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Palle Jeppesen - One of the best experts on this subject based on the ideXlab platform.
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Teduglutide for the treatment of adults with intestinal failure associated with short bowel syndrome: pooled safety data from four clinical trials.
Therapeutic advances in gastroenterology, 2020Co-Authors: Ulrich-frank Pape, Palle Jeppesen, Douglas L. Seidner, Kishore Iyer, Loris Pironi, Stephane M Schneider, Hak-myung Lee, Marek Kunecki, John CaminisAbstract:Background:In multiple clinical studies, Teduglutide reduced parenteral support (PS) with a consistent safety profile in adults with short bowel syndrome–associated intestinal failure (SBS–IF). The...
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Citrulline correlations in short bowel syndrome–intestinal failure by patient stratification: Analysis of 24 weeks of Teduglutide treatment from a randomized controlled study
Clinical nutrition (Edinburgh Scotland), 2019Co-Authors: Palle Jeppesen, Douglas L. Seidner, Simon M. Gabe, Hak-myung Lee, Clément OlivierAbstract:Summary Background & aims Disease-associated factors influence parenteral support (PS) reduction in response to Teduglutide in patients with intestinal failure associated-short bowel syndrome (SBS–IF). We sought to determine correlative relationships between plasma citrulline levels, small bowel length, and PS volume. Methods A post hoc analysis of plasma citrulline levels from patients in the STEPS 24-week study of Teduglutide in patients with SBS−IF. Plasma citrulline was assessed in all patients; patients were stratified 3 times into subgroups based on bowel anatomy, cause of SBS–IF, and baseline PS volumes. Correlation analyses used simple linear regression models. Statistical comparisons between study groups were conducted using 2-sided t tests for 2 independent mean differences. Results Baseline plasma citrulline correlated with remnant small bowel length (r = 0.355, P = 0.002), but not with baseline PS volume (r = −0.167, P = 0.14), in the overall population. There was a robust correlation between the baseline and Week 24 citrulline (r = 0.705, P Conclusion Baseline plasma citrulline showed significant correlations with small bowel length in patients with ≥50% colon remaining/no stoma/colon-in-continuity, and patients with SBS–IF causes other than IBD/vascular disease. Citrulline levels may correlate with PS changes in response to Teduglutide and more research may reveal a relationship between citrulline levels within the heterogeneous population of patients with SBS−IF. ClinicalTrials.gov NCT00798967 , ClinicalTrialsRegister.eu 2008-006193-15.
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Enteral Autonomy and Days Off Parenteral Support With Teduglutide Treatment for Short Bowel Syndrome in the STEPS Trials
JPEN. Journal of parenteral and enteral nutrition, 2019Co-Authors: Douglas L. Seidner, Clément Olivier, Simon M. Gabe, Hak-myung Lee, Palle JeppesenAbstract:Background Teduglutide response, in terms of parenteral support (PS) volume reduction, is associated with specific disease characteristics among adults with short bowel syndrome-associated intestinal failure (SBS-IF). Whether these associations apply to PS weaning with Teduglutide is unknown. Methods Adults with SBS-IF treated with Teduglutide in the phase III STEPS study and open-label extensions STEPS-2 and STEPS-3 were included in the analysis. Patients required PS ≥ 3 times weekly for ≥ 12 months at enrollment. The study population was stratified 3 times to create 3 distinct analysis populations based on bowel anatomy, etiology, and baseline PS volume. Outcomes included characteristics of patients who achieved PS independence and total and percentage of patients who had ≥ 1, ≥ 2, and ≥ 3 d/wk off PS at the end of STEPS, STEPS-2, and STEPS-3. Results Eight of 39 patients who received Teduglutide in STEPS obtained PS independence during the STEPS study series. Patients required > 6 months of Teduglutide treatment before enteral autonomy was achieved, regardless of underlying disease characteristics. Patients who attained PS independence and greater numbers of days per week off PS tended to have lower baseline PS volumes and noninflammatory bowel disease (non-IBD) etiology. Patients with ≥ 50% colon-in-continuity showed a trend for achieving greater numbers of days per week off PS. Conclusion Although this analysis was limited by low patient numbers, results suggest that SBS-IF characteristics of lower baseline PS volume and non-IBD etiology were associated with PS reduction benefits with Teduglutide in terms of days off per week and enteral autonomy.
