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Lenci I, Milana M, Signorello A, Grassi G, Baiocchi L. Secondary bile acids and the biliary epithelia: The good and the bad. World J Gastroenterol 2023; 29:357-366. [PMID: 36687129 PMCID: PMC9846939 DOI: 10.3748/wjg.v29.i2.357] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/12/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
The biliary tract has been considered for several decades a passive system just leading the hepatic bile to the intestine. Nowadays several researches demonstrated an important role of biliary epithelia (i.e. cholangiocytes) in bile formation. The study of biliary processes therefore maintains a continuous interest since the possible important implications regarding chronic cholestatic human diseases, such as primary biliary cholangitis or primary sclerosing cholangitis. Bile acids (BAs), produced by the liver, are the most represented organic molecules in bile. The physiologic importance of BAs was initially attributed to their behavior as natural detergents but several studies now demonstrate they are also important signaling molecules. In this minireview the effect of BAs on the biliary epithelia are reported focusing in particular on secondary (deriving by bacterial manipulation of primary molecules) ones. This class of BAs is demonstrated to have relevant biological effects, ranging from toxic to therapeutic ones. In this family ursodeoxycholic and lithocholic acid present the most interesting features. The molecular mechanisms linking ursodeoxycholic acid to its beneficial effects on the biliary tract are discussed in details as well as data on the processes leading to lithocholic damage. These findings suggest that expansion of research in the field of BAs/cholangiocytes interaction may increase our understanding of cholestatic diseases and should be helpful in designing more effective therapies for biliary disorders.
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Affiliation(s)
- Ilaria Lenci
- Hepatology Unit, Policlinico Tor Vergata, Rome 00133, Italy
| | - Martina Milana
- Hepatology Unit, Policlinico Tor Vergata, Rome 00133, Italy
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Ko WK, Lee SJ, Kim SJ, Han GH, Han IB, Hong JB, Sheen SH, Sohn S. Direct Injection of Hydrogels Embedding Gold Nanoparticles for Local Therapy after Spinal Cord Injury. Biomacromolecules 2021; 22:2887-2901. [PMID: 34097404 DOI: 10.1021/acs.biomac.1c00281] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
In this study, we created a hydrogel composed of glycol chitosan (gC) and oxidized hyaluronate (oHA). Gold nanoparticles (GNPs) were conjugated with ursodeoxycholic acid (UDCA). The GNP-UDCA complex was embedded into gC-oHA (CHA) hydrogels to form a CHA-GNP-UDCA gel. This CHA-GNP-UDCA gel was injected once into an epicenter of an injured region in SCI rats. Near-infrared (NIR) irradiation was then applied to the lesion as a means of local therapy. To optimize the viscosity for injection into a lesion, several volume ratios of gC and oHA were investigated using scanning electron microscopy and a rotating rheometer. The optimally synthesized CHA-GNP-UDCA gel under NIR irradiation suppressed the production of inflammatory cytokines in vitro. In addition, the optimized CHA-GNP-UDCA gel under NIR irradiation inhibited the cystic cavity of the lesion and significantly improved the hindlimb function. The production of inflammatory cytokines following SCI was significantly inhibited in the CHA-GNP-UDCA gel + NIR group. CHA-GNP-UDCA gels with NIR irradiation can therefore have therapeutic effects for those with spinal cord injuries.
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Affiliation(s)
- Wan-Kyu Ko
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13496, Republic of Korea.,Department of Biomedical Science, CHA University, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea
| | - Sang Jin Lee
- Department of Dental Materials, School of Dentistry, Kyung Hee University, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Seong Jun Kim
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13496, Republic of Korea.,Department of Biomedical Science, CHA University, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea
| | - Gong Ho Han
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13496, Republic of Korea.,Department of Biomedical Science, CHA University, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea
| | - In-Bo Han
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13496, Republic of Korea
| | - Je Beom Hong
- Department of Neurosurgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
| | - Seung Hun Sheen
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13496, Republic of Korea
| | - Seil Sohn
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13496, Republic of Korea
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Simental-Mendía LE, Simental-Mendía M, Sánchez-García A, Banach M, Serban MC, Cicero AFG, Sahebkar A. Impact of ursodeoxycholic acid on circulating lipid concentrations: a systematic review and meta-analysis of randomized placebo-controlled trials. Lipids Health Dis 2019; 18:88. [PMID: 30954082 PMCID: PMC6451779 DOI: 10.1186/s12944-019-1041-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 04/01/2019] [Indexed: 02/08/2023] Open
Abstract
Objective The aim of this meta-analysis of randomized placebo-controlled trials was to examine whether ursodeoxycholic acid treatment is an effective lipid-lowering agent. Methods PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched in order to find randomized controlled trials evaluating the effect of ursodeoxycholic acid on lipid profile. A random-effect model and the generic inverse variance weighting method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A random-effects meta-regression model was performed to explore the association between potential confounders and the estimated effect size on plasma lipid concentrations. Results Meta-analysis of 20 treatment arms revealed a significant reduction of total cholesterol following ursodeoxycholic acid treatment (WMD: − 13.85 mg/dL, 95% CI: -21.45, − 6.25, p < 0.001). Nonetheless, LDL-C (WMD: -6.66 mg/dL, 95% CI: -13.99, 0.67, p = 0.075), triglycerides (WMD: − 1.42 mg/dL, 95% CI: -7.51, 4.67, p = 0.648) and HDL-C (WMD: -0.18 mg/dL, 95% CI: -5.23, 4.87, p = 0.944) were not found to be significantly altered by ursodeoxycholic acid administration. In the subgroup of patients with primary biliary cirrhosis, ursodeoxycholic acid reduced total cholesterol (WMD: − 29.86 mg/dL, 95% CI: -47.39, − 12.33, p = 0.001) and LDL-C (WMD: -37.27 mg/dL, 95% CI: -54.16, − 20.38, p < 0.001) concentrations without affecting TG and HDL-C. Conclusion This meta-analysis suggests that ursodeoxycholic acid therapy might be associated with significant total cholesterol lowering particularly in patients with primary biliary cirrhosis.
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Affiliation(s)
- Luis E Simental-Mendía
- Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Mexico, Mexico
| | - Mario Simental-Mendía
- Department of Orthopedics and Traumatology, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, NL, Mexico
| | - Adriana Sánchez-García
- Endocrinology Division, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, NL, Mexico
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland.,Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | - Maria-Corina Serban
- Department of Functional Sciences, Discipline of Pathophysiology, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Arrigo F G Cicero
- Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. .,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran. .,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. .,Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, P.O. Box: 91779-48564, Mashhad, Iran.
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Poupon R, Corpechot C. Treatment of primary biliary cirrhosis. Expert Opin Orphan Drugs 2013. [DOI: 10.1517/21678707.2014.870031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Fekaj E, Gjata A, Maxhuni M. The effect of ursodeoxycholic acid in liver functional restoration of patients with obstructive jaundice after endoscopic treatment: a prospective, randomized, and controlled study. BMC Surg 2013; 13:38. [PMID: 24053627 PMCID: PMC3850516 DOI: 10.1186/1471-2482-13-38] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 09/09/2013] [Indexed: 02/06/2023] Open
Abstract
Background In patients with obstructive jaundice, multi-organ dysfunction may develop. Methods/Design This trial is a prospective, open-label, randomized, and controlled study with the objective to evaluate the effect of ursodeoxycholic acid in liver functional restoration in patients with obstructive jaundice after endoscopic treatment. The aim of this study is to evaluate the effect of ursodeoxycholic acid in liver functional restoration of patients with obstructive jaundice after endoscopic treatment. The hypothesis of this trial is that patients with obstructive jaundice, in which will be administered UDCA, in the early phase after endoscopic intervention will have better and faster functional restoration of the liver than patients in the control group. Patients with obstructive jaundice, randomly, will be divided into two groups: (A) test group in which will be administered ursodeoxycholic acid twenty-four hours after endoscopic procedure and will last fourteen days, and (B) control group. Serum-testing will include determination of bilirubin, alanine transaminase, aspartate transaminase, gama-glutamil transpeptidase, alkaline phosphatase, albumin, and cholesterol levels. These parameters will be determined one day prior endoscopic procedure, and on the third, fifth, seventh, tenth, twelfth and fourteenth days after endoscopic intervention. Discussion This trial is a prospective, open-label, randomized, and controlled study to asses the effect of ursodeoxycholic acid in liver functional restoration of patients with obstructive jaundice in the early phase after endoscopic treatment. Trial registration ClinicalTrials.gov, NCT01688375
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Affiliation(s)
- Enver Fekaj
- Department of Abdominal Surgery, University Clinical Centre of Kosovo, Rrethi i Spitalit, str: p,n,, Pristina 10000, Republic of Kosovo.
