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Current status of potential therapeutic candidates for the COVID-19 crisis.
Zhang, J, Xie, B, Hashimoto, K
Brain, behavior, and immunity. 2020;:59-73
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Abstract
As of April 15, 2020, the ongoing coronavirus disease 2019 (COVID-2019) pandemic has swept through 213 countries and infected more than 1,870,000 individuals, posing an unprecedented threat to international health and the economy. There is currently no specific treatment available for patients with COVID-19 infection. The lessons learned from past management of respiratory viral infections have provided insights into treating COVID-19. Numerous potential therapies, including supportive intervention, immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion, have been tentatively applied in clinical settings. A number of these therapies have provided substantially curative benefits in treating patients with COVID-19 infection. Furthermore, intensive research and clinical trials are underway to assess the efficacy of existing drugs and identify potential therapeutic targets to develop new drugs for treating COVID-19. Herein, we summarize the current potential therapeutic approaches for diseases related to COVID-19 infection and introduce their mechanisms of action, safety, and effectiveness.
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PROTECT Trial: A cluster-randomized study with hydroxychloroquine versus observational support for prevention or early-phase treatment of Coronavirus disease (COVID-19): A structured summary of a study protocol for a randomized controlled trial.
Nanni, O, Viale, P, Vertogen, B, Lilli, C, Zingaretti, C, Donati, C, Masini, C, Monti, M, Serra, P, Vespignani, R, et al
Trials. 2020;(1):689
Abstract
OBJECTIVES Hydroxychloroquine has shown to have antiviral activity in vitro against coronaviruses, specifically SARS-CoV-2. It is believed to block virus infection by increasing endosomal pH required for virus cell fusion and glycosylation of viral surface proteins. In addition to its antiviral activity, hydroxychloroquine has an immune-modulating activity that may synergistically enhance its antiviral effect in vivo, making it a potentially promising drug for the prevention and the cure of SARS-CoV-19. However, randomized controlled trials are needed to assess whether it can be used safely to treat COVID-19 patients or to prevent infection. The main objective of the present study is to evaluate the efficacy of hydroxychloroquine for (I) the prevention of COVID-19 or related symptoms in SARS-CoV-2-exposed subjects, such as as household members/contacts of COVID-19 patients and (II) the treatment of early-phase asymptomatic or paucisymptomatic COVID-19 patients. TRIAL DESIGN This is a controlled, open label, cluster-randomized, superiority trial with parallel group design. Subjects will be randomized either to receive hydroxychloroquine or to observation (2:1). PARTICIPANTS SARS-CoV-2-exposed subjects, including household members and/or contacts of COVID-19 patients and healthcare professionals (Group 1) or patients with COVID-19 (positive PCR test on a rhinopharyngeal or oropharyngeal swab for SARS-CoV-2), asymptomatic or paucisymptomatic in home situations who are not undergoing treatment with any anti COVID-19 medication (Group 2), will be enrolled. Paucisymptomatic patients are defined as patients with a low number of mild symptoms. All subjects must be aged ≥18 years, male or female, must be willing and able to give informed consent and must not have any contraindications to take hydroxychloroquine (intolerance or previous toxicity for hydroxychloroquine/chloroquine, bradycardia or reduction in heart rhythm with arrhythmia, ischemic heart disease, retinopathy, congestive heart failure with use of diuretics, favism or glucose-6-phosphate dehydrogenase (G6PD) deficiency, diabetes type 1, major comorbidities such as advanced chronic kidney disease or dialysis therapy, known history of ventricular arrhythmia, any oncologic/hematologic malignancy, severe neurological and mental illness, current use of medications with known significant drug-drug interactions, and known prolonged QT syndrome or current use of drugs with known QT prolongation). The study is monocentric and will be conducted at Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS. Subjects will be enrolled from a large epidemic region (North-Central Italy). The Public Health Departments of several Italian regions will collaborate by identifying potentially eligible subjects. INTERVENTION AND COMPARATOR The participants will be randomized (2:1 randomization) to receive either hydroxychloroquine (Arm A) or to Observation (Arm B). Hydroxychloroquine will be administered with the following schedule: Group1: A loading dose