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PloS One 2019Batroxobin, isolated from Bothrops moojeni, is a defibrinogenating agent used as a thrombin-like serine protease against fibrinogen for improving microcirculation. Here,...
Batroxobin, isolated from Bothrops moojeni, is a defibrinogenating agent used as a thrombin-like serine protease against fibrinogen for improving microcirculation. Here, we investigated whether, and if so, how batroxobin restores ischemic tissue injury in terms of anti-inflammatory effects. In an in vitro flow cytometry assay for human neutrophil extracellular traps (NETs), batroxobin (DF-521; Defibrase) inhibited human NETs induced by tumor necrosis factor-α (TNF-α) in the presence of human fibrinogen. Next, the effect of batroxobin was investigated by immunohistochemistry of the anterior tibial muscle (ATM) in an ischemic hindlimb model using C57BL/6J mice intraperitoneally injected with DF-521 versus the saline control. NETs and fibrinogen deposition in the ischemic ATM decreased in DF-521-treated mice on day 2 after ischemia. Meanwhile, reverse transcription-quantitative PCR assay of the ischemic ATM unveiled continuous downregulation in the expression of the genes; Tnf-α and nitric oxide synthase2 (Nos2) with hypoxia-inducible factor-1α (Hif-1α) and vascular endothelial growth factor-a (Vegf-a) from day 3 to day 7, but the upregulation of arginase-1 (Arg-1) and placental growth factor (Plgf) with myogenin (Myog) on day 7. Daily intraperitoneal DF-521 injection for the initial 7 days into mice with ischemic hindlimbs promoted angiogenesis and arteriogenesis on day 14. Moreover, DF-521 injection accelerated myofiber maturation after day 14. Laser doppler imaging analysis revealed that blood perfusion in DF-521-injected mice significantly improved on day 14 versus the saline control. Thus, DF-521 improves microcirculation by protecting NETs with tissue defibrinogenation, thereby protecting against severe ischemic tissue injury and accelerating vascular and skeletal muscular regeneration. To our knowledge, batroxobin might be the first clinically applicable NET inhibitor against ischemic diseases.
Topics: Adult; Animals; Anti-Inflammatory Agents; Batroxobin; Cells, Cultured; Disease Models, Animal; Extracellular Traps; Fibrinolytic Agents; Hindlimb; Humans; Inflammation; Ischemia; Male; Mice, Inbred C57BL; Middle Aged; Wound Healing; Young Adult
PubMed: 31419236
DOI: 10.1371/journal.pone.0220898 -
Frontiers in Neurology 2023
PubMed: 37840924
DOI: 10.3389/fneur.2023.1292836 -
The Journal of Toxicological Sciences May 1986The plasma levels and urinary excretion of batroxobin administered to 6 species of animals were examined by an enzyme immunoassay method. Defibrinogenating effect of...
The plasma levels and urinary excretion of batroxobin administered to 6 species of animals were examined by an enzyme immunoassay method. Defibrinogenating effect of batroxobin was also studied in those species. The plasma levels of immunoreactive batroxobin disappeared exponentially in all the animals and differences in half-life were observed to occur according to species. The elimination half-life of immunoreactive batroxobin in the plasma was the largest in dogs, followed by rats, monkeys, guinea pigs, mice and rabbits. The extent of the defibrinogenating effect was also noted to vary according to the species, being greatest in dogs and then monkeys, mice, rats, guinea pigs and rabbits. Following the continuous infusion of batroxobin into dogs, its level in the plasma remained high over a considerable period of time and the defibrinogenating effect lasted in corresponding to its plasma level. The urinary excretion of immunoreactive batroxobin was quite small in these species, being 0.2-1.9% of the original dose.