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Ma YQ, Li G, Xu JH, Zhang J, Zhang ZZ, Xiao HY, Li XF. Combination of submicroemulsion and phospholipid complex for novel delivery of ursodeoxycholic acid. Pharm Dev Technol 2013; 19:363-72. [DOI: 10.3109/10837450.2013.788517] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Döring B, Lütteke T, Geyer J, Petzinger E. The SLC10 carrier family: transport functions and molecular structure. CURRENT TOPICS IN MEMBRANES 2013. [PMID: 23177985 DOI: 10.1016/b978-0-12-394316-3.00004-1] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The SLC10 family represents seven genes containing 1-12 exons that encode proteins in humans with sequence lengths of 348-477 amino acids. Although termed solute carriers (SLCs), only three out of seven (i.e. SLC10A1, SLC10A2, and SLC10A6) show sodium-dependent uptake of organic substrates across the cell membrane. These include the uptake of bile salts, sulfated steroids, sulfated thyroidal hormones, and certain statin drugs by SLC10A1 (Na(+)-taurocholate cotransporting polypeptide (NTCP)), the uptake of bile salts by SLC10A2 (apical sodium-dependent bile acid transporter (ASBT)), and uptake of sulfated steroids and sulfated taurolithocholate by SLC10A6 (sodium-dependent organic anion transporter (SOAT)). The other members of the family are orphan carriers not all localized in the cell membrane. The name "bile acid transporter family" arose because the first two SLC10 members (NTCP and ASBT) are carriers for bile salts that establish their enterohepatic circulation. In recent years, information has been obtained on their 2D and 3D membrane topology, structure-transport relationships, and on the ligand and sodium-binding sites. For SLC10A2, the putative 3D morphology was deduced from the crystal structure of a bacterial SLC10A2 analog, ASBT(NM). This information was used in this chapter to calculate the putative 3D structure of NTCP. This review provides first an introduction to recent knowledge about bile acid synthesis and newly found bile acid hormonal functions, and then describes step-by-step each individual member of the family in terms of expression, localization, substrate pattern, as well as protein topology with emphasis on the three functional SLC10 carrier members.
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Affiliation(s)
- Barbara Döring
- SLC10 family research group, Institute of Pharmacology and Toxicology, Justus Liebig University Giessen, Biomedical Research Center (BFS), Giessen, Germany
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Poupon R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action. Clin Res Hepatol Gastroenterol 2012; 36 Suppl 1:S3-12. [PMID: 23141891 DOI: 10.1016/s2210-7401(12)70015-3] [Citation(s) in RCA: 164] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Chronic cholestasis and liver inflammation are the two main pathophysiological components of the two major classes of disease - primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) - leading to bile duct destruction and ultimately to cirrhosis and liver failure. Ursodeoxycholic acid (UDCA), initially introduced as a therapeutic approach to counteract the cholestatic components to PBC and PSC, was subsequently shown to exhibit unexpected anti-inflammatory and immunomodulatoty properties. The use of farnesoid X receptor (FXR) and TGR5 agonists in various animal models have confirmed early observations indicating that bile acids are not only toxicants and inflammagens, but also repressors of innate and adaptive immunity. Obeticholic acid is a bile-acid mimetic, with no toxic or inflammagen behavior, that strongly activates FXR to combat the toxic effects of high concentrations of bile acid. Because UDCA is not an FXR agonist, its combination with obeticholic acid could be a promising tool for the treatment of PBC and PSC. In this overview, the biological properties of UDCA, NorUDCA and FXR agonists are highlighted, as well as their overlapping mechanisms of action in inflammatory biliary disorders.
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Affiliation(s)
- Raoul Poupon
- Service d'Hépatologie et Centre de Référence des maladies inflammatoires des voies biliaires, Hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg Saint-Antoine, 75571 Paris cedex 12, France.
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Dibaise JK. Symptoms, stones, and surgery: predicting pain relief after cholecystectomy for gallstones. Clin Gastroenterol Hepatol 2011; 9:818-20. [PMID: 21683164 DOI: 10.1016/j.cgh.2011.05.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Revised: 05/23/2011] [Accepted: 05/23/2011] [Indexed: 02/07/2023]
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A validated RP-HPLC method for quantitative determination of related impurities of ursodeoxycholic acid (API) by refractive index detection. J Pharm Biomed Anal 2011; 54:845-9. [DOI: 10.1016/j.jpba.2010.10.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2010] [Revised: 09/23/2010] [Accepted: 10/02/2010] [Indexed: 11/23/2022]
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Mertens MC, Roukema JA, Scholtes VPW, De Vries J. Risk assessment in cholelithiasis: is cholecystectomy always to be preferred? J Gastrointest Surg 2010; 14:1271-9. [PMID: 20502977 PMCID: PMC2909424 DOI: 10.1007/s11605-010-1219-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2009] [Accepted: 04/28/2010] [Indexed: 01/31/2023]
Abstract
BACKGROUND As many patients with gallstone disease do not benefit from cholecystectomy, preoperative recognition of such high-risk patients is important. The aim of the study is to identify predictors of persisting symptoms at 6 months after cholecystectomy for patients with different preoperative symptomatology. METHOD Participants in this prospective study were consecutive patients (n = 172), age 18-65 years, with symptomatic cholelithiasis, undergoing a laparoscopic cholecystectomy. Predictors were identified using uni- and multivariate regression analyses. RESULTS At 6 months postcholecystectomy, patients with only preoperative biliary symptoms were most often free of symptoms (62.5%). Patients with only dyspeptic symptoms most often reported persistence of preexisting symptoms (63.2%). Preoperative non-specific symptoms predicted the report of postoperative biliary and/or dyspeptic symptoms (OR = 4.5-6.1). Persistence of preexisting pattern of symptoms was predicted by the use of psychotropic medication (OR = 5.3) and dyspeptic symptoms (OR = 4.5). Postoperative biliary symptoms were predicted by High Trait Anxiety (HTA) (OR = 10.6). CONCLUSION Surgeons should take account of individual risks of patients in the management of cholelithiasis. Instead of cholecystectomy, expectative management should be the first choice in patients with non-specific symptoms, with dyspeptic symptoms only, with HTA and in patients using psychotropic medication.
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Affiliation(s)
- Marlies C Mertens
- CoRPS-Center of Research on Psychology in Somatic Diseases, Department of Medical Psychology, Tilburg University, 5000 LE, Tilburg, the Netherlands
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Sinakos E, Marschall HU, Kowdley KV, Befeler A, Keach J, Lindor K. Bile acid changes after high-dose ursodeoxycholic acid treatment in primary sclerosing cholangitis: Relation to disease progression. Hepatology 2010; 52:197-203. [PMID: 20564380 PMCID: PMC2928060 DOI: 10.1002/hep.23631] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
UNLABELLED High-dose (28-30 mg/kg/day) ursodeoxycholic acid (UDCA) treatment improves serum liver tests in patients with primary sclerosing cholangitis (PSC) but does not improve survival and is associated with increased rates of serious adverse events. The mechanism for the latter undesired effect remains unclear. High-dose UDCA could result in the production of hepatotoxic bile acids, such as lithocholic acid (LCA), because of limited small bowel absorption of UDCA and conversion of UDCA by bacteria in the colon. We determined the serum bile acid composition in 56 patients with PSC previously enrolled in a randomized, double-blind controlled trial of high-dose UDCA versus placebo. Samples for analysis were obtained at the baseline and at the end of treatment. The mean changes in the UDCA level (16.86 versus 0.05 micromol/L) and total bile acid level (17.21 versus -0.55 micromol/L) were significantly higher in the UDCA group (n = 29) versus the placebo group (n = 27) when pretreatment levels were compared (P < 0.0001). LCA was also markedly increased (0.22 versus 0.01 micromol/L) in the UDCA group compared to the placebo group (P = 0.001). No significant changes were detected for cholic acid, deoxycholic acid, or chenodeoxycholic acid. Patients (n = 9) in the UDCA group who reached clinical endpoints of disease progression (the development of cirrhosis, varices, liver transplantation, or death) tended to have greater increases in their posttreatment total bile acid levels (34.99 versus 9.21 micromol/L, P < 0.08) in comparison with those who did not. CONCLUSION High-dose UDCA treatment in PSC patients results in marked UDCA enrichment and significant expansion of the total serum bile acid pool, including LCA.
