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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)

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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.

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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.

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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).

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The upregulated kinin B1 receptors exert a pivotal role in modulating inflammatory processes. In isolated human umbilical veins (HUVs), kinin B1 receptor is upregulated as a function of in vitro incubation time and proinflammatory stimuli. The aim of this study was to evaluate, using functional and biochemical methods, the involvement of extracellular signal-regulated kinase 5 (ERK5), p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK1/2) on the kinin B1 receptor upregulation process in HUV. Real-time polymerase chain reaction analysis revealed for the first time that kinin B1 receptor mRNA expression closely parallels the functional sensitization to kinin B1 receptor selective agonist des-Arg(10)-kallidin (DAKD) in HUV. Moreover, the selective inhibition of ERK5, p38 MAPK, and JNK, but not ERK1/2, produced a dose-dependent rightward shift of the concentration-response curves to DAKD after 5-hour incubation and a reduction in kinin B1 receptor mRNA expression. Biochemical analyses showed that ERK5, p38 MAPK, and JNK phosphorylation is maximal during the first 2 hours postisolation, followed by a significant reduction in the last 3 hours. None of the treatments modified the responses to serotonin, an unrelated agonist, suggesting a specific effect on kinin B1 receptor upregulation. The present work provides for the first time pharmacologic evidence indicating that ERK5 plays a significant role on kinin B1 receptor upregulation. Furthermore, we confirm the relevance of p38 MAPK and JNK as well as the lack of effect of ERK1/2 in this process. This study may contribute to a better understanding of MAPK involvement in inflammatory and immunologic diseases.

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El incremento del rastreo del cáncer de mama ha producido un aumento en el diagnóstico de tumores en estadios tempranos. Mientras que los tumores que expresan receptores hormonales son tratados con hormonoterapia, la decisión acerca del uso de quimioterapia citotóxica es más compleja. En pacientes seleccionados, el test multigénico de 21 genes ha demostrado ser pronóstico y predictivo del beneficio del tratamiento con citotóxicos. En forma más reciente, se ha desarrollado un algoritmo clínico-patológico denominado ihc4+c que ha demostrado ser equivalente a la plataforma de 21 genes en los estudios iniciales, a un costo menor. Sin embargo, existe escasa experiencia internacional y nula experiencia local en este campo. Objetivo: El objetivo del presente estudio es evaluar retrospectivamente el riesgo de recurrencia a distancia a 10 años provisto por ihc4+c y Onwcotype dx. Material y método: Se evaluó en forma retrospectiva el score ihc4+c en 25 pacientes con tumores receptores hormonales positivos de las cuales se disponía del score provisto por Oncotype DX. Resultados: Se encontró una coincidencia en la estratificación de riesgo global del 76%. En un 20%, ihc4+c determinó una disminución, mientras que en un 4% resultó en un aumento de la categoría de riesgo. Discusión: El presente estudio, primero en su tipo en la Argentina, demostró una concordancia global alta entre ihc4+c y Oncotype dx comparable a otros estudios publicados...

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Our purposes were to perform the pharmacological characterization of PGF(2alpha) receptor (prostanoid FP-receptor) involved in human umbilical vein contraction and confirm its expression in this tissue. Umbilical cords from healthy patients after full-term deliveries were employed. The vein was dissected out of cords and used for either isolated organ bath or reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assays. The natural prostanoid FP-receptor agonist, PGF(2alpha), and its selective analogues, latanoprost and bimatoprost free acids are full agonists (produce more than 80% of the maximal contractile response to 5-HT) in human umbilical vein. The agonist potency (pEC(50)) order was PGF(2alpha) (6.01+/-0.05)>latanoprost free acid (5.65+/-0.07)=bimatoprost free acid (5.59+/-0.08). The contractile effects of PGF(2alpha) and latanoprost free acid were blocked competitively by the prostanoid FP-receptor antagonist, AL-8810. The antagonist potencies (pK(B)) of AL-8810 vs. PGF(2alpha) (5.93+/-0.05) and vs. latanoprost free acid (6.40+/-0.08) in human umbilical vein are in good agreement with its ability to antagonize prostanoid FP receptors of rat, mouse and human cells. In all samples, clear signal was detected for cDNA amplification of prostanoid FP receptor and the specific prostanoid FP-receptor antibody recognized a protein of approximately 64 kDa. In conclusion, taking into account the obtained functional and biochemical data, we propose for the first time that human umbilical vein express prostanoid FP-receptors and these receptors could be involved in the vasoconstriction action of PGF(2alpha) in this tissue.

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The possible inhibition of kinin B(1) receptor up-regulation by arachidonoylethanolamide (anandamide) was evaluated in isolated human umbilical vein. Anandamide and its metabolically stable analogue, R-N-(2-Hydroxy-1-methylethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (R-(+)-methanandamide), produced a selective and dose-dependent inhibition of kinin B(1) receptor-sensitized contractile responses. The inhibitory effect of anandamide on B(1) receptor-sensitized responses failed to be modified either by 5-biphenyl-4-ylmethyl-tetrazole-1-carboxylic acid dimethylamide (LY2183240), a selective anandamide uptake inhibitor, or 6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-y l](4-methoxyphenyl) methanone (AM630), selective cannabinoid CB(2) receptor antagonist. However, the cannabinoid CB(1) receptor antagonist, N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), abolished anandamide effects on kinin B(1) receptor sensitization. The present results provide strong pharmacological evidence indicating that endocannabinoid anandamide inhibits kinin B(1) receptor up-regulation through cannabinoid CB(1) receptor stimulation in human umbilical vein.

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