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1.
Sci Rep ; 11(1): 24397, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1585779

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is an important factor in coronavirus disease (COVID-19) interactions. Losartan (LOS) belongs to the angiotensin receptor blocker (ARB) family. Additionally, the protective role of ACE2 restored by LOS has been suggested and clinically examined in the treatment of COVID-19 patients. Furthermore, clinical trials with LOS have been conducted. However, the mechanism through which LOS enhances ACE2 expression remains unclear. In addition, the response of ACE2 to LOS differs among patients. Our LOS-treated patient data revealed a correlated mechanism of ACE2 with components of the renin-angiotensinogen system. We observed a significant positive regulation of MAS1 and ACE2 expression. In the context of LOS treatment of COVID-19, ACE2 expression could depend on LOS regulated MAS1. Thus, MAS1 expression could predict the COVID-19 treatment response of LOS.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Losartan/pharmacology , Renin-Angiotensin System/drug effects , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/genetics , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Databases, Factual , Humans , Losartan/therapeutic use , /metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , SARS-CoV-2/isolation & purification , Up-Regulation/drug effects
2.
ASN Neuro ; 13: 17590914211057635, 2021.
Article in English | MEDLINE | ID: covidwho-1511685

ABSTRACT

Among the plethora of debilitating neurological disorders of COVID-19 syndrome in survivors, the scope of SARS-CoV-2-induced dysautonomia (DNS) is yet to be understood, though the implications are enormous. Herein, we present an inclusive mini-review of SARS-CoV-2-induced DNS and its associated complications. Although, the direct link between Covid-19 and DSN is still speculative, the hypothetical links are thought to be either a direct neuronal injury of the autonomic pathway or a para/post-infectious immune-induced mechanism. SARS-CoV-2 infection-induced stress may activate the sympathetic nervous system (SNS) leading to neuro-hormonal stimulation and activation of pro-inflammatory cytokines with further development of sympathetic storm. Sympathetic over-activation in Covid-19 is correlated with increase in capillary pulmonary leakage, alveolar damage, and development of acute respiratory distress syndrome. Furthermore, SARS-CoV-2 can spread through pulmonary mechanoreceptors and chemoreceptors to medullary respiratory center in a retrograde manner resulting in sudden respiratory failure. Taken together, DSN in Covid-19 is developed due to sympathetic storm and inhibition of Parasympathetic nervous system-mediated anti-inflammatory effect with development of cytokine storm. Therefore, sympathetic and cytokine storms together with activation of Renin-Angiotensin-System are the chief final pathway involved in the development of DSN in Covid-19.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , COVID-19/mortality , Renin-Angiotensin System/drug effects , Aged , Aged, 80 and over , Cohort Studies , Cytokine Release Syndrome , Female , France , Humans , Male , Middle Aged , Propensity Score , Prospective Studies
4.
Int J Mol Sci ; 22(21)2021 Oct 28.
Article in English | MEDLINE | ID: covidwho-1488613

ABSTRACT

The renin-angiotensin system (RAS) is a key regulator of blood pressure and hypertension. Angiotensin-converting enzyme 2 (ACE2) and angiotensin-converting enzyme I (ACE) are two main components of the RAS that play a major role in blood pressure homeostasis. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 as a receptor to enter cells. Despite some controversies, numerous studies have reported a significant association between the use of ACE inhibitors and reduced risk of COVID-19. In our previous studies, we produced and identified peptide sequences present in whey hydrolysates exhibiting high ACE inhibitory activity. Therefore, the aim of this work is to obtain an improved understanding of the function of these natural peptides as RAS inhibitors and investigate their potential therapeutic role in the COVID-19 pandemic. The molecular interactions between peptides IPP, LIVTQ, IIAE, LVYPFP, and human ACE2 were assessed by employing a molecular docking approach. The results show that natural whey-derived peptides have a dual inhibitory action against both ACE and ACE2. This dual activity distinguishes these ACE inhibitory peptides from synthetic drugs, such as Captopril and Lisinopril which were not shown to inhibit ACE2 activity, and may represent a potential strategy in the treatment of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , Peptides/chemistry , Peptides/pharmacology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Peptides/metabolism , Peptidyl-Dipeptidase A/chemistry , Renin-Angiotensin System/drug effects , Whey Proteins/chemistry
8.
Korean J Intern Med ; 36(Suppl 1): S123-S131, 2021 03.
Article in English | MEDLINE | ID: covidwho-1369806

