Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TCV-309 potently and specifically inhibited the diverse biological actions of PAF such as platelet aggregation, hypotension, increased vascular permeability, bronchoconstriction and death. TCV-309 did not cause hemolysis or vascular irritation. TCV-309 showed beneficial effects on experimental endotoxic shock, anaphylactic shock and disseminated intravascular coagulation.
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PMID:Pharmacological profile of TCV-309--a potent PAF antagonist. 144 98

Intravenous infusion of endotoxin (0.25 mg/kg/hr for 4 hr) was shown to induce disseminated intravascular coagulation (DIC) in rats, which resulted in hypofibrinogenemia, prolongation of prothrombin (PT) and partial thromboplastin time (PTT), thrombocytopenia, and elevated levels of fibrinogen/fibrin degradation products (FDP). Oral administration (100 mg/kg) of the selective PAF antagonist, SM-10661 ((+/-)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl), counteracted the changes caused by the endotoxin. Intravenous infusion of SM-10661 (6mg/kg bolus 2 min before endotoxin infusion + 6 mg/kg/hr for 4 hr infusion) also counteracted DIC. When suboptimal doses of gabexate mesilate, a synthetic protease inhibitor (3 mg/kg i.p.), and SM-10661 (2 mg/kg bolus + 2 mg/kg/hr for 4 hr infusion) were administered concomitantly, hematological parameters improved. The results suggest that PAF may play a role in the pathogenesis of DIC, and that together with the results already reported for other PAF antagonists, SM-10661 may be useful in the treatment of DIC.
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PMID:Effect of a selective PAF antagonist SM-10661 ((+/-)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl) on experimental disseminated intravascular coagulation (DIC). 181 39

The purpose of this study was to analyse the clinical course of 410 patients of severe surgical infections (primary 251, postoperative 159) during recent 5 years and to evaluate the important background factors which make these patients serious. As a result, the following patients such as, (1) who have refractory primary infections, for example malignant lymphoma, severe pancreatitis etc. (2) whose infectious foci were uncontrolled. (3) who had finally complicated a septic MOF or DIC, seemed to be especially critical even though recent advanced surgical therapy. To improve these severe conditions, we believe to need a renewed approach like so called "multi-disciplinary therapy", additionally with both conventional antibiotics administration and drainage for infectious foci. Several methods such as, (1) rational nutrition management using indirect calorimetry. (2) plasma exchange for removing toxic substances such as bacterial toxins, chemical mediators etc, from circulating blood. (3) pharmacological block of these toxic substances, were shown. In terms of the harmful chemical mediators, we supposed that both PAF (platelet activating factor) and oxygen free radical were extremely important in septic conditions from previous clinico-experimental studies. Therefore the effects of those pharmacological blockers such as PAF antagonists, SOD, protease inhibitor in experimental endotoxin shock were discussed in detail.
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PMID:[Clinico-experimental analysis of backgrounds of the severe surgical infections]. 194 10

Disseminated intravascular coagulation (DIC) or renal damage associated with septicemia was induced in rats by ligating the cecum or by injecting endotoxin. In the septicemia model, the number of E. coli and Bacteroides spp in the blood increased concomitantly with an increase of endotoxin. In this model the development of hypercoagulability with mild fibrinolysis was observed. Histopathologic findings in the kidneys, including the formation of microthrombi in the glomeruli and the vacuolization and dilatation of renal tubular cells, suggest the development of mild DIC. In the endotoxin-induced DIC model, both remarkable state of hypercoagulability and fibrinolysis were observed with fibrin thrombi in glomeruli. The administration of the platelet-activating factor antagonist, CV-6209, or of human antithrombin III, ameliorated DIC significantly by limiting the increases in prothrombin time, activated partial thromboplastin time and fibrin degradation products. These agents significantly reduced the deposition of fibrin in the glomeruli and significantly prolonged the survival time of the endotoxin injected rats. These observations suggest that the PAF antagonist CV-6209 and ATIII merit clinical evaluation in the management of DIC caused by septisemia.
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PMID:Effect of a platelet activating factor antagonist and antithrombin III on septicemia and endotoxemia in rats. 206 2

