Antimalarial phytochemicals as potential inhibitors of SARS-CoV-2 guanine N7-methyltransferase (nsp 14): an integrated computational approach.

The inhibition of capping enzymes such as guanine-N7-methyltransferase (GMT) is an attractive target for regulating viral replication, transcription, virulence, and pathogenesis. Thus, compounds that target the Severe Acute Respiratory Syndrome Corona Virus 2 GMT (S2GMT) will enhance drug development against COVID-19. In this study, an in-house library of 249 phytochemicals from African medicinal plants was screened using computational approaches including homology modeling, molecular docking, molecular dynamic simulations, binding free energy calculations based on molecular mechanics/Poisson-Boltzmann surface area (MMPBSA) and Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) analysis for inhibitors of S2GMT. The top-ten ranked phytochemicals (TTRP) obtained from the docking analysis to S2GMT were further docked to SARS-COV N7-MTase. Among the TTRP, the top-four ranked phytocompounds (TFRP) viz: 3 alkaloids (Isocryptolepine, 10'-Hydroxyusambarensine and Isostrychnopentamine) and a flavonoid (Mulberrofuran F) interacted strongly with critical catalytic residues whose interference either reduce or completely abolish N7-MTase activity, indicating their potential as capping machinery disruptors. The interactions of TFRP with the catalytic residues of S2GMT were preserved in a 100 ns simulated dynamic environment, thereby, demonstrating high degree of structural stability. The MMPBSA binding free energy calculations corroborated the docking scores with biscryptolepine having the highest binding free energy to S2GMT. The TFRP showed favourable drug-likeness and ADMET properties over a wide range of molecular descriptors. Therefore, the TFRP can be further explored as potential S2GMT inhibitors in in vitro and in vivo experiments.Communicated by Ramaswamy H. Sarma.

Predicted Environmental Risk Assessment of Antimicrobials with Increased Consumption in Portugal during the COVID-19 Pandemic; The Groundwork for the Forthcoming Water Quality Survey.

The environmental release of antimicrobial pharmaceuticals is an imminent threat due to ecological impacts and microbial resistance phenomena. The recent COVID-19 outbreak will likely lead to greater loads of antimicrobials in the environment. Thus, identifying the most used antimicrobials likely to pose environmental risks would be valuable. For that, the ambulatory and hospital consumption patterns of antimicrobials in Portugal during the COVID-19 pandemic (2020-2021) were compared with those of 2019. A predicted risk assessment screening approach based on exposure and hazard in the surface water was conducted, combining consumption, excretion rates, and ecotoxicological/microbiological endpoints in five different regions of Portugal. Among the 22 selected substances, only rifaximin and atovaquone demonstrated predicted potential ecotoxicological risks for aquatic organisms. Flucloxacillin, piperacillin, tazobactam, meropenem, ceftriaxone, fosfomycin, and metronidazole showed the most significant potential for antibiotic resistance in all analysed regions. Regarding the current screening approach and the lack of environmental data, it is advisable to consider rifaximin and atovaquone in subsequent water quality surveys. These results might support the forthcoming monitorisation of surface water quality in a post-pandemic survey.

ADR profile among healthcare workers on hydroxychloroquine prophylaxis in a tertiary care teaching hospital in India

Background: WHO has declared Coronavirus 2019 (COVID-19) as pandemic on 11th March 2020. Hydroxychloroquine (HCQ) chemoprophylaxis has been approved by the Indian Council of Medical Research (ICMR) for asymptomatic healthcare workers treating suspected or confirmed COVID-19 cases and asymptomatic household contacts of confirmed patients. However, there is a scarcity of data regarding the efficacy and safety of HCQ for COVID-19 prophylaxis and treatment. Background: The present study was designed to evaluate the adverse drug reaction (ADR) profile of HCQ prophylaxis among healthcare workers in a tertiary care teaching hospital in India. Methods: A Descriptive cross-sectional study was conducted in Kalpana Chawla Medical College and Hospital, Karnal for duration of 3 months (April-June 2020). The study was performed on the reported ADRs due to HCQ prophylaxis by the healthcare workers to the ADR monitoring centre of the institute during this period. Results: Gastrointestinal disturbance such as loose stool (16.4%) and hyperacidity (14.9%) were the most commonly reported ADRs during the study period. The incident rate of adverse drug reactions was 23.7%. The number of ADRs was found to be significantly (p<0.01) more in female as compared to male. We have observed that most of the reactions were reported following the 1st day loading dose. Conclusions: Our results showed that gastrointestinal system was most commonly affected. Loose stool and hyperacidity were most frequently reported ADRs due to HCQ prophylaxis. Larger studies are required to ensure the safety of the use of HCQ as prophylaxis for COVID 19.

