Comparative efficacy and safety of anticoagulants for prevention of venous thromboembolism after hip and knee arthroplasty

Background and purpose — New oral anticoagulants have been developed to prevent venous thromboembolism (VTE) after knee or hip arthroplasty. Although there have been several network meta-analyses (NMA) to compare different regimens, an NMA including 2 different enoxaparin doses and edoxaban has not been performed.

Methods — Standard NMA for fondaparinux, dabigatran, rivaroxaban, apixaban, edoxaban, and enoxaparin was performed. Outcome variables included a composite of total VTE and major/clinically relevant bleeding. The rank probabilities of each treatment outcome were summarized by the surface under the cumulative ranking curve.

Results — Fondaparinux, rivaroxaban, and apixaban were associated with a reduced risk of VTE compared with enoxaparin, while dabigatran was not. None of these 3 drugs increased bleeding compared with enoxaparin 30?mg twice daily. However, fondaparinux and rivaroxaban increased bleeding compared with enoxaparin 40?mg once daily, while apixaban did not. Apixaban was even associated with decreased major/clinically relevant bleeding compared with enoxaparin 30?mg twice daily or 40?mg once daily. When edoxaban was included in the NMA, edoxaban decreased VTE and did not increase bleeding compared with enoxaparin.

Interpretation — A higher efficacy of fondaparinux and rivaroxaban compared with enoxaparin was associated with increased bleeding tendency, while apixaban was superior to enoxaparin regarding both efficacy and safety. A clustered ranking plot showed that apixaban might be the most preferred regarding efficacy and safety. However, our results were driven by indirect statistical inference and were limited by the heterogeneity of the bleeding outcome definitions, drug initiation and continuation, and different surgery types.     

Microsurgical repair after crush-avulsion injury of the femoral vein in rats: prevention of microvascular thrombosis with recombinant human tissue-type plasminogen activator (rt-PA).

Vein thrombosis is often encountered in microsurgery, especially in the case of crush-avulsion injuries. The aim of this study was to investigate the effect of systemic administration of recombinant tissue-type plasminogen activator (rt-PA) on the patency of the femoral vein of the rat, which had previously sustained a crush-avulsion injury. The study consisted of 3 groups of male Wistar rats, 20 animals each. A standardized crush-avulsion injury model was used. After microvascular repair of the femoral vein, the animals received either normal saline (group A), heparin 100 U/kg body weight (group B), or rt-PA 3.5 mg/kg body weight (group C) systemically. Patency tests were performed at 20 minutes, 48 hours, and 1 week after blood flow reestablishment. According to our results, the patency rate of the rt-PA group was significantly higher than in both the control and heparin groups.     

Comparative study of isovolemic hemodilution with 3% albumin, dextran-40, and prophylactic enoxaparin (LMWH) on thrombus formation at venous microanastomosis in rats

The objective of the present investigation was to compare the effect of isovolemic hemodilution with 3% albumin, dextran-40, and enoxaparin on the prevention of thrombosis in femoral vein microanastomosis using an experimental model in rats. Forty male Wistar rats were allocated into four groups: group 1, control, thrombogenic model without previous treatment; group 2, hemodiluted, thrombogenic model with previous hemodilution; group 3, dextran-40, thrombogenic model with dextran infusion (10 ml/kg), and group 4, enoxaparin, thrombogenic model with administration of enoxaparin (0.5 mg/kg/day). Hemostatic parameters, hematologic examinations, patency of anastomosis, and histopathological examination were evaluated. The hemostatic parameters were similar in the four groups studied. Group hemodiluted, dextran-40, and enoxaparin showed significantly reduced number of red blood cells and platelets as compared with the control group. The hemodilution significantly increased the patency rates of the vein at 20 min and 48 h. Dextran-40 and enoxaparin improved the patency of the vein only at 20 min, but failed to show a significant increase in the final patency at 48 h. After 48 h, the rate of venous thrombosis, as evaluated microscopically, was significantly decreased in hemodiluted animals (1/8) as compared with controls (10/10); in rats treated with dextran-40 (7/10) and enoxaparin (5/10) the rate of venous thrombosis was significantly higher as compared with rats of the group hemodiluted. Based on these observations, it can be concluded that hemodilution with albumin 3% was a safe and more adequate procedure than the use of the schemes of administration of dextran-40 and enoxaparin used in this study to prevent thrombus formation at femoral vein microanastomosis in rats. Since hemodilution promotes reduction in blood viscosity and in erythrocyte and platelet aggregation as well as dilution of the coagulation factors themselves, its use could provide better microcirculatory blood perfusion, decreasing the risk of thrombosis, and making possible safer microsurgical procedures.     

