Single and repeated intravenous toxicity studies of pamiteplase (genetical recombination) in rats and monkeys.

Ishikawa, Atsuko; Ohata, Takeji; Imamura, Kazunori; Iwasaki, Makoto; Sakai, Toshiharu; Matsuzawa, Toshiaki; Okazaki, Shuzo

doi:10.2131/jts.22.2_117

Cited by 7 publications

(6 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the reason is not totally clear, this finding is unlikely to be related to the dose of rt-PA used. Although thrombus in squirrel monkey is a little resistant to rt-PA compared with human in vitro and equally responsive to that in baboon (Lijnen et al , 1984), reduction of α2-PI and fibrinogen occurred after intraveneous injection of 0.1 and 1 mg/kg rt-PA to squirrel monkeys (Ishikawa et al , 1997), and almost similar dosage was used in the experiments using baboons (Herijgers and Flameng, 1991; Kohmura et al , 1993). Individual analysis showed the tendency that the animals whose MCA blood flow was restored earlier by rt-PA (recanalized at 3.5, 5.2, 14.2 mins) showed light neurologic deficits, but those whose MCA thrombus was resistant to rt-PA (recanalized at 44.2, 48, 78.2 mins) had severe neurologic deficits and petechial intracerebral hemorrhages.…”

Section: Discussionmentioning

confidence: 99%

FK419, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, Ameliorates Brain Infarction Associated with Thrombotic Focal Cerebral Ischemia in Monkeys: Comparison with Tissue Plasminogen Activator

Maeda

Moriguchi

Mihara

et al. 2005

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

The binding of platelet glycoprotein (GP) IIb/IIIa to fibrinogen is the final common pathway in platelet aggregation, a process known to play a key role in the pathogenesis of ischemic brain damage. We compared the effects of FK419, a novel nonpeptide GPIIb/IIIa antagonist, with recombinant tissue plasminogen activator (rt-PA) on middle cerebral artery (MCA) patency and ischemic brain damage in a thrombotic stroke model in squirrel monkeys. FK419 not only inhibited in vitro platelet aggregation (IC 50 : 88 nmol/L), but also showed disaggregatory activity to aggregated platelet (EC 50 : 286 nmol/L). FK419 dose-dependently reduced the time to first reperfusion and total occlusion time of MCA blood flow when administered immediately after the termination of photoirradiation. FK419 reduced cerebral infarction and ameliorated neurologic deficits with similar dose-dependency. Although rt-PA reduced the time to first reperfusion, total occlusion time, and cerebral infarction, it did not significantly ameliorate neurologic deficits and induced petechial intracerebral hemorrhages. These results indicate: (1) FK419 restored cerebral blood flow after thrombotic occlusion of MCA, (2) FK419 reduced ischemic brain injury by its thrombolytic actions in a non-human primate stroke model, and (3) FK419 has superior antithrombotic efficacy and is safer than rt-PA.

show abstract

Section: Discussionmentioning

confidence: 99%

FK419, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, Ameliorates Brain Infarction Associated with Thrombotic Focal Cerebral Ischemia in Monkeys: Comparison with Tissue Plasminogen Activator

Maeda

Moriguchi

Mihara

et al. 2005

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…23 (vi) Pamiteplase (YM866, Solinase) This is another derivative of t-PA with a deletion of the kringle 1 domain (residues 92-173) and a substitution of Arg 274 in the cleavage site of sct-PA with Glu preventing its cleavage by plasmin. 107 Its half-life is about 30-47 min and is dose-dependent. Its in vitro fibrin affinity is more pronounced and the specific activity in vitro is the same as of t-PA. 23 An intravenous bolus injection of YM866 administered in a canine model of coronary thrombosis exerted a superior thrombolytic effect than t-PA without systemic activation of fibrinolysis in comparison with t-PA. 108 A clinical trial conducted in Japan comparing palmiteplase with t-PA showed that palmiteplase had TIMI-3 flow rates of 25% at 30 min (16% for t-PA) and 50% after 60 min (48% for t-PA), with similar thrombolytic effects.…”

