scholarly journals The need for a multi-level drug targeting strategy to curb the COVID-19 pandemic

10.52586/5064 ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 1723-1736
Author(s):  
George J. Kontoghiorghes ◽  
Stella Fetta ◽  
Christina N. Kontoghiorghe
Keyword(s):  
Drug Targeting ◽  
Multi Level ◽  
Targeting Strategy

scholarly journals Lysosomal-Immune Axis Is Associated with COVID 19 Disease Severity: Insights from Patient Single Cell Data

2021 ◽  
Author(s):  
Rahul Pande ◽  
Erin Teeple ◽  
Weixiao Huang ◽  
Katherine W. Klinger ◽  
Deepak Rajpal ◽  
...  
Keyword(s):  
Single Cell ◽  
Disease Severity ◽  
Drug Targeting ◽  
Rna Seq ◽  
Network Approach ◽  
Immune Pathways ◽  
Novel Drug ◽  
Cell Data ◽  
Targeting Strategy

AbstractSARS-COV-2 has become a leading cause of illness, hospitalizations, and deaths worldwide yet heterogeneity in disease morbidity remains a conundrum. In this study, we analyzed publicly available single-cell RNA-seq data from 75076 cells sequenced from clinically staged COVID-19 patients using a network approach and identified lysosomal-immune axis as a factor significantly associated with disease severity. Our results suggest modulation of lysosomal-immune pathways may present a novel drug-targeting strategy to attenuate SARS-Cov-2 infections.

scholarly journals Lysosomal-Immune Axis Is Associated with COVID 19 Disease Severity: Insights from Patient Single Cell Data

2021 ◽  
Author(s):  
Rahul Pande ◽  
Erin Teeple ◽  
Weixiao Huang ◽  
Katherine Klinger ◽  
Deepak Rajpal ◽  
...  
Keyword(s):  
Single Cell ◽  
Disease Severity ◽  
Drug Targeting ◽  
Rna Seq ◽  
Network Approach ◽  
Immune Pathways ◽  
Novel Drug ◽  
Cell Data ◽  
Targeting Strategy

Abstract SARS-COV-2 has become a leading cause of illness, hospitalizations, and deaths worldwide yet heterogeneity in disease morbidity remains a conundrum. In this study, we analyzed publicly available single-cell RNA-seq data from 75076 cells sequenced from clinically staged COVID-19 patients using a network approach and identified lysosomal-immune axis as a factor significantly associated with disease severity. Our results suggest modulation of lysosomal-immune pathways may present a novel drug-targeting strategy to attenuate SARS-Cov-2 infections.

scholarly journals Phospholipid-Based Prodrugs for Colon-Targeted Drug Delivery: Experimental Study and In-Silico Simulations

Pharmaceutics ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 186 ◽  
Author(s):  
Milica Markovic ◽  
Arik Dahan ◽  
Shahar Keinan ◽  
Igor Kurnikov ◽  
Aaron Aponick ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Targeting ◽  
Parent Drug ◽  
Drug Conjugates ◽  
Activation Rate ◽  
Site Of Action ◽  
Activation Mechanisms ◽  
Targeting Strategy ◽  
Rate Of Activation

