Dazhu Hongjingtian Injection for Ischemic Stroke: Protocol for a Prospective, Multicenter Observational Study.

BACKGROUND: Although results from in vitro studies and small randomized controlled trials have shown positive effects of Dazhu hongjingtian injection (DZHJTI) on acute ischemic stroke (AIS), their generalizability to routine clinical practice remains to be established. OBJECTIVE: The primary aim of this study is to evaluate the effectiveness of DZHJTI treatment for AIS with regard to changes in the stroke-related neurological deficit from baseline to outpatient follow-up, mortality, subsequent vascular events, disability, and traditional Chinese medicine syndrome in real-world clinical settings. By monitoring for adverse events or significant changes in vital signs and laboratory parameters, we also aim to assess the safety of DZHJTI. METHODS: This prospective, multicenter cohort study plans to enroll 2000 patients with AIS within 14 days of symptom onset from 30 hospitals across China. Eligible patients will be followed up for 6 months after initiating medication treatments. The primary outcome will be the change in the National Institute of Health Stroke Scale score from baseline to outpatient follow-up. The secondary outcomes include overall mortality, stroke recurrence, new-onset major vascular events, global disability, and improvement of traditional Chinese medicine syndrome in 6 months. Adverse events or clinically significant changes in vital signs and laboratory parameters, regardless of the severity, will be recorded during the trial to assess the safety of DZHJTI. An augmented inverse propensity weighted estimator will be used to reduce variability and improve accuracy in average treatment effects estimation. RESULTS: The clinical trial registration was approved in October 2022, and the recruitment and enrollment of participants started in November 2022. The study's outcomes are expected to be published in 2025 in reputable, peer-reviewed health-related research journals. CONCLUSIONS: This real-world cohort study is the first to assess the effectiveness and safety of DZHJTI in treating AIS. It may provide additional clinical evidence, including the duration of response, long-term drug effectiveness, and subgroup efficacy data. The study results will be valuable for clinicians and patients seeking optimal treatment for AIS and could lead to better use of DZHJTI and improved patient outcomes. TRIAL REGISTRATION: ITMCTR ITMCTR2022000005; http://tinyurl.com/554ns8m5. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52447.

Impact of low-level laser therapy as an adjunct to non-surgical periodontal treatment on the levels of tissue plasminogen activator and plasminogen activator inhibitor 1 in Stage 3-4, Grade C periodontitis patients: a split-mouth, randomized control study.

AIM: To investigate the effects of low-level laser therapy (LLLT) as an adjunct to non-surgical periodontal treatment (NSPT) on the plasminogen-activating system. MATERIALS AND METHODS: Stage 3-4 Grade C periodontitis and age-gender-matched healthy individuals participated in the split-mouth study (ClinicalTrials.gov identifier, NCT05233501). The study groups were Periodontitis/NSPT (Sham); Periodontitis/NSPT + LLLT (LLLT); Healthy (Control). Following NSPT, LLLT was applied on Days 0, 2 and 7. Clinical parameters were recorded at baseline and on Day 30. Gingival crevicular fluid (GCF) was collected at baseline, on days 7, 14, and 30; tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels were measured with ELISA. RESULTS: Clinical parameters, total GCF tPA (tPAt) and PAI-1 (PAI-1t) levels significantly reduced in LLLT and Sham groups (< 0.001). GCF tPAt levels in LLLT were significantly lower (< 0.05) than Sham on Day 7. GCF tPAt levels in periodontitis groups were significantly higher than the Control at baseline, on Days 7 and 14 (< 0.01). By Day 30, both groups decreased to control levels (> 0.05). GCF PAI-1t levels were significantly lower in LLLT than the Sham on day 30 (< 0.01), comparable to healthy controls (> 0.05). CONCLUSION: Adjunctive LLLT modulates the plasminogen activating system in severe periodontitis by altering GCF tPA and PAI-1 levels. CLINICAL RELEVANCE: LLLT as an adjunct to non-surgical periodontal treatment in patients with Stage 3-4 Grade C leads to reduced plasminogen activation.

Effects of intravenous thrombolysis with and without salvianolic acids for injection on the functional recovery of patients with acute ischemic stroke: A systematic review, meta-analysis, and trial sequential analysis.

In patients with acute ischemic stroke (AIS), the effect of salvianolic acids for injection (SAFI) as the secondary treatment after intravenous thrombolysis (IVT) is unclear. We aimed to evaluate the efficacy of SAFI for patients with AIS undergoing IVT. We searched seven electronic databases and two registries from inception to July 24, 2022, for randomized controlled trials (RCTs) assessing the effect of SAFI plus recombinant tissue plasminogen activator (rt-PA) on the functional recovery compared to rt-PA alone in patients with AIS. Two independent authors selected RCTs, extracted data, and assessed the risk of bias. A meta-analysis was conducted. Eight RCTs involving 682 patients with AIS were included. Compared to patients receiving intravenous rt-PA alone, those receiving intravenous rt-PA combined with SAFI had a higher likelihood of achieving favorable functional outcomes at 3 months. In addition, the use of SAFI for 2 weeks was associated with better neurological recovery. The evidence of benefit was confirmed by trial sequential analysis (TSA). The incidence of intracranial hemorrhage did not differ between the two groups. In patients with AIS, intravenous rt-PA combined with SAFI might achieve better functional outcomes. However, further high-quality studies are needed to firmly establish the clinical efficacy of SAFI.

