Metabolite identification in preclinical and clinical phase of drug development

2021 ◽  
Vol 22 ◽  
Author(s):  
Yali Wu ◽  
Lulu Pan ◽  
Zhendong Chen ◽  
Yuandong Zheng ◽  
Xingxing Diao ◽  
...  
Keyword(s):  
Drug Development ◽  
Kinase Inhibitors ◽  
Critical Role ◽  
Metabolite Identification ◽  
Correct Identification ◽  
Drug Candidates ◽  
Clinical Phase ◽  
Natural Medicines ◽  
Insight Into

: Metabolite identification plays a critical role in the phases during drug development. Drug metabolites can contribute to efficacy, toxicity, and drug-drug interaction. Thus, the correct identification of metabolites is essential to understand the behavior of drugs in humans. Drug administration authorities (e.g., FDA, EMA, and NMPA) emphasize evaluating the safety of human metabolites with exposure higher than 10% of the total drug-related components. Many previous reviews have summarized the various methods, tools, and strategies for the appropriate and comprehensive identification of metabolites. In this review, we focus on summarizing the importance of identifying metabolites in the preclinical and clinical phases of drug development. Summarized scenarios include the role of metabolites in pharmacokinetics/pharmacodynamics (PK/PD) analysis, disproportional exposure of metabolites that contribute to drug toxicity, changes in metabolite exposure in renal-impaired patients, covalent tyrosine kinase inhibitors (anticancer drugs), and metabolite identification of drug candidates from natural medicines. This review is aimed to provide meaningful insight into the significant role of metabolite identification in drug development.

Science and Theology for Everyone: How Climate Science is Shaping Christianity in the UK

2021 ◽  
Vol 62 (2) ◽  
pp. 147-157
Author(s):  
Caleb Gordon ◽  
Hannah Malcolm
Keyword(s):  
Critical Role ◽  
Climate Science ◽  
Significant Shift ◽  
Christian Life ◽  
Ethical Problems ◽  
Technical Leadership ◽  
Science And Theology ◽  
The Uk ◽  
Insight Into

This article analyses the growing participation of UK Christians in climate initiatives over the last five years. In many cases, climate science is cited as a necessary consideration for the fulfilment of already-existing Christian commitments. This represents a significant shift in the ways UK Christians understand the role of dialogue between theology and the sciences; previous science and theology dialogue has usually been treated as an area of expert concern, primarily offering insight into apologetics or specific ethical problems. By contrast, the dialogue between climate science and theology has seen the emergence of non-technical leadership amid the expectation that climate science plays a critical role in re-examining the meaning of Christian life, both for individuals and as communities.

scholarly journals ROLE OF EFFECTIVE PROJECT MANAGEMENT IN REDUCING DRUG DEVELOPMENT COST

2017 ◽  
Vol 10 (3) ◽  
pp. 53
Author(s):  
Faisal B A Zaidi ◽  
Salma Ahmed ◽  
Munish Makkad
Keyword(s):  
Project Management ◽  
Drug Development ◽  
Site Selection ◽  
Late Phase ◽  
Critical Role ◽  
Project Manager ◽  
Development Cost ◽  
The Cost ◽  
Patient Enrollment

ABSTRACTPharmaceuticals are passing through the difficult phase due to increasing numbers of patents expiry along with increasing cost of drug development.Protocol design, regulatory cycle time, site selection, patient enrollment and monitoring are some of the cost contributing elements for late phaseclinical trials. This paper applies the principles of project management and suggests means to reduce the cost of late phase drug development. It alsothrows light on the critical role that a project manager can play in overall drug development process.Keywords: Cost of drug development, Effective project management, Reduction in cost of drug development.

scholarly journals Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs

2018 ◽  
Author(s):  
David M. Kern ◽  
SeCheol Oh ◽  
Richard K. Hite ◽  
Stephen G. Brohawn
Keyword(s):  
Lipid Bilayers ◽  
Critical Role ◽  
Anion Channel ◽  
Lipid Binding ◽  
Channel Structure ◽  
Anion Channels ◽  
Cryo Electron Microscopy ◽  
Lipid Nanodiscs ◽  
Insight Into

AbstractHypoosmotic conditions activate volume-regulated anion channels in vertebrate cells. These channels are formed by leucine-rich repeat-containing protein 8 (LRRC8) family members and contain LRRC8A in homo- or hetero-hexameric assemblies. Here we present single-particle cryo-electron microscopy structures of LRRC8A in complex with the inhibitor DCPIB reconstituted in lipid nanodiscs. DCPIB plugs the channel like a cork in a bottle - binding in the extracellular selectivity filter and sterically occluding ion conduction. Constricted and expanded structures reveal coupled dilation of cytoplasmic LRRs and the channel pore, suggesting a mechanism for channel gating by internal stimuli. Conformational and symmetry differences between LRRC8A structures determined in detergent micelles and lipid bilayers related to reorganization of intersubunit lipid binding sites demonstrate a critical role for the membrane in determining channel structure. These results provide insight into LRRC8 gating and inhibition and the role of lipids in the structure of an ionic-strength sensing ion channel.

