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1.
JAMA Netw Open ; 5(3): e222735, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1748801

ABSTRACT

Importance: SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed. Objective: To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19. Design, Setting, and Participants: This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021. Interventions: Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge. Main Outcomes and Measures: The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (Pao2:Fio2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental o2, ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensin-converting enzymes 1 and 2)] were measured in a subgroup of participants. Results: A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo. Compared with placebo, losartan did not significantly affect Pao2:Fio2 ratio at 7 days (difference, -24.8 [95%, -55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], 9.4 [9.1-9.8] vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days). Conclusions and Relevance: This randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve Pao2:Fio2 ratio at 7 days. These data may have implications for ongoing clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04312009.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Losartan/therapeutic use , Lung Injury/prevention & control , Lung Injury/virology , Adult , Aged , COVID-19/diagnosis , Double-Blind Method , Female , Hospitalization , Humans , Lung Injury/diagnosis , Male , Middle Aged , Organ Dysfunction Scores , Respiratory Function Tests , United States
2.
Cell Signal ; 92: 110253, 2022 04.
Article in English | MEDLINE | ID: covidwho-1634748

ABSTRACT

Cardiovascular diseases are the leading cause of death worldwide. The renin-angiotensin-aldosterone system is one of the major regulators of cardiovascular homeostasis and the angiotensin II type 1 receptor (AT1R) mediates the main deleterious effects resulting from the hyperactivation of this hormonal system. Beta-arrestins are multifunctional proteins that regulate the desensitization and internalization of G protein-coupled receptors. After the discovery of beta-arrestins, many efforts have been made towards characterizing and distinguishing this new signaling pathway for drug discovery. Here, we summarize recent advances that address the beta-arrestin signaling in the cardiovascular system, focusing on the activation of the AT1R.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Cardiovascular Diseases/pathology , Receptor, Angiotensin, Type 1/metabolism , Renin-Angiotensin System/physiology , beta-Arrestins/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Cell Line , HEK293 Cells , Humans , Oligopeptides/therapeutic use , Signal Transduction/physiology
3.
Cells ; 10(7)2021 07 11.
Article in English | MEDLINE | ID: covidwho-1308299

ABSTRACT

Since the end of 2019, the medical-scientific community has been facing a terrible pandemic caused by a new airborne viral agent known as SARS-CoV2. Already in the early stages of the pandemic, following the discovery that the virus uses the ACE2 cell receptor as a molecular target to infect the cells of our body, it was hypothesized that the renin-angiotensin-aldosterone system was involved in the pathogenesis of the disease. Since then, numerous studies have been published on the subject, but the exact role of the renin-angiotensin-aldosterone system in the pathogenesis of COVID-19 is still a matter of debate. RAAS represents an important protagonist in the pathogenesis of COVID-19, providing the virus with the receptor of entry into host cells and determining its organotropism. Furthermore, following infection, the virus is able to cause an increase in plasma ACE2 activity, compromising the normal function of the RAAS. This dysfunction could contribute to the establishment of the thrombo-inflammatory state characteristic of severe forms of COVID-19. Drugs targeting RAAS represent promising therapeutic options for COVID-19 sufferers.


Subject(s)
COVID-19/metabolism , Renin-Angiotensin System , SARS-CoV-2/physiology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/drug therapy , COVID-19/pathology , Drug Discovery , Humans , Molecular Targeted Therapy , Renin-Angiotensin System/drug effects , SARS-CoV-2/drug effects
4.
Epidemiol Prev ; 44(5-6 Suppl 2): 323-329, 2020.
Article in English | MEDLINE | ID: covidwho-1068154

