Lactulose/Mannitol Test and Specificity, Sensitivity, and Area under Curve of Intestinal Permeability Parameters in Patients with Liver Cirrhosis and Crohn's Disease

Dastych, Milan; Novotná, Hana; Číhalová, J.

doi:10.1007/s10620-007-0184-8

Cited by 66 publications

(83 citation statements)

References 16 publications

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“…In the presence of gastrointestinal permeability enhancement technology (GIPET®, Merrion Pharmaceuticals Ltd, Dublin, Ireland), a number of poorly permeable drugs including zoledronic acid (Orazol®, Merrion Pharmaceuticals, Ireland) have had their oral bioavailability increased in man, and this was associated with an increase in the LMER by 50% [9]. In comparison with LMER values seen with aspirin (146-760% [31]) and Crohn's disease (520% [32]), the increase in epithelial permeability by C 10 is smaller, reversible and disappears when it is absorbed or removed.…”

Section: Resultsmentioning

confidence: 99%

Restoration of Rat Colonic Epithelium After In Situ Intestinal Instillation of the Absorption promoter, Sodium Caprate

Wang

Maher

Brayden

2010

Therapeutic Delivery

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Section: Resultsmentioning

confidence: 99%

Restoration of Rat Colonic Epithelium After In Situ Intestinal Instillation of the Absorption promoter, Sodium Caprate

Wang

Maher

Brayden

2010

Therapeutic Delivery

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“…In vivo data in humans indicate that increases in intestinal permeability induced by C 10 are a fraction of those seen with NSAIDs, both in magnitude as well as in respect of the time course. The increased epithelial permeability as defined by the lactulose:mannitol urinary excretion assay in healthy volunteers taking aspirin ranged from 146%-1967% [238][239][240][241] greater than control subjects, yet the increase with GIPET® was 50% (data not shown). While aspirin is not considered to be a more effective intestinal absorption promoter than C 10 , such studies suggest that the promoting actions of either monomeric, micellar or vesicular C 10 could relate to its physical interaction with the candidate drug.…”

Section: [4]mentioning

confidence: 99%

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Maher

Leonard²,

Jacobsen

et al. 2009

Advanced Drug Delivery Reviews

197

176

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A major challenge in oral drug delivery is the development of novel dosage forms to promote absorption of poorly permeable Class III drugs across the intestinal epithelium.To date, no absorption promoter has been approved in a formulation specifically designed for oral delivery of Class III molecules. Promoters that are designated safe for human consumption have been licensed for use in a recently approved buccal insulin spray delivery system and also for many years as part of an ampicillin rectal suppository.Unlike buccal and rectal delivery, oral formulations containing absorption promoters have the additional technical hurdle whereby the promoter and payload must be coreleased in high concentrations at the small intestinal epithelium in order to generate significant but rapidly reversible increases in permeability. The most advanced promoter in the clinic is the medium chain fatty acid (MCFA), sodium caprate (C 10 ) , a compound already approved as a direct food additive. We discuss how it has evolved to a matrix tablet format suitable for administration to humans under the headings of mechanism of action at the cellular and tissue level and in vitro and in vivo efficacy and safety studies.In specific clinical examples, we review how C 10 -based formulations are being tested for oral delivery of bisphosphonates using Gastro Intestinal Permeation Enhancement Technology, GIPET® (Merrion Pharmaceuticals, Ireland) and in a related solid dose format for anti-sense oligonucleotides (ISIS Pharmaceuticals, USA).Keywords: Oral drug delivery, Sodium caprate (C 10 ), absorption promoter, drug delivery platforms, clinical trials, oral formulation, drug delivery systems.3 TJs form a barrier to the uncontrolled absorption of noxious luminal antigens (gate function), and maintain epithelial polarity (fence function) [8,9]. In general, the TJ consists of a restrictive pathway (shunt) with a sharp molecular size cut off, and a second unrestrictive pathway (small pore) that permits paracellular permeation of molecules of radii <4.0 Å [10,11]. Depending on the intestinal region, TJ pore sizes range from 6-22Å, sufficient to permit mannitol (6.7 Å) and EDTA (10.8 Å) to permeate to an extent, whereas the passage of inulin (30-40 Å) and fluorescent-dextran 4kDa (FD-4, 26 Å) is essentially impeded [12][13][14][15][16].A number of approaches have been used to promote oral delivery of Class III drugs ( Alternatively, the use of nanoparticles comprising biocompatible polymers (e.g. chitosan,polylactide-co-glycolide, starch and glucans) can protect cargoes from GI proteases, increase GI retention and promote absorption across gut associated lymphoid tissue (GALT) and to a lesser extent, enterocytes [45][46][47]. Most data on nanoparticle absorption from rodent models suggest that M cells in the follicle-associated epithelium of Peyer's patches (PP) are the favored site of uptake for particles of diameter 500nm-1000nm [45].Given the paucity of M cells in the GI tract of adults, the relevance of PP uptake remains controversial ...

