scholarly journals Critical Considerations for the Design of Multi-Organ Microphysiological Systems (MPS)

2021 ◽  
Vol 9 ◽  
Author(s):  
Mridu Malik ◽  
Yang Yang ◽  
Parinaz Fathi ◽  
Gretchen J. Mahler ◽  
Mandy B. Esch
Keyword(s):  
Animal Models ◽  
Drug Toxicity ◽  
New Drugs ◽  
Drug Candidate ◽  
Preclinical Studies ◽  
Toxicity Screening ◽  
Drug Candidates ◽  
Microphysiological Systems

Identification and approval of new drugs for use in patients requires extensive preclinical studies and clinical trials. Preclinical studies rely on in vitro experiments and animal models of human diseases. The transferability of drug toxicity and efficacy estimates to humans from animal models is being called into question. Subsequent clinical studies often reveal lower than expected efficacy and higher drug toxicity in humans than that seen in animal models. Microphysiological systems (MPS), sometimes called organ or human-on-chip models, present a potential alternative to animal-based models used for drug toxicity screening. This review discusses multi-organ MPS that can be used to model diseases and test the efficacy and safety of drug candidates. The translation of an in vivo environment to an in vitro system requires physiologically relevant organ scaling, vascular dimensions, and appropriate flow rates. Even small changes in those parameters can alter the outcome of experiments conducted with MPS. With many MPS devices being developed, we have outlined some established standards for designing MPS devices and described techniques to validate the devices. A physiologically realistic mimic of the human body can help determine the dose response and toxicity effects of a new drug candidate with higher predictive power.

scholarly journals Impetigo Animal Models: A Review of Their Feasibility and Clinical Utility for Therapeutic Appraisal of Investigational Drug Candidates

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 694
Author(s):  
Solomon Abrha ◽  
Andrew Bartholomaeus ◽  
Wubshet Tesfaye ◽  
Jackson Thomas
Keyword(s):  
Animal Models ◽  
In Vivo Studies ◽  
Therapeutic Drug ◽  
Investigational Drug ◽  
Skin Infections ◽  
Drug Candidates ◽  
First Line Therapy ◽  
Superficial Skin

Impetigo (school sores), a superficial skin infection commonly seen in children, is caused by the gram-positive bacteria Staphylococcus aureus and/or Streptococcus pyogenes. Antibiotic treatments, often topical, are used as the first-line therapy for impetigo. The efficacy of potential new antimicrobial compounds is first tested in in vitro studies and, if effective, followed by in vivo studies using animal models and/or humans. Animal models are critical means for investigating potential therapeutics and characterizing their safety profile prior to human trials. Although several reviews of animal models for skin infections have been published, there is a lack of a comprehensive review of animal models simulating impetigo for the selection of therapeutic drug candidates. This review critically examines the existing animal models for impetigo and their feasibility for testing the in vivo efficacy of topical treatments for impetigo and other superficial bacterial skin infections.

scholarly journals Immune responses to azacytidine in animal models of inflammatory disorders: a systematic review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Sija Landman ◽  
Chiel van der Horst ◽  
Piet E. J. van Erp ◽  
Irma Joosten ◽  
Rob de Vries ◽  
...  
Keyword(s):  
Animal Models ◽  
Risk Of Bias ◽  
New Drugs ◽  
In Vivo Studies ◽  
Common Mechanism ◽  
Solid Organ ◽  
Inflammatory Disorders ◽  
Organ Rejection

AbstractInflammatory disorders like diabetes, systemic lupus erythematodes, inflammatory lung diseases, rheumatoid arthritis and multiple sclerosis, but also rejection of transplanted organs and GvHD, form a major burden of disease. Current classes of immune suppressive drugs to treat these disorders are never curative and side effects are common. Therefore there is a need for new drugs with improved and more targeted modes of action. Potential candidates are the DNA methyl transferase inhibitor 5-azacytidine (Aza) and its derivative 5-aza 2′deoxycitidine (DAC). Aza and DAC have been tested in several pre-clinical in vivo studies. In order to obtain an overview of disorders for which Aza and/or DAC can be a potential treatment, and to find out where information is lacking, we systematically reviewed pre-clinical animal studies assessing Aza or DAC as a potential therapy for distinct inflammatory disorders. Also, study quality and risk of bias was systematically assessed. In the 35 identified studies, we show that both Aza and DAC do not only seem to be able to alleviate a number of inflammatory disorders, but also prevent solid organ rejection and GvHD in in vivo pre-clinical animal models. Aza/DAC are known to upregulate FOXP3, a master transcription factor for Treg, in vitro. Seventeen studies described the effect on Treg, of which 16 studies showed an increase in Treg. Increasing Treg therefore seems to be a common mechanism in preventing inflammatory disorders by Aza/DAC. We also found, however, that many essential methodological details were poorly reported leading to an unclear risk of bias. Therefore, reported effects might be an overestimation of the true effect.

