Efficacy Of Tissue Plasminogen Activator Research Articles

Preparation and in vitro evaluation of tissue plasminogen activator-loaded nanoliposomes with anticoagulant coating

The clinical efficacy of tissue plasminogen activator (tPA) is limited by its lack of specific delivery, requiring large therapeutic doses that increase the risk of intracerebral hemorrhage, bleeding at the surgical site, and patient mortality after angioplasty. To address these limitations, this study aimed to develop a chitosan polysulfate (CsPs)-coated liposomal formulation for the sustained release of tPA. The CsPs-coated liposomes containing tPA (Liposome-tPA/CsPs) were fabricated using the thin-film hydration technique and their properties were compared to tPA-encapsulated nanoliposomes without a coating layer (Liposome-tPA). Liposome-tPA/CsPs showed a quasi-spherical morphology with a hydrodynamic diameter of 110 nm, while Liposome-tPA had a diameter of 80 nm. The thermal analysis showed that the degradation temperature and glass transition temperature (Tg) of Liposome-tPA/CsPs were higher than that of tPA alone, indicating improved temperature stability. The in vitro release study demonstrated a slow and sustained release of tPA from the Liposome-tPA/CsPs, with a concentration of 0.02 mg/ml at 1 h and 0.23 mg/ml at 180 h. The CsPs coating layer enhanced the antibacterial and antioxidant activity of the nanoliposomes. Liposome-tPA/CsPs exhibited higher cell viability compared to Liposome-tPA. It also achieved a higher percentage of thrombolysis, with complete clot dissolution observed after 3 h of treatment. These findings suggest that the Liposome-tPA/CsPs can be a promising approach to overcome the limitations associated with the systemic administration of tPA, potentially enhancing its clinical efficacy while reducing the risk of adverse events.

Effects of Concurrent Dosing on the Efficacy of Tissue Plasminogen Activator and Deoxyribonuclease in the Treatment of Pleural Infection.

The goal of this study was to evaluate how the administration of concurrent tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) therapy with variable dosing for complicated parapneumonic effusions and empyema affects patient outcomes in an inner-city community hospital. This retrospective analysis was performed at an inner-city hospital located in Raleigh, North Carolina. A list of all patients treated with tPA and DNase between July 1, 2015, and December 31, 2017, was generated and screened. Data were collected through a review of past medical records, including demographics, past medical history, and details about their hospital course. A total of 38 patients were found to have been treated with concurrent tPA and DNase for complicated parapneumonic effusion or empyema. Twenty (52.6%) patients received the full six doses of combined concurrent tPA/DNase. Of the 18 (47.4%) patients who did not receive the full six doses, 11 did not require the full six doses for effusion resolution, and seven had to discontinue therapy due to tube blockage or pain. Only seven (18.4%) patients had complications related to tPA/DNase administration, most commonly pain. Nineteen (50%) patients had complete radiological clearance of effusion, with 13 (34.2%) having partial clearance, and six (15.8%) having no change or worsening of their effusion. Eight (21.1%) patients needed further surgical management of their effusion. The current most common dosing pattern for combined tPA and DNase therapy of twice daily for three days may not be optimal for all patients. The dosing regimen should be individualized depending on clinical response.Concurrent dosing is safe.

Racial, Socioeconomic, and Geographic Disparities Persist in Stroke Intervention Use

The hard-won demonstrations of efficacy of tissue plasminogen activator (TPA) and endovascular thrombectomy (EVT) for ischemic stroke in pivotal

A systematic review and meta-analysis of interventions to increase stroke thrombolysis

