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2.
Int J Pharm ; 628: 122329, 2022 Nov 25.
Article in English | MEDLINE | ID: covidwho-2083078

ABSTRACT

Recently, the U.S. Food and Drug Administration (FDA) approved the first oral antiviral drug to treat mild to moderate cases of coronavirus disease. The combination of nirmatrelvir with an already used protease inhibitor class drug, ritonavir, has led to Paxlovid®. Several studies considered drug repositioning as the first trial for new drugs. The precise identification and quantification of polymorphs in raw materials and finished products are important to researchers involved in pharmaceutical development and quality control processes. In this work, we study the solid-state behavior of the antiretroviral drugs ritonavir and lopinavir in raw materials and in milled compositions. The results indicate that mixtures of ritonavir Forms I and II are found in different batches of raw materials from the same manufacturer; besides three equal crystalline samples, an amorphous batch was found in lopinavir. Furthermore, the milling process of the already amorphous lopinavir seems to facilitate the amorphization of ritonavir as well as the production of some unexpected crystalline forms of ritonavir. A phase transition of ritonavir Form I to Form II is only observed when co-milling with amorphous lopinavir. These findings reveal significant variations in phase purity of raw materials that affect the processing and solid-state properties, representing risks for the product quality.


Subject(s)
Coronavirus Infections , Ritonavir , Humans , Lopinavir/chemistry , Antiviral Agents , Coronavirus Infections/drug therapy , Drug Combinations
3.
Curr Opin Rheumatol ; 32(6): 572-582, 2020 11.
Article in English | MEDLINE | ID: covidwho-2077899

ABSTRACT

PURPOSE OF REVIEW: The purpose of this review is highlighting the most recent evidence on the clinical efficacy and toxicity of antimalarials in systemic lupus erythematosus (SLE). RECENT FINDINGS: New data confirm the effects of antimalarials in preventing SLE activity, damage and infections and in decreasing mortality. An important reduction in use of health resources is related to continued antimalarial use. Hydroxychloroquine (HCQ) may prevent preeclampsia in pregnant women with SLE. HCQ ocular toxicity is infrequent and could be associated with blood levels. Gastrointestinal and skin toxicity are underrecognized and could influence adherence. Prolongation of QT interval is extremely unusual with HCQ. Doses of HCQ of 200 mg/day seem to offer a good efficacy/toxicity balance. HCQ protection against herpes zoster and Pneumocystis jirovecii infection has been shown. On the contrary, HCQ prescription by doctors and adherence by patients are both under recommended standards. The recent coronavirus disease 2019 pandemic has resulted in a significant shortage of HCQ in many countries with possible consequences in the correct treatment of lupus patients. SUMMARY: Recent evidence reinforces the central role of HCQ in SLE therapy. The reduction in activity, damage accrual and mortality is consistent across studies, countries and ethnical groups. On the contrary, and despite the well established beneficial effects of prolonged regular HCQ therapy, many SLE patients do never take this drug or it is eventually stopped in the setting of severe flares, pregnancy or presumed toxicity. Every effort must be made to assure the correct prescription of HCQ and not to withdraw the drug unless unequivocal signs of toxicity are present.


Subject(s)
Antimalarials/therapeutic use , Betacoronavirus , Coronavirus Infections/epidemiology , Lupus Erythematosus, Systemic/drug therapy , Pandemics , Pneumonia, Viral/epidemiology , COVID-19 , Comorbidity , Coronavirus Infections/drug therapy , Female , Humans , Lupus Erythematosus, Systemic/epidemiology , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Treatment Outcome
5.
Viruses ; 14(10)2022 10 08.
Article in English | MEDLINE | ID: covidwho-2066562

ABSTRACT

Pig diarrhea is a universal problem in the process of pig breeding, which seriously affects the development of the pig industry. Porcine enteric coronaviruses (PECoVs) are common pathogens causing diarrhea in pigs, currently including transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus (PDCoV) and swine acute diarrhea syndrome coronavirus (SADS-CoV). With the prosperity of world transportation and trade, the spread of viruses is becoming wider and faster, making it even more necessary to prevent PECoVs. In this paper, the host factors required for the efficient replication of these CoVs and the compounds that exhibit inhibitory effects on them were summarized to promote the development of drugs against PECoVs. This study will be also helpful in discovering general host factors that affect the replication of CoVs and provide references for the prevention and treatment of other CoVs.


