Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of repeated oral administration of cefuroxime axetil were assessed in Beagles. The test material, an ester, is hydrolysed following absorption from the intestine to yield the therapeutically active moiety, cefuroxime, together with acetic acid and acetaldehyde; in this study cefuroxime and unhydrolyzed cefuroxime axetil were detected in the blood. Cefuroxime axetil was administered twice daily during 27 weeks by gavage of aqueous, suspensions, total daily doses were equivalent to 100, 400 or 1600 mg cefuroxime/kg/day. Apart from three cases of intercurrent illness, unrelated to treatment, the dogs remained in good health. Effects observed in the 1600 mg/kg group included vomiting and slight suppression of body weight gain. Minor variations in haematological measurements included rather low haemoglobin levels, packed cell volumes and erythrocyte counts. Slightly smaller numbers of neutrophils were thought to reflect reduced demand on normal defensive mechanisms due to continued antibiotic treatment. Prolongation of prothrombin time and activated partial thromboplastin time is attributed to disturbance of the intestinal microbial flora and reduced synthesis of vitamin K, on which the dog is highly dependent. Cefuroxime does not have the N-methylthiotetrazole side chain thought to be responsible for inhibition by other cephalosporins of the vitamin K-dependent step in the synthesis of clotting factors. Variations in plasma chemistry included rather low levels of plasma protein. Electrophoresis showed this to be a generalised reduction; only gamma globulins were proportionally decreased and this finding, like the low neutrophil counts, is attributed to the protective action of the antibiotic. Minor metabolic adjustments to the compound are reflected in plasma levels of cholesterol and triglycerides. This spectrum of findings was seen only to a very limited extent in the 400 mg/kg group; the 100 mg/kg group was, with very few exceptions, unaffected by the treatment. Macroscopic post mortem examination and microscopic examination of tissues revealed no treatment-related features indicative of toxicity. Cefuroxime axetil was thus shown to possess very little toxicity when administered repeatedly in large doses to Beagles. The lowest dose level in this study was ten times the proposed daily clinical dose in man.
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PMID:An evaluation of the safety of cefuroxime axetil during six months oral administration to beagle dogs. 382 Mar 42

The poly-(D, L-lactide) RESOMER R208 (Boehringer-Ingelheim, Germany) was modified with heparin to improve the blood contacting properties of the material. The immobilization of herapin was carried out by covalent binding with glutaraldehyde as the coupling agent. The reaction conditions, such as temperature and time, were varied to optimize the binding of heparin. The efficiency of the immobilization was monitored with respect to the total amount of coupled herapin with a toluidine blue assay and the anticoagulant activity of immobilized heparin with a factor Xa assay. The hemocompatibility of the modified polylactide was estimated after blood-material contact by the activation of platelets measured with an enzyme immuno assay for GMP140. Immobilization at ambient temperature and a reaction time of 2 h resulted in maximal heparin binding, high anticoagulant activity, and low thrombogenicity. Since the remaining unsaturated aldehyde groups of the coupling agent may cause a low hemocompatibility of the material, washing of the heparinized polylactide was carried out with ethanol. However, it was shown that washing diminished the anticoagulant activity of heparin and increased the thrombogenicity. The prolonged storage of heparinized polylactide in phosphate buffered saline for 8 days demonstrated that small quantities of heparin were released but the hemocompatibility was further improved, indicated by an increasing anticoagulant potential and a decrease in platelet activation with incubation time. A comparison of polylactide, heparinized polylactide, polypropylene, and Pellethane with respect to platelet activation by GMP140 assay and scanning electron microscopy, revealed that the heparinization of polylactide substantially improved the hemocompatibility of RESOMER R208, making the material comparable to Pellethane.
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PMID:Immobilization of heparin on polylactide for application to degradable biomaterials in contact with blood. 757 30

Acetaldehyde is the first metabolite of ethanol and has the potential to react with proteins and alter their function. This study evaluated the function of clotting proteins that had been preincubated with acetaldehyde as compared to those incubated with buffer or ethanol as controls. Thrombin, fibrinogen, thromboplastin, or whole plasma were preincubated with 1.8-447 mM acetaldehyde, 1.7-429 mM ethanol, or buffer for varying time periods prior to use in a clotting assay. Clot formation was measured with an automatic fibrometer. Acetaldehyde prolonged the clotting time but ethanol did not. These experiments indicate that circulating acetaldehyde would have the potential to react with proteins of the clotting system and alter their function. Therefore, it is possible that not all of the abnormalities in coagulation in alcohol abusers result from inadequate hepatic synthesis. Perhaps some of the deranged coagulation may be the result of the interaction of acetaldehyde with coagulation proteins.
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PMID:Acetaldehyde alters coagulation protein function. 795 11

