Mechanism of interferon induction by cannabidiol (CBD) and analogues in lung cancer cells

CBD, an FDA approved drug for epilepsy, may have therapeutic potential for other diseases and is currently being tested for efficacy in cancer-related clinical trials. As the literature about CBD, especially in vitro reports, is often contradictory, increasing our understanding of its specific action on a molecular level will allow to determine whether CBD can become a useful therapy or exacerbates specific cancers in a context-dependent manner. Due to its relative lipophilicity, CBD is challenging to dispense at therapeutic concentrations;therefore, one goal is to identify cannabinoid congeners with greater efficacy and reduced drug delivery challenges. We recently showed that CBD activates interferons as a mechanism of inhibiting SARS-CoV-2 replication in lung carcinoma cells. As factors produced by the innate immune system, interferons have been implicated in both pro-survival and growth arrest and apoptosis signaling in cancer. Here we show that CBD induces interferon production and interferon stimulated genes (ISGs) through a mechanism involving NRF2 and MAVS in lung carcinoma cells. We also show that CBDV, which differs from CBD by 2 fewer aliphatic tail carbons, has limited potency, suggesting that CBD specifically interacts with one or more cellular proteins rather than having a non-specific effect. We also identified other CBD-related cannabinoids that are more effective at inducing ISGs. Taken together, these results characterize a novel mechanism by which CBD activates the innate immune system in lung cancer cells and identify related cannabinoids that have possible therapeutic potential in cancer treatment.

Nanosponges: As a Dynamic Drug Delivery Approach for Targeted Delivery

Recent advancements in nanotechnology have resulted in improved medicine delivery to the target site. Nanosponges are three-dimensional drug delivery systems that are nanoscale in size and created by cross-linking polymers. The introduction of Nanosponges has been a significant step toward overcoming issues such as drug toxicity, low bioavailability, and predictable medication release. Using a new way of nanotechnology, nanosponges, which are porous with small sponges (below one microm) flowing throughout the body, have demonstrated excellent results in delivering drugs. As a result, they reach the target place, attach to the skin's surface, and slowly release the medicine. Nanosponges can be used to encapsulate a wide range of medicines, including both hydrophilic and lipophilic pharmaceuticals. The medication delivery method using nanosponges is one of the most promising fields in pharmacy. It can be used as a biocatalyst carrier for vaccines, antibodies, enzymes, and proteins to be released. The existing study enlightens on the preparation method, evaluation, and prospective application in a medication delivery system and also focuses on patents filed in the field of nanosponges.Copyright © 2023 The Authors.

Exosomes/EVs: BIOXOME: A NATURAL LIPOSOME MIMETIC AS DRUG DELIVERY SYSTEM

Background & Aim: Liposomes are spherical-shaped vesicles composed of one or more lipid bilayers. The ability of liposomes to encapsulate hydro- or lipophilic drugs allowed these vesicles to become a useful drug delivery system. Natural cell membranes, such as Bioxome, have newly emerged as new source of materials for molecular delivery systems. Bioxome are biocompatible and GMP-compliant liposome-like membrane that can be produced from more than 200 cell types. Bioxome self-assemble, with in-process self-loading capacity and can be loaded with a variety of therapeutic compounds. Once close to the target tissue, Bioxome naturally fuse with the cell membrane and release the inner compound. Orgenesis is interested in evaluating the potential of Bioxome as new drug delivery system for treatment of several diseases, including skin repair, local tumour or COVID19. Methods, Results & Conclusion(s): Bioxome were obtained from adipose- derived Mesenchymal Stem Cells, with a process of organic- solvent lipid extraction, followed by lyophilization and sonication assemblage. During the sonication process, Bioxome were charged or not with several cargos. Size distribution of empty Bioxome was detected by Particle Size Analyzer (NanoSight). Electron Microscopy (EM) was performed to assess Bioxome morphology. Lipid content was evaluated by electrospray ionization system. Dose response in vitro test on human lung fibroblasts treated or not with Bioxome encapsulating a specific cargo (API) against COVID19 were performed. NanoSight analysis showed that nanoparticle size in Bioxome samples ranged between 170+/-50 nm, with a concentration ranging between 109-1010+/-106 particles/mL. EM clearly showed the double phospholipid layers that composes the Bioxome. Stability study demonstrated that Bioxome are stable in size and concentration up to 90 days at +4Cdegree or even at RT. No change in size between encapsulated Bioxome with small size (~340 Da) cargo vs empty Bioxome was observed up to 30 days storage. Lipidomic analysis approach revealed that the yield of lipids and their composition are satisfactory for a therapeutic product using Bioxome. Lastly, in the in vitro model of COVID19, Bioxome encapsulating API effectively saved cells from death (20x vs untreated cells) and at lower doses of API than these of non-encapsulated cargo (0.005 microM vs 0.1 microM). Bioxome seems to be an excellent candidate for liposome mimetic tool as drug delivery system for targeting specific organs and diseases treatment.Copyright © 2023 International Society for Cell & Gene Therapy

