Profile of Recombinant Pro-urokinase Given by Intraarterial versus Intravenous Routes of Administration in a Canine Thrombosis Model

1999 ◽  
Vol 81 (02) ◽  
pp. 301-305 ◽  
Author(s):  
Nathan Lubbers ◽  
Richard Nelson ◽  
Craig Wegner ◽  
Bryan Cox ◽  
Sandra Burke
Keyword(s):  
Blood Flow ◽  
Dose Range ◽  
Vascular Occlusion ◽  
Experimental Period ◽  
Canine Model ◽  
Clot Lysis ◽  
Treatment Groups ◽  
Routes Of Administration ◽  
Thrombosis Model ◽  
Catheter Directed Thrombolysis

SummaryCatheter-directed thrombolysis has gained increasing acceptance for the treatment of patients who present with vascular occlusion; however, intravenous injection may be preferable in selected patients. Recombinant prourokinase (r-proUK) is a recently-developed fibrin-selective thrombolytic agent with specificity for clot-bound plasminogen. To compare the effects of r-proUK on clot lysis and restoration of blood flow when injected by either intraarterial or intravenous routes of administration, we utilized a dog model of arterial thrombosis in which a radiolabelled clot is formed in the femoral artery. The r-proUK was given by intravenous infusion to one group of 18 animals in doses ranging from 10,000 IU/kg to 100,000 IU/kg; a second group of 27 dogs was treated with r-proUK administered by the intra-arterial route in a dose range from 300 IU to 10,000 IU. Clot lysis was measured by monitoring the loss of counts from the radiolabelled clot over time; blood flow was also monitored throughout the experimental period. Animals which received intravenous treatment showed dose-related clot lysis ranging from 14% to 70% at 2 h, while those which received intra-arterial infusions showed lysis ranging from 22% to 79% over the same period. For similar degrees of clot lysis attained at the highest dose levels of 100,000 IU/kg and 10,000 IU, blood flow was restored to 77% and 35% of control levels in dogs which received intravenous and intraarterial treatment, respectively. The hemostatic protein fibrinogen was not reduced in any of the treatment groups. The results indicate that 100 times more intravenous than intra-arterial r-proUK is required to produce similar clot lysis in this canine model, and that the agent can be administered at this level without induction of a systemic lytic state.

Comparative Effects of Enoxaparin and Heparin on Arterial and Venous Clot Lysis with Alteplase in Dogs

1993 ◽  
Vol 69 (05) ◽  
pp. 454-459 ◽  
Author(s):  
Jean-Marie Stassen ◽  
Hans J Rapold ◽  
Ingrid Vanlinthout ◽  
Désiré Collen
Keyword(s):  
Steady State ◽  
Factor Xa ◽  
Clot Lysis ◽  
Intravenous Bolus ◽  
Treatment Groups ◽  
Thrombosis Model ◽  
Blinded Study ◽  
Arterial Patency ◽  
Acetyl Salicylate ◽  
Observation Period

