Molecular Dynamics and Free Energy Landscape Study of SARS-CoV-2 Omicron M-pro Boswellic acid Compounds of Boswellia Serrata Inhibitors

This work sheds light on the effect of boswellic acid compounds (Alpha boswellic acid, Beta boswellic acid, 11-keto beta boswellic acid and 3-Acetyl-11-keto beta boswellic acid) upon inhibiting SARS-CoV-2 M-pro and O-M-pro (Main protease). A good docking score (-8.4 kcal/mol) is found in the case of 3-Acetyl-11-keto beta boswellic acid as compared to the reference and three other boswellic acid compounds. ADMET results suggest that all these compounds are nontoxic and their pharmacokinetic properties are satisfactory. Moreover, a stability analysis with M-pro/O-M-pro through RMSD, RMSF, hydrogen bonds and Rg parameters in MD simulations is made and we found better values than the reference case. Pre and post-MD structures of Ligands-M-pro show a similar binding site whereas a drift can be noted for L-O-M-pro. 3-Acetyl-11-keto beta boswellic acid shows an average of five hydrogen bonds and it remains stable within the binding pocket of M-pro during the simulation period in comparison to other boswellic acids compounds. Various metastable conformations are observed for all compounds in FEL (free energy landscape), however, Acyclovir-M-pro, Alpha boswellic acid-M-pro and Beta boswellic acid-O-M-pro display only one global minimum. The results suggest that these compounds can be used as potential lead molecules for breakthroughs in drug discovery.

Herpes Zoster Co-Infection with COVID-19: A Case Series

Clinical presentation of COVID-19 infection can be variable in the current pandemic even in patients presenting to the clinic with a mild history of upper respiratory complaints. Various cutaneous manifestations have been noticed in COVID-19 patients with herpes zoster (HZ) being one among them. HZ is an infection that results when varicella zoster virus reactivates from its latent state in the posterior dorsal root ganglion. Here, we aim to expand our knowledge by reporting three cases of associated zoster infection in COVID-19 patients admitted to our intensive care unit in view of respiratory complaints. All the three patients admitted, had revealed lymphocytopenia at the time of HZ diagnosis, and were managed conservatively throughout the course. In all the cases, acyclovir/valacyclovir led to the resolution of lesions in 10 days. No postherpetic sequelae were observed. We here suggest that the clinical presentation of HZ at the time of the current pandemic should be considered as an alarming sign for a latent subclinical SARS CoV-2 infection and thorough follow-up of such patients be adopted.Copyright © 2021 Bali Journal of Anesthesiology. All rights reserved.

Metronidazole, acyclovir and tetrahydrobiopterin may be promising to treat COVID-19 patients, through interaction with interleukin-12.

COVID-19 patients have shown overexpressed serum levels of several pro-inflammatory cytokines, leading to a high mortality rate due to numerous complications. Also, previous studies demonstrated that the metronidazole (MTZ) administration reduced pro-inflammatory cytokines and improved the treatment outcomes for inflammatory disorders. However, the effect and mechanism of action of MTZ on cytokines have not been studied yet. Thus, the current study aimed to identify anti-cytokine therapeutics for the treatment of COVID-19 patients with cytokine storm. The interaction of MTZ with key cytokines was investigated using molecular docking studies. MTZ-analogues, and its structurally similar FDA-approved drugs were also virtually screened against interleukin-12 (IL-12). Moreover, their mechanism of inhibition regarding IL-12 binding to IL-12 receptor was investigated by measuring the change in volume and area. IL-12-metronidazole complex is found to be more stable than all other cytokines under study. Our study also revealed that the active sites of IL-12 are inhibited from binding to its target, IL-12 receptor, by modifying the position of the methyl and hydroxyl functional groups in MTZ. Three MTZ analogues, metronidazole phosphate, metronidazole benzoate, 1-[1-(2-Hydroxyethyl)-5-nitroimidazol-2-yl]-N-methylmethanimine-oxide, and two FDA-approved drugs acyclovir (ACV), and tetrahydrobiopterin (THB) were also found to prevent binding of IL-12 to IL-12 receptor similar to MTZ by changing the surface and volume of IL-12 upon IL-12-drug/ligand complex formation. According to the RMSD results, after 100 ns MD simulations of human IL-12-MTZ/ACV/THB drug complexes, it was also observed that each complex was swinging within a few Å compared to their corresponding docking poses, indicating that the docking poses were reliable. The current study demonstrates that three FDA-approved drugs, namely, metronidazole, acyclovir and tetrahydrobiopterin, are potential repurposable treatment options for overexpressed serum cytokines found in COVID-19 patients. Similar approach is also useful to develop therapeutics against other human disorders.