Evaluation of In Vitro Distribution and Plasma Protein Binding of Selected Antiviral Drugs (Favipiravir, Molnupiravir and Imatinib) against SARS-CoV-2.

There are a number of uncertainties regarding plasma protein binding and blood distribution of the active drugs favipiravir (FAVI), molnupiravir (MOLNU) and imatinib (IMA), which were recently proposed as therapeutics for the treatment of COVID-19 disease. Therefore, proton dissociation processes, solubility, lipophilicity, and serum protein binding of these three substances were investigated in detail. The drugs display various degrees of lipophilicity at gastric (pH 2.0) and blood pH (pH 7.4). The determined pKa values explain well the changes in lipophilic character of the respective compounds. The serum protein binding was studied by membrane ultrafiltration, frontal analysis capillary electrophoresis, steady-state fluorometry, and fluorescence anisotropy techniques. The studies revealed that the ester bond in MOLNU is hydrolyzed by protein constituents of blood serum. Molnupiravir and its hydrolyzed form do not bind considerably to blood proteins. Likewise, FAVI does not bind to human serum albumin (HSA) and α1-acid glycoprotein (AGP) and shows relatively weak binding to the protein fraction of whole blood serum. Imatinib binds to AGP with high affinity (logK' = 5.8-6.0), while its binding to HSA is much weaker (logK' ≤ 4.0). The computed constants were used to model the distribution of IMA in blood plasma under physiological and 'acute-phase' conditions as well.

Computational demonstration of cheminformatics and machine learning in coronavirus drug discovery

Computational tools in drug discovery involve the use of algorithms in predicting properties of potential drugs as ligands as well as biological targets in structural forms. This dates back to more than 30 years ago and have been perfected with time and advancement of technology. They are reliable to varying extents depending on the nature of the study, complexity among other factors. Computational tools help medicinal chemists, computational chemists, and structural biologists to design and optimize potential drugs as early as possible and reduce or completely avoid attrition in the drug discovery pipeline. The search for drugs to cure or manage COVID-19 is made relatively easier and more efficient by the use of computational tools to help understand the ADMET properties of possible drugs under development. This chapter demonstrates how computational tools in cheminformatics and machine learning can be used in the fight against COVID-19 from a medicinal chemistry perspective using selected parameters. © 2022 Elsevier Inc. All rights reserved.

Teicoplanin and vancomycin derivatives with perfluorilated alkyl groups are active against influenza and coronavirus

Background: As we have seen in the last six months, emerging and re-emerging viruses could be the biggest threat for the human population nowadays in our modern, accelerated and globalized world. Both of influenza and coronaviruses have the potential to cause serious pandemics worldwide. Unfortunately, there are no effective enough medications against most of these viruses. Aims: As some glycopeptide antibiotics and their derivatives proved to be effective against several viruses1, therefore we planned to synthesize some new derivatives equipped with highly fluorinated lipophilic groups. Methods: Perfluorobutyl and perfluorooctyl groups were conjugated to the N-terminus of teicoplanin pseudoaglycone and vancomycin aglycone derivatives through ethylene glycol and tetraethylene glycol linkers by means of photoinitiated addition and azide-alkyne click reaction. The effect of the derivatives were evaluated against several viruses including influenza and human coronavirus. Results: Vancomycin aglycone derivatives were inactive against all of the studied influenza strains, while 3 out of the 4 perfluorobutyl and perfluorooctyl derivatives of teicoplanin pseudoaglycone displayed very good activity against influenza H1N1, H3N2 and B strains. Two of the derivatives were active against human coronavirus as well. Conclusion: We hope that these results can open a new way in finding more effective antivirals based on glycopeptide antibiotics.