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Affiliation(s)
| | | | | | | | - Jill Keach
- Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Keith Lindor
- Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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Watanabe S, Kamei T, Tanaka K, Kawasuji K, Yoshioka T, Ohno M. Roles of bile acid conjugates and phospholipids in in vitro activation of pancreatic lipase by bear bile and cattle bile. JOURNAL OF ETHNOPHARMACOLOGY 2009; 125:203-206. [PMID: 19619630 DOI: 10.1016/j.jep.2009.07.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2009] [Revised: 07/07/2009] [Accepted: 07/11/2009] [Indexed: 05/28/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bear bile (BB) originally used as a traditional Chinese medicine has also been adopted in Japan as a traditional home remedy mainly for gastrointestinal problems due to impaired digestion. However, recently, efforts have been made to find alternatives to BB for ecological and ethical reasons. AIMS OF THE STUDY To find alternatives to BB for facilitating fat digestion, we compared the potency of cattle bile (CB) or synthetic mixtures of major bile components to activate pancreatic lipase with that of BB. MATERIALS AND METHODS The compositions of bile acid conjugates and phospholipids in BB and CB were determined by high-performance liquid chromatography and thin layer chromatography, respectively. The effects of BB and CB as well synthetic mixtures of bile acid conjugates and phospholipids on pancreatic lipase activity in vitro were examined. RESULTS BB and CB contained markedly different types and quantities of bile acid conjugates and phospholipids, although the potencies of BB and CB to activate pancreatic lipase were not significantly different. The potency of BB to activate pancreatic lipase was reconstituted by the major bile acid conjugates and phospholipids found in BB. In contrast, only bile acid conjugates found in CB could reconstitute its potency to activate pancreatic lipase. CONCLUSIONS Our observations indicate that CB or the synthetic mixture of bile components can be used as an alternative to BB for facilitating fat digestion.
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Affiliation(s)
- Shiro Watanabe
- Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
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Lepercq P, Gérard P, Béguet F, Grill JP, Relano P, Cayuela C, Juste C. Isolates from normal human intestinal flora but not lactic acid bacteria exhibit 7α- and 7β-hydroxysteroid dehydrogenase activities. MICROBIAL ECOLOGY IN HEALTH AND DISEASE 2009. [DOI: 10.1080/08910600410033393] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Pascale Lepercq
- From the Unité d'Ecologie et de Physiologie du Système Digestif, Institut National de la Recherche Agronomique, Jouy-en-Josas Cedex, Palaiseau, France
| | - Philippe Gérard
- From the Unité d'Ecologie et de Physiologie du Système Digestif, Institut National de la Recherche Agronomique, Jouy-en-Josas Cedex, Palaiseau, France
| | - Fabienne Béguet
- From the Unité d'Ecologie et de Physiologie du Système Digestif, Institut National de la Recherche Agronomique, Jouy-en-Josas Cedex, Palaiseau, France
| | - Jean-pierre Grill
- Laboratoire des BioSciences de l'Aliment, Faculté des Sciences et Techniques Vandoeuvre-lès-Nancy Cedex, Palaiseau, France
| | - Purification Relano
- Danone Vitapole, Nutrivaleur, Groupe Probiotiques et Fonctions Digestives, Palaiseau, France
| | - Chantal Cayuela
- Danone Vitapole, Nutrivaleur, Groupe Probiotiques et Fonctions Digestives, Palaiseau, France
| | - Catherine Juste
- From the Unité d'Ecologie et de Physiologie du Système Digestif, Institut National de la Recherche Agronomique, Jouy-en-Josas Cedex, Palaiseau, France
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Okonogi S, Yonemochi E, Oguchi T, Puttipipatkhachorn S, Yamamoto AK. Enhanced Dissolution of Ursodeoxycholic Acid from the Solid Dispersion. Drug Dev Ind Pharm 2008. [DOI: 10.3109/03639049709150502] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Yue PF, Yuan HL, Xie H, Xiao XH, Yang M, Liao MX, Zhu WF, Cai PL. Preparation, Characterization, and Bioavailability of Ursodeoxycholic Acid–Phospholipid Complex In Vivo. Drug Dev Ind Pharm 2008; 34:708-18. [DOI: 10.1080/03639040701842477] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Yue PF, Zhang WJ, Yuan HL, Yang M, Zhu WF, Cai PL, Xiao XH. Process optimization, characterization and pharmacokinetic evaluation in rats of ursodeoxycholic acid-phospholipid complex. AAPS PharmSciTech 2008. [PMID: 18446498 DOI: 10.1208/s12249-008-9040-1.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The purpose of this research was to study whether the bioavailability of ursodeoxycholic acid could be improved by administering ursodeoxycholic acid-phospholipid complex (UDCA-PLC) orally to rats. A central composite design approach was used for process optimization in order to obtain the acceptable UDCA-PLC. The physicochemical properties of the complex obtained by optimal parameters were investigated by means of scanning electron microscopy and X-ray diffraction. The pharmacokinetic parameters and bioavailability studies were conducted in rats of UDCA after oral administration of UDCA-PLC and UDCA tablet. Multiple linear regression analysis for process optimization revealed that the acceptable UDCA-PLC was obtained wherein the optimal values of X(1), X(2) and X(3) were 3, 60 degrees C and 3 h, respectively. The XRD studies of UDCA-PLC obtained by the optimal parameters demonstrated that UDCA and phospholipids in the UDCA-PLC were combined by non-covalent bonds, not form new compounds. But pharmacokinetic parameters of the complex in rats were T(max) 1.6 h, C(max) 0.1346 microg/ml, AUC(0-infinity) 11.437 microg x h/ml, respectively. The relative bioavailability of UDCA of UDCA-PLC was increased by 241%,compared with the reference ursodeoxycholic acid tablet.
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Affiliation(s)
- Peng-Fei Yue
- 302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing 100039, China
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Silveira MG, Lindor KD. Treatment of primary biliary cirrhosis: therapy with choleretic and immunosuppressive agents. Clin Liver Dis 2008; 12:425-43; x-xi. [PMID: 18456189 DOI: 10.1016/j.cld.2008.02.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of presumed autoimmune etiology affecting predominantly middle-aged women; it is a slowly progressive disease causing loss of intrahepatic bile ducts, resulting in advanced fibrosis, cirrhosis, and liver failure. Many drugs have been studied for treatment, including agents with choleretic and immunosuppressive properties. Ursodeoxycholic acid (UDCA) has been evaluated most widely. After liver failure, the only effective treatment is liver transplantation. Effective therapy reduces the need for transplantation and improves life expectancy. For advanced liver disease or incomplete response to UDCA, new therapies to cure or retard the progression of disease in PBC are needed.
