Efficacy and Safety of Dl-3-n-Butylphthalide Combined With Human Urinary Kallidinogenase in the Treatment of Acute Ischemic Stroke

Objectives Intravenous thrombolysis and mechanical endovascular thrombectomy are recommended for patients whose stroke onsets are within the first 6 hours; however, patients beyond this time window have very limited options. Dl-3-n-butylphthalide (NBP) and human urinary kallidinogenase (HUK) have shown potential clinical benefits in the treatment of acute ischemic stroke (AIS) patients. This research aims to investigate the efficacy and safety of NBP combined with HUK in the treatment of ischemic stroke patients. Patients and Methods We reviewed the 215 AIS patients registered in the database of the Fifth Affiliated Hospital of Sun Yat-sen University from April 2019 to October 2020. Among them, 65 patients received NBP sodium chloride injection treatment, 55 patients received HUK treatment, and 95 patients received NBP sodium chloride injection combined with HUK treatment. The recovery of neural function was evaluated by the National Institutes of Health Stroke Scale (NIHSS), and the recovery of daily function was evaluated by the modified Rankin Scale (mRS). The NIHSS and mRS scores after the 7-day treatment, 6-month independency rate (6-month mRS score ≤1), and related factors were compared among the 3 groups. The safety was monitored by recording adverse events. Results The NIHSS and mRS scores of 7-day and 6-month treatment in the NBP combined with HUK group were lower than the monotherapy (P < 0.05). In addition, the NBP combined with HUK treatment achieved an independency rate of 82.1%, whereas NBP and HUK treatments achieved only 53.8% and 63.6%, respectively (P < 0.001). Binary logistic regression showed that NBP combined with HUK therapy treatment could lead to a 5.28 times higher rate of patients' 6-month independency after AIS occurrence. No serious adverse events occurred in both the combined therapy and monotherapy. Conclusions Dl-3-n-butylphthalide combined with HUK is safe to treat AIS patients. It can significantly improve the neural function and the 6-month recovery of AIS patients.

[1]  Eun Sug Park,et al.  Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019 , 2020, Lancet.

[2]  Q. Dong,et al.  Human urinary kallidinogenase in treating acute ischemic stroke patients: analyses of pooled data from a randomized double-blind placebo-controlled phase IIb and phase III clinical trial , 2020, Neurological research.

[3]  Y. Lyu,et al.  Human urinary kallidinogenase or edaravone combined with butylphthalide in the treatment of acute ischemic stroke , 2019, Brain and behavior.

[4]  X-D Zhang,et al.  Influences of urinary kallidinogenase on neuronal apoptosis in cerebral infarction rats through Nrf2/ARE oxidative stress pathway. , 2019, European review for medical and pharmacological sciences.

[5]  Xiaoliang Wang,et al.  L-NBP, a multiple growth factor activator, attenuates ischemic neuronal impairments possibly through promoting neuritogenesis , 2019, Neurochemistry International.

[6]  Chong Liu,et al.  A Systematic Review of Neuroprotective Efficacy and Safety of DL-3-N-Butylphthalide in Ischemic Stroke. , 2019, The American journal of Chinese medicine.

[7]  H. Wiendl,et al.  Plasma kallikrein modulates immune cell trafficking during neuroinflammation via PAR2 and bradykinin release , 2018, Proceedings of the National Academy of Sciences.

[8]  Ming Liu,et al.  New evidence, new guideline: interpretation of the Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018 , 2018 .

[9]  M. Hamblin,et al.  Neural stem cell therapy for subacute and chronic ischemic stroke , 2018, Stem Cell Research & Therapy.

[10]  Xiaoliang Wang,et al.  Dl-3-n-Butylphthalide (NBP): A Promising Therapeutic Agent for Ischemic Stroke. , 2018, CNS & neurological disorders drug targets.

[11]  E. Arsava,et al.  Atherosclerotic intracranial internal carotid artery calcification and intravenous thrombolytic therapy for acute ischemic stroke. , 2018, Atherosclerosis.

[12]  Ping Zhang,et al.  N-Butylphthalide (NBP) ameliorated cerebral ischemia reperfusion-induced brain injury via HGF-regulated TLR4/NF-κB signaling pathway. , 2016, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[13]  J. Ke,et al.  Analysis of treatment effect of urinary kallidinogenase combined with edaravone on massive cerebral infarction , 2016, Biomedical reports.

