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Anticoagulant Activity (anticoagulant + activity)
Selected AbstractsSynthesis and Anticoagulant Activities of Substituted 2,4-Diketochromans, Biscoumarins, and Chromanocoumarins.CHEMINFORM, Issue 38 2006Ilia Manolov Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Relationship between antithrombotic activities of fucans and their structureDRUG DEVELOPMENT RESEARCH, Issue 4 2000Catherine Boisson-Vidal Abstract A low molecular weight fucan fraction extracted from the brown seaweed Ascophyllum nodosum was previously shown to exhibit dose-related venous antithrombotic activity with an ED80 of about 20 mg/kg, 2 h after a single subcutaneous injection HCII (Colliec et al. [1991] Thromb Res 64:143,154; Mauray et al. [1995] Thromb Haemast 74:1280,1285). Its activity was comparable to that of a low molecular weight heparin (Dalteparin®). This fucan fraction is one of several, with a range of different structure parameters, prepared by degradation of the whole native fucan. These low molecular weight fractions were compared using a Wessler stasis thrombosis model in rabbits and by determination of their in vitro and ex vivo anticoagulant activities. Intravenous administrations of these fractions reduced thrombosis in a dose-dependent manner. Partial removal of sulfate groups and/or partial degradation lead to a significant decrease in their anticoagulant and antithrombotic activities. The integrity of the regular pattern of sulphation of the fucoidan is necessary for antithrombotic activity. Drug Dev. Res. 51:216,224, 2000. © 2001 Wiley-Liss, Inc. [source] Ring-opening polymerization of benzylated 1,6-anhydro-,- D -lactose and specific biological activities of sulfated (1,6)-,- D -lactopyranansJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 3 2009Shuqin Han Abstract A new anhydro disaccharide monomer, 1,6-anhydro-2,3-di- o -benzyl-4- o -(2,,3,,4,,6,-tetra- o -benzyl-,- D -galactopyranosyl)-,- D -glucopyranose (benzylated 1,6-anhydro lactose (LSHBE)), was synthesized from D -lactose to investigate the polymerizability and biological activities of the resulting branched polysaccharides. The ring-opening polymerization of LSHBE was carried out with phosphorus pentafluoride as a catalyst under high vacuum to give a stereoregular benzylated (1 , 6)-,- D -lactopyranan. The molecular weights of poly(LSHBE)s increased with an increase in the amount of CH2Cl2 solvent, and polymerization temperatures were affected in both molecular weights and yields of the polymers. The copolymerization of LSHBE with benzylated 1,6-anhydro-,- D -glucopyranose (LGTBE) gave the corresponding copolysacchrides having different proportions of lactose and glucose units in good yields. After debenzylation to recover hydroxyl groups and then sulfation, sulfated homopoly(lactose)s and copoly(lactose and glucose)s were obtained. Sulfated homopoly(lactose)s had moderate anti-HIV (EC50 = 5.9 and 1.3 ,g/mL) and blood anticoagulant activities (AA = 18 and 13 unit/mg), respectively. Sulfated copoly(lactose and glucose) having 15 mol % lactose units gave high anti-HIV and blood anticoagulant activities of 0.3 ,g/mL and 54 unit/mg, respectively. These biological results suggest that the distance between branched units on the main chain plays an important role in the anti-HIV and blood anticoagulant activities. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 913,924, 2009 [source] New developments in the chemistry and biology of the bioactive constituents of tanshen,MEDICINAL RESEARCH REVIEWS, Issue 1 2007Xihong Wang Abstract Tanshen, the rhizome of Salvia miltiorrhiza Bunge, has been used in Chinese traditional medicine (TCM) for multiple therapeutic remedies. The major constituents of Tanshen include water-soluble phenolic acids and lipophilic tanshinones. Phenolic acids possess antioxidant and anticoagulant activities, whereas tanshinones show antibacterial, antioxidant, and antineoplastic activities. This review will focus on recent developments concerning the chemical constituents of Tanshen and their biological activities. These chemical and biological studies continue to increase our understanding about a scientific basis for the traditional clinical use of Tanshen and can also contribute to the development of new drug candidates. Recently, in the author's laboratory, a new compound, neo-tanshinlactone, was discovered to have potent selective antibreast cancer activity. This compound might serve as a lead for developing promising antibreast cancer clinical trials candidates. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 1, 133,148, 2007 [source] Cerebral palsy in siblings caused by compound heterozygous mutations in the gene encoding protein CDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 5 2010CHOONG YI FONG We report two sisters with extensive bilateral periventricular haemorrhagic infarction (PVHI) causing cerebral palsy (CP). The older sister presented at 20 months with cortical visual blindness, spastic diplegia, and purpura fulminans. The younger sister presented aged 3 days old with apnoeas and multifocal seizures. She subsequently had global developmental delay, cortical visual blindness, spastic quadriplegia, epilepsy, and purpura fulminans at age 2 years. Neuroimaging of both siblings showed bilateral PVHI consistent with bilateral cerebral intramedullary venous thrombosis occurring at under 28 weeks' gestation for the older sister and around time of birth for the younger sister. At latest follow-up, the older sister (13y) has spastic diplegia at Gross Motor Function Classification System (GMFCS) level II, and the younger sister (10y) has spastic quadriplegia at GMFCS level IV. Both sisters showed partial quantitative reduction in plasma protein C antigen and severe qualitative reduction in plasma protein C anticoagulant activity. They were heterozygous for two independent mutations in the protein C gene (PROC). There was no other risk factor for CP. To our knowledge, this is the first family reported with compound heterozygous PROC mutations as the likely genetic cause of familial CP. This report adds to the list of known monogenic causes of CP. [source] Mouse recombinant protein C variants with enhanced membrane affinity and hyper-anticoagulant activity in mouse plasmaFEBS JOURNAL, Issue 22 2009Michael J. Krisinger Mouse anticoagulant protein C (461 residues) shares 69% sequence identity with its human ortholog. Interspecies experiments suggest that there is an incompatibility between mouse and human protein C, such that human protein C does not function efficiently in mouse plasma, nor does mouse protein C function efficiently in human plasma. Previously, we described a series of human activated protein C (APC) Gla domain mutants (e.g. QGNSEDY-APC), with enhanced membrane affinity that also served as superior anticoagulants. To characterize these Gla mutants further in mouse models of diseases, the analogous mutations were now made in mouse protein C. In total, seven mutants (mutated at one or more of positions P10S12D23Q32N33) and wild-type protein C were expressed and purified to homogeneity. In a surface plasmon resonance-based membrane-binding assay, several high affinity protein C mutants were identified. In Ca2+ titration experiments, the high affinity variants had a significantly reduced (four-fold) Ca2+ requirement for half-maximum binding. In a tissue factor-initiated thrombin generation assay using mouse plasma, all mouse APC variants, including wild-type, could completely inhibit thrombin generation; however, one of the variants denoted mutant III (P10Q/S12N/D23S/Q32E/N33D) was found to be a 30- to 50-fold better anticoagulant compared to the wild-type protein. This mouse APC variant will be attractive to use in mouse models aiming to elucidate the in vivo effects of APC variants with enhanced anticoagulant activity. [source] Identification and isolation of cDNA clones encoding the abundant secreted proteins in the saliva proteome of Culicoides nubeculosusINSECT MOLECULAR BIOLOGY, Issue 3 2009C. L. Russell Abstract Culicoides spp. are vectors of several infectious diseases of veterinary importance and a major cause of allergy in horses and other livestock. Their saliva contains a number of proteins which enable blood feeding, enhance disease transmission and act as allergens. We report the construction of a novel cDNA library from Culicoides nubeculosus linked to the analysis of abundant salivary gland proteins by mass spectrometry. Fifty-four novel proteins