ABSTRACT

BACKGROUND/AIMS: There are concerns that the use of renin-angiotensin system (RAS) blockers may increase the risk of being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or progressing to a severe clinical course after infection. This this study aimed to investigate the influence of RAS blockers on the risk and severity of SARS-CoV-2 infection. METHODS: We conducted a retrospective cohort study analyzing nationwide claims data of 215,184 adults who underwent SARS-CoV-2 tests in South Korea. The SARS-CoV-2 positive rates and clinical outcomes were evaluated according to the use of RAS blockers in patients with hypertension (n = 64,243). RESULTS: In total, 38,919 patients with hypertension were on RAS blockers. The SARS-CoV-2 positive rates were significantly higher in the RAS blocker group than in the control group after adjustments (adjusted odds ratio [OR], 1.22; 95% confidence interval [CI], 1.10 to 1.36; p < 0.001), and matching by propensity score (adjusted OR, 1.16; 95% CI, 1.03 to 1.32; p = 0.017). Among the 1,609 SARS-CoV-2-positive patients with hypertension, the use of RAS blockers was not associated with poor outcomes, such as mortality (adjusted OR, 0.81; 95% CI, 0.56 to 1.17; p = 0.265), and a composite of admission to the intensive care unit and mortality (adjusted OR, 0.95; 95% CI, 0.73 to 1.22; p = 0.669). Analysis in the propensity scorematched population showed consistent results. CONCLUSION: In this Korean nationwide claims dataset, the use of RAS blockers was associated with a higher risk to SARS-CoV-2 infection but not with higher mortality or other severe clinical courses.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/therapeutic use , COVID-19/therapy , Hypertension/drug therapy , Renin-Angiotensin System/drug effects , Administrative Claims, Healthcare , Aged , Aged, 80 and over , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Antihypertensive Agents/adverse effects , COVID-19/diagnosis , COVID-19/mortality , Databases, Factual , Female , Humans , Hypertension/diagnosis , Hypertension/mortality , Hypertension/physiopathology , Male , Middle Aged , Retrospective Studies , Risk Assessment , Risk Factors , Severity of Illness Index , Treatment Outcome
9.
Lancet Respir Med ; 9(8): 863-872, 2021 08.
Article in English | MEDLINE | ID: covidwho-1340915

ABSTRACT

BACKGROUND: SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19. METHODS: ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUCSOFA), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596. FINDINGS: Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12). Discontinuation was associated with a significantly lower AUCSOFA (0·00 [0·00-9·25] vs 3·50 [0·00-23·50]; p=0·040), mean SOFA score (0·00 [0·00-0·31] vs 0·12 [0·00-0·78]; p=0·040), and 30-day SOFA score (0·00 [10-90th percentile, 0·00-1·20] vs 0·00 [0·00-24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group. INTERPRETATION: Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options. FUNDING: Austrian Science Fund and German Center for Cardiovascular Research.


Subject(s)
Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , COVID-19 , Hypertension , Renin-Angiotensin System , SARS-CoV-2 , Angiotensin Receptor Antagonists/administration & dosage , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Area Under Curve , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/therapy , Female , Humans , Hypertension/drug therapy , Hypertension/epidemiology , Male , Middle Aged , Organ Dysfunction Scores , Outcome and Process Assessment, Health Care , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Risk Adjustment/methods , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Severity of Illness Index , Withholding Treatment/statistics & numerical data
10.
J Am Heart Assoc ; 10(15): e021154, 2021 08 03.
Article in English | MEDLINE | ID: covidwho-1331849

