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  • 1.
    Al-Saffar, Anas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Meijer, Carl Hampus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gannavarapu, Venkata Ram
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hall, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Li, Yichen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Diaz Tartera, Hetzel O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Lördal, Mikael
    Department of Medicine, Division of Gastroenterology and Hepatology, Danderyds Sjukhus, Danderyd, Sweden.
    Ljung, Tryggve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Abbvie, Solna, Sweden.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Parallel Changes in Harvey-Bradshaw Index, TNFα, and Intestinal Fatty Acid Binding Protein  in Response to Infliximab in Crohn’s Disease2017In: Gastroenterology Research and Practice, ISSN 1687-6121, E-ISSN 1687-630X, p. 1-8, article id 1745918Article in journal (Refereed)
    Abstract [en]

    Intestinal fatty acid binding protein (I-FABP) indicates barrier integrity. Aims: determine if I-FABP is elevated in active Crohn's disease (CD) and if I-FABP parallels anti-TNF alpha antibody (infliximab) induced lowering of TNF alpha and Harvey-Bradshaw Index (HBI) as potential indicator of mucosal healing. I-FABP distribution along human gut was determined. Serum from 10 CD patients collected during first three consecutive infliximab treatments with matched pretreatment and follow-up samples one week after each treatment and corresponding HBI data were analyzed. I-FABP reference interval was established from 31 healthy subjects with normal gut permeability. I-FABP and TNF alpha were measured by ELISA; CRP was measured by nephelometry. Healthy tissue was used for I-FABP immunohistochemistry. Pretreatment CD patient TNF alpha was 1.6-fold higher than in-house reference interval, while I-FABP was 2.5-fold higher, which lowered at follow-ups. Combining all 30 infusion/follow-up pairs also revealed changes in I-FABP. HBI followed this pattern; CRP declined gradually. I-FABP was expressed in epithelium of stomach, jejunum, ileum, and colon, with the highest expression in jejunum and ileum. I-FABP is elevated in active CD with a magnitude comparable to TNF alpha. Parallel infliximab effects on TNF alpha, HBI, and I-FABP were found. I-FABP may be useful as an intestine selective prognostic marker in CD.

  • 2.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Frykholm, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Introducing the 6-4-0 fasting regimen and the incidence of prolonged preoperative fasting in children2018In: Pediatric Anaesthesia, ISSN 1155-5645, E-ISSN 1460-9592, Vol. 28, no 1, p. 46-52Article in journal (Refereed)
    Abstract [en]

    Background

    Children often starve for longer than recommended by current preoperative fasting guidelines.

    Aims

    We studied the effects of implementing a more lenient fasting regimen on the duration of clear fluid fasting, as well as the incidence of extended fasting in children.

    Methods

    Preoperative duration of clear fluid fasting was recorded for patients scheduled for procedures in a unit applying the standard 6-4-2 fasting regimen. This group was compared with a cohort in the same unit 1year after transitioning to a 6-4-0 fasting regimen. The latter includes no limitations on clear fluid intake until the child is called to theater. A third cohort from a unit in which the 6-4-0 fasting regimen has been implemented for over a decade was also studied for comparison.

    Results

    Patients fasting according to the 6-4-2 fasting regimen (n=66) had a median fasting time for clear fluids of 4.0h and a 33.3% incidence of fasting more than 6h. After transitioning to the 6-4-0 fasting regimen (n=64), median duration of fasting for clear fluids decreased to 1.0h, and the incidence of fasting more than 6h decreased to 6.3%. In the second unit (n=73), median fasting time was 2.2h and the proportion of patients fasting more than 6h was 21.9%.

    Conclusion

    The introduction and implementation of the 6-4-0 fasting regimen reduces median fluid fasting duration and the number of children subjected to extended fasting.

  • 3. Benno, Peter
    et al.
    Bark, Johan
    Collinder, Eje
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Midtvedt, Tore
    Norin, Elisabeth
    Major alterations in metabolic activity of intestinal microflora in Crohn's disease2012In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 47, no 2, p. 251-252Article in journal (Refereed)
  • 4. Bergquist, Henrik
    et al.
    Agreus, Lars
    Tillander, Lotta
    Johnsson, Folke
    Sorngard, Helene
    Sjostedt, Svante
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Structured Diagnostic and Treatment Approach Versus the Usual Primary Care Approach in Patients With Gastroesophageal Reflux Disease: A Cluster-randomized Multicenter Study2013In: Journal of Clinical Gastroenterology, ISSN 0192-0790, E-ISSN 1539-2031, Vol. 47, no 7, p. E65-E73Article in journal (Refereed)
    Abstract [en]

    Goals: To compare the clinical outcomes of gastroesophageal reflux disease (GERD) patients treated with an implemented new structured pathway (NSP) or according to existing local clinical practices [old clinical pathway (OCP)]. Background: GERD is a major challenge at the primary care level. Study: Primary care centers (n=24) were cluster randomized to handle patients suffering from symptoms suggestive of GERD according to the NSP (n=97) or the OCP (n=134). In the NSP, the GerdQ questionnaire score was used both for diagnosis and management including treatment. We used validated questionnaires to evaluate disease symptoms, quality of life, and costs at inclusion and at follow-up 2 to 6 months later. Results: On the basis of the Reflux Disease Questionnaire, 56% of the patients treated with the NSP reported total symptom relief at the follow-up compared with 33% in the OCP group (P=0.0013). The reflux symptoms after treatment affected daily activities to a lesser extent in the patients in the NSP group compared with the OCP group (10% vs. 13%, respectively, P=0.01). The utility score of the EuroQoL-5D questionnaire improved more in the NSP group than in the OCP group (0.05 vs. 0.02, respectively, P<0.001). The patients in the NSP group had an approximately 50% lower average total cost for GERD-related health care resources compared with the OCP group [301 Swedish Kronor (SEK) vs. 588 SEK, respectively, NS]. Conclusions: The management of GERD patients in primary care centers using a structured clinical pathway and the results of the GerdQ improves the clinical outcome compared with prevailing local routines (NCT00842387).