BackgroundAlthough the efficacy of tissue plasminogen activator (tPA) for acute ischemic stroke is well established, rates of tPA use remain low. For clinicians, advocates, and policy-makers seeking to increase tPA treatment rates, it is important to understand what interventions exist and their relative effectiveness.MethodsWe searched PubMed and EMBASE to identify all studies published between 1995 and January 8, 2015 documenting interventions to increase the use of tPA with broadly inclusive criteria. The principal summary measure was the percentage change in rate of tPA administration. Random effects meta-analytic models were built to summarize the effect of intervention compared to control overall and for intervention characteristics.ResultsThe search yielded 1457 results of which 25 met eligibility criteria. We identified 14 pre-post studies, ten randomized controlled trials, and one quasi-experiment. Included studies targeted their interventions at emergency medical services (EMS) (n = 14), telemedicine (n = 6), and public education (n = 6). In a random effects model, tPA administration was significantly higher in the intervention arm across all studies limiting enrollment to ischemic stroke patients (n = 16) with a risk ratio (RR) of 1.80 (95% confidence interval [CI], 1.45–2.22). A trend towards increased tPA administration was observed for all intervention approaches: risk ratio of 1.73 (95% CI, 1.44–2.09) for EMS, 1.58 (95% CI, 0.72–3.47) for telemedicine, and 1.89 (95% CI, 0.77–4.65) for public education, the latter not restricted to ischemic stroke patients.ConclusionsInterventions to increase tPA use appear to have considerable effectiveness. Our findings support the use of such interventions to improve stroke outcomes.

Efficacy of Tissue Plasminogen Activator (tPA) vs. Aspirin in Patients with a National Institute of Health Stroke Scale (NIHSS) Score Under 5 (P3.9-058)

Efficacy of Tissue Plasminogen Activator (tPA) vs. Aspirin in Patients with a National Institute of Health Stroke Scale (NIHSS) Score Under 5 (P3.9-058)

Safety and Efficacy of Tissue Plasminogen Activator and DNase for Complicated Pleural Effusions Secondary to Abdominal Pathology.

Exudative pleural effusions may arise secondary to inflammation of intra-abdominal structures. Pleural space loculations can complicate these effusions, preventing adequate chest tube drainage and leading to consideration of surgical intervention. Previous studies have demonstrated that intrapleural administration of tissue plasminogen activator (tPA) combined with human recombinant DNase can improve fluid drainage and reduce surgery for patients with loculated parapneumonic effusions; however, the efficacy of this treatment has not been evaluated for complicated pleural effusions attributed to intra-abdominal inflammation. We assessed the safety and efficacy of tPA/DNase for 17 pleural effusions associated with nonmalignant intra-abdominal pathology that did not drain adequately after placement of one or more chest tubes. Efficacy was measured by comparing post- to pretreatment fluid drainage rates, volumetric assessment of pleural fluid on radiographic images before and after treatment, and clinical improvement, including the need for surgical intervention. Symptomatic relief was assessed using the Borg scale for breathlessness. After a median of two doses of tPA/DNase, 23.5% of patients had chest pain and none had pleural bleeding. The volume of pleural fluid drained increased from a median of 325 ml to 890 ml per 24 hours after therapy (P = 0.018). The area of pleural space opacity on chest radiographs decreased from a median of 42.8-17.8% of the hemithorax (P = 0.001). tPA/DNase reduced the pleural fluid volume on chest computed tomographic imaging from a median of 294.4 ml to 116.1 ml. Borg scores improved from a median of 3 (interquartile range = 1-6) to 0 (interquartile range = 0-2) after therapy (P = 0.001). The median duration of chest tube placement and hospital stay were 4 and 11 days, respectively. Two patients required surgical intervention for lung entrapment. Overall, treatment was considered successful for 88.2% of patients. This retrospective case series suggests that intrapleural tPA/DNase can be safe and effective for patients with complicated pleural effusions attributed to abdominal pathology that do not drain adequately after chest tube placement. Additional studies are needed to determine whether the combination of tPA and DNase is more effective than tPA for this indication.

Tissue Plasminogen Activator as an Antiangiogenic Agent in Experimental Laser-Induced Choroidal Neovascularization in Mice.

