Structural-Based Virtual Screening of FDA-Approved Drugs Repository for NSP16 Inhibitors, Essential for SARS-COV-2 Invasion Into Host Cells: Elucidation From MM/PBSA Calculation.

NSP16 is one of the structural proteins of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) necessary for its entrance to the host cells. It exhibits 2'O-methyl-transferase (2'O-MTase) activity of NSP16 using methyl group from S-adenosyl methionine (SAM) by methylating the 5-end of virally encoded mRNAs and shields viral RNA, and also controls its replication as well as infection. In the present study, we used in silico approaches of drug repurposing to target and inhibit the SAM binding site in NSP16 using Food and Drug Administration (FDA)-approved small molecules set from Drug Bank database. Among the 2 456 FDA-approved molecules, framycetin, paromomycin, and amikacin were found to be significant binders against the SAM binding cryptic pocket of NSP16 with docking score of -13.708, -14.997 and -15.841 kcal/mol, respectively. Classical molecular dynamics (MD) simulation and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA)-based binding free energy calculation depicted that all these three framycetin, paromomycin, and amikacin might be promising therapeutic leads towards SARS-CoV-2 infections via host immune escape inhibition pathway.

Green synthesis of silver nanoparticles using Ocimum sanctum Linn. and its antibacterial activity against multidrug resistant Acinetobacter baumannii.

The biosynthesis of nanoparticles using the green route is an effective strategy in nanotechnology that provides a cost-effective and environmentally friendly alternative to physical and chemical methods. This study aims to prepare an aqueous extract of Ocimum sanctum (O. sanctum)-based silver nanoparticles (AgNPs) through the green route and test their antibacterial activity. The biosynthesized silver nanoparticles were characterised by colour change, UV spectrometric analysis, FTIR, and particle shape and size morphology by SEM and TEM images. The nanoparticles are almost spherical to oval or rod-shaped with smooth surfaces and have a mean particle size in the range of 55 nm with a zeta potential of -2.7 mV. The antibacterial activities of AgNPs evaluated against clinically isolated multidrug-resistant Acinetobacter baumannii (A. baumannii) showed that the AgNPs from O. sanctum are effective in inhibiting A. baumannii growth with a zone of inhibition of 15 mm in the agar well diffusion method and MIC and MBC of 32 µg/mL and 64 µg/mL, respectively. The SEM images of A. baumannii treated with AgNPs revealed damage and rupture in bacterial cells. The time-killing assay by spectrophotometry revealed the time- and dose-dependent killing action of AgNPs against A. baumannii, and the assay at various concentrations and time intervals indicated a statistically significant result in comparison with the positive control colistin at 2 µg/mL (P < 0.05). The cytotoxicity test using the MTT assay protocol showed that prepared nanoparticles of O. sanctum are less toxic against human cell A549. This study opens up a ray of hope to explore the further research in this area and to improve the antimicrobial activities against multidrug resistant bacteria.

Neuroprotective potential of erucic acid via inhibition of N2a cell lines and rotenone induced Parkinson's disease rat model.

OBJECTIVE: The objective of this study was to investigate the potential for erucic acid (EA), an omega-9 monounsaturated fatty acid, to act as a neuroprotective agent. MATERIALS AND METHODS: In this study, EA was investigated against N2a cell lines and a rotenone (ROT)-induced model of Parkinson's disease for its neuroprotective potential. The N2a cell line was incubated with fetal bovine serum, penicillin, and streptomycin supplemented with Dulbecco's Modified Eagle's Medium, and the following assays were carried out: (i) MTT, (ii) biocompatibility, (iii) DCFDA, and (iv) diphenylamine. A cell morphology study was also performed. Further, ROT 1 mg/kg s.c. and EA 3 and 10 mg/kg p.o. were given to rats on a daily basis for 21 days, and the following parameters were assessed: (i) neurobehavioral studies, (ii) oxidative stress markers, (iii) neuroinflammatory markers, (iv) neurotransmitters, and (v) histopathological study. RESULTS: The cell viability assay revealed that EA showed protection against ROT-induced toxicity in N2a cells, which was confirmed by a cell morphology study. EA decreased oxidative stress and % DNA fragmentation significantly. EA also prevented ROT-induced motor impairment and altered levels of oxidative stress markers, neurotransmitters, and neuroinflammatory markers significantly. When compared to the ROT group, a histological investigation of the EA group showed partial neuronal loss with the existence of intact neurons in between the vacuolated gaps. CONCLUSION: This study revealed that EA possesses profound neuroprotective properties in in vitro and in vivo studies. Additional research can be carried out to study the mechanism of EA with respect to its neuroprotective potential.

