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1.
Biomed Pharmacother ; 174: 116617, 2024 May.
Article in English | MEDLINE | ID: mdl-38643542

ABSTRACT

Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid commonly used for treating cholestatic liver disease. However, its efficacy on non-alcoholic steatohepatitis (NASH) was controversial. This study aimed to investigate the impact of a high dosage of UDCA on a mouse model of NASH. Forty 6-week-old mice were fed a high-fat high-cholesterol (HFHC) diet for 12 weeks to establish a mouse model of NASH, and then divided into four groups: two groups transitioned to a normal diet, and the other two groups maintained the HFHC diet. Each group was administered a daily dosage of 300 mg/kg of UDCA or saline for a period of 8 weeks. The 16 s ribosomal RNA genes extracted from mice fecal pellets were sequenced using next-generation sequencing techniques. Serum bile acid profiles were quantified using liquid chromatography electrospray ionization tandem mass spectrometry method. The results showed that UDCA treatment ameliorated liver inflammation, without affecting liver fibrosis. UDCA treatment reduced the relative abundance of the genera Bacteroides, Parabacteroides, and Intestinimonas, whereas increased the relative abundance of the genera norank_f_Muribaculaceae and Parasutterella in the HFHC-maintaining groups. The serum levels of total bile acids and total primary bile acids increased, whereas those of endogenous primary bile acids decreased after UDCA treatment. Correlation analysis showed that primary bile acids were negatively correlated with the genera norank_f_Christensenellaceae and unclassified_f_Ruminococcaceae. In conclusion, a high dosage of UDCA can alleviate liver inflammation, probably by modifying the composition of gut microbiota and serum bile acid profiles in NASH mice.


Subject(s)
Bile Acids and Salts , Disease Models, Animal , Gastrointestinal Microbiome , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease , Ursodeoxycholic Acid , Animals , Ursodeoxycholic Acid/pharmacology , Ursodeoxycholic Acid/administration & dosage , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/microbiology , Non-alcoholic Fatty Liver Disease/pathology , Gastrointestinal Microbiome/drug effects , Bile Acids and Salts/metabolism , Bile Acids and Salts/blood , Male , Mice , Diet, High-Fat , Liver/drug effects , Liver/metabolism , Liver/pathology
2.
J Control Release ; 369: 351-362, 2024 May.
Article in English | MEDLINE | ID: mdl-38552963

ABSTRACT

Polymeric prodrug nanoparticles have gained increasing attention in the field of anticancer drug delivery because of their dual functions as a drug carrier and a therapeutic agent. Doxorubicin (DOX) is a highly effective chemotherapeutic agent for various cancers but causes cardiotoxicity. In this work, we developed polymeric prodrug (pHU) nanoparticles that serve as both a drug carrier of DOX and a therapeutic agent. The composition of pHU includes antiangiogenic hydroxybenzyl alcohol (HBA) and ursodeoxycholic acid (UDCA), covalently incorporated through hydrogen peroxide (H2O2)-responsive peroxalate. To enhance cancer cell specificity, pHU nanoparticles were surface decorated with taurodeoxycholic acid (TUDCA) to facilitate p-selectin-mediated cancer targeting. TUDCA-coated and DOX-loaded pHU nanoparticles (t-pHUDs) exhibited controlled release of DOX triggered by H2O2, characteristic of the tumor microenvironment. t-pHUDs also effectively suppressed cancer cell migration and vascular endothelial growth factor (VEGF) expression in response to H2O2. In animal studies, t-pHUDs exhibited highly potent anticancer activity. Notably, t-pHUDs, with their ability to accumulate preferentially in tumors due to the p-selectin targeting, surpassed the therapeutic efficacy of equivalent DOX and pHU nanoparticles alone. What is more, t-pHUDs significantly suppressed VEGF expression in tumors and mitigated hepato- and cardiotoxicity of DOX. Given their cancer targeting ability, enhanced therapeutic efficacy and minimized off-target toxicity, t-pHUDs present an innovative and targeted approach with great translational potential as an anticancer therapeutic agent.


Subject(s)
Doxorubicin , Nanoparticles , Prodrugs , Doxorubicin/administration & dosage , Doxorubicin/pharmacology , Prodrugs/administration & dosage , Prodrugs/chemistry , Nanoparticles/chemistry , Animals , Humans , Cell Line, Tumor , Mice, Inbred BALB C , Neoplasms/drug therapy , Neoplasms/pathology , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/pharmacokinetics , Hydrogen Peroxide , Drug Carriers/chemistry , Ursodeoxycholic Acid/administration & dosage , Ursodeoxycholic Acid/chemistry , Drug Liberation , Mice, Nude , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Polymers/chemistry , Vascular Endothelial Growth Factor A/metabolism , Mice , Female , Drug Delivery Systems , Cell Movement/drug effects , Benzyl Alcohols/administration & dosage , Benzyl Alcohols/chemistry
3.
Ann Hepatol ; 29(3): 101490, 2024.
Article in English | MEDLINE | ID: mdl-38403070