  • 5. Bryant, Eleanor J.
    et al.
    King, Neil A.
    Falken, Ylva
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hoist, Jens Juul
    Blundell, John E.
    Naslund, Erik
    Relationships among tonic and episodic aspects of motivation to eat, gut peptides, and weight before and after bariatric surgery2013In: Surgery for Obesity and Related Diseases, ISSN 1550-7289, E-ISSN 1878-7533, Vol. 9, no 5, p. 802-808Article in journal (Refereed)
    Abstract [en]

    Background: The interaction between motivation to eat, eating behavior traits, and gut peptides after Roux-en-Y gastric bypass (RYGB) surgery is not fully understood. Methods: Appetite and hormone responses to a fixed liquid preload were assessed in 12 obese (body mass index 45 +/- 1.9 kg/m(2)) participants immediately before and 3 days, 2 months, and 1 year after RYGB surgery. Subjective appetite and plasma levels of ghrelin, leptin, insulin, and glucagon-like peptide-1 (GLP-1) were measured for a 3-hour postprandial period. Eating behavior traits were also measured using the Three Factor Eating Questionnaire 18 (TFEQR18). Results: There was a decrease in TFEQR18 emotional eating (EE) and uncontrolled eating (UE) from presurgery to 1 year postsurgery but no significant change in cognitive restraint (CR). These changes occurred independently of change in weight. In addition, there was a reduction in subjective appetite ratings and alterations in appetite peptides favoring an anorectic response. Presurgery EE was significantly related to fasting and area under the curve (AUC) ghrelin; UE was associated with AUC desire to eat, and there was a significant association between fasting desire to eat and ghrelin (fasting and AUC). One year postsurgery, UE was positively related to fasting insulin, and CR was negatively associated with GLP-1. UE and subjective hunger were positively correlated, while the relationship between desire to eat and ghrelin remained. onclusion: The relationships among subjective appetite ratings, eating behavior traits, and appetite peptides in obese patients both before and at 1 year after RYGB surgery may contribute to the reduction in a propensity to overeat (as measured by TFEQR18 factors) and weight loss. 

  • 6. Bucinskaite, V
    et al.
    Tolessa, T
    Pedersen, J
    Rydqvist, B
    Zerihun, L
    Holst, J J
    Hellström, Per M.
    Receptor-mediated activation of gastric vagal afferents by glucagon-like peptide-1 in the rat2009In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 21, no 9, p. 978-e78Article in journal (Refereed)
    Abstract [en]

    The vagus nerve plays a role in mediating effects of the two glucagon-like peptides GLP-1 and GLP-2 on gastrointestinal growth, functions and eating behaviour. To obtain electrophysiological and molecular evidence for the contribution of afferent pathways in chemoreception from the gastrointestinal tract, afferent mass activity in the ventral gastric branch of the vagus nerve and gene expression of GLP-1 receptors and GLP-2 receptors in the nodose ganglion were examined in Sprague–Dawley rats. Intravenous administration of GLP-1 (30–1000 pmol kg−1), reaching high physiological plasma concentrations, increased vagal afferent mass activity peaking (13–52% above basal level, < 0.05) 3–5 min after injection. Repeated administration of GLP-1 (1000 pmol kg−1; five times, 15 min intervals) elicited similar responses. Pretreatment with GLP-1 receptor antagonist exendin(9-39)amide (500 pmol kg−1) abolished the GLP-1 response to doses 30–300 pmol kg−1 but had no effect on the vagal response to gastric distension. For comparison, GLP-2 (1000 pmol kg−1) had no effect on vagal afferent activity. Vagal chemoreception of GLP-1 is supported by expression of the GLP-1 receptor gene in the nodose ganglion. However, the GLP-2 receptor was also expressed. To conclude, our results show that peripherally administered GLP-1, differently from GLP-2, activates vagal afferents, with no evidence of desensitisation. The GLP-1 effect was blocked by exendin(9-39)amide, suggesting that GLP-1 receptors on vagal afferent nerves mediate sensory input from the gastrointestinal tract or pancreas; either directly or indirectly via the release of another mediator. GLP-2 receptors appear not be functionally expressed on vagal afferents.

  • 7. Costabel, Ulrich
    et al.
    Bendstrup, Elisabeth
    Cottin, Vincent
    Dewint, Pieter
    Egan, Jim J. J.
    Ferguson, James
    Groves, Richard
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Kreuter, Michael
    Maher, Toby M.
    Molina-Molina, Maria
    Nordlind, Klas
    Sarafidis, Alexandre
    Vancheri, Carlo
    Pirfenidone in Idiopathic Pulmonary Fibrosis: Expert Panel Discussion on the Management of Drug-Related Adverse Events2014In: Advances in Therapy, ISSN 0741-238X, E-ISSN 1865-8652, Vol. 31, no 4, p. 375-391Article, review/survey (Refereed)
    Abstract [en]

    Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.

  • 8.
    Diaz Tartera, Hetzel O.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Al-Saffar, Anas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Halim, Mohammed Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Lindberg, G
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Gastroenterol & Hepatol Unit, Huddinge, Sweden.
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Validation of SmartPill® wireless motility capsule for gastrointestinaltransit time: Intra-subject variability, software accuracy and comparison with video capsule endoscopy2017In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 29, no 10, article id e13107Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There is interest in ultimately combining endoscopy and motility assessments. Gastric emptying (GET), small bowel (SBTT), colon (CTT) and whole gut transit (WGTT) times are conveniently obtained by SmartPill® wireless motility capsule (WMC) that records luminal pH, temperature and pressure. Reproducibility within same subjects and accuracy of software derived times (MotiliGI® ) were investigated for diagnostic application. GET and SBTT were separately measured using video capsule endoscopy (VCE). The aim of this investigation was to assess same subject reproducibility of WMC, accuracy of software derived transit times and relate to Pillcam® SB (small bowel) VCE motility data.

    METHODS: Seventy three healthy adults ingested a 260 kcal mixed meal followed by WMC tests. Food intake was permitted after 6 hours. Regional transit data was obtained for GET, SBTT and CTT, the sum yielding WGTT. Nineteen subjects repeated WMC tests 2 or 4 weeks later; a separate 70 underwent VCE while fasted.

    KEY RESULTS: Visually derived data from WMC yielded GET 3.46±0.27, SBTT 5.15±0.21, CTT 20.76±1.19 and WGTT 29.53±1.28 hours (mean±SEM). Pearson's correlation coefficients (r) against software derived results were: GET 0.78 (P<.0001), SBTT 0.28 (P<.05), CTT 0.96 (P<.0001), WGTT 0.99 (P<.0001). VCE yielded lower GET (0.71±0.08 hours) and SBTT (4.15±0.13 hours).

    CONCLUSIONS AND INFERENCES: GET, SBTT, CTT and WGTT obtained by WMC are commensurate with literature values, including by other methods. Visually and software derived transit times have strongest correlations for CTT and WGTT. WMC yields longer GET and SBTT than VCE, perhaps due to meal related effects on motility.

  • 9. Edholm, T
    et al.
    Cejvan, Kenan
    Abdel-Halim, S M
    Efendic, S
    Schmidt, P T
    Hellström, Per M.
    The incretin hormones GIP and GLP-1 in diabetic rats: effects on insulin secretion and small bowel motility2009In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 21, no 3, p. 313-321Article in journal (Refereed)
    Abstract [en]

    Incretin hormones often display inhibitory actions on gut motility. The aim of this study was to investigate if altered responsiveness to glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) as regards insulin release and small bowel motility could bring further clarity to the pathophysiology of diabetes in the Goto-Kakizaki (GK) rat. The isolated perfused pancreas was studied in male GK and Wistar rats (controls) under euglycemic and hyperglycemic conditions. Glucose-dependent insulinotropic peptide (10 nmol L−1) or GLP-1 (10 nmol L−1) were added to the medium and perfusate was collected and analysed for insulin. Moreover, GK and Wistar rats were supplied with bipolar electrodes in the small bowel and myoelectric activity was recorded during intravenous administration of GIP (1–400 pmol kg−1 min−1) or GLP-1 (0.1–20 pmol kg−1 min−1). Finally, tissue was collected from GK and Wistar rats for RNA extraction. Under euglycemia, GIP and GLP-1 stimulated the initial insulin response by 10-fold in GK rats (P < 0.05). At later hyperglycemia, the insulin response to GIP and GLP-1 was blunted to about one-third compared with controls (P < 0.05). In the bowel GLP-1 was about 2.6–16.7 times more potent than GIP in abolishing the migrating myoelectric complex in the GK and control rats. Polymerase chain reaction (PCR) showed GIP and GLP-1 receptor gene expression in pancreatic islets and in small bowel. The initially high, but later low insulin responsiveness to stimulation with GIP and GLP-1 along with inhibition of small bowel motility in the GK rat indicates a preserved incretin response on motility in diabetes type 2.