Rhino-orbital-cerebral-mucormycosis in COVID-19: A systematic review.

Since the onset of COVID-19 pandemic, parallel opportunistic infections have also been emerging as another disease spectrum. Among all these opportunistic infection, mucormycosis has become a matter of concern with its rapid increase of cases with rapid spread as compared to pre-COVID-19 era. Cases have been reported in post-COVID-19-related immune suppression along with the presence of comorbidity which adds on the deadly outcome. There is no systematic review addressing the issue of COVID-19-associated mucormycosis. This is the first systematic review of published studies of mucormycosis associated with COVID-19. The aim was to analyze the real scenario of the disease statement including all the published studies from first November 2019 to 30th June to analyze the contemporary epidemiology, clinical manifestations, risk factor, prognosis, and treatment outcome of COVID-19 associated rhino-orbito-cerebral-mucormycosis. A comprehensive literature search was done in following databases, namely, PubMed, Google Scholar, Scopus, and EMBASE using keywords mucormycosis, rhino orbital cerebral mucormycosis, COVID-19, and SARS-CoV-2 (from November 01, 2019 to June 30, 2021). Our study shows that, while corticosteroids have proved to be lifesaving in severe to critical COVID-19 patients, its indiscriminate use has come with its price of rhino-orbito-cerebral mucormycosis epidemic, especially in India especially in patients with preexisting diabetes mellitus with higher mortality. Corticosteroid use should be monitored and all COVID-19 patients should be closely evaluated/monitored for sequelae of immunosuppression following treatment.

A Comparative Study of Pharmacopoeial Quality Standards and Regulations of Radiopharmaceuticals.

Radiopharmaceutical preparations are the important pharmaceutical dosage forms used for the diagnosis and therapeutic purposes. Various pharmacopoeias are having methods for the quality control of these preparations in the form of monographs. Indian Pharmacopoeia (IP) also included these monographs in IP 2014 first time with the help of an experts' group on radiopharmaceutical, drawing expertise from elite stakeholder institutions and the core team of Indian Pharmacopoeia Commission. Since then, these standards are regularly updated through the IP addendum and bringing out new edition of IP. IP is a book of official methods as per Drugs and Cosmetic Act, 1940. These standards can be used in government laboratories, private laboratories, or academia in India and abroad. This review provides an overview of the journey of radiopharmaceuticals' standard setting in IP. A comprehensive comparative information of regulatory perspectives of radiopharmaceuticals in different jurisdictions such as the US, EU, and India is also presented.

Current status of in silico, preclinical and clinical study registries across the globe: A systematic review and meta-analysis.

INTRODUCTION: Registration of study protocols brings about transparency and traceability and the amount of publication bias can be estimated. In this study, we have collected and presented data regarding clinical study registries, preclinical, in vitro and in silico study registries across the globe. MATERIALS AND METHODS: We searched via Google Search Engine with appropriate keywords e.g. name of country (n = 198), name of continent (n = 7), registry, study registry, animal, in silico, virtual, simulation, preclinical, animal, clinical trial. The overall pooled prevalence of clinical study registries and WHO primary registries in per continent was calculated using Medcalc software. RESULTS: The overall pooled prevalence of clinical study registries were 13% in each continent. The prevalence of WHO primary study registries were 8.9% of the countries per continent. Overall, there are 17 primary registries associated with WHO ICTRP as primary registries, 2 partner registries and 6 registries are affiliated to ICMJE. However, the amount of preclinical animal study registry was quite less (n = 4). Regarding in vitro studies, only country specific in vitro fertilization registries were available, however, in other research domains, registries were absent. Only one simulation study registry was available. CONCLUSION: At priori study registration is essential to deal with selective reporting. Comparison between study protocol and final report allows us to know the protocol deviations and allows us to evaluate risk of bias and internal validity of the research findings. Although trialists are responsible for the completeness of records, yet the registries must have some measures for their periodic update and quality control of the data.