ABSTRACT

INTRODUCTION AND OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) is often accompanied by fetal and maternal complications. MATERIALS AND METHODS: Retrospective review of the clinical course of women with ICP and their neonates treated at our medical center over a 10-year period. Special attention was paid to the maternal and neonatal response to 2 different modes of ursodeoxycholic acid (UDCA) administration. RESULTS: Neonates of mothers with high total bile acid levels had a poorer composite neonatal outcome. Twenty-seven women who presented at an advanced stage of their pregnancies did not receive UDCA. UDCA was administered in 2 modes: either a full dose at admission (76 women) or a gradually increasing dose until the desired dosage was reached (25 women). The mean gestational age at delivery for the 94 neonates that were exposed to full UDCA dose was the lowest (36±2.3 weeks for the full dose, 37±1.4 weeks for the 30 neonates from the gradually increasing dose, 38±1.6 weeks for the 29 neonates from the no treatment group, p<0.001). The group of neonates that were exposed to full UDCA dose had the highest rate of unfavorable composite neonatal outcome (53% for full dose, 30% for gradually increasing dose, 24% for the no treatment group, p=0.006). CONCLUSIONS: Compared to the administration of a full UDCA dose, the administration of a gradually increasing dose of UDCA may be associated with a greater gestational age at delivery and fewer events of unfavorable composite neonatal outcomes. These novel findings should be retested prospectively in a large cohort of patients.


Subject(s)
Cholagogues and Choleretics , Cholestasis, Intrahepatic , Gestational Age , Pregnancy Complications , Ursodeoxycholic Acid , Humans , Ursodeoxycholic Acid/administration & dosage , Ursodeoxycholic Acid/therapeutic use , Female , Pregnancy , Cholestasis, Intrahepatic/drug therapy , Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/blood , Retrospective Studies , Pregnancy Complications/drug therapy , Pregnancy Complications/blood , Infant, Newborn , Cholagogues and Choleretics/administration & dosage , Cholagogues and Choleretics/adverse effects , Cholagogues and Choleretics/therapeutic use , Adult , Treatment Outcome , Pregnancy Outcome
4.
Lancet Gastroenterol Hepatol ; 6(12): 993-1001, 2021 12.
Article in English | MEDLINE | ID: mdl-34715031

ABSTRACT

BACKGROUND: Rapid weight loss is a major risk factor for the formation of cholesterol gallstones. Consequently, patients with morbid obesity undergoing bariatric surgery frequently develop symptomatic gallstone disease. This trial assessed the efficacy of ursodeoxycholic acid versus placebo for the prevention of symptomatic gallstone disease after bariatric surgery. METHODS: This multicentre, double-blind, randomised, placebo-controlled superiority trial enrolled patients with an intact gallbladder scheduled for laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy in three hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module to receive 900 mg ursodeoxycholic acid daily for 6 months or matched placebo. Randomisation was stratified by the presence of asymptomatic gallstones at baseline and type of surgery. Patients, clinicians, and study staff were masked to treatment allocation. The primary endpoint was symptomatic gallstone disease within 24 months, assessed in the modified intention-to-treat population (all randomly assigned eligible patients with any post-randomisation measurement). Prespecified subgroup analyses were done based on the stratification groups. Safety was assessed in all patients who took at least one dose of the study drug. This trial is registered with the Netherlands Trial Register, NL5954. FINDINGS: Between Jan 11, 2017, and Oct 22, 2018, 985 patients were randomly assigned to receive either ursodeoxycholic acid (n=492) or placebo (n=493). 967 patients were included in the modified intention-to-treat population, of whom 959 had data available for primary endpoint assessment. 189 (20%) patients had asymptomatic gallstones at baseline and 78 (8%) received a sleeve gastrectomy. Symptomatic gallstone disease occurred in 31 (6·5%) of 475 patients in the ursodeoxycholic acid group and in 47 (9·7%) of 484 patients in the placebo group (relative risk 0·67, 95% CI 0·43-1·04, p=0·071). Logistic regression showed a significant interaction between ursodeoxycholic acid and the presence of asymptomatic gallstones at baseline (p=0·046), with an effect of ursodeoxycholic acid in patients without (0·47, 0·27-0·84, p=0·0081), and no effect in patients with asymptomatic gallstones at baseline (1·22, 0·61-2·47, p=0·57). The effect was stronger in patients without gallstones at baseline undergoing RYGB (0·37, 0·20-0·71, p=0·0016), whereas the subgroup of patients undergoing sleeve gastrectomy was too small to draw clear conclusions. Adverse events were rare. In the ursodeoxycholic acid group, diarrhoea occurred in four (0·9%) of 444 patients and skin rash in two (0·5%) patients. In the placebo group, diarrhoea occurred in two (0·4%) of 453 patients and skin rash in two (0·4%) patients. The total number of serious adverse events did not significantly differ between the trial groups (75 [17%] in 444 patients in the ursodeoxycholic acid group and 102 [23%] in 453 patients in the placebo group). The most common serious adverse events were abdominal pain and internal hernia. No serious adverse event was attributed to the study drug. INTERPRETATION: Ursodeoxycholic acid prophylaxis did not significantly reduce the occurrence of symptomatic gallstone disease in all patients after bariatric surgery. In patients without gallstones before RYGB surgery, ursodeoxycholic acid treatment reduced the occurrence of symptomatic gallstone disease compared with placebo. Further research is needed to assess the efficacy of ursodeoxycholic acid after sleeve gastrectomy. FUNDING: The Netherlands Organization for Health Research and Development, Zambon Netherlands BV, Foundation for Clinical Research of the Slotervaart Hospital, the Spaarne Gasthuis Academy, and Amsterdam Gastroenterology Endocrinology Metabolism.