We investigate the antiangiogenic efficacy of tissue plasminogen activator (tPA) on experimental laser-induced choroidal neovascularization (CNV) in mice. After CNV was induced by laser photocoagulation in 92 C57BL/6J wild-type mice, tPA (4 or 40 international units [IU]/μl) or PBS was injected intravitreally immediately after laser injury. Fluorescein angiography was performed on day 7 to grade CNV leakage. The CNV volume was measured by confocal microscopy in eyes enucleated 7 days after laser injury. Immunohistochemical studies were performed 3 days after laser injury to evaluate fibrin/fibrinogen and CD31 expression. The possible adverse effects of tPA were assessed by electroretinography (ERG) and histology on day 7. Intravitreal administration of tPA significantly suppressed CNV leakage and CNV volume in a dose-dependent manner (P < 0.01). Intravitreal injection of tPA suppressed fibrin/fibrinogen and CD31 expression in laser-induced lesions. Histologic examination and ERG showed no evidence of retinal toxicity in eyes injected with tPA. Intravitreal injection of tPA suppressed fibrin/fibrinogen expression and laser-induced CNV. The current results suggested that tPA may be a potential therapeutic adjuvant for treating CNV.

Abstract 334: An Echogenic Clot Method for Thrombolysis Monitoring of Directed Lytics in Thrombotic Stroke

Background: We have previously demonstrated thrombolytic efficacy of tissue plasminogen activator (tPA)-loaded echogenic liposomes (TELIP), a directed therapeutic construct that features exposed tPA fibrin-binding sites, in a rabbit abdominal aorta thrombosis model. The most relevant animal model for evaluation of directed thrombolytic therapy for ischemic stroke is the rabbit thrombotic stroke model previously used to validate recombinant tPA (rtPA; Alteplase). The ability to precisely monitor tPA-mediated thrombus dissolution in vivo is important for quantitative assessment of directed TELIP efficacy. Hypothesis: A gas-free ultrasound contrast agent can be incorporated into blood clots at a concentration that does not affect the tPA-mediated clot dissolution rate, while enabling quantitative assessment of the clot dissolution rate. Methods: In 1.5-ml Eppendorf tubes, 0.2-ml clots were formed from a mixture of whole rabbit blood, 1 M calcium chloride, human thrombin and various amounts of microcrystalline cellulose. At 0-time, 50 μg rtPA in 0.5 ml porcine plasma was added to each tube. Washed clots in tubes were weighed with an analytical balance at 30, 60 and 90 minutes. Clot echogenicity at each time point was assessed with a Philips HDI 5000 ultrasound system using an L12-5 linear array probe positioned laterally to tubes placed in an anechoic chamber. Recorded Images were subjected to videodensitometric analysis that converted image reflectivity to mean gray scale values (MGSV). Results: We found that 1.12 mg/ml of microcrystalline cellulose in rabbit blood clots (0.2 ml) provided optimal echogenicity without affecting the clot dissolution rates (0.3-0.6 mg/min.) caused by 100 μg/ml of rtPA. The clot dissolution rate measured by videodensitometric analysis of serial sonograms of the echogenic clots agreed well with that determined by mass loss measurements (0.28% 0-time value/minute). Conclusions: We have developed a method for monitoring rtPA-mediated clot mass loss by ultrasound imaging techniques and validated it in vitro. This method will be important for demonstrating the enhanced efficacy and decreased hemorrhagic effects provided by directed tPA vehicles relative to systemic administration of the free thrombolytic.

Lytic efficacy of tissue plasminogen activator and ultrasound in porcine clots doped with barium sulfate in vitro

Swine and porcine tissue are employed routinely for preclinical models of ischemic stroke. In this study, we examined the lytic susceptibility of porcine whole-blood clots, prepared with and without barium sulfate, a radiopaque x-ray contrast agent. The degree of lytic efficacy in the two types of clots was compared for recombinant tissue plasminogen activator (rt-PA) concentrations ranging from 0 to 100 μg/mL. Subsequently, a in vitro flow model and time-lapse thrombolysis microscopy system was used to evaluate lysis in clots with and without barium sulfate in response to rt-PA and 120-kHz intermittent ultrasound exposure. The degree of lysis observed with both types of clots was similar for rt-PA concentrations up to 15.75 μg/mL. However, clots doped with barium sulfate demonstrated significantly lower lysis at higher rt-PA concentrations. Similarly, results obtained using the in vitro flow model showed that both types of clots underwent comparable lysis when treated with 15.75 μg/mL rt-PA. Further, using Definity® and 120-kHz ultrasound as an adjuvant to rt-PA did not enhance lysis in either porcine clot model compared to rt-PA alone. These results highlight the considerable differences in the degree of clot lysis between porcine clots and previously reported studies that used human clots.

