Use of in vitro/in silico cascades for screening potential safety issues in industry

2011 ◽  
Vol 205 ◽  
pp. S28
Author(s):  
M. Steemans
Keyword(s):  
In Silico ◽  
Safety Issues ◽  
Potential Safety

scholarly journals In Vitro Evaluation of Viability, Integrity, and Inflammation in Genital Epithelia upon Exposure to Pharmaceutical Excipients and Candidate Microbicides

2010 ◽  
Vol 54 (12) ◽  
pp. 5105-5114 ◽  
Author(s):  
Youssef Gali ◽  
Olivier Delezay ◽  
Joachim Brouwers ◽  
Noura Addad ◽  
Patrick Augustijns ◽  
...  
Keyword(s):  
Virus Transmission ◽  
Pharmaceutical Excipients ◽  
Safety Issues ◽  
Pharmaceutical Ingredients ◽  
Vaginal Microbicide ◽  
Potential Safety ◽  
Chamber Model ◽  
Sensitive Marker

ABSTRACT The use of microbicides is a promising approach for the prevention of HIV-1 transmission. Unfortunately, various candidates failed in clinical trials. In some cases, the candidate microbicide even resulted in enhanced virus transmission. Therefore, there is an urgent need to develop more predictive preclinical strategies to anticipate the in vivo efficiency/toxicity rate, including in vitro assays that evaluate effects on epithelial integrity and inflammation. The present study aims to identify potential safety issues concerning the use of microbicides and excipients commonly used in vaginal microbicide preparations. The toxicities of various active pharmaceutical ingredients (APIs; TMC-120, UC-781, tenofovir [PMPA], PRO-2000, and glycerol monolaurate [GML]) and excipients (preservatives, cosolvents, surfactants, and cyclodextrins) were evaluated using an in vitro dual-chamber model and uterine cervical explants. Epithelial viability and permeation of fluorescent virus-sized beads, as well as induction of interleukin-8 (IL-8; as a sensitive marker of an inflammatory response), were assessed. Surprisingly, cell viability and epithelial layer integrity were compromised by most excipients at concentrations near the typical concentration used in vaginal gels, and a significant increase in the production of IL-8 was observed at subtoxic concentrations. Within the APIs, TMC-120, UC-781, and PMPA showed higher selectivity indices than PRO-2000 and GML. In conclusion, identification of safety issues concerning the use of pharmaceutical excipients could help to formulate less toxic vaginal microbicide preparations.

scholarly journals Human Tissue in the Evaluation of Safety and Efficacy of New Medicines: A Viable Alternative to Animal Models?

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Robert A. Coleman
Keyword(s):  
In Silico ◽  
High Sensitivity ◽  
Test Methods ◽  
Biological Data ◽  
Human Cells ◽  
New Drugs ◽  
Safety And Efficacy ◽  
Potential Safety

The pharma Industry's ability to develop safe and effective new drugs to market is in serious decline. Arguably, a major contributor to this is the Industry's extensive reliance on nonhuman biology-based test methods to determine potential safety and efficacy, objective analysis of which reveals poor predictive value. An obvious alternative approach is to use human-based tests, but only if they are available, practical, and effective. While in vivo (phase 0 microdosing with high sensitivity mass spectroscopy) and in silico (using established human biological data), technologies are increasingly being used, in vitro human approaches are more rarely employed. However, not only are increasingly sophisticated in vitro test methods now available or under development, but the basic ethically approved infrastructure through which human cells and tissues may be acquired is established. Along with clinical microdosing and in silico approaches, more effective access to and use of human cells and tissues in vitro provide exciting and potentially more effective opportunities for the assessment of safety and efficacy of new medicines.

scholarly journals Do Nonsteroidal Anti-Inflammatory Drugs Affect Bone Healing? A Critical Analysis

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Ippokratis Pountos ◽  
Theodora Georgouli ◽  
Giorgio M. Calori ◽  
Peter V. Giannoudis
Keyword(s):  
Bone Healing ◽  
Bone Cells ◽  
Scientific Evidence ◽  
Science Research ◽  
Safety Issues ◽  
Potential Safety ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Control Pain

Nonsteroidal anti-inflammatory drugs (NSAIDs) play an essential part in our approach to control pain in the posttraumatic setting. Over the last decades, several studies suggested that NSAIDs interfere with bone healing while others contradict these findings. Although their analgesic potency is well proven, clinicians remain puzzled over the potential safety issues. We have systematically reviewed the available literature, analyzing and presenting the availablein vitroanimal and clinical studies on this field. Our comprehensive review reveals the great diversity of the presented data in all groups of studies. Animal andin vitrostudies present so conflicting data that even studies with identical parameters have opposing results. Basic science research defining the exact mechanism with which NSAIDs could interfere with bone cells and also the conduction of well-randomized prospective clinical trials are warranted. In the absence of robust clinical or scientific evidence, clinicians should treat NSAIDs as a risk factor for bone healing impairment, and their administration should be avoided in high-risk patients.

