scholarly journals Voltammetric Behaviour of Drug Molecules as a Predictor of Metabolic Liabilities

2020 ◽  
Vol 88 (4) ◽  
pp. 46 ◽  
Author(s):  
Hikari Fuchigami ◽  
Mandeep K. Bal ◽  
Dale A. C. Brownson ◽  
Craig E. Banks ◽  
Alan M. Jones
Keyword(s):  
Drug Stability ◽  
Pharmaceutical Research ◽  
Parent Drug ◽  
Vital Role ◽  
Oxidation Potential ◽  
The Body ◽  
Metabolic Stability ◽  
Drug Molecules ◽  
The Stability

Electron transfer plays a vital role in drug metabolism and underlying toxicity mechanisms. Currently, pharmaceutical research relies on pharmacokinetics (PK) and absorption, distribution, metabolism, elimination and toxicity (ADMET) measurements to understand and predict drug reactions in the body. Metabolic stability (and toxicity) prediction in the early phases of the drug discovery and development process is key in identifying a suitable lead compound for optimisation. Voltammetric methods have the potential to overcome the significant barrier of new drug failure rates, by giving insight into phase I metabolism events which can have a direct bearing on the stability and toxicity of the parent drug being dosed. Herein, we report for the first time a data-mining investigation into the voltammetric behaviour of reported drug molecules and their correlation with metabolic stability (indirectly measured via t½), as a potential predictor of drug stability/toxicity in vivo. We observed an inverse relationship between oxidation potential and drug stability. Furthermore, we selected and prepared short- (<10 min) and longer-circulation (>2 h) drug molecules to prospectively survey the relationship between oxidation potential and stability.

scholarly journals Drug Disposition in the Lower Gastrointestinal Tract: Targeting and Monitoring

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 161
Author(s):  
Glenn Lemmens ◽  
Arno Van Camp ◽  
Stephanie Kourula ◽  
Tim Vanuytsel ◽  
Patrick Augustijns
Keyword(s):  
Drug Absorption ◽  
Drug Disposition ◽  
Drug Stability ◽  
Ussing Chamber ◽  
Dissolution Kinetics ◽  
Comprehensive Overview ◽  
Drug Molecules ◽  
Epithelial Physiology

The increasing prevalence of colonic diseases calls for a better understanding of the various colonic drug absorption barriers of colon-targeted formulations, and for reliable in vitro tools that accurately predict local drug disposition. In vivo relevant incubation conditions have been shown to better capture the composition of the limited colonic fluid and have resulted in relevant degradation and dissolution kinetics of drugs and formulations. Furthermore, drug hurdles such as efflux transporters and metabolising enzymes, and the presence of mucus and microbiome are slowly integrated into drug stability- and permeation assays. Traditionally, the well characterized Caco-2 cell line and the Ussing chamber technique are used to assess the absorption characteristics of small drug molecules. Recently, various stem cell-derived intestinal systems have emerged, closely mimicking epithelial physiology. Models that can assess microbiome-mediated drug metabolism or enable coculturing of gut microbiome with epithelial cells are also increasingly explored. Here we provide a comprehensive overview of the colonic physiology in relation to drug absorption, and review colon-targeting formulation strategies and in vitro tools to characterize colonic drug disposition.

scholarly journals Nanosuspensions – An Update on Recent Patents, Methods of Preparation, and Evaluation Parameters

2020 ◽  
Vol 14 ◽  
Author(s):  
Harpreet Kaur Khanuja ◽  
Rajendra Awasthi ◽  
Meenu Mehta ◽  
Saurabh Satija ◽  
Alaa AA Aljabali ◽  
...  
Keyword(s):  
Drug Loading ◽  
Pharmaceutical Research ◽  
Vital Role ◽  
Solid Matrix ◽  
Colloidal Systems ◽  
Passive Targeting ◽  
Physico Chemical ◽  
Extensive Information ◽  
The Stability ◽  
Preparation And Evaluation

Background: Nanosuspensions are colloidal systems consisting of pure drug and stabilizers, without matrix or lyophilized into a solid matrix. Nanosuspensions improve the solubility of the drug both in the aqueous and organic phases. Nanosuspensions are also known as brick dust molecules, as they increase the dissolution of a system and improve absorption. Methods: Extensive information related to nanosuspensions and its associated patents were collected using PubMed and Google Scholar. Results: Over the last decade nanosuspensions have attracted tremendous interest in pharmaceutical research. It provides unique features including, improved solubility, high drug loading capacity, and passive targeting. These particles are costeffective, simple, and have lesser side effects with minimal dose requirements. However, the stability of nanosuspensions still warrants attention. Conclusion: Nanosuspensions plays a vital role in handling the numerous drug entities with difficult physico-chemical characteristics such as solubility and can further aid with a range of routes that include nasal, transdermal, occular, parenteral, pulmonary etc. This review highlights the relevance of nanosuspensions in achieving safe, effective and targeted drug delivery.