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“…Some authors used sugars [69,70,82], whereas others used isotope probes [68,71,72,73]; the latter are considered to be the gold standard, since these probes are not synthesized or digested in the human body [68]. However, an assessment of mucosal intestinal permeability by urinary excretion of orally administered, nonmetabolizable sugars gave us some information with regard to discrimination between transcellular and paracellular fluxes [83].…”

Section: Intestinal Hyperpermeabilitymentioning

confidence: 99%

“…Monosaccharides, such as mannitol, are absorbed through this transcellular pathway and reflect the extent of absorption of small molecules. Disaccharides, such as lactulose, are absorbed through the paracellular junction complex (the tight junctions) and extrusion zones of the intervillous spaces, which corresponds to the permeability of larger molecules [82,85]. Mannitol absorption as assessed by urinary excretion can be considered as an indicator of the mucosal absorptive area, and lactulose absorption as a measure of the integrity of the intestinal mucosal tight junctions [85,86].…”

Section: Intestinal Hyperpermeabilitymentioning

confidence: 99%

Changes of Intestinal Functions in Liver Cirrhosis

2016

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Background: Understanding of the gut-liver axis is important for the up-to-date management of liver cirrhosis, and changes of intestinal functions form the core of this interesting research field. Summary: Most investigators noted small intestinal dysmotility in their patients with liver cirrhosis. Marked changes in the contraction pattern were observed in early manometric studies. The orocecal transit time, particularly small intestinal transit, has generally been reported to be prolonged, which has been demonstrated in multiple investigations to be related to the severity of the liver disease (e.g., Child-Pugh class), the presence of small intestinal bacterial overgrowth (SIBO) and hepatic encephalopathy (HE) as well as a history of spontaneous bacterial peritonitis. Bacteriologically proven SIBO in proximal jejunal aspiration has been reported to be present in up to 59% of cirrhotic patients and is associated with systemic endotoxemia. Clinical and experimental studies suggest that delayed small bowel transit in liver cirrhosis may lead to SIBO, which could contribute to the symptoms of abdominal pain and diarrhea. In addition to autonomic neuropathy, metabolic derangements and diabetic state, SIBO itself may delay intestinal transit in cirrhotic patients. Several studies, both from the West and the East, have shown that the gut microbiota is altered in cirrhotic patients and particularly those with HE. Further, a quantitative change in Bacteroides/Firmicutes ratio, with a prevalence of potentially pathogenic bacteria (e.g., Enterobacteriaceae) and reduction in specific commensals (e.g., Lachnospiraceae), has been described. Structural and functional changes in the intestinal mucosa that contribute to increases in intestinal permeability for bacteria and their products have been observed in patients with liver cirrhosis, which is considered as an important pathogenetic factor for several complications. The mechanism of intestinal barrier dysfunction in cirrhosis is multifactorial, including alcohol, portal hypertension (vascular congestion and dysregulation), endotoxemia, SIBO, local inflammation and, most likely, immunological factors and medications. Key Messages: This review summarizes major achievements regarding intestinal dysfunction in cirrhosis for future gastroenterology research. The question of whether this intestinal barrier dysfunction is accompanied and/or at least partly caused by structural and functional changes in the epithelial tight junction proteins is as yet unsolved. Development of new strategies to modulate gut-liver interaction is urgently needed.

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Lactulose/Mannitol Test and Specificity, Sensitivity, and Area under Curve of Intestinal Permeability Parameters in Patients with Liver Cirrhosis and Crohn's Disease

Abstract: The lactulose/mannitol ratio was evaluated to have the highest diagnostic value to assess intestinal permeability.

Cited by 66 publications

References 16 publications

Restoration of Rat Colonic Epithelium After In Situ Intestinal Instillation of the Absorption promoter, Sodium Caprate

Restoration of Rat Colonic Epithelium After In Situ Intestinal Instillation of the Absorption promoter, Sodium Caprate

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Changes of Intestinal Functions in Liver Cirrhosis

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