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ABSTRACTIntroductionDrug absorption is often altered and typically diminished in patients with short bowel syndrome (SBS). It is important to understand the patient’s gastrointestinal anatomy, the absorptive capacity of the remaining bowel, and the physicochemical and pharmacokinetic properties of the drug to optimize oral pharmacotherapy.Areas coveredThe primary focus was to provide an updated understanding of the absorption of various drugs in patients with short bowel syndrome. Forty-seven studies covering 13 different drug classes were included in the review and study details, patient characteristics, drug characteristics and pharmacokinetic findings were summarized for each drug class.Expert opinionImproving and simplifying drug treatment in patients with SBS have high priority, but the patients are multi diseased so knowledge regarding absorption of drugs as e.g. antithrombotic agents, immunosuppressants is urgently needed. Therefore, it is crucial to advance our understanding of the fundamental factors involved in drug absorption, spanning from drug design to pathophysiology. With the growing knowledge in drug design and gastrointestinal pathophysiology, we anticipate the development of computer models that can accurately predict optimal absorption in the future.

Bile acid diarrhoea is a common but overlooked cause of chronic watery diarrhoea. Plasma 7α-hydroxy-4-cholesten-3-one (C4) is an alternative to the gold standard tauroselcholic [75Se] acid (SeHCAT) test. Low-certainty evidence supports sequestrant treatment, including colesevelam. We aimed to determine the efficacy and safety of colesevelam in bile acid diarrhoea.

The epidermal growth factor (EGF) is a growth factor with effects on many cell types and tissue. Morphometric and passive biomechanical properties were studied in isolated segments of the esophagus in 22 EGF-treated rats and 12 control rats. The rats were divided into groups with EGF treatment for 2, 4, 7, and 14 days (n=6 for each group except n=4 for the 14 days EGF-treatment group) or saline treatment (n=3 for each group). The mechanical test was performed as a distension experiment in vitrowhere the whole esophagus was stretched to its in situlength and distended with pressures up to 10 cm H2O using a ramp distension protocol. The pressure and outer diameter were recorded. Circumferential stress (force per area) and strain (deformation) were computed from the diameter and pressure data using the zero-stress state as reference. The zero-stress state was obtained by cutting esophageal rings radially. This caused the rings to open up into a sector. EGF induced pronounced morphometric changes, e.g., the wall thickness, wall cross-sectional area, and inner and outer circumferential lengths significantly increased during the EGF treatment. Histological analysis showed mucosa and submucosa growth during EGF treatment. The opening angle and residual strains increased with the highest value in the 14 days EGF-treated group (P< 0.05). The change in opening angle depended largely on the change in mucosa thickness. Furthermore, the circumferential stiffness of the esophagus reached a maximum after 7 days EGF treatment (P< 0.01). © 2003 Biomedical Engineering Society. PAC2003: 8719Rr, 8717Ee

Systemic treatment with epidermal growth factor (EGF) induce growth of the large intestine. The aim of this study was to investigate the morphological properties early in the course of EGF-induced large intestinal growth. The effects of systemic EGF treatment on the morphological properties at the zero-stress state along the large intestine were investigated. EGF-treated rats and control rats were allocated into group with EGF treatment for 2, 4, 7, and 14 days (N= 6 for each EGF treatment group except N= 4 for the 14-day group). The controls had saline injected (N= 3 for each group). The excised large intestine was subdivided into four segments: the ascending colon, transverse colon, descending colon, and rectum. The length and weight of each segment was measured. The zero-stress state was obtained by cutting rings of the large intestine radially, and the opening angle was measued on video images. The thickness and cross-sectional area of the mucosa and muscle layers, and the inner and outer circumference were measured. The total colon length did not increase, whereas the weight of the large intestine, muscosal thickness and mass, and inner and outer circumference increased significantly (P< 0.05). The increase was most prominent in the proximal colon after 7 days of EGF treatment. Later no further morphological changes were observed, except for a decrease in mucosal thickness in most segments and in mucosal cross-sectional area in the descending colon. In the controls and during the first week of EGF treatment, the opening angle was approximately 100 degrees. After 14 days the opening angle increased significantly in the ascending and transverse colon to approximately 172 and 135 degrees (P< 0.05). In conclusion, this study demonstrates that systemic EGF treatment caused remodeling of the morphology of the zero-stress state in the large intestine in a time-dependent manner. The growth was most pronounced in the ascending and transverse colon and involved mainly the mucosal layer.

