Administration Of Protamine Sulfate Research Articles

Heparin reversal with protamine sulfate after Percutaneous Hepatic Perfusion (PHP): is less more?

PurposePercutaneous hepatic perfusion (PHP) is a palliative intraarterial therapy for unresectable hepatic malignancies. During PHP, high-dose melphalan is infused via the hepatic artery to saturate tumor in the liver with the chemotherapeutic substance. The venous hepatic blood is filtered by an extracorporeal melphalan specific filtration system. Blood clotting in the extracorporeal filter system is prevented by administering unfractionated heparin (UFH) in high doses, which might be reversed with protamine sulfate after the procedure. Aim of this retrospective two-center-study was to analyze the potential effect of UFH reversal with protamine sulfate on complication rates following PHP.Materials and methodsAll patients receiving PHP treatment between 10/2014 and 04/2021 were classified according to their intraprocedural coagulation management: 92 patients/192 PHP received full UFH reversal with protamine (groupPROTAMINE); 13 patients/21 PHP in groupREDUCED_PROTAMINE received a reduced amount of protamine, and 28 patients/43 PHP did not receive UFH reversal with protamine (groupNO_PROTAMINE). Periinterventional clinical reports, findings and laboratory values were retrospectively evaluated. Complications and adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAEv5.0).ResultsThromboembolic events were recorded after 10 PHP procedures (5%) in groupPROTAMINE, six of which (3%) were major events (CTCAE grade 3-5). No (0%) thromboembolic events were recorded in groupREDUCED_PROTAMINE and groupNO_PROTAMINE. Hemorrhagic events were registered after 24 PHP (13%) in groupPROTAMINE, two of which (1%) were major (CTCAE grade 3-4). In groupREDUCED_PROTAMINE, only minor bleeding events were recorded, and one major hemorrhagic event was documented in groupNO_PROTAMINE (2%). There was a significant difference between the percentage of post-interventional thrombopenia in groupPROTAMINE (39%) and groupREDUCED_PROTAMINE (14%) versus groupNO_PROTAMINE (23%) (p=.00024). In groupPROTAMINE one patient suffered from a severe anaphylactic shock after the administration of protamine.ConclusionOur retrospective study implies that there might be a link between the practice of protamine sulfate administration to reverse the full hemodilutive effect of UFH after PHP and the post-interventional risk of thromboembolic events as well as clinically significant thrombopenia. Our data suggest that the standard use of protamine sulfate after PHP in low-risk patients without clinical signs of active bleeding should be critically re-evaluated.

Hypoglycemic and hypolipidemic effect of pentaamino acid fullerene C60 derivative in rats with metabolic disorder.

Pentaamino acid fullerene C60 derivative is a promising nanomaterial, which exhibited antihyperglycemic activity in high-fat diet and streptozotocin-induced diabetic rats. This study investigates the effect of pentaaminoacid C60 derivative (PFD) in rats with metabolic disorders. Rats were assigned to 3 groups (of 10 rats each) as follows: Group 1 (normal control), group 2 included the protamine-sulfate-treated rats (the untreated group of animals with the model metabolic disorder); group 3 (Protamine sulfate + PFD) included the protamine-sulfate-treated model rats that received an intraperitoneal injection of PFD. Metabolic disorder in rats was initiated by protamine sulfate (PS) administration. The PS + PFD group was injected intraperitoneally with PFD solution (3mg/kg). Protamine sulfate induces biochemical changes (hyperglycemia, hypercholesterolemia, and hypertriglyceridemia) in the blood and morphological lesions in rat liver and pancreas. The potassium salt of fullerenylpenta-N-dihydroxytyrosine in protamine sulfate-induced rats normalized blood glucose level and the serum lipid profile and improved hepatic function markers. Treatment with PFD restored pancreas islets and liver structure of protamine sulfate-induced rats compared to the untreated group. PFD is a promising compound for further study as a drug against metabolic disorders.

