Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyposensitivity to vasopressin is a well documented phenomenon in animals with portal hypertension and patients with cirrhosis subject to haemorrhage. Haemorrhage is associated with the endogenous release of bradykinin, which may subsequently stimulate the formation of nitric oxide (NO). The present study investigated the relative contribution of NO synthase (NOS) isoforms and the role of bradykinin in the pathogenesis of splanchnic hyposensitivity to a long-acting vasopressin analogue, glypressin, in rats with portal hypertension induced by partial portal vein ligation (PVL). At 14 days after the operation, systemic and portal haemodynamics were measured in stable or bleeding PVL rats receiving an intravenous infusion of glypressin (0.07 mg/kg). In the treatment groups, N(G)-nitro-L-arginine methyl ester (L-NAME; a non-selective NOS inhibitor), L-canavanine (a specific inhibitor of inducible NOS) or HOE 140 (a bradykinin B(2) receptor antagonist) was administered 45 min before the infusion of glypressin. In rats with a hypotensive haemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was re-infused before the administration of glypressin or various inhibitors. Splanchnic hyposensitivity to glypressin was demonstrated in the haemorrhage/transfused PVL rats. The infusion of L-NAME elevated the mean arterial pressure in the bleeding PVL rats without the modulation of portal pressure. The addition of L-NAME or HOE 140, but not L-canavanine, significantly and similarly potentiated the portal-hypotensive effects of glypressin. It is concluded that constitutive NOS and bradykinin are responsible, at least partly, for the splanchnic hyposensitivity to glypressin observed in the early stages of the haemorrhage/transfused rat model of portal hypertension.
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PMID:Splanchnic hyposensitivity to glypressin in a haemorrhage/transfused rat model of portal hypertension: role of nitric oxide and bradykinin. 1109 89

The endothelium, a continuous cellular monolayer lining the blood vessels, has an enormous range of important homeostatic roles. It serves and participates in highly active metabolic and regulatory functions including control of primary hemostasis, blood coagulation and fibrinolysis, platelet and leukocyte interactions with the vessel wall, interaction with lipoprotein metabolism, presentation of histocompatibility antigens, regulation of vascular tone and growth and further of blood pressure. Many crucial vasoactive endogenous compounds like prostacyclin, thromboxane, nitric oxide, endothelin, angiotensin, endothelium derived hyperpolarizing factor, free radicals and bradykinin are formed in the endothelial cells to control the functions of vascular smooth muscle cells and of circulating blood cells. These versatile and complex systems and cellular interactions are extremely vulnerable. The balances may be disturbed by numerous endogenous and exogenous factors including psychological and physical stress, disease states characterized by vasospasm, inflammation, leukocyte and platelet adhesion and aggregation, thrombosis, abnormal vascular proliferation, atherosclerosis and hypertension. The endothelial cells are also the site of action of many drugs and exogenous toxic substances (e.g. smoking, alcohol). As markers and assays for endothelial dysfunction, direct measurement of nitric oxide, its metabolites from plasma and urine, functional measurement of vascular nitric oxide dependent responses and assay of different circulating markers have been used. In numerous pathological conditions (e.g. atherosclerosis, hypertension, congestive heart failure, hyperhomocysteinemia, diabetes, renal failure, transplantation, liver cirrhosis) endothelial dysfunction has been described to exist. Some of them, as well as hormonal and nutritional factors and drug treatment will be discussed in this short review.
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PMID:Clinically important factors influencing endothelial function. 1153 60

Bradykinin, a nonapeptide with vasodilatory and permeabilizing activity, is generated through the cleavage of high-M(r) ('high-molecular-weight') kininogen by kallikrein, and its generation is facilitated by plasmin. In the ascitic fluid of patients with cirrhosis, there is massive cleavage of high-M(r) kininogen and activation of fibrinolysis, but bradykinin has never been measured directly. In the ascitic fluid of 24 patients with cirrhosis, we measured bradykinin-(1-9)-nonapeptide levels by RIA after liquid-phase and subsequent HPLC extraction, and those of its catabolic product bradykininin-(1-5)-pentapeptide by ELISA after liquid-phase extraction. Cleaved high-M(r) kininogen, activated factor XII and plasmin-antiplasmin complexes were measured in ascitic fluid and plasma. Plasma renin activity (PRA) was also determined. As a control, we also analysed plasma from 24 healthy subjects matched for sex and age with the patients. In the ascitic fluid from patients with cirrhosis, the median bradykinin-(1-9) concentration was 3.3 fmol/ml (range 0.2-29.0 fmol/ml), and the median bradykinin-(1-5) concentration was 210 fmol/ml (range 58-7825 fmol/ml). The levels of bradykinin-(1-5) in ascitic fluid were higher in patients with refractory ascites [median 1091 fmol/ml (range 58-7825 fmol/ml)] than in patients with responsive ascites [134 fmol/ml (72-1084 fmol/ml)] (P=0.010). Ascitic fluid levels of bradykinin-(1-9) were not related to the severity of ascites. PRA was higher in patients with refractory ascites [23.0 ng x h(-1) x ml(-1) (7.9-80.0 ng.h(-1).ml(-1))] than in patients with responsive ascites [6.9 ng x h(-1) x ml(-1) (0.9-29.4 ng x h(-1) x ml(-1))] (P=0.002). In ascitic fluid, 48% (19-68%) of high-M(r) kininogen was cleaved, and plasmin-antiplasmin complexes were more concentrated than in plasma (P=0.0001). In conclusion, in the ascitic fluid of patients with cirrhosis, both bradykinin-(1-9) and bradykinin-(1-5) are present, with cleavage of high-M(r) kininogen and activation of fibrinolysis. The highest levels of the long-lived metabolite bradykinin-(1-5) were found in the ascitic fluid of patients with refractory ascites and high PRA. Activation of the kinin system may therefore be involved in decompensating cirrhosis, but a cause-effect relationship remains to be established.
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PMID:Bradykinin in the ascitic fluid of patients with liver cirrhosis. 1172 53

