Thrombus-targeted nano-agents for NIR-II diagnostic fluorescence imaging-guided flap thromboembolism multi-model therapy.

In oral and maxillofacial surgery, flap repair is essential to the quality of postoperative life. Still, thrombosis is fatal for the survival of the flaps. Besides, some postoperative thrombotic diseases, such as pulmonary embolism, also intimidate patients' life. The traditional diagnostic methods are still limited by a large amount of hardware and suffer from inconvenience, delay, and subjectivity. Moreover, the treatments mainly rely upon thrombolytics, such as urokinase (UK) plasminogen activator, which may cause bleeding risk, especially intracerebral hemorrhage. Herein, a kind of poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing a first near-infrared window (NIR-I) phototheranostic agent Y8 and urokinase plasminogen activator (UK) as the core, and modified with the fibrin-targeting peptide Gly-Pro-Arg-Pro-Pro (GPRPP) were developed for the flap and postoperative thromboembolism treatment (named GPRPP-Y8U@P). The conjugated molecule Y8 endows GPRPP-Y8U@P with the capacity of NIR-II imaging and excellent photothermal/photodynamic therapeutic effects. In vivo experiments demonstrated that GPRPP-Y8U@P could quickly locate thrombus by NIR-II fluorescence imaging, and semi-quantitative analysis of the embolized blood vessels' paraffin section verified its thrombolytic efficiency. Additionally, the urokinase trapped in the NPs would not result in nonspecific bleeding, tremendously improving physical security and curative effects with minimizing side effects. Overall, the advantages of GPRPP-Y8U@P, such as precise localization of the thrombus, thrombus ablation in the site, and mild side effects, demonstrated the attractiveness of this approach for effective clinical monitoring of thrombus therapy.

Urokinase loaded black phosphorus nanosheets for sequential thrombolysis and reactive oxygen species scavenging in ischemic stroke treatment.

Ischemic stroke often causes devastating damage to human life and health. Excess production of reactive oxygen species (ROS) during thrombolysis will paradoxically result in neuronal injury. Neuroprotection from reperfusion injury must overcome the challenge of crossing the blood-brain barrier (BBB). A strategy including thrombolysis and ROS scavenging accompanied by BBB penetration is highly desirable for improving combination therapies in ischemic stroke. Herein, urokinase plasminogen activator (uPA) loaded on black phosphorus nanosheets (BPNs) is tested as a nanodrug for sequential thrombolysis and neuroprotection. The in vitro thrombolysis shows that the uPA-loaded BPNs can efficiently deliver uPA for thrombus dissolution. The residual BPNs after uPA release exhibit ROS scavenging effects, especially for the most common H2O2 and ˙OH species. Moreover, in vivo studies show that the BPNs can cross the BBB with the assistance of laser irradiation, owing to their good photothermal properties. Further experiments show the effectiveness of BPNs for attenuating reperfusion injury and achieving neuroprotection. These results highlight the promising potential of the present BPN-based nanodrugs for the treatment of ROS-related diseases.

Epigallocatechin Gallate Extends Therapeutic Window of Recombinant Tissue Plasminogen Activator Treatment for Brain Ischemic Stroke: A Randomized Double-Blind and Placebo-Controlled Trial.

OBJECTIVES: Recombinant tissue plasminogen activator (rt-PA) is a safe and effective treatment for acute brain ischemia stroke, albeit with a narrow therapeutic window. We aimed to assess the effect of epigallocatechin gallate (EGCG) in extending the rt-PA treatment window in this clinical trial among stroke patients. METHODS: Patients were randomly assigned according to their onset-to-treatment time (OTT) and were then treated with rt-PA simultaneously with EGCG or placebo. Treatment outcome was assessed by the National Institutes of Health stroke scale (NIHSS) and plasma levels of matrix metalloproteinases (MMP)-2 and 9. RESULTS: Administration of EGCG significantly improved treatment outcomes of patients in the delayed OTT strata, as evidenced by improved NIHSS scores. This improved treatment outcome was likely attributed to reduction in plasma levels of both MMP-2 and 9, as indicated by strong linear correlations between both MMPs and NIHSS scores in all patients. CONCLUSIONS: Epigallocatechin gallate could potentially be used as a supplement of traditional rt-PA treatment among stroke patients, particularly those with delayed OTT, to extend the otherwise narrow therapeutic window and improve the outcome in late stroke treatment.

