Development and Testing of Thrombolytics in Stroke

Dmitri Nikitin,최승범,Jan Mican,Martin Toul,Wi-Sun Ryu,Jiri Damborsky,Robert Mikulik,Dong-Eog Kim 대한뇌졸중학회 2021 Journal of stroke Vol.23 No.1

Despite recent advances in recanalization therapy, mechanical thrombectomy will never be a treatment for every ischemic stroke because access to mechanical thrombectomy is still limited in many countries. Moreover, many ischemic strokes are caused by occlusion of cerebral arteries that cannot be reached by intra-arterial catheters. Reperfusion using thrombolytic agents will therefore remain an important therapy for hyperacute ischemic stroke. However, thrombolytic drugs have shown limited efficacy and notable hemorrhagic complication rates, leaving room for improvement. A comprehensive understanding of basic and clinical research pipelines as well as the current status of thrombolytic therapy will help facilitate the development of new thrombolytics. Compared with alteplase, an ideal thrombolytic agent is expected to provide faster reperfusion in more patients; prevent re-occlusions; have higher fibrin specificity for selective activation of clot-bound plasminogen to decrease bleeding complications; be retained in the blood for a longer time to minimize dosage and allow administration as a single bolus; be more resistant to inhibitors; and be less antigenic for repetitive usage. Here, we review the currently available thrombolytics, strategies for the development of new clot-dissolving substances, and the assessment of thrombolytic efficacies in vitro and in vivo.

Postthrombolytic Antiplatelet Use for Patients with Intercerebral Hemorrhage without Extensive Parenchymal Involvement Does Not Worsen Outcome

Weihua Jia,Lichun Zhou,Xiaoling Liao,Yuesong Pan,Yongjun Wang 대한신경과학회 2015 Journal of Clinical Neurology Vol.11 No.4

Background and Purpose It is unclear whether postthrombolytic antiplatelet (AP) therapy after thrombolytic-related hemorrhage without extensive parenchymal involvement (THEPI) afects the clinical outcome. Tis study explored whether AP administration in patients with THEPI afects short- and long-term outcomes. Methods All of the data for this study were collected from the Trombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) registry. Patients with THEPI were assigned to either the AP (AP therapy should be commenced 24 h afer intravenous thrombolysis) or AP-naïve groups. THEPI was defned according to European-Australasian Acute Stroke Study II criteria. Te 90-day functional outcome, 7-day National Institutes of Health Stroke Scale (NIHSS) score, and 7-day and 90-day mortalities were compared between the AP and AP-naïve groups. Logistic regression analysis was used to evaluate the effects of AP therapy on the short- and long-term clinical outcomes. Results Of the 928 patients enrolled from those in the TIMS-China registry (n=1,440), 89 (9.6%) had nonsymptomatic intracerebral hemorrhage (ICH) within 24–36 h afer thrombolysis; 33 (37%) of these patients were given AP therapy (AP group) and 56 (63%) were not (APnaïve group). No significant differences were found for the risk of 7-day aggravated ICH (p=0.998), 7-day NIHSS score (p=0.5491), 7-day mortality [odds ratio (OR)=3.427; 95% confdence interval (95% CI)=0.344–34.160; p=0.294], 90-day mortality (OR=0.788, 95% CI=0.154– 4.040, p=0.775), or modifed Rankin score 5 or 6 at 90-days (OR=1.108, 95% CI=0.249–4.928, p=0.893) between the AP and AP-naïve groups afer THEPI. Conclusions Early administration of postthrombolytic AP therapy afer THEPI does not worsen either the short- or long-term outcome. AP therapy may be a reasonable treatment option for patients with THEPI to reduce the risk of ischemic stroke recurrence.