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Impact of Teduglutide on Quality of Life Among Patients With Short Bowel Syndrome and Intestinal Failure
JPEN. Journal of parenteral and enteral nutrition, 2019Co-Authors: Kristina Chen, Jipan Xie, Sneha S. Kelkar, Clément Olivier, James Signorovitch, Palle JeppesenAbstract:Background Teduglutide reduces or eliminates parenteral support (PS) dependency in patients with short bowel syndrome (SBS). Recent post hoc analyses demonstrated that effects are correlated with baseline PS volume. We assessed the SBS-related quality-of-life (QoL) impact of Teduglutide, particularly whether improvements are greater among subgroups achieving more PS volume reduction. Methods Using phase 3 trial data of Teduglutide in patients with SBS (NCT00798967), change in Short Bowel Syndrome-Quality of Life (SBS-QoL) scores from baseline were compared between Teduglutide vs placebo in the overall population and subgroups classified by baseline PS volume requirement, disease etiology, and bowel anatomy. Generalized estimating equation models were fitted to assess impact of Teduglutide on SBS-related QoL using data from all visits, adjusted for baseline characteristics. Results Of 86 patients, 43 each were randomized to Teduglutide or placebo (mean age: 51 vs 50 years, respectively). In adjusted analyses, Teduglutide had a nonsignificant reduction (improvement) of -8.6 points (95% CI: 2.6 to -19.8) in SBS-QoL sum score from baseline to Week-24 vs placebo. The impact of Teduglutide varied by subgroup. Patients treated with Teduglutide experienced significantly greater reductions in SBS-QoL sum score at Week-24 vs placebo in 2 subgroups, ie, the third (highest) tertile baseline PS volume (-27.3, 95% CI: -50.8 to -3.7) and inflammatory bowel disease (IBD; -29.6, 95% CI: -46.3 to -12.9). Results were similar for SBS-QoL subscale and item scores. Conclusions The impact of Teduglutide treatment on SBS-related QoL vs placebo varied among subgroups and was significant and most pronounced among patients with highest baseline PS volume requirement or IBD.
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Identifying a subpopulation with higher likelihoods of early response to treatment in a heterogeneous rare disease: a post hoc study of response to Teduglutide for short bowel syndrome.
Therapeutics and clinical risk management, 2018Co-Authors: Kristina Chen, Palle Jeppesen, Jipan Xie, Wenxi Tang, Jing Zhao, James SignorovitchAbstract:Purpose Teduglutide, a glucagon-like peptide-2 analog, has demonstrated efficacy in reducing parenteral support (PS) among patients with short bowel syndrome with intestinal failure (SBS-IF). This study aims to identify a subpopulation of SBS-IF patients for whom Teduglutide has an especially pronounced effect. Patients and methods Data were from a 24-week, Phase III trial (Study of Teduglutide Effectiveness in Parenteral Nutrition-Dependent SBS Subjects; NCT00798967) that randomized SBS-IF patients with PS dependency to receive Teduglutide (n=43) or placebo (n=43). Two prediction models (1 for each arm) were developed for response, defined as 20% reduction in weekly PS at Weeks 20 and 24. Potential predictors included demographics, disease characteristics, and concomitant medications. Patients were then ranked based on the effect score, an individualized predicted response rate difference with Teduglutide versus placebo. A subpopulation of patients with a pronounced benefit from Teduglutide versus placebo was identified. Baseline characteristics and clinical outcomes were compared between patients included versus those not included in the subpopulation. Results Six predictors of response to Teduglutide were selected: older age, volvulus as the cause of major intestinal resection, baseline PS volume >6 L per week, longer time since start of PS dependency, absence of ileocecal valve, and lower percentage of colon remaining. Higher percentage of colon remaining and volvulus were the selected predictors for response to placebo. A subpopulation of patients more likely to respond to Teduglutide was identified as those with the top 60% effect scores. The difference in response rate between Teduglutide and placebo was 62% in the subpopulation, which was substantially higher than the difference of 33% in the overall population. Mean PS day reduction was also significantly higher for Teduglutide compared to placebo in the subpopulation. Conclusion Pretreatment characteristics as predictors of response to Teduglutide versus placebo within 24 weeks were identifiable in the clinical trial population of SBS-IF patients.