The discovery of the kinin system is not recent, but its study in clinical field has been done only in the last years. This system is composed by substrates (kininogens) and plasma and tissue kallikreins are the specific activators of these substrates producing two vasoactive peptides called bradykinin and kallidin. The biologic effects of kinins are mediated by specific receptors called B1 and B2. The activation of this system is particularly important in blood pressure regulation and in inflammatory reactions. The kinin system is involved in many clinical situations including respiratory allergic reactions, septic shock, hypertension and its treatment, hypotensive transfusion reactions, heart diseases, pancreatitis, hereditary and acquired angioedema, Alzheimer's disease and liver cirrhosis with ascites. The study of the kinin system in clinical field, which had been limited by methodological difficulties, has now received an important stimulus by the recent availability of specific and sensitive methods of dosage.
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PMID:[The kinin system: biological mechanisms and clinical implications]. 1182 1

Icatibant [HOE 140, JE 049] is a potent, specific and selective peptidomimetic bradykinin beta2-receptor antagonist. It has a modified peptide structure, and is the first bradykinin receptor antagonist to act on the guinea-pig trachea without demonstrating agonist effects. Icatibant was originated by Hoechst Marion Roussel (now Sanofi-Aventis). Jerini is seeking a partner for development and marketing of icatibant for the treatment of refractory ascites in liver cirrhosis, angioedema and burns. In August 2004, Aventis merged with Sanofi-Synthelabo to form Sanofi-Aventis.Icatibant has shown an excellent safety profile in phase I studies. In December 2003, Jerini demonstrated positive results in the phase IIa study. Results obtained were statistically significant and clinically relevant. At the BIO 2004 International Annual Convention (BIO-2004) [San Francisco, CA, USA; 6-9 June 2004], Jerini reported plans to initiate phase IIb trials in this indication in the second half of 2004. Positive results from an icatibant formulation comparative study, in patients with acute attacks of hereditary angioedema, were announced in August 2004; IV and SC formulations showed no difference in efficacy and safety. It was announced in September 2004 by Jerini that a pivotal study, known as For Angioedema Subcutaneous Treatment (FAST) 1, had been initiated in the US and Canada. The protocol of a European study, to be known as FAST 2, is to be submitted to the authorities in September 2004. Jerini expects to launch the product in 2006. The US FDA granted icatibant, for the treatment of hereditary angioedema, fast-track designation in July 2004. In January 2003, the European Agency for the Evaluation of Medicinal Products granted icatibant orphan drug status in Europe for the treatment of angioedema. In November 2003, Jerini announced that effective December 2003, icatibant had orphan drug status in the US for the same indication.
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PMID:Icatibant: HOE 140, JE 049, JE049. 1556 38

Icatibant [HOE 140, JE 049] is a potent, specific and selective peptidomimetic bradykinin B2-receptor antagonist. It has a modified peptide structure, and is the first bradykinin receptor antagonist to act on the guinea-pig trachea without demonstrating agonist effects. Icatibant was originated by Hoechst Marion Roussel (now sanofi-aventis). Jerini AG is seeking a worldwide partner for the development and marketing of icatibant for the treatment of refractory ascites in liver cirrhosis and seeking a partner in Asia, North America, South America and Australia for angioedema. In August 2004, Aventis merged with Sanofi-Synthelabo to form sanofi-aventis. Icatibant has shown an excellent safety profile in phase I studies. In December 2003, Jerini demonstrated positive results in the phase IIa study. Results obtained were statistically significant and clinically relevant. At the BIO 2004 International Annual Convention (BIO-2004) [San Francisco, CA, USA; 6-9 June 2004], Jerini reported plans to initiate phase IIb trials in this indication in the second half of 2004. It was announced in September 2004 by Jerini that a pivotal registration study, known as FAST 1 (For Angioedema Subcutaneous Treatment), had been initiated in the US and Canada. The protocol of a European study, known as FAST 2, was submitted to the authorities in September 2004. Jerini is currently conducting pivotal/registration trials for angioedema in the US, Canada and Europe. During the 3rd Annual BioPartnering North America Conference (BPN-2005), Jerini announced that it expects to complete registration trials in the second half of 2005/first half of 2006, with a launch of icatibant for HAE in 2007. The US FDA granted fast-track status to icatibant in July 2004 for the treatment of HAE. Effective December 2003, icatibant gained orphan drug status in the US for the same indication. Previously, in January 2003, the European Agency for the Evaluation of Medicinal Products granted icatibant orphan drug status in Europe for the treatment of angioedema.
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PMID:Icatibant: HOE 140, JE 049, JE049. 1599 85

