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)

Resultados de un registro prospectivo de pacientes con desórdenes hipertensivos del embarazo en un centro de la Ciudad de Buenos Aires / Results of a Prospective Registry of Patients with Hypertensive Disorders of Pregnancy in a Center of the City of Buenos Aires

RESUMEN Introducción: Los desórdenes hipertensivos del embarazo (DHE) complican el 10% de los embarazos. Son la principal causa de mortalidad materna, y requieren un equipo multidisciplinario para su abordaje. Objetivos: Cuantificar prevalencia y definir características y evolución de los DHE en un centro con un programa dedicado para su abordaje. Material y métodos: Registro continuo y prospectivo desde noviembre 2019 hasta julio 2021 que incluyó todas las pacientes con DHE (Hipertensión arterial crónica - HTAC, hipertensión gestacional - HTg, preeclampsia precoz - PEp, preeclampsia tardía - PEt, preeclampsia sobreimpuesta - PESI, y eclampsia) y que cumplieran los criterios de inclusión. Se excluyeron las pacientes sin cobertura médica que impidiera su seguimiento ambulatorio a largo plazo en la institución. Se evaluaron características basales y evolución, tratamiento y persistencia de HTA luego del puerperio. Se analizó la incidencia de retardo en el crecimiento intrauterino (RCIU), parto pretérmino, mortalidad materna y muerte neonatal dentro de los primeros 28 días de vida. Resultados: Se realizaron 5825 partos/cesáreas y se incluyeron 152 pacientes que cumplieron criterios de inclusión, con HTg (37,5%), PEp (19,7%), PEt (38,8%), PESI (3,3%)), eclampsia (0,6%). Edad media 36,4 ± 5,6 años. El 38,1% recibió aspirina. Los antihipertensivos más utilizados fueron labetalol (65,8%) y enalapril (44,1 %) en el embarazo y el puerperio respectivamente. No hubo mortalidad materna, y la neonatal fue 3,6%. La persistencia de HTA fue del 20,0% Conclusión: La preeclampsia tardía fue el DHE más frecuente en la población analizada. Más de la mitad de las pacientes que desarrollaron DHE no recibían tratamiento preventivo con aspirina, evidenciándose un déficit en la identificación de la población de riesgo. Una de cada 5 pacientes con DHE quedó con hipertensión arterial crónica luego del puerperio.

ABSTRACT Background: Hypertensive disorders of pregnancy (HDP) complicate 10% of pregnancies. They are the main cause of maternal mortality and require a multidisciplinary team to address them. Objectives: The aim of this study was to quantify the prevalence and define the characteristics and outcome of HDP in a center with a program focused on its management. Methods: This was a continuous and prospective registry from November 2019 to July 2021 that included all patients with HDP [chronic hypertension (CHT), gestational hypertension (GHT), early-onset preeclampsia (EPE), late preeclampsia (LPE), superimposed preeclampsia (SIPE) and eclampsia] who met the inclusion criteria. Patients without medical coverage that prevented long-term outpatient follow-up at the institution were excluded. Baseline characteristics and evolution, treatment and persistent HT after puerperium were evaluated. The incidence of intrauterine growth retardation (IUGR), preterm delivery, maternal mortality and neonatal death within the first 28 days of life was analyzed. Results: Among a total f 5825 deliveries/caesarean sections, 152 patients with GHT (37.5%), EPE (19.7%), LPE (38.8%), SIPE (3.3%), and eclampsia (0.6%) who met the inclusion criteria were included in the study. Mean age was 36.4±5.6 years. Aspirin was administered to 38.1% of patients. The most commonly used antihypertensive drugs were labetalol (65.8%) and enalapril (44.1%) during pregnancy and puerperium, respectively. There was no maternal mortality, and neonatal mortality was 3.6%. Persistent HT was 20.0%. Conclusion: Late preeclampsia was the most frequent HDP in the population analyzed. More than half of the patients who developed HDP did not receive preventive treatment with aspirin, showing a deficit in the identification of the population at risk. One in 5 HDP patients remained with CHTN after puerperium.

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.

Randomized comparison between bare-metal stent plus colchicine versus drug-eluting stent alone in prevention of clinical adverse events after percutaneous coronary intervention.

The use of colchicine is associated with a significant reduction of cardiac adverse events in patients with coronary artery disease. Past small randomized trials with oral immunosuppressive or anti-inflammatory therapies have demonstrated a reduction of adverse clinical events after bare metal stent implantation. The potential role of adjunctive colchicine after bare-metal stent implantation, compared with drug-eluting stent alone, is unknown. The primary end point of the study will be to compare cost-effectiveness at 1 year of follow-up of coronary intervention with bare-metal stent implantation plus 1 mg of colchicine during 3 months versus percutaneous coronary intervention with drug-eluting stent implantation alone. ClinicalTrials.gov identifier: NCT04382443.

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).

Cardiac automaticity: basic concepts and clinical observations.

PURPOSE: The purpose of this report was to review the basic mechanisms underlying cardiac automaticity. Second, we describe our clinical observations related to the anatomical and functional characteristics of sinus automaticity. METHODS: We first reviewed the main discoveries regarding the mechanisms responsible for cardiac automaticity. We then analyzed our clinical experience regarding the location of sinus automaticity in two unique populations: those with inappropriate sinus tachycardia and those with a dominant pacemaker located outside the crista terminalis region. RESULTS: We studied 26 patients with inappropriate sinus tachycardia (age 34 ± 8 years; 21 females). Non-contact endocardial mapping (Ensite 3000, Endocardial Solutions) was performed in 19 patients and high-density contact mapping (Carto-3, Biosense Webster with PentaRay catheter) in 7 patients. The site of earliest atrial activation shifted after each RF application within and outside the crista terminalis region, indicating a wide distribution of atrial pacemaker sites. We also analyzed 11 patients with dominant pacemakers located outside the crista terminalis (age 27 ± 7 years; five females). In all patients, the rhythm was the dominant pacemaker both at rest and during exercise and located in the right atrial appendage in 6 patients, in the left atrial appendage in 4 patients, and in the mitral annulus in 1 patient. Following ablation, earliest atrial activation shifted to the region of the crista terminalis at a slower rate. CONCLUSIONS: Membrane and sub-membrane mechanisms interact to generate cardiac automaticity. The present observations in patients with inappropriate sinus tachycardia and dominant pacemakers are consistent with a wide distribution of pacemaker sites within and outside the boundaries of the crista terminalis.