Systematic analysis of protein targets associated with adverse events of drugs from clinical trials and post-marketing reports; Toward in vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia

2020 ◽  
Author(s):  
Zhang-He Goh
Keyword(s):  
Clinical Trials ◽  
Safety Assessment ◽  
Channel Blocker ◽  
Three Dimensional ◽  
Mitigation Strategies ◽  
Systematic Analysis ◽  
Protein Targets ◽  
Post Marketing ◽  
Dynamic Exposure

scholarly journals Systematic analysis of protein targets associated with adverse events of drugs from clinical trials and post-marketing reports

2020 ◽  
Author(s):  
Ines A. Smit ◽  
Avid M. Afzal ◽  
Chad H. G. Allen ◽  
Fredrik Svensson ◽  
Thierry Hanser ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Adverse Event Reporting System ◽  
Quantitative Information ◽  
Carbonic Anhydrases ◽  
Systematic Analysis ◽  
Post Marketing Surveillance ◽  
Post Marketing

AbstractAdverse drug reactions (ADRs) are undesired effects of medicines that can harm patients and are a significant source of attrition in drug development. ADRs are anticipated by routinely screening drugs against secondary pharmacology protein panels. However, there is still a lack of quantitative information on the links between these off-target proteins and the risk of ADRs in humans. Here, we present a systematic analysis of associations between measured and predicted in vitro bioactivities of drugs, and adverse events (AEs) in humans from two sources of data: the Side Effect Resource (SIDER), derived from clinical trials, and the Food and Drug Administration Adverse Event Reporting System (FAERS), derived from post-marketing surveillance. The ratio of a drug’s in vitro potency against a given protein relative to its therapeutic unbound drug plasma concentration was used to select proteins most likely to be relevant to in vivo effects. In examining individual target bioactivities as predictors of AEs, we found a trade-off between the Positive Predictive Value and the fraction of drugs with AEs that can be detected, however considering sets of multiple targets for the same AE can help identify a greater fraction of AE-associated drugs. Of the 45 targets with statistically significant associations to AEs, 30 are included on existing safety target panels. The remaining 15 targets include 8 carbonic anhydrases, of which CA5B was significantly associated with cholestatic jaundice. We include the full quantitative data on associations between in vitro bioactivities and AEs in humans in this work, which can be used to make a more informed selection of safety profiling targets.

scholarly journals Assessment of Toxicity and Safety Profiles of Nanoparticles

2020 ◽  
Vol 10 (1) ◽  
pp. 1877-1888
Keyword(s):  
Clinical Trials ◽  
Mechanism Of Action ◽  
Safety Assessment ◽  
Nanoparticle Synthesis ◽  
Safety Evaluation ◽  
Drug Molecules ◽  
The World ◽  
Strict Regulation

The world of medicine explored the use of nanoparticles in therapeutics in the last two decades. Owing to the advantages nanoparticles offer, they are proving beneficial to overcome many drawbacks faced by small drug molecules. Since the nature, architecture, shape, size, and mechanism of action of nanomedicines totally different from regularly used drugs, it is important to work on the possible toxicity these nanoparticles are causing so that its safety can be ensured. In today’s scenario, a lot of industries and institutes are synthesizing nano drugs, so it is important to check its toxicity and safety evaluation under in vivo and in vitro conditions, as it has come to fore that number of metal and carbon-based nanoparticles, although proving useful further display increased toxicity. Taken into consideration nanoparticle toxicity and safety, the present review discusses the exact working of nanoparticles at the molecular, cellular, and physiological levels and the toxicity associated with it. The present strategies for safety assessment have also been reviewed. The research involving nanomaterials in therapeutics demand strict regulation in nanoparticle synthesis, its usage, properly regulated clinical trials ensuring safety assessment.

scholarly journals Emerging multitarget tyrosine kinase inhibitors in the treatment of neuroendocrine neoplasms

2018 ◽  
Vol 25 (9) ◽  
pp. R453-R466 ◽  
Author(s):  
Federica Grillo ◽  
Tullio Florio ◽  
Francesco Ferraù ◽  
Elda Kara ◽  
Giuseppe Fanciulli ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Neuroendocrine Cells ◽  
Neuroendocrine Neoplasms ◽  
Systematic Analysis ◽  
Clinical Trial Registries

In the last few years, the therapeutic approach for neuroendocrine neoplasms (NENs) has changed dramatically following the approval of several novel targeted treatments. The multitarget tyrosine kinase inhibitor (MTKI), sunitinib malate, has been approved by Regulatory Agencies in pancreatic NENs. The MTKI class, however, includes several other molecules (approved for other conditions), which are currently being studied in NENs. An in-depth review on the studies published on the MTKIs in neuroendocrine tumors such as axitinib, cabozantinib, famitinib, lenvatinib, nintedanib, pazopanib, sorafenib and sulfatinib was performed. Furthermore, we extensively searched on the Clinical Trial Registries databases worldwide, in order to collect information on the ongoing clinical trials related to this topic. Our systematic analysis on emerging MTKIs in the treatment of gastroenteropancreatic and lung NENs identifiesin vitroandin vivostudies, which demonstrate anti-tumor activity of diverse MTKIs on neuroendocrine cells and tumors. Moreover, for the first time in the literature, we report an updated view concerning the upcoming clinical trials in this field: presently, phase I, II and III clinical trials are ongoing and will include, overall, a staggering 1667 patients. This fervid activity underlines the increasing interest of the scientific community in the use of emerging MTKIs in NEN treatment.