Development and validation of method for analysis of favipiravir and remdesivir in volumetric absorptive microsampling with ultra high-performance liquid chromatography-tandem mass spectrophotometry.

Favipiravir and remdesivir are drugs to treat COVID-19. This study aims to find an optimum and validated method for simultaneous analysis of favipiravir and remdesivir in Volumetric Absorptive Microsampling (VAMS) by Ultra High-Performance Liquid Chromatography-Tandem Mass Spectrophotometry. The use of VAMS can be an advantage because the volume of blood is small and the sample preparation process is simple. Sample preparation was done by precipitation of protein using 500 µL of methanol. Analysis was carried out by ultra high-performance liquid chromatography-tandem mass spectrophotometry with ESI+ and MRM with m/z 157.9 > 112.92 for favipiravir, 603.09 > 200.005 for remdesivir, and at m/z 225.968 > 151.991 for acyclovir as the internal standard. The separation was carried out using an Acquity UPLC BEH C18 column (100 × 2.1 mm; 1.7 m), 0.2% formic acid-acetonitrile (50:50), flow rate was 0.15 mL/min, and column temperature was 50°C. The analytical method has been validated with the requirements issued by the Food and Drug Administration (2018) and European Medicine Agency (2011). The calibration range of favipiravir is 0.5-160 µg/mL and 0.002-8 µg/mL for remdesivir.

Treatment of Long-Haul COVID Patients With Off-Label Acyclovir.

The SARS-CoV-2 virus (COVID-19) became a global pandemic in March 2020. This novel, highly infectious virus caused millions of infections and deaths around the world. Currently, there are few medications that are available for the treatment of COVID-19. Those affected are most commonly given supportive care, with some experiencing symptoms for months. We report a series of four cases depicting the successful use of acyclovir in the treatment of the virus SARS-CoV-2 in patients with long-haul symptoms, especially those in the realm of encephalopathy and neurological problems. Treatment with acyclovir in these patients resolved their symptoms and lowered their IgG and IgM titers, supporting the use of acyclovir as a safe and effective treatment for COVID-19 neurologic symptoms. We suggest the use of the antiviral medication, acyclovir, as a treatment for patients with long-term symptoms and unusual presentations of the virus, such as encephalopathy or coagulopathy.

A Peculiar Case of Idiopathic Herpes-Zoster-Like Stevens-Johnson Syndrome (SJS).

Epidermal necrolysis is a severe dermatological condition usually associated with adverse drug reactions involving the mucosa. Stevens-Johnson syndrome (SJS) is clinically diagnosed when an epidermal detachment of less than 10% of body surface area (BSA) is involved. In contrast, toxic epidermal necrolysis (TEN) is characterized when there is an epidermal detachment of more than 30% BSA. Epidermal necrolysis can be described as ulcerated, painful, and erythematous lesions typically appearing on the skin. Typical clinical presentations of SJS include epidermal detachment of less than 10% of BSA and mucosal involvement with prodromal flu-like symptoms. Atypical presentations of focal epidermal necrolysis include the presence of lesions in a dermatomal pattern, associated itching, and idiopathic cause. We report a rare case of suspected herpes-zoster virus (HZV)-like SJS with negative HZV serum PCR and negative varicella-zoster virus (VZV) biopsy immunostaining. This rare case of SJS was resolved with the administration of IV acyclovir and Benadryl.

