Telmisartán y losartán: las marcadas diferencias entre sus propiedades químicas y farmacológicas pueden explicar la diferencia en la eficacia terapéutica en pacientes hospitalizados con covid-19 / Telmisartan and losartan: marked differences in chemical and pharmacological properties may explain differences in therapeutic efficacy in hospitalized patients with COVID-19

El objetivo de este artículo es comparar las propiedades químicas y farmacológicas del telmisartán y el losartán, y su metabolito activo EXP3174, con el fin de entender por qué el telmisartán es efectivo en pacientes hospitalizados con Covid-19 mientras que el losartán no lo es. Se llevó a cabo una revisión bibliográfica exhaustiva de las propiedades químicas, farmacocinéticas y farmacodinámicas de ambos fármacos y se destacaron las diferencias más importantes que podrían estar relacionadas con su efectividad en pacientes con Covid-19. Se concluyó que las propiedades farmacológicas del telmisartán, como su mayor afinidad por el receptor AT1, su duración de acción prolongada y su capacidad para modular la inflamación podrían explicar su efectividad en pacientes con Covid-19. Por otro lado, las propiedades farmacológicas del losartán, como su menor afinidad por el receptor AT1 y su rápido metabolismo, pueden limitar su efectividad en pacientes con Covid-19. Estos resultados resaltan la importancia de comprender las propiedades químicas y farmacológicas de los medicamentos para identificar posibles candidatos terapéuticos efectivos en el tratamiento de Covid-19. (AU)

The objective of this article is to compare the chemical and pharmacological properties of telmisartan and losartan and their active metabolite EXP3174 to understand why telmisartan is effective in hospitalized patients with COVID-19 while losartan is not. A comprehensive literature review of the chemical, pharmacokinetic and pharmacodynamic properties of both drugs was done to highlight the most important differences that may be related to their efficacy in patients with COVID-19. It was concluded that the pharmacological properties of telmisartan, such as its higher affinity for the AT1 receptor, its long duration of action and its ability to modulate inflammation, could explain its efficacy in patients with COVID-19. On the other hand, the pharmacological properties of losartan, such as its lower affinity for the AT1 receptor and its rapid metabolism, may limit its efficacy in patients with COVID-19. These results highlight the importance of understanding the chemical and pharmacological properties of drugs to identify potential effective therapeutic candidates for the treatment of COVID-19. (AU)

Hyperbaric oxygen as an adjuvant treatment for patients with COVID-19 severe hypoxaemia: a randomised controlled trial.

BACKGROUND: Hyperbaric oxygen (HBO2) therapy has been proposed to treat hypoxaemia and reduce inflammation in COVID-19. Our objective was to analyse safety and efficacy of HBO2 in treatment of hypoxaemia in patients with COVID-19 and evaluate time to hypoxaemia correction. METHODS: This was a multicentre, open-label randomised controlled trial conducted in Buenos Aires, Argentina, between July and November 2020. Patients with COVID-19 and severe hypoxaemia (SpO2 ≤90% despite oxygen supplementation) were assigned to receive either HBO2 treatment or the standard treatment for respiratory symptoms for 7 days. HBO2 treatment was planned for ≥5 sessions (1 /day) for 90 min at 1.45 atmosphere absolute (ATA). Outcomes were time to normalise oxygen requirement to SpO2 ≥93%, need for mechanical respiratory assistance, development of acute respiratory distress syndrome and mortality within 30 days. A sample size of 80 patients was estimated, with a planned interim analysis after determining outcomes on 50% of patients. RESULTS: The trial was stopped after the interim analysis. 40 patients were randomised, 20 in each group, age was 55.2±9.2 years. At admission, frequent symptoms were dyspnoea, fever and odynophagia; SpO2 was 85.1%±4.3% for the whole group. Patients in the treatment group received an average of 6.2±1.2 HBO2 sessions. Time to correct hypoxaemia was shorter in treatment group versus control group; median 3 days (IQR 1.0-4.5) versus median 9 days (IQR 5.5-12.5), respectively (p<0.010). OR for recovery from hypoxaemia in the HBO2 group at day 3 compared with the control group was 23.2 (95% CI 1.6 to 329.6; p=0.001) Treatment had no statistically significant effect on acute respiratory distress syndrome, mechanical ventilation or death within 30 days after admission. CONCLUSION: Our findings support the safety and efficacy of HBO2 in the treatment of COVID-19 and severe hypoxaemia. TRIAL REGISTRATION NUMBER: NCT04477954.

