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)

Tyrosine (Tyr), tyrosine hydroxylase (TH), tryptophan (Trp), serotonin (5-HT), and 5-hydroxyindole acetic acid (5-HIAA) were assayed spectrofluorometrically and radioenzymatically in various regions of post-mortem brains of human patients with hepatic, uremic, and diabetic coma, liver cirrhosis without coma, and hepatic coma treated with parenteral administration of L-valine, a branched-chain amino acid. The results were as follows: In both hepatic and diabetic coma Tyr was increased as compared to non-comatose cirrhosis and controls, while TH acitivity was within normal limits, indicating sufficient oxygen supply of the brain in both types of coma. Brain DA showed a mild decrease in all types of metabolic coma. Brain Trp was not considerably changed in non-comatose cases of liver cirrhosis and after L-valine treatment of hepatic encephalopathy, but was significantly increased in hepatic coma, with highest elevation in the brainstem tegmentum. Both 5-HT and 5-HIAA were not significantly changed in non-comatose cirrhosis, while a general increase with prevalence for the brainstem was obvious in all types of metabolic coma. After L-valine treatment of hepatic coma, 5-HT levels were usually decreased below control values, while 5-HIAA levels were at or below controls. These results in human post-mortem brains confirm previous CSF and brain findings in experimental and human hepatic and uremic encephalopathies, indicating derangement of brain monoamine neurotransmitter metabolism which is attributed to imbalance of aromatic and branched-chain amino acids in plasma and brain. Increased cerebral 5-HT turnover, particularly in the ascending serotonergic brainstem systems, due to derangement of brain uptake of Trp is suggested to represent an important biochemical substrate of disorders of consciousness in hepatic failure and other types of metabolic encephalopathies. Clinical improvement of hepatic encephalopathy and of the underlying neurotransmitter derangements by administration of L-valine and the possible role of this competitive amino acid on intermediary metabolism and ammonia detoxification are discussed.
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PMID:Brain monoamines in hepatic encephalopathy and other types of metabolic coma. 3 73

The changes of humoral substances in the blood of cirrhotic rats were studied together with their effects on portal hemodynamics at different stages during the development of cirrhosis. The profiles of humoral substances and hemodynamics in two different cirrhotic rat models were also investigated. During the development of cirrhosis, glucagon increased markedly in all stages, histamine and vasoactive intestinal polypeptide (VIP) increased in the early stage, serotonin (5-HT) and somatostatin (SS) increased in the middle and late stages. There were different patterns of humoral substances in different cirrhotic models. Glucagon was the main humoral substance elevated in CCL4 induced cirrhosis, but histamine and 5-HT were mainly elevated in the blood in thioacetamide (TAA) induced cirrhosis. The hemodynamics altered differently in different stages during the development of cirrhosis and differently in the two cirrhotic rat models. Exchange transfusions between normal and cirrhotic rats resulted in an elevation of portal flow in normal rats, but no such changes were found after exchange pressure and an increase of portal blood transfusions between normal rats. The relationship between the humoral substances and portal hemodynamics is discussed. The results of this study strongly support the hypothesis of "humoral mechanism" in the pathogenesis of portal hypertension due to cirrhosis.
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PMID:Changes of blood humoral substances in experimental cirrhosis and their effects on portal hemodynamics. 212 49

The change of humoral substances in the blood of cirrhotic rat was studied at different stages of development, together with their effects on the portal hemodynamics. The profiles of humoral substances and hemodynamics in two different cirrhotic rat models, as well as the changes of portal hemodynamics in the normal rats after perfusion with the arterial blood from cirrhotic rats were also investigated. It was found that: during the development of cirrhosis, glucagon increased markedly at all stages, histamine and vasoactive intestinal polypeptide (VIP) increased at early stage only, while serotonin (5-HT) and somatostatin(SS) increased at middle and advanced stages. In the CCl4 induced cirrhosis, glucagon was the main humoral substance, whereas in the thioacetamide (TAA) induced cirrhosis, histamine and 5-HT were mainly elevated. The portal hemodynamics altered differently in different stages during the development of cirrhosis and in the two different cirrhotic rat models. The perfusion with the arterial blood from cirrhotic rats caused an increase of portal venous pressure and portal venous flow in normal rats.
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PMID:[Changes in humoral substances in induced cirrhosis and their effects on portal hemodynamics]. 257 72

The Authors, after having examined the factors responsible for the hyperprolactinemia in the cirrhotic, confirm the lack of a relationship between the increase in the prolactinic reserve and gynecomastia and between the amount of the prolactinic reserve and the degree of liver disorder. While hyperestrinism and the false transmitters lost most of their pathogenetic importance, other factors such as GABA, the Serotonin and the VIP, offered a new pathogenetic prospective. The prolactin reserve was studied in 63 patients affected by cirrhosis and in 25 affected by fibrosis and hepatic fibrosteatosis, pointing out an increase in the prolactin reserve in 61% of cirrhotic patients and an absence of pathological reports in patients affected by fibrotic hepatopathies. These data confirm the low pathogenetic responsability to be strictly ascribed to ethanol and the preminent role of liver cirrhosis and portal hypertension in the prolactin turnover.
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PMID:[Prolactin in chronic alcoholic liver diseases with and without gynecomastia]. 388 40