Medications safety for special population case studies: Pediatrics

Medication errors are among the most common medical errors, and studies have shown that the pediatric population is particularly vulnerable. Errors can occur at any stage of the medication process. We tried to build various cases, which highlighted different aspects of drug safety in pediatrics. The case studies focused on vancomycin infusion, supportive treatment in COVID-19-related multisystem inflammatory illness, side effect of antitubercular treatment drugs, management of respiratory failure, low cardiac functioning, acyclovir nephrotoxicity, stress ulcer, cyclophosphamide-induced hemorrhagic cystitis in rhabdomyosarcoma, blood pressure after aortic coarctation elective surgery, and use of paracetamol instead of NSAIDs in pediatrics. These cases would be useful in both as a diagnostic tool and as a way of monitoring certain conditions. © 2023 Elsevier Inc. All rights reserved.

Combination Therapy for the Treatment of Shingles with an Immunostimulatory Vaccine Virus and Acyclovir.

Practically the entire global population is infected by herpesviruses that establish lifelong latency and can be reactivated. Alpha-herpesviruses, herpes simplex viruses 1 and 2 (HSV-1/HSV-2) and varicella zoster virus (VZV), establish latency in sensory neurons and then reactivate to infect epithelial cells in the mucosa or skin, resulting in a vesicular rash. Licensed antivirals inhibit virus replication, but do not affect latency. On reactivation, VZV causes herpes zoster, also known as shingles. The 76-year-old first author of this paper published an autobiography of his own severe herpes zoster ophthalmicus (HZO) infection with orbital edema, which is considered an emergency condition. Acyclovir (ACV) treatment was complemented with an immunostimulatory viral therapy, which resolved most symptoms within a few days. The orally administered live-attenuated infectious bursal disease vaccine virus (IBDV) delivers its double-stranded RNA (dsRNA) cargo to host cells and activates the natural antiviral interferon (IFN) gene defense system from within the host cells. IBDV has already been demonstrated to be safe and effective against five different families of viruses, hepatitis A virus (HAV), hepatitis B and C virus (HBV/HCV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and varicella zoster virus (VZV). Here we propose a short phase I/II trial in elderly shingles patients who will be assigned to receive either ACV monotherapy or ACV combined with R903/78, an attenuated immunostimulatory IBDV strain. The primary endpoints will be safety, but the efficacy of the combination therapy against the ACV monotherapy also will be assessed.

Simultaneous Detection of Eight Antiviral Drugs for Treatment of COVID-19 in Source Water

The continuous outbreak of COVID-19 results in a large number of therapeutic drugs inevitably entering water bodies through different pathways, and there are problems of accurate and rapid detection in the treatment and ecological evaluation of these drugs. Therefore, it is necessary to establish a method for simultaneous detection of multiple antiviral drugs for treatment of COVID-19 in water. A method for the simultaneous detection of 8 antiviral drugs（ribavirin, oseltamivir, nevirapine, lamivudine,abacavir, stavudine, acyclovir and penciclovir） in source water was developed by optimizing the determining parameters of liquid chromatography-tandem mass spectrometry（LC-MS/MS）. The daughter ion response values of 8 antiviral drugs in this method were relatively high, which was beneficial to the detection of target compounds. The correlation coefficient（r） of the standard curve of 8 antiviral drugs was not less than 0.995 0, the method detection limit（MDL） and the lower limit of determination were in the range of 0.004-0.081 μg/L and 0.013-0.267 μg/L, respectively, and the spike recoveries and RSDs of actual water samples were 81.61%-113.03% and 0.84%-8.12%, respectively.

Rash with Atypical Pneumonia: Varicella Pneumonia in a Young Immunocompetent Male

Varicella pneumonia is a serious complication of varicella infection. It occurs more often in adults than in children, although it is now infrequently seen since the introduction of the chickenpox vaccines. In immunocompetent adults, varicella pneumonia has a reported incidence of about 1 in 400 cases of varicella infection and it also carries significant mortality. Here, we report a case of varicella pneumonia in a young male who was immunocompetent and had no comorbidities. This case teaches us to be always careful and thorough with our clinical assessment and to think about the alternative etiologies for the cause of atypical pneumonia even during the times of the COVID-19 pandemic and not get swayed by the sheer numbers of coronavirus infections.

