Health emergencies and interoceptive sensibility modulate the perception of non-evidence-based drug use: Findings from the COVID-19 outbreak.

Scientific evidence plays an important role in the therapeutic decision-making process. What happens when physicians are forced to make therapeutic decisions under uncertainty? The absence of scientific guidelines at the beginning of a pandemic due to an unknown virus, such as COVID-19, could influence the perceived legitimacy of the application of non-evidence-based therapeutic approaches. This paper reports on a test of this hypothesis, in which we administered an ad hoc questionnaire to a sample of 64 Italian physicians during the first wave of the COVID-19 pandemic in Italy (April 2020). The questionnaire statements regarding the legitimacy of off-label or experimental drugs were framed according to three different scenarios (Normality, Emergency and COVID-19). Furthermore, as the perception of internal bodily sensations (i.e., interoception) modulates the decision-making process, we tested participants' interoceptive sensibility using the Multidimensional Assessment of Interoceptive Awareness (MAIA). The results showed that participants were more inclined to legitimate non-evidence-based therapeutic approaches in the COVID-19 and Emergency scenarios than the Normality scenario. We also found that scores on the MAIA Trusting subscale positively predicted this difference. Our findings demonstrate that uncertain medical scenarios, involving a dramatic increase in patient volume and acuity, can increase risk-taking in therapeutic decision-making. Furthermore, individual characteristics of health care providers, such as interoceptive ability, should be taken into account when constructing models to prevent the breakdown of healthcare systems in cases of severe emergency.

Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking.

Screening already approved drugs for activity against a novel pathogen can be an important part of global rapid-response strategies in pandemics. Such high-throughput repurposing screens have already identified several existing drugs with potential to combat SARS-CoV-2. However, moving these hits forward for possible development into drugs specifically against this pathogen requires unambiguous identification of their corresponding targets, something the high-throughput screens are not typically designed to reveal. We present here a new computational inverse-docking protocol that uses all-atom protein structures and a combination of docking methods to rank-order targets for each of several existing drugs for which a plurality of recent high-throughput screens detected anti-SARS-CoV-2 activity. We demonstrate validation of this method with known drug-target pairs, including both non-antiviral and antiviral compounds. We subjected 152 distinct drugs potentially suitable for repurposing to the inverse docking procedure. The most common preferential targets were the human enzymes TMPRSS2 and PIKfyve, followed by the viral enzymes Helicase and PLpro. All compounds that selected TMPRSS2 are known serine protease inhibitors, and those that selected PIKfyve are known tyrosine kinase inhibitors. Detailed structural analysis of the docking poses revealed important insights into why these selections arose, and could potentially lead to more rational design of new drugs against these targets.

Drug-based therapeutic strategies for COVID-19-infected patients and their challenges.

Emerging epidemic-prone diseases have introduced numerous health and economic challenges in recent years. Given current knowledge of COVID-19, herd immunity through vaccines alone is unlikely. In addition, vaccination of the global population is an ongoing challenge. Besides, the questions regarding the prevalence and the timing of immunization are still under investigation. Therefore, medical treatment remains essential in the management of COVID-19. Herein, recent advances from beginning observations of COVID-19 outbreak to an understanding of the essential factors contributing to the spread and transmission of COVID-19 and its treatment are reviewed. Furthermore, an in-depth discussion on the epidemiological aspects, clinical symptoms and most efficient medical treatment strategies to mitigate the mortality and spread rates of COVID-19 is presented.

Exosomes as New Biomarkers and Drug Delivery Tools for the Prevention and Treatment of Various Diseases: Current Perspectives.

Exosomes are nano-sized vesicles secreted by most cells that contain a variety of biological molecules, such as lipids, proteins and nucleic acids. They have been recognized as important mediators for long-distance cell-to-cell communication and are involved in a variety of biological processes. Exosomes have unique advantages, positioning them as highly effective drug delivery tools and providing a distinct means of delivering various therapeutic agents to target cells. In addition, as a new clinical diagnostic biomarker, exosomes play an important role in many aspects of human health and disease, including endocrinology, inflammation, cancer, and cardiovascular disease. In this review, we summarize the development of exosome-based drug delivery tools and the validation of novel biomarkers, and illustrate the role of exosomes as therapeutic targets in the prevention and treatment of various diseases.