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Affiliation(s)
- Marina G Silveira
- Miles and Shirley Fiterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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22
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Yue PF, Zhang WJ, Yuan HL, Yang M, Zhu WF, Cai PL, Xiao XH. Process optimization, characterization and pharmacokinetic evaluation in rats of ursodeoxycholic acid-phospholipid complex. AAPS PharmSciTech 2008; 9:322-9. [PMID: 18446498 PMCID: PMC2976878 DOI: 10.1208/s12249-008-9040-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2007] [Accepted: 01/04/2008] [Indexed: 11/30/2022] Open
Abstract
The purpose of this research was to study whether the bioavailability of ursodeoxycholic acid could be improved by administering ursodeoxycholic acid-phospholipid complex (UDCA-PLC) orally to rats. A central composite design approach was used for process optimization in order to obtain the acceptable UDCA-PLC. The physicochemical properties of the complex obtained by optimal parameters were investigated by means of scanning electron microscopy and X-ray diffraction. The pharmacokinetic parameters and bioavailability studies were conducted in rats of UDCA after oral administration of UDCA-PLC and UDCA tablet. Multiple linear regression analysis for process optimization revealed that the acceptable UDCA-PLC was obtained wherein the optimal values of X(1), X(2) and X(3) were 3, 60 degrees C and 3 h, respectively. The XRD studies of UDCA-PLC obtained by the optimal parameters demonstrated that UDCA and phospholipids in the UDCA-PLC were combined by non-covalent bonds, not form new compounds. But pharmacokinetic parameters of the complex in rats were T(max) 1.6 h, C(max) 0.1346 microg/ml, AUC(0-infinity) 11.437 microg x h/ml, respectively. The relative bioavailability of UDCA of UDCA-PLC was increased by 241%,compared with the reference ursodeoxycholic acid tablet.
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Affiliation(s)
- Peng-Fei Yue
- />302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing, 100039 China
- />Key Lab of Modern Preparation of TCM, Ministry of Education, Nanchang, 330004 China
| | - Wen-Jin Zhang
- />302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing, 100039 China
| | - Hai-Long Yuan
- />302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing, 100039 China
| | - Ming Yang
- />Key Lab of Modern Preparation of TCM, Ministry of Education, Nanchang, 330004 China
| | - Wei-Feng Zhu
- />Key Lab of Modern Preparation of TCM, Ministry of Education, Nanchang, 330004 China
| | | | - Xiao-He Xiao
- />302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing, 100039 China
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23
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Lepercq P, Hermier D, David O, Michelin R, Gibard C, Beguet F, Relano P, Cayuela C, Juste C. Increasing ursodeoxycholic acid in the enterohepatic circulation of pigs through the administration of living bacteria. Br J Nutr 2007; 93:457-69. [PMID: 15946407 DOI: 10.1079/bjn20041386] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
We investigated the feasibility of increasing ursodeoxycholic acid (UDCA) in the enterohepatic circulation of pigs by administering living bacteria capable of epimerising endogenous amidated chenodeoxycholic acid (CDCA) to UDCA. We first demonstrated that combining Bifidobacterium animalis DN-173 010, as a bile salt-hydrolysing bacterium, and Clostridium absonum ATCC 27555, as a CDCA to UDCA epimerising bacterium, led to the efficient epimerisation of glyco- and tauro-CDCA in vitro, with respective UDCA yields of 55·8 (se 2·8) and 36·6 (se 1·5)%. This strain combination was then administered to hypercholesterolaemic pigs over a 3-week period, as two daily preprandial doses of either viable (six experimental pigs) or heat-inactivated bacteria (six controls). The main effects of treatment were on unconjugated bile acids (P=0·035) and UDCA (P<0·0001) absorbed into the portal vein, which increased 1·6–1·7- and 3·5–7·5-fold, respectively, under administration of living compared with inactivated bacteria. In bile, UDCA did not increase significantly, but the increase in biliary lithocholic acid with time in the controls was not observed in the experimental pigs (P=0·007), and the same trend was observed in faeces. All other variables (biliary lipid equilibrium, plasma lipid levels and partition of cholesterol between the different lipoprotein classes) remained unaffected by treatment throughout the duration of the experiment. In conclusion, it is feasible to increase the bioavailability of UDCA to the intestine and the liver by administering active bacteria. This may represent an interesting new probiotic activity, provided that in future it could be expressed by a safe food micro-organism.
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Affiliation(s)
- Pascale Lepercq
- Unité d'Ecologie et de Physiologie du Système Digestif, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas Cedex, France
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24
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Portincasa P, Vacca M, Moschetta A, Petruzzelli M, Palasciano G, van Erpecum KJ, van Berge-Henegouwen GP. Primary sclerosing cholangitis: Updates in diagnosis and therapy. World J Gastroenterol 2005; 11:7-16. [PMID: 15609388 PMCID: PMC4205387 DOI: 10.3748/wjg.v11.i1.7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic syndrome of unknown origin mostly found in males, and characterized by diffuse inflammation and fibrosis of both intra- and extra-hepatic bile ducts. So far, PSC is considered as an autoimmune hepatobiliary disease. In most cases the progression of PSC towards liver cirrhosis and liver failure is slow but irreversible, and liver transplantation is currently the only definitive treatment. In recent years, PSC has been an area of active research worldwide with great interest in etiology, pathogenesis, diagnosis, and therapeutic options such as hydrophilic ursodeoxycholic acid and immunosuppressive agent tacrolimus. Recent updates on clinical and therapeutic aspects of PSC are discussed in the present review.
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Affiliation(s)
- Piero Portincasa
- Section of Internal Medicine, Department of Internal and Public Medicine (DIMIMP), University Medical School, Bari, Italy.
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25
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Lepercq P, Gérard P, Béguet F, Raibaud P, Grill JP, Relano P, Cayuela C, Juste C. Epimerization of chenodeoxycholic acid to ursodeoxycholic acid byClostridium baratiiisolated from human feces. FEMS Microbiol Lett 2004. [DOI: 10.1111/j.1574-6968.2004.tb09568.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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26
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Roda E, Azzaroli F, Nigro G, Piazza F, Jaboli F, Ferrara F, Liva S, Giovanelli S, Miracolo A, Colecchia A, Festi D, Mazzeo C, Bacchi L, Roda A, Mazzella G. Improved liver tests and greater biliary enrichment with high dose ursodeoxycholic acid in early stage primary biliary cirrhosis. Dig Liver Dis 2002; 34:523-7. [PMID: 12236487 DOI: 10.1016/s1590-8658(02)80112-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Ursodeoxycholic acid is currently used for the treatment of primary biliary cirrhosis at 13-15 mg/kg/day, but liver tests of some patients do not return to normal at this dose. Studies reported here were designed to test whether a higher dose of ursodeoxycholic acid than is currently used would induce still greater biliary enrichment of ursodeoxycholic acid and whether such enrichment would lead to still further improvement in liver tests in patients with early primary biliary cirrhosis. METHODS A total of 20 patients with histologically proven primary biliary cirrhosis were enrolled. Patients had early stage primary biliary cirrhosis as serum bilirubin levels were normal and the Mayo risk score 4.2 +/- 0.5. Group 1 received 600, 1200 and 1800 mg/day of ursodeoxycholic acid; group 2 received 900, 1500 and 2100 mg/day. The order of periods was randomized. Each treatment period lasted 3 months followed by a further 3 months during which a standard dose of ursodeoxycholic acid was given. At the end of each treatment period, liver tests were evaluated, and biliary bile acid pattern of duodenal bile was determined using high pressure liquid chromatography. RESULTS Biliary bile acid became enriched in ursodeoxycholic acid in direct relationship to dosage [r = 0.84, p < 0.001). At doses of 1800 mg/day (25-35 mg/kg/day), biliary ursodeoxycholic acid averaged 69 +/- 6.6%. A progressive decrease of alanine aminotransferase [p < 0.0001), aspartate aminotransferase [p < 0.001) and alkaline phosphatase [p < 0.02) was observed with increasing concentrations of ursodeoxycholic acid in bile. Biochemical liver tests showed a stronger correlation with biliary concentrations of ursodeoxycholic acid than with the administered dose. CONCLUSIONS In early primary biliary cirrhosis, higher dose ursodeoxycholic acid appears to be more effective than doses currently recommended.