ABSTRACT

OBJECTIVES: to study the cumulative incidence, the demographics and health conditions of the population tested for COVID-19, and to map the evolving distribution of individual cases in the population of the Friuli Venezia Giulia Region (North-Eastern Italy). DESIGN: population-based observational study based on a record linkage procedure of databases included in the electronic health information system of the Friuli Venezia Giulia Region. SETTING AND PARTICIPANTS: the study group consisted of individuals who resided in the Friuli Venezia Giulia Region and who underwent COVID-19 testing from 01.03 to 24.04.2020. The study group was identified from the laboratory database, which contains all the microbiological testing performed in regional facilities. Tested people were categorized into positive or negative cases, based on test results. MAIN OUTCOME MEASURES: probability of being tested for and cumulative incidence of COVID-19. RESULTS: the cumulative probability of being tested for COVID-19 was 278/10,000 inhabitants, while the cumulative incidence was 22 cases/10,000. Out of 33,853 tested people, 2,744 (8.1%) turned out to be positive for COVID-19. Women were tested more often than men (337 vs 216/10,000), and they showed a higher incidence of infection than men (25 and 19 infected cases/10,000 residents, respectively). Both cumulative incidence and cumulative probability of being tested were higher in the elderly population. About 25% of infected people was hosted in retirement homes and 9% was represented by healthcare workers. Thirty seven percent of positive cases had hypertension, 15% cardiologic diseases, while diabetes and cancer characterized 11.7% and 10% of the infected population, respectively. The geographic distribution of positive cases showed a faster spread of the infection in the city of Trieste, an urban area with the highest regional population density. CONCLUSIONS: the COVID-19 pandemic did not hit the Friuli Venezia Giulia Region as hard as other Northern Italian Regions. In the early phase, as documented in this study, the COVID-19 pandemic particularly affected women and elderly people, especially those living in retirement homes in Trieste.


Subject(s)
COVID-19/epidemiology , Pandemics , SARS-CoV-2 , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , COVID-19/diagnosis , COVID-19 Testing/statistics & numerical data , Child , Child, Preschool , Comorbidity , Databases, Factual , Female , Geography, Medical , Homes for the Aged/statistics & numerical data , Hospitalization/statistics & numerical data , Humans , Incidence , Infant , Infant, Newborn , Italy/epidemiology , Male , Middle Aged , Procedures and Techniques Utilization , Retrospective Studies , Sex Distribution , Young Adult
5.
Iran J Allergy Asthma Immunol ; 19(5): 456-470, 2020 Oct 18.
Article in English | MEDLINE | ID: covidwho-1068112

ABSTRACT

The new coronavirus, known as "SARS-CoV-2"; is the cause of one of the most prevalent infectious viral diseases that was recently announced pandemic by the world health organization. Ongoing research in the fields of prevention, management, and therapy establishes a functional scaffold for clinics during the time of crisis. To obtain this goal, it is necessary that all pathophysiologic aspects of COVID-19 from infection to predisposing backgrounds of infection be identified, so that all the ambiguities of researchers regarding transmission mechanisms, variable clinical manifestation, and therapeutic response can be solved. Here, we firstly discuss about the homology screening between nCoV-2019 and beta-coronavirus family using phylogenetic analyses. Secondly, we analyzed the viral motifs to show that viral entry into the host cells requires a primary activation step performed by FURIN and FURIN-like-mediated enzymatic cleavage on the structural glycoprotein. The cleavage increases viral performance by 1000 folds. We then present a comprehensive view on host cells and the significance of gene variants affecting activation enzymes, supportive entry, and spread mechanisms in humans including renin-angiotensin-aldosterone system (RAAS) a pathway results in certain phenotypes or exacerbate infection-related phenotypes in different organs, hence causes variable clinical manifestations. This is followed by discussing about the importance of personalized medicine in nCoV-2019 exposure. Moreover, chemical drugs prescribed for individuals affected with COVID-19, as well as genes involved in drug transport and metabolisms are reviewed as a prelude to drug response. Finally, we suggest some therapeutic approaches developed based on new methods and technology such as anti-sense therapy and antibodies.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Furin/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , ADAM17 Protein/genetics , ADAM17 Protein/metabolism , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Anti-Bacterial Agents/therapeutic use , Azithromycin/therapeutic use , Betacoronavirus/genetics , COVID-19/drug therapy , COVID-19/physiopathology , COVID-19/transmission , Enzyme Inhibitors/therapeutic use , Furin/metabolism , Genetic Predisposition to Disease , Genome, Human , Genome, Viral , Humans , Hydroxychloroquine/therapeutic use , Phylogeny , Precision Medicine , Receptors, Coronavirus/genetics , Receptors, Coronavirus/metabolism , Renin-Angiotensin System/genetics , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
6.
PLoS One ; 15(12): e0244708, 2020.
Article in English | MEDLINE | ID: covidwho-999851

