ritonavir and Cytokine-Release-Syndrome

This critical appraisal aims to clarify which systematic reviews on COVID-19 treatment are based on high-value evidence. Hereby, the most profitable medicines can be suggested.. The mesh terms of "COVID-19 drug treatment" (Supplementary Concept) and "COVID-19 drug treatment" were sequentially utilized as search strategies in Medline and Science direct on October 18, 2020. Searches were confined to systematic reviews/meta-analyses. The Cochrane database was searched on November 1, 2020 with "COVID." With adding up four articles from other resources, 84 systematic reviews were considered for initial screening. Finally, 22 articles fulfilled the criteria and were assessed using PRISMA guidelines.. Increasing number of clinical trials from the onset of the COVID-19 pandemic has revealed that hydroxychloroquine and chloroquine are not only profitable but also deleterious. Lopinavir/ritonavir failed to maintain their initial efficacy in improving clinical symptoms and mortality rate. Steroids and tocilizumab were suggested in patients with intensely severe symptoms. Steroids reduced mechanical ventilation and death in severely ill patients. Plasma or immunoglobulins effects are absolutely controversial. Favorable impressions of remdesivir have been relied on for the early onset of this drug. Hypotension and abnormal liver function tests were realized as its side effects. Favipiravir has resulted in a higher viral clearance than remdesivir. However, this claim needs to be proved with subsequent clinical trials.. Currently, remdesivir and favipiravir are advantageous drugs that should be administered in the early phases. Their side effects are not well known and need to be found in the following research projects. Steroids and tocilizumab have been considered beneficial in the cytokine storm phase.

Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Chloroquine; COVID-19; COVID-19 Drug Treatment; Cytokine Release Syndrome; Databases, Factual; Humans; Hydroxychloroquine; Immunoglobulins; Lopinavir; Pandemics; Pyrazines; Respiration, Artificial; Ritonavir; SARS-CoV-2

SARS-CoV-2 is the agent responsible for COVID-19. The infection can be dived into three phases: mild infection, the pulmonary phase and the inflammatory phase. Treatment options for the pulmonary phase include: Hydroxychloroquine, Remdesivir, Lopinavir/Ritonavir. The inflammatory phase includes therapeutic options like Tocilizumab, Anakinra, Baricitinib, Eculizumab, Emapalumab and Heparin. Human clinical trials are starting to show some results, in some cases like that of Remdesivir and corticosteroids these are controversial. Coagulopathy is a common complication in severe cases, inflammation and coagulation are intertwined and cross-talking between these two responses is known to happen. A possible amplification of this cross-talking is suggested to be implicated in the severe cases that show both a cytokine storm and coagulopathy.

Topics: Adenosine Monophosphate; Alanine; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; Anticoagulants; Antiviral Agents; Azetidines; Betacoronavirus; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Disseminated Intravascular Coagulation; Drug Combinations; Heparin; Humans; Hydroxychloroquine; Inflammation; Interleukin 1 Receptor Antagonist Protein; Lopinavir; Pandemics; Pneumonia, Viral; Purines; Pyrazoles; Ritonavir; SARS-CoV-2; Sulfonamides

Coronavirus disease 2019, also known as COVID-19, is caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2. The infection has now catapulted into a full-blown pandemic across the world, which has affected more than 2 million people and has led to approximately 150,000 fatalities all over the world (WHO). In this review, we elaborate all currently available data that shed light on possible methods for treatment of COVID-19, such as antiviral drugs, corticosteroids, convalescent plasma, and potentially effective vaccines. Additionally, ongoing and discontinued clinical trials that have been carried out for validating probable treatments for COVID-19 are discussed. The review also elaborates the prospective approach and the possible advantages of using convalescent plasma and stem cells for the improvement of clinical symptoms and meeting the demand for an instantaneous cure.

