The efficacy of intravenous lidocaine and its side effects in comparison with intravenous morphine sulfate in patients admitted to the ED with right upper abdominal pain suspected of biliary colic.

BACKGROUND: Intravenous (IV) Lidocaine can be used as analgesic in acute pain management in the emergency department (ED). OBJECTIVE: Efficacy of IV Lidocaine in comparison with IV morphine in acute pain management in the ED. METHOD: This is a double-blind randomized clinical trial on adult (18-64 year) patients with right upper abdominal pain suspected of biliary colic who needed pain management. Participants randomly received IV lidocaine (5 cc = 100 mg) or morphine sulfate (5 cc = 5 mg). In both groups, patients' pain scores were recorded and assessed by Numeric Rating Scale (NRS) at baseline, 10, 20, 30, 45, 60 and 120 min after drug administration. Adverse side effects of lidocaine and morphine sulfate and changes in vital signs were also recorded and compared. RESULTS: A total number of 104 patients were enrolled in the study, including 49 men and 55 women. IV lidocaine reduced pain in less time in comparison with morphine sulfate. Mean (±SD) basic pain score was 8.23 (±1.76) in the lidocaine group and 8.73 (±0.96) in the morphine group. Patients' mean (±SD) pain score in both groups had no significant difference during the study except that of NRS2 (10 min after drug administration), which was 5.05 (±2.69) in lidocaine group compared with 6.39 (±2.06) in the morphine group and NRS4 (30 min after drug administration), which was significantly lower (P-value = 0.01) in the morphine group [3.84(±1.73) vs 4.41(±2.82)]. Only 9 patients had adverse effects in either group. CONCLUSION: The findings of this study suggest that IV lidocaine can be a good choice in pain management in biliary colic and can reduce pain in less time than morphine sulfate (in 10 min) without adding significant side effects; however, our primary outcome was the comparison of these two drugs after 60 min of drug administration in pain reduction which showed no significant difference between two groups.

Infectious Complications in Severe Acute Pancreatitis: Pathogens, Drug Resistance, and Status of Nosocomial Infection in a University-Affiliated Teaching Hospital.

BACKGROUND: Secondary infection is an important factor affecting mortality and quality of life in patients with severe acute pancreatitis. The characteristics of secondary infection, which are well known to clinicians, need to be re-examined in detail, and their understanding among clinicians needs to be updated accordingly. AIM: This study aims to investigate the characteristics and drug resistance of pathogens causing severe acute pancreatitis (SAP) secondary infection, to objectively present infection situation, and to provide reference for improved clinical management. METHODS: A retrospective analysis was performed on 55 consecutive patients with SAP who developed secondary infection with an accurate evidence of bacterial/fungal culture from 2016 to 2018. The statistics included the spectrum and distribution of pathogens, the drug resistance of main pathogens, and associations between multiple infectious parameters and mortality. RESULTS: A total of 181 strains of pathogens were isolated from (peri)pancreas; bloodstream; and respiratory, urinary, and biliary systems in 55 patients. The strains included 98 g-negative bacteria, 58 g-positive bacteria, and 25 fungi. Bloodstream infection (36.5%) was the most frequent infectious complication, followed by (peri)pancreatic infection (32.0%). Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Stenotrophomonas maltophilia were predominant among gram-negative bacteria. Gram-positive bacterial infections were mainly caused by Enterococcus faecium and Staphylococcus spp. Fungal infections were predominantly caused by Candida spp. The drug resistance of pathogens causing SAP secondary infection was generally higher than the surveillance level. Patients in the death group were older (55 ± 13 years vs. 46 ± 14 years; p = 0.039) and had longer intensive care unit (ICU) stay (14 vs. 8; p = 0.026) than those in the survival group. A. baumannii infection (68.4% vs. 33%; p = 0.013), number of pathogens ≥ 4 (10 vs. 6; p = 0.005), pancreatic infection (14 vs. 15, p = 0.024), and urinary infection (8 vs. 5; p = 0.019) were significantly associated with mortality. CONCLUSION: Gram-negative bacteria are the main pathogens causing SAP secondary infection, in which nosocomial infections play a major role. The drug resistance profile of gram-negative bacteria is seriously threatening, and the commonly used antibiotics in SAP are gradually losing their effectiveness. Much attention should be paid to the rational use of antibiotics, and strategies should be established for infection prevention in SAP.