I have experienced 35 cases of DIC in my department during last 8 years. These cases were divided into a septic and non-septic groups based on their back-ground, and compared their clinical symptoms and various laboratory findings. The results showed the septic DIC group could be characterized as follows: (1) impairment of the vital organs was more clearly manifested, while hemorrhagic symptoms were mild, (2) the laboratory tests showed almost no tendency for fibrinogen or alpha 2-PI to be decreased or PIC to be increased, (3) the blood PAF (Platelet Activating Factor) level was clearly higher and showed an inverse relationship with the platelet count. On the basis of these clinical findings, I speculated septic DIC involves suppression of secondary fibrinolysis and participation of PAF. In experiment A, I investigated the effects of endotoxin (Et) on the activity of plasminogen activator (PA) in the rabbit renal cortex. In both in vitro and in vivo systems, I could demonstrate the renal cortex PA activity was significantly suppressed by Et. Then, in experiment B, I could confirm, (1) PAF caused a drop in the blood pressure and a decrease in the platelet count that were similar to those induced by Et, and that Et caused a decrease in the platelet count that was inversely accompanied by an increase in PAF, (2) PAF antagonist showed greater efficacy than a protease inhibitor in suppressing the decrease in the blood platelet count.
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PMID:[Clinical and experimental studies of septic DIC in surgical patients, in terms of its characteristic features and pathogenesis]. 787 83

The effects of platelet activating factor antagonist (PAF-A) for sublethal endotoxemia after 70% or 84% hepatectomy in rats were studied. Endotoxin of 1mg/kg b.w. was intravenously given once on the first, third or fifth day hepatectomy. One week survival rates of 84%-hepatectomized rats with endotoxin injection on the third postoperative day was the lowest at 20%, and the lowest survival rate improved to 80% with PAF-A administration. Pathophysiology of PAF-A treated and nontreated rats with endotoxemia was investigated on the third day after 84% hepatectomy. There was no significant difference in SGOT, SGPT and blood glucose level between the two groups. PAF-A nontreated rats' prothrombin time was prolonged (p < 0.05) and serum fibrinogen level significantly decreased (p < 0.01), compared to treated rats. Platelet count distinctly decreased in both groups. Fibrin was pathologically proved in the glomeruli of the kidney in both groups. However, single cell necrosis of hepatocytes was significantly reduced by PAF-A administration. Rats without PAF-A had bloody ascites in 75% of cases and showed shock and pathologically pulmonary congestion. PAF may be related to DIC, shock, bloody ascites and high mortality rate in sublethal endotoxemia after massive hepatectomy. PAF-A was significantly effective for endotoxemia after hepatectomy.
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PMID:[Experimental studies on the relation of platelet activating factor (PAF) to high mortality in sublethal endotoxemia after massive hepatectomy and effects of its antagonist]. 833 21

To investigate the role of PAF in tumor-associated disseminated intravascular coagulation (DIC), we have established the tumor-induced DIC model in rats and examined the effect of PAF-antagonist as compared with commonly used anti-DIC drugs. Four days after the intraperitoneal inoculation of rat ascites hepatoma AH-130, DIC-like hematological parameter changes such as decrease in platelet count, prolongation of PTT and increase in FDP were observed. In addition, serum levels of GOT and GPT were increased, indicating that liver injury was provoked. PAF-antagonist SM-12502 inhibited the development of DIC (PT, PTT and FDP) and liver injury. These results indicate that PAF plays an important role in tumor-associated DIC as well as accompanying organ failure.
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PMID:Effect of SM-12502 on disseminated intravascular coagulation (DIC) in tumor-bearing rats. 913 Nov 47