Managing Delirium in a patient with Extracorporeal Membrane Oxygenation (ECMO) machine for bridge to lung transplant: A Case report

Background: Due to COVID pandemic, there have been increased needs for ECMO circuits to support patients with respiratory failure1. Unfortunately, due to pharmacokinetics alteration of commonly used sedative and psychotropic medications by the ECMO circuits2,new sedation approaches to manage delirium and agitation is required. We present a case of COVID pneumonia patient on ECMO support, whose delirium symptoms were managed with a novel psychopharmacotherapy protocol. Case: Mr. M is a 57-year-old male patient with past medical history of obesity, hypertension, admitted to Stanford Hospital due to COVID pneumonia, complicated by respiratory failure, required to be on Veno-Venous ECMO support with bridge to transplant. He had significant hyperactive delirium with Richmond Agitation-Sedation Scale (RASS) score of +3 and ICDSC score of 7 for most of the days, despite heavy conventional pharmacological sedation. We observe the same problems with most patients placed on the ECMO system, leading to an investigation and development of a new protocol. Discussion: Patient on ECMO support requires adequate sedation to prevent clinical deterioration that can result from hyperactive delirium (ie., chugging, blood clots or decannulation)2. Nevertheless, ECMO circuit’s significant alterations of drug pharmacokinetics, such as increased volume of distribution and sequestration of lipophilic and protein bound medications, with no clear guidelines on managing sedation/delirium in patients with ECMO support at this time2, we conducted an extensive literature search and developed a novel protocol. This new sedation approach includes alpha-2 agonists, opioids, barbiturates and calcium channel modulators with the lowest lipophilicity and protein binding potential of each medication in its class4,5,thus overcoming the challenges introduced by ECMO circuits. The new protocol allowed the patient to participate in lung transplant work-up, physical therapy, and eventually facilitated receiving bilateral lung transplantation. Conclusion/Implications: ECMO is a life saving device that can help patient with cardiac-respiratory failure, and its use has been increasing in clinical practice. However, there needs to be an improvement in successful sedation/delirium management to minimize adverse events, and optimize the success of this lifesaving technologies. References: 1. Cho HJ, et al. ECMO use in COVID-19: lessons from past respiratory virus outbreaks-a narrative review. Crit Care. 2020 Jun 6;24(1):301 2. deBacker J, et al. Sedation Practice in Extracorporeal Membrane Oxygenation-Treated Patients with Acute Respiratory Distress Syndrome: A Retrospective Study. ASAIO J. 2018 Jul/Aug;64(4):544-551 3. Lemaitre F, et al. Propofol, midazolam, vancomycin and cyclosporine therapeutic drug monitoring in extracorporeal membrane oxygenation circuits primed with whole human blood. Crit Care. 2015;19(1):40 4. Hansch C, et al. Hydrophobicity and central nervous system agents: on the principle of minimal hydrophobicity in drug design. J Pharm Sci. 1987 Sep;76(9):663-87 5. Bockbrader HN, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010 Oct;49(10):661-9

Anticoagulants: dose control methods and inhibitors

These days, anticoagulants are in great demand. They are used as a prophylaxis for thromboembolic complications in various diseases and conditions in general therapeutic practice, cardiology, neurology, as well as obstetrics to manage high-risk pregnancies. The relevance of anticoagulants competent use has come to the fore in connection with the emergence of a new disease – COVID-19 and its serious complications such as developing thrombotic storm, in which the timely applied anticoagulant therapy is the key to the success of therapy. The risk of bleeding should be considered when using any anticoagulant. Age, impaired renal function and concomitant use of antiplatelet agents are common risk factors for bleeding. Moreover, only vitamin K antagonists and heparin have specific antidotes – vitamin K and protamine, respectively. Inhibitors of other anticoagulants are universal presented as inactivated or activated prothrombin complex concentrate and recombinant factor VIIa. Hemodialysis effectively reduces dabigatran concentration, activated charcoal is effective in the case of recent oral administration of lipophilic drugs. Research on new antidotes of currently available anticoagulants is under way, similar to testing of new types of anticoagulants that are sufficiently effective in preventing and treating thromboembolic complications with minimal risk of hemorrhagic. The main contraindication to anticoagulants use is the doctor's ignorance of the mechanisms of drug action and opportunities for suppressing its effect.