Virtual Screening of Phyto Chemicals Against SARS-CoV-2 Targets

2021 ◽  
Vol 6 (3) ◽  
pp. 61-76
Author(s):  
Shahanas Naisam ◽  
Vidhya V. S. ◽  
Suvanish Kumar ◽  
Nidhin Sreekumar
Keyword(s):  
Dynamics Simulation ◽  
Spike Protein ◽  
Ligand Interaction ◽  
Docking Analysis ◽  
Drug Molecules ◽  
In Vivo Analysis ◽  
Protein Ligand Interaction ◽  
The Stability ◽  
3Cl Protease

The COVID-19 pandemic wave has recommenced and is spreading like wildfire across the globe. The well-reported antiviral potency of phyto compounds could offer potential drug molecules for the current predicament. The present study analyses the molecular interaction of selected phyto compounds and SARS-CoV-2 molecular target proteins, namely spike protein, RNA-dependent RNA polymerase, 3C-like proteases, and papain-like protease. Ten newly modeled ligands were also considered for the study. Molecular docking analysis was carried out independently using MOE, AutoDock Vina, Schrodinger-Glide, and the stability of protein-ligand interaction was validated through molecular dynamics simulation. Petunidin interacts with spike protein resulting in a good Gscore, binding energy, and H-bond interaction. Also, alions, letestuianin-A, (+)-pinitol show better interaction with RdRp, 3CL-protease, and papain-like protease, respectively. The presented work screens through 2314 ligands to yield top-ranked molecules which could be taken up to develop potential lead molecules via in-vivo analysis.

scholarly journals One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [99mTc]Tc-DB4 and [111In]In-SG4 in Mice Treated with Entresto

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1145
Author(s):  
Panagiotis Kanellopoulos ◽  
Aikaterini Kaloudi ◽  
Maritina Rouchota ◽  
George Loudos ◽  
Marion de Jong ◽  
...  
Keyword(s):  
Tumor Targeting ◽  
Metabolic Stability ◽  
Clinical Translation ◽  
Tumor Uptake ◽  
Gastrin Releasing Peptide ◽  
Cognate Receptor ◽  
One Step ◽  
The Stability ◽  
The Impact

Background: Peptide radioligands may serve as radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor uptake of biodegradable radiopeptides. Aiming to clinical translation of this methodology, we herein investigated the impact of the approved pill Entresto, releasing the potent NEP-inhibitor LBQ657 in vivo, on the stability and tumor uptake of two radiopeptides. Methods: The metabolic stability of [99mTc]Tc-DB4 (DB4, N4-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH2) and [111In]In-SG4 (SG4, DOTA-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) was tested in LBQ657/Entresto-treated mice vs. untreated controls. The uptake in gastrin-releasing peptide receptor (GRPR)-, or cholecystokinin subtype 2 receptor (CCK2R)-positive tumors respectively, was compared between LBQ657/Entresto-treated mice and untreated controls. Results: LBQ657/Entresto treatment induced marked stabilization of [99mTc] Tc-DB4 and [111In]In-SG4 in peripheral mice blood, resulting in equally enhanced tumor uptake at 4 h post-injection. Accordingly, the [99mTc]Tc-DB4 uptake of 7.13 ± 1.76%IA/g in PC-3 tumors increased to 16.17 ± 0.71/17.50 ± 3.70%IA/g (LBQ657/Entresto) and the [111In]In-SG4 uptake of 3.07 ± 0.87%IA/g in A431-CCK2R(+) tumors to 8.11 ± 1.45/9.61 ± 1.70%IA/g. Findings were visualized by SPECT/CT. Conclusions: This study has shown the efficacy of Entresto to notably improve the profile of [99mTc]Tc-DB4 and [111In]In-SG4 in mice, paving the way for clinical translation of this approach.

