S. Fishman

Patient Factors That Increase Infliximab Clearance and Shorten Half-life in Inflammatory Bowel Disease: A Population Pharmacokinetic Study

Background:Infliximab (IFX) is effective therapy for ulcerative colitis and Crohns disease, but it may be associated with side effects and loss of response. One loss of response mechanism is increased IFX clearance (IFX-CL), resulting in short half-life and decreased troughs. Methods:Patients were recruited, and relevant demographic, clinical, and laboratory data were recorded. IFX serum concentrations and antibodies against IFX (ATI) were measured for therapeutic drug monitoring and modeled using NONMEM. Results:There were 169 IFX concentrations (Crohns disease = 73, ulcerative colitis = 92, and diagnosis undetermined = 4). Patient factors significantly associated with high IFX-CL were low albumin, high body weight, and the presence of ATI (P ⩽ 0.001). Disease type did not affect IFX-CL. The typical IFX-CL was 0.381 L/d. ATI formation was associated with a 259% increase in IFX-CL. The estimated median IFX effective half-life was 5.6 ± 2.4 days. Patients with low weight are more likely to have low troughs because IFX CL is not linearly related to weight, but IFX dosing is weight-based (in mg/kg). Simulations investigating alternative dose strategies suggested that more reliably measurable concentrations over the dose interval were achieved when the dose interval was shortened than by increasing administered dose. Conclusions:IFX-CL is significantly influenced by patient factors, specifically, albumin, body weight, and ATI. There should be a decreasing IFX dose interval strategy, particularly for low albumin patients. Higher starting doses may benefit low body weight patients. Pharmacokinetic models and therapeutic drug monitoring may ensure that patients maintain measurable concentrations throughout dose intervals. Individualized dosing may improve outcomes for IFX-treated patients with Crohns disease and ulcerative colitis.

Dipeptidyl Peptidase 4-Deficient Rats Have Improved Bile Secretory Function in High Fat Diet-Induced Steatosis

Background/AimsRodent obesity models have been shown to display impaired bile secretory functions. We have shown that glucagon-like peptide 1 (GLP-1) attenuates hepatic lipogenesis, and in the present study we investigated whether GLP-1 also improves high fat diet-associated cholestatic injury.MethodsWild type (WT) and dipeptidyl peptidase 4-deficient rats (DPP4-) with chronic elevated serum levels of active GLP-1 were fed regular chow and a Western diet for 2xa0months. Primary hepatocytes were used to assess GLP-1 effects on mRNA expression and transcription of genes encoding bile acid synthesis enzymes and transporters.ResultsDPP4- exhibited attenuated liver injury as expressed by lower serum AST and ALT after 2xa0months of a Western diet. In addition, DPP4- had better insulin sensitivity, lower serum triglycerides, cholesterol and bile acids. Hepatic expression of cyp7A1, the rate limiting enzyme in conversion of cholesterol into bile acids, was strongly attenuated in DPP4- fed with a Western diet. Moreover, hepatic expression of bile transporter, ABCB11, was increased, facilitating a higher rate of bile secretion. Mechanistically, we showed that GLP-1 directly reduced basal and LXR-induced cyp7A1 mRNA expression and suppressed cyp7A1 transcription in transient transfection assays in primary hepatocytes. However, GLP-1 and its analog exendin 4 also induced mRNA expression of bile acid transporter ABCC3 in primary rat hepatocyte cultures.ConclusionsOur data suggest that GLP-1 analogs may serve as a novel therapeutic drug to alleviate obesity-induced liver injury by reducing bile acid synthesis and improving liver bile secretory function.