SummaryThe effects of Enoxaparin with a specific anti-thrombin (anti-IIa) activity of 32 U/mg and a specific anti-factor-XA (anti-Xa) activity of 96 U/mg, and of heparin with a specific anti-IIa and anti-Xa activity of 192 U/mg, on thrombolysis with alteplase (Actilyse®) were compared in a randomized blinded study using a combined arterial and venous thrombosis model in the dog. All dogs received an intravenous bolus of 5 mg/kg lysine-acetyl salicylate and 0.5 mg/kg alteplase over 60 min. Twenty-eight dogs were randomly assigned to seven treatment groups: placebo, Enoxaparin 1.5, 3 or 6 mg/kg, or heparin 0.5, 1 or 2 mg/kg, given as a 50% intravenous bolus and a 50% infusion over 2 h. Steady-state plasma levels ranged from 0.37 to 1.0 anti-IIa U/ml and 0.9 to 3.1 anti-Xa U/ml for Enoxaparin and from 0.4 to 2.3 anti-IIa U/ml and 0.42 to 3.2 anti-Xa U/ml for heparin. The activated thromboplastin time with 6 mg/kg Enoxaparin prolonged to 94 ± 19 s and with 2 mg/kg heparin to >150 s.The time to reflow was 120 ± 36 min with placebo, 19 ± 5 min with 6 mg/kg Enoxaparin (p = 0.03 vs control), and 22 ± 5 min with 2 mg/kg of heparin (p = 0.03 vs control). Arterial patency, expressed in min reflow during the 180 min observation period correlated significantly with the dose of anticoagulant given (r = 0.73, p = 0.003 for Enoxaparin and r = 0.61, p = 0.012 for heparin). When the dose of anticoagulant was expressed in anti-IIa U/kg, Enoxaparin was significantly more potent than heparin (patency times of 0.62 ± 0.15 and 0.21 ± 0.09 min per anti-IIa U/kg respectively, p = 0.04) but in terms of mg/kg or anti-Xa U/kg both anticoagulants were equipotent.Venous clot lysis also correlated significantly with the dose of anticoagulant given (r = 0.62, p = 0.011 for Enoxaparin and r = 0.76, p = 0.004 for heparin). When the dose of anticoagulant was expressed in anti-IIa U/kg Enoxaparin was equipotent to heparin, but in terms of mg/kg or anti-Xa U/kg heparin was more potent than Enoxaparin (6 ± 2% lysis per mg/kg Enoxaparin and 35 ± 9% lysis per mg/kg heparin, p= 0.001).In conclusion, Enoxaparin and heparin enhance arterial and venous clot lysis with alteplase differently; for arterial patency, potency correlates with anti-Xa activity whereas for venous clot lysis potency correlates with anti-IIa activity.

Comparison of Dose Regimens for the Administration of Recombinant Pro-urokinase in a Canine Thrombosis Model

1997 ◽  
Vol 77 (05) ◽  
pp. 1025-1033
Author(s):  
Sandra E Burke ◽  
Nathan L Lubbers ◽  
Richard A Nelson ◽  
Jack Henkin
Keyword(s):  
Myeloma Cell ◽  
Clot Lysis ◽  
Single Chain ◽  
Treatment Groups ◽  
Thrombosis Model ◽  
Mouse Myeloma Cell Line ◽  
Dosing Regimens ◽  
Important Addition ◽  
Group 5 ◽  
Mouse Myeloma

SummaryPro-urokinase represents an important addition to the array of thrombolytic drugs currently available for clinical use because of its high clot specificity but distinctly different mechanism compared with that of t-PA. Recombinant pro-urokinase (r-proUK) is a single-chain precursor of high molecular weight urokinase which has been expressed in a mouse myeloma cell line. The present study was conducted to determine the dosing regimen which would produce optimal clot lysis and restoration of blood flow 2 h after treatment with r-proUK, using a dog model of arterial thrombosis. Efficacy was indicated by lysis of a radiolabelled clot which was formed in the heat-damaged femoral arteries of 39 male beagle dogs. The animals were divided into six heparinized treatment groups, each receiving one of five dosing regimens or the vehicle for r-proUK. The total dose (80,000 U/kg) was divided into an initial loading bolus, followed by either a second bolus or by infusions for various time periods, as shown below:It was concluded that optimal clot lysis and restoration of femoral flow was accomplished using a regimen in which 50% of the dose was given as a bolus, followed immediately by the remaining 50% given as a 30 min intravenous infusion (Group 5). At the dose used in this study, r-proUK did not produce degradation of fibrinolytic or hemostatic plasma proteins.

Recombinant Pro-Urokinase Requires Heparin for Optimal Clot Lysis and Restoration of Blood Flow in a Canine Femoral Artery Thrombosis Model

1993 ◽  
Vol 69 (04) ◽  
pp. 375-380 ◽  
Author(s):  
Sandra E Burke ◽  
Nathan L Lubbers ◽  
Richard A Nelson ◽  
Jack Henkin
Keyword(s):  
Blood Flow ◽  
Femoral Artery ◽  
Control Level ◽  
Tissue Type ◽  
Clot Lysis ◽  
Small Scale ◽  
Thrombosis Model ◽  
Group 4 ◽  
Group 3