Topics: Adenosine Monophosphate; Adrenal Cortex Hormones; Alanine; Amides; Antibodies, Monoclonal, Humanized; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Serotherapy; COVID-19 Vaccines; Cytokine Release Syndrome; Drug Combinations; Humans; Hydroxychloroquine; Immunization, Passive; Immunologic Factors; Indoles; Interleukin 1 Receptor Antagonist Protein; Lopinavir; Pandemics; Pneumonia, Viral; Pyrazines; Ritonavir; SARS-CoV-2; Severity of Illness Index; Viral Vaccines

In December 2019, a novel coronavirus SARS-CoV-2, causing the disease COVID-19, spread from Wuhan throughout China and has infected people over 200 countries. Thus far, more than 3,400,000 cases and 240,000 deaths have occurred worldwide, and the coronavirus pandemic continues to grip the globe. While numbers of cases in China have been steadying, the number of infections outside China is increasing at a worrying pace. We face an urgent need to control the spread of the COVID-19 epidemic, which is currently expanding to a global pandemic. Efforts have focused on testing antiviral drugs and vaccines, but there is currently no treatment specifically approved. Traditional Chinese medicine (TCM) is grounded in empirical observations and the Chinese people use TCM to overcome these sorts of plagues many times in thousands of years of history. Currently, the Chinese National Health Commission recommended a TCM prescription of Qing-Fei-Pai-Du-Tang (QFPDT) in the latest version of the "Diagnosis and Treatment guidelines of COVID-19" which has been reported to provide reliable effects for COVID-19. While doubts about TCM still exist today, this review paper will describe the rationalities that QFPDT is likely to bring a safe and effective treatment of COVID-19.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Antiviral Agents; Betacoronavirus; Chloroquine; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cytokine Release Syndrome; Drug Combinations; Drugs, Chinese Herbal; Humans; Indoles; Janus Kinase Inhibitors; Lopinavir; Medicine, Chinese Traditional; Pandemics; Pneumonia, Viral; Ritonavir; SARS-CoV-2

Patients with coronavirus disease 2019 (COVID-19) may experience a cytokine storm with elevated interleukin-6 (IL-6) levels in response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). IL-6 suppresses hepatic enzymes, including CYP3A; however, the effect on drug exposure and drug-drug interaction magnitudes of the cytokine storm and resulting elevated IL-6 levels have not been characterized in patients with COVID-19. We used physiologically-based pharmacokinetic (PBPK) modeling to simulate the effect of inflammation on the pharmacokinetics of CYP3A metabolized drugs. A PBPK model was developed for lopinavir boosted with ritonavir (LPV/r), using clinically observed data from people living with HIV (PLWH). The inhibition of CYPs by IL-6 was implemented by a semimechanistic suppression model and verified against clinical data from patients with COVID-19, treated with LPV/r. Subsequently, the verified model was used to simulate the effect of various clinically observed IL-6 levels on the exposure of LPV/r and midazolam, a CYP3A model drug. Clinically observed LPV/r concentrations in PLWH and patients with COVID-19 were predicted within the 95% confidence interval of the simulation results, demonstrating its predictive capability. Simulations indicated a twofold higher LPV exposure in patients with COVID-19 compared with PLWH, whereas ritonavir exposure was predicted to be comparable. Varying IL-6 levels under COVID-19 had only a marginal effect on LPV/r pharmacokinetics according to our model. Simulations showed that a cytokine storm increased the exposure of the CYP3A paradigm substrate midazolam by 40%. Our simulations suggest that CYP3A metabolism is altered in patients with COVID-19 having increased cytokine release. Caution is required when prescribing narrow therapeutic index drugs particularly in the presence of strong CYP3A inhibitors.

Topics: Adult; COVID-19; COVID-19 Drug Treatment; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Cytokine Release Syndrome; Cytokines; Humans; Lopinavir; Metabolic Clearance Rate; Midazolam; Middle Aged; Models, Biological; Ritonavir

Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24, and 48 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 μg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antiviral Agents; Betacoronavirus; Biomarkers; C-Reactive Protein; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Drug Administration Schedule; Drug Combinations; Female; Hospitals, University; Humans; Hydroxychloroquine; Length of Stay; Lopinavir; Male; Middle Aged; Pandemics; Pneumonia, Viral; Retrospective Studies; Ritonavir; SARS-CoV-2; Severity of Illness Index; Survival Analysis