Possible application of melatonin treatment in human diseases of the biliary tract.

Melatonin was discovered in 1958 by Aaron Lerner. Its name comes from the ability of melatonin to change the shape of amphibian melanophores from stellate to roundish. Starting from the 1980s, the role of melatonin in the regulation of mammalian circadian and seasonal clocks has been elucidated. Presently, several other effects have been identified in different organs. For example, the beneficial effects of melatonin in models of liver damage have been described. This review gives first a general background on experimental and clinical data on the use of melatonin in liver damage. The second part of the review focuses on the findings related to the role of melatonin in biliary functions, suggesting a possible use of melatonin therapy in human diseases of the biliary tree.

Establishment of a surgical bile duct injection technique giving direct access to the bile ducts for studies of the murine biliary tree.

Cholangiopathies are progressive disorders with largely unknown pathoetiology and limited treatment options. We aimed to develop a novel surgical technique with direct access to the bile ducts that would complement existing mouse models of cholestasis, biliary inflammation, and fibrosis and present a new route of administration for testing of potential treatment strategies. We developed a surgical technique to access the murine biliary tree by injection of different solvents through catheterization of the gall bladder with simultaneous clamping of the common bile duct. To demonstrate the applicability of the technique, we injected either phosphate-buffered saline or dimethyl sulfoxide in concentrations of 50 or 65% and compared these groups with sham-operated mice. The surgery was optimized to achieve a mortality rate close to 0. There were no significant changes in pain, activity level, or mortality from the day of the surgery until euthanization for any groups. Injection of phosphate-buffered saline or 50% dimethyl sulfoxide was generally well-tolerated, whereas 65% dimethyl sulfoxide led to higher weight loss, an increase of serum alanine transaminase, and histological portal inflammation. There were no signs of inflammation in the gut. We have developed a bile duct injection technique that is well-tolerated, easily reproducible, and that may complement existing models of cholangiopathies. Direct access to the bile ducts without causing harm to the hepatobiliary or intestinal tissue may be valuable in future studies of normal biliary physiology and different pathophysiological mechanisms of disease and to test novel therapeutic strategies. NEW & NOTEWORTHY To evaluate tolerability of the bile duct to injection of both polar and nonpolar compounds, we established a novel biliary injection technique. This technique is well-tolerated, easily reproducible, and with direct access to the bile ducts for studies of the murine biliary tree. The bile duct injection technique may complement existing animal models and be a valuable tool in future studies of normal biliary physiology or pathophysiology and to test novel therapeutic strategies.

Rituximab Maintenance Therapy Reduces Rate of Relapse of Pancreaticobiliary Immunoglobulin G4-related Disease.

BACKGROUND & AIMS: IgG4-related disease (IgG4-RD), a multi-organ fibroinflammatory syndrome, typically responds to steroids. However, some cases are steroid resistant, and pancreaticobiliary IgG4-RD commonly relapses after steroid withdrawal. Rituximab induces remission of IgG4-RD, but the need for and safety of maintenance rituximab treatment are unknown. We compared outcomes of patients with pancreaticobiliary IgG4-RD treated with or without maintenance rituximab therapy. METHODS: We performed a retrospective study of patients with pancreaticobiliary IgG4-RD treated with rituximab at the Mayo Clinic in Rochester, Minnesota, from January 2005 through December 2015. The cohort was divided into patients who received only rituximab induction therapy (group 1, n = 14) and patients who received rituximab induction followed by maintenance therapy (group 2, n = 29). We collected data on recurrence of IgG4-RD symptoms and findings, as well as information on evaluations, treatment, and adverse events. RESULTS: Median follow-up times were similar between group 1 (34 mo) and group 2 (27 mo) (P = .99). Thirty-seven patients (86%) were in steroid-free remission 6 months after rituximab initiation. A higher proportion of patients in group 1 had disease relapse (3-year event rate, 45%) than in group 2 (3-year event rate, 11%) (P = .034). Younger age, higher IgG4 responder index score after induction therapy, and increased serum levels of alkaline phosphatase at baseline or after rituximab induction were associated with relapse. Infections developed in 6 of 43 patients, all in group 2 (P = .067 vs group 1); all but 1 occurred during maintenance therapy. CONCLUSIONS: In a retrospective study of patients with pancreaticobiliary IgG4-RD, we found rituximab maintenance therapy prolongs remission. Relapses are uncommon among patients receiving maintenance therapy, but maintenance therapy may increase risk of infection. Patients with factors that predict relapse could be candidates for rituximab maintenance therapy.

