug withdrawal from clinical development and clinical use and represents a major impediment to the development of new drugs. The mechanisms underlying drug-induced toxicities are varied; however, metabolic bioactivation to form reactive metabolites has been identified as a major contributor.1,2 These electrophilic species can covalently modify important biological macromolecules and thereby increase the risk of adverse drug reactions or idiosyncratic toxicity. Consequently, screening compounds for their propensity to form reactive metabolites has become an integral part of drug discovery programs. This screening process typically involves identification of structural alerts as well as the generation of reactive metabolites in vitro in subcellular hepatic fractions, followed by trapping the reactive species with nucleophiles and characterization via LC-MS. This article presents evidence for the bioactivation of a series of aminopyrazole derivatives via LC-MS detection of glutathione ethyl ester-trapped reactive intermediates formed in human liver microsomal incubations. These results indicate that the aminopyrazole motif, within specific contexts, may be considered a new structural alert for the potential formation of reactive metabolites.
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http://dx.doi.org/10.1021/acs.chemrestox.5b00202DOI Listing
September 2015

6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors.

J Med Chem 2015 Sep 30;58(17):6753-65. Epub 2015 Aug 30.

Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.

From a whole-organism high throughput screen of approximately 87000 compounds against Trypanosoma brucei brucei, we recently identified eight new unique compounds for the treatment of human African trypanosomiasis. In an effort to understand the structure-activity relationships around these compounds, we report for the first time our results on a new class of trypanocides, the pyrazine carboxamides. Attracted by the low molecular weight (270 g·mol(-1)) of our starting hit (9) and its potency (0.49 μM), the SAR around the core was explored, leading to compounds having an EC50 as low as 25 nM against T. b. brucei and being more than 1500 times less toxic against mammalian L6 and HEK293 cell lines. The most potent compounds in the series were exquisitely selective for T. brucei over a panel of other protozoan parasites, showing an excellent correlation with the human infective parasite Trypanosoma brucei rhodesiense, the most potent compound (65) having an EC50 of 24 nM. The compounds are highly drug-like and are able to penetrate the CNS, their only limitation currently being their rate of microsomal metabolism. To that effect, efforts to identify potential metabolites of selected compounds are also reported.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00438DOI Listing
September 2015

Induced pluripotent stem cells restore function in a human cell loss model of open-angle glaucoma.

Stem Cells 2015 Mar;33(3):751-61

Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA; Department of Biochemistry & Molecular Biology, Oregon Health & Science University, Portland, Oregon, USA; Department of Biochemistry & Physiology, University of Jordan, Amman, Jordan.

Normally, trabecular meshwork (TM) and Schlemm's canal inner wall endothelial cells within the aqueous humor outflow pathway maintain intraocular pressure within a narrow safe range. Elevation in intraocular pressure, because of the loss of homeostatic regulation by these outflow pathway cells, is the primary risk factor for vision loss due to glaucomatous optic neuropathy. A notable feature associated with glaucoma is outflow pathway cell loss. Using controlled cell loss in ex vivo perfused human outflow pathway organ culture, we developed compelling experimental evidence that this level of cell loss compromises intraocular pressure homeostatic function. This function was restored by repopulation of the model with fresh TM cells. We then differentiated induced pluripotent stem cells (iPSCs) and used them to repopulate this cell depletion model. These differentiated cells (TM-like iPSCs) became similar to TM cells in both morphology and expression patterns. When transplanted, they were able to fully restore intraocular pressure homeostatic function. This successful transplantation of TM-like iPSCs establishes the conceptual feasibility of using autologous stem cells to restore intraocular pressure regulatory function in open-angle glaucoma patients, providing a novel alternative treatment option.
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http://dx.doi.org/10.1002/stem.1885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359625PMC
March 2015

Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei.

J Med Chem 2014 Aug 17;57(15):6393-402. Epub 2014 Jul 17.

Medicinal Chemistry, ‡Centre for Drug Candidate Optimisation, and §Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.

A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 μM, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 μM against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.
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http://dx.doi.org/10.1021/jm500191uDOI Listing
August 2014

Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers.

J Med Chem 2014 May 18;57(9):3818-34. Epub 2014 Apr 18.

VA Medical Center , 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States.

The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.
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http://dx.doi.org/10.1021/jm500147kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018401PMC
May 2014

Simplified silvestrol analogues with potent cytotoxic activity.

ChemMedChem 2014 Jul 27;9(7):1556-66. Epub 2014 Mar 27.

Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052 (Australia); Department of Medical Biology, The University of Melbourne, VIC 3010 (Australia).

The complex natural products silvestrol (1) and episilvestrol (2) are inhibitors of translation initiation through binding to the DEAD-box helicase eukaryotic initiation factor 4A (eIF4A). Both compounds are potently cytotoxic to cancer cells in vitro, and 1 has demonstrated efficacy in vivo in several xenograft cancer models. Here we show that 2 has limited plasma membrane permeability and is metabolized in liver microsomes in a manner consistent with that reported for 1. In addition, we have prepared a series of analogues of these compounds where the complex pseudo-sugar at C6 has been replaced with chemically simpler moieties to improve drug-likeness. Selected compounds from this work possess excellent activity in biochemical and cellular translation assays with potent activity against leukemia cell lines.
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http://dx.doi.org/10.1002/cmdc.201400024DOI Listing
July 2014

Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: part 1.

J Med Chem 2014 Mar 13;57(6):2789-98. Epub 2014 Mar 13.

Department of Chemistry, University of Cape Town , Rondebosch, 7701 Cape Town, South Africa.

A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.
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http://dx.doi.org/10.1021/jm500098sDOI Listing
March 2014

Pain management for pediatric tonsillectomy: an integrative review through the perioperative and home experience.

J Spec Pediatr Nurs 2014 Jan 21;19(1):5-16. Epub 2013 Aug 21.

Cardiac Stepdown/PACU, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware.

Purpose: This integrative review aims to increase our understanding of current pain management care practices for children undergoing tonsillectomy.

Conclusions: Synthesis of the literature resulted in four main opportunities for care providers to manage pain: preoperative education and preparation, intraoperative surgical interventions, and postoperative pharmacologic and nonpharmacologic interventions in the post anesthesia care unit and home settings.

Practice Implications: Nurses have many opportunities to understand pain management practices and intervene to minimize pain experienced in pediatric outpatients undergoing tonsillectomy.
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http://dx.doi.org/10.1111/jspn.12048DOI Listing
January 2014

Two analogues of fenarimol show curative activity in an experimental model of Chagas disease.

J Med Chem 2013 Dec 4;56(24):10158-70. Epub 2013 Dec 4.

Epichem Pty Ltd. , Murdoch University Campus, South Street, Murdoch, Western Australia 6150, Australia.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.
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http://dx.doi.org/10.1021/jm401610cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884847PMC
December 2013
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