Efficacy and safety of bosentan in the treatment of persistent pulmonary hypertension of the newborn: a Metaanalysis / 中国当代儿科杂志

OBJECTIVES@#To systematically evaluate the efficacy and safety of bosentan in the treatment of persistent pulmonary hypertension of the newborn (PPHN).@*METHODS@#Chinese Journal Full-text Database, Weipu Database, Wanfang Data, China Biology Medicine disc, PubMed, Web of Science, Embase, and Cochrane Library were searched for literature on bosentan in the treatment of PPHN published up to August 31, 2021.@*RESULTS@#A total of 8 randomized controlled trials were included for Meta analysis. The results of the Meta analysis showed that compared with the control group, the bosentan treatment group had a significantly lower treatment failure rate (RR=0.23, P<0.001), a significantly greater reduction in pulmonary artery pressure [mean difference (MD)=-11.79, P<0.001)], significantly greater increases in oxygen partial pressure (MD=10.21, P=0.006) and blood oxygen saturation (MD=8.30, P<0.001), and a significantly shorter length of hospital stay (MD=-1.35, P<0.001). The descriptive analysis showed that the bosentan treatment group had a lower degree of tricuspid regurgitation than the control group after treatment. The main adverse reactions of bosentan treatment included abnormal liver function, anemia and edema. The results of subgroup analysis based on treatment regimen, research area, and drug dose were consistent with those before stratification.@*CONCLUSIONS@#Bosentan is effective in the treatment of PPHN. However, when using bosentan, attention should be paid to adverse reactions such as abnormal liver function.

A post marketing surveillance study on the efficacy and safety of bosentan for treatment of pulmonary arterial hypertension among adult Filipino patients

BACKGROUND@#Pulmonary arterial hypertension (PAH) is a chronic, debilitating disease affecting millions of adults worldwide. With improved knowledge on PAH and better management, long-term survival in patients has significantly increased in the past 20 years. Bosentan is a nonselective, dual endothelin receptor antagonist used in the treatment of PAH. While the drug has already been established to improve exercise capacity and patient survival globally, no study has investigated its clinical effectiveness and safety among Filipino patients yet. A post marketing study was conducted to determine the efficacy and safety of bosentan (125 mg administered twice daily) among adult Filipino patients with PAH.@*METHODS@#A non-randomized, non-comparative, open-label trial was conducted involving adult patients at a tertiary government hospital in Metro Manila. Study duration was from March to September 2012. Primary end points of the study were patients' response to efficacy and safety.@*RESULTS@#A total of 14 patients were enrolled in the study and 13 included in the analysis. Mean age of the participants was 34 ± 11.54 years. Remarkable changes were observed for 6WMD and small improvements noted for Borg dyspnea index and CPET. There was no difference between baseline and 12th week WHO functional classification. FEVl /FVC, MVV, RV /TLC and sRaw showed modest improvement; there was a notable difference in the systolic PAP vs baseline; PVR, PVRI, SVR and SVRI demonstrated the largest changes via cardiac catherization and iloprost. Four patients experienced at least one serious adverse event, with one reported as suspected unexpected serious adverse reaction. Out of 13 patients, 1 O (76.9%) considered bosentan as effective while 11 (84.6%) considered it safe.@*CONCLUSION@#Bosentan improved exercise capacity, pulmonary function and cardiopulmonary hemodynamics among study participants. The drug is generally well-tolerated and effective. Bosentan is among the useful options for treatment of adult Filipino patients with PAH.

Endothelin-1 receptor antagonists protect the kidney against the nephrotoxicity induced by cyclosporine-A in normotensive and hypertensive rats