Subject(s)
Coronavirus Infections , Coronavirus , Porcine epidemic diarrhea virus , Swine Diseases , Swine , Animals , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Coronavirus Infections/veterinary , Diarrhea/drug therapy , Diarrhea/veterinary
6.
Lancet Infect Dis ; 20(11): e276-e288, 2020 11.
Article in English | MEDLINE | ID: covidwho-2062013

ABSTRACT

As severe acute respiratory syndrome coronavirus 2 continues to spread worldwide, there have been increasing reports from Europe, North America, Asia, and Latin America describing children and adolescents with COVID-19-associated multisystem inflammatory conditions. However, the association between multisystem inflammatory syndrome in children and COVID-19 is still unknown. We review the epidemiology, causes, clinical features, and current treatment protocols for multisystem inflammatory syndrome in children and adolescents associated with COVID-19. We also discuss the possible underlying pathophysiological mechanisms for COVID-19-induced inflammatory processes, which can lead to organ damage in paediatric patients who are severely ill. These insights provide evidence for the need to develop a clear case definition and treatment protocol for this new condition and also shed light on future therapeutic interventions and the potential for vaccine development. TRANSLATIONS: For the French, Chinese, Arabic, Spanish and Russian translations of the abstract see Supplementary Materials section.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Systemic Inflammatory Response Syndrome/epidemiology , Systemic Inflammatory Response Syndrome/immunology , Adolescent , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antiviral Agents/therapeutic use , COVID-19 , Child , Child, Preschool , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Female , Humans , Immunoglobulins, Intravenous/therapeutic use , Infant , Infant, Newborn , Male , Mucocutaneous Lymph Node Syndrome/drug therapy , Mucocutaneous Lymph Node Syndrome/immunology , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Risk Factors , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/virology , Young Adult
7.
Virus Res ; 319: 198882, 2022 Oct 02.
Article in English | MEDLINE | ID: covidwho-2061967

ABSTRACT

To date, a total of seven human coronaviruses (HCoVs) have been identified, all of which are important respiratory pathogens. Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has led to a global pandemic causing millions of infections and deaths. Here, we summarize the discovery and fundamental virology of HCoVs, discuss their zoonotic transmission and highlight the weak species barrier of SARS-CoV-2. We also discuss the possible origins of SARS-CoV-2 variants of concern identified to date and discuss the experimental challenges in characterizing mutations of interest and propose methods to circumvent them. As the COVID-19 treatment and prevention landscape rapidly evolves, we summarize current therapeutics and vaccines, and their implications on SARS-CoV-2 variants. Finally, we explore how interspecies transmission of SARS-CoV-2 may drive the emergence of novel strains, how disease severity may evolve and how COVID-19 will likely continue to burden healthcare systems globally.


Subject(s)
COVID-19 , Coronavirus Infections , Pneumonia, Viral , Betacoronavirus/genetics , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Humans , Pneumonia, Viral/prevention & control , SARS-CoV-2/genetics
8.
J Glob Health ; 12: 05031, 2022 Aug 31.
Article in English | MEDLINE | ID: covidwho-2025296

