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At least 1,261 records · Page 70Linked to original sources
PubMed2003

Factor XI deficiency--from molecular genetics to clinical management.

Factor XI (FXI) deficiency is a rare bleeding disorder, but is known to occur more frequently in a number of well-defined populations. FXI deficiency is most notable for its variable clinical phenotype. The FXI gene is located at the distal end of the long arm of chromosome 4 and encodes a 607 amino acid mature protein, which is a zymogen for a serine protease. Although the serine protease domain is similar to that of many other coagulation factors, the heavy chain differs in that it contains four tandem Apple domains. FXI is also unique in that it exists as a homodimer, with this dimerization appearing essential for normal function. A total of 39 different FXI mutations have been identified to date, affecting both the catalytic and Apple domains. This article will review the molecular genetics of FXI deficiency with particular focus on the implications of these findings for the clinical management of this condition. The potential utility of alternatives to plasma-derived FXI concentrate, such as recombinant factor VIIa (rFVIIa, NovoSeven) will also be explored.

Amino Acid Sequence↗
PubMed1992

A finding of highly selective synthetic inhibitor of plasma kallikrein; its action to bradykinin generation, intrinsic coagulation and experimental DIC.

We found a novel and highly selective synthetic inhibitor of plasma kallikrein (PK), called PKSI-527; the Ki value was 0.81 microM. PKSI-527 inhibited the bradykinin (BK) generation induced by kaolin and prolonged partial thromboplastin time (PTT). PKSI-527 prevented the decrease of fibrinogen (Fg) levels due to i.v. injection of ellagic acid in mice and ameliorated the endotoxin (ET)-induced DIC in rats.

Animals↗
PubMed1999

Development of plasma kallikrein selective inhibitors.

During the course of the development of active center-directed plasmin inhibitors, it was found that N-(trans-4-aminomethylcyclohexanecarbonyl)-lysine-4-methoxycarb onylanilide inhibited plasma kallikrein more potently than other enzymes such as plasmin, urokinase, and thrombin, although the inhibitory activity was not as potent and enzyme selectivity not as high. Based on studies of structure-activity relationship, we designed and synthesized the plasma kallikrein selective inhibitor, N-(trans-4-aminomethylcyclohexanecarbonyl)-phenylalanine-4-carboxy methyl- anilide (Tra-Phe-APAA). Tra-Phe-APAA inhibited plasma kallikrein with a Ki value of 0.81 microM, while it inhibited glandular kallikrein, plasmin, urokinase, tissue plasminogen activator, factor Xa, factor XIIa, and thrombin with Ki values of > 500, 390, 200, > 500, > 500 > 500, and > 500 microM, respectively. We designated Tra-Phe-APAA as PKSI-527. Using PKSI-527 as an affinity ligand, we synthesized a new affinity gel (PKSI-Toyopearl) and employed it for the rapid purification of plasma kallikrein from human plasma. Human plasma activated with kaolin after acid treatment was applied to a PKSI-527-Toyopearl column. Adsorbed protein was eluted with 50 mM glycinehydrochloric acid buffer (pH 3.0). Plasma kallikrein was purified 181-fold with a yield of 85% from the kaolin-activated plasma.

Binding Sites↗
PubMed1992

Studies on tumor induced angiogenesis.

Methods were developed to test angiogenic response to human tumor implants and various biologic agents in the cornea of rabbits and non-human primates (Macaca arctoides). Crude PDGF preparations were found to have significant angiogenic effect. Purified, recombinant PDGF preparations were also effective inhibitors (e.g. pentoxifylline (Px) (which also were found to release PgI2 and t-PA) inhibited human tumor implant induced angiogenesis and reduced spontaneous metastases in 3 transplantable murine tumors (Furth-Columbia Wilms' tumor in Furth-Wistar rats, C-1300 neuroblastoma in A/J mice and HM-Kim mammary carcinoma in Wistar rats) but not in the NIH adenocarcinoma in Balb/c mice. Sodium diethyldithiocarbamate (DDTC), a metal complexing agent with special affinity to copper and anti-thyroid as well as, immune stimulating activity was shown to be anti-angiogenic and to potentiate the effect of Px. The anti-fibrinolytic agents epsilon amino caproic acid (EACA) and tranaxamic acid (t-AMCHA) were anti-angiogenic. DDTC and Px were synergistic from this point of view.

