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Frontiers in Neurology 2021The mechanism of action of Batroxobin included the decomposition of the fibrinogen to fibrin degradation products (FDPs) and D-dimer and mobilization of endothelial... (Review)
Review
The mechanism of action of Batroxobin included the decomposition of the fibrinogen to fibrin degradation products (FDPs) and D-dimer and mobilization of endothelial cells to release endogenous nt-PA and to promote thrombolysis. This review aims to summarize current study findings about batroxobin on correcting cerebral arterial, venous, and peripheral vascular diseases, to explore the mechanism of batroxobin on anti-thrombosis process. A thorough literature search was conducted utilizing the PubMed Central (PMC) and EMBASE databases to identify studies up to June 2021. Data from clinical studies and animal experiments about batroxobin were extracted, integrated and analyzed based on Cochrane handbook for systematic reviews of interventions approach and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), including the condition of subjects, the usage and dosage, research observation index and main findings. A total of 62 studies were enrolled in this systematic review, including 26 clinical studies and 36 animal experiments. The 26 clinical studies involved 873 patients with arterial ischemic events, 92 cases with cerebral venous thrombosis, 13 cases with cerebral cortical vein thrombosis, and 1,049 cases with peripheral vascular diseases. These patients included 452 males and 392 females aged 65.6 ± 5.53 years. The results revealed that batroxobin had broad effects, including improving clinical prognosis ( = 12), preventing thrombosis ( = 7), promoting thrombolysis ( = 6), and improving vascular cognitive dysfunction ( = 1). The effects of batroxobin on reducing neuronal apoptosis ( = 8),relieving cellular edema ( = 4), improving spatial memory ( = 3), and promoting thrombolysis ( = 13) were concluded in animal experiments. The predominant mechanisms explored in animal experiments involved promoting depolymerization of fibrinogen polymers ( = 6), regulating the expression of related molecules ( = 9); such as intercellular adhesion molecule, heat shock proteins, tumor necrosis factor), reducing oxidative stress ( = 5), and reducing inflammation response ( = 4). Batroxobin can correct both arterial and venous ischemic diseases by promoting depolymerization of fibrinogen polymers, regulating the expression of related molecules, reducing oxidative stress, and reducing the inflammation response.
PubMed: 34925203
DOI: 10.3389/fneur.2021.716778 -
Frontiers in Neurology 2022
PubMed: 36212651
DOI: 10.3389/fneur.2022.1021547 -
Journal of Clinical Medicine Oct 2022Ischemic cerebrovascular disease (ICD), the most common neurological disease worldwide, can be classified based on the onset time (acute/chronic) and the type of... (Review)
Review
Ischemic cerebrovascular disease (ICD), the most common neurological disease worldwide, can be classified based on the onset time (acute/chronic) and the type of cerebral blood vessel involved (artery or venous sinus). Classifications include acute ischemic stroke (AIS)/transient ischemic attack (TIA), chronic cerebral circulation insufficiency (CCCI), acute cerebral venous sinus thrombosis (CVST), and chronic cerebrospinal venous insufficiency (CCSVI). The pathogenesis of cerebral arterial ischemia may be correlated with cerebral venous ischemia through decreased cerebral perfusion. The core treatment goals for both arterial and venous ICDs include perfusion recovery, reduction of cerebral ischemic injury, and preservation of the neuronal integrity of the involved region as soon as possible; however, therapy based on the current guidelines for either acute ischemic events or chronic cerebral ischemia is not ideal because the recurrence rate of AIS or CVST is still very high. Therefore, this review discusses the neuroprotective effects of four novel potential ICD treatments with high translation rates, known as the BE COOL treatments (Batroxobin, oxygEn, Conditioning, and cOOLing), and subsequently analyzes how BE COOL treatments are used in clinical settings. The combination of batroxobin, oxygen, conditioning, and cooling may be a promising intervention for preserving ischemic tissues.
PubMed: 36294518
DOI: 10.3390/jcm11206193 -
Neural Regeneration Research Apr 2021Batroxobin is a thrombin-like serine protease from the venom of the Bothrops atrox and Bothrops moojeni snake species. Sirtuin 1 (Sirt1) has been shown to play an...