ABSTRACT

Background: Treatment of the coronavirus disease (COVID-19) is still challenging due to the lack of evidence-based treatment protocols and continuously changing epidemiological situations and vaccinations. Remdesivir (RDV) is among the few antiviral medications with confirmed efficacy for specific patient groups. However, real-world data on long-term outcomes for a short treatment course are scarce. Methods: This retrospective observational cohort study included real-life data collected during the second and third wave of the COVID-19 pandemic in Hungary (September 1, 2020-April 30, 2021) from inpatients at a University Center (n = 947). Participants consisted of two propensity score-matched cohorts (370/370 cases): Group RDV including patients receiving RDV and supplementary oxygen and Group standard of care (SOC) as control. The primary outcome was the effect of 5-day RDV treatment on 30- and 60-day all-cause mortality. Multivariate analyses were performed to assess the effect of RDV by different covariates. Results: Group RDV included significantly more patients from the alpha variant wave, with greater frequency of comorbidities diabetes and anemia, and larger degree of parenchymal involvement. All-cause mortality at 30- and 60-day were significantly lower in Group RDV compared to Group SOC. Significant risk reduction of 60-day all-cause mortality was observed for RDV treatment in men and patients with COPD or multiple comorbidities. Conclusions: Hospitalized COVID-19 patients with 5-day RDV treatment had significantly lower 30- and 60-day all-cause mortality, despite their more severe clinical condition. Men and patients with multiple comorbidities, including COPD, profited the most from RDV treatment in the long term. Due to the ongoing COVID-19 pandemic, effective treatment regimens are needed for hospitalized patients.


Subject(s)
COVID-19 , Coronavirus Infections , Coronavirus , Pulmonary Disease, Chronic Obstructive , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Betacoronavirus , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Humans , Male , Pandemics , Retrospective Studies , SARS-CoV-2
9.
Vet Microbiol ; 272: 109516, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1991332

ABSTRACT

Porcine epidemic diarrhea virus (PEDV) is one of the main pathogens causing severe diarrhea in piglets. Infection of the host induces apoptosis, causing huge economic losses to the pig industry. At present, the preventive and therapeutic effects of commercial vaccines are not satisfactory, and it is necessary to develop new anti-PEDV drugs. In this study, we screened the PEDV-inhibiting drug Buddlejasaponin IVb from the natural product library, and determined the inhibitory effect of Buddlejasaponin IVb on PEDV proliferation in a dose-dependent manner. By exploring the effect of Buddlejasaponin IVb on the life cycle of PEDV, it was found that Buddlejasaponin IVb mainly inhibits the replication and release stages of PEDV, but there is no report at home and abroad. In addition, Buddlejasaponin IVb can inhibit PEDV-activated NF-κB signaling pathway by downregulating PEDV or LPS induced elevation of cytokine levels (IL-6, IL-8, IL-1ß, TNF-α). Finally, we returned to in vivo experiments to explore the antiviral effects of the drug in pigs. The results show that Buddlejasaponin IVb can effectively relieve the clinical symptoms and intestinal damage caused by PEDV infection in pigs. Therefore, this study will provide an important basis for the research on antiviral drugs of PEDV and its members, and at the same time provide guidance for the actual production, which has important application prospects.


Subject(s)
Coronavirus Infections , Porcine epidemic diarrhea virus , Saponins , Swine Diseases , Animals , Antiviral Agents/pharmacology , Coronavirus Infections/drug therapy , Coronavirus Infections/veterinary , NF-kappa B/metabolism , Saponins/pharmacology , Swine , Swine Diseases/drug therapy
10.
Inflammopharmacology ; 30(5): 1927-1931, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-1990702

ABSTRACT

The efforts of the scientific world directed to identifying new antiviral drugs and therapies effective against SARS-CoV-2 continue. New oral antivirals against SARS-CoV-2 such as paxlovid have recently authorized. Evidence shows that these antivirals have good efficacy in reducing the risk of hospitalization in COVID-19 positive patients. Remdesivir is an authorized antiviral for the treatment of SARS-CoV-2 infection. To date, there are still few data in the literature on the safety profile and the risk of generating antiviral-resistant SARS-CoV-2 drug variants. In this manuscript we describe the evidence in the literature on the monotherapy use of paxlovid and monotherapy use of remdesivir, and the scientific hypothesis of using nirmatrelvir and remdesivir in association with the aim of increasing treatment efficacy, reducing the risk of adverse reactions and generating antiviral drug-resistant variants.