Cyclosporin-A (CsA) is an immunosuppressant associated with acute kidney injury and chronic kidney disease. Nephrotoxicity associated with CsA involves the increase in afferent and efferent arteriole resistance, decreased renal blood flow (RBF) and glomerular filtration. The aim of this study was to evaluate the effect of Endothelin-1 (ET-1) receptor blockade with bosentan (BOS) and macitentan (MAC) antagonists on altered renal function induced by CsA in normotensive and hypertensive animals. Wistar and genetically hypertensive rats (SHR) were separated into control group, CsA group that received intraperitoneal injections of CsA (40 mg/kg) for 15 days, CsA+BOS and CsA+MAC that received CsA and BOS (5 mg/kg) or MAC (25 mg/kg) by gavage for 15 days. Plasma creatinine and urea, mean arterial pressure (MAP), RBF and renal vascular resistance (RVR), and immunohistochemistry for ET-1 in the kidney cortex were measured. CsA decreased renal function, as shown by increased creatinine and urea. There was a decrease in RBF and an increase in MAP and RVR in normotensive and hypertensive animals. These effects were partially reversed by ET-1 antagonists, especially in SHR where increased ET-1 production was observed in the kidney. Most MAC effects were similar to BOS, but BOS seemed to be better at reversing cyclosporine-induced changes in renal function in hypertensive animals. The results of this work suggested the direct participation of ET-1 in renal hemodynamics changes induced by cyclosporin in normotensive and hypertensive rats. The antagonists of ET-1 MAC and BOS reversed part of these effects.

Curative effect of nitric oxide and bosentan on treatment of the interruption of aortic arch with ventricular septal defect and serious pulmonary hypertension: A randomized controlled study / 中国胸心血管外科临床杂志

@#Objective To analyze the curative effect of nitric oxide (NO) and bosentan on treatment of the interruption of aortic arch (IAA) with ventricular septal defect (VSD) and serious pulmonary hypertension (SPH). Methods Thirty-two children with IAA and VSD combined SPH from January 2015 to May 2017 confirmed by cardiac CT and ultrasound in Children’s Hospital of Hebei Province were enrolled including 17 males and 15 females, aged 1.10-4.30 months (mean, 2.71±0.98 months) and weighing 3.33-6.10 kg (mean, 4.57±0.88 kg). The 32 children were randomly divided into two groups (n=16 in each), a NO group and a bosentan group. All the patients underwent interruption of aortic arch and ventricular septal defect repair. When patients returned to cardiosurgery intensive care unit (CSICU) half an hour later, patients in the NO group inhaled NO 20 ppm for 36 h and those in the bosentan group were given bosentan by nasogastric feeding 15 mg, twice a day. The cardic index, pulmonary/systemic pressure ratio, oxygenation index at 3 h, 6 h, 12 h, 24 h, 36 h after surgery were evaluated, and the differences between the two groups were compared. Results The pulmonary/systemic pressure ratio in the two groups increased at first and then decreased, while oxygenation index in the two groups decreased at first and then increased, and the differences in the same groups atthe adjacent time points were statistically significant (P<0.05). The cardiac index in the two groups decreased at first and then increased, the differences in the same groups at the adjacent time points were statistically significant, except for 6 h and 12 h after surgery in the bosentan group (P>0.05). At postoperative 6 h, 12 h, the oxygenation index in the NO group was significantly higher than that in the bosentan group, and the pulmonary/systemic pressure ratio in the NO group was less than that in the bosentan group (P<0.01). The cardiac index in the NO group was higher than that of the bosentan group after 6 h, 12 h, 24 h of operation, which were statistically significant (P<0.05), and the cardic index of children in the NO group was greatly higher than that in the bosentan group after 12 h of surgery (P<0.01); at the same time point, the corresponding indexes were not statistically significant between the two groups (P>0.05). Conclusion NO inhalation in the treatment of IAA with VSD and SPH in children with early postoperative SPH is better than the bosentan, but in the late postoperative period, the effect is similar.

Genistein, bosentan and tadalafil in treatment of monocrotaline-induced pulmonary arterial hypertension in rats: a comparison of efficacy / 第二军医大学学报