  • 10. Edholm, T.
    et al.
    Degerblad, M.
    Grybäck, P.
    Hilsted, L.
    Holst, J. J.
    Jacobsson, H.
    Efendic, S.
    Schmidt, P. T.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis2010In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 22, no 11, p. 1191-e315Article in journal (Refereed)
    Abstract [en]

    Background 

    Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are major incretins with important effects on glucoregulatory functions. The aim of this study was to investigate effects of GIP and GLP-1 on gastric emptying and appetite after a mixed meal, and effects on insulin secretion and glucose disposal in humans.

    Methods 

    Randomized crossover single-blind study in 17 healthy volunteers receiving GIP (2 or 5 pmol kg−1 min−1, n = 8), GLP-1 (0.75 pmol kg−1 min−1, n = 9) or NaCl for 180 min with a radionuclide-labeled omelette and fruit punch (370 kcal). Outcome measures were gastric emptying rate, insulinogenic index, hunger, satiety, desire to eat, and prospective food consumption. Blood was analyzed for GIP, GLP-1, glucagon, C-peptide, peptide YY (PYY) and ghrelin.

    Key Results 

    Glucose-dependent insulinotropic polypeptide 2 and 5 pmol kg−1 min−1 decreased gastric half-emptying time from 128.5 ± 34.0 min in controls to 93.3 ± 6.3 and 85.2 ± 11.0 min (P < 0.05). Glucose-dependent insulinotropic polypeptide 5 pmol kg−1 min−1 decreased postprandial glucose (P < 0.001) and insulin (P < 0.05) with increased insulinogenic index. Glucose-dependent insulinotropic polypeptide had no effects on hunger, desire to eat, satiety or prospective consumption. Glucagon-like peptide-1 0.75 pmol kg−1 min−1 increased half-emptying time from 76.6 ± 7.6 min to 329.4 ± 71.6 (P < 0.01). Glucagon-like peptide-1 decreased plasma glucose and insulin (both P < 0.05–0.001), and increased insulinogenic index markedly. Hunger, desire to eat and prospective consumption were decreased (P < 0.05), and satiety borderline increased (P < 0.06).

    Conclusion & Inferences 

    The incretin effect of GIP and GLP-1 differs as GLP-1 exerts a strong glucoregulatory incretin through inhibition of gastric emptying, which GIP does not. Thus, GLP-1 as incretin mimetic may offer unique benefits in terms of weight loss in treatment of type 2 diabetes.

  • 11. Ehrsson, Ylva Tiblom
    et al.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brismar, Kerstin
    Sharp, Lena
    Langius-Eklöf, Ann
    Laurell, Göran
    Explorative study on the predictive value of systematic inflammatory and metabolic markers on weight loss in head and neck cancer patients undergoing radiotherapy2010In: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 18, no 11, p. 1385-1391Article in journal (Refereed)
    Abstract [en]

    Purpose

    This study aimed to explore the predictive value of systematic inflammatory and metabolic markers in head and neck (H&N) cancer patients during radiotherapy (RT).

    Methods

    Twenty-seven patients were evaluated. The protocol included serial blood tests [highly sensitive C-reactive protein (hsCRP), albumin, insulin-like growth factor 1 (IGF-1), IGF binding protein 1 (IGFBP-1) and ghrelin], measurements of body weight and assessment of oral mucositis.

    Results

    The mean nadir of weight loss was observed at the end of RT. At the time of diagnosis, mean hsCRP was 5.2 +/- 1.0 mg/L. HsCRP significantly increased during RT and decreased during the post-RT period. Mean maximum hsCRP was 35.8 +/- 8.5 mg/L, with seven patients reaching >40 mg/L. A numerical decrease of albumin (by 18.2%) and only small changes in IGF-1, IGFBP-1 and ghrelin levels were observed. None of the metabolic parameters was significantly associated with weight loss.

    Conclusions

    HsCRP increased in response to RT for H&N cancer as a sign of irradiation-induced inflammation. Weight loss was not preceded by changes of the metabolic parameters, indicating that assessment of the blood markers used in this study is of little value. Regular body weight measurement and assessment of oral mucositis are feasible, cheap and important procedures to control the metabolic homeostasis during RT.

  • 12. Ejskjaer, N.
    et al.
    Dimcevski, G.
    Wo, J.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gormsen, L. C.
    Sarosiek, I.
    Softeland, E.
    Nowak, T.
    Pezzullo, J. C.
    Shaughnessy, L.
    Kosutic, G.
    McCallum, R.
    Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study2010In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 22, no 10, p. 1069-1077Article in journal (Refereed)
    Abstract [en]

    Background 

    Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP-101, is in clinical development for treatment of gastroparesis. This double-blind, randomized, placebo-controlled study evaluated the safety and efficacy of multiple TZP-101 doses in patients with moderate to severe symptomatic diabetic gastroparesis.

    Methods 

    Patients were admitted to the hospital and adaptively randomized to receive a single 30-min intravenous infusion of 20, 40, 80, 160, 320, or 600 μg kg−1 TZP-101, (n = 57) or placebo, (n = 19) for four consecutive days. Symptoms were evaluated daily with the patient-rated Gastroparesis Cardinal Symptom Index (GCSI) and Gastroparesis Symptom Assessment (GSA). Clinicians rated gastroparesis symptoms on treatment day 4.

    Key Results 

    The 80 μg kg−1 dose was identified as the most effective dose. On day 4, there was statistically significant improvement compared with placebo in the severity of GCSI Loss of Appetite and Vomiting scores for that dose group (P = 0.034 and P = 0.006). In addition, at the 80 μg kg−1 dose, the proportion of patients with at least 50% improvement in vomiting score was significantly different (P = 0.019) compared with placebo. Meal-related GSA scores for Postprandial fullness were significantly improved in the 80 μg kg−1 TZP-101 group compared with placebo (P = 0.012). Clinicians rated the 80 μg kg−1 group better improved than placebo for overall symptom assessment (P = 0.047). Safety profiles were similar in the placebo and TZP-101 groups and all doses were well-tolerated.

  • 13. Ejskjaer, N
    et al.
    Vestergaard, E T
    Hellström, Per M.
    Gormsen, L C
    Madsbad, S
    Madsen, J L
    Jensen, T A
    Pezzullo, J C
    Christiansen, J S
    Shaughnessy, L
    Kosutic, G
    Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis2009In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 29, no 11, p. 1179-1187Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis.

