Chlorpheniramine Maleate Displays Multiple Modes of Antiviral Action Against SARS-CoV- 2: A Mechanistic Study (preprint)

Chlorpheniramine Maleate (CPM) has been identified as a potential antiviral compound against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In this study, we investigated the in vitro effects of CPM on key stages of the SARS-CoV-2 replication cycle, including viral adsorption, replication inhibition, and virucidal activity. Our findings demonstrate that CPM exhibits antiviral properties by interfering with viral adsorption, replication, and directly inactivating the virus. Molecular docking analysis revealed interactions between CPM and essential viral proteins, such as the main protease receptor, spike protein receptor, and RNA polymerase. CPM's interactions were primarily hydrophobic in nature, with an additional hydrogen bond formation in the RNA polymerase active site. These results suggest that CPM has the potential to serve as a multitarget antiviral agent against SARS-CoV-2 and potentially other respiratory viruses. Further investigations are warranted to explore its clinical implications and assess its efficacy in vivo.

A deep learning predictive model for public health concerns and hesitancy toward the COVID-19 vaccines.

Throughout the pandemic era, COVID-19 was one of the remarkable unexpected situations over the past few years, but with the decentralization and globalization of efforts and knowledge, a successful vaccine-based control strategy was efficiently designed and applied worldwide. On the other hand, excused confusion and hesitation have widely impacted public health. This paper aims to reduce COVID-19 vaccine hesitancy taking into consideration the patient's medical history. The dataset used in this study is the Vaccine Adverse Event Reporting System (VAERS) dataset which was created as a corporation between the Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) to gather reported side effects that may be caused by PFIEZER, JANSSEN, and MODERNA vaccines. In this paper, a Deep Learning (DL) model has been developed to identify the relationship between a certain type of COVID-19 vaccine (i.e. PFIEZER, JANSSEN, and MODERNA) and the adverse reactions that may occur in vaccinated patients. The adverse reactions under study are the recovery condition, possibility to be hospitalized, and death status. In the first phase of the proposed model, the dataset has been pre-proceesed, while in the second phase, the Pigeon swarm optimization algorithm is used to optimally select the most promising features that affect the performance of the proposed model. The patient's status after vaccination dataset is grouped into three target classes (Death, Hospitalized, and Recovered). In the third phase, Recurrent Neural Network (RNN) is implemented for both each vaccine type and each target class. The results show that the proposed model gives the highest accuracy scores which are 96.031% for the Death target class in the case of PFIEZER vaccination. While in JANSSEN vaccination, the Hospitalized target class has shown the highest performance with an accuracy of 94.7%. Finally, the model has the best performance for the Recovered target class in MODERNA vaccination with an accuracy of 97.794%. Based on the accuracy and the Wilcoxon Signed Rank test, we can conclude that the proposed model is promising for identifying the relationship between the side effects of COVID-19 vaccines and the patient's status after vaccination. The study displayed that certain side effects were increased in patients according to the type of COVID-19 vaccines. Side effects related to CNS and hemopoietic systems demonstrated high values in all studied COVID-19 vaccines. In the frame of precision medicine, these findings can support the medical staff to select the best COVID-19 vaccine based on the medical history of the patient.

Design, Synthesis and In Vitro Evaluation of Spirooxindole-Based Phenylsulfonyl Moiety as a Candidate Anti-SAR-CoV-2 and MERS-CoV-2 with the Implementation of Combination Studies.

The search for an effective anti-viral to inhibit COVID-19 is a challenge for the specialized scientific research community. This work investigated the anti-coronavirus activity for spirooxindole-based phenylsulfone cycloadducts in a single and combination protocols. The newly designed anti-SARS-CoV-2 therapeutics spirooxindoles synthesized by [3 + 2] cycloaddition reactions represent an efficient approach. One-pot multicomponent reactions between phenyl vinyl sulfone, substituted isatins, and amines afforded highly stereoselective anti-SARS-CoV-2 therapeutics spirooxindoles with three stereogenic centers. Herein, the newly synthesized spirooxindoles were assessed individually against the highly pathogenic human coronaviruses and proved to be highly potent and safer. Interestingly, the synergistic effect by combining the potent, tested spirooxindoles resulted in an improved antiviral activity as well as better host-cell safety. Compounds 4i and 4d represented the most potent activity against MERS-CoV with IC50 values of 11 and 23 µM, respectively. Both compounds 4c and 4e showed equipotent activity with the best IC50 against SARS-CoV-2 with values of 17 and 18 µM, respectively, then compounds 4d and 4k with IC50 values of 24 and 27 µM, respectively. Then, our attention oriented to perform a combination protocol as anti-SARS-CoV-2 for the best compounds with a different binding mode and accompanied with different pharmacophores. Combination of compound 4k with 4c and combination of compounds 4k with 4i proved to be more active and safer. Compounds 4k with 4i displayed IC50 = 3.275 µM and half maximal cytotoxic-concentration CC50 = 11832 µM. MD simulation of the most potential compounds as well as in silico ADMET properties were investigated. This study highlights the potential drug-like properties of spirooxindoles as a cocktail anti-coronavirus protocol.