Subject(s)
Cholagogues and Choleretics/therapeutic use , Cholelithiasis/prevention & control , Postoperative Complications/prevention & control , Ursodeoxycholic Acid/therapeutic use , Adult , Bariatric Surgery/adverse effects , Case-Control Studies , Cholagogues and Choleretics/administration & dosage , Cholagogues and Choleretics/adverse effects , Cholelithiasis/epidemiology , Cholelithiasis/etiology , Double-Blind Method , Female , Gastrectomy/adverse effects , Gastric Bypass/adverse effects , Humans , Laparoscopy/methods , Male , Middle Aged , Netherlands/epidemiology , Obesity, Morbid/complications , Obesity, Morbid/epidemiology , Obesity, Morbid/surgery , Outcome Assessment, Health Care , Placebos/administration & dosage , Safety , Treatment Outcome , Ursodeoxycholic Acid/administration & dosage , Ursodeoxycholic Acid/adverse effects
5.
Hepatol Commun ; 5(12): 2035-2051, 2021 12.
Article in English | MEDLINE | ID: mdl-34558841

ABSTRACT

Accumulation of cytotoxic bile acids (BAs) during cholestasis can result in liver failure. Glucuronidation, a phase II metabolism pathway responsible for BA detoxification, is regulated by peroxisome proliferator-activated receptor alpha (PPARα). This study investigates the efficacy of adjunct fenofibrate therapy to up-regulate BA-glucuronidation and reduce serum BA toxicity during cholestasis. Adult patients with primary biliary cholangitis (PBC, n = 32) and primary sclerosing cholangitis (PSC, n = 23), who experienced an incomplete response while receiving ursodiol monotherapy (13-15 mg/kg/day), defined as serum alkaline phosphatase (ALP) ≥ 1.5 times the upper limit of normal, received additional fenofibrate (145-160 mg/day) as standard of care. Serum BA and BA-glucuronide concentrations were measured by liquid chromatography-mass spectrometry. Combination therapy with fenofibrate significantly decreased elevated serum ALP (-76%, P < 0.001), aspartate transaminase, alanine aminotransferase, bilirubin, total serum BAs (-54%), and increased serum BA-glucuronides (+2.1-fold, P < 0.01) versus ursodiol monotherapy. The major serum BA-glucuronides that were favorably altered following adjunct fenofibrate include hyodeoxycholic acid-6G (+3.7-fold, P < 0.01), hyocholic acid-6G (+2.6-fold, P < 0.05), chenodeoxycholic acid (CDCA)-3G (-36%), and lithocholic acid (LCA)-3G (-42%) versus ursodiol monotherapy. Fenofibrate also up-regulated the expression of uridine 5'-diphospho-glucuronosyltransferases and multidrug resistance-associated protein 3 messenger RNA in primary human hepatocytes. Pearson's correlation coefficients identified strong associations between serum ALP and metabolic ratios of CDCA-3G (r2  = 0.62, P < 0.0001), deoxycholic acid (DCA)-3G (r2  = 0.48, P < 0.0001), and LCA-3G (r2  = 0.40, P < 0.001), in ursodiol monotherapy versus control. Receiver operating characteristic analysis identified serum BA-glucuronides as measures of response to therapy. Conclusion: Fenofibrate favorably alters major serum BA-glucuronides, which correlate with reduced serum ALP levels and improved outcomes. A PPARα-mediated anti-cholestatic mechanism is involved in detoxifying serum BAs in patients with PBC and PSC who have an incomplete response on ursodiol monotherapy and receive adjunct fenofibrate. Serum BA-glucuronides may serve as a noninvasive measure of treatment response in PBC and PSC.


Subject(s)
Bile Acids and Salts/metabolism , Cholangitis, Sclerosing/drug therapy , Cholestasis/drug therapy , Fenofibrate/administration & dosage , Glucuronides/blood , Liver Cirrhosis, Biliary/drug therapy , Adult , Cholangitis, Sclerosing/blood , Cholestasis/blood , Drug Therapy, Combination , Female , Hepatocytes/metabolism , Humans , Liver/metabolism , Liver Cirrhosis, Biliary/blood , Liver Function Tests , Male , Middle Aged , PPAR alpha/blood , Retrospective Studies , Treatment Outcome , Up-Regulation/drug effects , Ursodeoxycholic Acid/administration & dosage , Young Adult
6.
Dig Liver Dis ; 53(12): 1531-1538, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34011480

ABSTRACT

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive fibro-stenotic strictures and destruction of the biliary tree. Currently, there is no effective treatment which can delay its progression or ameliorate the transplant-free survival. Moreover, a major chontroversy in PSC is whether to use UDCA. More recently, novel pharmacological agents emerged aiming at: i) modulation of bile composition; ii) immunomodulation; iii) targeting the gut microbiome; iv) targeting fibrosis. Successful PSC therapy, however, will be most likely a personalized combination of different drugs plus endoscopic treatment. This review aims at offering an overview on the experimental pharmacological strategies currently exploited for PSC treatment.