Anaerobic coverage as definitive therapy does not affect clinical outcomes in community-onset bacteremic biliary tract infection without anaerobic bacteremia.

BACKGROUND: Antibiotics with anaerobic coverage are widely used for the treatment of biliary tract infection (BTI), even in the absence of isolated anaerobes. The current study aimed to investigate the differences in clinical outcomes in patients with community-onset bacteremic BTIs without anaerobic bacteremia, treated with vs. without anti-anaerobic coverage. METHODS: A retrospective analysis was conducted at a medical center in Taiwan from September 2014 to March 2016. Patients with community-onset bacteremic BTIs without anaerobic bacteremia and who were treated with appropriate antibiotics were analyzed. The clinical outcomes were compared between patients treated with and without anti-anaerobic coverage as definitive therapy after the blood culture reports were available. Multivariable and propensity score-adjusted analysis were used to identify the risk factors associated with treatment failure. RESULTS: Among the enrolled 87 patients, 63 and 24 patients were treated with and without anaerobic coverage, respectively. Escherichia coli (55.2%) and Klebsiella pneumoniae (23.0%) were the most common organisms isolated from the blood cultures. The rate of treatment failure (relapse and 28-day mortality) was similar between the groups with and without anaerobic coverage (20.6% vs. 16.7%, p = 0.677). Propensity score-adjusted multivariable analysis revealed that definitive therapy without anaerobic coverage was not a predisposing factor for treatment failure (OR = 0.92, 95% CI 0.18-4.67, p = 0.916). CONCLUSIONS: Definitive therapy without anaerobic coverage does not affect the outcomes of patients with community-onset bacteremic BTIs without anaerobes isolated from blood. Our results might provide a possible target for antibiotic stewardship interventions in BTIs.

Factors associated to prevalence and treatment of carbapenem-resistant Enterobacteriaceae infections: a seven years retrospective study in three tertiary care hospitals.

BACKGROUND: The increasing incidence of carbapenem-resistant Enterobacteriaceae (CRE), has resulted in a difficult problem in the current clinical anti-infective treatment. We performed a retrospective analysis of prevalence and treatment for CRE infections patients. METHODS: This study was conducted in three tertiary care hospitals from January 1, 2010 to December 30, 2016. Baseline data, treatment, and outcomes were collected in patients with ventilator-associated bacterial pneumonia (VABP), bacteremia, complicated urinary tract infection (cUTI)/acute pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), superficial wound infection (SWI), biliary tract infection (BTI), deep wound infection (DWI) and sterile body fluids infection (SBFI) due to CRE. RESULTS: One hundred twenty-four cases of CRE infection were identified: 31 VABP, 22 bacteremia, 18 cUTI/AP, 16 HABP, 16 SWI, 9 BTI, 7 DWI and 5 SBFI. The patient population had significant immunocompromised (33 of 124, 26.6%) and severe sepsis (43 of 124, 34.7%). The most common CRE pathogens were Klebsiella pneumoniae (84 of 124, 67.7%) and Enterobacter cloacae (24 of 124, 19.4%). And the production of IMP-type carbapenemase was the main antibiotic resistance mechanism. The majority of patients to take monotherapy for empiric therapy and dual therapy for direct treatment. Outcomes were universally poor (28-day mortality was 22.6%, 28 of 124) across all sites of infection. CONCLUSIONS: We identified a large number of cases of CRE infection in 7 years from different parts, most of these pathogens have been confirmed to produce IMP-type carbapenemases. The retrospective analysis of cases of such bacterial infections will help to control future infections of these pathogens. Despite the high mortality rate, we still found that the selection of quinolone antibiotics can be effective in the treatment of CRE producing IMP type enzymes.

Antimicrobial susceptibility of common pathogens isolated from postoperative intra-abdominal infections in Japan.