The combination of danhong injection plus tissue plasminogen activator ameliorates mouse tail thrombosis-induced by κ-carrageenan.

BACKGROUND: After thrombosis, t-PA thrombolysis is the first choice, but the use of t-PA can easily lead to hemorrhagic injury and neurotoxicity. The combination of Danhong injection (DHI) and tissue plasminogen activator (t-PA) therapy may be a new strategy to find high-efficiency anti-thrombosis and low bleeding risk. However, nothing is about the effect of DHI plus t-PA on platelet activation. PURPOSE: The present research was to explore the optimal dose of DHI and t-PA in vivo and mechanisms involved with the treatment of combining DHI and t-PA for thrombotic disease and determined whether DHI plus t-PA affects thrombotic processes related to platelet activation. METHODS: Mice were induced by administering κ-carrageenan intraperitoneally, the ratio of different doses of DHI and t-PA in vivo, and the optimal dose effects on platelet aggregation, platelet adhesion, thrombosis formation, and platelet activation were determined. The effects of the αIIbß3 signaling pathway were analyzed in mice. RESULTS: In vitro, DHI (62% v/v), t-PA (1 mg/ml), and DHI + t-PA (62% v/v + 1 mg/ml) decreased rat platelet aggregation and adhesion, with a stronger effect from the combination as compared to t-PA monotherapy. In vivo, injections of κ-carrageenan were used to induce BALB/c mice. The optimal dose of DHI, t-PA, and DHI + t-PA is 12 ml/kg, 10 mg/kg, and 12 ml/kg + 7.5 mg/kg. The administration of DHI (12 ml/kg), t-PA (10 mg/kg), and DHI + t-PA (12 ml/kg + 7.5 mg/kg) decreased thrombi in mouse tissue vessels. Furthermore, the reduction of thrombosis formation by DHI, t-PA, and DHI + t-PA was related to lower collagen deposition, and lowered expressions of collagen I, matrix metalloproteinase 2 (MMP-2), and metalloproteinase 9 (MMP-9) in mouse tails, with increased efficacy in combination as compared to t-PA alone. The anti-thrombosis actions of DHI, t-PA, and their combination regulated the expression of CD41, purinergic receptor (P2Y12), guanine nucleotide-binding protein G (q) subunit alpha (GNAQ), phosphatidylinositol phospholipase c beta (PLCß), Ras-related protein 1 (Rap1), RIAM, talin1, fibrinogen alpha chain (FG), kindlin-3, and RAS guany1-releasing protein 1 (RasGRP1). CONCLUSIONS: Based on expression, the mechanism responsible for thrombosis may be attributed to platelet activation via the αIIbß3 signaling pathway. Combination therapy with DHI and t-PA exerted potent thrombolytic effects. Thus, our data can be used as a foundation for further clinical studies examining the efficacy of traditional Chinese medicines for the treatment of thrombosis.

Effects of Danhong injection combined with intravenous thrombolysis on cardiac function, myocardial zymogram and lipoprotein-associated phospholipase A2 level in older adult patients with acute myocardial infarction / 中国基层医药

Objective:To investigate the effects of Danhong injection combined with intravenous recombinant tissue plasminogen activator (rt-PA) on cardiac function, myocardial zymogram and lipoprotein associated phospholipase A2 (Lp-PLA2) level in older adult patients with acute myocardial infarction (AMI). Methods:Eighty older adult patients with acute myocardial infarction who received treatment in Community-based General Hospital of Shaoxing Central Hospital, China between January 2017 and December 2019 were included in this study. They were randomly assigned to receive either intravenous thrombolysis with rt-PA (control group, n = 40) or Danhong injection combined with intravenous thrombolysis with rt-PA (observation group, n = 40). The changes in traditional Chinese medicine syndrome score, left ventricular ejection fraction, left ventricular end diastolic diameter, creatine kinase, creatine kinase-MB and lipoprotein associated phospholipase A2 level as well as adverse cardiovascular events were compared between the control and observation groups. Results:After treatment, the score of chest tightness, dark purple tongue, palpitation and shortness of breath in the two groups were decreased. After treatment, the score of chest tightness, dark purple tongue, palpitation and shortness of breath in the observation group was (2.13 ± 0.31) points, (1.98 ± 0.41) points, (1.77 ± 0.29) points, respectively, which was significantly lower than that in the control group [(2.98 ± 0.37) points, (2.52 ± 0.56) points, (2.13 ± 0.32) points, t = 11.137, 4.920, 5.272, all P < 0.001]. After treatment, left ventricular end diastolic diameter in each group was decreased compared with before treatment. After treatment, left ventricular end diastolic diameter in the observation group was significantly lower than that in the control group [(46.12 ± 4.11) mm vs. (49.74 ± 4.32) mm], and left ventricular ejection fraction in the observation group was significantly higher than that in the control group [(47.02 ± 3.55) % vs. (43.25 ± 4.10) %, t = 3.839, 4.396, both P < 0.001). After treatment, Lp-PLA2, creatine kinase, creatine kinase-MB levels in each group were decreased compared with before treatment. After treatment, Lp-PLA2, creatine kinase, creatine kinase-MB levels in the observation group were (171.02 ± 12.52) μg /L, (10.52 ± 2.11) U/L, (24.12 ± 3.52) U/L), respectively, which were significantly lower than those in the control group [(189.63 ± 11.98) μg/L, (14.71 ± 2.62) U/L, (32.79 ± 4.79) U/L), t = 6.792, 7.877, 9.224, all P < 0.001]. The incidence of adverse cardiovascular events in the observation group was significantly lower than that in the control group (5.00% vs. 22.50%, χ2 = 5.165, P < 0.05). Conclusion:Danhong injection combined with intravenous rt-PA for the treatment of acute myocardial infarction in older adult patients can greatly decrease traditional Chinese medicine syndrome score, improve cardiac function, regulate myocardial zymogram and Lp-PLA2 levels, and decrease the incidence of adverse cardiovascular events.

