Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel enzyme drug delivery system, Antibody, Targeted, Triggered, Electrically, Modified, Prodrug, Type, Strategy ("ATTEMPTS"), was developed in our laboratory to attenuate the toxicity associated with drug activity at non-targeted tissues. Tissue plasminogen activator is a prime example of an enzyme drug that exhibits systemic toxicity due to its indiscriminate activation of both targeted (i.e., clot-bound) and non-targeted (i.e., systemic) plasminogen. In brief, tissue plasminogen activator (t-PA) was modified to contain positive surface charges and then rendered inactive upon electrostatic binding with a negatively charged heparin-antifibrin antibody conjugate. After targeting the complex to the clot site, t-PA activity was restored by administration of protamine, a clinical heparin antidote. Cation-modified t-PA (CM-tPA) was obtained by chemical conjugation of t-PA with a poly(Arg)7Cys peptide using the crosslinker N-succinimidyl 3-2-(pyridlydithio)propionate (SPDP). Anti-fibrin IgG was chemically conjugated with heparin via oxidation of the carbohydrate moiety on its Fc region. Both in vitro characterization and in vivo studies using a rat thrombosis model clearly demonstrated that heparin-IgG conjugate induced inhibition of CM-tPA could be effectively reversed upon addition of protamine. Overall, the ATTEMPTS system was proven to induce clot dissolution without causing t-PA associated systemic toxicity due to the degradation of critical plasma factors by systemic plasmin production.
 ...
PMID:Application of "ATTEMPTS" for drug delivery. 1558 92

We investigated the effect of a high walnut and cashew diet on haemostatic variables in people with the metabolic syndrome. Factor analysis was used to determine how the haemostatic variables cluster with other components of the metabolic syndrome and multiple regression to determine possible predictors. This randomized, control, parallel, controlled-feeding trial included 68 subjects who complied with the Third National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol criteria. After a 3-week run-in following the control diet, subjects were divided into three groups receiving either walnuts or cashews (20 energy%) or a control diet for 8 weeks. The nut intervention had no significant effect on von Willebrand factor antigen, fibrinogen, factor VII coagulant activity, plasminogen activator inhibitor 1 activity, tissue plasminogen activator activity or thrombin activatable fibrinolysis inhibitor. Statistically, fibrinogen clustered with the body-mass-correlates and acute phase response factors, and factor VII coagulant activity clustered with high-density lipoprotein cholesterol (HDL-C). Tissue plasminogen activator activity, plasminogen activator inhibitor 1 activity and von Willebrand factor antigen clustered into a separate endothelial function factor. HDL-C and markers of obesity were the strongest predictors of the haemostatic variables. We conclude that high walnut and cashew diets did not influence haemostatic factors in this group of metabolic syndrome subjects. The HDL-C increase and weight loss may be the main focus of dietary intervention for the metabolic syndrome. Furthermore, diet composition may have only limited effects if weight loss is not achieved.
 ...
PMID:Clustering of haemostatic variables and the effect of high cashew and walnut diets on these variables in metabolic syndrome patients. 1609 34

The bed nucleus of stria terminalis is a basal forebrain region involved in regulation of hormonal and behavioral responses to stress. In this report we demonstrate that bed nucleus of stria terminalis has a high and localized expression of tissue plasminogen activator, a serine protease with neuromodulatory properties and implicated in neuronal plasticity. Tissue plasminogen activator activity in the bed nucleus of stria terminalis is transiently increased in response to acute restraint stress or i.c.v. administration of a major stress mediator, corticotropin-releasing factor. We show that tissue plasminogen activator is important in bed nucleus of stria terminalis function using two criteria: 1, Neuronal activation in this region as measured by c-fos induction is reduced in tissue plasminogen activator-deficient mice; and 2, a bed nucleus of stria terminalis-dependent behavior, potentiation of acoustic startle by corticotropin-releasing factor, is attenuated in tissue plasminogen activator-deficient mice. These studies identify a novel site of tissue plasminogen activator expression in the mouse brain and demonstrate a functional role for this protease in the bed nucleus of stria terminalis.
 ...
PMID:Tissue plasminogen activator in the bed nucleus of stria terminalis regulates acoustic startle. 1612 60

