Rationale for and study design of the sulodexide trials in Type 2 diabetic, hypertensive patients with microalbuminuria or overt nephropathy.

BACKGROUND: Patients with Type 2 diabetes and albuminuria are at high risk to progress to end-stage renal disease (ESRD). Although angiotensin receptor blockers confer renoprotection, many diabetic patients still develop overt nephropathy and reach ESRD. Glycosaminoglycans belong to the same family as heparin and heparinoids. Pilot studies with sulodexide, a glycosaminoglycan, have shown that sulodexide can reduce urinary albumin excretion rates in diabetic patients. No hard renal end-point data are available. METHODS: Two multicentre, double-masked, randomized placebo controlled trials were designed to study the renoprotective potential of sulodexide. The Sulodexide Microalbuminuria Trial examined the efficacy of sulodexide given over 26 weeks in 1000 patients with Type 2 diabetes, hypertension and microalbuminuria. The Sulodexide Overt Nephropathy Trial examined the efficacy of sulodexide in 2240 patients with Type 2 diabetes, hypertension and proteinuria > or = 900 mg/24 h. RESULTS: The primary outcome of The Sulodexide Microalbuminuria Trial was (i) conversion to normoalbuminuria and at least a 25% decrease in the urinary albumin creatinine ratio (UACR), or (ii) at least a 50% reduction in UACR. The primary outcome of The Sulodexide Overt Nephropathy Trial was time to a composite end point of doubling of serum creatinine or ESRD. CONCLUSIONS: The sulodexide nephropathy programme will document whether therapy with sulodexide confers renal protection in Type 2 diabetes and nephropathy.     

舒洛地希治疗下肢静脉溃疡的疗效和安全性

目的：研究舒洛地希治疗下肢静脉溃疡的疗效和安全性.方法：把114例患者随机分为对照组（n=53）和治疗组（n=61）,对照组患者采用伤口护理和压力绷带包扎法进行局部治疗,治疗组患者采用相同的局部治疗的同时,肌肉注射舒洛地希60 mg/d,共30 d.结果：20 d的治愈率：对照组为18.9%,治疗组为36.1%,有显著性差异（P＜0.05）;30 d的治愈率：对照组为32.0%,治疗组为52.5%,有显著性差异（P＜0.05）.治疗组溃疡面积的降低明显快于对照组.治疗过程中,所有患者均未出现严重不良反应.结论：舒洛地希治疗下肢静脉溃疡安全和有效.     

Sulodexide in the treatment of intermittent claudication. Results of a randomized, double-blind, multicentre, placebo-controlled study.

AIMS: Patients with peripheral arterial obstructive disease require treatment to prevent major cardiovascular events and to relieve intermittent claudication. The walking performance of peripheral arterial obstructive disease patients was used to evaluate the usefulness of sulodexide, a glycosaminoglycan containing fast moving heparin and dermatan sulphate. METHODS AND RESULTS: A randomized, multicentre, double-blind, placebo-controlled study was performed in 286 patients with Leriche-Fontaine stage II peripheral arterial obstructive disease. Patients received placebo (n=143) or sulodexide (n=143) for 27 weeks. The primary end-point was the doubling of the pain-free walking distance at the end of treatment, and this was achieved by 23.8% of patients treated with sulodexide and 9.1% of those on placebo (P=0.001). The pain-free walking distance increased on average (+/-SE) by 83.2+/-8.6 m (+64.7% from baseline) with sulodexide and 36.7+/-6.2 m (+29.9% from baseline) with placebo (P=0.001). The maximum walking distance increased by 142.3+/-15.8 m (+76.0% from baseline) and 54.5+/-8.4 m (+27.9% from baseline) (P<0.001), respectively. Results for patients with type II diabetes were similar to those for non-diabetic patients. Plasma fibrinogen decreased with sulodexide, but increased with placebo. CONCLUSION: Sulodexide improved the walking ability of peripheral arterial obstructive disease patients to a significantly greater extent than placebo, with a concurrent significant decrease in fibrinogen. The treatment was well tolerated.     