Topics: Animals; Batroxobin; Dogs; Fibrinogen; Guinea Pigs; Half-Life; Macaca fascicularis; Male; Mice; Mice, Inbred Strains; Peptide Hydrolases; Rabbits; Rats; Rats, Inbred Strains; Species Specificity
PubMed: 3522924
DOI: 10.2131/jts.11.135 -
The Cochrane Database of Systematic... Aug 2012Peripheral arterial disease (PAD) is frequently treated by balloon angioplasty. Restenosis/reocclusion of the dilated segments occurs often, depending on length of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Peripheral arterial disease (PAD) is frequently treated by balloon angioplasty. Restenosis/reocclusion of the dilated segments occurs often, depending on length of occlusion, lower leg outflow, stage of disease and presence of cardiovascular risk factors. To prevent reocclusion, patients are treated with antithrombotic agents. This is an update of a review first published in 2005.
OBJECTIVES
To determine whether any antithrombotic drug is more effective in preventing restenosis or reocclusion after peripheral endovascular treatment, compared to another antithrombotic drug, no treatment, placebo or other vasoactive drugs.
SEARCH METHODS
For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched 14 February 2012) and CENTRAL (2012, Issue 1).
SELECTION CRITERIA
We selected randomised controlled trials (RCTs). Participants were patients with symptomatic PAD treated by endovascular revascularisation of the pelvic or femoropopliteal arteries. Interventions were anticoagulant, antiplatelet or other vasoactive drug therapy compared with no treatment, placebo or any other vasoactive drug. Clinical endpoints were reocclusion, restenosis, amputation, death, myocardial infarction, stroke, major bleeding and other side effects, such as minor bleeding, puncture site bleeding, gastrointestinal side effects and haematoma.
DATA COLLECTION AND ANALYSIS
We independently extracted and assessed details of the number of randomised patients, treatment, study design, patient characteristics and risk of bias. Analysis was based on intention-to-treat data. To examine the effects of outcomes such as reocclusion, restenosis, amputation and major bleeding, we computed odds ratios (OR) with 95% confidence intervals (CI) using a fixed-effect model.
MAIN RESULTS
Twenty-two trials with a total of 3529 patients are included (14 in the original review and a further eight in this update). For the majority of comparisons, only one trial was available so results were rarely combined in meta-analyses. Individual trials were generally small and risk of bias was often unclear due to limitations in reporting. Three trials reported on drug versus placebo/control; results were consistently available for a maximum follow-up of only six months. At six months post intervention, a statistically significant reduction in reocclusion was found for high-dose acetylsalicylic acid (ASA) combined with dipyridamole (DIP) (OR 0.40, 95% CI 0.19 to 0.84), but not for low-dose ASA combined with DIP (OR 0.69, 95% CI 0.44 to 1.10; P = 0.12) nor in major amputations for lipo-ecraprost (OR 0.89, 95% CI 0.44 to 1.80). The remaining trials compared different drugs; results were more consistently available for a longer period of 12 months. At 12 months post intervention, no statistically significant difference in reocclusion/restenosis was detected for any of the following comparisons: high-dose ASA versus low-dose ASA (OR 0.98, 95% CI 0.64 to 1.48; P = 0.91), ASA/DIP versus vitamin K antagonists (VKA) (OR 0.65, 95% CI 0.40 to 1.06; P = 0.08), clopidogrel and aspirin versus low molecular weight heparin (LMWH) plus warfarin (OR 0.31, 95% CI 0.06 to 1.68; P = 0.18), suloctidil versus VKA: reocclusion (OR 0.59, 95% CI 0.20 to 1.76; P = 0.34), restenosis (OR 1.87, 95% CI 0.66 to 5.31; P = 0.24) and ticlopidine versus VKA (OR 0.71, 95% CI 0.37 to 1.36; P = 0.30). Treatment with cilostazol resulted in statistically significantly fewer reocclusions than ticlopidine (OR 0.32, 95% CI 0.13 to 0.76; P = 0.01). Compared with aspirin alone, LMWH plus aspirin significantly decreased occlusion/restenosis (by up to 85%) in patients with critical limb ischaemia (OR 0.15, 95% CI 0.06 to 0.42; P = 0.0003) but not in patients with intermittent claudication (OR 1.73, 95% CI 0.97 to 3.08; P = 0.06) and batroxobin plus aspirin reduced restenosis in diabetic patients (OR 0.28, 95% CI 0.13 to 0.60). Data on bleeding and other potential gastrointestinal side effects were not consistently reported, although there was some evidence that high-dose ASA increased gastrointestinal side effects compared with low-dose ASA, that clopidogrel and aspirin resulted in fewer major bleeding episodes compared with LMWH plus warfarin, and that abciximab resulted in more severe bleeding episodes.