Design a sturdy and secure authentication scheme capable of early detection of COVID-19 patients using WBANs

COVID-19 was first reported in China Wuhan and rapidly grown up to more than 58 countries based on the World Health Organization (WHO). Well ahead of any health emergency, the health care server has the ability to access these data via authorization and then s/he performs necessary actions. In order to protect medical data from malicious activities, authentication is the starting point for this. Authentication systems represent a network support factor to reduce ineffective users and radically eliminate phishing because authentication determines the identity of the real user. Many schemes and technologies have been suggested for authentication in wireless body area networks (WBANs). In this paper, we suggest a strong dynamic password authentication system for WBANs. We adopt a (different/new) way to calculate a password and make it coherent and dynamic for each login session. Our work also provides additional security properties to get rid of hub node impersonation attacks and resolve key escrow issues. Our scheme resist fishing attach which keep patient from any illegal change of drugs. By comparison, the proposed scheme is considered active and has strong security based on formal security analysis tools such as AVISPA. © 2022 Institute of Advanced Engineering and Science. All rights reserved.

HYBRID ENDOSCOPIC ULTRASOUND IN THE COVID-19 ERA FOR THE TISSUE DIAGNOSIS OF SOLID LESIONS: AN INITIAL EXPERIENCE FROM A TERTIARY CARE CENTRE IN PAKISTAN

AIM: Endoscopic Ultrasound (EUS) is well-established mode of intervention for tissue acquisition in solid organs with rapid on-site evaluation (ROSE). In the Covid-19 era implementation of infection control mechanisms has led modified hybrid technique to get high diagnostic yield for tissue sampling. Combination of Covid-19 SOPs and tissue acquisition method outline this hybrid technique to get high diagnostic Yield.We share our initial experience of EUS cases performed with this approach without ROSE. METHODS: All 84 cases who underwent EUS guided biopsy from June 2020 till December 2021 were included. The Procedure was done in a negative pressure room with all SOPs as per institutional guidelines for patient and staff safety with a minimum number of persons during procedure. RESULTS: Among these cases, 55 were male, mean age 56 years (range 22-90), Mean duration of procedure 25 min mean (10-90 min). 63 came for organ targeted for malignant pathology include pancreas 35, liver 02, lymph nodes 17, subepithelial lesions 06, mediastinal lesions 08, common-bile duct/gall bladder 04. 17 cases had a multi-targeted biopsy for the additional staging of disease. The number of 'passes' with the needle was average 02 with single pass 17, two pass 39, three passes 11, multitarget single pass in 17. Needle size (Franseen design) used for procedures was 22G in 78 cases and 25G in 6. Common tissue diagnoses include pancreatic adenocarcinoma 26, neuroendocrine tumours 04, tuberculosis 05, gastrointestinal stromal tumours 02, leiomyoma 03, lymphoma 03, metastatic renal cell carcinoma 04, squamous cell carcinoma 04, cholangiocarcinoma/ gall bladder adenocarcinoma 07, Sarcoma 02 and solid pseudopapillary epithelial neoplasm of pancreas (SPEN) 01. There were no immediate or early complications in all cases. CONCLUSIONS: Hybrid EUS in Covid 19 Era has emerged as a useful/cost-effective and safe approach to get tissue yield without the need for ROSE.

