Efectividad y seguridad del ambrisentan en pacientes con hipertensión pulmonar grupo 1 / Effectiveness and safety of ambrisentan in patients with pulmonary hypertension group 1

Introducción: la Hipertensión pulmonar (HTP) es una enfermedad progresiva caracterizada por el aumento de la presión arterial pulmonar (por encima de 25 mm HG) debido al aumento de la resistencia vascular pulmonar. La enfermedad lleva a falla cardíaca ventricular derecha y muerte prematura. Actualmente es causante de alta morbilidad y mortalidad entre los pacientes que la sufren, presentando una tasa de supervivencia media una vez diagnosticada la enfermedad de alrededor de 3,6 años. Esta evaluación tecnológica se desarrolló en el marco de la actualización integral del Plan Obligatorio de Salud para el año 2015. Objetivo: evaluar la efectividad y seguridad del uso de ambrisentan para el tratamiento de pacientes con hipertensión arterial pulmonar idiopática y asociada. Metodología: la evaluación fue realizada de acuerdo con un protocolo definido a priori. Se realizó una búsqueda sistemática hasta noviembre de 2014 en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects y LILACS, sin restricciones de idioma ni fecha de publicación. Se identificaron las RSL y ECA que cumplieran los criterios de elegibilidad. La calidad de los estudios fue valorada con la herramienta AMSTAR. Las características de los estudios fueron extraídas a partir de las publicaciones originales.Se actualizó la búsqueda de la RSL para identificar nuevos ECA. Los resultados se presentan de acuerdo al reporte de la RSL. Se realizó un meta-análisis de novo con los ECA que compararon solo ambrisentan. Resultados: se identificó una RSL de calidad alta por AMSTAR y moderada por GRADE que incluye dos ECA (393 pacientes). El ambrisentan disminuye el riesgo de muerte (OR=0,24 (IC 95% 0,06-0,99)) comparado contra placebo. No existe evidencia a favor para la mejoría de clase funcional (OR=1,08 (IC 95%0,72-1,62)). La mejoría en la prueba de la caminata de 6 minutos, fue en promedio de 43,02 metros (IC95% 25,68 a 60,36) en comparación con el placebo. La calidad de vida, mejoró estadísticamente significativa en la función física del SF-36 (3.41,+/-6.96) comparada con placebo (-0.20, +/-7.14). La hospitalización fue menor en el grupo de ambrisentan (OR=0,39 (IC95% 0,16-0,97)) comparado contra placebo. Conclusiones: de acuerdo con los hallazgos de una RSL de alta calidad el ambrisentan es una tecnología segura, con efectos a favor, ya que disminuye la mortalidad de los pacientes con HTP, mejora la distancia recorrida en la prueba de 6 minutos, mejora la prueba de disnea de Borg, disminuye la hospitalización y mejora la CVRS en el constructo de función física. No se encontró evidencia para el desenlace de atrioseptostomía. En general el ambrisentan es bien tolerado, comparado con el placebo, el perfil de seguridad de la tecnología en cuanto a hepatoxicidad es a favor del ambrisentan. Los eventos adversos más frecuentes reportados en el grupo de ambrisentan fueron edema periférico, cefalea, sinusitis, flushing y congestión nasal comparados contra el placebo.

Effects of thrombolytic drugs and a selective endothelin-1 receptor antagonist on acute pulmonary thromboembolism in dogs / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>It has been shown that neurohumoral factors other than mechanical obstruction are involved in the pathophysiology of acute pulmonary thromboembolism (APTE). The aim of this study was to investigate the effects of thrombolytic drugs, a selective endothelin-1 receptor (ET-1R) antagonist alone or their combination on APTE in a canine model.</p><p><b>METHODS</b>Twenty dogs were randomly assigned to five groups: sham, model, urokinase (UK), BQ123, and combination (UK plus BQ123). The dogs in the sham group underwent sham surgery. APTE was induced in the other four groups by intravenous injection of autologous blood clots. Dogs in the UK, BQ123 and combination groups received UK, BQ123 (a selective ET-1R antagonist), or UK plus BQ123, respectively. The dogs in the model group were given saline. Mean pulmonary artery pressure (mPAP), serum concentrations of ET-1, thromboxane (TXB2), and tumor necrosis factor (TNF)-alpha were determined at different time points following the induction of APTE.</p><p><b>RESULTS</b>UK and BQ123 alone markedly decreased mPAP in APTE. By comparison, the reduction was more significant in the combination group. Compared with the sham group ((-0.90 +/- 0.61) mmHg), mPAP increased by (7.44 +/- 1.04), (3.42 +/- 1.12) and (1.14 +/- 0.55) mmHg in the model group, UK alone and BQ123 alone groups, respectively, and decreased by (2.24 +/- 0.67) mmHg in the combination group (P < 0.01). Serum ET-1 concentrations in the BQ123 and combination groups were (52.95 +/- 8.53) and (74.42 +/- 10.27) pg/ml, respectively, and were significantly lower than those in the model and UK groups ((84.56 +/- 7.44) and (97.66 +/- 8.31) pg/ml respectively; P < 0.01). Serum TNF-alpha concentrations were significantly lower in the BQ123 group than in the model, UK and combination groups (P < 0.05).</p><p><b>CONCLUSIONS</b>Our results indicate that the selective ET-1R antagonist BQ123 not only reduces the increase of mPAP and serum ET-1 level, but also inhibits the production of TNF-alpha, and attenuates the local inflammatory response induced by APTE. Selective ET-1R antagonists may be beneficial to the treatment of APTE, particularly when used in combination with a thrombolytic agent.</p>

