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 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 A novel computational approach for toxicogenomics biomarker discovery in drug development pipeline

2018 ◽  
Vol 25 ◽  
pp. 57-66
Author(s):  
MM Rana ◽  
MN Hasan ◽  
MS Ahmed ◽  
MNH Mollah
Keyword(s):  
Drug Development ◽  
Safety Assessment ◽  
Biomarker Discovery ◽  
Early Stage ◽  
New Drugs ◽  
Glutathione Depletion ◽  
Glutathione Metabolism ◽  
High Dose ◽  
Metabolism Pathway ◽  
Development Pipeline

In the early stage of drug development process, it is urgent to judge the toxicity effect of some common chemical compounds (CCs) that is not yet well investigated. Biomarker genes (BGs) and dose of CCs can help to draw a deduction about a drug for safety assessment. Classical toxicology method uses large number of samples to extract clinical results which is both time consuming and costly. However, conventional molecular methods can perform to identify only BGs and fail to detect source factor influencing these BGs. The aim of this study is to propose a suitable algorithm that can identify more promising and essential toxicity biomarkers related to some common CCs for safety assessment of new drugs. The glutathione is an effective metabolite of detoxification process in liver. Glutathione depletion analysis is one of the major key research areas in drug development pipeline. In this paper, we studied glutathione depletion analysis of some reported CCs (acetaminophen, methapyrilene and nitrofurazone). We develop an algorithm combining ANOVA and principal component analysis (PCA) using visualization technique to find biomarker genes and associated glutathione depleting CCs and their corresponding doses. There are numerous numbers of genes in the glutathione metabolism pathway regulated as differentially expressed (DE) genes due to the toxic effect of these CCs and proposed algorithm identify only five genes (Mgst2, Gclc, G6pd, Gsr and Srm) that are also foremost genes in the glutathione metabolism pathway. Proposed algorithm states that high dose of all the CCs are responsible for glutathione depletion, nevertheless middle dose of acetaminophen and nitrofurazone also cause glutathione depletion. The proposed algorithm has an additional benefit over the conventional method to discover new chemical entities toxicity.J. bio-sci. 25: 57-66, 2017

Predictivity/Translatability of Toxicities Observed in Nonclinical Toxicology Studies to Clinical Safety Outcomes in Drug Development: Case Examples

2019 ◽  
Vol 39 (2) ◽  
pp. 141-150
Author(s):  
Nicola J. Stagg ◽  
Hanan N. Ghantous ◽  
Robert Roth ◽  
Kenneth L. Hastings
Keyword(s):  
Drug Development ◽  
Annual Meeting ◽  
Clinical Studies ◽  
Early Termination ◽  
New Drugs ◽  
Clinical Safety ◽  
Case Examples ◽  
Palm Springs ◽  
Starting Dose ◽  
Good Concordance

Nonclinical toxicology studies are conducted to characterize the potential toxicities and establish a safe starting dose for new drugs in clinical studies, but the question remains as to how predictable/translatable the nonclinical safety findings are to humans. In many cases, there is good concordance between nonclinical species and patients. However, there are cases for which there is a lack of predictivity or translatability that led to early termination of clinical studies due to unanticipated toxicities or early termination of programs before making it to the clinic due to unacceptable nonclinical toxicities assumed to be translatable. A few case examples of safety findings that are translatable versus safety findings that are not translatable and why they are not translateable were presented as a symposium at the 38th Annual Meeting of the American College of Toxicology in Palm Springs, California, and are discussed in this article.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Wei-Jin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Cathepsin L ◽  
Human Cells ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals Lights and Shadows in Immuno-Oncology Drug Development

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 691
Author(s):  
Milana Bergamino Sirvén ◽  
Sonia Pernas ◽  
Maggie C. U. Cheang
Keyword(s):  
Drug Development ◽  
Checkpoint Inhibitors ◽  
Late Phase ◽  
New Drugs ◽  
Successful Outcome ◽  
Different Types ◽  
Cancer Types ◽  
Clinical Trial Designs ◽  
Oncology Drug Development ◽  
Critical Aspects

The rapidly evolving landscape of immuno-oncology (IO) is redefining the treatment of a number of cancer types. IO treatments are becoming increasingly complex, with different types of drugs emerging beyond checkpoint inhibitors. However, many of the new drugs either do not progress from phase I-II clinical trials or even fail in late-phase trials. We have identified at least five areas in the development of promising IO treatments that should be redefined for more efficient designs and accelerated approvals. Here we review those critical aspects of IO drug development that could be optimized for more successful outcome rates in all cancer types. It is important to focus our efforts on the mechanisms of action, types of response and adverse events of these novel agents. The use of appropriate clinical trial designs with robust biomarkers of response and surrogate endpoints will undoubtedly facilitate the development and subsequent approval of these drugs. Further research is also needed to establish biomarker-driven strategies to select which patients may benefit from immunotherapy and identify potential mechanisms of resistance.

scholarly journals Characterization and applications of chimeric mice with humanized livers for preclinical drug development

