Intraluminal pH in the stomach, duodenum, and proximal jejunum in normal subjects and patients with exocrine pancreatic insufficiency

Ovesen, Lars; Bendtsen, Flemming; Tage-Jensen, U; Pedersen, Niels Tinggaard; Gram, B.R.; Rune, S. J.

doi:10.1016/0016-5085(86)90873-5

Cited by 184 publications

(114 citation statements)

References 9 publications

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“…These defense mechanisms protect the mucosal cells from the intense acid stress continuously present in the gastroduodenal lumen (36,42). In the presence of luminal acid, the mucosal epithelial cells will be irreversibly acidified, leading to cellular necrosis (28,37).…”

mentioning

confidence: 99%

A novel small molecule CFTR inhibitor attenuates HCO₃⁻ secretion and duodenal ulcer formation in rats

Akiba¹,

Jung²,

Ouk³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ϫ ) secretion (DBS). Although impaired DBS is observed in CF mutant mice and in CF patients, which would predict increased ulcer susceptibility, duodenal injury is rarely observed in CF patients and is reduced in CF mutant mice. To explain this apparent paradox, we hypothesized that CFTR dysfunction increases cellular [HCO 3 Ϫ ] and buffering power. To further test this hypothesis, we examined the effect of a novel, potent, and highly selective CFTR inhibitor, CFTR inh-172, on DBS and duodenal ulceration in rats. DBS was measured in situ using a standard loop perfusion model with a pH stat under isoflurane anesthesia. Duodenal ulcers were induced in rats by cysteamine with or without CFTR inh-172 pretreatment 1 h before cysteamine. Superfusion of CFTR inh-172 (0.1-10 M) over the duodenal mucosa had no effect on basal DBS but at 10 M inhibited acid-induced DBS, suggesting that its effect was limited to CFTR activation. Acid-induced DBS was abolished at 1 and 3 h and was reduced 24 h after treatment with CFTRinh-172, although basal DBS was increased at 24 h. CFTR inh-172 treatment had no effect on gastric acid or HCO 3 Ϫ secretion. Duodenal ulcers were observed 24 h after cysteamine treatment but were reduced in CFTR inh-172-pretreated rats. CFTRinh-172 acutely produces CFTR dysfunction in rodents for up to 24 h. CFTR inhibition reduces acid-induced DBS but also prevents duodenal ulcer formation, supporting our hypothesis that intracellular HCO 3 Ϫ may be an important protective mechanism for duodenal epithelial cells.

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mentioning

confidence: 99%

A novel small molecule CFTR inhibitor attenuates HCO₃⁻ secretion and duodenal ulcer formation in rats

Akiba¹,

Jung²,

Ouk³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…25,26) Generally, gastric pH tends to be acidic, whereas pH in the distal small intestine is slightly alkaline. The changes in gastrointestinal pH may affect peptide solubility and stability, which in turn influences its bioavailability.…”

Section: Effects Of Ph On Exenatide Stabilitymentioning

confidence: 99%

An Investigation into the Gastrointestinal Stability of Exenatide in the Presence of Pure Enzymes, Everted Intestinal Rings and Intestinal Homogenates

Sun

Wang

Sun

et al. 2016

Biological & Pharmaceutical Bulletin

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The purpose of this study was to investigate the gastrointestinal stability of exenatide to determine the key factor(s) contributing to peptide degradation during the oral delivery process. The effects of pH and various digestive enzymes on the degradation kinetics of exenatide were determined. Moreover, the degradation clearances of peptide were also examined using rat everted intestinal rings and intestinal homogenates from various intestinal locations. Exenatide was comparatively stable within a pH range of 1.2-8. However, obvious degradation was observed in the presence of digestive enzymes. The order of enzymes, in terms of ability to degradate exenatide, was chymotrypsin>aminopeptidase N>carboxypeptidase A>trypsin>pepsin. Chymotrypsin showed the greatest ability to degrade exenatide (half-life t 1/2 , 5.784 10 2 h), whereas aminopeptidase N and carboxylpeptidase A gave t 1/2 values of 3.53 and 10.16 h, respectively. The degradation of exenatide was found to be peptide concentration-and intestinal site-dependent, with a lower clearance in the upper part of the duodenum and the lower part of the ileum. When using intestinal homogenates as enzyme sources, the order, in terms of peptide degradation ability, was ileum>jejunum>duodenum. However, no significant difference was observed in the remaining peptide concentrations throughout 2 h of incubation, which may be due to the involvement of cytosolic enzymes. These results revealed key factors contributing to peptide degradation, and suggest that the inhibition of chymotrypsin and site-specific delivery of exenatide might be advantageous in overcoming metabolic obstacles during its oral delivery.Key words exendin-4; enzymatic degradation; gastrointestinal stability; kinetics Exenatide is a synthetic 39-amino-acid peptide amide with the same amino acid sequence as exendin-4 which was originally isolated from lizard venom, and the sequence of exenatide is shown in Fig. 1. 1) It bears a 53% structural homology to glucagon-like peptide-1 (GLP-1) and can be used as a GLP-1 receptor agonist.2) In comparison with GLP-1, exenatide has a longer half-life due to its resistance to dipeptidyl peptidase IV degradation, and is mainly degraded and eliminated in the kidney after absorption into the systemic circulation.3) Exenatide was approved by the U.S. Food and Drug Administration (FDA) for the treatment of type 2 diabetes in 2005.4) Generally, the medication is administrated subcutaneously twice daily. More recently in 2012, exenatide-loaded extended-release microspheres were approved by the FDA, which allowed it to be injected once a week for the treatment of type 2 diabetes. Although this long-acting medication can significantly reduce the frequency of injections, the therapeutic application of exenatide is still limited due to patient noncompliance related to both the expense associated with injection and pain at the site of injection. Therefore, non-injection routes of administration for exenatide have been the focus of attention over the past several years.5-10) Among...