Features of the Blood Supply of Cardiac Myxoma which Can Cause Bleeding

With a mortality rate of 1 % to 5 %, surgical treatment of cardiac myxomas (CM) may be complicated by the development of intra- or postoperative bleeding, among other things.
 The aim. To present an unusual case of surgical treatment of left atrial myxoma with the occurrence of intraoperative bleeding, which was due to extremely rare features of the coronary circulation with a special blood supply to the base of the CM.
 Case report. Female patient R., 65 years old, case record No.3686, was admitted to the National Amosov Institute of Cardiovascular Surgery of the National Academy of Medical Sciences of Ukraine with diagnosis of CM. Coronary angiography revealed unique features of coronary circulation: an arteriovenous malformation from the distal parts of the circumflex branch of the left coronary artery with discharge into the right parts of the heart was revealed. On 9/20/2022, urgent operation of resection of the myxoma of the left atrium (LA) was performed. After removal of the myxoma and sealing of the heart, accumulation of arterial blood was found in the area of the inferior vena cava (IVC) and the interatrialsulcus. Revision of the left atrium cavity was performed again:all intracardiac sutures in the area of the myxoma base were duplicated. After repeated resealing of the heart chambers, bleeding from the IVC region stopped after administration of protamine sulfate and tight tamponade of the space under the IVC. Tampons were removed from the pericardial cavity after 72 hours.
 Results. The source of the bleeding could be the site of the malformation of the coronary arteries, which is a tangle of small vessels located in the projection of the base of the myxoma below the point where the IVC meets the right atrium. During the histological examination of the myxoma, large full-blood vessels of the sinusoidal type were revealed, around which, due to damage to their thin walls, hematomas formed, giving the tumor a spotted appearance. The peculiarity of this tumor was the presence of a very large vascular plexus at its base; it had the appearance of a cluster of sections of numerous, different-sized, deformed and remodeled arteries. These data were confirmed by coronary angiography.
 Conclusions. Studying the data of coronary angiography with the analysis offeatures of localization of coronary arteries, as well as the presence of possible coronary malformations, can provide information that allows predicting the possibility of their damage, especially in the case of localization in the place of possible surgical manipulation. In the event of bleeding, one of the optimal methods of its elimination is the use of long-term tamponade.

Correlations between the Circulating Level of Cell-Derived Microparticles and Surgical Variables in Heart Valve Surgery with Cardiopulmonary Bypass.

Cell-derived microparticles (MPs) as membrane vesicles are procoagulant. They play a role in surgical hemostasis. In this study, the correlations between the circulating level of cell-derived MPs and surgical variables in heart valve surgery were investigated. The present prospective case-series study was conducted in Rajaie Cardiovascular Medical and Research Center from January through March 2021. Forty patients undergoing heart valve surgery with cardiopulmonary bypass (CPB) were enrolled. Before the induction of anesthesia and 30 minutes after the administration of protamine sulfate, venous blood samples were collected. After MP isolation, the concentration of MPs was determined via the Bradford method. Flow cytometry analysis was performed to determine the MP count and phenotype. Intraoperative variables and postoperative routine coagulation tests were defined as surgical variables. Postoperative coagulopathy was defined as an activated partial thromboplastin time (aPTT) ≥48 seconds or an international normalized ratio (INR) >1.5. The total concentration of MPs and the MP count increased significantly after surgery compared with before surgery. The postoperative concentration of MPs was positively correlated with the CPB time (P=0.030, ρ=0.40). The preoperative concentration of MPs was significantly lower in patients with higher postoperative aPTT and INR (P=0.003, P= -0.50 and P=0.020, P= -0.40, respectively). In multivariate logistic regression analysis, the preoperative MP concentration (OR, 1.00; 95% CI, 1.00 to 1.01; P=0.017) was considered a risk factor for postoperative coagulopathy. The levels of MPs, especially platelet-derived MPs, rose after surgery, in correlation with the CPB time. Given the role of MPs in the induction of coagulation and inflammation, they can be considered therapeutic goals for preventing postoperative complications. In addition, the preoperative levels of MPs are a risk factor for predicting the occurrence of postoperative coagulopathy in heart valve surgery.