Antithrombotic prescriptions for many general surgery patients significantly increases the likelihood of post-operative bleeding complications

BackgroundThe investigators hypothesized that despite cessation recommendations for peri-operative antithrombotic management in the elective setting, the use of these drugs is likely associated with increased odds for bleeding complications.MethodsHumana® insurance claims (22 million covered lives) from 2007 through 2017 were analyzed. Only patients undergoing elective general surgery procedures were included. Patient Safety Indicator 09 (PSI-09) coding for post-operative hemorrhage and hematoma were analyzed.ResultsDespite the existence of peri-operative management guidelines, patients prescribed antithrombotic agents were 2.3 times more likely to develop post-operative bleeding complications (OR: 2.3436, 95% CI: 2.2155–2.4792, P < 0.0001). Nearly all antithrombotics prescribed in the pre-operative period led to a two-fold increased likelihood of post-operative bleeding—the odds ratios of enoxaparin and rivaroxaban approached seven.ConclusionThe data should remind surgeons to closely monitor the peri-operative management and post-operative course of patients pre-operatively prescribed antithrombotics—especially enoxaparin and rivaroxaban given the high risk of postoperative bleeding complications.     

Microvascular repair following a modified crush-avulsion injury in a rat model: effect of recombinant human tissue-type plasminogen activator on the patency rate

The failure rate of replantations following a crush-avulsion type injury is high. This study has been designed to reproduce an effective standardized crush-avulsion injury model to the femoral artery of the rat and evaluate the antithrombotic efficacy of systemic intravenous administration of recombinant human tissue-type plasminogen activator (rt-PA). The crush-avulsion injury was reproduced by using a bulldog clamp and two hemostats and followed by microvascular repair. The animals were divided into three groups of 20 rats each and received either normal saline, heparin 100 U/kg body weight, or rt-PA 3.5 mg/kg body weight intravenously. Patency tests were performed 20 min and 48 h after blood flow reestablishment. Results showed that this experimental crush-avulsion injury model ensures low patency in the control group, whereas systemic rt-PA administration improves the patency rate statistically significantly compared to control and heparin groups at both 20 min and 48 h postrevascularization.     

Effects of enoxaparin,standard heparin,and streptokinase on the patency of anastomoses in severely crushed arteries

The effects of topical irrigation with three antithrombotic agents on the patency of anastomosed arteries following crush injury were examined. Following an impact crush injury with a 25 kg crush load, the femoral arteries of rats were divided and then anastomosed. During anastomoses, the vessel lumina were topically irrigated with saline, streptokinase, standard heparin, or enoxaparin (a low molecular weight heparin). The results were evaluated by patency test and histology up to day 56. The thrombosis rate at days 1 and 7 was statistically lower (P<0.05) in the standard heparin and the enoxaparin groups than in the other two groups. The difference between the standard heparin and the enoxaparin groups was not statistically significant. Histology at day 1 showed that thrombus in the occluded vessels adhered to the exposed adventitia in the crushed area or the adventitia was covered by fibrin, red blood cells, and platelet mesh in the patent vessels. The results showed that 1) topical irrigation with standard heparin or enoxaparin solution significantly reduced the thrombosis rate at the anastomosis site of the crushed arteries; and 2) enoxaparin was as effective an antithrombotic agent as standard heparin when topically applied during microvascular anastomoses. © 1995 Wiley-Liss, Inc.     

Comparison of minor bleeding complications using dabigatran or enoxaparin after cemented total hip arthroplasty

Background

Orally administered chemical thromboprophylactic agents for total hip replacement (THR) have become popular in recent years. Certain clinical trials suggest that the efficacy and the risk of major bleeding after administration of direct thrombin inhibitor dabigatran etexilate are equivalent to the clinical trial comparator, subcutaneous low-molecular-weight heparin enoxaparin. Our aim was to compare and evaluate the incidence of minor haemorrhagic and soft-tissue adverse effects of enoxaparin and dabigatran.

