Structured Review

Gilead Sciences lopinavir ritonavir
Antiretroviral regimens associated with reduction in serum liver enzyme levels from baseline. (A) After 4 weeks of treatment, only mice receiving Truvada and Kaletra experienced a significant mean reduction in alkaline phosphatase levels as compared to placebo, whereas by the end of 12 weeks therapy mice treated with regimens containing Truvada with or without Kaletra experienced significant reduction. (B) A significant reduction in serum alanine transaminase levels was observed in mice receiving Truvada and Kaletra but not Combivir and Kaletra [Combivir (zidovudine and lamivudine), Truvada (tenofovir and emtricitabine), Kaletra <t>(lopinavir</t> and <t>ritonavir);</t> data shown as means ± SEM; * P
Lopinavir Ritonavir, supplied by Gilead Sciences, used in various techniques. Bioz Stars score: 99/100, based on 1 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
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Images

1) Product Images from "Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease"

Article Title: Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease

Journal: Liver International

doi: 10.1111/liv.12699

Antiretroviral regimens associated with reduction in serum liver enzyme levels from baseline. (A) After 4 weeks of treatment, only mice receiving Truvada and Kaletra experienced a significant mean reduction in alkaline phosphatase levels as compared to placebo, whereas by the end of 12 weeks therapy mice treated with regimens containing Truvada with or without Kaletra experienced significant reduction. (B) A significant reduction in serum alanine transaminase levels was observed in mice receiving Truvada and Kaletra but not Combivir and Kaletra [Combivir (zidovudine and lamivudine), Truvada (tenofovir and emtricitabine), Kaletra (lopinavir and ritonavir); data shown as means ± SEM; * P
Figure Legend Snippet: Antiretroviral regimens associated with reduction in serum liver enzyme levels from baseline. (A) After 4 weeks of treatment, only mice receiving Truvada and Kaletra experienced a significant mean reduction in alkaline phosphatase levels as compared to placebo, whereas by the end of 12 weeks therapy mice treated with regimens containing Truvada with or without Kaletra experienced significant reduction. (B) A significant reduction in serum alanine transaminase levels was observed in mice receiving Truvada and Kaletra but not Combivir and Kaletra [Combivir (zidovudine and lamivudine), Truvada (tenofovir and emtricitabine), Kaletra (lopinavir and ritonavir); data shown as means ± SEM; * P

Techniques Used: Mouse Assay

2) Product Images from "Current COVID-19 treatments: Rapid review of the literature"

Article Title: Current COVID-19 treatments: Rapid review of the literature

Journal: Journal of Global Health

doi: 10.7189/jogh.11.10003

SARS-CoV-2 gene targets. Proteins are translated from the SARS-CoV-2 genome. Lopinavir targets 3CL protease produced by the ORF1a gene. Remdesivir and ribavirin targets RNA-dependent RNA polymerase (RdRp) translated from ORF1b. Chloroquine/ hydroxychloroquine, convalescent plasma and monoclonal antibodies have effects against the spike protein.
Figure Legend Snippet: SARS-CoV-2 gene targets. Proteins are translated from the SARS-CoV-2 genome. Lopinavir targets 3CL protease produced by the ORF1a gene. Remdesivir and ribavirin targets RNA-dependent RNA polymerase (RdRp) translated from ORF1b. Chloroquine/ hydroxychloroquine, convalescent plasma and monoclonal antibodies have effects against the spike protein.

