• Journal of Chest Surgery
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• v.32 no.4
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• pp.364-367
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• 1999

Background: The efficacy of the hemostasis of prophylactic aprotinin after cardiac valve replacement was evaluated from January 1994 to December 1996 at Pusan National University Hospital. Material and Method: In a randomized study, 20 patients received aprotinin(2${\times}$106 KIU as a loading dose for 30 minutes after anesthesia, 1${\times}$106 KIU for priming and 5${\times}$105 KIU/hr as a maintenance dose from the completion of loading dose till skin closure) and another 20 untreated patients served as controls. Result: Aprotinin produced a significant reduction in postoperative blood loss compared with controls and significantly decreased total exposure to allogenic blood products compared with the control group(p<0.05). Conclusion: We conclude that aprotinin effectively reduces postoperative blood loss and trasfusion in patient undergoing cardiac valve replacement.

• Journal of Chest Surgery
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• v.26 no.10
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• pp.749-752
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• 1993

The 26 patients were randomly selected among patients who underwent valve replacement from February 1992 through September 1993 at National Medical Center. They were divided into two groups, one control group[n=13], the other aprotinin group[n=13]. The aprotinin group recieved 15000 KIU/kg aprotinin in the CPB priming volume and 35000 KIU/kg aprotinin intravenously during operation. We checked preoperative and postoperative hemoglobin, platelet, prothrombin time, activated partial thromboplastin time, creatinine phosphokinase and lactic dehydrogenase. There was no difference in the patient`s above clinical parameters between both groups. The platelet count in both groups decreaced after operation. These findings demonstrated that the effectiveness of aprotinin was not associated with platelet number but probably associated with a protection of platelet function and a prevention of hyperfibrinolysis. The intraoperative and postoperative blood loss and requirement of blood were significantly reduced in aprotinin group.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.2
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• pp.123-129
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• 2009

Aprotinin is used clinically in cardiopulmonary bypass surgery to reduce transfusion requirements and the inflammatory response. The mechanism of action for the anti-inflammatory effects of aprotinin is still unclear. We examined our hypothesis whether inhibitory effects of aprotinin on cytokine-induced inducible nitric oxide synthase (iNOS) expression (IL-$l\beta$ plus TNF-$\alpha$), reactive oxygen species (ROS) generation, and vascular smooth muscle cell (VSMC) proliferation were due to HO-l induction in rat VSMCs. Aprotinin induced HO-l protein expression in a dose-dependent manner, which was potentiated during inflammatory condition. Aprotinin reduced cytokine mixture (CM)-induced iNOS expression in a dose dependent manner. Furthermore, aprotinin reduced CM-induced ROS generation, cell proliferation, and phosphorylation of JNK but not of P38 and ERK1/2 kinases. Aprotinin effects were reversed by pre-treatment with the HO-l inhibitor, tin protoporphyrin IX (SnPPIX). HO-l is therefore closely involved in inflammatory-stimulated VSMC proliferation through the regulation of ROS generation and JNK phosphorylation. Our results suggest a new molecular basis for aprotinin anti-inflammatory properties.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.4
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• pp.309-313
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• 2009

Spontaneous hypertensive rats (SHR) are an established model of genetic hypertension. Vascular smooth muscle cells (VSMC) from SHR proliferate faster than those of control rats (Wistar-Kyoto rats; WKY). We tested the hypothesis that induction of heme oxygenase (HO)-1 induced by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats. Aprotinin treatment inhibited VSMC proliferation in SHR more than in normotensive rats. These inhibitory effects were associated with cell cycle arrest in the G1 phase. Tin protoporphyrin IX (SnPPIX) reversed the anti-proliferative effect of aprotinin in VSMC from SHR. The level of cyclin D was higher in VSMC of SHR than those of WKY. Aprotinin treatment downregulated the cell cycle regulator, cyclin D, but upregulated the cyclin-dependent kinase inhibitor, p21, in VSMC of SHR. Aprotinin induced HO-1 in VSMC of SHR, but not in those of control rats. Furthermore, aprotinin-induced HO-1 inhibited VSMC proliferation of SHR. Consistently, VSMC proliferation in SHR was significantly inhibited by transfection with the HO-1 gene. These results indicate that induction of HO-1 by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats.