    AIM:

    To assess safety and effects of TZP-101 in diabetes patients with symptomatic gastroparesis.

    METHODS:

    Adults with type 1 or type 2 diabetes mellitus received placebo and TZP-101 (80, 160, 320 or 600 microg/kg) infusions in a cross-over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic-euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses.

    RESULTS:

    Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate-to-severe gastroparesis symptoms and > or =29% retention 4 h after a radiolabelled solid meal were enrolled. TZP-101 produced significant reductions in solid meal half-emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP-101 infusion were not statistically significant. Most adverse events were mild and self-limiting and there were no identifiable differences in numbers or types of adverse events between TZP-101 and placebo.

    CONCLUSIONS:

    This proof-of-concept study demonstrates that the ghrelin agonist TZP-101 is well-tolerated in diabetes patients with moderate-to-severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.

  • 14. Ejskjaer, N.
    et al.
    Wo, J.
    Esfandyari, T.
    Jamal, M.
    Dimcevski, G.
    Tarnow, L.
    Malik, R.
    Hellstrom, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Mondou, E.
    Quinn, J.
    Rousseau, F.
    Richard, M.
    Gastric emptying, glycaemia, and upper GI symptoms are independent factors in diabetic gastroparesis2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, p. S493-S493Article in journal (Other academic)
  • 15. Ejskjaer, N.
    et al.
    Wo, J. M.
    Esfandyari, T.
    Mazen Jamal, M.
    Dimcevski, G.
    Tarnow, L.
    Malik, R. A.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Mondou, E.
    Quinn, J.
    Rousseau, F.
    Mccallum, R. W.
    A phase 2a, randomized, double-blind 28-day study of TZP-102 a ghrelin receptor agonist for diabetic gastroparesis2013In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 25, no 2, p. e140-e150Article in journal (Refereed)
    Abstract [en]

    Background Gastroparesis causes significant morbidity and treatment options are limited. TZP-102 a novel, macrocyclic, selective, oral ghrelin receptor agonist, was evaluated in a randomized, double-blind, placebo-controlled trial in patients with diabetic gastroparesis. Methods A total of 92 outpatients were randomized to once-daily administrations of 10-mg (n=22), 20-mg (n=21), 40-mg (n=23) TZP-102 or placebo (n=26). The primary endpoint was the change from baseline in gastric half-emptying time (T1/2) utilizing 13C-breath test methodology and secondary endpoints included symptom improvement using patient-reported gastroparesis symptom scores (PAGI-SYM questionnaire) and patient and physician overall treatment evaluations (OTE). Key Results Gastric T1/2 changes were not statistically significant between TZP-102 and placebo after 28days of treatment at any dose. Clinical improvements (-1.0 to -1.4 point mean decrease in symptom severity) occurred in the Gastroparesis Cardinal Symptom Index (GCSI) component of the PAGI-SYM, which was significant vs placebo for all TZP-102 doses combined. Improvements became evident after 1week of treatment. Significantly, more patients given TZP-102 (any dose) had a 50% reduction in baseline GCSI score (28.8%vs 7.7% placebo). Safety profiles were similar across groups. All TZP-102 doses were well-tolerated with no adverse cardiac, weight, or glucose control outcomes. Conclusions &amp; Inferences TZP-102 for 28days, at doses of 10-40mg once daily, was well-tolerated and resulted in a reduction in symptoms of gastroparesis. The lack of correlation between symptom improvement and gastric emptying change is consistent with previous studies in diabetic gastroparesis, and emphasizes the value of patient-defined outcomes in determining therapeutic benefit.

  • 16. Falken, Y.
    et al.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Abraham-Nordling, M.
    Kressner, U.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Naslund, E.
    Intravenous ghrelin accelerates postoperative gastric emptying and time to first bowel movement in humans2013In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 25, no 6, p. 474-480Article in journal (Refereed)
    Abstract [en]

    Background Ghrelin has been shown to stimulate gastric emptying in healthy humans and patients with delayed gastric emptying. The aim of this study is to assess the effect of ghrelin on gastric emptying on day 2 after open colorectal surgery. Methods Twenty-four patients (mean age 69.2 +/- 1.4, BMI 25.8 +/- 0.8kgm2) were randomized to saline or ghrelin infusion (15pmolkg1min1) during 3h before and on day 2 after open colorectal surgery. Of these, 20 were assessed both before and after surgery. At start of infusion, a liquid meal (480kcal, 200mL) was administered together with 1.5g acetaminophen. Plasma was obtained at regular intervals together with visual analogue scales for hunger, satiety and nausea. Acetaminophen was analyzed as a marker of gastric emptying. Plasma glucose, insulin, acyl-ghrelin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinoptrophic peptide (GIP), pancreatic polypeptide and peptide YY (PYY) were analyzed. Key Results Gastric emptying was faster during ghrelin infusion compared to saline before and after surgery (P<0.02). In addition, plasma glucose was increased (P<0.05). With ghrelin infusion, plasma insulin was unchanged except for lower values postoperatively (P<0.05). Ghrelin did not alter plasma concentrations of gut peptides. After surgery, ghrelin shortened the time to first bowel movement compared to saline (2.1 +/- 0.3 vs 3.5 +/- 0.4days, P=0.02). Conclusions & Inferences A 3-h ghrelin infusion increased the gastric emptying rate and hastened the time to first bowel movement after surgery. Ghrelin/ghrelin receptor agonists have a therapeutic potential in postoperative ileus; Karolinska Clinical Trial Registry nr CT20110084.

  • 17. Falkén, Y.
    et al.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Holst, J. J.
    Näslund, E.
    Changes in Glucose Homeostasis after Roux-en-Y Gastric Bypass Surgery for Obesity at Day Three, Two Months, and One Year after Surgery: Role of Gut Peptides2011In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 96, no 7, p. 2227-2235Article in journal (Refereed)
    Abstract [en]

    Context:

    Endocrine effects of gastric bypass (GBP) surgery for obesity on glucose homeostasis are not fully understood.

    Main Objective:

    The main objective of the study was to assess the changes in plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), leptin, somatostatin, glucose-dependent insulinotropic peptide, enteroglucagon, and glucagon early after GBP.

    Method:

    Twelve obese subjects (body mass index 45.3 ± 1.9 kg/m2) were subjected to a liquid meal without lipids before and 3 d, 2 months, and 1 yr after GBP. Plasma concentrations of glucose, insulin, leptin, and gut peptide hormones were assessed before and for 180 min after the meal. Satiety was measured with visual analog scales. The absorption rate of acetaminophen added to the liquid meal was measured. Insulin resistance was measured by the homeostasis model assessment of insulin resistance.