scholarly journals Systematic Analysis of Protein Targets Associated with Adverse Events of Drugs from Clinical Trials and Postmarketing Reports

2020 ◽  
Author(s):  
Ines A. Smit ◽  
Avid M. Afzal ◽  
Chad H. G. Allen ◽  
Fredrik Svensson ◽  
Thierry Hanser ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Systematic Analysis ◽  
Protein Targets

scholarly journals Toward in vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia

2020 ◽  
Author(s):  
Hongbin Wan ◽  
Gianluca Selvaggio ◽  
Robert A. Pearlstein
Keyword(s):  
Three Dimensional ◽  
Underlying Disease ◽  
Mitigation Strategies ◽  
Structural Basis ◽  
Head Group ◽  
List Type ◽  
Current Disruption ◽  
Binding Interface ◽  
Safety Parameters

AbstractThe human ether-a-go-go-related voltage-gated cardiac ion channel (commonly known as hERG) conducts the rapid outward repolarizing potassium current in cardiomyocytes (IKr). Inadvertent blockade of this channel by drug-like molecules represents a key challenge in pharmaceutical R&D due to frequent overlap between the structure-activity relationships of hERG and many primary targets. Building on our previous work, together with recent cryo-EM structures of hERG, we set about to better understand the energetic and structural basis of promiscuous blocker-hERG binding in the context of Biodynamics theory. We propose a two-step blocker binding process consisting of: Diffusion of a single fully solvated blocker copy into a large cavity lined by the intracellular cyclic nucleotide binding homology domain (the initial capture step). Occupation of this cavity is a necessary but insufficient condition for ion current disruption.Translocation of the captured blocker along the channel axis (the IKr disruption step), such that: The head group, consisting of a quasi-linear moiety, projects into the open pore, accompanied by partial de-solvation of the binding interface.One tail moiety packs along a kink between the S6 helix and proximal C-linker helix adjacent to the intra-cellular entrance of the pore, likewise accompanied by mutual de-solvation of the binding interface (noting that the association barrier is comprised largely of the total head + tail group de-solvation cost).Blockers containing a highly planar moiety that projects into a putative constriction zone within the closed channel become trapped upon closing, as do blockers terminating prior to this region.A single captured blocker molecule may associate and dissociate from the pore many times before exiting the CNBHD cavity.Lastly, we highlight possible flaws in the current hERG safety index (SI) and propose an alternate in vivo-relevant strategy factoring in: Benefit/risk.The predicted arrhythmogenic fractional hERG occupancy (based on action potential simulations of the undiseased human ventricular cardiomyocyte).Alteration of the safety threshold due to underlying disease.Risk of exposure escalation toward the predicted arrhythmic limit due to patient-to-patient pharmacokinetic variability, drug-drug interactions, overdose, and use for off-label indications in which the hERG safety parameters may differ from their on-label counterparts.

scholarly journals Three dimensional and microphysiological bone marrow models detect in vivo positive compounds

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rhiannon David ◽  
Sarah Gee ◽  
Kainat Khan ◽  
Amy Wilson ◽  
Ann Doherty
Keyword(s):  
Bone Marrow ◽  
Safety Assessment ◽  
Animal Studies ◽  
Three Dimensional ◽  
Pharmacological Effects ◽  
Polymerase Inhibitor ◽  
Genotoxicity Testing

AbstractMicronucleus (MN) assessment is a valuable tool in safety assessment. However, several compounds are positive in the in vivo bone marrow (BM) MN assay but negative in vitro, reflecting that BM complexity is not recapitulated in vitro. Importantly, these compounds are not genotoxic; rather, drug-driven pharmacological-effects on the BM increase MN, however, without mechanistic understanding, in vivo positives stop drug-progression. Thus, physiologically-relevant BM models are required to bridge the gap between in vitro and in vivo. The current study aimed to investigate the utility of two human 3D BM models (fluidic and static) for MN assessment. MN induction following treatment with etoposide and Poly-ADP Ribose Polymerase inhibitor (PARPi) and prednisolone (negative in vitro, positive in vivo) was determined in 2D L5178Y and human BM cells, and the 3D BM models. Etoposide (0–0.070 µM) and PARPi (0–150 µM) induced MN in both 3D BM models indicating their utility for genotoxicity testing. Interestingly, PARPi treatment induced a MN trend in 3D more comparable to in vivo. Importantly, prednisolone (0–1.7 mM) induced MN in both 3D BM models, suggesting recapitulation of the in vivo microenvironment. These models could provide a valuable tool to follow up, and eventually predict, suspected pharmacological mechanisms, thereby reducing animal studies.