scholarly journals A broadly neutralizing biparatopic Nanobody protects mice from lethal challenge with SARS-CoV-2 variants of concern

2021 ◽  
Author(s):  
Teresa R. Wagner ◽  
Daniel Schnepf ◽  
Julius Beer ◽  
Karin Klingel ◽  
Natalia Ruetalo ◽  
...  
Keyword(s):  
Lethal Dose ◽  
Survival Rates ◽  
Drug Candidate ◽  
Lethal Challenge ◽  
Drug Candidates ◽  
High Affinity ◽  
Neutralizing Capacity ◽  
Future Drug

The ongoing COVID-19 pandemic and the frequent emergence of new SARS-CoV-2 variants of concern (VOCs), requires continued development of fast and effective therapeutics. Recently, we identified high-affinity neutralizing nanobodies (Nb) specific for the receptor-binding domain (RBD) of SARS-CoV-2, which are now being used as biparatopic Nbs (bipNbs) to investigate their potential as future drug candidates. Following detailed in vitro characterization, we chose NM1267 as the most promising candidate showing high affinity binding to several recently described SARS-CoV-2 VOCs and strong neutralizing capacity against a patient isolate of B.1.351 (Beta). To assess if bipNb NM1267 confers protection against SARS-CoV-2 infection in vivo, human ACE2 transgenic mice were treated by intranasal route before infection with a lethal dose of SARS-CoV-2. NM1267-treated mice showed significantly reduced disease progression, increased survival rates and secreted less infectious virus via their nostrils. Histopathological analyses and in situ hybridization further revealed a drastically reduced viral load and inflammatory response in lungs of NM1267-treated mice. These data suggest, that bipNb NM1267 is a broadly active and easily applicable drug candidate against a variety of emerging SARS-CoV-2 VOCs.

scholarly journals Finding melanoma drugs through a probabilistic knowledge graph

2016 ◽  
Author(s):  
James P McCusker ◽  
Michel Dumontier ◽  
Rui Yan ◽  
Sylvia He ◽  
Jonathan S Dordick ◽  
...  
Keyword(s):  
Systems Biology ◽  
Probabilistic Methods ◽  
Drug Candidate ◽  
Knowledge Graph ◽  
Web Interface ◽  
Drug Candidates ◽  
Probabilistic Knowledge ◽  
Data Explosion

Metastatic cutaneous melanoma is an aggressive skin cancer with some progression-slowing treatments but no known cure. The omics data explosion has created many possible drug candidates, however filtering criteria remain challenging, and systems biology approaches have become fragmented with many disconnected databases. Using drug, protein, and disease interactions, we built an evidence-weighted knowledge graph of integrated interactions. Our knowledge graph-based system, ReDrugS, can be used via an API or web interface, and has generated 25 high quality melanoma drug candidates. We show that probabilistic analysis of systems biology graphs increases drug candidate quality compared to non-probabilistic methods. Four of the 25 candidates are novel therapies, three of which have been tested with other cancers. All other candidates have current or completed clinical trials, or have been studied in in vivo or in vitro. This approach can be used to identify candidate therapies for use in research or personalized medicine.

Environmental Toxicology Assays Using Organ-on-Chip

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Patarajarin Akarapipad ◽  
Kattika Kaarj ◽  
Yan Liang ◽  
Jeong-Yeol Yoon
Keyword(s):  
Drug Toxicity ◽  
Environmental Toxicology ◽  
In Vitro Assays ◽  
Annual Review ◽  
Publication Date ◽  
Environmental Toxicants ◽  
Toxicity Screening ◽  
On Chip

Adverse effects of environmental toxicants to human health have traditionally been assayed using in vitro assays. Organ-on-chip (OOC) is a new platform that can bridge the gaps between in vitro assays (or 3D cell culture) and animal tests. Microenvironments, physical and biochemical stimuli, and adequate sensing and biosensing systems can be integrated into OOC devices to better recapitulate the in vivo tissue and organ behavior and metabolism. While OOCs have extensively been studied for drug toxicity screening, their implementation in environmental toxicology assays is minimal and has limitations. In this review, recent attempts of environmental toxicology assays using OOCs, including multiple-organs-on-chip, are summarized and compared with OOC-based drug toxicity screening. Requirements for further improvements are identified and potential solutions are suggested. Expected final online publication date for the Annual Review of Analytical Chemistry, Volume 14 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Activity of benzothiazoles and chemical derivatives onPlasmodium falciparum