On entropy measures of polycyclic hydroxychloroquine used for novel coronavirus (COVID-19) treatment

The molecular structure of hydroxychloroquine (HCQ) used in the treatment of malaria is recently suggested for emergency used in COVID-19. The chemical compound of HCQ is produced by chemical alteration of ethylene oxide from human products, such as waxy maize starch. The molecular graph is a graph comprising of atoms called vertices and the chemical bond between molecules is called edges. A topological index is a numerical representation of a chemical structure which correlates certain physico-chemical characteristics of underlying chemical compounds besides its numerical representation. To distinguish the creation of entropy-based measures from the structure of chemical graphs, several graph properties have been utilized. For computing the structural information of chemical graphs, the graph entropies have become the information-theoretic quantities. The graph entropy measure has attracted the research community due to its potential application in discrete mathematics, biology, and chemistry. In this paper, our contribution is to explore graph entropies for molecular structure of HCQ based on novel information function, which is the number of different degree vertices along with the number of edges between various degree vertices. More precisely, we have explored the degree-based topological characteristics of hydroxyethyl starch conjugated with hydroxychloroquine (HCQ-HEC). Also, we computed entropies of this structure by making a relation of degree-based topological indices with the help of information function. Moreover, we presented the numerical and graphical comparison of the computed results.

Topological study of hydroxychloroquine conjugated molecular structure used for novel coronavirus (COVID-19) treatment

The novel coronavirus disease 2019 (Covid-19) is a mutating and recombining pandemic that potentially spreading through an infected person in droplet-generated forms that have affected more than 200 countries and endanger the entire globe. There is no clear strategy for the care of COVID-19 cases. Moreover, experts across the globe are working actively to develop medicinal or anti-virus drugs. On the basis of recent clinical findings and recommendations, the study examined a variety of new medications that have shown antiviral activity against SARS-CoV-2, among other drugs, antimalarial medications Chloroquine (CQ) and Hydroxychloroquine (HCQ) have gained significant publicity to have promising effects against SARS-CoV-2. Linking a bioactive substance to a biocompatible polymer typically provides various concerns, such as improved drug solubilization, improved modification, precise restriction, and controlled discharge. An enormous number of medical analyses have confirmed that the characteristics of medical drugs have a nearby connection with their atomic structure. Medication properties can be acquired by considering the atomic structure of relating drugs. The calculation of the topological index of a medication structure empowers researchers to have a superior comprehension of the physical science and bio-organic attributes of drugs. Ev-degree and ve-degree based topological indices are two novel degrees based indices as of late defined in graph theory. Ev-degree and ve-degree based topological indices have been defined as corresponding to their relating partners. In this paper, we have computed topological indices based on ev-degree and ve-degree for the Hydroxyethyl Starch and Hydroxychloroquine (HCQ-HEC) bioconjugate molecular structure.

Cardiovascular side effects of medications for skin diseases

Although many conditions can be successfully managed using the wide range of locally applied physical and pharmacological therapies, systemic administration of drugs is often necessary in dermatology. This chapter gives a brief survey of some of the most important systemic agents used by dermatologists, agents that may induce cardiovascular side effects or, sometimes, may benefit cardiovascular function. © Springer Nature Switzerland AG 2021.

