Bosentan for Increased Pulmonary Vascular Resistance in a Patient with Single Ventricle Physiology and a Bidirectional Glenn Shunt

We present a case of the successful use of bosentan for increased pulmonary vascular resistance (PVR) in a 10-year-old male who underwent late single ventricle surgical palliation for double-inlet left ventricle with pulmonary artery banding and a bidirectional Glenn shunt. The patient was treated with bosentan for 16 weeks, with decreases in mean pulmonary artery pressure from 23 to 16 mmHg on the right and from 31 to 21 mmHg on the left, and a decrease of the transpulmonary gradient by 7–8 mmHg. Cardiopulmonary exercise testing demonstrated an increase in peak oxygen consumption (VO₂) by 8% and peak work rate by 10%. Bosentan is a relatively new oral therapy option for increased PVR in patients with single ventricle physiology and bidirectional Glenn shunts.     

The Effects of Endothelin Receptor Blockade by Bosentan on the Healing of a Bowel Anastomosis in an Experimental Crohn’s Disease Model

Objective  It was previously described that endothelins may contribute to the pathogenesis of Crohn’s disease. In this study, it was aimed to investigate the effects of endothelin receptor blockade by bosentan on the healing of a bowel anastomosis in an experimental Crohn’s disease model. Material and Methods  Twenty-eight Sprague–Dawley rats were divided into four groups. Groups I and II were used as sham-operated and control groups, respectively. Bowel inflammation induced by intrajejunal injection of iodoacetamide in groups III and IV. Rats in group IV were treated with oral preparation of bosentan 60 mg/kg/day. Three days after induction of the inflammation, partial resection of test loop and anastomosis was performed. Re-laparotomy was performed, anastomosis bursting pressures and peritonitis scores were measured, and tissue samples were obtained for the measurements of tissue hydroxylproline level and mucosal damage index 4 days later. Results  The mean mucosal damage index and peritonitis score of group IV were significantly lower, and the mean tissue hydroxyproline level and anastomotic bursting pressure of group IV were significantly higher than those of group III. Conclusion  The blockade of endothelin receptors by bosentan decreases the severity of iodoacetamide induced intestinal inflammation, increases the wound healing in the inflamed intestinal tissue, and decreases the severity of peritonitis. This study was supported by The Coordination Committee of Scientific Researches and Projects of Fırat University.     

波生坦及氨氯地平对脱氧皮质酮-盐型高血压大鼠肾脏纤维化和微血管的影响

目的:比较波生坦和氨氯地平对脱氧皮质酮(DOCA)-盐型高血压大鼠(DHR)肾脏纤维化和微血管的影响,探讨内皮素-1(ET-1)在DHR肾脏损害中的作用及可能机制。方法:30只10周龄清洁级雄性SD大鼠,切除左侧肾脏,1周后存活24只,随机分成对照组、波生坦组、氨氯地平组和安慰剂组。对照组给予饮自来水,另3组予DOCA[50mg/(kg·周)]皮下注射,饮盐水,同时分别予波生坦、氨氯地平和安慰剂;5周时测定24h尿蛋白排泄量(24h-UPER)、血压、尿素氮(BUN)和血肌酐(Scr);处死后评估病理切片肾小球硬化和肾小管间质损害程度;观察转化生长因子β1(TGF-β1)和Smad7的表达,分析肾组织毛细血管指数和增生内皮细胞数。结果:与对照组相比,安慰剂组血压、24h-UPER增加,肾脏有较明显的组织学改变,肾内TGF-β1和Smad7的蛋白表达明显上调,波生坦能较显著地抑制上述异常(P0.05)。各组肾功能指标在正常范围内。安慰剂组中肾小球毛细血管指数(GCI)和肾小管周毛细血管指数(PCI)和增生内皮细胞数较对照组明显减少,波生坦、氨氯地平均能显著增加毛细血管和新生毛细血管数(P<0.01),但氨氯地平组增加程度不如波生坦组,差异有统计学意义(P<0.05)。TGF-β1与GCI、PCI和增生内皮细胞数具有显著的负相关性。结论:ET-1在DHR肾脏损害中发挥重要作用,其机制可能为通过上调TGF-β1和Smad7蛋白表达及直接抑制新生血管形成,间接加速毛细血管毁损而加重肾缺血和肾损害。     

Low‐dose combination therapy of severe digital ulcers in diffuse progressive systemic sclerosis with the endothelin‐1 receptor antagonist bosentan and the phosphodiesterase V inhibitor sildenafil

Digital ulcers in progressive systemic sclerosis (PSS) are often refractory to therapy. A frequently chronic aggressive course can lead to the loss of acral limbs involved. A 73‐year‐old woman developed a dramatic worsening of her ulcerations despite maximum conventional therapy. Switching therapy to bosentan and sildenafil, both in low‐dose regimens, resulted for the first time in ten years in a complete healing of the ulcers. If substantiated in a series of patients, the additive and perhaps synergistic clinical benefits of combining bosentan and sildenafil may be a valuable option for the treatment of acral ulcers in PSS.     

Congenital Right Pulmonary Artery Agenesis with Atrial Septal Defect and Pulmonary Hypertension

Unilateral pulmonary artery agenesis is a rare congenital anomaly caused by a backward displacement of the conical artery of the truncus arteriosus. It is commonly associated with additional cardiovascular abnormalities. A 7‐year‐old girl was admitted to our clinic with the complaint of shortness of breath upon exertion. Chest radiography revealed a hypoplastic right lung. Absence of the right pulmonary artery with atrial septal defect and pulmonary hypertension was demonstrated by echocardiography, computed tomography, and cardiac catheterization. Bosentan is effectively used to treat pulmonary arterial hypertension.     

Drug eruption due to bosentan in a patient with systemic sclerosis

We present the case of a 60-year-old female patient with systemic sclerosis complicated by pulmonary hypertension. Ten days after the initiation of treatment with bosentan, high fever and skin eruptions were noted. In the previous reports, the frequency of drug-induced skin eruptions has not been well documented. Since the use of bosentan is expected to increase, we should be aware of the previously unknown adverse effects as well as skin eruptions.     

No effects of bosentan on microvasculature in patients with limited cutaneous systemic sclerosis

The endothelium-derived vasoconstrictor molecule endothelin-1 (ET-1) has been suggested to play a role in the pathogenesis of Raynaud’s phenomenon (RP) and systemic sclerosis (SSc). We studied the effect of bosentan on microvascular structure and function in patients with RP secondary to limited cutaneous SSc in a mechanistic pilot study. In this single center, open study, 15 patients with limited cutaneous SSc were treated with bosentan for 16 weeks with a follow-up period of 4 weeks. Changes in microvascular structure and function were studied with assessment of vasodilatory microvascular responses using laser Doppler fluxmetry combined with iontophoresis, capillary permeability using fluorescence videomicroscopy, nailfold capillary microscopy, and serological markers of endothelial activation. No significant changes were seen in vasodilator responses to acetylcholine and sodium nitroprusside following bosentan treatment. No effect was noted on capillary permeability during treatment. The number of nailfold capillaries remained unchanged. The endothelial activation marker vascular cell adhesion molecule did not change during treatment, but levels of thrombomodulin significantly decreased after 12 weeks of treatment. Bosentan did not induce significant changes in vasodilator responses, capillary permeability, and capillary density during treatment, so no evidence was obtained for structural improvement of microvascular structure and function in this short-time mechanistic pilot study in patients with lcSSc.