The Stability of Veins Under Torsion

2012 ◽  
Author(s):  
Justin R. Garcia ◽  
Hai-Chao Han
Keyword(s):  
Diabetes Mellitus ◽  
Health Risks ◽  
Mechanical Stability ◽  
Thrombus Formation ◽  
Body Movement ◽  
Critical Value ◽  
The Body ◽  
Clinical Interest ◽  
The Stability

Twisted veins are observed throughout the body and are often associated with health risks such as hypertension and diabetes mellitus [1]. Recently, it has been shown that veins will buckle and become tortuous when lumen pressure exceeds a critical value [2]. However, veins also undergo twist deformations in vivo due to body movement, vein grafting, and microanastomosis procedures which may lead to reduced patency, kinking, and thrombus formation [3, 4]. In spite of this, little data is available regarding the stability of veins when subject to twist deformations. Therefore, it is of clinical interest to investigate the mechanical stability of veins under torsion.

scholarly journals Advanced characterizations of nanoparticles for drug delivery: investigating their properties through the techniques used in their evaluations

2017 ◽  
Vol 6 (4) ◽  
pp. 355-372 ◽  
Author(s):  
Syed Mahmood ◽  
Uttam Kumar Mandal ◽  
Bappaditya Chatterjee ◽  
Muhammad Taher
Keyword(s):  
Drug Delivery ◽  
Advanced Characterization ◽  
Data Interpretation ◽  
Review Article ◽  
The Body ◽  
Drug Molecule ◽  
Drug Molecules ◽  
Preparation Techniques

AbstractNanomedicine has achieved a huge success in delivering a wide variety of drug molecules into the target site of the body. In this respect, the characterization of nanoformulation is very important to investigate the drug molecule together with its carrier as a nanoform during formulation, storage, and in vivo transport through the body. This review article summarizes important advanced characterization techniques of nanoformulation with respect to their theories, use of required instrumental parameters, sample preparation techniques, data interpretation, etc., to exploit them for the best possible results. This review article also sheds a glimpse to the shortcomings of these techniques together with further advancements required in future.

On the Stability Analysis of the Human Spine

2003 ◽  
Author(s):  
M. El-Rich ◽  
A. Shirazi-Adl
Keyword(s):  
Stability Analysis ◽  
Material Handling ◽  
Muscle Activation ◽  
The Body ◽  
Abdominal Pressure ◽  
Human Spine ◽  
Manual Material Handling ◽  
The Stability ◽  
Force Relationship

The stability of the human spine in compression has attracted a considerable amount of attention in recent years. The passive ligamentous thoracolumbar and lumbar spines are known to exhibit large displacements or hypermobility (i.e., instability in an imperfect column) under compression loads &lt;100N. Since such compression loads are only a small fraction of those supported by the spine even in regular daily activities, let aside the manual material handling tasks, the question arises as to how the spine is stablized in vivo? Various stabilizing mechanisms have been proposed and investigated; wrapping loading [Shirazi-Adl and Parnianpour, 2000], postural adaptations [Shirazi-Adl and parnianpor, 1999], intra-abdominal pressure [Cholewicki et al, 1999] and muscle activation/coactivation [Bergmark, 1989; Crisco and Panjabi, 1991]. In this work, a novel kinematics-based methad [Shirazi-Adl et al., 2002] is first applied to compute muscle forces and internal loads in standing postures under gravity with or without 200N loads held either on sides or close to the body in front. The stability of the system under given loads and prescribed postures is sudsequently examined using both linear bucking analysis based on the deformed configurations and nonlinear analysis while employing a liner stiffness-force relationship for muscules [Bergmark, 1989; Crico and Panjabi, 1991]. The relative accuracy of foregoing methods in stability analysis of some sample structures is also investigated. Moreover, the effect of co-activity on stability of the spine in neutral postures is studied.

scholarly journals Assessment of Pharmacokinetics and Metabolism Profiles of SCH 58261 in Rats Using Liquid Chromatography–Mass Spectrometric Method

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2209 ◽  
Author(s):  
Yuri Park ◽  
Min-Ho Park ◽  
Jin-Ju Byeon ◽  
Seok-Ho Shin ◽  
Byeong ill Lee ◽  
...  
Keyword(s):  
Bile Duct ◽  
Oral Administration ◽  
The Body ◽  
Metabolic Stability ◽  
In Vivo Model ◽  
Spectrometric Method ◽  
Mass Spectrometric Method ◽  
Sch 58261