Towards effective and safe thrombolysis and thromboprophylaxis: preclinical testing of a novel antibody-targeted recombinant plasminogen activator directed against activated platelets.

RATIONALE: Fibrinolysis is a valuable alternative for the treatment of myocardial infarction when percutaneous coronary intervention is not available in a timely fashion. For acute ischemic stroke, fibrinolysis is the only treatment option with a very narrow therapeutic window. Clinically approved thrombolytics have significant drawbacks, including bleeding complications. Thus their use is highly restricted, leaving many patients untreated. OBJECTIVE: We developed a novel targeted fibrinolytic drug that is directed against activated platelets. METHODS AND RESULTS: We fused single-chain urokinase plasminogen activator (scuPA) to a small recombinant antibody (scFvSCE5), which targets the activated form of the platelet-integrin glycoprotein IIb/IIIa. Antibody binding and scuPA activity of this recombinant fusion protein were on par with the parent molecules. Prophylactic in vivo administration of scFvSCE5-scuPA (75 U/g body weight) prevented carotid artery occlusion after ferric chloride injury in a plasminogen-dependent process compared with saline (P<0.001), and blood flow recovery was similar to high-dose nontargeted urokinase (500 U/g body weight). Tail bleeding time was significantly prolonged with this high dose of nontargeted urokinase, but not with equally effective targeted scFvSCE5-scuPA at 75 U/g body weight. Real-time in vivo molecular ultrasound imaging demonstrates significant therapeutic reduction of thrombus size after administration of 75 U/g body weight scFvSCE5-scuPA as compared with the same dose of a mutated, nontargeting scFv-scuPA or vehicle. The ability of scFvSCE5-scuPA to lyse thrombi was lost in plasminogen-deficient mice, but could be restored by intravenous injection of plasminogen. CONCLUSIONS: Targeting of scuPA to activated glycoprotein IIb/IIIa allows effective thrombolysis and the potential novel use as a fibrinolytic agent for thromboprophylaxis without bleeding complications.

Rescue therapy of difficult-to-treat indwelling central venous catheter-related bacteremias in cancer patients: a review for practical purposes.

Device-related bacteremia is the most frequent complication in patients with indwelling central venous catheter. Guidelines recommend treatment based on epidemiology and antimicrobial susceptibility tests, but catheter removal is advocated in the presence of particular clinical conditions or pathogen isolations. Anti-infective drugs might become less effective in the presence of pathogens with increases in minimal inhibitory concentrations or slime production, and sometimes catheter removal is not feasible, for example, in patients with limited vascular sites or in the presence of life-threatening clinical conditions. Catheter lock with anti-infective drugs (antibacterials or antifungals) or other substances with anti-infective properties (e.g., taurolidine, 70% ethanol, 2M HCl) might represent a possible rescue treatment in the presence of difficult-to-treat infections and/or when the device cannot be removed. In the present review, the authors summarize these possible therapeutic options. The aim of the report is not to perform a systematic review of the literature, but to give an 'easy to read' text for everyday practice.

[Rapid pore cranial drilling and ventricular drainage in the treatment of ventricular hemorrhage caused by thalamic hemorrhage: an analysis of 401 cases].

