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https://www.readbyqxmd.com/read/28446883/in-vitro-and-in-vivo-profile-of-ppl-101-and-ppl-103-mixed-opioid-partial-agonist-analgesics-with-low-abuse-potential
#1
Taline V Khroyan, Andrea Cippitelli, Nicholas Toll, John A Lawson, William Crossman, Willma E Polgar, Lawrence Toll
Opiates are still the most effective and widely used treatments for acute and chronic pain. However, the problems associated with morphine and other standard opioid analgesics severely limit their effectiveness in the clinic. PPL-101 and PPL-103 derived from morphine and morphinan ring systems contain a chiral N-substituent, which confers it with a unique combination of high-binding affinities and partial agonist activities at mu, delta, and kappa opioid receptors, leading to unique in vivo pharmacology compared to other conventional opioids...
2017: Frontiers in Psychiatry
https://www.readbyqxmd.com/read/28445047/development-of-selective-orally-active-gpr4-antagonists-with-modulatory-effects-on-nociception-inflammation-and-angiogenesis
#2
Juraj Velcicky, Wolfgang Miltz, Berndt Oberhauser, David Orain, Andrea Vaupel, Klaus Weigand, Janet Dawson King, Amanda Littlewood-Evans, Mark Nash, Roland Feifel, Pius Loetscher
A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While compound 1a showed promising efficacy in several disease models, its binding to a H3 receptor as well as a hERG channel prevented it from further development. Therefore, a new round of optimization addressing the key liabilities was performed and led to discovery of compound 13 with an improved profile. Compound 13 showed significant efficacy in the rat antigen induced arthritis as well as in the hyperalgesia and angiogenesis model at a well-tolerated dose of 30 mg/kg...
April 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28444087/civil-liability-of-the-ophthalmologist-in-the-s%C3%A3-o-paulo-court-of-appeals
#3
Isabel de Fátima Alvim Braga, Kelly de Oliveira Vieira, Thiago Gonçalves Dos Santos Martins
Objective: To conduct a data survey on the subject of medical claims involving civil liability in ophthalmology at the São Paulo Court of Appeals. Methods: A case law research was carried out on the São Paulo Court of Appeals website searching for the keyword "ophthalmologist" for all years until 2016. Results: Of the 65 cases found, 29 were selected. There has been an increase in the number of claims in ophthalmology, especially in surgical procedures on the anterior chamber of the eye...
2017: Einstein
https://www.readbyqxmd.com/read/28441614/learning-from-an-analysis-of-closed-malpractice-litigation-involving-myocardial-infarction
#4
Kuan-Han Wu, Yung-Lin Yen, Chien-Hung Wu, Chi-Yuan Hwang, Shih-Yu Cheng
OBJECTIVE: To examine the epidemiologic data, identify the pattern of dispute, and determine clinical litigious errors by analyzing closed malpractice claims involving myocardial infarction (MI) in Taiwanese courts. METHODS: A retrospective descriptive study was performed to analyze the verdicts pertaining to MI from the population-based database of the Taiwan judicial system between 2002 and 2013. The results of adjudication, involved specialists, primary dispute leading to lawsuits, and litigious errors were recorded...
April 13, 2017: Journal of Forensic and Legal Medicine
https://www.readbyqxmd.com/read/28441487/the-isomeric-preference-of-an-atypical-dopamine-transporter-inhibitor-contributes-to-its-selection-of-the-transporter-conformation
#5
Ara M Abramyan, Sebastian Stolzenberg, Zheng Li, Claus J Loland, Frank Noé, Lei Shi
Cocaine, a widely abused psychostimulant, inhibits the dopamine transporter (DAT) by trapping the protein in an outward-open conformation, whereas atypical DAT inhibitors such as benztropine have low abuse liability and prefer less outward-open conformations. Here, we use a spectrum of computational modeling and simulation approaches to obtain the underlying molecular mechanism in atomistic detail. Interestingly, our quantum mechanical calculations and molecular dynamics (MD) simulations suggest that a benztropine derivative JHW007 prefers a different stereoisomeric conformation of tropane in binding to DAT compared to that of a cocaine derivative, CFT...