ABSTRACT

Background Considering the widespread risk of collider bias and confounding by indication in previous research, the associations between renin-angiotensin aldosterone system (RAAS) inhibitor use and COVID-19 remain unknown. Accordingly, this study tested the hypothesis that RAAS inhibitors influence the summation effect of COVID-19 and its progression to severe outcomes. Methods and Results This nationwide cohort study compared all residents of Sweden, without prior cardiovascular disease, in monotherapy (as of January 1, 2020) with a RAAS inhibitor to those using a calcium channel blocker or a thiazide diuretic. Comparative cohorts were balanced using machine-learning-derived propensity score methods. Of 165 355 people in the analysis (51% women), 367 were hospitalized or died with COVID-19 (246 using a RAAS inhibitor versus 121 using a calcium channel blocker or thiazide diuretic; Cox proportional hazard ratio [HR], 0.97; 95% CI, 0.74-1.27). When each outcome was assessed separately, 335 people were hospitalized with COVID-19 (HR, 0.92; 95% CI, 0.70-1.22), and 64 died with COVID-19 (HR, 1.22; 95% CI, 0.68-2.19). The severity of COVID-19 outcomes did not differ between those using a RAAS inhibitor and those using a calcium channel blocker or thiazide diuretic (ordered logistic regression odds ratio, 1.01; 95% CI, 0.89-1.14). Conclusions Despite potential limitations, this study is among the best available evidence that RAAS inhibitor use in primary prevention does not increase the risk of severe COVID-19 outcomes; presenting strong data from which scientists and policy makers alike can base, with greater confidence, their current position on the safety of using RAAS inhibitors during the COVID-19 pandemic.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19 , Hypertension/drug therapy , Risk Assessment , Aged , Antihypertensive Agents/classification , Antihypertensive Agents/therapeutic use , COVID-19/epidemiology , COVID-19/prevention & control , Calcium Channel Blockers/therapeutic use , Female , Humans , Hypertension/epidemiology , Hypertension/prevention & control , Male , Middle Aged , Outcome Assessment, Health Care , Renin-Angiotensin System/drug effects , Risk Assessment/methods , Risk Assessment/statistics & numerical data , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Sodium Chloride Symporter Inhibitors/therapeutic use , Sweden/epidemiology
11.
J Cardiovasc Pharmacol ; 78(5): e648-e655, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1331600

ABSTRACT

ABSTRACT: The novel coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly evolved into a global pandemic. The substantial morbidity and mortality associated with the infection has prompted us to understand potential risk factors that can predict patient outcomes. Hypertension has been identified as the most prevalent cardiovascular comorbidity in patients infected with COVID-19 that demonstrably increases the risk of hospitalization and death. Initial studies implied that renin-angiotensin-aldosterone system inhibitors might increase the risk of viral infection and aggravate disease severity, thereby causing panic given the high global prevalence of hypertension. Nonetheless, subsequent evidence supported the administration of antihypertensive drugs and noted that they do not increase the severity of COVID-19 infection in patients with hypertension, rather may have a beneficial effect. To date, the precise mechanism by which hypertension predisposes to unfavorable outcomes in patients infected with COVID-19 remains unknown. In this mini review, we elaborate on the pathology of SARS-CoV-2 infection coexisting with hypertension and summarize potential mechanisms, focusing on the dual roles of angiotensin-converting enzyme 2 and the disorders of renin-angiotensin-aldosterone system in COVID-19 and hypertension. The effects of proinflammatory factors released because of immune response and gastrointestinal dysfunction in COVID-19 are also discussed.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Hypertension/enzymology , Renin-Angiotensin System , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , COVID-19/enzymology , COVID-19/mortality , COVID-19/therapy , Comorbidity , Host-Pathogen Interactions , Humans , Hypertension/drug therapy , Hypertension/mortality , Hypertension/physiopathology , Inflammation Mediators/metabolism , Prognosis , Renin-Angiotensin System/drug effects , Risk Assessment , Risk Factors , Severity of Illness Index
12.
Hipertens Riesgo Vasc ; 37(4): 169-175, 2020.
Article in Spanish | MEDLINE | ID: covidwho-1322115

ABSTRACT

The first case of COVID-19 was reported on 31 December 2019 in Wuhan, China. Ever since there has been unprecedented and growing interest in learning about all aspects of this new disease. Debate has been generated as to the association between antihypertensive therapy with renin-angiotensin-aldosterone system (RAAS) inhibitors and SARS-CoV-2 infection. While many questions as yet remain unanswered, the aim of this report is to inform health professionals about the current state of knowledge. Because this is an ever-evolving topic, the recommendation is that it be updated as new evidence becomes available. Below, we provide a review of pre-clinical and clinical studies that link coronavirus to the RAAS.