Objective To compare the effects of genistein,bosentan,and tadalfil in treatment of monocrotaline-induced pulmonary arterial hypertension (PAH) in rats.Methods Monocrotaline-induced PAH SD-rat model was established by injecting monocrotaline (50 mg/kg) intraperitoneally (n=48),while the rats in control group (n=8)were given normal saline injection.Then all model rats were randomly divided into 6 groups (n=8) according to different drugs given by gavage after 3 weeks:PAH group (PAH rats were treated with normal saline),genistein G30,G60,G120 groups (PAH rats were treated with genistein 30,60,120 mg· kg-1 · d-1,respectively),bosentan group (PAH rats were treated with bosentan 5 mg · kg-1 · d-1),and tadalafil group (PAH rats were treated with tadalafil 0.5 mg · kg-1 · d-1).After 2 weeks of treatment,survival rate,tricupid regurgitation (TR),pulmonary artery diameter (PAD),mean pulmonary arterial pressure (PAP),acetylcholine (Ach)-induced endothelium-dependent relaxation (EDdR),sodium nitroprusside (SNP)-induced endothelium-independent relaxation (EDiR),right ventricular hypertrophy index (RVHI),and lung phathological of rats in each group were compared.Results Compared with the control group,the TR,PAD,mean PAP and RVHI of rats were significantly increased in PAH group (P＜0.05).Compared with the PAH group,the TR and RVHI of rats were significantly decreased in G60 and G-120 groups,PAD was significantly decreased in G120 group,mean PAP was significantly decreased in G30,G-60 and G120 groups,survival rate was significantly increased in G120 group,and endothelium-dependent relaxation was significantly improved in G30,G60 and G120 groups,while pulmonary vascular luminal stenosis,wall thickening and vascular smooth muscle cell proliferation were significantly inhibited in G30,G60 and G120 groups (P＜0.05).However,the above effects of genistein were less than bosentan and tadalafil (P＜0.05).Conclusion Genistein has a certain effect on monocrotaline-induced PAH in rat;although its efficacy is less than that of bosentan and tadalafil,genistein is cheaper,easy to obtain and has less side effects,and is also expected to be a new auxiliary drug for PAH.

Pulmonary Hypertension in Patient with Neurofibromatosis Type 1 / 고신대학교의과대학학술지

Neurofibromatosis type 1 (NF1) is a rare genetic disease. Precapillary pulmonary hypertension (PH) with NF1 is an extremely severe complication. A 65-year-old woman was admitted in our hospital with 3-year history of gradually worsening dyspnea on exertion (New York Heart Association functional class III-IV). Considering her clinical feature and examination findings, she could be diagnosed as PH associated with NF1. She was treated with endothelin receptor antagonist. However her dyspnea was not significantly improved. This is the first Korean case of NF1 patient with PH which confirmed with right heart catheterization.

Clinical effect of Bosentan combined with Vardenafil on postoperative pulmonary hypertension associated with congenital heart and its influence on function of vascular endothelium / 药物评价研究

Objective To explore the clinical effect of bosentan combined with vardenafil on postoperative pulmonary hypertension associated with congenital heart and its influence on function of vascular endothelium.Methods 80 congenital heart disease patients with postoperative pulmonary hypertension,who were treated in our hospital from November,2011 to December,2015 were enrolled in the present study.They were randomly divided into observation group and control group,with each group of 40 cases.Both group received conventional therapy of oxygen and dieresis.The clinical effect,clinical symptom improvement,cardiac function were compared between the two groups.Results The clinical effect of control group was 80.0％ (32/40),which was significantly lower than that of observation group (90.0％,P ＜ 0.05).The sPAP,mPAP in both group were significantly decreased,and the Qp/Qs level was obviously increased (P ＜ 0.05);Borg score and NYHAFC score as well as the level of VEGF were largely decreased,and those of observation group were significantly lower than control group (P ＜ 0.05).In the terms of adverse reactions,there was no statistical difference between the two groups.Conclusion Bosentan combined with vardenafil was effective on postoperative pulmonary hypertension associated with congenital heart,which can significantly improve the clinical symptoms of patients with dyspnea,improve the cardiac function,worthy of clinical promotion.

Genistein, bosentan and tadalafil in treatment of monocrotaline-induced pulmonary arterial hypertension in rats: A comparison of efficacy / 第二军医大学学报

Objective To compare the effects of genistein, bosentan, and tadalfil in treatment of monocrotaline-induced pulmonary arterial hypertension (PAH) in rats. Methods Monocrotaline-induced PAH SD-rat model was established by injecting monocrotaline (50 mg/kg) intraperitoneally (n = 48). while the rats in control group (72 = 8) were given normal saline injection. Then all model rats were randomly divided into 6 groups (72=8) according to different drugs given by gavage after 3 weeks; PAH group (PAH rats were treated with normal saline), genistein (G30. G60, G120 groups (PAH rats were treated with genistein 30, 60, 120 mg • kg-1 • d-1, respectively), bosentan group (PAH rats were treated with bosentan 5 mg • kg-1 • d-l), and tadalafil group (PAH rats were treated with tadalafil 0. 5 mg • kg-1 • d-l). After 2 weeks of treatment, survival rate, tricupid regurgitation (TR), pulmonary artery diameter (PAD), mean pulmonary arterial pressure (PAP), acetylcholine (ACh)-induced endothelium dependent relaxation (EDdR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation (EDiR). right ventricular hypertrophy index (RVHI), and lung phathological of rats in each group were compared. Results Compared with the control group, the TR. PAD. mean PAP and RVHI of rats were significantly increased in PAH group (P<0. 05). Compared with the PAH group, the TR and RVHI of rats were significantly decreased in G60 and G120 groups, PAD was significantly decreased in G120 group, mean PAP was significantly decreased in G30, G60 and G120 groups, survival rate was significantlyincreased in G120 group, and endothelium dependent relaxation was significantly improved in G30, G60 and G120 groups, while pulmonary vascular luminal stenosis, wall thickening and vascular smooth muscle cell proliferation were significantly inhibited in G30, G60 and G120 groups (P