April 25, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28440344/toxicogenomic-module-associations-with-pathogenesis-a-network-based-approach-to-understanding-drug-toxicity
#6
J J Sutherland, Y W Webster, J A Willy, G H Searfoss, K M Goldstein, A R Irizarry, D G Hall, J L Stevens
Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP')...
April 25, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28439755/what-do-key-stakeholders-think-about-hiv-self-testing-in-canada-results-from-a-cross-sectional-survey
#7
N Pant Pai, M Smallwood, D Gulati, N Lapczak, A Musten, C Gaydos, C Johnston, M Steben, T Wong, N Engel, J Kim
Human immunodeficiency virus (HIV) self-testing presents an empowering alternative to facility-based testing for reaching undiagnosed HIV infected individuals, but is not currently available in Canada. We surveyed stakeholders (clinical providers, public health professionals, researchers) engaged in HIV testing initiatives nationwide to identify the concerns, opportunities and challenges to implementing HIV self-testing in Canada. An online cross-sectional survey was disseminated by the Canadian Institutes of Health Research Centre for REACH 2...
April 24, 2017: AIDS and Behavior
https://www.readbyqxmd.com/read/28438156/relative-contribution-of-type-1-and-type-2-diabetes-loci-to-the-genetic-etiology-of-adult-onset-non-insulin-requiring-autoimmune-diabetes
#8
Rajashree Mishra, Alessandra Chesi, Diana L Cousminer, Mohammad I Hawa, Jonathan P Bradfield, Kenyaita M Hodge, Vanessa C Guy, Hakon Hakonarson, Didac Mauricio, Nanette C Schloot, Knud B Yderstræde, Benjamin F Voight, Stanley Schwartz, Bernhard O Boehm, Richard David Leslie, Struan F A Grant
BACKGROUND: In adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as 'latent autoimmune diabetes in adults' (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes. METHODS: We tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model...
April 25, 2017: BMC Medicine
https://www.readbyqxmd.com/read/28436345/evidence-that-polygenic-risk-for-psychotic-disorder-is-expressed-in-the-domain-of-neurodevelopment-emotion-regulation-and-attribution-of-salience
#9
J van Os, Y van der Steen, Md A Islam, S Gülöksüz, B P Rutten, C J Simons
BACKGROUND: The liability-threshold model of psychosis risk predicts stronger phenotypic manifestation of the polygenic risk score (PRS) in the healthy relatives of patients, as compared with healthy comparison subjects. METHODS: First-degree relatives of patients with psychotic disorder (871 siblings and 812 parents) and healthy comparison subjects (n = 523) were interviewed three times in 6 years. Repeated measures of two psychosis phenotypes, the Community Assessment of Psychic Experiences (CAPE; self-report - subscales of positive, negative and depressive symptoms) and the Structured Interview for Schizotypy - Revised (SIS-R; clinical interview - subscales of positive and negative schizotypy), were examined for association with PRS...
April 24, 2017: Psychological Medicine
https://www.readbyqxmd.com/read/28435905/transurethral-resection-of-the-prostate-bladder-explosion-and-hyponatremic-encephalopathy-a-rare-case-report-of-malpractice
#10
Giuseppe Vacchiano, Aldo Rocca, Rita Compagna, Anna Ginevra Immacolata Zamboli, Vera Cirillo, Lorenza Di Domenico, Veronica Di Nardo, Giuseppe Servillo, Bruno Amato
We present an original case report of a bladder explosion during a TURP intervention for benign prostatic hypertrophy, that was brought on by the absorption of about 5 liters of glycine 1.5% and then onset of a severe hyponatremia. The quick and inappropriate correction of this electrolyte imbalance led the onset of encephalopathy and the death of the patient. The authors discuss the pathogenesis of these uncommon diseases and, considering the most recent Italian Legislation, they highlight the importance to respect good clinical practice standards and guidelines to ensure the most appropriate treatments for the patient and remove any assumptions of medical liability...