ABSTRACT

BACKGROUND: Retrospective studies on the use of Renin-Angiotensin-Aldosterone System blockade in patients with Coronavirus Disease 2019 (COVID-19) have been informative but conflicting, and prospective studies are required to demonstrate the safety, tolerability, and outcomes of initiating these agents in hospitalized patients with COVID-19 and hypertension. METHODS AND FINDINGS: This is a single center feasibility study encompassing two cohorts: (1) prospective cohort (April 21, 2020 to May 29, 2020) and (2) retrospective cohort (March 7, 2020 to April 1, 2020) of hospitalized patients with real-time polymerase chain reaction (PCR) positive SARS-CoV-2 by nasopharyngeal swab. Key inclusion criteria include BP > 130/80 and a requirement of supplemental oxygen with FiO2 of 25% or higher to maintain SpO2 > 92%. Key exclusion criteria included hyperkalemia and acute kidney injury (AKI) at the time of enrollment. Prospective cohort consisted of de novo initiation of losartan and continuation for a minimum of 7 days and assessed for adverse events (AKI, hyperkalemia, transaminitis, hypotension) and clinical outcomes (change in SpO2/FiO2 and inflammatory markers, need for ICU admission and mechanical ventilation). Retrospective cohort consisted of continuation of losartan (prior-to-hospitalization) and assessment of similar outcomes. In the prospective cohort, a total of 250 hospitalized patients were screened and inclusion/exclusion criteria were met in 16/250 patients and in the retrospective cohort, a total of 317 hospitalized patients were screened and inclusion/exclusion criteria were met in 14/317 patients. Most common adverse event was hypotension, leading to discontinuation in 3/16 (19%) and 2/14 (14%) patients in the prospective and retrospective cohort. No patients developed AKI in the prospective cohort as compared to 1/14 (7%) patients in the retrospective cohort, requiring discontinuation of losartan. Hyperkalemia occurred in 1/16 (6%) and 0/14 patients in the prospective and retrospective cohorts, respectively. In the prospective cohort, 3/16 (19%) and 2/16 (13%) patients required ICU admission and mechanical ventilation. In comparison, 3/14 (21%) required ICU admission and mechanical ventilation in the retrospective cohort. A majority of patients in both cohorts (14/16 (88%) and 13/14 (93%) patients from the prospective and retrospective cohort) were discharged alive from the hospital. A total of 9/16 (prospective) and 5/14 (retrospective) patients completed a minimum 7 days of losartan. In these 9 patients in the prospective cohort, a significant improvement in SpO2/FiO2 ratio was observed from day 1 to 7. No significant changes in inflammatory markers (initiation, peak, and day 7) were observed in either cohort. CONCLUSION: In this pilot study we demonstrate that losartan was well-tolerated among hospitalized patients with COVID-19 and hypertension. We also demonstrate the feasibility of patient recruitment and the appropriate parameters to assess the outcomes and safety of losartan initiation or continuation, which provides a framework for future randomized clinical trials.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , COVID-19/pathology , Hypertension/drug therapy , Losartan/therapeutic use , Aged , Angiotensin II Type 1 Receptor Blockers/adverse effects , Blood Pressure/drug effects , Female , Humans , Losartan/adverse effects , Male , Middle Aged , Pilot Projects , Prospective Studies , Retrospective Studies , SARS-CoV-2
7.
J Cardiovasc Pharmacol Ther ; 26(3): 244-252, 2021 May.
Article in English | MEDLINE | ID: covidwho-992304