舒洛地特对糖尿病大鼠骨质疏松症的影响

目的：评价低分子肝素类抗凝药物舒洛地特（Sulo-dexide）对糖尿病大鼠骨质疏松症的影响．方法：将SD大鼠随机分为3组：正常对照组（C组）、糖尿病模型组（D组）、舒洛地特治疗组（S组）．D组给予腹腔注射单剂量链脲佐菌素（STZ）诱导;S组每日给予舒洛地特10mg／（kg·d）灌胃;C,D组大鼠每日给予等量生理盐水灌胃,观察12wk后各组大鼠体质量及血糖变化．应用显微镜观察大鼠骨组织显微结构并进行骨组织形态密度计量学分析,用双能X线骨密度测量仪（DEXA）测定股骨骨密度（BMD）．采用逆转录-聚合酶链反应（RT-PCR）检测骨组织骨保护素（OPG）mRNA,核因子-KB受体活化因子配体（RANKL）mRNA的表达．结果：12wk末光镜下均可见D,S组骨组织骨质疏松表现,且2组骨质疏松程度相似．D,S组平均骨小梁厚度（MTPT）均显著低于C组（P〈0．01）;平均骨小梁间距或弥散度（MTPS）均显著高于C组（P〈0．01）;S组与D组骨组织相比较,MTPT及MTPS无显著性差异．与C组相比较,D,S组骨组织BMD值显著降低（P〈0．01）;S组骨组织BMD值与D组无显著性差异．D,S组骨组织OPGmRNA明显低于C组（P〈0．05）,但RANKLmRNA表达均高于C组（P〈0．05）．D组与S组相比较,OPG mRNA及RANKL mRNA的表达无显著性差异．结论：糖尿病大鼠存在明显骨量减少和骨质疏松,舒洛地特对糖尿病大鼠骨质疏松症的骨质改变无明显影响．     

The blood pressure lowering potential of sulodexide – a systematic review and meta‐analysis

AimsSulodexide is a highly purified mixture of glycosaminoglycans that has been studied for its anti‐albuminuric potential. Considering the effects of glycosaminoglycans on endothelial function and sodium homeostasis, we hypothesized that sulodexide may lower blood pressure (BP). In this meta‐analysis, we therefore investigated the antihypertensive effects of sulodexide treatment.MethodsWe selected randomized controlled trials that investigated sulodexide treatment of at least 4 weeks and measured BP at baseline and after treatment. Two reviewers independently extracted data on study design, risk of bias, population characteristics and outcome measures. In addition, we contacted authors and pharmaceutical companies to provide missing data.ResultsEight studies, totalling 3019 subjects (mean follow‐up 4.4 months) were included. Mean age was 61 years and mean baseline BP was 135/75 mmHg. Compared with control treatment, sulodexide resulted in a significant systolic (2.2 mmHg [95% CI 0.3, 4.1], P = 0.02) and diastolic BP reduction (1.7 mmHg [95% CI 0.6, 2.9], P = 0.004). Hypertensive patients displayed the largest systolic BP and diastolic BP reductions (10.2/5.4 mmHg, P < 0.001). Higher baseline systolic and diastolic BP were significantly associated with larger systolic (r ²=0.83, P < 0.001) and diastolic BP (r ²=0.41, P = 0.02) reductions after sulodexide treatment. In addition, systolic (r ²=0.41, P = 0.03) and diastolic BP reductions (r ²=0.60, P = 0.005) were significantly associated with albuminuria reduction.ConclusionOur data suggest that sulodexide treatment results in a significant BP reduction, especially in hypertensive subjects. This indicates that endothelial glycosaminoglycans might be an independent therapy target in cardiovascular disease. Future studies should further address the BP lowering potential of sulodexide.     

