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David F Kisor,1 Natasha J Petry,2,3 David R Bright4 1Manchester University, Department of Pharmaceutical Sciences and Pharmacogenomics, Fort Wayne, IN, USA; 2North Dakota State University, College of Health Professions, Department of Pharmacy Practice, Fargo, ND, USA; 3Sanford Imagenetics, Sioux Falls, ND, USA; 4Ferris State University, Department of Pharmaceutical Sciences, Big Rapids, MI, USACorrespondence: David F KisorManchester University, Department of Pharmaceutical Sciences and Pharmacogenomics, 10627 Diebold Road, Fort Wayne, IN, 46845, USATel +1 260-470-2747Fax +1 260-470-4440Email dfkisor@manchester.eduAbstract: Pharmacogenomics (PGx) is expanding across health-care practice settings, including the community pharmacy. In the United States, models of implementation of PGx in the community pharmacy have described independent services and those layered on to medication therapy management. The drug–gene pair of clopidogrel-CYP2C19 has been a focus of implementation of PGx in community pharmacy and serves as an example of the evolution of the application of drug–gene interaction information to help optimize drug therapy. Expanded information related to this drug–gene pair has been provided by the US Food and Drug Administration and clinical PGx guidelines have and continue to be updated to support clinical decision-making. Most recently direct-to-consumer (DTC) PGx has resulted in patient generated sample collection and submission to a genetic testing-related company for analysis, with reporting of genotype and related phenotype information directly to the patient without a health-care professional guiding or even being involved in the process. The DTC testing approach needs to be considered in the development or modification of PGx service models in the community pharmacy setting. The example of clopidogrel-CYP2C19 is discussed and current models of PGx implementation in the community pharmacy in the United States are presented. New approaches to PGx services are offered as implementation continues to evolve and may now include DTC information.Keywords: pharmacogenomics, pharmacogenetics, clopidogrel, community pharmacy, implementation

Benjamin Q Duong,1 Meghan J Arwood,2 J Kevin Hicks,3 Amber L Beitelshees,4 Francesco Franchi,5 John T Houder,2 Nita A Limdi,6 Kelsey J Cook,7,8 Aniwaa Owusu Obeng,9 Natasha Petry,10 Sony Tuteja,11 Amanda R Elsey,2 Larisa H Cavallari,2 Kristin Wiisanen2 on behalf of the IGNITE Network1Department of Precision Medicine, Nemours/Alfred I. DuPont Hospital for Children, Wilmington, DE, USA; 2Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics & Precision Medicine, University of Florida College of Pharmacy, Gainesville, FL, USA; 3Department of Individualized Cancer Management, Moffitt Cancer Center, Tampa, FL, USA; 4Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; 5Department of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA; 6University of Alabama School at Birmingham, Birmingham, AL, USA; 7Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Jacksonville, FL, USA; 8Department of Precision Medicine, Nemours Children’s Specialty Care, Jacksonville, FL, USA; 9The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 10Department of Pharmacy Practice, North Dakota State University College of Health Professions, Fargo, ND, USA; 11Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USACorrespondence: Kristin WiisanenDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics & Precision Medicine, University of Florida College of Pharmacy, P.O. Box 100486, Gainesville, FL 32610-0486, USATel +1 352-273-5114Email kwiisanen@cop.ufl.eduIntroduction: Clinical adoption of genomic medicine has lagged behind the pace of scientific discovery. Practice-based resources can help overcome implementation challenges.Methods: In 2015, the IGNITE (Implementing GeNomics In pracTicE) Network created an online genomic medicine implementation resource toolbox that was expanded in 2017 to incorporate the ability for users to create targeted implementation guides. This expansion was led by a multidisciplinary team that developed an evidence-based, structured framework for the guides, oversaw the technical process/build, and pilot tested the first guide, CYP2C19-Clopidogrel Testing Implementation.Results: Sixty-five resources were collected from 12 institutions and categorized according to a seven-step implementation framework for the pilot CYP2C19-Clopidogrel Testing Implementation Guide. Five months after its launch, 96 CYP2C19-Clopidogrel Testing Implementation Guides had been created. Eighty percent of the resources most frequently selected by users were created by IGNITE to fill an identified resource gap. Resources most often included in guides were from the test reimbursement (22%), Implementation support gathering (22%), EHR integration (17%), and genetic testing workflow steps (17%).Conclusion: Lessons learned from this implementation guide development process provide insight for prioritizing development of future resources and support the value of collaborative efforts to create resources for genomic medicine implementation.Keywords: pharmacogenomics, CYP2C19, clopidogrel, implementation, precision medicine, personalized medicine, clinical pharmacogenomics, CYP2D6

Genetic testing has the potential to revolutionize primary care, but few health systems have developed the infrastructure to support precision population medicine applications or attempted to evaluate its impact on patient and provider outcomes. In 2018, Sanford Health, the nation’s largest rural nonprofit health care system, began offering genetic testing to its primary care patients. To date, more than 11,000 patients have participated in the Sanford Chip Program, over 90% of whom have been identified with at least one informative pharmacogenomic variant, and about 1.5% of whom have been identified with a medically actionable predisposition for disease. This manuscript describes the rationale for offering the Sanford Chip, the programs and infrastructure implemented to support it, and evolving plans for research to evaluate its real-world impact.