Materials and methods

122 patients who were treated by elective cemented primary THR were enrolled in our quasi-randomised study. Two groups were formed according to which perioperative thromboprophylactic agent was used: 61 patients in enoxaparin group versus 61 patients in dabigatran group. Thigh volume changes, calculated perioperative blood loss, area of haematoma, wound bleeding, duration of wound discharge and intensity of serous wound discharge on postoperative day 3 and day 7 were recorded.

Results

The duration and intensity of serous wound discharge differed significantly between the two groups. Duration of wound discharge after drain removal was 2.2 (±2.7) days in the dabigatran group and 1.2 (±1.9) days in the enoxaparin group (p < 0.05). Significant increase in serous discharge was found in the dabigatran group (p < 0.05) on third and seventh postoperative days compared to the enoxaparin group.

Conclusion

Both thromboprophylactic agents were found to have appropriate antithrombotic effects after THR. However, dabigatran was associated with an increased incidence of prolonged serous wound discharge, which might cause longer hospitalization and might instigate the use of prolonged antibiotic prophylaxis.     

The Pony as an Animal Model for Vascular Implants

This study evaluated the pony as a potentially suitable model for vascular implant research. Healthy, conditioned ponies were randomly assigned to one of three groups: group I, carotid artery autografts (n = 6); group II, e-PTFE carotid interpositional grafts (n = 5); and group III, e-PTFE carotid interpositional grafts plus aspirin (10 mg/kg) and dipyridamole (3.5 mg/kg) drug administration. It was found that autografts remained patent longest (mean = 396.2 days; grafts were still patent at time of writing) followed by group III grafts (157.5 days), with group II grafts remaining patent for the shortest duration (61.1 days), (p < 0.01). Patency was determined using two-dimensional real-time ultrasonography with Doppler velocimetry and/or arteriography. It was demonstrated that the pony's response to antithrombotic drugs was consistent and comparable to that in other animal models, both with respect to platelet function and affect on patency rate. The combination of the ease of surgical manipulation, drug administration, and platelet function testing, the comparable size of the pony and its heart and blood vessels to that of an adult human, the long life span of ponies, and the patency results of this study have demonstrated that the pony is a valuable animal model for vascular research.     

The pony as an animal model for vascular implants

This study evaluated the pony as a potentially suitable model for vascular implant research. Healthy, conditioned ponies were randomly assigned to one of three groups: group I, carotid artery autografts (n = 6); group II, e-PTFE carotid interpositional grafts (n = 5); and group III, e-PTFE carotid interpositional grafts plus aspirin (10 mg/kg) and dipyridamole (3.5 mg/kg) drug administration. It was found that autografts remained patent longest (mean = 396.2 days; grafts were still patent at time of writing) followed by group III grafts (157.5 days), with group II grafts remaining patent for the shortest duration (61.1 days), (p less than 0.01). Patency was determined using two-dimensional real-time ultrasonography with Doppler velocimetry and/or arteriography. It was demonstrated that the pony's response to antithrombotic drugs was consistent and comparable to that in other animal models, both with respect to platelet function and affect on patency rate. The combination of the ease of surgical manipulation, drug administration, and platelet function testing, the comparable size of the pony and its heart and blood vessels to that of an adult human, the long life span of ponies, and the patency results of this study have demonstrated that the pony is a valuable animal model for vascular research.     

Safety and Efficacy of Rivaroxaban in Primary Total Hip and Knee Arthroplasty

BackgroundAn optimal venous thromboembolism prophylaxis agent should balance efficacy and safety. While rivaroxaban provides effective venous thromboembolism prophylaxis after total joint arthroplasty, it may be associated with higher rates of bleeding. This study aimed to compare the safety and efficacy of rivaroxaban to aspirin and enoxaparin.MethodsA large national database was queried for patients who underwent elective primary total hip (THA) or total knee arthroplasty (TKA) from January 2015 through December 2020 who received rivaroxaban, aspirin, or enoxaparin. Multivariate analyses were performed to assess the 90-day risk of bleeding and thromboembolic complications. Among TKA patients identified, 86,721 (10.8%) received rivaroxaban, 408,038 (50.8%) received aspirin, and 108,377 (13.5%) received enoxaparin. Among THA patients, 42,469 (9.5%) received rivaroxaban, 242,876 (54.5%) received aspirin, and 59,727 (13.4%) received enoxaparin.ResultsAfter accounting for confounding factors, rivaroxaban was associated with increased risk of transfusion (TKA: adjusted odds ratio [aOR] = 2.58, P < .001; THA: aOR 1.64, P < .001), pulmonary embolism (TKA: aOR = 1.25, P = .007), and deep vein thrombosis (TKA: aOR = 1.13, P = .022) compared to aspirin. Compared to enoxaparin, rivaroxaban was associated with an increased risk of combined bleeding events (TKA: aOR = 1.07, P < .001, THA: aOR = 1.11, P < .001), but decreased risk of combined prothrombotic events (THA: aOR = 0.85, P = .036).ConclusionRivaroxaban chemoprophylaxis following TKA and THA was associated with an increased risk of bleeding and prothrombotic complications compared to aspirin and enoxaparin.     