SummaryHeparin is often used as an adjunct to thrombolytic therapy in order to prevent reocclusion of the patent vessels in patients with thrombotic disease. Controversy exists as to whether heparin is required for effective clot lysis with tissue-type plasminogen activator, while in vitro data and small scale clinical trials have suggested an enhancement of pro-urokinase efficacy by heparin. The present study was conducted to determine whether heparin pre-treatment is required to produce optimal clot lysis and blood flow restoration in response to recombinant pro-urokinase (r-proUK). In four groups of dogs, blood clots labelled with 125Iodine were formed in the femoral artery and were monitored continuously for loss of counts as an indicator of clot lysis. Femoral artery blood flow was measured simultaneously. Group 1 received vehicle (n = 5), while group 2 was given vehicle + heparin (n = 6; 500 U bolus + 350 U/h). This dose of heparin increased the activated partial thromboplastin time (APTT) by at least 1.5 times the control level for the 4 h observation period. Group 3 received r-proUK alone at a dose of 100,000 U/kg (50% given as a 1-min bolus injection, 50% as a 30 min infusion) (n = 8), while group 4 was treated with the same dose of r-proUK in the presence of heparin as described (n = 8). Clot lysis at 4 h in groups 1 and 2 was 26 ± 3% and 28 ± 5%, respectively; flow was not restored in either group. In group 3, clot lysis was 50 ± 4% while group 4 showed lysis of 85 ± 5% (p <0.05). However, flow was not restored in any dog in group 3, while five of eight dogs in group 4 showed complete restoration of blood flow. In the remaining three dogs, flow was restored to 70–91% of control levels. The data suggest that a regimen of heparin pretreatment with continued infusion markedly increases the efficacy of r-proUK in this model and results in significant restoration of blood flow.

A simplified mitral valve method for two-dimensional echo Doppler blood flow calculation: Validation in an open-chest canine model and initial clinical studies

1987 ◽  
Vol 113 (2) ◽  
pp. 335-340 ◽  
Author(s):  
Erik J. Meijboom ◽  
Suzanna Horowitz ◽  
Lilliam M. Valdes-Cruz ◽  
Douglas F. Larson ◽  
Nicolaas Bom ◽  
...  
Keyword(s):  
Blood Flow ◽  
Mitral Valve ◽  
Clinical Studies ◽  
Canine Model ◽  
Two Dimensional ◽  
Flow Calculation ◽  
Open Chest

scholarly journals Dose Range Finding Studies with Two RPGR Transgenes in a Canine Model of X-Linked Retinitis Pigmentosa Treated with Subretinal Gene Therapy

2020 ◽  
Vol 31 (13-14) ◽  
pp. 743-755 ◽  
Author(s):  
Chunjuan Song ◽  
Valérie L. Dufour ◽  
Artur V. Cideciyan ◽  
Guo-Jie Ye ◽  
Malgorzata Swider ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Retinitis Pigmentosa ◽  
Dose Range ◽  
Canine Model ◽  
Range Finding

Noninvasive measurement of forearm blood flow and oxygen consumption by near-infrared spectroscopy

1994 ◽  
Vol 76 (3) ◽  
pp. 1388-1393 ◽  
Author(s):  
R. A. De Blasi ◽  
M. Ferrari ◽  
A. Natali ◽  
G. Conti ◽  
A. Mega ◽  
...  
Keyword(s):  
Blood Flow ◽  
Oxygen Consumption ◽  
Infrared Spectroscopy ◽  
Near Infrared Spectroscopy ◽  
Healthy Subjects ◽  
Near Infrared ◽  
Forearm Blood Flow ◽  
Vascular Occlusion ◽  
Venous Occlusion ◽  
The Subject

We applied near-infrared spectroscopy (NIRS) for the simultaneous measurement of forearm blood flow (FBF) and oxygen consumption (VO2) in the human by inducing a 50-mmHg venous occlusion. Eleven healthy subjects were studied both at rest and after hand exercise during vascular occlusion. FBF was also measured by strain-gauge plethysmography. FBF measured by NIRS was 1.9 +/- 0.8 ml.100 ml-1.min-1 at rest and 8.2 +/- 2.9 ml.100 ml-1.min-1 after hand exercise. These values showed a correlation (r = 0.94) with those obtained by the plethysmography. VO2 values were 4.6 +/- 1.3 microM O2 x 100 ml-1.min-1 at rest and 24.9 +/- 11.2 microM O2 x 100 ml-1.min-1 after hand exercise. The scatter of the FBF and VO2 values showed a good correlation between the two variables (r = 0.93). The results demonstrate that NIRS provides the particular advantage of obtaining the contemporary evaluation of blood flow and VO2, allowing correlation of these two variables by a single maneuver without discomfort for the subject.

