Ulinastatin(UTI), 우리스틴 주사, 급성 췌장염, acute pancreatitis

Ulinastatin과 급성췌장염

우리스틴 주 50000IU/ml (오만)	우리스틴 주 100000IU/2ml (십만)
Mechanism - 사람의 뇨/혈액에서 발견된 glycoprotein and serine protease inhibitor. - 각종 면역 매개 물질(neutrophil elastase, trypsin, α-chymotrypsin, plasmin, cathepsin G)을 억제하여 항염증 작용 - pro-interleukin 1-β → IL-1-β 억제하여 순차적으로 pro-inflammatory cytokines(IL-6, IL-8, TNF-α)의 활성화를 억제
국내허가사항
1. 급성 순환 부전(출혈성 쇼크, 세균성 쇼크, 외상성 쇼크, 화상 쇼크). = Shock 2.  급성 췌장염(외상성 수술후 및 내시경적 역행성 췌담관 조영(ERCP) 후의 급성 췌장염을 포함), 만성 재발성 췌장염의 급성 악화기. = Pancreatitis
국내허가사항 용법용량
1. 급성 순환 부전 100,000 IU qd-tid 2. 급성 췌장염, 만성 재발성 췌장염의 급성 악화기 25,000-50,000 IU qd-tid

 

 

 

장소	억제 대상	급성 췌장염에서의 효과
Pancreatic tissue	Trypsin, Chymotrypsin, Elastase	Halt autodigestion of pancreas
Neutrophils at local inflammation site	Neutrophilic elastase, Cathepsin G, Proteinase 3	Inhibition of local inflammation and collateral tissue damage
Blood plasma	Clotting factors IXa, Xa, XIa, and XIIa	Inhibition of microvascular thrombi formation.
	Thrombin and plasmin	Inhibition of dysregulated coagulation and fibrinolysis, thus breaking the vicious inflammation-coagulation cycle

 

 

whats' ERCP?

 

- 담도, 담낭, 췌장, 유두부에서 발생한 다양한 질병의 진단과 치료를 목적

즉 담도결석, 담도암, 만성 또는 급성 췌장염, 췌장암, 담도나 췌장의 선천성 기형 등의 다양한 질환의 진단이나 치료. 경우에 따라서는 복통이나 설명할 수 없는 식욕부진 또는 체중감소 등으로 다른 일반적인 검사를 해도 진단이 되지 않는 경우보다 정확한 검사를 위해 이 검사를 시행

- 사용되는 약물 

국소마취제 : 내시경 삽입시 구역 방지를 위해 사용

진경제 : 검사 중 위/장의 움직임을 최소화

진정제 : 수면내시경을 통해 환자의 고통 감소

 

ref : 세브란스 병원

 

 

Study (1)

[1] The use of gabexate mesylate and ulinastatin for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis

 

호의 주(gabexate)와 우리스틴 주(ulinastatin), 대조군 간의 ERCP 이후 췌장 보호 효과를 알아보기 위한 연구이다. 

 

 

 

 

 

 

일반적인 trypsinogen의 전환으로 trypsin(protease)가 활성화되어 췌장염이 발생하는 것으로 여겨진다. 활성화된 trypsin은 다양한 cascade들을 촉발시킬 것이다. 이러한 메커니즘에서 착안하여 protease inhibitor가 췌장염의 치료에 유용할 것이라 기대하였으나 그 결과는 controversial 하다.

뿐만 아니라 gabexate와 비교 시 unilastatin이 더 강한 췌장 효소 억제제임을 experimental models을 통해 보여주었지만 [2] 실제 임상에서 PEP(post-ERCP pancreatitis) 예방 효과는 두 약제가 비슷하다. [3]

 

Study (2)

[2] Therapeutic effects of human urinary trypsin inhibitor on acute experimental pancreatitis

 

Abstract

Therapeutic effects of human urinary trypsin inhibitor (MTI) on acute pancreatitis were examined. MTI potently inhibited not only proteases such as trypsin or alpha-chymotrypsin, but also inhibited lipase or creatine phosphokinase which are considered to be related to pancreatitis. Although gabexate mesilate (gabexate) and aprotinin also strongly inhibited trypsin, their inhibition spectra against pancreatic enzymes were narrower and aprotinin also strongly inhibited trypsin, their inhibition against pancreatic enzymes were narrower than MTI. MTI inhibited proteases released from pancreatic slice by trypsin more potently than gabexate or aprotinin. The therapeutic effects of MTI on experimental acute trypsin-induced pancreatitis in dogs or rats were stronger than those of gabexate or aprotinin. These results suggest that MTI may suppress pathogenesis and development of pancreatitis in several ways, for example, by directly inhibiting trypsin and by inhibiting tissue-damaging enzymes released from the pancreas by stimulation with trypsin.