OBJECTIVE: To summarize the clinical efficacies and experiences of using rapid pore cranial drilling and external ventricular drainage (EVD) in the treatment of ventricular hemorrhage caused by thalamic hemorrhage. METHODS: Retrospective analysis was conducted for 401 patients at 5 hospitals from May 1983 to December 2010. They underwent EVD with an infusion of urokinase for intraventricular hemorrhage caused by thalamic hemorrhage. There were 212 males and 189 females with an age range of 19 - 78 years. RESULTS: After a 1-month therapy, the outcomes were cure 147/401 (36.7%), improvement 192/401 (47.9%) and others (death and against-advice discharge) 62/401 (15.4%). After 1-3-month treatment, their prognoses were evaluated by activity of daily living (ADL): ADLI 147/401, ADLII 82/401, ADLIII 76/401, ADLIV 19/401, ADLV 15/401, death 43/401 and against-advice discharge 19/401. During a follow-up period of 1 - 3 years, 274 patients showed the following outcomes: ADLI 122/243, ADLII 63/243, ADLIII 58/243 while 31 patients died from pulmonary infection. CONCLUSION: The procedure of EVD (including an infusion of urokinase) with rapid pore cranial drilling is preferred treatment for ventricular hemorrhage caused by thalamic hemorrhage.

Intra-arterial adjuvant tirofiban after unsuccessful intra-arterial thrombolysis of acute ischemic stroke: preliminary experience in 16 patients.

INTRODUCTION: Intra-arterial (IA) thrombolysis with plasminogen activator is well-known, but the use of IA tirofiban as an adjuvant for IA thrombolysis is not well-known. We investigated the feasibility of IA tirofiban as an adjuvant after unsuccessful IA recanalization with urokinase (UK) for acute ischemic stroke. METHODS: We retrospectively analyzed all 16 consecutive patients (11 men and five women; mean age, 61.3 years; range, 36-85 years) who were treated with IA tirofiban after isolated IA thrombolysis with UK or bridging therapy with systemic recombinant tissue plasminogen activator (rt-PA; 0.6 mg/Kg) and IA UK for acute ischemic stroke. Outcome measures included angiographic recanalization (thrombolysis in cerebral infarction, TICI), symptomatic and asymptomatic intracerebral hemorrhage (ICH), mortality, and functional independence at 3 months (modified Rankin Scale, 0-2). RESULTS: Among the 16 patients treated with IA tirofiban as an adjuvant, 10 patients had conventional dose (<25 ug/kg, bolus) and six patients had high dose (≥25 ug/kg, bolus) of IA tirofiban after unsuccessful IA thrombolysis whether systemic rt-PA used or not. Successful angiographic recanalization (TICI grade 2b or 3) was achieved in 13 patients (13/16) and a functional independence at 3 months in eight patients (8/16). Three months after therapy, three patients had died. There were two patients of symptomatic ICH and four asymptomatic ICH. CONCLUSION: Conventional dose of IA tirofiban as an adjuvant during IA thrombolysis for acute ischemic stroke seems feasible. However, further dose escalation studies should be performed regarding the IA use of tirofiban for acute ischemic stroke.

[Advancement on thrombolytic characteristic, function and clinical application of different fibrinolytic enzymes].

Cardio-cerebral vascular diseases endanger people's health very seriously. Thrombolytic therapy is effective in curing thrombotic diseases at present. Microorganism is an important source of thrombolytic drug. Plasminogen activators are widely used as thrombolytic drugs clinically, while they are still exists some defects. This article analyzed research and development status of kinds of thrombolytic drugs from microorganisms, and evaluated their clinical efficacy and safety, aiming at showing the direction to search new and effective thrombolytic drugs and prevent and treat thromboembolic disease.

[Nutritional support and treatment of chylothorax with octreotide]. / Soporte nutricional y tratamiento con octreótido del quilotórax.