Fulminant (life-threatening) COVID-19 can be associated with acute respiratory failure (ARF), multi-system organ failure and cytokine release syndrome (CRS). We present a rare case of fulminant COVID-19 associated with reverse-takotsubo-cardiomyopathy (RTCC) that improved with therapeutic plasma exchange (TPE).. A 40 year old previous healthy male presented in the emergency room with 4 days of dry cough, chest pain, myalgias and fatigue. He progressed to ARF requiring high-flow-nasal-cannula (flow: 60 L/minute, fraction of inspired oxygen: 40%). Real-Time-Polymerase-Chain-Reaction (RT-PCR) assay confirmed COVID-19 and chest X-ray showed interstitial infiltrates. Biochemistry suggested CRS: increased C-reactive protein, lactate dehydrogenase, ferritin and interleukin-6. Renal function was normal but lactate levels were elevated. Electrocardiogram demonstrated non-specific changes and troponin-I levels were slightly elevated. Echocardiography revealed left ventricular (LV) basal and midventricular akinesia with apex sparing (LV ejection fraction: 30%) and depressed cardiac output (2.8 L/min) consistent with a rare variant of stress-related cardiomyopathy: RTCC. His ratio of partial arterial pressure of oxygen to fractional inspired concentration of oxygen was < 120. He was admitted to the intensive care unit (ICU) for mechanical ventilation and vasopressors, plus antivirals (lopinavir/ritonavir), and prophylactic anticoagulation. Infusion of milrinone failed to improve his cardiogenic shock (day-1). Thus, rescue TPE was performed using the Spectra Optia™ Apheresis System equipped with the Depuro D2000 Adsorption Cartridge (Terumo BCT Inc., USA) without protective antibodies. Over 5 days he received daily TPE (each lasting 4 hours). His lactate levels, oxygenation, and LV function normalized and he was weaned off vasopressors. His inflammation markers improved, and he was extubated on day-7. RT-PCR was negative on day-17. He was discharged to home isolation in good condition.. Stress-cardiomyopathy may complicate the course of fulminant COVID-19 with associated CRS. If inotropic therapy fails, TPE without protective antibodies may help rescue the critically ill patient.

Topics: Adult; Antiviral Agents; Betacoronavirus; Cardiotonic Agents; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cytokine Release Syndrome; Drug Combinations; Echocardiography; Humans; Lopinavir; Male; Pandemics; Plasma Exchange; Pneumonia, Viral; Respiration, Artificial; Respiratory Distress Syndrome; Ritonavir; SARS-CoV-2; Shock, Cardiogenic; Takotsubo Cardiomyopathy

Since December 2019, Coronavirus Disease 2019 (COVID-19) has emerged as a global pandemic. We aimed to investigate the clinical characteristics and analyzed the risk factors for prolonged viral RNA shedding. We retrospectively collected data from 112 hospitalized COVID-19 patients in a single center in Wuhan, China. Factors associated with prolonged viral RNA shedding (≥28 days) were investigated. Forty-nine (43.8%) patients had prolonged viral RNA shedding. Patients with prolonged viral shedding were older and had a higher rate of hypertension. Proinflammatory cytokines, including interleukin-2R (IL-2R) and tumor necrosis factor-α (TNF-α), were significantly elevated in patients with prolonged viral shedding. Multivariate analysis revealed that hypertension, older age, lymphopenia and elevated serum IL-2R were independent risk factors for prolonged viral shedding. This comprehensive investigation revealed the distinct characteristics between patients with or without prolonged viral RNA shedding. Hypertension, older age, lymphopenia and high levels of proinflammatory cytokines may be correlated with prolonged viral shedding.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; China; Comorbidity; COVID-19; COVID-19 Drug Treatment; Cytokine Release Syndrome; Diabetes Mellitus; Drug Combinations; Female; Hospitalization; Humans; Hydroxychloroquine; Hypertension; Interferons; Lopinavir; Lymphopenia; Male; Middle Aged; Receptors, Interleukin-2; Retrospective Studies; Risk Factors; Ritonavir; RNA, Viral; SARS-CoV-2; Severity of Illness Index; Tumor Necrosis Factor-alpha; Virus Shedding