The principle of empirical therapy for patients with intra-abdominal infections (IAI) should include antibiotics with activity against Enterobacteriaceae and Bacteroides fragilis group species. Coverage of Pseudomonas aeruginosa, Enterobacter cloacae, and Enterococcus faecalis is also recommended for hospital-associated IAI. A nationwide survey was conducted to investigate the antimicrobial susceptibility of pathogens isolated from postoperative IAI. All 504 isolates were collected at 26 institutions and referred to a central laboratory for susceptibility testing. Lower susceptibility rates to ciprofloxacin and cefepime were demonstrated in Escherichia coli. Among E. coli, 24.1% of strains produced extended-spectrum ß-lactamase (ESBL). Carbapenems, piperacillin/tazobactam, cephamycins/oxacephem, aminoglycosides, and tigecycline had high activity against E. coli, including ESBL-producing isolates. Among E. cloacae, low susceptibility rates to ceftazidime were demonstrated, whereas cefepime retained its activity. P. aeruginosa revealed high susceptibility rates to all antimicrobials tested except for imipenem. Among B. fragilis group species, low levels of susceptibility were observed for cefoxitin, moxifloxacin, and clindamycin, and high susceptibility rates were observed for piperacillin/tazobactam, meropenem, and metronidazole. Ampicillin, piperacillin, and glycopeptides had good activity against E. faecalis. Imipenem had the highest activity against E. faecalis among carbapenems. In conclusion, we suggested the empirical use of antimicrobials with the specific intent of covering the main organisms isolated from postoperative IAI. Piperacillin/tazobactam, meropenem, or doripenem, are appropriate in critically ill patients. Combination therapy of cefepime (aztreonam in patients with ß-lactam allergy) plus metronidazole plus glycopeptides, imipenem/cilastatin or cephamycins/oxacephem plus ciprofloxacin plus metronidazole are potential therapeutic options.

Complicated peribiliary cysts in patient without any prior liver disease.

Peribiliary cysts involve cystic dilation of the extramural peribiliary glands in the liver hilum and portal tracts. Most peribiliary cysts are asymptomatic. We present the case of a patient without any prior liver disease who developed obstructive jaundice and a liver abscess due to peribiliary cysts. Peribiliary cysts usually appear in patients with severe chronic liver disease and are asymptomatic, although they sometimes appear in patients without prior liver disease and cause serious complications.

Curcumin in Hepatobiliary Disease: Pharmacotherapeutic Properties and Emerging Potential Clinical Applications.

Curcumin, an aromatic phytoextract from the turmeric (Curcuma longa) rhizome, has been used for centuries for a variety of purposes, not the least of which is medicinal. A growing body of evidence suggests that curcumin has a broad range of potentially therapeutic pharmacological properties, including anti-inflammatory, anti-fibrotic, and anti-neoplastic effects, among others. Clinical applications of curcumin have been hampered by quality control concerns and limited oral bioavailability, although novel formulations appear to have largely overcome these issues. Recent in vitro and in vivo studies have found that curcumin's cytoprotective and other biological activities may play a role in an array of benign and malignant hepatobiliary conditions, including but not limited to non-alcoholic fatty liver disease, cholestatic liver disease (e.g. primary sclerosing cholangitis), and cholangiocarcinoma. Here we provide an overview of fundamental principles, recent discoveries, and potential clinical hepatobiliary applications of this pleiotropic phytocompound.

[Mascs of functional disorders of the biliary tract].

The survey of its own and literature data describes the clinical "masks" of the primary and second functional disorders of the biliary tract, describes the mechanisms of their formation, which include the plural disturbances of the organs interactions, psycho - emotional and vegetative disturbances, development ofbiliar and pancreatic insufficiency. It is shown that Hymecromone (Odeston) can be successfully used, as the base means, with the treatment of patients with primary and second functional disorders of the biliary tract with different clinical "masks" of this pathology.

[Effect of post-liver transplantation administration of ursodeoxycholic acid on serum liver tests and biliary complications: a randomized clinical trial].