Intra-Arterial Therapy for Cardioembolic Internal Carotid Artery Terminus Occlusion: The Past and Present Status in Real Practice

정승욱,정철규,김재형,최병세,김범준,한문구,배희준,권배주,차상훈 대한영상의학회 2015 대한영상의학회지 Vol.73 No.4

Purpose: There is little data on the effect of intra-arterial therapy (IAT) in acute cardioembolic internal carotid artery terminus (ICAT) occlusion that has poor prognosis. We determined procedural and clinical outcomes in patients with acute cardioembolic ICAT occlusion treated with different methods of IAT. Materials and Methods: On retrospective review of our registry, patients with cardioembolic ICAT occlusion were categorized as thrombolytic-based IAT group (TLG) and thrombectomy-based IAT group (TEG) according to the primary endovascular technique. Subsequently, procedural and clinical outcomes were compared. Results: Fifty-five patients had cardioembolic ICAT occlusion and 18 patients were assigned to TLG and 37 patients to TEG. The rate of complete reperfusion was significantly higher and the groin puncture to reperfusion time was significantly shorter in TEG than those in TLG. There was a trend towards functional outcome at 3 months in the TEG group; however, it was not statistically significant (p = 0.06). Age, baseline Albert Stroke program early CT score and puncture to reperfusion time were factors affecting unfavorable outcome at 3 months, on multivariable analysis. Conclusion: Thrombectomy-based IAT has advantages over thrombolytic-based IAT in terms of the reduction of groin puncture to reperfusion time and improvement of the rate of complete reperfusion.

Thrombolytic Era에서의 급성 심근 경색증의 임상적 고찰 : An Analysis for Cause of Death in the Thrombolytic Era