Subject(s)
Cholagogues and Choleretics/administration & dosage , Cholangitis, Sclerosing/drug therapy , Ursodeoxycholic Acid/administration & dosage , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Bile/drug effects , Biliary Tract , Cholagogues and Choleretics/pharmacokinetics , Cholangitis, Sclerosing/microbiology , Disease Progression , Dose-Response Relationship, Drug , Fibric Acids/administration & dosage , Fibric Acids/pharmacology , Gastrointestinal Microbiome/drug effects , Humans , Immunomodulation/drug effects , Ursodeoxycholic Acid/pharmacology
7.
Pharm Dev Technol ; 26(5): 599-609, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33759695

ABSTRACT

Ursodeoxycholic acid (UDCA) is used in the oral therapy of hepatobiliary cholestatic diseases. Due to UDCA low aqueous solubility, two pediatric oral suspensions (25 mg/mL) were formulated with a few excipients, suspension A (SA) and suspension B (SB) with a vehicle, including two suspending agents. Physical, chemical and microbiological stability and a rheological study were performed at three different conditions (5 °C ± 3 °C, 25 °C ± 2 °C/60% RH ± 5% RH and 40 °C ± 2 °C/75% RH ± 5% RH) for 120 days. Moreover, dissolution study, content uniformity, related substances, and a study of relative oral bioavailability were also carried out. Both suspensions were physically, chemically and microbiologically stable throughout the study. SA and SB can be stored at 25 °C and 5 °C for at least 120 days whereas SA can be kept at 40 °C for at least 90 days and SB for 120 days. They both met USP specifications for dissolution, content uniformity, and related substances. SA and SB showed an improved relative oral bioavailability compared to the solid dosage form and they both displayed similar relative oral bioavailability with no significant differences between them. The developed suspensions proved to be safe and adequate and they are ideal for pediatric use for their acceptability, accurate dose administration and treatment adherence.


Subject(s)
Cholagogues and Choleretics/administration & dosage , Excipients/chemistry , Ursodeoxycholic Acid/administration & dosage , Administration, Oral , Animals , Biological Availability , Chemistry, Pharmaceutical , Cholagogues and Choleretics/chemistry , Cholagogues and Choleretics/pharmacokinetics , Drug Stability , Drug Storage , Humidity , Male , Rats , Rats, Sprague-Dawley , Rheology , Solubility , Suspensions , Temperature , Ursodeoxycholic Acid/chemistry , Ursodeoxycholic Acid/pharmacokinetics
8.
PLoS One ; 16(2): e0246161, 2021.
Article in English | MEDLINE | ID: mdl-33600468

ABSTRACT

Ursodeoxycholic acid (commercially available as ursodiol) is a naturally occurring bile acid that is used to treat a variety of hepatic and gastrointestinal diseases. Ursodiol can modulate bile acid pools, which have the potential to alter the gut microbiota community structure. In turn, the gut microbial community can modulate bile acid pools, thus highlighting the interconnectedness of the gut microbiota-bile acid-host axis. Despite these interactions, it remains unclear if and how exogenously administered ursodiol shapes the gut microbial community structure and bile acid pool in conventional mice. This study aims to characterize how ursodiol alters the gastrointestinal ecosystem in conventional mice. C57BL/6J wildtype mice were given one of three doses of ursodiol (50, 150, or 450 mg/kg/day) by oral gavage for 21 days. Alterations in the gut microbiota and bile acids were examined including stool, ileal, and cecal content. Bile acids were also measured in serum. Significant weight loss was seen in mice treated with the low and high dose of ursodiol. Alterations in the microbial community structure and bile acid pool were seen in ileal and cecal content compared to pretreatment, and longitudinally in feces following the 21-day ursodiol treatment. In both ileal and cecal content, members of the Lachnospiraceae Family significantly contributed to the changes observed. This study is the first to provide a comprehensive view of how exogenously administered ursodiol shapes the healthy gastrointestinal ecosystem in conventional mice. Further studies to investigate how these changes in turn modify the host physiologic response are important.


Subject(s)
Body Weight , Gastrointestinal Microbiome , Receptors, Cytoplasmic and Nuclear/metabolism , Ursodeoxycholic Acid/pharmacology , Animals , Body Weight/drug effects , Cecum/microbiology , Feces/microbiology , Female , Gastrointestinal Microbiome/drug effects , Ileum/microbiology , Male , Metabolome/drug effects , Mice, Inbred C57BL , Receptors, G-Protein-Coupled/metabolism , Ursodeoxycholic Acid/administration & dosage , Weight Loss/drug effects
9.
Am J Physiol Endocrinol Metab ; 320(4): E671-E679, 2021 04 01.
Article in English | MEDLINE | ID: mdl-33459181

ABSTRACT

Bile acids (BA) regulate postprandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The postprandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effects of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on postprandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon, and ghrelin. Twelve healthy volunteers underwent a mixed meal test 60 min after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg), or no BA in a randomized crossover study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin, and fibroblast growth factor 19 were measured prior to BA administration at -60 and 0 min (just prior to mixed meal) and 15, 30, 60, 120, 180, and 240 min after the meal. UDCA and CDCA provoked differential gut hormone responses; UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced postprandial secretion of GIP, with an associated reduction in postprandial insulin secretion. Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmed in obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions.NEW & NOTEWORTHY Oral CDCA and UDCA have different effects on gut and pancreatic hormone secretion. A single dose of CDCA increased fasting secretion of the hormones GLP-1 and OXM with an accompanying increase in insulin secretion. CDCA also reduced postprandial GIP secretion, which was associated with reduced insulin. In contrast, UDCA did not change gut hormone secretion fasting or postprandially. Oral CDCA could be beneficial to patients with obesity and diabetes.