hydroxychloroquine 400 mg twice daily on day 1, followed by a weekly dose of hydroxychloroquine 200 mg twice daily on days 8, 15 and 22, for a total of one month of treatment. Group 2: A loading dose hydroxychloroquine 400 mg twice daily on day 1 followed by 200 mg twice daily for a total of 5-7 days. The comparator in this trial is observation given that currently neither treatment is administered to asymptomatic or paucisymptomatic subjects, nor prophylaxis is available for contacts. Hydroxychloroquine will be shipped to subjects within 24 hours of randomization. Given the extraordinary nature of the COVID-19 pandemic, only telephonic interviews will be carried out and electronic Patient Reported Outcomes (ePRO) completed. During treatment, each subject will be contacted every other day for the first week and weekly thereafter (Group 2) or weekly (Group 1) by a study physician to assess early onset of any COVID-19 symptom or any adverse reaction to hydroxychloroquine and to check subject compliance. Furthermore, all subjects will receive periodic ePROs which may be completed through smartphone or tablets to record drug self-administration and onset of any symptom or adverse event. All subjects will be followed up for a total of 6 months by periodic telephonic interviews and ePROs. MAIN OUTCOMES The primary endpoint/outcome measure for this trial is: for Group 1, the proportion of subjects who become symptomatic and/or swab-positive in each arm within one month of randomization; for Group 2, the proportion of subjects who become swab-negative in each arm within 14 days of randomization. RANDOMIZATION All household members and/or contacts of each COVID-19 index case, and the COVID-19 patient himself/herself, fulfilling all inclusion criteria will be grouped into a single cluster and this cluster will be randomized (2:1) to either arm A or arm B. Information on each subject will be recorded in specific data records. Randomization lists will be stratified according to the following factors regarding COVID-19 index cases: 1. COVID-19 risk level on the basis of province of residence (high vs. low/intermediate); 2. Index case is a healthcare professional (yes vs.no) 3. Index case with COVID-19 treatment (yes vs. no) An independent statistician not otherwise involved in the trial will generate the allocation sequence, and COVID-19 response teams will be unaware of the allocation of clusters. Randomization will be performed through an interactive web-based electronic data-capturing database. An Independent Data Monitoring Committee has been established. BLINDING (MASKING): This study is open label. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): For Group 1, a sample size of about 2000 SARS-CoV-2-exposed subjects such as household members and/or contacts of COVID-19 patients will take part in the study. Assuming around 1.5-2.0 asymptomatic household members and/or contacts for each COVID-19 patient, we expect to identify approximately 1000-1300 COVID-19 index cases to be randomized. An interim analysis on efficacy is planned using standard alpha-spending function. For Group 2, sufficient power for primary objective (negative swab within 14 days of randomization) will be reached given a sample size of 300 asymptomatic or paucisymptomatic COVID-19 subjects in home situations not treated for COVID-19 (25%-30% of about 1000-1300 expected index cases). Since up to date reduced evidence about COVID-19 infection epidemiology, the continuous update of diagnostic and therapeutic approaches, the sample size estimation could be updated after a one third of population will be recruited and eventually modified according to a substantial protocol amendment. An interim analysis at 100 enrolled COVID-19 patients is planned. We have planned a Generalized Estimating Equation analysis, which is more efficient than a cluster level analysis, to take advantage of subject-specific covariates. The above reported sample size analysis is therefore to be considered conservative. TRIAL STATUS The current version of the PROTECT trial protocol is 'Final version, 15 April 2020'. The study started on 9th May 2020. The first patient was enrolled on 14th May 2020. Recruitment is expected to last through September 2020. TRIAL REGISTRATION The PROTECT trial is registered in the EudraCT database (no. 2020-001501-24) and in ClinicalTrials.gov ( NCT04363827 ), date of registration 24 April 2020. FULL PROTOCOL The full PROTECT protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interests of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol (Protocol final version, 15th April 2020). The study protocol has been reported in accordance with Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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Understanding the COVID-19 pandemic from a gender perspective.
