FIBRINOLYTIC POTENCY OF NON ANTICOAGULANT, OXI-EEDUCED SLOW AND FAST MOVING HEPARINS

1987 ◽  
Author(s):  
R Porta ◽  
R Pescador ◽  
R Niada ◽  
M Mantovani ◽  
G Prino
Keyword(s):  
Fast Moving ◽  
Fibrinolytic Activity ◽  
Animal Species ◽  
Ex Vivo ◽  
Biological Activities ◽  
Anticoagulant Activity ◽  
Risk Patients ◽  
Slow Moving ◽  
Different Doses

It is well known that heparin is able to induce an increase of fibrinolytic activity when i.v. administered in man and in several animal species. Nevertheless, its anticoagulant properties can cause serious problems of bleeding and this restricts the therapeutic use of heparin. An oxi-reductive process applied to heparin leads to a conpound with reduced anticoagulant activity. Moreover, heparin can be separated into slow moving (SM) and fast moving (FM) components on the basis of electrcphoretic properties. The SM and FM components display quantitatively different biological activities. The aim of this paper was to verify if the oxi-reduction could affect or not the fibrinolytic activities of SM and FM. SM and FM, prepared by ethanolic precipitation from parent heparin, were oxidized by periodate and stabilized by reduction (RO-SM and RO-FM). The USP, APTT and anti Xa titres were determined in vitro using sheep plasma and kits from Boehrirger Biochemia (APTT) and Sigpia (Anti Xa). Fibrinolytic activities were assessed ex vivo after i.v. injection into rabbits at different doses to find out the effective dose hundred (ED100). The euglobulin fraction obtained from plasma was applied on human fibrin plates and the lysis areas were measured. The Table gives the resultsThe oxi-reduction decreased dramatically the anticoagulant activities of SM and FM heparins while their fibrinolytic activities were practically unaffected. Tne oxi-reduced heparins could be helpful therapeutic agents in pathological conditions characterized by a diminished fibrinolytic activity. They could represent an effective alternative to heparin; the very lew anticoagulant activities reduce the risk of bleeding, specially in the high risk patients, while the good fibrinolytic activity, comparable to heparin, could allow the dissolution of fibrin clots.

Effects of Two Different Doses of Hirudin on APTT, Determined with Eight Different Reagents

1995 ◽  
Vol 73 (02) ◽  
pp. 219-222 ◽  
Author(s):  
Manuel Monreal ◽  
Luis Monreal ◽  
Rafael Ruiz de Gopegui ◽  
Yvonne Espada ◽  
Ana Maria Angles ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Anticoagulant Activity ◽  
Subcutaneous Administration ◽  
In Vitro Study ◽  
Ex Vivo Model ◽  
Suitable Candidate ◽  
Significant Prolongation ◽  
High Doses ◽  
Different Doses

SummaryThe APTT has been considered the most suitable candidate to monitor the anticoagulant activity of hirudin. However, its use is hampered by problems of standardization, which make the results heavily dependent on the responsiveness of the reagent used. Our aim was to investigate if this different responsiveness of different reagents when added in vitro is to be confirmed in an ex vivo study.Two different doses of r-hirudin (CGP 39393), 0.3 mg/kg and 1 mg/kg, were administered subcutaneously to 20 New Zealand male rabbits, and the differences in prolongation of APTT 2 and 12 h later were compared, using 8 widely used commercial reagents. All groups exhibited a significant prolongation of APTT 2 h after sc administration of hirudin, both at low and high doses. But this prolongation persisted 12 h later only when the PTTa reagent (Boehringer Mannheim) was used. In general, hirudin prolonged the APTT most with the silica- based reagents.In a further study, we compared the same APTT reagents in an in vitro study in which normal pooled plasma was mixed with increasing amount of hirudin. We failed to confirm a higher sensitivity for silica- containing reagents. Thus, we conclude that subcutaneous administration of hirudin prolongs the APTT most with the silica-based reagents, but this effect is exclusive for the ex vivo model.

