Therapeutic Potential of Danyankang Capsule in High-Fat Diet-Induced Cholelithiasis and Its Impact on Liver FXR Signaling and Gut Microbiota.

Cholelithiasis, commonly known as gallstones, represents a prevalent hepatobiliary disorder. This study aimed to elucidate the therapeutic role and mechanism of Danyankang capsulein treating cholelithiasis induced by a high-fat diet in C57BL/6 mice. The therapeutical potential of Danyankang was assessed through biochemical analyses, histopathological examinations, protein detection, and 16S rDNA sequencing. A high-fat diet resulted in cholelithiasis manifestation in mice, with discernable abnormal serum biochemical indices and disrupted biliary cholesterol homeostasis. Danyankang treatment notably ameliorated liver inflammation symptoms and rectified serum and liver biochemical abnormalities. Concurrently, it addressed biliary imbalances. Elevated expressions of toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB)/pNF-κB, HMGCR, CYP7A1, and CYP8B1 observed at the inception of cholelithiasis, were notably reduced upon Danyankang administration. Furthermore, 16S rDNA analysis revealed a decline in species number and diversity of the intestinal flora in cholelithiasis-treated mice, while the decline was reversed with Danyankang treatment. Danyankang capsules reduced the abundance of Verrucomicrobiota and increased the abundance of Actinobacteriota and Proteobacteria. In conclusion, the present study demonstrates that Danyankang exerts potent therapeutic efficacy against high-fat diet-induced cholelithiasis. This beneficial outcome is potentially linked to the inhibition of the TLR4/pNF-κB and SHP/CYP7A1/CYP8B1 signaling pathways, as well as the enhancement of intestinal flora species abundance.

Therapeutic effect of yinchenhao decoction on cholelithiasis via mucin in the gallbladder and intestine.

Cholelithiasis is a common and frequently occurring disease worldwide that belongs to the category of jaundice in traditional Chinese medicine. Yinchenhao decoction (YD) consists of Artemisia capillaris Thunb., Gardenia jasminoides J.Ellis, and Rheum palmatum L., and is traditionally used to treat jaundice, which has a significant therapeutic effect on cholelithiasis. Our study aimed to investigate the pathological mechanism of cholelithiasis and the therapeutic mechanism of YD via mucin in the gallbladder and intestine. YD was prepared and analyzed using HPLC. The supersaturation stability experiment was designed by the solvent-shift method. The cell transport experiment was conducted by coculture monolayers. The animal experiment was performed using a cholelithiasis model with a high-cholesterol diet. The related indicators were detected by automatic biochemical analyzer, PCR, western blot, or ELISA. Statistics were analyzed using χ2-tests and t-tests. As the results, in cholelithiasis, MUC5AC highly expressed in the gallbladder shortened cholesterol supersaturation and promoted cholesterol crystallization via the inflammatory cytokine signaling pathway; MUC2 highly expressed in the small intestine prolonged cholesterol supersaturation and promoted cholesterol absorption via the inflammatory cytokine signaling pathway. YD inhibited mucin expression in the gallbladder and intestine in a concentration-dependent manner for cholelithiasis treatment by inhibiting the inflammatory cytokine signaling pathway, which was attributed to the active components, including chlorogenic acid, geniposide, and rhein.

Obeticholic acid as a second-line treatment for low phospholipid-associated cholelithiasis syndrome.

BACKGROUND: Low phospholipid-associated cholelithiasis (LPAC) syndrome is a rare genetic cause of hepatolithiasis. A pathogenic variant of the ABCB4 gene is reported in half of all patients. Ursodeoxycholic acid (UDCA) is the only drug approved. However, in some patients, UDCA fails to prevent recurrence of symptoms and complications. Experimental evidence suggests that agonists of the farnesoid-X receptor (FXR), the main transcription factor regulating ABCB4, may be beneficial in this context. AIM: To study the efficacy of obeticholic acid (OCA) in patients with LPAC syndrome with an inadequate response or intolerance to UDCA. METHODS: This was a retrospective study of patients with LPAC syndrome treated with OCA, a selective FXR agonist. RESULTS: We reviewed the records of five OCA-treated patients (4 women; median age 29; ABCB4 variant in 4; no hepatic fibrosis). All patients received OCA at an initial dose of 5 mg daily and then 10 mg daily for a median period of 36 months in combination with UDCA (4 patients) or as a monotherapy (one patient). There were no adverse effects reported. Four patients had improvement in their symptoms - three completely and one partially. One patient had no clinical benefit. Abnormalities of blood liver tests persisted in one patient despite resolution of symptoms. Radiological signs of hepatolithiasis persisted in three of the four patients who responded clinically to OCA. CONCLUSIONS: These preliminary observations suggest that OCA may have the potential to effectively treat LPAC syndrome in patients with inadequate response or intolerance to UDCA. Larger studies are needed to confirm these data.

Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials.

OBJECTIVE: To examine the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases. DESIGN: Systematic review and pairwise and network meta-analysis. DATA SOURCES: PubMed, EMBASE, Web of Science, and CENTRAL from inception until 31 July 2021. ELIGIBILITY CRITERIA: Randomised controlled trials of adult patients with type 2 diabetes who received dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors compared with placebo or other antidiabetes drugs. MAIN OUTCOME MEASURES: Composite of gallbladder or biliary diseases, cholecystitis, cholelithiasis, and biliary diseases. DATA EXTRACTION AND DATA SYNTHESIS: Two reviewers independently extracted the data and assessed the quality of the studies. The quality of the evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development and Evaluations framework (GRADE) approach. The meta-analysis used pooled odds ratios and 95% confidence intervals. RESULTS: A total of 82 randomised controlled trials with 104 833 participants were included in the pairwise meta-analysis. Compared with placebo or non-incretin drugs, dipeptidyl peptidase-4 inhibitors were significantly associated with an increased risk of the composite of gallbladder or biliary diseases (odds ratio 1.22 (95%confidence interval 1.04 to 1.43); risk difference 11 (2 to 21) more events per 10 000 person years) and cholecystitis (odds ratio 1.43 (1.14 to 1.79); risk difference 15 (5 to 27) more events per 10 000 person years) but not with the risk of cholelithiasis and biliary diseases. The associations tended to be observed in patients with a longer duration of dipeptidyl peptidase-4 inhibitor treatment. In the network meta-analysis of 184 trials, dipeptidyl peptidase-4 inhibitors increased the risk of the composite of gallbladder or biliary diseases and cholecystitis compared with sodium-glucose cotransporter-2 inhibitors but not compared with glucagon-like peptide-1 receptor agonists. CONCLUSIONS: Dipeptidyl peptidase-4 inhibitors increased the risk of cholecystitis in randomised controlled trials, especially with a longer treatment duration, which requires more attention from physicians in clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021271647.

Surgical Infection Society Guidelines for Antibiotic Use in Patients Undergoing Cholecystectomy for Gallbladder Disease.

Background: Manifestations of gallbladder disease range from intermittent abdominal pain (symptomatic cholelithiasis) to potentially life-threatening illness (gangrenous cholecystitis). Although surgical intervention to treat acute cholecystitis is well defined, the role of antibiotic administration before or after cholecystectomy to decrease morbidity or mortality is less clear. Methods: The Surgical Infection Society's Therapeutics and Guidelines Committee convened to develop guidelines for antibiotic use in patients undergoing cholecystectomy for gallbladder disease to prevent surgical site infection, other infection, hospital length of stay, or mortality. PubMed, Embase, and the Cochrane Database were searched for relevant studies. Evaluation of the published evidence was performed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system. Using a process of iterative consensus, all authors voted to accept or reject each recommendation. Results: We recommend against routine use of peri-operative antibiotic agents in low-risk patients undergoing elective laparoscopic cholecystectomy. We recommend use of peri-operative antibiotic agents for patients undergoing laparoscopic cholecystectomy for acute cholecystitis. We recommend against use of post-operative antibiotic agents after elective laparoscopic cholecystectomy for symptomatic cholelithiasis. We recommend against use of post-operative antibiotic agents in patients undergoing laparoscopic cholecystectomy for mild or moderate acute cholecystitis. We recommend a maximum of four days of antibiotic agents, and perhaps a shorter duration in patients undergoing cholecystectomy for severe (Tokyo Guidelines grade III) cholecystitis. Conclusions: This guideline summarizes the current Surgical Infection Society recommendations for antibiotic use in patients undergoing cholecystectomy for gallbladder disease.

