Background and aims: Glucagon- like peptide 2 (GLP- 2) may improve intestinal absorption in short bowel syndrome (SBS)patients with an end jejunostomy. Teduglutide (ALX- 0600), a dipeptidyl peptidase IV resistant GLP-...Background and aims: Glucagon- like peptide 2 (GLP- 2) may improve intestinal absorption in short bowel syndrome (SBS)patients with an end jejunostomy. Teduglutide (ALX- 0600), a dipeptidyl peptidase IV resistant GLP- 2 analogue, prolongs the intestinotrophic properties of GLP- 2 in animal models. The safety and effect of teduglutide were investigated in SBS patients with and without a colon in continuity. Methods: Teduglutide was given subcutaneously for 21 days once or twice daily to 16 SBS patients in the per protocol investigational group, 10 with end jejunostomy (doses of 0.03 (n = 2), 0.10 (n = 5), or 0.15 (n = 3) mg/kg/day), one with< 50% colon in continuity (dose 0.03 mg/kg/day), and five with ≥ 50% colon in continuity (dose 0.10 mg/kg/day). Nutrient balance studies, D- xylose tests, and intestinal mucosa biopsies were performed at baseline, on the last three days of treatment, and after three weeks of follow up. Pre- study fasting native GLP- 2 levels were determined for the five patients with ≥ 50% colon in continuity. Results: Pooled across groups and compared with baseline, teduglutide increased absolute (+ 743 (477) g/day; p < 0.001) and relative (+ 22 (16)% ; p< 0.001) wet weight absorption, urine weight (+ 555 (485) g/day; p < 0.001), and urine sodium excretion (+ 53 (40) mmol/day; p< 0.001). Teduglutide decreased faecal wet weight (- 711 (734) g/day; p = 0.001) and faecal energy excretion (- 808 (1453) kJ/day (- 193 (347) kcal/day); p = 0.040). In SBS patients with end jejunostomy, tedug- lutide significantly increased villus height (+ 38 (45)% ; p = 0.030), crypt depth (+ 22 (18)% ; p = 0.010), and mitotic index (+ 115 (108)% ; p = 0.010). Crypt depth and mitotic index did not change in colonic biopsies from SBS patients with colon in continuity. The most common side effects were enlargement of the stoma nipple and mild lower leg oedema. The improvements in intestinal absorption and decreases in faecal excretion noted after treatment had reversed after the drug free follow up period. A controlled study with a more robust design is ongoing in order to determine the optimal dosage of teduglutide for SBS patients to achieve the maximal effect and utility of this drug in clinical practice. Conclusion: Teduglutide, at three dose levels for 21 days, was safe and well tolerated, intestinotrophic, and significantly increased intestinal wet weight absorption in SBS patients with an end jejunostomy or a colon in continuity.展开更多
Short bowel syndrome(SBS)with intestinal failure(IF)is a rare but severe complication of Crohn’s disease(CD),which is the most frequent benign condition that leads to SBS after repeated surgical resections,even in th...Short bowel syndrome(SBS)with intestinal failure(IF)is a rare but severe complication of Crohn’s disease(CD),which is the most frequent benign condition that leads to SBS after repeated surgical resections,even in the era of biologics and small molecules.Glucagon-like peptide-2 analogues have been deeply studied recently for the treatment of SBS-IF.These drugs have a significant intestinotrophic effect and the potential to reduce the chronic dependence of SBSIF patients on parenteral support or nutrition.Teduglutide has been approved for the treatment of SBS-IF,and apraglutide is currently in clinical development.The use of these drugs was examined with a focus on their use in CD patients.展开更多
Current treatments for inflammatory bowel disease(IBD)treatment consist of anti-inflammatory products.In this study,we sought to induce the physiological secretion of glucagon-like peptide 2,a peptide with intestinal ...Current treatments for inflammatory bowel disease(IBD)treatment consist of anti-inflammatory products.In this study,we sought to induce the physiological secretion of glucagon-like peptide 2,a peptide with intestinal growth-promoting activity,via nanoparticles while simultaneously providing with immunomodulation by tailoring the nanoparticle surface.To this end,we developed hybrid lipid hyaluronate-KPV conjugated nanoparticles loaded with teduglutide for combination therapy in IBD.The nanocarriers induced(or did not induce)immunosuppression depending on the presence(or absence)of a hyaluronan-KPV functionalization.This strategy holds promise as a nanoparticle platform for combined mucosal healing and immunomodulation in IBD treatment.展开更多