Microvascular repair following crush-avulsion type injury with vein grafts: effect of direct inhibitors of thrombin on patency rate

The aim of this study was to develop a standardized effective thrombogenic arterial anastomosis model, as usually encountered in clinical practice, and to offer a detailed evaluation of the antithrombotic effect of thrombin's direct inhibitors, antithrombin III and hirudin, as locally applied. Wistar rats were divided into four groups of 12 animals each. The carotid artery sustained a standardized crush-avulsion-type injury (groups B-D). A segment of the afflicted area was removed and replaced by a microvenous graft. Group A had no crush-avulsion injury inflicted; a microvenous graft replaced a simple resection from the center of the carotid artery. During microvascular anastomoses, normal saline (groups A and B), recombinant hirudin (group C), or antithrombin III (group D) were locally applied. Bleeding times were recorded, and patency tests were performed 20 min, 48 h, and 1 week after blood flow reestablishment. All grafts were harvested and examined histologically. Patency tests, 1 week postrevascularization, demonstrated that this experimental crush-avulsion injury model ensured low patency in group B (25%), whereas group A, which had no injury inflicted, achieved a 100% patency rate. The local application of hirudin and antithrombin III significantly increased bleeding times as well as the patency rate (92% and 75%, respectively) compared to group B. These findings indicate the efficiency of the experimental model and the potential use of thrombin's direct inhibitors in microvascular surgery.     

Exploration of the intravascular stenting method for sub 1-mm vessels

The intravascular stenting (IVaS) method was published by Narushima and Koshima in 2008. This method involves using a monofilament nylon stent to make the anastomosis of small vessels easier. The aim of this study was to explore the IVaS technique to determine its advantages, disadvantages, and usefulness for inexperienced microsurgeons and also for more experienced practitioners during difficult anastomoses. The study was approved by the Catholic University of Louvain Animal Experimentation Ethics Committee. The study was done on 20 Wistar rats; each rat acting as his own control. Group 1 had an anastomosis done with the IVaS technique on the femoral artery. Group 2 had a classic end-to-end anastomosis without a stent. All anastomoses were performed by the same trainee surgeon with 4 months experience in microsurgery. The diameter of the external artery, distance between the double clamp forceps, stent length, number of sutures, stent preparation, and installation time and suture time were all measured. Anastomotic patency was verified using O'Brien's Patency test. The rats were anesthetized 1 week later to reassess the patency of the vessels. While the anastomotic time was shorter in the stent group, the preparation time was longer and so the total time to perform the anastomosis in both groups was the same. All vessels were patent at the completion of the anastomosis. At 1 week, patency rates were identical (83.3%) in both groups. The study shows an improvement in suturing time in the IVaS group. The time saved is equivalent to the time required for preparation and installation of the stent. At 7 days, the Patency test was identical for the two groups (83.3%). IVaS technique is a useful method of vessels anastomosis especially for junior surgeons. The reason why the patency rate was not 100% at 1 week may be because of excessive manipulation of the stent causing thrombosis in the IVaS group and imperfections in suturing technique by a trainee surgeon. Different aspects of the method are open for discussion such as consideration of the stent size and execution of the anastomosis. The IVaS technique helps in the execution of anastomosis in microsurgery and allows for more precise suturing. Care, however, must be taken in its execution and manipulation so as to avoid any lesions of the intima of the vessels.     