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“…These simultaneous movements result in net H ＋ absorption and net HCO3 -secretion consistent with the function of the Jacobs-Stewart cycle. 2 ], we were able to measure uptake and secretion of H ＋ and CO 2 by the mucosa, and also measure the transmucosal absorption of H ＋ and CO 2 into portal vein. Our data powerfully implicates membrane-bound and cytosolic CAs in net transmucosal acid movement.…”

Section: Fig 4 Model Of Transmucosal Duodenal Co2/h ＋ Movement and Smentioning

confidence: 99%

“…56 Further preliminary studies have revealed that mild acid (pH 4)-induced intracellular acidification of duodenal villus cells is enhanced by S3226, whereas S3226 has no effect on intracellular acidification in the presence of strong luminal acid (pH 2.2), suggesting that NHE3 in the 'reverse mode' is not involved in H ＋ absorption in the presence of luminal acid (unpublished observations). ii) Transport as CO 2 Acid equivalents may enter the cell as CO 2 gas, which is then hydrated by CA to HCO 3 -and H ＋ .…”

Section: Luminal Hmentioning

confidence: 99%

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Duodenal Carbonic Anhydrase: Mucosal Protection, Luminal Chemosensing, and Gastric Acid Disposal

Kaunitz

Akiba

2006

Keio J. Med.

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Abstract. The duodenum serves as a buffer zone between the stomach and jejunum. Over a length of only 25 cm, large volumes of strong acid secreted by the stomach must be converted to the neutral-alkaline chyme of the hindgut lumen, generating large volumes of CO 2 , which the duodenum then absorbs. The duodenal mucosa consists of epithelial cells connected by low-resistance tight junctions, forming a leaky epithelial barrier. Despite this high permeability, the epithelial cells, under intense stress from luminal mineral acid and highly elevated Pco 2 , maintain normal functioning. Furthermore, the duodenum plays an active role in foregut acid-base homeostasis, absorbing large amounts of H ＋ and CO 2 that are recycled by the gastric parietal cells. Prompted by the high expression of cytosolic and membrane carbonic anhydrase (CAs) in duodenal epithelial cells, and the intriguing observation that CA activity appears to augment cellular acid stress, we formulated a novel hypothesis regarding the role of CA in duodenal acid absorption, epithelial protection, and chemosensing. In this review, we will describe how luminal CO 2 /H

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Intraluminal pH in the stomach, duodenum, and proximal jejunum in normal subjects and patients with exocrine pancreatic insufficiency

Cited by 184 publications

References 9 publications

A novel small molecule CFTR inhibitor attenuates HCO₃⁻ secretion and duodenal ulcer formation in rats

A novel small molecule CFTR inhibitor attenuates HCO₃⁻ secretion and duodenal ulcer formation in rats

An Investigation into the Gastrointestinal Stability of Exenatide in the Presence of Pure Enzymes, Everted Intestinal Rings and Intestinal Homogenates

Duodenal Carbonic Anhydrase: Mucosal Protection, Luminal Chemosensing, and Gastric Acid Disposal

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Intraluminal pH in the stomach, duodenum, and proximal jejunum in normal subjects and patients with exocrine pancreatic insufficiency

Cited by 184 publications

References 9 publications

A novel small molecule CFTR inhibitor attenuates HCO3− secretion and duodenal ulcer formation in rats

A novel small molecule CFTR inhibitor attenuates HCO3− secretion and duodenal ulcer formation in rats

An Investigation into the Gastrointestinal Stability of Exenatide in the Presence of Pure Enzymes, Everted Intestinal Rings and Intestinal Homogenates

Duodenal Carbonic Anhydrase: Mucosal Protection, Luminal Chemosensing, and Gastric Acid Disposal

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Product

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A novel small molecule CFTR inhibitor attenuates HCO₃⁻ secretion and duodenal ulcer formation in rats

A novel small molecule CFTR inhibitor attenuates HCO₃⁻ secretion and duodenal ulcer formation in rats