• Journal of Chest Surgery
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• v.28 no.6
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• pp.549-556
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• 1995

We investigated the effects of aprotinin, a protease inhibitor, on isolated rat heart subjected to cardioplegia and global ischemia for 4 hours and then reperfused for 40 minutes. Before ischemia, hearts were perfused with either aprotinin 1x105KIU/L[Aprotinin group,n=8 or no aprotinin[control group,n=8 added to Krebs-Henseleite solution for 30 minutes. Hemodynamic and biochemical parameters such as heart rate, LVP, dP/dt, coronary flow and creatine kinase were measured before cardioplegia and after reperfusion 10,20,30,40 minutes. After completion of experiment, wet and dry heart weight were measured for tissue water and water content evaluation. On reperfusion, recovery of LVP of aprotinin group at each time point was significantly better than that of control group[p<0.05 , and of dP/dt at reperfusion 40 minutes[p=0.034 . No statistically significant differences in heart rate, coronary flow and CK were observed between the two groups, but aprotinin group seemed to have better recovery. No significant differences in tissue water and water content were observed between the two group.These results suggest that pretreatment of aprotinin is effective in myocardial preservation in prolonged hypothermic ischemia and reperfusion.

• Journal of Life Science
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• v.17 no.4 s.84
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• pp.515-521
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• 2007

Aprotinin, a serine protease inhibitor, has been used to ameliorate the inevitable consequences, including blood component injury after cardiac surgery with cardiopulmonary bypass (CPB). However, there are many arguments on its dosage or usage. We assessed whether administration of low dose of aprotinin in only priming solution has any beneficial effect or reduces its side effects on cardiac surgery. Thirty patients scheduled for elective cardiac surgery were randomly assigned to aprotinin group (n=15) which received aprotinin in priming solution (two million kallikrein inhibitory unit, KIU) and added one million KIU at 1 hour after the beginning of CPB or control group (n=15) which did not receive it. Hematological and biochemical variables, cytokines and cardiac marker levels, and postoperative outcomes were compared between two groups at before, during or after operation. Platelet count in aprotinin group was higher than that of control group at postoperative 24 hr. Activated partial thromboplastin time in aprotinin group was longer than that of control group at intensive care unit (ICU). Troponin-I level and postoperative blood loss volumes in aprotinin group were lower than those of control group at ICU. There were no significant differences between the two groups on the others. These results showed that low dosage of only priming solution during cardiac surgery with CPB reduced platelet destruction and postoperative bleeding, and attenuates myocardial damage. However, further studies need to be carried out with more population or pediatric patients for evaluating various aprotinin usage.

• Journal of Chest Surgery
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• v.31 no.1
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• pp.32-39
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• 1998

High-dose aprotinin(Hammersmith regimen) has been widely used for years to control postoperative bleeding and reduce blood consumption in cardiac surgery but had known to cause some side-effects and had disadvantage in cost-effectiveness. The prospective controlled study of 33 patients undergoing cardiopulmonary bypass was performed to evaluate the efficacy for reducing postoperative bleeding and unfavorable effects of low-dose aprotinin. The level of hemoglobin and platelet in the blood and the amount of postoperative bleeding were assessed preoperatively, and postoperatively for the study of hemostatic function. The level of BUN and serum creatinine in the blood, levels of urine creatinine, total protein, albumin, alpha-1-microglobulin and creatinine clearance were assessed before and after the operation for the study of renal function. The aprotinin group had a significant reduction in chest tube drainage; 243$\pm$ 123 ml versus 406$\pm$303 ml(P=0.037) during 6 hours immediate-postoperatively, 494$\pm$358 ml versus 869$\pm$570 ml(P=0.045) during 24 hours postoperatively. The ratio of alpha-1-microglobulin/creatinine and microalbumin/creatinine in the urine were slightly increased in the aprotinin group postoperatively in comparison with the control group but there were no statistically significant difference(55$\pm$23 versus 24$\pm$10 in the alpha-1-microglobulin/creatinine, 56$\pm$19 versus 38$\pm$25 in the microalbumin/creatinine at post- operative 3rd day). There were no significant difference between two groups in other parameters of renal function, too. This study showed that low-dose aprotinin is an effective means of reducing postoperative bleeding without inducing significant renal dysfunction.

