scholarly journals Synthesis of the Nakanishi Ring-Locked Retinoid

2011 ◽  
Vol 2011 ◽  
pp. 1-8
Author(s):  
Jamie B. Côté ◽  
Tan D. Quach ◽  
Andrey P. Demenev ◽  
David S. Garvey ◽  
Judd M. Berman
Keyword(s):  
Therapeutic Agents ◽  
Proof Of Concept ◽  
Synthetic Route ◽  
Biological Tool ◽  
Purification Protocol ◽  
Over Time

An optimized synthetic route to prepare ring-locked retinoid 1a has been developed. We fully describe a purification protocol that provides isomerically pure 1a in support of on-going proof of concept studies for the development of therapeutic agents to treat human ADRP. Additionally, we have found that isomerically pure 1a can be stored in amber vials under argon at −20°C for use over time (up to six months) without degradation. Thus, enabling 1a to be an accessible and valuable biological tool.

Synthesis and Biological Properties of some New Lead Sulphonamide and Carboxamide Scaffolds Bearing Coumarin Moiety (Mini Review)

2020 ◽  
Vol 20 ◽  
Author(s):  
Cosmas Chinweike Eze ◽  
Mercy Amarachukwu Ezeokonkwo ◽  
Benjamin Ebere Ezema ◽  
Abraham Efeturi Onoabedje ◽  
David Izuchukwu Ugwu
Keyword(s):  
Biological Properties ◽  
Therapeutic Agents ◽  
Amide Group ◽  
Pharmacological Properties ◽  
Important Class ◽  
Synthetic Route ◽  
Therapeutic Activities

: Coumarin, sulphonamide and amide scaffolds exhibit diverse pharmacological features and constitute an important class of therapeutic agents. In this review, we have discussed the synthesis, biological properties, and SAR of coumarins containing sulphonamide or amide group in the last seven years. Many reviews on the therapeutic activities of coumarins, sulphonamides, and amides have been published, hence the authors focused on coumarin-linked sulphonamide or amide scaffolds. The review provides information on the synthetic route to new coumarins containing sulphonamide or amide groups with improved pharmacological properties.

Increasing Treatment Lifetime through Sustained Release of Scale Inhibitor from Scale Inhibitor Nanoparticles

SPE Journal ◽  
2021 ◽  
pp. 1-7
Author(s):  
Huili Guan ◽  
Austin Lim ◽  
Joshua Hernandez ◽  
Jenn-Tai Liang
Keyword(s):  
Sustained Release ◽  
Functional Group ◽  
Proof Of Concept ◽  
Linear Scale ◽  
Scale Inhibitor ◽  
Concept Study ◽  
Inhibition Concentration ◽  
Calcium And Magnesium ◽  
Inhibitor Treatment ◽  
Over Time

Summary Scale can cause flow assurance issues because of damage to the near-wellbore region and in production facilities. Scale inhibitors are often used to help mitigate these problems. The main focus of this proof-of-concept study is to examine the ability of a newly developed crosslinked nanosized scale inhibitor (NSI) particle to inhibit scale formation through sustained release of scale inhibitor into a model brine and increase scale inhibitor treatment lifetime. Results from minimum inhibition concentration (MIC) measurements showed that, at 95°C, the MIC decreased gradually from 10 ppm at day 0 to 5 ppm after 9 days and eventually reached a very low MIC of 2 ppm after 49 days. These findings are consistent with our hypothesis that the sustained release of linear scale inhibitor from the NSI would result in a decrease in MIC over time caused by an increased amount of linear scale inhibitor being released into the model brine. Also, attaching 2-acrylamido-2-methyl-1-propanesulfonic functional group (AMPS) to NSI successfully inhibits the pseudoscale formation when the scale inhibitor comes into contact with the calcium and magnesium in the model brine. Results from sandpack floods showed that NSI increased the treatment lifetime from 3 pore volumes (PV) postflush throughput, for the traditional scale inhibitor, to 35 to 105 PV postflush throughput. These results support our hypothesis that sustained release of the trapped NSI nanoparticles can improve the treatment lifetime.

scholarly journals A Reusable Perfused Human Cadaver Model for Surgical Training: An Initial Proof of Concept Study

