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Investigation of orally delivered carbon monoxide for postoperative ileus

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Abstract
Endogenously produced carbon monoxide (CO) has antioxidant and anti-inflammatory effects which is why CO has been investigated as a possible therapeutic agent for inflammatory disorders in different body systems, including the gastrointestinal (GI) tract. In an effort to develop an easy to use platform for CO delivery to the GI tract, we recently introduced the Oral CO Release System (OCORS) and demonstrated its preventive effect for experimental colitis in a rodent model. Building off on a comprehensive preclinical dataset on efficacy of inhaled and intraperitoneal CO in reducing postoperative ileus (POI), which is being defined as GI transit retardation after abdominal surgery, we evaluated an adapted OCORS platform to ameliorate POI by local CO delivery to the murine small intestine. To match design characteristics of OCORS with the murine physiology we developed a miniaturized version of the OCORS and tailored its release pattern to release CO for 2 h following first order kinetics. Upon intragastric gavage of 20 tablets, 55% of the tablets reached the murine small intestine after 1 h while triggering a blood carboxyhemoglobin rise to 5.2%. Although this is in line with previous systemic CO dosing protocols, GI muscular inflammation and transit retardation by small intestinal manipulation, performed at 1 h after gavage of 20 tablets, was not prevented while the positive control - intravenous nitrite - prevented POI. The results show that local CO treatment of POI is insufficient - suggesting a strong systemic component for effective therapy - thereby providing critical insight into effective design of CO drug delivery in POI.
Keywords
Carbon monoxide, Carboxyhemoglobine, Gastric emptying, Oral tablet, Postoperative ileus, Release, Therapeutic gas, DRUG-DELIVERY, GASTROINTESTINAL INFLAMMATION, OXIDATIVE STRESS, HEME OXYGENASE-1, COLONIC SURGERY, MOLECULES, RELEASE, CO, THERAPEUTICS, LAPAROSCOPY

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Citation

Please use this url to cite or link to this publication:

Chicago
Van Dingenen, Jonas, Christoph Steiger, Markus Zehe, Lorenz Meinel, and Romain Lefebvre. 2018. “Investigation of Orally Delivered Carbon Monoxide for Postoperative Ileus.” European Journal of Pharmaceutics and Biopharmaceutics 130: 306–313.
APA
Van Dingenen, Jonas, Steiger, C., Zehe, M., Meinel, L., & Lefebvre, R. (2018). Investigation of orally delivered carbon monoxide for postoperative ileus. EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, 130, 306–313.
Vancouver
1.
Van Dingenen J, Steiger C, Zehe M, Meinel L, Lefebvre R. Investigation of orally delivered carbon monoxide for postoperative ileus. EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS. 2018;130:306–13.
MLA
Van Dingenen, Jonas, Christoph Steiger, Markus Zehe, et al. “Investigation of Orally Delivered Carbon Monoxide for Postoperative Ileus.” EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS 130 (2018): 306–313. Print.
@article{8573035,
  abstract     = {Endogenously produced carbon monoxide (CO) has antioxidant and anti-inflammatory effects which is why CO has been investigated as a possible therapeutic agent for inflammatory disorders in different body systems, including the gastrointestinal (GI) tract. In an effort to develop an easy to use platform for CO delivery to the GI tract, we recently introduced the Oral CO Release System (OCORS) and demonstrated its preventive effect for experimental colitis in a rodent model. Building off on a comprehensive preclinical dataset on efficacy of inhaled and intraperitoneal CO in reducing postoperative ileus (POI), which is being defined as GI transit retardation after abdominal surgery, we evaluated an adapted OCORS platform to ameliorate POI by local CO delivery to the murine small intestine. To match design characteristics of OCORS with the murine physiology we developed a miniaturized version of the OCORS and tailored its release pattern to release CO for 2 h following first order kinetics. Upon intragastric gavage of 20 tablets, 55\% of the tablets reached the murine small intestine after 1 h while triggering a blood carboxyhemoglobin rise to 5.2\%. Although this is in line with previous systemic CO dosing protocols, GI muscular inflammation and transit retardation by small intestinal manipulation, performed at 1 h after gavage of 20 tablets, was not prevented while the positive control - intravenous nitrite - prevented POI. The results show that local CO treatment of POI is insufficient - suggesting a strong systemic component for effective therapy - thereby providing critical insight into effective design of CO drug delivery in POI.},
  author       = {Van Dingenen, Jonas and Steiger, Christoph and Zehe, Markus and Meinel, Lorenz and Lefebvre, Romain},
  issn         = {0939-6411},
  journal      = {EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS},
  keyword      = {Carbon monoxide,Carboxyhemoglobine,Gastric emptying,Oral tablet,Postoperative ileus,Release,Therapeutic gas,DRUG-DELIVERY,GASTROINTESTINAL INFLAMMATION,OXIDATIVE STRESS,HEME OXYGENASE-1,COLONIC SURGERY,MOLECULES,RELEASE,CO,THERAPEUTICS,LAPAROSCOPY},
  language     = {eng},
  pages        = {306--313},
  title        = {Investigation of orally delivered carbon monoxide for postoperative ileus},
  url          = {http://dx.doi.org/10.1016/j.ejpb.2018.07.009},
  volume       = {130},
  year         = {2018},
}

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