Review of Emerging Pharmacotherapy for the Treatment of Coronavirus Disease 2019

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID-19) can manifest on a spectrum of illness from mild disease to severe respiratory failure requiring intensive care unit admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacologic management of patients with COVID-19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immunomodulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS-CoV-2. Critically ill patients with COVID-19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID-19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.     

Everolimus

Everolimus is an immunosuppressant that blocks growth factor-mediated proliferation of haematopoietic and nonhaematopoietic cells. Oral everolimus 0.75 or 1.5mg twice daily significantly reduced the incidence of the primary composite endpoint, efficacy failure 6 months after transplantation, compared with azathioprine 1-3 mg/kg/day, in adult cardiac transplant recipients. All patients also received baseline immunosuppression with cyclosporin and corticosteroids. The incidence of efficacy failure remained significantly lower in everolimus recipients than in those receiving azathioprine 1 and 2 years after cardiac transplantation. However, graft and patient survival rates at 1 year were similar in patients receiving everolimus or azathioprine. The incidence of graft vasculopathy 2 years after transplantation was significantly lower in cardiac transplant recipients receiving everolimus 0.75 mg twice daily than in those receiving azathioprine. The combined incidence of biopsy-confirmed acute rejection, graft loss, death, or loss to follow-up was similar in adult patients receiving everolimus 1.5 or 3 mg/day or mycophenolate mofetil (MMF) 2 g/day 1 or 3 years after renal transplantation. Patients also received baseline immunosuppression with cyclosporin and corticosteroids. Compared with azathioprine and MMF, everolimus is associated with a lower incidence of cytomegalovirus infection in cardiac and renal transplant recipients. Everolimus has been associated with thrombocytopenia, leucopenia and elevated serum lipids and creatinine.     

Tacrolimus: a further update of its use in the management of organ transplantation

Extensive clinical use has confirmed that tacrolimus (Prograf) is a key option for immunosuppression after transplantation. In large, prospective, randomised, multicentre trials in adults and children receiving solid organ transplants, tacrolimus was at least as effective or provided better efficacy than cyclosporin microemulsion in terms of patient and graft survival, treatment failure rates and the incidence of biopsy-proven acute and corticosteroid-resistant rejection episodes. Notably, the lower incidence of rejection episodes after renal transplantation in tacrolimus recipients was reflected in improved cost effectiveness. In bone marrow transplant (BMT) recipients, the incidence of tacrolimus grade II-IV graft-versus-host disease was significantly lower with tacrolimus than cyclosporin treatment. Efficacy was maintained in renal and liver transplant recipients after total withdrawal of corticosteroid therapy from tacrolimus-based immunosuppression, with the incidence of acute rejection episodes at up to 2 years' follow-up being similar with or without corticosteroids. Tacrolimus provided effective rescue therapy in transplant recipients with persistent acute or chronic allograft rejection or drug-related toxicity associated with cyclosporin treatment. Typically, conversion to tacrolimus reversed rejection episodes and/or improved the tolerability profile, particularly in terms of reduced hyperlipidaemia. In lung transplant recipients with obliterative bronchiolitis, conversion to tacrolimus reduced the decline in and/or improved lung function in terms of forced expiratory volume in 1 second. Tolerability issues may be a factor when choosing a calcineurin inhibitor. Cyclosporin tends to be associated with a higher incidence of significant hypertension, hyperlipidaemia, hirsutism, gingivitis and gum hyperplasia, whereas the incidence of some types of neurotoxicity, disturbances in glucose metabolism, diarrhoea, pruritus and alopecia may be higher with tacrolimus treatment. Renal function, as assessed by serum creatinine levels and glomerular filtration rates, was better in tacrolimus than cyclosporin recipients at up to 5 years' follow-up. CONCLUSION: Recent well designed trials have consolidated the place of tacrolimus as an important choice for primary immunosuppression in solid organ transplantation and in BMT. Notably, in adults and children receiving transplants, tacrolimus-based primary immunosuppression was at least as effective or provided better efficacy than cyclosporin microemulsion treatment in terms of patient and graft survival, treatment failure and the incidence of acute and corticosteroid-resistant rejection episodes. The reduced incidence of rejection episodes in renal transplant recipients receiving tacrolimus translated into a better cost effectiveness relative to cyclosporin microemulsion treatment. The optimal immunosuppression regimen is ultimately dependent on balancing such factors as the efficacy of the individual drugs, their tolerability, potential for drug interactions and pharmacoeconomic issues.     