We have previously reported that systemic epidermal growth factor (EGF) treatment in rats reduces the amount of adipose tissue despite an unaltered food intake. The mitochondrial uncoupling proteins (UCP2 and UCP3) are thought to uncouple the respiratory chain and thus to increase energy expenditure. In order to find out whether the UCP system was involved in the EGF-induced weight loss, the effects of EGF on UCP2 and UCP3 in adipose tissue and skeletal muscle were investigated in the present study. Eight rats were treated with placebo or EGF (150 μg/kg/day) for seven days via mini-osmotic pumps. The EGF-treated rats gained significantly less body weight during the study period than the placebo-treated animals and had significantly less adipose tissue despite a similar food intake. The placebo group and the EGF group had similar UCP2 mRNA expression (in both adipose tissue and skeletal muscle), whereas the EGF-treated group compared to the placebo group had significantly higher UCP3 mRNA expression in both skeletal muscle (3.76 ± 0.90 vs 8.41 ± 0.87, P < 0.05) and in adipose tissue (6.38 ± 0.71 vs 12.48 ± 1.79, P < 0.05). In vitro studies with adipose tissue fragments indicated that the EGF effect probably is mediated indirectly as incubations with EGF (10 μM) were unable to affect adipose tissue UCP expression, whereas incubations with bromopalmitate stimulated both UCP2 and UCP3 mRNA expression twofold. Thus, EGF treatment in vivo was found to enhance UCP3 mRNA expression in both adipose tissue and skeletal muscle, which may indicate that the EGF effect on body composition might involve up-regulation of UCP3 in skeletal muscle and adipose tissue.

The aim was to investigate if extent and time course of acute radiation damage to epidermis and intestine could be moderated by epidermal growth factor (EGF). Twelve-to-sixteen weeks old female CDFl mice were treated either by single dose local irradiation to the right hind leg or total body irradiation (TBI). The endpoints were skin score and lethality, respectively. Human recombinant EGF was given s.c. or i.p. at a dose of 5-10 μg/day either before or after irradiation. Body weight was significantly higher for EGF treated animals compared with controls treated with saline. However, EGF did not reduce the median skin score following local irradiation and did not increase LD50 (days 1 -6) following TBI. Further studies using more specific assays are necessary to determine if radiation damage to less toxic levels can be ameliorated by EGF.

Epidermal growth factor (EGF) is an important factor for maintaining the esophageal functional integrity. Goettingen minipigs were treated with either placebo or subcutaneous EGF (30 μg/kg/day) for four weeks. Wistar rats were treated with either placebo or subcutaneous EGF (150 μg/kg/day) for four weeks. At sacrifice, esophageal samples were obtained for histology, immunochemistry, and lectin characterization. In pigs, the thickness of the esophageal epithelium was almost doubled in the EGF-treated animals. Characterization with lectins revealed a normal pattern of differentiation. Subcutaneously administered EGF was visualized on cells located basally in the esophageal epithelium. In rats EGF-treatment increased the esophageal volume of the epithelium, the lamina propria of the mucosa, and the subnucosa. In conclusion, systemic EGF challenge induces growth of the esophageal epithelium with an unaltered pattern of differentiation. This supports previous studies demonstrating a beneficial effects of systemic EGF-treatment on sclerotherapyp-induced esophageal damage.

The dose- and time-dependent effects ofendoscopic sclerotherapy on luminal cross-sectional areaand wall distensibility were studied in pigs at 5 and 12cm proximal to the gastroesophageal junction by means of impedance planimetry. Sixteen healthyanimals underwent two sessions of endoscopicsclerotherapy two weeks apart with injections of either5 or 10 ml of 1% Polidocanol in the distal 7 cm of the esophagus each time. The animals wereinvestigated before sclerotherapy, two weeks after eachsession, and finally six weeks after the last session.Six healthy animals were studied as controls. Endoscopic sclerotherapy caused luminal narrowing in thesclerosed zone followed by normalization six weeks afterthe last treatment (P < 0.05 in both groups). Walldistensibility decreased in the sclerosed zone after treatment with 10 ml sclerosant (P <0.05) followed by partial normalization, while no effectwas found after 5 ml sclerosant (P > 0.2).Progressive dilations were observed in the proximalesophagus in both groups and were most pronounced in the10 ml group (P < 0.05). Wall distensibility did notchange proximal to the site of sclerotherapy in eithergroup (P > 0.1).

Abstract: Systemic treatment with epidermal growth factor (EGF) induces growth of all wall layers of the urinary tract in pigs and rats. In this study, we describe the time-dependent growth of the ureter and bladder. Forty-eight female Wistar rats were allocated into five groups receiving EGF treatment (150 μg/kg per day) for 0 (controls), 1, 2, 3 or 4 weeks before being killed. The 24-h urine excretion was increased only in the group treated for 4 weeks with EGF. Measured by a simple infusion device, EGF significantly increased the bladder capacity by more than 50% in all the EGF-treated groups. The volumes of the wall layers of the ureter and bladder were quantified using stereology. After 4 weeks of treatment with EGF, the total volumes of the ureter and bladder were 1.8- and 2.1-fold larger than in the control group (the urothelium was 2.8- and 3.5-fold larger and the muscular coat 1.6- and 1.6-fold larger in the ureter and bladder, respectively). In conclusion, the EGF-induced growth of the urinary tract is characterized by increased bladder capacity, and increased volume of all wall layers – most prominently the urothelium.