Carla J Rash, Nancy M Petry Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA Abstract: This review discusses the research evidence for psychological treatment of gambling disorder. Several treatment options for gamblers have been explored, ranging from self-help and peer support, to brief and motivational interventions, to more intensive therapy approaches. Involvement in peer support programs seems to be optimal when combined with professional treatment; however, engagement and retention in peer support is limited. Self-directed interventions appear to benefit some gamblers; however, the involvement of therapist support, either in person or by telephone, may bolster these effects and such support need not be extensive. These self-directed options reduce the barriers associated with treatment-seeking, and may reach a wider range of gamblers than professionally delivered treatments alone. Brief and motivational approaches similarly may extend treatment options to more gamblers, namely at-risk and problem gamblers and those not seeking treatment. Of more extensive therapies, no consistent benefit of one approach emerges, although cognitive–behavioral interventions have been most often applied. Overall, several treatments have been developed for gambling disorder and results are promising, but variability in findings suggests a need for further systematic evaluation. Keywords: gambling treatment, cognitive behavioral treatment, brief interventions, pathological gambling, problem gambling, behavioral addictions

Sydnones are heterocyclic compounds which display important biological activities, including their abilities to react in 1,3-dipolar additions for applications in the development of new prodrugs. Capitalizing on our preliminary work on the mechanosynthesis of sydnones, an extension of this work to two related families of molecules, diarylsydnones and iminosydnones is reported. A ball-milling approach towards the synthesis of diaryl sydnones was developed, a necessary step for the synthesis of potential sydnone-based ligands of metal complexes. A mechanochemistry-based synthesis of iminosydnones was optimized, including the preparation of active pharmaceutical ingredients (API) related to feprosidnine, linsidomine, mesocarb and molsidomine. This work demonstrated that the ball-milling procedures were efficient and time saving through avoiding purification steps, and reduced the use of organic solvents.

There is a growing interest surrounding morpholine-2,5-dione-based materials due to their impressive biocompatibility as well as their capacity to break down by hydrolytic and enzymatic pathways. In this study, the ring-opening (co)polymerization of leucine-derived 3S-(isobutyl)morpholine-2,5-dione (MD) and lactide (LA) was performed via ball-milling using a catalytic system composed of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 3-[3,5-bis(trifluoromethyl)phenyl]-1-cyclohexylthiourea (TU). Once the homopolymerizations of MD and LA optimized and numerous parameters were studied, the mechanochemical ring-opening copolymerization of these monomers was explored. The feasibility of ring-opening copolymerizations in mechanochemical systems was demonstrated and a range of P(MD- co -LA) copolymers were produced with varying proportions of MD (23%, 48%, and 69%). Furthermore, the beneficial cocatalytic effects of TU with regards to ROP control were found to be operative within mechanochemical systems. Further parallels were observed between solution- and mechanochemical-based ROPs.

Sydnones are mesioionic compounds studied for years for their versatile reactivity in substitution reactions, sydnone-alkyne or sydnone-alkene cycloaddition reactions. This perspective article focuses on the use of sydnones in coordination complexes, either through a metalation on one of the carbons of the sydnone ring, its modification to obtain polydentate ligands, or its use as a polar moiety that could influence the properties of the final complex. Such compounds are valuable either from a synthetic point of view or for their biological properties.

The design of conjugates displaying simultaneously high selectivity and high affinity for different subtypes of integrins is a current challenge. The arginine-glycine-aspartic acid amino acid sequence (RGD) is one of the most efficient short peptides targeting these receptors. We report herein the development of linear and cyclic fluoro-C-glycoside"RGD" conjugates, taking advantage of the robustness and hydrophilicity of C-glycosides. As attested by in vitro evaluation, the design of these C-glyco"RGD" with a flexible three-carbon triazolyl linker allows distinct profiles towards α IIb β 3 and α v β 3 integrins. Molecular-dynamics simulations confirm the suitability of cyclic C-glyco-c(RGDfC) to target α v β 3 integrin. These C-glyco"RGD" could become promising biological tools in particular for Positron Emission Tomography imaging., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

N-Phenyl-4-(2-pyridinyl) sydnone was shown to act as a four-electron donor N,O-ligand in unprecedented coordination complexes featuring three different metallic centers (Co, Cu, and Zn). Starting with various anilines, the use of a ball-mill efficiently enabled the synthesis of N-arylglycines, subsequent nitrosylation and cyclization into sydnones, and further metalation.

Ball milling was exploited to prepare a substituted proline building block by mechanochemical nucleophilic substitution. Subsequently, the mechanocoupling of hindered proline amino acid derivatives was developed to provide proline-proline dipeptides under solvent-free conditions. A deprotection-cyclization sequence yielded the corresponding diketopiperazines that were obtained with a high stereoselectivity which could be explained by DFT calculations. Using this method, an enantiopure disubstituted Pro-Pro diketopiperazine was synthesized in 4 steps, making 5 new bonds using a ball mill.