P Jeppesen - One of the best experts on this subject based on the ideXlab platform.
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citrulline correlations in short bowel syndrome intestinal failure by patient stratification analysis of 24 weeks of Teduglutide treatment from a randomized controlled study
Clinical Nutrition, 2020Co-Authors: P Jeppesen, Douglas L. Seidner, S M Gabe, Hak-myung Lee, Clément OlivierAbstract:Summary Background & aims Disease-associated factors influence parenteral support (PS) reduction in response to Teduglutide in patients with intestinal failure associated-short bowel syndrome (SBS–IF). We sought to determine correlative relationships between plasma citrulline levels, small bowel length, and PS volume. Methods A post hoc analysis of plasma citrulline levels from patients in the STEPS 24-week study of Teduglutide in patients with SBS−IF. Plasma citrulline was assessed in all patients; patients were stratified 3 times into subgroups based on bowel anatomy, cause of SBS–IF, and baseline PS volumes. Correlation analyses used simple linear regression models. Statistical comparisons between study groups were conducted using 2-sided t tests for 2 independent mean differences. Results Baseline plasma citrulline correlated with remnant small bowel length (r = 0.355, P = 0.002), but not with baseline PS volume (r = −0.167, P = 0.14), in the overall population. There was a robust correlation between the baseline and Week 24 citrulline (r = 0.705, P Conclusion Baseline plasma citrulline showed significant correlations with small bowel length in patients with ≥50% colon remaining/no stoma/colon-in-continuity, and patients with SBS–IF causes other than IBD/vascular disease. Citrulline levels may correlate with PS changes in response to Teduglutide and more research may reveal a relationship between citrulline levels within the heterogeneous population of patients with SBS−IF. ClinicalTrials.gov NCT00798967 , ClinicalTrialsRegister.eu 2008-006193-15.
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factors associated with response to Teduglutide in patients with short bowel syndrome and intestinal failure
Gastroenterology, 2017Co-Authors: P Jeppesen, Douglas L. Seidner, Simon M. Gabe, Clément OlivierAbstract:Abstract Background & Aims Clinical studies showed Teduglutide to increase urine production and reduce need for parenteral support volume in patients with short bowel syndrome (SBS) with intestinal failure, increasing intestinal wet weight absorption and reducing diarrhea. However, the effects of Teduglutide on parenteral support vary among patients. We performed a post-hoc analysis of a phase 3 placebo-controlled study to identify characteristics of patients in whom Teduglutide has the largest effects on parenteral support volume response. Methods We collected data from 85 patients with SBS with intestinal failure, according to the European Society for Clinical Nutrition and Metabolism classification system, who received Teduglutide or placebo between 25 November 2008 and 04 January 2011 at 27 sites in 10 countries. Changes in parenteral support volume were evaluated according to baseline parenteral support volume, bowel anatomy (group 1, jejunostomy/ileostomy; group 2, ≥50% colon in continuity without stoma; and group 3, other colon anatomies), and disease features (with inflammatory bowel disease, mesenteric vascular diseases, or other conditions). Correlation analyses were conducted using simple linear regression models, with unadjusted r 2 values reported. Two-sided t tests were used for comparisons between treatment groups. Results We correlated parenteral support volume reduction with Teduglutide treatment and baseline parenteral support volume (y = –0.3870x + 90.0279, r2=0.61; P P =.0112) but also compared with Teduglutide-treated patients in group 2 (reduction of 355±306 mL/day; P =.0066). Teduglutide had an intermediate effect on patients in group 3. A minority of patients with SBS and inflammatory bowel diseases had colon in continuity (10.5% [n=2/19]), whereas most patients with SBS and vascular or other diseases had colon in continuity (84.4% [n=27/32] and 67.6% [n=23/34], respectively). Conclusions In a post-hoc analysis of data from a phase 3 study of the effects of Teduglutide on patients with SBS, we associated reduced parenteral support volume with baseline parenteral support volume, bowel anatomy, and SBS features. These findings may inform initial parenteral support volume adjustments and management of these severely disabled patients. ClinicalTrials.gov no: NCT00798967; ClinicalTrialsRegister.eu no: 2008-006193-15