김승정,박시훈,조홍근,신길자 梨花女子大學校 醫科大學 醫科學硏究所 1998 EMJ (Ewha medical journal) Vol.21 No.2

목적: 급성 심근 경색증에서 혈전용해 치료를 시행하여 관상 동맥의 재관류가 이루어진 경우 뚜렷하게 사망률이 감소된 결과를 보고한 많은 연구들이 있었다. 재관류가 이루어진 경우와 그렇지 않은 경우에 각각의 사망률이 TIMI-1 trial(1987)에서는 8.1%와 14.8%, TAMI tir-al(1993)에서는 4.5%와 17.5%로 뚜렷한 차이를 보여주었다. 그에 따라 최근에 혈전용해 치료는 급성 심근경색증 환자의 초기 치료에서 가장 중요한 치료방법의 하나로 정착되었다. 그러나 아직까지 심인성 쇽으로 발현한 경우 등에 있어서는 혈전용해치료의 유용성이 인정되고 있지 않다. 따라서 본 연구에서는 급성 심근 경색증 환자들에게서 임상적 경과를 분석하여 환자들의 사망에 관계되는 요소들을 발견하여 치료방법의 개선점을 밝혀보고자 하였다. 방법: 본 연구는 1993년 9월부터 1995년 8월까지 이화여자대학교 의과대학 부속 목동병원에 급성 심근 경색증으로 내원하였던 112명의 환자들을 대상으로 하였다. 모든 환자들에 대해서 관상동맥 질환의 위험요인, 심전도 소견, 내원시의 Killip class, 혈전용해제 투여 여부 및 합병증 등에 대해서 조사하여 다음과 같은 결과를 얻었다. 결과: 1) 환자들의 평균연령은 59±11세였고 남녀비는 2.1:1 이었다. 2) 환자들의 내우너 당시의 Killip class는 Ⅰ이 58명(52%), Ⅱ 43명(38%), Ⅲ 7명(6%), Ⅳ가 4명(4%)이었다. 3) 환자들이 흉통의 발현후 병원에 도착하기까지 지연된 평균 시간은 2시간 40분이었고 48%인 54명의 환자에서 흉통 발생후 2시간 이내에 병원에 도착하였다. 4) 심근경색의 부위는 하벽 42명(37.5%), 전벽 24명(21.4%), 전측벽 22명(19.6%), 하후벽 9명(8.0%), 측벽 4명(3.6%), 전하벽 3명(2.7%), 후벽 1명(0.9%), 측후벽 1명(0.9%), 전측하벽 1명(0.9%), 전측후벽 1명(0.9%), 비Q파 경색이 4명(3.6%) 이었다. 5) 총 112명의 환자 중 80명(71%)에서 관상 동맥 조영술을 시행하였다. 평균 좌심실 구혈율은 48±11%였다. 단일 혈관 질환이 49명(61%), 이혈관 질환은 18명(23%), 삼혈관 질환이 7명(8%)이었고 정상 관동맥 조영 소견을 보인 경우가 6명(8%)이 있었다. 6) 환자들의 치료는 보존적인 치료를 받았던 경우가 23명(21%)이었고 80명(71%)에서 혈전용해제 투여를 하였다. 9명(8%)의 환자에서는 응급 경피적 관상동맥 풍선 성형술(direct percutaneous coronary angiop-lasty)을 시행하였다. 7) 심근 경색증의 합병증으로는 심낭 삼출이 9명(8%), 좌심실류가 7명(6%), 심실성 부정맥이 5명(4%)이 있었다. 8) 12명의 환자들이 사망하여 사망율은 10.7%였다. 사망한 환자들의 평균 연령은 67±10세였고 평균 병원 도착 시간 지연은 3시간 30분이었다. 12명중 7명의 환자에서 혈전용해제를 투여하였다. 내원 당시의 환자들의 Killip class는 Ⅰ은 없었고 Ⅱ 6명, Ⅲ 4명, Ⅳ가 2명으로 사망한 환자들과 생존 환자들 사이에 p 값이 0.05이하로 의의있는 차이를 보였던 것은 환자들의 연령 및 내원 당시의 환자의 Killip class였다. 본 연구를 통해 급성 심근 경색증의 사망률이 국내의 다른 보고와 비교해 볼 때 비교적 낮음을 관찰하였다. 이는 환자들의 응급실 도착 시간이 다른 보고에 비해 빨랐으며 이에 따라 혈전용해제 치료를 받은 예가 많았기 때문으로 분석된다. 본 연구에서 급성 심근 경색증 환자들의 사망에 관여한 가장 중요한 인자는 환자들의 연령과 내원 당시의 Killip class이다. 최근과 같이 혈전용해제 투여가 급성 심근 경색증의 치료의 근간이 되고 있는 시점에서 특히 고 위험군의 환자들에게는 혈전용해제 치료 뿐 아니라 다른 치료 방법, 즉 응급 경피적 관상 동맥 풍선 성형술이나 관상동맥 우회술(coronary artery bypass graft)등을 강구해야 할 것이다. Background : Many studies have reported that successful reperfusion with intravenous throm-bolytic therapy in acute myocardial infarction(MI) decrease in-hospital and longterm mortality. Therefore thrombolytic therapy is used as an important treatment of early acute myocardial infarction. But the thrombolytic therapy has not been established in the patients representing cardiogenic shock. The purposes of the article are to characterize the clinical findings and to analyze the causes of death in the thrombolytic era, and therefore to improve the treatment modalities. Methods : A retrospective clinical study was done on 112 patients with acute myocardial infarction, who had been admitted to Ewha Womans University Mokdong Hospital from September 1993 to August 1995. All patients was evaluated for coronary risk factors, EKG findings, Killip class on admission, coronary angiographic findings, treatment modality such as thrombolytic therapy, direct percutaneous transluminal coronary angioplasty(PTCA) and conservative treatment, and complications. Result : 1) Patients' mean age was 59±11 years, and the male:female ratio was 2.1:1. 2) Patients' Killip class on arrival at emergency room was Ⅰin 52%, Ⅱ in 38%, Ⅲ in 6% and Ⅳ in 4%. 3) The mean pre-hospital time delay was 2 hours and 40 minutes, and 54 patients(48%) arrived at emergency room within 2 hours after onset of chest pain. 4) The location of the infarction were inferior wall(37.5%), anterior wall(21.4%), anterolateral wall(19.6%), inferoposterior wall(8.0%), lateral wall(3.6%), anteroinferior wall(2.7%), lateroposterior wall(0.9%), posterior wall(0.9%), anterolateroinferior wall(0.9%), anterolateroposterior wall(0.9%), and Non-Q infarction(3.6%). 5) Coronary angiography were performed in 80 patients(71%), and mean ejection fraction was 48±11%, and mean wall motion score index was 1.9±0.6. One vessel disease was 49(61%), two vessel disease was 18(23%), three vessel disease was 7(8%), and normal finding was 6(8%). 6) The conservative treatment was done in 23(21%), and thrombolytic therapy in 80(71%). The nine patients(8%) were treated with direct percutaneous transluminal coronary angioplasty(PTCA). 7) The complications of infarction were pericardial effusion(8%), left ventricular aneurysm(6%), and ventricular tachycardia(4%). 8) Twelve patients(10.7%) were expired. Their mean age was 67±10 years, and mean pre-hospital time delay was 3 hours 30 minutes. The thrombolytic therapy was used in seven patients. Mortalities were observed 0%, 50%, 33%, and 18% in patients with Killip classification Ⅰ,Ⅱ,Ⅲ, and Ⅳ, respectively. Patient's age and Killip class on admission were the most important prognostic factors were patients' age and Killip class on arrival at emergency room. Thus, even in the thrombolytic era, other treatment modality(e.g. direct percutaneous transluminal coronary angioplasty and coronary artery bypass graft) would be considered.

