Once-Weekly Semaglutide in Adults with Overweight or Obesity.

BACKGROUND: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed. METHODS: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions. RESULTS: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]). CONCLUSIONS: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): Data from randomized controlled trials.

AIM: Glucagon-like peptide 1 receptor agonists (GLP1-RA) have been associated with an increased risk of pancreatitis and pancreatic cancer. Prior meta-analyses of randomized controlled trials failed to show any significant increase of risk; however, those meta-analyses did not include the recently published cardiovascular outcome trials (CVOT) with GLP1-RA, which provide a substantial additional body of data. The aim of the present meta-analysis is to assess the effect of GLP1-RA on pancreatitis, pancreatic cancers and cholelithiasis. MATERIALS AND METHODS: A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide or semaglutide) was performed, collecting all randomized clinical trials with a duration >11 weeks, enrolling patients with type 2 diabetes and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. RESULTS: Of the 113 trials fulfilling inclusion criteria, 13 did not report information on pancreatitis, whereas 72 reported no events in all treatment groups. The incidence of pancreatitis and pancreatic cancer with GLP1-RA was not significantly different from that observed in comparator arms (MH-OR [95% CI] 0.93 [0.65-1.34], P = .71, and 0.94 [0.52-1.70], P = .84, respectively), whereas, a significantly increased risk of cholelithiasis (MH-OR [95% CI] 1.30 [1.01-1.68], P = .041) was detected. CONCLUSIONS: Presently available data confirm the safety of GLP-1 receptor agonists for pancreatitis. Conversely, therapy with those drugs is associated with an increased risk of cholelithiasis, which deserves further investigation.

The cholecystokinin-1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice.

BACKGROUND: A defect in gallbladder contraction function plays a key role in the pathogenesis of gallstones. The cholecystokinin-1 receptor (CCK-1R) antagonists have been extensively investigated for their therapeutic effects on gastrointestinal and metabolic diseases in animal studies and clinical trials. However, it is still unknown whether they have a potential effect on gallstone formation. DESIGN: To study whether the CCK-1R antagonists enhance cholelithogenesis, we investigated cholesterol crystallization, gallstone formation, hepatic lipid secretion, gallbladder emptying function and intestinal cholesterol absorption in male C57BL/6J mice treated by gavage with devazepide (4 mg/day/kg) or vehicle (as controls) twice per day and fed the lithogenic diet for 21 days. RESULTS: During 21 days of feeding, oral administration of devazepide significantly accelerated cholesterol crystallization and crystal growth to microlithiasis, with 40% of mice forming gallstones, whereas only agglomerated cholesterol monohydrate crystals were found in mice receiving vehicle. Compared to the vehicle group, fasting and postprandial residual gallbladder volumes in response to the high-fat meal were significantly larger in the devazepide group during cholelithogenesis, showing reduced gallbladder emptying and bile stasis. Moreover, devazepide significantly increased hepatic secretion of biliary cholesterol, but not phospholipids or bile salts. The percentage of intestinal cholesterol absorption was higher in devazepide-treated mice, increasing the bioavailability of chylomicron-derived cholesterol in the liver for biliary hypersecretion into bile. These abnormalities induced supersaturated bile and rapid cholesterol crystallization. CONCLUSIONS: The potent CCK-1R antagonist devazepide increases susceptibility to gallstone formation by impairing gallbladder emptying function, disrupting biliary cholesterol metabolism and enhancing intestinal cholesterol absorption in mice.

Association of Statin Therapy and Risks of Cholelithiasis, Biliary Tract Diseases, and Gallbladder Procedures: Retrospective Cohort Analysis of a US Population.