Effects of endothelin A receptor antagonist BQ123 on the proliferation and apoptosis of prostate cancer cell line PC-3M / 中华男科学杂志

<p><b>OBJECTIVE</b>To investigate the anti-tumor effect of the endothelin A receptor antagonist BQ123 on human prostate cancer cell line PC-3M in vitro by observing its impact on the proliferation and apoptosis of human prostate cancer cells.</p><p><b>METHODS</b>The inhibiting effect of BQ123 on the proliferation of PC-3M cells was observed by MTT assay, erosion trace test and Transwell chamber chemotaxis assay, and its induction of their apoptosis determined by Annexin V-FITC/PI staining and cytometry.</p><p><b>RESULTS</b>BQ123 exhibited increased inhibition of PC-3M cells in a time-dependent manner, with inhibition rates of 22.32%, 44.88% and 64.47% at 24 h, 48 h and 72 h, respectively (P < 0.05). The migration distances of the PC-3M cells in the BQ123 group were (103.42 +/- 75.63) microm, (243.75 +/- 121.53) microm and (422.07 +/- 36.01) microm at 12 h, 24 h and 48 h, obviously lower than (162.93 +/- 19.87) microm, (317.19 +/- 43.19) microm and (692.74 +/- 40.84) microm in the control group (P < 0.05). The number of the PC-3M cells that invaded the inferior chamber in the BQ123 group was (79.2 +/- 9.58), significantly decreased as compared with (92.6 +/- 5.94) in the control (P < 0.05). The apoptosis rate of PC-3M exposed to BQ123 was (15.03 +/- 0.93)%, significantly higher than (9.38 +/- 1.37)% in the control (P < 0.05). The ratio of PC-3M cells in different cycles showed no significant differences.</p><p><b>CONCLUSION</b>BQ123 inhibits the proliferation of PC-3M cells and induces their apoptosis in vitro, which may give a new idea on the studies of prostate cancer therapies.</p>

Involvement of endothelin-1 in hypoxia-induced cardiomyocyte apoptosis / 中国应用生理学杂志

<p><b>AIM</b>To investigate the effect of endogenous endothelin-1 (ET-1) on cardiomyocyte apoptosis induced by hypoxia and its possible mechanism.</p><p><b>METHODS</b>Cultured neonatal rat cardiomyocytes were divided into control group and ET receptor antagonist group. Control group was given DMEM only and ET receptor antagonist group was treated with ET receptor subtype A (ET(A)) receptor antagonist BQ610 and BQ123 or ET(B) receptor antagonist BQ788 and subjected to hypoxia for 24 h. The presence of apoptosis in cardiomyocytes was evaluated by TUNEL analysis and flow cytometry (FCM).</p><p><b>RESULTS</b>TUNEL analysis showed that the percentage of positive apoptotic cells in BQ610 5 micromol/L group was 13.2% +/- 3.7%, significantly lower than that in hypoxia group (24.2% +/- 2.2%, P < 0.01). FCM showed that BQ123 (0.04, 0.2 and 1.0 micromol/L) inhibited hypoxia-induced cardiomyocyte apoptosis and increased cardiomyocyte survival rate in a dose-dependent manner, while BQ788 did not show such effects.</p><p><b>CONCLUSION</b>These findings suggest that endogenous ET-1 aggravates hypoxia-induced cardiomyocyte apoptosis and this effect is mediated through ET(A) receptor-dependent pathways.</p>

The effect of endothelin receptor in androgen-independent prostate cancer / 中华外科杂志

<p><b>OBJECTIVE</b>To study the expression of ET receptor and the apoptosis after intervened with ET receptor antagonist in androgen-independent prostate cancer.</p><p><b>METHODS</b>PC3, an androgen-independent prostate cancer cell line, was used. The expression of ETA and ETB receptor in PC3 was measured through RT-PCR. After intervened with selective ETA and ETB receptor antagonist, the apoptosis in PC3 was studied through flow cytometry and electron microscope.</p><p><b>RESULTS</b>Clear signal was obtained in PC3 for ETA receptor mRNA transcript, while the signal for ETB receptor mRNA transcript was very weak. The expression of ETA receptor mRNA was obviously reduced and the apoptosis of PC3 cell was observed after intervened with selective ETA receptor antagonist. There was no change after intervened with selective ETB receptor antagonist.</p><p><b>CONCLUSION</b>ET-1 exerts its effects through the ETA receptor subtype and ETB receptor is silenced in PC3. The expression of ETA was reduced and the apoptosis was observed in PC3 when ETA receptor was blocked. It was dose-dependent.</p>