• Journal of Chest Surgery
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• 제32권4호
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• pp.364-367
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• 1999

배경: 1994년 1월부터 1996년 12월까지 부산대학교병원 흉부외과에서 인공판막 치환술을 받은 40명의 환자를 대상으로 aprotinin 투여군 20명과 투여하지않은 대조군 20명으로 나누어 비교 분석하였다. 대상 및 방법: Aprotinin 투여군은 수술시작 30분이내에 200만 KIU를 정주하고 충전액에 100만 KIU를 첨가하였고 유지용량으로 수술하는 동안 시간당 50만 KIU를 투여하였다. 술전과 술후 혈색소치, 혈소판치, prothrombin time을 측정하였고 출혈량은 술후 6시간, 24시간 술후 총량을 측정하였다. 결과: 출혈량은 Aprotinin 투여군에서 대조군보다 통계학적으로 유의하게 적었고 수혈량도 Aprotinin 투여군에서 대조군보다 적었다. 결론: 저자는 aprotinin의 사용이 개심술시 출혈량과 수혈요구량을 현저히 줄이고 술후 지혈에도 도움을 준다고 생각된다.

• Journal of Chest Surgery
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• 제26권10호
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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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• 제13권2호
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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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• 제13권4호
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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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• 제28권6호
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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.

• 생명과학회지
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• 제17권4호
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• pp.515-521
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• 2007

Serine protease 억제약물인 aprotinin은 체외순환을 동반한 심장수술 후 필연적으로 발생하는 혈액성분 손상을 포함한 유해한 합병증을 감소시키기 위해 사용한다. 그러나 이 약물의 용량이나 사용법에 대해 여전히 논란의 여지가 있다. 본 연구자들은 심장수술 동안 심폐기 충전액에 저 용량의 aprotinin을 투여하여 그 효과를 연구하였다. 30명의 성인 심장수술 환자들을 대상으로 aprotinin 투여군(n=15)과 대조군(n=15)으로 나눈 뒤 수술 전, 동안, 후의 시기에 혈액학적 및 생화학적 변수들, 사이토카인 및 심장 표지자, 수술 후 각종 임상결과들을 비교분석 하였다. 혈소판수와 activated partial thromboplastin time은 수술 후 24시간 때 아프로티닌군이 대조군 보다 유의하게 높았다. Troponin-I 농도와 수술 후 출혈량은 아프로티닌군이 대조군보다 유의하게 낮았다. 이러한 결과들을 볼 때 심장수술시 저 용량의 aprotinin을 심폐기 충전액에 첨가하는 방법은 혈소판의 파괴를 줄여줘 수술 후 출혈량의 감소를 제공해주며 심근보호 효과가 있는 것으로 판단된다. 향후 더 많은 성인 환자군과 소아환자에 대한 다양한 연구가 더 많이 수행되어야 할 것으로 사료된다.

• Journal of Chest Surgery
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• 제31권1호
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• pp.32-39
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• 1998

체외순환에 의한 개심술시 술후 출혈을 줄이고 아울러 혈액제재 투여를 감소하기 위하여 여러병원에서 최근 수년간 aprotinin을 Hammersmith 요법에 준하여 고용량으로 투여해 오면서 위 약제의 부작용이나 경제적 비용도 함께 고려되어 오고있다. 특히 aprotinin은 신장에서 대사되기 때문에 다른 부작용보다 aprotinin이 미치는 신기능장애에 대하여서도 논의되고 있다. aprotinin을 저용량으로 투여하였을 때 그 지혈효과와 아울러 신기능에 미치는 영향을 조사하기 위하여 체외순환을 시행한 33 명의 환자를 각각 무작위로 실험군(16명)과 대조군(17 명)으로 나누어 전향적 연구를 시행하였다. 출혈 감소의 정도를 파악하기 위하여 혈중 혈색소와 혈소판수치 및 수술후 출혈량을 수술전, 수술후에 측정하였고, 신기능 장애정도를 파악하기 위하여 혈중 BUN과 creatinine, 그리고 뇨 creatinine, 총단백질량, albumin, 및 alpha-1-microglobulin 수치를 수술전후로 측정하였다. 수술직후 6 시간동안 출혈량은 대조군보다 aprotinin군에서 상당히 감소되어(406$\pm$303 ml vs 243$\pm$123 ml ; P = 0.037) 통계적으로 유의한 차이를 보였을 뿐만아니라 수술후 24 시간 동안 출혈량도 통계적으로 의미있게 감소되었다( 869$\pm$570 ml vs 494$\pm$358 ml ; P = 0.045). 뇨중 alpha-1-microglobulin/creatinine 이나 microalbumin/creatinine는 대조군에 비하여 aprotinin군에서 수술후에 증가되었으나 통계적으로 유의한 차이는 없었다 (수술후 3 일째 alpha-1-microglobulin/creatinine; 24$\pm$10 vs 55$\pm$23, microalbumin/creatinine ; 38$\pm$25 vs 56$\pm$19 ). 일반적인 다른 신기능지표상에서도 두 군에서 유의한 차이는 없었다. 본연구에서 aprotinin을 저용량으로 투여함으로써 개심술시 체외순환후 발생하는 출혈량을 줄일 수 있을 뿐만 아니라 신기능에 영향이 없었다.

• Journal of Chest Surgery
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• 제29권2호
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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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• 제29권9호
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• pp.989-995
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• 1996

체외순환을 이용한 개심술후 혈소판기능부전에 의한 비정상적인 출혈은 수술 사망율 및 이환율의 증가를 초래한다. 본 논문에서는 체외순환시 aprotinin을 투여하여 임상적 지혈 및 혈소판기능보존에 대한 효과를 관찰하기 위해 인공판막치 환술을 받은 40명의 환자를 대상으로 low-dose aprotinln 투여군 20명, 대조군 20명으로 나누어 그 효과를 비교 분석하였다. Aprotinin 투여군에서 대조군에 비해 약 40%의 출혈감소(622.0$\pm$ 186m1 versus 1021 $\pm$483.5ml, p<0.01) 및 약 63%의 혈색소 손실(14.7 $\pm$6.8g versus 39.7$\pm$ 16.4g, p<0.01)을 줄일 수 있었으며 약 70%의 수혈감 소(197.7$\pm$ 56.3ml versus 651.2 $\pm$ 147.5ml, p<0.01) 효과를 얻을 수 있었다. 또한 투여 군에서 혈소판 응집 능이 효과적으로 보존되었다(P<0.05). 체외순환중 activated clotting time이 투여 군에서 연장되어 heparin의 항응고작용에 대해 상승효과가 있었으며 aprotinin의 투여와 관련된 합병증은 없었다. 이상의 결과에서 체외순환을 이용한 개심술에 있어서 low-dose aprotinin의 투여는 술후 출혈량 및 혈 액과 혈액제제의 사용감소에 효과가 있으며 이는 혈소판응집능의 효과적 \ulcorner보존에 의한 것으로 사료된다.

• Journal of Chest Surgery
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• 제33권3호
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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.