A Comparative Ex Vivo Study of Plasminogen Activators and Proteases for Fibrinolytic Activity and Side Effects in Rabbits

1977 ◽  
Vol 37 (01) ◽  
pp. 154-161 ◽  
Author(s):  
B. A Janik ◽  
S. E Papaioannou
Keyword(s):  
Side Effects ◽  
Effective Dose ◽  
Fibrinolytic Activity ◽  
Ex Vivo ◽  
Plasminogen Activators ◽  
Assay System ◽  
Coagulation Parameters ◽  
Ex Vivo Assay

SummaryUrokinase, streptokinase, Brinase, trypsin, and SN 687, a bacterial exoprotease, have been evaluated in an ex vivo assay system. These enzymes were injected into rabbits and the fibrinolytic activity as well as other coagulation parameters were measured by in vitro techniques. Dose-response correlations have been made using the euglobulin lysis time as a measure of fibrinolytic activity and the 50% effective dose has been determined for each enzyme. Loading doses, equal to four times the 50% effective dose, were administered to monitor potential toxicity revealing that Brinase, trypsin, and SN 687 were very toxic at this concentration.Having established the 50% effective dose for each enzyme, further testing was conducted where relevant fibrinolytic and coagulation parameters were measured for up to two days following a 50% effective dose bolus injection of each enzyme. Our results have demonstrated that urokinase and streptokinase are plasminogen activators specifically activating the rabbit fibrinolytic system while Brinase, trypsin and SN 687 increase the general proteolytic activity in vivo.The advantages of this ex vivo assay system for evaluating relative fibrinolytic potencies and side effects for plasminogen activators and fibrinolytic proteases have been discussed.

scholarly journals Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2867
Author(s):  
Lucia Kovacikova ◽  
Marta Soltesova Prnova ◽  
Magdalena Majekova ◽  
Andrej Bohac ◽  
Cimen Karasu ◽  
...  
Keyword(s):  
Aldose Reductase ◽  
Diabetic Complications ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Biological Activities ◽  
In Vivo Models ◽  
Aldose Reductase Inhibitors ◽  
Reductase Inhibitors ◽  
Promising Therapeutic Approach

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure–activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of ‘drug-likeness”. Novel promising structures of putative multifunctional ARIs/AOs are designed.

scholarly journals EFFECT OF MURRAYA KOENIGII LEAVES EXTRACT ON GLUCONEOGENESIS AND GLYCOGENOLYSIS IN ISOLATED RAT HEPATOCYTES CULTURE

2018 ◽  
Vol 11 (11) ◽  
pp. 264
Author(s):  
Rohan S Phatak ◽  
Chitra C Khanwelkar ◽  
Kailas D Datkhile ◽  
Pratik P Durgawale
Keyword(s):  
Glycogen Content ◽  
Ex Vivo ◽  
Rat Hepatocytes ◽  
Diabetic Rats ◽  
Murraya Koenigii ◽  
Isolated Rat Hepatocytes ◽  
Genes Expression ◽  
Different Doses ◽  
Isolated Rat

Objectives: The present study was aimed to investigate the in vitro activity of Murraya koenigii extracts through various carbohydrate metabolic pathways in the isolated rat hepatocyte models.Methods: Different doses of metformin, aqueous and methanol extracts of M. koenigii leaves were evaluated in the MTT, glucose, and glycogen content assays in the cultured in vitro rat hepatocytes.Results: The study showed that there was a significant increase in activity with respect to the increased concentration of extracts. Slight effect was observed in the isolated rat hepatocytes culture, M. koenigii leaves extract may exert cytoprotective and hypoglycemic action.Conclusion: It may be needed to determine the effect of ex vivo rat hepatocytes isolated from diabetic rats. Effects of the plant or isolated compounds on the genes expression of signaling pathways should be investigated in further studies.