A New Proposal for Management of Severe Frostbite in the Austere Environment

Despite advances in outdoor clothing and medical management of frostbite, individuals still experience catastrophic amputations. This is a particular risk for those in austere environments, due to resource limitations and delayed definitive treatment. The emerging best therapies for severe frostbite are thrombolytics and iloprost. However, they must be started within 24 hours after rewarming for recombinant tissue plasminogen activator (rt-PA) and within 48 hours for iloprost. Evacuation of individuals experiencing frostbite from remote environments within 24 to 48 hours is often impossible. To date, use of these agents has been confined to hospitals, thus depriving most individuals in the austere environment of the best treatment. We propose that thrombolytics and iloprost be considered for field treatment to maximize chances for recovery and reduce amputations. Given the small but potentially serious risk of complications, rt-PA should only be used for grade 4 frostbite where amputation is inevitable, and within 24 hours of rewarming. Prostacyclin has less risk and can be used for grades 2 to 4 frostbite within 48 hours of rewarming. Until more field experience is reported with these agents, their use should probably be restricted to experienced physicians. Other modalities, such as local nerve blocks and improving oxygenation at high altitude may also be considered. We submit that it remains possible to improve frostbite outcomes despite delayed evacuation using resource-limited treatment strategies. We present 2 cases of frostbite treated with rt-PA at K2 basecamp to illustrate feasibility and important considerations.

Annexin A2

Hemorrhagic transformation, incomplete reperfusion, neurotoxicity, and the short treatment time window comprise major challenges for thrombolytic therapy. Improving tissue plasminogen activator therapy has become one of the highest priorities in the stroke field. Recent efforts have been aimed at identifying new strategies that might enhance the thrombolytic efficacy of tissue plasminogen activator at the same time as reducing its associated complications related to hemorrhage and neurotoxicity. We believe that the combination of low-dose tissue plasminogen activator with recombinant annexin A2 (a tissue plasminogen activator and plasminogen coreceptor) might constitute a promising approach. Our pilot study using a focal embolic stroke model in rats supports this hypothesis.

Intravenous Tissue Plasminogen Activator in Patients With Cocaine-Associated Acute Ischemic Stroke

The safety of thrombolytic therapy in patients with cocaine-associated acute ischemic stroke (CIS) is unknown. We conducted a retrospective review of patients with CIS who presented to our stroke center. Thrombolytic treatment was compared between cocaine-positive (n=29) and cocaine-negative (n=75) patients. We also compared patients with CIS treated with tissue plasminogen activator versus those who did not receive tissue plasminogen activator (n=58). Safety outcomes were determined by the incidence of symptomatic intracerebral hemorrhage, in-hospital mortality, and modified Rankin Scale at hospital discharge. There were no complications in tissue plasminogen activator-treated patients with CIS. Cocaine-positive and cocaine-negative treated patients had similar stroke severity and safety outcomes. Patients with CIS treated with tissue plasminogen activator had more severe strokes on baseline National Institutes of Health Stroke Scale but similar safety outcomes compared with nontreated patients with CIS. Thrombolytic therapy for CIS appears to be safe in this small study. Further research is needed to more definitively assess safety and efficacy of tissue plasminogen activator for CIS.