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long term Teduglutide for the treatment of patients with intestinal failure associated with short bowel syndrome
Clinical and translational gastroenterology, 2016Co-Authors: Lauren K. Schwartz, Stephen J Okeefe, N.n. Youssef, Ulrich-frank Pape, Ken Fujioka, S M Gabe, Georg Lamprecht, Benjamin Li, P JeppesenAbstract:Long-Term Teduglutide for the Treatment of Patients With Intestinal Failure Associated With Short Bowel Syndrome
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gut hormones in the treatment of short bowel syndrome and intestinal failure
Current Opinion in Endocrinology Diabetes and Obesity, 2015Co-Authors: P JeppesenAbstract:PURPOSE OF REVIEW: The approval of Teduglutide, a recombinant analog of human glucagon-like peptide (GLP) 2, by the US Food and Drug Administration (Gattex) and the European Medicines Agency (Revestive) has illustrated the potential of selected gut hormones as treatments in patients with short-bowel syndrome and intestinal failure. Gut hormones may improve the structural and functional intestinal adaptation following intestinal resection by decreasing a rapid gastric emptying and hypersecretion, by increasing the intestinal blood flow, and by promoting intestinal growth. This review summarizes the findings from phase 2 and 3 Teduglutide studies, and pilot studies employing GLP-1 and agonists for this orphan condition. RECENT FINDINGS: In a 3-week, phase 2, metabolic balance study, Teduglutide increased the intestinal wet weight absorption by approximately 700 g/day and reduced fecal energy losses by approximately 0.8 MJ/day (∼200 Kcal/day). In two subsequent 24-week, phase 3 studies, Teduglutide reduced the need for parenteral support in the same magnitude. Adverse events were mainly of gastrointestinal origin and consistent with the known mechanism of action of Teduglutide. Pilot studies suggest that GLP-1 may be less potent. Synergistic effects may be seen by co-treatment with GLP-2. SUMMARY: Gut hormones promote intestinal adaptation and absorption, decreasing fecal losses, thereby decreasing or even eliminating the need for parenteral support. This will aid the intestinal rehabilitation in these severely disabled short-bowel syndrome patients.
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Long-term Teduglutide for the treatment of patients with intestinal failure associated with short bowel syndrome
'Springer Science and Business Media LLC', 2015Co-Authors: Lk Schwartz, N.n. Youssef, S M Gabe, Sj O'keefe, Fujioka K, Lamprecht G, Uf Pape, Li B, P JeppesenAbstract:In the pivotal 24-week, phase III, placebo-controlled trial, Teduglutide significantly reduced parenteral support (PS) requirements in patients with short bowel syndrome (SBS). STEPS-2 was a 2-year, open-label extension of that study designed to evaluate long-term safety and efficacy of Teduglutide.Enrolled patients had completed 24 weeks of either Teduglutide (TED/TED) or placebo (PBO/TED) in the initial placebo-controlled study or qualified for that study, but were not treated (NT/TED) because of full enrollment. Patients received subcutaneous Teduglutide 0.05 mg/kg/day for up to 24 months (NT/TED and PBO/TED) or up to 30 months (TED/TED). Clinical response was defined as 20-100% reduction from baseline in weekly PS volume; baseline was considered the beginning of Teduglutide treatment in the initial placebo-controlled study (TED/TED) or STEPS-2 (NT/TED and PBO/TED). Descriptive statistics summarized changes in efficacy and safety variables.Of 88 enrolled patients, 65 (74%) completed STEPS-2. The most common treatment-emergent adverse events were abdominal pain (34%), catheter sepsis (28%), and decreased weight (25%). Mean weight, body mass index, and serum albumin remained stable. In patients who completed the study, clinical response was achieved in 28/30 (93%) TED/TED, 16/29 (55%) PBO/TED, and 4/6 (67%) NT/TED patients. Mean PS volume reductions from baseline were 7.6 (66%), 3.1 (28%), and 4.0 (39%) l/week in the TED/TED, PBO/TED, and NT/TED groups, respectively. Thirteen patients achieved full enteral autonomy.In patients with SBS, long-term Teduglutide treatment resulted in sustained, continued reductions in PS requirements. Overall health and nutritional status was maintained despite PS reductions
Maria Witte - One of the best experts on this subject based on the ideXlab platform.