Subject(s)
COVID-19 , Coronavirus Infections , Pneumonia, Viral , Adenosine Monophosphate/analogs & derivatives , Adult , Alanine/analogs & derivatives , Antiviral Agents/adverse effects , Betacoronavirus , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Hospitalization , Humans , Pandemics , Pneumonia, Viral/drug therapy , SARS-CoV-2
11.
Cell Rep Med ; 3(9): 100735, 2022 09 20.
Article in English | MEDLINE | ID: covidwho-1984242

ABSTRACT

We here investigate the impact of antiviral treatments such as remdesivir on intra-host genomic diversity and emergence of SARS-CoV2 variants in patients with a prolonged course of infection. Sequencing and variant analysis performed in 112 longitudinal respiratory samples from 14 SARS-CoV2-infected patients with severe disease progression show that major frequency variants do not generally arise during prolonged infection. However, remdesivir treatment can increase intra-host genomic diversity and result in the emergence of novel major variant species harboring fixed mutations. This is particularly evident in a patient with B cell depletion who rapidly developed mutations in the RNA-dependent RNA polymerase gene following remdesivir treatment. Remdesivir treatment-associated emergence of novel variants is of great interest in light of current treatment guidelines for hospitalized patients suffering from severe SARS-CoV2 disease, as well as the potential use of remdesivir to preventively treat non-hospitalized patients at high risk for severe disease progression.


Subject(s)
COVID-19 , Coronavirus Infections , Pneumonia, Viral , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/adverse effects , Betacoronavirus , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Disease Progression , Humans , Pandemics , Pneumonia, Viral/chemically induced , RNA, Viral/therapeutic use , RNA-Dependent RNA Polymerase , SARS-CoV-2/genetics
14.
Cad Saude Publica ; 38(7): e00001022, 2022.
Article in English | MEDLINE | ID: covidwho-1963142

ABSTRACT

Off-label use of azithromycin, hydroxychloroquine, and ivermectin (the "COVID kit") has been suggested for COVID-19 treatment in Brazil without clinical or scientific evidence of efficacy. These drugs have known adverse drug reactions (ADR). This study aimed to analyze if the sales of drugs in the "COVID kit" are correlated to the reported number of ADR after the COVID-19 pandemic began. Data was obtained from the Brazilian Health Regulatory Agency (Anvisa) website on reported sales and ADRs for azithromycin, hydroxychloroquine, and ivermectin for all Brazilian states. The period from March 2019 to February 2020 (before the pandemic) was compared to that from March 2020 to February 2021 (during the pandemic). Trend adjustment was performed for time series data and cross-correlation analysis to investigate correlation between sales and ADR within the same month (lag 0) and in the following months (lag 1 and lag 2). Spearman's correlation coefficient was used to assess the magnitude of the correlations. After the pandemic onset, sales of all investigated drugs increased significantly (69.75% for azithromycin, 10,856,481.39% for hydroxychloroquine, and 12,291,129.32% for ivermectin). ADR levels of all medications but azithromycin were zero before the pandemic, but increased after its onset. Cross-correlation analysis was significant in lag 1 for all drugs nationwide. Spearman's correlation was moderate for azithromycin and hydroxychloroquine but absent for ivermectin. Data must be interpreted cautiously since no active search for ADR was performed. Our results show that the increased and indiscriminate use of "COVID kit" during the pandemic correlates to an increased occurrence of ADRs.