新型冠状病毒肺炎疫情期间器官移植受者随访与免疫抑制方案调整建议

目的： 探讨新冠肺炎（COVID-19）疫情期间，器官移植受者如何随访，如何调整免疫抑制方案。方法： 查阅文献、指南及咨询器官移植医生，提出器官移植受者在COVID-19疫情期间的随访注意事项和免疫抑制方案调整建议。结果： 特殊时期鼓励病情稳定受者通过互联网随访，适当延长门诊随访时间，根据病情适当调整免疫抑制剂种类、用量，避免免疫抑制过度而诱发感染。结论： 本文可帮助器官移植医护工作者、患者及其家属积极应对疫情，对减少器官移植受者的感染风险，降低病死率等具有重要意义。     

Amid COVID-19 pandemic: Challenges with access to care for COPD patients

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammation in the lungs that causes obstruction in the airway, poor airflow, and irreversible loss of lung function. In clinical practice, comprehensive care for COPD patients includes the diagnosis using spirometry, clinical examination and comprehensive pharmacological and non-pharmacological management. The diagnosis is based on symptoms, dyspnea and lung function impairment and can be mild to very severe. Symptoms are examined using the COPD assessment test (CAT) score, and dyspnea grade are examined using a modified MRC from GOLD guidelines. When mild, the care includes self-management education, smoking cessation, lifestyle modifications, vaccination, and short-acting bronchodilators. Self-management education involves inhaler device training, breathing technique, early recognition of acute exacerbations and writing action plans. As the disease progresses, other care measures are added. These measures include the addition of long-acting inhaler therapies, pulmonary rehabilitation, oral therapies, oxygen and lung transplantation. During the final stages of COPD, patients receive end-of-life care (Bourbeau et al., 2019).¹The novel coronavirus disease (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is spread through respiratory droplets. This infectious disease has led to a pandemic and is affecting the lives of many around the world, including Canadians. During this pandemic, the non-essential health services, including caring for patients with COPD, have been put on hold to reduce the risk of spread. Other implications of this pandemic for COPD patients include the health risk in case of infection. A meta-analysis including studies from January to March 2020 in Wuhan showed that pre-existing COPD worsens the risk of COVID-19 progression and leads to poorer prognostics. The sub-group analysis showed a significantly higher risk of ICU requirements and death in COPD patients who are infected with the SARS-CoV-2 virus. Studies suggest strong efforts to mitigate the risk of infection in this population (Zhao et al., May 2020).² This makes caring for this population even more critical during the pandemic.     

The epidemiology,diagnosis and treatment of COVID-19

In December 2019, the outbreak of the novel coronavirus disease (COVID-19) in China spread worldwide, becoming an emergency of major international concern. SARS-CoV-2 infection causes clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus. Human-to-human transmission via droplets, contaminated hands or surfaces has been described, with incubation times of 2-14 days. Early diagnosis, quarantine, and supportive treatments are essential to cure patients. This paper reviews the literature on all available information about the epidemiology, diagnosis, isolation and treatments of COVID-19. Treatments, including antiviral agents, chloroquine and hydroxychloroquine, corticosteroids, antibodies, convalescent plasma transfusion and vaccines, are discussed in this article. In addition, registered trials investigating treatment options for COVID-19 infection are listed.     