Iron-deficiency anemia following herpetic esophagitis in a previously healthy female.

Introduction: Herpetic Esophagitis is caused by the Herpes Simplex virus, which generally affects immunocompromised individuals and is rarely seen in healthy individuals. Symptoms are usually self-limiting. Case presentation: We report the case of a 68-year-old female who presented with odynophagia, dysphagia, and epigastric pain with no other underlying disease. Endoscopic findings of soft, nodular, and friable growths just above the squamocolumnar junction with diffuse ulcerations in the distal esophagus, led to the diagnosis. It was confirmed with a histopathological report which revealed multinucleated giant cells with eosinophilic intranuclear inclusions. During follow-up, laboratory investigations revealed iron deficiency anemia, which was the consequence of GI bleeding. Clinical discussion: Herpes Simplex virus esophagitis can occur in immunocompetent individuals and even it can cause food impaction and GI bleeding, which can lead to Iron deficiency anemia. Conclusion: Hence, follow-up of patients is important for early diagnosis and intervention of any complications that may arise.

Parvovirus infection causing prolonged QT intervals and cardiac arrest

AimsTo review an unusual case of an infant presenting with parvovirus infection causing prolonged QT intervals and cardiac arrest.MethodsWe reviewed the case history of the patient to discuss the presentation, management and progress since admission.ResultsA 14-month-old boy presented with cough and increased work of breathing for 1 day at district general hospital. He had suspected Parvovirus infection (causing slapped cheeks) 10 days ago. Due to worsening respiratory distress he was tried with various non invasive respiratory support. As he was not responding, he was intubated and ventilated. He was covered with ceftriaxone and acyclovir. During intubation he developed cardiac arrest requiring chest compressions,1 dose of adrenaline and a normal saline bolus. Return of spontaneous circulation happened after 2 minutes. He was transferred to tertiary unit for continuation of care. 2D ECHO showed normal cardiac structure with normal coronary arteries, but markedly dilated left ventricle, left atrium with left ventricular ejection fraction 30%. His was supported with milrinone and adrenaline as inotropes. He was transferred to quaternary centre in view of ECG changes of prolonged QT interval (600msec) global T wave inversion, broad based T wave, poor R wave progression across precordial leads. He was admitted there for 3 weeks before getting discharged to DGH. He received aspirin, bisoprolol, captopril, magnesium strycophosphate, furosemide, spironolactone, lactulose, melatonin, nystatin. After discharge at 1month follow up LVEF was 35%. His NT proBNP peaked to 35000pg/ml during intensive care admission which subsequently normalised to 3000. At discharge QT interval normalised to 480 msec with normal T wave morphology. 24-hour Holter showed sinus rhythm and inverted T waves. Blood cultures showed staphylococcus aureus for which he received 14 days of IV flucloxacillin. His respiratory secretions showed enterovirus, adenovirus and coronavirus 63. His acute kidney injury also resolved. He had normal EEG. His genetic tests for mitochondrial DNA WLS panel and family (parents’ and sibling) genetic tests for prolonged QT were normal. He was seen at cardiac function clinic and inherited arrythmia clinic and diuretics and beta blockers were stopped. Follow up plan about phenotypic exercise testing at later age and avoiding medications causing prolonged QT interval was agreed.ConclusionParvovirus infection can cause transient prolongation of QT interval which can precipitate cardia arrest. In these rare events supporting the child through the acute phase of illness ensures gradual recovery and improvement of the QT prolongation. Currently its not understood as to why this happens but could be postulated to an underlying myocarditis or inflammatory event causing changes in the conducting systems.

Incidence and Risk Factors of Bilateral Herpetic Keratitis: 2022 Update.

Simultaneously occurring bilateral herpetic keratitis is a rare clinical manifestation of ocular herpes. Immunocompromised patients are more susceptible to develop bilateral disease. The purpose of this study is to review recent literature on the topic and to highlight latest updates, regarding risk factors and possible correlations to the disease, as well as new therapeutic options.

