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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT02820064
Other study ID # 38RC15.303
Secondary ID
Status Recruiting
Phase N/A
First received June 28, 2016
Last updated December 5, 2016
Start date January 2016
Est. completion date January 2017

Study information

Verified date December 2016
Source University Hospital, Grenoble
Contact Eric FONTAINE, Professor
Email efontaine@chu-grenoble.fr
Is FDA regulated No
Health authority France: Committee for the Protection of PersonnesFrance: Agence Nationale de Sécurité du Médicament et des produits de santé
Study type Interventional

Clinical Trial Summary

Chronic Obstructive Pulmonary Disease (COPD) is characterized by chronic systemic hypoxia and low-grade inflammation as well as by an alteration of arginine (ARG) metabolism. As ARG is synthetized from circulating citrulline (CIT), an alteration of CIT homeostasis, particularly its production by ornithine transcarbamylase (OCT) in small intestine could be involved. We hypothesized that hypoxia +/- inflammation, classically associated to COPD, has effects on OCT regulation in enterocytes.

This study aims at exploring the effects of hypoxia and inflammation on the production of citrulline by ornithine transcarbamylase (OTC) activity in enterocytes from explant cultures of duodenal tissue.


Description:

Citrulline is an amino-acid almost exclusively released by the small intestine after its synthesis from glutamine by the OTC in enterocytes. Citrulline from the small intestine is released into the portal vena and, because it does not enter hepatocytes, it reaches the systemic circulation to be metabolized in arginine by kidneys. By this way, is an important source of endogenous ARG. Moreover, evidence suggests that circulating citrulline could have a direct action on the regulation of muscle protein synthesis. Therefore, the administration of citrulline might be an interesting nutritional strategy to preserve or restore muscle mass and function. Muscle mass is a determinant of respiratory function and muscle weakness explains for a large part morbidity and mortality in patients suffering from Chronic Obstructive Pulmonary Disease (COPD).

Evidence suggests that citrulline plasmatic levels would be lower in several states involving systemic inflammation and hypoxia. Indeed, it has been observed in rats that hypoxia leads to a sharp decline in plasma CIT concentration and also in human (hypocitrullinemia has been observed in Intensive Care Unit patients and in subjects suffering from sepsis and trauma) but the cause of relationship is not yet established. Therefore, it may be supposed that a decreased plasma CIT level could be responsible for a decrease in de novo ARG synthesis leading to an impairment of NO production (endothelial dysfunction) in these pathological situations.

Because chronic hypoxia and systemic inflammation are both systemic traits of patients suffering from COPD, the fact that hypoxia and/or systemic inflammation might directly affect OCT, decreasing intestinal citrulline production which, in turn, could contribute to endothelial dysfunction and muscle weakness is considered.

In order to explore this hypothesis, the potential consequences of hypoxia and inflammation (alone or in association) on citrulline synthesis by the OCT in human enterocytes will be determined, thanks to an "explant" culture model of duodenal tissue. Duodenal biopsies will be removed during oesophago-gastro-duodenoscopies performed in the Hepato-gastro-enterology unit of Grenoble University Hospital, among patients expected to undergo a gastroscopy for any diagnostic purpose. 30 patients will be selected during a period of 6 months. After complete information and written agreement, 8 biopsy specimens will be removed from the duodenum of each patient and processed for organ culture.

Then, duodenal biopsies will be incubated in the presence or not of cytokines and exposed or not to hypoxia. Indeed, 4 groups will be constituted: a control group (no stimulus), a group exposed to hypoxic conditions, a group exposed to inflammatory conditions (cytokines) and a group exposed to both hypoxic an inflammatory conditions.

As primary endpoint, for each group, the OTC activity and the citrulline production in the culture medium will be studied.


Recruitment information / eligibility

Status Recruiting
Enrollment 30
Est. completion date January 2017
Est. primary completion date January 2017
Accepts healthy volunteers No
Gender Both
Age group 18 Years and older
Eligibility Inclusion Criteria:

- Digestive disease known or suspected which justify an oeso-gastro-endoscopy with digestive biopsies, excepted a disease with duodenal localization known or strongly suspected.