Liposome composition in drug delivery design, synthesis, characterization, and clinical application.

Liposomal drug delivery represents a highly adaptable therapeutic platform for treating a wide range of diseases. Natural and synthetic lipids, as well as surfactants, are commonly utilized in the synthesis of liposomal drug delivery vehicles. The molecular diversity in the composition of liposomes enables drug delivery with unique physiological functions, such as pH response, prolonged blood circulation, and reduced systemic toxicity. Herein, we discuss the impact of composition on liposome synthesis, function, and clinical utility.

Drug repurposing: Iron in the fire for older drugs.

Repositioning or "repurposing" of existing therapies for indications of alternative disease is an attractive approach that can generate lower costs and require a shorter approval time than developing a de novo drug. The development of experimental drugs is time-consuming, expensive, and limited to a fairly small number of targets. The incorporation of separate and complementary data should be used, as each type of data set exposes a specific feature of organism knowledge Drug repurposing opportunities are often focused on sporadic findings or on time-consuming pre-clinical drug tests which are often not guided by hypothesis. In comparison, repurposing in-silico drugs is a new, hypothesis-driven method that takes advantage of big-data use. Nonetheless, the widespread use of omics technology, enhanced data storage, data sense, machine learning algorithms, and computational modeling all give unparalleled knowledge of the methods of action of biological processes and drugs, providing wide availability, for both disease-related data and drug-related data. This review has taken an in-depth look at the current state, possibilities, and limitations of further progress in the field of drug repositioning.

The Current Status and Challenges in the Development of Vaccines and Drugs against Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2).

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-19 (COVID-19), which is characterized by clinical manifestations such as pneumonia, lymphopenia, severe acute respiratory distress, and cytokine storm. S glycoprotein of SARS-CoV-2 binds to angiotensin-converting enzyme II (ACE-II) to enter into the lungs through membrane proteases consequently inflicting the extensive viral load through rapid replication mechanisms. Despite several research efforts, challenges in COVID-19 management still persist at various levels that include (a) availability of a low cost and rapid self-screening test, (b) lack of an effective vaccine which works against multiple variants of SARS-CoV-2, and (c) lack of a potent drug that can reduce the complications of COVID-19. The development of vaccines against SARS-CoV-2 is a complicated process due to the emergence of mutant variants with greater virulence and their ability to invoke intricate lung pathophysiology. Moreover, the lack of a thorough understanding about the virus transmission mechanisms and complete pathogenesis of SARS-CoV-2 is making it hard for medical scientists to develop a better strategy to prevent the spread of the virus and design a clinically viable vaccine to protect individuals from being infected. A recent report has tested the hypothesis of T cell immunity and found effective when compared to the antibody response in agammaglobulinemic patients. Understanding SARS-CoV-2-induced changes such as "Th-2 immunopathological variations, mononuclear cell & eosinophil infiltration of the lung and antibody-dependent enhancement (ADE)" in COVID-19 patients provides key insights to develop potential therapeutic interventions for immediate clinical management. Therefore, in this review, we have described the details of rapid detection methods of SARS-CoV-2 using molecular and serological tests and addressed different therapeutic modalities used for the treatment of COVID-19 patients. In addition, the current challenges against the development of vaccines for SARS-CoV-2 are also briefly described in this article.

Existing Drugs Considered as Promising in COVID-19 Therapy.