Application of 4-aminoquinoline antimalarial drugs in virus infection

A number of in Vitro experiments and clinical studies have shown that classical quinoline antimalarial drugs such as quinine, chloroquine, hydroxychloroquine, mefloquine, not only have anti-plasmodial effects, but also have a wide range of antiviral effects against influenza Virus, hepatitis Virus, yellow fever virus, human immunodeficiency Virus and coronavirus infections. This review briefly describes the research advances and clinical application of the antiviral effects of 4- aminoquinoline drugs, hoping to provide useful information for in-depth research and utilization of anti-malarial drugs for combating Virus infections.

An internet-based cross-sectional study on infection control practices and drug use for COVID-19 prevention in Nigerian adults.

Introduction: COVID-19 has affected several millions of people globally and various means have been employed to curb the spread. This nationwide survey investigated adherence to infection control protocols and drug uptake among Nigerian adults. Methods: this was a descriptive cross-sectional survey using an internet-based questionnaire to investigate adherence to infection control practices and drug use among adults, who have been resident in Nigeria for at least 6 months. The data was analyzed using Stata software version 16 with levels of significance at p<0.05. Results: a total of 1235 adults participated in the study. The respondents were aged 18-78 years with a mean age of 36.3 ±11.1 years. Over half (53.0%) of the participants were between 31-50 years. The male to female ratio was 1: 1.45. Majority (92.6%) had a minimum of tertiary educational qualification. One hundred (27.1%) reported a positive test result for COVID-19. A total of 1,204 (97.5%) admitted to wearing of face masks, 1,125 (91.1%) washed hands regularly, 1,142 (92.5%) used hand sanitizers while physical distancing was maintained in 985 (79.8%). A total of 854 (69.2%) were on at least a drug or herbal based therapy. Herbal based remedies were used in 112 (9.1%), supplements in 763 (61.8%), antibiotics in 210 (17%), ivermectin in 205 (16.6%), and antimalarials in 128 (10.4%) participants. Conclusion: adherence to behavioural measures was high among the population, with widespread uptake of supplements, antibiotics, and antimalarial drugs. The high uptake of antibiotics emphasizes the need to step up regulatory policies for antibiotic use.

The Chloroquine Story in the First Year of the COVID-19 Pandemic

The emergence of COVID-19 has caused worldwide concern due to its high infectivity and mortality. Research groups around the world have prioritised drug development against COVID-19. Repurposing of already approved drugs, including the antimalarial drug chloroquine, has attracted considerable attention. The aim of this article is to (i) provide an overview of the recent chemical methods used to synthesise chloroquine and hydroxychloroquine, and (ii) provide insight into the data collected in 2020 on their efficacy against COVID-19. Unfortunately, the promising early results have not been confirmed and a clear and unambiguous conclusion on their clinical efficacy has not yet been drawn. (English) [ FROM AUTHOR] Pojava COVIDA-19 uzrokovala je globalnu zabrinutost zbog visoke zaraznosti i mortaliteta. Stoga je razvoj lijekova protiv COVIDA-19 postao prioritet istraživačkim skupinama diljem svijeta. Pri tom je posebnu pozornost privukla moguća prenamjena prethodno odobrenih lijekova, uključujući i antimalarijski lijek klorokin. Cilj ovog rada je (i) prikazati pregled recentnih kemijskih metoda primijenjenih za sintezu klorokina i hidroksiklorokina te (ii) dati uvid u podatke o njihovoj učinkovitosti protiv COVIDA-19 prikupljene tijekom 2020. Nažalost, početni obećavajući rezultati nisu potvrđeni, a jasni i nedvosmisleni zaključci o kliničkoj učinkovitosti klorokina i hidroksiklorokina još nisu postignuti. (Croatian) [ FROM AUTHOR] Copyright of Kemija u Industriji is the property of Croatian Society of Chemical Engineers and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Investigation of imported malaria cases at a COVID-19 isolation point in Qingdao