Tripeptide aldehydes such as Boc-D-Phe-Pro-Arg-H (51) exhibit potent direct inhibition of thrombin. This distinction offers important insight for the design of more potent and selective serine protease inhibitors which may be useful pharmacological tools and hold promise for development of clinically useful agents. The structure-activity relationships (SAR) on a series of anticoagulant peptides with high selectivity for the enzyme thrombin are discussed. The SAR is centered on a series of di- and tripeptide arginine aldehydes based on the structure of 51. The structural and conformational role of the amino acid residue in position 1 was investigated by substitution with conformationally restricted aromatic amino acids, aromatic acids, and a dipeptide isostere containing the psi[CH2N] amide bond replacement. Many of these peptides demonstrate potent antithrombotic activity along with selectivity toward thrombin, determined by comparison of in vitro inhibitory effects on trypsin, plasmin, factor Xa, and tissue plasminogen activator. Compound 5f, D-1-Tiq-Pro-Arg-H.sulfate is highly active and the most selective tripeptide aldehyde inhibitor of thrombin reported to date.
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PMID:Highly selective tripeptide thrombin inhibitors. 842 61

Acetaldehyde (AcH) (447 mM) exerts an inhibition on Factor Xa, as followed by a clotting assay, but does not inhibit the hydrolysis of the synthetic fluorogenic substrate, N-tBOC-Ile-Glu-Gly-Arg-7-amido-4-methylcoumarin. These data suggest that AcH, although not reacting at the catalytic site of Factor Xa nor at the binding site for the synthetic substrate, does interact with the functional groups on the enzyme that bind to its natural substrate, prothrombin. As a consequence of such interaction, the charge and conformation of Factor Xa is altered, thereby limiting effective activation of prothrombin. Additionally, alkylation of factor Xa may also affect its capacity to associate with Factor Va for the activation of prothrombin. AcH also reacts with Factor X, prolonging clotting times when the zymogen is activated with Russell's viper venom (RVV). It also reduces the rate of hydrolysis of the fluorogenic substrate after activation of the alkylated zymogen by RVV. These data lead to the considerations that AcH-modified Factor X is no longer as effectively activated by RVV due to an alteration of its charge/conformation. Additional possibilities include a likely alkylation of the Factor Xa moiety of Factor X by AcH such that the activation product has an altered charge/conformation compared to native Factor Xa, including possible alkylation of its binding site(s) for prothrombin. The reduced rate of hydrolysis of the synthetic fluorogenic substrate for Factor Xa by the alkylated, activated Factor X lends further support to the generation of a modified Factor Xa by RVV, which may have a lower binding or catalytic rate for the fluorogenic substrate. These results support the suggestion that chronic consumption of alcohol may prolong the reported coagulation times as a result of reaction of alcohol's primary metabolite, AcH, with clotting factors, thereby reducing their physiological potential.
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PMID:Coagulation protein function. IV. Effect of acetaldehyde upon factor X and factor Xa, the proteins at the gateway to the common coagulation pathway. 894 47

A series of arginine aldehyde inhibitors was designed as transition state (TS) analogues based on the known factor Xa specific substrate Cbz-D-Arg-Gly-Arg-pNA. BnSO2-(D)Arg-Gly-Arg-H (20) was found to be the most potent and selective inhibitor of factor Xa and prothrombinase activity in this series.
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PMID:Design, synthesis and structure-activity relationship of a series of arginine aldehyde factor Xa inhibitors. Part 1: structures based on the (D)-Arg-Gly-Arg tripeptide sequence. 1063 32

We analyzed the influence of the atherogenic oxidized low density lipoproteins (LDL) on the activity of the platelet prothrombinase complex, a major contributor to overall thrombin formation in vivo. Platelet dependent thrombin generation was found to be strongly stimulated by in vitro oxidized LDL. The enhancement was additive to that observed with the platelet agonist thrombin. Oxidized LDL increased the platelet binding of annexin-V, suggesting that the augmented surface exposure of aminophospholipids promoted the prothrombinase activity. All of the stimulatory activity of the oxidized LDL could be recovered in the microemulsions prepared from the lipid portion of the modified particles. Phospholipid vesicles were prepared containing the total lipids of the oxidized LDL but lacking specifically in one lipid component. Following the selective removal of the ethanolamine phospholipids (PE) from the LDL lipids, the platelet-dependent thrombin formation was markedly reduced. Vesicles enriched with the isolated PE fraction alone enhanced the thrombin generation. Analyses with autoxidized phospholipids indicated that oxidation products of unsaturated diacyl-PE were mainly responsible for the increased prothrombinase activity. Oxidized LDL and its PE fraction lost their stimulatory activity after treatment with NaCNBH(3), a chemical reductant of Schiff base adducts. Phospholipid vesicles supplemented with synthetic aldehyde-PE adducts largely reproduced the stimulation of the thrombin generation. We conclude that the oxidized LDL particles elicit a pronounced prothrombotic response by increasing the activity of the platelet prothrombinase complex. Specific oxidative modifications of the LDL-associated ethanolamine phospholipids are mainly responsible for this stimulation.
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PMID:Modified phosphatidylethanolamine as the active component of oxidized low density lipoprotein promoting platelet prothrombinase activity. 1127 48