THE USE OF MICROBIOLOGICAL AND LABORATORY DATA IN THE CHOICE OF EMPIRICAL ANTIBIOTIC THERAPY IN PATIENTS UNDERGOING LAPAROSCOPIC CHOLECYSTECTOMY - THE ROLE OF LOCAL ANTIBIOGRAMS.

Antibiotic therapy is indicated during acute cholecystitis. However, in the treatment of uncomplicated cholelithiasis, prophylactic use of antibiotics is controversial. Microbiological and laboratory data are the basis for the choice of antibiotic treatment. However, monitoring and updating local antibiograms is important because they ensure effective therapy in the given clinical environment. The study included 110 consecutive patients who underwent laparoscopic cholecystectomy, divided into the group of uncomplicated cholelithiasis (n=60) and the group of acute cholecystitis (n=50). Preoperative data included age, sex, body mass index, leukocytes, C-reactive protein, and ultrasound examination. Bile samples for bacteriological testing were obtained under aseptic conditions during the surgery. Cultures were evaluated for aerobic, anaerobic and fungal organisms using routine tests. After the surgery, gallbladder specimens were sent for histopathological examination. In the group of uncomplicated cholelithiasis, 6/60 positive samples were found, and in the group of acute cholecystitis, there were 25/50 positive microbiological findings. Citrobacter sp. and Enterococcus faecalis predominated in the group of uncomplicated cholelithiasis, and Escherichia coli, Enterococcus faecalis, Proteus mirabilis and Citrobacter sp. in the group of acute cholecystitis. Antibiotics were administered to 49/50 patients with acute cholecystitis and to 32/60 patients with uncomplicated cholelithiasis. Cefazolin was the most frequently used antibiotic and also the most resistant antibiotic. To conclude, the administration of antibiotics in elective patients is not justified. The results of this study indicate that third-generation cephalosporin or ciprofloxacin + metronidazole should be administered in mild and moderate acute cholecystitis, and fourth-generation cephalosporin + metronidazole in severe acute cholecystitis in this local setting. The appropriate use of antibiotic agents is crucial and should be integrated into good clinical practice and standards of care.

Safety of Semaglutide.

The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (PIONEER: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.

Hepatic expression of cholesterol regulating genes favour increased circulating low-density lipoprotein in HIV infected patients with gallstone disease: a preliminary study.

BACKGROUND: HIV endemic populations are displaying higher incidence of metabolic disorders. HIV and the standard treatment are both associated with altered lipid and cholesterol metabolism, however gallstone disease (a cholesterol related disorder) in Sub-Saharan African populations is rarely investigated. METHODS: This study sought to evaluate hepatic expression of key genes in cholesterol metabolism (LDLr, HMGCR, ABCA1) and transcriptional regulators of these genes (microRNA-148a, SREBP2) in HIV positive patients on antiretroviral therapy presenting with gallstones. Liver biopsies from HIV positive patients (cases: n = 5) and HIV negative patients (controls: n = 5) were analysed for miR-148a and mRNA expression using quantitative PCR. RESULTS: Circulating total cholesterol was elevated in the HIV positive group with significantly elevated LDL-c levels(3.16 ± 0.64 mmol/L) relative to uninfected controls (2.10 ± 0.74 mmol/L; p = 0.04). A scavenging receptor for LDL-c, LDLr was significantly decreased (0.18-fold) in this group, possibly contributing to higher LDL-c levels. Transcriptional regulator of LDLr, SREBP2 was also significantly lower (0.13-fold) in HIV positive patients. Regulatory microRNA, miR-148a-3p, was reduced in HIV positive patients (0.39-fold) with a concomitant increase in target ABCA1 (1.5-fold), which regulates cholesterol efflux. CONCLUSIONS: Collectively these results show that HIV patients on antiretroviral therapy display altered hepatic regulation of cholesterol metabolizing genes, reducing cholesterol scavenging, and increasing cholesterol efflux.

Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults.