Subject(s)
Bile Acids and Salts/pharmacology , Gastrointestinal Hormones/metabolism , Postprandial Period/drug effects , Administration, Oral , Adult , Bile Acids and Salts/administration & dosage , Bile Acids and Salts/blood , Chenodeoxycholic Acid/administration & dosage , Chenodeoxycholic Acid/pharmacology , Cross-Over Studies , Eating/physiology , Female , Healthy Volunteers , Humans , Male , Middle Aged , Secretory Pathway/drug effects , United Kingdom , Ursodeoxycholic Acid/administration & dosage , Ursodeoxycholic Acid/pharmacology , Young Adult
10.
BMC Pregnancy Childbirth ; 21(1): 51, 2021 Jan 12.
Article in English | MEDLINE | ID: mdl-33435904

ABSTRACT

BACKGROUND: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. METHODS: We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. DISCUSSION: Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. TRIAL IDENTIFIERS: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.


Subject(s)
Antipruritics/therapeutic use , Cholestasis, Intrahepatic/drug therapy , Pregnancy Complications/drug therapy , Rifampin/therapeutic use , Ursodeoxycholic Acid/therapeutic use , Antipruritics/administration & dosage , Australia , Female , Humans , Pregnancy , Pregnancy Outcome , Rifampin/administration & dosage , Treatment Outcome , Ursodeoxycholic Acid/administration & dosage
11.
J Hepatol ; 74(1): 58-65, 2021 01.
Article in English | MEDLINE | ID: mdl-32717289

ABSTRACT

BACKGROUND & AIMS: Obeticholic acid (OCA) is an agonist of the nuclear bile acid receptor farnesoid X receptor, which regulates hepatic bile acid metabolism. We tested whether OCA treatment would influence hepatic transport of conjugated bile acids in patients with primary biliary cholangitis (PBC) who responded inadequately to treatment with ursodeoxycholic acid (UDCA). METHODS: Eight UDCA-treated patients with PBC with alkaline phosphatase ≥1.5 times the upper limit of normal range participated in a double-blind, placebo-controlled study. While continuing on UDCA, the patients were randomised to two 3-month crossover treatment periods with placebo and OCA, in random order, separated by a 1-month washout period without study treatment. After each of the two treatment periods, we determined rate constants for transport of conjugated bile acids between blood, hepatocytes, biliary canaliculi, and bile ducts by positron emission tomography of the liver using the conjugated bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar). The hepatic blood perfusion was measured using infusion of indocyanine green and Fick's principle. RESULTS: Compared with placebo, OCA increased hepatic blood perfusion by a median of 11% (p = 0.045), the unidirectional uptake clearance of 11C-CSar from blood into hepatocytes by a median of 11% (p = 0.01), and the rate constant for secretion of 11C-CSar from hepatocytes into biliary canaliculi by a median of 73% (p = 0.03). This resulted in an OCA-induced decrease in the hepatocyte residence time of 11C-CSar by a median of 30% (p = 0.01), from group median 11 min to 8 min. CONCLUSIONS: This study of UDCA-treated patients with PBC showed that, compared with placebo, OCA increased the hepatic transport of the conjugated bile acid tracer 11C-CSar, and thus endogenous conjugated bile acids, from hepatocytes into biliary canaliculi. As a result, OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids. LAY SUMMARY: Primary biliary cholangitis is a chronic liver disease in which the small bile ducts are progressively destroyed. We tested whether the treatment with obeticholic acid (OCA) would improve liver excretion of bile acids compared with placebo in 8 patients with primary biliary cholangitis. A special scanning technique (PET scan) showed that OCA increased the transport of bile acids from blood to bile. OCA thereby reduced the time that potentially toxic bile acids reside in the liver by approximately one-third.


Subject(s)
Bile Acids and Salts/metabolism , Bile Ducts, Intrahepatic , Chenodeoxycholic Acid/analogs & derivatives , Liver Cirrhosis, Biliary , Positron-Emission Tomography/methods , Receptors, Cytoplasmic and Nuclear/agonists , Aged , Alkaline Phosphatase/blood , Bile Ducts, Intrahepatic/diagnostic imaging , Bile Ducts, Intrahepatic/physiopathology , Biological Transport/drug effects , Chenodeoxycholic Acid/administration & dosage , Chenodeoxycholic Acid/pharmacokinetics , Double-Blind Method , Female , Gastrointestinal Agents/administration & dosage , Gastrointestinal Agents/pharmacokinetics , Gastrointestinal Agents/pharmacology , Hepatocytes/pathology , Humans , Liver Cirrhosis, Biliary/diagnosis , Liver Cirrhosis, Biliary/drug therapy , Liver Cirrhosis, Biliary/metabolism , Middle Aged , Treatment Outcome , Ursodeoxycholic Acid/administration & dosage , Ursodeoxycholic Acid/pharmacokinetics
12.
Neurosci Lett ; 741: 135493, 2021 01 10.
Article in English | MEDLINE | ID: mdl-33181233