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Affiliation(s)
- E Roda
- Department of Internal Medicine and Gastroenterology, University of Bologna, S. Drsola-Malpighi Hospital, Italy
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27
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Okonogi S, Puttipipatkhachorn S, Yamamoto K. Thermal behavior of ursodeoxycholic acid in urea: identification of anomalous peak in the thermal analysis. Drug Dev Ind Pharm 2001; 27:819-23. [PMID: 11699833 DOI: 10.1081/ddc-100107245] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The objective of this study was to clarify the thermal behavior of ursodeoxycholic acid (UDCA) in mixtures with urea. Physical mixtures of UDCA and urea in various ratios were prepared, and the thermal analysis of these sample mixtures was investigated using conventional differential scanning calorimetry (DSC) and variable-temperature powder X-ray diffractometry (VTXRD). The hot-stage microscopy (HSM) and powder X-ray diffractometry (PXRD) were used as complementary techniques. From the DSC results of all sample mixtures, it was found that there was no endothermic peak at the melting temperature of intact UDCA crystals. The DSC thermograms of each ratio showed only the endothermic peak at about 136 degrees C due to the melt of urea and the anomalous endothermic peak at about 155 degrees C 157 degrees C. The VTXRD study revealed that the crystals of urea completely disappeared at a temperature of 140 degrees C. At this temperature, it was identified that the VTXRD pattern obtained was of UDCA crystals. The crystalline peaks gradually decreased in intensity at a temperature of 150 degrees C When the temperature was up to 160 degrees C, the identical crystalline peaks of UDCA crystals completely disappeared. It was concluded that the anomalous endothermic peak at 155 degrees C-157 degrees C was the peak due to the dissolution of UDCA crystals in the surrounding melted urea.
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Affiliation(s)
- S Okonogi
- Faculty of Pharmacy, Chiang Mai University, Thailand
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28
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Nobilis M, Pour M, Kunes J, Kopecký J, Kvĕtina J, Svoboda Z, Sládková K, Vortel J. High-performance liquid chromatographic determination of ursodeoxycholic acid after solid phase extraction of blood serum and detection-oriented derivatization. J Pharm Biomed Anal 2001; 24:937-46. [PMID: 11248487 DOI: 10.1016/s0731-7085(00)00563-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Ursodeoxycholic acid (3 alpha,7 beta-dihydroxy-5 beta-cholanoic acid, UDCA) is a therapeutically applicable bile acid widely used for the dissolution of cholesterol-rich gallstones and in the treatment of chronic liver diseases associated with cholestasis. UDCA is more hydrophilic and less toxic than another therapeutically valuable bile acid, chenodeoxycholic acid (CDCA), the 7 alpha-epimer of UDCA. Procedures for sample preparation and HPLC determination of UDCA in blood serum were developed and validated. A higher homologue of UDCA containing an additional methylene group in the side chain was synthetized and used as an internal standard (IS). Serum samples with IS were diluted with a buffer (pH=7). The bile acids and IS were captured using solid phase extraction (C18 cartridges). The carboxylic group of the analytes was derivatized using 2-bromo-2'-acetonaphthone (a detection-oriented derivatization), and reaction mixtures were analyzed (HPLC with UV 245 nm detection; a 125--4 mm column containing Lichrospher 100 C18, 5 microm; mobile phase: acetonitrile--water, 6:4 (v/v)). Following validation, this method was used for pharmacokinetic studies of UDCA in humans.
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Affiliation(s)
- M Nobilis
- Institute of Experimental Biopharmaceutics, Joint Research Centre of PRO.MED.CS Praha a.s. and Academy of Sciences of the Czech Republic, Heyrovského 1207, CZ-500 02 Hradec Králové, Czech Republic.
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29
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Okonogi S, Oguchi T, Yonemochi E, Puttipipatkhachorn S, Yamamoto K. Physicochemical Properties of Ursodeoxycholic Acid Dispersed in Controlled Pore Glass. J Colloid Interface Sci 1999; 216:276-284. [PMID: 10421735 DOI: 10.1006/jcis.1999.6331] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The objective of this study was to reduce the crystallinity of ursodeoxycholic acid (UDCA) by solid dispersion with controlled pore glass (CPG). To evaluate the effect of pore diameter and pore volume of CPG on the crystalline properties of UDCA, we used powder X-ray diffractometry (PXRD) and differential scanning calorimetry (DSC). PXRD patterns and the DSC data indicated the presence of UDCA in a crystalline state in the physical mixtures. It was found that amorphous UDCA could be formed via solid dispersion with CPG obtained by a solvent method. The DSC thermograms of solid dispersions showed that there were two states of UDCA, amorphous and crystalline. The amount of crystalline fraction in the solid dispersions depended on the pore size, pore volume, and the specific surface area of CPG. When UDCA was mixed with different pore diameters of CPG, it was found that UDCA molecules preferentially interacted with pores of smaller size. Copyright 1999 Academic Press.
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Affiliation(s)
- S Okonogi
- Faculty of Pharmacy, Chiang Mai University, Chiang Mai, 50200, Thailand
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30
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Ochsenk�hn T, Bayerd�rffer E, Meining A, Schinkel M, Thiede C, N�ssler V, Sackmann M, Hatz R, Neubauer A, Paumgartner G. Colonic mucosal proliferation is related to serum deoxycholic acid levels. Cancer 1999. [DOI: 10.1002/(sici)1097-0142(19990415)85:8<1664::aid-cncr4>3.0.co;2-o] [Citation(s) in RCA: 94] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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31
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Makino I, Tanaka H. From a choleretic to an immunomodulator: historical review of ursodeoxycholic acid as a medicament. J Gastroenterol Hepatol 1998; 13:659-64. [PMID: 9715413 DOI: 10.1111/j.1440-1746.1998.tb00707.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Affiliation(s)
- I Makino
- Second Department of Internal Medicine, Asahikawa Medical College, Japan
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32
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Nakamura K, Yoneda M, Yokohama S, Tamori K, Sato Y, Aso K, Aoshima M, Hasegawa T, Makino I. Efficacy of ursodeoxycholic acid in Japanese patients with type 1 autoimmune hepatitis. J Gastroenterol Hepatol 1998; 13:490-5. [PMID: 9641646 DOI: 10.1111/j.1440-1746.1998.tb00674.x] [Citation(s) in RCA: 103] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ursodeoxycholic acid (UDCA) has been shown to have beneficial effects on patients with primary biliary cirrhosis, suggesting that UDCA has immunomodulating effects. We investigated the effect of UDCA in patients with autoimmune hepatitis (AIH) which is characterized by immunological abnormalities. Eight patients with type 1 AIH were treated with 600 mg of UDCA per day for 2 years. Based on the criteria of the International Autoimmune Hepatitis Group, five patients were diagnosed as definite and three as probable type 1 AIH. Liver function tests were performed every 4 weeks, before and during UDCA therapy and the serum levels of anti-nuclear antibodies (ANA), smooth muscle antibodies (SMA), immunoglobulin G and gamma globulin were determined every 3 months. The levels of serum aspartate aminotransferase and alanine aminotransferase significantly decreased from 154 +/- 24 IU/L and 170 +/- 17 IU/L before UDCA therapy to 31 +/- 3 IU/L and 25 +/- 5 IU/L (P < 0.001) after 1 year of treatment and 28 +/- 2 IU/L and 23 +/- 4 IU/L (P < 0.001) after 2 years of treatment. After 2 years of treatment, the levels of serum immunoglobulin G and gamma globulin significantly decreased (P < 0.05) and ANA titres (5/8 patients) were reduced and SMA (3/5 patients) became negative. Furthermore, hepatic histopathological changes of four patients were assessed after 1 year of treatment, and an improvement of intrahepatic inflammation, but not fibrosis, was observed. In conclusion, these results suggest that UDCA has a beneficial therapeutic effect in patients with type 1 autoimmune hepatitis.
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Affiliation(s)
- K Nakamura
- Second Department of Medicine, Asahikawa Medical College, Nishikagura, Japan
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33
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Abstract
Patients with Crohn's disease (CD) have an increased risk of developing gallstones, but the mechanisms are unknown. In a previous study, we found a subnormal cholesterol saturation in the bile of patients with short ileal resections due to CD. The aim of this study was to test the hypothesis that (a) CD patients with a long ileal resection have an altered biliary composition and (b) that CD patients with short or long ileal resection have an increased content of bilirubin in their bile. Biliary lipid composition, cholesterol saturation, bile acid pattern, and bilirubin concentration were determined in fasting duodenal bile of 10 CD patients with long ileal resections and in 4 patients with short resections. Ten healthy subjects served as controls. Cholesterol saturation was significantly lower in those CD patients who had a long or short resection compared with the healthy subjects. Bile acid composition in the CD patients was characterized by a significant decrease in the deoxycholic acid fraction and a prominent increase in the ursodeoxycholic acid fraction. The bilirubin concentrations, expressed as micromoles of bilirubin per millimole bile acid, were 45-50% higher in patients who had a long or a short ileal resection compared with healthy controls. Based on these results, CD patients who had had an ileal resection seem not to be at an increased risk of cholesterol gallstone formation but rather at risk of developing pigment stones.