BACKGROUND: Gallstone disease is a leading cause of morbidity in Western countries and carries a high economic burden. Statin medications decrease hepatic cholesterol biosynthesis and may, therefore, lower the risk of cholesterol cholelithiasis by reducing the cholesterol concentration in the bile. Population-based evidence, however, is sparse. OBJECTIVE: To assess the risk of gallbladder diseases among statin users compared with nonusers in an American patient cohort. METHODS: We performed a retrospective cohort study of patients enrolled in the San Antonio Tricare health system using data between October 2003 and March 2012. We defined 2 groups: statin users (use for 90 days or greater) and nonusers (no prior statin). A propensity score based on 82 variables was generated to match statin users and nonusers 1:1. Outcomes included incidence of cholelithiasis, biliary tract diseases, and gallbladder procedures. RESULTS: A total of 43 438 patients were identified; 13 626 (31.4%) were statin users, and 29 812 (68.6%) were nonusers. We matched 6342 pairs of statin users and nonusers based on propensity score. The odds ratios (ORs) in statin users in comparison to nonusers were similar for cholelithiasis (OR = 0.86; 95% CI = 0.73, 1.02), biliary tract disease (OR = 0.85; 95% CI = 0.67-1.08), and gall bladder procedures (OR = 0.85; 95% CI = 0.69, 1.04). CONCLUSIONS: Statin use was not significantly associated with either an increased or decreased risk of cholelithiasis or gallbladder disease.

Liraglutide-related cholelithiasis.

Liraglutide is a glucagon-like peptide-1 analog and recently started to be using as an incretin-based treatment for diabetes mellitus. Liraglutide causes some adverse affects including nausea, vomiting, acute nasopharyngitis and acute pancreatitis. However, development of liraglutide-dependent cholelithiasis has not been reported in the literature. A 75-year-old female patient had been diagnosed with type 2 diabetes mellitus for 10 years and she has been treated by liraglutide for 6 months. The patient was admitted to the emergency service due to sudden onset of abdominal pain. After laboratory and imaging studies, she was diagnosed with acute cholecystitis and cholelithiasis. And then patient's oral intake was stopped, intravenous fluid and ceftriaxone 2 g/day were started. Furthermore, liraglutide treatment discontinued and ursodeoxycholic acid (UDCA) was started to treat cholelithiasis. During follow-up, abdominal pain completely relieved. Hepatobiliary ultrasonography in sixth month follow-up showed entirely regression of cholelithiasis. Any liraglutide-related cholelithiasis case has not been reported in the literature previously. Therefore, our case is the first case. Especially, elderly diabetic patients who are started to liraglutide treatment should be monitored closely for the formation of cholelithiasis. UDCA treatment would be an alternative prior to surgical treatment for liraglutide-related cholelithiasis.

Fasting and bed rest, even for a relatively short period, are risk factors for ceftriaxone-associated pseudolitiasis.

BACKGROUND: Cholelithiasis is one of the side-effects of ceftriaxone (CTRX). Reportedly, the cholelithiasis resolves relatively soon after cessation of CTRX, hence, it is called pseudolithiasis. Previous reports have suggested that biliary pseudolithiasis can cause not only gallstone attacks, but also severe adverse events, such as cholecystitis and pancreatitis. The purpose of this study was to prospectively elucidate the risk factors and clinical features of CTRX-associated pseudolithiasis in pediatric patients. METHODS: We prospectively examined the incidence and clinical outcome of CTRX-associated biliary pseudolithiasis. Subjects included infants and children who were admitted to hospital with acute disease. Ultrasonography was used to confirm the absence of stones and sludge in the gallbladder before CTRX therapy, and in assessment of pseudolithiasis on days 3, 5, 7 and 10 after initiation of CTRX in all subjects. The pseudolithiasis group was then compared with the non-pseudolithiasis group in terms of age, sex, CTRX dose, CTRX duration, duration of fever, fasting period, period of bed rest, and blood test results. RESULTS: Sixty patients were enrolled in the study. Eleven of them had biliary pseudolithiasis on ultrasonography (18.3%). Formation of biliary pseudolithiasis was prevalent in the fasting and bed rest groups, appearing relatively early in these groups. CONCLUSIONS: Special attention should be paid to the degree of oral intake and patient activity when CTRX is prescribed. We recommend regular ultrasonographic follow up of patients receiving CTRX, to evaluate the formation of biliary pseudolithiasis.

Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial.

BACKGROUND: Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. METHODS: We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m(2) or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, NCT00309283. FINDINGS: Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. INTERPRETATION: These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. FUNDING: Polycystic Kidney Disease Foundation.

Cumulative exposure to ritonavir-boosted atazanavir is associated with cholelithiasis in patients with HIV-1 infection.

