scholarly journals Corticosteroids for Severe Coronavirus Disease 2019: High Time for High Dose Clinical Trials?

2021 ◽  
Author(s):  
A. Arturo Leis ◽  
Joseph L. Verheijde ◽  
Parminder J.S. Vig ◽  
Dobrivoje S. Stokic
Keyword(s):  
Clinical Trials ◽  
Critically Ill ◽  
Randomized Clinical Trials ◽  
Standard Of Care ◽  
Pulse Therapy ◽  
Therapeutic Benefit ◽  
Lessons Learned ◽  
High Dose ◽  
Short Period ◽  
Need To Evaluate

Over 3 million deaths into the COVID-19 pandemic, low dose corticosteroids are still the chief therapeutic intervention to decrease mortality in critically ill COVID-19 patients. However, the persistently high mortality rate (approximately 30%) and the global surge in cases in 2021 associated with new more contagious variants of SARS-CoV-2 underscore the urgent need to evaluate whether the current corticosteroid regimens achieve the best possible outcomes. Our review of clinical, virological, and immunological data suggest that corticosteroids reduce COVID-19 mortality more when initiated in the second or third weeks after symptom onset, after viral infectivity has waned and SARS-CoV-2 immunopathology is maximal. At this time, clinical deterioration is driven by aberrant hyperinflammation. To counteract the hyperinflammation, we present credible arguments that high dose corticosteroids, defined in this Perspective as intravenous (i.v.) methylprednisolone 500-1000 mg/day for 3-7 days or the equivalent doses of other corticosteroids, can be administered with little or no risk of worsening viral replication and with expected benefits that greatly outweigh potential harm. Since the 1970s, the strategy of administering supraphysiologic doses of i.v. methylprednisolone (termed ‘pulse’ therapy) over a short period to enhance therapeutic benefit while decreasing harmful effects has become an accepted standard of care to effectively suppress inflammation in many autoimmune and immune-mediated disorders. It is particularly useful in conditions requiring rapid immunosuppression and anti-inflammatory effect and has recently been used to control inflammation in SARS-CoV-2 related complications, including multisystem inflammatory syndrome in children (MIS-C) and organizing pneumonia. In aggregate, awareness of the need for more aggressive immunosuppression and lessons learned over a half-century from the successful treatment of various inflammatory disorders, provide a sound scientific and ethics rationale for expeditiously conducting high dose corticosteroid randomized clinical trials (RCTs) in critically ill patients with COVID-19.

scholarly journals Lessons Learnt from Evidence-Based Approach of Using Chinese Herbal Medicines in Liver Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Zhan Zheng ◽  
William Chi-Shing Cho ◽  
Ling Xu ◽  
Juyong Wang ◽  
Daniel Man-Yuen Sze
Keyword(s):  
Clinical Trials ◽  
Liver Cancer ◽  
Randomized Clinical Trials ◽  
Herbal Medicines ◽  
Therapeutic Benefit ◽  
Lessons Learned ◽  
Syndrome Differentiation ◽  
Evidence Based ◽  
Chinese Herbal ◽  
Tcm Syndrome

This paper is a systematic review of evidence-based studies of the effectiveness of Chinese herbal medicine (CHM) in the treatment of liver cancer. After a detailed analysis of the literature, five animal studies and four human clinical trials met the criteria for inclusion. Analysis revealed that results of the clinical trials, whilst encouraging, need to be interpreted with caution as problems with study designs may lead to apparent benefits being attributable to various forms of bias. However, as each of the CHM agents used in these studies appeared to be potentially beneficial, further well-designed and controlled randomized clinical trials are warranted. The second part of this review focused on the lessons learned from the relationships between Traditional Chinese Medicine (TCM) theory, TCM Syndrome Differentiation, and modern scientific understanding of mechanisms of action of CHM agents. The understanding of TCM Syndrome Differentiation may allow identification of different patterns of disharmony and may provide important guidance to the prescription of CHM. Furthermore, quality control using both biological and chemical fingerprinting of CHM is important to ensure batch-to-batch consistency to deliver sustained therapeutic benefit. Also, careful assessment of herb-drug interactions is paramount for safety and integrative use of western chemotherapeutic and CHM agents.