 

Study (3)

[3] Comparison between ulinastatin and gabexate mesylate for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis

 

Background

It has been reported that the administration of ulinastatin, gabexate mesylate, or somatostatin may be effective in the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. However, few randomized trials of ulinastatin and gabexate mesylate for the prevention of post-ERCP pancreatitis have been reported. The aim of this study was to compare the efficacy of ulinastatin and gabexate mesylate for the prevention of post-ERCP pancreatitis.

 

Result

The overall incidence of post-ERCP pancreatitis was 2.9% (two patients), comprising one patient in the ulinastatin group and one patient in the gabexate group (2.9% vs 2.9%, respectively). Neither of these two patients developed severe pancreatitis. There were no significant differences in the serum levels of pancreatic enzymes or in the levels of pain between the two groups.

 

Conclusion

There was no clinical difference between the effect of preventive administration of ulinastatin and that of gabexate mesylate on the incidence of post-ERCP pancreatitis. Ulinastatin may be equivalent in efficacy to gabexate for reducing the incidence of post-ERCP pancreatitis.

 

 

Study (4)

[4] Role of ulinastatin in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: the Emperor's New Clothes or Aladdin's Magic Lamp?

 

[1] 논문의 결과에서 gabexate의 prophylaxis 효과는 입증되었으나 ulinastatin의 prophylaxis 효과는 입증하지 못하였다. 다른 연구에서 ulinastatin을 ERCP 직전에 150,000 IU을 전량 맞았을 때, PEP과 hyper-amylasemia prophylaxis에 효과적이었다는 결과를 보여주어 [4] 본 연구와 주입 지속시간과 주입 선량 강도 차이를 고려하면 이를 다르게 하였을 때 긍정적인 결과를 기대할 수 있겠다.

 

 

As for ulinastatin in contrast to placebo, a total of 1039 patients, with a sample size ranging from 40 to 416, were included in the 5 studies analyzed. The total dose of ulinastatin in 4 reports producing statistically significant results was all above 150,000 U, whereas that used in the trial with a negative result was only 100,000 U.

⇒ ulinastin 용량에 따른 결과 차이?!

 

 

 

The subgroup analyses according to different criteria generated conflicting results. 
When the trial that was designed as low-dose ulinastatin administered after the procedure for treatment of patients in high risk was excluded, the remaining studies showed a significant difference between the ulinastatin and placebo groups.
In addition, the prophylactic efficacy of ulinastatin in the multicenter subgroup was not detected, but it was shown in the single-center subgroup.

 

 

In conclusion, ulinastatin shows to be of value on preventing post-ERCP pancreatitis and hyperamylasemia for patients in average risk, when given intravenously at a dose of not less than 150,000 U, just before ERCP. More high-quality trials are needed to consolidate or overthrow the present deductions, especially new complementary data from Western countries.

 

 

Study (5)

[5] Role of Ulinastatin, a trypsin inhibitor, in severe acute pancreatitis in critical care setting: A retrospective analysis.

 

200,000 IU bid for 5 days regimen으로 치료받은 환자와 대조군(standard care)과 비교하였다.

이때 standard care에는 fluid resuscitation, enteral feeding, pain management, antibiotic(if infection)이 있다.

 

	Ulinastatin group	Control group
환자 수	25 명	23 명
Intervention	200,000 IU bid for 5 days  +Standard care	Standard care

 

이때의 사망률은 69.6 % vs 16 %(p=0.0003)로 ulinastatin 투여 그룹이 favored 결과가 나왔다.

 

 

투여 5일 후의 장기부전의 resolution을 비교한 표이다.

reference : 

(1) Yoo, Young Wook, et al. "The use of gabexate mesylate and ulinastatin for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis." Gut and Liver 6.2 (2012): 256.

(2) Ohnishi, Haruo, et al. "Therapeutic effects of human urinary trypsin inhibitor on acute experimental pancreatitis." Nihon yakurigaku zasshi. Folia pharmacologica Japonica 81.3 (1983): 235.

(3) Ueki T, Otani K, Kawamoto K, et al. Comparison between ulinastatin and gabexate mesylate for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a prospective, randomized trial. J Gastroenterol. 2007;42:161–167. 

(4) Chen S, Shi H, Zou X, Luo H. Role of ulinastatin in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: the Emperor's New Clothes or Aladdin's Magic Lamp? Pancreas. 2010;39:1231–1237.

(5) Lagoo, Jui Yeshavant, et al. "Role of Ulinastatin, a trypsin inhibitor, in severe acute pancreatitis in critical care setting: A retrospective analysis." Journal of critical care 45 (2018): 27-32.

(6) KIMS