YiQiFuMai Lyophilized Injection ameliorates tPA-induced hemorrhagic transformation by inhibiting cytoskeletal rearrangement associated with ROCK1 and NF-κB signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Thrombolytic therapy with tissue plasminogen activator (tPA) after ischemic stroke exacerbates blood-brain barrier (BBB) breakdown and leads to hemorrhagic transformation (HT). YiQiFuMai Lyophilized Injection (YQFM) is a modern preparation derived from Sheng-mai San (a traditional Chinese medicine). YQFM attenuates the BBB dysfunction induced by cerebral ischemia-reperfusion injury. However, whether YQFM can suppress tPA-induced HT remains unknown. AIM OF THE STUDY: We investigated the therapeutic effect of YQFM on tPA-induced HT and explored the underlying mechanisms in vivo and in vitro to improve the safety of tPA use against stroke. METHODS: Male C57BL/6J mice were subjected to 45 min of ischemia and 24 h of reperfusion. tPA (10 mg/kg) were infused 2 h after occlusion and YQFM (0.671 g/kg) was injected 2.5 h after occlusion. The in vitro effect of YQFM (100, 200, 400 µg/mL) on tPA (60 µg/mL)-induced dysfunction of the microvascular endothelial barrier in the brain following oxygen-glucose deprivation/reoxygenation (OGD/R) was observed in bEnd.3 cells. RESULTS: YQFM suppressed tPA-induced high hemoglobin level in the brain, mortality, neurologic severity score, BBB permeability, expression and activation of matrix metalloproteinase (MMP)-9 and MMP-2, and degradation of tight-junction proteins. Furthermore, YQFM significantly blocked tPA-induced brain microvascular endothelial permeability and phosphorylation of Rho-associated kinase (ROCK)1, myosin light chain (MLC), cofilin and p65 in vivo and in vitro. CONCLUSION: YQFM suppressed tPA-induced HT by inhibiting cytoskeletal rearrangement linked with ROCK-cofilin/MLC pathways and inhibiting the nuclear factor-kappa B pathway to ameliorate BBB damage caused by tPA.

Preparation of Peptide and Recombinant Tissue Plasminogen Activator Conjugated Poly(Lactic-Co-Glycolic Acid) (PLGA) Magnetic Nanoparticles for Dual Targeted Thrombolytic Therapy.

Recombinant tissue plasminogen activator (rtPA) is the only thrombolytic agent that has been approved by the FDA for treatment of ischemic stroke. However, a high dose intravenous infusion is required to maintain effective drug concentration, owing to the short half-life of the thrombolytic drug, whereas a momentous limitation is the risk of bleeding. We envision a dual targeted strategy for rtPA delivery will be feasible to minimize the required dose of rtPA for treatment. For this purpose, rtPA and fibrin-avid peptide were co-immobilized to poly(lactic-co-glycolic acid) (PLGA) magnetic nanoparticles (PMNP) to prepare peptide/rtPA conjugated PMNPs (pPMNP-rtPA). During preparation, PMNP was first surface modified with avidin, which could interact with biotin. This is followed by binding PMNP-avidin with biotin-PEG-rtPA (or biotin-PEG-peptide), which was prepared beforehand by binding rtPA (or peptide) to biotin-PEG-maleimide while using click chemistry between maleimide and the single -SH group in rtPA (or peptide). The physicochemical property characterization indicated the successful preparation of the magnetic nanoparticles with full retention of rtPA fibrinolysis activity, while biological response studies underlined the high biocompatibility of all magnetic nanoparticles from cytotoxicity and hemolysis assays in vitro. The magnetic guidance and fibrin binding effects were also confirmed, which led to a higher thrombolysis rate in vitro using PMNP-rtPA or pPMNP-rtPA when compared to free rtPA after static or dynamic incubation with blood clots. Using pressure-dependent clot lysis model in a flow system, dual targeted pPMNP-rtPA could reduce the clot lysis time for reperfusion by 40% when compared to free rtPA at the same drug dosage. From in vivo targeted thrombolysis in a rat embolic model, pPMNP-rtPA was used at 20% of free rtPA dosage to restore the iliac blood flow in vascular thrombus that was created by injecting a blood clot to the hind limb area.