In ulcerative colitis (UC), the inflammation is localized in the colon, and one of the successful strategies for colon-targeting drug delivery is the prodrug approach. In this work, we present a novel phospholipid (PL)-based prodrug approach, as a tool for colonic drug targeting in UC. We aim to use the phospholipase A2 (PLA2), an enzyme that is overexpressed in the inflamed colonic tissues of UC patients, as the PL-prodrug activating enzyme, to accomplish the liberation of the parent drug from the prodrug complex at the specific diseased tissue(s). Different linker lengths between the PL and the drug moiety can dictate the rate of activation by PLA2, and subsequently determine the amount of free drugs at the site of action. The feasibility of this approach was studied with newly synthesized PL-Fmoc (fluorenylmethyloxycarbonyl) conjugates, using Fmoc as a model compound for testing our hypothesis. In vitro incubation with bee venom PLA2 demonstrated that a 7-carbon linker between the PL and Fmoc has higher activation rate than a 5-carbon linker. 4-fold higher colonic expression of PLA2 was demonstrated in colonic mucosa of colitis-induced rats when compared to healthy animals, validating our hypothesis of a colitis-targeting prodrug approach. Next, a novel molecular dynamics (MD) simulation was developed for PL-based prodrugs containing clinically relevant drugs. PL-methotrexate conjugate with 6-carbon linker showed the highest extent of PLA2-mediated activation, whereas shorter linkers were activated to a lower extent. In conclusion, this work demonstrates that for carefully designed PL-drug conjugates, PLA2 overexpression in inflamed colonic tissues can be used as prodrug-activating enzyme and drug targeting strategy, including insights into the activation mechanisms in a PLA2 binding site.

Verlaufsanalyse wöchentlicher Selbst- und Fremdeinschätzungen in der Langzeittherapie suchtkranker Jugendlicher

2019 ◽  
Vol 47 (2) ◽  
pp. 126-137
Author(s):  
Ferdinand Keller ◽  
Tatjana Stadnitski ◽  
Jakob Nützel ◽  
Renate Schepker
Keyword(s):  
Allen Vier ◽  
Multi Level

Zusammenfassung. Fragestellung: Über Veränderungen in der emotionalen Befindlichkeit von Jugendlichen während einer Suchttherapie ist wenig bekannt. Methode: Die Jugendlichen füllten wöchentlich einen entsprechenden Fragebogen aus, analog ihre Bezugsbetreuer eine parallelisierte Kurzfassung. Von 42 Jugendlichen liegen insgesamt 853 Bogen und von den Bezugsbetreuern 708 Bogen vor. Die Fragebogen wurden zunächst faktorenanalytisch hinsichtlich ihrer Dimensionalität ausgewertet, anschließend wurden gruppenbezogene Verlaufsanalysen (Multi-Level-Modelle) und Abhängigkeitsanalysen auf Einzelfallebene (Zeitreihenanalysen) durchgeführt. Ergebnisse: Im Jugendlichenfragebogen ergaben sich vier Faktoren: negative Befindlichkeit, Wertschätzung von Therapie/Betreuung, Motivation und Suchtdynamik. Die Übereinstimmung zwischen den Jugendlichen- und der (einfaktoriellen) Betreuereinschätzung fiel insgesamt niedrig bis mäßig aus, brachte aber auf Einzelfallebene differenziertere Ergebnisse. Im Verlauf nahmen die Werte auf allen vier Jugendlichenskalen ab. Einzig der Verlauf der Wertschätzung in der Eingewöhnungsphase war prädiktiv für den späteren Abbruch der Maßnahme: Bei den Abbrechern nahm die Wertschätzung ab, während sie bei den Beendern initial stieg. Schlussfolgerungen: Der bedeutsamste Faktor in Bezug auf die Therapiebeendigung suchtkranker Jugendlicher scheint die Wertschätzung von Therapie/Betreuung zu sein, während die Motivation jugendtypische Schwankungen aufweist. Der Suchtdynamik kam eine deutlich weniger bedeutende Rolle zu als allgemein angenommen. Programme in der Langzeittherapie sollten die Wertschätzung von Therapie/Betreuung künftig mehr fokussieren als die Suchtdynamik.

A Multi-level Measure Of Safety Climate And Associations With Safety Behaviors In The Fire Service

2017 ◽  
Author(s):  
Todd D. Smith ◽  
Mari-Amanda Dyal ◽  
Yongjia Pu ◽  
Stephanie Dickinson ◽  
David M. DeJoy
Keyword(s):  
Safety Climate ◽  
Fire Service ◽  
Safety Behaviors ◽  
Multi Level
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