Techniques Used: Produced

Progression to cytokine storm. Peak viral replication occurs in the initial 7-10 days and primary immune response usually occurs by day 10-14 which is followed by virus clearance [ 1 ]. Therefore, therapies appear to be most beneficial when given before 14 days of infection. Days 0-5: incubation period. SARS-CoV-2 enter cell via ACE2 receptors on human type 1/2 pneumocytes and start replicating. Hydroxychloroquine (HCQ) targets glycosylation of viral surface. Lopinavir, remdesivir targets the viral replication. Until day 10: moderate symptoms. The initial immune response produces IL-18, IP-10, MCP-1 and MIP-1α which starts to recruit specific immune cells. Interferon (IFN), HCQ and convalescent plasma (CP) is most effective. Day 10: severe infection leading to risk of mortality. Macrophages via BTK, T-cells via JAK, neutrophils and B-cells produce cytokines, resulting in a cytokine storm by day 14. Ruxolitinib, baricitinib, tocilizumab, anakinra, acalabrutinib and corticosteroids can be used [ 1 ].
Figure Legend Snippet: Progression to cytokine storm. Peak viral replication occurs in the initial 7-10 days and primary immune response usually occurs by day 10-14 which is followed by virus clearance [ 1 ]. Therefore, therapies appear to be most beneficial when given before 14 days of infection. Days 0-5: incubation period. SARS-CoV-2 enter cell via ACE2 receptors on human type 1/2 pneumocytes and start replicating. Hydroxychloroquine (HCQ) targets glycosylation of viral surface. Lopinavir, remdesivir targets the viral replication. Until day 10: moderate symptoms. The initial immune response produces IL-18, IP-10, MCP-1 and MIP-1α which starts to recruit specific immune cells. Interferon (IFN), HCQ and convalescent plasma (CP) is most effective. Day 10: severe infection leading to risk of mortality. Macrophages via BTK, T-cells via JAK, neutrophils and B-cells produce cytokines, resulting in a cytokine storm by day 14. Ruxolitinib, baricitinib, tocilizumab, anakinra, acalabrutinib and corticosteroids can be used [ 1 ].

Techniques Used: Infection, Incubation

3) Product Images from "Effect of COVID‐19 medications on corrected QT interval and induction of torsade de pointes: Results of a multicenter national survey, et al. Effect of COVID‐19 medications on corrected QT interval and induction of torsade de pointes: Results of a multicenter national survey"

Article Title: Effect of COVID‐19 medications on corrected QT interval and induction of torsade de pointes: Results of a multicenter national survey, et al. Effect of COVID‐19 medications on corrected QT interval and induction of torsade de pointes: Results of a multicenter national survey

Journal: International Journal of Clinical Practice

doi: 10.1111/ijcp.14182

Survival function estimated by the Kaplan‐Meier analysis among the eight different drug regimens used to treat COVID‐19. Log‐rank P‐value was significant among the patients who received hydroxychloroquine or lopinavir‐ritonavir with and without azithromycin combination therapy
Figure Legend Snippet: Survival function estimated by the Kaplan‐Meier analysis among the eight different drug regimens used to treat COVID‐19. Log‐rank P‐value was significant among the patients who received hydroxychloroquine or lopinavir‐ritonavir with and without azithromycin combination therapy

Techniques Used:

4) Product Images from "Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial"

Article Title: Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial

Journal: Intensive Care Medicine

doi: 10.1007/s00134-021-06448-5

Organ support-free days and mortality. A Organ support-free days in patients allocated to lopinavir-ritonavir, hydroxychloroquine, combination therapy and control among critically ill patients in the COVID-19 Antiviral Therapy Domain of the REMAP-CAP trial. Distributions of organ support-free days are displayed as the cumulative proportion ( y axis) for each study group by day ( x axis). Curves that rise more slowly are more favorable. The height of each curve at “ − 1” indicates the in‐hospital mortality for each intervention. The height of each curve at any time point indicates the proportion of patients who had that number of organ support-free days or fewer. The difference in the height of the curves at any point represents the difference in the percentile in the distribution of organ support-free days associated with that number of days alive and free of organ support. B Organ support-free days are displayed as horizontally stacked proportions by study group. Red represents worse values and blue represents better values. On primary analysis of organ support-free days, the three interventions decreased organ support-free days compared to control, with corresponding median adjusted ORs and 95% credible intervals of 0.73 (0.55–0.99), 0.57 (0.35–0.83) and 0.41 (0.24–0.72), respectively, yielding high posterior probabilities of futility (99% or greater) and high posterior probabilities of harm compared to control (98%, 99.9% and > 99.9%, respectively). C Empirical distribution of survival for lopinavir–ritonavir, hydroxychloroquine, combination therapy and control. Lopinavir-ritonavir, hydroxychloroquine and combination therapy resulted in reduced survival over 90 days compared to control, with adjusted median hazard ratios (95% CrI) of 0.83 (0.65, 1.07), 0.71 (0.45, 0.97), 0.58 (0.36, 0.92), yielding high probabilities of harm compared with control of 92% and 98.4% and 98.7%, respectively
Figure Legend Snippet: Organ support-free days and mortality. A Organ support-free days in patients allocated to lopinavir-ritonavir, hydroxychloroquine, combination therapy and control among critically ill patients in the COVID-19 Antiviral Therapy Domain of the REMAP-CAP trial. Distributions of organ support-free days are displayed as the cumulative proportion ( y axis) for each study group by day ( x axis). Curves that rise more slowly are more favorable. The height of each curve at “ − 1” indicates the in‐hospital mortality for each intervention. The height of each curve at any time point indicates the proportion of patients who had that number of organ support-free days or fewer. The difference in the height of the curves at any point represents the difference in the percentile in the distribution of organ support-free days associated with that number of days alive and free of organ support. B Organ support-free days are displayed as horizontally stacked proportions by study group. Red represents worse values and blue represents better values. On primary analysis of organ support-free days, the three interventions decreased organ support-free days compared to control, with corresponding median adjusted ORs and 95% credible intervals of 0.73 (0.55–0.99), 0.57 (0.35–0.83) and 0.41 (0.24–0.72), respectively, yielding high posterior probabilities of futility (99% or greater) and high posterior probabilities of harm compared to control (98%, 99.9% and > 99.9%, respectively). C Empirical distribution of survival for lopinavir–ritonavir, hydroxychloroquine, combination therapy and control. Lopinavir-ritonavir, hydroxychloroquine and combination therapy resulted in reduced survival over 90 days compared to control, with adjusted median hazard ratios (95% CrI) of 0.83 (0.65, 1.07), 0.71 (0.45, 0.97), 0.58 (0.36, 0.92), yielding high probabilities of harm compared with control of 92% and 98.4% and 98.7%, respectively