Tissue plasminogen activator was used for a blocked peritoneal dialysis catheter in a child with no vascular access. The catheter was salvaged using tissue plasminogen activator and dialysis could be carried out without any difficulty.
 ...
PMID:Tissue plasminogen activator for blocked peritoneal dialysis catheters. 1625 99

The purpose of this study was to identify plasminogen activators (PA) and their specific inhibitors in human cell-free saliva and to investigate their expression in salivary gland tissue. Saliva samples were obtained from 34 patients visiting a neurological out-patient department. The activities of tissue and urokinase plasminogen activators (tPA and uPA, respectively), the relative inhibition of tPA, and the amounts of plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2, respectively) in cell-free saliva were studied. The activities of tPA and uPA, and tPA inhibition, were measured using in-house microtiter plate assays, and PAI-1 and PAI-2 levels were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits. Immunohistochemistry was used to evaluate the expression of PAs and PAIs in the salivary gland. Tissue plasminogen activator activity was found in most samples, with a mean activity of 0.63 IU ml(-1). uPA was observed in only a few samples. PAI-1 was not detected, but PAI-2 was present in all samples (with a mean value of 11.1 ng ml(-1)). The mean PAI-2 level in women was 12.4 and in men was 7.6 ng ml(-1). The activity of tPA and the relative inhibition of tPA seemed to be inversely associated. Tissue plasminogen activator, PAI-1, and PAI-2 were evident in salivary gland tissue, whereas the expression of uPA was low. The tPA activity in saliva suggests an active proteolysis. Plasminogen activator inhibitor 2 was found to be the main inhibitor of PAs in saliva.
 ...
PMID:Plasminogen activators and their inhibitors in human saliva and salivary gland tissue. 1646 Mar 37

The aim of this study was to compare fibrinolysis in normal pregnancy and pre-eclampsia using individual markers of thrombosis and fibrinolysis with the contribution of a new parameter, global fibrinolytic capacity. Coagulation was determined with thrombin-antithrombin complex and prothrombin fragment 1+2 (F 1+2) and fibrinolysis markers. Tissue plasminogen activator, plasminogen activator inhibitor-1 and global fibrinolytic capacity were determined in 14 normal pregnancies and 29 women with pre-eclampsia. global fibrinolytic capacity was also determined in 14 age-matched healthy women. The Mann-Whitney U test and Pearson correlation test were used for statistical analysis. Thrombin-antithrombin complex, prothrombin fragment 1+2 levels, and global fibrinolytic capacity levels in pre-eclamptic women were significantly higher than in women with normal pregnancies (P < 0.05). Tissue plasminogen activator, plasminogen activator inhibitor-1 levels were also significantly higher in the pre-eclampsia group (P < 0.001 and P < 0.05 respectively). No significant correlation was found between global fibrinolytic capacity and thrombin-antithrombin complex, prothrombin fragment 1+2 levels, tissue plasminogen activator or plasminogen activator inhibitor-1 activity. Our results suggest that both thrombin formation and fibrinolysis are increased in pre-eclampsia compared with normal pregnancy. The increased global fibrinolytic capacity indicates that fibrinolysis remains preserved in pre-eclampsia. We suggest that global fibrinolytic capacity may be a useful parameter for accurately measuring in-vivo fibrinolysis globally, instead of with single parameters which may overlook the complex interactions between coagulation and fibrinolytic systems.
 ...
PMID:Increased global fibrinolytic capacity as a clue for activated fibrinolysis in pre-eclampsia. 1678 10

Intravenous tissue plasminogen activator is the only therapy approved by the US Food and Drug Administration (FDA) for the treatment of acute ischemic strokes. The National Institutes of Health (NIH)-sponsored study that led to the approval of tissue plasminogen activator to be used in acute ischemic strokes included only individuals 18 years of age and older. We report a case of a pediatric patient who suffered a dominant-hemisphere acute ischemic stroke who was treated with intravenous tissue plasminogen activator. Our patient's symptoms began to resolve 4 hours after treatment, and he had a complete recovery after 8 hours. The clinical outcome was excellent and without complications. Tissue plasminogen activator administration can be safe and effective in younger patients. Randomized, controlled, double-blind studies are needed.
 ...
PMID:Administration of intravenous tissue plasminogen activator in a pediatric patient with acute ischemic stroke. 1697 Aug 53

Multiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system. It manifests as acute focal inflammatory demyelination and axonal loss with limited remyelination and results in the chronic multifocal sclerotic plaques. Previously published data showed impaired fibrinolysis in MS. Tissue plasminogen activator t-PA is a serine protease that catalyses the activation of plasmin, which mediates the effects of fibrinolytic system. Alu insertion/deletion (I/D) genetic polymorphism in TPA gene in MS patients has not been analysed previously. The major inhibitor of t-PA is plasminogen activator inhibitor-1 (PAI-1). Its gene expression is modulated by functional genetic polymorphism in the promoter (4G/5G). In the present study, an association of two genetic polymorphisms with MS, its progression and subtype were analysed. TPA DD/PAI-1 4G4G genotype combination has reached a borderline significance for reduced risk for MS (OR = 0.543, 95% CI 0.301-0.978, P = 0.04), suggesting a gene-gene interaction. The explanation for this interaction may be a complex interplay between these two pleiotropic proteins within the brain tissue and in plasma.
 ...
PMID:PAI and TPA gene polymorphisms in multiple sclerosis. 1798 6

In the pivotal clinical trials of intravenous tissue plasminogen activator (TPA) therapy, a low rate of early arterial recanalization was suspected because only a few stroke patients may have had early dramatic clinical improvement. Tissue plasminogen activator activity can be enhanced with ultrasound, including 2 MHz transcranial Doppler (TCD). Transcranial Doppler identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. For the first time in clinical medicine, the international multicenter CLOTBUST trial showed that ultrasound enhances the thrombolytic activity of a drug in humans, thereby confirming multidisciplinary experimental research conducted worldwide for the past 30 years. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 h after TPA bolus occurred in 25% of patients treated with TPA+TCD compared with 8% who received TPA alone (P=0.02). Complete clearance of a thrombus and dramatic recovery of brain functions during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the target CLOTBUST group resulted in a trend of 13% more patients achieving favorable outcome at 3 months. To further enhance the ability of TPA to break up thrombi, current ongoing clinical trials include phase II studies of 2 MHz TCD with ultrasound contrast agents or (microbubbles): TCD+TPA+Levovist; TCD+TPA+MRX nano-platform (C(3)F(8)). Intra-arterial TPA delivery can be enhanced with 1 x 7-2 x 1 MHz pulsed wave ultrasound (EKOS catheter, IMS trial). Dose escalation studies of microbubbles, ultrasound exposure, and the development of an operator-independent ultrasound device are underway.
 ...
PMID:Ultrasound enhanced thrombolysis for stroke. 1870 65

In a rat embolic stroke (eMCAO) model, the effects of 100% normobaric hyperoxia (NBO) with delayed recombinant tissue plasminogen activator (tPA) administration on ischemic lesion size and safety were assessed by diffusion- and perfusion (PWI)-weighted magnetic resonance imaging. NBO or room air (Air) by a face mask was started at 30 mins posteMCAO and continued for 3.5 h. Tissue plasminogen activator or saline was started at 3 h posteMCAO. Types and location of hemorrhagic transformation were assessed at 24 h and a spectrophotometric hemoglobin assay quantified hemorrhage volume at 10 h. In NBO-treated animals the apparent diffusion coefficient/PWI mismatch persisted during NBO treatment. Relative to Air groups, NBO treatment significantly reduced 24 h infarct volumes by approximately 30% and approximately 15% with or without delayed tPA, respectively (P<0.05). There were significantly more hemorrhagic infarction type 2 hemorrhages in Air/tPA versus Air/saline animals (P<0.05). Compared with Air/tPA, the combination of NBO with tPA did not increase hemorrhage volume at 10 h (4.0+/-2.4 versus 6.6+/-2.6 microL, P=0.065) or occurrence of confluent petechial hemorrhages at 24 h (P>0.05), respectively. Our results suggest that early NBO treatment in combination with tPA at a later time point may represent a safe and effective strategy for acute stroke treatment.
 ...
PMID:Normobaric hyperoxia and delayed tPA treatment in a rat embolic stroke model. 1876 95


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>