ABSTRACT

BACKGROUND: Speculations whether treatment with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARB) predisposes to severe coronavirus disease 2019 (COVID-19) or worsens its outcomes. This study assessed the association of ACE-I/ARB therapy with the development of severe COVID-19. METHODS: This multi-center, prospective study enrolled patients hospitalized for COVID-19 and receiving one or more antihypertensive agents to manage either hypertension or cardiovascular disease. ACE-I/ARB therapy associations with severe COVID-19 on the day of hospitalization, intensive care unit (ICU) admission, mechanical ventilation and in-hospital death on follow-up were tested using a multivariate logistic regression model adjusted for age, obesity, and chronic illnesses. The composite outcome of mechanical ventilation and death was examined using the adjusted Cox multivariate regression model. RESULTS: Of 338 enrolled patients, 245 (72.4%) were using ACE-I/ARB on the day of hospital admission, and 197 continued ACE-I/ARB therapy during hospitalization. Ninety-eight (29%) patients had a severe COVID-19, which was not significantly associated with the use of ACE-I/ARB (OR 1.17, 95% CI 0.66-2.09; P = .57). Prehospitalization ACE-I/ARB therapy was not associated with ICU admission, mechanical ventilation, or in-hospital death. Continuing ACE-I/ARB therapy during hospitalization was associated with decreased mortality (OR 0.22, 95% CI 0.073-0.67; P = .008). ACE-I/ARB use was not associated with developing the composite outcome of mechanical ventilation and in-hospital death (HR 0.95, 95% CI 0.51-1.78; P = .87) versus not using ACE-I/ARB. CONCLUSION: Patients with hypertension or cardiovascular diseases receiving ACE-I/ARB therapy are not at increased risk for severe COVID-19 on admission to the hospital. ICU admission, mechanical ventilation, and mortality are not associated with ACE-I/ARB therapy. Maintaining ACE-I/ARB therapy during hospitalization for COVID-19 lowers the likelihood of death. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT4357535.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/epidemiology , COVID-19/physiopathology , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/epidemiology , Adult , Age Factors , Aged , Aged, 80 and over , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , C-Reactive Protein/biosynthesis , COVID-19/mortality , Female , Hematologic Tests , Hospital Mortality , Humans , Hypertension/drug therapy , Hypertension/epidemiology , Intensive Care Units/statistics & numerical data , Logistic Models , Male , Middle Aged , Obesity/epidemiology , Prospective Studies , Respiration, Artificial/statistics & numerical data , SARS-CoV-2 , Severity of Illness Index
8.
BMJ Open ; 10(12): e040768, 2020 12 07.
Article in English | MEDLINE | ID: covidwho-962846

ABSTRACT

INTRODUCTION: The COVID-19 epidemic grows and there are clinical trials of antivirals. There is an opportunity to complement these trials with investigation of angiotensin II type 1 receptor blockers (ARBs) because an ARB (losartan) was effective in murine influenza pneumonia. METHODS AND ANALYSIS: Our innovative design includes: ARBs; alignment with the WHO Ordinal Scale (primary endpoint) to align with other COVID-19 trials; joint longitudinal analysis; and predictive biomarkers (angiotensins I, 1-7, II and ACE1 and ACE2). Our hypothesis is: ARBs decrease the need for hospitalisation, severity (need for ventilation, vasopressors, extracorporeal membrane oxygenation or renal replacement therapy) or mortality of hospitalised COVID-19 infected adults. Our two-pronged multicentre pragmatic observational cohort study examines safety and effectiveness of ARBs in (1) hospitalised adult patients with COVID-19 and (2) out-patients already on or not on ARBs. The primary outcome will be evaluated by ordinal logistic regression and main secondary outcomes by both joint longitudinal modelling analyses. We will compare rates of hospitalisation of ARB-exposed versus not ARB-exposed patients. We will also determine whether continuing ARBs or not decreases the primary outcome. Based on published COVID-19 cohorts, assuming 15% of patients are ARB-exposed, a total sample size of 497 patients can detect a proportional OR of 0.5 (alpha=0.05, 80% power) comparing WHO scale of ARB-exposed versus non-ARB-exposed patients. ETHICS AND DISSEMINATION: This study has core institution approval (UBC Providence Healthcare Research Ethics Board) and site institution approvals (Health Research Ethics Board, University of Alberta; Comite d'etique de la recerche, CHU Sainte Justine (for McGill University and University of Sherbrook); Conjoint Health Research Ethics Board, University of Calgary; Queen's University Health Sciences & Affiliated Hospitals Research Ethics Board; Research Ethics Board, Sunnybrook Health Sciences Centre; Veritas Independent Research Board (for Humber River Hospital); Mount Sinai Hospital Research Ethics Board; Unity Health Toronto Research Ethics Board, St. Michael's Hospital). Results will be disseminated by peer-review publication and social media releases. TRIAL REGISTRATION NUMBER: NCT04510623.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , COVID-19/drug therapy , Angiotensin II Type 1 Receptor Blockers/pharmacokinetics , Humans , Logistic Models , Multicenter Studies as Topic , Pandemics , Pragmatic Clinical Trials as Topic , Prospective Studies , SARS-CoV-2 , Treatment Outcome
10.
Minerva Cardioangiol ; 68(4): 339-346, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-890930

