抑肽酶对长期低温保存兔肺的保护作用的研究

目的 :探讨抑肽酶对长期低温保存兔肺保护作用。方法 :应用离体兔肺缺血再灌注模型 ,15只白兔随机分为三组 (抑肽酶组、对照组 1、对照组 2 ) ,抑肽酶组和对照组 1用Euro -Collins液进行肺灌洗和低温保存(10℃ ,2 4h)后 ,以新鲜兔血离体灌注 30min。抑肽酶组在兔血中加入抑肽酶 (2 5万KIU) ;对照组 1不用抑肽酶。对照组 2取自正常兔肺 ,不进行肺灌洗和保存。灌注中测定肺动脉氧差 (△PO2 ) ,肺动脉压 (PAP) ,灌注完毕取肺电镜观察微观结构。应用TUNEL(末端脱氧核糖核酸转移酶 (TdT)介导的dUTP缺口末端标记 )技术检测肺细胞凋亡情况。结果 :与对照组 1比较 ,抑肽酶组的动静脉氧差较大 (2 0min时差异显著 ,P <0 .0 5 ) ,肺动脉压较低 (P <0 .0 5 )。电镜观察对照组 1肺结构破坏重。细胞凋亡检测显示对照组 1细胞凋亡数目高于抑肽酶组 (P =0 .0 0 18)和对照组 2 (P =0 .0 0 0 1) ,抑肽酶组细胞凋亡数目高于对照组 2 (P =0 .0 0 0 )。结论 :抑肽酶对于长期低温保存的兔肺有保护作用。细胞凋亡可作为评价肺移植后保护效果的指标之一。     

Effects of aprotinin on endothelium-dependent relaxation of large coronary arteries

Objective: Aprotinin is widely used in heart surgery for reduction of intraoperative blood loss. But recent reports presenting results from rat aorta experiments claimed that aprotinin selectively impairs endothelium-dependent relaxation (EDR) as well as basal NO availability in concentrations similar to doses routinely used in cardiovascular surgery. An impairment of coronary EDR by aprotinin would be a great danger for any cardiothoracic intervention. We therefore tested the influence of aprotinin in the coronary arteries of a non-rodent species. Methods: Fresh coronary arteries of pigs were obtained from the local slaughterhouse and transported to our laboratory in cold oxygenated Krebs–Henseleit solution. Five-millimeter long rings were consecutively tested with or without aprotinin in concentrations of 500 KIU/ml (n = 7) or 1000 KIU/ml (n = 6) in oxygenated normothermic Krebs–Henseleit solution. PGF₂ (10 μmol/l) was used for inducing contraction and substance P (10 nmol/l) for inducing EDR, which was calculated in percentage of the precontraction. Indomethacin (10 μmol/l) was added in all measurements to eliminate the influence of prostaglandins. In additional similar experiments (n = 5), the influence of 1000 KIU/ml aprotinin on the EDR caused by the endothelium-derived hyperpolarizing factor (EDHF) was tested using l-NNA (300 μmol/l) to block all NO formation. Results: The EDR of pig coronaries (82 ± 5% or 80 ± 5% of the precontraction in the control tests before and after aprotinin exposure) was not significantly changed by 500 KIU/ml aprotinin (78 ± 7%). A small, but significant reduction of less than 1/10 of the EDR was induced by 1000 KIU/ml aprotinin (74 ± 5%). After accounting for l-NNA for NO blockage, no aprotinin-related difference remained (59 ± 6% vs 60 ± 6% in controls). Conclusion: For clinically relevant concentrations of aprotinin up to 500 KIU/ml, no significant reduction of the EDR can be found in epicardial coronary arteries of the pig. For higher doses of 1000 KIU/ml, a reduction in NO production seems to be the cause of the small but significant reduction of the EDR by aprotinin. Therefore, danger for impairment of coronary EDR by aprotinin at clinical dosage levels, as suggested by studies on rat aortas, seems to be absent in coronary arteries of a large mammalian model.     