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Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency.
Digestive diseases and sciences, 2020Co-Authors: Johannes Reiner, Peggy Berlin, Jakob Wobar, Holger Schäffler, Karen Bannert, Manuela Bastian, Brigitte Vollmar, Robert Jaster, Georg Lamprecht, Maria WitteAbstract:In short bowel syndrome, epithelial surface loss results in impaired nutrient absorption and may lead to intestinal insufficiency or intestinal failure. Nucleotide oligomerization domain 2 (Nod2) dysfunction predisposes to the development of intestinal failure after intestinal resection and is associated with intestinal barrier defects. Epithelial barrier function is crucial for intestinal absorption and for intestinal adaptation in the short bowel situation. The aim of the study was to characterize the effects of the GLP-2 analogue Teduglutide in the small intestine in the presence and absence of Nod2 in a mouse model of short bowel syndrome. Mice underwent 40% ICR and were thereafter treated with Teduglutide versus vehicle injections. Survival, body weight, stool water, and sodium content and plasma aldosterone concentrations were determined. Intestinal and kidney tissue was examined with light and fluorescence microscopy, Ussing chamber studies and quantitative PCR in wild type and transgenic mice. Teduglutide reduced intestinal failure incidence in Nod2 k.o. mice. In wt mice, Teduglutide attenuated intestinal insufficiency as indicated by reduced body weight loss and lower plasma aldosterone concentrations, lower stool water content, and lower stool sodium losses. Teduglutide treatment was associated with enhanced epithelial paracellular pore function and enhanced claudin-10 expression in tight junctions in the villus tips, where it colocalized with sodium–glucose cotransporter 1 (SGLT-1), which mediates Na-coupled glucose transport. In the SBS situation, Teduglutide not only maximizes small intestinal mucosal hypertrophy but also partially restores small intestinal epithelial function through an altered distribution of claudin-10, facilitating sodium recirculation for Na-coupled glucose transport and water absorption.
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Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency
Digestive Diseases and Sciences, 2020Co-Authors: Johannes Reiner, Peggy Berlin, Jakob Wobar, Holger Schäffler, Karen Bannert, Manuela Bastian, Brigitte Vollmar, Robert Jaster, Georg Lamprecht, Maria WitteAbstract:Background In short bowel syndrome, epithelial surface loss results in impaired nutrient absorption and may lead to intestinal insufficiency or intestinal failure. Nucleotide oligomerization domain 2 (Nod2) dysfunction predisposes to the development of intestinal failure after intestinal resection and is associated with intestinal barrier defects. Epithelial barrier function is crucial for intestinal absorption and for intestinal adaptation in the short bowel situation. Aims The aim of the study was to characterize the effects of the GLP-2 analogue Teduglutide in the small intestine in the presence and absence of Nod2 in a mouse model of short bowel syndrome. Methods Mice underwent 40% ICR and were thereafter treated with Teduglutide versus vehicle injections. Survival, body weight, stool water, and sodium content and plasma aldosterone concentrations were determined. Intestinal and kidney tissue was examined with light and fluorescence microscopy, Ussing chamber studies and quantitative PCR in wild type and transgenic mice. Results Teduglutide reduced intestinal failure incidence in Nod2 k.o. mice. In wt mice, Teduglutide attenuated intestinal insufficiency as indicated by reduced body weight loss and lower plasma aldosterone concentrations, lower stool water content, and lower stool sodium losses. Teduglutide treatment was associated with enhanced epithelial paracellular pore function and enhanced claudin-10 expression in tight junctions in the villus tips, where it colocalized with sodium–glucose cotransporter 1 (SGLT-1), which mediates Na-coupled glucose transport. Conclusions In the SBS situation, Teduglutide not only maximizes small intestinal mucosal hypertrophy but also partially restores small intestinal epithelial function through an altered distribution of claudin-10, facilitating sodium recirculation for Na-coupled glucose transport and water absorption.
Douglas L. Seidner - One of the best experts on this subject based on the ideXlab platform.