Calming the cytokine storm of COVID-19 through inhibition of JAK2/STAT3 signaling

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the unprecedented COVID-19 pandemic, which has infected over 178 million people worldwide. Even with new vaccines, global herd immunity will not be reached soon. New cases and viral variants are being reported at an alarming rate. Effective antiviral treatment is urgently needed. Patients with severe COVID-19 suffer from life-threatening respiratory failure due to acute respiratory distress syndrome in their lungs, a leading cause of COVID-19 mortality. This lung hyper-inflammation is induced by virus-caused massive tissue damage that is associated with uncontrolled cytokine release, known as a cytokine storm, through JAK/STAT signaling pathways. Here, we review the FDA-approved JAK inhibitors that are being clinically evaluated and repurposed for the treatment of patients with severe COVID-19 by calming SARS-CoV-2 infection.     

Basiliximab: a review of its use as induction therapy in renal transplantation

Basiliximab (Simulect), a chimeric (human/murine) monoclonal antibody, is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents.Basiliximab significantly reduced acute rejection compared with placebo in renal transplant recipients receiving dual- (cyclosporin microemulsion and corticosteroids) or triple-immunotherapy (azathioprine- or mycophenolate mofetil-based); graft and patient survival rates at 12 months were similar. Significantly more basiliximab than placebo recipients were free from the combined endpoint of death, graft loss or acute rejection 3 years, but not 5 years, after transplantation.The incidence of adverse events was similar in basiliximab and placebo recipients, with no increase in the incidence of infection, including cytomegalovirus (CMV) infection. Malignancies or post-transplant lymphoproliferative disorders after treatment with basiliximab were rare, with a similar incidence to that seen with placebo at 12 months or 5 years post-transplantation. Rare cases of hypersensitivity reactions to basiliximab have been reported.The efficacy of basiliximab was similar to that of equine antithymocyte globulin (ATG) and daclizumab, and similar to or greater than that of muromonab CD3. Basiliximab was as effective as rabbit antithymocyte globulin (RATG) in patients at relatively low risk of acute rejection, but less effective in high-risk patients. Numerically or significantly fewer patients receiving basiliximab experienced adverse events considered to be related to the study drug than ATG or RATG recipients. The incidence of infection, including CMV infection, was similar with basiliximab and ATG or RATG.Basiliximab plus baseline immunosuppression resulted in no significant differences in acute rejection rates compared with baseline immunosuppression with or without ATG or antilymphocyte globulin in retrospective analyses conducted for small numbers of paediatric patients. Limited data from paediatric renal transplant recipients suggest a similar tolerability profile to that in adults. Basiliximab appears to allow the withdrawal of corticosteroids or the use of corticosteroid-free or calcineurin inhibitor-sparing regimens in renal transplant recipients.Basiliximab did not increase the overall costs of therapy in pharmacoeconomic studies.CONCLUSION: Basiliximab reduces acute rejection without increasing the incidence of adverse events, including infection and malignancy, in renal transplant recipients when combined with standard dual- or triple-immunotherapy. The overall incidence of death, graft loss or acute rejection was significantly reduced at 3 years; there was no significant difference for this endpoint 5 years after transplantation. Malignancy was not increased at 5 years. The overall efficacy, tolerability, ease of administration and cost effectiveness of basiliximab make it an attractive option for the prophylaxis of acute renal transplant rejection.     

糖皮质激素治疗新型冠状病毒肺炎的有效性和安全性分析

目的探讨糖皮质激素治疗新型冠状病毒肺炎(简称新冠肺炎)的有效性和安全性,为新冠肺炎的诊治和药学监护提供参考。方法查阅文献,总结既往糖皮质激素在社区获得性重症肺炎、严重急性呼吸综合征(SARS)、中东呼吸综合征(MERS)等肺部疾病治疗中的应用情况,结合新冠肺炎最新诊疗方案并参考一线用药经验,总结糖皮质激素治疗的临床疗效和使用注意事项。结果与结论糖皮质激素辅助性治疗新冠肺炎的风险与获益尚无定论。新冠肺炎的诊治过程中可在参考国内外指南、文献并结合一线救治经验的基础上短疗程、小剂量使用糖皮质激素,但应严格把握用药指征,加强药学监护。建议开展大样本、多中心、随机对照试验研究其风险与获益,研究导致新冠肺炎进展的关键炎性因子,并阐明患者的个体差异,为针对性选用/开发抗炎药物或单克隆抗体药物奠定理论基础。     