ABSTRACT

In recent months SARS-CoV-2 has spread rapidly throughout the world. The case fatality rate is higher in cardiovascular disease and hypertension. Other comorbidities do not seem to confer the same risk, therefore the understanding of the relationship between infection and cardiovascular system could be a crucial point for the fight against the virus. A great interest is directed towards the angiotensin 2 converting enzyme (ACE 2) which is the SARS-CoV-2 receptor and creates important connections between the virus replication pathway, the cardiovascular system and blood pressure. All cardiovascular conditions share an imbalance of the renin angiotensin system in which ACE 2 plays a central role. In the early pandemic period, much confusion has appeared about the management of therapy with angiotensin converting enzyme inhibitors and angiotensin receptor blockers especially in infected patients and in those at risk of critical illness in case of infection. In this article we will try to reorder the major opinions currently emerging on this topic.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Antihypertensive Agents/therapeutic use , COVID-19 , Coronavirus Infections/physiopathology , Humans , Pandemics , Pneumonia, Viral/physiopathology , Renin-Angiotensin System
11.
Hypertens Res ; 43(11): 1257-1266, 2020 11.
Article in English | MEDLINE | ID: covidwho-725057

ABSTRACT

Since the beginning of the coronavirus disease 2019 (COVID-19) outbreak initiated on the Diamond Princess Cruise Ship at Yokohama harbor in February 2020, we have been doing our best to treat COVID-19 patients. In animal experiments, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) are reported to suppress the downregulation of angiotensin converting enzyme 2 (ACE2), and they may inhibit the worsening of pathological conditions. We aimed to examine whether preceding use of ACEIs and ARBs affected the clinical manifestations and prognosis of COVID-19 patients. One hundred fifty-one consecutive patients (mean age 60 ± 19 years) with polymerase-chain-reaction proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who were admitted to six hospitals in Kanagawa Prefecture, Japan, were analyzed in this multicenter retrospective observational study. Among all COVID-19 patients, in the multiple regression analysis, older age (age ≥ 65 years) was significantly associated with the primary composite outcome (odds ratio (OR) 6.63, 95% confidence interval (CI) 2.28-22.78, P < 0.001), which consisted of (i) in-hospital death, (ii) extracorporeal membrane oxygenation, (iii) mechanical ventilation, including invasive and noninvasive methods, and (iv) admission to the intensive care unit. In COVID-19 patients with hypertension, preceding ACEI/ARB use was significantly associated with a lower occurrence of new-onset or worsening mental confusion (OR 0.06, 95% CI 0.002-0.69, P = 0.02), which was defined by the confusion criterion, which included mild disorientation or hallucination with an estimation of medical history of mental status, after adjustment for age, sex, and diabetes. In conclusion, older age was a significant contributor to a worse prognosis in COVID-19 patients, and ACEIs/ARBs could be beneficial for the prevention of confusion in COVID-19 patients with hypertension.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Betacoronavirus , Coronavirus Infections/mortality , Hypertension/drug therapy , Pneumonia, Viral/mortality , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19 , Confusion/prevention & control , Coronavirus Infections/psychology , Coronavirus Infections/therapy , Female , Humans , Hypertension/complications , Male , Middle Aged , Pandemics , Pneumonia, Viral/psychology , Pneumonia, Viral/therapy , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index
12.
Arch Cardiovasc Dis ; 113(8-9): 572-578, 2020.
Article in English | MEDLINE | ID: covidwho-716489

