scholarly journals Microphysiological systems in early stage drug development: Perspectives on current applications and future impact

2021 ◽  
Vol 46 (3) ◽  
pp. 99-114
Author(s):  
Anna K. Kopec ◽  
Ryuji Yokokawa ◽  
Nasir Khan ◽  
Ikuo Horii ◽  
James E. Finley ◽  
...  
Keyword(s):  
Drug Development ◽  
Early Stage ◽  
Microphysiological Systems

scholarly journals A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open-Access Malaria Box

2018 ◽  
Vol 62 (4) ◽  
pp. e01505-17 ◽  
Author(s):  
R. S. Jumani ◽  
K. Bessoff ◽  
M. S. Love ◽  
P. Miller ◽  
E. E. Stebbins ◽  
...  
Keyword(s):  
Mouse Model ◽  
Drug Development ◽  
Early Stage ◽  
New Drugs ◽  
Cryptosporidium Hominis ◽  
Content Type ◽  
Knockout Mouse Model ◽  
Malaria Box

ABSTRACTCryptosporidiosis causes life-threatening diarrhea in children under the age of 5 years and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to the need for new drugs, better knowledge of drug properties that drivein vivoefficacy is needed to facilitate drug development. We report the identification of a piperazine-based lead compound forCryptosporidiumdrug development, MMV665917, and a new pharmacodynamic method used for its characterization. The identification of MMV665917 from the Medicines for Malaria Venture Malaria Box was followed by dose-response studies,in vitrotoxicity studies, and structure-activity relationship studies using commercial analogues. The potency of this compound againstCryptosporidium parvumIowa and field isolates was comparable to that againstCryptosporidium hominis. Furthermore, unlike nitazoxanide, clofazimine, and paromomycin, MMV665917 appeared to be curative in a NOD SCID gamma mouse model of chronic cryptosporidiosis. MMV665917 was also efficacious in a gamma interferon knockout mouse model of acute cryptosporidiosis. To determine if efficacy in this mouse model of chronic infection might relate to whether compounds are parasiticidal or parasitistatic forC. parvum, we developed a novelin vitroparasite persistence assay. This assay suggested that MMV665917 was parasiticidal, unlike nitazoxanide, clofazimine, and paromomycin. The assay also enabled determination of the concentration of the compound required to maximize the rate of parasite elimination. This time-kill assay can be used to prioritize early-stageCryptosporidiumdrug leads and may aid in planningin vivoefficacy experiments. Collectively, these results identify MMV665917 as a promising lead and establish a new method for characterizing potential anticryptosporidial agents.

scholarly journals Using Ex Vivo Porcine Jejunum to Identify Membrane Transporter Substrates: A Screening Tool for Early—Stage Drug Development

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 340
Author(s):  
Yvonne E. Arnold ◽  
Yogeshvar N. Kalia
Keyword(s):  
Drug Development ◽  
Ex Vivo ◽  
Early Stage ◽  
Ussing Chamber ◽  
Organic Anion ◽  
Membrane Transporters ◽  
Peptide Transporter ◽  
Multi Drug Resistance ◽  
Cancer Resistance ◽  
Chamber System

Robust, predictive ex vivo/in vitro models to study intestinal drug absorption by passive and active transport mechanisms are scarce. Membrane transporters can significantly impact drug uptake and transporter-mediated drug–drug interactions can play a pivotal role in determining the drug safety profile. Here, the presence and activity of seven clinically relevant apical/basolateral drug transporters found in human jejunum were tested using ex vivo porcine intestine in a Ussing chamber system. Experiments using known substrates of peptide transporter 1 (PEPT1), organic anion transporting polypeptide (OATP2B1), organic cation transporter 1 (OCT1), P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multi drug resistance-associated protein 2 and 3 (MRP2 and MRP3), in the absence and presence of potent inhibitors, showed that there was a statistically significant change in apparent intestinal permeability Papp,pig (cm/s) in the presence of the corresponding inhibitor. For MRP2, a transporter reportedly present at relatively low concentration, although Papp,pig did not significantly change in the presence of the inhibitor, substrate deposition (QDEP) in the intestinal tissue was significantly increased. The activity of the seven transport proteins was successfully demonstrated and the results provided insight into their apical/basolateral localization. In conclusion, the results suggest that studies using the porcine intestine/Ussing chamber system, which could easily be integrated into the drug development process, might enable the early-stage identification of new molecular entities that are substrates of membrane transporters.