Patients with chylothorax present a high risk for malnourishment since continuous loss of chylo leads to a significant impairment of their nutritional status. Chylothorax treatment, which initially is conservative, includes dietary measures and medications such as octreotide that decreases chylothorax flow. In this paper we present the case of a patient with chylothorax treated by means of pleural drainage, parenteral nutrition, and octreotide, and we review the most appropriate nutritional support as well as the efficacy and safety of octreotide in chylothorax therapy. The types of nutritional intervention that may be done are a low-fat diet supplemented with intermediate-chain triglycerides (ICT), fat-free enteral nutrition or EN with a high percentage of ICT, and parenteral nutrition. There is no consensus on which is the most appropriate measure. We found very few comparative studies, and the literature is based on single cases or case series. Some authors consider parenteral nutrition as the first choice, whereas others recommend starting with a specific diet and using parenteral nutrition only in specific cases. Parenteral nutrition must cover the patient's demands together with compensating the protein and energy losses due to chylothorax. The use of lipid emulsions is no contraindicated since they do not reach the lymphatic system. With regards to EN, the formulations may be lipid-free or with low lipid content. There is no agreement on when to start them once the drainage of chylo decreases. There are cases and case series indicating that octreotide use in chylothorax seems to be safe and effective. There is no consensus on when to start the therapy, the most appropriate dose, or the time to withdraw the treatment.

[Effects of rhubarb aglycone combined with thrombolysis on brain microvascular basement membrane impairment in rats with thrombus-occluded cerebral ischemia].

OBJECTIVE: To explore the protective effects of rhubarb aglycone combined with urokinase (UK) thrombolysis on brain microvascular basement membrane impairment in rats with thrombus-occluded cerebral ischemia by regulating the expression of IgG, CoLIV and LN in rats brain, by which the level of injury of brain microvascular basement membrane could be detected. METHOD: Rats were randomly divided into sham-operated, model, thrombolysis, rhubarb aglycone and combination (rhubarb aglycone combined with thrombolysis) groups. Moreover, rats in model, thrombolysis, rhubarb aglycone and combination groups were randomly divided into 3, 6, and 9 h groups respectively. Model of thrombus-occluded cerebral ischemia was duplicated by using the combination of rats' auto-thrombus with inserting the nylon thread. Rats were administrated with thrombolysis therapy through artery at 3, 6, and 9 h after cerebral ischemia. At 24 h of administration through artery, intracranial hemorrhage ratio (ICHR) and mortality of rats were observed, and then the brain of rats was taken. In the study, expression of IgG, CoLIV and LN in rats brain were measured. RESULT: Thrombolysis at 9 h of cerebral ischemia made rats mortality and BHR increase, administration of combined therapy could make them decrease. Expression of IgG level in rats brain of 9 h and 6 h model groups increased, while CoLIV and LN expression decreased significantly. In each administration 9 h group, IgG level was lower, and CoLIV and LN were higher, such changes appeared significantly in rhubarb aglycone and association groups. CONCLUSION: Brain microvascular basement membrane impairment could be caused by the therapy of delayed thrombolysis, which made the mortality and BHR increase. Rhubarb aglycone combined with the therapy of thrombolysis could perform the protective effects on brain microvascular basement membrane and then decrease the ICHR and mortality caused by thrombolysis after cerebral ischemia.

Retrospective analysis of thrombolysis therapy for 64 cases of acute myocardial infarction with elevated ST segment.

OBJECTIVE: To explore the cardiac protective effect of integrative therapy in acute myocardial infarction (AMI) with elevated ST segment after reperfusion. METHODS: Sixty-four AMI patients who having received decimalization by thrombolysis were assigned to two groups by retrospective analysis, 36 patients in the treated group and 28 in the control group. Both were treated by intravenous administering of urokinase for thrombolysis, and to the treated group, intravenous dripping of Xueshuantong Injection (, XST) was added. Serum levels of myocardial associated enzymes were monitored before treatment and at various time points after thrombolysis, and the heart function parameters were detected with color echocardiography before treatment and on the 7th and 14th day of treatment. The patients were followed up for 6 months to observe the incidence of cardiac events. RESULTS: The differences between groups at the peak and peak appearing time of creatine kinase and creatine kinase isoenzyme were not significant. All the heart function parameters on the 7th and 14th day in the treated group were improved and superior to those at the corresponding time points in the control group (P<0.05, P<0.01). Incidence of some heart events in the treated group within the 6-month follow-up period was lesser than that in the control group (P<0.05). CONCLUSION: XST Injection could provide effective protection for the heart after reperfusion.