    Results:

    All subjects lost weight (body mass index 30.3 ± 1.8 kg/m2 at 1 yr). Fasting glucose was significantly lower on d 3 (P < 0.05). There was a progressive decrease in the homeostasis model assessment of insulin resistance after 2 months postoperatively. Postprandially, there was a progressive rise of GLP-1 and enteroglucagon and a transient increase in pancreatic glucagon release over the study period. There was a leftward shift of the time course of plasma glucose and insulin. Somatostatin release was lower on d 3 (P < 0.05) but then unchanged. The absorption rate of acetaminophen was twice as fast after GBP compared with before surgery and did not change over time. Satiety scores increased markedly postoperatively.

    Conclusion:

    Both enhanced insulin sensitivity and incretin hormones, such as GLP-1, contribute to the early control of glucose homeostasis. Progressively increasing postprandial levels of enteroglucagon (oxyntomodulin) and GLP-1 facilitate weight loss and enhance insulin effectiveness.

  • 18. Falkén, Y.
    et al.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sanger, G. J.
    Dewit, O.
    Dukes, G.
    Grybäck, P.
    Holst, J. J.
    Näslund, E.
    Actions of prolonged ghrelin infusion on gastrointestinal transit and glucose homeostasis in humans2010In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 22, no 6, p. e192-e200Article in journal (Refereed)
    Abstract [en]

    Background

    Ghrelin is produced by enteroendocrine cells in the gastric mucosa and stimulates gastric emptying in healthy volunteers and patients with gastroparesis in short-term studies. The aim of this study was to evaluate effects of intravenous ghrelin on gastrointestinal motility and glucose homeostasis during a 6-h infusion in humans.

    Methods

    Ghrelin  (15 pmol kg−1 min−1) or saline was infused intravenously for 360 min after intake of radio-opaque markers, acetaminophen, and lactulose after a standardized breakfast in 12 male volunteers. Gastric emptying, orocecal transit, colonic transit, postprandial plasma concentrations of glucose, insulin, glucagon-like peptide-1 (GLP-1), and peptide YY were assessed. In vitro studies of gastrointestinal muscle contractility were performed.

    Key Results

    The gastric emptying rate was faster for ghrelin compared to saline (P = 0.002) with a shorter half-emptying time (50.3 ± 3.9 vs 59.9 ± 4.4 min, P = 0.004). There was no effect of ghrelin on orocecal or colonic transit. Postprandial elevations of plasma glucose, insulin, and GLP-1 occurred 15 min earlier and were higher with ghrelin. The insulinogenic index did not change during ghrelin infusion. Basal in vitro contractility was unaffected by ghrelin.

    Conclusions & Inferences

    The effect of a 6-h ghrelin infusion on gastrointestinal motility is limited to the stomach without affecting orocecal or colonic transit. Plasma glucose, insulin, and GLP-1 are elevated postprandially, probably as a result of the hastened gastric emptying. Changes in glucose homeostasis as a consequence of stimulated gastric emptying and hormone release, need to be taken into account in the use of pharmacological stimulants for the treatment of motility disorders.

  • 19.
    Farmer, A. D.
    et al.
    Aalborg Univ, Aalborg Univ Hosp, Aalborg & Clin Inst, Mech Sense,Dept Gastroenterol & Hepatol, Aalborg, Denmark.;Queen Mary Univ London, Neurogastroenterol Grp, Ctr Neurosci & Trauma, Blizard Inst,Wingate Inst Neurogastroenterol,Bart, London, England.;Univ Hosp North Midlands, Dept Gastroenterol, Stoke On Trent, Staffs, England..
    Wegeberg, A. -ML.
    Brock, B.
    Aarhus Univ Hosp, Dept Clin Biochem, Aarhus, Denmark..
    Hobson, A. R.
    Funct Gut Clin, London, England..
    Mohammed, S. D.
    Queen Mary Univ London, Neurogastroenterol Grp, Ctr Neurosci & Trauma, Blizard Inst,Wingate Inst Neurogastroenterol,Bart, London, England..
    Scott, S. M.
    Queen Mary Univ London, Neurogastroenterol Grp, Ctr Neurosci & Trauma, Blizard Inst,Wingate Inst Neurogastroenterol,Bart, London, England..
    Bruckner-Holt, C. E.
    Univ Hosp North Midlands, Dept Gastroenterol, Stoke On Trent, Staffs, England..
    Semler, J. R.
    Medtronic, Sunnyvale, CA USA..
    Hasler, W. L.
    Univ Michigan Hlth Syst, Div Gastroenterol, Ann Arbor, MI USA..
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Drewes, A. M.
    Aalborg Univ, Aalborg Univ Hosp, Aalborg & Clin Inst, Mech Sense,Dept Gastroenterol & Hepatol, Aalborg, Denmark..
    Brock, C.
    Aalborg Univ, Aalborg Univ Hosp, Aalborg & Clin Inst, Mech Sense,Dept Gastroenterol & Hepatol, Aalborg, Denmark.;Univ Copenhagen, Dept Pharmacotherapy & Dev, Copenhagen, Denmark..
    Regional gastrointestinal contractility parameters using the wireless motility capsule: inter-observer reproducibility and influence of age, gender and study country2018In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 47, no 3, p. 391-400Article in journal (Refereed)
    Abstract [en]

    Background:

    The wireless motility capsule concurrently measures temperature, pH and pressure as it traverses the gastrointestinal tract. Aims: To describe normative values for motility/contractility parameters across age, gender and testing centres.

    Methods:

    Healthy participants underwent a standardised wireless motility capsule assessment following an overnight fast and consumption of a meal of known nutritional content. Traces were divided into regions of interest and analysed using 2 software packages (MotiliGI and GIMS Data Viewer). Inter-observer agreement was independently assessed by 2 investigators.

    Results:

    Normative data for motility/contractility parameters (maximum amplitude, mean peak amplitude, contraction frequency and motility index) are presented for 107 individuals (62 male, median age 40years, range 18-78). MotiliGI-Gastric, small bowel and colonic maximal contraction amplitude correlated with age (r = .24, P = .01; r = .22, P = .02; and r = .2, P = .04 respectively). Small bowel motility index was higher in females than males (150.412 vs 122 +/- 7.6, P = .04). Inter-observer agreement was excellent for transit times, pH and contractility/motility parameters. GIMS Data viewer-Gastric, small bowel and colonic log(e) motility index correlated with the respective area under the contraction curve, total contractions, sum of amplitudes and contraction frequency (all r>.35, P < .0003) but not with transit times.

    Conclusions:

    Our analysis provides normative data for motility/contractility parameters. Log motility index summarises a number of measures. In future, the measurement of contractile activity with the wireless motility capsule may potentially aid in the diagnosis of disease states such as visceral myopathic disorders.