Chang, WH
Taiwanese journal of obstetrics & gynecology. 2020;(6):801-807
Abstract
Under the threat of the new coronavirus pandemic, women have been uniquely impacted financially, economically, and socially. However, in terms of disease incidence and lethality, women perform better than men. The main reason is that, in addition to women's own hormonal protection, women's immune systems are superior to those of men. Women also exhibit more protective behavior (e.g., hand-washing) and more closely follow protection guidelines, which greatly reduces the chance of infection. In the future, more studies that adopt a gender perspective are needed to understand the various dilemmas faced by women in infectious diseases and pandemics; only then can women demonstrate better outcomes.
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Part II. high-dose methotrexate with leucovorin rescue for severe COVID-19: An immune stabilization strategy for SARS-CoV-2 induced 'PANIC' attack.
Frohman, EM, Villemarette-Pittman, NR, Cruz, RA, Longmuir, R, Rowe, V, Rowe, ES, Varkey, TC, Steinman, L, Zamvil, SS, Frohman, TC
Journal of the neurological sciences. 2020;:116935
Abstract
Here, in Part II of a duology on the characterization and potential treatment for COVID-19, we characterize the application of an innovative treatment regimen for the prevention of the transition from mild to severe COVID-19, as well as detail an intensive immunotherapy intervention hypothesis. We propose as a putative randomized controlled trial that high-dose methotrexate with leucovorin (HDMTX-LR) rescue can abolish 'PANIC', thereby 'left-shifting' severe COVID-19 patients to the group majority of those infected with SARS-CoV-2, who are designated as having mild, even asymptomatic, disease. HDMTX-LR is endowed with broadly pleiotropic properties and is a repurposed, generic, inexpensive, and widely available agent which can be administered early in the course of severe COVID-19 thus rescuing the critical and irreplaceable gas-exchange alveoli. Further, we describe a preventative treatment intervention regimen for those designated as having mild to moderate COVID-19 disease, but who exhibit features which herald the transition to the severe variant of this disease. Both of our proposed hypothesis-driven questions should be urgently subjected to rigorous assessment in the context of randomized controlled trials, in order to confirm or refute the contention that the approaches characterized herein, are in fact capable of exerting mitigating, if not abolishing, effects upon SARS-CoV-2 triggered 'PANIC Attack'. Confirmation of our immunotherapy hypothesis would have far-reaching ramifications for the current pandemic, along with yielding invaluable lessons which could be leveraged to more effectively prepare for the next challenge to global health.
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Exposome and Immunity Training: How Pathogen Exposure Order Influences Innate Immune Cell Lineage Commitment and Function.
Adams, K, Weber, KS, Johnson, SM
International journal of molecular sciences. 2020;(22)
Abstract
Immune memory is a defining characteristic of adaptive immunity, but recent work has shown that the activation of innate immunity can also improve responsiveness in subsequent exposures. This has been coined "trained immunity" and diverges with the perception that the innate immune system is primitive, non-specific, and reacts to novel and recurrent antigen exposures similarly. The "exposome" is the cumulative exposures (diet, exercise, environmental exposure, vaccination, genetics, etc.) an individual has experienced and provides a mechanism for the establishment of immune training or immunotolerance. It is becoming increasingly clear that trained immunity constitutes a delicate balance between the dose, duration, and order of exposures. Upon innate stimuli, trained immunity or tolerance is shaped by epigenetic and metabolic changes that alter hematopoietic stem cell lineage commitment and responses to infection. Due to the immunomodulatory role of the exposome, understanding innate immune training is critical for understanding why some individuals exhibit protective phenotypes while closely related individuals may experience immunotolerant effects (e.g., the order of exposure can result in completely divergent immune responses). Research on the exposome and trained immunity may be leveraged to identify key factors for improving vaccination development, altering inflammatory disease development, and introducing potential new prophylactic treatments, especially for diseases such as COVID-19, which is currently a major health issue for the world. Furthermore, continued exposome research may prevent many deleterious effects caused by immunotolerance that frequently result in host morbidity or mortality.
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[Exploration of omics mechanism and drug prediction of coronavirus-induced heart failure based on clinical bioinformatics].
