554 results match your criteria clinical liabilities


Analysis and recommendations regarding surgeons' liabilities during an acute health crisis.

Leg Med (Tokyo) 2021 Apr 7;51:101880. Epub 2021 Apr 7.

St. George's, University of London, London, UK. Electronic address:

The SARS-CoV-2 pandemic has highlighted discrepancies between surgeons' professional duties and legal protections when acting outside their specialities during the pandemic. These discrepancies between legal and professional standards leave surgeons and the NHS vulnerable to litigation. In the following article, we explore the liabilities that have arisen for surgeons during this period in the United Kingdom and Canada. Read More

View Article and Full-Text PDF

Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition.

Environ Health Perspect 2021 Apr 12;129(4):47008. Epub 2021 Apr 12.

Division for Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.

Background: Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thoroughly evaluated for their inhibitory effects on AChE activity. AChE inhibitors can have therapeutic applications (e. Read More

View Article and Full-Text PDF

In Vitro Safety "Clinical Trial" of the Cardiac Liability of Drug Polytherapy.

Clin Transl Sci 2021 Mar 30. Epub 2021 Mar 30.

Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California, 94720, USA.

Only a handful of FDA Emergency Use Authorizations exist for drug and biologic therapeutics that treat SARS-CoV-2 infection. Potential therapeutics include repurposed drugs, some with cardiac liabilities. We report on a chronic preclinical drug screening platform, a cardiac microphysiological system (MPS), to assess cardiotoxicity associated with repurposed hydroxychloroquine (HCQ) and azithromycin (AZM) polytherapy in a mock Phase I safety clinical trial. Read More

View Article and Full-Text PDF

Interaction of clinical-stage antibodies with heme predicts their physiochemical and binding qualities.

Commun Biol 2021 Mar 23;4(1):391. Epub 2021 Mar 23.

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006, Paris, France.

Immunoglobulin repertoires contain a fraction of antibodies that recognize low molecular weight compounds, including some enzymes' cofactors, such as heme. Here, by using a set of 113 samples with variable region sequences matching clinical-stage antibodies, we demonstrated that a considerable number of these antibodies interact with heme. Antibodies that interact with heme possess specific sequence traits of their antigen-binding regions. Read More

View Article and Full-Text PDF

Stability of monoclonal antibodies after simulated subcutaneous administration.

J Pharm Sci 2021 Mar 12. Epub 2021 Mar 12.

Lonza Pharma and Biotech, Drug Product Services, Hochbergerstr. 60A, 4057 Basel, Switzerland. Electronic address:

Changes in the environment from the drug product to the human physiology might lead to physical and/or chemical modifications of the protein drug, such as in vivo aggregation and fragmentation. Although subcutaneous (SC) injection is a common route of administration for therapeutic proteins, knowledge on in vivo stability in the SC tissue is limited. In this study, we developed a physiologic in vitro model simulating the SC environment in patients. Read More

View Article and Full-Text PDF

The Cost-Effectiveness of Reverse Total Shoulder Arthroplasty Versus Open Reduction Internal Fixation for Proximal Humerus Fractures in the Elderly.

Iowa Orthop J 2020 ;40(2):20-29

Department of Orthopaedic Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.

Background: Open reduction and internal fixation (ORIF) of proximal humerus fractures in elderly individuals (age >70) carries a relatively high short-term complication and reoperation rate but is generally durable once healed. Reverse total shoulder arthroplasty (RTSA) for fractures may be associated with superior short-term quality of life but carries the lifelong liabilities of joint replacement. The tradeoff between short and long-term risks, coupled with disparities in quality of life and cost, makes this clinical decision amenable to cost-effectiveness analysis. Read More

View Article and Full-Text PDF
January 2020

The Vital Role of Proteomics in Characterizing Novel Protein Degraders.

SLAS Discov 2021 Apr 20;26(4):518-523. Epub 2021 Feb 20.

Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Boston, MA, USA.