舒洛地特对腹膜透析大鼠腹膜结构和功能的作用

目的观察舒洛地特对慢性腹膜透析大鼠腹膜结构和功能的作用。方法 36只SD雄性大鼠随机分为4组:空白对照组(n=6)、模型组(n=10)、低剂量[10 mg/(kg.d)]舒洛地特组(n=10)、高剂量[20 mg/(kg.d)]舒洛地特组(n=10)。透析8周后行1 h腹膜平衡试验(PET);使用全自动生化分析仪测定1 h腹膜平衡试验透出液中尿素氮(Durea)、透出液中总蛋白(Dtp)、初始腹透液葡萄糖浓度(D0)、透出液葡萄糖浓度(D1)、血浆尿素氮(Purea)及血浆总蛋白(Ptp),并计算D/Purea(说明腹膜对尿素氮清除效率)、D/Ptp(评估腹膜透析液中总蛋白丢失情况)、D1/D0(表示腹透超滤的能力)。取壁层腹膜行H-E及Masson染色观察腹膜结构变化,半定量计算腹膜厚度、腹膜单位面积血管及炎症细胞数;计算腹透液中白细胞数;ELISA法检测腹透液MCP-1及TNF-α水平;免疫组化检测壁层腹膜TGF-β1表达情况。结果与对照组相比,长期腹透大鼠腹膜间皮细胞减少,间皮下基质增厚,炎症细胞增多,血管增生明显(P<0.05),腹膜超滤量和D1/D0减少,D/Purea及D/Ptp增加(P<0.05),腹透液中白细胞数、MCP-1及TNF-α水平上调(P<0.05),脏层腹膜TGF-β1表达上调;给予舒洛地特干预后腹膜结构改变减轻,腹膜组织炎症细胞浸润和血管增生减少,腹膜功能改善,腹透液MCP-1及TNF-α水平下调(P<0.05),脏层腹膜TGF-β1表达下调。结论舒洛地特可能通过抑制腹膜慢性炎症来达到抑制腹膜纤维化及改善腹膜功能的作用。     

舒洛地特对老年高血压肾损害患者肾功能的影响

目的研究舒洛地特对老年高血压肾损害患者肾功能的保护作用。方法将90例老年高血压肾损害患者随机分为常规治疗组、缬沙坦组和舒洛地特组,均n=30,在分别给予基础治疗同时,用药2组分别服用缬沙坦80 mg.d-1和舒洛地特250 LSU.d-1,观察3 mo。检测治疗前后收缩压、舒张压、肾功能、血清光抑素C(cystatin C)、丙氨酸转氨酶、天冬氨酸转氨酶、空腹血糖、三酰甘油、总胆固醇以及24 h尿蛋白定量、尿β2-微球蛋白(β2-MG)、α1微球蛋白(α1-MG)和尿N-乙酰-β-D葡萄糖苷酶。结果 3组患者治疗前后血压均无明显变化。常规治疗组治疗后各指标均无显著变化(P>0.05);缬沙坦组和舒洛地特组治疗后尿素氮、肌酐和尿酸无显著变化(P>0.05),而24 h尿蛋白、尿α1-MG、β2-MG和NAG均显著减少(P<0.01);舒洛地特组血cystatin C明显减少(P<0.01),与缬沙坦组比较,舒洛地特组各指标减少更加显著(P<0.05或P<0.01)。结论舒洛地特可降低老年高血压肾损害患者的尿蛋白,对肾脏具有良好的保护作用。     

舒洛地特对糖尿病大鼠肾组织中IGF-1和VEGF表达的影响

目的 研究IGF-l和VEGF在大鼠糖尿病肾病(DN)发生发展中的作用,观察舒洛地特对DN的保护作用.方法 将72只大鼠平均分A组、B组、C组.每组平均分成3个小组(4,8,12周组).A组为对照组,B、C组为糖尿病模型组,A组、B组予生理盐水灌胃,C组予舒洛地特悬浊液灌胃.处死前ld分别测定24 h尿白蛋、血糖,记录各组大鼠体质量及肾质量.分别检测肾组织细胞中胰岛素样生长因子-1(IGF-1)和血管内皮生长因子(VEGF)的表达.结果 IGF-1和VEGF在A组各时间段比较均无显著性差异,B组表达明显强于A组(P均＜0.01),C组在各时间点的表达明显轻于B组(P＜0.01).结论 随着DN进展,肾组织IGF-1和VEGF表达逐渐增强,舒洛地特能降低IGF-l和VEGF的表达,可能是其肾脏保护作用的分子机制之一.