January 2017: Open Medicine (Warsaw, Poland)
https://www.readbyqxmd.com/read/28430956/achieving-high-reliability-in-histology-%C3%A2-an-improvement-series-to-reduce-errors
#11
Yael K Heher, Yigu Chen, Sergey Pyatibrat, Edward Yoon, Jeffrey D Goldsmith, Kenneth E Sands
Objectives: Despite sweeping medical advances in other fields, histology processes have by and large remained constant over the past 175 years. Patient label identification errors are a known liability in the laboratory and can be devastating, resulting in incorrect diagnoses and inappropriate treatment. The objective of this study was to identify vulnerable steps in the histology workflow and reduce the frequency of labeling errors (LEs). Methods: In this 36-month study period, a numerical step key (SK) was developed to capture LEs...
November 1, 2016: American Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28430581/association-between-en1-rs4144782-and-susceptibility-of-knee-osteoarthritis-a-case-control-study
#12
Li Haohuan, Zhang Xiaolong, Cao Yiping, Hu Song, Peng Fei, Zhou Jianlin, Li Jianping
Osteoarthritis (OA) is a complex disease that affects the whole joint, resulting from the combined influence of biomechanical factors and genetic factors. The heritable component for primary OA accounts for about 60% of variation in population liability to the disease. So far, genome-wide association studies (GWAS) and candidate gene studies have established many OA-related loci. However, these findings account for only a rather small fraction of the genetic component. To further reveal the genetic architecture of OA, we conducted this case-control study to explore the association of locus EN1 rs4144782 and knee OA susceptibility in a Chinese population...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28429885/intravenous-self-administration-of-benzydamine-a-non-steroidal-anti-inflammatory-drug-with-a-central-cannabinoidergic-mechanism-of-action
#13
Riccardo Avvisati, Maria Meringolo, Emiliana Stendardo, Elisa Malavasi, Silvia Marinelli, Aldo Badiani
Benzydamine (BZY) is a non-steroidal anti-inflammatory drug used for the topical treatment of inflammations of the oral and vaginal mucosae. Virtually nothing is known about the central pharmacological actions of BZY. Yet there are reports of voluntary systemic overdosage of BZY in drug addicts, resulting in a euphoric, hallucinatory state. In the present study, we investigated the reinforcing properties of BZY in a rat self-administration paradigm. We found that BZY has a powerful reinforcing effect and that this effect is greatly facilitated in animals that already had substance experience, having previously self-administered heroin and cocaine, indicating cross sensitization between BZY and other common drugs of abuse...
April 21, 2017: Addiction Biology
https://www.readbyqxmd.com/read/28427995/conditioned-taste-avoidance-conditioned-place-preference-and-hyperthermia-induced-by-the-second-generation-bath-salt-%C3%AE-pyrrolidinopentiophenone-%C3%AE-pvp
#14
Katharine H Nelson, Briana J Hempel, Matthew M Clasen, Kenner C Rice, Anthony L Riley
BACKGROUND: α-Pyrrolidinopentiophenone (α-PVP) has been reported to be rewarding in a variety of pre-clinical models. Given that a number of drugs of abuse have both rewarding and aversive effects, the balance of which influences addiction potential, the present study examined the aversive properties of α-PVP by assessing its ability to induce taste avoidance. This assessment was made in a combined taste avoidance/place conditioning design that also allowed an evaluation of the relationship between α-PVP's aversive and rewarding effects...
April 17, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28427946/is-an-early-age-at-illness-onset-in-schizophrenia-associated-with-increased-genetic-susceptibility-analysis-of-data-from-the-nationwide-danish-twin-register
#15
Rikke Hilker, Dorte Helenius, Birgitte Fagerlund, Axel Skytthe, Kaare Christensen, Thomas M Werge, Merete Nordentoft, Birte Glenthøj
BACKGROUND: Early age at illness onset has been viewed as an important liability marker for schizophrenia, which may be associated with an increased genetic vulnerability. A twin approach can be valuable, because it allows for the investigation of specific illness markers in individuals with a shared genetic background. METHODS: We linked nationwide registers to identify a cohort of twin pairs born in Denmark from 1951 to 2000 (N=31,524 pairs), where one or both twins had a diagnosis in the schizophrenia spectrum...