Subject(s)
COVID-19 , Coronavirus Infections , Drug-Related Side Effects and Adverse Reactions , Pneumonia, Viral , Azithromycin/adverse effects , Brazil/epidemiology , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Drug-Related Side Effects and Adverse Reactions/epidemiology , Humans , Hydroxychloroquine/adverse effects , Ivermectin/adverse effects , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology
15.
Ann Afr Med ; 21(2): 113-117, 2022.
Article in English | MEDLINE | ID: covidwho-1954253

ABSTRACT

Background: Coronavirus disease-2019 (COVID-19) pandemic has engulfed the whole world with millions getting infected and losing their lives. Health care professionals (HCPs) who are in the front line of fighting with COVID-19 are particularly vulnerable and it is crucial to protect them from COVID-19. In this regard, the Indian Council of Medical Research (ICMR) has recommended hydroxychloroquine (HCQS) chemoprophylaxis in HCPs. However, considering the lack of sufficient evidence the HCP are in a dilemma about this aspect. Moreover, there is a paucity of data on use of HCQS as a chemoprophylaxis among Indian HCP. Hence, this study was carried out to study the extent of use and also the perception of Indian HCP toward use of HCQS as a chemoprophylaxis for COVID-19. Materials and Methods: This was a cross-sectional study done on 205 HCPs working across India. The responses were collected electronically using a prevalidated semi-structured questionnaire. Results: 62.9% (129/205) respondents reported having taken HCQS chemo-prophylaxis for COVID-19 while 34.7% (76/205) did not take it. Among HCP, who did not take the prophylaxis, the main reasons cited were concern about adverse effects (61.5%) and lack of robust evidence (24%). Only 14% of respondents felt that there was sufficient evidence to justify use of HCQS for prophylaxis while an overwhelming majority (86%) felt otherwise or were uncertain. Conclusion: The majority of participants felt that despite a lack of proven efficacy, ICMR guidelines on HCQS prophylaxis in COVID-19 are justified considering the pandemic situation. Our study also found that HCQS is well tolerated by participants and there was no reported serious adverse effect and cardiac-related side effects among them.


Résumé Contexte: La pandémie de maladie à coronavirus-2019 (COVID-19) a englouti le monde entier avec des millions de personnes infectées et perdant leur des vies. Les professionnels de la santé (HCP) qui sont en première ligne dans la lutte contre le COVID-19 sont particulièrement vulnérables et il est essentiel de les protéger du COVID-19. À cet égard, le Conseil indien de la recherche médicale (ICMR) a recommandé l'hydroxychloroquine (HCQS) chimioprophylaxie chez les professionnels de la santé. Cependant, compte tenu du manque de preuves suffisantes, le professionnel de la santé est confronté à un dilemme à propos de cet aspect. En outre, il y a peu de données sur l'utilisation du HCQS comme chimioprophylaxie parmi les professionnels de la santé indiens. Par conséquent, cette étude a été menée pour étudier l'étendue de l'utilisation et aussi la perception des professionnels de la santé indiens à l'égard de l'utilisation du HCQS comme chimioprophylaxie pour le COVID-19. Matériel et Méthodes: c'était un étude transversale réalisée sur 205 professionnels de la santé travaillant en Inde. Les réponses ont été recueillies par voie électronique à l'aide d'un système semi-structuré prévalidé questionnaire. Résultats: 62,9% (129/205) des répondants ont déclaré avoir suivi une chimioprophylaxie HCQS pour le COVID-19, tandis que 34,7% (76/205) ne l'a pas pris. Parmi les professionnels de la santé qui n'ont pas pris de prophylaxie, les principales raisons invoquées étaient la préoccupation concernant les effets indésirables (61,5%) et le manque de preuves solides (24%). Seulement 14% des répondants estimaient qu'il y avait des preuves suffisantes pour justifier l'utilisation du HCQS à des fins prophylactiques alors qu'un une écrasante majorité (86%) pensait le contraire ou était incertaine. Conclusion: La majorité des participants ont estimé que malgré un manque de efficacité, les lignes directrices de l'ICMR sur la prophylaxie du HCQS dans le COVID-19 sont justifiées compte tenu de la situation pandémique. Notre étude a également révélé que Le HCQS est bien toléré par les participants et aucun effet indésirable grave ni effet secondaire cardiaque n'a été signalé parmi eux. Mots-clés: Chimioprophylaxie, COVID-19, hydroxychloroquine, Conseil indien de la recherche médicale.


