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)

The traditional concept of adipose tissue as a passive reservoir for energy storage is no longer valid because it has been demonstrated that adipose tissue is a complex, essential, and highly active metabolic and endocrine organ that not only responds to afferent signals from traditional hormone systems and the central nervous system (CNS), but also expresses and secretes factors with important endocrine functions. These factors include leptin and other cytokines. Adipose tissue is also a major site for metabolism of sex steroids and glucocorticoids. The important endocrine function of adipose tissue is emphasized by adverse metabolic consequences of both adipose tissue excess and deficiency. Adipose tissue excess, particularly in visceral compartment, is associated with insulin resistance, hyperglycemia, dyslipidemia, hypertension, and prothrombotic and proinflammatory states. Liver is one of the principal targets of lipid-associated damage by mechanisms that involve apoptosis activation by source of tumoral necrosis factor-alpha and caspase activation and liberation of oxygen-reactive species by oxidative stress and enzymatic chains such as P450, CYP2E1, and CYP3A4, resulting in a continuum involving non alcohol-related fatty liver, non-alcoholic steatohepatitis with or without fibrosis, and liver cirrhosis. This work presents an overview of endocrine functions of adipose tissue and its influence on mechanisms of liver damage.
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PMID:[Obesity and steatohepatitis. Histologic aspects]. 1564 70

We focused on the establishment of a trial procedure for the collection and distribution of Japanese liver tissues obtained from waste surgical resections for drug development and research use. The following procedures were prepared for this project: the pretreatment of liver tissues before storage, their storage at 4 degrees C, the transport of liver samples, the setting up of a communication network among the participating hospitals and laboratories and the approval of each ethics committee. Thirteen liver samples (1.6-7.6 g) obtained from patients whose livers were excised due to cirrhosis, hepatocellular carcinoma, cholangiocarcinoma, or metastasis from colorectal carcinoma and were donated for research. Informed consent was obtained from every patient. Freshly isolated human hepatocytes were prepared from nine liver samples (viability 34.3-86.1%). Four samples were unsuitable to prepare hepatocytes. The profile of testosterone metabolism as 6beta-, 2beta-, 16beta-, 16alpha- and 2alpha-hydroxytestosterone and androstenedione in freshly isolated hepatocytes was shown to be specific for human liver. The 6beta-hydroxylation activity catalyzed by CYP3A4/5 indicated a high level of metabolism (139-996 pmol/min/million cells). Levels of 7-ethoxycoumarin O-deethylation and glucronidation activities were sufficient for analysis in freshly isolated human hepatocytes. We conclude that liver tissues from waste surgical resections supplied from a participating hospital can constitute a valuable source of freshly isolated human hepatocytes for drug development and safety evaluation.
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PMID:[Network for the collection and distribution of Japanese liver tissues resected surgically for drug development and research use]. 1654 56

Several fluid retentive states such as heart failure, cirrhosis of the liver, and syndrome of inappropriate antidiuretic hormone secretion are associated with inappropriate elevation in plasma levels of arginine vasopressin (AVP), a neuropeptide that is secreted by the hypothalamus and plays a critical role in the regulation of serum osmolality and in circulatory homeostasis. The actions of AVP are mediated by three receptor subtypes V1a, V2, and V1b. The V1a receptor regulates vasodilation and cellular hypertrophy while the V2 receptor regulates free water excretion. The V1b receptor regulates adrenocorticotropin hormone release. Conivaptan is a nonpeptide dual V1a/V2 AVP receptor antagonist. It binds with high affinity, competitively, and reversibly to the V1a/V2 receptor subtypes; its antagonistic effect is concentration dependent. It inhibits CYP3A4 liver enzyme and elevates plasma levels of other drugs metabolized by this enzyme. It is approved only for short-term intravenous use. Infusion site reaction is the most common reason for discontinuation of the drug. In animals conivaptan increased urine volume and free water clearance. In heart failure models it improved hemodynamic parameters and free water excretion. Conivaptan has been shown to correct hyponatremia in euvolemic or hypervolemic patients. Its efficacy and safety for short-term use have led to the Food and Drug Administration (FDA) approval of its intravenous form for the correction of hyponatremia in euvolemic and hypervolemic states. Despite its ability to block the action of AVP on V1a receptors, no demonstrable benefit from this action was noted in patients with chronic compensated heart failure and it is not approved for this indication. Consideration should be given to further evaluation of its potential benefits in patients with acute decompensated heart failure.
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PMID:Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected]. 1791 59

