Method of preventing bleeding caused by use of streptokinase in experiment

FIELD: veterinary medicine.

SUBSTANCE: solution is administered intravenously to chinchilla male rabbits one hour prior to surgical interference. The solution is prepared as follows: sterile distilled water for injection is added to the lyophilised fibrin-monomer with urea, so that the resulting solution contains fibrin monomer at a concentration of 11 mg/ml and urea at a concentration of 150 mg/ml, and stirred until complete dissolution of the substance. At that the dose of fibrin-monomer is 0.25 mg/kg.

EFFECT: method is highly effective the prevention of bleeding caused by the use of streptokinase, prior to surgical interferences.

1 ex, 2 dwg

 

The invention relates to medicine, namely to experimental surgery, and can be used for the purpose of prevention of bleeding with the use of streptokinase in the experiment.

Streptokinase is widely used in the treatment of myocardial infarction, pulmonary embolism (Saveliev B. C., Chazov E. I., Gusev E. I., Kirienko A. I., Akchurin R. C, Andriyashkin V. V., Arutyunov G. P., Bitsadze V. O., etc. Russian clinical recommendations for diagnosis, treatment and prevention of venous thromboembolism. Phlebology. 2010; 4(1): 2-37; Torbicki A., A. Perrier, Konstantinides s, Agnelli g, Galie N., Pruszczyk P. et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). European Heart Journal 2008; 29(18): 2276-2315.). According to various studies, one of life-threatening complications during treatment with streptokinase are bleeding at different sites, developing due to excessive activation of plasminogen, the formation of large amount of plasmin, which leads to the disintegration not only of fibrin clots, but the blood coagulation factors-fibrinogen (factor I), factors V and VIII. The frequency of severe bleeding during treatment with streptokinase, according to randomized studies, ranges from 3.5% to 7.2%. (A Prospective Trial of Intravenous Streptokinase in Acute Myocardial Infarction (I. S. A. M.) // New England Journal of Medicine// 1986; 314: 1465-71).

In this�the present time there is no single approach to prevention of bleeding with the use of streptokinase. Existing methods are directed only to the correction of hemostasis in case held the bleeding. Therefore, the search for methods of prevention of bleeding with the use of streptokinase is currently relevant.

The known method of treatment of bleeding caused by the use of streptokinase, through the use of tranexamic acid. Tranexamic acid has the ability to inhibit the activation of plasminogen to plasmin, thus has a hemostatic effect in the activation of the fibrinolytic reactions (Internal (Tranexamic acid): instruction, application, and formula //Code AS 1197-18-8// Register of medicines, radar // 2013). Indications for its use: bleeding or the risk of development against the background of generalized amplification of fibrinolysis (bleeding during surgery and in the postoperative period, postpartum hemorrhage, manual separation of the placenta, chorionic detachment, bleeding in pregnancy, malignant neoplasms pancreatic and prostate cancer, hemophilia, hemorrhagic complications of fibrinolytic therapy, thrombocytopenic purpura, leukemia, liver disease, prior therapy with streptokinase).

In generalized fibrinolysis the drug is administered intravenously in a single dose of 15 mg/kg of body weight every 6-8 hours, speed of 1 m�/min.

When prostatectomy or surgery on the bladder is injected during the operation of 1 g, then 1 g every 8 h for 3 days, and then move inwards until the disappearance of gross hematuria.

At high risk of bleeding, systemic inflammatory response injected dose of 10-11 mg/kg over 20-30 min before the intervention.

However, the use of tranexamic acid is associated with side effects such as rashes, itching, loss of appetite, nausea, diarrhea, heartburn, drowsiness, impaired color vision, seizures and acute renal failure (Montes FR, Pardo DF, Carreno M, With Arciniegas, Dennis RJ, Umana JP // Risk factors associated with postoperative seizures in patients undergoing cardiac surgery who received tranexamic acid: a case-control study. Annals of Cardiac Anaesthtsia. 2012 Jan-Mar; 15(1): 6-12).

In addition, the combined application of tranexamic acid with other hemostatic drugs can activate the coagulation cascade and thrombus formation (Royston D. Tranexamic acid in cardiac surgery: is there a cause for concern?// Critical Care Journal. 2010; 14(5): 194; Sander M, Spies CD, Martiny V, Rosenthal C, Wernecke KD, von Heymann C. Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: a retrospective analysis. Critical Care Journal. 2010; 14(4):R148).