The ATP binding cassette subfamily B member 4 (ABCB4) gene on chromosome 7 encodes the ABCB4 protein (alias multidrug resistance protein 3 [MDR3]), a P-glycoprotein in the canalicular membrane of the hepatocytes that acts as a translocator of phospholipids into bile. Several variants in ABCB4 have been shown to cause ABCB4 deficiency, accounting for a disease spectrum ranging from progressive familial cholestasis type 3 to less severe conditions like low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy or drug-induced liver injury. Furthermore, whole genome sequencing has shown that ABCB4 variants are associated with an increased incidence of gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis or elevated liver function tests. Diagnosis of ABCB4 deficiency-related diseases is based on clinical presentation, serum biomarkers, imaging techniques, liver histology and genetic testing. Nevertheless, the clinical presentation can vary widely and clear genotype-phenotype correlations are currently lacking. Ursodeoxycholic acid is the most commonly used medical treatment, but its efficacy has yet to be proven in large controlled clinical studies. Future pharmacological options may include stimulation/restoration of residual function by chaperones (e.g. 4-phenyl butyric acid, curcumin) or induction of ABCB4 transcription by FXR (farnesoid X receptor) agonists or PPARα (peroxisome proliferator-activated receptor-α)-ligands/fibrates. Orthotopic liver transplantation remains the last and often only therapeutic option in cirrhotic patients with end-stage liver disease or patients with intractable pruritus.

Cholelithiasis After Sleeve Gastrectomy and Effectiveness of Ursodeoxycholic Acid Treatment.

Aim: Few adverse effects may occur after bariatric surgery, one being the formation of gallstones. The aim of this study is to determine the incidence of cholelithiasis after laparoscopic sleeve gastrectomy (LSG) and whether ursodeoxycholic acid (UDCA) treatment reduces gallstone formation. Materials and Methods: Gall bladders of all patients planned for LSG were preoperatively checked by ultrasonography (USG). Patients who had no documented gallbladder pathology before LSG and who had USG at 12th month and 2 years follow-up after LSG were included in the study. The incidences of newly developed cholelithiasis, cholecystectomy, and endoscopic retrograde cholangiopancreatography (ERCP) requirement in patients who did not receive any UDCA treatment (pre-2015 protocol, n = 128) was compared with the corresponding numbers in patients who regularly used 500 mg/day oral UDCA for 6 months after the LSG (post-2015 protocol, n = 152). Results: Between January 2012 and October 2018, 717 LSGs were performed in two centers and after exclusions, 280 patients were eligible for evaluation. Sixty-four of 280 (23%) patients developed cholelithiasis after LSG and cholecystectomy was performed in 24 patients (8.6%) for symptomatic cholelithiasis. In the non-UDCA group, 48 patients developed cholelithiasis (n = 48/128, 37.5%) compared with 16 patients in the UDCA group (n = 16/152, 10.5%) (P < .001). Compared with 5 patients in the UDCA group, 19 patients underwent cholecystectomy (39.6%) in the non-UDCA group due to symptomatic cholelithiasis (P = .55) and 5 of these patients also required an ERCP. No ERCP became necessary in the UDCA group (P = .2). Conclusions: An almost fourfold decrease in the rate of new gall stone formation with 500 mg daily UDCA treatment was impressive and may suggest routine UDCA treatment after LSG. Given the rate of exclusions and follow-up differences among the groups, certainly, randomized trials, with less exclusion are needed to provide conclusive evidence.

Familial low phospholipid-associated cholelithiasis resulting from an autosomal dominant ABCB4 mutation.

Low phospholipid-associated cholelithiasis (LPAC) syndrome is characterized by early intrahepatic and symptomatic gallstones leading to cholangitis, acute pancreatitis and biliary colic. It has been associated with loss of function variants in the ABCB4 gene. ABCB4 encodes for a phospholipid translocator at the canalicular membrane of the hepatocyte, which "flops" phosphatidylcholine into bile. The autosomal recessive form is the most common, although autosomal dominant forms have also been described. We report the first family with autosomal dominant LPAC syndrome due to heterozygosity of the loss of function mutation c.2932T>C in ABCB4, identified by targeted next generation sequencing.