scholarly journals Implementation of quality and risk management strategies in wound care trials

2016 ◽  
Vol 3 (3) ◽  
pp. 89
Author(s):  
Brianna M. Krafcik ◽  
Marina Malikova
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Risk Mitigation ◽  
Wound Care ◽  
Management Strategies ◽  
Mitigation Strategies ◽  
Internal Quality ◽  
Serious Adverse Events ◽  
Systematic Analysis ◽  
Over Time

<p class="abstract"><strong>Background:</strong> Systematic analysis of risk factors in multiple wound care clinical trials was performed to develop proactive risk mitigation strategies and improve the quality of trials conducted.</p><p class="abstract"><strong>Methods:</strong> This internal, single center internal quality control (QC) audit of eight recently completed prospective, randomized wound care clinical trials assessed the rate of serious adverse events (SAEs) and compared two wound indications: diabetic foot ulcers (DFU) and venous leg ulcers (VLU).  Additionally, adherence to study protocol and compliance with current regulatory requirements was examined based on the rate of protocol deviations over time.</p><p class="abstract"><strong>Results:</strong> A comparison of SAE occurrences between DFU and VLU studies showed twice as many SAEs per subject in the DFU studies as compared to the VLU studies. The most common categories were infections, both of the wound and of other anatomic locations. The onboarding of new study coordinators and multiple coordinators working independently on one trial over time consistently showed an increase in the number of deviations per active subject, particularly immediately following the date of hire. The most common categories for deviations were out-of-window visits and missed study procedures.  </p><p><strong>Conclusions:</strong> Assessment of potential issues in prospective wound care studies can lead to earlier mitigation of risks, quality improvement in data obtained and increased efficiency of studies conducted in this field. Effective training and retention of research coordinators can reduce the number of deviations, and an understanding of the frequency and types of adverse events can provide an expectation for those conducting trials in a particular indication.</p>

In vitro and in vivo polysaccharides assembly: ultrastructural and cytochemical study of growing plant cell wall components.

1978 ◽  
Vol 36 (2) ◽  
pp. 434-435
Author(s):  
D. Reis ◽  
B. Vian ◽  
J. C. Roland
Keyword(s):  
Cell Wall ◽  
Self Assembly ◽  
Plant Cell Wall ◽  
Higher Plants ◽  
Three Dimensional ◽  
Cytochemical Study ◽  
Wall Components

Wall morphogenesis in higher plants is a problem still open to controversy. Until now the possibility of a transmembrane control and the involvement of microtubules were mostly envisaged. Self-assembly processes have been observed in the case of walls of Chlamydomonas and bacteria. Spontaneous gelling interactions between xanthan and galactomannan from Ceratonia have been analyzed very recently. The present work provides indications that some processes of spontaneous aggregation could occur in higher plants during the formation and expansion of cell wall.Observations were performed on hypocotyl of mung bean (Phaseolus aureus) for which growth characteristics and wall composition have been previously defined.In situ, the walls of actively growing cells (primary walls) show an ordered three-dimensional organization (fig. 1). The wall is typically polylamellate with multifibrillar layers alternately transverse and longitudinal. Between these layers intermediate strata exist in which the orientation of microfibrils progressively rotates. Thus a progressive change in the morphogenetic activity occurs.

Three-Dimensional Subcellular Organization of Hepatocytes in Intact Liver: Simultaneous Visualization of Cytoskeletal and Membrane Markers by Confocal Microscopy

1996 ◽  
Vol 54 ◽  
pp. 288-289
Author(s):  
Greg V. Martin ◽  
Ann L. Hubbard
Keyword(s):  
Three Dimensional ◽  
Integral Membrane Proteins ◽  
Polarized Secretion ◽  
Microscope Images ◽  
Computer Aided ◽  
Intracellular Organelles ◽  
Cytoskeletal Elements ◽  
Simultaneous Visualization

The microtubule (MT) cytoskeleton is necessary for many of the polarized functions of hepatocytes. Among the functions dependent on the MT-based cytoskeleton are polarized secretion of proteins, delivery of endocytosed material to lysosomes, and transcytosis of integral plasma membrane (PM) proteins. Although microtubules have been shown to be crucial to the establishment and maintenance of functional and structural polarization in the hepatocyte, little is known about the architecture of the hepatocyte MT cytoskeleton in vivo, particularly with regard to its relationship to PM domains and membranous organelles. Using an in situ extraction technique that preserves both microtubules and cellular membranes, we have developed a protocol for immunofluorescent co-localization of cytoskeletal elements and integral membrane proteins within 20 µm cryosections of fixed rat liver. Computer-aided 3D reconstruction of multi-spectral confocal microscope images was used to visualize the spatial relationships among the MT cytoskeleton, PM domains and intracellular organelles.

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