Twenty-Four Hour Ambulatory Gastric and Duodenal pH Profiles in Cystic Fibrosis: Effect of Duodenal Hyperacidity on Pancreatic EnzymeFunction and Fat Absorption

Barraclough, M. A.; Taylor, C J

doi:10.1097/00005176-199607000-00009

Cited by 66 publications

(47 citation statements)

References 13 publications

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“…Bicarbonate-rich fluid secretion is necessary for neutralization of acid entering the duodenum from the stomach. It was shown previously that the duodenal pH in the CF mouse is abnormally acidic due to lack of CFTR (9), which is similar to human CF patients (1).…”

supporting

confidence: 56%

Inflammation of the cystic fibrosis mouse small intestine

Norkina¹,

Kaur²,

Ziemer³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

142

188

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The CFTR null mouse [cystic fibrosis (CF) mouse] has a severe intestinal phenotype that serves as a model for CF-related growth deficiency, meconium ileus, and distal intestinal obstructive syndrome. DNA microarray analysis was used to investigate gene expression in the CF mouse small intestine. Sixty-one genes exhibited a statistically significant twofold or greater increase in expression, and 98 genes were downregulated twofold or greater. Of the upregulated genes, most were associated with inflammation and included markers for cells of the innate immune system (mast cells and neutrophils) and for acute-phase genes (serum amyloid A and complement factors). The downregulated genes include 10 cytochrome P-450 genes; several are involved in lipid metabolism, and several are involved in various transport processes. Confirmation by quantitative RT-PCR showed gene expression was significantly increased for mast cell protease 2 (27-fold), hematopoietic cell transcript 1 (17-fold), serum amyloid A3 (2.9-fold), suppressor of cytokine signaling 3 (2.0-fold), leucine-rich α2-glycoprotein (21-fold), resistin-like molecule-β (49-fold), and Muclin (2.5-fold) and was significantly decreased for cytochrome P-450 4a10 (28-fold) and cubilin (114-fold). Immune cell infiltration was confirmed histologically by staining for mast cells and neutrophils. These data demonstrate that the CF intestine exhibits an inflammatory state with upregulation of components of the innate immune system.

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supporting

confidence: 56%

Inflammation of the cystic fibrosis mouse small intestine

Norkina¹,

Kaur²,

Ziemer³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

142

188

View full text Add to dashboard Cite

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“…Enhanced gastric acid secretion in patients with CF has been previously observed (49)(50)(51); however, these findings differ from studies in DF508-CFTR mice that exhibit reduced gastric acid secretion in comparison to control mice (52). Duodenal pH in humans with CF (45,53) and CFTR-KO mice (46,47) has also been shown to be lower than in non-CF controls. Although our studies demonstrated no differences in gastrointestinal pH in newborn CF ferrets, we cannot conclude that alterations in pH may occur with increased age and/or after feeding.…”

mentioning

confidence: 64%

Bioelectric Characterization of Epithelia from Neonatal CFTR Knockout Ferrets

Fisher¹,

Tyler

Zhang³

et al. 2013

Am J Respir Cell Mol Biol

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Cystic fibrosis (CF) is a life-shortening, recessive, multiorgan genetic disorder caused by the loss of CF transmembrane conductance regulator (CFTR) chloride channel function found in many types of epithelia. Animal models that recapitulate the human disease phenotype are critical to understanding pathophysiology in CF and developing therapies. CFTR knockout ferrets manifest many of the phenotypes observed in the human disease, including lung infections, pancreatic disease and diabetes, liver disease, malnutrition, and meconium ileus. In the present study, we have characterized abnormalities in the bioelectric properties of the trachea, stomach, intestine, and gallbladder of newborn CF ferrets. Short-circuit current (I SC ) analysis of CF and wild-type (WT) tracheas revealed the following similarities and differences: (1) amiloride-sensitive sodium currents were similar between genotypes; (2) responses to 4,49-diisothiocyano-2,29-stilbene disulphonic acid were 3.3-fold greater in CF animals, suggesting elevated baseline chloride transport through non-CFTR channels in a subset of CF animals; and (3) a lack of 3-isobutyl-1-methylxanthine (IBMX)/forskolin-stimulated and N-(2-Naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene) glycine hydrazide (GlyH-101)-inhibited currents in CF animals due to the lack of CFTR. CFTR mRNA was present throughout all levels of the WT ferret and IBMX/forskolin-inducible I SC was only observed in WT animals. However, despite the lack of CFTR function in the knockout ferret, the luminal pH of the CF ferret gallbladder, stomach, and intestines was not significantly changed relative to WT. The WT stomach and gallbladder exhibited significantly enhanced IBMX/ forskolin I SC responses and inhibition by GlyH-101 relative to CF samples. These findings demonstrate that multiple organs affected by disease in the CF ferret have bioelectric abnormalities consistent with the lack of cAMP-mediated chloride transport.