Efficacy and safety of dihydroorotate dehydrogenase (DHODH) inhibitors "leflunomide" and "teriflunomide" in Covid-19: A narrative review.

Dihydroorotate dehydrogenase (DHODH) is rate-limiting enzyme in biosynthesis of pyrimidone which catalyzes the oxidation of dihydro-orotate to orotate. Orotate is utilized in the biosynthesis of uridine-monophosphate. DHODH inhibitors have shown promise as antiviral agent against Cytomegalovirus, Ebola, Influenza, Epstein Barr and Picornavirus. Anti-SARS-CoV-2 action of DHODH inhibitors are also coming up. In this review, we have reviewed the safety and efficacy of approved DHODH inhibitors (leflunomide and teriflunomide) against COVID-19. In target-centered in silico studies, leflunomide showed favorable binding to active site of MPro and spike: ACE2 interface. In artificial-intelligence/machine-learning based studies, leflunomide was among the top 50 ligands targeting spike: ACE2 interaction. Leflunomide is also found to interact with differentially regulated pathways [identified by KEGG (Kyoto Encyclopedia of Genes and Genomes) and reactome pathway analysis of host transcriptome data] in cogena based drug-repurposing studies. Based on GSEA (gene set enrichment analysis), leflunomide was found to target pathways enriched in COVID-19. In vitro, both leflunomide (EC50 41.49 ± 8.8 µmol/L) and teriflunomide (EC50 26 µmol/L) showed SARS-CoV-2 inhibition. In clinical studies, leflunomide showed significant benefit in terms of decreasing the duration of viral shredding, duration of hospital stay and severity of infection. However, no advantage was seen while combining leflunomide and IFN alpha-2a among patients with prolonged post symptomatic viral shredding. Common adverse effects of leflunomide were hyperlipidemia, leucopenia, neutropenia and liver-function alteration. Leflunomide/teriflunomide may serve as an agent of importance to achieve faster virological clearance in COVID-19, however, findings needs to be validated in bigger sized placebo controlled studies.

Indian contribution toward biomedical research and development in COVID-19: A systematic review.

COVID-19 pandemic led to an unprecedented collaborative effort among industry, academia, regulatory bodies, and governments with huge financial investments. Scientists and researchers from India also left no stone unturned to find therapeutic and preventive measures against COVID-19. Indian pharmaceutical companies are one of the leading manufacturers of vaccine in the world, are utilizing its capacity to its maximum, and are one among the forerunners in vaccine research against COVID-19 across the globe. In this systematic review, the information regarding contribution of Indian scientists toward COVID-19 research has been gathered from various news articles across Google platform apart from searching PubMed, WHO site, COVID-19 vaccine tracker, CTRI, clinicaltrials.gov, and websites of pharmaceutical companies. The article summarizes and highlights the various therapeutic and vaccine candidates, diagnostic kits, treatment agents, and technology being developed and tested by Indian researcher community against COVID-19.

COVID-19-associated rhino-orbital-cerebral mucormycosis: A systematic review, meta-analysis, and meta-regression analysis.

