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51.
Krondahl Eva Orzechowski Achim Ekström Gunilla Lennernäs Hans 《Pharmaceutical research》1997,14(12):1780-1785
Purpose. To study intestinal transport and metabolism of three new -selective tetrapeptide enkephalin analogues, LEF537, LEF553 and TAPP These peptides are stabilized against enzymatic hydrolysis by having a D-aminoacid in position 2 and a blocked COOH-terminal.
Methods. We used a single-pass perfusion technique to study the transport of the peptides in rat jejunum. To reduce luminal and/or brush-border metabolism during the perfusion we used protease inhibitors (Pefabloc® SC, bestatin and thiorphan). The rate of metabolism was studied by incubations in rat jejunal homogenate, rat jejunal fluid and human gastric and jejunal fluid with and without these inhibitors.
Results. The jejunal permeabilities (Peff) of the peptides were 0.43–0.78 10–4 cm/s without inhibitors and 0.09–0.45 10–4 cm/s in presence of the inhibitors. All three peptides were rather rapidly degraded by enzymes in rat jejunal homogenate with half-lives of between 11.9 ± 0.5 and 31.7 ± 1.5 min. The addition of inhibitors to the homogenate prolonged the half-lives substantially for LEF553 (167 ± 35 min) and TAPP (147 ± 2 min), but only slightly for LEF537 (16.4 ± 0.5 min). LEF553 and TAPP were both hydrolyzed in rat and human jejunal fluid, while LEF537 was metabolized less in these fluids. When LEF553 and TAPP were incubated with intestinal fluid in the presence of inhibitors, metabolism was almost completely inhibited. There was no metabolism for any of the peptides in human gastric juice.
Conclusions. The replacement of the terminal free carboxylic group with an amide group did not increase the stability of the peptides in jejunal tissue enough to allow successful oral drug delivery. 相似文献
52.
Annaert Pieter Kinget Renaat Naesens Lieve de Clercq Erik Augustijns Patrick 《Pharmaceutical research》1997,14(4):492-496
Purpose. To evaluate intestinal transport, uptake and metabolism characteristics of the bis(pivaloyloxymethyl)-ester [bis(POM)-ester] of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine [PMEA].
Methods. Intestinal transport, uptake and metabolism of bis(POM)-PMEA were studied using an in vitro cell culture system of the intestinal mucosa (Caco-2 monolayers). Concentrations of bis(POM)-PMEA and its metabolites mono(POM)-PMEA and PMEA were determined using a reversed-phase HPLC method. Enzymatic stability of bis(POM)-PMEA was evaluated by incubation with purified liver carboxylesterase, homogenates of Caco-2 cells and scraped pig small intestinal mucosa.
Results. The use of bis(POM)-PMEA as a prodrug of PMEA resulted in a significant increase in transport of total PMEA [bis(POM)-PMEA, mono(POM)-PMEA and PMEA] across Caco-2 monolayers. While transepithelial transport of PMEA (500 M) was lower than 0.1% during a 3 hr incubation period, transport of total PMEA after addition of bis(POM)-PMEA (100 M) amounted to 8.8% over the same incubation period. Only 23% of the amount transported appeared as intact bis-ester at the basolateral side, while 33% of this amount was free PMEA and 44% was mono(POM)-PMEA, suggesting susceptibility of the prodrug to chemical and enzymatic degradation. Uptake studies revealed that only negligible amounts of bis(POM)-PMEA (< 0.2%) were present inside the cells. Very high intracellular concentrations of PMEA were found 1.2 mM, after a 3 hr incubation with 50 M bis(POM)-PMEA), which suggests that PMEA was trapped inside the cells probably due to its negative charge. This explains that efflux of PMEA was relatively slow (25% of the intracellular amount in 3 hr). Enzymatic degradation of the prodrug by carboxylesterase was confirmed by incubation of bis(POM)-PMEA with purified enzyme (Km = 87 M and Vmax = 9.5 M/min). Incubation of bis(POM)-PMEA (10 M) with cell homogenate of Caco-2 monolayers and pig small intestinal mucosa produced similar degradation profiles.