The known method of treatment of bleeding caused during treatment with streptokinase, through the use of Aprotinin. Aprotinin is a polyvalent inhibitor of serine proteases derived from internal�Enni bodies of cattle, inhibiting plasmin is able to reduce the fibrinolytic activity of blood and reduce the severity of bleeding. Bleeding initial dose of 300000 Acre (225564 KIE), the next - 140000 Acre (105263 KIE) every 4 hours by slow intravenous injection.

(Aprotinin (Aprotinin): instruction, application, and formula // Code With AS 9087-70-1 // Register of medicines, radar //2013).

However, the known method has many side effects: myocardial infarction, stroke, anaphylactic shock, acute renal failure, psychotic reactions (Aprotinin (trasylol): possible serious adverse reactions. // Drug safety and pharmacovigilance. - 2011. - No. 3. - P. 29-28; Mouton R, Finch D, Davies I, et al. Effect of aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet 2008; 371:475-482).

The authors offer a safe and effective method of prevention of bleeding caused by the use of streptokinase in the experiment, allowing clinically important to prevent bleeding.

The technical result of the claimed invention is to provide an effective method of prevention of bleeding caused by the use of streptokinase, before surgery.

The technical result is achieved by intravenous injection of a solution of the fibrin-monomer at a dose of 0.25 mg/kg one hour prior to the operational vmichael�STW.

The effectiveness of the proposed method is confirmed by figures 1 and 2 in the form of tables.

Figure 1 shows the selection of an effective and safe dose fibrin-monomer.

Figure 2 illustrates the indicators of bleeding in animals of control and test groups.

In the figures 1 and 2 are given the following notation:

1.where- sample mean; m - standard error of the sample mean.

2. The volume of blood loss (%of volume of circulating blood - BCC) is a part of blood lost from the total circulating volume (CBV), expressed as a percentage.

3. The concentration of D-dimers (ng/ml) - the content of degradation products of stabilized fibrin in the blood plasma, which are the markers of formation of fibrin and its dissolution under the action of plasmin.

4. The rate of bleeding (mg/s) is the volume of blood loss (in mg) per minute (C).

5. p - level of statistical significance of differences compared parameters.

6. n - number of animals in the group. The method is as follows.

In the experiment used male rabbits breed "Chinchilla" average weight 2-4 kg.

To prevent bleeding, use a derived fibrinogen from human blood plasma - fibrin-monomer (LLC firm "Technology Standard"), which is a freeze-dried soluble� white powder with urea, packaged in penicillin vial, closed with a rubber stopper and compressed aluminum cap, in the amount of 22 mg in vial. The solution is prepared as follows: a vial of freeze-dried fibrin monomer with urea was added 2 ml of sterile distilled water for injection, stirred neat rocking without the formation of foam to dissolve substances within 2-3 minutes. The resulting solution contained a fibrin-monomer at a concentration of 11 mg/ml and urea at a concentration of 150 mg/ml.

As a control, placebo - urea solution not containing the active substance fibrin-monomer at a concentration of 150 mg/kg. Into the vial with freeze-dried urea was added 2 ml of sterile distilled water for injection, stirred neat shake until dissolved substances within 2-3 minutes.

The most effective dosage fibrin-monomer was chosen experimentally. In the experiment we used 68 male rabbits. All animals were divided into 7 groups. Dose fibrin-monomer was selected from the range of dosages from 0.1 mg/kg to 5.0 mg/kg of body weight. The data is confirmed by figure 1.

Experimental design

The first group consisted of 8 animals who received intravenous placebo was administered in a volume of 0.5 ml. After one hour after administration of placebo solution take�and blood sampling from the edge of the ear vein for measuring the concentration of D-dimer in plasma. Described that the increase in the concentration of D-dimers in plasma is accompanied by venous thrombosis and pulmonary embolism (Saveliev B. C., Chazov E. I., Gusev E. I., Kirienko A. I., Russian clinical recommendations for diagnosis, treatment and prevention of venous thromboembolism // Phlebology. - 2010. - Vol. 4, No. 1, issue 2. - P. 2-37). After that, animals were anesthetized and they performed a median laparotomy the white line of the abdomen under General anesthesia. In the wound and removed the left lobe of the liver and the diaphragmatic surface applied standard in size and depth of the injury using a special device-limiter (metal plate with a round hole in the center). Cut the segment in a vertical projection had the appearance of a circle or ellipse, its size and shape were constant (Manual on experimental (preclinical) study of new pharmacological substances / under the editorship of R. J. overall mechanism. - 2 ed. revised and enlarged extra - M.: JSC "Publishing house "Medicine", 2005. - 828 S.). Formed bleeding wound with smooth edges and a uniform curvature with a diameter of about 1.5 cm, a depth of about 0.5 cm After applying standard injury measured volume of blood loss. This indicator was measured by promotivni preweighed dry sterile wipes the blood from the wound the liver to the full OST�setups bleeding with the formation of a stable clot. Tissues were weighed on an electronic balance immediately after promisiunea. The weight of all the napkins summarized and accommodate the volume of blood lost. Blood loss volume was calculated as percentage of the total circulating volume.