Techniques Used:

Screening, randomization, and follow-up of patients in the REMAP-CAP COVID-19 Antiviral Therapy Domain randomized controlled trial. a Patients could meet more than one ineligibility criterion (Table S2, Supplementary Appendix). b Details of platform exclusions are provided in the Supplementary Results (Supplementary Appendix). c The primary analysis of organ support-free days (OSFD) and hospital survival were conducted on the REMAP-CAP intention-to-treat cohort which included all patients enrolled in the trial who met COVID-19 severe state criteria and were randomized within at least one domain, adjusting for patient factors and for assignment to interventions in other domains (Table S3, Supplementary Appendix). ^Contraindications include hypersensitivity, receiving the study drug as usual medication prior to hospitalization, human immune deficiency (HIV) infection (contraindication of lopinavir-ritonavir), severe liver failure (contraindication of lopinavir-ritonavir), receiving amiodarone as a usual medication prior to this hospitalization or any administration of amiodarone within the 72 h prior to assessment (contraindication of lopinavir-ritonavir) and high clinical risk of sustained ventricular dysrhythmia (contraindication of hydroxychloroquine) (Table S2, Supplementary Appendix)
Figure Legend Snippet: Screening, randomization, and follow-up of patients in the REMAP-CAP COVID-19 Antiviral Therapy Domain randomized controlled trial. a Patients could meet more than one ineligibility criterion (Table S2, Supplementary Appendix). b Details of platform exclusions are provided in the Supplementary Results (Supplementary Appendix). c The primary analysis of organ support-free days (OSFD) and hospital survival were conducted on the REMAP-CAP intention-to-treat cohort which included all patients enrolled in the trial who met COVID-19 severe state criteria and were randomized within at least one domain, adjusting for patient factors and for assignment to interventions in other domains (Table S3, Supplementary Appendix). ^Contraindications include hypersensitivity, receiving the study drug as usual medication prior to hospitalization, human immune deficiency (HIV) infection (contraindication of lopinavir-ritonavir), severe liver failure (contraindication of lopinavir-ritonavir), receiving amiodarone as a usual medication prior to this hospitalization or any administration of amiodarone within the 72 h prior to assessment (contraindication of lopinavir-ritonavir) and high clinical risk of sustained ventricular dysrhythmia (contraindication of hydroxychloroquine) (Table S2, Supplementary Appendix)

Techniques Used: Infection

5) Product Images from "Perspective on the Role of Antibodies and Potential Therapeutic Drugs to Combat COVID-19"

Article Title: Perspective on the Role of Antibodies and Potential Therapeutic Drugs to Combat COVID-19