5-Amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c) pyrimidine (SCH 58261) is one of the new chemical entities that has been developed as an adenosine A2A receptor antagonist. Although SCH 58261 has been reported to be beneficial, there is little information about SCH 58261 from a drug metabolism or pharmacokinetics perspective. This study describes the metabolism and pharmacokinetic properties of SCH 58261 in order to understand its behaviors in vivo. Rats were used as the in vivo model species. First, an LC–MS/MS method was developed for the determination of SCH 58261 in rat plasma. A GastroPlus™ simulation, in vitro microsomal metabolic stability, and bile duct-cannulated studies were also performed to understand its pharmacokinetic profile. The parameter sensitivity analysis of GastroPlus™ was used to examine the factors that influence exposure when the drug is orally administered. The factors are as follows: permeability, systemic clearance, renal clearance, and liver first-pass effect. In vitro microsomal metabolic stability indicates how much the drug is metabolized. The extrapolated hepatic clearance value of SCH 58261 was 39.97 mL/min/kg, indicating that the drug is greatly affected by hepatic metabolism. In vitro microsomal metabolite identification studies revealed that metabolites produce oxidized and ketone-formed metabolites via metabolic enzymes in the liver. The bile duct-cannulated rat study, after oral administration of SCH 58261, showed that a significant amount of the drug was excreted in feces. These results imply that the drug is not absorbed well in the body after oral administration. Taken together, SCH 58261 showed quite a low bioavailability when administered orally and this was likely due to significantly limited absorption, as well as high metabolism in vivo.

scholarly journals Atomic-scale compositional mapping reveals Mg-rich amorphous calcium phosphate in human dental enamel

2016 ◽  
Vol 2 (9) ◽  
pp. e1601145 ◽  
Author(s):  
Alexandre La Fontaine ◽  
Alexander Zavgorodniy ◽  
Howgwei Liu ◽  
Rongkun Zheng ◽  
Michael Swain ◽  
...  
Keyword(s):  
Calcium Phosphate ◽  
Amorphous Calcium Phosphate ◽  
Dental Enamel ◽  
Atom Probe ◽  
Vital Role ◽  
The Body ◽  
Atomic Scale ◽  
Chemical Attack ◽  
Direct Observations

Human dental enamel, the hardest tissue in the body, plays a vital role in protecting teeth from wear as a result of daily grinding and chewing as well as from chemical attack. It is well established that the mechanical strength and fatigue resistance of dental enamel are derived from its hierarchical structure, which consists of periodically arranged bundles of hydroxyapatite (HAP) nanowires. However, we do not yet have a full understanding of the in vivo HAP crystallization process that leads to this structure. Mg2+ ions, which are present in many biological systems, regulate HAP crystallization by stabilizing its precursor, amorphous calcium phosphate (ACP), but their atomic-scale distribution within HAP is unknown. We use atom probe tomography to provide the first direct observations of an intergranular Mg-rich ACP phase between the HAP nanowires in mature human dental enamel. We also observe Mg-rich elongated precipitates and pockets of organic material among the HAP nanowires. These observations support the postclassical theory of amelogenesis (that is, enamel formation) and suggest that decay occurs via dissolution of the intergranular phase. This information is also useful for the development of more accurate models to describe the mechanical behavior of teeth.

Glucosidic pathways of glycogen breakdown and glucose production by muscle from postexercised frogs

1993 ◽  
Vol 265 (5) ◽  
pp. R1141-R1147 ◽  
Author(s):  
P. A. Fournier ◽  
H. Guderley
Keyword(s):  
Glucose Production ◽  
Liver Glycogen ◽  
The Body ◽  
Strenuous Exercise ◽  
Catabolic State ◽  
Metabolic Transition ◽  
Glucose Accumulation ◽  
The Stability ◽  
Glycogen Breakdown

Muscle and body glucose in frogs increases markedly during the initial hour of recovery after strenuous exercise. The liver is not the major source responsible for this accumulation. This is indicated by the stability of liver glycogen levels after exercise and by the observation that hepatectomized and normal frogs accumulate similar amounts of glucose in their muscles and body during recovery. The renal contribution cannot account for this increase in body glucose. Most of the glucose that accumulates in the body after exercise has a muscular origin, as indicated by the facts that two-thirds of the body glucose is found in muscle and that the intracellular levels of muscle glucose are much higher than those of the plasma. The glucose that accumulates outside muscle may also have a muscular origin. The glucosidic pathways of glycogen breakdown are the only metabolic avenue with sufficient capacity to account for the amount of glucose accumulated in muscle during the first hour of recovery. These results indicate that the ability of an isolated preparation of frog muscle to liberate glucose during recovery from exercise (Fournier et al. J. Biol. Chem. 267: 8234-8238, 1992) is not an artifactual metabolic curiosity but rather a metabolic reality that takes place in vivo. Glucose accumulation during recovery is thought to facilitate the metabolic transition of frog carbohydrate metabolism from a catabolic state, characteristic of exercise, to an anabolic one.

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