Evaluation of the Preventive Effect of Protamine Sulfate Administration after Heart Surgery on Drainage of Blood Secretions

Evaluation of the Preventive Effect of Protamine Sulfate Administration after Heart Surgery on Drainage of Blood Secretions

Transbrachial Secondary Vascular Access in Transcatheter Aortic Valve Replacement Procedures: A Single-Centre Retrospective Analysis

Transfemoral transcatheter aortic valve replacement (TAVR) procedures require secondary vascular access for inserting accessory catheters and performing percutaneous repair of femoral artery injury. Use of the transbrachial approach for secondary vascular access in TAVR procedures has not been reported. This study identified 48 patients at the current institution who had undergone transfemoral TAVR utilising transbrachial secondary vascular access. Efficacy and safety of this strategy for achieving a successful totally percutaneous procedure were examined. Study endpoints were occurrence of vascular complications and bleeding related to transbrachial access, as well as periprocedural and 1-year mortality. Mean patient age was 80±7 years and Society of Thoracic Surgeons Predicted Risk of Mortality score was 10.6±3.1. Sizes of sheaths inserted into the brachial artery were 6 Fr (85%), 8 Fr (2%), and 9 Fr (13%). Transbrachial access was used for delivering stent grafts to the femoral artery in 13% of the patients, inflation of an occlusive balloon within the iliac artery in 10%, and treatment of iatrogenic femoral artery stenosis in 2%. Successful valve replacement was achieved in all cases. Brachial sheaths were removed by manual compression following administration of protamine sulfate. There were no major access site complications or VARC-3 type ≥2 bleeding related to the brachial vascular access. Brachial artery occlusion occurred in two patients (4%) who underwent surgical vascular repair. Two (2) additional patients developed mild arm ischaemia, which was treated conservatively. Periprocedural mortality was 0% and early mortality was 8%. Transbrachial secondary access in TAVR procedures was feasible and enabled percutaneous vascular repair in cases of femoral artery injury.

Combining Heparin and a FX/Xa Aptamer to Reduce Thrombin Generation in Cardiopulmonary Bypass and COVID-19.

Known limitations of unfractionated heparin (UFH) have encouraged the evaluation of anticoagulant aptamers as alternatives to UFH in highly procoagulant settings such as cardiopulmonary bypass (CPB). Despite progress, these efforts have not been totally successful. We take a different approach and explore whether properties of an anticoagulant aptamer can complement UFH, rather than replace it, to address shortcomings with UFH use. Combining RNA aptamer 11F7t, which targets factor X/Xa, with UFH (or low molecular weight heparin) yields a significantly enhanced anticoagulant cocktail effective in normal and COVID-19 patient blood. This aptamer-UFH combination (1) supports continuous circulation of human blood through an ex vivo membrane oxygenation circuit, as is required for patients undergoing CPB and COVID-19 patients requiring extracorporeal membrane oxygenation, (2) allows for a reduced level of UFH to be employed, (3) more effectively limits thrombin generation compared to UFH alone, and (4) is rapidly reversed by the administration of protamine sulfate, the standard treatment for reversing UFH clinically following CPB. Thus, the combination of factor X/Xa aptamer and UFH has significantly improved anticoagulant properties compared to UFH alone and underscores the potential of RNA aptamers to improve medical management of acute care patients requiring potent yet rapidly reversible anticoagulation.

Reversal Activity and Toxicity of Heparin-Binding Copolymer after Subcutaneous Administration of Enoxaparin in Mice.

Uncontrolled bleeding after enoxaparin (ENX) is rare but may be life-threatening. The only registered antidote for ENX, protamine sulfate (PS), has 60% efficacy and can cause severe adverse side effects. We developed a diblock copolymer, heparin-binding copolymer (HBC), that reverses intravenously administered heparins. Here, we focused on the HBC inhibitory activity against subcutaneously administered ENX in healthy mice. BALB/c mice were subcutaneously injected with ENX at the dose of 5 mg/kg. After 110 min, vehicle, HBC (6.25 and 12.5 mg/kg), or PS (5 and 10 mg/kg) were administered into the tail vein. The blood was collected after 3, 10, 60, 120, 360, and 600 min after vehicle, HBC, or PS administration. The activities of antifactors Xa and IIa and biochemical parameters were measured. The main organs were collected for histological analysis. HBC at the lower dose reversed the effect of ENX on antifactor Xa activity for 10 min after antidote administration, whereas at the higher dose, HBC reversed the effect on antifactor Xa activity throughout the course of the experiment. Both doses of HBC completely reversed the effect of ENX on antifactor IIa activity. PS did not reverse antifactor Xa activity and partially reversed antifactor IIa activity. HBC modulated biochemical parameters. Histopathological analysis showed changes in the liver, lungs, and spleen of mice treated with HBC and in the lungs and heart of mice treated with PS. HBC administered in an appropriate dose might be an efficient substitute for PS to reverse significantly increased anticoagulant activity that may be connected with major bleeding in patients receiving ENX subcutaneously.