Journal: The Protein Journal

doi: 10.1007/s10930-020-09921-0

Inhibitory functions and roles of different antibodies and re-purposed drugs for battling COVID-19. The COVID-19 (coronavirus disease of 2019) infection begins with the attachment of the spike protein of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) to the ACE2 (angiotensin converting enzyme 2) human receptor. Various monoclonal (mAb) and polyclonal antibodies are being designed and convalescent plasma collected from the donor patients are being used to inhibit the attachment of the novel virus. This is followed by the virus and host membrane fusion and entry of the virus which is inhibited by drugs like Hydroxychloroquine (HCQ) and Chloroquine (CQ). Once the uncoating occurs and the viral RNA is released, it starts replicating with the help of the enzyme RNA dependent RNA polymerase (RdRp). Drugs like Remdesivir, Favipiravir and Ribavirin, interfere with the activity of this enzyme. In order to further generate viral proteins, the processing (capping) of the viral RNA is required for maintaining its stability. This processing is inhibited by drugs like Ribavirin. On the other hand, combination of Lopinavir and Ritonavir is used for inhibiting the proteases like 3CL pro (chymotrypsin like cysteine protease) which are mainly responsible for the proteolytic cleavage and generation of non-structural proteins involved in viral replication. Once the viral assembly is complete and the new virions are ready, the exocytosis of these virions occur. This is inhibited by drugs like CQ and HCQ. The infection by the novel virus and release of the new virions which infect the neighbouring cells of the body lead to an exaggerated cytokine release which can be managed using drugs like corticosteroids, various mAbs targeting different cytokines and cytokine receptors, etc.
Figure Legend Snippet: Inhibitory functions and roles of different antibodies and re-purposed drugs for battling COVID-19. The COVID-19 (coronavirus disease of 2019) infection begins with the attachment of the spike protein of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) to the ACE2 (angiotensin converting enzyme 2) human receptor. Various monoclonal (mAb) and polyclonal antibodies are being designed and convalescent plasma collected from the donor patients are being used to inhibit the attachment of the novel virus. This is followed by the virus and host membrane fusion and entry of the virus which is inhibited by drugs like Hydroxychloroquine (HCQ) and Chloroquine (CQ). Once the uncoating occurs and the viral RNA is released, it starts replicating with the help of the enzyme RNA dependent RNA polymerase (RdRp). Drugs like Remdesivir, Favipiravir and Ribavirin, interfere with the activity of this enzyme. In order to further generate viral proteins, the processing (capping) of the viral RNA is required for maintaining its stability. This processing is inhibited by drugs like Ribavirin. On the other hand, combination of Lopinavir and Ritonavir is used for inhibiting the proteases like 3CL pro (chymotrypsin like cysteine protease) which are mainly responsible for the proteolytic cleavage and generation of non-structural proteins involved in viral replication. Once the viral assembly is complete and the new virions are ready, the exocytosis of these virions occur. This is inhibited by drugs like CQ and HCQ. The infection by the novel virus and release of the new virions which infect the neighbouring cells of the body lead to an exaggerated cytokine release which can be managed using drugs like corticosteroids, various mAbs targeting different cytokines and cytokine receptors, etc.

Techniques Used: Infection, Activity Assay

Related Articles

other:

Article Title: Urine tenofovir and emtricitabine concentrations provide biomarker for exposure to HIV preexposure prophylaxis
Article Snippet: In this study of persons prescribed daily oral Truvada, we observed complete concordance in detection of drugs between urine and plasma, indicating detection of TFV and FTC in urine predicts detection in plasma.

Infection:

Article Title: Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets
Article Snippet: .. Emtricitabine-tenofovir (Truvada) is a prescription medicine for HIV approved by the U.S. FDA for preexposure prophylaxis to reduce the risk of HIV infection in adults and adolescents. .. As a nucleotide analogue, it is reported that the active triphosphate form of this tenofovir diphosphate inhibits activity for RNA-dependent RNA polymerase (RdRp) of HIV and hepatitis B virus (HBV) ( , ).

Article Title: Highly synergistic drug combination prevents vaginal HIV infection in humanized mice
Article Snippet: .. Discussion An oral regimen of TDF and FTC (Truvada, Gilead Sciences, Foster City, CA) is FDA-approved for HIV-1 PrEP , so we hypothesized that topical delivery of these ARV agents also would provide protection from vaginal HIV-1 infection. .. Using this binary combination, we achieved full protection from simian/human immunodeficiency virus (SHIV) infection in the rigorous, repeat low-dose vaginal exposure model using normally cycling female pigtailed macaques as well as from vaginal and rectal HIV-1 infection in humanized BLT mice .