AUTHORS' CONCLUSIONS
There is limited evidence suggesting that restenosis/reocclusion at six months following peripheral endovascular treatment is reduced by use of antiplatelet drugs compared with placebo/control, but associated information on bleeding and gastrointestinal side effects is lacking. There is also some evidence of variation in effect according to different drugs with cilostazol reducing reocclusion/restenosis at 12 months compared with ticlopidine and both LMWH and batroxobin combined with aspirin appearing beneficial compared with aspirin alone. However, available trials are generally small and of variable quality and side effects of drugs are not consistently addressed. Further good quality, large-scale RCTs, stratified by severity of disease, are required.
Topics: Angioplasty, Balloon; Anticoagulants; Constriction, Pathologic; Humans; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Secondary Prevention
PubMed: 22895926
DOI: 10.1002/14651858.CD002071.pub3 -
BMC Veterinary Research Jul 2012The clinical use of autologous platelet concentrates (also known as platelet-rich plasma) on the field of regenerative therapy, in the last decade has been the subject...
BACKGROUND
The clinical use of autologous platelet concentrates (also known as platelet-rich plasma) on the field of regenerative therapy, in the last decade has been the subject of several studies especially in equine medicine and surgery. The objectives of this study was: 1) to describe and compare the cellular population in whole blood, lower fraction (A) and upper fraction (B) of platelet concentrates, 2) to measure and compare the transforming growth factor beta 1 (TGF-β1) concentration in plasma and both platelet concentrates after be activated with calcium gluconate or batroxobin plus calcium gluconate and, 3) to determine correlations between cell counts in platelet concentrates and concentrations of TGF-β1. Blood samples were taken from 16 dogs for complete blood count, plasma collection and platelet concentrates preparation. The platelet concentrates (PC) were arbitrarily divided into two fractions, specifically, PC-A (lower fraction) and PC-B (upper fraction). The Platelet concentrates were analyzed by hemogram. After activated with calcium gluconate or batroxobin plus calcium gluconate, TGF-β1 concentration was determined in supernatants of platelet concentrates and plasma.
RESULTS
There were differences statistically significant (P < 0.05) for the platelet count and leukocyte count and TGF-β1 concentration between whole blood, plasma and both platelet concentrates. A significant correlation was found between the number of platelets in both platelet concentrates and TGF-β1 concentration. Platelet collection efficiency was 46.34% and 28.16% for PC-A and PC-B, respectively. TGF-β1 concentration efficiency for PC activated with calcium gluconate was 47.75% and 31.77%, for PC-A and PC-B, respectively. PC activated with batroxobin plus CG showed 46.87% and 32.24% for PC-A and PC-B, respectively.
CONCLUSIONS
The methodology used in this study allows the concentration of a number of platelets and TGF-β1 that might be acceptable for a biological effect for clinical or experimental use as a regenerative therapy in dogs.
Topics: Animals; Batroxobin; Blood Platelets; Calcium Gluconate; Dogs; Gene Expression Regulation; Transforming Growth Factor beta
PubMed: 22830991
DOI: 10.1186/1746-6148-8-121 -
Clinical Radiology Sep 2022To determine whether the injection of haemocoagulase into the biopsy tract can reduce pneumothorax and pulmonary haemorrhage after computed tomography (CT)-guided...
AIM
To determine whether the injection of haemocoagulase into the biopsy tract can reduce pneumothorax and pulmonary haemorrhage after computed tomography (CT)-guided percutaneous transthoracic lung biopsy (PTLB).
MATERIALS AND METHODS
A retrospective study was performed involving patients with undiagnosed pulmonary lesions scheduled for PTLB between January 2020 and March 2021. Patients were assigned to the haemocoagulase group or the non-haemocoagulase group. After CT-guided biopsies were performed with a 17 G coaxial system, patients in the haemocoagulase group received a haemocoagulase injection (0.2-0.5 units) in the biopsy tract as the sheath was withdrawn. Postoperative image studies were performed to evaluate complications, including pneumothorax and pulmonary haemorrhage. Factors, including the patient's position, lesion location, and pathological results, were evaluated to determine their associations with the complications.
