Lumbrokinase

As a kind of proteolytic enzyme extracted from earthworms, lumbrokinase has been used as an antithrombotic drug clinically. Nevertheless, its potential in anti-cancer, especially in anti-non-small cell lung cancer (NSCLC), as a single form of treatment or in combination with other therapies, is still poorly understood. In this study, we explored the anti-tumor role and the responsive molecular mechanisms of lumbrokinase in suppressing tumor angiogenesis and chemoresistance development in NSCLC and its clinical potential in combination with bevacizumab and chemotherapeutics. Lumbrokinase was found to inhibit cell proliferation in a concentration-dependent manner and caused metastasis suppression and apoptosis induction to varying degrees in NSCLC cells. Lumbrokinase enhanced the anti-angiogenesis efficiency of bevacizumab by down-regulating BPTF expression, decreasing its anchoring at the VEGF promoter region and subsequent VEGF expression and secretion. Furthermore, lumbrokinase treatment reduced IC50 values of chemotherapeutics and improved their cytotoxicity in parental and chemo-resistant NSCLC cells via inactivating the NF-κB pathway, inhibiting the expression of COX-2 and subsequent secretion of PGE2. LPS-induced NF-κB activation reversed its inhibition on NSCLC cell proliferation and its synergy with chemotherapeutic cytotoxicity, while COX-2 inhibitor celecoxib treatment boosted such effects. Lumbrokinase combined with bevacizumab, paclitaxel, or vincristine inhibited the xenograft growth of NSCLC cells in mice more significantly than a single treatment. In conclusion, lumbrokinase inhibited NSCLC survival and sensitized NSCLC cells to bevacizumab or chemotherapeutics treatment by targeted down-regulation of BPTF/VEGF signaling and inactivation of NF-κB/COX-2 signaling, respectively. The combinational applications of lumbrokinase with bevacizumab or chemotherapeutics are expected to be developed as promising candidate therapeutic strategies to improve the efficacy of the original monotherapy in anti-NSCLC.

BACKGROUND: Lumbrokinase has been widely used for patients with acute ischemic stroke (AIS) in China; however, because rigorously designed studies are lacking, safety and efficacy of lumbrokinase in the treatment of acute ischemic stroke remains largely unknown. In this multicenter, randomized, and controlled trial, we aim to compare lumbrokinase plus aspirin versus aspirin alone in patients with acute ischemic stroke. METHODS: A total of 220 eligible participants will be randomized to either the intervention or control group with a 1:1 ratio. These participants must be diagnosed with acute ischemic stroke for the first time, whose symptoms appear within 72 h. Their NIHSS score must be greater than 5 and less than 15, and their age must be between 35 and 85 years old. They must have not received intravenous thrombolysis, arterial thrombolysis, or intravascular intervention. Participants in the intervention group will be treated with lumbrokinase plus aspirin for the first 90 days. Participants in the control group will use placebo plus aspirin for the first 90 days. Then, all participants will be treated with aspirin only and followed up for another 90 days (180-day follow-up). The primary outcome is the modified Rankin Scale (mRS) score. The secondary outcomes are National Institutes of Health Stroke Scale (NIHSS) score, Activity of Daily Living (ADL) Scale score, coagulation function, and serum hypersensitive C-reactive protein. The exploratory outcomes are fasting lipid panel, recurrence rate, the occurrence of cardiovascular and cerebrovascular events, and the mortality rate. Safety evaluations include liver function and kidney function, serum fibrinogen, adverse events, serious adverse events, and bleeding events. Adherence of participants will also be assessed. DISCUSSION: This trial will investigate the efficacy and safety of lumbrokinase plus aspirin as compared to aspirin alone in the treatment of acute ischemic stroke. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000032952 . Registered on May 16, 2020. © 2022. The Author(s).

To explore the clinical efficacy and safety of lumbrokinase in the treatment of acute and moderate risk pulmonary thromboembolism. Methods: The clinical data of 60 patients with acute and moderate risk pulmonary thromboembolism, who were collected from January 2010 to October 2015 in Hunan Provincial People's Hospital, were retrospectively analyzed. According to the different treatments, 60 patients were randomly divided into a lumbrokinase group (lumbrokinase in combination with low molecular heparin and sequential warfarin, n=30) and a control group (low molecular heparin and sequential warfarin, n=30). The clinical efficacy and safety were compared between the two groups. Results: Compared with the control group, maximum short axis, ratio of right and left ventricles, systolic pulmonary artery pressure, and the main pulmonary artery diameter in the lumbrokinase group were significant changed after the treatment for 10, 20 and 30 d. NT-proBNP level in the lumbrokinase group after the treatment for 10, 20 and 30 d was significantly reduced than that in the the control group (P<0.05). However, the value of PO2 significantly increased after 10, 20 and 30 d, and there was no significant difference between 20 d and 30 d (P>0.05). D-dimer in the two groups was obviously increased after treatment for 10 d, but it was significantly reduced after treatment for 20 d or 30 d (P<0.05). The clinical efficacy of the lumbrokinase group was better than that in the control group, with significant difference (P<0.05). Conclusion: Combination of lumbrokinase with low molecular heparin and sequential warfarin is a safe and efficient strategy in treating the patients with acute and moderate risk pulmonary thromboembolism. It is worthy of clinical popularization and application. Publisher: 目的：探讨蚓激酶对急性中危肺血栓栓塞的治疗效果及安全性。方法：回顾性分析2010年1月至2015年10月在湖南省人民医院住院治疗的60例急性中危肺血栓栓塞患者的临床资料，依据治疗方式不同分为蚓激酶组(蚓激酶联合低分子肝素钠序贯华法林组)和对照组(低分子肝素钠序贯华法林组)，每组30例。比较两组在治疗前、治疗后10，20及30 d的临床疗效及安全性。结果：CT肺动脉造影(CT pulmonary angiography，CTPA)和超声心动图结果表明蚓激酶组右心室最大短轴直径、左心室最大短轴直径、右心室最大短轴直径与左心室最大短轴直径比值、肺动脉收缩压和主肺动脉直径在治疗后10，20及30 d与对照组比较差异均有统计学意义(P<0.05)，且两组在治疗后10，20及30 d比较差异均有统计学意义(P<0.05)。与对照组比较，蚓激酶组N末端B型脑钠肽原(NT-proBNP)在治疗后10，