OBJECTIVES: This study aimed to examine the effect of long-term treatment with ritonavir-boosted atazanavir (atazanavir/ritonavir) on cholelithiasis. METHODS: A single-centre, cross-sectional study was conducted to elucidate the prevalence of cholelithiasis in patients with HIV-1 infection who underwent abdominal ultrasonography between January 2004 and March 2013. Univariate and multivariate logistic regression analyses were applied to estimate the effects of >2 years of atazanavir/ritonavir exposure on cholelithiasis as the primary exposure. RESULTS: Of the 890 study patients, 84 (9.4%) had >2 years of atazanavir/ritonavir exposure. Cholelithiasis was twice as frequent in those treated for >2 years with atazanavir/ritonavir [15 (18%) of 84 patients] compared with those treated for <2 years [72 (8.9%) of 806 patients] (P = 0.018). Univariate analysis showed a significant association between >2 years of atazanavir/ritonavir exposure and cholelithiasis (OR = 2.216; 95% CI = 1.206-4.073; P = 0.010) and the association almost persisted in multivariate analysis (adjusted OR = 1.806; 95% CI = 0.922-3.537; P = 0.085). Long-term treatment (>2 years) with other commonly used protease inhibitors, such as ritonavir-boosted lopinavir and ritonavir-boosted darunavir, was not associated with cholelithiasis in univariate and multivariate analysis. Additional analysis showed that >1 year of exposure to atazanavir/ritonavir was significantly associated with cholelithiasis (OR = 1.857; 95% CI = 1.073-3.214; P = 0.027), whereas >1 year of exposure to ritonavir-boosted lopinavir and ritonavir-boosted darunavir was not. CONCLUSIONS: Long-term treatment of patients with HIV-1 infection for >2 years with atazanavir/ritonavir was associated with an increased risk of cholelithiasis compared with patients with shorter exposure. Long-term exposure to atazanavir/ritonavir appears to increase the risk of cholelithiasis in patients with HIV-1 infection.

Review of the impact of antineoplastic therapies on the risk for cholelithiasis and acute cholecystitis.

BACKGROUND: Development of cholecystitis in patients with malignancies can potentially disrupt their treatment and alter prognosis. This review aims to identify antineoplastic interventions associated with increased risk of cholecystitis in cancer patients. METHODS: A comprehensive search strategy was developed to identify articles pertaining to risk factors and complications of cholecystitis in cancer patients. FDA-issued labels of novel antineoplastic drugs released after 2010 were hand-searched to identify more therapies associated with cholecystitis in nonpublished studies. RESULTS: Of an initial 2,932 articles, 124 were reviewed in the study. Postgastrectomy patients have a high (5-30 %) incidence of gallstone disease, and 1-7 % develop symptomatic disease. One randomized trial addressing the role of cholecystectomy concurrent with gastrectomy is currently underway. Among other risk groups, patients with neuroendocrine tumors treated with somatostatin analogs have a 15 % risk of cholelithiasis, and most are symptomatic. Hepatic artery based therapies carry a risk of cholecystitis (0.02-24 %), although the risk is reduced with selective catheterization. Myelosuppression related to chemotherapeutic agents (0.4 %), bone marrow transplantation, and treatment with novel multikinase inhibitors are associated with high risk of cholecystitis. CONCLUSIONS: There are several risk factors for gallbladder-related surgical emergencies in patients with advanced malignancies. Incidental cholecystectomy at index operation should be considered in patients planned for gastrectomy, and candidates for regional therapies to the liver or somatostatin analogs. While prophylactic cholecystectomy is currently recommended for patients with cholelithiasis receiving myeloablative therapy, this strategy may have value in patients treated with multikinase inhibitors, immunotherapy, and oncolytic viral therapy based on evolving evidence.

Ceftriaxone-induced pseudolithiasis in children treated for perforated appendicitis.