Applications of genome editing tools in stem cells towards regenerative medicine: An update

2021 ◽  
Vol 16 ◽  
Author(s):  
Wilfried A Kues ◽  
Dharmendra Kumar ◽  
Naresh L Selokar ◽  
Thirumala Rao Talluri
Keyword(s):  
Regenerative Medicine ◽  
Genome Editing ◽  
Genome Engineering ◽  
Zinc Finger Nucleases ◽  
Transcription Activator ◽  
Gene Engineering ◽  
Safety Issues ◽  
Potential Safety ◽  
Traditional Therapies

: Precise and site specific genome editing through application of emerging and modern gene engineering techniques, namely zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) have swiftly progressed the application and use of the stem cell technology in the sphere of in-vitro disease modelling and regenerative medicine. Genome editing tools facilitate the manipulating of any gene in various types of cells with target specific nucleases. These tools aid in elucidating the genetics and etiology behind different diseases and have immense promise as novel therapeutics for correcting the genetic mutations, make alterations and cure diseases permanently that are not responding and resistant to traditional therapies. These genome engineering tools have evolved in the field of biomedical research and have also shown to have a significant improvement in clinical trials. However, their widespread use in research revealed potential safety issues, which need to be addressed before implementing such techniques in clinical purposes. Significant and valiant attempts are being made in order to surpass those hurdles. The current review outlines the advancements of several genome engineering tools and describes suitable strategies for their application towards regenerative medicine.

IN VITRO/IN SILICO CHARACTERIZATION OF ACTIVE AND PASSIVE STRESSES IN CARDIAC MUSCLE

2012 ◽  
Vol 10 (2) ◽  
pp. 171-188 ◽  
Author(s):  
Markus Boel ◽  
Oscar J. Abilez ◽  
Ahmed N Assar ◽  
Christopher K. Zarins ◽  
Ellen Kuhl
Keyword(s):  
Cardiac Muscle ◽  
In Silico ◽  
In Silico Characterization

Role of 4-O Galloylchlorogenic Acid in Lung Cancer- An Insilico Approach

2017 ◽  
Vol 9 (5) ◽  
Author(s):  
Jaynthy C. ◽  
N. Premjanu ◽  
Abhinav Srivastava
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
In Silico ◽  
Computational Study ◽  
Regulation Mechanism ◽  
Down Regulation ◽  
Fruit Extract ◽  
In Vitro Techniques ◽  
Discovery Studio

Cancer is a major disease with millions of patients diagnosed each year with high mortality around the world. Various studies are still going on to study the further mechanisms and pathways of the cancer cell proliferation. Fucosylation is one of the most important oligosaccharide modifications involved in cancer and inflammation. In cancer development increased core fucosylation by FUT8 play an important role in cell proliferation. Down regulation of FUT8 expression may help cure lung cancer. Therefore the computational study based on the down regulation mechanism of FUT8 was mechanised. Sapota fruit extract, containing 4-Ogalloylchlorogenic acid was used as the inhibitor against FUT-8 as target and docking was performed using in-silico tool, Accelrys Discovery Studio. There were several conformations of the docked result, and conformation 1 showed 80% dock score between the ligand and the target. Further the amino acids of the inhibitor involved in docking were studied using another tool, Ligplot. Thus, in-silico analysis based on drug designing parameters shows that the fruit extract can be studied further using in-vitro techniques to know its pharmacokinetics.

Discovery of New AKT1 Inhibitors by Combination of In silico Structure Based Virtual Screening Approaches and Biological Evaluations

2019 ◽  
Author(s):  
Filip Fratev ◽  
Denisse A. Gutierrez ◽  
Renato J. Aguilera ◽  
suman sirimulla
Keyword(s):  
Virtual Screening ◽  
Success Rate ◽  
Protein Interactions ◽  
In Silico ◽  
Biological Data ◽  
In Vitro Binding ◽  
Vitro Binding ◽  
Screening Protocol ◽  
Screening Approaches

AKT1 is emerging as a useful target for treating cancer. Herein, we discovered a new set of ligands that inhibit the AKT1, as shown by in vitro binding and cell line studies, using a newly designed virtual screening protocol that combines structure-based pharmacophore and docking screens. Taking together with the biological data, the combination of structure based pharamcophore and docking methods demonstrated reasonable success rate in identifying new inhibitors (60-70%) proving the success of aforementioned approach. A detail analysis of the ligand-protein interactions was performed explaining observed activities.<br>

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