Parasitology ◽  
2004 ◽  
Vol 129 (5) ◽  
pp. 525-542 ◽  
Author(s):  
S. HOUT ◽  
N. AZAS ◽  
A. DARQUE ◽  
M. ROBIN ◽  
C. DI GIORGIO ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
New Drugs ◽  
Health Concern ◽  
Biological Research ◽  
Monocytic Cells ◽  
Drug Candidates ◽  
Chemical Derivatives ◽  
Anthranilic Acids

Malaria is a major health concern particularly in Africa which has about 90% of the worldwide annual clinical cases. The increasing number of drug-resistantPlasmodium falciparumjustifies the search for new drugs in this field. Antimalarial activity of 2-substituted 6-nitro- and 6-amino-benzothiazoles and their anthranilic acids has been tested. Anin vitrostudy has been performed on W2 and 3D7 strains ofP. falciparumand on clinical isolates from malaria-infected patients. Toxicity has been assessed on THP1 human monocytic cells. For the most active drug candidates, thein vitrostudy was followed byin vivoassaysonP. berghei-infected mice and byin vitroassays in order to determine the stage-dependency and the mechanism of action. Of 39 derivatives testedin vitro, 2 had specific antimalarial properties. Each compound was active on all stages of the parasite, but one was markedly active on mature schizonts, while the other was more active on young schizont forms. Both drugs were also active on mitochondrial membrane potential.In vivodata confirmed efficiency with a sustained decrease of parasitaemia. Products A12 and C7 may be considered as potential antimalarial worthy of further chemical and biological research.

scholarly journals A Ruthenium(II) Complex Containing a Redox-Active Semiquinonate Ligand as Potential Chemotherapeutic Agent: From Synthesis to In Vivo Studies

2019 ◽  
Author(s):  
Anna Notaro ◽  
Angelo Frei ◽  
Riccardo Rubbiani ◽  
Marta Jakubaszek ◽  
Uttara Basu ◽  
...  
Keyword(s):  
Chemotherapeutic Agent ◽  
Biological Properties ◽  
In Vivo Studies ◽  
Drug Candidate ◽  
Paramagnetic Resonance ◽  
In Vivo Models ◽  
Drug Candidates ◽  
X Ray Crystallography

Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a surge for new chemotherapeutic drugs. More specifically, the discovery of new drug candidates able to overcome severe side effects, the occurrence of resistance and the inefficacy toward metastatic tumours is highly desirable. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely [Ru(DIP)2(sq)]PF6 (Ru-sq) (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated to the catecholate moiety. Several pieces of experimental evidence (e.g., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrate that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of Ru-sq was then scrutinised in vitro and in vivo, and the results highlight the tremendous potential of this complex as a chemotherapeutic agent against cancer. Ru-sq was notably found have a much higher cytotoxic activity than cisplatin on several cell lines (i.e. in the nanomolar range), and, contrary to cisplatin, to have mitochondrial disfunction as one of its modes of action. The multicellular targets of Ru-sq could potentially be the key to overcome one of the main drawbacks of cisplatin i.e. the occurrence of resistance. Moreover, Ru-sq exhibited impressing activity on Multi Cellular Tumour Spheroids (MCTS) model, leading to a growth inhibition of the tumour even 13 days after treatment (20 μM). Very importantly, using two different in vivo models, it could be demonstrated that this compound is extremely well-tolerated by mice and has a very promising activity, curing, in some cases, tumour-bearing mice.<br>

scholarly journals In Vitro and In Vivo Trypanocidal Effects of the Cyclopalladated Compound 7a, a Drug Candidate for Treatment of Chagas' Disease

2010 ◽  
Vol 54 (8) ◽  
pp. 3318-3325 ◽  
Author(s):  
Alisson L. Matsuo ◽  
Luis S. Silva ◽  
Ana C. Torrecilhas ◽  
Bruno S. Pascoalino ◽  
Thiago C. Ramos ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Chagas Disease ◽  
Cell Invasion ◽  
Mammalian Cells ◽  
New Drugs ◽  
Drug Candidate ◽  
Acute Form ◽  
Intracellular Amastigote