The second group consisted of 9 animals, which were injected intravenously fibrin-monomer at a dose of 0.1 mg/kg.

The third group consisted of 11 animals, which were injected intravenously fibrin-monomer at a dose of 0.25 mg/kg.

The fourth group consisted of 10 animals, which were injected intravenously fibrin-monomer at a dose of 0.5 mg/kg.

The fifth group consisted of 10 animals, which were injected intravenously fibrin-monomer at a dose of 1.0 mg/kg.

The sixth group consisted of 11 animals, which were injected intravenously injected fibrin-monomer at a dose of 2.5 mg/kg.

The seventh group consisted of 9 animals, which were injected intravenously fibrin-monomer at a dose of 5.0 mg/kg.

One hour after injection of a solution of the fibrin-monomer in animals from each group underwent blood sampling from the edge of the ear vein for measuring the concentration of D-dimer in plasma. After that, animals were anesthetized and they performed a median laparotomy the white line of the abdomen under General anesthesia with liver injury and determine the amount of blood loss as described above.

As can be seen from figure 1, the most effective doses of fibrin-monomer for statistically significant�CSOs reduce blood loss are 0.25 mg/kg and 2.5 mg/kg. At the same time dose fibrin-monomer above 1.0 mg/kg have significant thrombogenicity, which was estimated from the increase in the concentration of D-dimers in plasma, which is a classical marker of fibrinopeptide and fibrinolysis. Thus as the most effective and safe for further experiments was determined by the dose fibrin-monomer 0.25 mg/kg.

To investigate the efficacy of the proposed method, all the animals were divided into two groups. The first group of animals control (n=12; received intravenous streptokinase and placebo. The second group of animals - experienced (n=8) received intravenous streptokinase and fibrin-monomer.

Experimental design

1. Control group: Before the introduction of streptokinase is performed blood sampling from the edge of the ear vein (Manual on experimental (preclinical) study of new pharmacological substances. Ed. by R. Y. overall mechanism, 2nd ed., revised and enlarged extra-M.: JSC "Publishing house "Medicine", 2005, 828 S.) to study the initial indicators of hemostasis system. The drug streptokinase is administered intravenously at a dose of 10,000 IU/kg for 5 minutes. Further, over 1 hour by intravenous administration of a placebo solution at a dose of 0.5 ml. Exposure 1 hour. Thereafter repeated blood sampling for analysis of indicators of hemostasis system.

After blood collection the animals drug�iroute, and they performed a median laparotomy the white line of the abdomen under General anesthesia. In the wound appears, the left lobe of the liver and the diaphragmatic surface applied standard in size and depth of the injury using a special device-limiter (metal plate with a round hole in the center). Cut the segment in a vertical projection had the appearance of a circle or ellipse, its size and shape were constant (Manual on experimental (preclinical) study of new pharmacological substances. Ed. by R. Y. overall mechanism, 2nd ed., revised and enlarged extra-M.: JSC "Publishing house "Medicine", 2005, 828 S.). Formed bleeding wound with smooth edges and a uniform curvature with a diameter of about 1.5 cm, a depth of about 0.5 cm.

After applying standard injury measured volume of blood loss. This rate is determined by promotivni preweighed dry sterile wipes the blood from the wound to the liver to stop the bleeding with the formation of a stable clot. Wipes are weighed on an electronic balance immediately after promisiunea. The weight of the stack of napkins, and considering the amount of blood lost. The volume of blood loss is calculated as percentage of the total circulating volume.