[Clinical study on interventional therapy with Chinese and Western medicine for avascular necrosis of femoral head].

OBJECTIVE: To study the clinical effect of interventional therapy with Chinese and Western medicine for avascular necrosis of femoral head (ANFH). METHODS: A total of 168 ANFH patients (285 hips) were subjected to interventional therapy with Chinese and Western medicine (prostaglandin E1 injection, uroki-nase and Compound Danshen Injection) and examined by digital substruction arterography (DSA) before and after treatment. The imaging of DSA and clinical effect were observed and compared. RESULTS: After treatment, hip pain and joint dysfunction were alleviated to different degrees, and the blood vessel count shown by DSA significantly increased. The effect was obviously better in patients of Grade III than in those of other grades. CONCLUSION: Interventional therapy with Chinese and Western medicine could improve the blood circulation of the femoral head, and is an effective method for the treatment of ANFH.

[Effect of yirong oral liquid on the reperfusion injury in rats with cerebral infarction undergoing thrombolysis].

OBJECTIVE: To observe the effect of Yirong Oral Liquid (YROL) on reperfusion injury in rats with cerebral infarction undergoing thrombolysis. METHODS: Clinical reperfusion under thrombolysis was simulated by applying thrombolysis on reversible local cerebral ischemic rat model. In the rat model, effect of YROL on parameters concerning anti-oxidation capability, cerebral edema and ultrastructure of brain were observed. RESULTS: YROL could alleviate the cerebral edema after reperfusion, markedly increase the activity of superoxide dismutase in blood plasma, decrease the content of malonyldialdehyde, inhibit the post-reperfusion lipid peroxidation, and significantly reduce the ischemia/reperfusion injury of nerve cells in brain of rat. CONCLUSION: YROL has definite protecting effect on brain.

[Clinical observation on effect of tongnao huoluo acupuncture therapy in treating acute cerebral infarction at ultra-early or acute stage].

OBJECTIVE: To evaluate the efficacy and safety of Tongnao Huoluo acupuncture (TNHLA) therapy in treating acute cerebral infarction at ultra-early stage (within 6 hrs after attack) or acute stage (within 6-48 hrs after attack). METHODS: The effect of TNHLA in the two stages was observed separately (treated group) and compared with the effect treated with immediate thrombolysis by intravenously given urokinase 12 million units in ultra-early stage or simple body acupuncture in acute stage (control group), and with those treated with intravenous dripping of normal saline (placebo group). In the meantime, all groups treated with low molecular dextran injection for 14 days, cytidine diphosphate choline and entric soluble aspirin for 28 days. RESULTS: Effect of TNHLA in the treated group was insignificantly different to that after thrombolysis of the control group in the ultra-early stage, but significantly higher than that of body acupuncture in acute stage. The intracranial hemorrhage rates in the treated, control, and placebo group were 3.3%, 4.0%, and 8.0% respectively. CONCLUSION: TNHLA is effective and safe in treating acute cerebral infarction at ultra-early stage or acute stage.

Lung endothelium targeting for pulmonary embolism thrombolysis.