scholarly journals Management of Optic Neuritis in Canada: Survey of Ophthalmologists and Neurologists

2008 ◽  
Vol 35 (2) ◽  
pp. 179-184 ◽  
Author(s):  
Edward J. Atkins ◽  
Carolyn D. Drews-Botsch ◽  
Nancy J. Newman ◽  
Olivier Calvetti ◽  
Seegar Swanson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Optic Neuritis ◽  
Randomized Clinical Trials ◽  
Mail Survey ◽  
Standard Of Care ◽  
High Dose ◽  
Acute Optic Neuritis ◽  
Disease Modifying ◽  
Disease Modifying Agents ◽  
The Impact

ABSTRACTBackground:Acute isolated optic neuritis is often the first manifestation of multiple sclerosis (MS), and its management remains controversial. Over the past decade, with the advent of new disease-modifying agents, management of isolated optic neuritis has become more complicated.Objectives:To evaluate the current practice patterns of Canadian ophthalmologists and neurologists in the management of acute optic neuritis, and to evaluate the impact of recently published randomized clinical trials.Design:Mail survey.Methods:All practicing ophthalmologists and neurologists in Canada were mailed a survey evaluating the management of isolated acute optic neuritis and familiarity with recent clinical trials. Surveys for 1158 were mailed, and completed surveys were collected anonymously through a datafax system. Second and third mailings were sent to non-respondents 6 and 12 weeks later.Results:The final response rate was 34.5%. Although many acute optic neuritis patients initially present to ophthalmologists, neurologists are the physicians primarily managing these patients. Ordering magnetic resonance imaging, and treating with high dose intravenous steroids has become the standard of care. However, 15% of physicians (14% of ophthalmologists and 16% of neurologists) continue to prescribe low dose oral steroids, and steroids are being given for reasons other than to shorten the duration of visual symptoms by 73% of ophthalmologists and 50% of neurologists. More neurologists than ophthalmologists are familiar with recent clinical trials involving disease-modifying agents.Conclusion:Although the management of acute optic neuritis has been evaluated in large clinical trials that were published in major international journals, some ophthalmologists and neurologists are not following evidence-based recommendations.

scholarly journals Safety and Efficacy of Four Drug Versus Three Drug Regimens Among Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Saad Ullah Malik ◽  
Nazma Hanif ◽  
Priyanka Kumari ◽  
Khadija Noor Sami ◽  
Chase Warner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Standard Of Care ◽  
Drug Regimen ◽  
P Value ◽  
Newly Diagnosed ◽  
Drug Regimens ◽  
Grade 3

