scholarly journals Pharmacokinetic Study and Optimal Formulation of New Anti-Parkinson Natural Compound Schisantherin A

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Fei Sa ◽  
Bao Jian Guo ◽  
Sai Li ◽  
Zai Jun Zhang ◽  
Hok Man Chan ◽  
...  
Keyword(s):  
Pharmacokinetic Profile ◽  
Absolute Bioavailability ◽  
Drug Candidate ◽  
Vacuum Degasser ◽  
Ultraviolet Detector ◽  
Novel Approach ◽  
Cns Drugs ◽  
Oral Therapeutic ◽  
Shed Light ◽  
Schisantherin A

Our recent studies showed that schisantherin A (StA) is a promising candidate for PD treatment, but the pharmacokinetic profile of StA is largely unknown. The effects of different formulations on the pharmacokinetics and bioavailability of StA were investigated by HPLC equipped with a vacuum degasser, a quaternary pump, a manual sampler, and an ultraviolet detector. The absolute bioavailability of StA in nanoemulsion formulation was significantly increased from 4.3% to 47.3%. To the best of our knowledge, this is the first report of absolute bioavailability for StA in rats and successful increase of bioavailability of StA by nanoemulsion formulation. The pharmacokinetic profiles of StA could be significantly improved by a safe nanoemulsion formulation. This study provides a successful example of advanced delivery system for improving the bioavailability of potential central nervous system (CNS) drug candidate with poor solubility. This novel approach could be an effective alternative solution to overcome the shortcomings of conventional poor drug delivery of CNS drugs. The results of present study not only indicate that StA has potential to be developed as a promising oral therapeutic agent for the management of PD but also shed light on novel way to improve bioavailability of PD drugs.

scholarly journals Catalpol in Diabetes and its Complications: A Review of Pharmacology, Pharmacokinetics, and Safety

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3302 ◽  
Author(s):  
Ying Bai ◽  
Ruyuan Zhu ◽  
Yimiao Tian ◽  
Rui Li ◽  
Beibei Chen ◽  
...  
Keyword(s):  
Diabetic Complications ◽  
Pharmacokinetic Profile ◽  
Underlying Mechanism ◽  
Oral Dosage ◽  
Drug Candidate ◽  
General View ◽  
Knowledge Infrastructure ◽  
Novel Scaffold ◽  
Chinese National Knowledge Infrastructure ◽  
Shed Light

This review aimed to provide a general view of catalpol in protection against diabetes and diabetic complications, as well as its pharmacokinetics and safety concerns. The following databases were consulted with the retrieval of more than 100 publications through June 2019: PubMed, Chinese National Knowledge Infrastructure, WanFang Data, and web of science. Catalpol exerts an anti-diabetic effect in different animal models with an oral dosage ranging from 2.5 to 200 mg/kg in rats and 10 to 200 mg/kg in mice. Besides, catalpol may prevent the development of diabetic complications in kidney, heart, central nervous system, and bone. The underlying mechanism may be associated with an inhibition of inflammation, oxidative stress, and apoptosis through modulation of various cellular signaling, such as AMPK/PI3K/Akt, PPAR/ACC, JNK/NF-κB, and AGE/RAGE/NOX4 signaling pathways, as well as PKCγ and Cav-1 expression. The pharmacokinetic profile reveals that catalpol could pass the blood-brain barrier and has a potential to be orally administrated. Taken together, catalpol is a well-tolerated natural compound with promising pharmacological actions in protection against diabetes and diabetic complications via multi-targets, offering a novel scaffold for the development of anti-diabetic drug candidate. Further prospective and well-designed clinical trials will shed light on the potential of clinical usage of catalpol.