Chen, XM, Cao, F, Zhang, HM, Chen, HR, Zhang, JD, Zhi, P, Li, ZY, Wang, YX, Lu, XC
Zhonghua xin xue guan bing za zhi. 2020;(7):587-592
Abstract
Objective: Present study investigated the mechanism of heart failure associated with coronavirus infection and predicted potential effective therapeutic drugs against heart failure associated with coronavirus infection. Methods: Coronavirus and heart failure were searched in the Gene Expression Omnibus (GEO) and omics data were selected to meet experimental requirements. Differentially expressed genes were analyzed using the Limma package in R language to screen for differentially expressed genes. The two sets of differential genes were introduced into the R language cluster Profiler package for gene ontology (GO) and Kyoto gene and genome encyclopedia (KEGG) pathway enrichment analysis. Two sets of intersections were taken. A protein interaction network was constructed for all differentially expressed genes using STRING database and core genes were screened. Finally, the apparently accurate treatment prediction platform (EpiMed) independently developed by the team was used to predict the therapeutic drug. Results: The GSE59185 coronavirus data set was searched and screened in the GEO database, and divided into wt group, ΔE group, Δ3 group, Δ5 group according to different subtypes, and compared with control group. After the difference analysis, 191 up-regulated genes and 18 down-regulated genes were defined. The GEO126062 heart failure data set was retrieved and screened from the GEO database. A total of 495 differentially expressed genes were screened, of which 165 were up-regulated and 330 were down-regulated. Correlation analysis of differentially expressed genes between coronavirus and heart failure was performed. After cross processing, there were 20 GO entries, which were mainly enriched in virus response, virus defense response, type Ⅰ interferon response, γ interferon regulation, innate immune response regulation, negative regulation of virus life cycle, replication regulation of viral genome, etc. There were 5 KEGG pathways, mainly interacting with tumor necrosis factor (TNF) signaling pathway, interleukin (IL)-17 signaling pathway, cytokine and receptor interaction, Toll-like receptor signaling pathway, human giant cells viral infection related. All differentially expressed genes were introduced into the STRING online analysis website for protein interaction network analysis, and core genes such as signal transducer and activator of transcription 3, IL-10, IL17, TNF, interferon regulatory factor 9, 2'-5'-oligoadenylate synthetase 1, mitogen-activated protein kinase 3, radical s-adenosyl methionine domain containing 2, c-x-c motif chemokine ligand 10, caspase 3 and other genes were screened. The drugs predicted by EpiMed's apparent precision treatment prediction platform for disease-drug association analysis were mainly TNF-α inhibitors, resveratrol, ritonavir, paeony, retinoic acid, forsythia, and houttuynia cordata. Conclusions: The abnormal activation of multiple inflammatory pathways may be the cause of heart failure in patients after coronavirus infection. Resveratrol, ritonavir, retinoic acid, amaranth, forsythia, houttuynia may have therapeutic effects. Future basic and clinical research is warranted to validate present results and hypothesis.
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Smoking and COVID-19: Adding Fuel to the Flame.
Kashyap, VK, Dhasmana, A, Massey, A, Kotnala, S, Zafar, N, Jaggi, M, Yallapu, MM, Chauhan, SC
International journal of molecular sciences. 2020;(18)
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, an infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), has led to more than 771,000 deaths worldwide. Tobacco smoking is a major known risk factor for severe illness and even death from many respiratory infections. The effects of smoking on COVID-19 are currently controversial. Here, we provide an overview of the current knowledge on the effects of smoking on the clinical manifestations, disease progression, inflammatory responses, immunopathogenesis, racial ethnic disparities, and incidence of COVID-19. This review also documents future directions of smoking related research in COVID-19. The current epidemiological finding suggests that active smoking is associated with an increased severity of disease and death in hospitalized COVID-19 patients. Smoking can upregulate the angiotensin-converting enzyme-2 (ACE-2) receptor utilized by SARS-CoV-2 to enter the host cell and activate a 'cytokine storm' which can lead to worsen outcomes in COVID-19 patients. This receptor can also act as a potential therapeutic target for COVID-19 and other infectious diseases. The COVID-19 pandemic sheds light on a legacy of inequalities regarding gender, racial, and ethnic health disparities associated with active smoking, thus, smoking cessation may help in improving outcomes. In addition, to flatten the COVID-19 curve, staying indoors, avoiding unnecessary social contact, and bolstering the immune defense system by maintaining a healthy diet/living are highly desirable.