Bosentan and Rifampin Interactions Modulate Influx Transporter and Cytochrome P450 Expression and Activities in Primary Human Hepatocytes

The incidence of polypharmacy-which can result in drug-drug interactions-has increased in recent years. Drug-metabolizing enzymes and drug transporters are important polypharmacy modulators. In this study, the effects of bosentan and rifampin on the expression and activities of organic anion-transporting peptide (OATP) and cytochrome P450 (CYP450) 2C9 and CYP3A4 were investigated in vitro. HEK293 cells and primary human hepatocytes overexpressing the target genes were treated with bosentan and various concentrations of rifampin, which decreased the uptake activities of OATP transporters in a dose-dependent manner. In primary human hepatocytes, CYP2C9 and CYP3A4 gene expression and activities decreased upon treatment with 20 μM bosentan+200 μM rifampin. Rifampin also reduced gene expression of OATP1B1, OATP1B3, and OATP2B1 transporter, and inhibited bosentan influx in human hepatocytes at increasing concentrations. These results confirm rifampin- and bosentan-induced interactions between OATP transporters and CYP450.

Efficacy of Bosentan in patients after Fontan procedures: a double-blind, randomized controlled trial / 华中科技大学学报（医学）（英德文版）

Fontan surgery is a widely used palliative procedure that significantly improves the survival period of patients with complex congenital heart disease (CHD). However, it does not decrease postoperative complication rate. Previous studies suggested that elevated mean pulmonary artery pressure (mPAP) and vascular resistance lead to decreased exercise tolerance and myocardial dysfunction. Therapy with endothelial receptor antagonists (Bosentan) has been demonstrated to improve the patients' prognosis. A double-blind, randomized controlled trial was performed to explore the efficacy of Bosentan in treating patients who underwent the Fontan procedure. Eligible participants were randomly divided into Bosentan group and control group. Liver function was tested at a local hospital and the results were reported to the phone inspector every month. If the results suggested abnormal liver function, treatment would be adjusted or terminated. All the participants finished the follow-up study, with no patients lost to follow-up. Unblinding after 2-year follow-up, no mortality was observed in either group. However, secondary end-points were found to be significantly different in the comparable groups. The cardiac function and 6-min walking distance in the Bosentan group were significantly superior to those in the control group (P=0.018 and P=0.027). Bosentan could improve New York Heart Association (NYHA) functional status and improve the results of the 6-min walking test (6MWT) in Fontan patients post-surgery, and no other benefits were observed. Furthermore, a primary meta-analysis study systematically reviewed all the similar clinical trails worldwide and concluded an overall NYHA class improvement in Fontan patients who received Bosentan treatments.

Successful Treatment of Newly Developed, Intractable Digital Ulcers and Gangrene with Bosentan in Systemic Sclerosis

In systemic sclerosis, digital ulcers and gangrene are somewhat common clinical characteristics of obliterative vasculopathy. These manifestations increase morbidities, such as pain, infections, and acroosteolysis. However, patient responses to the appropriate treatments are often inadequate. We treated a patient with systemic sclerosis who had a refractory digital ulcer and gangrene with bosentan, an endothelin receptor antagonist, and observed improvement. Here we systematically review this case.