Use of endoscopic septotomy for the treatment of late staple-line leaks after laparoscopic sleeve gastrectomy

Backgroundu2002Staple-line leak following laparoscopic sleeve gastrectomy is a dire adverse event. While the treatment of acute and early leaks is well established, there is still dispute regarding late and chronic leaks. We describe an endoscopic approach combining septotomy and sleeve stricture dilation for treating late/chronic leaks. Methodsu2002Ten consecutive patients with late/chronic proximal leaks were treated at our center. The septum separating the sleeve lumen from the perigastric cavity was progressively dissected over several sessions and the downstream stricture was pneumatically dilated. The technical and clinical success rates were evaluated. Results: All ten patients were treated successfully. Eight patients had sleeve strictures that were dilated in conjunction with septotomy. A mean of five sessions over the course of 43 days was needed to complete treatment. In two patients with a small perigastric cavity and no stricture, septotomy was achieved with through-the-scope balloon dilation of the fistula. No adverse events were encountered. Conclusionsu2002Septotomy accompanied by stricture dilation seems highly effective and safe in late and chronic leaks following sleeve gastrectomy.

A novel colonoscope with panoramic visualization detected more simulated polyps than conventional colonoscopy in a live swine model

Background and study aims: The Aer-O-Scope™ Colonoscope System (AOS) combines panoramic 360° view with standard forward view. We assessed the AOS’s ability to identify lesions implanted in live swine, compared to conventional colonoscopy (CC). Patients and methods: Twelve swine colons were surgically ligated and beads sewn within. Five procedures (3 AOS and 2 CC) were performed on each swine and findings reported. Physicians were blinded to number, size, and color of beads. The sequence of procedures and physicians was randomized. Pigs, physicians, and colonoscopes were randomly alternated between examination rooms, maintaining physician blindness. Two independent blinded physicians interpreted procedure videos offline. Results: A total of 259u200a/273 (94.9u200a%) of lesions were visualized by AOS compared to 158u200a/182 with CC (86.8u200a%) (Pu200a=u200a0.002). Miss rates of lesions ≥u200a6u200amm were 2.6u200a% and 10.5u200a%, respectively (Pu200a=u200a0.022), and 6.9u200a% and 15.1u200a%, respectively, for lesionsu200a<u200a6u200amm (Pu200a=u200a0.031). Mean agreement between AOS and CC for lesion detection was 88.3u200a%. The benefit of AOS was maintained in offline video review. Conclusions: AOS, featuring panoramic 360° view, demonstrated high detection rates for simulated colonic lesions in a live swine model.

P283 SORTILIN DEFICIENCY IMPROVES HEPATIC AND ADIPOSE TISSUE INSULIN RESISTANCE AND INFLAMMATION IN DIET-INDUCED OBESITY

Background and Aims: Sortilin is a trafficking molecule directing newly synthesized molecules from the trans-Golgi network to secretory pathways, endosomes, lysosomes or cell surface. Several of the molecules trafficked by sortilin, such as acidic sphingomyelinase (ASM) and sphingolipid activating proteins (SAPs), regulate the synthesis of ceramide, a major modulator of insulin signaling. We hypothesized that in sortilin mice, reduced hepatic ASM may improve insulin sensitivity and reduce steatosis in a diet-induced obesity (DIO) model. Methods: DIO and insulin resistance were induced by feeding high fat diet for 10 weeks to WT and sortilin mice. Results: Sortilin mice had significantly reduced body weight and visceral fat, despite similar food intake. Sortilin mice had better insulin tolerance test and displayed increased insulin signaling in both liver and adipose tissue as demonstrated by increased Akt phosphorylation. In accordance with the proposed role of sortilin in ASM trafficking, ASM activity in both liver and adipose tissue of sortilin mice was significantly reduced. Sortilin mice had almost no steatosis and a three-fold reduction in total hepatic triglyceride levels compared to WT mice. In addition, expression of proinflammatory cytokines was reduce in both livers and adipose tissue of sortilin. Looking at ceramide synthesis enzymes, we observed a significant reduction in ceramide synthase 6, which synthesizes long chain ceramides, in both liver and adipose tissue of sortilin. Conclusions: Sortilin deficiency induces a beneficial metabolic phenotype in DIO, with respect to both liver and adipose tissue, which may be mediated in part by reduced ASM activity and reduced ceramide levels.