PURPOSE: Ceftriaxone has been associated with development of pseudolithiasis. In our institution, it is used for treatment of perforated appendicitis in children. This study evaluated the occurrence of ceftriaxone-related pseudolithiasis in this population. METHODS: After obtaining IRB approval, we performed a retrospective chart review over 51 months. We included patients undergoing laparoscopic appendectomy for perforated appendicitis. All patients were treated with ceftriaxone post-operatively. Patients without initial or post-treatment gallbladder imaging available for review were excluded. RESULTS: There were 71 patients who met inclusion criteria with a mean (±SD) age of 10.8 ± 3.8 years. Of these, 14 % (n = 10) developed stones or sludge in the gallbladder. The mean duration of ceftriaxone therapy was 8.7 ± 3.8 days. The average time to post-antibiotic imaging was 11.5 ± 10.3 days from initiation of antibiotics. There was no significant difference in duration of ceftriaxone therapy in the children that developed pseudolithiasis or sludge (10.0 ± 4.9 days) compared to those that did not (8.5 ± 3.6, p = 0.26). One child (10 %) with pseudolithiasis went on to become symptomatic, requiring a laparoscopic cholecystectomy. CONCLUSIONS: In our experience, ceftriaxone use for perforated appendicitis is associated with a significant incidence of biliary pseudolithiasis, and is unrelated to duration of ceftriaxone therapy.

Efficacy and safety of deferasirox at low and high iron burdens: results from the EPIC magnetic resonance imaging substudy.

The effect of deferasirox dosing tailored for iron burden and iron loading based on liver iron concentration (LIC) was assessed over 1 year in less versus more heavily iron-overloaded patients in a substudy of the Evaluation of Patients' Iron Chelation with Exjade®. Deferasirox starting dose was 10-30 mg/kg/day, depending on blood transfusion frequency, with recommended dose adjustments every 3 months. Therapeutic goals were LIC maintenance or reduction in patients with baseline LIC <7 or ≥7 mg Fe/g dry weight (dw), respectively. Changes in LIC (R2-magnetic resonance imaging) and serum ferritin after 1 year were assessed. Adverse events (AEs) and laboratory parameters were monitored throughout. Of 374 patients, 71 and 303 had baseline LIC <7 and ≥7 mg Fe/g dw, respectively; mean deferasirox doses were 20.7 and 27.1 mg/kg/day (overall average time to dose increase, 24 weeks). At 1 year, mean LIC and median serum ferritin levels were maintained in the low-iron cohort (-0.02 ± 2.4 mg Fe/g dw, -57 ng/mL; P = not significant) and significantly decreased in the high-iron cohort (-6.1 ± 9.1 mg Fe/g dw, -830 ng/mL; P < 0.0001). Drug-related gastrointestinal AEs, mostly mild to moderate, were more frequently reported in the <7 versus ≥7 mg Fe/g dw cohort (39.4 versus 20.8 %; P = 0.001) and were not confounded by diagnosis, dosing, ethnicity, or hepatitis B and/or C history. Reported serum creatinine increases did not increase in low- versus high-iron cohort patients. Deferasirox doses of 20 mg/kg/day maintained LIC <7 mg Fe/g dw and doses of 30 mg/kg/day were required for net iron reduction in the high-iron cohort, with clinically manageable safety profiles. The higher incidence of gastrointestinal AEs at lower iron burdens requires further investigation.

[A case of ceftriaxone-associated pseudolithiasis in an adult patient that disappeared after the discontinuation of ceftriaxone].

We report a case of a 47-year-old female patient with ceftriaxone (CTRX)-associated pseudolithiasis. CTRX was administered at a dosage of 2g/day for 8 days because of colonic diverticulitis. A routine abdominal computed tomography (CT) scan was performed to investigate the diverticulitis. However, the CT scan demonstrated stones and sludge in the gallbladder, which had not been present before CTRX administration. Therefore, we diagnosed the patient with pseudolithiasis caused by CTRX and stopped CTRX administration. The stones and sludge disappeared 6 days after stopping CTRX administration. This underreported adverse effect of CTRX should be considered when treating both children and adult patients.

Complicated atazanavir-associated cholelithiasis: a report of 14 cases.

Fourteen human immunodeficiency virus (HIV)-infected patients receiving an atazanavir (ATV)-based antiretroviral regimen developed complicated cholelithiasis. ATV was found in biliary calculi in 8 of 11 cases: infrared spectrometry analysis of calculi revealed that ATV made up a median of 89% (range, 10%-100%) of the total calculus composition. Development and management of ATV-associated cholelithiasis are discussed.

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.

A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patients with asthma.