文摘Background and aims: Glucagon- like peptide 2 (GLP- 2) may improve intestinal absorption in short bowel syndrome (SBS)patients with an end jejunostomy. Teduglutide (ALX- 0600), a dipeptidyl peptidase IV resistant GLP- 2 analogue, prolongs the intestinotrophic properties of GLP- 2 in animal models. The safety and effect of teduglutide were investigated in SBS patients with and without a colon in continuity. Methods: Teduglutide was given subcutaneously for 21 days once or twice daily to 16 SBS patients in the per protocol investigational group, 10 with end jejunostomy (doses of 0.03 (n = 2), 0.10 (n = 5), or 0.15 (n = 3) mg/kg/day), one with< 50% colon in continuity (dose 0.03 mg/kg/day), and five with ≥ 50% colon in continuity (dose 0.10 mg/kg/day). Nutrient balance studies, D- xylose tests, and intestinal mucosa biopsies were performed at baseline, on the last three days of treatment, and after three weeks of follow up. Pre- study fasting native GLP- 2 levels were determined for the five patients with ≥ 50% colon in continuity. Results: Pooled across groups and compared with baseline, teduglutide increased absolute (+ 743 (477) g/day; p < 0.001) and relative (+ 22 (16)% ; p< 0.001) wet weight absorption, urine weight (+ 555 (485) g/day; p < 0.001), and urine sodium excretion (+ 53 (40) mmol/day; p< 0.001). Teduglutide decreased faecal wet weight (- 711 (734) g/day; p = 0.001) and faecal energy excretion (- 808 (1453) kJ/day (- 193 (347) kcal/day); p = 0.040). In SBS patients with end jejunostomy, tedug- lutide significantly increased villus height (+ 38 (45)% ; p = 0.030), crypt depth (+ 22 (18)% ; p = 0.010), and mitotic index (+ 115 (108)% ; p = 0.010). Crypt depth and mitotic index did not change in colonic biopsies from SBS patients with colon in continuity. The most common side effects were enlargement of the stoma nipple and mild lower leg oedema. The improvements in intestinal absorption and decreases in faecal excretion noted after treatment had reversed after the drug free follow up period. A controlled study with a more robust design is ongoing in order to determine the optimal dosage of teduglutide for SBS patients to achieve the maximal effect and utility of this drug in clinical practice. Conclusion: Teduglutide, at three dose levels for 21 days, was safe and well tolerated, intestinotrophic, and significantly increased intestinal wet weight absorption in SBS patients with an end jejunostomy or a colon in continuity.
文摘Short bowel syndrome(SBS)with intestinal failure(IF)is a rare but severe complication of Crohn’s disease(CD),which is the most frequent benign condition that leads to SBS after repeated surgical resections,even in the era of biologics and small molecules.Glucagon-like peptide-2 analogues have been deeply studied recently for the treatment of SBS-IF.These drugs have a significant intestinotrophic effect and the potential to reduce the chronic dependence of SBSIF patients on parenteral support or nutrition.Teduglutide has been approved for the treatment of SBS-IF,and apraglutide is currently in clinical development.The use of these drugs was examined with a focus on their use in CD patients.
基金Belgian F.R.S.-FNRS(Fonds de la recherche scientifique)under grants WELBIO-CR-2022A-02The Excellence Of Science(EOS:program no.EOS 30770923 and 40007505)+4 种基金supported by the Marie Skłodowska-Curie Actions for an Individual European Fellowship under the European Union’s Horizon 2020 research and innovation program(grant agreement no.887609)by a FRS-FNRS fellowship(grant agreement no.40000747)(Belgium)partially supported by the FRS-FNRS(convention T.0013.19)FRFS-WELBIO,with the support of the Wallon region(under grant agreement WELBIO-CR-2022 S-01)has received funding from the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation program(grant agreement No.850997-NanoGut).
文摘Current treatments for inflammatory bowel disease(IBD)treatment consist of anti-inflammatory products.In this study,we sought to induce the physiological secretion of glucagon-like peptide 2,a peptide with intestinal growth-promoting activity,via nanoparticles while simultaneously providing with immunomodulation by tailoring the nanoparticle surface.To this end,we developed hybrid lipid hyaluronate-KPV conjugated nanoparticles loaded with teduglutide for combination therapy in IBD.The nanocarriers induced(or did not induce)immunosuppression depending on the presence(or absence)of a hyaluronan-KPV functionalization.This strategy holds promise as a nanoparticle platform for combined mucosal healing and immunomodulation in IBD treatment.