The pharmacokinetics of femoxetine (a 5-HT uptake inhibitor with antidepressive effect) was studied in 12 patients with liver cirrhosis and in 6 healthy controls after a single oral dose of femoxetine HC1. The average blood concentration of femoxetine, as assessed by the values of AUC (area under the plasma concentration/time curve), was significantly higher in the patients with liver cirrhosis than in the healthy controls in spite of dose reduction in the patients. The elimination half-life of femoxetine was within the normal limits in most of the patients. The oral clearance of femoxetine was considerably lower in patients, (0.65-4.02 1/hr/kg) than in the controls (8.13- greater than 50 1/hr/kg). It was not directly related to the metabolic function of the liver, measured as the galactose elimination capacity being 0.015-0.024 mmol/min./kg and 0.033-0.041 mmol/min./kg, respectively. When treating patients with reduced liver function, it is recommended to reduce the doses and to monitor closely the plasma levels.
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PMID:Femoxetine clearance in patients with liver cirrhosis. 652 8

The pharmacokinetics of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) with antidepressant properties, are well established. After oral administration, the drug is almost completely absorbed from the gastrointestinal tract, and the extent of absorption is unaffected by the presence of food. Despite complete absorption, oral bioavailability in man is approximately 50% on account of first-pass hepatic metabolism. Peak plasma fluvoxamine concentrations are reached 4 to 12 hours (enteric-coated tablets) or 2 to 8 hours (capsules, film-coated tablets) after administration. Steady-state plasma concentrations are achieved within 5 to 10 days after initiation of therapy and are 30 to 50% higher than those predicted from single dose data. Fluvoxamine displays nonlinear steady-state pharmacokinetics over the therapeutic dose range, with disproportionally higher plasma concentrations with higher dosages. Plasma fluvoxamine concentrations show no clear relationship with antidepressant response or severity of adverse effects. Fluvoxamine undergoes extensive oxidative metabolism, most probably in the liver. Nine metabolites have been identified, none of which are known to be pharmacologically active. The specific cytochrome P450 (CYP) isoenzymes involved in the metabolism of fluvoxamine are unknown. CYP2D6, which is crucially involved in the metabolism of paroxetine and fluoxetine, appears to play a clinically insignificant role in the metabolism of fluvoxamine. The drug is excreted in the urine, predominantly as metabolites, with only negligible amounts ( < 4%) of the parent compound. Fluvoxamine shows a biphasic pattern of elimination with a mean terminal elimination half-life of 12 to 15 hours after a single oral dose; this is prolonged by 30 to 50% at steady-state. Plasma protein binding of fluvoxamine (77%) is low compared with that of other SSRIs. Fluvoxamine pharmacokinetics are substantially unaltered by increased age or renal impairment. However, its elimination is prolonged in patients with hepatic cirrhosis. Fluvoxamine inhibits oxidative drug metabolising enzymes (particularly CYP1A2, and less potently and much less potently CYP3A4 and CYP2D6, respectively) and has the potential for clinically significant drug interactions. Drugs whose metabolic elimination is impaired by fluvoxamine include tricyclic antidepressants (tertiary, but not secondary, amines), alprazolam, bromazepam, diazepam, theophylline, propranolol, warfarin and, possibly, carbamazepine. Fluvoxamine is a second generation antidepressant that selectively inhibits neuronal reuptake of serotonin (5-hydroxytryptamine; 5-HT). Fluvoxamine exhibits antidepressant activity similar to that of the tricyclic antidepressants, but has a somewhat improved tolerability profile, particularly with respect to a lower incidence of anticholinergic effects and reduced cardiotoxic potential. However, gastrointestinal adverse effects, especially nausea, are seen more frequently with fluvoxamine than with the tricyclic antidepressants. Fluvoxamine does not have an asymmetric carbon in its structure (fig. 1) and therefore does not exist as optical isomers. For this reason, the potentially confounding problem of stereoisomerism does not arise with fluvoxamine.
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PMID:Overview of the pharmacokinetics of fluvoxamine. 884 17

The present experiment employed the immunohistochemical technique and morphological observation to investigate the expression and distribution of C3, C4, IgG, IgE 5-HT in portal hypertensive pigs with pathological change of gastric mucosa and gastric parietal vessels. The wall of gastric mucosal mirco-vessels in portal hypertensive pigs had a positive or strong positive reaction of C3, C4, IgG, IgE and 5-HT with obvious injury of gastric mucosa normal pigs imparted negative or feeble positive reaction, suggesting that during portal hypertension, the gastric mucosal micro-vessels has deposit of immunocomplexes resulting in the injury of the micro-vessels. It might be a factor involved in the pathogenesis of the gastric mucosal lesion during portal hypertension with cirrhosis.
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PMID:Role of injury of gastric parietal vessels by immunocomplexes in the mechanism of gastric mucosal lesion in portal hypertension with cirrhosis. 963 85