Neutral endopeptidase degrades atrial natriuretic peptide (ANP) and bradykinin and may generate endothelin-1 from big-endothelin. In advanced cirrhosis, sodium retention is accompanied by elevated plasma ANP levels, and infusion of ANP causes hypotension, but in normal humans increasing the concentration of ANP through the inhibition of neutral endopeptidase, localized in renal proximal tubule cells, causes natriuresis without any arterial pressure drop. The purpose of this study was the assessment of kidney neutral endopeptidase expression and responses to candoxatrilat (a specific inhibitor of this enzyme) in rats with CCl4-induced cirrhosis. Two groups of control rats (n = 5) were injected with vehicle or 3 mg/kg candoxatrilat. Three groups of cirrhotic rats with ascites (n = 10) received vehicle alone or 3 or 10 mg/kg candoxatrilat. In cirrhotic rats, Western blot analysis revealed a 170% increase in renal neutral endopeptidase protein content (P < 0.03), mainly in the proximal nephron and macula densa, and both candoxatrilat dosages increased plasma ANP levels, urinary volume, and urinary excretion of sodium, ANP, and cGMP compared with vehicle alone (all P < 0.03). Candoxatrilat (10 mg/kg) also reduced tubular solute-free water reabsorption (P < 0.03) in cirrhotic rats, but renal blood flow, arterial pressure, and plasma renin activity were unaffected. Neutral endopeptidase inhibition has natriuretic and aquaretic actions in cirrhosis without any effect on blood pressure and kidney perfusion due to a significant overexpression of this enzyme in renal cortex.
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PMID:Overexpression of kidney neutral endopeptidase (EC 3.4.24.11) and renal function in experimental cirrhosis. 1644 55

Bradykinin is an endothelium-dependent vasodilator and inflammatory mediator. The aim of the present study was to examine the effects of bradykinin on peripheral vascular tone in patients with cirrhosis and ascites. Forearm blood flow was measured using venous occlusion plethysmography in 8 patients with biopsy-proven alcohol-induced cirrhosis, ascites, and portal hypertension, and 8 age- and sex-matched healthy controls. On 1 occasion, subjects received an intrabrachial infusion of the selective bradykinin antagonist B9340 (1.5-13.5 nmol/min) followed by a control vasoconstrictor norepinephrine (60-540 pmol/min), and on another occasion bradykinin (100-900 pmol/min) followed by the endothelium-independent vasodilator, sodium nitroprusside (SNP, 2-8 microg/min). Bradykinin and SNP caused a dose-dependent vasodilatation (P < 0.001 for both) that did not differ between the 2 groups. Although norepinephrine caused a similar dose-dependent vasoconstriction in both groups (P < 0.001), B9340 had no effect on forearm blood flow in either group (at 13.5 nmol/min in patients; -5%, 95% CI -13-3). Bradykinin does not provide a major contribution to the maintenance of peripheral vascular tone in patients with cirrhosis and ascites. Our findings also suggest that, in contrast to cardiovascular disease, patients with liver cirrhosis do not have marked endothelial dysfunction.
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PMID:Bradykinin does not contribute to peripheral vascular tone in patients with cirrhosis and ascites. 1668 69

There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental.
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PMID:Therapeutic potential of icatibant (HOE-140, JE-049). 1871 Mar 62

Changes in glycosylation, most notably fucosylation, have been associated with the development of hepatocellular carcinoma (HCC). In this report, the levels of fucosylated kininogen (Fc-Kin) and fucosylated alpha-1-antitrypsin were analyzed individually and in combination with the currently used marker, alpha-fetoprotein, and a previously identified biomarker, Golgi protein 73 (GP73), for the ability to distinguish between a diagnosis of cirrhosis and HCC. This analysis was done on serum from 113 patients with cirrhosis and 164 serum samples from patients with cirrhosis plus HCC. The levels of Fc-Kin and fucosylated alpha-1-antitrypsin were significantly higher in patients with HCC compared with those with cirrhosis (P < 0.0001). Greatest performance was achieved through the combination of Fc-Kin, alpha-fetoprotein, and GP73, giving an optimal sensitivity of 95%, a specificity of 70%, and an area under the receiver operating characteristic of 0.94. In conclusion, the altered glycosylation of serum glycoproteins can act as potential biomarkers of primary HCC when used independently or in combination with other markers of HCC.
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PMID:Novel fucosylated biomarkers for the early detection of hepatocellular carcinoma. 1945 16


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