- Gastroscopy performed under general anaesthesia

- Patient's written agreement obtained

Non inclusion-criteria:

- Age < 18

- Therapeutical endoscopy (that is to say when a therapeutical act will be performed as balloon dilation, digestive or biliary prosthesis, drainage, diverticulotomy, polypectomy, variceal ligation...) either expected or

- Duodenal pathology (known or strongly suspected with the clinical and biological elements)

- Duodenal biopsies are not allowed to be performed: vascular lesions, digestive haemorrhage, clotting disorder.

- Antiplatelet drug and anticoagulant drug

- Lack of written agreement

- Subjects hospitalized in an emergency state or without agreement

- Subjects who cannot be contacted in emergency.

Exclusion criteria:

subjects will be excluded from the study:

- if an unexpected therapeutic act has to be performed during the endoscopy

- if duodenal duodenal atrophy or lesions are discovered during the endoscopy

- if duodenal lesions are discoverd at the histological examination

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science


Related Conditions & MeSH terms


Intervention

Procedure:
duodenal biopsy during gastroduodenal endoscopy
Patients for who and esophagogastroduodenoscopy in order to diagnose is performed. 8 duodenal biopsy specimens will be removed.

Locations

Country Name City State
France Grenoble University Hospital Grenoble

Sponsors (2)

Lead Sponsor Collaborator
University Hospital, Grenoble AGIR à Dom

Country where clinical trial is conducted

France, 

References & Publications (31)

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Boustière C, Veitch A, Vanbiervliet G, Bulois P, Deprez P, Laquiere A, Laugier R, Lesur G, Mosler P, Nalet B, Napoleon B, Rembacken B, Ajzenberg N, Collet JP, Baron T, Dumonceau JM; European Society of Gastrointestinal Endoscopy.. Endoscopy and antiplatelet agents. European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2011 May;43(5):445-61. doi: 10.1055/s-0030-1256317. — View Citation

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Breuillard C, Cynober L, Moinard C. Citrulline and nitrogen homeostasis: an overview. Amino Acids. 2015 Apr;47(4):685-91. doi: 10.1007/s00726-015-1932-2. Review. — View Citation

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Coëffier M, Miralles-Barrachina O, Le Pessot F, Lalaude O, Daveau M, Lavoinne A, Lerebours E, Déchelotte P. Influence of glutamine on cytokine production by human gut in vitro. Cytokine. 2001 Feb 7;13(3):148-54. — View Citation

Dumortier J, Ponchon T, Scoazec JY, Moulinier B, Zarka F, Paliard P, Lambert R. Prospective evaluation of transnasal esophagogastroduodenoscopy: feasibility and study on performance and tolerance. Gastrointest Endosc. 1999 Mar;49(3 Pt 1):285-91. — View Citation

Faure C, Morio B, Chafey P, Le Plénier S, Noirez P, Randrianarison-Huetz V, Cynober L, Aussel C, Moinard C. Citrulline enhances myofibrillar constituents expression of skeletal muscle and induces a switch in muscle energy metabolism in malnourished aged rats. Proteomics. 2013 Jul;13(14):2191-201. doi: 10.1002/pmic.201200262. — View Citation

Faure C, Raynaud-Simon A, Ferry A, Daugé V, Cynober L, Aussel C, Moinard C. Leucine and citrulline modulate muscle function in malnourished aged rats. Amino Acids. 2012 Apr;42(4):1425-33. doi: 10.1007/s00726-011-0841-2. — View Citation

Giangreco E, D'agate C, Barbera C, Puzzo L, Aprile G, Naso P, Bonanno G, Russo FP, Nicoletti A, Incarbone S, Trama G, Russo A. Prevalence of celiac disease in adult patients with refractory functional dyspepsia: value of routine duodenal biopsy. World J Gastroenterol. 2008 Dec 7;14(45):6948-53. — View Citation

Giudicelli R. [Esophageal perforations. Results of a national survey]. Ann Chir. 1992;46(2):183-7. French. — View Citation

Heresbach D, Napoléon B. Delchier J.C. and al. Consensus en endoscopie digestive. Acta endo (2009) 39 :206-2011.

Hubert-Buron A, Leblond J, Jacquot A, Ducrotté P, Déchelotte P, Coëffier M. Glutamine pretreatment reduces IL-8 production in human intestinal epithelial cells by limiting IkappaBalpha ubiquitination. J Nutr. 2006 Jun;136(6):1461-5. — View Citation

Jonker R. and al. Whole body de novo ARG production and NO synthesis are reduced in COPD patients. Clin.Nutr. 2013;32(S1):S5-S6.