[14]  Hongyu Xie,et al.  Exogenous human urinary kallidinogenase increases cerebral blood flow in patients with acute ischemic stroke , 2016, Neurosciences.

[15]  Jiang Li,et al.  L‐3‐n‐butylphthalide Promotes Neurogenesis and Neuroplasticity in Cerebral Ischemic Rats , 2015, CNS neuroscience & therapeutics.

[16]  H. Diener,et al.  Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. , 2015, The New England journal of medicine.

[17]  Eric E. Smith,et al.  Randomized assessment of rapid endovascular treatment of ischemic stroke. , 2015, The New England journal of medicine.

[18]  Yicheng Zhu,et al.  Ninety‐day administration of dl‐3‐n‐butylphthalide for acute ischemic stroke: a randomized, double‐blind trial , 2013, Chinese medical journal.

[19]  P. Aceto,et al.  Low values of left ventricular ejection time in the post-anhepatic phase may be associated with occurrence of primary graft dysfunction after orthotopic liver transplantation: results of a single-centre case-control study. , 2012, European review for medical and pharmacological sciences.

[20]  Y. Islamoğlu,et al.  Effect of hypoglycemic drugs on aspirin resistance in patients with diabetes mellitus. , 2012, European review for medical and pharmacological sciences.

[21]  Ming Liu,et al.  Efficacy and safety of human urinary kallidinogenase injection for acute ischemic stroke: A systematic review , 2012, Journal of evidence-based medicine.

[22]  Dawn Kleindorfer,et al.  Recombinant Tissue-Type Plasminogen Activator Use for Ischemic Stroke in the United States: A Doubling of Treatment Rates Over the Course of 5 Years , 2011, Stroke.

[23]  Qiaoyun Shi,et al.  Novel neuroprotectant chiral 3-n-butylphthalide inhibits tandem-pore-domain potassium channel TREK-1 , 2011, Acta Pharmacologica Sinica.

[24]  Z. Pei,et al.  Enhanced angiogenesis with dl-3n-butylphthalide treatment after focal cerebral ischemia in RHRSP , 2009, Brain Research.

[25]  C. Liying,et al.  Effects of dl-3-butylphthalide soft capsules on treatment of acute ischemlC stroke: multi-center, randomized, double-blind, double-dummy and aspirin-control study , 2008 .

[26]  K. Okumura,et al.  Role of Bradykinin, Nitric Oxide, and Angiotensin II Type 2 Receptor in Imidapril-Induced Angiogenesis , 2008, Hypertension.

[27]  C. Feng,et al.  A multicenter,randomized,double-blinded and placebo-controlled study of acute brain infarction treated by human urinary kallidinogenase , 2007 .

[28]  R. Sapolsky,et al.  Akt Contributes to Neuroprotection by Hypothermia against Cerebral Ischemia in Rats , 2005, The Journal of Neuroscience.

[29]  李玲,et al.  Effects of dl-3-Butylphthalide on treatment of acute ischemic stroke with moderate symptoms: a multi-center, randomized, double-blind, placebo-control trial , 2005 .

[30]  Li Shun-we.  Effects of dl-3-Butylphthalide on treatment of acute ischemic stroke with moderate symptoms: a multi-center, randomized, double-blind, placebo-control trial , 2005 .

[31]  Xiaoliang Wang,et al.  Alterations in the expression of lipid and mechano-gated two-pore domain potassium channel genes in rat brain following chronic cerebral ischemia. , 2004, Brain research. Molecular brain research.

[32]  Y. Feng,et al.  Inhibitory effects of chiral 3-n-butylphthalide on inflammation following focal ischemic brain injury in rats. , 2000, Acta pharmacologica Sinica.

[33]  H. Xu,et al.  Effects of 3-n-butylphthalide on production of vasoactive substances by cerebral and aortic endothelial cells. , 1999, Zhongguo yao li xue bao = Acta pharmacologica Sinica.

[34]  V. Hachinski,et al.  The North American Symptomatic Carotid Endarterectomy Trial : surgical results in 1415 patients. , 1999, Stroke.

[35]  X. Hao.  Effects of 3 n butylphthalide on neutrophil endothelial cell adhesion and endothelial cell injury induced by anoxia/reoxygenation, interleukin 1 and tumor necrosis factor α 1 , 1999 .

[36]  J. Bamford,et al.  Classification and natural history of clinically identifiable subtypes of cerebral infarction , 1991, The Lancet.