Acute phase treatment in central retinal artery occlusion: thrombolysis, hyperbaric oxygen therapy or both?

Central retinal artery occlusion (CRAO) is a neuro-ophthalmological emergency. There is a finite time window for acute interventions such as revascularization (e.g. intravenous thrombolysis-IVT) and retinal oxygenation (e.g. hyperbaric oxygen therapy-HBOT) therapies. Case 1: A 35-year-old female presented with CRAO in the right eye (OD) confirmed by fluorescein angiography (FA) and optical coherence tomography (OCT). She underwent 4 sessions of HBOT (100% O2 at 2.4 atmosphere absolute for 90 min). Afterwards, visual defect on the nasal field was kept but visual acuity (VA) improved from counting fingers to 1.0. Case 2: A 65-year-old male presented with CRAO in his left eye (OS) with 1.5 h of evolution. Orbital sonography and OCT confirmed the presence of an embolus and he underwent IVT with rTPA (0.9 mg/kg). VA improved from light perception to 0.1. Case 3: A 21-year-old male presented acute visual loss in his OD with 2.5 h of evolution. OCT and retinography identified CRAO. He was submitted to IVT (rTPA-0.9 mg/kg) followed by 12 sessions of HBOT. VA improved from hand motion to 1.0. Our case series depicts the approaches and possible outcomes in acute management of an infrequent, but highly morbid, cerebroretinovascular disorder. Future clinical trials are warranted to tackle current difficulties in CRAO treatment.

Glycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling.

Peroxynitrite (ONOO-) and high mobility group box 1 protein (HMGB1) are important cytotoxic factors contributing to cerebral ischemia-reperfusion injury. However, the roles of ONOO- in mediating HMGB1 expression and its impacts on hemorrhagic transformation (HT) in ischemic brain injury with delayed t-PA treatment remain unclear. In the present study, we tested the hypothesis that ONOO- could directly mediate the activation and release of HMGB1 in ischemic brains with delayed t-PA treatment. With clinical studies, we found that plasma nitrotyrosine (NT, a surrogate marker of ONOO-) was positively correlated with HMGB1 level in acute ischemic stroke patients. Hemorrhagic transformation and t-PA-treated ischemic stroke patients had increased levels of nitrotyrosine and HMGB1 in plasma. In animal experiments, we found that FeTmPyP, a representative ONOO- decomposition catalyst (PDC), significantly reduced the expression of HMGB1 and its receptor TLR2, and inhibited MMP-9 activation, preserved collagen IV and tight junction claudin-5 in ischemic rat brains with delayed t-PA treatment. ONOO- donor SIN-1 directly induced expression of HMGB1 and its receptor TLR2 in naive rat brains in vivo and induced HMGB1 in brain microvascular endothelial b.End3 cells in vitro. Those results suggest that ONOO- could activate HMGB1/TLR2/MMP-9 signaling. We then addressed whether glycyrrhizin, a natural HMGB1 inhibitor, could inhibit ONOO- production and the antioxidant properties of glycyrrhizin contribute to the inhibition of HMGB1 and the neuroprotective effects on attenuating hemorrhagic transformation in ischemic stroke with delayed t-PA treatment. Glycyrrhizin treatment downregulated the expressions of NADPH oxidase p47 phox and p67 phox and iNOS, inhibited superoxide and ONOO- production, reduced the expression of HMGB1, TLR2, MMP-9, preserved type IV collagen and claudin-5 in ischemic brains. Furthermore, glycyrrhizin significantly decreased the mortality rate, attenuated hemorrhagic transformation, brain swelling, blood-brain barrier damage, neuronal apoptosis, and improved neurological outcomes in the ischemic stroke rat model with delayed t-PA treatment. In conclusion, peroxynitrite-mediated HMGB1/TLR2 signaling contributes to hemorrhagic transformation, and glycyrrhizin could be a potential adjuvant therapy to attenuate hemorrhagic transformation, possibly through inhibiting the ONOO-/HMGB1/TLR2 signaling cascades.

[Effect of modified Buyang Huanwu Decoction on hemorrhagic transformation after rt-PA intravenous thrombolysis in patients with super early cerebral infarction].