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predictors and timing of response to Teduglutide in patients with short bowel syndrome dependent on parenteral support
Clinical nutrition ESPEN, 2021Co-Authors: Kristina Chen, Jipan Xie, Sneha S. Kelkar, Clément Olivier, F Joly, Douglas L. SeidnerAbstract:Summary Background and Aims This study aimed to identify predictors and estimate time to Teduglutide response among adult patients with short bowel syndrome with intestinal failure (SBS-IF) dependent on parenteral support (PS). Methods Post-hoc analysis was performed on individual patient data from Teduglutide-treated patients in the phase III Teduglutide trial STEPS and the STEPS-2 extension. Response was defined as ≥ 20% PS volume reduction from baseline for two consecutive visits. Early responders experienced the reduction at 20 and 24 weeks during STEPS while late responders experienced the reduction during STEPS-2. Timing and predictors for response were assessed among the treated population using Cox proportional hazard model. Time to response was compared in aetiological subgroups using Kaplan-Meier analysis. Patient characteristics and time to response were compared between early vs late responders. Results A total of 34 patients were included in this analysis; overall median time to response was 4.3 months. The presence of stoma predicted a positive response to Teduglutide (hazard ratio [HR]: 5.6; 95% confidence interval [CI]: 1.4-21.9; p=0.013). Vascular disease (vs. inflammatory bowel disease [IBD]) as cause of major intestinal resection (HR: 0.2; 95% CI: 0.0-0.8; p=0.015), presence of ileocecal valve (HR: 0.1; 95% CI: 0.0-0.8; p=0.047) and female sex (HR: 0.3; 95% CI: 0.1-1.0; p=0.026) are negatively associated with response. In subgroup analyses, patients with IBD (vs. vascular disease), with (vs. without) a stoma, and without (vs. with) colon-in-continuity had a shorter time to response (all p Conclusions Time to response to Teduglutide depends on bowel anatomy and SBS-IF aetiology. IBD, presence of a stoma, and absence of ileocecal valve were associated with earlier response to Teduglutide. These findings may enhance management of patients with SBS-IF; however, due to sample size limitations, additional studies are needed to confirm these findings.
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citrulline correlations in short bowel syndrome intestinal failure by patient stratification analysis of 24 weeks of Teduglutide treatment from a randomized controlled study
Clinical Nutrition, 2020Co-Authors: P Jeppesen, Douglas L. Seidner, S M Gabe, Hak-myung Lee, Clément OlivierAbstract:Summary Background & aims Disease-associated factors influence parenteral support (PS) reduction in response to Teduglutide in patients with intestinal failure associated-short bowel syndrome (SBS–IF). We sought to determine correlative relationships between plasma citrulline levels, small bowel length, and PS volume. Methods A post hoc analysis of plasma citrulline levels from patients in the STEPS 24-week study of Teduglutide in patients with SBS−IF. Plasma citrulline was assessed in all patients; patients were stratified 3 times into subgroups based on bowel anatomy, cause of SBS–IF, and baseline PS volumes. Correlation analyses used simple linear regression models. Statistical comparisons between study groups were conducted using 2-sided t tests for 2 independent mean differences. Results Baseline plasma citrulline correlated with remnant small bowel length (r = 0.355, P = 0.002), but not with baseline PS volume (r = −0.167, P = 0.14), in the overall population. There was a robust correlation between the baseline and Week 24 citrulline (r = 0.705, P Conclusion Baseline plasma citrulline showed significant correlations with small bowel length in patients with ≥50% colon remaining/no stoma/colon-in-continuity, and patients with SBS–IF causes other than IBD/vascular disease. Citrulline levels may correlate with PS changes in response to Teduglutide and more research may reveal a relationship between citrulline levels within the heterogeneous population of patients with SBS−IF. ClinicalTrials.gov NCT00798967 , ClinicalTrialsRegister.eu 2008-006193-15.
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Teduglutide for the treatment of adults with intestinal failure associated with short bowel syndrome: pooled safety data from four clinical trials.