Adenocarcinoma↗
PubMed1976

Transurethral electroresection of prostatic adenoma. Early results.

In 1972 and 1973 all together 186 men were operated upon with transurethral electroresection of prostatic adenoma. During the period no adenomectomies were performed by "open" methods. All the patients were operated upon by one surgeon. The early results of the operation were analysed. The operation appeared to imply only a very small strain on the patients. None of the men died during their stay in hospital. The men spent on the average 5 days in hospital after the operation. This figure includes those men in whom the adenoma removed was large, i.e. 88 cases in which the operative specimens weighed 30 to 124 g. The need of blood transfusions was small during and after the operation. Transfusions were never necessary in those cases where the operative specimens were small. In the 88 cases where specimens were large 25% required blood transfusion. Most patients had urinary incontinence for a few days to four months after the operation. They were afterwards all continent except 4 who were completely incontinent postoperatively. In all of these cases incontinence was due, at least partly, to cerebral lesions. It is claimed that with the irrigation fluid used, i.e. isotonic water solution of sorbitol and acetic acid, there is no need to limit the operation time and therefore not the size of the adenomas which can be resected. The surgeon can work quietly and without haste until the entire adenoma has been removed.

Aged↗
PubMed2006

[The "Seville" Consensus Document on Alternatives to Allogenic Blood Transfusion. Sociedades españolas de Anestesiología (SEDAR), Medicina Intensiva (SEMICYUC), Hematología y Hemoterapia (AEHH), Transfusión sanguínea (SETS) Trombosis y Hemostasia (SETH)].

The Consensus Document on Alternatives to Allogenic Blood Transfusion (AABT) has been drawn up by a panel of experts from 5 scientific societies. The Spanish Societies of Anesthesiology (SEDAR), Critical Care Medicine and Coronary Units (SEMICYUC), Hematology and Hemotherapy (AEHH), Blood Transfusion (SETS) and Thrombosis and Hemostasis (SETH) have sponsored and participated in this Consensus Document. Alternatives to blood transfusion have been divided into pharmacological and non-pharmacological, with 4 modules and 12 topics. The main objective variable was the reduction of allogenic blood transfusions and/or the number of transfused patients. The extent to which this objective was achieved by each AABT was evaluated using the Delphi method, which classifies the grade of recommendation from A (supported by controlled studies) to E (non-controlled studies and expert opinion). The experts concluded that most of the indications for AABT were based on middle or low grades of recommendation, "C", "D", or "E", thus indicating the need for further controlled studies.

Aminocaproic Acid↗
PubMed1976

Tissue plasminogen activator in the pathogenesis of protein-losing gastroenteropathy.

Tissue fibrinolytic activity, mainly due to activator of tissue plasminogen was increased in the biopsied gastric mucosa of patients with protein-losing gastropathy. Antiplasmin therapy with trans-AMCHA (trans-4-aminomethyl cyclohexane carboxylic acid) was dramatically effective, except in the case of a patient with intestinal lymphangiectasia. These findings suggest that increased fibrinolysis in the gastrointestinal mucosa may play an important role in enhancing mucosal permeability to plasma proteins.

Adult↗
PubMed1997

Effects of plasma kallikrein specific inhibitor and active-site blocked factor VIIa on the pulmonary vascular injury induced by endotoxin in rats.