抑肽酶对瓣膜置换术患者心肌粘附分子表达及细胞凋亡的影响

目的探讨抑肽酶对二尖瓣置换术患者围体外循环（CPB）期心肌细胞及心肌血管内皮细胞上细胞间粘附分子-1（ICAM-1）、血管细胞粘附分子-1（VCAM-1）表达及心肌细胞凋亡的影响。方法择期二尖瓣置换术患者30例,年龄24～59岁,体重46～73 kg,心功能分级Ⅱ级或Ⅲ级,随机分为2组（n=15）：对照组和抑肽酶组,抑肽酶组于CPB转机前,预充液中加入抑肽酶300万KIU,对照组则给予等容量生理盐水,分别于CPB前和CPB停止时取右心房心肌组织标本,采用免疫组织化学SP法染色,检测心肌细胞和心肌血管内皮细胞上ICAM-1、VCAM-1的表达,采用病理图像分析系统对ICAM-1、VCAM-1表达的灰度值作定量分析,采用TUNEL法检测凋亡心肌细胞。结果抑肽酶组CPB停止时ICAM-1、VCAM-1的表达低于对照组（P〈0.01）;2组CPB停止时心肌细胞凋亡指数较CPB前增高（P〈0.05）,抑肽酶组CPB停止时心肌细胞凋亡指数低于对照组（P〈0.05）。结论预充液中加入抑肽酶300万KIU可抑制二尖瓣置换术患者CPB期间心肌细胞和心肌血管内皮细胞ICAM-1、VCAM-1的表达及心肌细胞的凋亡。     

Bioavailability of 1-deamino-8-D-arginine vasopressin with an enzyme inhibitor (aprotinin) from the small intestine in healthy volunteers

Objective: The bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP), with and without an enzyme inhibitor, was studied in six healthy, male volunteers aged 19–34 years, followed for 8 h after each drug administration. Methods: For i.v. administration the subjects received 4 μg dDAVP. For intestinal administration 500 μg dDAVP was administered directly, in two separate sessions, in the first part of the duodenum via a triple-lumen channel tube. In one session a solution of isotonic polyethylene glycol (PEG) was given as a continuous enteral perfusion. In the other session a solution of PEG and aprotinin was administered enterally at the constant rate of 5 ml⋅min⁻¹ for 4 h. Plasma dDAVP was measured using a specific, sensitive radioimmunoassay and intestinal juice was collected for measurement of lipase, chymotrypsin and pH every 30 min for 5 h. Results: The intestinal chymotrypsin activity was decreased after perfusion of aprotinin while the lipase activity was not modified. After i.v. administration, the half-life of elimination of dDAVP was 1.56 h and plasma clearance 1.24 ml⋅min⋅kg⁻¹. The mean bioavailability after duodenal administration of dDAVP + aprotinin was 0.46% compared with 0.09% after duodenal administration of dDAVP alone. The bioavailability of dDAVP after direct duodenal administration of an aqueous solution was similar to that after swallowing a tablet in a previous study and increased 5 times when given together with a perfusion of an enzyme inhibitor. Received: 27 October 1995/Accepted in revised form: 26 February 1996     

45. Die Schocklunge - ein neues Behandlungsprinzip

Zusammenfassung In einer retrospektiven Studie werden an 2 Kollektiven von je 38 und 60 Patienten mit Pneumonitis (Schocklunge) zwei Behandlungsmethoden verglichen. Die erste Gruppe erhielt Heparin in Kombination mit Aprotinin. Im zweiten Kollektiv gaben wir Heparin, Frischplasma, Nicotinsäure, Methylprednisolon und alpha-Receptor-Blocker. In dem ersten Kollektiv betrug die Gesamtletalität 50%. Von den beatmeten Patienten verstarben 64%. Im zweiten Kollektiv betrug die Gesamtletalität 26,5%. Von den beatmeten Patienten verstarben 33%. Auf Grund unserer Erfolge halten wir zum jetzigen Zeitpunkt eine Kombinationstherapie mit Aprotonin für nicht mehr indiziert.     

抑肽酶对成年豚鼠心肌再灌注损伤的保护作用

目的：探索抑肽酶的心肌保护作用。方法：建立离体心脏顺行灌注后左心做功模型，２０只成年豚鼠随机分为Ａ、Ｂ两组，分别以４℃Ｓｔ．ＴｈｏｍａｓＨｏｓｐｉｔａｌｃａｒｄｉｏｐｌｅｇｉｃｓｏｌｕｔｉｏｎＮｏ．２（ＳＴＳ）和ＳＴＳ＋抑肽酶（１５０ＫＩｕｍＬＳＴＳ）为心停搏液，测定缺血（９０分钟，２０℃）前、后和再灌注（６０分钟）时心脏动力学指标，心肌腺苷酸和丙二醛含量，并行心肌电镜观察。结果：Ｂ组再灌注后的心功能恢复，腺苷酸贮备和超微结构的改善明显高于或优于Ａ组，而丙二醛含量显著低于Ａ组（Ｐ＜０．０５）。结论：抑肽酶加入ＳＴＳ中可减少氧自由基产生，对成年豚鼠心肌缺血再灌注损伤有保护作用。     

Identification of a novel pulmonary oedema producing toxin from Indian red scorpion (Mesobuthus tamulus) venom.