scholarly journals Interaction of Enteropathogenic and Shiga Toxin-Producing Escherichia coli and Porcine Intestinal Mucosa: Role of Intimin and Tir in Adherence

2005 ◽  
Vol 73 (9) ◽  
pp. 6005-6016 ◽  
Author(s):  
Francis Girard ◽  
Isabelle Batisson ◽  
Gad M. Frankel ◽  
Josée Harel ◽  
John M. Fairbrother
Keyword(s):  
Escherichia Coli ◽  
Shiga Toxin ◽  
Actin Polymerization ◽  
Animal Species ◽  
Ex Vivo ◽  
Epec Strain ◽  
E Coli ◽  
In Vitro Organ Culture

ABSTRACT The ileal in vitro organ culture (IVOC) model using tissues originating from colostrum-deprived newborn piglets has proven to be an effective way to study the attaching and effacing (A/E) phenotype of porcine enteropathogenic Escherichia coli (EPEC) ex vivo. The aim of this study was to investigate the role of intimin subtype and Tir in the adherence of EPEC and Shiga-toxin-producing E. coli (STEC), isolated from different animal species, to porcine intestinal IVOC. Moreover, the role of intimin in Tir-independent adherence of the human EPEC strain E2348/69 was investigated using intimin and Tir-deficient derivatives. Our results demonstrated that A/E E. coli strains (AEEC) from various animal species and humans induce the A/E phenotype in porcine ileal IVOC and that intimin subtype influences intestinal adherence and tropism of AEEC strains. We also showed that a tir mutant of EPEC strain E2348/69 demonstrates close adherence to the epithelial cells of porcine ileal IVOC segments, with microvillous effacement but with no evidence of actin polymerization or pedestal formation, and that intimin seems to be involved in this phenotype. Overall, this study provides further evidence for the existence of one or more host-cell-encoded intimin receptor(s) in the pig gut.

scholarly journals In vitro and in vivo activities of flavonoids – apigenin, baicalin, chrysin, scutellarin – in regulation of hypertension – a review for their possible effects in pregnancy-induced hypertension

2019 ◽  
Vol 65 (1) ◽  
pp. 55-70 ◽  
Author(s):  
Marcin Ożarowski ◽  
Radosław Kujawski ◽  
Przemysław Ł. Mikołajczak ◽  
Karolina Wielgus ◽  
Andrzej Klejewski ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Chemical Compounds ◽  
New Drugs ◽  
Future Application ◽  
Mediators Of Inflammation ◽  
And Function

Summary Flavonoids and their conjugates are the most important group of natural chemical compounds in drug discovery and development. The search for pharmacological activity and new mechanisms of activity of these chemical compounds, which may inhibit mediators of inflammation and influence the structure and function of endothelial cells, can be an interesting pharmacological strategy for the prevention and adjunctive treatments of hypertension, especially induced by pregnancy. Because cardiovascular diseases have multi-factorial pathogenesis these natural chemical compounds with wide spectrum of biological activities are the most interesting source of new drugs. Extracts from one of the most popular plant used in Traditional Chinese Medicine, Scutellaria baicalensis Georgi could be a very interesting source of flavonoids because of its exact content in quercetin, apigenin, chrysin and scutellarin as well as in baicalin. These flavonoids exert vasoprotective properties and many activities such as: anti-oxidative via several pathways, anti-in-flammatory, anti-ischaemic, cardioprotective and anti-hypertensive. However, there is lack of summaries of results of studies in context of potential and future application of flavonoids with determined composition and activity. Our review aims to provide a literature survey of in vitro, in vivo and ex vivo pharmacological studies of selected flavonoids (apigenin, chrysin and scutellarin, baicalin) in various models of hypertension carried out in 2008–2018.