Kise Y, Suzuki R, Shimada H, Tanaka H, Oshiba G, Chino O, Makuuchi H. Idiopathic submucosal hematoma of esophagus complicated by dissecting aneurysm, followed-up endoscopically during conservative treatment. Endoscopy. 2001 Apr;33(4):374-8. Review. — View Citation

Lacy PD, Lee JM, O'Morain CA. Temporomandibular joint dislocation: an unusual complication of upper gastrointestinal endoscopy. Am J Gastroenterol. 2000 Dec;95(12):3653-4. — View Citation

Lecleire S, Coeffier M, Leblond J, Hubert A, Lemoulan S, Petit A, Ducrotte P, Dechelotte P, Marion R. Modulation of nitric oxide and cytokines production by L-arginine in human gut mucosa. Clin Nutr. 2005 Jun;24(3):353-9. — View Citation

Moinard C, Cynober L. Citrulline: a new player in the control of nitrogen homeostasis. J Nutr. 2007 Jun;137(6 Suppl 2):1621S-1625S. Review. — View Citation

Napoléon B, Boneu B, Maillard L, Samama CM, Schved JF, Gay G, Ponchon T, Sautereau D, Canard JM; Board of the French Society for Digestive Endoscopy (SFED).. Guidelines of the French Society for Digestive Endoscopy (SFED). Endoscopy. 2006 Jun;38(6):632-8. — View Citation

Osowska S, Duchemann T, Walrand S, Paillard A, Boirie Y, Cynober L, Moinard C. Citrulline modulates muscle protein metabolism in old malnourished rats. Am J Physiol Endocrinol Metab. 2006 Sep;291(3):E582-6. — View Citation

Osowska S, Moinard C, Neveux N, Loï C, Cynober L. Citrulline increases arginine pools and restores nitrogen balance after massive intestinal resection. Gut. 2004 Dec;53(12):1781-6. — View Citation

Prat F. Recommandations de la SFED 2005 : De la pratique des biopsies oeso-gastro-duodénales.

Recommandations de bonnes pratiques sur les antiagrégants plaquettaires: prise en compte des risques thrombotique et hémorragique en cas de geste endoscopique HAS-SFED, oct 2012.

Reimund JM, Wittersheim C, Dumont S, Muller CD, Kenney JS, Baumann R, Poindron P, Duclos B. Increased production of tumour necrosis factor-alpha interleukin-1 beta, and interleukin-6 by morphologically normal intestinal biopsies from patients with Crohn's disease. Gut. 1996 Nov;39(5):684-9. — View Citation

The economic burden of lung disease. European white lung book 2013:16-27.

Ventura G, Moinard C, Sinico F, Carrière V, Lasserre V, Cynober L, De Bandt JP. Evidence for a role of the ileum in the control of nitrogen homeostasis via the regulation of arginine metabolism. Br J Nutr. 2011 Jul;106(2):227-36. doi: 10.1017/S0007114511000079. — View Citation

Ventura G, Noirez P, Breuillé D, Godin JP, Pinaud S, Cleroux M, Choisy C, Le Plénier S, Bastic V, Neveux N, Cynober L, Moinard C. Effect of citrulline on muscle functions during moderate dietary restriction in healthy adult rats. Amino Acids. 2013 Nov;45(5):1123-31. doi: 10.1007/s00726-013-1564-3. — View Citation

Vu CK, Korman MG, Bejer I, Davis S. Gastrointestinal bleeding after cold biopsy. Am J Gastroenterol. 1998 Jul;93(7):1141-3. Review. — View Citation

Windmueller HG, Spaeth AE. Source and fate of circulating citrulline. Am J Physiol. 1981 Dec;241(6):E473-80. — View Citation

Zubarik R, Eisen G, Mastropietro C, Lopez J, Carroll J, Benjamin S, Fleischer DE. Prospective analysis of complications 30 days after outpatient upper endoscopy. Am J Gastroenterol. 1999 Jun;94(6):1539-45. — View Citation

* Note: There are 31 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary OCT activity in biopsy specimens OCT activity in duodenal biopsy specimens will be measured at the end of the incubation period and compared between the 4 different groups (standard/inflammatory/hypoxic:inflammatory+hypoxic conditions) OCT activity in biopsies after incubation No
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