  • 20. Farmer, Adam D
    et al.
    Ban, Vin F
    Coen, Steven J
    Sanger, Gareth J
    Barker, Gareth J
    Gresty, Michael A
    Giampietro, Vincent P
    Williams, Steven C
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Andrews, Paul L R
    Aziz, Qasim
    Visually induced nausea causes characteristic changes in cerebral, autonomic and endocrine function in humans2015In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 593, no 5, p. 1183-1196Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Nausea is a highly individual and variable experience. The reasons for this variability are incompletely understood although psychophysiological factors have been proposed. Herein we describe objective psychophysiological changes induced by the subjective sensation of motion sickness. In comparison to subjects who did not develop nausea, nausea-sensitive subjects demonstrated electrogastrographic and autonomic changes, which included an increase in sympathetic nervous system activity with a concomitant reduction in parasympathetic activity. Furthermore, differences were also evident in plasma ghrelin, and subcortical and cortical activity. These data have a number of important implications for future research examining the physiological mechanisms that underlie nausea: ○The physiological, hormonal and cortical patterns identified herein represent potential biomarkers of the physiological mechanisms of nausea. ○Reverse translation of the physiological factors identified may facilitate refinement of animal models used to investigate novel anti-emetic agents and emetic liability of candidate drugs, increasing their validity and translation of finding to humans.

    ABSTRACT: An integrated understanding of the physiological mechanisms involved in the genesis of nausea remains lacking. We aimed to describe the psychophysiological changes accompanying visually induced motion sickness, using a motion video, hypothesizing that differences would be evident between subjects who developed nausea in comparison to those who did not. A motion, or a control, stimulus was presented to 98 healthy subjects in a randomized crossover design. Validated questionnaires and a visual analogue scale (VAS) were used for the assessment of anxiety and nausea. Autonomic and electrogastrographic activity were measured at baseline and continuously thereafter. Plasma vasopressin and ghrelin were measured in response to the motion video. Subjects were stratified into quartiles based on VAS nausea scores, with the upper and lower quartiles considered to be nausea sensitive and resistant, respectively. Twenty-eight subjects were exposed to the motion video during functional neuroimaging. During the motion video, nausea-sensitive subjects had lower normogastria/tachygastria ratio and cardiac vagal tone but higher cardiac sympathetic index in comparison to the control video. Furthermore, nausea-sensitive subjects had decreased plasma ghrelin and demonstrated increased activity of the left anterior cingulate cortex. Nausea VAS scores correlated positively with plasma vasopressin and left inferior frontal and middle occipital gyri activity and correlated negatively with plasma ghrelin and brain activity in the right cerebellar tonsil, declive, culmen, lingual gyrus and cuneus. This study demonstrates that the subjective sensation of nausea is associated with objective changes in autonomic, endocrine and brain networks, and thus identifies potential objective biomarkers and targets for therapeutic interventions.

  • 21.
    Frigstad, S. O.
    et al.
    Vestre Viken Hosp Trust, Dept Med, Baerum Hosp, Drammen, Norway.;Ostfold Hosp Trust, Dept Res, Gralum, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Hammarlund, P.
    Angelholms Hosp, Dept Med, Angelholm, Sweden..
    Bonderup, O.
    Silkeborg Reg Hosp, Dept Gastroenterol, Silkeborg, Denmark..
    Rannem, T.
    Nordsjaelland Hosp, Dept Gastroenterol, Hillerod, Denmark..
    Haaber, A.
    Herlev Gentofte Hosp, Dept Gastroenterol, Hellerup, Denmark..
    Fallingborg, J.
    Aalborg Univ Hosp, Dept Med Gastroenterol, Aalborg, Denmark..
    Blom, H.
    Sunderby Hosp, Dept Med, Lulea, Sweden..
    Bajor, A.
    Sahlgrens Univ Hosp, Dept Internal Med, Gothenburg, Sweden.;SAS, Dept Med, Boras, Sweden..
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Anaemia and iron deficiency in gastroenterology: a Scandinavian prospective, observational study of iron isomaltoside in clinical practice2017In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 11, p. S351-S351Article in journal (Other academic)
  • 22. Frigstad, S. O.
    et al.
    Rannem, T.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hammarlund, P.
    Bonderup, O.
    A Scandinavian prospective observational study of iron isomaltoside 1000 treatment: Clinical practice and outcomes in iron deficiency anaemia in patients with IBD2015In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 9, no S1, p. S320-S320Article in journal (Other academic)
  • 23.
    Frigstad, Svein Oskar
    et al.
    Vestre Viken Hosp Trust, Baerum Hosp, Dept Med, Drammen, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Haaber, Anne
    Gentofte Univ Hosp, Dept Gastroenterol, Hellerup, Denmark..
    Bajor, Antal
    Sodra Alvsborg Hosp, Dept Internal Med, Boras, Sweden..
    Fallingborg, Jan
    Aalborg Univ Hosp, Dept Gastroenterol & Hepatol, Aalborg, Denmark..
    Hammarlund, Per
    Angelholm Hosp, Dept Gastroenterol, Angelholm, Sweden..
    Bonderup, Ole K.
    Silkeborg Reg Hosp, Dept Gastroenterol, Silkeborg, Denmark..
    Blom, Hakan
    Sunderby Hosp, Dept Med, Lulea, Sweden..
    Rannem, Terje
    Nordsjaelland Hosp, Dept Gastroenterol, Frederikssund, Denmark..
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    The NIMO Scandinavian Study: A Prospective Observational Study of Iron Isomaltoside Treatment in Patients with Iron Deficiency2017In: Gastroenterology Research and Practice, ISSN 1687-6121, E-ISSN 1687-630X, Vol. 2017, article id 4585164Article in journal (Refereed)
    Abstract [en]

    Background. Intravenous iron allows for efficient and well-tolerated treatment in iron deficiency and is routinely used in diseases of the gastrointestinal tract. Objective. The aims of this study were to determine the probability of relapse of iron deficiency over time and to investigate treatment routine, effectiveness, and safety of iron isomaltoside. Methods. A total of 282 patients treated with iron isomaltoside were observed for two treatments or a minimum of one year. Results. Out of 282 patients, 82 had Crohn's disease and 67 had ulcerative colitis. Another 133 patients had chronic blood loss, malabsorption, or malignancy. Patients who received an iron isomaltoside dose above 1000 mg had a 65% lower probability of needing retreatment compared with those given 1000 mg. A clinically significant treatment response was shown, but in 71/191 (37%) of patients, anaemia was not corrected. The mean dose given was 1100 mg, lower than the calculated total iron need of 1481 mg. Adverse drug reactions were reported in 4% of patients. Conclusion. Iron isomaltoside is effective with a good safety profile, and high doses reduce the need for retreatment over time. Several patients were anaemic after treatment, indicating that doses were inadequate for full iron correction.