Informe de evaluación rápida de tecnología sobre seguridad y efectividad de bosentán para hipertensión arterial pulmonar / Rapid evaluation report of technology on safety and effectiveness of bosentan for pulmonary arterial hypertension

La hipertensión pulmonar arterial (HPA) es una enfermedad rara, con una prevalencia de aproximadamente 15 a 50 casos por millón. Es de mayor prevalencia en ciertos grupos, como por ejemplo, pacientes infectados con VIH, pacientes con esclerosis múltiple, con enfermedad sickle cell, entre otros. No existe mucha información al respecto en Latinoamérica. La incidencia de esta enfermedad es de aproximadamente 2.4 casos por millón de habitantes (según información mexicana). En Argentina han calculado en base a información internacional - 1 a 2 casos por millón de habitantes - que existen entre 600 a 2000 pacientes con la enfermedad a un promedio de 90 a 300 casos nuevos por año. En Chile se acoge a la incidencia de 1-2 pacientes nuevos por millón de habitantes por año. Actualización en el diagnóstico y terapéutica en hipertensión pulmonar arterial. La HPA afecta con mayor frecuencia a las mujeres en una relación 1,7:1 y, comúnmente, se expresa en la cuarta década de la vida. Debido a lo poco específico de sus síntomas, desafortunadamente la mayoría de los diagnósticos se dan en estadios avanzados de la enfermedad (III y IV). El diagnóstico habitualmente es efectuado entre 18 y 24 meses posteriores al inicio de los síntomas, debido al carácter inespecífico de ellos, tales como disnea, fatiga o dolor torácico, de modo que es frecuente pesquisar enfermos con severa limitación funcional y estrecho margen terapéutico. La terapia con bosentán mejora los síntomas y hemodinamia en pacientes con hipertensión pulmonar aguda. Se recomienda cubrir con restricciones.(AU)

Bosentan up-front or sequential add-on combination treatment for pulmonary arterial hypertension: Long-term effects and prognosis / 第二军医大学学报

Objective To investigate the long-term effects and safety of bosentan combination treatment (up-front combination and sequential add-on combination) for pulmonary arterial hypertension (PAH) patients and the prognosis of the patients. Methods In this open and observational study, a total of 104 patients who were diagnosed as having PAH in the Department of Pulmonary Circulation and Cardiology, Shanghai Pulmonary Hospital, were given bosentan (twice a day) before treatment from Jul. 2007 to Jan. 2013. According to the treatment regimen, the patients were divided into up-front combination group or sequential add-on combination group, and the patients were followed up till Jun. 2013. Then the improvements and the survival rates of the patients were evaluated and compared before and after treatment. Results The median treatment time with bosentan was (22.6±15.8) months. The WHO functional class had no obvious worsening in 68.1% of patients with bosentan treatment, with the situation improved in 6 patients and steady in 56. The lgNT-proBNP value was decreased from 2.8±0.8 to 2.5±0.2, but showing no significant difference (P=0.15). Echocardiogram examination found that the pulmonary arterial systolic pressure (PASP) decreased from (95.2±21.3)mmHg (1 mmHg = 0.133 kPa) to (88.6±24.4)mmHg (P=0.009); ejection fraction (EF) increased from (73.6±9.3)% to (77.4±9.0)%(P=0.02); transverse size of right artial (RA-T size) and transverse size of right ventricular (RV-T size) showed no changes. Hemodynamic observations found that the mean PAP(mPAP) and mean right arterial pressure (mRAP) showed no change; pulmonary vascular resistance (PVR) decreased from (16.4±8.4)Wood U/m2to (13.9±8.0)Wood U/m2, but showing no significant difference (P=0.06); and cardiac output (CO) increased from (3.8±2.0) L/min to (4.8±2.3) L/min (P=0.04). The results of Kaplan-Meier survival estimates for 1, 2, 3, 4 and 5 years were 92.5%, 83.7%, 71.7%, 67.2% and 57.6%, respectively. The 1, 2, 3 and 4 years survival rates of patients were 95.1%, 88.9%, 84.2% and 77.7% in the up-front combination group, and 92.3%, 79.4%, 53.3% and 26.6% in the sequential add-on combination group, respectively, with significant difference found between the two groups(P=0.038). Only one patient in our study stopped bosentan due to severe facial edema. Conclusion Long-term bosentan combination treatment can prevent cardiac function worsening in PAH patients, increasing cardiac output and with satisfactory safety. Moreover, up-front combination therapy with bosentan has a better prognosis than sequential add-on combination therapy for PAH patients.