RESULTS
A total of 100 patients were included, with 44 men and a mean age of 53 years old. The overall incidences of pneumothorax and pulmonary haemorrhage were 15% and 13%, respectively. The incidences of pneumothorax and pulmonary haemorrhage were statistically significantly lower in the haemocoagulase group (8% and 6%, respectively) than in the non-haemocoagulase group (22% and 20%, respectively; p=0.04 and 0.03, respectively). There was no statistically significant difference in haemoptysis between the haemocoagulase (6%) and non-haemocoagulase (2%) groups (p=0.23). There were also no statistically significant associations of pneumothorax or pulmonary haemorrhage with the patients' positions, lesion location, or pathological results.
CONCLUSION
Biopsy tract haemocoagulase injection reduced the incidences of postoperative pneumothorax and pulmonary haemorrhage after PTLB.
Topics: Batroxobin; Female; Hemorrhage; Humans; Image-Guided Biopsy; Lung; Lung Diseases; Male; Middle Aged; Pneumothorax; Radiography, Interventional; Retrospective Studies; Risk Factors; Tomography, X-Ray Computed
PubMed: 35788268
DOI: 10.1016/j.crad.2022.05.019 -
CNS Neuroscience & Therapeutics May 2019The objective of this study was to evaluate cerebral venous recanalization with magnetic resonance black-blood thrombus imaging (MRBTI) in patients with cerebral venous...
AIMS
The objective of this study was to evaluate cerebral venous recanalization with magnetic resonance black-blood thrombus imaging (MRBTI) in patients with cerebral venous thrombosis (CVT) who underwent batroxobin treatment in combination with anticoagulation.
METHODS
A total of 31 CVT patients were enrolled in this real-world registry study. The patients were divided into batroxobin (n = 21) and control groups (n = 10). In addition to the same standard anticoagulation as in the control group, patients in the batroxobin group underwent intravenous batroxobin for a total of three times.
RESULTS
In the batroxobin group compared with the control group, we found better odds of recanalization degree [adjusted OR (95%CI) of 8.10 (1.61-40.7)] and segment-stenosis attenuation [adjusted OR (95%CI) of 4.48 (1.69-11.9)] with batroxobin treatment. We further noted a higher ratio of patients with the attenuation of stenosis [adjusted OR (95%CI) of 26.4 (1.10-635)]; as well as a higher ratio of segments with stenosis reversion [adjusted OR (95%CI) of 4.52 (1.48-13.8)]. However, neurological deficits between the two groups showed no statistical difference at 90-day follow-up (P > 0.05).
CONCLUSIONS
Batroxobin may promote venous sinus recanalization and attenuate CVT-induced stenosis. Further randomized study of this promising drug may be warranted to better delineate the amount of benefit.
Topics: Adult; Anticoagulants; Batroxobin; Constriction, Pathologic; Drug Therapy, Combination; Female; Fibrinolytic Agents; Humans; Intracranial Thrombosis; Magnetic Resonance Imaging; Male; Registries; Treatment Outcome; Venous Thrombosis
PubMed: 30675757
DOI: 10.1111/cns.13093 -
The Journal of Toxicological Sciences Aug 1986125I-Labeled batroxobin was prepared and following its intravenous and subcutaneous administrations to rats and dogs, the blood radioactivity was determined. In the both...