scholarly journals A comparison of surgical pulmonary embolectomy and catheter-directed lysis for life-threatening pulmonary emboli

2019 ◽  
Vol 30 (3) ◽  
pp. 388-393 ◽  
Author(s):  
Amalia A Winters ◽  
Michael J McDaniel ◽  
Jose N Binongo ◽  
Rena C Moon ◽  
Wissam A Jaber ◽  
...  
Keyword(s):  
Regression Models ◽  
Pulmonary Emboli ◽  
Short Term ◽  
Pulmonary Embolectomy ◽  
Treatment Groups ◽  
Catheter Directed Thrombolysis ◽  
Risk Patients ◽  
Life Threatening ◽  
Rv Function

Abstract OBJECTIVES Patients with life-threatening pulmonary emboli (PE) have traditionally been treated with anticoagulation alone, yet emerging data suggest that more aggressive therapy may improve short-term outcomes. The purpose of this study was to compare postoperative outcomes between catheter-directed thrombolysis (CDL) and surgical pulmonary embolectomy (SPE) in the treatment of life-threatening PE. METHODS A retrospective single-centre observational study was conducted for patients who underwent SPE or CDL at a single US academic centre. Preprocedural and postprocedural echocardiographic data were collected. Unadjusted regression models were constructed to assess the significance of the between-group postoperative differences. RESULTS A total of 126 patients suffered a life-threatening PE during the study period [60 SPE (47.6%), 66 CDL 52.4%]. Ten (24.4%) SPE patients and 10 (15.2%) CDL patients had massive PEs marked by preprocedural hypotension. Six (10.0%) SPE patients and 4 (6.0%) CDL patients suffered a preprocedure cardiac arrest (P = 0.41). In-hospital mortality rate was 3.3% (2) for SPE, and 3.0% (2) for CDL (P = 0.99). SPE patients were more likely to require prolonged ventilation (15.0% vs 1.5%, P = 0.01). No significant differences were found in other major complications. At baseline echocardiography, 76.9% of SPE patients and 56.9% of CDL patients had moderate or severe right ventricular (RV) dysfunction. Both treatment groups showed marked and durable improvement in echocardiographic markers of RV function from baseline at midterm follow-up. CONCLUSIONS Both SPE and CDL can be applied to well-selected high-risk patients with low rates of morbidity and mortality. Further research is necessary to delineate which patients would benefit most from either SPE or CDL following a life-threatening PE.

scholarly journals A comparative study of assessing organic matter decomposition between composting and vermicomposting process

2021 ◽  
Vol 6 (4) ◽  
pp. 768-776
Author(s):  
MZ Rahman ◽  
AKMA Kabir ◽  
MA Hashem ◽  
SMA Islam ◽  
MR Haque ◽  
...  
Keyword(s):  
Organic Matter ◽  
Crude Protein ◽  
Degradation Rate ◽  
Experimental Period ◽  
Ash Content ◽  
Cattle Manure ◽  
Crude Fiber ◽  
Treatment Groups ◽  
Fiber Degradation ◽  
Typical Temperature

The aim of the study was to compare the efficiency of organic matter degradation between composting and vermicomposting as well as the possibility of making compost and vermicompost using cattle manure. The experiment was conducted with two treatments, where one was conventional composting (T1) and another was vermicomposting (T2) from cattle manure. The sample from composted materials was collected at 0, 20, 40 and 60th day of experiment. Parameter studied were dry matter (DM), crude fiber (CF), crude protein (CP), ether extract (EE), ash content of the samples as well as pH and temperature change during the experimental period. Results found that a significant higher DM (P<0.01) was found in T1 compared to T2. The CF degradation rate was significantly higher (P<0.01) in T2 compared to T1 group. The CP content also found significantly higher (P<0.05) in T2 compared to T1 group. There were no significant differences in EE and ash content as well as pH between the treatment groups. A typical temperature curve was found in T1 during active composting phase but the temperature was more or less same in T2 during the whole experimental period. From the experiment, it was found that crude fiber degradation rate is faster and CP content was higher in the T2 compared to T1 that might be indicated that vermicomposting is more beneficial than composting. Asian J. Med. Biol. Res. December 2020, 6(4): 768-776

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