BACKGROUND: Till now, no meta-analysis is available to address the clinical profile, risk factors, different interventions, and outcomes among COVID-19-associated rhino-orbito-cerebral mucormycosis (C-ROCM) cases. MATERIALS AND METHODS: Eight literature databases were screened using appropriate keywords from November 1, 2019, to June 30, 2021. The objectives were to analyze the clinical and microbiological profile, risk factor/comorbidity, intervention, and outcome. "R-metafor package" was used for analysis. RESULTS: A total of 23 studies were included. The mean age of presentation of C-ROCM was 54.6 years. The most common presentation was ptosis (72.7%), lid edema (60.6%), proptosis (60.6%), ophthalmoplegia (57.3%), loss of vision (53.7%), facial edema (34.7%), and nasal-blockage (11.8%). Evidence of intracranial spread was seen in 42.8% of cases. Rhizopus was the most common fungus (57.1%) isolated in fungal culture. Among C-ROCM patients, diabetes was the commonest comorbid condition, and the use of corticosteroids related to COVID-19 treatment was the most common risk factor (85.75%). Compared to controlled diabetics, C-ROCM was significantly higher among uncontrolled diabetics (odds ratio [OR] 0.15, 95% confidence interval [C.I.] 0.041-0.544, P = 0.0010). However, no significant association was seen between C-ROCM and COVID-19 severity (OR 0.930, 95% C.I. 0.212-4.087, P = 0.923). For treatment, amphotericin-B was the most common antifungal drug used which was followed by surgical options. However, mortality was high (prevalence 0.344, 95% C.I. 0.205-0.403) despite treatment. CONCLUSION: Although local rhino-orbito symptoms were the first to appear, rapid intracranial extension was seen in a significant number of C-ROCM cases. Uncontrolled diabetes and excessive use of corticosteroid were the most common risk factors present among the C-ROCM cases. High index clinical suspicion is imperative (specifically among COVID-19 patients with diabetes), and routine screening may be helpful.

Efficacy and safety of steroid therapy in COVID-19: A rapid systematic review and Meta-analysis.

PURPOSE: Although the use of steroids in the management of COVID-19 has been addressed by a few systematic review and meta-analysis, however, they also used data from "SARS-CoV" and "MERS-CoV." Again, most of these studies addressed only one severity category of patients or addressed only one efficacy endpoint (mortality). In this context, we conducted this meta-analysis to evaluate the efficacy and safety of steroid therapy among all severity categories of patients with COVID-19 (mild to moderate and severe to critical category) in terms of "mortality," "requirement of mechanical ventilation," "requirement of ICU" and clinical cure parameters. METHODS: 11 databases were screened. Only randomized controlled trials (RCTs) or high quality (on the basis of risk of bias analysis) comparative-observational studies were included in the analysis. RevMan5.3 was used for the meta-analysis. RESULTS: A total of 15 studies (3 RCT and 12 comparative-observational studies) were included. In the mechanically-ventilated COVID-19 population, treatment with dexamethasone showed significant protection against mortality (single study). Among severe and critically ill combined population, steroid administration was significantly associated with lowered mortality (risk ratio [RR] 0.83 [0.76-0.910]), lowered requirement of mechanical ventilation (RR 0.59 [0.51-0.69]), decreased requirement of intensive care unit (ICU) (RR 0.62 [0.45-0.86]), lowered length of ICU stay (single-study) and decreased duration of mechanical ventilation (two-studies). In mild to moderate population, steroid treatment was associated with a higher "duration of hospital stay," while no difference was seen in other domains. In patients at risk of progression to "acute respiratory distress syndrome," steroid administration was associated with "reduced requirement of mechanical ventilation" (single-study). CONCLUSION: This study guides the use of steroid across patients with different severity categories of COVID-19. Among mechanically ventilated patients, steroid therapy may be beneficial in terms of reduced mortality. Among "severe and critical" patients; steroid therapy was associated with lowered mortality, decreased requirement of mechanical ventilation, and ICU. However, no benefit was observed in "mild to moderate" population. To conclude, among properly selected patient populations (based-upon clinical severity and biomarker status), steroid administration may prove beneficial in patients with COVID-19.

Therapeutic options for management of Hori's nevus: A systematic review.