Section: (Iv) Monteplase (E6010)mentioning

confidence: 99%

The evolution of recombinant thrombolytics: Current status and future directions

Adivitiya

Khasa

2016

Bioengineered

View full text Add to dashboard Cite

Cardiovascular disorders are on the rise worldwide due to alcohol abuse, obesity, hypertension, raised blood lipids, diabetes and age-related risks. The use of classical antiplatelet and anticoagulant therapies combined with surgical intervention helped to clear blood clots during the inceptive years. However, the discovery of streptokinase and urokinase ushered the way of using these enzymes as thrombolytic agents to degrade the fibrin network with an issue of systemic hemorrhage. The development of second generation plasminogen activators like anistreplase and tissue plasminogen activator partially controlled this problem. The third generation molecules, majorly t-PA variants, showed desirable properties of improved stability, safety and efficacy with enhanced fibrin specificity. Plasmin variants are produced as direct fibrinolytic agents as a futuristic approach with targeted delivery of these drugs using liposome technlogy. The novel molecules from microbial, plant and animal origin present the future of direct thrombolytics due to their safety and ease of administration.

show abstract

“…Also Arg274 in the cleavage site of single-chain t-PA is substituted by Glu, which leads to no cleavage by plasmin. [86] The half-life is dose-dependent and is about 30-47 min. [75] The in-vitro affinity to fibrin should be pronounced and the specific activity in vitro the same as that of t-PA. [75] In a canine model of coronary artery thrombosis pamiteplase had a superior thrombolytic effect to t-PA, without systemic fibrinolytic activation.…”

Section: Lanoteplasementioning

confidence: 99%

“…Pamiteplase (YM866, Solinase) is another variant of t‐PA, where the kringle 1 domain is lost (residues 92–173). Also Arg274 in the cleavage site of single‐chain t‐PA is substituted by Glu, which leads to no cleavage by plasmin [86] . The half‐life is dose‐dependent and is about 30–47 min [75] .…”

Section: Third‐generation Plasminogen Activatorsmentioning

confidence: 99%

Serine-proteases as plasminogen activators in terms of fibrinolysis

Flemmig

Melzig

2012

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

Objectives This review should give an overview about the natural human plasminogen activators and their various modified variants as well as similar substances isolated from animals, microorganisms and plants. When a blood clot is formed in a blood vessel, it avoids the oxygen supply of the surrounding tissue. A fast fibrinolytic therapy should redissolve the blood vessel and reduce the degradation of the tissue. All proteases that are part of the human blood coagulation and fibrinolytic system belong to the serine protease family. t-PA (tissue plasminogen activator) and u-PA (urokinase plasminogen activator) are the naturally occurring fibrinolytic agents that are also used in therapy. Key findings Despite many years of research, t-PA is still the gold standard in fibrinolytic therapy. But it has to be given as an infusion, which needs time. Modified fibrinolytic substances are, were, or perhaps will be in the market. They have different advantages over t-PA, but often the disadvantages predominate. Conclusion Many substances have been developed but an optimal fibrinolytic agent combined with a simple administration is not in therapeutic use to date.

show abstract

Single and repeated intravenous toxicity studies of pamiteplase (genetical recombination) in rats and monkeys.

Cited by 7 publications

References 4 publications

FK419, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, Ameliorates Brain Infarction Associated with Thrombotic Focal Cerebral Ischemia in Monkeys: Comparison with Tissue Plasminogen Activator

FK419, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, Ameliorates Brain Infarction Associated with Thrombotic Focal Cerebral Ischemia in Monkeys: Comparison with Tissue Plasminogen Activator

The evolution of recombinant thrombolytics: Current status and future directions

Serine-proteases as plasminogen activators in terms of fibrinolysis

Contact Info

Product

Resources

About