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.

-759C>T Polymorphism of the HTR2C Gene is Associated with Second Generation Antipsychotic-Induced Weight Gain in Female Patients with Schizophrenia.

Introduction: The HTR2C gene is an important candidate in pharmacogenetic studies of antipsychotic-induced weight gain (AIWG). However, inconsistent results have been obtained. The present study investigated the association between -759C>T, functional polymorphism of the HTR2C receptor, and AIWG. Methods: A prospective cohort of 48 female inpatients with schizophrenia and related illness treated according to normal clinical practice with second generation antipsychotics (SGAs) risperidone, clozapine, quetiapine, and olanzapine were evaluated. Patients were weighted at admission and again at 6 weeks of hospitalization. Weight gain was defined as an increase≥7% of baseline weight. The association between polymorphisms HTR2C and weight gain was evaluated. Multiple logistic regression was run to determine potential confounders. Results: Patients with the T allele at position -759 (TT or CT) gained less weight as compared to patients who did not have the allele. This association was not affected by possible confounding factors such as age, baseline BMI, and prior psychopharmacological treatment. Discussion: The T allele at position -759 protects against AIWG in female patients with schizophrenia.

EV-077 in vitro inhibits platelet aggregation in type-2 diabetics on aspirin.

INTRODUCTION: This study aimed to characterize the in vitro effect of EV-077, a compound that antagonises the binding of prostanoids and isoprostanes to the thromboxane receptor (TP) and inhibits the thromboxane synthase (TS), on platelet aggregation of patients with type-2 diabetes and coronary artery disease (CAD) on chronic aspirin treatment. The effect of EV-077 on 8-iso-PGE(2)-mediated TP receptor contraction of human arteries was also investigated. MATERIALS AND METHODS: Fifty-two type-2 diabetics with CAD on chronic aspirin (100 mg) treatment were studied. Arachidonic acid-induced platelet aggregation was measured by impedance aggregometry in platelet-rich plasma (PRP) and whole blood anticoagulated with hirudin, and by light transmission aggregometry in citrate-anticoagulated PRP following 10-min in vitro exposure to EV-077 (100 nmol/l) or control. The effect of EV-077 was measured on isometric contraction of 24 human umbilical arteries induced by isoprostane 8-iso-PGE(2). RESULTS: Arachidonic acid (1 mmol/l) induced substantial aggregation in hirudin-anticoagulated whole blood (63 ± 4 AU), which was significantly reduced by in vitro exposure to EV-077 (38 ± 3 AU, P<0.001). Virtually no arachidonic acid-induced aggregation in citrate-anticoagulated or hirudin-anticoagulated PRP was observed. EV-077 potently, competitively and reversibly inhibited TP mediated contraction of umbilical arteries by 8-iso-PGE(2) (P<0.01). CONCLUSIONS: Aspirin did not completely inhibit arachidonic acid-induced platelet aggregation in whole blood from type-2 diabetics with CAD. This aggregation is likely induced by prostanoids and/or isoprostanes produced by leukocytes, because it was significantly reduced by EV-077. The TP receptor-mediated contraction of human arteries induced by isoprostane 8-iso-PGE(2) was effectively inhibited by EV-077.

Vasoconstrictor effects of 8-iso-prostaglandin E2 and 8-iso-prostaglandin F(2alpha) on human umbilical vein.

The present study was undertaken to determine whether 8-iso-prostaglandin E2 and 8-iso-prostaglandin F(2alpha) posses contractile action on human umbilical vein and to evaluate the possible involvement of prostanoid TP receptors in this effect. Human umbilical vein rings were mounted in organ baths and concentration-response curves to 8-iso-prostaglandin E2 or 8-iso-prostaglandin F(2alpha) were constructed. Both isoprostanes evoked concentration-dependent contraction. 8-iso-prostaglandin E2 (pEC50=6.90+/-0.03) was significantly more potent than 8-iso-prostaglandin F(2alpha) (pEC50=6.10+/-0.04). However, both isoprostanes were equieffective. The prostanoid TP receptor antagonists, ICI-192,605 (4-(Z)-6-(2-o-Chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl)hexenoic acid) and SQ-29548 (7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-[1S(1alpha,2alpha(Z),3alpha,4alpha)]-5-Heptenoic acid) produced a competitive rightward shift of 8-iso-prostaglandin E2 concentration-response curves with pKB values of 8.91+/-0.04 and 8.07+/-0.07, respectively. When ICI-192,605 (1 nM) and SQ-29548 (10 nM) were evaluated against 8-iso-prostaglandin F(2alpha) they produced a parallel rightward displacement of 8-iso-prostaglandin F(2alpha) concentration-response curves without affecting the maximum responses giving pA2 values of 9.02+/-0.12 and 8.26+/-0.13, respectively. In conclusion, the present study describes for the first time the vasoconstrictor action of 8-iso-prostaglandin E2 and 8-iso-prostaglandin F(2alpha) in human umbilical vein. Furthermore, the affinity values obtained with ICI-192,605 and SQ-29548 provide strong pharmacological evidence of prostanoid TP receptors involvement in this effect.