A Rare Case of Herpes Esophagitis in an Immunocompetent Elderly Patient.

Herpes esophagitis is common among immunocompromised hosts but is relatively rare among immunocompetent patients. Its symptoms are vague because many different symptoms can be induced by esophageal lesions. Here, we report a case of herpes esophagitis in an elderly immunocompetent patient. A 91-year-old woman visited our community hospital with a complaint of appetite loss for several days. Although she did not have any symptoms of epigastric, oral, or retrosternal pain, multiple ulcers were detected in her esophagus. Biopsy of the edge of the ulcer showed giant cells, indicating a herpes virus infection. She was diagnosed with herpes esophagitis and treated with acyclovir for one week. Her symptoms completely resolved after treatment, and she was discharged. Herpes esophagitis can manifest as vague symptoms in immunocompetent elderly patients. Therefore, herpes esophagitis must be considered in the differential diagnosis of elderly patients presenting with vague symptoms.

Encephalopathy as a form of presentation of COVID-19

Introduction: SARS-CoV-2 virus, responsible for COVID-19, has a high contagion rate and is capable of producing conditions at different levels in the body, and includes the central nervous system, with manifestations such as febrile and afebrile seizures, status epilepticus, encephalopathies and encephalitis. Objective: To describe a patient with encephalopathy, as a form of presentation of COVID-19. Clinical case: A 25-year-old patient with a history of post-traumatic obstructive hydrocephalus, with ventricular peritoneal shunt, positive for COVID-19, who developed neurological manifestations, in the absence of respiratory manifestations. He was treated according to the protocol for patients with COVID-19, anti-cerebral edema measures and use of the CIGB-258 peptide. The patient had a favorable evolution towards recovery Conclusions: In patients with encephalopathy of unknown cause, in the context of the COVID-19 pandemic, SARS-CoV-2 infection should be considered. The evolution can be favorable with the use of general measures and anti-cerebral edema. © 2021, Editorial Ciencias Medicas. All rights reserved.

In-silico ADME and Docking-based Virtual Screening Study Aiming at the Sigma-Covalent Inhibition of SARS-CoV-2 RdRp

The objectives of the study were to examine the virtual screening of the compounds and sigma-covalent inhibition of SARS-CoV-2 RdRp (RNA-Dependent RNA-Polymerase), which is conserved and is an essential enzyme for RNA transcription and replication of this virus. In this study, we collected around 1225 similar compounds of Penciclovir and Acyclovir inhibitors from PubChem and predicted ADME (Adsorption, Distribution, Metabolism and Excretion) molecular descriptors using Swiss-ADME server. Virtually screened 24/1225 compounds based on drug-likeliness five rules (Lipinski, Ghose, Veber, Egan, and Muegge) and lead-likeliness properties. Further 10/24 compounds screened, based on high binding affinity and RMSD<3.5 angstrom against RdRp structure using PyRx docking software. Furthermore, the molecular interactions of 10 compounds studied using Discovery studio software and finally screened five PubChem compounds 57201841, 135408972, 54552823, 135409422 and 467850, based on bioactivity score using Molinsipiration cheminformatics software. All these five compounds showed up anti-SARS CoV-2 activity, though further in-vitro studies are required.

Antiviral Electrospun Polymer Composites: Recent Advances and Opportunities for Tackling COVID-19

The ongoing COVID-19 pandemic caused by SARS-CoV-2 has significantly affected the world, creating a global health emergency. For controlling the virus spread, effective and reliable diagnostic and therapeutic measures are highly expected. Using proper biomedical materials to produce detection kits/devices and personal protective equipment (PPE), such as swabs and masks, has become the focus since they play critical roles in virus diagnostics and prevention. Electrospun polymer composites have garnered substantial interest due to their potential to provide antiviral healthcare solutions. In this review, we summarized the recent efforts in developing advanced antiviral electrospun polymer composites for virus detection and prevention. We highlighted some novel strategies for developing effective antiviral personal protective equipment (PPE), including self-sterilization, reusability, and potential antiviral drug encapsulation. Besides, we discussed the current challenges and future perspectives for improving the materials' performance to achieve better virus detection, antiviral, prevention, and therapeutics.