2. Experimental group: Before the introduction of streptokinase is the blood from CRA�howl vein of the ear (Manual on experimental (preclinical) study of new pharmacological substances. Ed. by R. Y. overall mechanism, 2nd ed., revised and enlarged extra-M.: JSC "Publishing house "Medicine", 2005, 828 S.) to study the initial indicators of hemostasis system.

The drug streptokinase is administered intravenously at a dose of 10,000 IU/kg for 5 minutes. Further, over 1 hour by intravenous administration of the drug fibrin monomer in a dosage of 0.25 mg/kg Exposure 1 hours. Thereafter repeated blood sampling for analysis of indicators of hemostasis system.

After blood collection the animals narcotized and midline laparotomy is performed along the white line of the abdomen under General anesthesia. In the wound appears, the left lobe of the liver and the diaphragmatic surface applied standard in size and depth of the injury using a special device-limiter (metal plate with a round hole in the center). Cut the segment in a vertical projection had the appearance of a circle or ellipse, its size and shape were constant (Manual on experimental (preclinical) study of new pharmacological substances. Ed. by R. Y. overall mechanism, 2nd ed., revised and enlarged extra-M.: JSC "Publishing house "Medicine", 2005, 828 S.). Formed bleeding wound with smooth edges and a uniform curvature with a diameter of about 1.5 cm, a depth of about 0.5 cm.

After applying standard injury measured volume of blood loss. This figure is opredelaetsa� by promotivni preweighed dry sterile wipes the blood from the wound of the liver, to stop the bleeding with the formation of a stable clot. Wipes are weighed on an electronic balance immediately after promisiunea. The weight of the stack of napkins and considering the amount of blood lost. The volume of blood loss is calculated as percentage of the total circulating volume.

The method is illustrated by figure 2, which shows the comparative data of the volume of blood loss (%BV), bleeding time, rate of bleeding, allowing to demonstrate the effectiveness of the proposed method.

Figure 2 shows that the volume of blood loss (%BV) in the experimental group compared to the control group in 9,87 times. Bleeding time in experimental group less than the control group at 2.48 times the rate of bleeding is less than in the control group at 3.88 times.

In addition, the hemostatic effect of the drug fibrin monomer was not accompanied by increased fibrinopeptide and the danger of the formation of thrombosis, which is indicated by the lack of increase in the level of D-dimers in plasma.

The study shows that the use of the drug fibrin-monomer in the background prior to the introduction of streptokinase is an effective way to prevent bleeding. The inventive method leads to a significant reduction in volume, tempo and time cu�bootery in experiment animals, but it does not increase the likelihood of intravascular thrombosis.

The proposed method will find wide application in practical medicine.

Method of prevention of bleeding caused by the use of streptokinase in the experiment, namely that the rabbits male breed chinchilla one hour prior to surgery intravenous solution, which is prepared as follows: in freeze-dried fibrin-monomer with urea added sterile distilled water for injection so that the resulting solution contained a fibrin-monomer at a concentration of 11 mg/ml and urea at a concentration of 150 mg/ml, and was stirred until complete dissolution of the substance, the dose fibrin-monomer is 0.25 mg/kg.



 

Same patents:

FIELD: veterinary medicine.

SUBSTANCE: solution is administered intravenously to chinchilla male rabbits one hour prior to surgical interference. The solution is prepared as follows: sterile distilled water for injections is added to lyophilised fibrin-monomer with urea, so that the resulting solution contains fibrin-monomer at a concentration of 11 mg/ml and the urea at a concentration of 150 mg/ml, and stirred until complete dissolution of the substance. The dose of fibrin-monomer is 0.25 mg/kg.

EFFECT: method is highly effective for prevention of bleeding caused by the use of dabigatran etexilate in the experiment.

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Biogel // 2503464

FIELD: medicine, pharmaceutics.

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EFFECT: using the declared invention enables preparing the agents requiring no toxic reagents to be used, have a minimal risk of allergic reactions, and are easy to prepare and use.

2 tbl, 4 dwg, 5 ex

FIELD: medicine.

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EFFECT: invention enables fixing the cell suspension reliably on the burn wound surface with using no minor chemical elements and additives when processing the cell material.

1 ex

FIELD: medicine.

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1 ex

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1 tbl, 3 ex

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EFFECT: increased accessibility and reduced expenses on utilized thrombin-like enzyme, increased plasminogen-stimulating effect of de-AA fibrin monomer.

3 dwg, 6 ex

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