sequences are described including those of the enzymes maltase, hyaluronidase and two serine proteases demonstrated to be present in Culicoides salivary glands, as well as several members of the D7 family and protease inhibitors with putative anticoagulant activity. In addition, several families of abundant proteins with unknown function were identified including some of the major candidate allergens that cause insect bite hypersensitivity in horses. [source] The amounts and deposition patterns of fibrin-type fibrinoid at the villous surface are altered in pregnancy at high altitudeJOURNAL OF ANATOMY, Issue 5 2002T. M. Mayhew In pregnancy at high altitude, there is preplacental (hypobaric) hypoxia and intrauterine fetal growth is restricted. Previous studies on placentas from Amerindian and nonindigenous women completing term pregnancies at low (LA; 400 m) and high (HA; 3600 m) altitudes in Bolivia showed that HA placentas had smaller surface areas of villi and smaller volumes of fibrin type fibrinoid (FTF). Recently we devised a stereological method for testing whether perivillous FTF (pFTF) is randomly distributed at the surface of villous trophoblast. Here the method is applied to test 2 experimental hypotheses: [1] deposition of pFTF is nonrandom regardless of altitude and [2] deposition patterns differ between altitudes. Uniform random samples of microscopical fields were drawn from Masson trichrome stained sections and intersection counts used to estimate the surface areas of, and patterns of pFTF on, 4 regions of trophoblast: nonsyncytial knots (nonSK), syncytial knots (SK), syncytial bridges (SB) and denudation sites (DEN). Absolute areas were compared by 2-way analyses of variance. Expected and observed distributions were compared by (2 and contingency table analyses. At LA the mean (SEM) volume of FTF was 8.4 (1.54) cm3 and villous surface area was 7.0 (0.43) m2. At HA FTF volume was reduced by about 50% (P < 0.01) and villous surface by 20% (P < 0.01). The surface composition of trophoblast in LA placentas was nonSK (91%), SK (5%) and SB and DEN (both less than 3%). Relative surfaces were not significantly altered in HA placentas but, due to the impoverished growth of villi at HA, the changes represented a real decline in absolute surface of nonSK. At HA, the total surface of pFTF on trophoblast decreased by about 40%, from 4430 (564) cm2,2570 (406) cm2 (P < 0.01). At both altitudes pFTF deposition was preferentially found at DEN (12-fold greater than expected for a random distribution). Pattern differences were detected between altitudes. In HA placentas the amount of pFTF deposited on nonSK regions was about 45% less (P < 0.05); apparent changes on SK and SB regions were not significant. These histometric findings suggest that the coagulation-fibrinolysis steady state is altered at HA and favours greater fibrinolysis. At least some of the fibrinolytic or anticoagulant activity seems to reside in or on thinner regions of villous trophoblast and the placenta may be a relatively privileged site in terms of fibrinolysis. Also, reduced deposition of pFTF is probably linked to changes in the steady state of trophoblast turnover which seems to be perturbed in HA pregnancies. [source] Effects of factor XI deficiency on ferric chloride-induced vena cava thrombosis in miceJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2006X. WANG Summary.,Background:,Increased plasma levels of coagulation factor (F) XI are a risk factor for venous thrombosis. Objective:,To further explore the relationship between FXI and venous thrombosis, we evaluated FXI-deficient and wild-type mice in a ferric chloride (FeCl3)-induced vena cava thrombosis model. Methods and Results:,Thrombosis was induced by 3-min topical application of filter papers containing increasing concentrations of FeCl3 and the thrombus was measured at 30 min. In contrast to wild-type mice, FXI-deficient mice failed to form a thrombus with 5% FeCl3, and were partially protected against 7.5% and 10% FeCl3, respectively. The protective effect was substantially stronger than a high dose of heparin (1000 units kg,1, i.v.), clopidogrel (30 mg kg,1, p.o.) or argatroban (30 mg kg,1, i.p.). These antithrombotic agents resulted in off-scale bleeding in a tail