COVID-19相关性心血管疾病的研究进展

新型冠状病毒肺炎(COVID-19)已迅速发展成全球卫生紧急事件.新型冠状病毒,即SARS-CoV-2,可影响多个器官,特别是肺脏和心脏.研究发现心脏生物标志物特别是超敏肌钙蛋白(hs-cTnI)和肌酸激酶(CK)的升高,在新型冠状病毒肺炎患者中很常见,有助于疾病诊断和危险分层.同时发现既往有心血管疾病的患者更易感染新...     

Calcineurin inhibitor-free immunosuppression in pediatric renal transplantation: a viable option?

The introduction, in the mid-1980s, of calcineurin inhibitors - namely ciclosporin (cyclosporine) and later tacrolimus - has significantly improved short-term renal graft survival by lowering acute rejection rates in both adult and pediatric kidney transplantation. Nonetheless, long-term transplant survival is still not satisfactory, with calcineurin inhibitor-induced chronic nephrotoxicity being one of the main causes of progressive nephron loss and declining renal transplant function. Hence, different immunosuppressant regimens have been proposed to avoid or ameliorate calcineurin inhibitor-induced nephrotoxicity. These comprise the use of non-depleting or depleting antibodies for calcineurin inhibitor minimization, calcineurin inhibitor avoidance, or calcineurin inhibitor withdrawal from mycophenolate mofetil-based immunosuppressant protocols. De novo use of a mammalian target of rapamycin (mTOR) inhibitor (sirolimus or everolimus) or conversion from a calcineurin inhibitor to an mTOR inhibitor may constitute another therapeutic option to avoid or reduce calcineurin inhibitor-induced nephrotoxicity. To date, complete calcineurin inhibitor avoidance seems to be inappropriate because other relatively potent immunosuppressant agents such as lymphocyte-depleting antibodies are needed for rejection prophylaxis, which are frequently accompanied by a higher incidence of infections and an unacceptably high acute rejection rate under calcineurin inhibitor avoidance. In some studies, calcineurin inhibitor withdrawal in adult and pediatric kidney allograft recipients with stable or declining transplant function has been associated with an amelioration of renal function; however, this is attained at the cost of a higher acute rejection rate in 10-20% of patients. It has been frequently stressed that conversion from a calcineurin inhibitor-based regimen to an mTOR inhibitor-based immunosuppressant regimen should be performed early (e.g. 3 or 6 months post-transplant) in patients with well-preserved renal transplant function without significant proteinuria in order to prevent, or at least limit, calcineurin inhibitor-induced tissue damage and provide long-term benefit. It should be borne in mind though that the use of an mTOR inhibitor carries the risk of potential adverse events such as aggravation of proteinuria, hyperlipidemia, myelosuppression, and hypergonadotropic hypogonadism. Even though everolimus may be better tolerated than sirolimus, studies on everolimus for calcineurin inhibitor-free immunosuppression in the pediatric kidney transplant patient population are lacking. At present, the safest therapeutic strategy for pediatric renal allograft recipients with chronic calcineurin inhibitor-induced nephrotoxicity appears to be a mycophenolate mofetil-based regimen with low-dose calcineurin inhibitor therapy and corticosteroids; available published data show that dual immunosuppression with mycophenolate mofetil and corticosteroids, as well as an mTOR inhibitor plus mycophenolate mofetil plus corticosteroid-based regimens, are associated with an increased risk of acute rejection episodes. In individual patients with evidenced chronic allograft dysfunction and over-immunosuppression leading to recurrent infections, dual maintenance immunosuppression with mycophenolate mofetil and corticosteroids may be appropriate. As stated in the annual report issued by the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry, currently the most popular immunosuppressant protocol consists of a calcineurin inhibitor combined with mycophenolate mofetil and corticosteroids: 59.1% and 53.2% of patients with a functioning graft receive a calcineurin inhibitor plus mycophenolate mofetil plus corticosteroid-based immunosuppression at 1 and 5 years post-transplant, respectively. 91.4% and 87.8% of patients are administered a calcineurin inhibitor-containing regimen 1 and/or 5 years after transplantation, respectively. Undoubtedly, the use of calcineurin inhibitor-free immunosuppressant regimens with or without antibody induction, plus an mTOR inhibitor and mycophenolate mofetil, requires more comprehensive long-term investigations to determine whether acceptable rejection rates and conservation of renal function can be achieved.     

