Thrombolytic Activity of YM866, a Novel Modified Tissue-Type Plasminogen Activator, in a Photochemically Induced Platelet-Rich Thrombosis Model

1994 ◽  
Vol 23 (6) ◽  
pp. 884-889 ◽  
Author(s):  
Tomihisa Kawasaki ◽  
Seiji Kaku ◽  
Toichi Takenaka ◽  
Kennichi Yanagi ◽  
Norio Ohshima
Keyword(s):  
Plasminogen Activator ◽  
Tissue Type ◽  
Thrombolytic Activity ◽  
Tissue Type Plasminogen Activator ◽  
Thrombosis Model ◽  
Type Plasminogen Activator

Thrombolytic Treatment with Tissue-type Plasminogen Activator (t-PA) Containing Liposomes in Rabbits: a Comparison with Free t-PA

1995 ◽  
Vol 73 (03) ◽  
pp. 488-494 ◽  
Author(s):  
J L M Heeremans ◽  
R Prevost ◽  
M E A Bekkers ◽  
P Los ◽  
J J Emeis ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Therapeutic Index ◽  
Tissue Type ◽  
Jugular Vein Thrombosis ◽  
Thrombolytic Activity ◽  
Tissue Type Plasminogen Activator ◽  
Liposome Encapsulation ◽  
Thrombosis Model ◽  
Lysis Activity ◽  
Type Plasminogen Activator

SummaryIn this study, we aimed at improving the therapeutic index of tissue- type Plasminogen Activator (t-PA) as thrombolytic agent in the treatment of myocardial infarction. Liposome-encapsulated t-PA was tested in a rabbit jugular vein thrombosis model: administration of free t-PA (t-PA) as a bolus injection in the ear vein was compared to a similar administration of liposomal t-PA (t-PA-lip), liposomal t-PA in plasminogen-coated liposomes (Plg-t-PA-lip), a mixture of free t-PA and empty liposomes (t-PA+empty lip) and a saline-blank (blank) in terms of thrombolytic activity and side effects.Liposomal t-PA (t-PA-lip/Plg-t-PA-lip) showed a significantly better thrombolysis efficiency than equimolar doses of free t-PA (t-PA/ t-PA+ empty lip): about 0.24 mg/kg of liposomal t-PA practically equalled the lysis-activity of a dose of free t-PA of 1.0 mg/kg (t-PAlmg/kg). On the other hand, liposome encapsulation did not affect the systemic activation of alpha2-antiplasmin and plasminogen by t-PA.We conclude that for this model an improvement in thrombolytic efficacy of t-PA is achieved by liposome encapsulation of t-PA. As t-PA-lip and Plg-t-PA-lip -treatment induced similar results, targeting of liposomal t-PA by coupled glu-Plg remains a topic to be optimized in future studies.

scholarly journals Thrombolytic properties of human tissue-type plasminogen activator, single-chain urokinase-type plasminogen activator, and synergistic combinations in venous thrombosis models in dogs and rabbits

Blood ◽  
1989 ◽  
Vol 73 (5) ◽  
pp. 1207-1212
Author(s):  
DJ Spriggs ◽  
JM Stassen ◽  
Y Hashimoto ◽  
D Collen
Keyword(s):  
Plasminogen Activator ◽  
Rabbit Model ◽  
Synergistic Interaction ◽  
Tissue Type ◽  
Single Chain ◽  
Tissue Type Plasminogen Activator ◽  
Vein Thrombosis ◽  
Thrombosis Model ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator

Thrombolysis with single and combined four-hour intravenous (IV) infusions of recombinant tissue-type plasminogen activator (rt-PA), recombinant single-chain urokinase-type plasminogen activator of 54,000 molecular weight (mol wt) (rscu-PA), and rscu-PA-32 kD, an rscu-PA derivative of 32,000 mol wt was studied in a femoral vein thrombosis model in the dog and in a jugular vein thrombosis model in the rabbit. In both species, the dose-response curves were linear, and no systemic activation of the fibrinolytic system or fibrinogen breakdown was observed. The steady-state levels of rt-PA-, rscu-PA-, and rscu-PA-32 kD-related antigens in plasma were proportional to the infusion rates. In the dog model, 25% lysis was obtained with 0.11 mg/kg rt-PA, 0.8 mg/kg rscu-PA, and 0.37 mg/kg rscu-PA-32 kD. Combinations of rt-PA and rscu-PA were 2.6 times more active (P less than .005) than anticipated on the basis of their pharmacologic additive effects, whereas combinations of rt-PA and rscu-PA-32 kD were 2.7 times more active (P less than .05). In the rabbit model, 25% lysis was obtained with 0.24 mg/kg rt-PA, 0.75 mg/kg rscu-PA, and 1.25 mg/kg rscu-PA-32 kD. Combinations of rt-PA and rscu-PA have a fivefold synergistic interaction, but surprisingly no synergism was observed between rt-PA and rscu-PA-32 kD. This study shows that synergism between rt-PA and rscu-PA occurs both in rabbits and dogs in a relatively narrow concentration range that allows a fractional reduction of the total equipotent dose by a factor of 2.5-fold to fivefold. Combination therapy is not associated with systemic fibrinolytic activation. This range of synergistic interaction, although limited, may be useful in devising the best thrombolytic therapy for patients with thromboembolic disease.

scholarly journals Pharmacokinetics and thrombolytic properties of deletion mutants of human tissue-type plasminogen activator in rabbits

Blood ◽  
1988 ◽  
Vol 71 (1) ◽  
pp. 216-219
Author(s):  
D Collen ◽  
JM Stassen ◽  
G Larsen
Keyword(s):  
Plasminogen Activator ◽  
Human Tissue ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Tissue Type ◽  
Jugular Vein Thrombosis ◽  
Thrombolytic Activity ◽  
Tissue Type Plasminogen Activator ◽  
Deletion Mutagenesis ◽  
Type Plasminogen Activator

The following mutants of human tissue-type plasminogen activator (t-PA) were constructed by deletion mutagenesis of t-PA cDNA, expressed in Chinese hamster ovary cells and purified to homogeneity: (a) t-PA-delta FE:t-PA lacking both the fibronectin fingerlike (F) domain and the epidermal growth factor (E) domain, (b) t-PA-delta FE1X:t-PA-delta FE with the glycosylated 117Asn mutagenized to Gln, and (c) t-PA-delta FE3X:t-PA-delta FE with the three known glycosylated Asn residues replaced by Gln. The mutant and natural t-PA (Mel-t-PA obtained from melanoma cell culture) were infused intravenously for four hours into rabbits with jugular vein thrombosis at doses ranging between 0.12 and 0.75 mg/kg. Fifty percent thrombolysis, determined by interpolation, was obtained with 0.4 mg/kg Mel-t-PA, 0.37 mg/kg t-PA-delta FE, 0.2 mg/kg t-PA-delta FE1X, and 0.40 mg/kg t-PA-delta FE3X. These infusion rates resulted in plateau levels of t-PA antigen in plasma of 0.055, 2.1, 0.6, and 0.5 micrograms/mL, respectively. At 50% lysis, the residual fibrinogen 30 minutes after the end of the infusion was 100%, 81%, 100% and 85% of baseline, and the residual alpha 2-antiplasmin was 82%, 55%, 85%, and 90%, respectively. These results indicate that t-PA- delta FE1X and t-PA-delta FE3X have a specific thrombolytic activity and fibrin specificity comparable to that of Mel-t-PA. t-PA-delta FE has a comparable specific thrombolytic activity but a lower fibrin specificity than Mel-t-PA. After the end of the infusion, t-PA-related antigen disappeared from plasma with an initial t1/2 of four minutes for Mel-t-PA, 25 minutes for t-PA-delta FE, 42 minutes for t-PA-delta FE1X, and 14 minutes for t-PA-delta FE3X. It is concluded that t-PA can be modified by deletion mutagenesis to yield variants with a markedly longer half-life in the blood. Some of these variants have a specific thrombolytic activity and fibrin specificity similar to that of natural t-PA. These variants may be useful to identify the structures in t-PA responsible for its clearance, specific thrombolytic activity, and fibrin specificity in vivo.