Transmission Assay:

Article Title: Prevention of Vaginal SHIV Transmission in Macaques by a Coitally-Dependent Truvada Regimen
Article Snippet: Simian/human immunodeficiency virus (SHIV) infection of macaques is a well-established model of HIV transmission that can be used to investigate the efficacy of oral and topical PrEP in preventing rectal and vaginal transmission , . .. We have previously modeled the efficacy of daily oral FTC, TDF, and Truvada against rectal SHIV transmission in rhesus macaques and found that the combination of FTC and TDF at human equivalent doses provided a level of protection similar to that recently seen in the iPrEX trial among highly adherent participants . .. We also found that intermittent Truvada regimens containing one dose given 1–7 days prior to exposure followed by a second dose 2 h after exposure, or two peri-coital doses administered within 24 h were as effective as daily PrEP .

Mouse Assay:

Article Title: Oral Administration of the Nucleoside EFdA (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Provides Rapid Suppression of HIV Viremia in Humanized Mice and Favorable Pharmacokinetic Properties in Mice and the Rhesus Macaque
Article Snippet: EFdA was dissolved in sterile phosphate-buffered saline (PBS) and administered to 7 mice per group twice daily by subcutaneous injection in 200 μl at a range of dosage levels (0.3, 1, 3, and 10 mg/kg of body weight/day) beginning the day before HIV inoculation. .. TDF plus FTC (Truvada) was dissolved in 0.5% medium-viscosity sodium carboxymethylcellulose (Sigma) and administered to 7 mice twice daily by oral gavage in 200 μl at a total dosage of 100 mg/kg/day (60 mg/kg day TDF plus 40 mg/kg/day FTC). ..

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    Gilead Sciences therapeutic approaches for sars cov 2
    COVID-19 disease course and therapeutic windows of opportunity for DMARDs Schematic depicts the evolution of a severe <t>SARS-CoV-2</t> infection and therapeutic windows of opportunity for the indicated DMARDs according to the timing of the different ongoing immunopathological processes from the initial viral inoculum to multi-organ failure. (A) SARS-CoV-2 binds to the host receptor ACE2 (yellow and green receptors), and viral docking is eased by TRMPSS2 (blue co-receptor) cleaving viral spike protein. (B-C) In the asymptomatic phase, host cell infection, viral diffusion in the human body, and virion production predominate. Mucosal and local innate immunity (natural killer cells, neutrophils and monocyte-macrophages) react to viral replication, causing cytopathic effects and pro-inflammatory mediators release, and the onset of signs and symptoms occurs. (D) Cellular immunity (B cells, CD4 T cells, CD8 T cells) develop locally and systemically, and symptoms and signs increase in severity. (E) An imbalance between effective and hyper-activated immune responses can result in cytokine storm, which deteriorates lung injury, precipitating or determining respiratory insufficiency. (F) At this stage, potentially protective neutralising antibodies could also trigger antibody-dependent enhancement and the activation of the classical pathway of complement system, enhancing viral replication and further proinflammatory cytokine release. (G) The imbalance between inflammation and coagulopathy as well as SARS-CoV-2 infection of endothelial cells and pericytes determine concurrent micro- and macro-thrombotic events enhancing organ damage. (H) These uncontrolled processes trigger reinforcing and self-maintaining pathological loops (dashed arrows) that eventually lead to systemic cellular and organ dysfunction resulting in multi-organ failure. ACE2=angiotensin-converting enzyme 2. DMARD=disease-modifying anti-rheumatic drug. TNF=tumour necrosis factor. TRMPSS2=transmembrane protease serine 2.
    Therapeutic Approaches For Sars Cov 2, supplied by Gilead Sciences, used in various techniques. Bioz Stars score: 99/100, based on 1 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
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    Gilead Sciences kaletra
    Antiretroviral regimens associated with reduction in serum liver enzyme levels from baseline. (A) After 4 weeks of treatment, only mice receiving Truvada and <t>Kaletra</t> experienced a significant mean reduction in alkaline phosphatase levels as compared to placebo, whereas by the end of 12 weeks therapy mice treated with regimens containing Truvada with or without Kaletra experienced significant reduction. (B) A significant reduction in serum alanine transaminase levels was observed in mice receiving Truvada and Kaletra but not Combivir and Kaletra [Combivir (zidovudine and lamivudine), Truvada (tenofovir and emtricitabine), Kaletra (lopinavir and ritonavir); data shown as means ± SEM; * P
    Kaletra, supplied by Gilead Sciences, used in various techniques. Bioz Stars score: 99/100, based on 1 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
    https://www.bioz.com/result/kaletra/product/Gilead Sciences
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    COVID-19 disease course and therapeutic windows of opportunity for DMARDs Schematic depicts the evolution of a severe SARS-CoV-2 infection and therapeutic windows of opportunity for the indicated DMARDs according to the timing of the different ongoing immunopathological processes from the initial viral inoculum to multi-organ failure. (A) SARS-CoV-2 binds to the host receptor ACE2 (yellow and green receptors), and viral docking is eased by TRMPSS2 (blue co-receptor) cleaving viral spike protein. (B-C) In the asymptomatic phase, host cell infection, viral diffusion in the human body, and virion production predominate. Mucosal and local innate immunity (natural killer cells, neutrophils and monocyte-macrophages) react to viral replication, causing cytopathic effects and pro-inflammatory mediators release, and the onset of signs and symptoms occurs. (D) Cellular immunity (B cells, CD4 T cells, CD8 T cells) develop locally and systemically, and symptoms and signs increase in severity. (E) An imbalance between effective and hyper-activated immune responses can result in cytokine storm, which deteriorates lung injury, precipitating or determining respiratory insufficiency. (F) At this stage, potentially protective neutralising antibodies could also trigger antibody-dependent enhancement and the activation of the classical pathway of complement system, enhancing viral replication and further proinflammatory cytokine release. (G) The imbalance between inflammation and coagulopathy as well as SARS-CoV-2 infection of endothelial cells and pericytes determine concurrent micro- and macro-thrombotic events enhancing organ damage. (H) These uncontrolled processes trigger reinforcing and self-maintaining pathological loops (dashed arrows) that eventually lead to systemic cellular and organ dysfunction resulting in multi-organ failure. ACE2=angiotensin-converting enzyme 2. DMARD=disease-modifying anti-rheumatic drug. TNF=tumour necrosis factor. TRMPSS2=transmembrane protease serine 2.