The epidemiological data were collected from travellers who returned from Guinea on the 23rd of September, 2020 and were diagnosed with malaria at a COVID-19 quarantine site in Qingdao, Shandong Province. The epidemiological characteristics, diagnosis and treatment of the cases and the epidemiology investigation and the rapid test screening results for other travellers on from the same flight and the interventions in reaction to the imported malaria cases were analyzed. The results showed that 4 out of 231 Guinean returned travellers had developed malaria symptoms, including chills and fever, during the isolation period. Rapid diagnostic test (RDT) indicated Plasmodium falciparum infection. Considering the patients' travel history, clinical manifestations, and laboratory RDT test results, a confirmed diagnosis of imported P. falciparum malaria was made. The four malaria cases, who are male workers aged 29 to 55, were transferred to Jiaozhou People's Hospital for treatment. All four patients were administrated of artemether tablets upon diagnosis. One of the cases experienced severe malaria complications and were administrated with 12 doses (60 mg/dose) of artesunate intravenously for five days. The other three patients were treated with dihydroartemisinin and piperaquine phosphate tablets for one course of 8 tablets in 2 days (40 mg dihydroartemisinin and 320 mg piperaquine phosphate), respectively. Among the 231 returned travellers, 111(48.1%) had a history of malaria overseas. There were 23 positive cases detected by RDT, including the four symptomatic cases. The other 19 cases were asymptomatic. One of the asymptomatic cases became symptomatic three months later and was diagnosed as an imported P. malariae infection. Laboratory blood smear microscopic tests at the Jiaozhou City and Qingdao Municipal Center For Disease Control and Prevention showed negative results for the four malaria cases and the 19 RDT positive case. The samples from the four malaria cases were rechecked by the provincial reference laboratory of Shandong Institute of parasitic Disease. The results were negative for malaria infection by microscopic examination but positive for P. falciparum infection by nucleic acid test. It is suggested that during the routine control of COVID-19, the awareness of COVID-19 and malaria should be established among the returned travellers from high malaria-endemic areas. The health education "gate" should be moved forward to improve the treatment compliance for malaria cases and reduce the relapse or recrudescence caused by sub-optimal treatment.

Antimalarials - old drugs are new again.

The aim of this study was to discuss the therapeutic mechanism of action of antimalarials, in particular hydroxychloroquine (HCQ), in patients with lupus erythematosus. It examines the results of recent studies indicating the need to revise the indications, dosage and duration of safe therapy, thus limiting the possibility of adverse effects. Historically, HCQ was recommended for patients with arthritis as a predominant symptom, whereas today, it is recommended for all lupus patients, even those with lupus nephritis and pregnant women; it has a favourable therapeutic profile, particularly regarding its effect on the activity of the disease, and the possibility of prolonging survival time and preventing organ damage and dysfunction. Antimalarials are basic, disease-modifying antirheumatic drugs, which not only relieve the symptoms of inflammation, but also affect the underlying processes; therefore, they should be administered chronically, and the expected effects may sometimes take a long time to become apparent. In the past, the recommended dose was 6.5 mg/kg ideal body weight, whereas today it is up to 5.0 mg/kg real body weight. A very important aspect of long-term therapy is the strict adherence to the medical prescription; hence, the introduction of a new formulation containing 400 mg of hydroxychloroquine sulphate per tablet is an interesting proposal.

Antiparasitic Drugs against SARS-CoV-2: A Comprehensive Literature Survey.

More than two years have passed since the viral outbreak that led to the novel infectious respiratory disease COVID-19, caused by the SARS-CoV-2 coronavirus. Since then, the urgency for effective treatments resulted in unprecedented efforts to develop new vaccines and to accelerate the drug discovery pipeline, mainly through the repurposing of well-known compounds with broad antiviral effects. In particular, antiparasitic drugs historically used against human infections due to protozoa or helminth parasites have entered the main stage as a miracle cure in the fight against SARS-CoV-2. Despite having demonstrated promising anti-SARS-CoV-2 activities in vitro, conflicting results have made their translation into clinical practice more difficult than expected. Since many studies involving antiparasitic drugs are currently under investigation, the window of opportunity might be not closed yet. Here, we will review the (controversial) journey of these old antiparasitic drugs to combat the human infection caused by the novel coronavirus SARS-CoV-2.