Conclusions. The use of the bis(POM)-prodrug significantly enhances the intestinal permeability of PMEA. Intracellular trapping of PMEA in the intestinal mucosa may result in slow release of PMEA to the circulation after oral administration of bis(POM)-PMEA. 相似文献
53.
Geza Remak MD Omar D. Hottenstein PhD Dr. Eugene D. Jacobson MD 《Digestive diseases and sciences》1994,39(8):1655-1664
We evaluated the effects of potential factors in autoregulatory escape from norepinephrine-induced vasoconstriction in rat anterior mesenteric artery. We determined mesenteric artery blood flow velocity with a pulsed Doppler, sonic flowmeter, and systemic arterial blood pressure with a transducer. A 4-min norepinephrine infusion (0.125–1.0 × 10–8 M/min) intravenously evoked a dose-dependent, initial vasoconstriction that was followed by rapid escape of blood flow toward or above the control value during sustained norepinephrine administration. Neonatal capsaicin treatment enhanced vasoconstrictor responses to norepinephrine but failed to affect escape parameters. Propranolol decreased norepinephrine-induced escape dose dependently. Adenosine deaminase attenuated escape, and the combination of this enzyme plus propranolol nearly abolished escape from norepinephrine-induced vasoconstriction. Methylene blue also diminished autoregulatory escape. These findings suggest that norepinephrine-induced autoregulatory escape involves simultaneous -adrenoceptor, purinergic, and endothelial mediation. Norepinephrine-evoked mesenteric vasoconstriction appears to involve predominantly 2-adrenoceptors and is modulated by peptidergic sensory nerves and adenosine.NIH grant number supporting these studies: USPHS # DK37050. 相似文献
54.
About 30% of patients who have a Roux-en-Y gastrojejunostomy after gastrectomy suffer from abdominal pain, nausea, vomiting
of food and bloating made worse by eating. This syndrome, called the Roux stasis syndrome, is caused, in part, by a motility
disorder of the Roux limb. Transection of the jejunum during the construction of the limb separates the limb from the natural
small intestinal pacemaker located in the duodenum. Ectopic pacemakers then appear in the limb and trigger retrograde contractions
in its proximal portion. These contractions slow transit through the limb and result in Roux stasis. Current nonsurgical treatment
of the syndrome includes the use of prokinetic agents and intestinal pacing, neither of which has demonstrated long-term benefits.
A near-total gastrectomy may speed upper gastrointestinal transit somewhat, but stasis in the Roux limb often persists. Our
current approach aims at preventing the syndrome by the use of an ‘uncut’ Roux limb, an operation which preserves myoneural
continuity between the duodenal pacemaker and the Roux limb and so prevents the appearance of ectopic pacemakers and stasis
in the limb. 相似文献
55.
Previous studies have shown that transplantation of fetal rat small bowel into the greater omentum of adult recipient animals can be successfully carried out. However, the surface area of the omentum limits the length of implantable fetal small bowel. Furthermore, clinical experience has shown that due to adhesions, the greater omentum is no longer suitable as an implantation site after multiple laparotomies, which often precede a short-bowel syndrome. We wanted to examine whether recipient mesentery is a further possible site of fetal gut implantation. Four weeks after transplantation of the fetal graft into the mesentery of adult rats, mature intestine was found in 80% of the animals. Macroscopically, the developed transplants looked like bowel duplications"; light-microscopic examinations documented their morphologic integrity. 相似文献
56.
《Seminars in Pediatric Surgery》2022,31(3):151181
Advancements in donor management, organ preservation and operative techniques, as well as immunosuppressive therapies, have provided children with intestinal failure and its complications a chance not only for enteral autonomy but also long-term survival through intestinal transplantation (ITx). First described in the 1960’s, experience has grown in managing these complex patients both pre- and post-transplant. The goals of this review are to provide a brief history of intestinal transplantation and intestinal rehabilitation in pediatric patients, followed by focused discussions of the indications for ITx, induction and maintenance immunosuppression therapies, common post-operative complications, and outcomes/quality of life post-transplant. 相似文献
57.