OBJECTIVE: Endogenous hydrophobic bile acids may be a pathogenetic factor of biliary complications after orthotopic liver transplantation (OLT).This study was designed to investigate the effects of hydrophilic ursodeoxycholic acid (UDCA), when administered early after OLT, on serum liver tests and on the incidence of biliary complications. METHODS: A total of 112 adult patients undergoing OLT were randomly assigned to one of two groups for receipt of UDCA (13 to 15 mg/kg/d for 4 weeks, n=56) or a placebo (n=56). All patients underwent serum liver testing and measurement of serum bile acids during the 4 weeks following OLT.Patients with T-tube underwent measurement of biliary bile acids during the 4 weeks following OLT.Biliary complications, as well as patient and graft survival rates, were analyzed during the follow-up period (mean of 65.6 months). RESULTS: At post-OLT days 7, 21 and 28, the UDCA-treated patients showed significantly lower levels of alanine aminotransferase, aspartate aminotransferase and gamma glutamyl transpeptidase (all P less than 0.05).In addition, the UDCA-treated patients showed significantly lower incidence of biliary sludge and casts within the first year post-OLT (3.6% vs.14.3%; x2=3.953, P=0.047). However, there were no significant differences for the incidence of other biliary complications at post-OLT years 1, 3 and 5.The graft and patient survival rates were also similar between the two groups. CONCLUSION: UDCA, when administered early after OLT, improves results from serum liver tests and decreases the incidence of biliary sludge and casts within the first postoperative year.

[Ursodeoxycholic acid-enhanced efficiency and safety of statin therapy in patients with liver, gallbladder, and/or biliary tract diseases: the RACURS study].

AIM: To evaluate the efficiency and safety of using statins in combination with ursodeoxycholic acid (UDCA) in patients with this or another liver disease at high risk for cardiovascular events (CVE). SUBJECTS AND METHODS: A register of 262 patients at high risk for CCE who needed statin therapy and have concomitant chronic liver and biliary tract diseases was created in 5 cities of the Russian Federation. RESULTS: After addition of statins or adjustment of their doses, the patients were recommended to include UDCA into their therapy. Six months after stabilization of the dose of statins, the whole group showed a significant reduction in the levels of total cholesterol and low-density lipoprotein (LDL) cholesterol. Assessment of the laboratory parameters responsible for the safety of statin intake revealed no deterioration in the trend in the activity of alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, lactate dehydrogenase, as well as an increase in the serum level of bilirubin. The data obtained using a special questionnaire indicated that 196 patients had taken UDCA and 56 had not. The UDCA and non-UDCA subgroups did not differ in age, weight, or baseline lipid metabolic disturbances. An additional analysis showed that by the end of 6 months, the goal levels of LDL cholesterol in the UDCA and non-UDCA groups were reached in 37 and 20%, respectively (p = 0.01). CONCLUSION: UDCA added to statin therapy in patients at high risk for CVE and concurrent liver diseases contributes to an additional reduction in total cholesterol and LDL cholesterol and prevents enhanced hepatic transaminase activities.

[New aspects of pharmacological effects of ursodeoxycholic acid].

The paper reviews the use of hepatoprotective agents in chronic liver diseases (CLD) and biliary disorders. A variety of clinical studies have shown the beneficial effect of ursodeoxycholic acid (UDCA) in liver disease worldwide. Besides the well-known mechanisms of action of UDCA we could show its prebiotic effect. Several studies have demonstrated that UDCA serves as a potential therapeutic agent for a number non-hepatobiliary disorders including cardiovascular disease, immune disorders, organ transplantation and other.

TGR5 in cholangiocytes.

PURPOSE OF REVIEW: TGR5 (Gpbar-1) is an emerging drug target for metabolic, intestinal and liver diseases. In liver, the highest expression of TGR5 is found in biliary epithelial cells. This review focusses on the function of TGR5 in cholangiocytes and the potential role of the receptor in biliary diseases. RECENT FINDINGS: TGR5 is localized in the primary cilium and the apical membrane domain of cholangiocytes, where the receptor exerts secretory, proliferative and antiapoptotic effects. Recent human and animal studies using bile acid analogues suggest a therapeutic potential for TGR5 in primary biliary cirrhosis but not in primary sclerosing cholangitis. SUMMARY: TGR5 has protective functions in cholangiocytes. Further studies are needed to determine the therapeutic potential of TGR5 agonists and antagonists in biliary diseases.

Changing trend in bile microbiology and antibiotic susceptibilities: over 12 years of experience.