2019 ◽  
Vol 184 (Supplement_1) ◽  
pp. 43-47 ◽  
Author(s):  
Jenny M Held ◽  
Robert B McLendon ◽  
Christian S McEvoy ◽  
Travis M Polk
Keyword(s):  
Surgical Training ◽  
Tap Water ◽  
Regional Perfusion ◽  
Whole Body ◽  
Suture Repair ◽  
Second Phase ◽  
Proof Of Concept ◽  
Handling Characteristics ◽  
Surgical Trainees ◽  
Over Time

Abstract Objectives Today’s surgical trainees have less exposure to open vascular and trauma procedures. Lightly embalmed cadavers may allow a reusable model that maximizes resources and allows for repeat surgical training over time. Methods This was a three-phased study that was conducted over several months. Segments of soft-embalmed cadaver vessels were harvested and perfused with tap water. To test durability, vessels were clamped, then an incision was made and repaired with 5-0 polypropylene. Tolerance to suturing and clamping was graded. In a second phase, both an arterial-synthetic graft and an arterial-venous anastomosis were performed and tested at 90 mmHg perfusion. In the final phase, lower extremity regional perfusion was performed and vascular control of a simulated injury was achieved. Results Seven arteries and six veins from four cadavers were explanted. All vessels accommodated suture repair over 6 weeks. There was minor leaking at all previous clamp sites. In the anastomotic phase, vessels tolerated grafting, clamping, and perfusion without tearing or leaking. Regional perfusion provided a life-like training scenario. Conclusions Explanted vessels of soft-embalmed cadavers show adequate durability over time with realistic vascular surgery handling characteristics. This shows promise as initial proof of concept for a reusable perfused cadaver model. Further study with serial regional and whole-body perfusion is warranted.

scholarly journals Injectable Thermosensitive Formulation Based on Polyurethane Hydrogel/Mesoporous Glasses for Sustained Co-Delivery of Functional Ions and Drugs

Pharmaceutics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 501 ◽  
Author(s):  
Monica Boffito ◽  
Carlotta Pontremoli ◽  
Sonia Fiorilli ◽  
Rossella Laurano ◽  
Gianluca Ciardelli ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Chemical Degradation ◽  
Burst Release ◽  
Injectable Hydrogels ◽  
Micro Particles ◽  
Custom Made ◽  
Thermosensitive Hydrogels ◽  
Polyurethane Hydrogel ◽  
Over Time ◽  
Incipient Wetness Method

Mini-invasively injectable hydrogels are widely attracting interest as smart tools for the co-delivery of therapeutic agents targeting different aspects of tissue/organ healing (e.g., neo-angiogenesis, inflammation). In this work, copper-substituted bioactive mesoporous glasses (Cu-MBGs) were prepared as nano- and micro-particles and successfully loaded with ibuprofen through an incipient wetness method (loaded ibuprofen approx. 10% w/w). Injectable hybrid formulations were then developed by dispersing ibuprofen-loaded Cu-MBGs within thermosensitive hydrogels based on a custom-made amphiphilic polyurethane. This procedure showed almost no effects on the gelation potential (gelation at 37 °C within 3–5 min). Cu2+ and ibuprofen were co-released over time in a sustained manner with a significantly lower burst release compared to MBG particles alone (burst release reduction approx. 85% and 65% for ibuprofen and Cu2+, respectively). Additionally, released Cu2+ species triggered polyurethane chemical degradation, thus enabling a possible tuning of gel residence time at the pathological site. The overall results suggest that hybrid injectable thermosensitive gels could be successfully designed for the simultaneous localized co-delivery of multiple therapeutics.

scholarly journals Functional intersection of the kallikrein-related peptidases (KLKs) and thrombostasis axis

2010 ◽  
Vol 391 (4) ◽  
Author(s):  
Michael Blaber ◽  
Hyesook Yoon ◽  
Maria A. Juliano ◽  
Isobel A. Scarisbrick ◽  
Sachiko I. Blaber
Keyword(s):  
Initial Conditions ◽  
Tissue Injury ◽  
Large Body ◽  
Therapeutic Agents ◽  
Specific Interactions ◽  
Complete Understanding ◽  
Functional Interaction ◽  
Regulatory Interactions ◽  
Normal Health ◽  
Over Time

Abstract A large body of emerging evidence indicates a functional interaction between the kallikrein-related peptidases (KLKs) and proteases of the thrombostasis axis. These interactions appear relevant for both normal health as well as pathologies associated with inflammation, tissue injury, and remodeling. Regulatory interactions between the KLKs and thrombostasis proteases could impact several serious human diseases, including neurodegeneration and cancer. The emerging network of specific interactions between these two protease families appears to be complex, and much work remains to elucidate it. Complete understanding how this functional network resolves over time, given specific initial conditions, and how it might be controllably manipulated, will probably contribute to the emergence of novel diagnostics and therapeutic agents for major diseases.