Hori's nevus is a pigmentation disorder reported mainly in middle-aged Asian women. There is no systematic review addressing its pharmacotherapy. The population for our systematic review was patients with a clinical/histological diagnosis of Hori's nevus (both sex, any age group). We screened five literature databases using relevant keywords. All RCTs, observational studies and case series mentioning at least one intervention and outcome of that intervention were included. Nineteen studies were included in the final systematic review from total 680 identified nonduplicate records. Different forms of laser (alexandrite laser [QSAL and PSAL], Nd:YAG laser [QSNYL high fluence, low fluence, 532 followed by 1064 nm], Er: YAG and Nd:YAG combination, ruby laser [QSRL], CO2 laser followed by QSRL) and dermabrasion were found to be useful in treatment of Hori' nevus. Among alexandrite lasers, PSAL is more efficacious and safe than QSAL. In case of high fluence QSNYL, hyperpigmentation rate is quite high while low fluence QSNYL requires more number of treatment sessions. The combined 1064 nm + 532 nm protocol is better in terms of efficacy and safety. Er:YAG + Nd:YAG combination have similar efficacy and added advantage of synergistic action and no adverse event.

Biovigilance: A Global Perspective.

A biological is a substance which either comprises, contains, or is derived from human cells or human tissues. The use of biological products is associated with the risk of infection transmission, allergic reactions, and other adverse events (AEs). The science and activities relating to the detection, assessment, understanding, and prevention of AEs or any other problems related to biological products (blood, cells, tissues, organs, and vaccine in international perspective) are termed as biovigilance. With more and more biologicals being marketed and the rapid revolutionary changes in transplant-related services, the importance of biovigilance is increasing day by day. Although specific types of vigilance systems (pharmacovigilance and materiovigilance) exist, activities related to "biovigilance" are still in an infancy stage. Many developed countries such as the USA, Europe, and Australia have implemented nationwide biovigilance programs. In India, the National Institute of Biologicals, in collaboration with the Indian Pharmacopoeia Commission, has launched the Biovigilance Programme of India. In this article, the biovigilance systems of different countries across the globe have been reviewed along with highlights of the current biovigilance needs.

Pivotal role of Pharmacovigilance Programme of India in containment of antimicrobial resistance in India.

Misuse of antimicrobials has become one of the grave concerns of public health. In last two decades, this has been largely contributing in the emergence of antimicrobial resistance (AMR) among all the pathogens. A 2013 report of Centres for Disease Control and Prevention, USA figured that at least 2 million people get an antibiotic-resistant infection every year and as many as 23,000 people lost their life. A multi-country survey in Southeast Asia region conducted by World Health Organization (WHO) in 2015, identified several gaps in knowledge and awareness about the optimal use of antimicrobials and AMR. Following this, the Ministry of Health and Family Welfare (MoHFW), Government of India, developed National Action Plan in the year 2017 to combat AMR. Pharmacovigilance Programme of India (PvPI) being a flagship programme of MoHFW holds the responsibility of ensuring safety of medicines used by India population and has recently identified AMR as one of the strategic priorities. This article intends to provide insights of the recent attempts and deliberate efforts made by PvPI in the containment of AMR in India and it also intends to sensitize healthcare fraternity on restricting AMR in public interest.

Cefixime-associated acute generalized exanthematous pustulosis: Rare cases in India.

BACKGROUND: Cefixime is a widely used third-generation cephalosporin schedule H1 drug, which is prescribed for the treatment of otitis media, respiratory tract infections, and uncomplicated urinary tract infections and is effective against infections caused by Enterobacteriaceae and Haemophilus influenzae species in India. The National Coordination Centre (NCC)-Pharmacovigilance Programme of India (PvPI), Indian Pharmacopoeia Commission (IPC), has received rare individual case safety reports (ICSRs) for acute generalized exanthematous pustulosis (AGEP) associated with the use of cefixime. MATERIALS AND METHODS: IPC, NCC-PvPI also acts as a national collaborating center for pharmacovigilance activities under the aegis of Ministry of Health and Family Welfare, Government of India; moreover, it is a member country in global pharmacovigilance system, World Health Organization-Uppsala Monitoring Centre, Sweden. There are more than 250 government/corporate medical colleges and hospitals acting as regional adverse drug reaction monitoring centers, actively functioning under PvPI. Furthermore, various stakeholders including consumers and pharmaceutical industries also play a significant contribution. NCC-PvPI receives spontaneous ICSRs from various stakeholders. RESULTS: NCC-PvPI, IPC has received a total of four spontaneous ICSRs for cefixime-induced AGEP. After clinical evaluation of reported ICSRs, a strong causal relationship was established between AGEP and cefixime and was supported by published literature and histopathological examination of skin. Based on the statistics with positive information component (IC025 Value: 0.17) and proportionality relative risk (PRR:3.4), PvPI considered cefixime-associated AGEP may be a potential signal. CONCLUSION: Hence, initially, AEGP is considered by PvPI as drug safety alert in July 2016. Therefore, to enhance the safety of population in rational usage of medication, as a result, there is a need for physicians and health-care professionals to sensitize about serious adverse reaction while prescribing the cefixime as signal in India.