bleeding time assay, whereas the bleeding time of FXI-deficient mice was unchanged compared to wild-type mice. In addition to its known effect on the coagulation cascade, enhanced clot lysis was demonstrated in FXI-deficient mouse and human plasma compared to those supplemented with FXIa. Conclusion:,Given the strong antithrombotic efficacy (possibly contributed by strong anticoagulant activity associated with increased fibrinolytic activity) and mild bleeding diathesis associated with FXI deficiency, therapeutic inhibition of FXI may be a reasonable therapeutic strategy to treat or prevent venous thrombosis. [source] Variable region heavy chain glycosylation determines the anticoagulant activity of a factor VIII antibodyJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2006M. JACQUEMIN Summary.,Background:,N -glycosylation occurs in the variable region of about 10% of antibodies but the role of carbohydrate at this location is still poorly understood. Objectives:,We investigated the function of N -glycosylation in the variable region of the heavy chain of a human monoclonal antibody, mAb-LE2E9, that partially inhibits factor VIII (FVIII) activity during coagulation. Methods and results:,Enzymatic deglycosylation indicated that the oligosaccharides do not determine the affinity of the antibody but enhance its FVIII neutralizing activity. A mutant antibody lacking the N -glycosylation site in the variable region of the heavy chain inhibited FVIII activity by up to 40%, while inhibition by the native antibody was 80%. To evaluate the physiological effect of such a FVIII inhibition, we investigated the ability of the mutant antibody devoid of N -glycosylation in the variable region to prevent thrombosis in mice with a strong prothombotic phenotype resulting from a type II deficiency mutation in the heparin binding site of antithrombin. Despite its moderate inhibition of FVIII activity, the mutant antibody significantly prevented thrombosis in treated animals. We also carried out glycan analysis of native and mutant antibodies. Conclusions:,Modification of glycosylation in the variable region of antibodies contributes to the diversity of FVIII type II inhibition possibly by steric hindrance of the active site of FVIII by glycans, and may provide a novel strategy to modulate the functional activity of therapeutic antibodies. [source] Direct anticoagulant activity of protein S-C4b binding protein complex in Heerlen heterozygotes and normals,JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2004M. J. Heeb Summary.,Background:,Plasma protein S normally circulates free (40%) or complexed with C4b-binding protein (PS-C4BP); only free protein S is a cofactor for activated protein C during factor (F) Va inactivation. Protein S-Heerlen lacks a carbohydrate group, leading to low plasma free protein S levels, but normal levels of PS-C4BP. Objectives:,Because protein S-Heerlen is not associated with thrombosis, we investigated whether PS-C4BP is directly anticoagulant in plasma and whether PS-Heerlen-C4BP has enhanced direct anticoagulant activity. Methods:,An assay for protein S direct activity was applied to Heerlen-heterozygous plasmas. Free and complexed protein S were repeatedly isolated from normal and Heerlen-heterozygous plasmas and tested for direct anticoagulant activity in prothrombinase assays and in plasma. Results:,Heerlen-heterozygous plasmas were deficient in free and total protein S antigen but had normal to high protein S direct anticoagulant activity. Purified Heerlen-heterozygous PS-C4BP was 7-fold more potent than normal PS-C4BP in inhibiting full prothrombinase activity, and 22-fold more potent in inhibiting prothrombin activation in the absence of FVa; it also specifically prolonged plasma clotting times 14-fold more than normal PS-C4BP. Heerlen-heterozygous PS-C4BP did not compete for limiting phospholipids any better than normal PS-C4BP. However, ligand blots and surface plasmon resonance studies showed that Heerlen-heterozygous PS-C4BP bound more avidly to FXa than did normal PS-C4BP (apparent Kd = 4.3 nm vs. 82 nm). Conclusions:,Plasma-derived PS-C4BP has direct anticoagulant activity in plasma and in purified systems. Enhanced direct activity of PS-Heerlen-C4BP may compensate for low free