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3.
Drugs ; 81(5): 605-610, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1159706

ABSTRACT

Voclosporin (Lupkynis™) is an oral calcineurin inhibitor immunosuppressant that is being developed by Aurinia Pharmaceuticals. In January 2021, based on positive results from the pivotal phases II and III trials, oral voclosporin received its first approval in the USA for use in combination with a background immunosuppressive therapy regimen for adults with active lupus nephritis. Voclosporin is also being explored for the novel coronavirus disease 2019 (COVID-19) in kidney transplant recipients. This article summarizes the milestones in the development of voclosporin leading to this first approval for lupus nephritis.


Subject(s)
COVID-19/drug therapy , Calcineurin Inhibitors/therapeutic use , Cyclosporine/therapeutic use , Immunosuppressive Agents/therapeutic use , Kidney Transplantation , Animals , COVID-19/complications , Calcineurin Inhibitors/pharmacokinetics , Calcineurin Inhibitors/pharmacology , Cyclosporine/pharmacokinetics , Cyclosporine/pharmacology , Drug Approval , Humans , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/pharmacology , Lupus Nephritis/drug therapy
4.
Ann Transplant ; 26: e929279, 2021 Mar 12.
Article in English | MEDLINE | ID: covidwho-1154830

ABSTRACT

Coronavirus disease 19 (COVID-19) has been an ongoing pandemic since December 2019. Unfortunately, kidney transplant recipients are a high-risk group during the disease course, and scientific data are still limited in this patient group. Beyond the dosage of immunosuppressive drugs, pharmacological immunosuppression may also alter the infection response in the COVID-19 course. The effects of immunosuppressive agents on the development and process of infection should not be decided only by determining how potent they are and how much they suppress the immune system; it is also thought that the direct effect of the virus, increased oxidative stress, and cytokine storm play a role in the pathogenesis of COVID-19 disease. There are data about immunosuppressive drugs like calcineurin inhibitors (CNI) or mammalian target of rapamycin inhibitors (mTORi) therapy related to their beneficial effects during any infection course. Limited data suggest that the use of CNI or mTORi may have beneficial effects on the process. In this hypothetical review, the probable impacts of CNI and mTORi on the pathogenesis of the COVID-19 were investigated.


Subject(s)
COVID-19/immunology , Calcineurin Inhibitors/therapeutic use , Graft Rejection/prevention & control , Immunosuppressive Agents/therapeutic use , Kidney Transplantation , Postoperative Complications/immunology , Protein Kinase Inhibitors/therapeutic use , Adaptive Immunity/drug effects , COVID-19/diagnosis , Calcineurin Inhibitors/pharmacology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Cytokine Release Syndrome/virology , Graft Rejection/immunology , Humans , Immunity, Innate/drug effects , Immunocompromised Host , Immunosuppressive Agents/pharmacology , Oxidative Stress/drug effects , Oxidative Stress/immunology , Postoperative Complications/diagnosis , Postoperative Complications/virology , Protein Kinase Inhibitors/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors
6.
Eur Respir J ; 56(5)2020 Nov.
Article in English | MEDLINE | ID: covidwho-648811

ABSTRACT

While severe coronavirus infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), cause lung injury with high mortality rates, protective treatment strategies are not approved for clinical use.We elucidated the molecular mechanisms by which the cyclophilin inhibitors cyclosporin A (CsA) and alisporivir (ALV) restrict MERS-CoV to validate their suitability as readily available therapy in MERS-CoV infection.Calu-3 cells and primary human alveolar epithelial cells (hAECs) were infected with MERS-CoV and treated with CsA or ALV or inhibitors targeting cyclophilin inhibitor-regulated molecules including calcineurin, nuclear factor of activated T-cells (NFATs) or mitogen-activated protein kinases. Novel CsA-induced pathways were identified by RNA sequencing and manipulated by gene knockdown or neutralising antibodies. Viral replication was quantified by quantitative real-time PCR and 50% tissue culture infective dose. Data were validated in a murine MERS-CoV infection model.Both CsA and ALV reduced MERS-CoV titres and viral RNA replication in Calu-3 cells and hAECs, improving epithelial integrity. While neither calcineurin nor NFAT inhibition reduced MERS-CoV propagation, blockade of c-Jun N-terminal kinase diminished infectious viral particle release but not RNA accumulation. Importantly, CsA induced interferon regulatory factor 1 (IRF1), a pronounced type III interferon (IFNλ) response and expression of antiviral genes. Downregulation of IRF1 or IFNλ increased MERS-CoV propagation in the presence of CsA. Importantly, oral application of CsA reduced MERS-CoV replication in vivo, correlating with elevated lung IFNλ levels and improved outcome.We provide evidence that cyclophilin inhibitors efficiently decrease MERS-CoV replication in vitro and in vivo via upregulation of inflammatory antiviral cell responses, in particular IFNλ. CsA might therefore represent a promising candidate for treating MERS-CoV infection.