Depression: An insight into Heterocyclic and Cyclic Hydrocarbon Compounds inspired from Natural Sources

2021 ◽  
Vol 19 ◽  
Author(s):  
Abdul Jalil Shah ◽  
Reyaz Hassan Mir ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Pottoo ◽  
Mubashir Hussain Masoodi ◽  
...  
Keyword(s):  
Gaba Receptors ◽  
Herbal Medicines ◽  
Aminobutyric Acid ◽  
Cyclic Hydrocarbon ◽  
Natural Sources ◽  
Drug Candidates ◽  
Signalling Molecules ◽  
Symptoms Of Depression ◽  
Insight Into

: Depression, a well know mental disorder has global prevalence, nearly affecting 17% of population. Due to various limitations of the currently available drugs, people have been adopting traditional herbal medicines to alleviate the symptoms of depression. It is notable to mention that natural products, their derivatives, and their analogs are the main source for new drug candidates in depression. The mechanisms include interplay with γ-aminobutyric acid (GABA) receptors, serotonergic, dopaminergic noradrenergic systems, and elevation of BDNF levels. The focus of this review is to revisit the role of signalling molecules in depression and highlight the use of plant-derived natural compounds to counter depression in the CNS.

scholarly journals Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy

2019 ◽  
Vol 20 (9) ◽  
pp. 2241 ◽  
Author(s):  
Debarati Banik ◽  
Sara Moufarrij ◽  
Alejandro Villagra
Keyword(s):  
Histone Deacetylase Inhibitors ◽  
Critical Role ◽  
Preclinical Studies ◽  
Clinical Use ◽  
Combination Therapies ◽  
Drug Candidates ◽  
Cellular Processes ◽  
Fda Approval

Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration. Finally, we have included examples of ongoing trials for each of the above categories of HDACis as standalone agents or in combination with immunotherapeutic approaches.

The Cognitive Component of Elite High Jumpers’ Preperformance Routines

2020 ◽  
Vol 34 (2) ◽  
pp. 99-110
Author(s):  
Thomas Gretton ◽  
Lindsey Blom ◽  
Dorice Hankemeier ◽  
Lawrence Judge
Keyword(s):  
Thematic Analysis ◽  
Critical Role ◽  
Valuable Insight ◽  
Psychological Skills ◽  
Cognitive Content ◽  
Successful Performance ◽  
Cognitive Component ◽  
Inductive Thematic Analysis ◽  
Insight Into

Preperformance routines are microlevel performance processes utilized by athletes to facilitate the attainment of an optimal state and enhance the chance for successful performance. Despite continued examination of these routines, only a small proportion of research has been directed toward the cognitive component of these routines. This study explored the cognitive component of elite high jumpers’ preperformance routines, and specifically the consistency of the cognitive content (i.e., psychological skills and strategies). Data were acquired over an 8-week high-jump season and subjected to inductive thematic analysis. Results revealed the consistent implementation of the cognitive content (e.g., visualization) but an inconsistent design of this content (i.e., the content of the visualization). Furthermore, results underline the critical role of high-jump coaches and an athlete’s need to be adaptable and competent in utilizing various types of preperformance routine. This study offers valuable insight into the complexities and inconsistencies of the cognitive component of high jumpers’ preperformance routines.

Cryo-EM structure of 90S small ribosomal subunit precursors in transition states

Science ◽  
2020 ◽  
Vol 369 (6510) ◽  
pp. 1477-1481 ◽  
Author(s):  
Yifei Du ◽  
Weidong An ◽  
Xing Zhu ◽  
Qi Sun ◽  
Jia Qi ◽  
...  
Keyword(s):  
Structural Changes ◽  
Critical Role ◽  
Ribosomal Subunit ◽  
Rna Degradation ◽  
Ribosomal Subunits ◽  
Cryo Electron Microscopy ◽  
Nuclear Exosome ◽  
Assembly Intermediate ◽  
Insight Into

The 90S preribosome is a large, early assembly intermediate of small ribosomal subunits that undergoes structural changes to give a pre-40S ribosome. Here, we gained insight into this transition by determining cryo–electron microscopy structures of Saccharomyces cerevisiae intermediates in the path from the 90S to the pre-40S. The full transition is blocked by deletion of RNA helicase Dhr1. A series of structural snapshots revealed that the excised 5′ external transcribed spacer (5′ ETS) is degraded within 90S, driving stepwise disassembly of assembly factors and ribosome maturation. The nuclear exosome, an RNA degradation machine, docks on the 90S through helicase Mtr4 and is primed to digest the 3′ end of the 5′ ETS. The structures resolved between 3.2- and 8.6-angstrom resolution reveal key intermediates and the critical role of 5′ ETS degradation in 90S progression.