三种抗凝药物在单侧全膝关节置换术后预防静脉血栓性疾病的病例对照研究

目的:探讨3种不同抗凝药物在单侧全膝关节置换术后预防静脉血栓栓塞症的有效性和安全性。方法:收集2011年11月至2014年3月因膝关节骨性关节炎行单侧全膝关节置换术患者149例临床资料,其中男66例,女83例;年龄48～76岁。按抗凝药物不同分为阿司匹林组、低分子肝素组和利伐沙班组,阿司匹林组48例,男23例,女25例,平均年龄(61.52±13.42)岁;低分子肝素组54例,男20例,女34例,平均年龄(64.37±11.81)岁;利伐沙班组47例,男23例,女24例,平均年龄(63.83±12.04)岁。分别观察3组患者术后6、8、12周下肢深静脉血栓形成,肺栓塞及出血并发症(包括切口瘀斑、切口血肿等局部并发症,消化系统、心脑血管系统、泌尿系统出血等出血事件).结果:阿司匹林组48例,下肢深静脉血栓形成 4例,肺栓塞1例,出血并发症2例;低分子肝素组54例,下肢深静脉血栓形成3例,肺栓塞1例,出血并发症3例;利伐沙班组47例,下肢深静脉血栓形成3例,肺栓塞0例,出血并发症11例。3组下肢深静脉血栓形成、肺栓塞发生率差异无统计学意义(P>0.05),出血并发症发生率利伐沙班组高于阿司匹林、低分子肝素组。结论:阿司匹林、低分子肝素、利伐沙班均能有效预防全膝关节置换术后深静脉血栓的发生,且疗效相近。利伐沙班引起出血并发症发生率高,安全性须进一步研究。     

几种抗凝药物预防损伤后小动脉血栓形成的实验研究

目的观察利伐沙班、氯吡格雷、依诺肝素钠等几种抗凝药物预防损伤后小动脉血栓形成的效果。方法损伤大鼠股动脉制作血栓模型,将大鼠分5组：a组：术前至术后1周,每日1次依诺肝素钠注射;b组：术前至术后1周,每日1次利伐沙班灌胃;c组：术前至术后1周,每日1次氯吡格雷灌胃;d组（肝素对照组）：术前至术后1周,每日2次注射肝素;e组（空白对照组）：术前至术后1周,每日1次注射等容量生理盐水。术后2h及1周检查吻合口通畅情况,术后1周测定大鼠血浆活化的部分凝血活酶时间（APTT）和凝血酶原时间（PT）。结果a、b、c、d组各时间点的吻合12I通畅率比e组均有非常显著性的提高,但其中c组较低,差异均有统计学意义,a、b、d组基本相同,差异无统计学意义;a组切口皮下出现张力性血肿1处,d组切口皮下出现张力性血肿4处,其他组未出现血肿;d组术后1周A阿T、PT较其它4组延长,与空白对照组及c组相比差异性有显著性意义（P〈0．05）,a、b、c三组问及其与对照组相比APlT、PT差异无统计学意义（P〉0．05）。结论利伐沙班、氯吡格雷、依诺肝素钠等抗凝药物在不增加出血倾向的前提下能预防损伤小动脉吻合口的血栓形成,氯毗格雷相对利伐沙班、依诺肝素抗凝效果较差,其中利伐沙班仅须每日1次口服给药,使用方便,依从性、耐受性更好,可作为显微外科抗凝用药的理想选择。     

Rivaroxaban and dabigatran etexilate: two new oral anticoagulants for extended postoperative prevention of venous thromboembolism after elective total hip arthroplasty

Extended thromboprophylaxis is vital in patients undergoing total hip arthroplasty (THA) because of the prolonged risk of venous thromboembolism (VTE). Despite evidence that extended prophylaxis can reduce the incidence of symptomatic VTE in this high-risk patient population and the evidence-based guideline recommendations, a large proportion of patients still do not receive an adequate duration of thromboprophylaxis. This is partly due to the limitations of conventional anticoagulants, such as the subcutaneous route of administration or the requirement for routine coagulation monitoring and dose adjustment. New oral anticoagulants (such as the direct thrombin inhibitor dabigatran etexilate and the Factor Xa inhibitor rivaroxaban) could address the current unmet need. Phase III clinical studies in VTE prevention in patients undergoing THA and total knee arthroplasty (TKA) showed that dabigatran etexilate was non-inferior to the EU regimen of enoxaparin, but did not achieve non-inferiority to the US regimen of enoxaparin. In contrast, rivaroxaban demonstrated superiority to both enoxaparin regimens for the prevention of VTE after THA and TKA, without a significant increase in major bleeding rates. Their convenient, once-daily, fixed dosing, with no need for routine coagulation monitoring, could facilitate adherence to evidence-based guideline recommendations of extended thromboprophylaxis after THA.     