58.
H. Özbey C. Boneval Ü. Alkaç B. Bavbek G. Çakiroğlu T. Salman A. Çelik 《Pediatric surgery international》1996,11(8):547-549
It is known that polycythemia decreases the fluidity of the blood and impairs tissue perfusion due to red-cell sludging in the microcirculation. In this study, the effect of polycythemic hyperviscosity (PH) on bowel necrosis was evaluated in an experimental model of intestinal ischemia. Twenty-eight Wistar albino rats (90–170 g) were divided into two groups: group 1 was transfused to create hyperviscosity and then intestinal ischemia was produced (n = 16); in group 2 ischemia was produced without transfusion (n = 12). Intestinal ischemia was produced by clamping the superior mesenteric artery and the collateral arcades of the right colic artery for 30 min. Gross and histopathologic evaluations were performed by either immediate necropsy or relaparotomy 24 h later. Microscopic findings were graded from 0 to 3 according to the degree of ischemic changes. In group 1, 2 animals (12.5%) died before 24 h postoperatively; coagulation necrosis with grade 2 or 3 ischemic changes was observed in 10 animals (62.5%). In group 2 only a few hypertrophied Peyer's patches and capillary dilation were found, and all histopathologic changes were between grades 0 and 1. The difference between the histopathologic gradings of the two groups was significant (P < 0.001). It appears that in addition to reduced splanchnic blood flow, a secondary effect of PH is needed to induce ischemic coagulation necrosis. PH of the newborn must be considered a risk factor for necrotizing enterocolitis, so-called spontaneous intestinal perforations, and even intestinal atresia.Presented at the 1st European Congress of Pediatric Surgery, Graz/Austria, May 4–6, 1995 相似文献
59.
Purpose. Oral bioavailability for antisense oligonucleotides has recently been reported but the mechanistic details are not known. The proposed oral delivery of nucleic acids will, therefore, require an understanding of the membrane binding interactions, cell uptake and transport of oligonucleotides across the human gastro-intestinal epithelium. In this initial study, we report on the cell-surface interactions of oligonucleotides with human intestinal cells.
Methods. We have used the Caco-2 cell line as an in vitro model of the human intestinal epithelium to investigate the membrane binding interactions of 20-mer phosphodiester (PO) and phosphorothioate (PS) oligonucleotides.
Results. The cellular association of both an internally [3H]-labelled and a 5end [32P]-labelled PS oligonucleotide (3.0% at 0.4 µM extracellular concentration) was similar and was an order of magnitude greater than that of the 5end [32P]-labelled PO oligonucleotide (0.2%) after 15 minutes incubation in these intestinal cells. The cellular association of PS was highly saturable with association being reduced to 0.9% at 5 µM whereas that of PO was less susceptible to competition (0.2% at 5 µM, 0.1% at 200 µM). Differential temperature-dependence was demonstrated; PS interactions were temperature-independent whereas the cellular association of PO decreased by 75% from 37°C to 17°C. Cell association of oligonucleotides was length and pH-dependent. A decrease in pH from 7.2 to 5.0 resulted in a 2- to 3-fold increase in cell-association for both backbone types. This enhanced association was not due to changes in lipophilicity as the octanol:aqueous buffer distribution coefficients remained constant over this pH range. The ability of NaCl washes to remove surface-bound PS oligonucleotides in a concentration-dependent manner suggests their binding may involve ionic interactions at the cell surface. Cell-surface washing with the proteolytic enzyme, Pronase®, removed approximately 50% of the cell-associated oligonucleotide for both backbone types.
Conclusions. Binding to surface proteins seems a major pathway for binding and internalization for both oligonucleotide chemistries and appear consistent with receptor (binding protein)-mediated endocytosis. Whether this binding protein-mediated entry of oligonucleotides can result in efficient transepithelial transport, however, requires further study. 相似文献
60.