    Journal: The Lancet. Rheumatology

    Article Title: The role of antirheumatics in patients with COVID-19

    doi: 10.1016/S2665-9913(21)00062-X

    Figure Lengend Snippet: COVID-19 disease course and therapeutic windows of opportunity for DMARDs Schematic depicts the evolution of a severe SARS-CoV-2 infection and therapeutic windows of opportunity for the indicated DMARDs according to the timing of the different ongoing immunopathological processes from the initial viral inoculum to multi-organ failure. (A) SARS-CoV-2 binds to the host receptor ACE2 (yellow and green receptors), and viral docking is eased by TRMPSS2 (blue co-receptor) cleaving viral spike protein. (B-C) In the asymptomatic phase, host cell infection, viral diffusion in the human body, and virion production predominate. Mucosal and local innate immunity (natural killer cells, neutrophils and monocyte-macrophages) react to viral replication, causing cytopathic effects and pro-inflammatory mediators release, and the onset of signs and symptoms occurs. (D) Cellular immunity (B cells, CD4 T cells, CD8 T cells) develop locally and systemically, and symptoms and signs increase in severity. (E) An imbalance between effective and hyper-activated immune responses can result in cytokine storm, which deteriorates lung injury, precipitating or determining respiratory insufficiency. (F) At this stage, potentially protective neutralising antibodies could also trigger antibody-dependent enhancement and the activation of the classical pathway of complement system, enhancing viral replication and further proinflammatory cytokine release. (G) The imbalance between inflammation and coagulopathy as well as SARS-CoV-2 infection of endothelial cells and pericytes determine concurrent micro- and macro-thrombotic events enhancing organ damage. (H) These uncontrolled processes trigger reinforcing and self-maintaining pathological loops (dashed arrows) that eventually lead to systemic cellular and organ dysfunction resulting in multi-organ failure. ACE2=angiotensin-converting enzyme 2. DMARD=disease-modifying anti-rheumatic drug. TNF=tumour necrosis factor. TRMPSS2=transmembrane protease serine 2.

    Article Snippet: Although the first vaccines have been approved and vaccination campaigns are underway, much of the research done this far has focused on early therapeutic approaches for SARS-CoV-2 (eg, lopinavir-ritonavir, remdesivir, azithromycin, interferon, hydroxychloroquine).