Subject(s)
Betacoronavirus , Coronavirus Infections/physiopathology , Pandemics , Pneumonia, Viral/physiopathology , Renin-Angiotensin System/physiology , ADAM17 Protein/physiology , Angiotensin II/physiology , Angiotensin Receptor Antagonists/adverse effects , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/adverse effects , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Humans , Hypertension/complications , Hypertension/physiopathology , Lung/physiopathology , Models, Biological , Pandemics/prevention & control , Peptidyl-Dipeptidase A/drug effects , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Receptors, Virus/drug effects , Renin-Angiotensin System/drug effects , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/physiopathology , SARS-CoV-2 , Serine Endopeptidases/physiology , Viral Vaccines , Virus Internalization/drug effects
13.
Pharmacol Res ; 158: 104906, 2020 08.
Article in English | MEDLINE | ID: covidwho-1318937

ABSTRACT

The coronavirus disease (COVID-19) has spread all around the world in a very short period of time. Recent data are showing significant prevalence of arterial hypertension and cardiovascular diseases (CVD) among patients with COVID-19, which raised many questions about higher susceptibility of patients with these comorbidities to the novel coronavirus, as well as the role of hypertension and CVD in progression and the prognosis of COVID-19 patients. There is a very limited amount of data, usually obtained from a small population, regarding the effect of the underlying disease on the outcome in patients with COVID-19. The evaluation of the treatment of these comorbidities at baseline and during COVID-19 is scarce and the results are conflicting. Hypertension and CVD, after the adjustment for other clinical and demographic parameters, primarily age, did not remain independent predictors of the lethal outcome in COVID-19 patients. Some investigations speculated about the association between the renin-angiotensin-aldosterone system (RAAS) and susceptibility to COVID-19, as well as the relationship between RAAS inhibitors and the adverse outcome in these patients. Withdrawing or switching RAAS inhibitors would have uncertain benefits, but it would definitely have many disadvantages such as uncontrolled hypertension, cardiac function deterioration and renal function impairment, which could potentially induce more complications in patients with COVID-19 than the infection of coronavirus itself. The aim of this review article was to summarize the prevalence of hypertension and CVD in patients with COVID-19, their influence on the outcome and the effect of treatment of hypertension and CVD in COVID-19 patients.


Subject(s)
Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/epidemiology , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Hypertension/drug therapy , Hypertension/epidemiology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Renin-Angiotensin System/drug effects , Betacoronavirus , COVID-19 , Comorbidity , Coronavirus Infections/diagnosis , Disease Progression , Humans , Pandemics , Pneumonia, Viral/diagnosis , Prognosis , SARS-CoV-2
14.
Am Heart J ; 240: 46-57, 2021 10.
Article in English | MEDLINE | ID: covidwho-1316364

ABSTRACT

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are known to impact the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The association between chronic therapy with these medications and infection risk remains unclear. OBJECTIVES: The objective was to determine the association between prior ACEI or ARB therapy and SARS-CoV-2 infection among patients with hypertension in the U.S. Veteran's Affairs health system. METHODS: We compared the odds of SARS-CoV-2 infection among three groups: patients treated with ACEI, treated with ARB, or treated with alternate first-line anti-hypertensives without ACEI/ARB. We excluded patients with alternate indications for ACEI or ARB therapy. We performed an augmented inverse propensity weighted analysis with adjustment for demographics, region, comorbidities, vitals, and laboratory values. RESULTS: Among 1,724,723 patients with treated hypertension, 659,180 were treated with ACEI, 310,651 with ARB, and 754,892 with neither. Before weighting, patients treated with ACEI or ARB were more likely to be diabetic and use more anti-hypertensives. There were 13,278 SARS-CoV-2 infections (0.8%) between February 12, 2020 and August 19, 2020. Patients treated with ACEI had lower odds of SARS-CoV-2 infection (odds ratio [OR] 0.93; 95% CI: 0.89-0.97) while those treated with ARB had similar odds (OR 1.02; 95% CI: 0.96-1.07) compared with patients treated with alternate first-line anti-hypertensives without ACEI/ARB. In falsification analyses, patients on ACEI did not have a difference in their odds of unrelated outcomes. CONCLUSIONS: Our results suggest the safety of continuing ACEI and ARB therapy. The association between ACEI therapy and lower odds of SARS-CoV-2 infection requires further investigation.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/therapeutic use , COVID-19/epidemiology , Hypertension/drug therapy , Renin-Angiotensin System/drug effects , Adrenergic beta-Antagonists/therapeutic use , Aged , Angiotensin II Type 2 Receptor Blockers , Calcium Channel Blockers/therapeutic use , Case-Control Studies , Comorbidity , Confidence Intervals , Diabetes Mellitus/epidemiology , Female , Humans , Male , Middle Aged , Odds Ratio , Propensity Score , Receptors, Virus , SARS-CoV-2 , Sodium Chloride Symporter Inhibitors/therapeutic use , United States/epidemiology , United States Department of Veterans Affairs , Veterans/statistics & numerical data
15.
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
16.
Molecules ; 26(13)2021 Jul 05.
Article in English | MEDLINE | ID: covidwho-1295889