Making Better Decisions During Synthetic Route Design: Leveraging Prediction to Achieve Greenness-by-Design

2019 ◽  
Author(s):  
Jun Li ◽  
Martin Eastgate
Keyword(s):  
Proof Of Concept ◽  
Synthetic Route ◽  
High Complexity ◽  
Route Design ◽  
Synthetic Routes ◽  
Catalyzed Reactions ◽  
Metal Catalyzed ◽  
Potential Efficiency

This paper expands our work predicting Process Mass Intensity (PMI), as a methodology for exploring the potential efficiency of proposed synthetic routes. In the present work, we integrate a method for predicting the PMI contributions of high complexity reagents, needed to enable certain transformations. We focus on ligands for metal catalyzed reactions - and develop an approach for predicting which ligands may function in CN couplings - as a proof of concept. We leverage this to enable the integration of the PMI contribution of the ligands into a predictions of a routes efficiency, enabling an understanding of the holistic impact of a route decision..

scholarly journals Standardization of an Experimental Murine Model of Invasive Pulmonary Aspergillosis

2006 ◽  
Vol 50 (10) ◽  
pp. 3501-3503 ◽  
Author(s):  
Donald C. Sheppard ◽  
John R. Graybill ◽  
Laura K. Najvar ◽  
Lisa Y. Chiang ◽  
Thomas Doedt ◽  
...  
Keyword(s):  
Murine Model ◽  
Liposomal Amphotericin ◽  
Invasive Pulmonary Aspergillosis ◽  
Therapeutic Agents ◽  
Pulmonary Aspergillosis ◽  
High Level ◽  
Aerosol Infection ◽  
Interlaboratory Reproducibility ◽  
Over Time ◽  
Experimental Murine Model

ABSTRACT Evaluating new therapeutic agents for invasive aspergillosis requires animal models that are reproducible among different laboratories. We therefore evaluated a murine model of aerosol infection in two independent laboratories and found a high level of both intra- and interlaboratory reproducibility of survival, fungal burden over time, and the efficacy of liposomal amphotericin B.

scholarly journals Collaborative Models for Translational Neuroscience and Rehabilitation Research

2009 ◽  
Vol 23 (7) ◽  
pp. 633-640 ◽  
Author(s):  
Bruce H. Dobkin
Keyword(s):  
Neurological Diseases ◽  
Academic Research ◽  
Therapeutic Agents ◽  
Government Agencies ◽  
Translational Neuroscience ◽  
Collaborative Models ◽  
Laboratory Capacity ◽  
Narrow Width ◽  
Ongoing Assessment ◽  
Over Time

Little formal research has been conducted on strategies to structure basic, preclinical, and clinical research to increase the likelihood of discovering efficacious interventions for patients with neurological diseases. How academic research is organized and funded by government agencies and foundations seems likely to affect the quality and rate of production of valued therapeutic agents. Few models for translational biomedical research, however, have been defined and no strategies have been compared. Given the narrow width of expertise and laboratory capacity of individual investigators, the complexity of identifying and manipulating mechanisms of disease components over time, and the demand for solutions from society, our continued reliance on funding therapeutic discovery through standalone investigators and projects seems counterproductive. Models are described for funding collaborations of basic and clinical scientists to work in iterative, adaptable, cross-disciplinary interactions around key progress-limiting questions. Problem-oriented collaborations require leadership, incentives, trust, ongoing assessment, and an efficient infrastructure that overcomes barriers. These models are as testable as the hypotheses that drive scientific research.

scholarly journals SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

2021 ◽  
Author(s):  
Pascal Demange ◽  
Etienne Joly ◽  
Julien Marcoux ◽  
Patrick R. A. Zanon ◽  
Dymytrii Listunov ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Protein Quality ◽  
Ubiquitin Proteasome System ◽  
Therapeutic Agents ◽  
Control Mechanisms ◽  
Proof Of Concept ◽  
Unfolded Protein ◽  
Ubiquitin Proteasome ◽  
Protein Response ◽  
Cytotoxic Mechanism