  • 24. Gibbons, C.
    et al.
    Caudwell, P.
    Finlayson, G.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Naslund, E.
    Blundell, J.
    Gastrointestinal Peptide Response To Fat And Carbohydrate: Implications For Satiety Control2013In: Annals of Nutrition and Metabolism, ISSN 0250-6807, E-ISSN 1421-9697, Vol. 63, no Suppl. 1, p. 458-458Article in journal (Other academic)
  • 25.
    Gibbons, Catherine
    et al.
    Univ Leeds, Sch Psychol, Appetite Control & Energy Balance Grp, Leeds LS2 9JZ, W Yorkshire, England.
    Blundell, John E
    Univ Leeds, Sch Psychol, Appetite Control & Energy Balance Grp, Leeds LS2 9JZ, W Yorkshire, England.
    Caudwell, Phillipa
    Univ Leeds, Sch Psychol, Appetite Control & Energy Balance Grp, Leeds LS2 9JZ, W Yorkshire, England.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Näslund, Erik
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, SE-18288 Stockholm, Sweden.
    Finlayson, Graham
    Univ Leeds, Sch Psychol, Appetite Control & Energy Balance Grp, Leeds LS2 9JZ, W Yorkshire, England.
    The Role of Episodic Postprandial Peptides in Exercise-Induced Compensatory Eating2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 11, p. 4051-4059Article in journal (Refereed)
    Abstract [en]

    Context: Prolonged physical activity gives rise to variable degrees of body weight and fat loss, and is associated with variability in appetite control. Whether these effects are modulated by postprandial, peptides is unclear. We examined the role of postprandial peptide response in compensatory eating during 12 weeks of aerobic exercise and in response to high-fat, low-carbohydrate (HFLC) and low-fat, high-carbohydrate (LFHC) meals.

    Methods: Of the 32 overweight/obese individuals, 16 completed 12 weeks of aerobic exercise and 16 nonexercising control subjects were matched for age and body mass index. Exercisers were classified as responders or nonresponders depending on net energy balance from observed compared with expected body composition changes from measured energy expenditure. Plasma samples were collected before and after meals to compare profiles of total and acylated ghrelin, insulin, cholecystokinin, glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY) between HFLC and LFHC meals, pre- and postexercise, and between groups.

    Results: No differences between pre- and postintervention peptide release. Responders had greater suppression of acylated ghrelin (P < 0.05) than nonresponders, as well as higher postprandial levels of GLP-1 (P < 0.001) and total PYY (P < 0.001) compared with nonresponders and control subjects.

    Conclusion: No impact on postprandial peptide release was found after 12 weeks of aerobic exercise. Responders to exercise-induced weight loss showed greater suppression of acylated ghrelin and greater release of GLP-1 and total PYY at baseline. Therefore, episodic postprandial peptide profiles appear to form part of the pre-existing physiology of exercise responders and suggest differences in satiety potential may underlie exercise-induced compensatory eating.

  • 26. Gibbons, Catherine
    et al.
    Caudwell, Phillipa
    Finlayson, Graham
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Naslund, Erik
    Blundell, John E.
    Comparison of Postprandial Profiles of Ghrelin, Active GLP-1, and Total PYY to Meals Varying in Fat and Carbohydrate and Their Association With Hunger and the Phases of Satiety2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 5, p. E847-E855Article in journal (Refereed)
    Abstract [en]

    Context: The relationship between postprandial peptides at circulating physiological levels and short-term appetite control is not well understood. Objective: The purpose of this study was first to compare the postprandial profiles of ghrelin, glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) after isoenergetic meals differing in fat and carbohydrate content and second to examine the relationships between ghrelin, GLP-1, and PYY with hunger, fullness, and energy intake. Design: Plasma was collected before and periodically after the meals for 180 minutes, after which time ad libitum food was provided. Simultaneous ratings of hunger and fullness were tracked for 180 minutes through phases identified as early (0-60 minutes) and late (60-180 minutes) satiety. Setting: This study was conducted at the Psychobiology and Energy Balance Research Unit, University of Leeds. Participants: The participants were 16 healthy overweight/obese adults. Main Outcome Measures: Changes in hunger and fullness and metabolic markers were indicators of the impact of the meals on satiety. Results: Ghrelin was influenced similarly by the 2 meals [F-(1,F- 12) = 0.658, P = .433] and was significantly associated with changes in hunger (P < .05), which in turn correlated with food intake (P < .05). GLP-1 and PYY increased more by the high-fat meal [F-(1,F- 15) = 5.099 and F-(1,F- 14) = 5.226, P < .05]. GLP-1 was negatively associated with hunger in the late satiety phase and with energy intake (P < .05), but the PYY profile was not associated with hunger or fullness, nor was PYY associated with food intake. Conclusions: The results demonstrate that under these conditions, these peptides respond differently to ingested nutrients. Ghrelin and GLP-1, but not PYY, were associated with short-term control of appetite over the measurement period.

  • 27. Gibbons, Catherine
    et al.
    Finlayson, Graham
    Caudwell, Phillipa
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Näslund, Erik
    Blundell, John E
    Postprandial profiles of CCK after high fat and high carbohydrate meals and the relationship to satiety in humans2016In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 77, p. 3-8Article in journal (Refereed)
    Abstract [en]

    CONTEXT: CCK is understood to play a major role in appetite regulation. Difficulties in measuring CCK have limited the potential to assess its profile in relation to food-induced satiety. Improvements in methodology and progress in theoretical understanding of satiety/satiation make it timely for this to be revisited.

    OBJECTIVE: First, examine how physiologically relevant postprandial CCK8/33(s) profiles are influenced by fat (HF) or carbohydrate (HCHO) meals. Second, to examine relationships between postprandial CCK and profiles of satiety (hunger/fullness) and satiation (meal size).

    PARTICIPANTS AND DESIGN: Sixteen overweight/obese adults (11 females/5 males) participated in a randomised-crossover study (46 years, 29.8kg/m(2)) in a university research centre. Plasma was collected preprandially and for 180min postprandially. Simultaneously, ratings of hunger/fullness were tracked for 180min before an ad libitum lunch was provided.

    RESULTS: CCK8/33(s) levels increased more rapidly and reached a higher peak following HF compared to HCHO breakfast (F(1,15)=14.737, p<0.01). Profiles of hunger/fullness did not differ between conditions (F(1,15)=0.505, p=0.488; F(1,15)=2.277, p=0.152). There was no difference in energy intake from the ad libitum meal (HF-3958 versus HCHO-3925kJ; t(14)=0.201, p=0.844). CCK8/33(s) profiles were not associated with subjective appetite during early and late phases of satiety; nor was there an association between CCK8/33(s) and meal size.

    CONCLUSIONS: These results demonstrate CCK levels were higher after HF meal compared to HCHO isocaloric meal. There was no association between CCK levels and intensity of satiety, or with meal size. Under these circumstances, CCK does not appear to play a unique independent role in satiety/satiation. CCK probably acts in conjunction with other peptides and the action of the stomach.

