Method of prevention of bleeding caused by use of dabigatran etexilate 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 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.

2 dwg, 1 ex

 

The invention relates to medicine, namely to experimental surgery, and can be used for prevention of bleeding with the use of anticoagulant dabigatran of etexilate.

Anticoagulants are widely used in patients with cardiac and surgical patients for the prevention or treatment of thrombosis. However, their use entails the risk of possible complications such as bleeding (Saveliev, B. C. Russian clinical recommendations for diagnosis, treatment and prevention of venous thromboembolism. / I. S. Savel'ev, E. I. Chazov, E. I. Gusev, A. I. Kirienko, etc. / / Phlebology. - 2010. - T. 4. - No. 1. - Vol.2. - P. 2-37).

For the purpose of prevention of thromboembolic complications in patients with atrial fibrillation and orthopedic surgery used oral anticoagulant dabigatran etexilate (Diagnosis and treatment of atrial fibrillation: rivers. RKO, UNOA and ASH. M - 2012. - 112 p.; Momot, A. P. Thromboprophylactic the enoxaparin and dabigatran after hip replacement surgery. / A. P. Momot, V. I. Merkulov, E. V. Grigorieva and others // Bulletin of traumatology and orthopedics. N. And. Priorov. - 2011. - No. 2. - P. 67-70). However, despite the efficiency of its use is unsafe because a side effect in patients receiving dabigatran of etexilate are bleeding.

Currently in�time there is no way of prevention of bleeding caused by the use of dabigatran etexilate. Specific antidote to dabigatran etexilate missing, as indicated not only publication in this area (Siegal, D. M. Reversal of novel oral anticoagulants in patients with major bleeding. / D. M. Siegal, A. Cuker // J. Thromb Thrombolysis. [Electronic resource] - 2013. - Vol.35, N 3. - P. 391-398. - Access mode: http://http://www.ncbi.nlm.nih.gov/pubmed?term=Cuker%20A[Author]&cauthor=true&cauthor_uid=23389753), but the manufacturer of this drug (instructions for use of the drug, registration number LSR-007065/09; registration date: 07.09.09).

From domestic and foreign sources not found an effective method of prevention of bleeding caused by the use of dabigatran etexilate.

A method of reducing bleeding after administration of dabigatran etexilate through the use of fresh frozen plasma (Abraham, N. S. Novel anticoagulants: bleeding risk and management strategies. / N. S. Abraham, D. L. Castillo // Curr Opin Gastroenterol. [Electronic resource] - 2013. - Vol.29, N 6. - P. 676-683. - Access mode: http://www.ncbi.nlm.nih.gov/pubmed/24100724), which contains the entire complex of the participants of the blood coagulation system, physiological anticoagulants and fibrinolytic reactions.

However, fresh frozen plasma has low efficiency for bleeding associated with dabigatran of etexilate (Akwaa, F. Treatment of bleeding complications when using oral anticoagulants for prevention of strokes. / F. Akwaa, A. C. Spyropoulos // Curr Treat Options Cardiovasc [�electronic resource] - 2013. - Vol.15, N 3. - P. 288-298. - Access mode: http://www.ncbi.nlm.nih.gov/pubmed/23494907), and its use carries a risk of infectious complications, allergic reactions, immunosuppression (Koloskov, A. V. Modern concepts of the indications for transfusion of fresh frozen plasma. / V. A. Koloskov // Hematology and Transfusiology. - 2005. - No. 6. - P. 41-45).

The known method of correction of hemorrhagic complications after administration of dabigatran etexilate by applying anti-inhibitor coagulant complex (Feiba), consisting of four vitamin K-dependent coagulation factors II, VIIa, IX, X (Leong San Tong Khoo, T. L. The use of FEIBA® in the correction of coagulation abnormalities induced by dabigatran. / T. L. Leong San Tong Khoo, C. Weatherburn, G., Kershaw, C. J. Reddel, J. Curnow, S. Dunkley // Int J Lab Hematol. [Electronic resource] - 2013. - Vol.35, 35 N. - P. 222-224. - Access mode: http://www.ncbi.nlm.nih.gov/pubmed/23020832).

However, the known method is ineffective, as there are no clinically meaningful to stop the bleeding caused by the intake of dabigatran etexilate (Akwaa, F. Treatment of bleeding complications when using oral anticoagulants for prevention of strokes. / F. Akwaa, A. C. Spyropoulos // Curr Treat Options Cardiovasc [Electronic resource] - 2013. - Vol.15, N 3. - P. 288-298. - Access mode: http://www.ncbi.nlm.nih.gov/pubmed/23494907). Furthermore, the use of anti-inhibitor coagulant complex (Feiba) associated with a high risk of thrombosis (K. Tomokiyo, Y. Nakatomi, T. Araki, K. Teshima, N. Nakano, T. Nakagaki, S. Miyamoto, A. Funatsu, S. Iwanaga // Vox Sang [Electronic resource] - 2003. - Vol85, # 4. - P. 290-299. - Access mode: http://www.ncbi.nlm.nih.gov/pubmed/14633255; instruction on the use of drugs, registration number P # 013644/01 registration date: 04.05.08).

The authors offer a safe and effective method of prevention of bleeding caused by the use of dabigatran etexilate, 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 dabigatran etexilate 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 surgical intervention.

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

Fig.1 presents a selection of effective and safe dose fibrin-monomer.

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

Fig.1 and 2 are given the following notation:

1.X±mwhereX- sample mean; m - standard error� sample mean.