Primary hepatic carcinoid and neuroendocrine carcinoma (NEC) are rare tumors. We experienced three carcinoids and two NEC originating in the liver during the past 25 years and attempted to elucidate the clinicopathological and immunohistochemical features of these tumors. The patients had no endocrine symptoms despite two of them having elevated plasma serotonin. Three of the five patients died of the tumor after operation with an average survival time of 20.6 months. All tumors were large (up to 26 cm in diameter), four of them solitary and one multinodular, and were not associated with liver cirrhosis. The carcinoid tumors showed insular, trabecular or glandular arrangement of argyrophilic cells, whereas in the NEC this histological pattern was distorted. Immunohistochemically the tumors showed expression of chromogranin A (all cases), chromogranin B (three cases), pancreastatin and chromostatin (four cases, respectively), prohormone convertase PC3 (three cases), carcinoembryonic antigen (CEA) and CA19-9 (two cases), cytokeratin 56 kDa (three cases), 160 kDa neurofilament (two cases) and neuron-specific enolase (two cases). Serotonin and glucagon were sporadically detected in two tumors. The most useful marker to confirm the diagnosis was chromogranin A, which was cleaved to pancreastatin and chromostatin in the tumor tissue, and was more reliable than other markers of neuroendocrine differentiation.
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PMID:Primary hepatic carcinoid and neuroendocrine carcinoma: clinicopathological and immunohistochemical study of five cases. 1036 51

Anorexia or loss of appetite, one of the most typical symptoms observed in experimental and human cirrhosis, has been proposed to be associated with altered brain serotonin (5-HT) metabolism. In order to evaluate this hypothesis, brain 5-HT, its precursor tryptophan (TRP) and its metabolite 5-hydroxyindole-acetic acid (5-HIAA) were measured in brains of rats with thioacetamide (TAA)-induced liver cirrhosis. Thioacetamide at a dose of 500 mg/l in drinking water was administered for 6 weeks and during this period food intake was carefully measured in order to monitor the loss of appetite or decrease in food intake observed in cirrhosis. Concentrations of brain TRP, 5-HT and 5-HIAA were measured by HPLC with electrochemical detection. In TAA-treated rats, concentrations of 5-HT, TRP and 5-HIAA were increased in brain (44%, 33% and 36% of controls, p < 0.01). In plasma and liver of cirrhotic rats, TRP levels were increased (195% and 43%; p < 0.01). Plasma glucose and albumin levels were decreased (50%; p < 0.01 and 31%). Food intake, growth rate and locomotor activity of TAA-treated rats also decreased (73%, 22% and 73% of controls; p < 0.01). The results of this study show that brain 5-HT concentration in rats is increased in TAA-treated rats and it may, therefore, play an important role in the pathogenesis of anorexia associated with TAA-induced cirrhosis.
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PMID:Is anorexia in thioacetamide-induced cirrhosis related to an altered brain serotonin concentration? 1504 80

The human cardiovascular system is exposed to plasma 5-hydroxytryptamine (5-HT, serotonin), usually released from platelets. 5-HT can produce harmful acute and chronic effects. The acute cardiac effects of 5-HT consist of tachycardia (preceded on occasion by a brief reflex bradycardia), increased atrial contractility and production of atrial arrhythmias. Acute inotropic, lusitropic and arrhythmic effects of 5-HT on human ventricle become conspicuous after inhibition of phosphodiesterase (PDE) activity. Human cardiostimulation is mediated through 5-HT4 receptors. Atrial and ventricular PDE3 activity exerts a protective role against potentially harmful cardiostimulation. Chronic exposure to high levels of 5-HT (from metastatic carcinoid tumours), the anorectic drug fenfluramine and its metabolites, as well as the ecstasy drug 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA) are associated with proliferative disease and thickening of cardiac valves, mediated through 5-HT2B receptors. 5-HT2B receptors have an obligatory physiological role in murine cardiac embryology but whether this happens in humans requires research. Congenital heart block (CHB) is, on occasion, associated with autoantibodies against 5-HT4 receptors. Acute vascular constriction by 5-HT is usually shared by 5-HT1B and 5-HT2A receptors, except in intracranial arteries which constrict only through 5-HT1B receptors. Both 5-HT1B and 5-HT2A receptors can mediate coronary artery spasm but only 5-HT1B receptors appear involved in coronary spasm of patients treated with triptans or with Prinzmetal angina. 5-HT2A receptors constrict the portal venous system including oesophageal collaterals in cirrhosis. Chronic exposure to 5-HT can contribute to pulmonary hypertension through activation of constrictor 5-HT1B receptors and proliferative 5-HT2B receptors, and possibly through direct intracellular effects.
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PMID:5-hydroxytryptamine receptors in the human cardiovascular system. 1696 Sep 82


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