• Journal of Chest Surgery
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• v.29 no.2
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• pp.185-190
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• 1996

The effect of low-dose aprotinin on hemostasis in patients undergoing cardiopulmonary bypass (CPB) for repeat valve replacement and coronary artery bypass operations were investigated. Thirty patients undergoing elective CPB from February 1993 through February 1995 at Catholic Medical Center were studied. the patients were randomly divided into two groups(15 patients per group) : group 1, receive 1, 000, 000 KIU/kg aprotinin in the CPB priming volume and 20, 000 KIU/kg aprotinin intravenously each hour during CPB ; group 2, without aprotinin administration served as the controls. The result showed that the early postoperative (during the first 24 hours) and mean postoperative total blood loss of the aprotinin group were significantly reduced than the control group (317.2 $\pm$ 89.6ml in the aprotinin group versus 821.3 $\pm$ 441.2rnl in the control group, p<0.01 ; 767.2 $\pm$ 214.1 ml in the aprotinin group versus 1562.5 $\pm$ 735.2 rnl in the control gorup, p<0.01). Total use of packed red ells and fresh frozen plasma was higher in control group(1.22 $\pm$ 0.3 units versus 4.21 $\pm$ 1.7units of packed red cells, p<0.01 : and 2.37 $\pm$ 0.4units versus 6.72 $\pm$ 0.88uni1s of fresh prozen plasma, p<0.05). We conclude the low-dose aprotinin was positive influence on postoperative blood loss in undergoing highly bleeding potency cardiac operation.

• Journal of Chest Surgery
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• v.29 no.9
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• pp.989-995
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• 1996

Excessive blood loss secondary to cardiopulmonary bypass(CPB) may be encountered after open heart surgery and platelet dysfunction appears to be especially responsible for this problem. To evaluate the effect of low-dose aprotinin during hypothermic CPB on platelet aggregation, anticoagulation and clinical hemostasis,.40 patients undergoing valve replacement using hypothermic CPB procedures were randomized to give either a low dose aprotinin(2$\times$ 106 KIU in the CPB priming sol- ution, n=20) or a placebo(n=20). During postoperative 24 hours, blood and hemoglobin loss were lower in the aprotinin group (225.5 $\pm$ 121.9ml, and 11.3$\pm$2.4g) than the control group(572.2$\pm$)35.5ml and 26.3$\pm$9.8g)(P<0.01). The total blood and hemoglobin loss were lower in the aprotinin group (622.0$\pm$ 186m1 and 14.7$\pm$6.8g) than the con- trol group (102.1 $\pm$483.5ml and 39.7$\pm$ 16.4g) (P<0.01). The amonut of packed red cell needed decreased in the aprotinin group: 197.7$\pm$56.3ml vers s 651.2: 147.5ml (P<0.01). Hemoglobin concentration, platelet counts and fibrinogen checked at fixed times perioperatively did not differ between the two groups. Platelet aggregation was induced by ADP, collagen, epinephrine and ristocetin before and after CPB. Maximum platelet aggregation was significantly reduced after CPB in control group (ranging from -31 % to -58% relative to prebypass values). Significant prolongation of activated clotting time(ACT) after 5 minute and 30 minute of hypothermic CPB were observed: 955.9 $\pm$35.1 and 967.5$\pm$32.7sec versus 743.8 $\pm$ 52.1 and 731.2: 54.6sec (P<0.01). There was no complication associated with aprotinin infusion. These results demonstrate that low-dose aprotinin significantly reduces blood loss and blood requirment and provides improved postoperative hemostasis which might be related to protection of platelet aggregation capacity.