ABSTRACT

Neuroprotection targeting mitochondrial dysfunction has been proposed as a potential therapeutic strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has been shown to prevent neuronal damage; however, the role of UDCA in PD is poorly understood. This study aimed to investigate the neuroprotective effects of UDCA on PD and its underlying mechanisms. We used MPTP/MPP+-induced PD models, including MPTP-induced mice, primary cultures of mice mesencephalic neurons and MPP+-treated neuro-2a cells to examine the effects of UDCA on PD pathogenesis. The results showed that UDCA improved behavioral performance and protected dopaminergic neurons in MPTP mice. UDCA improved cell viability and decreased cell death in MPP+-treated cells. UDCA inhibited reactive oxygen species accumulation, mitochondrial membrane potential collapse, and ATP depletion in neuro-2a cells. UDCA improved movement dysfunction, ameliorated autophagic flux and alleviated apoptosis. Furthermore, UDCA could activate the AMPK/mTOR and PINK1/Parkin pathways. In conclusion, UDCA may improve PD by regulating mitochondrial function, autophagy, and apoptosis, involving AMPK/mTOR and PINK1/Parkin pathways. These results open new perspectives for pharmacological use of UDCA in PD.


Subject(s)
Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Neuroprotective Agents/administration & dosage , Oxidative Stress/drug effects , Parkinsonian Disorders/metabolism , Ursodeoxycholic Acid/administration & dosage , Animals , Apoptosis/drug effects , Autophagy/drug effects , Cell Line, Tumor , Male , Mice, Inbred C57BL , Mitochondria/drug effects , Parkinsonian Disorders/drug therapy , Signal Transduction/drug effects
13.
Hepatology ; 73(3): 1061-1073, 2021 03.
Article in English | MEDLINE | ID: mdl-32946600

ABSTRACT

BACKGROUND AND AIMS: Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. APPROACH AND RESULTS: We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty-four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention-to-treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma-glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5-year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. CONCLUSIONS: We presented the largest-ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end-stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo-controlled treatment trials are needed to identify effective treatments for pediatric PSC.


Subject(s)
Cholangitis, Sclerosing/drug therapy , Ursodeoxycholic Acid/therapeutic use , Vancomycin/therapeutic use , Administration, Oral , Adolescent , Bilirubin/blood , Child , Female , Humans , Male , Propensity Score , Retrospective Studies , Serum Albumin/analysis , Treatment Outcome , Ursodeoxycholic Acid/administration & dosage , Vancomycin/administration & dosage
14.
BJOG ; 128(6): 1066-1075, 2021 05.
Article in English | MEDLINE | ID: mdl-33063439

ABSTRACT

OBJECTIVE: To evaluate whether a particular group of women with intrahepatic cholestasis of pregnancy (ICP), based on their presenting characteristics, would benefit from treatment with ursodeoxycholic acid (UDCA). DESIGN: Secondary analysis of the PITCHES trial (ISRCTN91918806). SETTING: United Kingdom. POPULATION OR SAMPLE: 527 women with ICP. METHODS: Subgroup analyses were performed to determine whether baseline bile acid concentrations or baseline itch scores moderated a woman's response to treatment with UDCA. MAIN OUTCOME MEASURES: Bile acid concentration and itch score. RESULTS: In women with baseline bile acid concentrations less than 40 µmol/l, treatment with UDCA resulted in increased post-randomisation bile acid concentrations (geometric mean ratio 1.19, 95% CI 1.00-1.41, P = 0.048). A test of interaction showed no significance (P = 0.647). A small, clinically insignificant difference was seen in itch response in women with a high baseline itch score (-6.0 mm, 95% CI -11.80 to -0.21, P = 0.042), with a test of interaction not showing significance (P = 0.640). Further subgroup analyses showed no significance. Across all women there was a weak relationship between bile acid concentrations and itch severity. CONCLUSIONS: There was no subgroup of women with ICP in whom a beneficial effect of treatment with UDCA on bile acid concentration or itch score could be identified. This confirms that its routine use in women with this condition for improvement of bile acid concentration or itch score should be reconsidered. TWEETABLE ABSTRACT: PITCHES: No group of women with ICP has been found in whom UDCA reduces bile acid concentrations or pruritus.


Subject(s)
Bile Acids and Salts/blood , Cholestasis, Intrahepatic , Pregnancy Complications , Pruritus , Ursodeoxycholic Acid , Adult , Cholagogues and Choleretics/administration & dosage , Cholagogues and Choleretics/adverse effects , Cholestasis, Intrahepatic/blood , Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/drug therapy , Cholestasis, Intrahepatic/physiopathology , Double-Blind Method , Female , Humans , Outcome Assessment, Health Care , Pregnancy , Pregnancy Complications/blood , Pregnancy Complications/diagnosis , Pregnancy Complications/drug therapy , Pregnancy Complications/physiopathology , Pruritus/diagnosis , Pruritus/drug therapy , Pruritus/etiology , Severity of Illness Index , Stillbirth/epidemiology , Symptom Assessment/methods , United Kingdom , Ursodeoxycholic Acid/administration & dosage , Ursodeoxycholic Acid/adverse effects
15.
Rev. Soc. Bras. Clín. Méd ; 19(3): 176-180, set 2021.
Article in Portuguese | LILACS | ID: biblio-1391950

ABSTRACT

A busca pelo corpo perfeito pode gerar graves consequências para a população que faz uso indiscriminado de substâncias visando a resultados rápidos. O caso relatado se refere a um pa- ciente de 21 anos, do sexo masculino, na cidade de São Paulo (SP), que apresentou quadro de síndrome colestática 15 dias após uso do anabolizante estanazolol para fins estéticos na ativi- dade física, evoluindo com hepatite medicamentosa grave, com aumento de transaminases, hiperrubilinemia às custas de bilirrubina direta e fatores de coagulação, sem resposta satis- fatória ao tratamento de suporte convencional, com melhora significativa após introdução de corticoterapia.