Panhypopituitarism Induced by COVID-19 Infection

Introduction: Coronavirus disease 2019 (COVID-19) infection has led to multiple endocrinopathies. We present a case of panhypopituitarism induced by COVID -19 infection. Case Description: 76 yo male with history of type 2 diabetes, hypertension, and 1.5 cm stable, nonfunctioning, pituitary macroadenoma diagnosed in 2017 had multiple admissions for altered mental status and hyponatremia following COVID-19 infection in April 2020. Workup revealed low free T4 0.60 ng/dL (0.8-1.8), low random cortisol 1.8 mcg/dL(2.9-19.4), high prolactin 33.5 ng/mL (2-18), low total testosterone < 10 ng/dl (175-781), SHBG 32.7 nmol/L (13.3-89.5), and low gonadotropins. While hospitalized, he was diagnosed with pan-hypopituitarism and started on glucocorticoids and levothyroxine. Repeat MRI pituitary done after discharge, documented stability of the macroadenoma without hemorrhage. To date, the patient remains on glucocorticoid replacement and thyroid hormone replacement in stable state. Discussion: Hypopituitarism from any etiology has an incidence of 4.2 per 100,000. Hormone replacement therapy remains the mainstay of treatment. This case represents a patient who had unexplained recurrent hyponatremia after COVID-19 infection and later diagnosed with pan-hypopituitarism. Given the continued pandemic, more endocrinopathies related to the COVID-19 infection have been reported. We have data for other viral infections, such as SARS and Dengue, documenting pituitary dysfunction. Review of literature documents SARS infection leading to post infectious hypophysitis with resulting secondary hypocortisolism and hypothyroidism. The cause was thought to be virus binding to pituitary angiotensin-converting enzyme 2 (ACE2) receptors. There is also data supporting COVID-19 infection leading to pituitary apoplexy and hypophysitis, though the number of cases reported is limited. The pathophysiology is thought to be the COVID 19 virus binding to pituitary ACE2 receptors for which it has a 10-20-fold higher affinity. Furthermore, the hypothalamus also expresses ACE2 receptors making it a target for the virus. The binding leads to cellular destruction and autoimmune collateral damage. Hypothalamic pituitary dysfunction could be due to direct effect of virus. The virus can also lead to reversible hypophysitis.

Lipid polymer hybrid nanocarriers as a combinatory platform for different anti-SARS-CoV-2 drugs supported by computational studies† † Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra04576h

The COVID-19 pandemic caused by SARS-CoV-2 has demonstrated the potential of emergent pathogens to severely damage public health and global economies. As a consequence of the pandemic, millions of people have been forced into self-isolation, which has negatively affected the global economy. More efforts are needed to find new innovative approaches that could fundamentally change our understanding and management of this disaster. Herein, lipid polymer hybrid nanoparticles (LPH NPs) were utilized as a platform for the delivery of azithromycin or niclosamide in combination with piroxicam. The obtained systems were successfully loaded with both azithromycin and piroxicam (LPHAzi–Pir) with entrapment efficiencies (EE%) of 74.23 ± 8.14% and 51.52 ± 5.45%, respectively, or niclosamide and piroxicam (LPHNic–Pir) with respective EE% of 85.14 ± 3.47% and 48.75 ± 4.77%. The prepared LPH NPs had a core–shell nanostructure with particle size ≈ 125 nm and zeta potential ≈ −16.5 irrespective of drug payload. A dose-dependent cellular uptake of both LPH NPs was observed in human lung fibroblast cells. An enhanced in vitro antiviral efficacy of both LPHAzi–Pir and LPHNic–Pir was obtained over the mixed solution of the drugs. The LPH NPs of azithromycin or niclosamide with piroxicam displyed a promising capability to hinder the replication of SARS-CoV-2, with IC50 of 3.16 and 1.86 μM, respectively. These results provide a rationale for further in vivo pharmacological as well as toxicological studies to evaluate the potential activity of these drugs to combat the COVID-19 outbreak, especially the concept of combination therapy. Additionally, the molecular docking of macrolide bioactive compounds against papain-like protease (PDB ID:6wuu) was achieved. A ligand-based study, especially rapid overlay chemical structure (ROCS), was also examined to identify the general pharmacophoric features of these compounds and their similarity to reported anti-SARS-CoV-2 drugs. Molecular dynamic simulation was also implemented. Drug repurposing approach to combat SARS-CoV-2: lipid polymer hybrid nanoparticles (LPH) for the delivery of azithromycin or niclosamide in combination with piroxicam.

Evaluation of Biochemical and Hematological Parameters in Glucose-6-Phosphate Dehydrogenase Deficiency Patients Associated Covid19 infection

G6PD-deficiency is the most prevalent enzymopathy over the world and this deficit is expected to impact about 400 million individuals worldwide. Africa, Southern-Europe and the Middle-East, including Iraq, have the greatest incidence rates in this deficiency. Aim of study: The main objective of the current research study the relationship between specific biochemical parameters and Covid19 infection associated G6PDD patients in Mosul City. A cross study in a group of 43 as 21 males and 22 females participants with Covid19 positively infection associated G6PDD, 51 Covid19 patients with any chronic diseases as 24 males, 27 females and 40 healthy controls as 21 males and 19 females participants by paid a visit outpatient clinics and private hospitals in Mosul city from the date of 15/1 to 15/2 of 2021. Whole blood samples were collected from all volunteers' patients and healthy to be analyze for serum G6PD activity, GOT, GPT, ALP, LDH and also analyze CBC. The results were showed that the majority patients of the Covid-9 with G6PDD indicated lower levels of serum G6PD activity in Covid19 patients with G6PDD more than Covid-19compared to healthy control, Also Covid19 with G6PDD having an effect increases of Total WBC and decreases in levels of Hb and PCV more than Covid19 patients. © 2022 National Information and Documentation Center.