Protamine sulfate duringtranscatheter aortic valve implantation(PS TAVI) - asingle-center, single-blind, randomized placebo-controlled trial.

Bleeding complications after transcatheter aortic valve implantation (TAVI) negatively affect the post-procedural prognosis. Routine use of protamine sulfate (PS) to reverse unfractionated heparin after TAVI was never assessed in a randomized controlled trial. The aim of this study was to assess the impact of PS on bleeding complications after TAVI. Between December 2016 and July 2020 311 patients qualified to TAVI in one academic center were screened. Patients that met the inclusion criteria were randomized to either PS or normal saline administration at the moment of optimal valve deployment. Baseline, procedural, and follow-up data for up to 30 days were collected and analyzed. The primary endpoint (PE) was a composite of life-threatening and major bleeding according to Valve Academic Research Consortium within 48 hours after the procedure. Overall, 100 patients (48 males, median age 82 years) met the inclusion criteria and were included in the study. Forty-seven subjects (47%) were randomized to PS. The primary endpoint occurred in 29% of the study population. Despite numerically lower rates of PE in patients randomized to PS, a statistical significance was not reached (21% in the PS group and 36% in the placebo group; odds ratio [OR], 0.48; 95% confidence intervals [CI] 0.2-1.2; P = 0.11). There were no significant differences in secondary endpoints. Routine protamine sulfate administration did not significantly decrease the rate of major and life-threatening bleeding complications after TAVI. Larger studies are required to assess the impact of routine PS use.

The role of hydrocortisone pre-treatment in decreasing side effects of protamine sulfate administration during cardiac surgery: a randomised controlled trial

BackgroundOne of the challenges during cardiac surgery is to keep patients fully anticoagulated during the cardiopulmonary bypass time and reversing anticoagulation at the end of surgery. For that purpose, heparin and its approved reversal agent, protamine sulfate have been widely used. Protamine sulfate is known to have side effects which can be life-threatening including anaphylaxis, which can affect the outcome for the entire procedure. In this randomized control study, we investigated the effect of using hydrocortisone pre-treatment to decrease the side effects of protamine sulfate. The primary hypothesis was that patients pre-treated with hydrocortisone would have less variation in intraoperative hemodynamic parameters. MethodsIn this parallel group, randomized, controlled trial with 1:1 allocation ratio, we compared the hemodynamic parameters in patients who had cardiac surgery using cardiopulmonary bypass from July 2019 to April 2020. The study allocated patients into two groups. The intervention group included patients who received hydrocortisone before giving protamine sulfate and the control group received normal saline. ResultsNo clinically significant differences were reported between basic characteristics of the two groups. In the intervention group, mean reduction of systolic blood pressure was 6.2 mmHg (±2.6) while it was 14.5 mmHg (± 3.7) for control group, P<0.01, Cohen's effect size (d) = 2.61 (95% CI: 2.23-2.99). Mean reduction in diastolic blood pressure where 5.7 mmHg (±3.5) in the intervention group and 11.2 mmHg (±3.1) in the control group, P<0.01, d= 1.64 (95% CI: 1.32-1.97). Means for mean arterial blood pressure were decreased by 5.9 mmHg (± 2.9) in the intervention group and 12.3 mmHg (± 2.9) in the control group, respectively, P<0.01, d=2.18 (95% CI: 1.83-2.53). Heart rate increased in the control group, mean increase being 15.4 bpm (± 5.5), more than in the intervention group 10.7 bpm (± 3.2), P<0.01, d=1.05 (95% CI: 0.75-1.34). No side effects were reported during the intraoperative procedure. ConclusionHydrocortisone can be used effectively as a prophylactic agent to minimize intraoperative hemodynamic deterioration resulting from protamine sulfate in adult cardiac surgery patients.