PURPOSE: Rapidly changing medical environments may have changed the microbiology of infected bile. The aim of our study was to identify the changing trends in microorganisms in biliary infections and examine their susceptibilities against currently recommended antibiotics. METHODS: Bile cultures taken between 1998 and 2010 at Seoul National University Hospital, a tertiary medical center, were retrospectively reviewed. From 1,403 patients, 3,425 microorganisms were isolated from 2,217 cultures. The cultures were then tested to determine the types of microorganisms and their antibiotic susceptibility. RESULTS: The five most frequently isolated microorganisms were Enterococcus (22.7 %) followed by Escherichia (13.2 %), Pseudomonas (10.9 %), Klebsiella (10.3 %), and Enterobacter (7.2 %). The trend in annual incidence indicated a growing emergence of Enterococcus (P < 0.001). Among Enterococcus, E. faecium acquired a dominant position (50.6 %), showing an increasing trend over the study period (P = 0.026). The incidence of vancomycin-resistant Enterococcus also showed an increasing trend (P < 0.001). Many of the commonly used antibiotics provided inadequate coverage for the more frequently encountered microorganisms. Multiple regression revealed that benign causes of obstruction and non-operative treatment harbor an increased risk for enterococcal growth (P = 0.001 and P = 0.027, respectively). CONCLUSIONS: In contrast to earlier reports, we found that Enterococcus has emerged as the most frequently isolated microorganism from bile. The importance of enterococcal infection should be recognized, and currently recommended antibiotics need to be re-evaluated since in our bile cultures most provided inadequate coverage for the more frequently encountered microorganisms. The changes in the trends of microorganisms isolated from bile should be considered in cases where patients present with biliary obstruction.

Clinical impact of extended-spectrum ß-lactamase-producing Enterobacteriaceae in patients with biliary tract infection.

BACKGROUND: Clinical outcomes associated with Gram-negative bacterial isolates with extended spectrum beta-lactamase (ESBL) in patients with biliary tract infection are largely unknown. The objective of the present study was to compare the demographics, risk factors, and clinical outcomes between patients with biliary tract infection caused by ESBL-producing and non-producing Klebsiella pneumoniae and Escherichia coli. METHODS: Between February 2005 and August 2010, we collected 159 cases with biliary tract infection caused by K. pneumoniae and E. coli identified by blood or bile cultures obtained before endoscopic or surgical treatment performed at our institution. We also retrospectively collected the data of patients' demographic characteristics, co-morbid conditions, antimicrobial therapy, and clinical outcomes. RESULTS: Among the 159 strains isolated, 21 strains (13.2 %) were positive for phenotypical ESBL-test. Sepsis was more common in ESBL-positive strains, but did not reach statistical significance (23.8 % for ESBL-positive strains and 9.4 % for ESBL-negative strains, P = 0.066). Thirty-day mortality was significantly higher in ESBL-positive strains (3/21, 14.3 %) compared to ESBL-negative strains (4/138, 2.9 %, P = 0.049). However, there were no significant differences in overall survival between ESBL-positive and ESBL-negative strains. By multivariate analysis, inadequate antimicrobial therapy (HR 4.06, 95 % CI 1.08-16.46, P = 0.049) and sepsis (HR 6.54, 95 % CI 1.26-33.85, P = 0.025) were independent and significant predictors of 30-day mortality. CONCLUSION: ESBL status of bacterial isolates for patients with biliary tract infection caused by K. pneumoniae and E. coli has clinical impact, especially on the short-term outcomes of those patients.

Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO⁻3 output.