protein S levels and low cofactor activity in individuals with protein S-Heerlen. [source] Poor anticoagulant response to tissue factor pathway inhibitor in patients with venous thrombosisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2003B. Tardy-Poncet Summary., Tissue factor pathway inhibitor (TFPI) is of major importance in regulating the coagulation triggering effects of tissue factor. An association between TFPI deficiency and thrombosis has still not been clearly demonstrated. We evaluated the anticoagulant activity of exogenous TFPI added either to the plasma of patients with venous thrombosis (n = 118) or to the plasma of healthy controls similar in terms of mean age and sex ratio (n = 107). A poor anticoagulant response to TFPI, defined as TFPI resistance, was observed in 4.7% of controls and in 11.0% of patients. TFPI resistance was associated with an almost threefold increase in the risk of thrombosis and could therefore represent a novel hemostatic risk factor for venous thrombosis. [source] Improved resolution in two-dimensional 1H NMR spectra of peptides by band-selective, homonuclear decoupling during both the evolution and acquisition periods: application to characterization of the binding of peptides by heparinMAGNETIC RESONANCE IN CHEMISTRY, Issue 8 2006Jing Wang Abstract Two-dimensional 1H NMR experiments that achieve band-selective, homonuclear decoupling in both the indirectly detected F1 and directly detected F2 dimensions were used to assign the highly overlapped 1H NMR spectrum of the peptide Ac-SRGKARVRAKVKDQTK-NH2, both free in solution and bound to heparin. Band-selective, homonuclear decoupling during the evolution period was achieved using a double pulsed field gradient spin-echo (DPFGSE) with semi-selective shaped pulses; band-selective, homonuclear decoupling during the acquisition period was achieved by time-shared semi-selective shaped pulse decoupling. Regular TOCSY, ROESY and NOESY spectra and TOCSY, ROESY and NOESY spectra measured with band-selective, homonuclear decoupling in the evolution (F1) dimension (BASHD-TOCSY, ROESY and NOESY spectra) and with band-selective, homonuclear decoupling in both the F1 and F2 dimensions (D-(or Double)-BASHD-TOCSY, ROESY and NOESY spectra) are reported and compared for the peptide and its heparin complex. Complete assignment of the 1H-NMR spectra of the free and heparin-complexed peptide was achieved with the high resolution of the D-BASHD-TOCSY, ROESY and NOESY spectra. Characterization of the heparin-complexed peptide is of interest because of the ability of the peptide to neutralize the anticoagulant activity of heparin. Copyright © 2006 John Wiley & Sons, Ltd. [source] The effect of IVX-0142, a heparin-derived hypersulfated disaccharide, on the allergic airway responses in asthmaALLERGY, Issue 9 2008M. Duong Background:, IVX-0142 is a heparin-derived hypersulfated disaccharide devoid of anticoagulant activity while possessing anti-allergic and anti-inflammatory activity in preclinical studies. In a proof-of-concept study, the allergen inhalation challenge model was used to investigate the effect of IVX-0142 in mild atopic asthma. Methods:, Nineteen subjects, not on controller medications, were randomized to an evaluator-blind, placebo-controlled, cross-over study. The effect of a single nebulized dose of IVX-0142 (80 mg) or placebo administered 30 min prior to allergen inhalation was evaluated on the allergic airway responses, airway responsiveness, and airway inflammation. Results:, When compared with placebo, 14 and 13 subjects experienced a relatively smaller maximum fall in forced expiratory volume in 1 s (maxFEV1%) for the early airway response (EAR) and late airway response (LAR) with IVX-0142, respectively (P < 0.01). The degree of attenuation in the EAR [maxFEV1% (mean ± SE) 26.5 ± 2.8%vs placebo 31.0 ± 2.8%, P = 0.059] and LAR (15.6 ± 2.9%vs placebo 19.0 ± 2.9%, P = 0.24) with IVX-0142, however, was small and did not reach statistical significance compared with placebo. Similarly, a trend in the attenuation of allergen-induced increase in the absolute sputum cell counts was also observed. No difference in the allergen-induced increase in airway hyper-responsiveness and exhaled nitric oxide was noticed. Conclusions:, The