Moisture sorption properties research of chemical reference substances based on dynamic vapor sorption analysis technology / 中国药学杂志

OBJECTIVE: To investigate the moisture sorption properties of chemical reference substances (CRSs) by using dynamic vapor sorption (DVS) analysis technology in order to establish the distribution conditions, packaging materials, and usages of national chemical reference substances. METHODS: DVS analysis was adopted to acquire the moisture sorption dynamic profiles of five chemical reference substances of different moisture sorption types to evaluate their moisture sorption trend and capacities under different humidities. RESULTS: According to moisture sorption dynamics, we can found the hygroscopicity of disodium etidronate, sodium aminosalicylate, valaciclovir hydrochloride, aspirin and bosentan, and we have given advices about how to use these CRSs and what kind of bottles they should be packed in. CONCLUSION: DVS analysis can be used to record moisture sorption data in real time and visually observe water-CRS interactions under different humidities, which is an important technology for guiding the establishment and distribution of CRSs.

Effects of Bosentan in Treatment of Severe Pulmonary Hypertension Related to Congenital Heart Disease / 昆明医科大学学报

Objective To observe the clinical efficacy of bosentan in treatment of severe pulmonary hypertension related to congenital heart disease (CHD-PAH) .Methods 5 patients with severe CHD-PAH patients received bosentan therapy, then pulmonary artery pressure, pulmonary vascular resistance (PVR), 6min walk test,right ventricular end-systolic diameter (RVSD) changes were observed and statistically analyzed after six months medication. Results Pulmonary arterial systolic pressure (sPAP) was significanfly decreased from (96±11) mmHg to (86±10) mmHg, <0.01.pulmonary arterial diastolic pressure (dPAP) was significanfly decreased from (56±10) mmHg to (46±9) mmHg ( <0.01),pulmonary arterial mean pressure (mPAP) was significanfly decreased from (73 ±11) mmHg to (59 ±10) mmHg ( <0.05), pulmonary vascular resistance was significanfly decreased from (17.8±1.9) Wood to (13.1±1.7) Wood (<0.01) . 6min walk test was improved from (136±40) m to (198±55) m, <0.01.right ventricular end-systolic diameter significanfly decreased from (40±5) mm to (36±6) mm after 6 months therapy ( <0.05) . Conclusion Bosentan can decrease pulmonary arterial systolic pressure, improve exercise tolerance, improve right ventricular function in patients with severe CHD-PAH.

Apoptosis and Inflammation Associated Gene Expressions in Monocrotaline-Induced Pulmonary Hypertensive Rats after Bosentan Treatment

BACKGROUND AND OBJECTIVES: Vascular wall remodeling in pulmonary hypertension can be caused by an aberration in the normal balance between proliferation and apoptosis of endothelial cell in the pulmonary artery. The objective of this study was to evaluate the effect of bosentan on apoptosis in monocrotaline (MCT)-induced pulmonary hypertension. MATERIALS AND METHODS: Sprague-Dawley rats were divided into three groups: control (C) group, M group (MCT 60 mg/kg) and B group (MCT 60 mg/kg plus bosentan 20 mg/day orally). Gene expressions of Bcl (B cell leukemia/lymphoma)-2, caspase-3, complement component (C)-6, vascular endothelial growth factor (VEGF), interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-alpha) were analyzed by real time polymerase chain reaction and western blot analysis. RESULTS: The messenger ribonucleic acid (mRNA) expressions of caspase-3 and VEGF were significantly increased in the M group compared with the C group, and significantly decreased in the B group compared with the M group in week 4. mRNA expression of IL-6 was significantly decreased in weeks 1, 2, and 4 in the B group compared with the M group. mRNA expression of TNF-alpha was significantly decreased on day 5 and in weeks 1 and 2 in the B group compared with the M group. CONCLUSION: Bosentan may have potential for preventing apoptosis and inflammation.

Antagonistas de los receptores de la endotelina para la hipertensión arterial pulmonar / Endothelin receptor antagonists for pulmonary arterial hypertension / Antagonistas dos receptores de endotelina para a hipertensão arterial pulmonar