Therapeutic advances in gastroenterology, 2020Co-Authors: Ulrich-frank Pape, Palle Jeppesen, Douglas L. Seidner, Kishore Iyer, Loris Pironi, Stephane M Schneider, Hak-myung Lee, Marek Kunecki, John CaminisAbstract:Background:In multiple clinical studies, Teduglutide reduced parenteral support (PS) with a consistent safety profile in adults with short bowel syndrome–associated intestinal failure (SBS–IF). The...
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Citrulline correlations in short bowel syndrome–intestinal failure by patient stratification: Analysis of 24 weeks of Teduglutide treatment from a randomized controlled study
Clinical nutrition (Edinburgh Scotland), 2019Co-Authors: Palle Jeppesen, Douglas L. Seidner, Simon M. Gabe, Hak-myung Lee, Clément OlivierAbstract:Summary Background & aims Disease-associated factors influence parenteral support (PS) reduction in response to Teduglutide in patients with intestinal failure associated-short bowel syndrome (SBS–IF). We sought to determine correlative relationships between plasma citrulline levels, small bowel length, and PS volume. Methods A post hoc analysis of plasma citrulline levels from patients in the STEPS 24-week study of Teduglutide in patients with SBS−IF. Plasma citrulline was assessed in all patients; patients were stratified 3 times into subgroups based on bowel anatomy, cause of SBS–IF, and baseline PS volumes. Correlation analyses used simple linear regression models. Statistical comparisons between study groups were conducted using 2-sided t tests for 2 independent mean differences. Results Baseline plasma citrulline correlated with remnant small bowel length (r = 0.355, P = 0.002), but not with baseline PS volume (r = −0.167, P = 0.14), in the overall population. There was a robust correlation between the baseline and Week 24 citrulline (r = 0.705, P Conclusion Baseline plasma citrulline showed significant correlations with small bowel length in patients with ≥50% colon remaining/no stoma/colon-in-continuity, and patients with SBS–IF causes other than IBD/vascular disease. Citrulline levels may correlate with PS changes in response to Teduglutide and more research may reveal a relationship between citrulline levels within the heterogeneous population of patients with SBS−IF. ClinicalTrials.gov NCT00798967 , ClinicalTrialsRegister.eu 2008-006193-15.
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Enteral Autonomy and Days Off Parenteral Support With Teduglutide Treatment for Short Bowel Syndrome in the STEPS Trials
JPEN. Journal of parenteral and enteral nutrition, 2019Co-Authors: Douglas L. Seidner, Clément Olivier, Simon M. Gabe, Hak-myung Lee, Palle JeppesenAbstract:Background Teduglutide response, in terms of parenteral support (PS) volume reduction, is associated with specific disease characteristics among adults with short bowel syndrome-associated intestinal failure (SBS-IF). Whether these associations apply to PS weaning with Teduglutide is unknown. Methods Adults with SBS-IF treated with Teduglutide in the phase III STEPS study and open-label extensions STEPS-2 and STEPS-3 were included in the analysis. Patients required PS ≥ 3 times weekly for ≥ 12 months at enrollment. The study population was stratified 3 times to create 3 distinct analysis populations based on bowel anatomy, etiology, and baseline PS volume. Outcomes included characteristics of patients who achieved PS independence and total and percentage of patients who had ≥ 1, ≥ 2, and ≥ 3 d/wk off PS at the end of STEPS, STEPS-2, and STEPS-3. Results Eight of 39 patients who received Teduglutide in STEPS obtained PS independence during the STEPS study series. Patients required > 6 months of Teduglutide treatment before enteral autonomy was achieved, regardless of underlying disease characteristics. Patients who attained PS independence and greater numbers of days per week off PS tended to have lower baseline PS volumes and noninflammatory bowel disease (non-IBD) etiology. Patients with ≥ 50% colon-in-continuity showed a trend for achieving greater numbers of days per week off PS. Conclusion Although this analysis was limited by low patient numbers, results suggest that SBS-IF characteristics of lower baseline PS volume and non-IBD etiology were associated with PS reduction benefits with Teduglutide in terms of days off per week and enteral autonomy.
Georg Lamprecht - One of the best experts on this subject based on the ideXlab platform.
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Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency.