Many drugs, including most antiarrhythmics (some of which are now of limited clinical use) are eliminated by the hepatic route. If liver function is impaired, it can be anticipated that hepatic clearance will be delayed, which can lead to more pronounced drug accumulation with multiple dosing. Consequently, the potential risks of adverse events could be increased, especially as antiarrhythmics have a narrow therapeutic index. The present review summarises the available pharmacokinetic data on the most popular antiarrhythmic drugs to identify the enzymes involved in the metabolism of the various agents and confirm whether liver disease affects their elimination. Despite long usage of some of these drugs (e.g. amiodarone, diltiazem, disopyramide, procainamide and quinidine), surprisingly few data are available in patients with liver disease, making it difficult to give recommendations for dosage adjustment. In contrast, for carvedilol, lidocaine (lignocaine), propafenone and verapamil, sufficient clinical studies have been performed. For these drugs, a marked decrease in systemic and/or oral clearance and significant prolongation of the elimination half-life have been documented, which should be counteracted by a 2- to 3-fold reduction of the dosage in patients with moderate to severe liver cirrhosis. For sotalol, disopyramide and procainamide, renal clearance contributes considerably to overall elimination, suggesting that dosage reductions are probably unnecessary in patients with liver disease as long as renal function is normal. The hepatically eliminated antiarrhythmics are metabolised mainly by different cytochrome P450 (CYP) isoenzymes (e.g. CYP3A4, CYP1A2, CYP2C9, CYP2D6) and partly also by conjugations. As the extent of impairment in clearance is in the same range for all of these agents, it could be assumed that they have a common vulnerability and that, consequently, hepatic dysfunction will affect CYP-mediated phase I pathways in a similar fashion. The severity of liver disease has been estimated clinically by the validated Pugh score, and functionally by calculation of the clearance of probe drugs (e.g. antipyrine). Both approaches can be helpful in estimating/predicting impairments in drug metabolism, including antiarrhythmics. In conclusion, hepatic impairment decreases the elimination of many antiarrhythmics to such an extent that dosage reductions are highly recommended in such populations, especially in patients with cirrhosis.
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PMID:Antiarrhythmics: elimination and dosage considerations in hepatic impairment. 1802 86

Tolvaptan is a selective arginine vasopressin (AVP) V(2) receptor blocker used to induce free water diuresis in the treatment of euvolemic or hypervolemic hyponatremia. Currently the orally active medication is in the final stages prior to approval by the FDA for outpatient therapy. It appears to be safe and effective at promoting aquaresis and raising serum sodium levels in both short- and long-term studies. Tolvaptan is also effective for treatment of congestive heart failure (CHF) exacerbation, but whether there are long standing beneficial effects on CHF is still controversial. Prolonged use of tolvaptan leads to increased endogenous levels of AVP and perhaps over-stimulation of V(1A) receptors. Theoretically this activation could lead to increased afterload and cardiac myocyte fibrosis, causing progression of CHF. However, after 52 weeks of tolvaptan therapy there was no worsening of left ventricular dilatation. In addition, tolvaptan is metabolized by the CYP3A4 system; thus physicians should be aware of the potential for increased interactions with other medications. Tolvaptan is a breakthrough in the therapy of hyponatremia as it directly combats elevated AVP levels associated with the syndrome of inappropriate secretion of antidiuretic hormone, congestive heart failure, and cirrhosis of the liver.
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PMID:Tolvaptan and its potential in the treatment of hyponatremia. 1933 22