2020 ◽  
Vol 36 (1) ◽  
Author(s):  
Chise Tateno ◽  
Yuha Kojima
Keyword(s):  
Liver Function ◽  
Drug Development ◽  
Mass Production ◽  
Human Hepatocytes ◽  
In Vitro Studies ◽  
New Drugs ◽  
Pharmaceutical Companies ◽  
Chimeric Mice ◽  
Preclinical Drug Development

AbstractWe have succeeded in stable mass production of chimeric PXB-mice, whose liver is repopulated by human hepatocytes at a ratio of more than 70%, and we are providing these mice to academia and pharmaceutical companies to support the development of new drugs or studies of liver function. Furthermore, we isolated human hepatocytes, called PXB-cells, from the chimeric mice, and provide them for clients weekly for in vitro studies. In this review, we summarize the existing characterizations of PXB-mice and PXB-cells and their present and future applications.

scholarly journals Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1647
Author(s):  
Keishi Kisoh ◽  
Go Sugahara ◽  
Yuko Ogawa ◽  
Suzue Furukawa ◽  
Yuji Ishida ◽  
...  
Keyword(s):  
Drug Development ◽  
Drug Efficacy ◽  
Developed Countries ◽  
Liver Disorder ◽  
New Drugs ◽  
Peroxisome Proliferator ◽  
Chimeric Mice ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Nash Model

Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH.

scholarly journals Comparative Analysis of the QbD Approach in the Pharmaceutical Industry

2019 ◽  
Vol 8 (4) ◽  
pp. 20-26 ◽  
Author(s):  
S. A. Rozhnova ◽  
A. V. Tsypkina
Keyword(s):  
Comparative Analysis ◽  
Drug Development ◽  
Systematic Approach ◽  
New Drugs ◽  
Pharmaceutical Development ◽  
Drug Products ◽  
New Drug ◽  
Eurasian Economic Union ◽  
Pharmaceutical Manufacturers ◽  
Economic Union

Introduction. In the development and introduction of medicines into production, the aim of pharmaceutical manufacturers is to comply with the principle of «Quality-by-Design» (QbD). The International Council for Harmonisation (ICH) has created a number of GxP standards, which have become the regulatory framework for the development of documentation regulating the requirements for the development and production of drug products for countries focused on bringing their products to the world pharmaceutical market. The analysis of the system of regulation of pharmaceutical stages of development of new drugs in the territory of the Eurasian Economic Union was not considered, but for the formation of a systematic approach to the management of the process of pharmaceutical development it is necessary to describe them.Aim. To analyze the possibility of applying the QbD principle to the process of drug development at domestic pharmaceutical enterprises.Materials and methods. Content analysis of scientific publications, system and comparative analysis, sociological methods of research in the field of pharmaceutical development.Results and discussions. Regulatory state requirements to the organization and conduct of drug development procedures are analyzed and described. A number of systemic and sectoral problems typical for domestic pharmaceutical manufacturers in the organization of the development and implementation of new drug products. It is established that one of the main problems for Russian enterprises was the organization of the process as a whole and its individual procedures. To solve the problem of organization of procedures for the development and implementation of new medicines, we formed a methodological support, developed on the basis of a systematic approach and international requirements from the quality system.Conclusion. The main problem identified by the manufacturers is the lack of methodological support for the organization of the processes of pharmaceutical development and the introduction of new drugs in the part of research going to the stage of preclinical and clinical development. The decisions adopted by the Eurasian Economic Union do not affect such aspects of pharmaceutical development regulation as the organization of processes, their management and methodological support aimed at the implementation of the QbD principle. To solve this problem, we have developed guidelines for the implementation of the processes of pharmaceutical development and the introduction of new drug products, which allowed us to apply unified and formalized approaches to their organization. 

scholarly journals Assessing the Clinical Benefit of Systemic Adjuvant Therapies for Early Breast Cancer

2017 ◽  
Vol 77 (10) ◽  
pp. 1079-1087 ◽  
Author(s):  
Volker Möbus ◽  
Susanne Hell ◽  
Marcus Schmidt
Keyword(s):  
Breast Cancer ◽  
Early Breast Cancer ◽  
Clinical Benefit ◽  
Early Stage ◽  
Survival Rates ◽  
Disease Free Survival ◽  
New Drugs ◽  
Early Stage Breast Cancer ◽  
Risk Of Recurrence ◽  
Adjuvant Therapies

AbstractOncologic therapy is currently undergoing significant changes. A number of innovative targeted medications currently in clinical development have raised high expectations. With that in mind, discussions about terms such as “clinical benefit” and “clinical relevance” are highly topical. This also applies to further developments in the field of adjuvant systemic therapies for early-stage breast cancer. As the treatment aim is curative, assessment of the clinical benefit of adjuvant therapies must be largely based on efficacy outcomes. The focus must be on improving disease-free survival rates and lowering the risk of recurrence. Because of the current low mortality rates, statements about overall survival rates are only possible after very long observation periods. Consequently, new drugs in adjuvant therapies should be considered as offering a clinical benefit, if they reduce the risk of recurrence below current low levels of risk. The evidence for established adjuvant therapy standards in early-stage breast cancer can be used as objective criteria for comparison. This review article considers the requirements for clinical benefit of new adjuvant therapies for early breast cancer, based on examples from adjuvant endocrine therapy, adjuvant polychemotherapy and adjuvant anti-HER2 therapy.

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