Telmisartan for treatment of Covid-19 patients: An open multicenter randomized clinical trial.

Background: Angiotensin receptor blockers (ARBs), such as telmisartan, have been postulated to treat Covid-19-induced lung inflammation. Methods: This is a parallel-group, randomized, two-arm, open-label, adaptive, multicenter superiority trial with 1:1 allocation ratio. Participants included patients from 18 years of age hospitalized with Covid-19 with 4 or fewer days since symptom onset enrolled at a university and a community hospital in Buenos Aires, Argentina. Exclusion criteria included prior intensive care unit (ICU) admission and use of ARBs/angiotensin converting enzyme inhibitors at randomization. Control arm received standard care alone and treatment arm telmisartan 80 mg twice daily for 14 days. Primary outcomes were C-reactive protein (CRP) plasma levels at day 5 and 8 after randomization. Secondary outcomes included time to discharge within 15 days, admission to ICU and death at 15- and 30-days. NCT04355936 (Completed). Findings: A pragmatic decision to end the study before the third interim analysis was made on Oct. 30th due to sharp reduction in recruitment. A total of 162 patients were randomized. 158 patients enrolled between May 14 and October 30 2020, were included in the analysis, 80 in the standard care and 78 in the telmisartan added to standard care group. Baseline absolute CRP serum levels were 5.53 ± 6.19 mg/dL (95% CI 6.91 to 4.15, n = 80) and 9.04 ± 7.69 (95% CI 9.04 to 10.82, n = 74) in the standard care and telmisartan added to standard care groups, respectively. Day 5 control-group CRP levels were 6.06 ± 6.95 mg/dL (95% CI 7.79-4.35, n = 66) while telmisartan group were 3.83 ± 5.08 mg/dL (95% CI 5.08-2.59, n = 66, p = 0.038). Day 8 CRP levels were 6.30 ± 8.19 mg/dL (95% CI 8.79-3.81, n = 44) and 2.37 ± 3.47 mg/dL (95% CI 3.44-1.30, n = 43, p = 0.0098) in the control and telmisartan groups, respectively (all values expressed as mean ± SD). Kaplan-Meier analysis showed that telmisartan-treated patients had a lower median time-to-discharge (control=15 days; telmisartan=9 days). Death by day 30 was reduced in the telmisartan-treated group (control 22.54%, 16/71; telmisartan 4.29%, 3/70 participants; p = 0.0023). Composite ICU, mechanical ventilation or death was reduced by telmisartan treatment at days 15 and 30. No adverse events were reported. Interpretation: Our study suggests that the ARB telmisartan, a widely used antihypertensive drug, is safe and could reduce morbidity and mortality in hospitalized patients infected with SARS -CoV-2 by anti-inflammatory effects. Further studies employing telmisartan are needed for confirmation of our results and to define its true therapeutic value as a tool against Covid-19.

Angiotensin Receptor Blockers for COVID-19: Pathophysiological and Pharmacological Considerations About Ongoing and Future Prospective Clinical Trials.

COVID-19 pandemic demands a swift response to find therapeutic tools that effectively reduce morbidity and mortality. Despite initial fears, evidence from retrospective observational studies supports the inhibition of the renin-angiotensin system as an emerging pathway to delay or moderate angiotensin II-driven lung inflammation. This has triggered several prospective clinical trials. In this commentary we provide an overview and analysis of current ongoing clinical trials aimed at evaluating the therapeutic efficacy of angiotensin receptor blocker (ARB) use in COVID-19. The relevance of the results of these trials will have to be interpreted depending on the stage and severity of the disease and in light of the start time of their prescription related to the time of diagnosis of COVID-19 as well as the administered doses.

Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID-19.

In late 2019, a new coronavirus emerged in Wuhan Province, China, causing lung complications similar to those produced by the SARS coronavirus in the 2002-2003 epidemic. This new disease was named COVID-19 and the causative virus SARS-CoV-2. The SARS-CoV-2 virus enters the airway and binds, by means of the S protein on its surface to the membrane protein ACE2 in type 2 alveolar cells. The S protein-ACE2 complex is internalized by endocytosis leading to a partial decrease or total loss of the enzymatic function ACE2 in the alveolar cells and in turn increasing the tissue concentration of pro-inflammatory angiotensin II by decreasing its degradation and reducing the concentration of its physiological antagonist angiotensin 1-7. High levels of angiotensin II on the lung interstitium can promote apoptosis initiating an inflammatory process with release of proinflammatory cytokines, establishing a self-powered cascade, leading eventually to ARDS. Recently, Gurwitz proposed the tentative use of agents such as losartan and telmisartan as alternative options for treating COVID-19 patients prior to development of ARDS. In this commentary article, the authors make the case for the election of telmisartan as such alternative on the basis of its pharmacokinetic and pharmacodynamic properties and present an open-label randomized phase II clinical trial for the evaluation of telmisartan in COVID-19 patients (NCT04355936).

Alterations in triglyceride rich lipoproteins are related to endothelial dysfunction in metabolic syndrome.

UNLABELLED: Our aim was to analyze the effect of circulating triglyceride rich lipoprotein (TRL) on endothelial function in metabolic syndrome (MetS). METHODS: We studied 40 patients with MetS (ATPIII), divided into those presenting normal endothelial function (n=19) and those with endothelial dysfunction (n=21) by means of the evaluation of pulse wave velocity, before and after brachial artery ischemia. In fasting serum we measured lipid and lipoprotein profile, insulin and glucose (HOMA-IR). Moreover, isolated TRL (d<1006g/l) were chemically characterized. In parallel, using randomly selected TRL from MetS patients with endothelial dysfunction (n=6) and MetS patients with normal endothelial function (n=6), the ability of TRL to inhibit ACh-induced vasorelaxation (10(-9)-10(-5)mM) on aortic rings previously pre-contracted by noradrenaline (10(-8)mM) was evaluated. RESULTS: Interestingly, TRL isolated from MetS patients presenting endothelial dysfunction showed triglyceride over-enrichment (59.1±4.8 vs. 54.1±4.7%; p=0.04), even after adjusting by potential confounders (p=0.05). In addition, while TRL resulting from both MetS groups significantly inhibited endothelium dependent vasorelaxation (p<0.001), TRL from MetS patients with endothelial dysfunction showed a strong tendency to a greater inhibition of vasorelaxation (p=0.06). Moreover, TRL-triglyceride (%) showed a strong tendency to correlate with the grade of vasorelaxation inhibition exerted by TRL (r=0.60; p=0.05). CONCLUSION: These results, taken together, would allow inferring for the first time that the predominance of triglyceride over-enriched TRL in circulation in MetS would induce endothelial dysfunction, contributing to the inherent cardiovascular risk of MetS.

Assessment of endothelial function by means of flow-mediated changes using pulse wave velocity.