To study the effect of modified Buyang Huanwu Decoction on the hemorrhagic transformation after intravenous thrombolysis of recombinant tissue type plasminogen activator(rt-PA) in patients with super early(onset time<4. 5 h) cerebral infarction. From March 2016 to July 2018,at the brain disease zone of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine,212 cases of super early cerebral infarction were selected and divided into two group according to the randomized complete blocks designs: control group(106 cases) and traditional Chinese medicine group(106 cases). The control group was treated with rt-PA intravenous thrombolysis,while the traditional Chinese medicine group was treated with modified Buyang Huanwu Decoction in addition to the therapy of the control group. Both groups were treated for 14 days. Neurological deficit score,serum matrix metalloproteinase-9(MMP-9),neuron specific enolase(NSE),vascular endothelial growth factor(VEGF) and plasma cellular fibronectin(c-FN) levels,the incidence of hemorrhagic transformation,clinical efficacy and adverse drug reactions before and after treatment were compared between the two groups. According to the findings,at the 14 thday after treatment,the rank sum test of the grade data showed that the clinical efficacy of the traditional Chinese medicine group was better than that of the control group(Z =-2. 033,P = 0. 042); on the basis of χ2 test,the total efficiency of the traditional Chinese medicine group was higher than that of the control group(χ2= 4. 895,P =0. 027); the hemorrhagic transformation rate of the traditional Chinese medicine group was lower than that of the control group within14 days of treatment(χ2= 3. 962,P = 0. 047). MMP-9 levels in the traditional Chinese medicine group were lower than those in the control group at the 3 rd,5 th,7 th,10 th,14 thd after treatment(t =-2. 474,-3. 022,-5. 163,-6. 998,-9. 821; P = 0. 014,0. 003,0,0,0). The improvement of c-FN,NSE,VEGF and NIHSS scores in the traditional Chinese medicine group was superior to that of the control group after 14 days of treatment(t =-2. 343,-3. 187,-2. 129,-3. 105; P = 0. 020,0. 002,0. 034,0. 002). No obvious adverse reactions of modified Buyang Huanwu Decoction were observed during 14 days of treatment. Modified Buyang Huanwu Decoction could reduce the expressions of MMP-9,c-FN,NSE and VEGF after rt-PA intravenous thrombolysis in patients with super early cerebral infarction,and decrease the hemorrhagic transformation rate after thrombolysis,with high safety.

Traumatic submacular hemorrhage: available treatment options and synthesis of the literature.

Sub-macular hemorrhage (SMH) is a hematic collection between the neurosensory retina and the retinal pigment epithelium; one of its causes is ocular blunt trauma, that usually affects young patients. Persisting SMH leads to a damage of photoreceptors mediated by three main mechanisms: iron-related toxicity, impairment of diffusion of oxygen and nutriment, mechanical damage due to clot contraction. Since early photoreceptors' damage has been reported within 24 h, it is suggested to provide an early treatment, although there are no guidelines or consensus between authors regarding treatment strategies. The aim of this review was to present and compare available treatment options, like intravitreal tissue plasminogen activator (tPA) associated with pneumatic displacement, pneumatic displacement alone, subretinal tPA injection with pneumatic displacement, and intravitreal anti-vascular endothelial growth factor (VEGF) injection. All procedures obtained consistent results, though the most effective seemed to be pars plana vitrectomy, subretinal tPA and gas tamponade, probably due to a quicker liquefaction and displacement of the clot. Limitations concern the greater invasiveness and the higher incidence of complications. Alternatively, intravitreal injection of tPA and gas may represent a less invasive option with fewer complications. Intravitreal injection of gas and prone position could be preferred in young patients without coexisting ocular pathology, being a minimally invasive treatment, with lower risk of complications and a good visual recovery. Anti-VEGF agent have found, to date, limited employment in cases of traumatic SMH even though they may be useful as alternative or adjuvant therapy. Most of the published literature consists of small studies and case reports, therefore further investigations and larger clinical trials are required to fully understand safety and efficacy of the procedures. A preoperative comprehensive evaluation may be helpful to realize a surgical plan tailored on patient.

Effect of modified Buyang Huanwu Decoction on hemorrhagic transformation after rt-PA intravenous thrombolysis in patients with super early cerebral infarction / 中国中药杂志

To study the effect of modified Buyang Huanwu Decoction on the hemorrhagic transformation after intravenous thrombolysis of recombinant tissue type plasminogen activator(rt-PA) in patients with super early(onset time<4. 5 h) cerebral infarction. From March 2016 to July 2018,at the brain disease zone of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine,212 cases of super early cerebral infarction were selected and divided into two group according to the randomized complete blocks designs: control group(106 cases) and traditional Chinese medicine group(106 cases). The control group was treated with rt-PA intravenous thrombolysis,while the traditional Chinese medicine group was treated with modified Buyang Huanwu Decoction in addition to the therapy of the control group. Both groups were treated for 14 days. Neurological deficit score,serum matrix metalloproteinase-9(MMP-9),neuron specific enolase(NSE),vascular endothelial growth factor(VEGF) and plasma cellular fibronectin(c-FN) levels,the incidence of hemorrhagic transformation,clinical efficacy and adverse drug reactions before and after treatment were compared between the two groups. According to the findings,at the 14 thday after treatment,the rank sum test of the grade data showed that the clinical efficacy of the traditional Chinese medicine group was better than that of the control group(Z =-2. 033,P = 0. 042); on the basis of χ2 test,the total efficiency of the traditional Chinese medicine group was higher than that of the control group(χ2= 4. 895,P =0. 027); the hemorrhagic transformation rate of the traditional Chinese medicine group was lower than that of the control group within14 days of treatment(χ2= 3. 962,P = 0. 047). MMP-9 levels in the traditional Chinese medicine group were lower than those in the control group at the 3 rd,5 th,7 th,10 th,14 thd after treatment(t =-2. 474,-3. 022,-5. 163,-6. 998,-9. 821; P = 0. 014,0. 003,0,0,0). The improvement of c-FN,NSE,VEGF and NIHSS scores in the traditional Chinese medicine group was superior to that of the control group after 14 days of treatment(t =-2. 343,-3. 187,-2. 129,-3. 105; P = 0. 020,0. 002,0. 034,0. 002). No obvious adverse reactions of modified Buyang Huanwu Decoction were observed during 14 days of treatment. Modified Buyang Huanwu Decoction could reduce the expressions of MMP-9,c-FN,NSE and VEGF after rt-PA intravenous thrombolysis in patients with super early cerebral infarction,and decrease the hemorrhagic transformation rate after thrombolysis,with high safety.