COVID-19 is a respiratory disease caused by newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease at first was identified in the city of Wuhan, China in December 2019. Being a human infectious disease, it causes high fever, cough, breathing problems. In some cases it can be fatal, especially in people with comorbidities like heart or kidney problems and diabetes. The current COVID-19 treatment is based on symptomatic therapy, so finding an appropriate drug against COVID-19 remains an immediate and crucial target for the global scientific community. Two main processes are thought to be responsible for the COVID-19 pathogenesis. In the early stages of infection, disease is determined mainly by virus replication. In the later stages of infection, by an excessive immune/inflammatory response, leading to tissue damage. Therefore, the main treatment options are antiviral and immunomodulatory/anti-inflammatory agents. Many clinical trials have been conducted concerning the use of various drugs in COVID-19 therapy, and many are still ongoing. The majority of trials examine drug reposition (repurposing), which seems to be a good and effective option. Many drugs have been repurposed in COVID-19 therapy including remdesivir, favipiravir, tocilizumab and baricitinib. The aim of this review is to highlight (based on existing and accessible clinical evidence on ongoing trials) the current and available promising drugs for COVID-19 and outline their characteristics.

COVID-19 and metabolic comorbidities: An update on emerging evidences for optimal therapies.

Type 2 diabetes mellitus, obesity, hypertension, and other associated metabolic complications have been demonstrated as a crucial contributor to the enhanced morbidity and mortality of patients with coronavirus disease 2019 (COVID-19). Data on the interplay between metabolic comorbidities and the outcomes in patients with COVID-19 have been emerging and rapidly increasing. This implies a mechanistic link between metabolic diseases and COVID-19 resulting in the exacerbation of the condition. Nonetheless, new evidences are emerging to support insulin-mediated aggressive glucose-lowering treatment as a possible trigger of high mortality rate in diabetic COVID-19 patients, putting the clinician in a confounding and difficult dilemma for the treatment of COVID-19 patients with metabolic comorbidities. Thus, this review discusses the pathophysiological link among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), angiotensin-converting enzyme 2 (ACE2), metabolic complications, and severe inflammation in COVID-19 development, especially in those with multi-organ injuries. We discuss the influence of several routinely used drugs in COVID-19 patients, including anti-inflammatory and anti-coagulant drugs, antidiabetic drugs, renin-angiotensin-aldosterone system inhibitors. Especially, we provide a balanced overview on the clinical application of glucose-lowering drugs (insulin and metformin), angiotensin-converting-enzyme inhibitors, and angiotensin receptor blockers. Although there is insufficient evidence from clinical or basic research to comprehensively reveal the mechanistic link between adverse outcomes in COVID-19 and metabolic comorbidities, it is hoped that the update in the current review may help to better outline the optimal strategies for clinical management of COVID-19 patients with metabolic comorbidities.

Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis.

Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.

Improved multidetector asymmetrical-flow field-flow fractionation method for particle sizing and concentration measurements of lipid-based nanocarriers for RNA delivery.

Lipid-based nanoparticles for RNA delivery (LNP-RNA) are revolutionizing the nanomedicine field, with one approved gene therapy formulation and two approved vaccines against COVID-19, as well as multiple ongoing clinical trials. As for other innovative nanopharmaceuticals (NPhs), the advancement of robust methods to assess their quality and safety profiles-in line with regulatory needs-is critical for facilitating their development and clinical translation. Asymmetric-flow field-flow fractionation coupled to multiple online optical detectors (MD-AF4) is considered a very versatile and robust approach for the physical characterisation of nanocarriers, and has been used successfully for measuring particle size, polydispersity and physical stability of lipid-based systems, including liposomes and solid lipid nanoparticles. However, the unique core structure of LNP-RNA, composed of ionizable lipids electrostatically complexed with RNA, and the relatively labile lipid-monolayer coating, is more prone to destabilization during focusing in MD-AF4 than previously characterised nanoparticles, resulting in particle aggregation and sample loss. Hence characterisation of LNP-RNA by MD-AF4 needs significant adaptation of the methods developed for liposomes. To improve the performance of MD-AF4 applied to LNP-RNA in a systematic and comprehensive manner, we have explored the use of the frit-inlet channel where, differently from the standard AF4 channel, the particles are relaxed hydrodynamically as they are injected. The absence of a focusing step minimizes contact between the particle and the membrane, reducing artefacts (e.g. sample loss, particle aggregation). Separation in a frit-inlet channel enables satisfactory reproducibility and acceptable sample recovery in the commercially available MD-AF4 instruments. In addition to slice-by-slice measurements of particle size, MD-AF4 also allows to determine particle concentration and the particle size distribution, demonstrating enhanced versatility beyond standard sizing measurements.