Cell-based fluorescence assay for evaluation of new-drugs potential for phospholipidosis in an early stage of drug development

2007 ◽  
Vol 58 (6) ◽  
pp. 375-382 ◽  
Author(s):  
Hisako Fujimura ◽  
Eriha Dekura ◽  
Michie Kurabe ◽  
Noriko Shimazu ◽  
Mieko Koitabashi ◽  
...  
Keyword(s):  
Drug Development ◽  
Early Stage ◽  
Fluorescence Assay ◽  
New Drugs

scholarly journals Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling

2015 ◽  
Vol 7 (4) ◽  
pp. 383-391 ◽  
Author(s):  
Hasan Erbil Abaci ◽  
Michael L. Shuler
Keyword(s):  
Drug Development ◽  
Development Studies ◽  
Human Tissues ◽  
Design Strategies ◽  
Physiologically Based Pharmacokinetics ◽  
Microfluidic Platforms ◽  
Chip Design ◽  
Microphysiological Systems ◽  
Physiologically Based

Advances in maintaining multiple human tissues on microfluidic platforms has led to a growing interest in the development of microphysiological systems for drug development studies.

scholarly journals Microphysiological Systems: Stakeholder Challenges to Adoption in Drug Development

2021 ◽  
pp. 1-13
Author(s):  
Passley Hargrove-Grimes ◽  
Lucie A. Low ◽  
Danilo A. Tagle
Keyword(s):  
Human Physiology ◽  
Pharmaceutical Industry ◽  
Drug Development ◽  
End Users ◽  
Regulatory Agencies ◽  
Functional Level ◽  
Multiple Stakeholder ◽  
Widespread Adoption ◽  
Microphysiological Systems

Microphysiological systems (MPS) or tissue chips/organs-on-chips are novel <i>in vitro</i> models that emulate human physiology at the most basic functional level. In this review, we discuss various hurdles to widespread adoption of MPS technology focusing on issues from multiple stakeholder sectors, e.g., academic MPS developers, commercial suppliers of platforms, the pharmaceutical and biotechnology industries, and regulatory organizations. Broad adoption of MPS technology has thus far been limited by a gap in translation between platform developers, end-users, regulatory agencies, and the pharmaceutical industry. In this brief review, we offer a perspective on the existing barriers and how end-users may help surmount these obstacles to achieve broader adoption of MPS technology.

Challenges and opportunities for IBD drug development: from early stage to regulatory approval

Gut ◽  
2020 ◽  
Vol 69 (7) ◽  
pp. 1157-1161 ◽  
Author(s):  
Silvio Danese ◽  
Elmer Schabel ◽  
Mark Andrew Ainsworth ◽  
Laurent Peyrin-Biroulet
Keyword(s):  
Drug Development ◽  
Early Stage ◽  
Regulatory Approval ◽  
Challenges And Opportunities

A Transcellular Assay to Assess the P-gp Inhibition in Early Stage of Drug Development

2013 ◽  
Vol 6 (4) ◽  
pp. 285-291 ◽  
Author(s):  
Jan-Shiang Taur ◽  
Edgar Schuck ◽  
Nancy Wong
Keyword(s):  
Drug Development ◽  
Early Stage

scholarly journals Inflammation as a Risk Factor in Cardiotoxicity: An Important Consideration for Screening During Drug Development

2021 ◽  
Vol 12 ◽  
Author(s):  
Chiara Campana ◽  
Rafael Dariolli ◽  
Mohamed Boutjdir ◽  
Eric A. Sobie
Keyword(s):  
Drug Development ◽  
Cardiac Electrophysiology ◽  
Computational Models ◽  
Disease Modeling ◽  
Early Stage ◽  
Heart Function ◽  
Integrative Approach ◽  
Stage Of Development ◽  
Drug Risk ◽  
Proarrhythmic Risk

Numerous commonly prescribed drugs, including antiarrhythmics, antihistamines, and antibiotics, carry a proarrhythmic risk and may induce dangerous arrhythmias, including the potentially fatal Torsades de Pointes. For this reason, cardiotoxicity testing has become essential in drug development and a required step in the approval of any medication for use in humans. Blockade of the hERG K+ channel and the consequent prolongation of the QT interval on the ECG have been considered the gold standard to predict the arrhythmogenic risk of drugs. In recent years, however, preclinical safety pharmacology has begun to adopt a more integrative approach that incorporates mathematical modeling and considers the effects of drugs on multiple ion channels. Despite these advances, early stage drug screening research only evaluates QT prolongation in experimental and computational models that represent healthy individuals. We suggest here that integrating disease modeling with cardiotoxicity testing can improve drug risk stratification by predicting how disease processes and additional comorbidities may influence the risks posed by specific drugs. In particular, chronic systemic inflammation, a condition associated with many diseases, affects heart function and can exacerbate medications’ cardiotoxic effects. We discuss emerging research implicating the role of inflammation in cardiac electrophysiology, and we offer a perspective on how in silico modeling of inflammation may lead to improved evaluation of the proarrhythmic risk of drugs at their early stage of development.

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