Clinical Efficacy of Modified Qingqi Huatan Wan in Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease and Its Effect on Inflammatory Reaction, Airway Remodeling and Thrombokinesis / 中国实验方剂学杂志

Objective:To explore the clinical efficacy of Modified Qingqi Huatan Wan in treatment of acute exacerbation of chronic obstructive pulmonary disease and its effect on inflammatory reaction, airway remodeling and thrombokinesis. Method:A total of 80 patients of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) were randomly divided into control group (40 cases) and therapy group (40 cases) by random number table. The control group was treated with conventional therapy. In addition to the therapy for the control group, the patients in therapy group also received modified Qingqi Huatan Wan. The treatment course was 14 days for both groups. Scores of traditional Chinese medicine(TCM) syndrome, chronic obstructive pulmonary disease and asthma physiology Score (CAPS), and chronic obstructive pulmonary disease patients self-assessment test questionnaire (CAT) were compared. The secondary indicators were pulmonary function, arterial blood gas analysis, and blood rheology indexes. In addition, the levels of serum nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), transforming growth factor-beta1 (TGF-β1) and plasma tissue-plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), von-willebrand factor (v-WF), clinical efficacy and safety were evaluated. Result:The total clinical effective rate was 94.74% in therapy group,which was higher than 78.38% in control group (χ2=4.341,P2, serum NF-κB, IL-6, IL-8, MMP-2, TIMP-2, TGF-β1 and plasma PAI-1, v-WF in therapy group were lower than those in control group(P2, PaO2, FEV1, FEV1%, FEV1/FVC in therapy group were higher than those in control group(PPConclusion:Modified Qingqi Huatan Wan can control the symptoms safely, alleviate CAPS and lung function, effectively reduce the inflammatory response and inhibit the formation of airway remodeling and thrombosis, and its mechanism may be protect the lung tissue by reducing the level of inflammatory cytokines, regulating the balance of MMP-2/TIMP-2 and t-PA/PAI-1 and improving extracellular matrix and vascular endothelial function.

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches.

Ischemic stroke is a devastating and debilitating medical condition with limited therapeutic options. However, accumulating evidence indicates a central role of inflammation in all aspects of stroke including its initiation, the progression of injury, and recovery or wound healing. A central target of inflammation is disruption of the blood brain barrier or neurovascular unit. Here we discuss recent developments in identifying potential molecular targets and immunomodulatory approaches to preserve or protect barrier function and limit infarct damage and functional impairment. These include blocking harmful inflammatory signaling in endothelial cells, microglia/macrophages, or Th17/γδ T cells with biologics, third generation epoxyeicosatrienoic acid (EET) analogs with extended half-life, and miRNA antagomirs. Complementary beneficial pathways may be enhanced by miRNA mimetics or hyperbaric oxygenation. These immunomodulatory approaches could be used to greatly expand the therapeutic window for thrombolytic treatment with tissue plasminogen activator (t-PA). Moreover, nanoparticle technology allows for the selective targeting of endothelial cells for delivery of DNA/RNA oligonucleotides and neuroprotective drugs. In addition, although likely detrimental to the progression of ischemic stroke by inducing inflammation, oxidative stress, and neuronal cell death, 20-HETE may also reduce susceptibility of onset of ischemic stroke by maintaining autoregulation of cerebral blood flow. Although the interaction between inflammation and stroke is multifaceted, a better understanding of the mechanisms behind the pro-inflammatory state at all stages will hopefully help in developing novel immunomodulatory approaches to improve mortality and functional outcome of those inflicted with ischemic stroke.

Comparison of Acute Ischemic Stroke Care and Outcomes Between Comprehensive Stroke Centers and Primary Stroke Centers in the United States.