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Multi-centre, three arm, randomized controlled trial on the use of methylprednisolone and unfractionated heparin in critically ill ventilated patients with pneumonia from SARS-CoV-2 infection: A structured summary of a study protocol for a randomised controlled trial.
Busani, S, Tosi, M, Mighali, P, Vandelli, P, D'Amico, R, Marietta, M, Forfori, F, Donati, A, Cinnella, G, De Monte, A, et al
Trials. 2020;(1):724
Abstract
OBJECTIVES To assess the hypothesis that an adjunctive therapy with methylprednisolone and unfractionated heparin (UFH) or with methylprednisolone and low molecular weight heparin (LMWH) are more effective in reducing any-cause mortality in critically-ill ventilated patients with pneumonia from SARS-CoV-2 infection compared to LMWH alone. TRIAL DESIGN The study is designed as a multi-centre, interventional, parallel group, superiority, randomized, investigator sponsored, three arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned to one of the three treatment groups in a ratio 1:1:1. PARTICIPANTS Inpatients will be recruited from 8 Italian Academic and non-Academic Intensive Care Units INCLUSION CRITERIA (ALL REQUIRED): 1. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) 2. Positive pressure ventilation (either non-invasive or invasive) from > 24 hours 3. Invasive mechanical ventilation from < 96 hours 4. PaO2/FiO2 ratio lower than 150 mmHg 5. D-dimer level > 6 times the upper limit of normal reference range 6. C-reactive Protein > 6-fold upper the limit of normal reference range EXCLUSION CRITERIA 1. Age < 18 years 2. On-going treatment with anticoagulant drugs 3. Platelet count < 100.000/mm3 4. History of heparin-induced thrombocytopenia 5. Allergy to sodium enoxaparin or other LMWH, UFH or methylprednisolone 6. Active bleeding or on-going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment 7. Recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery 8. Chronic assumption or oral corticosteroids 9. Pregnancy or breastfeeding or positive pregnancy test. In childbearing age women, before inclusion, a pregnancy test will be performed if not available 10. Clinical decision to withhold life-sustaining treatment or "too sick to benefit" 11. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition) 12. Lack or withdrawal of informed consent INTERVENTION AND COMPARATOR • LMWH group: patients in this group will be administered enoxaparin at standard prophylactic dosage. • LMWH + steroid group: patients in this group will receive enoxaparin at standard prophylactic dosage and methylprednisolone. • UFH + steroid group: patients in this group will receive UFH at therapeutic dosages and methylprednisolone. UFH will be administered intravenously in UFH + steroid group at therapeutic doses. The infusion will be started at an infusion rate of 18 UI/kg/hour and then modified to obtain aPTT Ratio in between the range of 1.5-2.0. aPTT will be periodically checked at intervals no longer than 12 hours. The treatment with UFH will be administered up to ICU discharge. After ICU discharge anticoagulant therapy may be interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical judgement of the attending physician. Enoxaparin will be administered in both LMWH group and LMWH + steroid group at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered subcutaneously once a day up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician. Methylprednisolone will be administered in both LMWH + steroid group and UHF + steroid group intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14. MAIN OUTCOMES Primary Efficacy Endpoint: All-cause mortality at day 28 Secondary Efficacy Endpoints: - Ventilation free days (VFDs) at day 28, defined as the total number of days that patient is alive and free of ventilation (either invasive or non-invasive) between randomization and day 28 (censored at hospital discharge). - Need of rescue administration of high-dose steroids or immune-modulatory drugs; - Occurrence of switch from non-invasive to invasive mechanical ventilation during ICU stay; - Delay from start of non-invasive ventilation to switch to invasive ventilation; - All-cause mortality at ICU discharge and hospital discharge; - ICU free days (IFDs) at day 28, defined as the total number of days between ICU discharge and day 28. - Occurrence of new infections from randomization to day 28; including infections by Candida, Aspergillus, Adenovirus, Herpes Virus e Cytomegalovirus - Occurrence of new organ dysfunction and grade of dysfunction during ICU stay. - Objectively confirmed venous thromboembolism, stroke or myocardial infarction; Safety endpoints: - Occurrence of major bleeding, defined as transfusion of 2 or more units of packed red blood cells in a day, bleeding that occurs in at least one of the following critical sites [intracranial, intra-spinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal], bleeding