Batroxobin is a thrombin-like serine protease from the venom of the Bothrops atrox and Bothrops moojeni snake species. Sirtuin 1 (Sirt1) has been shown to play an important role in neuroprotection after traumatic brain injury. However, its underlying mechanism of action remains poorly understood. The purpose of this study was to investigate whether the mechanism by which batroxobin participates in the activation of astrocytes is associated with Sirt1. Mouse models of nigrostriatal pathway injury were established. Immediately after modeling, mice were intraperitoneally administered 39 U/kg batroxobin. Batroxobin significantly reduced the expression of cleaved caspase-3 in both the substantia nigra and striatum, inhibited neuronal apoptosis, and promoted the recovery of rat locomotor function. These changes coincided with a remarkable reduction in astrocyte activation. Batroxobin also reduced Sirt1 expression and extracellular signal-regulated kinase activation in brain tissue. Intraperitoneal administration of the Sirt1-specific inhibitor EX527 (5 mg/kg) 30 minutes prior to injury could inhibit the abovementioned effects. In mouse astrocyte cultures, 1 ng/mL batroxobin attenuated interleukin-1β-induced activation of astrocytes and extracellular signal-regulated kinase. EX527 could also inhibit the effects of batroxobin. These findings suggest that batroxobin inhibits astrocyte activation after nigrostriatal pathway injury through the Sirt1 pathway. This study was approved by the Animal Ethics Committee of China Medical University, China (approval No. CMU2020037) on July 19, 2015.
PubMed: 33063734
DOI: 10.4103/1673-5374.295343 -
Clinical and Applied... 2021Uncontrolled bleeding associated with trauma and surgery is the leading cause of preventable death. Batroxobin, a snake venom-derived thrombin-like serine protease, has...
Uncontrolled bleeding associated with trauma and surgery is the leading cause of preventable death. Batroxobin, a snake venom-derived thrombin-like serine protease, has been shown to clot fibrinogen by cleaving fibrinopeptide A in a manner distinctly different from thrombin, even in the presence of heparin. The biochemical properties of batroxobin and its effect on coagulation have been well characterized . However, the efficacy of batroxobin on hemostatic clot formation is not well studied due to the lack of reliable hemostasis models. Here, we studied the efficacy of batroxobin and slounase, a batroxobin containing activated factor X, on hemostatic clot composition and bleeding using intravital microcopy laser ablation hemostasis models in micro and macro vessels and liver puncture hemostasis models in normal and heparin-induced hypocoagulant mice. We found that prophylactic treatment in wild-type mice with batroxobin, slounase and activated factor X significantly enhanced platelet-rich fibrin clot formation following vascular injury. In heparin-treated mice, batroxobin treatment resulted in detectable fibrin formation and a modest increase in hemostatic clot size, while activated factor X had no effect. In contrast, slounase treatment significantly enhanced both platelet recruitment and fibrin formation, forming a stable clot and shortening bleeding time and blood loss in wild-type and heparin-treated hypocoagulant mice. Our data demonstrate that, while batroxobin enhances fibrin formation, slounase was able to enhance hemostasis in normal mice and restore hemostasis in hypocoagulant conditions via the enhancement of fibrin formation and platelet activation, indicating that slounase is more effective in controlling hemorrhage.
Topics: Animals; Batroxobin; Blood Coagulation; Blood Coagulation Tests; Hemorrhage; Hemostatics; Humans; Male; Mice
PubMed: 34047195
DOI: 10.1177/10760296211018510 -
Journal of Thoracic Disease Jan 2023Hemocoagulase batroxobin is used to prevent hemostasis or bleeding in surgical and trauma patients; however, the role of batroxobin in patients with hemoptysis is not...
BACKGROUND
Hemocoagulase batroxobin is used to prevent hemostasis or bleeding in surgical and trauma patients; however, the role of batroxobin in patients with hemoptysis is not well understood. We evaluated the risk factors and prognosis of acquired hypofibrinogenemia in hemoptysis patients treated systemically with batroxobin.
METHODS
We retrospectively reviewed the medical charts of hospitalized patients who were administered batroxobin for hemoptysis. Acquired hypofibrinogenemia was defined as a plasma fibrinogen level >150 mg/dL at baseline, decreasing to <150 mg/dL after batroxobin administration.