majority of mild atopic asthmatics demonstrated a reduction in the EAR and LAR to IVX-0142. However, the treatment effect observed with a single prechallenge dose of IVX-0142 was small and heterogeneous. The potential anti-allergic and anti-inflammatory effects using multiple higher doses need to be evaluated. [source] Outcome of aneurysmal subarachnoid haemorrhage in patients on maintenance haemodialysisNEPHROLOGY, Issue 1-2 2000Gakusen Nishihara SUMMARY: To investigate the outcome of aneurysmal subarachnoid haemorrhage (SAH) in patients on maintenance haemodialysis (HD), eight patients on maintenance HD and 245 patients not on HD who suffered from SAH, all of whom were surgically treated at our institution between 1993 and 1997, were reviewed. The clinical features and 3-month outcome of SAH were analysed in the eight HD patients (three males, five females) and compared with those in the 245 non-HD patients (77 males, 168 females). Although there were no significant differences in the patient's age, gender and pre-operative grading of SAH with the Hunt and Hess grading scale, the mortality rate in HD patients was significantly higher than that in non-HD patients (50% [4/8] vs 13% [32/245]; P < 0.01). It was concluded that the outcome of aneurysmal SAH in HD patients was extremely poor. The explanation for the worse prognosis in HD patients seems not to lie in systemic heparization but in a vulnerability to SAH, because SAH in all HD patients occurred after anticoagulant activity from the previous dialysis had already disappeared. [source] Synthesis and Pharmacological Investigations of Some 4-Hydroxycoumarin DerivativesARCHIV DER PHARMAZIE, Issue 2 2003Ilia Manolov Abstract The synthesis of ten coumarin derivatives of 4-hydroxycoumarin and various unsaturated ketones and aldehydes is described. The structures of the synthesized compounds were confirmed by IR, 1H-NMR, and mass-spectral data. Acute toxicity studies of the compounds were performed on mice by oral and intraperitoneal administration. A comparative pharmacological study of the in vivo anticoagulant effects of the derivatives with respect to warfarin, showed that the compounds have anticoagulant activity. Compounds 4-hydroxy-3-[1-phenyl-2-(4,-chlorobenzoyl)ethyl]-2H -1-benzopyran-2-one 2b, 4-hydroxy-3-[1-(4-fluorophenyl)-3-oxobutyl]-2H -1-benzopyran-2-one 3a, and 3, 3,- p -bromobenzylidene-bis-(4-hydroxy-2H -1-benzopyran-2-one) 4b showed slight acute toxicity and a greater anticoagulant effect than warfarin. [source] Structure of the heterodimeric neurotoxic complex viperotoxin F (RV-4/RV-7) from the venom of Vipera russelli formosensis at 1.9,Å resolutionACTA CRYSTALLOGRAPHICA SECTION D, Issue 10 2003Markus Perbandt The presynaptic viperotoxin F is the major lethal component of the venom of Vipera russelli formosensis (Taiwan viper). It is a heterodimer of two highly homologous (65% identity) but oppositely charged subunits: a basic and neurotoxic PLA2 (RV-4) and an acidic non-toxic component with a very low enzymatic activity (RV-7). The crystal structure of the complex has been determined by molecular replacement and refined to 1.9,Å resolution and an R factor of 22.3% with four RV-4/RV-7 complexes in the asymmetric unit, which do not exhibit any local point-group symmetry. The complex formation decreases the accessible surface area of the two subunits by ,1425,Å2. Both PLA2s are predicted to have very low, if any, anticoagulant activity. The structure of viperotoxin F is compared with that of the heterodimeric neurotoxin vipoxin from the venom of another viper, V. ammodytes meridionalis. The structural basis for the differences between the pharmacological activities of the two toxins is discussed. The neutralization of the negative charge of the major ligand for Ca2+, Asp49, by intersubunit salt bridges is probably a common mechanism of self-stabilization of heterodimeric Viperinae snake-venom neurotoxins in the absence of bound calcium. [source] Expression of Human Recombinant Antibody Fragments Capable of Partially Inhibiting the Phospholypase Activity of Crotalus durissus terrificus VenomBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2009Juliana G. Oliveira It is composed of two different subunits: CA, crotapotin, and CB (basic