ABSTRACT Chagas' disease, a neglected tropical infection, affects about 18 million people, and 100 million are at risk. The only drug available, benznidazole, is effective in the acute form and in the early chronic form, but its efficacy and tolerance are inversely related to the age of the patients. Side effects are frequent in elderly patients. The search for new drugs is thus warranted. In the present study we evaluated the in vitro and in vivo effect of a cyclopalladated compound (7a) against Trypanosoma cruzi, the agent of Chagas' disease. The 7a compound inhibits trypomastigote cell invasion, decreases intracellular amastigote proliferation, and is very effective as a trypanocidal drug in vivo, even at very low dosages. It was 340-fold more cytotoxic to parasites than to mammalian cells and was more effective than benznidazole in all in vitro and in vivo experiments. The 7a cyclopalladate complex exerts an apoptosis-like death in T. cruzi trypomastigote forms and causes mitochondrion disruption seen by electron microscopy.

scholarly journals Sex Specific Determinants in Osteoarthritis: A Systematic Review of Preclinical Studies

2020 ◽  
Vol 21 (10) ◽  
pp. 3696 ◽  
Author(s):  
Deyanira Contartese ◽  
Matilde Tschon ◽  
Monica De Mattei ◽  
Milena Fini
Keyword(s):  
Gene Expression ◽  
Systematic Review ◽  
Sex Differences ◽  
Animal Models ◽  
Molecular Mechanisms ◽  
Joint Disease ◽  
In Vivo Studies ◽  
Preclinical Studies

Osteoarthritis (OA) is a highly prevalent joint disease that primarily affects about 10% of the world’s population over 60 years old. The purpose of this study is to systematically review the preclinical studies regarding sex differences in OA, with particular attention to the molecular aspect and gene expression, but also to the histopathological aspects. Three databases (PubMed, Scopus, and Web of Knowledge) were screened for eligible studies. In vitro and in vivo papers written in English, published in the last 11 years (2009–2020) were eligible. Participants were preclinical studies, including cell cultures and animal models of OA, evaluating sex differences. Independent extraction of articles and quality assessments were performed by two authors using predefined data fields and specific tools (Animals in Research Reporting In Vivo Experiments (ARRIVE) guideline and Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool). Twenty-three studies were included in the review: 4 in vitro studies, 18 in vivo studies, and 1 both in vitro and in vivo study. From in vitro works, sex differences were found in the gene expression of inflammatory molecules, hormonal receptors, and in responsiveness to hormonal stimulation. In vivo research showed a great heterogeneity of animal models mainly focused on the histopathological aspects rather than on the analysis of sex-related molecular mechanisms. This review highlights that many gaps in knowledge still exist; improvementsin the selection and reporting of animal models, the use of advanced in vitro models, and multiomics analyses might contribute to developing a personalized gender-based medicine.

Brain-on-a-chip Devices for Drug Screening and Disease Modeling Applications

2019 ◽  
Vol 24 (45) ◽  
pp. 5419-5436 ◽  
Author(s):  
Beatrice Miccoli ◽  
Dries Braeken ◽  
Yi-Chen Ethan Li
Keyword(s):  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Drug Screening ◽  
Disease Modeling ◽  
New Drugs ◽  
Screening Process ◽  
Pharmacological Screening ◽  
The Brain

:Neurodegenerative disorders are related to the progressive functional loss of the brain, often connected to emotional and physical disability and, ultimately, to death. These disorders, strongly connected to the aging process, are becoming increasingly more relevant due to the increase of life expectancy. Current pharmaceutical treatments poorly tackle these diseases, mainly acting only on their symptomology. One of the main reasons of this is the current drug development process, which is not only expensive and time-consuming but, also, still strongly relies on animal models at the preclinical stage.:Organ-on-a-chip platforms have the potential to strongly impact and improve the drug screening process by recreating in vitro the functionality of human organs. Patient-derived neurons from different regions of the brain can be directly grown and differentiated on a brain-on-a-chip device where the disease development, progression and pharmacological treatments can be studied and monitored in real time. The model reliability is strongly improved by using human-derived cells, more relevant than animal models for pharmacological screening and disease monitoring. The selected cells will be then capable of proliferating and organizing themselves in the in vivo environment thanks to the device architecture, materials selection and bio-chemical functionalization.:In this review, we start by presenting the fundamental strategies adopted for brain-on-a-chip devices fabrication including e.g., photolithography, micromachining and 3D printing technology. Then, we discuss the state-of-theart of brain-on-a-chip platforms including their role in the study of the functional architecture of the brain e.g., blood-brain barrier, or of the most diffuse neurodegenerative diseases like Alzheimer’s and Parkinson’s. At last, the current limitations and future perspectives of this approach for the development of new drugs and neurodegenerative diseases modeling will be discussed.

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