Immunosuppression in elderly renal transplant recipients: are current regimens too aggressive?

Renal transplantation is an accepted and successful treatment modality in elderly patients with end-stage renal disease. In comparison with maintenance dialysis, transplantation has been shown to confer a mortality benefit as well as improvements in quality of life in older individuals with end-stage renal disease. Despite this, overall outcomes of renal transplantation in elderly individuals have, in general, been less successful than those of younger renal transplant recipients. Largely, this has been due to the particular vulnerability of elderly patients to the immunosuppressive medications used in renal transplantation. This review article covers these issues in some detail and briefly discusses some of the pharmacokinetic, pharmacodynamic, physiological and immunological differences between younger and older transplant recipients. Elderly renal transplant recipients have both a higher rate of patient death and allograft loss censored for death. Upon multivariate analysis, age of the recipient is strongly associated with allograft loss independent of other known factors. Acute rejections are less frequent in older individuals; however the consequence of a rejection if it occurs is negative for long-term graft survival. On the other hand, death by infection is vastly increased in older versus younger renal transplant recipients. In general, the pharmacokinetics of the immunosuppressive agents are little affected by age, but the tolerance to these agents seems to decrease with increasing age. Elderly renal transplant recipients present a very difficult clinical challenge. As the elderly become an ever-increasing segment of the renal transplant population, new and innovative immunosuppressive strategies will have to be considered and applied.     

新型冠状病毒肺炎诊疗方案推荐的潜在抗病毒药物述评

目的 为临床抗新型冠状病毒(SARS-CoV-2)治疗及药学监护提供参考。方法 结合SARS-CoV-2的特点和可能的致病机理,围绕国家卫生健康委员会《新型冠状病毒肺炎诊疗方案(试行第七版)》推荐的潜在抗病毒药物,以及中国药学会《新型冠状病毒感染:医院药学工作指导与防控策略专家共识》的相关内容,从这些药物的背景信息、药理作用、药物警戒等方面进行综合评述。结果 与结论通过综合述评,为临床新型冠状病毒肺炎的抗病毒治疗及药学监护提供了药物治疗学相关知识,也为抗SARS-CoV-2的药物研究提供了参考。     

Baricitinib,a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19

In December 2019, a novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly broke out in China and rapidly spread all over the world. Recently, a cell surface protein, known as angiotensin-converting enzyme II (ACE2), has been identified to be involved in receptor-mediated endocytosis for SARS-CoV-2 entry to the cells. Many studies have reported the clinical characteristics of COVID-19: sudden deterioration of disease around 1–2 weeks after onset; much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; extremely high pro-inflammatory cytokines and C reactive protein (CRP). About 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. Baricitinib intracellularly inhibits the proinflammatory signal of several cytokines by suppressing Janus kinase (JAK) JAK1/JAK2. It has been demonstrated clinical benefits for the patients with rheumatoid arthritis (RA), active systemic lupus erythematosus and atopic dermatitis with good efficacy and safety records. Baricitinib is expected to interrupt the passage and intracellular assembly of SARS-CoV-2 into the target cells mediated by ACE2 receptor, and treat cytokine storm caused by COVID-19. Several clinical trials are currently investigating the drug, and one of which has been completed with encouraging results. In this paper, we will elaborate the role of cytokine storm mediated by JAK-STAT pathway in severe COVID-19, the possible mechanisms of baricitinib on reducing the viral entry into the target cells and cytokine storm, the key points of pharmaceutical care based on the latest research reports, clinical trials progress and drug instruction from the US FDA, so as to provide reference for the treatment of severe COVID-19.     