Conformation as the Therapeutic Target for Neurodegenerative Diseases

2017 ◽  
Vol 14 (4) ◽  
pp. 393-402 ◽  
Author(s):  
Rajaraman Krishnan ◽  
Franz Hefti ◽  
Haim Tsubery ◽  
Michal Lulu ◽  
Ming Proschitsky ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Specific Binding ◽  
Drug Candidate ◽  
High Affinity ◽  
Novel Approach ◽  
Multiple Protein ◽  
Clinical Benefits ◽  
Effective Drugs

Therapeutic strategies that target pathways of protein misfolding and the toxicity of intermediates along these pathways are mainly at discovery and early development stages, with the exception of monoclonal antibodies that have mainly failed to produce convincing clinical benefits in late stage trials. The clinical failures represent potentially critical lessons for future neurodegenerative disease drug development. More effective drugs may be achieved by pursuing the following two strategies. First, conformational targeting of aggregates of misfolded proteins, rather than less specific binding that includes monomer subunits, which vastly outnumber the toxic targets. Second, since neurodegenerative diseases frequently include more than one potential protein pathology, generic targeting of aggregates by shape might also be a crucial feature of a drug candidate. Incorporating both of these critical features into a viable drug candidate along with high affinity binding has not been achieved with small molecule approaches or with antibody fragments. Monoclonal antibodies developed so far are not broadly acting through conformational recognition. Using GAIM (General Amyloid Interaction Motif) represents a novel approach that incorporates high affinity conformational recognition for multiple protein assemblies, as well as recognition of an array of assemblies along the misfolding pathway between oligomers and fibers. A GAIM-Ig fusion, NPT088, is nearing clinical testing.

scholarly journals In Vitro Activity and Preclinical Profile of TMC435350, a Potent Hepatitis C Virus Protease Inhibitor

2009 ◽  
Vol 53 (4) ◽  
pp. 1377-1385 ◽  
Author(s):  
Tse-I Lin ◽  
Oliver Lenz ◽  
Gregory Fanning ◽  
Thierry Verbinnen ◽  
Frédéric Delouvroy ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Intestinal Tract ◽  
Pharmacokinetic Profile ◽  
Absolute Bioavailability ◽  
Time Curve ◽  
Biochemical Assays ◽  
Single Oral Administration ◽  
Half Maximal Effective Concentration

ABSTRACT The hepatitis C virus (HCV) NS3/4A serine protease has been explored as a target for the inhibition of viral replication in preclinical models and in HCV-infected patients. TMC435350 is a highly specific and potent inhibitor of NS3/4A protease selected from a series of novel macrocyclic inhibitors. In biochemical assays using NS3/4A proteases of genotypes 1a and 1b, inhibition constants of 0.5 and 0.4 nM, respectively, were determined. TMC435350 inhibited HCV replication in a cellular assay (subgenomic 1b replicon) with a half-maximal effective concentration (EC50) of 8 nM and a selectivity index of 5,875. The compound was synergistic with alpha interferon and an NS5B inhibitor in the replicon model and additive with ribavirin. In rats, TMC435350 was extensively distributed to the liver and intestinal tract (tissue/plasma area under the concentration-time curve ratios of >35), and the absolute bioavailability was 44% after a single oral administration. Compound concentrations detected in both plasma and liver at 8 h postdosing were above the EC99 value measured in the replicon. In conclusion, given the selective and potent in vitro anti-HCV activity, the potential for combination with other anti-HCV agents, and the favorable pharmacokinetic profile, TMC435350 has been selected for clinical development.

The Compound ATH434 Prevents Alpha-Synuclein Toxicity in a Murine Model of Multiple System Atrophy

2021 ◽  
pp. 1-11
Author(s):  
David I. Finkelstein ◽  
Jay J. Shukla ◽  
Robert A. Cherny ◽  
Jessica L. Billings ◽  
Eiman Saleh ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Pharmacokinetic Profile ◽  
Alpha Synuclein ◽  
Redox Activity ◽  
Substantia Nigra Pars Compacta ◽  
Drug Candidate ◽  
Older Volunteers ◽  
Control Food ◽  
Alpha Synuclein Aggregation