125I-Labeled batroxobin was prepared and following its intravenous and subcutaneous administrations to rats and dogs, the blood radioactivity was determined. In the both species following the intravenous injections, the decrease in radioactivity was biexponential. Following subcutaneous administration, radioactivity became maximal at 6h and decreased in a manner similar to that of the beta-phase of the intravenous injection. The blood concentration of fibrinogen in dogs was also determined. After the intravenous injection, fibrinogen became undetectable 1h later, and appeared again in the blood at 24h. After the subcutaneous injection, the decrease was not so rapid. Fibrinogen resumed its original levels at 7 day after the administration in both the routes. Radioactivity after the both injections was excreted generally in the urine in about the same amounts. The total urinary and fecal excretions in rats and dogs were 80 and 95%, respectively. The distribution of radioactivity in the tissues was examined by counting technique and whole-body autoradiography. Radioactivity predominantly accumulated in the thyroid and stomach and could also be found in the kidneys and liver in fair amounts. The distribution patterns of radioactivity for both the routes of administrations and also for male and pregnant rats were basically the same. In fetus rats, a slight distribution was noted. From the results of gel filtration chromatography and trichloroacetic acid fractionation, [125I] batroxobin was metabolized soon after the administration to afford low molecular substances such as 125I-ion in the plasma and urine.
Topics: Animals; Autoradiography; Batroxobin; Chromatography, Gel; Dogs; Feces; Fibrinogen; Iodine Radioisotopes; Peptide Hydrolases; Rats; Rats, Inbred Strains; Species Specificity; Tissue Distribution
PubMed: 3540318
DOI: 10.2131/jts.11.155 -
Neuroscience Bulletin Aug 2013Expansion of the secondary injury following primary spinal cord injury is a major pathological event that increases destruction in the spinal cord, so measures to reduce...
Expansion of the secondary injury following primary spinal cord injury is a major pathological event that increases destruction in the spinal cord, so measures to reduce secondary injury are needed. Our previous study demonstrated that, at the front of the expanding secondary injury in the spinal cord, there is an ischemic area in which many neurons can still be rescued. Therefore, enhancement of blood circulation in the cord may be helpful, and indeed, we found that a traditional Chinese medicine, shu-xue-tong, efficiently reduces the secondary injury. The aim of the present study was to investigate the effect of reducing fibrinogen with Batroxobin, a drug widely used clinically for ischemia, in rats with spinal cord contusion. We found that both 2 and 4 Batroxobin units (BU)/kg efficiently decreased the plasma fibrinogen, and 2 BU/kg significantly increased spinal blood flow, enhanced neuronal survival, mitigated astrocyte and microglia activation, and improved locomotor recovery. However, 4 BU/kg had no effect on the secondary spinal cord injury. These data suggest that Batroxobin has multiple beneficial effects on spinal cord injury, indicating a potential clinical application.
Topics: Animals; Batroxobin; Cell Survival; Disease Models, Animal; Fibrinogen; Fibrinolytic Agents; Immunohistochemistry; Laser-Doppler Flowmetry; Microglia; Neurons; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord; Spinal Cord Injuries
PubMed: 23852558
DOI: 10.1007/s12264-013-1354-7 -
ACS Biomaterials Science & Engineering 2015Controlling perioperative bleeding is of critical importance to minimize hemorrhaging and fatality. Patients on anticoagulant therapy such as heparin have diminished...
Controlling perioperative bleeding is of critical importance to minimize hemorrhaging and fatality. Patients on anticoagulant therapy such as heparin have diminished clotting potential and are at risk for hemorrhaging. Here we describe a self-assembling nanofibrous peptide hydrogel (termed SLac) that on its own can act as a physical barrier to blood loss. SLac was loaded with snake-venom derived Batroxobin (50 g/mL) yielding a drug-loaded hydrogel (SB50). SB50 was potentiated to enhance clotting even in the presence of heparin. In vitro evaluation of fibrin and whole blood clotting helped identify appropriate concentrations for hemostasis in vivo. Batroxobin-loaded hydrogels rapidly (within 20s) stop bleeding in both normal and heparin-treated rats in a lateral liver incision model. Compared to standard of care, Gelfoam, and investigational hemostats such as Puramatrix, only SB50 showed rapid liver incision hemostasis post surgical application. This snake venom-loaded peptide hydrogel can be applied via syringe and conforms to the wound site resulting in hemostasis. This demonstrates a facile method for surgical hemostasis even in the presence of anticoagulant therapies.
PubMed: 26753175
DOI: 10.1021/acsbiomaterials.5b00356