Evidence-based treatment during the SARS-CoV-2 pandemic: Identifying the knowns and unknowns of nebulization

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus 19 (COVID-19), has resulted in a worldwide pandemic and currently represents a major public health issue. Among the considerations for patients with respiratory disease is the optimal delivery of inhaled bronchodilators to maximize patient care. Despite the lack of evidence, there is heightened concern about the potential risk for transmission of SARS-CoV-2 in the form of aerosolized respiratory droplets during the nebulized treatment of patients with COVID-19. In this commentary, the lack of evidence regarding nebulization and transmission of coronaviruses are discussed.     

Corticosteroid-free strategies in liver transplantation

Corticosteroid avoidance is feasible and may be desirable in liver transplantation. Approximately 50% of liver transplant recipients who use calcineurin inhibitors and azathioprine do not need corticosteroids. The availability of newer agents, such as mycophenolate mofetil and antibody therapy, has increased the percentage of patients who do not need to use corticosteroids to about 75%. The feasibility of corticosteroid-free immunosuppression has been established by controlled trials demonstrating non-inferiority with respect to patterns of rejection as well as patient and graft survival. However, the evidence available to date does not unequivocally establish the benefits of corticosteroid-free immunosuppression, although some advantage has been established relating to post-transplant diabetes mellitus, cytomegalovirus infection and growth patterns in children. The effect of corticosteroid-free immunosuppression in hepatitis C liver transplant recipients is yet to be resolved.     

Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence

COVID-19, the disease caused by SARS-CoV-2, is a highly contagious disease. The World Health Organization has declared the ongoing outbreak to be a global public health emergency. Currently, the research on SARS-CoV-2 is in its primary stages. Based on current published evidence, this review systematically summarizes the epidemiology, clinical characteristics, diagnosis, treatment and prevention of COVID-19. It is hoped that this review will help the public to recognize and deal with SARS-CoV-2, and provide a reference for future studies.     

Rabbit antithymocyte globulin induction therapy in adult renal transplantation

Rabbit antithymocyte globulin (rATG) and horse antithymocyte globulin (horse ATG) are the polyclonal antithymocyte agents available for use in solid organ transplantation in the United States. Horse ATG is indicated for induction immunosuppression and for treatment of acute rejection episodes after kidney transplantation; rATG is indicated for treatment of acute rejection only. However, rATG is commonly used in clinical practice as an induction immunosuppressive agent, instigating many questions regarding appropriate dosing, tolerability, safety, and efficacy. Available evidence supports the use of rATG as an induction agent in adult renal transplant recipients. The use of this product for induction therapy has been studied in conjunction with a full-dose, triple-therapy maintenance regimen (sequential quadruple immunosuppression) consisting of a calcineurin inhibitor, an antimetabolite, and corticosteroids. Rabbit ATG has a proven safety and efficacy profile both as treatment of acute rejection and as induction therapy in patients undergoing kidney transplantation. The most common adverse events associated with rATG are cytokine release syndrome, thrombocytopenia, and lymphopenia. Results of early studies showed an increased rate of cytomegalovirus disease associated with rATG treatment, but recent studies indicate that routine administration of modern antiviral prophylaxis can reduce this risk. Current practice with rATG is evolving to minimize lifelong exposure to calcineurin inhibitors and corticosteroids.