Preparation of Acyclovir-Containing Solid Foam by Ultrasonic Batch Technology.

In recent years, the application of solid foams has become widespread. Solid foams are not only used in the aerospace field but also in everyday life. Although foams are promising dosage forms in the pharmaceutical industry, their usage is not prevalent due to decreased stability of the solid foam structure. These special dosage forms can result in increased bioavailability of drugs. Low-density floating formulations can also increase the gastric residence time of drugs; therefore, drug release will be sustained. Our aim was to produce a stable floating formula by foaming. Matrix components, PEG 4000 and stearic acid type 50, were selected with the criteria of low gastric irritation, a melting range below 70 °C, and well-known use in oral drug formulations. This matrix was melted at 54 °C in order to produce a dispersion of active substance and was foamed by different gases at atmospheric pressure using an ultrasonic homogenizer. The density of the molded solid foam was studied by the pycnometer method, and its structure was investigated by SEM and micro-CT. The prolonged drug release and mucoadhesive properties were proved in a pH 1.2 buffer. According to our experiments, a stable foam could be produced by rapid homogenization (less than 1 min) without any surfactant material.

Development and Validation of a Method for Quantification of Favipiravir as COVID-19 Management in Spiked Human Plasma.

In the current work, a simple, economical, accurate, and precise HPLC method with UV detection was developed to quantify Favipiravir (FVIR) in spiked human plasma using acyclovir (ACVR) as an internal standard in the COVID-19 pandemic time. Both FVIR and ACVR were well separated and resolved on the C18 column using the mobile phase blend of methanol:acetonitrile:20 mM phosphate buffer (pH 3.1) in an isocratic mode flow rate of 1 mL/min with a proportion of 30:10:60 %, v/v/v. The detector wavelength was set at 242 nm. Maximum recovery of FVIR and ACVR from plasma was obtained with dichloromethane (DCM) as extracting solvent. The calibration curve was found to be linear in the range of 3.1-60.0 µg/mL with regression coefficient (r2) = 0.9976. However, with acceptable r2, the calibration data's heteroscedasticity was observed, which was further reduced using weighted linear regression with weighting factor 1/x. Finally, the method was validated concerning sensitivity, accuracy (Inter and Intraday's % RE and RSD were 0.28, 0.65 and 1.00, 0.12 respectively), precision, recovery (89.99%, 89.09%, and 90.81% for LQC, MQC, and HQC, respectively), stability (% RSD for 30-day were 3.04 and 1.71 for LQC and HQC, respectively at -20 °C), and carry-over US-FDA guidance for Bioanalytical Method Validation for researchers in the COVID-19 pandemic crisis. Furthermore, there was no significant difference for selectivity when evaluated at LLOQ concentration of 3 µg/mL of FVIR and relative to the blank.

COVID-19-Induced Encephalitis: A Case Report of a Rare Presentation With a Prolonged Electroencephalogram.

Encephalitis is one of the rare complications of coronavirus disease 2019 (COVID-19) that can be missed and confused with other causes of encephalitis. There was a 36-year-old male known to have glucose-6 phosphate dehydrogenase deficiency, who was brought to the emergency department with fever and confusion of one-week duration. Altered mental status work-up, including cerebrospinal fluid analysis, was done and turned out to be nondiagnostic. Multiple prolonged video-electroencephalographic recordings were done and showed different abnormalities suggestive of encephalitis. The diagnosis of COVID-19-induced encephalitis was made by exclusion of other encephalitis-related etiologies in the presence of a positive COVID-19 polymerase chain reaction (PCR) test, and treatment was initiated accordingly. Over a period of three weeks, the patient showed progressive improvement and was discharged home with regular follow-up in the neurology clinic. Upon follow-up in the clinic, the patient was fully independent but with multiple abnormal electroencephalographic recordings showing generalized encephalopathy with no epileptic discharges.