Searching for the perfect body image can cause severe conse- quences to the population using substances indiscriminately to reach results fast. The case reported refers to a male patient, 21 years old, from the city of São Paulo (SP), who developed choles- tatic syndrome 15 days after the use of the steroid Stanazol for aesthetic purposes during physical activity, progressing with se- vere drug-induced hepatitis, transaminases, bilirubin, and coagu- lation factors increase with no satisfactory response to the con- ventional support treatment, and significant improvement after the introduction of corticotherapy.


Subject(s)
Humans , Male , Adult , Young Adult , Stanozolol/toxicity , Chemical and Drug Induced Liver Injury/drug therapy , Glucocorticoids/therapeutic use , Anabolic Agents/toxicity , Ursodeoxycholic Acid/administration & dosage , Bilirubin/blood , Biopsy , Cholagogues and Choleretics/therapeutic use , Prednisone/administration & dosage , Cholestasis/diagnosis , Cholestasis/pathology , Cholesterol/blood , Cholestyramine Resin/administration & dosage , Catastrophic Illness , Chemical and Drug Induced Liver Injury/diagnosis , Chemical and Drug Induced Liver Injury/pathology , Transaminases/blood , Hydroxyzine/administration & dosage , Liver/pathology , Anticholesteremic Agents/therapeutic use , Antipruritics/therapeutic use
16.
Lancet ; 396(10266): 1915-1926, 2020 12 12.
Article in English | MEDLINE | ID: mdl-33308474

ABSTRACT

Primary biliary cholangitis is an autoimmune liver disease that predominantly affects women. It is characterised by a chronic and destructive, small bile duct, granulomatous lymphocytic cholangitis, with typical seroreactivity for antimitochondrial antibodies. Patients have variable risks of progressive ductopenia, cholestasis, and biliary fibrosis. Considerations for the cause of this disease emphasise an interaction of chronic immune damage with biliary epithelial cell responses and encompass complex, poorly understood genetic risks and environmental triggers. Licensed disease-modifying treatment focuses on amelioration of cholestasis, with weight-dosed oral ursodeoxycholic acid. For patients who do not respond sufficiently, or patients with ursodeoxycholic acid intolerance, conditionally licensed add-on therapy is with the FXR (NR1H4) agonist, obeticholic acid. Off-label therapy is recognised as an alternative, notably with the pan-PPAR agonist bezafibrate; clinical trial agents are also under development. Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.


Subject(s)
Autoimmune Diseases , Cholagogues and Choleretics/administration & dosage , Cholangitis/diagnosis , Cholangitis/drug therapy , Ursodeoxycholic Acid/administration & dosage , Biomarkers , Chenodeoxycholic Acid/administration & dosage , Chenodeoxycholic Acid/analogs & derivatives , Cholangitis/physiopathology , Fatigue/etiology , Humans , Pruritus/etiology , Risk Factors
18.
Sci Rep ; 10(1): 15284, 2020 09 17.
Article in English | MEDLINE | ID: mdl-32943714

ABSTRACT

Acute myocardial ischaemia and reperfusion (I-R) are major causes of ventricular arrhythmias in patients with a history of coronary artery disease. Ursodeoxycholic acid (UDCA) has previously been shown to be antiarrhythmic in fetal hearts. This study was performed to investigate if UDCA protects against ischaemia-induced and reperfusion-induced arrhythmias in the adult myocardium, and compares the effect of acute (perfusion only) versus prolonged (2 weeks pre-treatment plus perfusion) UDCA administration. Langendorff-perfused adult Sprague-Dawley rat hearts were subjected to acute regional ischaemia by ligation of the left anterior descending artery (10 min), followed by reperfusion (2 min), and arrhythmia incidence quantified. Prolonged UDCA administration reduced the incidence of acute ischaemia-induced arrhythmias (p = 0.028), with a reduction in number of ventricular ectopic beats during the ischaemic phase compared with acute treatment (10 ± 3 vs 58 ± 15, p = 0.036). No antiarrhythmic effect was observed in the acute UDCA administration group. Neither acute nor prolonged UDCA treatment altered the incidence of reperfusion arrhythmias. The antiarrhythmic effect of UDCA may be partially mediated by an increase in cardiac wavelength, due to the attenuation of conduction velocity slowing (p = 0.03), and the preservation of Connexin43 phosphorylation during acute ischaemia (p = 0.0027). The potential antiarrhythmic effects of prolonged UDCA administration merit further investigation.