급성 심근경색증 환자에서 혈전용해요법의 시간지연에 영향을 미치는 요인

정진옥,김윤철,성보영,김준경,전준용,류정곤,성인환,전은석 대한순환기학회 1997 Korean Circulation Journal Vol.27 No.8

항응고제 및 혈전용해제와 관련된 뇌실질내출혈

박상준,최창화,차승헌 대한신경외과학회 1998 Journal of Korean neurosurgical society Vol.27 No.11

Initial Electrocardiographic Findings Associated with Failed Resolution of ST-segment Elevation after Thrombolytic Therapy in Acute ST-segment Elevation Myocardial Infarction (STEMI)

( Ji Ung Na ),( Pil Cho Choi ),( Jeong Hun Lee ) 대한응급의학회 2012 대한응급의학회지 Vol.23 No.3

Purpose: Electrocardiography is a non-invasive tool for use in prediction of reperfusion and outcome of acute myocardial infarction. We attempted to determine initial electrocardiographic findings associated with failed resolution of STsegment elevation (STE) among patients with ST-segment Elevation Myocardial Infarction (STEMI) treated with a thrombolytic agent Methods: This retrospective study included patients with STEMI who were treated with a thrombolytic agent at the emergency department between October 2008 and March 2011. During the study period, among 331 patients with STEMI, 43 patients were enrolled. Resolution of STE was evaluated by comparison of initial electrocardiography (ECG) with follow-up ECG, taken 90 minutes after thrombolytic therapy. Determination of success or failure of resolution of STE was based on the electrocardiographic criteria of the American College of Cardiology and the American Heart Association (ACC/AHA). Patients were divided into two groups according to these criteria, and initial electrocardiographic findings were compared for the two groups. Results: Of a total of 43 patients, 22(55.16%) demonstrated failed resolution of STE after thrombolytic therapy. The risk of failed resolution of STE was approximately nine times higher in the anterior location of STE, compared to the inferior location of STE (OR 9.09, 95% CI, 1.46-94.69, p<0.01). In addition, the absence of reciprocal ST depression was associated with a six times higher risk of failed resolution of STE, compared with the presence of reciprocal ST depression (OR 6, 95% CI, 1.17-39.23, p=0.01). However, other electrocardiographic findings, including abnormal Q-wave, wide QRS complex, and QTc prolongation did not differ statistically between the two groups. Conclusion: Failed STE resolution after thrombolytic therapy was more frequent in STEMI patients with ST elevation in an anterior location or without reciprocal ST depression.

Investigation of antinociceptive, anti-inflammatory and thrombolytic activity of Caesalpinia digyna (Rottl.) leaves by experimental and computational approaches

Nazim Uddin Emon,Israt Jahan,Mohammed Aktar Sayeed 경희대학교 융합한의과학연구소 2020 Oriental Pharmacy and Experimental Medicine Vol.20 No.3