2. The volume of blood loss (%BV) - the 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. APTT (seconds) - activated partial thromboplastin time.

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" weighing 2-4 kg. For the prevention of 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 vial, which is prepared as follows: a vial of freeze-dried fibrin monomer with urea was added 2 ml of sterile distilled water for injection, was stirred in neat rocking without the formation of foam to dissolve substances within 2-3 minutes. The resulting solution contained FIB�in the monomer at a concentration of 11 mg/ml and urea at a concentration of 150 mg/ml.

As control was used a solution of placebo - urea solution in a concentration of 150 mg/ml, containing no active substance is a fibrin-monomer. A vial of freeze-dried urea solution 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. The experiment 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 Fig.1.

Scheme of the experiment.

The first group consisted of 8 animals who received intravenous placebo was administered in a volume of 0.5 ml. one hour after injection of the placebo solution was performed 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 liparoto�Oia on 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. / Ed. by R. Y. 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 to the liver to stop the 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-monomial�R 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 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 in Fig.1, the most effective doses of fibrin-monomer for a statistically significant reduction of blood loss are 0.25 mg/kg and 2.5 mg/kg (p<0.001 in both cases). 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 chosen dose fibrin-monomer,25 mg/kg.

To investigate the efficacy of the proposed method, all the animals were divided into two groups: the first group - the control group consisting of 10 animals, received dabigatran etexilate and placebo; the second group, consisting of 12 animals, received dabigatran etexilate and the fibrin monomer.

Scheme of the experiment.

1. Two days before the experiment, the control group of animals of the edge of the ear vein was taking blood (Manual on experimental (preclinical) study of new pharmacological substances. / Ed. by R. Y. overall mechanism. - 2 ed. revised and enlarged extra - M.: JSC "Publishing house Medicine", 2005. - 828 S.) to study the initial indicators of hemostasis system. The most sensitive tests of coagulation by the action of dabigatran etexilate are: activated partial thromboplastin clotting time, thrombin clotting time and ehitatava clotting time (Momot A. P. monitoring of the use of dabigatran as a means of prevention of thromboembolic complications after hip arthroplasty. / A. P. Momot, E. V. Grigoriev, L. P. Ryvkina // Clinical laboratory diagnostics: Scientific and practical journal. - 2012. - No. 5. - Pp. 40-42. - ISSN 0869-2084). On the day of the experiment animals of the control group was administered enterally dabigatran etexilate at a dose of 15-20 mg per kg of body weight. This dose� of the drug were greater than five times the average therapeutic dose for therapeutic use in humans (Pradax (Pradaxa), Boehringer Ingelheim Pharma GmbH & Co. KG, Germany, registration number: LSR-007065/09 from 07.09.09). Two hours was performed blood sampling from the edge of the ear vein for evaluation of the hemostatic system.

After blood immediately intravenous placebo was administered in a volume of 0.5 ml. one hour after injection of a solution placebo 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. / 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 indicator was measured 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.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.

2. Two days before the experiment, the animals of the experimental group from the edge of the ear vein was taking blood (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.

On the day of experiment the animals of the experimental group was administered enterally dabigatran etexilate at a dose of 15-20 mg per kg of body weight. This dose was five times greater than average therapeutic dose for therapeutic use in humans (Pradax (Pradaxa), Boehringer Ingelheim Pharma GmbH & Co. KG, Germany, registration number: LSR-007065/09 from 07.09.09). Two hours was performed blood sampling from the edge of the ear vein for evaluation of the hemostatic system.

After blood was intravenously administered immediately fibrin-monomer at a dose of 0.25 mg/kg one hour after injection of a solution of the fibrin-monomer 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 injury with a special propose�tion-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 indicator was measured 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. 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 effectiveness of the proposed method is illustrated by Fig.2, in which the comparison of the data volume of blood loss, the concentration of D-dimers and the hemostatic system, which allows to demonstrate the effectiveness of the proposed method. As can be seen from the table of Fig.2, the volume of blood loss (%of volume of circulating blood) in the experimental group compared with the control was lower by 2.3 times (p<0.01).

Submitted by d�NYM comparing indices of hemostasis in both groups of animals demonstrated the effect of dabigatran etexilate in the form of a sharp elongation of activated partial thromboplastin time, thrombin time and chitokoloki clotting time, which corresponded to the previously described changes in the hemostatic system of the human blood plasma (Momot A. P. monitoring of the use of dabigatran as a means of prevention of thromboembolic complications after hip arthroplasty. / A. P. Momot, E. V. Grigoriev, L. P. Ryvkina // Clinical laboratory diagnostics: Scientific and practical journal. - 2012. - No. 5. - Pp. 40-42. - ISSN 0869-2084).

Thus, the claimed method is highly effective, as it not only reduces the amount of blood loss, but does not increase the likelihood of thrombosis.

Method of prevention of bleeding caused by the use of dabigatran etexilate, 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 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.



 

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23 cl, 5 ex, 8 tbl, 3 dwg

FIELD: analytical methods in medicine.

SUBSTANCE: invention relates to use of fibrin monomer to determine tissue activator of plasminogen and/or its inhibitor. Method consists in treatment of fibrinogen with thrombin-like enzyme ancistron isolated from poison of snake Agkistrodon halys inhabiting Russian Federation areas followed by dissolution of resulting crosslinked fibrin via dialysis against 0.001 N HCl to give transparent solution containing purified de-AA fibrin monomer.

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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