Effect of minimally invasive extracorporeal circulation on endothelial dysfunction in cardiac ­surgery patients

Aim. To assess the changes in endothelial dysfunction in patients undergoing cardiac surgery with minimally invasive extracorporeal circulation (MiECC).&#x0D; Methods. The study included 50 patients who were undergoing coronary artery bypass grafting (CABG) surgery with cardiopulmonary bypass (CPB). The patients were divided assigned to either a minimally invasive cardiopulmonary bypass system (group 1, n=15) or standard extracorporeal circuit (group 2, n=35). Changes in the laboratory parameters were assessed 5 times: before the operation, 5 minutes after protamine sulfate administration, 12 hours after the operation, 7 days after the patient's discharged from the hospital and one month after the operation. The activity of von Willebrand factor, factor VIII, and the number of activated platelets were examined in all patients in venous blood.&#x0D; Results. After protamine sulfate administration, the activity of von Willebrand factor was increased to 164% in the group 1, and up to 193% in the group 2, with a tendency to increase the indicator after 12 hours. The peak of endothelial dysfunction, with the growth of von Willebrand factor and factor VIII, occurs on the 7th day after the operation. In patients of the group with MiECC, von Willebrand factor activity was decreased at the hospital discharge and returned to normal in 1 month. The number of activated platelets increases mainly in group 2 (6% versus 4% in group 1, p=0.29). The expression of P-selectin was significantly higher in group 2 at the hospital discharge (5.5% versus 3.1% in group 1, p 0.001), and in 1 month (4.5% versus 2.3% in group 1, p 0.001).&#x0D; Conclusion. In patients with minimally invasive cardiopulmonary bypass, platelet activation decreases, endothelial dysfunction, accompanied by an increase in the von Willebrand factor and factor VIII activity, is less pronounced; the seventh day after surgery is a period of the high risk of thrombogenic complications.

PROTAMINE VASOPLEGIA: A RARE SIDE EFFECT

Protamine vasoplegia is a state of endothelial dysregulation that produces profound vasodilatation which is refractory to vasopressors. This syndrome leads to systemic hypoperfusion and may progress to death. It can result after administration of protamine sulphate. We report a case about this rare

Coagulation assessment with thromboelastography during abdominal endovascular aneurysm repair in a patient with hemophilia A

BackgroundAs both APTT and APTT-based coagulation method cannot distinguish heparin effect from intrinsic coagulation factor deficiency, we implemented thromboelastography (TEG) for the coagulation assessment in a patient with hemophilia A undergoing an endovascular surgery with heparinization.Case presentationA 68-year-old male with hemophilia A underwent endovascular aortic repair for abdominal aortic aneurism. TEG results showed recovery of coagulation time (R) in both kaolin assay (CK) and kaolin-heparinase assay (CKH) after factor VIII replacement before heparinization. Against our expectations, R-CKH was slightly prolonged (9.0 min) during heparinization. After the administration of protamine sulfate, R in both assays showed similar values within the normal ranges.ConclusionsThe combination of CK and CKH assays could be useful to estimate factor VIII (FVIII) level when heparin concentration is low or without heparin; however, caution should be necessary for estimation of FVIII level by TEG under the effect of medium- or high-dose heparin.

Use of protamine sulfate during transfemoral transcatheter aortic valve implantation – a preliminary assessment of administration rate and impact on complications