UNLABELLED: Chronic cholangiopathies have limited therapeutic options and represent an important indication for liver transplantation. The nuclear farnesoid X receptor (FXR) and the membrane G protein-coupled receptor, TGR5, regulate bile acid (BA) homeostasis and inflammation. Therefore, we hypothesized that activation of FXR and/or TGR5 could ameliorate liver injury in Mdr2(-/-) (Abcb4(-/-)) mice, a model of chronic cholangiopathy. Hepatic inflammation, fibrosis, as well as bile secretion and key genes of BA homeostasis were addressed in Mdr2(-/-) mice fed either a chow diet or a diet supplemented with the FXR agonist, INT-747, the TGR5 agonist, INT-777, or the dual FXR/TGR5 agonist, INT-767 (0.03% w/w). Only the dual FXR/TGR5 agonist, INT-767, significantly improved serum liver enzymes, hepatic inflammation, and biliary fibrosis in Mdr2(-/-) mice, whereas INT-747 and INT-777 had no hepatoprotective effects. In line with this, INT-767 significantly induced bile flow and biliary HCO 3- output, as well as gene expression of carbonic anhydrase 14, an important enzyme able to enhance HCO 3- transport, in an Fxr-dependent manner. In addition, INT-767 dramatically reduced bile acid synthesis via the induction of ileal Fgf15 and hepatic Shp gene expression, thus resulting in significantly reduced biliary bile acid output in Mdr2(-/-) mice. CONCLUSION: This study shows that FXR activation improves liver injury in a mouse model of chronic cholangiopathy by reduction of biliary BA output and promotion of HCO 3--rich bile secretion.

Ingredients of Huangqi decoction slow biliary fibrosis progression by inhibiting the activation of the transforming growth factor-beta signaling pathway.

BACKGROUND: Huangqi decoction was first described in Prescriptions of the Bureau of Taiping People's Welfare Pharmacy in Song Dynasty (AD 1078), and it is an effective recipe that is usually used to treat consumptive disease, anorexia, and chronic liver diseases. Transforming growth factor beta 1 (TGFß1) plays a key role in the progression of liver fibrosis, and Huangqi decoction and its ingredients (IHQD) markedly ameliorated hepatic fibrotic lesions induced by ligation of the common bile duct (BDL). However, the mechanism of IHQD on hepatic fibrotic lesions is not yet clear. The purpose of the present study is to elucidate the roles of TGFß1 activation, Smad-signaling pathway, and extracellular signal-regulated kinase (ERK) in the pathogenesis of biliary fibrosis progression and the antifibrotic mechanism of IHQD. METHODS: A liver fibrosis model was induced by ligation of the common bile duct (BDL) in rats. Sham-operation was performed in control rats. The BDL rats were randomly divided into two groups: the BDL group and the IHQD group. IHQD was administrated intragastrically for 4 weeks. At the end of the fifth week after BDL, animals were sacrificed for sampling of blood serum and liver tissue. The effect of IHQD on the TGFß1 signaling pathway was evaluated by western blotting and laser confocal microscopy. RESULTS: Decreased content of hepatic hydroxyproline and improved liver function and histopathology were observed in IHQD rats. Hepatocytes, cholangiocytes, and myofibroblasts in the cholestatic liver injury released TGFß1, and activated TGFß1 receptors can accelerate liver fibrosis. IHQD markedly inhibited the protein expression of TGFß1, TGFß1 receptors, Smad3, and p-ERK1/2 expression with no change of Smad7 expression. CONCLUSION: IHQD exert significant therapeutic effects on BDL-induced fibrosis in rats through inhibition of the activation of TGFß1-Smad3 and TGFß1-ERK1/2 signaling pathways.

Understanding and treating abdominal pain and spasms in organic gastrointestinal diseases: inflammatory bowel disease and biliary diseases.

Abdominal pain and spasms are common symptoms in organic gastrointestinal diseases, yet are associated with significant unmet need in terms of recognition and treatment. The aim of this review was to help physicians to understand the pathophysiology and impact to patients of abdominal pain and spasms in inflammatory bowel disease (IBD) and biliary diseases. This may in turn help in the selection of the most appropriate treatment to improve patients' overall daily functioning and quality of life in addition to reducing health resource utilization. Relative to the healthy colon, the mechanisms of pain generation in IBD include peripheral sensitization, including visceral hypersensitivity, central processing and modulation, and associated features or modifiers. Calcitonin gene related peptide, substance P, transient receptor potential vanilloid type, and serotonin biosynthesis in the colon are implicated in these processes. For biliary pain, important factors include pressure change or high pressure in the gallbladder, gallbladder ejection fraction, and change in the shape of gallbladder. Pain management is multifactorial and may involve psychological and physical methods and drugs (nonsteroidal anti-inflammatory agents, opioids, antispasmodics, with regional and epidural analgesia reserved for severe cases) after appropriate risk-benefit assessment. Antispasmodic agents may be effective in selected patients with IBD, especially those who are in remission and have mild/moderate chronic pain.