La hipertensión arterial pulmonar (HAP) es consecuencia de una alteración aguda o crónica de la vasculatura pulmonar, que se caracteriza por el aumento de la presión arterial pulmonar como consecuencia del aumento de la resistencia vascular pulmonar. La fisiopatología de la HAP se caracteriza por la vasoconstricción pulmonar vascular, la proliferación de células musculares lisas, y la trombosis. Estos cambios son el resultado de un desequilibrio entre agentes vasodilatadores (prostaciclina, óxido nítrico, péptido intestinal vaso activo) y vasoconstrictores (tromboxano A2, endotelina, serotonina), los inhibidores de factores de crecimiento y mitógenos, y factores antitrombóticos y protrombóticos. Los recientes avances en el tratamiento están dirigidos a restablecer el equilibrio entre estos sistemas. Los antagonistas de los receptores de endotelina (bosentán, ambrisentán), inhibidores de la fosfodiesterasa tipo 5 (sildenafilo, tadalafilo), y prostaciclina (epoprostenol, iloprost, treprostinil, beraprost) representan las diferentes clases de medicamentos que se utilizan actualmente en monoterapia y en combinación para el tratamiento de la HAP. El propósito de esta revisión es proporcionar al lector una actualización del tratamiento de la HAP con antagonistas de los receptores de la endotelina.

Pulmonary arterial hypertension (PAH) is a consequence of acute or chronic disorder of the pulmonary vasculature, which is characterized by increased pulmonary artery pressure as a result of increased pulmonary vascular resistance. The pathophysiology of PAH is characterized by pulmonary vascular vasoconstriction, smooth muscle cell proliferation, and thrombosis. These changes are a result of an imbalance between vasodilators (prostacyclin, nitric oxide, vasoactive intestinal peptide) and vasoconstrictors (thromboxane A2, endothelin, serotonin), growth inhibitors and mitogenic factors, and antithrombotic and prothrombotic factors. Recent advances in treatment are directed at restoring the balance between these systems. Endothelin receptor antagonists (bosentan, ambrisentan), phosphodiesterase type 5 inhibitors (sildenafil, tadalafil), and prostacylin (epoprostenol, iloprost, treprostinil, beraprost) represent the different classes of medications that are currently used in monotherapy and in combination to treat PAH. The purpose of this review is to provide the reader with an update on the treatment of PAH with antagonists of endothelin receptors.

A hipertensão arterial pulmonar (HAP) é uma consequência da doença aguda ou crônica da vasculatura pulmonar, o que é caracterizado pelo aumento da pressão da artéria pulmonar, como um resultado da resistência vascular pulmonar aumentada. A fisiopatologia de HAP é caracterizada pela vasoconstrição pulmonar vascular, proliferação de células de músculo liso, e trombose. Estas alterações são um resultado de um desequilíbrio entre os vasodilatadores (prostaciclina, o óxido nítrico, o péptido intestinal vasoativo) e vasoconstritores (tromboxano A2, endotelina, serotonina), e inibidores de crescimento de fatores miogênicos, e fatores antitrombóticos e pró-trombóticos. Avanços recentes no tratamento são dirigidos para o restabelecimento do equilíbrio entre estes sistemas. Antagonistas do receptor da endotelina (bosentan, ambrisentan), inibidores da fosfodiesterasa tipo 5 (sildenafilo, tadalafilo) e prostaciclina (epoprostenol, iloprost, treprostinil, beraprost) representam as diferentes classes de medicamentos que são usados atualmente em monoterapia e em combinação para tratar HAP. O objetivo desta revisão é fornecer ao leitor uma atualização sobre o tratamento da HAP com os antagonistas dos receptores de endotelina.

A Case of Patient with Eisenmenger Syndrome Admitted to Intensive Care Unit Due to Septic Shock Complicated with Newlydiagnosed Down Syndrome and Moyamoya Disease / 대한구급학회지

Eisenmenger syndrome is a severe form of pulmonary arterial hypertension related to congenital cardiac defects. Many patients die at a young age from such complications. The treatment of primary pulmonary hypertension is being applied to Eisenmenger syndrome such as endothelin receptor antagonists, phosphodiesterase-5 blockers, and prostacyclin. We experienced a case of 29-year female with ventricular septal defect-related Eisenmenger syndrome complicated with Down syndrome and Moyamoya disease, who was admitted to intensive care unit due to enteritis-associated septic shock. After the combination treatment with iloprost and sildenafil within the intensive care unit, the patient was able to wean mechanical ventilation without further applications of invasive rescue therapy such as extracorporeal membrane oxygenator. She was later discharged with bosentan. She maintained bosentan therapy for 34 months continuously without aggravations of symptom but eventually died with intracranial hemorrhage, a complication of Moyamoya disease. To our knowledge, this is the first case report of Eisenmenger syndrome accompanied by mosaic Down syndrome and Moyamoya disease.