Local modes

2002 ◽  
Vol 80 (12) ◽  
pp. 1635-1642 ◽  
Author(s):  
Bryan R Henry ◽  
Henrik G Kjaergaard
Keyword(s):  
Atmospheric Chemistry ◽  
Molecular Conformation ◽  
Critical Role ◽  
Historical Background ◽  
Local Mode ◽  
Local Modes ◽  
Band Profile ◽  
Methyl Rotation ◽  
Insight Into

The historical background for the development of the local mode approach is reviewed, including the critical role of the radiation field. The harmonically coupled anharmonic oscillator model is described. Local modes have been used in the interpretation of XH stretching overtone spectra. These spectra can be used as sensitive probes of molecular properties such as bond length and molecular conformation. Examples of these spectral features are discussed. An intensity theory has been developed that permits the accurate calculation of relative and absolute overtone intensities. In molecules with low barriers to methyl rotation, torsional states contribute to the XH stretching band profile. A successful theoretical approach is presented that accounts for these effects and provides insight into the vibrational dynamics. The application of calculated local mode overtone spectra to atmospheric chemistry is discussed.Key words: local mode, overtone, vibrational intensity.

Akt Activation Regulates Macrophage Survival and Differentiation: Role of M-CSF and Endogenous ROS.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2208-2208
Author(s):  
Yijie Wang ◽  
Mandy M. Zeigler ◽  
Greg K. Lam ◽  
Melissa G. Hunter ◽  
Tim D. Eubank ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Survival ◽  
Kinase Inhibitors ◽  
Critical Role ◽  
Annexin V ◽  
Mononuclear Phagocytes ◽  
Ros Generation ◽  
Blood Monocytes ◽  
Human Alveolar Macrophage

Abstract Previous reports from our laboratory showed M-CSF promotes PI 3-kinase activation resulting in the production of reactive oxygen species (ROS) and PI 3-kinase inhibitors, and the antioxidants diphenyleneiodonium (DPI) and n-acetyl cysteine (NAC) suppressed M-CSF-stimulated Erk activation. In this study, we hypothesized that M-CSF-induced generation of ROS affected Akt1 activation and sought to define the role of Akt1 in monocyte/macrophage survival and differentiation. We found that the production of ROS following M-CSF-treatment was inhibited by the antioxidant DPI. The addition of either DPI or NAC to the monocytes in the presence of M-CSF resulted in decrease cell survival as measured by Annexin V/PI and DNA fragmentation. In the cells treated with the antioxidants, there was a reduction in pAKT protein levels compared to M-CSF alone treatment suggesting that ROS contributed to Akt activity and cell survival. Macrophages from p47phox −/− mice, lacking a key component of the NADPH oxidase complex required for ROS generation were examined for M-CSF-induced survival and Akt1 activation. Bone marrow macrophages from p47phox −/ − mice and wild type (WT) littermates were isolated and differentiated in RPMI-1640 medium in the presence of 20 ng/ml of M-CSF for 5 days. We observed a reduction in Akt1 phosphorylation, cellular survival and increase in apoptosis measured by Annexin V/PI staining in p47phox −/ − macrophages compared to WT controls. Since macrophages from the p47phox−/− mice had reduced Akt1 activity and cell survival to M-CSF stimulation, we next wanted to independently evaluate the role of Akt in macrophage survival and differentiation. We therefore examined macrophages from mice that had targeted expression of activated Akt1 (Myr-Akt1) in mononuclear phagocytes. Bone marrow from Myr-Akt1 mice and (WT) littermates was isolated and cultured in the presence of 20 ng/ml of M-CSF for 5 days. We found that Myr-Akt1 cells had enhanced survival and reduced apoptosis versus WT cells. Interestingly, Myr-Akt1 mice had normal circulating numbers of monocytes, but had splenomegaly and increased numbers of mature macrophages in their spleens by CD68 staining. Since the expression of Myr-Akt1 in BMM enhanced cell survival, we were interested in the effect in human monocytes. Peripheral blood monocytes (PBM) were transiently transfected with Myr-Akt1 constructs. We observed a decrease in Annexin V/PI staining indicating promotion of cell survival in PBM expressing Myr-Akt compared to untransfected PBM. Since Akt1 appeared to be important for macrophage survival/differentiation, we examined its contribution in human alveolar macrophage homeostasis and found that freshly isolated macrophages had constitutive Akt1 activity and had increased levels of Akt1 protein. This data support a critical role for Akt1 in macrophage differentiation in mice. Together, our findings may provide insight in the pathogenesis of monocyte/macrophage homeostasis.

High-Molecular-Weight, High-Unsaturation Copolymers of Isobutylene and Conjugated Dienes. I. Synthesis

1976 ◽  
Vol 49 (4) ◽  
pp. 960-966 ◽  
Author(s):  
W. A. Thaler ◽  
D. J. Buckley
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Cationic Polymerization ◽  
Critical Role ◽  
Conjugated Dienes ◽  
Solution Properties ◽  
Insight Into

Abstract This investigation has provided insight into the critical role of solution properties on the course of cationic polymerization and has led to a technique for reconciling the opposing demands for synthesis of isoolefin-diene copolymers both free from gel and high in molecular weight. By this technique, the synthesis of a broad range of intermediate-unsaturation elastomers of quality has been realized.

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