The experiments were conducted to identify the toxin that produces pulmonary oedema in Mesobuthus tamulus (BT) envenomed animals. Crude BT venom was subjected to Sephadex gel filtration (G-75) and the fractions were screened for optical density (OD), neurotoxicity (prolongation of compound action potential in frog sciatic nerve) and lethality. All these parameters exhibited a peak between 54-94 ml eluates. Fractions of this peak were pooled (SP) and loaded on to carboxymethyl cellulose column. The column was then eluted with increasing buffer concentrations at constant pH and temperature. Eluates were screened for neurotoxicity and OD. Four peaks of neurotoxic activity (T1-T4) were detected. T2 and T3 were lethal whereas T1 and T4 were non-lethal. T2 exhibited mainly neurotoxicity and failed to augment phenyldiguanide (PDG)-induced reflex response or to produce pulmonary oedema. T3 was having minimal neurotoxic actions but augmented PDG-reflex and produced pulmonary oedema. The effects of T3 persisted even after dialysis with 8 kDa cut-off filter but not those of T2. The T3 effects resembled toxic manifestations of BT venom and were blocked by aprotinin pre-treatment. T3 demonstrated a band at approximately 100 kDa in SDS-PAGE. The results demonstrate the presence of a lethal, high molecular weight, pulmonary oedema producing toxin in BT venom.     

抑肽酶用于减少脊柱矫形手术出血的观察

目的探讨在脊柱矫形手术应用大剂量抑肽酶减少出血量的疗效。方法对30例应用抑肽酶的脊柱矫形手术的出血量与对照组的资料进行临床分析。结果用药组比对照组的出血量显著减少。结论术前应用大剂量抑肽酶可显著减少脊柱矫形手术的出血量。     

The Effect of Antifibrinolytic Prophylaxis on Postoperative Outcomes in Patients Undergoing Cardiac Operations

Antifibrinolytic agents such as aprotinin and epsilon aminocaproic acid limit postoperative bleeding and blood transfusion in patients undergoing cardiac operations using cardiopulmonary bypass (CPB). Recent evidence suggests that these agents have adverse side effects that influence operative mortality and morbidity. We studied postoperative bleeding, transfusion rates, and operative outcomes in our patients in order to assess the efficacy of these agents during cardiac operations requiring CPB. We reviewed records of 520 patients undergoing a variety of cardiac operations between January 2005 and May 2009. We measured multiple variables including pre-operative risk factors, antifibrinolytic agent used, and outcomes of operation, such as measures of bleeding and blood transfusion, as well as serious operative morbidity and mortality. Postoperative bleeding rates varied significantly between patients receiving aprotinin and those receiving aminocaproic acid (P < 0.05). There was an associated 12% decrease in operative site bleeding in aprotinin-treated patients compared with aminocaproic acid. There was no significant difference in the transfusion rates of packed red blood cells between patients receiving aminocaproic acid or aprotinin (P > 0.05), though individuals in the aprotinin group did receive FFP more frequently than patients in the aminocaproic acid group (P < 0.05). There was no significant difference in morbidity and mortality rates between patients in either drug group (P > 0.05). Our study shows that aprotinin is more effective at controlling operative site bleeding than aminocaproic acid. Reduced operative site bleeding did not portend better outcome or differences in transfusion requirements. Aminocaproic acid remains a safe and cost-effective option for antifibrinolytic prophylaxis because of unavailability of aprotinin.     

Soluble Adhesion Molecules in Coronary Surgery and Cardiopulmonary Bypass with Pump Prime Aprotinin

Objective : The purpose of the present study was to establish whether pump prime aprotinin could influence soluble adhesion molecules in patients undergoing elective coronary artery bypass surgery. Design : Thirty patients admitted for first-time elective coronary artery bypass surgery were randomized into control or aprotinin groups. Patients in the aprotinin group received 280 mg of aprotinin in the pump prime. Plasma levels of soluble adhesion molecules were analyzed perioperatively. Results : There were no significant changes in plasma sE-selectin after the operation in either group. Plasma sP-selectin increased significantly up to 20 h after reperfusion to the myocardium. Plasma sICAM-1 decreased in the early stage after cardiopulmonary bypass (CPB), then recovered at 4 h after reperfusion and a significant increase in sICAM-1 was observed 20 h later. There were no significant differences between the groups in postoperative changes in sP-selectin ( p = 0.21) and sICAM-1 ( p = 0.91). Conclusion : Pump prime aprotinin did not influence plasma levels of E-selectin, P-selectin and ICAM-1 in the present patients. The present results do not support the concept of an anti-inflammatory effect of pump prime aprotinin.