Digestive diseases and sciences, 2020Co-Authors: Johannes Reiner, Peggy Berlin, Jakob Wobar, Holger Schäffler, Karen Bannert, Manuela Bastian, Brigitte Vollmar, Robert Jaster, Georg Lamprecht, Maria WitteAbstract:In short bowel syndrome, epithelial surface loss results in impaired nutrient absorption and may lead to intestinal insufficiency or intestinal failure. Nucleotide oligomerization domain 2 (Nod2) dysfunction predisposes to the development of intestinal failure after intestinal resection and is associated with intestinal barrier defects. Epithelial barrier function is crucial for intestinal absorption and for intestinal adaptation in the short bowel situation. The aim of the study was to characterize the effects of the GLP-2 analogue Teduglutide in the small intestine in the presence and absence of Nod2 in a mouse model of short bowel syndrome. Mice underwent 40% ICR and were thereafter treated with Teduglutide versus vehicle injections. Survival, body weight, stool water, and sodium content and plasma aldosterone concentrations were determined. Intestinal and kidney tissue was examined with light and fluorescence microscopy, Ussing chamber studies and quantitative PCR in wild type and transgenic mice. Teduglutide reduced intestinal failure incidence in Nod2 k.o. mice. In wt mice, Teduglutide attenuated intestinal insufficiency as indicated by reduced body weight loss and lower plasma aldosterone concentrations, lower stool water content, and lower stool sodium losses. Teduglutide treatment was associated with enhanced epithelial paracellular pore function and enhanced claudin-10 expression in tight junctions in the villus tips, where it colocalized with sodium–glucose cotransporter 1 (SGLT-1), which mediates Na-coupled glucose transport. In the SBS situation, Teduglutide not only maximizes small intestinal mucosal hypertrophy but also partially restores small intestinal epithelial function through an altered distribution of claudin-10, facilitating sodium recirculation for Na-coupled glucose transport and water absorption.
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Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency
Digestive Diseases and Sciences, 2020Co-Authors: Johannes Reiner, Peggy Berlin, Jakob Wobar, Holger Schäffler, Karen Bannert, Manuela Bastian, Brigitte Vollmar, Robert Jaster, Georg Lamprecht, Maria WitteAbstract:Background In short bowel syndrome, epithelial surface loss results in impaired nutrient absorption and may lead to intestinal insufficiency or intestinal failure. Nucleotide oligomerization domain 2 (Nod2) dysfunction predisposes to the development of intestinal failure after intestinal resection and is associated with intestinal barrier defects. Epithelial barrier function is crucial for intestinal absorption and for intestinal adaptation in the short bowel situation. Aims The aim of the study was to characterize the effects of the GLP-2 analogue Teduglutide in the small intestine in the presence and absence of Nod2 in a mouse model of short bowel syndrome. Methods Mice underwent 40% ICR and were thereafter treated with Teduglutide versus vehicle injections. Survival, body weight, stool water, and sodium content and plasma aldosterone concentrations were determined. Intestinal and kidney tissue was examined with light and fluorescence microscopy, Ussing chamber studies and quantitative PCR in wild type and transgenic mice. Results Teduglutide reduced intestinal failure incidence in Nod2 k.o. mice. In wt mice, Teduglutide attenuated intestinal insufficiency as indicated by reduced body weight loss and lower plasma aldosterone concentrations, lower stool water content, and lower stool sodium losses. Teduglutide treatment was associated with enhanced epithelial paracellular pore function and enhanced claudin-10 expression in tight junctions in the villus tips, where it colocalized with sodium–glucose cotransporter 1 (SGLT-1), which mediates Na-coupled glucose transport. Conclusions In the SBS situation, Teduglutide not only maximizes small intestinal mucosal hypertrophy but also partially restores small intestinal epithelial function through an altered distribution of claudin-10, facilitating sodium recirculation for Na-coupled glucose transport and water absorption.
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long term Teduglutide for the treatment of patients with intestinal failure associated with short bowel syndrome
Clinical and translational gastroenterology, 2016Co-Authors: Lauren K. Schwartz, Stephen J Okeefe, N.n. Youssef, Ulrich-frank Pape, Ken Fujioka, S M Gabe, Georg Lamprecht, Benjamin Li, P JeppesenAbstract:Long-Term Teduglutide for the Treatment of Patients With Intestinal Failure Associated With Short Bowel Syndrome