Structure- and Ligand-Based in silico Studies towards the Repurposing of Marine Bioactive Compounds to Target SARS-CoV-2.

This work was a structured virtual screening for marine bioactive compounds with reported antiviral activities which were subjected to structure-based studies against SARS-CoV-2 co-crystallized proteins. The molecular docking of marine bioactive compounds against the main protease (Mpro, PDB ID: 6lu7 and 6y2f), the spike glycoprotein (PDB ID: 6vsb), and the RNA polymerase (PDB ID: 6m71) of SARS-CoV-2 was performed. Ligand-based approach with the inclusion of rapid overlay chemical structures (ROCS) was also addressed in order to examine the probability of these marine compounds sharing relevance and druggability with the reported drugs. Among the examined marine library, the highest scores in different virtual screening aspects were displayed by compounds with flavonoids core, acyl indole, and pyrrole carboxamide alkaloids. Moreover, a complete overlay with the co-crystallized ligands of Mpro was revealed by sceptrin and debromo-sceptrin. Thalassoilin (A-B) which was found in the Red Sea exhibited the highest binding and similarity outcomes among all target proteins. These data highlight the importance of marine natural metabolites in regard to further studies for discovering new drugs to combat the COVID-19 pandemic.

In silicodomain structural model analysis of coronavirus orf1ab polyprotein

The world today is battling with a coronavirus infection which is considered a global pandemic. Coronavirus infection is mainly attributed to the varying technique of the replication and releaseof different genomic components of the virus. In this study, the aim is to establish the physical and chemical features, as well as the basic structural and functional properties of Coronavirus ORF1ab domain. A molecular approach was adopted in this study using the Swiss Model & Phyre2 server while the prediction of the active ligand binding sites was done using Phyre2.The analysis of the structure of the protein showed that it has good structural and heat stability, as well as better hydrophilic features and acidic in nature. Based on the Homology modelling, only 2 binding active sites were noted with catalytic function being mediated by Zn2+ as the metallic heterogen ligand for binding sites prediction. The proteins mostly exhibited helical secondary configurations. This study can help in predicting and understanding the role of this domain protein in active coronavirus infection.

An in silico perception for newly isolated flavonoids from peach fruit as privileged avenue for a countermeasure outbreak of COVID-19.

3'-Hydroxy-4'-methoxy-chroman-7-O-ß-d-glucopyranoside 4 was first isolated from a natural source, together with three known compounds, the ferulic acid heptyl ester 1, naringenin 2, and 4,2',4'-trihydroxy-6'-methoxychalcone-4'-O-ß-d-glucopyranoside 3, which were isolated from peach [Prunus persica (L.) Batsch] fruits. These compounds were subjected to different virtual screening strategies in order to examine their activity to combat the COVID-19 outbreak. The study design composed of some major aspects: (a) docking with main protease (Mpro), (b) docking with spike protein, (c) 3D shape similarity study (Rapid Overlay Chemical Similarity-ROCS) to the clinically used drugs in COVID-19 patients, and finally, (d) the rule of five and the estimated pre-ADMT properties of the separated flavonoids. Docking study with Mpro of SARS-CoV-2 (PDB ID:6LU7, and 6Y2F) showed that compound 3, its aglycone part, and compound 4 have a strong binding mode to a protease receptor with key amino acids, especially Gln:166AA, and having a similar docking pose to co-crystalized ligands. Docking with the spike protein of SARS-CoV-2 illustrated that compounds 3 and 4 have a good binding affinity to PDB ID:6VSB through the formation of HBs with Asp:467A and Asn:422A. According to ROCS analysis, compounds 1, 3, and 4 displayed high similarities to drugs that prevent SARS-Co2 entry to the lung cells or block the inflammatory storm causing lung injury. Compounds 3 and 4 are good candidates for drug development especially because they showed predicted activity against SARS-CoV-2 through different mechanisms either by preventing genome replication or by blocking inflammatory storm that trigger lung injury. These compounds were isolated from peach fruit, and the study supports data and continues with the recommendation of peach fruits in controlling and managing COVID-19 cases.