ABSTRACT

COVID-19 is a pandemic disease caused by the SARS-CoV-2 virus, which is potentially fatal for vulnerable individuals. Disease management represents a challenge for many countries, given the shortage of medicines and hospital resources. The objective of this work was to review the medicinal plants, foods and natural products showing scientific evidence for host protection against various types of coronaviruses, with a focus on SARS-CoV-2. Natural products that mitigate the symptoms caused by various coronaviruses are also presented. Particular attention was placed on natural products that stabilize the Renin-Angiotensin-Aldosterone System (RAAS), which has been associated with the entry of the SARS-CoV-2 into human cells.


Subject(s)
Biological Products/pharmacology , Coronavirus/drug effects , Phytotherapy/methods , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Biological Products/metabolism , COVID-19/drug therapy , COVID-19/virology , Humans , Pandemics , Plant Extracts/metabolism , Plants/chemistry , Renin-Angiotensin System/drug effects
17.
Sci Rep ; 11(1): 13588, 2021 06 30.
Article in English | MEDLINE | ID: covidwho-1290939

ABSTRACT

Acute kidney injury (AKI) is a severe complication of coronavirus disease (COVID-19) that negatively affects its outcome. Concern had been raised about the potential effect of renin-angiotensin-aldosterone system (RAAS) blockades on renal outcomes in COVID-19 patients. However, the association between RAAS blockade use and incident AKI in COVID-19 patients has not been fully understood. We investigated the association between RAAS blockade exposure and COVID-19-related AKI in hospitalized patients through meta-analysis. Electronic databases were searched up to 24th December 2020. Summary estimates of pooled odds ratio (OR) of COVID-19-related AKI depending on RAAS blockade exposure were obtained through random-effects model. The random-effect meta-analysis on fourteen studies (17,876 patients) showed that RAAS blockade use was significantly associated with increased risk of incident AKI in hospitalized COVID-19 patients (OR 1.68; 95% confidence interval 1.19-2.36). Additional analysis showed that the association of RAAS blockade use on COVID-19-related AKI remains significant even after stratification by drug class and AKI severity. RAAS blockade use is significantly associated with the incident AKI in hospitalized COVID-19 patients. Therefore, careful monitoring of renal complications is recommended for COVID-19 patients with recent RAAS blockade use due to the potential risk of AKI.


Subject(s)
Acute Kidney Injury/etiology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/therapeutic use , COVID-19/complications , Renin-Angiotensin System/drug effects , Aged , Databases, Factual , Female , Hospitalization , Humans , Male , Middle Aged , Odds Ratio , Risk Factors
18.
J Hypertens ; 39(4): 795-805, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1290201

ABSTRACT

Concerns over ACE inhibitor or ARB use to treat hypertension during COVID-19 remain unresolved. Although studies using more robust methodologies provided some clarity, sources of bias persist and it remains critical to quickly address this question. In this review, we discuss pernicious sources of bias using a causal model framework, including time-varying confounder, collider, information, and time-dependent bias, in the context of recently published studies. We discuss causal inference methodologies that can address these issues, including causal diagrams, time-to-event analyses, sensitivity analyses, and marginal structural modeling. We discuss effect modification and we propose a role for causal mediation analysis to estimate indirect effects via mediating factors, especially components of the renin--angiotensin system. Thorough knowledge of these sources of bias and the appropriate methodologies to address them is crucial when evaluating observational studies to inform patient management decisions regarding whether ACE inhibitors or ARBs are associated with greater risk from COVID-19.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19 , Renin-Angiotensin System/drug effects , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Humans , Hypertension/drug therapy , Observational Studies as Topic , SARS-CoV-2
19.
High Blood Press Cardiovasc Prev ; 28(4): 405-416, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1283824