BACKGROUND: To improve stroke care, the Brain Attack Coalition recommended establishing primary stroke center (PSC) and comprehensive stroke center (CSC) certification. This study aimed to compare ischemic stroke care and in-hospital outcomes between CSCs and PSCs. METHODS AND RESULTS: We analyzed patients with acute ischemic stroke who were hospitalized at stroke centers participating in Get With The Guidelines-Stroke from 2013 to 2015. Multivariable logistic regression models were generated to examine the association between stroke center certification (CSC versus PSC) and performances and outcomes. This study included 722 941 patients who were admitted to 134 CSCs and 1047 PSCs. Both CSCs and PSCs had good conformity to 7 performance measures and the summary defect-free care measure. Among emergency department admissions, CSCs had higher intravenous tPA (tissue-type plasminogen activator) and endovascular thrombectomy rates than PSCs (14.3% versus 10.3%, 4.1% versus 1.0%, respectively). Door to intravenous tPA time was shorter at CSCs (median, 52 versus 61 minutes; adjusted risk ratio, 0.92; 95% confidence interval, 0.89-0.95). More patients at CSCs had door to intravenous tPA time ≤60 minutes (79.7% versus 65.1%; adjusted odds ratio, 1.48; 95% confidence interval, 1.25-1.75). For transferred patients, CSCs and PSCs had comparable overall performance in defect-free care, except higher endovascular thrombectomy therapy rates. The overall in-hospital mortality was higher at CSCs in both emergency department admissions (4.6% versus 3.8%; adjusted odds ratio, 1.14; 95% confidence interval, 1.01-1.29) and transferred patients (7.7% versus 6.8%; adjusted odds ratio, 1.17; 95% confidence interval, 1.05-1.32). In-hospital outcomes were comparable between CSCs and PSCs in patients who received intravenous tPA or endovascular thrombectomy. CONCLUSIONS: CSCs and PSCs achieved similar overall care quality for patients with acute ischemic stroke. CSCs exceeded PSCs in timely acute reperfusion therapy for emergency department admissions, whereas PSCs had lower risk-adjusted in-hospital mortality. This information may be important for acute stroke triage and targeted quality improvement.

Baicalin Attenuates Blood-Brain Barrier Disruption and Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke Rats with Delayed t-PA Treatment: Involvement of ONOO--MMP-9 Pathway.

Tissue plasminogen activator (t-PA) has a restrictive therapeutic window within 4.5 h after ischemic stroke with the risk of hemorrhagic transformation (HT) and neurotoxicity when it is used beyond the time window. In the present study, we tested the hypothesis that baicalin, an active compound of medicinal plant, could attenuate HT in cerebral ischemia stroke with delayed t-PA treatment. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 4.5 h and then continuously received t-PA infusion (10 mg/kg) for 0.5 h and followed by 19-h reperfusion. Baicalin (50, 100, 150 mg/kg) was administrated via femoral vein at 4.5 h after MCAO cerebral ischemia. Delayed t-PA infusion significantly increased the mortality rate, induced HT, blood-brain barrier (BBB) damage, and apoptotic cell death in the ischemic brains and exacerbated neurological outcomes in cerebral ischemia-reperfusion rats at 24 h after MCAO cerebral ischemia. Co-treatment of baicalin significantly reduced the mortality rates, ameliorated the t-PA-mediated BBB disruption and HT. Furthermore, baicalin showed to directly scavenge peroxynitrite and inhibit MMP-9 expression and activity in the ischemic brains with the delayed t-PA treatment. Baicalin had no effect on the t-PA fibrinolytic function indicated by t-PA activity assay. Taken together, baicalin could attenuate t-PA-mediated HT and improve the outcomes of ischemic stroke treatment possibly via inhibiting peroxynitrite-mediated MMP-9 activation.

Drip-and-Ship Thrombolytic Therapy for Acute Ischemic Stroke.

BACKGROUND: Neuroendovascular therapy is a common treatment for patients with acute ischemic stroke of the anterior circulation who fail to respond to recombinant tissue plasminogen activator. However, although most hospitals can provide recombinant tissue plasminogen activator therapy, many cannot perform neuroendovascular therapy. Thus, use of a drip-and-ship treatment-liaison system allowing recombinant tissue plasminogen activator-treated patients to be transferred to facilities offering neuroendovascular therapy is important. METHODS: We retrospectively analyzed 16 drip-and-ship patients transferred to our hospital for additional neuroendovascular therapy after they received intravenous recombinant tissue plasminogen activator at prior hospitals between June 2009 and March 2017. RESULTS: The mean patient age was 68 ± 17 years. Ten patients had cardiogenic embolism and 6 had atherothrombosis. Additional neuroendovascular therapy was performed in 14 patients. Median National Institute of Health Stroke Scale and diffusion-weighted image-Alberta Stroke Program Early Computed Tomography Scores before recombinant tissue plasminogen activator therapy were 14 and 8, respectively. Occluded or stenotic lesions of the cerebral arteries were detected by magnetic resonance angiography in the internal carotid artery (n = 4), middle cerebral artery (n = 10), and basilar artery (n = 3) (1 patient had tandem lesions). Mean intervals from onset-to-recombinant tissue plasminogen activator, recombinant tissue plasminogen activator-to-our hospital (door), door-to-puncture, and onset-to-recanalization were 166, 65, 32, and 334 minutes, respectively. No patients showed symptomatic intracranial hemorrhage. CONCLUSIONS: Magnetic resonance imaging/angiography performed in previous hospitals allows initiation of reperfusion therapy immediately after transfer. Thus, drip-and-ship plus neuroendovascular therapy is a safe and useful system for treatment of patients with acute infarcts.

Adjunctive Therapy Approaches for Ischemic Stroke: Innovations to Expand Time Window of Treatment.