RESULTS
Overall, 183 patients were enrolled, of whom 75 had acquired hypofibrinogenemia after the administration of batroxobin. There was no statistical difference in the median age of the patients in the non-hypofibrinogenemia and hypofibrinogenemia groups (72.0 74.0 years, respectively). The patients in the hypofibrinogenemia group showed a higher rate of intensive care unit (ICU) admission (11.1% 22.7%; P=0.041) and tended to have more massive hemoptysis than those in the non-hyperfibrinogenemia group (23.1% 36.0%; P=0.068). The patients in the hypofibrinogenemia group further showed a higher requirement for transfusion (10.2% 38.7%; P<0.000) than those in the non-hyperfibrinogenemia group. Low levels of baseline plasma fibrinogen and a prolonged and higher total dose of batroxobin were associated with the development of acquired hypofibrinogenemia. Acquired hypofibrinogenemia was associated with increased 30-day mortality [hazard ratio (HR), 4.164; 95% confidence interval (CI), 1.318-13.157].
CONCLUSIONS
The plasma fibrinogen levels in patients who were administered batroxobin for hemoptysis should be monitored, and batroxobin should be discontinued if hypofibrinogenemia occurs.
PubMed: 36794140
DOI: 10.21037/jtd-22-717 -
Ear, Nose, & Throat Journal Jan 2024Sudden sensorineural hearing loss (SSNHL) manifests as an abrupt decline in hearing by at least 30 dB within a 3 day period. Intratympanic dexamethasone injection...
Sudden sensorineural hearing loss (SSNHL) manifests as an abrupt decline in hearing by at least 30 dB within a 3 day period. Intratympanic dexamethasone injection (ITDI) has gained recognition as a potential treatment for SSNHL. This study aims to investigate the efficacy of combining batroxobin with ITDI (Bat and ITDI) in treating SSNHL patients and its influence on peripheral blood inflammatory indicators. SSNHL patients were retrospectively categorized into the control group (treated with Bat) and the observation group (treated with Bat and ITDI). The study involved analyzing clinical baseline data, evaluating clinical efficacy, and comparing the total effective rates among SSNHL patients with different audiometric curve types in the observation group. Routine blood tests were performed on peripheral blood samples to calculate the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), and to determine C-reactive protein (CRP) levels. Adverse reactions and complications were closely monitored. Following treatment, both groups displayed improvements in hearing, with the observation group exhibiting a significantly higher total effective rate (75.90%) than the control group (59.78%). For patients with 3 distinct types of sudden hearing loss (high-frequency, flat-frequency, total deafness), Bat and ITDI treatment demonstrated increased total effective rate for patients with different sudden hearing loss types (high-frequency, flat-frequency, and total deafness). Both groups experienced reduced peripheral blood CRP levels and the NLR/PLR values, with the observation group demonstrating lower values. Additionally, across the 4 audio metric subtypes, the levels of peripheral blood CRP, NLR, and PLR decreased in SSNHL patients, and the observation group had a lower incidence of adverse reactions compared to the control group. Bat and ITDI emerge as notably more effective for SSNHL patients, displaying potential for reducing peripheral blood inflammatory indicator levels and mitigating the incidence of adverse reactions or complications, thereby enhancing safety.
PubMed: 38282309
DOI: 10.1177/01455613231222381 -
Journal of Clinical Medicine Feb 2023We aimed to characterize the clinical profiles and short-term outcomes of adult patients with full-frequency idiopathic sudden sensorineural hearing loss (ISSNHL)...
We aimed to characterize the clinical profiles and short-term outcomes of adult patients with full-frequency idiopathic sudden sensorineural hearing loss (ISSNHL) treated uniformly with combination therapy, and to determine the prognostic predictors for the combination therapy. A total of 131 eligible cases hospitalized in our department from January 2018 to June 2021 were retrospectively reviewed. All enrolled cases received a standardized combination therapy employing intravenous methylprednisolone, batroxobin, and extract during the 12 days of hospitalization. The clinical and audiometric profiles were compared between recovered patients and their unrecovered counterparts. The overall recovery rate was 57.3% in the study. Accompanying vertigo (odds ratio = 0.360, = 0.006) and body mass index (BMI, odds ratio = 1.158, = 0.016) were two independent predictors of hearing outcomes of the therapy. The male gender and cigarette-smoking history were marginally associated with good hearing prognosis ( = 0.051 and 0.070, respectively). Patients with BMI ≥ 22.4 kg/m had a better chance of hearing recovery ( = 0.02). Conclusions: Accompanying vertigo and low BMI (<22.4 kg/m) were independently associated with poor prognosis for full-frequency ISSNHL in combination therapy. Male gender and cigarette-smoking history might be considered positive effects on hearing prognosis.
PubMed: 36836013
DOI: 10.3390/jcm12041478 -
Frontiers in Neurology 2023Sudden sensorineural hearing loss (SSNHL) can cause great panic in patients. Whether it is advantageous to add intravenous batroxobin in the treatment of SSNHL remains...
