| 1. |
- Cano-Cebrian, Maria-Jose, et al.
(författare)
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Chemotherapeutics Combined with Luminal Irritants : Effects on Small-Intestinal Mannitol Permeability and Villus Length in Rats
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:3
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Tidskriftsartikel (refereegranskat)abstract
- Chemotherapy causes intestinal mucositis, which includes villous atrophy and altered mucosal barrier function. However, there is an uncertainty regarding how the reduced small-intestinal surface area affects the mucosal permeability of the small marker probe mannitol (MW 188), and how the mucosa responds to luminal irritants after chemotherapy. The aims in this study were to determine (i) the relationship between chemotherapy-induced villus atrophy and the intestinal permeability of mannitol and (ii) how the mucosa regulate this permeability in response to luminal ethanol and sodium dodecyl sulfate (SDS). This was investigated by treating rats with a single intraperitoneal dose of doxorubicin, irinotecan, or 5-fluorouracil. After 72 h, jejunum was single-pass perfused and mannitol permeability determined at baseline and after 15 min luminal exposure to 15% ethanol or 5 mg/mL SDS. Tissue samples for morphological analyses were sampled from the perfused segment. All three chemotherapeutics caused a similar 30% reduction in villus length. Mannitol permeability increased with irinotecan (1.3-fold) and 5-fluorouracil (2.5-fold) and was reduced with doxorubicin (0.5-fold), suggesting that it is not epithelial surface area alone that regulates intestinal permeability to mannitol. There was no additional increase in mannitol permeability induced by luminal ethanol or SDS in the chemotherapy-treated rats compared to controls, which may be related to the relatively high basal permeability of mannitol compared to other common low-permeability probes. We therefore suggest that future studies should focus on elucidating the complex interplay between chemotherapy in combination with luminal irritants on the intestinal permeability of other probes.
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| 2. |
- Dahlgren, David, et al.
(författare)
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Effect of paracellular permeation enhancers on intestinal permeability of two peptide drugs, enalaprilat and hexarelin, in rats
- 2021
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Ingår i: Acta Pharmaceutica Sinica B. - : INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES. - 2211-3835 .- 2211-3843. ; 11:6, s. 1667-1675
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Tidskriftsartikel (refereegranskat)abstract
- Transcellular permeation enhancers are known to increase the intestinal permeability of enalaprilat, a 349 Da peptide, but not hexarelin (887 Da). The primary aim of this paper was to investigate if paracellular permeability enhancers affected the intestinal permeation of the two peptides. This was investigated using the rat single-pass intestinal perfusion model with concomitant blood sampling. These luminal compositions included two paracellular permeation enhancers, chitosan (5 mg/mL) and ethylenediaminetetraacetate (EDTA, 1 and 5 mg/mL), as well as low luminal tonicity (100 mOsm) with or without lidocaine. Effects were evaluated by the change in lumen-to-blood permeability of hexarelin and enalaprilat, and the blood-to-lumen clearance of (51)chromium-labeled EDTA (CLCr-EDTA), a clinical marker for mucosal barrier integrity. The two paracellular permeation enhancers increased the mucosal permeability of both peptide drugs to a similar extent. The data in this study suggests that the potential for paracellular permeability enhancers to increase intestinal absorption of hydrophilic peptides with low molecular mass is greater than for those with transcellular mechanism-of-action. Further, the mucosal blood-to-lumen flux of Cr-51-EDTA was increased by the two paracellular permeation enhancers and by luminal hypotonicity. In contrast, luminal hypotonicity did not affect the lumen-to-blood transport of enalaprilat and hexarelin. This suggests that hypotonicity affects paracellular solute transport primarily in the mucosal crypt region, as this area is protected from luminal contents by a constant water flow from the crypts.
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| 3. |
- Dahlgren, David, et al.