Absence of Potentiation with Murine Antiplatelet GPIIb/IIIa Antibody of Thrombolysis with Recombinant Tissue-Type Plasminogen Activator (rt-PA) in a Canine Venous Thrombosis Model

1989 ◽  
Vol 61 (01) ◽  
pp. 093-096 ◽  
Author(s):  
D Spriggs ◽  
H K Gold ◽  
Y Hashimoto ◽  
E Van Houtte ◽  
J Vermylen ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Venous Thrombosis ◽  
Plasminogen Activator ◽  
Femoral Vein ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Thrombosis Model ◽  
Type Plasminogen Activator ◽  
Coronary Artery Thrombosis ◽  
Canine Coronary Artery

SummaryF(ab’)2 fragments of a murine monoclonal anti-platelet GPIIb/ IIIa antibody (7E3) are a potent platelet aggregation inhibitor, which in a canine coronary artery thrombosis model accelerate lysis with recombinant tissue-type plasminogen activator (rt-PA) and prevent reocclusion (7).In the present study, we have investigated the potential value of platelet aggregation inhibition as adjunctive therapy to lysis of venous thrombi, by measuring the thrombolytic potency of 7E3- F(ab’)2 and rt-PA used alone or in combination, in dogs with a 125I-fibrin labeled femoral vein thrombus. The dose-response of thrombolysis with rt-PA infused over 4 hours was linear: doses of 0.075 mg/kg, 0.15 mg/kg and 0.3 mg/kg produced 37 ± 3, 57 ± 11 and 83 ± 4% lysis respectively, against a background value of 20 ± 2%. With F(ab’)2 fragments of 7E3 given as a bolus of 1.2 mg/ kg, which saturated 70% of the platelet GPIIb/IIIa receptors and prolonged the bleeding to more than 30 min, lysis was not significantly increased over background. Combination of 0.3 or 0.6 mg/kg of 7E3-F(ab’)2 with either 0.03 or 0.06 mg/kg of rt-PA did not produce more lysis than obtained with a comparable dose of rt-PA alone. No significant changes in plasma fibrinogen or α2- antiplasmin were observed with either agent alone or with the combination. It is concluded that extensive inhibition of platelet aggregation does not potentiate the thrombolytic effect of rt-PA in this venous thrombosis model.

Thrombolytic Activity of Two Chimeric Recombinant Plasminogen Activators (FK2tu-PA and K2tu-PA) in Rabbits

1992 ◽  
Vol 68 (03) ◽  
pp. 331-335 ◽  
Author(s):  
Giancarlo Agnelli ◽  
Claudia Pascucci ◽  
Mario Colucci ◽  
Giuseppe G Nenci ◽  
Antonio Mele ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activators ◽  
Tissue Type ◽  
Single Chain ◽  
Jugular Vein Thrombosis ◽  
Thrombolytic Activity ◽  
Thrombosis Model ◽  
Type Plasminogen Activator ◽  
Kringle 2 ◽  
Higher Doses

SummaryThe aim of this study was to evaluate the thrombolytic activity of two hybrid plasminogen activators (HPAs) in a rabbit jugular vein thrombosis model. In the two HPAs the kringle-2 domain (K2tu-PA) or the finger and the kringle-2 domains (FK2tu-PA) of tissue-type plasminogen activator (t-PA) are linked to the catalytic protease domain of single chain urokinase type plasminogen activator (scu-PA). The two HPAs were compared with rt-PA and scu-PA on a weight/weight basis. K2tu-PA, FK2tu-PA, rt-PA and scu-PA were infused at doses of 0.4, 0.8 and 1.2 mg/kg over 3 h. Saline served as control. Saline produced 11 ± 2% thrombolysis. The three doses of K2tu-PA led to 38 ± 4%, 66 ± 5% and 89 ± 7% thrombolysis, respectively; the three doses of FK2tu-PA: 18 ± 3%, 29 ± 5% and 33 ± 6%, respectively; the three doses of rt-PA 32 ± 2%, 49 ± 3% and 68 ± 6%, respectively; the three doses of scu-PA 16 ± 2%, 24 ± 3% and 32 ± 4%, respectively. K2tu-PA and rt-PA showed a statistically significant higher thrombolytic activity than FK2tu-PA and scu-PA at the three tested doses (p <0.01). The thrombolytic activity of K2tu-PA was significantly higher than rt-PA at the two higher doses (p <0.01). Both K2tu-PA and rt-PA produced a statistically significant reduction of fibrinogen, α2-antiplasmin and plasminogen 3 h after the start of the infusions of the two higher doses. No statistically significant differences between K2tu-Pa and rt-PA were observed. Concomitant with the lower thrombolytic activity, the systemic proteolytic effects of FK2tu-PA and scu-PA were less pronounced. We conclude that the two HPAs we tested are effective thrombolytic agents. K2tu-PA deserves particular attention in future experiments.

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