Pharmacological properties of chloroquine and hydroxychloroquine and their application in treatment of corona virus disease 2019 (COVLD-19)

Amid the global outbreak and epidemic of Corona Virus Disease 2019 (COVlD-19), it is urgent to find effective and safe therapies against COVlD-19. Preliminary clinical studies on COVID-19 showed that chloroquine and hydroxychloroquine were effective. However, it is necessary to pay atten- tion to medication application of chloroquine and hydroxychloroquine, since they have a large volume of distribution, a long haIf-life and the risk of adverse reactions of retinopathy with the long-term applica- tion of larger doses. In order to better understand these two drugs in current medical practice, this article outlines the history of clinical application and development of chloroquine and hydroxychloroquine, focusing on their pharmacokinetic characteristics and adverse reactions as well as the recent use against COVID-19 and their potential pharmacological action mechanism. It is hoped that this article can contribute to clinical use.

Research progress in anti-coronavirus effect and safety of chloroquine

Coronavirus, identified as a zoonotic pathogen, can cause pulmonary infections and even a pandemic. Corona Virus Disease 2019 (COVID-19), which was induced by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), struck the world in December 2019. There is no specific drug for coronavirus. As a classical antimalarial drug, chloroquine has been proved to have antiviral activity by changing the pH of endocytosis, via autophagy reactions and by changing the glycosylation mode of the virus envelope. At the cellular level, chloroquine has inhibitory effects on SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV- 2. Recent clinical research results are beginning to show that chloroquine can improve the success rate and prognosis. Chloroquine has been used less clinically in recent years due to the many adverse reactions it causes. The safety of chloroquine used in coronavirus infection requires in-depth evaluation. This article summarizes research progress in the anti-coronavirus effect and safety of chloroquine in order to provide reference for its clinical application.

Assessment of knowledge, practice and perception of Nigerian medical practitioners on COVID-19 and its treatment using antimalarial drugs

Pharmaceutical interventions are being investigated as possible treatment options for COVID-19. Antimalarial drugs-Hydroxychloroquine and chloroquine are also being investigated in clinical trials due to their antiviral effects though their efficacy in the treatment of COVID-19 is largely inconclusive. This study assessed the knowledge, perception, and practice of prescribing these drugs in the treatment of COVID-19 by practicing medical doctors in Nigeria. The survey was conducted online using Google forms sent via a link on WhatsApp © and Facebook © through the authors' contacts to medical doctors in the six geo-political zones of Nigeria from April-May 2020. Ethical issues were addressed by ensuring the anonymity of respondents, voluntary participation, and non-incentivized. Descriptive statistics were used to determine the mean and frequencies of data generated using SPSS version 22. Responses were obtained from 145 medical doctors with mean age of 37.78+or-6.47 years and 10.9+or-5.58 years of practice experience. All the respondents knew that the virus affects the lungs. Over 48% of the doctors believed in the efficacy of the antimalarial drugs, and more than half of them thought it would be more effective for mild disease presentation. About 46.8% of respondents agreed to prescribe the drug to COVID-19 patients, and most based their decisions on case reports, recommendations of NCDC or WHO. However, 75.9% believed a randomized control trial should be conducted to determine the efficacy and safety of the drugs. Practicing doctors in Nigeria are knowledgeable on COVID-19, and their perceptions and decision to prescribe antimalarial drugs are largely dependent on clinical trial outcomes.

Effectiveness of antiviral drugs as COVID-19 therapy

SARS-CoV 2 firstly emerged in China on December 2019 and it was spreading rapidly across the world until now. At this time, there is no vaccine or medication approved by the FDA. However, there are some FDA approved medicines for treating other diseases that can be used for Covid-19 based on tests. This review focuses on therapy efficacy, work mechanism, pharmacokinetic profile, safety, and future perspective. Article review related to therapy on Covid-19 patients, particularly antiviral therapy which was the combination of lopinavir and ritonavir, chloroquine, hydroxychloroquine, remdesivir, and favipiravir. The reviewed relevant articles were observational study, in vitro test, case report, and clinical test. A total of 13 articles met the requirement, 9 articles discussed the result of therapy during the medication of COVID-19 patients, 2 reports of in vitro test, and 2 results of clinical trials. From several studies that had been conducted, remdesivir, combination of lopinavir and ritonavir, as well as favipiravir showed benefits in various clinical studies on Covid-19 patients. Meanwhile, chloroquine and hydroxychloroquine showed limited effects and did not affect the decrease of mortality.