IntroductionBleeding complications after transcatheter aortic valve implantation (TAVI) are an important issue and negatively affect survival. The rate and impact of protamine sulfate (PS) administration on bleeding complications after TAVI remain unclear.AimTo assess the impact of PS on bleeding complications after TAVI.Material and methodsBetween March 2010 and November 2016 two hundred fifty-eight patients qualified for TAVI in one academic center were screened. Baseline, procedural and follow-up data up to 30 days were collected and analyzed. The primary endpoint (PE) was major bleeding according to the Valve Academic Research Consortium up to 48 h after the procedure.ResultsOverall, 186 patients (96 females, mean age: 80 years) met the inclusion criteria. Thirty-nine (21%) subjects received PS. PE occurred in 24.7% of the study population. There were no significant differences in terms of the PE rate between the groups (25.6% in the PS group and 24.7% in the remaining cohort, p = 0.9, odds ratio (OR) = 1.05, confidence interval (CI): 0.47–2.4, p = 0.9). Multivariate analysis identified female gender (OR = 2.2, CI: 1.08–4.4, p = 0.03) as an independent predictor of PE occurrence. Similarly, female gender (OR = 2, CI: 1.06–3.84, p = 0.03) as well as general anesthesia (GA, OR = 2.23, CI: 1.13–4.63, p = 0.02) and dose of unfractionated heparin per kilogram (UFH/kg, OR = 1.02, CI: 1–1.03 per 1 IU increment, p = 0.02) predicted the occurrence of a composite of major and minor bleeding.ConclusionsIn this analysis, PS administration did not decrease the PE rate. Female gender predicted PE occurrence. Randomized, placebo-controlled trials are required to accurately assess the impact of PS.

Влияние гепарина и этанола на активность лактатдегидрогеназы в митохондриальной и цитоплазматической фракциях клеток печени крыс

Experiments on rats have shown that ethanol at a dose of 4.5 g/kg leads to an increase in the activity of lactate dehydrogenase (LDH) in rat liver cells in a direct reaction in subcellular fractions. In the cytoplasmic fraction, the LDH activity in the reverse reaction decreased. Pre-administration of heparin to animals at a dose of 250 IU/kg partially neutralizes the effects of intraperitoneal administration of ethanol, which is expressed in a decrease in the activity of LDH in rat liver cells in a direct reaction in subcellular fractions. Binding of endogenous heparin to protamine sulfate and subsequent administration of ethanol leads to an increase in LDH activity in the mitochondrial fraction of rat liver cells.

Randomized clinical trial of an elastomeric sealant for hemostasis in thoracic aortic surgery

ObjectivesThis study aimed to demonstrate the efficacy and safety of a newly developed elastomeric sealant, which does not require any blood coagulation system to exert its effect, during thoracic aortic surgery.MethodsThis is a multicenter, randomized study conducted in six hospitals in Japan. A total of 81 patients undergoing replacement surgery of a thoracic aortic aneurysm using cardiopulmonary bypass were randomized with a ratio of 2–:1 for those patients designated to receive the sealant (Group S, 54 patients) or those without the usage of the sealant (Group C, 27 patients). The primary endpoints were bleeding from each anastomosis at two time points: (1) immediately before applying protamine and (2) 15 min after applying protamine. The patients were followed for 6 months.ResultsThe number of anastomoses checked for bleeding was 196 in Group S and 117 in Group C. Before protamine sulfate administration, complete hemostasis was obtained in 155 anastomoses (79%) in Group S compared to 45 anastomoses (38%) in Group C (p < 0.001). Fifteen minutes after the administration of protamine sulfate infusion, bleeding stopped completely in 173 anastomoses (88%) in Group S and in 71 anastomoses (61%, p < 0.001) in Group C. Between the two groups, there were no marked differences in the patient background or in the incidence of major adverse events.ConclusionsThe sealant is effective in achieving hemostasis, even under fully heparinized conditions. The novel sealant is safe and effective in thoracic aortic surgery, one of the most demanding surgical situations for hemostasis.

The effect of goutweed (Aegopodium podagraria L.) preparations and metformin on the uric acid exchange in rats with the metabolic disorders induced by protamine sulphate against the background of atherogenic diet