ABSTRACT

Severe acute respiratory syndrome coronavirus 2, which is responsible for the current coronavirus disease 2019 pandemic, uses angiotensin-converting enzyme 2 as a gateway into host cells. In this review, we summarise the biology of this enzyme, which plays a key role in cardiovascular homeostasis. Blockers of the renin-angiotensin system modify the expression and activity of angiotensin-converting enzyme 2 in different ways. The effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the expression and enzyme activity of angiotensin-converting enzyme 2 are reviewed, and the consequences of these treatments for the severity of coronavirus disease 2019 infection are discussed.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Renin-Angiotensin System/drug effects , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Humans , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , SARS-CoV-2
13.
Med Clin (Barc) ; 155(9): 375-381, 2020 11 13.
Article in English, Spanish | MEDLINE | ID: covidwho-714754

ABSTRACT

BACKGROUND AND OBJECTIVES: In the last months great efforts have been developed to evaluate the more efficient therapeutic agents in the management of patients with COVID-19. Currently, no specific drug combination has consistently demonstrated an association with mortality. The aim of this study was to assess the pattern of associations observed between the different in-hospital treatments administered to a series of 238 patients admitted for COVID-19 and their relationship with mortality. METHODS: The electronic medical records of patients that discharged or died from COVID-19 in the Hospital Universitario San Cecilio (Granada, Spain) between March 16 and April 10, 2020 were analysed. From these records, information was obtained on sex, age, comorbidities at admission, clinical information, analytical parameters, imaging tests and empirical treatments used. The outcome variable was the in-hospital mortality. To estimate the associations between the different therapeutic alternatives and the risk of mortality, hazard ratios adjusted for age, sex, previous pathologies and severity at discharge were estimated using Cox regression models. RESULTS: The most frequently used combination of drugs was low molecular weight heparins, hydroxychloroquine, and ritonavir/lopinavir. None of the analysed treatments showed independent association with mortality. The drugs that showed a greater inverse association with mortality were tocilizumab and corticoids. CONCLUSIONS: The observed association patterns are consistent with previous literature. It seems necessary to design randomized controlled clinical trials that evaluate the possible protector effect of tocilizumab and corticoids in the risk of mortality for some subgroups of COVID-19 hospitalized patients.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adrenal Cortex Hormones/therapeutic use , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Comorbidity , Coronavirus Infections/mortality , Drug Therapy, Combination , Female , Humans , Hydroxychloroquine/therapeutic use , Inpatients/statistics & numerical data , Lopinavir/therapeutic use , Male , Pandemics , Pneumonia, Viral/mortality , Proportional Hazards Models , Retrospective Studies , Ritonavir/therapeutic use , SARS-CoV-2 , Spain , Treatment Outcome
15.
Postgrad Med J ; 97(1145): 175-179, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-691133

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread in nearly 200 countries in less than 4 months since its first identification; accordingly, the coronavirus disease 2019 (COVID 2019) has affirmed itself as a clinical challenge. The prevalence of pre-existing cardiovascular diseases in patients with COVID19 is high and this dreadful combination dictates poor prognosis along with the higher risk of intensive care mortality. In the setting of chronic heart failure, SARS-CoV-2 can be responsible for myocardial injury and acute decompensation through various mechanisms. Given the clinical and epidemiological complexity of COVID-19, patiens with heart failure may require particular care since the viral infection has been identified, considering an adequate re-evaluation of medical therapy and a careful monitoring during ventilation.