An agile discovery method of drugs for infectious diseases and tentative exploration of its application in drug discovery for COVID-19

OBJECTIVE: To establish an agile discovery method of drugs or natural products for epidemics (aCODE) for the development of anti-infectious disease drugs. METHODS: Five infectious diseases (HIV infection, human influenza, Paramyxoviridae infections, bacterial infections and whooping cough) involving more than 40 drugs approved by the United States Food and Drug Administration (FDA) were selected. An experimental group and two negative control groups (A and B) for each disease were set up. The experimental group randomly selected (500 times) M FDA-approved indications as seed drugs for the disease, while negative control group A used all FDA-approved infectious drugs for non-current diseases instead of seed drugs, and negative control group B used all non-infectious disease drugs for non-infectious diseases instead of seed drugs. M ranged from 2 to 20, the target gene information of the seed drug was input, and the feature vector of the seed drug set was calculated. Candidate compounds were predicted through similarity search of drug feature vectors. The size of the inter- section between the predicted drug and the positive set of drugs approved by the FDA for the disease, and the significance of the intersection were calculated. After the establishment of the aCODE method, four drugs (lopinavir, ribavirin, ritonavir and chloroquine) were selected as seed drugs for COVlD-19 to predict the composition of natural products. Using natural products with known anti-coronavirus activities as the verification set, the significance of the prediction results was calculated. RESULTS: In the case of the five infectious diseases, the proportion of positive drugs in the results of prediction in the experimental group increased with the number of seed drugs, while the positive rate of the two negative control groups remained basically unchanged or somewhat trended down. The aCODE method, when applied to COVlD-19 drug screening, could effectively predict drugs with potential anti-SARS-Cov-2 activity (P=0.0046). CONCLUSION: With the aCODE method, the more the seed drugs, the more accu- rate the characteristics of the disease-related gene modules calculated from this group of seed drugs, and the higher the proportion of positive drugs in the prediction result. This method may contribute to the discovery of drugs for COVID-19.

A scalable process for the synthesis of key intermediates novoldiamine & hydroxynovaldiamine and their utility in chloroquine, hydroxychloroquine and mepacrine synthesis

A highly efficient and scalable process for the synthesis of novoldiamine and hydroxynovaldiamine is accomplished from levulinic acid, which is easily accessible from the natural feedstock. These diamines are used as the key intermediates for the synthesis of chloroquine, hydroxychloroquine and mepacrine. The key steps involved in this process are the coupling of levulinic acid with secondary amine assisted by 1, 1'-carbonyldiimidazole and one-pot reduction of oxime-amide functional groups to get the corresponding diamine.

Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge.

The antimalarial hydroxychloroquine (HCQ) has demonstrated several crucial properties for the treatment of systemic lupus erythematosus (SLE). Herein, we reviewed the main HCQ pharmacologic features, detailed its mechanism of action, and summarized the existing guidelines and recommendations for HCQ use in rheumatology with a systematic literature search for the randomized controlled trials focused on lupus. HCQ has been shown to decrease SLE activity, especially in mild and moderate disease, to prevent disease flare and to lower the long-term glucocorticoid need. The numerous benefits of HCQ are extended to pregnancy and breastfeeding period. Based on cohort studies, antithrombotic and metabolic HCQ's effects were shown, including lipid-lowering properties, which might contribute to an improved cardiovascular risk. Moreover, early HCQ use in antinuclear antibodies positive individuals might delay the progression to SLE. Finally, HCQ has a significant favorable impact on long-term outcomes such as damage accrual and mortality in SLE. Based on these multiple benefits, HCQ is now the mainstay long-term treatment in SLE, recommended by current guidelines in all patients unless contraindications or side effects. The daily dose associated with the best compromise between efficacy and safety is matter of debate. The concern regarding retinal toxicity rather than proper efficacy data is the one that dictated the daily dosage of ⩽5 mg/kg/day actual body weight currently agreed upon.