Efficacy of a new mutated recombinant tissue-type plasminogen activator in beagles with acute coronary artery thrombi

Abstract

Abstract:

BACKGROUND: Development of new coronary thrombolytic agents is hot in the market. A new drug, mutated recombinant tissue-type plasminogen activator (rtPAm), is the product of mutation of tPA by changing binding loci with plasminogen activator inhibitor (PAI)-1 to reduce the degradation. In vitro test has demonstrated that the activity of rtPAm is much higher than rtPA in the absence of PAI. The present study is to observe the efficacy of mutated recombinant tissue-type plasminogen activator (rtPAm) in coronary thrombolytic therapy.

METHODS: A total of 30 adult beagles were equally divided into 5 groups after thrombi: vehicle group, urokinase group, rtPAm low-dose group, rtPAm medium-dose group, and rtPAm high-dose group. Thrombolytic effect and myocardial infarction were observed after thrombolytic therapy.

RESULTS: In the urokinase group, time to reperfusion was (15.8±3.8) minutes. TIMI 2 flow was demonstrated in 4 beagles, TIMI 3 flow in 2, and re-occlusion in 4 after 90 minutes respectively. In the low-dose rtPAm group, time to reperfusion was (15±4.5) minutes; TIMI 2 flow was demonstrated in 2 beagles, TIMI 3 flow in 4, and re-occlusion in 2 after 90 minutes. In the high-dose rtPAm group, time to reperfusion was (7.5±2.6) minutes. None of the beagles showed re-occlusion after 90 minutes. The infarction areas were (2.1+0.9)% in the medium-dose rtPAm group and (0.7+0.4)% in the high-dose rtPAm group, which decreased significantly than those in the low-dose rtPAm group. The aggregation rate in the medium-dose and high-dose rtPAm groups decreased significantly than that in the urokinase group.

CONCLUSION: rtPAm may serve as a thrombolytic agent with platelet-targeted fibrinolysis and antiplatelet aggregation activities.

Key words: Urokinase, RtPA, Thrombi, D-dime, Platelet aggregation

Jing Bai, Lin-bo Ye, Hong Jiang, Dong-dong Zhao, Hong-yao Hu. Efficacy of a new mutated recombinant tissue-type plasminogen activator in beagles with acute coronary artery thrombi[J]. World Journal of Emergency Medicine, 2010, 1(2): 126-131.

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Parameters	Vehicle	Urokinase	Low-dose rtPAm	Medium-dose rtPAm	High-dose rtPAm
Heart rate (bpm)
Pre-operation	167±8	169±10	165±7	168±9	166±10
Values 15 min after coronary occlusions	166±7	166±8	165±10	169±9	163±8
Values 60 min after coronary occlusions	167±9	165±7	163±8	167±10	168±9
Values 90 min after coronary occlusions	163±8	167±9	166±8	162±7	164±9
Mean blood pressure (mmHg)
Pre-operation	120±7	126±8	124±9	127±8	123±7
Values 15 min after coronary occlusions	123±9	125±7	128±10	126±9	124±8
Values 60 min after coronary occlusions	122±6	123±9	125±9	129±10	127±9
Values 90 min after coronary occlusions	127±7	124±8	123±7	123±8	128±7

Groups	Time to occlusion (min)	Incidence of reperfusion		Time to reperfusion (min)	Incidence of re-occlusion	Time to re-occlusion (min)
Groups	Time to occlusion (min)	TIMI=2	TIMI=3	Time to reperfusion (min)	Incidence of re-occlusion	Time to re-occlusion (min)
Vehicle control	7.4±2.1	0	0	0	0	0
Urokinase	7.8±2.4	4/6	2/6	15.8±3.8	4/6	17.5±2.9
Low-dose rtPAm	7.1±2.7	2/6	4/6	15±4.5	2/6	17.5±3.5
Medium-dose rtPAm	7.5±2.0	0/6	6/6^*	10±4.5	0/6^Δ
High-dose rtPAm	7.5±2.6	0/6	6/6^*	8.3±4.1	0/6^Δ

Groups	Thrombosis	Values 30 min after administration	Values 60 min after administration	Values 90 min after administration
Vehicle	0.2±0.04	0.21±0.03	0.19±0.03	0.2±0.06
Urokinase	0.21±0.03	1.4±0.35^Δ	1.5±0.33^Δ	1.8±0.37^Δ
Low-dose rtPAm	0.21±0.04	1.6±0.38^Δ	1.6±0.38^Δ	1.8±0.32^Δ
Medium-dose rtPAm	0.22±0.06	2.0±0.41	2.3±0.42	2.0±0.48
High-dose rtPAm	0.23±0.04	2.1±0.42^*	2.5±0.40^*	2.3±0.47^*

Groups	Pre-operation	Thrombosis	Values 30 min after administration	Values 60 min after administration	Values 90 min after administration
Vehicle	33±8	17±4	26±9	28±8	30±10
Urokinase	34±7	16±8	24±7	27±4	29±3
Low-dose rtPAm	32±8	15±6	19±4^*	18±5^*	28±4
Medium-dose rtPAm	40±6	14±7	17±3^*	18±4^*	25±6
High-dose rtPAm	35±7	20±7	14±3^Δ	10±2^Δ	18±3^Δ

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[2]	Li Yu, Ding Long, Xiao-Ling Wu, Jun-hui Yang, Yuan-chao Yang, Geng Feng. Prognostic significance of urokinase-type plasminogen activator and its receptor in patients with systemic inflammatory response syndrome [J]. World Journal of Emergency Medicine, 2011, 2(3): 185-189.