    Techniques: Infection, Diffusion-based Assay, Activation Assay

    Activation of pathogenic T cells and inflammatory monocytes following SARS-CoV-2 infection and the mechanism of action of tocilizumab. Tocilizumab inhibits sIL-6R and mIL-6R-mediated signaling and can potentially improve the clinical outcomes in severe COVID-19. ARDS, acute respiratory distress syndrome; GM-CSF, granulocyte-macrophage colony-stimulating factor; gp130, glycoprotein 130; IL-6, interleukin 6; mIL-6R, membrane-bound IL-6 receptor; sIL-6R, soluble IL-6 receptor; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

    Journal: International Immunopharmacology

    Article Title: Subcutaneous tocilizumab in adults with severe and critical COVID-19: A prospective open-label uncontrolled multicenter trial

    doi: 10.1016/j.intimp.2020.107102

    Figure Lengend Snippet: Activation of pathogenic T cells and inflammatory monocytes following SARS-CoV-2 infection and the mechanism of action of tocilizumab. Tocilizumab inhibits sIL-6R and mIL-6R-mediated signaling and can potentially improve the clinical outcomes in severe COVID-19. ARDS, acute respiratory distress syndrome; GM-CSF, granulocyte-macrophage colony-stimulating factor; gp130, glycoprotein 130; IL-6, interleukin 6; mIL-6R, membrane-bound IL-6 receptor; sIL-6R, soluble IL-6 receptor; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

    Article Snippet: Accordingly, potential therapeutic approaches comprise antiviral agents to eradicate SARS-CoV-2 (such as remdesivir, lopinavir/ritonavir, and favipiravir) and immunomodulator agents (such as tocilizumab, dexamethasone, and interferon beta) to dampen inflammation by modulating proinflammatory cytokines .

    Techniques: Activation Assay, Infection

    Concomitant anti COVID-19 therapies administered during hospitalization for each patient. The point zero vertical bar represents the time of tocilizumab administration. The horizontal lines indicate the timing and duration of hydroxychloroquine (A), lopinavir-ritonavir (B) and remdesivir (C) administration for each patient.

    Journal: European Journal of Internal Medicine

    Article Title: Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy

    doi: 10.1016/j.ejim.2020.05.011

    Figure Lengend Snippet: Concomitant anti COVID-19 therapies administered during hospitalization for each patient. The point zero vertical bar represents the time of tocilizumab administration. The horizontal lines indicate the timing and duration of hydroxychloroquine (A), lopinavir-ritonavir (B) and remdesivir (C) administration for each patient.

    Article Snippet: Although at present the only recognized standard treatment of COVID-19 pneumonia is oxygen support and the management of ARDS, several therapeutic approaches have been proposed and tested including antivirals (lopinavir/ritonavir, hydroxychloroquine, remdesivir) , , , , and anti-inflammatory drugs (corticosteroids, COX-2 inhibitors, (IL)-6 and (IL)-1 receptor antagonists) .

    Techniques:

    Antiretroviral regimens associated with reduction in serum liver enzyme levels from baseline. (A) After 4 weeks of treatment, only mice receiving Truvada and Kaletra experienced a significant mean reduction in alkaline phosphatase levels as compared to placebo, whereas by the end of 12 weeks therapy mice treated with regimens containing Truvada with or without Kaletra experienced significant reduction. (B) A significant reduction in serum alanine transaminase levels was observed in mice receiving Truvada and Kaletra but not Combivir and Kaletra [Combivir (zidovudine and lamivudine), Truvada (tenofovir and emtricitabine), Kaletra (lopinavir and ritonavir); data shown as means ± SEM; * P

    Journal: Liver International

    Article Title: Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease

    doi: 10.1111/liv.12699

    Figure Lengend Snippet: Antiretroviral regimens associated with reduction in serum liver enzyme levels from baseline. (A) After 4 weeks of treatment, only mice receiving Truvada and Kaletra experienced a significant mean reduction in alkaline phosphatase levels as compared to placebo, whereas by the end of 12 weeks therapy mice treated with regimens containing Truvada with or without Kaletra experienced significant reduction. (B) A significant reduction in serum alanine transaminase levels was observed in mice receiving Truvada and Kaletra but not Combivir and Kaletra [Combivir (zidovudine and lamivudine), Truvada (tenofovir and emtricitabine), Kaletra (lopinavir and ritonavir); data shown as means ± SEM; * P

    Article Snippet: Conflict of interest: AbbVie and Gilead Sciences are providing medications for ongoing clinical trial using Truvada and Kaletra for patients with PBC.

    Techniques: Mouse Assay