Subject(s)
COVID-19/therapy , Heart Failure/therapy , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/complications , COVID-19/drug therapy , COVID-19/physiopathology , Diagnosis, Differential , Diuretics/therapeutic use , Edema, Cardiac/diagnostic imaging , Fluid Therapy , Heart Failure/complications , Heart Failure/physiopathology , Humans , Myocardium/metabolism , Pulmonary Edema/diagnostic imaging , SARS-CoV-2 , Tomography, X-Ray Computed , Troponin/metabolism , Ultrasonography , Water-Electrolyte Balance
16.
Endocr Metab Immune Disord Drug Targets ; 20(6): 807-811, 2020.
Article in English | MEDLINE | ID: covidwho-689779
17.
Int J Mol Med ; 46(2): 467-488, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-678269

ABSTRACT

The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID­19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID­19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning , Pneumonia, Viral/drug therapy , Virus Internalization/drug effects , Angiotensin II Type 1 Receptor Blockers/classification , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme 2 , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , Bromhexine/pharmacology , Bromhexine/therapeutic use , COVID-19 , Chlorpromazine/pharmacology , Chlorpromazine/therapeutic use , Clinical Trials as Topic/methods , Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Diminazene/pharmacology , Diminazene/therapeutic use , Drug Repositioning/methods , Drug Repositioning/standards , Drug Repositioning/trends , Esters , Gabexate/analogs & derivatives , Gabexate/pharmacology , Gabexate/therapeutic use , Guanidines , Humans , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Peptidyl-Dipeptidase A/therapeutic use , Pneumonia, Viral/epidemiology , Pneumonia, Viral/mortality , Receptor, Angiotensin, Type 1/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/therapeutic use , SARS-CoV-2 , Signal Transduction/drug effects
19.
Clin Appl Thromb Hemost ; 26: 1076029620936776, 2020.
Article in English | MEDLINE | ID: covidwho-657787

ABSTRACT

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/complications , Pandemics , Pneumonia, Viral/complications , Thrombophilia/etiology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Anticoagulants/therapeutic use , Arterial Occlusive Diseases/etiology , Arterial Occlusive Diseases/physiopathology , Arterial Occlusive Diseases/virology , COVID-19 , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Catheterization, Swan-Ganz , Combined Modality Therapy , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Endothelium, Vascular/physiopathology , Endothelium, Vascular/virology , Fibrinolytic Agents/therapeutic use , Humans , Hyperbaric Oxygenation , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , Pulmonary Embolism/etiology , Pulmonary Embolism/therapy , Pulmonary Embolism/virology , Respiratory Distress Syndrome/etiology , SARS-CoV-2 , Thrombolytic Therapy/instrumentation , Thrombolytic Therapy/methods , Thrombophilia/physiopathology , Thrombophilia/therapy , Venous Thrombosis/etiology , Venous Thrombosis/physiopathology , Venous Thrombosis/virology , Virus Internalization/drug effects
20.
Am J Med Sci ; 360(4): 338-341, 2020 10.
Article in English | MEDLINE | ID: covidwho-650676

ABSTRACT

Severe Acute Respiratory Distress Syndrome caused by a novel human coronavirus SARS-CoV-2 named COVID-19 and declared as a pandemic. This paper reviews the possibility of repurposing angiotensin type 1 receptor (AT1R) antagonists and vitamin D to treat COVID-19. ACE2 protein found on the cell membranes is the target of SARS-CoV-2 for entering into the host cells. Viral spike protein-binding with ACE2 down-regulates it. As ACE2 is known to protect the lung from injuries, SARS-CoV-2-induced ACE2 deficiency may expose patients to lung damage. AT1R antagonists and vitamin D increase the expression of ACE2 independently. Besides, vitamin D suppresses the compensatory increase in renin levels following the inhibition of the renin-angiotensin system by AT1R antagonists. Therefore, a combination of AT1R antagonists and vitamin D may offer protection against COVID-19 induced lung injury.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Severe Acute Respiratory Syndrome/drug therapy , Vitamin D/therapeutic use , Vitamins/therapeutic use , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/complications , Host-Pathogen Interactions , Humans , Pandemics , Peptidyl-Dipeptidase A/blood , Pneumonia, Viral/blood , Pneumonia, Viral/complications , Renin-Angiotensin System/drug effects , SARS-CoV-2 , Severe Acute Respiratory Syndrome/virology , Virus Internalization , Vitamin D/pharmacology , Vitamins/pharmacology
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