Endothelial dysfunction is a leading cause of early development of cardiovascular diseases. Endothelial function can be assessed using ultrasound methods to watch the arterial flow-mediated dilation. It is also possible to find changes in pulse wave velocity (PWV) after induced ischemia related to the vessel diameter changes. Pre- and post-induced ischemia carotid-radial PWV was recorded in 226 hypertensive patients (150 women [63.5+/-12.4 years old] and 76 men [63.2+/-11.8 years old] and 55 healthy patients (38 women [63.1+/-12.6 years old] and 17 men [54.8+/-12.8 years old]). The authors considered normal endothelial function a PWV reduction of 5% from baseline. To assess nondependent endothelial dilation the authors performed carotid-radial PWV after sublingual administration of 5 mg of isosorbide dinitrate in a group of patients with abnormal flow-mediated dilation. A significant PWV reduction of 9.8% in normal patients and only 1.2% among hypertensive patients (P<.0005) was found. After sublingual isosorbide dinitrate intake the authors observed a greater fall in PWV (14%) than that observed in healthy people after induced ischemia. Carotid-radial PWV after induced ischemia decreased significantly in normal participants. No significant changes were observed in hypertensive patients. These results may offer a reliable tool to assess endothelial function in medium-size arteries.

La velocidad de la onda del pulso como método para evaluar la función endotelial / Evaluation of Endothelial Function through Pulse Wave Velocity

Introducción La disfunción endotelial está presente precozmente en la aterosclerosis y constituye la base fisiopatológica de ella y de la enfermedad cardiovascular (CV). La función endotelial puede estudiarse por ultrasonografía, que permite observar la vasodilatación mediada por flujo (VMF). También puede evaluarse por el cambio en la velocidad de la onda del pulso (VOP), que de acuerdo con la ecuación de Moens-Korteweg concuerda con los resultados obtenidos por otros métodos. Objetivos Investigar la función endotelial a través de las variaciones de la velocidad de la onda del pulso (VOP) carótido-radial preinducción y posinducción de isquemia braquial. Material y métodos La VOP carótido-radial se determinó en 248 pacientes hipertensos (160 mujeres, 63,6 ± 12,3 años y 88 hombres, 63,1 ± 11,6 años) y en 56 normotensos (38 mujeres, 63,1 ± 12,6 años y 18 hombres, 56,1 ± 13,7 años). Se consideró respuesta endotelial normal la reducción de la VOP > 5%. En pacientes con respuesta anormal se realizó la medición luego de la administración de 5 mg de dinitrato de isosorbide sublingual con el objeto de registrar la vasodilatación no dependiente del endotelio como forma de validación del método. Resultados La VOP se redujo el 9,3% en promedio en el grupo de sujetos sanos, mientras que en los pacientes esta reducción fue de sólo el 1,5% (p < 0,0005). La reducción de la VOP con dinitrato de isosorbide sublingual fue aún mayor que la de los individuos normales (18,2%) (p < 0,0001). Conclusiones La medición de la VOP carótido-radial preinducción y posinducción de isquemia discriminó el comportamiento endotelial entre personas normotensas e hipertensas. Este hallazgo consolida su utilidad para la medición de la función endotelial.

Background Endothelial dysfunction occurs early in the development of atherosclerosis and constitutes the physiopathologic basis of this condition and of cardiovascular disease (CVD). Ultrasound is useful to study endothelial function through the assessment of flow-mediated dilation (FMD). Endothelial function may also be evaluated by the change in pulse wave velocity (PWV) with results that are similar to those obtained by other methods according to the Moens-Korteweg equation. Objectives To evaluate endothelial function through the changes in the carotid-radial PWV before and after inducing ischemia at the level of the brachial artery. Material and Methods Carotid-radial PWV was determined in 24 hypertensive patients (160 women, 63.6±12.3 years and 88 men, 63.1±11.6 years) and in 56 controls (38 women, 63.1±12.6 years and 18 men, 56.1±13.7 years). A reduction in PWV <5% was considered a normal endothelial response. Patients with abnormal response received 5 mg of sublingual isosorbide dinitrate to evaluate endothelium-independent vasodilation for validation of the method. Results An average reduction by 9.3% was recorded in healthy subjects compared to a reduction by 1.5% in hypertensive patients (p<0.0005). The reduction in PWV after the administration of sublingual isosorbide dinitrate was even greater compared to normal subjects (18.2%) (p<0.0001). Conclusions The measurement of carotid-radial PWV before and after inducing ischemia is a reliable method to evaluate endothelial function.