Methods and processes for the reanalysis of the NINDS tissue plasminogen activator for acute ischemic stroke treatment trial

Treatment group imbalances in baseline stroke severity in the NINDS intravenous t-PA for acute stroke treatment trial led to controversy regarding the efficacy of tissue plasminogen activator (t-PA) in the treatment of acute ischemic stroke. Describe the steps used to independently re-evaluate this trial. NIH appointed an independent multidisciplinary committee that gained access to the original data. We undertook analyses of t-PA efficacy accounting for this imbalance, as well as analyses to identify subgroups that experienced additional harm or benefit from t-PA. Analyses of time from stroke onset to treatment (OTT), blood pressure, and intracerebral hemorrhage are given as illustrations. Despite subgroup imbalances in baseline stroke severity, when t-PA was administered to acute ischemic stroke patients according to study protocol, there was a statistically significant and clinically important benefit of t-PA treatment resulting in a higher likelihood of having a favorable clinical outcome at 3 months. Moreover, we were unable to identify subgroups of patients between which t-PA treatment effect differed, albeit these analyses had low power. These data failed to support the NINDS investigators' conclusion that effect of t-PA therapy diminished with increasing values of OTT within the protocol-specified 3 h time limit. In addition, the blood pressure measurements were highly variable and inconsistently determined so as to be too unreliable for inclusion in analysis. With new NIH requirements for data-sharing, the frequency of re-analysis of clinical trial data may increase substantially. This re-evaluation provides a blueprint for future re-evaluations of other trials. These best practices include re-analysis of the study data, after suitable replication, by an independent multidisciplinary committee, including a skilled statistical programmer analyst. Primary investigators should address significant errors determined in such re-analyses.

Genetics of stroke: a review of recent advances

Stroke is a multifactorial disease responsible for nearly 10% of deaths each year in industrialized countries. While some monogenic forms of stroke have been described, the vast majority result from the common polygenic form of the disease. Progress in molecular genetics has allowed the identification, through genome-wide linkage analysis, of various candidate genes, including the genes encoding PDE4D and ALOX5AP. Since then, genetic research has been extensively performed from single candidate genes to whole-genome scan studies, in parallel with the development of high-throughput technologies in molecular diagnostics. Additionally, the safety and efficacy of tissue plasminogen activator, the only approved therapy for the acute phase of stroke, is modulated by genetic background associated with the occurrence of hemorrhagic transformations and with the revascularization of the cerebral arteries. In the near future, understanding the contribution of stroke genetic factors will lead to improvements in prevention and treatments for neurovascular diseases.

USING TPA FOR ACUTE STROKE IN A RURAL SETTING

Controversy continues regarding the safety and efficacy of tissue plasminogen activator (tPA) for stroke outside major centers. We reviewed charts from 1998 to 2004 of 493 patients admitted with TIA or stroke to our small rural hospital. There was a 4% tPA treatment rate with no symptomatic intracranial hemorrhage and zero mortality. IV tPA can be safe and effective in the treatment of acute stroke despite the size of the institution.

Using tPA for acute stroke in a rural setting

Controversy continues regarding the safety and efficacy of tissue plasminogen activator (tPA) for stroke outside major centers. We reviewed charts from 1998 to 2004 of 493 patients admitted with TIA or stroke to our small rural hospital. There was a 4% tPA treatment rate with no symptomatic intracranial hemorrhage and zero mortality. IV tPA can be safe and effective in the treatment of acute stroke despite the size of the institution.

Tissue Plasminogen Activator Combined With Human Recombinant Deoxyribonuclease Is Effective Therapy for Empyema in a Rabbit Model