Quinolonas: revision historica / Quinolones: historic review

En las últimas tres décadas, se produjo el desarrollo farmacoterapéutico de las quinolonas. El primer producto, que se incorporó al comercio en el año 1965, fue el ácido nalidíxico (quinolona de primera generación) y luego, los químicos sintetizaron varios miles de derivados modificando primariamente la posición N-1y las posiciones C-6, C-7 y C-8 sobre el anillo quinolona-naftiridona. Los cambios estructurales incorporados en los nuevos compuestos aumentaron las propiedades farmacodinámicas y mejoraron los perfiles farmacocinéticos. Las quinolonas de tercera generación (levofloxacina, clinafloxacina, sparfloxacina, grepafloxacina, DU-6859a y trovafloxacina) presentan varias ventajas sobre las quinolonas de primera generación (ácido nalidíxico, cinoxacina y ácido oxolínico) y sobre las quinolonas de segunda generación (norfloxacina, enoxacina, ciprofloxacina, pefloxacina, ofloxacina, lomefloxacina y fleroxacina). Las nuevas fluoroquinolonas son bien absorbidas en el duodeno y el yeyuno, poseen grandes volúmenes de distribución y se ha demostrado en el hombre su penetración en diferentes tejidos y líquidos corporales, alcanzando concentraciones iguales o mayores que aquellas observdas en el plasma. Las quinolonas de tercera generación son antimicrobianos de amplio espectro, con elevada potencia in vitro en la actidad frente a las bacterias gram-positivas y gram-negativas, incluyendo anaerobios y patógenos intracelulares.

Amplicación de la respuesta contráctil a noradrenalina por serotonina en la arteria umbilical humana / Amplification of contractile response by serotonin on noradrenaline in the human umbilical artery

Durante el transcurso del embarazo, se ha observado el incremento progresivo de los niveles plasmáticos de serotonina (5-HT). Además, se ha descripto el aumento de la concentración de noradrenalina (NA) durante el parto. Por otro lado, en diferentes arterias se ha observado que concentraciones efectivas mínimas de 5-HT pueden producir un aumento o "amplificación" de la respuesta contráctil a un segundo agonista. A partir de estos trabajos, se consideró relevante determinar la existencia de una interacción sinérgica entre la 5-HT y la NA en la arteria umbilical humana (AUH), y los posibles mecanismos involucrados en este fenómeno. Para ello, se emplearon tiras de esta arteria incubadas en solución de Krebs a 37 grados Celsius, burbujeadas con carbógeno en las que se evaluó la respuesta contráctil isométrica. La máxima respuesta contráctil a NA fue del 21 por ciento con respecto a la respuesta máxima de vasoconstricción, obtenida con 5-HT. Por otro lado, cuando se administró previamente una dosis efectiva mínima de 5-HT, la respuesta a la NA resultó significativamente mayor que la control (0,53 ñ 0,06 g y 0,24 ñ 0,06, respectivamente, p < 0,01). Esta respuesta "amplificada" a NA se correlacionó inversamente con el grado de contracción previa con 5-HT, cuando ésta tenía valores entre el 3 y 30% del máximo. Además, precontracciones superiores al 40 por ciento abolieron las respuestas a la NA. En otra serie de experimentos, la incubación previa con diltiazem, bioqueante de los canales de calcio, produjo una disminución de la respuesta tanto control como amplificada a NA. En este trabajo se demuestra la existencia de un efecto amplificador de la 5-HT sobre las respuestas a NA en la AUH y se discute la posible relevancia clínica en la preeclampsia y los mecanismos involucrados en este fenómeno.