Hepatocellular adenomas (HCA) and some hepatocellular carcinomas (HCC) arise in the non-cirrhotic liver. Although the liver is involved in the metabolism of a huge number of exogenous and endogenous substances, little is known about the role of metabolic enzymes in the development of liver tumors in the absence of cirrhosis. We analyzed the expression of glutathione S-transferases (GST) and cytochrome P450 enzymes (CYP) in 23 HCA, 20 HCC, and 22 focal nodular hyperplasias (FNH) using immunohistochemistry. The liver tissue revealed consistent specific staining for GST alpha, CYP1A1, 1A2, 2E1, and 3A4. In HCA and HCC, GST alpha expression was significantly reduced (p<0.001 and 0.043). Reduced GST alpha expression was significantly associated with steatosis in HCA and HCC (n=12, p=0.006), but not in non-neoplastic liver tissue. CYP3A4 expression was also reduced in HCA and HCC (p=0.03 and 0.02), and this was correlated with diabetes mellitus type 2 (p=0.02). In conclusion, HCA and HCC revealed changes in the expression of certain metabolic enzymes as compared with the non-neoplastic liver tissue or FNH. Therefore, reduced expression of GST alpha and CYP3A4 may indicate specific metabolic defects in the tumor tissue characterizing subgroups of HCA and HCC.
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PMID:Expression of xenobiotic and steroid hormone metabolizing enzymes in hepatocellular tumors of the non-cirrhotic liver. 1959 26

The urinary ratio of 6 beta-hydroxycortisol/cortisol (6 beta-OHC/C) as a biomarker of CYP3A4 metabolizing activity has been studied in Egyptian patients with chronic liver cirrhosis associated with previous hepatic Schistosomiasis infection to determine any possible alteration in enzyme activity. The ratio of 6-beta OHC/C was determined in morning urine samples collected from 8:00 a.m. to 12:00 p.m. in healthy adults (n = 36) and patients with liver cirrhosis (n = 57). The median age for control was 27 years (range: 18-50 years) and 50 years (range: 27-75 years) for patients. 6 beta-OHC was detected in urine by ELIZA kits (Stabiligen, France). Patients with liver cirrhosis were categorized according to Child Pugh Classification into Child B (n = 28) and Child C (n = 29) classes. Cholestasis was observed in 9/28 of Child B class and 8/29 of Child C class of patients. The control subjects showed gender-related difference in the urinary ratio of 6 beta-OHC/C. A significant reduction (P < 0.001) in 6 beta-OHC/C ratio was observed only in Child C patients in comparison with control subjects. Regression analysis showed a significant correlation (P < 0.05) between 6 beta-OHC/C ratio and serum albumin. The influence of cholestasis on the urinary ratio of 6-beta OHC/C was observed on cirrhotic patients of Child B class. In conclusion, patients with chronic liver cirrhosis might have a reduction of metabolizing activity of CYP3A4 enzymes which could be identified by measuring the urinary ratio of 6 beta-OHC/C. This reduction is more apparent in severe liver injury (Child C class). Therefore, it is important to understand the metabolic fate of drugs metabolized by 3A4 enzymes in patients with liver cirrhosis to avoid drug accumulation that might lead to development of drug toxicity.
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PMID:Study of the Urinary Ratio of 6 beta-Hydroxycortisol/Cortisol as a Biomarker of CYP3A4 Activity in Egyptian Patients with Chronic Liver Diseases. 1969 Jun 46