Introduction: During recent years there has been a boom in the availability of treatments for multiple myeloma (MM). Based on the status of disease (newly diagnosed or relapsed/refractory), several regimens have successfully improved progression free survival (PFS) and overall survival (OS) in these two types of patients. Triple drug regimen is considered the current standard of care for newly diagnosed MM patients. However, with the advent of four drug regimens, some studies demonstrated a significant improvement in PFS and OS compared to standard of care where as others showed marginal to no difference. Also, it remains unclear whether the benefits of using four drug regimen outweigh the risks. Thus, the aim of our meta-analysis was to compare the efficacy and safety of four drug versus three drug regimens among newly diagnosed multiple myeloma patients. Methods: We built a PICO based search strategy using keywords like "multiple myeloma", "randomized clinical trials" and ran literature search on PubMed, Embase, Wiley Cochrane Library, Web of Science and ClinicalTrials.gov ranging from the date of inception till 16th July, 2020. A pre-validated data extraction sheet was used to extract data on PFS, OS and ≥Grade 3 hematologic adverse events at the longest follow-up. We included only randomized clinical trials (RCTs) comparing four versus three drug regimen in newly diagnosed MM patients. We excluded studies other than RCTs, studies conducted on relapsed refractory MM patients or other plasma cell dyscrasias. A generic variance weighted random effects model (DerSimonian and Laird) was used to derive hazard ratio estimates along with their 95% confidence intervals (CIs) for PFS and OS. Risk ratio along with its 95% CIs was estimated for Grade ≥3 hematologic adverse events. Heterogeneity was assessed with Cochrane Q -statistic and was quantified with I2 test (I2 >50% was consistent with a high degree of heterogeneity). A pre-specified sensitivity analysis was also performed for risk of adverse events. Cochrane Collaboration's tool was used to assess the quality of included RCTs and GRADE was used to rate the quality of evidence. Results: Initial search retrieved 7622 titles. After duplicate removal, 4880 articles were left. Following initial screening, 58 articles were considered for full text review. Of these only 3 studies (n=2277) met inclusion criteria. Four drug regimens included daratumumab, bortezomib, melphalan-prednisone (D-VMP), daratumumab, bortezomib, thalidomide-dexamethasone (D-VTd) and bortezomib and melphalan prednisone and thalidomide (VMPT-VT) respectively. Whereas, three drug regimens were bortezomib, melphalan-prednisone (VMP), bortezomib, thalidomide-dexamethasone (VTd) and bortezomib, melphalan and prednisone (VMP) respectively. There was a significant improvement in PFS when 4 vs 3 drug regimens were compared in patients with newly diagnosed MM (HR: 0.53, 95% CI: 0.46-0.62, p-value:<0.001, I2: 0%). Also, OS improved significantly in four drug regimen group (HR: 0.62, 95% CI: 0.51-0.76, p-value:<0.001, I2: 3.5%). There was no statistically significant difference in any grade ≥3 hematologic adverse events when 4 vs 3 drug regimens were compared (RR: 1.26, 95% CI: 0.93-1.73, p-value:0.14, I2: 93%). Sensitivity analysis after removing D-VTd regimen from any grade ≥3 hematologic adverse events revealed similar results (RR: 1.05, 95% CI: 0.97-1.13, p-value:0.23, I2: 23%) confirming the robustness of analysis. When each hematologic adverse event was looked at separately, there was no difference between 4 vs 3 drug regimen in rates of anemia (RR: 0.99, 95% CI: 0.76-1.28, p-value:0.92, I2: 0%), neutropenia (RR: 1.39, 95% CI: 1.00-1.94, p-value:0.05, I2: 85%) and thrombocytopenia (RR: 1.13, 95% CI: 0.92-1.39, p-value:0.24, I2: 33%). There was low risk of bias and strength of evidence was of moderate. Conclusion: Using four drug regimens, compared to three drug regimens, significantly improves PFS and OS among newly diagnosed multiple myeloma patients without any difference in the risk of ≥3 grade hematologic adverse events. Further randomized clinical trials are required to establish four drug regimen as standard of care for patients with newly diagnosed multiple myeloma. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Asthma: Anti-Immunoglobulin E Therapy with Omalizumab for Asthma

2007 ◽  
Vol 41 (9) ◽  
pp. 1397-1410 ◽  
Author(s):  
Leslie Hendeles ◽  
Christine A Sorkness
Keyword(s):  
Clinical Trials ◽  
Cost Effectiveness ◽  
Randomized Clinical Trials ◽  
Inhaled Corticosteroids ◽  
Immunoglobulin E ◽  
Data Extraction ◽  
Symptom Control ◽  
High Dose ◽  
Search Term ◽  
Ige Mediated