BACKGROUND: Pulmonary embolism occurs frequently in hospitalized patients. Thrombolytic therapy, currently used as the major treatment, has often been associated with severe bleeding complications and has thereby been life-threatening. We have developed a novel therapeutic method based on our newly created pulmonary endothelium-specific antibody. METHODS AND RESULTS: We isolated membrane proteins of rat pulmonary vascular luminal endothelium and obtained a monoclonal antibody, RE8F5, which antigen was uniquely expressed by the pulmonary capillary endothelium. In vivo biodistribution showed that RE8F5 and its urokinase conjugate were rapidly and specifically accumulated in lung. Urokinase and the conjugate were compared in rats with pulmonary, hepatic, and lower-limb embolus. In a pulmonary embolus model, the conjugate exhibited 12-fold enhanced thrombolytic potency over urokinase, whereas plasma fibrinogen and bleeding time were unaffected. In 2 other models, no significant thrombolysis was induced by the conjugate. In contrast, thrombolysis by urokinase was found to be comparable to the pulmonary embolus model. In addition, urokinase caused significant consumption of fibrinogen in all experiments. CONCLUSIONS: These data show that urokinase equipped with lung endothelium-specific antibody is an ideal treatment for pulmonary embolism, with a high efficacy of thrombolysis and low risk of bleeding.

Modulation of PAI-1 and tPA activity and thrombolytic effects of corilagin.

In this study, Charlton's and Tomihisa's methods were modified to investigate the thrombolytic effect of corilagin from the Chinese herbal plant Phyllanthus urinaria L., as well as its effect on carotid artery patency status. The activity of type 1 plasminogen activator inhibitor (PAI-1) in rat plasma or platelet-released substances and tissue-type plasminogen activator (tPA) in rat plasma was assayed by use of a chromogenic substrate. The results showed that corilagin had a dose-dependent thrombolytic effect in rats. 5 mg/kg of corilagin produced a nearly similar reperfusion rate to that of 20000 U/kg of urokinase, whereas it produced a lower reocclusion rate than urokinase. Corilagin significantly inhibited PAI-1 activity in rat plasma or platelet-released substances while it elevated plasma tPA activity, in a concentration-dependent manner. Corilagin, however, had no influence on rabbit platelet aggregation. It is indicated that corilagin inhibited PAI-1 activity and increased tPA activity, and this property of corilagin is assumed to be responsible for the thrombolytic effect. Abbreviations. PO:persistent occlusion CR:cyclic reflow PP:persistent patency PAI-1:type 1 plasminogen activator inhibitor tPA:tissue-type plasminogen activator PBS:phosphate buffer solution IC (50):50 % of inhibitory concentration PRP:platelet-rich plasma ADP:adenosine diphosphate AA:arachidonic acid PAF:platelet-activating factor

Prognosis of central retinal artery occlusion: local intraarterial fibrinolysis versus conservative treatment.

BACKGROUND AND PURPOSE: Local intraarterial fibrinolysis (LIF) is one of several methods used in treating central retinal artery occlusion (CRAO). We investigated whether LIF is more effective than conservative methods in the treatment of CRAO. METHODS: In this retrospective study, a total of 178 patients (125 men and 53 women) with CRAO were treated at the Eye Hospital of the University of Freiburg from 1980 to 2000. The average age of the patients was 66.8 years (SD, 12 years). In group I, 116 patients were treated conservatively by anterior chamber paracentesis, massage of the globe, isovolemic hemodilution, acetazolamide, Pentoxifyllin, acetylsalicylic acid, and reduction of arterial hypertension. Some combination but not all of the mentioned conservative methods were used in the conservatively treated patients. In group II, 62 patients receiving LIF received local injection of urokinase or recombinant tissue plasminogen activator into the proximal part of the ophthalmic artery. In case of ipsilateral carotid artery occlusion or high grade stenosis (14 of 62 patients), the thrombolytic agent was administered into the internal maxillary artery. RESULTS: Among 178 patients, the CRAO was subtotal in 130 (73.0%), incomplete in 39 (21.9%), and total in nine (5.1%). Statistical calculations showed a significantly better visual acuity in group II patients, who were treated with LIF, in comparison with group I patients, who were treated conservatively (P =.0022). CONCLUSION: For patients with CRAO, LIF is superior to conservative treatment.