UR-12670 is a novel and potent PAF antagonist, eg., it displaces [3H]WEB-2086 from PAF receptors in rabbit platelet membranes (Ki = 0.6 nM) and inhibits PAF-induced increase in vascular permeability in rat trachea (100%), thymus (44%), seminal vesicles (100%) and stomach (54%) at a dose of 0.01 mg/kg i.v. Since PAF is thought to be an important mediator in endotoxic shock, the effect of pretreatment with UR-12670 on changes in vascular permeability, disseminated intravascular coagulation (DIC) and plasma biochemical parameters were determined in a rat model of acute endotoxemia. UR-12670 and the reference PAF antagonist, lexipafant (10 mg/kg i.v.), strongly inhibited lipopolysaccharide (LPS, 25 mg/kg i.v.)-induced plasma leakage in the trachea (49 and 100%, respectively) and seminal vesicles (81 and 100%), as assessed by the Evans blue extravasation method. Only lexipafant inhibited the increase in vascular permeability in the thymus (36%). Neither PAF antagonist was effective in the stomach. Both UR-12670 and lexipafant at 10 mg/kg i.v. attenuated the LPS-induced variation of some DIC markers, such as activated partial thromboplastin time increase (56 and 58%, respectively) and the fibrinogen concentration decrease (53 and 31%), whereas the increase in prothrombin time was not affected. Increased plasma acid phosphatase (ACP, a lysosomal activation marker) and lactate dehydrogenase (LDH, a tissue damage marker) activity elicited by LPS was attenuated by pretreatment with 10 mg/kg i.v. of either UR-12670 or lexipafant (ACP: 55 and 48%; LDH: 50 and 33%). LPS-induced hyperglycemia (46 and 37%) and hyperlactacidemia (100% both) were also inhibited. UR-12670 protected against several shock symptoms, confirming the role of PAF in the pathogenesis of rodent endotoxemia.
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PMID:Effects of a new platelet-activating factor antagonist, UR-12670, on several endotoxic shock markers in rats. 951 29

To investigate whether vaccination could induce lethal shock and which mechanisms are involved in this phenomenon, we tested a panel of autoantigens or diabetes-irrelevant peptides or proteins in nonobese diabetic (NOD), Balb/c, and C57Bl/6 mice. Of the antigens tested, only nondiabetogenic hen egg white lysozyme induced a severe form of shock exclusively in NOD mice. The mechanism involved is suggestive of a Th(2)-mediated anaphylactic reaction possibly connected to activation of PAF and triggering of DIC.
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PMID:Hen egg white lysozyme vaccination induces acute shock in NOD mice. 1467 62

Inappropriate platelet activation is a feature of acute and chronic diseases such as disseminated intravascular coagulation (DIC) and atherosclerosis. Since proinflammatory microbial-derived agonists can be involved in the pathogenesis of these diseases, we examined the potential role of TLR4 (mediating responses to LPS) and TLR2 (which responds to bacterial lipopeptides) in platelet activation. Our data suggested low-level expression of TLR2 and TLR4 on platelets, determined by flow cytometry, and we also observed expression of TLR4 on a megakaryocytic cell line by both flow cytometry and immunohistochemistry. Stimulation of the platelets with the TLR4 agonist LPS, and the synthetic TLR2 agonist Pam3CSK4, resulted in no platelet aggregation, no increase in CD62P surface expression and no increase in the cytosolic concentration of Ca2+. The TLR agonists were also unable to directly activate platelets primed with epinephrine, or pretreated with a low concentration of ADP or PAF. Pretreatment of platelets with LPS or Pam3CSK4 also failed to modulate the platelet response to submaximal concentrations of the classical platelet agonists ADP and PAF. We conclude that the TLR agonists LPS and Pam3CSK4 have no direct effect on platelet activation and that platelet TLRs may be a remnant from megakaryocytes. TLR2 and TLR4 agonists are thought to have a significant role in diseases such as atherosclerosis and DIC, but our research suggests that this is through a mechanism other than direct platelet activation or by modification of platelet responses to other agonists.
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PMID:Agonists of toll-like receptor (TLR)2 and TLR4 are unable to modulate platelet activation by adenosine diphosphate and platelet activating factor. 1627 Jun 39


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