Drug safety alerts of pharmacovigilance programme of India: A scope for targeted spontaneous reporting in India.

BACKGROUND: The National Coordination Centre-Pharmacovigilance Programme of India (NCC-PvPI), Indian Pharmacopoeia Commission works under the aegis of Ministry of Health and Family Welfare, Government of India. It promotes patient safety in India and also supports postmarketing surveillance programs. Currently, almost hundred thousand case reports are submitted to NCC-PvPI each year through its 250 ADR Monitoring Centers (AMCs) located across India, and India is the one of the top ten contributor countries under WHO-Uppsala Monitoring Centre since 2012 and start issuing drug safety alerts from March 2016. AIM: This study aims to highlight the drug safety alerts issued by NCC-PvPI from March 2016 to June 2017 and urgent need for further monitoring by adopting targeted spontaneous reporting (TSR) methodology at AMCs and its impact on the NCC's drug safety database, i.e., VigiFlow in India. METHODOLOGY: A retrospective analysis was done for the reported unlisted ADRs by various AMCs to PvPI through VigiFlow, i.e., individual case safety report (ICSR) management system at NCC, where these unlisted drug-ADR combinations considered and issued as drug safety alerts for further reporting these to NCC, if any detected at healthcare settings during routine clinical practice by healthcare professionals. RESULTS: From July 2011 to June 2017, NCC-PvPI was collated 250,787 ICSRs and contributed to WHO international drug safety database, i.e., VigiBase, from these ICSRs; NCC-PvPI was issued 56 drug safety alerts from March 2016 to June 2017. CONCLUSION: In India, spontaneous reporting of ADRs existed since 1998 under passive surveillance method, but there is an urgent need to initiate TSR, which is a complementary method to spontaneous reporting on these drug safety alerts for further regulatory action by Central Drugs Standard Control Organization.

Risk of Intussusception with Rotavirus Vaccine.

OBJECTIVE: To study the case series for intussusception associated with the vaccination of rotavirus vaccine in children. METHODS: The study of spontaneous adverse event monitoring such as intussusception due to rotavirus vaccine was carried out from the year 2011 through 2015. The individual case safety reports (ICSRs) of this event were collated, assessed and recorded as per the requirement of Suspected Adverse Drug Reactions Reporting form of Pharmacovigilance Programme of India (PvPI). RESULTS: In the present study, 10 ICSRs of intussussception due to rotavirus vaccine were reported to PvPI. Of which 3 ICSRs were found to be causal relationship with rotavirus vaccine, as evidenced by the adequate information provided in ICSRs. CONCLUSIONS: Since intussusception, the emerging safety as one of the important safety concern, healthcare professionals are advised to monitor and report to the concerned authority for appropriate action.

Pharmacovigilance Programme of India: Recent developments and future perspectives.

Promoting safe use of medicines is a priority of Indian Pharmacopoeia Commission that functions as the National Coordination Center (NCC) for Pharmacovigilance Programme of India (PvPI). One hundred and seventy-nine adverse drug reactions (ADRs) monitoring centers currently report ADRs to NCC. Current India contribution to global safety database reaches 3% and the completeness score is 0.93 out of 1. NCC is taking several measures to enhance patient safety including capacity building for monitoring, surveillance, collaboration with national health programs and other organizations to increase ADR reporting and to ensure that PvPI is a vital knowledge database for Indian regulators. The Central Drugs Standard Control Organization has notified important safety label changes on drugs such as carbamazepine and piperacillin + tazobactam in the year 2015, other drugs are under monitoring for regulatory interventions.