RATIONALE: IL-4 and IL-13 share many biological functions important in the development of allergic airway inflammation and are implicated in the pathogenesis of asthma. AMG 317 is a fully human monoclonal antibody to IL-4Ralpha that blocks both IL-4 and IL-13 pathways. OBJECTIVES: To evaluate efficacy and safety of AMG 317 in patients with moderate to severe asthma. METHODS: In this phase 2, randomized, double-blind, placebo-controlled study, patients received weekly subcutaneous injections of placebo or AMG 317 (75-300 mg) for 12 weeks, followed by a 4-week follow-up period. The primary endpoint was change from baseline at Week 12 in Asthma Control Questionnaire (ACQ) symptom score. MEASUREMENTS AND MAIN RESULTS: Mean ACQ change (SE) was -0.49 (0.09) in placebo (n = 74), and -0.43 (0.11), -0.58 (0.12), and -0.70 (0.09) in the AMG 317 75 mg (n = 73), 150 mg (n = 73), and 300 mg (n = 74) groups, respectively (treatment effect P = 0.25). No statistically significant differences were observed in the secondary endpoints. Numerical decreases in number of and time to exacerbations were noted in patients receiving AMG 317 150 mg and 300 mg. Preplanned analyses by tertile of baseline ACQ revealed that patients with higher baseline ACQ scores (>or=2.86) were more likely to respond to AMG 317. Serious adverse events were reported in three patients, each noted as not related to study drug. CONCLUSIONS: AMG 317 did not demonstrate clinical efficacy across the overall group of patients. Clinically significant improvements were observed in several outcome measures in patients with higher baseline ACQ scores. AMG 317 was safe and well tolerated in this study population. Clinical trial registered with www.clinicaltrials.gov (NCT 00436670).

Possible vicarious contrast excretion causing symptomatic cholelithiasis.

A case report of a unique malleable, rubbery, white mass found at cholecystectomy after a diagnosis of symptomatic cholelithiasis. This likely represents either a unique form of a calcium-containing or contrast-containing stone. There are no reported incidents of vicarious contrast stones and calcium-containing stones are reported to be crystalline and hard.

Drug-induced Cholelithiasis.

BACKGROUND: The prevalence of cholelithiasis in developed countries is high and its cause is multifactorial, with a negligible proportion of drug-induced cholelithiasis. METHODS: Relevant studies were identified by PubMed, Google Scholar and Science Direct. Reference lists of retrieved articles were also reviewed. The most relevant and up-to-date information was incorporated. RESULTS: There is a wide range of drugs that can induce lithiasis. While the risk of developing lithiasis is high with some drugs (ceftriaxone, atazanavir, somatostatin analogues), it is lower or even questionable with others. Some drugs precipitate in the bile and may account for up to 100% of the weight of the stone. CONCLUSION: Cholelithiasis can be induced by a wide range of drugs with different mechanisms of action. The aim of the article is to draw attention to this lesser known fact and the need to take into account the risk of developing lithiasis prior to therapy initiation.

Ceftriaxone-associated biliary pseudolithiasis in children: do we know enough?

Ceftriaxone is an antibiotic agent frequently used in paediatric hospital practice for the treatment of severe bacterial infections. The use of this agent can result in cholelithiasis and/or biliary sludge, more commonly in children than in adults. This systematic review was aimed at analysing available literature concerning ceftriaxone-associated biliary pseudolithiasis in paediatric patients, with a special emphasis on the clinical aspects. A literature analysis was performed using Medline and Embase electronic databases (articles published in English up to December 2019), with the search terms and combinations as follows:'ceftriaxone', 'cholelithiasis', 'biliary sludge' 'gallstones' 'neonates' 'children' 'clinical aspects' 'management'. Several case reports, case series and prospective/retrospective studies have documented a relationship between ceftriaxone treatment and biliary pseudolithiasis in the paediatric population, even though literature data regarding neonates and infants are scarce. Ceftriaxone-associated biliary pseudolithiasis is dose-dependent and usually asymptomatic but, sometimes, it may present with abdominal pain, nausea and emesis. Abdominal ultrasonography should be performed when this complication is suspected. Generally, ceftriaxone-associated cholelithiasis resolves over a variable period of time (days to months) after cessation of therapy. Therefore, a conservative approach to this condition is advocated, but a prolonged follow-up may be necessary. A personalized assessment of factors predisposing to ceftriaxone-associated biliary pseudolithiasis before prescribing the drug can allow to minimize the risk of developing it, with significant advantages in terms of human and economic costs.