Subject(s)
Arrhythmias, Cardiac/drug therapy , Heart/drug effects , Myocardial Ischemia/complications , Ursodeoxycholic Acid/administration & dosage , Animals , Anti-Arrhythmia Agents/administration & dosage , Coronary Vessels/drug effects , Male , Myocardial Reperfusion/methods , Myocardial Reperfusion Injury/complications , Myocardium/pathology , Perfusion/methods , Rats , Rats, Sprague-Dawley
19.
Updates Surg ; 72(4): 1125-1133, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32666477

ABSTRACT

BACKGROUND: Although bariatric surgery (BS) predisposes patients to development of gallstone formation, a preventive strategy is still in debate. AIM: To compare the incidence of gallstone formation between patients treated with ursodeoxycholic acid (UDCA) vs. placebo for a duration of 6 months following BS. METHODS: This multicenter randomized, double-blind controlled trial entails treatment with UDCA vs. an identical-looking placebo. The primary outcome was gallstone formation, as measured by abdominal ultrasound. RESULTS: The data of 209 subjects were enrolled in the study, and 92 subjects completed the study and were analyzed (n = 46 for each study group). The high dropout rate was mainly due to difficulties in adding more medications and swallowing the pill. Among the subjects who completed the study, 77.2% were women, and their mean age and pre-surgery BMI were 42.2 ± 10.2 years and 44.4 ± 6.1 kg/m2, respectively. Gallstone formation was recorded in 45.7% (n = 21) vs. 23.9% (n = 11) of subjects among placebo vs. UDCA groups, respectively, p = 0.029. Subgroup-analysis, according to surgery type, found that the results were significant only for SG subjects (p = 0.041), although the same trend was observed for OAGB/RYGB. Excess Weight Loss percent (%EWL) at 6 months post-surgery was 66.0 ± 17.1% vs. 71.8 ± 19.5% for the placebo and UDCA groups, respectively; p = 0.136. A trend towards a reduction in prescribed comorbidity medications was noted within-groups during the follow-up period, as compared to baseline, with no between-group differences (p ≥ 0.246). Moreover, no between-group differences were found for blood test results (p ≥ 0.063 for all). CONCLUSION: Administration of UDCA significantly decreased gallstone formation at 6 months at following BS. CLINICALTRIALS. GOV NUMBER: NCT02319629.


Subject(s)
Bariatric Surgery/adverse effects , Gallstones/prevention & control , Postoperative Complications/prevention & control , Ursodeoxycholic Acid/administration & dosage , Adult , Double-Blind Method , Female , Follow-Up Studies , Gallstones/etiology , Humans , Male , Middle Aged , Obesity/surgery , Placebo Effect , Postoperative Complications/etiology , Time Factors
20.
J Hepatol ; 73(3): 559-565, 2020 09.
Article in English | MEDLINE | ID: mdl-32275981

ABSTRACT

BACKGROUND & AIMS: Recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT) is frequent and can impair graft and patient survival. Ursodeoxycholic acid (UDCA) is the current standard therapy for PBC. We investigated the effect of preventive exposure to UDCA on the incidence and long-term consequences of PBC recurrence after LT. METHODS: We performed a retrospective cohort study in 780 patients transplanted for PBC, between 1983-2017 in 16 centers (9 countries), and followed-up for a median of 11 years. Among them, 190 received preventive UDCA (10-15 mg/kg/day). The primary outcome was histological evidence of PBC recurrence. The secondary outcomes were graft loss, liver-related death, and all-cause death. The association between preventive UDCA and outcomes was quantified using multivariable-adjusted Cox and restricted mean survival time (RMST) models. RESULTS: While recurrence of PBC significantly shortened graft and patient survival, preventive exposure to UDCA was associated with reduced risk of PBC recurrence (adjusted hazard ratio [aHR] 0.41; 95% CI 0.28-0.61; p <0.0001), graft loss (aHR 0.33; 95% CI 0.13-0.82; p <0.05), liver-related death (aHR 0.46; 95% CI 0.22-0.98; p <0.05), and all-cause death (aHR 0.69; 95% CI 0.49-0.96; p <0.05). On RMST analysis, preventive UDCA led to a survival gain of 2.26 years (95% CI 1.28-3.25) over a period of 20 years. Exposure to cyclosporine rather than tacrolimus had a complementary protective effect alongside preventive UDCA, reducing the cumulative incidence of PBC recurrence and all-cause death. CONCLUSIONS: Preventive UDCA after LT for PBC is associated with a reduced risk of disease recurrence, graft loss, and death. A regimen combining cyclosporine and preventive UDCA is associated with the lowest risk of PBC recurrence and mortality. LAY SUMMARY: Recurrence of primary biliary cholangitis after liver transplantation is frequent and can impair graft and patient survival. We performed the largest international study of transplanted patients with primary biliary cholangitis to date. Preventive administration of ursodeoxycholic acid after liver transplantation was associated with reduced risk of disease recurrence, graft loss, liver-related and all-cause mortality. A regimen combining cyclosporine and preventive ursodeoxycholic acid was associated with the best outcomes.


Subject(s)
Cholagogues and Choleretics/administration & dosage , Graft Rejection/mortality , Graft Rejection/prevention & control , Liver Cirrhosis, Biliary/etiology , Liver Cirrhosis, Biliary/prevention & control , Liver Transplantation/adverse effects , Ursodeoxycholic Acid/administration & dosage , Aged , Cyclosporine/therapeutic use , Drug Therapy, Combination/methods , Female , Follow-Up Studies , Humans , Immunosuppressive Agents/therapeutic use , Liver Cirrhosis, Biliary/mortality , Liver Cirrhosis, Biliary/surgery , Male , Middle Aged , Recurrence , Retrospective Studies , Risk , Survival Rate , Treatment Outcome
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