There have been no controlled studies to test the efficacy of tissue plasminogen activator (tPA) or recombinant human deoxyribonuclease (rhDNase) in the treatment of empyema. In vitro studies show that streptokinase without rhDNase does not liquefy empyemic material from rabbits. However, the combination of streptokinase and streptodornase and rhDNase have been shown to liquefy pus in vitro. The aim of this study was to determine if tPA or rhDNase, or a combination of the two, is more effective than saline solution in the treatment of empyema in rabbits. Empyema was induced in rabbits using 10(9) Pasteurella multicoda organisms in infusion agar injected via a surgically placed chest tube. Once empyema was verified, a blinded investigator administered one of four treatments via the chest tube: 3 mL of saline solution; 4 mg of alteplase (recombinant tPA); 1 mg of rhDNase; or 4 mg of alteplase and 1 mg of rhDNase. The rabbits received a treatment every 12 h following the initial for a total of six treatments. The animals were killed at day 10, and the degree of empyema and pleural peel was scored macroscopically on a scale of 0 to 4. The combination group had a significantly lower mean empyema score (1.83 +/- 0.75) than did the saline solution group (3.86 +/- 0.38, p = 0.001), rhDNase group (3.17 +/- 0.75, p = 0.012), and alteplase group (3.71 +/- 0.49, p = 0.02) [+/- SD]. The total volume of pleural fluid was markedly higher in the alteplase and rhDNase combination group (142 +/- 79.1 mL) or the alteplase group (231 +/- 78.0 mL) compared to either the rhDNase group (0.8 +/- 1.6 mL) or the saline solution group (5.8 +/- 14.0 mL). The combination of alteplase and rhDNase is more effective in the treatment of rabbit empyema than either agent alone. The intrapleural injection of alteplase alone or in combination with rhDNase leads to the production of large amounts of pleural fluid.

An Open-Label Study to Evaluate the Safety and Efficacy of Tissue Plasminogen Activator in Treatment of Severe Frostbite

An Open-Label Study to Evaluate the Safety and Efficacy of Tissue Plasminogen Activator in Treatment of Severe Frostbite

An Open-Label Study to Evaluate the Safety and Efficacy of Tissue Plasminogen Activator in Treatment of Severe Frostbite

Severe frostbite can have devastating consequences with loss of limbs and digits. One of the mechanisms of cold injury to human tissue is vascular thrombosis. The effect of tissue plasminogen activator (tPA) and heparin in limb and digit preservation in severe frostbite patients has not been previously studied. Intra-arterial (6 patients) or intravenous (i.v., 13 patients) tPA and IV heparin were used in patients with severe frostbite. All patients between January 1, 1989 and February 1, 2003 with severe frostbite not improved by rapid rewarming, with absent Doppler pulses in distal limb or digits, without perfusion by Technetium (Tc) 99m three-phase bone scan, and no contraindication to tPA use were eligible. Efficacy was assessed on the basis of predicted digit amputation before therapy, given the clinical and Tc-99m scan results, versus partial or complete digits removed. There were no complications with i.v. tPA. Two patients with intra-arterial TPA had bleeding complications. We know from historical Tc-99m scan data which digits were at risk for amputation. In this study, there were 174 digits at risk in 18 patients and only 33 were amputated. Intravenous tPA and heparin after rapid rewarming is safe and reduced predicted digit amputations considerably. Patients with no response to thrombolytic therapy were those with more than 24 hours of cold exposure, warm ischemia times greater than 6 hours, or evidence of multiple freeze-thaw cycles. Our algorithm for treatment of severe frostbite now includes use of i.v. tPA for patients without contraindications.

Lost in translation: taking neuroprotection from animal models to clinical trials

Caffeinol has been proposed as a neuroprotectant for human trials. This review covers a variety of animal models used and various attempts to take animal protocols to human trials. The accompanying paper discusses the rabbit model that was used to identify the efficacy of tissue plasminogen activator (tPA) treatment. To date, this is the only model that was able to achieve laboratory to clinical translational success. Use of caffeinol as a cytoprotective agent in rat models yielded exciting results, which led to clinical trials. However, caffeinol given with tPA in rabbits leads to increased hemorrhage. Caffeinol alone does not prove to be neuroprotective, as vasodilation by itself is not efficacious. However, vasodilation combined with thrombolysis (caffeinol with tPA) poses an increased risk of hemorrhage. For a more translational approach to study neuroprotection and neuroprotective agents in human trials, it is necessary to demonstrate the efficacy of the procedure and purported agents in several animal models.