Mass spectrometry-based proteomics profiling is a discovery tool that enables researchers to understand the mechanisms of action of drug candidates. When applied to proteolysis targeting chimeras (PROTACs) such approaches provide unbiased perspectives of the binding, degradation selectivity, and mechanism related to efficacy and safety. Specifically, global profiling experiments can identify direct degradation events and assess downstream pathway modulation that may result from degradation or off-target inhibition. Read More

View Article and Full-Text PDF

Clinical and Translational Implications of an Emerging Developmental Substructure for Autism.

Annu Rev Clin Psychol 2021 Feb 12. Epub 2021 Feb 12.

Centre for Brain & Cognitive Development, Birkbeck, University of London, London WC1E 7HX, United Kingdom.

A vast share of the population-attributable risk for autism relates to inherited polygenic risk. A growing number of studies in the past five years have indicated that inherited susceptibility may operate through a finite number of early developmental liabilities that, in various permutations and combinations, jointly predict familial recurrence of the convergent syndrome of social communication disability that defines the condition. Here, we synthesize this body of research to derive evidence for a novel developmental substructure for autism, which has profound implications for ongoing discovery efforts to elucidate its neurobiological causes, and to inform future clinical and biomarker studies, early interventions, and personalized approaches to therapy. Read More

View Article and Full-Text PDF
February 2021

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site.

Elife 2021 Feb 8;10. Epub 2021 Feb 8.

Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States.

Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here, we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with , to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. Read More

View Article and Full-Text PDF
February 2021

Injectable Capsaicin for the Management of Pain Due to Osteoarthritis.

Molecules 2021 Feb 3;26(4). Epub 2021 Feb 3.

Translational Research in Pain (TRiP) Program, Comparative Pain Research and Education Centre, Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA.

Capsaicin is a potent agonist of the TRPV1 channel, a transduction channel that is highly expressed in nociceptive fibers (pain fibers) throughout the peripheral nervous system. Given the importance of TRPV1 as one of several transduction channels in nociceptive fibers, much research has been focused on the potential therapeutic benefits of using TRPV1 antagonists for the management of pain. However, an antagonist has two limitations. Read More

View Article and Full-Text PDF
February 2021

Psychosocial evaluation matters.

Liver Transpl 2021 Jan 23. Epub 2021 Jan 23.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Transplant clinicians who focus on psychosocial issues know how critical the pre-transplant psychosocial evaluation is for facilitating patients' successful negotiation of the transplantation process. This is particularly the case in liver transplantation: psychosocial factors such as substance use and dependence have often directly contributed to the need for transplantation, and substance use history is often entwined with other psychosocial liabilities such as poor mental health and weak social support. Indeed, the overall value of the psychosocial evaluation as part of the medical work-up for liver and other types of solid organ transplantation is well-recognized in clinical practice guidelines and recommendations. Read More

View Article and Full-Text PDF
January 2021

Cardiovascular microphysiological systems (CVMPS) for safety studies - a pharma perspective.

Lab Chip 2021 02;21(3):458-472

Integrative Pharmacology, Integrated Science and Technology, AbbVie, 1 Waukegan Rd, N Chicago, IL 60064, USA.

The integrative responses of the cardiovascular (CV) system are essential for maintaining blood flow to provide oxygenation, nutrients, and waste removal for the entire body. Progress has been made in independently developing simple in vitro models of two primary components of the CV system, namely the heart (using induced pluripotent stem-cell derived cardiomyocytes) and the vasculature (using endothelial cells and smooth muscle cells). These two in vitro biomimics are often described as immature and simplistic, and typically lack the structural complexity of native tissues. Read More

View Article and Full-Text PDF
February 2021

Investigating dihydroorotate dehydrogenase inhibitor mediated mitochondrial dysfunction in hepatic in vitro models.

Toxicol In Vitro 2021 Apr 16;72:105096. Epub 2021 Jan 16.

Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Ashton street Liverpool, L69 3GE, UK. Electronic address:

Inhibition of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzymatic step in de novo pyrimidine synthesis, has broad immunosuppressive effects in vivo and shows promise as a therapeutic target for the treatment of malignancies, viral infections and auto-immune diseases. Whilst there are numerous DHODH inhibitors under development, leflunomide and teriflunomide are the only FDA approved compounds on the market, each of which have been issued with black-box warnings for hepatotoxicity. Mitochondrial dysfunction is a putative mechanism by which teriflunomide and leflunomide elicit their hepatotoxic effects, however it is as yet unclear whether this is shared by other nascent DHODH inhibitors. Read More

View Article and Full-Text PDF

Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors.

MAbs 2021 Jan-Dec;13(1):1850395

BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA.

We report here the discovery and optimization of a novel T cell retargeting anti-GUCY2C x anti-CD3ε bispecific antibody for the treatment of solid tumors. Using a combination of hybridoma, phage display and rational design protein engineering, we have developed a fully humanized and manufacturable CD3 bispecific antibody that demonstrates favorable pharmacokinetic properties and potent efficacy. Anti-GUCY2C and anti-CD3ε antibodies derived from mouse hybridomas were first humanized into well-behaved human variable region frameworks with full retention of binding and T-cell mediated cytotoxic activity. Read More

View Article and Full-Text PDF
January 2021

Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid Withdrawal.

Cell Mol Neurobiol 2021 Jan 12. Epub 2021 Jan 12.

Department of Pharmacodynamics, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA.

Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea "kratom" and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. Read More

View Article and Full-Text PDF
January 2021

Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic Fibrosis.

J Med Chem 2021 01 5;64(1):343-353. Epub 2021 Jan 5.

Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium.

Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small molecules can partially restore the CFTR function. Correctors are small molecules that enhance the amount of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel. Read More

View Article and Full-Text PDF
January 2021

In Vitro Safety "Clinical Trial" of the Cardiac Liability of Hydroxychloroquine and Azithromycin as COVID19 Polytherapy.

bioRxiv 2020 Dec 28. Epub 2020 Dec 28.

Despite global efforts, there are no effective FDA-approved medicines for the treatment of SARS-CoV-2 infection. Potential therapeutics focus on repurposed drugs, some with cardiac liabilities. Here we report on a preclinical drug screening platform, a cardiac microphysiological system (MPS), to assess cardiotoxicity associated with hydroxychloroquine (HCQ) and azithromycin (AZM) polytherapy in a mock clinical trial. Read More

View Article and Full-Text PDF
December 2020

Nanomedicine Reformulation of Chloroquine and Hydroxychloroquine.

Molecules 2020 Dec 31;26(1). Epub 2020 Dec 31.

Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21702, USA.

The chloroquine family of antimalarials has a long history of use, spanning many decades. Despite this extensive clinical experience, novel applications, including use in autoimmune disorders, infectious disease, and cancer, have only recently been identified. While short term use of chloroquine or hydroxychloroquine is safe at traditional therapeutic doses in patients without predisposing conditions, administration of higher doses and for longer durations are associated with toxicity, including retinotoxicity. Read More

View Article and Full-Text PDF
December 2020

Comorbid Depression and Anxiety Symptoms in Chinese Adolescents: Testing the Explanatory Power of a Diathesis-Anxiety Model.

Res Child Adolesc Psychopathol 2021 Apr 25;49(4):503-517. Epub 2020 Nov 25.

Department of Psychology, University of Illinois At Urbana-Champaign, Champaign, 61820, Illinois, USA.

Anxiety and depressive symptoms frequently co-occur in adolescence and confer greater distress compared to experiencing either symptom alone. A causal model (anxiety symptoms predicting depressive symptoms), a correlated liabilities model (vulnerabilities interacting with stressors to predict both symptoms), and a diathesis-anxiety model (vulnerabilities interacting with anxiety symptoms to predict depressive symptoms) have all been proposed as explanations for the relation between depression and anxiety. To date, however, research has mostly examined these models among North American/Western European adolescents. Read More

View Article and Full-Text PDF

Pathological Mechanisms and Potential Therapeutic Targets of Pulmonary Arterial Hypertension: A Review.