Subject(s)
COVID-19 , Coronavirus Infections , Pneumonia, Viral , COVID-19/drug therapy , COVID-19/prevention & control , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Cross-Sectional Studies , Health Personnel , Humans , Hydroxychloroquine/adverse effects , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Surveys and Questionnaires
16.
Front Cell Infect Microbiol ; 12: 856711, 2022.
Article in English | MEDLINE | ID: covidwho-1924078

ABSTRACT

Porcine epidemic diarrhea virus (PEDV) could cause lethal diarrhea and dehydration in suckling piglets, which can adversely affect the development of the global swine industry. The lack of effective therapeutical and prophylactic treatment especially for PEDV variant strains underlines the importance of effective antiviral strategies, such as identification of novel antiviral agents. In the present study, the antiviral activity of cinchonine against PEDV was investigated in Vero CCL81 and LLC-PK1 cells at a non-cytotoxic concentration determined by Cell Counting Kit-8 assay in vitro. We found that cinchonine exhibited a significant suppression effect against PEDV infection and its inhibitory action was primarily focused on the early stage of PEDV replication. Moreover, we also observed that cinchonine could significantly induce autophagy by detecting the conversion of LC3-I to LC3-II by using western blot analysis. Cinchonine treatment could inhibit PEDV replication in a dose-dependent manner in Vero CCL81 cells, while this phenomenon disappeared when autophagy was attenuated by pre-treatment with autophagy inhibitor 3MA. Consequently, this study indicated that cinchonine can inhibit PEDV replication via inducing cellular autophagy and thus from the basis for successful antiviral strategies which potentially suggest the possibility of exploiting cinchonine as a novel antiviral agent.


Subject(s)
Coronavirus Infections , Porcine epidemic diarrhea virus , Swine Diseases , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Autophagy , Chlorocebus aethiops , Cinchona Alkaloids , Coronavirus Infections/drug therapy , Coronavirus Infections/veterinary , Porcine epidemic diarrhea virus/physiology , Swine , Swine Diseases/drug therapy , Vero Cells , Virus Replication
17.
Viruses ; 14(6)2022 06 06.
Article in English | MEDLINE | ID: covidwho-1911617

ABSTRACT

Porcine epidemic diarrhea virus (PEDV) belongs to the genus Alphacoronavirus of the family Coronaviridae that causes severe diarrhea and high mortality in neonatal suckling piglets. Currently, there is no effective medication against this pathogen. Cepharanthine (CEP), tetrandrine (TET), and fangchinoline (FAN) are natural bis-benzylisoquinoline alkaloids with anti-inflammatory, antitumor, and antiviral properties. Here, we first found that CEP, TET, and FAN had anti-PEDV activity with IC50 values of 2.53, 3.50, and 6.69 µM, respectively. The compounds could block all the processes of viral cycles, but early application of the compounds before or during virus infection was advantageous over application at a late stage of virus replication. FAN performed inhibitory function more efficiently through interfering with the virus entry and attachment processes or through attenuating the virus directly. CEP had a more notable effect on virus entry. With the highest SI index of 11.8 among the three compounds, CEP was chosen to carry out animal experiments. CEP in a safe dosage of 11.1 mg/kg of body weight could reduce viral load and pathological change of piglet intestinal tracts caused by PEDV field strain challenge, indicating that CEP efficiently inhibited PEDV infection in vivo. All of these results demonstrated that the compounds of bis-benzylisoquinoline alkaloids could inhibit PEDV proliferation efficiently and had the potential of being developed for PED prevention and treatment.