单侧全膝关节置换术后依诺肝素与利伐沙班抗凝效果的随机对照研究

背景：全膝关节置换（total knee arthroplasty,TKA）术后使用低分子肝素抗凝已被证实具有较好的有效性和安全性,而新的口服抗凝药物—利伐沙班在中国患者中的临床效果有待证实。目的：分析依诺肝素与利伐沙班在一期单侧TKA术后的抗凝效果。方法：2010年1月至2010年4月因膝关节骨关节炎（osteoarthritis,OA）行一期单侧TKA患者75例,前瞻性随机分为A组（术后使用2周依诺肝素抗凝）、B组（术后先后使用2周依诺肝素抗凝及2周利伐沙班抗凝）和C组（术后使用4周利伐沙班抗凝）。结果：3组患者间在平均年龄、体重指数、术前及术后2周HSS评分、手术时间、术后2周下肢周径变化最大值等指标方面无显著性差异;术后2周时下肢静脉彩超结果均未发现明显血栓形成,但A组术后4周时1例患者出现术侧腓肠肌内肌间静脉血栓,经单纯抗凝治疗6周后血栓消失。术后2周内A组及B组术后皮下淤斑最大面积显著大于C组（P〈0.05）,而A、B两组间无显著性差异。结论：依诺肝素及利伐沙班在预防TKA术后静脉血栓栓塞症（venous thromboembolism,VTE）方面均有良好效果,但依诺肝素抗凝后皮下淤斑现象较利伐沙班更明显。术后抗凝2周可能不足以预防迟发性VTE。     

Dose response of enoxaparin at the cremaster muscle flap microcirculation

The effects of different dosages of enoxaparin (Lovenox), a low molecular-weight heparin, on microcirculation were investigated. The cremaster muscle model for intravital microscopy was used. Four groups were studied: in group I (n = 6), the controls no agent was given; in group II (n = 6), enoxaparin (2 mg/kg s.c.), in group III, (n = 6), enoxaparin (4 mg/kg s.c.); and in group IV, (n = 6), exoxaparin (8 mg/kg s.c.). These agents were injected before muscle dissection. All animals were observed under intravital microscopy, and measurements of capillary density and red blood cell velocity were taken at 2, 3, 5, and 7 h following subcutaneous enoxaparin injection. Statistical analysis revealed that the capillary density significantly increased in group II and group III, respectively, (by 33% (P < 0.0001) and 25% (P < 0.01) when compared to group I at the fifth hour. Group IV was not significantly different from group I in capillary density. There was no significant difference in red blood cell velocity in any of the groups. Propensity for bleeding was not observed in any of the groups during the dissections and observation periods except in group IV. In conclusion subcutaneous administration of 2 mg/kg enoxaparin improves (by 33%) capillary density without any bleeding complications at the cremaster muscle flap microcirculation at the fifth hour following injection (P < 0.0001). (c) 2005 Wiley-Liss, Inc. Microsurgery 25:147-151, 2005.     

Per-operative topical administration of ZK 36 374 (Iloprost) acts favorably on patency of small artery anastomoses in rats

Aspirin (group I, 20 mg/kg, 0.5 hour preoperatively, ip, xylocaine (group II, topical administration of 1 ml of a 2% solution), and ZK 36,374 (Iloprost) either pre- or per- or postoperatively (group III, 10 micrograms/kg 0.5 hour peroperatively iv; group IV, topical administration of 1 ml of a solution containing 25 micrograms/ml peroperatively; and group V, 10 micrograms/kg 0.5 hour postoperatively iv) were given to groups of BN female rats in order to improve the patency rate of small artery (less than 0.5 mm) anastomoses. The rats in group VI received saline peroperatively by topical application, this group served as a control. The patency was established by means of arteriography and macroscopical examination. Neither aspirin nor xylocaine improved the number of successful anastomoses. However, Iloprost administered topically, while performing the anastomosis, substantially improved the patency rate when compared with group VI, the control group. In the control group only five out of 21 animals showed patent anastomoses, whereas in group IV (Iloprost, topical administration) seven out of ten operations were successful. The results suggest that Iloprost applied locally could be helpful in clinical microsurgery for elective operations as well as in replantation surgery.     