BACKGROUND
Sudden sensorineural hearing loss (SSNHL) can cause great panic in patients. Whether it is advantageous to add intravenous batroxobin in the treatment of SSNHL remains to be determined. This study aimed to compare the short-term efficacy of therapy combined with intravenous batroxobin and that without intravenous batroxobin in SSNHL patients.
METHODS
This retrospective study harvested the data of SSNHL patients hospitalized in our department from January 2008 to April 2021. The hearing levels on the admitted day (before treatment) and the discharge day were considered pre-treatment hearing and post-treatment hearing, respectively. The hearing gain was the difference value of pre-treatment hearing and post-treatment hearing. We used Siegel's criteria and the Chinese Medical Association of Otolaryngology (CMAO) criteria to evaluate hearing recovery. The complete recovery rate, overall effective rate, and hearing gain at each frequency were considered outcomes. Propensity score matching (PSM) was conducted to balance the baseline characteristics between the batroxobin group and the non-batroxobin group. Sensitivity analysis was carried out in flat-type and total-deafness SSNHL patients.
RESULTS
During the study period, 657 patients with SSNHL were admitted to our department. Among them, a total of 274 patients met the enrolled criteria of our study. After PSM, 162 patients (81 in each group) were included in the analysis. Once the hospitalized treatment was completed, the patients would be discharged the next day. Logistic regression analysis of the propensity score-matched cohort indicated that both the complete recovery rates [Siegel's criteria, OR: 0.734, 95% CI: 0.368-1.466, = 0.381; CMAO criteria, OR: 0.879, 95% CI: 0.435-1.777, = 0.720] and the overall effective rates [Siegel's criteria and CMAO criteria, OR: 0.741, 95% CI: 0.399-1.378, = 0.344] were not significantly different between the two treatment groups. Sensitivity analysis has shown similar results. For flat-type and total-deafness SSNHL patients, no significant difference was found in post-treatment hearing gain at each frequency between the two groups after PSM.
CONCLUSION
There was no significant difference in short-term hearing outcomes between treatment with batroxobin and treatment without batroxobin in SSNHL patients by Siegel's and CMAO criteria after PSM. Future studies for better therapy regimens of SSNHL are still needed.
PubMed: 37139065
DOI: 10.3389/fneur.2023.1102297 -
The Journal of Biological Chemistry Jun 2013Batroxobin is a thrombin-like serine protease from the venom of Bothrops atrox moojeni that clots fibrinogen. In contrast to thrombin, which releases fibrinopeptide A...
Batroxobin is a thrombin-like serine protease from the venom of Bothrops atrox moojeni that clots fibrinogen. In contrast to thrombin, which releases fibrinopeptide A and B from the NH2-terminal domains of the Aα- and Bβ-chains of fibrinogen, respectively, batroxobin only releases fibrinopeptide A. Because the mechanism responsible for these differences is unknown, we compared the interactions of batroxobin and thrombin with the predominant γA/γA isoform of fibrin(ogen) and the γA/γ' variant with an extended γ-chain. Thrombin binds to the γ'-chain and forms a higher affinity interaction with γA/γ'-fibrin(ogen) than γA/γA-fibrin(ogen). In contrast, batroxobin binds both fibrin(ogen) isoforms with similar high affinity (Kd values of about 0.5 μM) even though it does not interact with the γ'-chain. The batroxobin-binding sites on fibrin(ogen) only partially overlap with those of thrombin because thrombin attenuates, but does not abrogate, the interaction of γA/γA-fibrinogen with batroxobin. Furthermore, although both thrombin and batroxobin bind to the central E-region of fibrinogen with a Kd value of 2-5 μM, the α(17-51) and Bβ(1-42) regions bind thrombin but not batroxobin. Once bound to fibrin, the capacity of batroxobin to promote fibrin accretion is 18-fold greater than that of thrombin, a finding that may explain the microvascular thrombosis that complicates envenomation by B. atrox moojeni. Therefore, batroxobin binds fibrin(ogen) in a manner distinct from thrombin, which may contribute to its higher affinity interaction, selective fibrinopeptide A release, and prothrombotic properties.
Topics: Animals; Batroxobin; Binding Sites; Fibrinopeptide A; Humans; Protein Binding; Protein Isoforms; Thrombin
PubMed: 23612970
DOI: 10.1074/jbc.M113.464750