There is increasing evidence that endogenously generated aldehydes formed as a result of lipid peroxidation are involved in the pathophysiological effects associated with oxidative stress in cells and tissues. Malondialdehyde (MDA), a major product of lipid peroxidation, can modify amines present on the cell surface and thereby introduce negative charges that can affect the interfacial ionic layer. We show that lipid peroxidation of RBC generates MDA adducts that, similar to phosphatidylserine (PS), bind annexin V in a Ca(2+)-dependent manner. Like PS, these adducts also promote the "PS-dependent" prothrombinase assays, albeit to lower levels. These results indicate that annexin V binding cannot be used as an exclusive indicator of cell surface PS and raise the possibility that some phenomenon attributed to PS may, in fact, also involve aldehyde-lipid adducts.
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PMID:Binding of annexin V to membrane products of lipid peroxidation. 1146 26

Research on synthetic peptides at the Institute for Drug Research (IDR) is exemplified by an overview of the projects that resulted in significant results. The first synthesis of oxytocin, a pituitary hormone, in 1953 launched the research on synthetic peptides all over the world. This synthesis was reproduced by Bodanszky at the IDR in 1954, then, after some improvements, the process was presented to Richter to produce synthetic oxytocin for therapeutic purposes. Significant result was the first synthesis of the 39-member whole molecule of human ACTH, another pituitary hormone. A short SAR study on luteinizing hormone-releasing hormone (LHRH) led to an interesting analog, Cit-8-LHRH, and somewhat later, to the D-Cit-6-LHRH analogues, of which SB-75 become marketed under the name Cetrorelix. Studies on the brain peptides, enkephalins, resulted in GYKI-14,238, the first analog that showed analgesic activity upon systemic administration and whose human efficacy could also be proven during clinical examination. Significant results were also achieved in the research on anticoagulant peptides. The first highly potent peptide aldehyde inhibitor of thrombin, GYKI-14,166, was identified at the IDR as well as its stable analog, GYKI-14,766. This compound was selected for detailed preclinical study, licensed to Eli Lilly Company, got the generic name efegatran, and entered clinical trials. The first non-covalent peptide inhibitor of thrombin, GYKI-14,525, was also identified at the IDR. Thus IDR really provided the prototype of original thrombin inhibitors in the mid 70's, and analogues were prepared in many laboratories through two decades. IDR's current research program's objective includes a quest for peptide originals that can inhibit both thrombin and factor Xa in solution and also within plasma clots in which these enzymes are entrapped. Structures with such inhibitory profile were identified among the efegatran-related alpha-hydroxy acid and ethoxycarbonyl-amino acid derivatives. The follow-up molecules are even more promising as antithrombotics, and may also be useful for treatment of disseminated intravascular coagulation, an often fatal syndrome, so we continue working on this project.
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PMID:[Research on synthetic peptides of biological interest]. 1176 93

The effect of low concentrations of acetaldehyde on activated partial thromboplastin time (APTT) and prothrombin time (PT) of Accuclot coagulation plasmas was monitored over a prolonged time to mimic effects observed in alcoholism. A prolongation of the APTT from 31.9 +/- 0.7 s to 32.6 +/- 0.9 s (n = 8; P =.007) was observed after a 30-min preincubation time with 140 microM acetaldehyde. However, a minimum of 3.6 mM acetaldehyde was required to extend the APTT from 36.6 +/- 1.0 s to 41.2 +/- 0.8 s (P =.001) over an 18-h exposure time. Plasma acetaldehyde levels as low as 2.24 mM caused elevation of PTs from 12.5 +/- 0.5 s to 14.4 +/- 0.2 s (P =.005) after a 24-h preincubation time. These findings seem to indicate that short-term contact of acetaldehyde with plasma, probably yielding reversible interactions, may interfere with APTTs to a greater extent than long-term contact, which would presumably yield stable, irreversible interactions. In comparing the effects of 8.94, 17.9, 89.4, and 447 mM acetaldehyde on the PTs of Level I, II, and III plasma, the PTs were most increasingly prolonged in Level III plasma and least prolonged in Level I plasma at each acetaldehyde concentration, although the plasmas have comparable protein concentrations. These findings seem to indicate that coagulation factors are sensitive to inactivation by acetaldehyde.
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PMID:Short- and long-term effects of acetaldehyde on plasma. 1195 47


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