• Journal of Chest Surgery
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• v.33 no.3
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• pp.221-229
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• 2000

Background: Thromboxane A2 and endothelin-1 are the potent vasoconstrictors affecting pulmonary pathophysiology in response to whole body inflammatin following CPB. Aprotinin, as an antiiflammatory agent, may decrease the release of such vasoactive substance from pulmonary tissues, preventing pulmonary hypertension after cardiopulmonary bypass. Material and Method: Ten mongrel dogs(Bwt. ac. 20kg) were subjected to cardioupulmonary bypass for 2 hours and postbypass pulmonary vascular resistance(0, 1, 2, 3 hours) were compared with prebypass level. The dogs were divided into 2 groups; control group(n-5) and aprotinin group(n=5). In the aprotinin group, aprotinin was administered as follows; 50,000 KIU/kg mixed in pump priming solution, 50,000 KIU/kg prebypass intravenous infusion over 30 minutes, 10,000 KIU/kg/hour postbypass continuous infusion. Prebypass and postbypass 0, 1, 2, 3 hour pulmonary vascular resistance were measured. At prebypass and postbypass 0, 90, 180 minutes, blood samples were obtained from pulmonary arterial and left atrial catherers for the assay of plasma thromboxane B2 a stable metabolite of thromboxane A2, and endothelin-1 concentrations. Result: The ratios of pustbypass over prebypass pulmonary vascular at postbypass 0, 1, 2, 3 hours were 1.28$\pm$0.20, 1.82$\pm$0.23, 1.90$\pm$0.19, 2.14$\pm$0.18 in control group, 1.58$\pm$0.18, 1.73$\pm$0.01, 1.66$\pm$0.10, 1.50$\pm$0.08 in aprotinin group ; the ratios gradually increased in control group while decreased or fluctuated after postbypass 1 hour in aprotinin group. There was statistically significant difference between control group and aprotinin group at postbypass 3 hours(P=0.014). Pulmonary arterial plasma concentration of thromboxane B2(pg/ml) at prebypass, postbypass 0, 90, 180 minutes were 346.4$\pm$61.9, 529.3$\pm$197.6, 578.3$\pm$255.8, 493.3$\pm$171.3 in control group, 323.8$\pm$118.0, 422.6$\pm$75.6, 412.3$\pm$59.9, 394.5$\pm$154.0 in aprotinin group. Left atrial concentrations were 339.3$\pm$89.2, 667.0$\pm$65.7, 731.2$\pm$192.7, 607.5$\pm$165.9 in control group, 330.0$\pm$111.2, 468.4$\pm$190.3, 425.4$\pm$193.6, 4.7.3$\pm$142.8 in aprotinin group. These results showed decrement of pulmonary thromboxane A2 generation in aprotinin group. Pulmonary arterial concentrations of endothelin-1(fmol/ml) at the same time sequence were 7.84$\pm$0.31, 13.2$\pm$0.51, 15.0$\pm$1.22, 16.3$\pm$1.73 in control group, 7.76$\pm$0.12, 15.3$\pm$0.71, 22.6$\pm$6.62, 14.9$\pm$1.11 in aprotinin group. Left atrial concentrations were 7.61$\pm$17.2, 57.1$\pm$28.4, 18.9$\pm$18.2, 31.5$\pm$20.5 in control group, 5.61$\pm$7.61, 37.0$\pm$26.2, 28.6$\pm$21.7, 37.8$\pm$30.6 in aprotinin group. These results showed that aprotinin had no effect on plasma endothelin-1 concentration after cardiopulmonary bypass. Conclusion: Administration of aprotinin during cardiopulmonary bypass could attenuate the increase in pulmonary vascular resistance after bypass. Inhibition of pulmonary thromboxane A2 generation was thought to be one of the mechanism of this effect. Aprotinin had no effect on postbypass endothelin-1 concentration.