Subject(s)
Coronavirus Infections/prevention & control , Cyclophilins/antagonists & inhibitors , Cyclosporine/pharmacology , Interferons/metabolism , Middle East Respiratory Syndrome Coronavirus/drug effects , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Animals , Calcineurin Inhibitors/pharmacology , Cell Culture Techniques , Coronavirus Infections/metabolism , Disease Models, Animal , Humans , Interferon Regulatory Factor-1/drug effects , Interferon Regulatory Factor-1/metabolism , Interferons/drug effects , Mice , Middle East Respiratory Syndrome Coronavirus/physiology , Virus Replication/drug effects
7.
Gastroenterol Hepatol ; 43(8): 457-463, 2020 Oct.
Article in English, Spanish | MEDLINE | ID: covidwho-639589

ABSTRACT

SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Immunosuppressive Agents/adverse effects , Liver Transplantation , Pandemics , Pneumonia, Viral/epidemiology , Adaptive Immunity , Antiviral Agents/pharmacology , Betacoronavirus/immunology , Betacoronavirus/physiology , COVID-19 , Calcineurin Inhibitors/adverse effects , Calcineurin Inhibitors/pharmacology , Calcineurin Inhibitors/therapeutic use , Contraindications, Drug , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Disease Susceptibility , Drug Interactions , Everolimus/adverse effects , Everolimus/pharmacology , Everolimus/therapeutic use , Glucocorticoids/adverse effects , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Humans , Immunity, Innate , Immunocompromised Host , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Mycophenolic Acid/adverse effects , Mycophenolic Acid/pharmacology , Mycophenolic Acid/therapeutic use , Pneumonia, Viral/immunology , Postoperative Complications/immunology , Postoperative Complications/prevention & control , SARS-CoV-2 , Sirolimus/adverse effects , Sirolimus/pharmacology , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors
8.
Transpl Infect Dis ; 22(6): e13404, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-635705

ABSTRACT

Severe acute respiratory syndrome Coronavirus 2 (SARS-Cov2) outbreak has caused a pandemic rapidly impacting on the way of life of the entire world. This impact in the specific setting of transplantation and immunosuppression has been poorly explored to date. Discordant data exist on the impact of previous coronavirus outbreaks on immunosuppressed patients. Overall, only a very limited number of cases have been reported in literature, suggesting that transplanted patients not necessarily present an increased risk of severe SARS-Cov2-related disease compared to the general population. We conducted a literature review related to the impact of immunosuppression on coronavirus infections including case reports and series describing immunosuppression management in transplant recipients. The role of steroids, calcineurin inhibitors, and mycophenolic acid has been explored more in detail. A point-in-time snapshot of the yet released literature and some considerations in relation to the use of immunosuppression in SARS-Cov2 infected transplant recipients are provided here for the physicians dealing with immunocompromised patients.


Subject(s)
COVID-19/immunology , Immunocompromised Host , Transplant Recipients , COVID-19/complications , COVID-19/epidemiology , Calcineurin Inhibitors/pharmacology , Cyclosporine/pharmacology , Female , Humans , Kidney Transplantation , Male , Pandemics , SARS-CoV-2 , Steroids/administration & dosage , Tacrolimus/pharmacology
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