The tincture and the extract of the aerial part of goutweed (Aegopodium podagraria L.) are characterized with a favorable effect on the lipid and uric acid metabolism, as well as with the antidiabetic activity. The tincture is capable of increasing metformin efficacy in the experiment. Taking into account the role of uric acid metabolism disorders in the pathogenesis of “diseases of civilization” it is expedient to assess the possibility of correcting these disorders by goutweed preparations combined with metformin.Aim. To determine the effect of goutweed tincture and the extract, as well as their combinations with metformin on the uric acid metabolism in rats with the primary disorder of the lipid metabolism.Materials and methods. The model presupposed administration of protamine sulfate to rats against the background of the atherogenic diet was used. The tincture and the extract of goutweed (1 g/kg and 1 ml/kg intragastrically, respectively), metformin (50 mg/kg intragastrically) and their combinations were administered during the whole period of the model simulation. The xanthine oxidase (XO) activity in the liver and kidneys, the content of uric acid in these organs and blood plasma, as well as its renal excretion under conditions of water loading were measured.Results. In rats receiving the atherogenic diet combined with protamine sulfate the uric acid level in the kidneys and its renal excretion moderately decreased, while the XO activity and the uric acid level in the liver and blood plasma remained unchanged. Against the background of metformin, the goutweed tincture, or their combination, as well as the combination of metformin with the extract the inhibition of the liver XO activity was registered, against the background of the tincture (per se and in the combination with metformin), as well as the extract, there was also suppression of the kidney XO activity. The content of uric acid in the liver did not change significantly in all groups, uricemia decreased only after administration of the tincture per se and slightly increased against the background of metformin combined with the extract (compared to other groups of treated animals, but not with the intact control); the uric acid level in the kidneys significantly reduced in rats treated with the combination of metformin and the extract, the similar tendency was observed in the untreated control group and both groups receiving the tincture. Against the background of the tincture and the extract per se the uric acid excretion increased (in rats receiving the tincture diuresis was elevated, so there were no increase in the uric acid concentration in the urine, which occurred against the background of the extract). After the combined administration of the extract with metformin there was no change of the uric acid excretion although its urinary content remained elevated against the background of low diuresis. The stimulatory effect of the tincture on the renal excretion of uric acid was not revealed when combining with metformin, while normourocemia and the effect on the XO activity in the liver and kidneys maintained. Conclusions. The combination of goutweed tincture with metformin is promising for further studies.

The effects of goutweed (Aegopodium Podagraria L.) preparations and their combinations with metformin in rats with the disorders of the lipid and carbohydrate metabolism induced by protamine sulphate

The improvement of the therapy of the metabolic syndrome, obesity, and type 2 diabetes is an important task which may be realized through the co-administration of herbal and synthetic medicines. The tincture and extract obtained from the aerial part of goutweed (Aegopodium podagraria L.) have been shown to possess antidiabetic and organoprotective properties. Goutweed tincture exerts a permissive effect on the action of metformin in dexamethasone-treated diabetic rats. Aim. The objective of this study is to determine the efficacy of the combined use of goutweed tincture and extract with metformin on the model of the primary disorder of the lipid metabolism. Materials and Methods. The model was used that presupposed administration of protamine sulfate to rats (10 mg/kg per day intramuscularly) against the background of atherogenic diet with the additional administration of cholestrol. Goutweed extract and tincture (1 g/kg and 1 ml/kg intragastrically, respectively), metformin (50 mg/kg intragastrically) and their combinations were administered during the whole period of model development. The lipid composition of the liver and blood plasma, as well as the content of glycogen in the liver were studied, and, as this model is accompanied with insulin resistance, glucose tolerance test was carried out. Results. It has been shown that all studied drugs and their combinations normalize the lipid composition of the liver, reducing the content of cholesterol and triglycerides and increasing the level of phospholipids. They do not significantly influence on the lipid spectrum of the blood plasma, tend to elevate the level of liver glycogen, their efficacy does not change in combined use. Goutweed tincture and metformin in combination, but not per se, completely normalize area under glucose curve that is significantly increased in the untreated group, the extract does not change this value. Conclusions. Goutweed extract and tincture normalize the lipid composition of the liver in rats with lipid and carbohydrate metabolism disorders caused by protamine sulfate and atherogenic diet, the tincture also exerts a permissive effect on the action of metformin on glucose metabolism, but not on lipid metabolism. (For citation: Tovchiga OV, Gorbatch TV, Shtrygol’ SYu, et al. The effects of goutweed (Aegopodium podagraria L.) preparations and their combinations with metformin in rats with the disorders of the lipid and carbohydrate metabolism induced by protamine sulphate. Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(2):31-41. doi: 10.17816/RCF15231-41).