Effect of oral ursodeoxycholic acid on cholelithiasis following laparoscopic sleeve gastrectomy for morbid obesity.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is a definitive solution for morbid obesity and its related co-morbidities. Cholelithiasis is a postoperative complication of LSG. The use of ursodeoxycholic acid (UDCA) after LSG is a proposed solution to reduce the incidence of cholelithiasis. OBJECTIVE: To evaluate the effect of UDCA prophylaxis on cholelithiasis following LSG in morbidly obese patients. SETTING: Two university hospitals in Egypt, Cairo, and Beni Suef Universities' hospitals. METHODS: This prospective study was conducted between July 2015 and March 2018 and included 200 patients scheduled for LSG. They were randomly divided into 2 groups. The UDCA group received a postoperative prophylaxis regimen for prevention of cholelithiasis in the form of 250 mg twice daily of UDCA for 6 months. The control group did not receive prophylactic treatment. Abdominal ultrasound was done at 3, 6, 9, and 12 months for all patients to detect cholelithiasis. The primary outcome measure was cholelithiasis. RESULTS: Only 6% of the UDCA group developed cholelithiasis compared with 40% in the control group (P < .001). Age, sex, initial body mass index, and excess weight loss at 6 months did not significantly affect cholelithiasis. CONCLUSION: UDCA treatment for 6 months after LSG is effective in the prevention of cholelithiasis.

Oral medical dissolution of gallstones in patients with gallstone disease

Being the main treatment for cholelithiasis, laparoscopic cholecystectomy does not always solve the problem. It often entails postcholecystectomy syndrome (PCS). Oral medication to dissolve gallstones with bile acids is alternative therapy for some patients. However, lack of efficacy and limited medical indications make it necessary to apply combination treatment tactics. This study was conducted to investigate the dissolution of gallstones during the combined effects of ursodeoxycholic acid (UDCA) and rosuvastatin as well as to assess the results of eradication therapy in the presence of H. pylory as a measure to prevent cholelithiasis in the course of treatment.

ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum.

ATP-binding cassette subfamily B member 4 (ABCB4) is a phospholipid translocator at the canalicular membrane of the hepatocyte, which "flops" phosphatidylcholine into bile. Dysfunction of this transporter due to ABCB4 gene variants can cause liver diseases and has been called ABCB4 deficiency. Several diseases including progressive familial intrahepatic cholestasis type 3 (PFIC3), low phospholipid-associated cholelithiasis (LPAC), a subgroup of patients developing intrahepatic cholestasis of pregnancy (ICP), drug-induced liver injury and chronic cholangiopathy with biliary fibrosis and cirrhosis were attributed to ABCB4 deficiency and characterized in the past decade. LPAC and ICP are usually caused by monoallelic variants, whereas patients affected by PFIC3 are homozygous or compound heterozygous carriers of ABCB4 variants. Treatment with ursodeoxycholic acid is often effective, but as the more severe forms of ABCB4 deficiency progress, nevertheless, new diagnostic and therapeutic approaches are warranted. Current functional classifications for ABCB4 deficiency-associated mutations can guide the development of novel genotype-based targeted pharmacotherapies for these conditions. Recently, increasing evidence from genome-wide association studies is emerging on associations of ABCB4 variants with hepatobiliary malignancies.

Neonatal cholelithiasis in Down syndrome: Is hypothyroidism involved? A case-report.

We report a 3-month-old male with Down syndrome (DS), prolonged jaundice and poor weight gain, that showed biliary lithiasis and undiagnosed congenital hypothyroidism (CH).CH should be considered in DS, especially in presence of gastrointestinal symptoms or malformations. Clinicians should be aware of the increased risk of gallstones in hypothyroid children with DS, even in neonatal age.

Evaluación de la estabilidad hemodinámica en pacientes sometidos a cirugía abdominal tratados con morfina durante la inducción anestésica / Evaluation of hemodynamic stability in patients undergoing abdominal surgery treated with morphine during anesthesia induction

