Effects of long-term rifampicin administration in primary biliary cirrhosis. Gastroenterology
Liver Unit, Hospital Clínic i Provincial, University of Barcelona, Spain. Gastroenterology
(Impact Factor: 16.72).
07/1992; 102(6):2077-80. DOI: 10.1016/0168-8278(89)90386-3
The effects of rifampicin treatment (10 mg.kg-1.day-1) on pruritus and cholestasis were evaluated in 16 patients with primary biliary cirrhosis and pruritus followed up for 2-24 months. Assessment of pruritus severity, liver tests, aminopyrine breath test, and bile acids was done at 2 weeks and every 3 months after the beginning of the study. Two patients (12.5%) were withdrawn after 2 months of treatment because they had hepatitis caused by rifampicin. Four patients were withdrawn after 4 months because of liver transplantation (3 cases) and the development of leg edema associated with administration of rifampicin. The remaining 10 patients received therapy for 14.4 +/- 0.7 months and did not experience side effects. Pruritus improved in all patients and disappeared in 11 patients (79%) after 3 months of treatment. Moreover, all patients followed up for more than 1 year were free of pruritus. The alkaline phosphatase level decreased significantly, and the aminopyrine breath test results increased significantly after 2 weeks of treatment (P less than 0.001) and did not change thereafter. In the 9 patients treated for 15 months, alkaline phosphatase levels decreased to 63% of the basal levels and aminopyrine breath test results increased to 153% of baseline values. Transaminases, gamma-glutamyltransferase, and total bile salt levels decreased significantly after 2 weeks of treatment but returned to baseline after 3 months. No changes in bilirubin and cholesterol levels were observed. It is concluded that long-term rifampicin treatment is effective for relieving pruritus in primary biliary cirrhosis, but liver enzymes should be monitored to detect drug-induced hepatitis.
Available from: Andreas E Kremer
- "Various prospective randomized, placebo-controlled trials have proven that rifampicin at doses of 300—600 mg/d    and 10 mg/kg per day , respectively, is an effective and safe treatment of cholestatic pruritus . Hepatotoxicity, after treatment for several weeks or months, may be an adverse effect of rifampicin in up to 12% of cholestatic patients , requiring the monitoring of serum transaminase levels at regular intervals . If rifampicin is ineffective, the -opoid antagonist naltrexone should be regarded as third line therapy. "
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ABSTRACT: Pruritus is frequently reported by patients with cholestatic hepatobiliary diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy and hereditary cholestatic syndromes, but may accompany almost any other liver disease. Increased concentrations of bile salts, histamine, progesterone metabolites or endogenous opioids have been controversially discussed as potential pruritogens in cholestasis in the past. Most recently, novel insights unravelled lysophosphatidic acid (LPA), a potent neuronal activator, as a potential pruritogen in pruritus of cholestasis. Nevertheless, the pathogenesis of pruritus in cholestasis is still not clearly defined and current antipruritic treatment strategies provide relief only in a part of the affected patients. Based on recent experimental and clinical findings, this review outlines the actual insight in pathogenesis of pruritus in cholestasis and summarizes evidence-based and experimental therapeutic interventions for cholestatic patients suffering from itch.
Available from: Gernot Zollner
- "A range of additional nuclear (e.g., PXR, CAR and PPARa) and bile acid (e.g., TGR5) receptor agonists, which impact on detoxification and alternative export mechanisms, bile composition, fibrosis and inflammatory responses are currently under investigation with promising results in animal models of cholestasis. Some drugs such as rifampicin and phenobarbital have been used in the pre-UDCA area for the treatment of cholestatic pruritus and jaundice and later turned out to be activators of PXR and CAR, respectively  . Also agonists of peroxisome proliferator-activated receptor alpha (PPARa, NR1C1) are promising therapeutic approaches in human cholestatic liver disease since fibrates showed beneficial effects on biochemical parameters of cholestasis and/or transaminases in PBC patients with suboptimal response to UDCA   . "
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ABSTRACT: Recent progress in basic research has enhanced our understanding of the molecular mechanisms of normal bile secretion and their alterations in cholestasis. Genetic transporter variants contribute to an entire spectrum of cholestatic liver diseases and can cause hereditary cholestatic syndromes or determine susceptibility and disease progression in acquired cholestatic disorders. Cholestasis is associated with complex transcriptional and post-transcriptional alterations of hepatobiliary transporters and enzymes participating in bile formation. Ligand-activated nuclear receptors for bile acids and other biliary compounds play a key role in the regulation of genes required for bile formation. Pharmacological interventions in cholestasis may aim at modulating such novel regulatory pathways. This review will summarize the principles of molecular alterations in cholestasis and will give an overview of potential clinical implications.
Available from: medigraphic.com
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ABSTRACT: Hepatobiliary transport systems mediate hepatic uptake and biliary excretion of bile acids, bilirubin and other biliary constituents. Hereditary or acquired defects of these transporters may cause or maintain cholestasis and jaundice under various clinical conditions including progressive familial intrahepatic cholestasis (PFIC) 1-3 or its milder forms, benign recurrent intrahepatic cholestasis (BRIC) 1 and 2 , Dubin-Johnson syndrome, drug and inflammation-induced cholestasis and intrahepatic cholestasis of pregnancy. Moreover, induction of alternative efflux pumps for bile acids/bilirubin and phase I/II detoxifying enzymes may counteract hepatic accumulation of potentially toxic biliary constituents in cholestasis by providing alternative escape routes. Transcriptional and post-transcriptional regulation of hepatobiliary transporters in health and disease is mediated by multiple factors such as bile acids, proinflammatory cytokines, drugs and hormones. Ligand-activated nuclear receptors (NR) and hepatocyte-enriched transcription factors play a critical role in transcriptional transporter regulation. Many hepatobiliary transporter alterations in cholestatic liver disease can now be explained by ligand binding of accumulating cholephiles to NRs. Moreover, NR-mediated actions may be targeted by pharmacological ligands. Understanding the transcriptional mechanisms leading to transporter changes therefore not only represents a key for understanding the pathophysiology of the cholestatic liver disease, but also represents a prerequisite for designing novel therapeutic strategies.
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