The influence of goutweed (Aegopodium podagraria L.) tincture and metformin on the histopathological changes of the internal organs in dyslipidemic rats

Topicality. Combined use of herbal originated substances with the conventional drugs is a promising area of therapy improvement. The tincture and the extract obtained from goutweed (Aegopodium podagraria L.) are able to normalizecarbohydrate and lipid metabolism, the tincture partially increases the efficacy of metformin in the experiment. The aim of this study was to evaluate the influence of goutweed tincture and the extract as well as their combinationswith metformin on the histological structure of the internal organs of rats with lipid metabolism disorders.Materials and methods. Combined use of atherogenic diet and protamine sulfate administration was applied.Results and discussion. In the untreated group the histological examination allowed identifying the changes in kidneys (granular dystrophy of tubular epithelium, focal perivascular lymphocytic infiltration, focal sclerosis of the arterial walls); heart (granular dystrophy of cardiomyocytes, perivascular sclerotic with limited lymphohistiocytic infiltration and foci of ischemic changes in myocardium); liver (expressed granular dystrophy of hepatocytes, widening of space of Disse, signs of compensatory hypertrophy); while there were no changes in aorta. Metformin (50 mg/kg intragastrically) failed to demonstrate a normalizing influence on the liver structure, and necrobiosis and vacuolar dystrophy of hepatocytes were evident, it did not influence significantly of the kidney structure, and exerted a protective effect on the structure of the blood vessels of the heart, still not eliminating ischemic changes. Goutweed extract (1 g/kg intragastrically) and the tincture (1 ml/kg intragastrically) counteracted the changes in the structure of the kidney vessels and myocardium, including ischemic changes, while the liver histopathological changes were similar to those in metformin group. After combined administration of goutweed tincture and metformin as well as the extract and metformin at doses stated above the protective activity in regard to the heart structure was maintained, against the background of metformin with the tincture such activity in regard to the kidney structure was also evident; the toxicity of the investigated drugs was not enhanced, and there was no increase in the severity of the liver changes.Conclusions. Further ivestigation of goutweed preparations with metformin is expedient.

Local use of ankaferd blood clotter in emergent beating heart coronary artery bypass grafting.

Background:Severe beeding which requiring massive blood transfusion after emergent beating heart surgery is shown to be 1–3%. Therefore, complications and side effects of transfusion can be seen. The aim of this study was to investigate the effectiveness of Ankaferd blood clotter (ABC) as a new topical herbal blood clotter to decrease mediastinal bleeding in emergent beating heart CABG patients who medicated with clopidogrel and acetyl salisilic acite (ASA) prior to CABG surgery.Materials and Methods:25 CABG patients received a high dose clopidogrel (600 mgr) and 300 mgr ASA have been included into the study (ABC group). 25 patients have also been included into the study for comparison (placebo group, PG). After the administration of protamine sulphate, a 10 ml of ABC solution has been sprayed to the surgical area including mediastinum and epicardial sac. We compared mediastinal drenaige, reoperation due to tamponade, and required blood and blood products in both groups.Results:The mean amount of bleeding after operation was 230 ml in ABC group, and 490 ml in CG (P=0.001). In ICU, bleeding in ABC group and CG was 410ml and 680ml, respectively (P=0.0022). The mean total bleeding from mediastinum was 530±280 mL and 990±440 mL In ABC and CG group, respectively (P=0.001). The amount of autotransfusion was as follows: 175 mL in ABC group, and 290 mL in CG (P=0.002). No patient needed the surgical revision in ABC group, but four patients (16%) from CG group because of cardiac tamponade. Seventeen patients from CG required blood transfusion due to low hematocrite level postoperatively. In CG, the mean hematocrite level was 17±2,3. Transfusion of fresh frozen plasma and platelets in ABC group and CG were as follows: 0.2 and 0 in ABC group, and 0.3and 0.4 in CG.Conclusion:Our study showed that the local use of 10 mL ABC reduces bleeding significantly. Therefore, transfusion requirements of PRBC, platelets, and total blood units in patients on clopidogrel and ASA undergoing emergent beating heart CABG. To provide cardiac tamponade because of excessive mediastinal bleeding and requirement of blood transfusion after emergent CABG patients who previously administered clopidogrel and ASA, we propose local use of ABC solution as a potent coagulant agent.