Tolvaptan is a new agent in the treatment of normovolemic and hypervolemic hyponatremia. It is a V(2) receptor antagonist inducing free water diuresis. It has been recently approved in USA and Europe for the treatment of hyponatremia associated with SIADH, cirrhosis as well as heart failure, while in hypovolemic hyponatremia its use is contraindicated. The drug also appears to be effective in the acute exacerbations of heart failure that need hospitalization. In the short-term tolvaptan seems to relieve acute congestive symptoms and improves mortality. However, the long-term effects on mortality are still controversial. The favorable short-term effects are ascribed to the selective V(2) receptor blocking, while the unopposed stimulation of V(1A) may give an explanation for the lack of long-term benefit. The drug should be initiated in the hospital setting because careful monitoring of fluid balance is recommended. It is administered orally giving the advantage of continuation in the outpatient setting. Moreover tolvaptan may have a role in the treatment of autosomal dominant polycystic kidney disease (ADPKD). Its effectiveness has been shown in animal models and Phase 3 clinical trial as well as an open-label study is now active. Since tolvaptan is metabolized by the cytochrome CYP3A4 in the liver physicians should be aware of possible drug to drug interactions. Resulting from large studies tolvaptan appears well tolerated. Common side effects are thirst, dry mouth and polyuria. Tolvaptan opens a new page not only in the treatment of normovolemic and hypervolemic hyponatremia but also in the treatment of acute decompensated heart failure and probably in ADPKD.
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PMID:Tolvaptan: a new therapeutic agent. 2086 52

Vinflunine is a novel tubulin-targeted agent that is currently indicated as a monotherapy in bladder cancer patients. The recommended dose of 320 mg/m(2) is given as an intravenous infusion once every 3 weeks. Vinflunine is metabolized through CYP3A4 and mainly eliminated via the feces. A phase I trial was designed to explore the tolerability and pharmacokinetics of vinflunine in cancer patients with ranging degrees of liver dysfunction (LD). A sequential design was used for patient accrual, with the objective of determining the maximum tolerated dose (MTD) and the recommended dose (RD) of vinflunine in 3 groups of increasing LD levels. Vinflunine and its only active metabolite 4-O-deacetylvinflunine were quantified in serial whole blood samples. PK parameters were derived and compared between LD groups and with a reference PK database. Vinflunine and 4-O-deacetylvinflunine PK parameters were not affected in any of the explored LD levels. Geometric mean values for vinflunine total clearance were 47.8, 37.5 and 45.4 L/h in the 3 groups of increasing degrees of LD, as compared to 42.5 L/h in reference patients with no LD. No relationship was found between vinflunine clearance and the presence or absence of cirrhosis, nor was it found with the presence or absence of liver metastasis or with liver-related biochemical parameters. Based on the observed tolerability profile, the recommended doses of i.v. vinflunine are 320 mg/m(2), 250 mg/m(2) or 200 mg/m(2) for patients with increasing degrees of liver dysfunction.
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PMID:Phase I and pharmacokinetic study of IV vinflunine in cancer patients with liver dysfunction. 2299 1

There is increasing evidence that tyrosine kinase inhibitors (TKIs) have significant blood glucose lowering effects. A 70-year old Caucasian male with liver cirrhosis Child-Pugh A, advanced hepatocellular carcinoma and diabetes had a stable glycemic control being treated with glibenclamide (3.5 mg twice daily). After the first daily dose of the TKI sorafenib (800 mg) the patient experienced acute nocturnal disorientation and somnolence with a corresponding blood glucose of 37 mg/dl. After administration of glucose intravenously the neurological disturbances were completely reversible. As there was no intercurrent deterioration neither of hepatic nor of renal function, the severe hypoglycemia can likely be attributed to a drug-drug interaction of sorafenib with the sulfonylurea. The complete inhibition of the CYP2C9 and CYP3A4 mediated metabolic pathway of glibenclamide through sorafenib might have resulted in a rapid accumulation of glibenclamide. Profound blood glucose lowering effects of sorafenib might have additionally contributed to the hypoglycemic episode.
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PMID:Severe hypoglycemia due to possible interaction between glibenclamide and sorafenib in a patient with hepatocellular carcinoma. 2384 93


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