The study aimed to report in vitro thrombolytic and in vivo anti-nociceptive activity of methanolic extract of Caesalpinia digyna (MECD) followed by in silico PASS prediction, ADME analysis with toxicity and molecular docking study of antinociception (Cox-1, Cox-2) and thrombolytic (Tissue plasminogen activator). The clot lysis of human blood for thrombolytic study, acetic acid induced writing and formalin-induced licking in mice at several doses (50, 100, 200 and 400 mg/kg, b.w.; p.o.) of MECD for anti-inflammatory and antinoceptive activities were performed. In thrombolytic study, a significant 32.78% (P < 0.001) of the blood clot lysis revealed by MECD, while 70.32% (P < 0.001) and 3.84% were yields for positive control (streptokinase) and negative control (saline water), respectively. MECD developed a significant dose-dependent antinociception in acetic acid-induced abdominal writhing experiment while the 400 mg/kg exhibited maximum inhibition (59.27%; P < 0.001). Similarly at comparable dose concentrations, MECD produced significant (P < 0.001) dose-dependent activity in both neurogenic and inflammatory which was generated by intraplantar injections of formalin (2.5%, 20 μL/paw). In PASS prediction, isolated compounds caesalpinine A and caesalpinine C exhibited potential thrombolytic and antinociceptive activity followed by Lipinski rule for drug—like property where the compounds found to be effective in molecular docking study. The current finding suggesting MECD have potential thrombolytic and anti-nociceptive activity.

급성 심근 경색증에서 혈전 용해술이 Residual Ischemia와 Cardiac Event에 미치는 영향

이준희,김경래 대한응급의학회 1995 대한응급의학회지 Vol.6 No.1

Background : Thrombolytic therapy was known as first treatment of choice in patients with acute myocardial infarction(AMI). This study was designed to assess the effect on residual is chemia and cardiac event (postinfarct angina, recurrent myocardial infarction, cardiac death) after thrombolytic therapy for AMI. Method and Results : We reviewed 42 patients, admitted with AMI during three years from January 1991 to December 1993. all patients performed treadmill test or thallium scintigraphy and had out-patient follow-up checking over one year. Twenty one patients were recieved by thrombolytic therapy (Group A) and the remaining twenty one patients were not (Group B). Mean age was 58±8 years in group A and 60±11 years in group B. Residual ischemia was reduced by thrombolytic therapy, 19% in group A compared with 48% in group B(P<0.05). No significant differences in incidence of cardiac event were found between the two groups(19% and 19%). Conclusion : Thrombolytic therapy reduced the residual ischemia after AMI but did not reduced the incidence of cardiac event in long term follow-up.

Initial Electrocardiographic Findings Associated with Failed Resolution of ST-segment Elevation after Thrombolytic Therapy in Acute ST-segment Elevation Myocardial Infarction (STEMI)

나지웅,최필조,이정훈 대한응급의학회 2012 大韓應急醫學會誌 Vol.23 No.3

Purpose: Electrocardiography is a non-invasive tool for use in prediction of reperfusion and outcome of acute myocardial infarction. We attempted to determine initial electrocardiographic findings associated with failed resolution of STsegment elevation (STE) among patients with ST-segment Elevation Myocardial Infarction (STEMI) treated with a thrombolytic agent Methods: This retrospective study included patients with STEMI who were treated with a thrombolytic agent at the emergency department between October 2008 and March 2011. During the study period, among 331 patients with STEMI, 43 patients were enrolled. Resolution of STE was evaluated by comparison of initial electrocardiography (ECG) with follow-up ECG, taken 90 minutes after thrombolytic therapy. Determination of success or failure of resolution of STE was based on the electrocardiographic criteria of the American College of Cardiology and the American Heart Association (ACC/AHA). Patients were divided into two groups according to these criteria, and initial electrocardiographic findings were compared for the two groups. Results: Of a total of 43 patients, 22(55.16%) demonstrated failed resolution of STE after thrombolytic therapy. The risk of failed resolution of STE was approximately nine times higher in the anterior location of STE, compared to the inferior location of STE (OR 9.09, 95% CI, 1.46-94.69,p<0.01). In addition, the absence of reciprocal ST depression was associated with a six times higher risk of failed resolution of STE, compared with the presence of reciprocal ST depression (OR 6, 95% CI, 1.17-39.23, p=0.01). However, other electrocardiographic findings, including abnormal Q-wave, wide QRS complex, and QTc prolongation did not differ statistically between the two groups. Conclusion: Failed STE resolution after thrombolytic therapy was more frequent in STEMI patients with ST elevation in an anterior location or without reciprocal ST depression.