Potential Effects of COVID-19 on Cytochrome P450-Mediated Drug Metabolism and Disposition in Infected Patients.

Coronavirus Disease 2019 (COVID-19) has been a global health crisis since it was first identified in December 2019. In addition to fever, cough, headache, and shortness of breath, an intense increase in immune response-based inflammation has been the hallmark of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) virus infection. This narrative review summarizes and critiques pathophysiology of COVID-19 and its plausible effects on drug metabolism and disposition. The release of inflammatory cytokines (e.g., interleukins, tumor necrosis factor α), also known as 'cytokine storm', leads to altered molecular pathophysiology and eventually organ damage in the lung, heart, and liver. The laboratory values for various liver function tests (e.g., alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin) have indicated potential hepatocellular injury in COVID-19 patients. Since the liver is the powerhouse of protein synthesis and the primary site of cytochrome P450 (CYP)-mediated drug metabolism, even a minor change in the liver function status has the potential to affect the hepatic clearance of xenobiotics. It has now been well established that extreme increases in cytokine levels are common in COVID-19 patients, and previous studies with patients infected with non-SARS-CoV-2 virus have shown that CYP enzymes can be suppressed by an infection-related cytokine increase and inflammation. Alongside the investigational COVID-19 drugs, the patients may also be on therapeutics for comorbidities; especially epidemiological studies have indicated that individuals with hypertension, hyperglycemia, and obesity are more vulnerable to COVID-19 than the average population. This complicates the drug-disease interaction profile of the patients as both the investigational drugs (e.g., remdesivir, dexamethasone) and the agents for comorbidities can be affected by compromised CYP-mediated hepatic metabolism. Overall, it is imperative that healthcare professionals pay attention to the COVID-19 and CYP-driven drug metabolism interactions with the goal to adjust the dose or discontinue the affected drugs as appropriate.

Challenges in Biomaterial-Based Drug Delivery Approach for the Treatment of Neurodegenerative Diseases: Opportunities for Extracellular Vesicles.

Biomaterials have been the subject of numerous studies to pursue potential therapeutic interventions for a wide variety of disorders and diseases. The physical and chemical properties of various materials have been explored to develop natural, synthetic, or semi-synthetic materials with distinct advantages for use as drug delivery systems for the central nervous system (CNS) and non-CNS diseases. In this review, an overview of popular biomaterials as drug delivery systems for neurogenerative diseases is provided, balancing the potential and challenges associated with the CNS drug delivery. As an effective drug delivery system, desired properties of biomaterials are discussed, addressing the persistent challenges such as targeted drug delivery, stimuli responsiveness, and controlled drug release in vivo. Finally, we discuss the prospects and limitations of incorporating extracellular vesicles (EVs) as a drug delivery system and their use for biocompatible, stable, and targeted delivery with limited immunogenicity, as well as their ability to be delivered via a non-invasive approach for the treatment of neurodegenerative diseases.

Influence of prior comorbidities and chronic medications use on the risk of COVID-19 in adults: a population-based cohort study in Tarragona, Spain.