ABSTRACT

INTRODUCTION: The safety of renin-angiotensin-aldosterone system inhibitors (RAASi) among COVID-19 patients has been controversial since the onset of the pandemic. METHODS: Digital databases were queried to study the safety of RAASi in COVID-19. The primary outcome of interest was mortality. The secondary outcome was seropositivity improvement/viral clearance, clinical manifestation progression, and progression to intensive care units. A random-effect model was used to compute an unadjusted odds ratio (OR). RESULTS: A total of 49 observational studies were included in the analysis consisting of 83,269 COVID-19 patients (RAASi n = 34,691; non-RAASi n = 48,578). The mean age of the sample was 64, and 56% were males. We found that RAASi was associated with similar mortality outcomes as compared to non-RAASi groups (OR 1.07; 95% CI 0.99-1.15; p > 0.05). RAASi was associated with seropositivity improvement including negative RT-PCR or antibodies, (OR 0.96; 95% CI 0.93-0.99; p < 0.05). There was no association between RAASi versus control with progression to ICU admission (OR 0.99; 95% CI 0.79-1.23; p > 0.05) or higher odds of worsening of clinical manifestations (OR 1.04; 95% CI 0.97-1.11; p > 0.05). Metaregression analysis did not change our outcomes for effect modifiers including age, sex, comorbidities, RAASi type, or study type on outcomes. CONCLUSIONS: COVID-19 is not a contraindication to hold or discontinue RAASi as they are not associated with higher mortality or worsening symptoms. Continuation of RAASi might be associated with favorable outcomes in COVID-19, including seropositivity/viral clearance.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/virology , Renin-Angiotensin System/drug effects , SARS-CoV-2/pathogenicity , Aged , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , COVID-19/diagnosis , COVID-19/mortality , COVID-19/physiopathology , Contraindications, Drug , Disease Progression , Female , Host-Pathogen Interactions , Humans , Male , Middle Aged , Observational Studies as Topic , Prognosis , Randomized Controlled Trials as Topic , Risk Assessment , Risk Factors
20.
Drug Dev Res ; 82(1): 38-48, 2021 02.
Article in English | MEDLINE | ID: covidwho-1279360

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-COV-2), a novel coronavirus responsible for the recent infectious pandemic, is known to downregulate angiotensin-converting enzyme-2 (ACE2). Most current investigations focused on SARS-COV-2-related effects on the renin-angiotensin system and especially the resultant increase in angiotensin II, neglecting its effects on the kinin-kallikrein system. SARS-COV-2-induced ACE2 inhibition leads to the augmentation of bradykinin 1-receptor effects, as ACE2 inactivates des-Arg9-bradykinin, a bradykinin metabolite. SARS-COV-2 also decreases bradykinin 2-receptor effects as it affects bradykinin synthesis by inhibiting cathepsin L, a kininogenase present at the site of infection and involved in bradykinin production. The physiologies of both the renin-angiotensin and kinin-kallikrein system are functionally related suggesting that any intervention aiming to treat SARS-COV-2-infected patients by triggering one system but ignoring the other may not be adequately effective. Interestingly, the snake-derived bradykinin-potentiating peptide (BPP-10c) acts on both systems. BPP-10c strongly decreases angiotensin II by inhibiting ACE, increasing bradykinin-related effects on the bradykinin 2-receptor and increasing nitric oxide-mediated effects. Based on a narrative review of the literature, we suggest that BPP-10c could be an optimally effective option to consider when aiming at developing an anti-SARS-COV-2 drug.


Subject(s)
Bradykinin/administration & dosage , COVID-19/drug therapy , Peptide Fragments/administration & dosage , Snake Venoms/administration & dosage , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Animals , Bradykinin/metabolism , COVID-19/metabolism , Humans , Peptide Fragments/metabolism , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Snake Venoms/metabolism
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