Effects of eplerenone on heart and kidney in two-kidney, one-clip rats

BACKGROUND: The role of aldosterone has been less investigated compared to the renin-angiotensin-aldosterone system in renovascular hypertension. The purpose of the present study was to compare the effects of a selective aldosterone receptor blocker, eplerenone (EP), and an angiotensin II receptor type 1 antagonist (AT1RA), losartan (LO) on cardiac and renal damage produced by two-kidney, one-clip (2K-1C) renovascular hypertension in rats. METHOD: Wistar rats (n = 48) were placed on one of six groups. Group 1 received sham operation. From group 2 to 6, all rats were made as 2K-1C renovascular hypertension. Group 2 received vehicle. Group 3 orally received 100 mg/kg/day of EP from the initiation of the study. Group 4 received 100 mg/kg/day of LO, from the initiation of the study. Groups 5 and 6 received EP and LO from the 4th week after the clipping respectively. Systolic blood pressure (SBP) and urinary protein excretion (UPE) were measured before and every 2 weeks. The remnant kidney was obtained for histopathological analysis and for measurement of endothelial cell nitric oxide synthase (ecNOS) gene expression (GE). RESULTS: SBP increased in the placebo group (132.1 +/- 2.4 vs. 115.0 +/- 0.6 mm Hg in sham group at week 10, p = 0.019). Treatment with LO or EP from the beginning of the study decreased SBP significantly as measured in the sham group at week 10. The placebo group developed significant UPE (21.7 +/- 1.9 mg/day) compared with the sham group (13.4 +/- 0.8 mg/day, p < 0.05). Treatment with both LO (12.5 +/- 1.5 mg/day, p < 0.01 vs. placebo) and EP (14.8 +/- 1.0 mg/ day, p < 0.05 vs. placebo) significantly decreased UPE. On the other hand, the late start of treatment with EP failed to decrease the increased UPE. UPEs were not significantly different between the LO- and EP-treated groups throughout the study. There was no significant pathological change in heart and kidney in all groups. In heart, ecNOS GE was significantly increased in the EP-treated (from the beginning of the study) rats compared with placebo group (0.47 +/- 0.01 vs. 0.43 +/- 0.01, p < 0.05). LO did not have an effect on ecNOS GE in heart. In aorta, ecNOS GE was significantly increased in the two EP-treated groups compared with the placebo group (0.22 +/- 0.01, 0.22 +/- 0.02 vs. 0.15 +/- 0.01, p < 0.05, respectively). LO also did not have an effect on ecNOS GE in aorta. In kidney, ecNOS GE was significantly increased in the LO group (from the beginning of the study) and two EP-treated groups compared with placebo. CONCLUSION: This study demonstrated that EP treatment significantly reduced SBP and UPE compared with placebo in both development and established 2K-1C renovascular hypertension. EP was as effective as LO in lowering the blood pressure of this renin-dependent animal model.     

Trimetazidine has protective effects on spermatogenesis in a streptozotocin‐induced diabetic rat model

The aim of this study was to investigate the protective effects of trimetazidine (TMZ), as an antioxidant agent, on streptozotocin (STZ)‐induced diabetic rats. A total of 50 male Sprague Dawley rats were randomly classified into five groups as follows: Group 1 (control), Group 2 (STZ‐induced diabetic rats), Group 3 (STZ‐induced diabetic rats treated orally with 1 cc/day isotonic saline), Group 4 (diabetic rats treated orally with 10 mg/kg/day TMZ) and Group 5 (diabetic rats treated orally with 20 mg/kg/day TMZ). After 8 weeks, orchiectomy was carried out. Histopathological and electron microscopic examinations were performed in all groups. In groups 1 and 5, the structural and ultra‐structural findings of the testicular tissue and spermatogenesis were found normal. In groups 2, 3 and 4, similar results were obtained in terms of the impaired testicular architecture and degeneration of spermatogenesis. The administration of an optimal dose of TMZ protects against the harmful effects of diabetes mellitus on spermatogenesis in rats. TMZ therapy can be used to maintain normal spermatogenesis in diabetic rats.