The acute respiratory distress syndrome (ARDS) is a serious complication of sepsis. To evaluate the role of the coagulation system in the pathogenesis of ARDS in sepsis, we examined the effects of the administration of a synthetic plasma kallikrein specific inhibitor (PKSI) and of active-site blocked factor VIIa (DEGR-VIIa) on the pulmonary vascular injury induced by E. coli endotoxin (ET) in rats. Administration of PKSI prevented the pulmonary vascular injury induced by ET as well as pulmonary histological changes in animals administered ET, but it did not affect the intravascular coagulation. The opposite effect was seen with DEGR-VIIa, which prevented the intravascular coagulation but not the pulmonary vascular injury. PKSI did not inhibit the activation of the complement system induced by ET leading to the activation of neutrophils. Findings suggest that PKSI may prevent the pulmonary vascular injury induced by ET by inhibiting kallikrein, which activates the neutrophils. The intrinsic pathway of coagulation may be more important than the extrinsic pathway in the pulmonary vascular injury produced by ET.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Identifying patients at risk of intraoperative and postoperative transfusion in isolated CABG: toward selective conservation strategies.

BACKGROUND: Allogeneic blood product use during cardiac operation is often reported to exceed 40% despite published guidelines and costly blood conservation strategies. We developed a predictive model, based on eight preoperative risk factors, of allogeneic blood product transfusion rates in patients undergoing a cardiac procedure. METHODS: All 3,046 consecutive, isolated coronary artery bypass graft (CABG) procedures at a university hospital from 1995 to 1998 were included. A logistic regression model was created to identify independent predictors of allogeneic blood product transfusion. This model was validated using a prospective patient sample. RESULTS: Overall use of allogeneic blood products was 23% with a crude operative mortality of 2.1%. In isolated, elective, first-time CABG cases, 16.9% received allogeneic blood products. Independent predictors of blood product usage in CABG patients were preoperative hemoglobin 12.0 or less, emergent operation, renal failure, female sex, age 70 years or older, left ventricular ejection fraction 0.40 or less, redo procedure, and low body surface area. Prospective validation of this model on 2,117 consecutive isolated CABG patients demonstrated an observed-to-expected allogeneic blood product transfusion rate ratio of 1.06. CONCLUSIONS: This internally validated logistic regression risk model is a sensitive and specific predictor of allogeneic blood product use in patients undergoing isolated CABG. Utilization of this model allows for preoperative risk stratification and may allow for more rational resource allocation of costly blood conservation strategies and blood bank resources.

Adult↗
PubMed2004

Menorrhagia due to a qualitative deficiency of plasminogen activator inhibitor-1: case report and literature review.

A case is presented of a 26-year-old woman who was referred to the hematology clinic because of her report of a family history of plasminogen activator inhibitor-1 (PAI-1) deficiency. Since menarche, she had suffered from severe menorrhagia, but she had assumed that this was unrelated to her mother's history of repeated life-threatening bleeding. Her menorraghia was evident by using greater than 100 pads per period, bleeding as long as 4 continuous months, and even bleeding through her clothes despite using both tampons and pads. Evaluation with pelvic examination, endometrial biopsy, and pelvic ultrasound was unremarkable. Medroxyprogesterone acetate treatment for her dysfunctional uterine bleeding was unsuccessful. Laboratory evaluation revealed iron deficiency anemia but otherwise normal platelets, bleeding time, prothrombin time, activated partial thromboplastin time, and vonWillebrand's studies. Despite any preconceptions, examination for a fibrinolytic defect ultimately demonstrated a PAI-1 antigen level of 11.4 ng/mL (4.0-43 ng/mL) and PAI-1 activity less than 5 AU/mL (5-37 AU/mL) and clinically supported a diagnosis of a hereditary, qualitative PAI-1 defect. She was treated with aminocaproic acid with return to relatively normal menses. Future treatment should also prevent excessive bleeding during trauma, surgery, or childbirth. Further evaluation of this patient and her family is planned and may help elucidate the important role of PAI-1 in the complicated balance between hemostasis and hemorrhage.

Adult↗
PubMed1999

Effect of Saiboku-to, an Oriental Herbal Medicine, on gastric lesion induced by restraint water-immersion stress or by ethanol treatment.