A Novel Congenital Bleeding Disorder Related to High Plasma Heparin-Like Anticoagulant Activity.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4074-4074
Author(s):  
Zhaoyue Wang ◽  
Haiyen Yang ◽  
Xia Bai ◽  
Wei Zhang ◽  
Changgeng Ruan
Keyword(s):  
Ex Vivo ◽  
Anticoagulant Activity ◽  
Coagulation Factors ◽  
High Plasma ◽  
Bleeding Disorder ◽  
Normal Plasma ◽  
Normal Ranges ◽  
Coagulation Tests ◽  
Plasma Heparin

Abstract Heparin or heparin-like compounds present in human plasma in minute amounts. It has been reported that a very few patients with such diseases as plasma cell neoplasms, acute monoblastic leukemia and acquired immune deficincy syndrome have an increased plasma heparin-like anticoagulant activity. Recently, we found a 10-year-old girl who was physically and developmentally normal, but had recurrent episodes of prolonged bleeding and hematoma starting in her early childhood, which could be stopped by transfusion of fresh frozen plasma or prothrombin complex concentrate. The coagulation tests of her plasma were regularly repeated since she was 2 years old, and always revealed a markedly prolonged APTT (61.8–104 seconds, normal 28–40 seconds) and TT (36–50.1 seconds, normal 14–21 seconds), and a slightly prolonged PT (15.9–25 seconds, normal 11–14.5 seconds). Fibrinogen, prothrombin and other coagulation factors as well as anticoagulant and fibrinolytic systems were all normal. The results of immunologic measurements were either negative or within normal ranges. Treatment of the patient’s plasma in vitro with either protamine or heparinase could completely normalize the coagulation abnormalities, but not with normal plasma. The anticoagulant activity of her plasma corresponded to 0.2 heparin U/mL when measured by a TT assay using normal plasma as substrate and standardized with porcine heparin. Her plasma heparin concentration was 0.22 heparin U/mL when measured using a colometric assay. In ex vivo study, the abnormal coagulation tests could effectively be corrected when the patient was intravenously administed with protamine. Considering these characteristic laboratory features of the patient, we suppose it would probably represent a novel congenital bleeding disorder related to high plasma heparin-like anticoagulant activity which, to our knowledge, had not been described before.

The Antithrombotic Effect of Borneol Related to Its Anticoagulant Property

2008 ◽  
Vol 36 (04) ◽  
pp. 719-727 ◽  
Author(s):  
Yan-Hong Li ◽  
Xiao-Ping Sun ◽  
Yin-Qing Zhang ◽  
Ning-Sheng Wang
Keyword(s):  
Platelet Aggregation ◽  
Fibrinolytic Activity ◽  
Ex Vivo ◽  
Anticoagulant Activity ◽  
Thrombin Time ◽  
Inhibitory Effects ◽  
Antithrombotic Activity ◽  
Coagulation Parameters ◽  
Venous Shunt

Borneol is consumed excessively in China and Southeast Asian countries particularly in combined formula for preventing cardiovascular disease, but few studies were conducted on its effects on thrombosis. In this study, the antithrombotic and antiplatelet activities of borneol were investigated on thrombosis in vivo and on platelet aggregation ex-vivo. In addition, the coagulation parameters and influence on fibrinolytic activity were also assessed. The results showed that borneol had concentration dependent inhibitory effects on arterio-venous shunt and venous thrombosis but no effect on ADP and AA-induced platelet aggregation. Meanwhile, borneol prolonged the coagulation parameters for prothrombin time (PT) and thrombin time (TT), but did not show any fibrinolytic activity. It suggested that the antithrombotic activity of borneol and its action in combined formula for preventing cardiovascular diseases might be due to anticoagulant activity rather than antiplatelet activity.