that necessitates surgical intervention and bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death); - Occurrence of clinically relevant non-major bleeding, defined ad acute clinically overt bleeding that does not meet the criteria for major and consists of any bleeding compromising hemodynamic; spontaneous hematoma larger than 25 cm2, intramuscular hematoma documented by ultrasonography, haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures; haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention or any other bleeding requiring temporary cessation of a study drug. RANDOMIZATION A block randomisation will be used with variable block sizes (block size 4-6-8), stratified by 3 factors: Centre, BMI (<30/≥30) and Age (<75/≥75). Central randomisation will be performed using a secure, web-based, randomisation system with an allocation ratio of 1:1:1. The allocation sequence will be generated by the study statistician using computer generated random numbers. BLINDING (MASKING): Participants to the study will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The target sample size is based on the hypothesis that the combined use of UHF and steroid versus the LMWH group will significantly reduce the risk of death at day 28. The overall sample size in this study is expected to be 210 with a randomization 1:1:1 and seventy patients in each group. Assuming an alpha of 2.5% (two tailed) and mortality rate in LMWH group of 50%, as indicated from initial studies of ICU patients, the study will have an 80% power to detect at least a 25 % absolute reduction in the risk of death between: a) LMHW + steroid group and LMWH group or b) UHF + steroid group and LMWH group. The study has not been sized to assess the difference between LMHW + steroid group and UHF + steroid group, therefore the results obtained from this comparison will need to be interpreted with caution and will need further adequately sized studies confirm the effect. On the basis of a conservative estimation, that 8 participating sites admit an average of 3 eligible patients per month per centre (24 patients/month). Assuming that 80 % of eligible patients are enrolled, recruitment of 210 participants will be completed in approximately 10 months. TRIAL STATUS Protocol version 1.1 of April 26th, 2020. Recruitment start (expected): September 1st, 2020 Recruitment finish (expected): June 30th, 2021 TRIAL REGISTRATION EudraCT number 2020-001921-30 , registered on April 15th, 2020 AIFA approval on May 4th, 2020 FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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Review on the potential action mechanisms of Chinese medicines in treating Coronavirus Disease 2019 (COVID-19).
Huang, YF, Bai, C, He, F, Xie, Y, Zhou, H
Pharmacological research. 2020;:104939
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Abstract
The Coronavirus Disease 2019 (COVID-19) has been declared as a global pandemic, but specific medicines and vaccines are still being developed. In China, interventional therapies with traditional Chinese medicine for COVID-19 have achieved significant clinical efficacies, but the underlying pharmacological mechanisms are still unclear. This article reviewed the etiology of COVID-19 and clinical efficacy. Both network pharmacological study and literature search were used to demonstrate the possible action mechanisms of Chinese medicines in treating COVID-19. We found that Chinese medicines played the role of antivirus, anti-inflammation and immunoregulation, and target organs protection in the management of COVID-19 by multiple components acting on multiple targets at multiple pathways. AEC2 and 3CL protein could be the direct targets for inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Quercetin, kaempferol, luteolin, isorhamnetin, baicalein, naringenin, and wogonin could be the main active ingredients of Chinese medicines for the management of COVID-19 by targeting on AEC2 and 3CL protein and inhibiting inflammatory mediators, regulating immunity, and eliminating free radicals through COX-2, CASP3, IL-6, MAPK1, MAPK14, MAPK8, and REAL in the signaling pathways of IL-17, arachidonic acid, HIF-1, NF-κB, Ras, and TNF. This study may provide meaningful and useful information on further research to investigate the action mechanisms of Chinese medicines against SARS-CoV-2 and also provide a basis for sharing the "China scheme" for COVID-19 treatment.
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10.
MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19.
Bilezikian, JP, Bikle, D, Hewison, M, Lazaretti-Castro, M, Formenti, AM, Gupta, A, Madhavan, MV, Nair, N, Babalyan, V, Hutchings, N, et al
European journal of endocrinology. 2020;(5):R133-R147
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Abstract
The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.