Background: An elevation in iron levels, together with an accumulation of α-synuclein within the oligodendrocytes, are features of the rare atypical parkinsonian disorder, Multiple System Atrophy (MSA). We have previously tested the novel compound ATH434 (formally called PBT434) in preclinical models of Parkinson’s disease and shown that it is brain-penetrant, reduces iron accumulation and iron mediated redox activity, provides neuroprotection, inhibits alpha synuclein aggregation and lowers the tissue levels of alpha synuclein. The compound was also well-tolerated in a first-in-human oral dosing study in healthy and older volunteers with a favorable, dose-dependent pharmacokinetic profile. Objective: To evaluate the efficacy of ATH434 in a mouse MSA model. Methods: The PLP-α-syn transgenic mouse overexpresses α-synuclein, demonstrates oligodendroglial pathology, and manifests motor and non-motor aspects of MSA. Animals were provided ATH434 (3, 10, or 30 mg/kg/day spiked into their food) or control food for 4 months starting at 12 months of age and were culled at 16 months. Western blot was used to assess oligomeric and urea soluble α-synuclein levels in brain homogenates, whilst stereology was used to quantitate the number of nigral neurons and glial cell inclusions (GCIs) present in the substantia nigra pars compacta. Results: ATH434 reduced oligomeric and urea soluble α-synuclein aggregation, reduced the number of GCIs, and preserved SNpc neurons. In vitro experiments suggest that ATH434 prevents the formation of toxic oligomeric species of synuclein. Conclusion: ATH434 is a promising small molecule drug candidate that has potential to move forward to trial for treating MSA.

A Comprehensive Study on Internet of Things Based on Key Artificial Intelligence Technologies and Industry 4.0

2021 ◽  
pp. 171-191
Author(s):  
Banu Çalış Uslu ◽  
Seniye Ümit Oktay Fırat
Keyword(s):  
Artificial Intelligence ◽  
Internet Of Things ◽  
Information Exchange ◽  
Industry 4.0 ◽  
New Technology ◽  
Smart Devices ◽  
Complex Environments ◽  
Novel Approach ◽  
Key Technologies ◽  
Shed Light

Under uncertainty, understanding and controlling complex environments is only possible with an ability to use distributed computing by the way of information exchange between devices to be able to understand the response of the system to a particular problem. From transformation of raw data in a huge distribution of network into the meaningful information, to use the understood knowledge to make rapid decisions needs to have a network composed of smart devices. Internet of things (IoT) is a novel approach, where these smart devices can communicate with each other by using key technologies of artificial intelligence (AI) in order to make timely autonomous decisions. This emerging technical advancement and realization of horizontal and vertical integration caused the fourth stage of industrialization (Industry 4.0). The objective of this chapter is to give detailed information on both IoT based on key AI technologies and Industry 4.0. It is expected to shed light on new work to be done by providing explanations about the new areas that will emerge with this new technology.

The Chiral Bioconversion and Pharmacokinetic Analysis of Trelagliptin in Beagle Dog Plasma by LC–MS/MS

2019 ◽  
Vol 58 (1) ◽  
pp. 31-36
Author(s):  
Li Zhou ◽  
Wang Xi ◽  
Hui Zhang ◽  
Lili Sun ◽  
Jinlong Yu ◽  
...  
Keyword(s):  
Internal Standard ◽  
Pharmacokinetic Profile ◽  
Gradient Elution ◽  
Ammonium Bicarbonate ◽  
Absolute Bioavailability ◽  
Pharmacokinetic Analysis ◽  
Beagle Dog ◽  
Dog Plasma ◽  
Liquid Chromatography Tandem Mass ◽  
Sensitivity Specificity

Abstract A simple and enantioselective method was developed and validated for the simultaneous determination of (R)- and (S)-trelagliptin in beagle dog plasma by chiral liquid chromatography tandem mass spectrometry. Trelagliptin enantiomers and (R)-rabeprazole (as internal standard, IS) were extracted from plasma samples by liquid–liquid extraction and separated on a CHIRALCEL OX-3R column using acetonitrile-5 ammonium bicarbonate as the mobile phase in gradient elution mode. The multiple reactions monitoring transitions of m/z 358.1→341.2 and 359.9→150.1 were used to quantify trelagliptin enantiomers and IS, respectively. This method was validated for sensitivity, specificity, linearity, precision, accuracy and stability of specific analytes under various conditions. And it was successfully applied to evaluating the pharmacokinetic profile of trelagliptin enantiomers in beagle dogs after single intravenous administration of (R)-trelagliptin injection (at 1 mg/kg) and oral administration (at 6.7 mg/kg). In this study, no chiral bioconversion of (R)-trelagliptin to (S)-trelagliptin in beagle dog plasma was observed. The absolute bioavailability of (R)-trelagliptin was identified to be 128.2%.

scholarly journals Is Psychological Value a Missing Building Block in Societal Sustainability?