Hypotensive effects of the triterpene oleanolic acid for cardiovascular prevention

2020 ◽  
Vol 13 ◽  
Author(s):  
A. Sureda ◽  
M. Monserrat-Mesquida ◽  
S. Pinya ◽  
P. Ferriol ◽  
S. Tejada
Keyword(s):  
Blood Pressure ◽  
Oleanolic Acid ◽  
Ex Vivo ◽  
Biological Activities ◽  
Cardiovascular Prevention ◽  
In Vivo Studies ◽  
Antihypertensive Activity ◽  
In Vitro Tests

Background:: Hypertension is a high prevalent chronic disease worldwide and a major cardiovascular risk factor. Oleanolic acid (3β-hydroxy-olea-12-en-28-oic acid) is a wide distributed bioactive pentacyclic triterpenoid with diverse biological activities such as anti-inflammatory, hepaprotective anti-diabetic or anti-hypertensive. Objective:: The aim of this study was to review and highlight the available data about antihypertensive activity of oleanolic acid and the described mechanisms of action. Method:: Extensive searches were made in the available literature on oleanolic acid and the data investigating its antihypertensive effects were analysed. Results:: Most of research has been performed on animal models of hypertension, ex vivo studies with aortic ring and some in vitro tests with cell cultures, whereas clinical trials are still lacking. Treatment of hypertensive animals with oleanolic acid significantly ameliorated the rise in the systolic blood pressure. In addition, the hypotensive effects of oleanolic acid are also related to a potent diuretic-natriuretic activity and nephroprotection. In vitro studies have characterized the participation of various signalling pathways that modulate the release of vasodilation mediators. Conclusion:: In vitro and in vivo studies suggest that oleanolic acid effectively reduce blood pressure and could be an interesting co-adjuvant to conventional treatment of hypertension.

scholarly journals Restricted immune activation and internalisation of anti-idiotype complexes between drug and antidrug antibodies

2018 ◽  
Vol 77 (10) ◽  
pp. 1471-1479 ◽  
Author(s):  
Karin A van Schie ◽  
Simone Kruithof ◽  
Pleuni Ooijevaar-de Heer ◽  
Ninotska I L Derksen ◽  
Fleur S van de Bovenkamp ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Activation ◽  
Immune Complexes ◽  
Ex Vivo ◽  
Biological Activities ◽  
Size Exclusion ◽  
Exclusion Chromatography ◽  
Soluble Immune Complexes ◽  
High Concentrations

ObjectivesTherapeutic antibodies can provoke an antidrug antibody (ADA) response, which can form soluble immune complexes with the drug in potentially high amounts. Nevertheless, ADA-associated adverse events are usually rare, although with notable exceptions including infliximab. The immune activating effects and the eventual fate of these ‘anti-idiotype’ complexes are poorly studied, hampering assessment of ADA-associated risk of adverse events. We investigated the in vitro formation and biological activities of ADA-drug anti-idiotype immune complexes using patient-derived monoclonal anti-infliximab antibodies.MethodsSize distribution and conformation of ADA-drug complexes were characterised by size-exclusion chromatography and electron microscopy. Internalisation of and immune activation by complexes of defined size was visualised with flow imaging, whole blood cell assay and C4b/c ELISA.ResultsSize and conformation of immune complexes depended on the concentrations and ratio of drug and ADA; large complexes (>6 IgGs) formed only with high ADA titres. Macrophages efficiently internalised tetrameric and bigger complexes in vitro, but not dimers. Corroborating these results, ex vivo analysis of patient sera demonstrated only dimeric complexes in circulation.No activation of immune cells by anti-idiotype complexes was observed, and only very large complexes activated complement. Unlike Fc-linked hexamers, anti-idiotype hexamers did not activate complement, demonstrating that besides size, conformation governs immune complex potential for triggering effector functions.ConclusionsAnti-idiotype ADA-drug complexes generally have restricted immune activation capacity. Large, irregularly shaped complexes only form at high concentrations of both drug and ADA, as may be achieved during intravenous infusion of infliximab, explaining the rarity of serious ADA-associated adverse events.

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