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“…With respect to the luminal pH of small intestine, almost identical patterns were observed between children aged 8-14 years and adults, of which the pH gradually increases along the entire small intestine from 6.4 to 7.4 (14). Another study reported the similar duodenal pH between children aged 0.5-12 years and adults (15). Limited information pertaining to the luminal pH of small intestine was reported for neonates by Barbero et al (16), through our comprehensive literature searches in MEDLINE and EMBASE databases (from inception to June, 2014).…”

mentioning

confidence: 78%

Similarities and Differences in Gastrointestinal Physiology Between Neonates and Adults: a Physiologically Based Pharmacokinetic Modeling Perspective

Zheng

2014

AAPS J

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Abstract. Physiologically based pharmacokinetic (PBPK) modeling holds great promise for anticipating the quantitative changes of pharmacokinetics in pediatric populations relative to adults, which has served as a useful tool in regulatory reviews. Although the availability of specialized software for PBPK modeling has facilitated the widespread applications of this approach in regulatory submissions, challenges in the implementation and interpretation of pediatric PBPK models remain great, for which controversies and knowledge gaps remain regarding neonatal development of the gastrointestinal tract. The commentary highlights the similarities and differences in the gastrointestinal pH and transit time between neonates and adults from a PBPK modeling prospective. Understanding the similarities and differences in these physiological parameters governing oral absorption would promote good practice in the use of pediatric PBPK modeling to assess oral exposure and pharmacokinetics in neonates.KEY WORDS: gastric emptying; gastrointestinal pH; neonates; physiologically based pharmacokinetic modeling; small intestinal transit time.Although physiologically based pharmacokinetic (PBPK) modeling holds great promise for facilitating pediatric drug development and regulatory review, the implementation and interpretation of pediatric PBPK models continues to face challenges, in which controversies and knowledge gaps remain regarding neonatal development of the gastrointestinal tract. In this context, we would like to offer some comments on the recent article of Khalil and Läer (1). In the work by Khalil and Läer (1), inaccurate predictions of oral pharmacokinetics of sotalol, using two PBPK models, were observed in neonates. The authors ascribed the poor predictions to factors related to the absorption rather than elimination or distribution processes and highlighted the lack of many age-specific physiological alterations in the parameterization of the used pediatric absorption models. Apart from the ontogeny of intestinal transporters and drugmetabolizing enzymes, the authors argued that gastrointestinal pH profiles and transit time should be considered as agerelated physiological variables to improve the predictive power of pediatric PBPK models. In this commentary, we provide additional information to facilitate a better understanding of the similarities and differences in gastrointestinal physiology between neonates and adults, which are of critical importance when using PBPK models to simulate oral pharmacokinetics in neonates.Despite the neutral pH in newborn stomach at delivery has been well recognized (2,3), much of the literature is replete with contradictory information on the maturation of gastric pH during the neonatal period. Some suggested that the neonatal gastric pH is greater than 5, which is quite different from the adult level (4-6); but others believed that the gastric pH of neonates stays within a more acidic range of 2-3, which is similar to that of adults (7,8). Upon careful examination of the reported n...

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Twenty-Four Hour Ambulatory Gastric and Duodenal pH Profiles in Cystic Fibrosis: Effect of Duodenal Hyperacidity on Pancreatic EnzymeFunction and Fat Absorption

Cited by 66 publications

References 13 publications

Inflammation of the cystic fibrosis mouse small intestine

Inflammation of the cystic fibrosis mouse small intestine

Bioelectric Characterization of Epithelia from Neonatal CFTR Knockout Ferrets

Similarities and Differences in Gastrointestinal Physiology Between Neonates and Adults: a Physiologically Based Pharmacokinetic Modeling Perspective

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