The effect of saiboku-to on gastric lesions induced by restraint water-immersion stress and ethanol has been examined in rats. Thirty minutes after oral administration of saiboku-to, the rats were placed in restraint cages and immersed in water at 23 degrees C for 7 h, or orally administered 99.5% ethanol (1 mL) and placed in normal cages for 1 h. The stress for 7 h or the ethanol treatment for 1h induced erosion in the glandular area of the stomach. Histology showed that the surface epithelial cells were desquamated and part of the lamina propria mucosae was injured. The evaluation of lesion index, the cumulative length of the gastric lesion, on the gross appearance of the stomach, revealed that saiboku-to dose-dependently inhibited both the water-immersion stress-induced gastric erosion and ethanol-induced gastric erosion. To determine whether the anti-erosion effect of saiboku-to was because of a mild irritant effect, saiboku-to or 20% ethanol, which is known as a typical mild irritant, were given orally. After 30 min a strong irritant, 99.5% ethanol, was given orally. Histological examination was performed 30 min after administration of saiboku-to or the mild irritant, and 1 h after administration of the strong irritant. The mild irritant induced a reduction in surface epithelial cells 30 min after administration. Furthermore, the mild irritant protected the stomach against mucosal erosion produced by the strong irritant. Saiboku-to protected the strong irritant-induced erosion without producing mild irritation as observed in stomach treated with 20% ethanol. Pretreatment with saiboku-to also inhibited the decrease in the levels of hexosamine, gastric mucus glycoprotein, induced by the strong irritant. In pylorus-ligated rats, saiboku-to dose-dependently inhibited gastric acid secretion, a gastric aggressive factor. These results suggest that the anti-erosion effect of saiboku-to which is not a mild irritant, involves both inhibition of aggressive factors, such as gastric acid secretion, and augmentation of defensive factors, such as gastric mucus cells.

Animals↗
PubMed1997

Glycosylation at Asn-289 facilitates the ligand-induced conformational changes of human Glu-plasminogen.

Glu-plasminogen exists in two major glycoforms (I and II). Glycoform I contains carbohydrate chains linked to Asn-289 and Thr-346, whereas glycoform II is glycosylated only at Thr-346. Disparities in carbohydrate content lead to differences in the important functional properties of the zymogen, e.g. the kinetics of activation. The kinetics of the large ligand-induced conformational changes of each of the Glu-plasminogen glycoforms have been studied using stopped-flow fluorescence. The results are in accordance with a conformational change governed by positive co-operative binding at two weak lysine-binding sites. Additional glycosylation at Asn-289 in Glu-plasminogen I results in a two-fold increase in the overall dissociation constant of a ligand, trans-4-aminomethyl-cyclohexane carboxylic acid. This effect stems directly from the reaction step during which the conformational changes occur. This implies a higher population of Glu-plasminogen I in the open conformation even in the absence of ligands, and thus accounts for a higher rate of activation of Glu-plasminogen I, in comparison with Glu-plasminogen II.

Asparagine↗
PubMed1999

Amino acids and peptides. LIII. Synthesis and biological activities of some pseudo-peptide analogs of PKSI-527, a plasma kallikrein selective inhibitor: the importance of the peptide backbone.

Pseudo-peptide analogs of trans-4-aminomethylcyclohexanecarbonyl-L-phenylalanyl-4-aminopheny l acetic acid (PKSI-527, plasma kallikrein selective inhibitor), in which an amide bond (peptide bond) has been replaced by a CH2-NH bond, i.e., trans-4-aminomethylcyclohexanecarbonyl-L-phenylalanyl-psi (CH2-NH)-4-aminophenyl acetic acid (I), trans-4-aminomethylcyclohexanecarbonyl-psi (CH2-NH)-L-phenylalanyl-4-aminophenyl acetic acid (II) and trans-4-aminomethylcyclohexanecarbonyl-D-phenylalanyl-psi (CH2-NH)-4-aminophenyl acetic acid (III) were synthesized. These pseudo-peptide analogs did not exhibit any detectable inhibitory activity against plasma kallikrein (PK), plasmin (PL), urokinase (UK), thrombine (TH) or trypsin (TRY). These results indicate that both carbonyl groups in the PKSI-527 are important for the manifestation of potent inhibitory activity against plasma kallikrein.

Animals↗
PubMed1989

Effect of hyperbaric oxygen therapy on essential haematuria.