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Affiliation(s)
- A Lapidus
- Department of Gastroenterology and Hepatology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden
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34
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Coleman JP, Kirby LC, Setchell KD, Hylemon PB, Pandak M, Heuman DM, Vlahcevic ZR. Metabolic fate and hepatocyte toxicity of reverse amide analogs of conjugated ursodeoxycholate in the rat. J Steroid Biochem Mol Biol 1998; 64:91-101. [PMID: 9569014 DOI: 10.1016/s0960-0760(97)00138-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Reverse amide analogs of conjugated bile acids were tested for their effects on the viability of cultured primary rat hepatocytes, for their transport and metabolism in the intact rat, and for their susceptibility to hydrolysis by intestinal bacteria. Succinylnorursodeoxycholanylamide (SNUDCN) and its parent C23 amine showed the same general lack of toxicity toward hepatocytes as the normal conjugates of ursodeoxycholic acid, at concentrations up to 500 microM. The 3alpha,7alpha,12alpha-trihydroxy analog and its parent amine were more toxic than the corresponding dihydroxy compounds, although their effects were similar to those observed for the normal conjugates of cholic acid. Following intraduodenal infusion, greater than 80% of administered SNUDCN appeared in the bile of bile fistula rats. Analysis of bile fractions indicated the presence of SNUDCN (81.5 mol% of original amount) and two metabolites, the taurine conjugate of SNUDCN (9.4 mol%) and SNUDCN containing an additional hydroxy group (9.1 mol%). Although SNUDCN underwent an efficient first pass enterohepatic circulation, it displayed a shorter biological half life than taurocholate (T1/2: 8.9 h vs 39.6 h, respectively). The reverse amide analogs were not hydrolyzed by any of a variety of intestinal bacteria known to hydrolyze normal conjugated bile acids. Despite the shorter half-life, the reverse amide analogs may be of potential use in the targeting of therapeutic bile acids to the colon.
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Affiliation(s)
- J P Coleman
- Department of Microbiology and Immunology, School of Medicine, East Carolina University, Greenville, NC, USA.
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35
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Eriksson LS, Olsson R, Glauman H, Prytz H, Befrits R, Rydén BO, Einarsson K, Lindgren S, Wallerstedt S, Wedén M. Ursodeoxycholic acid treatment in patients with primary biliary cirrhosis. A Swedish multicentre, double-blind, randomized controlled study. Scand J Gastroenterol 1997; 32:179-86. [PMID: 9051880 DOI: 10.3109/00365529709000190] [Citation(s) in RCA: 54] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Ursodeoxycholic acid (UDCA) has been shown to improve serum levels of liver enzymes and bilirubin in primary biliary cirrhosis (PBC). However, it is still uncertain whether UDCA treatment also improves symptoms, liver histology, and survival without liver transplantation. METHODS We randomized 116 patients with PBC to receive 0.5 g UDCA (n = 60) or placebo (n = 56) daily for 2 years. During the next 2 years, 80% of the UDCA-treated patients and 65% of the placebo-treated patients continued to take UDCA. RESULTS UDCA improved serum enzyme values but not survival, symptoms, serum bilirubin levels, or liver histology. There was no significant difference in response between initially symptomatic and asymptomatic patients. CONCLUSIONS UDCA in a dosage of 7.7 mg/kg body weight is of little benefit in PBC. This does not exclude the possibility that larger doses have beneficial effects.
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36
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Matsumoto S, Ikeda S, Maeshiro K, Okamoto K, Miyazaki R. Management of giant common bile duct stones in high-risk patients using a combined transhepatic and endoscopic approach. Am J Surg 1997; 173:115-6. [PMID: 9074375 DOI: 10.1016/s0002-9610(96)00406-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Endoscopic sphincterotomy (EST) for removing common bile duct stones is regarded as the safest and most successful method, particularly in patients with a high surgical risk. However, giant immobile stones still continue to present a therapeutic problem. METHODS In our 12 patients, when endoscopic sphincterotomy and lithotomy proved to be unsuccessful a transhepatic choledochoscopic lithotomy was attempted. RESULTS The stones were fragmented using choledochoscopic electrohydraulic lithotripsy and then were completely removed through both the transhepatic route and an EST opening in all 12 patients. The number of sessions required for these choledochoscopic procedures combined with EST was fewer than that required for only a transhepatic approach (2.5 +/- 1.3 versus 3.2 +/- 1.2), which thus resulted in a shorter hospital stay. Minor complications occurred in three patients with bleeding (two from the bile duct, one from the EST opening) and in two with postprocedure chills and fever. CONCLUSIONS A combined lithotomy through duodenoscopic and choledochoscopic approaches is considered to be an efficient method for removing giant biliary calculi in patients who are not successfully treated by an ordinary duodenoscopic lithotomy.
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Affiliation(s)
- S Matsumoto
- First Department of Surgery, Fukuoka University School of Medicine, Japan
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37
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Petroni ML, Jazrawi RP, Lanzini A, Zuin M, Pazzi P, Fracchia M, Boga E, Facchinetti D, Alvisi V, Galatola G, Bland JM, Heaton KW, Podda M, Northfield TC. Repeated bile acid therapy for the long-term management of cholesterol gallstones. J Hepatol 1996; 25:719-24. [PMID: 8938551 DOI: 10.1016/s0168-8278(96)80244-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND/AIMS Following non-surgical treatment, cholesterol gallstones recur in a high proportion of patients, and recurrence cannot be predicted nor effectively prevented. Our aim was to test prospectively the viability and the efficacy of repeated bile acid therapy, in which recurrent stones are diagnosed at an early stage by regular ultrasound monitoring and promptly retreated, as a strategy for the management of these patients in clinical practice. METHODS One hundred and seventy-two consecutive patients were recruited upon achieving complete gallstone dissolution using non-surgical therapy (bile acids or lithotripsy plus bile acids), and followed up at 6-monthly intervals by ultrasound scan. Gallstone recurrence was promptly treated by a combination of ursodeoxycholic acid plus chenodeoxycholic acid (5 mg/kg per day each) for a period of 2 years, or less if complete redissolution was achieved. Median follow-up period was 34 months (range 6-70). RESULTS Forty-five patients had gallstone recurrence; of these, 39 underwent one or more repeated courses of bile acid therapy (follow-up data available in 27). Gallstone recurrence rate was 15% at 1 year and 47% at 5 years. Average annual redissolution rate of recurrent gallstones (intention to treat) was 41%. The proportion of gallstone-free patients in the whole population was 88%, 84%, 77%, 78%, 75% at 1-5 years, respectively, and rose to > 90% at 3 years onwards in patients with single primary stones. CONCLUSIONS We conclude that repeated bile acid therapy maintains the majority of patients gallstone free, and is therefore an effective long-term management strategy, especially in patients with primary single gallstones.
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Affiliation(s)
- M L Petroni
- St. George's Hospital Medical School, London, UK
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Crosignani A, Battezzati PM, Setchell KD, Invernizzi P, Covini G, Zuin M, Podda M. Tauroursodeoxycholic acid for treatment of primary biliary cirrhosis. A dose-response study. Dig Dis Sci 1996; 41:809-15. [PMID: 8674405 DOI: 10.1007/bf02213140] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Tauroursodeoxycholic acid, a highly hydrophilic bile acid, may be of therapeutic value for chronic cholestatic liver diseases. We performed a dose-response study on 24 patients with primary biliary cirrhosis who were randomly assigned to receive 500, 1000, or 1500 mg daily of tauroursodeoxycholic acid for six months. Biliary enrichment with ursodeoxycholic acid ranged from 15% to 48% and was not related with the dose. Serum liver enzyme levels decreased significantly after the first month of treatment with all the three doses. No significant difference among the three doses was found, although further reduction over time occurred with 1000 and 1500mg daily. Plasma total and HDL cholesterol significantly decreased in patients administered the two higher doses. Diarrhea was the only side effect. In conclusion, a dose of about 10mg/kg body wt/day of tauroursodeoxycholic acid should be used for long-term studies in patients with primary biliary cirrhosis.