Los opioides son los fármacos más potentes utilizados para atenuar los efectos cronotrópicos y vasoconstrictores que se producen durante la laringoscopia. Se realizó un estudio descriptivo transversal con el objetivo de evaluar la estabilidad hemodinámica de los pacientes ingresados al Hospital Central Universitario Dr. Antonio María Pineda para cirugía abdominal tratados con morfina durante la inducción anestésica. La muestra incluyó 30 pacientes con una edad promedio de 38 ± 4,6 años, predominio del sexo masculino (56,6%) y ASA II (53,3%). Los procedimientos quirúrgicos más frecuentes fueron colecistectomía (40%), hernioplastia umbilical (20%) e inguinal (16,6%). Durante la inducción, 26,7%, 10% y 50% de los pacientes registró un aumento de la PAS, PAD y PAM > 20 mmHg en comparación con los valores basales. A los 5 minutos post-inducción, todos los pacientes mostraron disminución de los valores de la presión arterial sistólica y diastólica y sólo 10% de los pacientes de la PAM. No se registraron efectos adversos a la morfina. Estos resultados demuestran que la morfina a una dosis de 0,1 mg/kg por vía endovenosa 30 minutos antes de la inducción permite brindar mayor confort para el paciente con mínimos cambios hemodinámicos y sin efectos adversos(AU)

Opioids are the most potent drugs used to mitigate the chronotropic and vasoconstrictor effects that occur during laryngoscopy. A cross-sectional descriptive study was conducted in order to evaluate the hemodynamic stability of morphine during anesthetic induction in patients undergoing abdominal surgery in the Hospital Central Universitario Dr. Antonio María Pineda. The sample included 30 patients with an average age of 38 ± 14.63 years predominantly male (56.67%) and ASA II (53.33%). 40% of patients underwent cholecystectomy and 20% umbilicoplasty and 16.67% inguinal hernia repair. During anesthesia induction, 26.7%, 10% and 50% of patients showed an increase in systolic, diastolic and mean blood pressure > 20 mmHg compared to basal values. Five minutes post induction, all patients showed decreased values of systolic and diastolic blood pressure and only 10% of patients showed changes in mean arterial blood pressure. No adverse effects were recorded. These results show that morphine at a dose of 0.1 mg/kg intravenously 30 minutes before induction allows greater comfort for the patient with minimal hemodynamic changes and no adverse effects(AU)

Bile Acid Derivatives: From Old Molecules to a New Potent Therapeutic Use: An Overview.

Bile acids or bile salts, belong to a large family of biological steroid derivatives found predominantly in the bile of mammals and other vertebrates. These amphipathic molecules possess numerous functions, including eliminating cholesterol from the body, driving the flow of bile to eliminate catabolites, emulsifying fat-soluble vitamins to enable their absorption, aiding in motility and in reducing the bacteria flora found in the small intestine and biliary tract. In this review, we investigate progress towards synthetic bile acid derivatives, with special emphasis on how they might be used for various biological applications and the challenges that remain in developing these compounds as potent drugs of the future especially in the field of microbiology (antimicrobial activities) and cancer (anticancer agents). We will emphasize the fact that even few researches are devoted around these peculiar structures. All the researches pointed out the important potential of such derivatives for the design of new classes of drugs.

Cholelithiasis - always infected?

This study aims to present results regarding the presence and identification of bacterial strains found in bile and gallstones located in the gallbladder and bile ducts in patients operated on due to cholelithiasis. MATERIALS AND METHODS: Bacterial culture was evaluated in 92 patients. There were 54 women (59%) and 38 men (41%) who underwent surgery on account of cholelithiasis and /or gallstones in bile ducts between 2013 and 2014. Bile and gallstone samples were cultured intraoperatively for bacteria; bacterial strains were identified, and their sensitivity to antibiotics was determined. Molecular methods (NGS and Sanger method) were used to separate bacterial strains in one of the gallbladder stones and the results were compared with bacterial strains grown from the bile. RESULTS: Bile cultures were positive in 46 patients that is, 50% of the study group. The following bacteria strains were grown: Enterococcus spp. (44%), Escherichia coli (37%) and Klebsiella spp. (35%). Candidiasis accompanied by bacterial infection was detected in 7 patients (15%). Molecular testing of gallstones revealed DNA of Enterococcus spp., Escherichia spp., Streptococcus spp. and Clostridium spp. In the bile culture of the same patient Enterococcus spp. (avium and faecalis) was detected. Conclusion 1. More than one pathogen was grown on samples obtained from 31 patients (70%) with bile infection. 2. The most common pathogens include Enterococcus spp., Escherichia coli and Klebsiella spp. 3. Bacterial infections are often accompanied by a fungal infection (Candida albicans) 4. Bacterial strains grown from a gallstone sample partially corresponded with strains identified in the bile of the same patient.