Aging Dis 2020 Dec 1;11(6):1623-1639. Epub 2020 Dec 1.

1Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease characterized by pulmonary vasculature reconstruction and right ventricular dysfunction. The mortality rate of PAH remains high, although multiple therapeutic strategies have been implemented in clinical practice. These drugs mainly target the endothelin-1, prostacyclin and nitric oxide pathways. Read More

View Article and Full-Text PDF
December 2020

Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum.

Epidemiol Psychiatr Sci 2020 Nov 17;29:e182. Epub 2020 Nov 17.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.

Aims: Psychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum.

Methods: The sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. Read More

View Article and Full-Text PDF
November 2020

Can We Panelize Seizure?

Toxicol Sci 2021 Jan;179(1):3-13

Health and Environmental Sciences Institute, Washington, District of Columbia 20005.

Seizure liability remains a significant cause of attrition in drug discovery and development, leading to loss of competitiveness, delays, and increased costs. Current detection methods rely on observations made in in vivo studies intended to support clinical trials, such as tremors or other abnormal movements. These signs could be missed or misinterpreted; thus, definitive confirmation of drug-induced seizure requires a follow-up electroencephalogram study. Read More

View Article and Full-Text PDF
January 2021

The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase.

Leuk Res 2020 11 29;98:106458. Epub 2020 Sep 29.

Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.

Asciminib is a potent, orally bioavailable, investigational drug that specifically and potently inhibits the tyrosine kinase activity of native ABL1, together with that of the chimeric BCR-ABL1 oncoprotein which causes chronic myeloid leukemia (CML). In contrast to ATP-competitive BCR-ABL1 kinase inhibitors employed to treat CML that target multiple kinases, asciminib binds to the myristate binding pocket on the kinase domains of ABL1 and BCR-ABL1. Hitherto no drugs have been developed whose mechanism of action involves interacting with myristate binding pockets on proteins, and analysis of the structures of such binding sites in proteins other than ABL1/ABL2/BCR-ABL1 strongly suggest that asciminib will not bind to these with high affinity. Read More

View Article and Full-Text PDF
November 2020

Transcriptional regulators and alterations that drive melanoma initiation and progression.

Oncogene 2020 11 6;39(48):7093-7105. Epub 2020 Oct 6.

Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.

Although melanoma is the least frequent type of skin cancer, it accounts for the majority of skin cancer-related deaths. Large-scale sequencing efforts have led to the classification of melanoma into four major subtypes (i.e. Read More

View Article and Full-Text PDF
November 2020

Small-molecule BACE1 inhibitors: a patent literature review (2011 to 2020).

Expert Opin Ther Pat 2021 Jan 17;31(1):25-52. Epub 2020 Dec 17.

Medicinal Chemistry, Janssen Research & Development , Beerse, Belgium.

Introduction: Inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) has been extensively pursued as potential disease-modifying treatment for Alzheimer's disease (AD). Clinical failures with BACE inhibitors have progressively raised the bar forever cleaner candidates with reduced cardiovascular liability, toxicity risk, and increased selectivity over cathepsin D (CatD) and BACE2.

Areas Covered: This review provides an overview of patented BACE1 inhibitors between 2011 and 2020 per pharmaceutical company or research group and highlights the progress that was made in dialing out toxicity liabilities. Read More

View Article and Full-Text PDF
January 2021

Retrospective analysis of medical malpractice claims in tertiary hospitals of China: the view from patient safety.

BMJ Open 2020 09 24;10(9):e034681. Epub 2020 Sep 24.

School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Objectives: The study analysed medical malpractice claims to assess patient safety in hospitals. The information derived from malpractice claims reflects potential risks and could help lead to reducing medical errors and improving patient safety.