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Affiliation(s)
- A Crosignani
- Institute of Internal Medicine, School of Medicine, Ospedale San Paolo, Milan, Italy
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39
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Setchell KD, Rodrigues CM, Podda M, Crosignani A. Metabolism of orally administered tauroursodeoxycholic acid in patients with primary biliary cirrhosis. Gut 1996; 38:439-46. [PMID: 8675100 PMCID: PMC1383076 DOI: 10.1136/gut.38.3.439] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The metabolism of tauroursodeoxycholic acid orally administered and its effects on the bile acid pool of patients with asymptomatic/mildly symptomatic primary biliary cirrhosis is described. Patients were randomly assigned 500, 1000, or 1500 mg/day of tauroursodeoxycholate for six months. Biliary and serum bile acids were measured before and during treatment by gas chromatography-mass spectrometry and by high performance liquid chromatography. During tauroursodeoxycholate administration, the proportion of total ursodeoxycholate in bile reached mean (SEM) 34.4 (4.5)%, 32.8 (2.8)%, and 41.6 (3.0)% with doses of 500, 1000, and 1500 mg/day, respectively. Significant decreases in the proportions of chenodeoxycholate and cholate resulted. The glycine/taurine ratio of the biliary bile acid pool decreased from 1.9 at baseline, to 1.1 with the highest dose. Ursodeoxycholate in bile was conjugated with glycine and taurine, indicating that tauroursodeoxycholate undergoes significant deconjugation and reconjugation during its enterohepatic recycling. The proportion of lithocholate in bile remained unchanged. Fasting serum conjugated ursodeoxycholate concentration positively correlated with the tauroursodeoxycholate dose, and the increased proportion of ursodeoxycholate was accompanied by substantial decreases in the endogenous bile acids. Compared with previously published data for ursodeoxycholic acid therapy, these findings indicate that the shift toward a more hydrophilic bile acid pool is greater and potentially more favourable with tauroursodeoxycholate, and this is because of the reduced intestinal biotransformation of tauroursodeoxycholate.
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Affiliation(s)
- K D Setchell
- Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, OH 45229, USA
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Rodrigues CM, Kren BT, Steer CJ, Setchell KD. The site-specific delivery of ursodeoxycholic acid to the rat colon by sulfate conjugation. Gastroenterology 1995; 109:1835-44. [PMID: 7498648 DOI: 10.1016/0016-5085(95)90750-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND & AIMS Because ursodeoxycholate has been shown to act as a tumor-suppressive agent in the colon, the absorption and metabolism of its sulfate conjugates were examined in rats to show that sulfation would facilitate the site-specific delivery of ursodeoxycholate to the colon. METHODS Bile acids were measured in intestinal contents, feces, urine, plasma, and liver tissue after oral administration of ursodeoxycholate and its C-3, C-7, and C-3,7 sulfate derivatives. RESULTS Ursodeoxycholate was found in the jejunum after administration of all bile acids, but the mass was greatest for ursodeoxycholic acid administration. In the colon, lithocholic acid, normally found in negligible amounts, became the major bile acid after ursodeoxycholate administration. In contrast, reductions in mass and proportions of lithocholate and deoxycholate occurred after administering the C-7 sulfates. The fecal lithocholate/deoxycholate ratio, a risk marker for colon cancer, increased markedly after administration of ursodeoxycholate and its C-3 sulfate, but did not change after administering the C-7 sulfates. Unlike ursodeoxycholate or its C-3 sulfate, which increased liver concentrations of lithocholate and ursodeoxycholate, the C-7 sulfates had the opposite effect, which was consistent with poor absorption. CONCLUSIONS Sulfation of ursodeoxycholate, specifically at the C-7 position, protects the molecule from bacterial degradation and inhibits its intestinal absorption, thereby facilitating delivery to the colon.
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Affiliation(s)
- C M Rodrigues
- Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio, USA
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41
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Abstract
Bile acids are natural detergents and the end-products of cholesterol metabolism. Their functions are mostly digestive: induction of bile flow and solubilization of biliary and alimentary lipids. They circulate along the enterohepatic cycle, and probably also along a shorter route, the cholehepatic shunt. They are relatively hydrophobic and perpetuate or worsen the hepatic lesions when their excretion is impaired in cholestasis, because of their affinity for biological membranes. Their functions depend on their relative hydrophilicity and ionization, ie on their structure and state of conjugation. They have an immunosuppressive effect in vivo and in vitro. Ursodeoxycholic acid (UDC) is a hydrophilic bile acid used in chronic cholestatic diseases. Biological improvement has been proven in autoimmune cholangiopathies in adults, and cystic fibrosis-associated liver disease in children. Clinical studies are on the way for other indications. It is still too early to evaluate the long-term clinical benefits, eg the reduction in needs for liver transplantation. UDC acid may induce a bicarbonate-rich hypercholeresis through the cholehepatic shunt, that would explain its efficacy in cystic fibrosis. In disorders of bile acid synthesis or transport, it could shunt the enzymatic block, or reestablish the bile flow through its osmotic effect. Like other bile acids it interacts with membranes, and is thought to stabilize them. In chronic cholestasis it would protect the membranes against the adverse effect of non-excreted endogenous bile acids. This interaction can also explain its immunosuppressive effect, through non-specific inhibition of transmission at the cell surface. That would explain the preferential clinical efficacy of UDC in autoimmune cholestasis, and stimulate its evaluation in "immunological" indications, such as liver transplantation and hepatic graft versus host disease.
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Affiliation(s)
- F Lacaille
- Département de pédiatrie, hôpital des Enfants-Malades, Paris, France
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42
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Sánchez Pozzi EJ, Mottino AD, Sisti A, Roma MG. Differential effect of ursodeoxycholate and its taurine conjugate on biliary transport maximum of bilirubin in the rat. Life Sci 1995; 57:973-81. [PMID: 7643722 DOI: 10.1016/0024-3205(95)02032-e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The effects of ursodeoxycholate and its taurine conjugate on biliary Tm of bilirubin were evaluated in rats. Ursodeoxycholate was administered at four different doses (4, 8, 12 or 16 mumol per 100 g body wt i.v., followed by an i.v. infusion of 0.3, 0.6, 0.9 or 1.2 mumol/min per 100 g body wt, respectively), whereas tauroursodeoxycholate was administered only at the maximal dose. A dose-dependent diminution of bilirubin Tm was observed during ursodeoxycholate administration, which ranged from no effect at the lowest dose to a virtual excretory blockage at the highest dose. This was associated with an increase in bilirubin concentrations in both plasma and liver as well as in the fractional amount of conjugated pigment in both sites, suggesting an impairment of bilirubin transfer at the canalicular level. Incomplete taurine conjugation of ursodeoxycholate well correlated with these effects. Unlike ursodeoxycholate, tauroursodeoxycholate had no inhibitory effect on bilirubin Tm, although a slight inhibition of bilirubin uptake and bilirubin conjugation became apparent. Taken together, these results suggest that ursodeoxycholate interferes with the hepatobiliary transport of bilirubin by impairing its transfer at the canalicular level and that incomplete taurine conjugation appears to be a key factor determining this effect.
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Affiliation(s)
- E J Sánchez Pozzi
- Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET-U.N.R., Rosario, Argentina
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Li YW, Zhu XY, But PP, Yeung HW. Ethnopharmacology of bear gall bladder: I. JOURNAL OF ETHNOPHARMACOLOGY 1995; 47:27-31. [PMID: 7564418 DOI: 10.1016/0378-8741(95)01249-d] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Both bear and pig bile solutions were shown to have anti-inflammatory, anticonvulsion and analgesic effects, and also to prolong the survival time of mice in hypoxic conditions. It is possible that pig gall bladders could be developed as an alternative to bear gall bladders for uses in certain prescriptions of Chinese medicine.