Subject(s)
Benzylisoquinolines , Coronavirus Infections , Porcine epidemic diarrhea virus , Swine Diseases , Animals , Benzylisoquinolines/pharmacology , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Coronavirus Infections/veterinary , Diarrhea , Swine , Swine Diseases/pathology
18.
Protein Pept Lett ; 29(7): 574-583, 2022.
Article in English | MEDLINE | ID: covidwho-1879360

ABSTRACT

The coronavirus family consists of pathogens that seriously affect human and animal health. They mostly cause respiratory or enteric diseases, which can be severe and life-threatening, such as coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome (SARS), and Middle East Respiratory Syndrome (MERS) in humans. The conserved coronaviral papain-like protease is an attractive antiviral drug target because it is essential for coronaviral replication, and it also inhibits host innate immune responses. This review focuses on the latest research progress relating to the mechanism of coronavirus infection, the structural and functional characteristics of coronavirus papain-like protease, and the potent inhibitors of the protease.


Subject(s)
Coronavirus Infections/drug therapy , Coronavirus Papain-Like Proteases/chemistry , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Humans , Papain/chemistry , Peptide Hydrolases/chemistry , Protease Inhibitors/pharmacology
19.
Clin Pharmacol Ther ; 112(4): 824-835, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-1858580

ABSTRACT

Chloroquine and azithromycin were developed in combination for the preventive treatment of malaria in pregnancy, and more recently were proposed as coronavirus disease 2019 (COVID-19) treatment options. Billions of doses of chloroquine have been administered worldwide over the past 70 years but concerns regarding cardiotoxicity, notably the risk of torsades de pointes (TdP), remain. This investigation aimed to characterize the pharmacokinetics and electrocardiographic effects of chloroquine and azithromycin observed in a large previously conducted healthy volunteer study. Healthy adult volunteers (n = 119) were randomized into 5 arms: placebo, chloroquine alone (600 mg base), or chloroquine with either 500 mg, 1,000 mg, or 1,500 mg of azithromycin all given daily for 3 days. Chloroquine and azithromycin levels, measured using liquid-chromatography tandem mass spectrometry, and electrocardiograph intervals were recorded at frequent intervals. Time-matched changes in the PR, QRS, and heart rate-corrected JT, and QT intervals were calculated and the relationship with plasma concentrations was evaluated using linear and nonlinear mixed-effects modeling. Chloroquine and azithromycin pharmacokinetics were described satisfactorily by two- and three-compartment distribution models, respectively. No drug-drug interaction between chloroquine and azithromycin was observed. Chloroquine resulted in concentration-dependent prolongation of the PR, QRS, JTc and QTc intervals with a minimal additional effect of azithromycin. QRS widening contributed ~ 28% of the observed QT prolongation. Chloroquine causes significant concentration-dependent delays in both ventricular depolarization and repolarization. Co-administration of azithromycin did not significantly increase these effects. The arrhythmogenic risk of TdP associated with chloroquine may have been substantially overestimated in studies which did not separate electrocardiograph QRS and JT prolongation.


Subject(s)
Antimalarials , COVID-19 , Coronavirus Infections , Long QT Syndrome , Pneumonia, Viral , Torsades de Pointes , Adult , Azithromycin/adverse effects , COVID-19/drug therapy , Chloroquine , Coronavirus Infections/drug therapy , DNA-Binding Proteins/therapeutic use , Electrocardiography , Healthy Volunteers , Humans , Hydroxychloroquine , Long QT Syndrome/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Torsades de Pointes/drug therapy
20.
J Infect Dis ; 225(10): 1765-1772, 2022 05 16.
Article in English | MEDLINE | ID: covidwho-1853084

ABSTRACT

BACKGROUND: REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells. METHODS: Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (n = 36) or placebo (n = 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation. RESULTS: Preclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic. CONCLUSIONS: REGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.


Subject(s)
Coronavirus Infections , Middle East Respiratory Syndrome Coronavirus , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Dipeptidyl Peptidase 4/metabolism , Humans , Immunoglobulin G , Mice , Spike Glycoprotein, Coronavirus
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