Design, Setting: We analysed 4380 medical malpractice claims from 351 grade-A tertiary hospitals in China for 2008-2017. Read More

View Article and Full-Text PDF
September 2020

Dependence, withdrawal and rebound of CNS drugs: an update and regulatory considerations for new drugs development.

Brain Commun 2019 16;1(1):fcz025. Epub 2019 Oct 16.

Controlled Substance Scientific Solutions LLC, 4601 North Park Avenue #506, Chevy Chase, MD 20815-4572, USA.

The purpose of this article is to describe dependence and withdrawal phenomena related to CNS drugs discontinuation and to clarify issues related to the evaluation of clinical drug withdrawal and rebound as they relate to safety in new drug development. The article presents current understanding and definitions of drug dependence and withdrawal which are also relevant and important features of addiction, though not the same. Addiction, called substance use disorder in DSM-5, affects an individual's brain and behaviour, represents uncontrollable drug abuse and inability to stop taking a drug regardless of the harm it causes. Read More

View Article and Full-Text PDF
October 2019

A Two-Tiered In Vitro Approach to De-Risk Drug Candidates for Potential Bile Salt Export Pump Inhibition Liabilities in Drug Discovery.

Drug Metab Dispos 2020 11 17;48(11):1147-1160. Epub 2020 Sep 17.

Departments of Pharmacokinetics, Pharmacodynamics & Drug Metabolism (PPDM) (M.J.H., R.H., I.K., J.S., Q.C., R.E.), Genetics and Pharmacogenomics (K.Q.T.), and Safety Assessment and Laboratory Animal Resources (SALAR) (A.B., J.M., F.D.S.), Merck & Co., Inc., Kenilworth, New Jersey.

Hepatocellular accumulation of bile salts by inhibition of bile salt export pump (BSEP/) may result in cholestasis and is one proposed mechanism of drug-induced liver injury (DILI). To understand the relationship between BSEP inhibition and DILI, we evaluated 64 DILI-positive and 57 DILI-negative compounds in BSEP, multidrug resistance protein (MRP) 2, MRP3, and MRP4 vesicular inhibition assays. An empirical cutoff (5 μM) for BSEP inhibition was established based on a relationship between BSEP IC values and the calculated maximal unbound concentration at the inlet of the human liver (fu*I, assay specificity = 98%). Read More

View Article and Full-Text PDF
November 2020

Characterization of indoleamine-2,3-dioxygenase 1, tryptophan-2,3-dioxygenase, and Ido1/Tdo2 knockout mice.

Toxicol Appl Pharmacol 2020 11 29;406:115216. Epub 2020 Aug 29.

Safety Assessment & Laboratory Animal Resources, Merck & Co, Inc., West Point, PA, USA.

Indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase 2 (TDO2) degrade tryptophan (Trp) to kynurenine (Kyn), and these enzymes have promise as therapeutic targets. A comprehensive characterization of potential safety liabilities of IDO1 and TDO2 inhibitors using knockout (KO) mice has not been assessed, nor has the dual Ido1/Tdo2 KO been reported. Here we characterized male and female mice with KOs for Ido1, Tdo2, and Ido1/Tdo2 and compared findings to the wild type (WT) mouse strain, evaluated for 14 days, using metabolomics, transcriptional profiling, behavioral analysis, spleen immunophenotyping, comprehensive histopathological analysis, and serum clinical chemistry. Read More

View Article and Full-Text PDF
November 2020

Artificial Intelligence in Cutaneous Oncology.

Front Med (Lausanne) 2020 10;7:318. Epub 2020 Jul 10.

Department of Biomedical Engineering, Yonsei University, Wonju, South Korea.

Skin cancer, previously known to be a common disease in Western countries, is becoming more common in Asian countries. Skin cancer differs from other carcinomas in that it is visible to our eyes. Although skin biopsy is essential for the diagnosis of skin cancer, decisions regarding whether or not to conduct a biopsy are made by an experienced dermatologist. Read More

View Article and Full-Text PDF