subunit of cortoxin isolated from C. d. terrificus), a weakly toxic phospholipase A2 with high enzymatic activity. The phospholipases A2 are abundant in snake venoms and are responsible for disruption of cell membrane integrity via hydrolysis of its phospholipids. However, in addition to their normal digestive action, a wide range of pharmacological activities, such as neurotoxic, myotoxic, oedema-inducing, hypotensive, platelet-aggregating, cardiotoxic, and anticoagulant effects have been attributed to venom phospholipases A2. In this study, we used a non-immune human single-chain fragment variable library, Griffin.1 (Medical Research Council, Cambridge, UK) for selection of recombinant antibodies against antigens present in C. d. terrificus venom and identification of specific antibodies able to inhibit the phospholipase activity. Two clones were identified as capable of inhibiting partially this activity in vitro. These clones were able to reduce in vivo the myotoxic and oedema-inducing activity of CB and the lethality of C. d. terrificus venom and crotoxin, but had no effect on the in vitro anticoagulant activity of CB. These results demonstrate the potential of using recombinant single-chain fragment variable libraries in the production of antivenoms. [source] Highly Potent and Selective Substrate Analogue Factor Xa Inhibitors Containing D -Homophenylalanine Analogues as P3 Residue: Part 2CHEMMEDCHEM, Issue 7 2007Anne Stürzebecher Dr. Abstract A series of highly potent substrate-analogue factor Xa inhibitors containing D -homophenylalanine analogues as the P3 residue has been identified by systematic optimization of a previously described inhibitor structure. An initial lead, benzylsulfonyl- d- hPhe-Gly-4-amidinobenzylamide (3), inhibits fXa with an inhibition constant of 6.0,nM. Most modifications of the P2 amino acid and P4 benzylsulfonyl group did not improve the affinity and selectivity of the compounds as fXa inhibitors. In contrast, further variation at the P3 position led to inhibitors with significantly enhanced potency and selectivity. Inhibitor 27, benzylsulfonyl- D -homo-2-pyridylalanyl(N-oxide)-Gly-4-amidinobenzylamide, inhibits fXa with a Ki value of 0.32,nM. The inhibitor has strong anticoagulant activity in plasma and doubles the activated partial thromboplastin time and prothrombin time at concentrations of 280,nM and 170,nM, respectively. Compound 27 inhibits the prothrombinase complex with an IC50 value of 5,nM and is approximately 50 times more potent than the reference inhibitor DX-9065a in this assay. [source] Can we differentiate the low-molecular-weight heparins?CLINICAL CARDIOLOGY, Issue S1 2000Alexander G.G. Turpie M.B., F.A.C.C., F.A.C.P., F.R.C.P.(LOND., F.R.C.P.C., GLASG.) Abstract The low-molecular-weight heparins (LMWHs) have a number of therapeutic advantages, relative to standard unfractionated heparin (UFH). They are readily bioavailable when injected subcutaneously and can be given in fixed doses, allowing for far simpler administration. Several LMWHs are now commercially available, each demonstrating different physical and chemical properties and different activities in animal models of anticoagulation or hemorrhage. in clinical comparisons with placebo in the treatment of unstable coronary artery disease (UCAD), the LMWHs dal-teparin sodium and nadroparin calcium have demonstrated good anticoagulant efficacy. in comparisons with UFH, on the other hand, only enoxaparin has shown superior anticoagulant activity, as reported in the results of the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) and Thrombolysis in Myocardial Infarction (TIMI) 1 IB trials. However, close scrutiny of the methodology of the clinical trials in UCAD reveals considerable differences in study designs, dosage regimens, duration of administration of active treatments, and the timing and definition of endpoints. Therefore, it would not be scientifically sound to compare results with the different LMWHs based on the current available studies. It is also not possible to draw any conclusions with regard to the relative efficacy of the different LMWHs, since there are no properly-sized comparative data between dal-teparin sodium, enoxaparin sodium, and nadroparin calcium. [source] | ||||||||||||||||