(författare)
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Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat
- 2020
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal drug disappearance, as well as the effect of permeation enhancers on drug permeability. However, it is uncertain how accurate the rat single-pass intestinal perfusion model predicts regional intestinal permeability and absorption in human. There is also a shortage of systematic in vivo investigations of the direct effect of permeation enhancers in the small and large intestine. In this rat single-pass intestinal perfusion study, the jejunal and colonic permeability of two low permeability drugs (atenolol and enalaprilat) and two high-permeability ones (ketoprofen and metoprolol) was determined based on plasma appearance. These values were compared to already available corresponding human data from a study conducted in our lab. The colonic effect of four permeation enhancers-sodium dodecyl sulfate, chitosan, ethylenediaminetetraacetic acid (EDTA), and caprate-on drug permeability and transport of chromium EDTA (an established clinical marker for intestinal barrier integrity) was determined. There was no difference in jejunal and colonic permeability determined from plasma appearance data of any of the four model drugs. This questions the validity of the rat single-pass intestinal perfusion model for predicting human regional intestinal permeability. It was also shown that the effect of permeation enhancers on drug permeability in the colon was similar to previously reported data from the rat jejunum, whereas the transport of chromium EDTA was significantly higher (p < 0.05) in the colon than in jejunum. Therefore, the use of permeation enhancers for increasing colonic drug permeability has greater risks than potential medical rewards, as indicated by the higher permeation of chromium EDTA compared to the drugs.
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| 4. |
- Erhardt, Tobias, et al.
(författare)
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Decadal-scale progression of the onset of Dansgaard-Oeschger warming events
- 2019
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 15:2, s. 811-825
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Tidskriftsartikel (refereegranskat)abstract
- During the last glacial period, proxy records throughout the Northern Hemisphere document a succession of rapid millennial-scale warming events, called Dansgaard-Oeschger (DO) events. A range of different mechanisms has been proposed that can produce similar warming in model experiments; however, the progression and ultimate trigger of the events are still unknown. Because of their fast nature, the progression is challenging to reconstruct from paleoclimate data due to the limited temporal resolution achievable in many archives and cross-dating uncertainties between records. Here, we use new high-resolution multi-proxy records of sea-salt (derived from sea spray and sea ice over the North Atlantic) and terrestrial (derived from the central Asian deserts) aerosol concentrations over the period 10-60 ka from the North Greenland Ice Core Project (NGRIP) and North Greenland Eemian Ice Drilling (NEEM) ice cores in conjunction with local precipitation and temperature proxies from the NGRIP ice core to investigate the progression of environmental changes at the onset of the warming events at annual to multi-annual resolution. Our results show on average a small lead of the changes in both local precipitation and terrestrial dust aerosol concentrations over the change in sea-salt aerosol concentrations and local temperature of approximately one decade. This suggests that, connected to the reinvigoration of the Atlantic meridional overturning circulation and the warming in the North Atlantic, both synoptic and hemispheric atmospheric circulation changes at the onset of the DO warming, affecting both the moisture transport to Greenland and the Asian monsoon systems. Taken at face value, this suggests that a collapse of the sea-ice cover may not have been the initial trigger for the DO warming.
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| 5. |
- Sinnl, Giulia, et al.
(författare)
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A multi-ice-core, annual-layer-counted Greenland ice-core chronology for the last 3800 years : GICC21
- 2022
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 18:5, s. 1125-1150
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Tidskriftsartikel (refereegranskat)abstract
- Ice-core timescales are vital for the understanding of past climate; hence they should be updated whenever significant amounts of new data become available. Here, the Greenland ice-core chronology GICC05 was revised for the last 3835 years by synchronizing six deep ice cores and three shallow ice cores from the central Greenland ice sheet. A new method was applied by combining automated counting of annual layers on multiple parallel proxies and manual fine-tuning. A layer counting bias was found in all ice cores because of site-specific signal disturbances; therefore the manual comparison of all ice cores was deemed necessary to increase timescale accuracy. After examining sources of error and their correlation lengths, the uncertainty rate was quantified to be 1 year per century. The new timescale is younger than GICC05 by about 13 years at 3835 years ago. The most recent 800 years are largely unaffected by the revision. Between 800 and 2000 years ago, the offset between timescales increases steadily, with the steepest offset occurring between 800 and 1100 years ago. Moreover, offset oscillations of about 5 years around the average are observed between 2500 and 3800 years ago. The non-linear offset behavior is attributed to previous mismatches of volcanic eruptions, to the much more extensive dataset available to this study, and to the finer resolution of the new ice-core ammonium matching. By analysis of the common variations in cosmogenic radionuclides, the new ice-core timescale is found to be in alignment with the IntCal20 curve (Reimer et al., 2020).
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| 6. |
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