April 6, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28426285/the-yin-and-yang-of-autism-genetics-how-rare-de-novo-and-common-variations-affect-liability
#16
Pauline Chaste, Kathryn Roeder, Bernie Devlin
The etiology of autism spectrum disorder (ASD) is complex, involving both genetic and environmental contributions to individual and population-level liability. Early researchers hypothesized that ASD arises from polygenic inheritance, but later results, such as the identification of mutations in certain genes that are responsible for syndromes associated with ASD, led others to propose that de novo mutations of major effect would account for most cases. This yin and yang of monogenic causes and polygenic inheritance continues to this day...
April 19, 2017: Annual Review of Genomics and Human Genetics
https://www.readbyqxmd.com/read/28423437/-expert-assessment-of-traumatic-disc-herniations
#17
Martin Schwarze, Marc-André Weber, Florin M Bucur, Marcus Schiltenwolf
In numerous legal areas, expert assessments are needed to clarify the causality of herniated discs: Was the damage caused by an accident? The literature mentions specific requirements regarding the trauma mechanism as well as temporal criteria, which prescribe the causality test. These are essentially high-energy traumas with immediate functional impairments. Accident-related MRI examinations are of paramount importance in the expert assessment process to confirm the primary body harm. In examining the causality constituting liability, competitive causes must be assessed...
April 19, 2017: Zeitschrift Für Orthopädie und Unfallchirurgie
https://www.readbyqxmd.com/read/28422076/zeglobaltox-an-innovative-approach-to-address-organ-drug-toxicity-using-zebrafish
#18
Carles Cornet, Simone Calzolari, Rafael Miñana-Prieto, Sylvia Dyballa, Els van Doornmalen, Helma Rutjes, Thierry Savy, Davide D'Amico, Javier Terriente
Toxicity is one of the major attrition causes during the drug development process. In that line, cardio-, neuro-, and hepatotoxicities are among the main reasons behind the retirement of drugs in clinical phases and post market withdrawal. Zebrafish exploitation in high-throughput drug screening is becoming an important tool to assess the toxicity and efficacy of novel drugs. This animal model has, from early developmental stages, fully functional organs from a physiological point of view. Thus, drug-induced organ-toxicity can be detected in larval stages, allowing a high predictive power on possible human drug-induced liabilities...
April 19, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28420448/association-of-cognitive-function-and-liability-to-addiction-with-childhood-herpesvirus-infections-a-prospective-cohort-study
#19
Michael M Vanyukov, Vishwajit L Nimgaonkar, Levent Kirisci, Galina P Kirillova, Maureen D Reynolds, Konasale Prasad, Ralph E Tarter, Robert H Yolken
Liability to substance use disorder (SUD) is largely nonspecific to particular drugs and is related to behavior dysregulation, including reduced cognitive control. Recent data suggest that cognitive mechanisms may be influenced by exposure to neurotropic infections, such as human herpesviruses. In this study, serological evidence of exposure to human herpesvirus Herpes simplex virus Type 1 (HSV-1), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) as well as Toxoplasma gondii was determined in childhood (age ~11 years) in 395 sons and 174 daughters of fathers with or without SUD...
April 19, 2017: Development and Psychopathology
https://www.readbyqxmd.com/read/28418656/informing-the-selection-of-screening-hit-series-with-in-silico-absorption-distribution-metabolism-excretion-and-toxicity-profiles
#20
John M Sanders, Douglas C Beshore, J Chris Culberson, James I Fells, Jason E Imbriglio, Hakan Gunaydin, Andrew M Haidle, Marc Labroli, Brian E Mattioni, Nunzio Sciammetta, William D Shipe, Robert P Sheridan, Linda M Suen, Andreas Verras, Abbas M Walji, Elizabeth M Joshi, Tjerk Bueters
High-throughput screening (HTS) has enabled millions of compounds to be assessed for biological activity, but challenges remain in the prioritization of hit series. While biological, absorption, distribution, metabolism, excretion, and toxicity (ADMET), purity, and structural data are routinely used to select chemical matter for further follow-up, the scarcity of historical ADMET data for screening hits limits our understanding of early hit compounds. Herein, we describe a process that utilizes a battery of in-house quantitative structure activity relationship (QSAR) models to generate in silico ADMET profiles for hit series to enable more complete characterizations of HTS chemical matter...
April 18, 2017: Journal of Medicinal Chemistry
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