Forty-three patients with essential haematuria were studied for 35 days to determine the efficacy of hyperbaric oxygen (OHP) exposure on haemostatic ability. Out of 15 untreated patients, haematuria persisted for the study period in all but one patient (6.7%). Out of 11 patients who received 90 mg/day of carbazochrome sodium sulfate and 750 mg/day of tranexanic acid excellent haemostatic results had been obtained in 2 (18.2%). Results of exposure of 17 patients to 2 atm. pressure of OHP for 90 min daily were excellent in 10 (58.8%) and good in one (5.9%). No serious adverse effects had been noted following OHP treatment. These results indicate that OHP can be applied for the treatment of essential haematuria if routine haemostatic drugs fail to improve the condition.

Adrenochrome↗
PubMed1987

The effects of proteolytic enzymes on in vitro ovulation in the rabbit.

The involvement of proteolytic enzymes in follicle rupture was assessed by use of the in vitro perfused rabbit ovary. Streptokinase (10 and 100 units/ml) induced ovulation in the absence of gonadotropin. Ovulation failed to occur in contralateral control ovaries. The time of ovulation in streptokinase- and human chorionic gonadotropin--treated ovaries was similar, but significantly more ova from streptokinase-treated ovaries were immature (p less than 0.001). Other ovaries were pretreated with trans-4-(aminomethyl)-cyclohexane-carboxylic acid, an inhibitor of the conversion of plasminogen to plasmin, and then perfused with human chorionic gonadotropin (50 IU). Ovulatory efficiency was significantly reduced by trans-4-(aminomethyl)-cyclohexane-carboxylic acid at 10 or 1 mmol/L (p less than 0.001), but ovum maturity was unaffected. Aprotinin (100 or 10 micrograms/ml), a potent inhibitor of plasmin, significantly inhibited human chorionic gonadotropin-induced ovulation (p less than 0.001) but did not affect oocyte maturation. Scanning electron microscopy of detergent-treated streptokinase-perfused ovaries revealed loosening and decomposition of collagen in the tunica albuginea. These results suggest proteolytic enzyme involvement in follicle rupture.

Animals↗
PubMed1993

Syntheses and inhibitory effects on gastric lesions of 4-guanidinomethylbenzoic acid arylamides.

A novel series of 4-guanidinomethylbenzoic acid (GMBA) arylamides was synthesized. Several showed more potent inhibitory effects on stress-induced gastric lesion in rats than cetraxate. We selected 4-guanidinomethylbenzoic acid (2'-ethoxycarbonyl)phenylamide 3 for further pharmacological assessments because it had low toxicity. Compound 3 showed significant inhibitory effects on stress-, HCl-ethanol- and indomethacin-induced gastric lesions and gastric secretion, the ED50 values being 34.4, 45.0 and 23.0 mg/kg (p.o.) and 240 mg/kg (i.d.), respectively. Furthermore, this compound restored the reduction of gastric mucus caused by the stress-loading and inhibited compound 48/80-induced ulcer.

Animals↗
PubMed2002

Enzymatic preparation of D-beta-acetylthioisobutyric acid and cetraxate hydrochloride using a stereo- and/or regioselective hydrolase, 3,4-dihydrocoumarin hydrolase from Acinetobacter calcoaceticus.

3,4-Dihydrocoumarin hydrolase (DCH) from Acinetobacter calcoaceticus F46, which was previously found on screening for aromatic lactone-hydrolyzing enzymes, catalyzes the hydrolysis of several linear esters. The substrate specificity of the enzyme toward linear esters was quite characteristic, i.e., (1) it was specific toward methyl esters, (2) it recognized the configuration at the 2-position, and (3) it hydrolyzed diesters to monoesters. DCH hydrolyzed the methyl esters of beta-acetylthioisobutyrate and cetraxate. The products of these reactions were identified as D-beta-acetylthioisobutyrate and cetraxate, respectively, i.e., the hydrolysis reactions catalyzed by DCH were stereo- and/or regioselective. With recombinant Escherichia coli cells expressing the DCH gene as a catalyst, stereospecific hydrolysis of methyl beta-acetylthioisobutyrate and regioselective hydrolysis of methyl cetraxate proceeded efficiently.

Acinetobacter calcoaceticus↗