Abstract: Systemic treatment with epidermal growth factor (EGF) induces growth of all wall layers of the urinary tract in pigs and rats. We have previously described that the EGF stimulated urothelium in Goettingen minipigs accumulates glycoproteins. The aim of the present study was to examine and partly characterize glycoproteins in the urothelium and in the urine from rats treated with EGF. Seventy-two female Wistar rats were allocated into five groups receiving EGF treatment (150 μg/kg per day) for 0 (controls), 1, 2, 3 and 4 weeks before being killed. Glycoconjugates were characterized by means of lectins on tissue sections, and using Western blotting, in bladder extracts and in urine. The characterization mostly focused on the expression of the mucin-type core structures T and Tn using the lectins peanut agglutinin (PNA) and Vicia villosa (VVA) and specific monoclonal antibodies. The thickened EGF-stimulated urothelium retained the normal differentiation pattern as judged from the appearance on electron microscopy and from the expression of carbohydrate structures. Within the urothelium and in the urine there was increased expression of mucin-type glycoproteins suggesting increased urothelial production and excretion of mucin-type glycoproteins. In conclusion, the EGF stimulated hyperplastic urothelium most probably excretes increased amounts of mucin-type glycoproteins to the urine but it retains the normal pattern of differentiation as assessed by lectin characterization.

AbstractWe examined whether the reduction in fat mass induced by EGF treatment in mature animals was via activation of hormone-sensitive lipase (HSL) and thereby the induction of lipolysis, or through inhibition of lipoprotein lipase activity thus reducing fat uptake in adipose tissue. Sixteen male rats were treated with placebo or EGF 150 µg/kg/day for 7 days via mini-osmotic pumps. The results demonstrate that systemic EGF treatment reduces the amount of adipose tissue, most likely due to increased lipolysis as HSL activity as well as HSL mRNA were increased. The circulating levels of free fatty acids were slightly increased and leptin levels reflected the decrease in adipose tissue mass.

Human epidermal growth factor (EGF), a small polypeptide (6 kDa) with mitogenic properties, has been implicated in the protection of gastrointestinal mucosal integrity. The efficacy of EGF in the prevention and healing of sclerotherapy-induced esophageal lesions was investigated in 24 minipigs with surgically induced portal hypertension. In addition, the effect of EGF on intragastric acidity and pharmacokinetics was investigated as possible means to explain its protective mechanism of action. The animals underwent three weekly sessions of sclerotherapy with polidocanol 2% and were concomitantly and for an additional three weeks treated with either placebo or EGF administered paravenously in the esophagus and/or subcutaneously. The subcutaneous treatment with EGF significantly (P<0.05) reduced esophageal stricture and scar formations associated with sclerotherapy. Gastric pH values were significantly (P<0.01) elevated only in animals receiving subcutaneous injections of EGF. Furthermore, the subcutaneous administration of EGF was associated with unexpected prolonged plasma concentration of the peptide. These results suggest a possible clinical value of EGF as an adjunctive treatment with the sclerotherapy.

Chronic treatment with epidermal growth factor (EGF) stimulates growth of all wall layers of the urinary tract in pigs and rats. Herein, we investigated the acute effects of EGF on detrusor smooth muscle activity. For in vivoexamination, awake rats received EGF (75 μg/kg) intravenously and detrusor smooth muscle activity was monitored cystometrically. The EGF bolus caused no alteration in diuresis but a doubling of the micturition frequency, a 25% increase in micturition pressures, and increased irregular baseline contractile activity. For in vitroexamination detrusor smooth muscle strips were exposed to EGF (1 μg/ml). EGF caused contraction and increase in the spontaneous activity. In conclusion, EGF increases rat detrusor smooth muscle contractile activity in vivoand in vitro.The finding suggests that a direct effect of EGF on bladder smooth muscles is part of the genesis to the growth of the detrusor smooth muscle observed after chronic EGF treatment.

To investigate the effects of insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) on the rat prostate. In addition, we investigated the effect of ornithine decarboxylase (ODC) inhibition with alpha-diflouromethylornitine (DFMO) on the expected growth of the prostate.

1. From two independent experimental studies conducted in 48 minipigs with oesophageal sclerotherapy and concomitant treatment with epidermal growth factor, blood samples together with bone marrow biopsies were analysed for safety data. 2. Four to five weeks of systemic treatment with epidermal growth factor induced a decline in blood haemoglobin concentration in a time- and dose-dependent and reversible manner but without an effect on leucocyte or platelet counts. 3. The bone marrow expressed decreased amounts of haematopoietic tissue and reduced numbers of erythropoietic cells. 4. Four to five weeks of systemic treatment with epidermal growth factor induced reversible increases in serum concentrations of creatinine and urea, most likely reflecting renal impairment. 5. Groups in which creatinine and urea were not increased also had reduced blood haemoglobin concentrations. 6. These findings suggest that epidermal growth factor selectively impaired the erythropoiesis and stress the importance of risk-benefit analysis concerning the potential therapeutic applications of epidermal growth factor.