ABSTRACTHundreds of cytotoxic natural or synthetic lipidic compounds contain chiral alkynylcarbinol motifs, but the mechanism of action of those potential therapeutic agents remains unknown. Using a genetic screen in haploid human cells, we discovered that the enantiospecific cytotoxicity of numerous terminal alkynylcarbinols, including the highly cytotoxic dialkynylcarbinols, involves a bioactivation by HSD17B11, a short-chain dehydrogenase/reductase (SDR) known to oxidize the C-17 carbinol center of androstan-3-alpha,17-beta-diol to the corresponding ketone. A similar oxidation of dialkynylcarbinols generates dialkynylketones, that we characterize as highly protein-reactive electrophiles. We established that, once bioactivated in cells, the dialkynylcarbinols covalently modify several proteins involved in protein-quality control mechanisms, resulting in their lipoxidation on cysteines and lysines through Michael addition. For some proteins, this triggers their association to cellular membranes and results in endoplasmic reticulum stress, unfolded protein response activation, ubiquitin-proteasome system inhibition and cell death by apoptosis. Finally, as a proof-of-concept, we show that generic lipidic alkynylcarbinols can be devised to be bioactivated by other SDRs, including human RDH11 and HPGD/15-PGDH. Given that the SDR superfamily is one of the largest and most ubiquitous, this unique cytotoxic mechanism-of-action could be widely exploited to treat diseases, in particular cancer, through the design of tailored prodrugs. Graphical abstract

scholarly journals Namilumab or infliximab compared to standard of care in hospitalised patients with COVID-19 (CATALYST): a phase 2 randomised adaptive trial

2021 ◽  
Author(s):  
Benjamin A Fisher ◽  
Tonny Veenith ◽  
Daniel Slade ◽  
Charlotte Gaskell ◽  
Matthew Rowland ◽  
...  
Keyword(s):  
Usual Care ◽  
Clinical Outcomes ◽  
Standard Of Care ◽  
Phase 2 ◽  
Proof Of Concept ◽  
Open Label ◽  
Hospitalised Patients ◽  
Factor Inhibitor ◽  
Poor Outcomes ◽  
Over Time

Background Dysregulated inflammation is associated with poor outcomes in Coronavirus disease 2019 (COVID-19). We assessed the efficacy of namilumab, a granulocyte-macrophage colony-stimulating factor inhibitor and infliximab, a tumour necrosis factor inhibitor in hospitalised patients with COVID-19 in order to prioritise agents for phase 3 trials. Methods In this randomised, multi-arm, parallel group, open label, adaptive phase 2 proof-of-concept trial (CATALYST) we recruited hospitalised patients ≥16 years with COVID-19 pneumonia and C-reactive protein (CRP) ≥40mg/L in nine UK hospitals. Participants were randomly allocated with equal probability to usual care, or usual care plus a single 150mg intravenous dose of namilumab (150mg) or infliximab (5mg/kg). Randomisation was stratified for ward versus ICU. The primary endpoint was improvement in inflammation in intervention arms compared to control as measured by CRP over time, analysed using Bayesian multi-level models. ISRCTN registry number 40580903. Findings Between 15th June 2020 and 18th February 2021 we randomised 146 participants: 54 to usual care, 57 to namilumab and 35 to infliximab. The probabilities that namilumab and infliximab were superior to usual care in reducing CRP over time were 97% and 15% respectively. Consistent effects were seen in ward and ICU patients and aligned with clinical outcomes, such that the probability of discharge (WHO levels 1-3) at day 28 was 47% and 64% for ICU and ward patients on usual care, versus 66% and 77% for patients treated with namilumab. 134 adverse events occurred in 30/55 (54.5%) namilumab patients compared to 145 in 29/54 (53.7%) usual care patients. 102 events occurred in 20/29 (69.0%) infliximab patients versus 112 events in 17/34 (50.0%) usual care patients. Interpretation Namilumab, but not infliximab, demonstrated proof-of-concept evidence for reduction in inflammation in hospitalised patients with COVID-19 pneumonia which was consistent with secondary clinical outcomes. Namilumab should be prioritised for further investigation in COVID-19. Funding Medical Research Council.

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