Tissue plasminogen activator (tPA) thrombolysis remains the gold standard treatment for ischemic stroke. A time-constrained therapeutic window, with the drug to be given within 4.5 h after stroke onset, and lethal side effects associated with delayed treatment, most notably hemorrhagic transformation (HT), limit the clinical use of tPA. Co-administering tPA with other agents, including drug or non-drug interventions, has been proposed as a practical strategy to address the limitations of tPA. Here, we discuss the pharmacological and non-drug approaches that were examined to mitigate the complications-especially HT-associated with delayed tPA treatment. The pharmacological treatments include those that preserve the blood-brain barrier (e.g., atovarstatin, batimastat, candesartan, cilostazol, fasudil, minocycline, etc.), enhance vascularization and protect the cerebrovasculature (e.g., coumarin derivate IMM-H004 and granulocyte-colony stimulating factor (G-CSF)), and exert their effects through other modes of action (e.g., oxygen transporters, ascorbic acid, etc.). The non-drug approaches include stem cell treatments and gas therapy with multi-pronged biological effects. Co-administering tPA with the abovementioned therapies showed promise in attenuating delayed tPA-induced side effects and stroke-induced neurological and behavioral deficits. Thus, adjunctive treatment approach is an innovative therapeutic modality that can address the limitations of tPA treatment and potentially expand the time window for ischemic stroke therapy.

The effect of low-level laser therapy as an adjunct to non-surgical periodontal treatment on gingival crevicular fluid levels of transforming growth factor-beta 1, tissue plasminogen activator and plasminogen activator inhibitor 1 in smoking and non-smoking chronic periodontitis patients: A split-mouth, randomized control study.

BACKGROUND AND OBJECTIVE: This study aimed to investigate the effects of low-level laser therapy (LLLT) as an adjunct to scaling and root planing (SRP) on smoking and non-smoking patients with chronic periodontitis. MATERIAL AND METHODS: The study was conducted using a split-mouth design with 30 patients with chronic periodontitis (15 smokers, 15 non-smokers) and 30 healthy individuals matched for age, sex and smoking status as controls. Groups were constituted as follows: Cp+SRP+Sham: non-smokers with chronic periodontitis treated with SRP; Cp+SRP+LLLT: non-smokers with chronic periodontitis treated with SRP+LLLT; SCp+SRP+Sham: smokers with chronic periodontitis treated with SRP; SCp+SRP+LLLT: smokers with chronic periodontitis treated with SRP+LLLT; C: control group comprised of periodontally healthy non-smokers; SC: control group comprised of periodontally healthy smokers. LLLT was first applied on the same day as SRP and again on days 2 and 7 after SRP treatment. Clinical parameters were recorded before non-surgical periodontal treatment (baseline) and on day 30. Gingival crevicular fluid samples were collected before periodontal treatment (baseline) and during follow-up visits on days 7, 14 and 30. Gingival crevicular fluid transforming growth factor (TGF)-ß1, tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) levels were measured using enzyme-linked immunosorbent assay. RESULTS: All clinical parameters showed significant reductions between baseline and day 30 following SRP treatment in both the LLLT and sham groups (P<.001). No significant differences were observed between the LLLT and sham groups of either the smokers or non-smokers (P>.05). Gingival crevicular fluid PAI-1 levels decreased significantly in the SCp+SRP+sham and SCp+SRP+LLLT groups (P<.05), and gingival crevicular fluid tPA levels decreased significantly in the Cp+SRP+sham, Cp+SRP+LLLT and SCp+SRP+LLLT groups (P<.05). Gingival crevicular fluid TGF-ß1 levels decreased significantly in all treatment groups (P<.05). Although no significant differences were found between the gingival crevicular fluid PAI-1, tPA and TGF-ß1 levels of the LLLT versus sham groups (P>.05) at any of the time points measured, both LLLT groups showed significant reductions in tPA/PAI-1 ratios over time. CONCLUSION: Within the limits of this study, LLLT may be understood to play a role in the modulation of periodontal tissue tPA and PAI-1 gingival crevicular fluid levels, particularly in smoking patients with chronic periodontitis, and may thus be recommended as an adjunct to non-surgical periodontal treatment.

A Simple Adaptable Blood-Brain Barrier Cell Model for Screening Matrix Metalloproteinase Inhibitor Functionality.

The blood-brain barrier is a multicellular and basement membrane unit that regulates molecular transport between the blood and central nervous system. Many cerebral pathologies, such as acute stroke and chronic vascular dementia, result in a disrupted blood-brain barrier, increasing its permeability and allowing the entry of potentially neurotoxic molecules. The activation of matrix metalloproteinases mediates further blood-brain barrier damage. The inhibition of matrix metalloproteinases is a potential strategy for stroke therapy. As inhibitors are developed, efficient context-specific screening methods will be required. Models of the blood-brain barrier have been extensively used to study neuropathologies and the effect of various treatment options.Herein, we describe a co-culture model of the blood-brain barrier composed of brain microvascular endothelial cells and astrocytes grown on an artificial basement membrane-coated membrane insert. Our cell model forms a barrier and is a simple first approximation of blood-brain barrier integrity. As currently developed, the model may be applied to testing the effect of matrix metalloproteinases and matrix metalloproteinase inhibitors on blood-brain barrier physiology and pathophysiology. The model is a quick and effective evaluation tool for generating nonclinical data in a living cell system before proceeding to animal models.