Objective: To evaluate data on anti-immunoglobulin E (anti-IgE) therapy for asthma. Data Sources: Information was selected from PubMed from 1989 to May 2007 using the search term omalizumab and included randomized, controlled trials. These studies evaluated asthma treatment with omalizumab and focused on its efficacy, tolerability, and cost-effectiveness in this population. Study Selection and Data Extraction: All randomized clinical trials were reviewed (23 were identified and 19 were included; 3 were not relevant and 1 contained duplicative data). Other articles using the search words anti-IgE therapy and cost-effectiveness were evaluated; relevant information was extracted. Data Synthesis: IgE-dependent mechanisms play an important role in the development and maintenance of airway inflammation in asthma. Omalizumab is a subcutaneously administered monoclonal anti-IgE antibody that reduces unbound IgE concentrations and promotes down-regulation of IgE receptors. Results from clinical trials in adults, adolescents, and children with poorly controlled IgE-mediated asthma have shown that omalizumab improves symptom control and allows patients to be managed with lower doses of inhaled corticosteroids (ICS). It has been well tolerated in clinical trials lasting as long as 52 weeks, but injection-site reactions are common (45% in omalizumab group vs 43% in placebo group) and anaphylaxis has occurred in 0.2% of patients. A consensus expert panel has recommended that omalizumab should be considered for patients 12 years of age or older with allergic asthma who are inadequately controlled on guideline-based therapy and require maintenance therapy with systemic corticosteroids or high-dose ICSs, or who have poor adherence to ICS therapy. Conclusions: Anti-IgE therapy provides an effective and generally safe approach to the treatment of patients with IgE-mediated asthma who are not adequately controlled by conventional guideline-based medications. However, the potential benefit must be weighed against the cost and inconvenience of this new therapy.

How I Treat AL Amyloidosis

Blood ◽  
2021 ◽  
Author(s):  
Giovanni Palladini ◽  
Giampaolo Merlini
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Correct Diagnosis ◽  
Clinical Manifestations ◽  
Standard Of Care ◽  
Organ Involvement ◽  
Al Amyloidosis ◽  
Amyloid Deposits ◽  
Organ Response ◽  
Effective Drugs

The treatment of patients with systemic light chain (AL) amyloidosis is a challenge to hematologists. Despite its generally small size, the underlying clone causes a rapidly progressing, often devastating multiorgan dysfunction through the toxic light chains that form amyloid deposits. Clinical manifestations are deceitful and too often recognized at an irreversible stage. However, hematologists are in the unique position to diagnose AL amyloidosis at a pre-symptomatic stage checking biomarkers of amyloid organ involvement in patients with monoclonal gammopathies at higher risk to develop the disease. Adequate technology and expertise are needed for a prompt and correct diagnosis, particularly for ruling out non-AL amyloidoses that are now also treatable. Therapy should be carefully tailored based on severity of organ involvement and clonal characteristics, and early and continual monitoring of response is critical. Three recent randomized clinical trials moved AL amyloidosis to evidence-based era. Above all, the daratumumab-bortezomib combination is a new standard-of-care for newly diagnosed patients inducing rapid and deep responses that translate into high rates of organ response. The availability of new effective drugs allows to better personalize the therapy, reduce toxicity, and improve outcomes. Patients should be treated within clinical trials whenever possible.

Therapeutic Mechanisms of Treatment in Cervical and Vaginal Cancer

2012 ◽  
Vol 08 (01) ◽  
pp. 55 ◽  
Author(s):  
Charles AKunos ◽  
Keyword(s):  
Clinical Trials ◽  
Molecular Biology ◽  
Randomized Clinical Trials ◽  
Health Resources ◽  
Standard Of Care ◽  
Advanced Stage ◽  
Screening Programs ◽  
Therapeutic Mechanisms ◽  
Limited Health ◽  
Incident Cases

Cervical and vaginal cancers remain serious health problems. Worldwide, more than 530,000 women annually are diagnosed with these diseases, with most new incident cases occurring in nations with limited health resources and underdeveloped screening programs. For women whose disease is too bulky or widespread for surgery, radiochemotherapy should be looked upon as the standard of care. Randomized clinical trials have indicated that radiochemotherapy strategies that disrupt the repair of damaged DNA are key to the management of advanced stage cervical and vaginal cancers. Here, from a viewpoint of cancer cell molecular biology, treatments for advanced stage cervical and vaginal cancers are discussed.

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