Cholesterol lowering effect in the gall bladder of dogs by a standardized infusion of Herniaria hirsuta L.

ETNOPHARMACOLOGICAL RELEVANCE: Infusions of Herniaria hirsuta L., Herniaria glabra L. and Herniaria fontanesii J.Gay are well known in Moroccon folk medicine for the treatment of biliary dyskinesia, (uro)lithiasis or as a diuretic. Herniariae Herba which can contain H. glabra and H. hirsuta is known in Europe as an urological drug. AIM OF THE STUDY: To investigate the efficacy of a standardized infusion of Herniaria hirsuta against choleltihiasis, and evaluation of its genotoxicity. METHODS AND MATERIALS: An analytical HPLC-UV method to quantify flavonoids and saponins present in the extract of H. hirsuta was developed and validated. An in vivo experiment to evaluate the cholesterol lowering effect of a infusion of H. hirsuta in the gall bladder of dogs was carried out. Dogs were divided into 3 groups i.e. control dogs (CG), dogs treated with ursodeoxycholic acid (UDCA) (2×7.35mg/kg body weight/day) and dogs treated with the standardized infusion (HG) (2×48.5mg/kg body weight/day). Dogs were fed a fatty diet during 120 days after which a diet without additional fat was introduced till day 180. Treatment started 30 days after introduction of the fatty diet and lasted till the end of the experiment. A bile and blood sample of each dog was collected every 30 days, after which the concentration of cholesterol was determined. An Ames test was performed according to the OECD-guidelines. RESULTS: The validated HPLC-UV method showed a linear calibration model and an acceptable precision for the total flavonoid content (total content 4.51%) as well as the total saponin content (12.74%). The in vivo experiments already showed a minor difference for bile cholesterol between CG and HG after 30 days of treatment with the infusion, and the difference was more pronounced after 90 days of treatment. Even 30 days after discontinuation of the cholesterol-rich diet a significant difference remained between CG and HG. There was no statistically significant difference in blood cholesterol. The Ames test showed that the infusion of H. hirsuta could be considered as being free from genotoxic risks. CONCLUSION: A method for the standardization of a infusion of Herniaria hirsuta was developed and validated. Prolonged use of this standardized H. hirsuta extract resulted in a cholesterol-lowering effect in the bile of dogs. Since this pharmacological effect prevents the formation of gallstones and can contribute to solving existing gallstones, a standardized infusion of H. hirsuta may have a positive effect in the treatment of gallstones in human patients.

Research on choleretic effect of menthol, menthone, pluegone, isomenthone, and limonene in DanShu capsule.

Danshu capsule (DSC) is a medicinal compound in traditional Chinese medicine (TCM). It is commonly used for the treatment of acute & chronic cholecystitis as well as choleithiasis. To study its choleretic effect, healthy rats were randomly divided into DSC high (DSCH, 900mg/kg), medium (DSCM, 450mg/kg), and low (DSCL, 225mg/kg) group, Xiaoyan Lidan tablet (XYLDT, 750mg/kg), and saline group. The bile was collected for 1h after 20-minute stabilization as the base level, and at 1h, 2h, 3h, and 4h after drug administration, respectively. Bile volume, total cholesterol, and total bile acid were measured at each time point. The results revealed that DSC significantly stimulated bile secretion, decreased total cholesterol level and increased total bile acid level. Therefore, it had choleretic effects. To identify the active components contributing to its choleretic effects, five major constituents which are menthol (39.33mg/kg), menthone (18.02mg/kg), isomenthone (8.18mg/kg), pluegone (3.31mg/kg), and limonene (4.39mg/kg) were tested on our rat model. The results showed that menthol and limonene could promote bile secretion when compared to DSC treatment (p > 0.05); Menthol, menthol and limonene could significantly decrease total cholesterol level (p<0.05 or p<0.01) as well as increase total bile acid level (p<0.05 or p<0.01); Isomenthone, as a isomer of menthone, existed slightly choleretic effects; Pluegone had no obvious role in bile acid efflux. These findings indicated that the choleretic effects of DSC may be attributed mainly to its three major constituents: menthol, menthone and limonene.