2018 ◽  
Vol 10 (12) ◽  
pp. 4550 ◽  
Author(s):  
João Carvalho ◽  
Célio Sousa
Keyword(s):  
Value Creation ◽  
Ecological Value ◽  
Bottom Line ◽  
Organizational Survival ◽  
Psychological Dimension ◽  
Novel Approach ◽  
The Social ◽  
Social Product ◽  
The Impact ◽  
Shed Light

Value creation is a constitutive and defining aspect in organizational ventures. This is unsurprising, as it is required for organizational survival and sustainability. Approaches based on the creation of economic, social and ecological value draw attention to the multiple and multiplicative nature of value creation. While academia still acknowledges the conceptual value of such approaches, a framework that add a psychological dimension to the established Elkington’s triple-bottom line model seems particularly refreshing and inspiring. Relying on the concepts of psychological value and sustainability, this paper presents the outcomes of an exploratory empirical study involving managers and users/customers of four organizations in the social sector in Portugal. This study discusses how managers and users/customers of these organizations make sense of and value psychological value. The outcomes of the interviews with both managers and users/customers shed light into the unexplored, hazy and neglected analytical links that may exist between psychological value and broader perspectives on sustainability. We conclude that this novel approach enhances our understanding about the impact that a social product can have in societal sustainability.

scholarly journals #Brexit: Leave or remain? the role of user’s community and diachronic evolution on stance detection

2020 ◽  
Vol 39 (2) ◽  
pp. 2341-2352
Author(s):  
Mirko Lai ◽  
Viviana Patti ◽  
Giancarlo Ruffo ◽  
Paolo Rosso
Keyword(s):  
Social Studies ◽  
The Political ◽  
Political Discussion ◽  
Social Communities ◽  
Network Community ◽  
Novel Approach ◽  
Shift Dynamics ◽  
Shed Light

Interest has grown around the classification of stance that users assume within online debates in recent years. Stance has been usually addressed by considering users posts in isolation, while social studies highlight that social communities may contribute to influence users’ opinion. Furthermore, stance should be studied in a diachronic perspective, since it could help to shed light on users’ opinion shift dynamics that can be recorded during the debate. We analyzed the political discussion in UK about the BREXIT referendum on Twitter, proposing a novel approach and annotation schema for stance detection, with the main aim of investigating the role of features related to social network community and diachronic stance evolution. Classification experiments show that such features provide very useful clues for detecting stance.

scholarly journals Illicit Genres: The Case of Threatening Communications

Sakprosa ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 1-53
Author(s):  
Marie Bojsen-Møller ◽  
Sune Auken ◽  
Amy J. Devitt ◽  
Tanya Karoli Christensen
Keyword(s):  
Genre Theory ◽  
Situational Factors ◽  
Genre Studies ◽  
Factors Affecting ◽  
Test Items ◽  
Societal Benefits ◽  
Novel Approach ◽  
Rhetorical Genre ◽  
Threatening Communications ◽  
Shed Light

This study takes a novel approach to the study of threatening communications by arguing that they can be characterized as a genre – a genre that generally carries strong connotations of intimidation, fear, aggression, power, and coercion. We combine the theoretical framework of Rhetorical Genre Studies (RGS) with results from theoretical and empirical analyses of threats to arrive at a more comprehensive perspective of threats. Since threats do not form part of any regular curriculum of genres, we designed a survey to test how recognizable they are. While scholars on threats describe threatening communications as remarkably varied in form and contextual features, the majority of our respondents categorized test items as threats without prompts of any kind, indicating that threats are a recognizable genre. We propose that threatening communications belong to a wider category of illicit genres: i.e. genres that generally disrupt and upset society and commonly affect their targets negatively. The uptakes of illicit genres are very different from those of other genres, as the users of the genres often actively avoid naming them, making uptake communities significant shapers of illicit genres. The present study contributes to research on threatening communications, since genre theory sheds light on important situational factors affecting the interpretation of a text as a threat – this is a particularly contentious question when it comes to threats that are indirectly phrased. The study also contributes to genre theory by pointing to new territory for genre scholars to examine, namely illicit genres. Studies of illicit genres also have wider, societal benefits as they shed light on different kinds of problematic rhetorical behavior that are generally considered destructive or even dangerous.

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