Meta-analysis of randomized controlled trials of bosentan for treatment of pulmonary arterial hypertension

BACKGROUND/AIMS: We assessed the efficacy and safety of bosentan in patients with pulmonary arterial hypertension (PAH). METHODS: We surveyed randomized controlled trials (RCTs) of the efficacy and safety of bosentan in patients with PAH using MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and manual searches. Meta-analysis of RCTs was performed to determine treatment efficacy and safety outcomes. Results are presented as odds ratios (ORs) or weighted mean differences (WMDs). RESULTS: Meta-analysis of seven RCTs including a total of 410 patients and 296 controls revealed that the 6-minute work distance was significantly higher in the bosentan group than in the placebo group (WMD, 46.19; 95% confidence interval [CI], 21.20 to 71.19; p = 2.9 x 10(-5)). Compared with the placebo, bosentan significantly reduced the mean pulmonary arterial pressure in patients with PAH (WMD, -6.026; 95% CI, -8.785 to -3.268, p = 1.8 x 10(-6)). The bosentan therapy group worsened less clinically than the placebo group (OR, 0.252; 95% CI, 0.140 to 0.454; p = 4.6 x 10(-7)). The incidence of serious adverse events did not differ between the bosentan and placebo groups (OR, 0.948; 95% CI, 0.556 to 1.614; p = 0.843). However, the results of the abnormal liver function test (LFT) were significantly higher in the bosentan group than in the placebo group (OR, 2.312; 95% CI, 1.020 to 5.241; p = 0.045). CONCLUSIONS: This meta-analysis shows that bosentan can treat PAH effectively. However, bosentan increased the incidence of abnormal LFT results compared with the placebo.

Tratamiento específico de la hipertensión arterial pulmonar. Experiencia de la policlínica de hipertensión pulmonardel Hospital Maciel, período 2009-2011 / Specific treatment of pulmonary arterial hypertension. Experience of the pulmonary hypertension clinic at the polyclinic Hospital Maciel, period 2009-2011

Introducción:la hipertensión pulmonar (HP) es una condición hemodinámica definida por un aumento de la presiónarterial pulmonar media (PmAP) 25 mmHg en reposo estimada mediante el cateterismo cardíaco derecho (CCD). Secomunica la experiencia adquirida en el diagnóstico, seguimiento y tratamiento de la hipertensión arterial pulmonar(HAP) y de la HP tromboembólica crónica (HPTEC) de la policlínica de HP del Hospital Maciel. Métodos: se analiza una cohorte de 15 pacientes (2009-2011). Se estimaron la clase funcional (CF), la prueba de caminata de 6 minutos (P6M), la excursión sistólica del plano del anillo tricuspídeo (ESPAT) y la velocidad sistólica pico(Sm). La severidad hemodinámica fue estimada por CCD. Se definió respuesta vasorreactiva aguda (RVA) positiva porel descenso de la PmAP 10 mmHg, alcanzando un valor absoluto 40 mmHg sin cambios o aumento del índice cardíaco (IC). Los datos se expresaron como media ± DS. Se empleó el test de t student pareado para comparar el efecto deltratamiento específico y el test de Kruskal-Wallis para comparaciones entre los grupos, con una p<0,05.Resultados:la edad promedio fue de 43 ± 12 años, 12 (80%) mujeres. Diez (67%) del grupo 1 y 5 (33%) del grupo 4. El20% se presentó en CF I-II y 80% en CF III-IV. El tiempo de seguimiento fue de 19 ± 11 meses. La ESPAT y la Sm basales fueron de 17 ± 7 mm y 11 ± 2 cm/s, respectivamente. La PmAP fue de 54 ± 15 mmHg, la presión auricular derecha 11± 6 mmHg, IC 2,1 ± 0,7 l/min/m2, resistencia vascular pulmonar 1.087 ± 625 dinas.s.cm-5, capacitancia pulmonar 1,3 ±0,6 ml/mmHg. Un paciente presentó RVA positiva. Se empleó sildenafil (100%), bosentan (50%) e iloprost (43%); en71% el tratamiento fue combinado. No se registró hepatotoxicidad por bosentan durante el período de seguimiento. Unpaciente murió por rechazo a recibir tratamiento específico. Los 14 pacientes restantes presentaron una mejoría de laCF (3,0 ± 0,8 versus 2,1 ± 0,8, p<0,05), así como de la P6M ...