Long-term effects of proximal small bowel exclusion by duodenal-jejunal bypass liner on weight reduction and glycemic control in diabetic patients

BACKGROUNDnExclusion of the proximal gut from nutrient absorption entails significant metabolic benefits. The duodenal-jejunal bypass liner (DJBL) is the first endoscopic device that excludes the first part of the gut by covering it.nnnOBJECTIVESnTo assess weight and glycemic control at the end of treatment and after 1 year of follow-up.nnnSETTINGnBariatric endoscopy service in a tertiary medical center.nnnMETHODSnDiabetic patients were treated with DJBL and followed prospectively between 2013 and 2016. Data were collected during scheduled visits.nnnRESULTSnOut of 51 patients treated, 39 completed at least 9 months with the device. Complications were recorded for the entire cohort. Percent of total weight loss was 15.05% ± 6.0% after 12 months of treatment (P < .001 versus baseline). Twelve months postretrieval, percent of total weight loss decreased to 8.75% ± 5.07% (P < .001 versus baseline). Patients with baseline body mass index ≥35 kg/m2 experienced greater percent total weight loss changes over time (P < .001). There was a significant effect on hemoglobin A1C levels over time (Pu202f=u202f.003), and the nadir was reached at 9 months of treatment (median 6.05% versus 7.20% at baseline, P < .001). Insulin users had consistently higher median hemoglobin A1C values compared with insulin nonusers (P < .001). Adverse events were experienced by 12 of 51 patients (23.5%), of which 4 cases (7.8%) were severe.nnnCONCLUSIONSnProximal bowel bypass by DJBL is an effective tool for weight reduction and glycemic control. Metabolic achievements are partially preserved at 1 year after device removal. Because DJBL entails a considerable rate of side effects, strategies to mitigate them are warranted.

Discriminatory metabolic and inflammatory parameters in serum and omental adipose tissue of obese patients with different insulin sensitivity

Objective Metabolically healthy obese phenotype is defined by high insulin sensitivity and lack of metabolic syndrome, parameters regulated by omental adipose tissue inflammation, ectopic fat deposition and adipose tissue dysfunction. Our study aimed to identify novel metabolic and inflammatory markers in serum and omental adipose tissue which characterize the “unhealthy” obese patients and distinguish them from obese patients with better metabolic profile. Design Cross-sectional study. Patients Subjects included 75 obese patients undergoing bariatric surgery at the Tel-Aviv Medical Center (mean age 43.9 ± 13.9, mean BMI 41 ± 8.4). The HOMA median value was used as a cut-off to differentiate between patients with better or worse insulin resistance. Measurements Demographic data, fasting serum insulin, glucose, bile acids, serum metabolic and inflammatory markers were obtained. During the bariatric surgery, omental adipose tissue was harvested and analyzed for metabolic and inflammatory markers using qRT-PCR. Logistic regressions were used to calculate odds ratio and 95% confidence interval for the prediction of the metabolic profile. Results Serum markers that were significantly higher among the obese with HOMA >6 were total bile acids. In the omental adipose tissue the inflammatory markers TNFα and ADAM17 were significantly higher among obese patients with HOMA >6. In multivariate analysis, the strongest predictor for insulin resistance was ADAM17 (OR = 1.82, 1.06–3.14, P = 0.031). Conclusions The study highlighted the predictive value of serum bile acids in identifying obese patients at high risk. Secondly, omental adipose tissue ADAM17 was revealed as a novel and strongest independent predictor for higher insulin resistance in morbidly obese patients.

357 DIPEPTIDYL PEPTIDASE 4-DEFICIENT RATS ARE PROTECTED FROM HIGH FAT DIET-INDUCED CHOLESTATIC INJURY

357 DIPEPTIDYL PEPTIDASE 4-DEFICIENT RATS ARE PROTECTED FROM HIGH FAT DIET-INDUCED CHOLESTATIC INJURY I. Zvibel, S. Ben Shlomo, L. Rabinowich, I. Goldiner, E.M. Santo, Z. Halpern, R. Oren, S. Fishman. Gastroenterology, Internal Medicine D, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Gastroenterology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel E-mail: isab@tasmc.health.gov.il