OBJECTIVE: To investigate possible relationships between pre-existing medical conditions (including common comorbidities and chronic medications) and risk for suffering COVID-19 disease in middle-aged and older adults. DESIGN: Population-based retrospective cohort study. SETTING: Twelve primary care centres (PCCs) in Tarragona (Spain). PARTICIPANTS: 79 083 people (77 676 community-dwelling and 1407 nursing-home residents), who were all individuals aged >50 years affiliated to the 12 participating PCCs. OUTCOMES: Baseline cohort characteristics (age, sex, vaccinations, comorbidities and chronic medications) were established at study start (1st. March 2020) and primary outcome was time to COVID-19 confirmed by PCR among cohort members throughout the epidemic period (from 1st. March 2020 to 23rd. May 2020). Risk for suffering COVID-19 was evaluated by Cox regression, estimating multivariable HRs adjusted for age, sex, comorbidities and medications use. RESULTS: During the study period, 2324 cohort members were PCR-tested, with 1944 negative and 380 positive results, which means an incidence of 480.5 PCR-confirmed COVID-19 cases per 100 000 persons-period. Assessing the total study cohort, only age (HR 1.02; 95% CI 1.01 to 1.03; p=0.002), nursing-home residence (HR 21.83; 95% CI 16.66 to 28.61; p<0.001) and receiving diuretics (HR 1.35; 95% CI 1.04 to 1.76; p=0.026) appeared independently associated with increased risk. Smoking (HR 0.62; 95% CI 0.41 to 0.93; p=0.022), ACE inhibitors (HR 0.68; 95% CI 0.47 to 0.99; p=0.046) and antihistamine (HR 0.47; 95% CI 0.22 to 1.01; p=0.052) were associated with a lower risk. Among community-dwelling individuals, cancer (HR 1.52; 95% CI 1.03 to 2.24; p=0.035), chronic respiratory disease (HR 1.82; 95% CI 1.08 to 3.07; p=0.025) and cardiac disease (HR 1.53; 95% CI 1.06 to 2.19; p=0.021) emerged to be also associated with an increased risk. Receiving ACE inhibitors (HR 0.66; 95% CI 0.44 to 0.99; p=0.046) and influenza vaccination (HR 0.63; 95% CI 0.44 to 0.91; p=0.012) was associated with decreased risk. CONCLUSION: Age, nursing-home residence and multiple comorbidities appear predisposing for COVID-19. Conversely, receiving ACE inhibitors, antihistamine and influenza vaccination could be protective, which should be closely investigated in further studies specifically focused on these concerns.

Intravitreal injections during COVID-19 outbreak: Real-world experience from an Italian tertiary referral center.

We report our experience during COVID-19 outbreak for intravitreal injections in patients with maculopathy. We proposed a treatment priority levels and timings; the "High" priority level includes all monocular patients; the "Moderate" is assigned to all patients with an active macular neovascularization; the patients affected by diabetic macular edema or retinal vein occlusion belong to the "Low" class. This organization allowed us to treat the most urgent patients although the injections performed had a 91.7% drop compared to the same period of 2019.

Fight against novel coronavirus: A perspective of medicinal chemists.

The ongoing novel coronavirus disease (COVID-19) pandemic makes us painfully perceive that our bullet shells are blank so far for fighting against severe human coronavirus (HCoV). In spite of vast research work, it is crystal clear that the evident does not warrant the commercial blossoming of anti-HCoV drugs. In this circumstance, drug repurposing and/or screening of databases are the only fastest option. This study is an initiative to recapitulate the medicinal chemistry of severe acute respiratory syndrome (SARS)-CoV-2 (SARS-CoV-2). The aim is to present an exquisite delineation of the current research from the perspective of a medicinal chemist to allow the rapid development of anti-SARS-CoV-2 agents.

Sulfobutylether-ß-cyclodextrin.

This review presents the early history, the motivation, the research and some of the backstories behind the discovery and development of sulfobutylether-ß-cyclodextrin as a novel parenterally safe solubilizer and stabilizer. A specific sulfobutylether-ß-cyclodextrin with an average degree of 6.5 sulfobutyl-groups variably substituted on the 2-, 3- and 6-hydroxyls of the seven glucopyranose (dextrose) units of ß-cyclodextrin, is known by its commercial name, Captisol®. Today it is in 13 FDA approved injectables and numerous clinical candidates. It is also an example of a novel product discovered and initially preclinically developed at an academic institution.