BACKGROUND: This study was aimed to evaluate the safety and tolerability of Lumbrokinase DLBS1033 in healthy adult subjects. METHODS: This was a 2-arm, randomized, double-blind, placebo-controlled, cross-over study over 14 days of treatment with DLBS1033 490 mg 3 times daily. Eligible subjects were enrolled at Period 1 and allocated to receive either test drug or placebo, and underwent a clinical assessment including vital signs, electrocardiography, laboratory examination (hemostasis parameters, routine hematology, liver and renal function), the presence of hemorrhagic symptoms and allergic reactions. Afterwards, they went on to a 2-week washout period, and then were crossed-over to receive the alternate drug at Period 2. The procedure of Period 1 was repeated in the same manner with the alternate drug at Period 2. RESULTS: Of 20 subjects enrolled, one subject was lost to follow-up on Evaluation Day-14 of Period 2. Bleeding risk was relatively low as demonstrated by insignificant differences in hemostasis parameters between DLBS1033 and Placebo. Neither were there significant differences between DLBS1033 and Placebo in terms of hematological parameter, each blood chemistry parameter (liver function, renal function, lipid profile, fasting blood glucose), abnormality proportions of urine test, stool occult blood, and ECG interpretation. There were no hemorrhagic symptoms (petechiae, epistaxis, hematoma) and allergic reactions encountered by study subjects during the treatment with DLBS1033 and Placebo. MAJOR CONCLUSION: DLBS1033 given at the dose of 490 mg 3 times daily was safe and tolerable in healthy adults. © Georg Thieme Verlag KG Stuttgart · New York.

BACKGROUND: Elevated fibrinogen (Fg) level is a known risk factor for ischemic stroke. There are few clinical trials on oral fibrinogen-depleting therapies for secondary ischemic stroke prevention. We aimed to assess the effects of one-year therapy with oral lumbrokinase enteric-coated capsules on secondary ischemic stroke prevention. METHODS: This is a multicenter, randomized, parallel group and controlled study that began treatment in hospitalized patients with ischemic stroke and continued for 12 months. Patients were randomized to either the control group that received the standard stroke treatment or the fibrinogen-depleting group that received the standard stroke treatment plus enteric-coated lumbrokinase capsules. The NIH Stroke Scale scores (NIHSSs) and plasma Fg level were recorded. The carotid artery intima-media thickness (IMT) and status of plaques were examined through carotid ultrasound examination. Primary outcomes included all-cause mortality, any event of recurrent ischemic stroke/transient ischemic attack (TIA), hemorrhagic stroke, myocardial infarction and angina, and other noncerebral ischemia or hemorrhage. Kaplan-Meier survival analysis and the Long-rank test were used to compare total vascular end point incidence between the two groups. Comparison of median values between two groups was done by the Student t test, one-way analysis of variance (ANOVA), or non-parametric rank sum test. RESULTS: A total of 310 patients were enrolled, 192 patients in the treatment group and 118 patients in the control group. Compared to the control group, the treatment group showed favorable outcomes in the Fg level, carotid IMT, the detection rate of vulnerable plaques, the volume of carotid plaques, NIHSS scores, and incidence of total vascular (6.78% and 2.08%, respectively) and cerebral vascular events (5.93% and 1.04%, respectively) (P < 0.05). In the treatment group, the volume of carotid plaques was significantly related to the carotid IMT, the plaque diameter, width and number (P = 0.000, 0.000, 0.000, 0.022; F = 13.51, 2.52, 11.33, -3.29, but there was a weak correlation with the Fg level (P = 0.056). After 1-year therapy, the incidence of overall vas

This paper aimed to investigate the effect of lumbrokinase on the anticoagulation and fibrinolysis in treating cerebral infarction. Lumbrokinase was used in patients with cerebral infarction. Patients were randomly divided into treatment group (n = 31) and control group (n = 20). Single blind method was used in this investigation. The Chinese stroke score was used to evaluate the results of treatment before and after administration of lumbrokinase. Kaolin partial thromboplastin time (KPTT), prothrombin time (PT), fibrinogen content, vWF content were analyzed, and tissue plasminogen activator (t-PA) activity, plasminogen activator inhibitor (PAI) activity, D-dimer level were assayed. In both groups, the stroke score decreased after administration, but in the treatment group, it was more obvious. In the treatment group, KPTT was prolonged, t-PA activity and D-dimer level increased, while the content of fibrinogen decreased significantly. There were no significant changes of PT and PAI activity in both groups. It is concluded that lumbrokinase is beneficial to the treatment of cerebral infarction. The effect of lumbrokinase is related to the inhibition of intrinsic coagulation pathway and the activation of fibrinolysis via an increase of t-PA activity.