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Affiliation(s)
- Y W Li
- Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing
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44
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Roda A, Cerré C, Fini A, Sipahi AM, Baraldini M. Experimental evaluation of a model for predicting micellar composition and concentration of monomeric species in bile salt binary mixtures. J Pharm Sci 1995; 84:593-8. [PMID: 7658350 DOI: 10.1002/jps.2600840514] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The critical micellar concentration (cmc) values of some mixed systems containing two bile salts were determined by a maximum pressure bubble method and compared with those derived from a theoretical model developed for nonionic surfactants to assess the applicability of this model to such systems. Some assumptions on which the presumed validity of this model was based are discussed. The following binary mixtures were investigated: sodium chenodeoxycholate with cholate, ursocholate and ursodeoxycholate, either unconjugated or conjugated with taurine and glycine at different mole fractions (0, 0.25, 0.5, 0.75, 1) in 0.15 M NaCl. For these mixtures, experimentally determined data were in good agreement with values predicted by the theoretical model: both the cmc and the surface tension at this concentration of the mixtures were intermediate between those of the two pure bile salts; also, as the total bile salt concentration increased, the mixed micelles became enriched with the bile salt having the highest cmc, whereas the total monomer activity, determined by a potentiometric method employing a bile salt-selective electrode, increased only slightly. To test this model in an in vitro system, surface tension was also measured in ox bile samples that were enriched by 50% with sodium ursodeoxycholate, chenodeoxycholate, or their taurine amidates. The cmc and the surface tension at this concentration of the artificial bile increased when enriched with a bile salt with a cmc higher than that of endogenous salts (e.g. ursodeoxycholate versus taurocholate), whereas the reverse occurred for mixtures enriched with a bile salt with a lower cmc, such as chenodeoxycholate.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- A Roda
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna, Italy
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45
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Poupon R, Poupon RE. Ursodeoxycholic acid therapy of chronic cholestatic conditions in adults and children. Pharmacol Ther 1995; 66:1-15. [PMID: 7630925 DOI: 10.1016/0163-7258(94)00073-c] [Citation(s) in RCA: 56] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Cholestasis can be defined as the manifestation of defective bile acid transport from the liver to the intestine. Most chronic cholestatic conditions can progress towards cirrhosis. At this stage, liver transplantation is the treatment of choice. Most of the drugs so far evaluated show some degree of efficacy but have major side effects. Given that ursodeoxycholic acid (UDCA) has no apparent toxicity in humans, it was postulated that long-term treatment with this drug might displace endogenous bile acids and thus reverse their suspected toxicity. We demonstrated that long-term UDCA therapy slows the progression of primary biliary cirrhosis and reduces the need for liver transplantation. In this review, we give the rationale for the use of UDCA in cholestasis and discuss its possible mechanisms of action. We also give an overview of current data on UDCA therapy of chronic cholestatic disorders in adults and children.
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Affiliation(s)
- R Poupon
- Unité d'Hépato-Gastroentérologie, Hôpital Saint-Antoine, Paris, France
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46
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47
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Yamashiro Y, Ohtsuka Y, Shimizu T, Nittono H, Urao M, Miyano T, Kawakami S, Hayasawa H. Effects of ursodeoxycholic acid treatment on essential fatty acid deficiency in patients with biliary atresia. J Pediatr Surg 1994; 29:425-8. [PMID: 8201513 DOI: 10.1016/0022-3468(94)90584-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
To assess whether ursodeoxycholic acid (UDCA) treatment has any beneficial effect on essential fatty acid (EFA) deficiency in patients who have had a Kasai operation for extrahepatic atresia (EBA), responses of serum fatty acids to UDCA administration (15 mg/kg/d) were investigated in eight jaundice-free patients and in eight patients with jaundice (serum total bilirubin > or = 1.0 mg/dL). All patients were also given taurine supplementation (100 mg/kg/d). Serum fatty acid composition was determined before and 6 months after UDCA treatment. Serum total bile acid concentration and serum total bilirubin value, as a part of conventional liver function tests, were measured before and during UDCA therapy. Before UDCA treatment, the concentrations of linoleic acid and arachidonic acid were significantly lower (P > .05 for the former; P > .01 for the latter) in both the jaundice and jaundice-free groups than in the controls. After 6 months of treatment, the linoleic acid concentration significantly increased (P > .05), to the normal range, in the jaundice-free group, but not in the jaundice group. The arachidonic acid concentration did not increase significantly in either group. The serum total bile acid concentration was lower in six of the eight jaundice-free patients and in four of the eight jaundice patients. The serum total bilirubin value decreased in six of the eight jaundice-free patients and in four of the eight jaundice patients; however, the degree of improvement was not statistically significant in either group. No side effects developed, and there were no changes in blood chemistry values unrelated to liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- Y Yamashiro
- Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan
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49
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Plaisier PW, Brakel K, van der Hul RL, Bruining HA. Radiographic features of oral cholecystograms of 448 symptomatic gallstone patients: implications for nonsurgical therapy. Eur J Radiol 1994; 18:57-60. [PMID: 8168584 DOI: 10.1016/0720-048x(94)90368-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Since radiographic findings on oral cholecystography (OCG) have implications for the eligibility for nonsurgical therapy of elderly patients, we investigated the OCGs of 448 symptomatic gallstone patients (109 male, 339 female; mean age, 49.8 +/- 14 (range, 21-88)). Opacification of the gallbladder was found in 323 cases (72.1%). Calcifications of gallstones were found in 85 opacified gallbladders (26.3%). Solitary and multiple stones were calcified in 35.3% and 18.2%, respectively (P < 0.0005). When divided into two groups (< or = 40 years and > 40 years), there was a significant increase in calcifications (P < 0.02) and a non-significant increase in opacification with increasing age. It is concluded that age is a determinant for calcification of gallstones and not opacification of the gallbladder. Since multiple stones are proportionately observed more in clinical studies than in epidemiologic studies, it is suggested that multiplicity of stones predisposes to biliary complaints. That solitary stones are more likely to be calcified than multiple stones, adds to the hypothesis that solitary and multiple stones have a different pathogenesis. Elderly patients, in whom non-surgical therapy is most likely to be indicated and cost-effective, are less likely to be suitable for this form of treatment, since age is a determinant for stone calcification.
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Affiliation(s)
- P W Plaisier
- Department of Surgery, University Hospital, Erasmus University Rotterdam, Netherlands
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50
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Sánchez Pozzi EJ, Luquita MG, Catania VA, Rodríguez Garay EA, Mottino AD. Inhibition of rat liver microsomal bilirubin UDP-glucuronosyltransferase by ursodeoxycholic acid. Life Sci 1994; 55:111-20. [PMID: 8015354 DOI: 10.1016/0024-3205(94)90102-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Ursodeoxycholic acid and its endogenous metabolite tauroursodeoxycholic acid inhibited in vitro the microsomal bilirubin UDP-glucuronosyltransferase from rat liver. The magnitude of the inhibition correlated well with the loss of integrity of microsomal vesicles, suggesting that bile salts needed to reach the lumen to exert their inhibitory effects. The endogenous bile acids cholic acid, chenodeoxycholic acid and deoxycholic acid also exhibited inhibitory effects on bilirubin glucuronidation in digitonin-disrupted microsomes. Ursodeoxycholic acid inhibitory capacity was similar to that of chenodeoxycholic acid and deoxycholic acid but greater than that of cholic acid, the major endogenous bile salt. Kinetic studies, performed in detergent-activated preparations, showed that the inhibitions produced by ursodeoxycholic and tauroursodeoxycholic acids were competitive toward both bilirubin and UDP-glucuronic acid. The estimated Ki(app) for both substrates did not differ statistically between ursodeoxycholic and tauroursodeoxycholic acids. Both bile salts were weak inhibitors toward bilirubin but rather strong inhibitors toward UDP-glucuronic acid.
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Affiliation(s)
- E J Sánchez Pozzi
- Instituto de Fisiología Experimental, CONICET-U.N.R. Facultad de Ciencias Bioquímicas y Farmacéuticas, Rosario, Argentina
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