Synthesis of New 1,2,3,4-Tetrahydroquinoline Hybrid of Ibuprofen and Its Biological Evaluation

Herein we report the obtaining of 1-(3,4-dihydroquinolin-1(2H)-yl)-2- (4-isobutylphenyl)propan-1-one and its characterization. The newly obtained hybrid and its derivatives (hybrids of ibuprofen with 1,2,3,4-tetrahydroisoquinoline, and piperidine) were screened for their in vitro antioxidant, antitryptic, and inhibition of albumin denaturation activity. The lipophilicity was established using both reversed-phase thin layer chromatography and in silico calculations.

The use of phenobarbital in ECMO

INTRODUCTION: A high prevalence of critically ill patients have difficulty obtaining an appropriate level of sedation. Additional challenges may arise in patients requiring extracorporeal membrane oxygenation (ECMO). The utility of phenobarbital, a barbiturate sedative hypnotic that produces sedation through GABAA receptor agonism, in adult ECMO patients has yet to be described within the literature. DESCRIPTION: A 46-year-old male (95 kg) with asthma, hyperlipidemia and recently diagnosed COVID19, was admitted to the ICU for acute hypoxic respiratory failure and subsequently initiated on VV ECMO. By day 13, his sedation regimen consisted of the following: hydromorphone 12 mg/hr, midazolam 15 mg/hr, ketamine 1.4 mg/kg/hr and dexmedetomidine 1.4 mcg/kg/min, along with oral diazepam 15 mg every 6 hours. Propofol use was limited because of hypertriglyceridemia. Despite this, he was dyschronous with the ventilator. A recommendation was made to use phenobarbital. The patient was loaded with 10 mg/kg using ideal body weight (IBW), followed by 1 mg/kg twice daily. At steady state, a serum level was checked and resulted at 10.8 ug/mL. Simultaneously, the patient was more synchronous and did not require any escalation in sedation. Following a decompensatory event, a repeat bolus of 5 mg/kg IBW was given, followed by a 2 mg/kg twice daily regimen. A second steady state level was checked and resulted at 16.7 ug/mL. DISCUSSION: This case highlights the potential role for phenobarbital in ECMO patients refractory to conventional sedation, and sheds light on pharmacokinetic (PK) considerations. Phenobarbital is a relatively lipophilic drug with a LogP value of 1.47 and limited protein binding (48% protein bound). Given this PK profile, we anticipated that the degree of sequestration in the ECMO circuit would be low. We performed therapeutic drug monitoring and obtained serum levels at steady state and compared the findings to non-ECMO patients. Although no optimal phenobarbital level for sedation has been defined, extrapolation from therapeutic levels for epilepsy (15-40 ug/mL) was made. Based on our results, we concluded that limited drug sequestration occurred within the circuit and no dosing adjustment may be needed. The standard dose may be similar to non- ECMO patients and should be guided by therapeutic drug monitoring.

Lipophilicity, Pharmacokinetic Properties, and Molecular Docking Study on SARS-CoV-2 Target for Betulin Triazole Derivatives with Attached 1,4-Quinone.

A key parameter in the design of new active compounds is lipophilicity, which influences the solubility and permeability through membranes. Lipophilicity affects the pharmacodynamic and toxicological profiles of compounds. These parameters can be determined experimentally or by using different calculation methods. The aim of the research was to determine the lipophilicity of betulin triazole derivatives with attached 1,4-quinone using thin layer chromatography in a reverse phase system and a computer program to calculate its theoretical model. The physiochemical and pharmacokinetic properties were also determined by computer programs. For all obtained parameters, the similarity analysis and multilinear regression were determined. The analyses showed that there is a relationship between structure and properties under study. The molecular docking study showed that betulin triazole derivatives with attached 1,4-quinone could inhibit selected SARS-CoV-2 proteins. The MLR regression showed that there is a correlation between affinity scoring values (ΔG) and the physicochemical properties of the tested compounds.