  • 28. Gillberg, L.
    et al.
    Berg, S.
    de Verdier, P. J.
    Lindbom, L.
    Werr, J.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Effective treatment of mouse experimental colitis by alpha 2 integrin antibody: comparison with alpha 4 antibody and conventional therapy2013In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 207, no 2, p. 326-336Article in journal (Refereed)
    Abstract [en]

    Aim To compare the therapeutic effect of a2 and a4 integrin-blocking antibodies to conventional inflammatory bowel disease drugs methotrexate, 5-aminosalicylic acid and azathioprine in the dextran sulphate sodium mouse colitis model. Methods Colitis was induced in balb/c mice with 2.53.0% dextran sulphate sodium. Treatment was given daily for 7 days after the onset of colitis, by rectal installation. Clinical signs of disease were assessed daily using a disease activity index. After 19 days, all animals were killed and colon samples collected for histological grading and mRNA/protein analysis. All treatment groups were compared with an untreated control group and a treatment group receiving dextran sulphate sodium alone to monitor the potential degree of clinical remission. Results Treatment with anti-a2 antibodies and methotrexate reduced the body weight loss. At the end of treatment, anti-a2 antibodies reduced rectal bleeding, while methotrexate reduced the disease activity index score. Histological evaluation showed that anti-a2 antibodies, methotrexate, 5-aminosalicylic acid and azathioprine treatment reduced the acute inflammation; methotrexate was the only treatment with effect on the crypt score. Compared with the dextran sulphate sodium alone group, the methotrexate group showed down-regulation of IL-1 beta at the mRNA level, while the anti-a2 antibody group displayed decreased protein expression of iNOS and IL-1 beta. Conclusions Specific blocking of extravascular trafficking of leucocytes with a2-antibodies could be a new beneficial drug target in inflammatory bowel disease.

  • 29. Gillberg, L.
    et al.
    Varsanyi, M.
    Sjöström, M.
    Lördal, M.
    Lindholm, J.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nitric oxide pathway-related gene alterations in inflammatory bowel disease2012In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 47, no 11, p. 1283-1297Article in journal (Refereed)
    Abstract [en]

    Objective: To reveal specific gene activation in nitric oxide (NO)-related inflammation we studied differential gene expression in inflammatory bowel disease (IBD). Methods. Total RNA was isolated from 20 biopsies of inflamed mucosa from Crohn's disease (CD) and ulcerative colitis (UC) patients each as well as from six controls, labeled with 32P-dCTP and hybridized to a human NO gene array. Significant genes were analyzed for functional gene interactions and heatmaps generated by hierarchical clustering. A selection of differentially expressed genes was further evaluated with immunohistochemical staining. Results. Significant gene expression differences were found for 19 genes in CD and 23 genes in UC compared to controls, both diseases with high expression of ICAM1 and IL-8. Correlation between microarray expression and corresponding protein expression was significant (r 0.47, p 0.002). Clustering analysis together with functional gene interaction analysis revealed clusters of coregulation and coexpression in CD and UC: transcripts involved in angiogenesis, inflammatory response mediated by the transcription factor hypoxia-inducible factor 1, and tissue fibrosis. Also, a fourth cluster with transcripts regulated by the transcription factor Sp1 was found in UC. Conclusions. Expression analysis in CD and UC revealed disease-specific regulation of NO-related genes, which might be involved in perpetuating inflammatory disease activity in IBD.

  • 30. Gryback, P
    et al.
    Bajc, M
    Granerus, G
    Lyrenas, E
    Hermansson, G
    Beckman, KW
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Olsson, E
    Fernstrom, A
    Jacobsson, H
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Undersökning av ventrikeltömning med gammakamera. Kliniskt användbar, enhetlig metod nu fastställd: [Examination of gastric emptying with gamma camera. Clinically useful,uniform method now established]2000In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 97, no 15, p. 1811-1816Article in journal (Other academic)
    Abstract [en]

    Although more than 30 years have passed since the introduction of scintigraphic testing of gastric emptying there has been no well-defined standard. Eight Swedish hospitals have established a nationally standardized method for scintigraphic testing of gastric emptying of solids. 160 healthy subjects participated. The meal consisted of a 99mTc-labeled omelet (1300 kJ) and 150 ml unlabeled soft drink (290 kJ). There were no differences in calculated variables between the centers. Premenopausal women showed slower emptying than postmenopausals and men of any age, making separate reference values for younger women necessary.

  • 31. Gustavsson, A
    et al.
    Järnerot, G
    Hertervig, E
    Friis-Liby, I
    Blomquist, L
    Karlén, P
    Grännö, C
    Vilien, M
    Ström, M
    Verbaan, H
    Hellström, Per M.
    Magnuson, A
    Halfvarson, J
    Tysk, C
    Clinical trial: colectomy after resue therapy in ulcerative colitis-3-year follow-up of the Swedish-Danish controlled infliximab study2010In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 32, no 8, p. 984-989Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The long-term efficacy of infliximab as rescue therapy in steroid-refractory ulcerative colitis is not well described.

    AIM:

    To examine the long-term efficacy of infliximab as a rescue therapy through a 3-year follow-up of a previous placebo-controlled trial of infliximab in acute steroid-refractory ulcerative colitis.

    METHOD:

    In the original study, 45 patients were randomized to a single infusion of infliximab 5 mg/kg or placebo, and at 3 months, 7/24 patients given infliximab were operated vs. 14/21 patients given placebo. Three years or later, patients were asked to participate in a clinical follow-up.

    RESULTS:

    Another seven patients underwent colectomy during follow-up: five in the infliximab group and two in the placebo group. After 3 years, a total of 12/24 (50%) patients given infliximab and 16/21 (76%) given placebo (P = 0.012) had a colectomy. None of eight patients in endoscopic remission at 3 months later had a colectomy compared with 7/14 (50%) patients who were not in remission (P=0.02). There was no mortality.

    CONCLUSION:

    The benefit of rescue therapy with infliximab in steroid-refractory acute ulcerative colitis remained after 3 years. The main advantage of infliximab treatment occurred during the first 3 months, whereas subsequent colectomy rates were similar in the two groups. Mucosal healing at 3 months influenced later risk of colectomy.

  • 32.
    Halim, Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Degerblad, Marie
    Karolinska Institutet.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Juul Holst, Jens
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Glucagon-like peptide-1 inhibits prandial gastrointestinal motility through myenteric neuronal mechanisms in humans2018In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 2, p. 575-585Article in journal (Refereed)
    Abstract [en]

    Context: Glucagon-like peptide-1 (GLP-1) secretion from L-cells and postprandial inhibition of gastrointestinal motility.

    Objective: Investigate whether physiological plasma concentrations of GLP-1 can inhibit human postprandial gastrointestinal motility; determine target mechanism of GLP-1 and analogue ROSE-010 action.

    Design: Single-blind parallel study.

    Setting: University research laboratory.

    Participants: Healthy volunteers investigated with antroduodenojejunal manometry. Human gastric, intestinal and colonic muscle strips.

    Interventions: Motility indices (MI) obtained before and during infusion of saline or GLP-1 were compared. Plasma GLP-1 and glucagon-like peptide-2 (GLP-2) measured by radioimmunoassay. Gastrointestinal muscle strips, pre-contracted with bethanechol/electric field stimulation (EFS), investigated for GLP-1- or ROSE-010-induced relaxation. GLP-1, GLP-2 and their receptors localized by immunohistochemistry. Action mechanisms studied employing exendin(9-39)amide, Lω-nitro-monomethylarginine (L-NMMA), 2´,5´-dideoxyadenosine (DDA), tetrodotoxin (TTX).

    Main outcome measures: Hypothesize postprandial gastric relaxation induced by GLP-1, the mechanism of which intrinsic neuronally-mediated.

    Results: Food intake increased MI to 6.4±0.3 (antrum), 5.7±0.4 (duodenum) and 5.9±0.2 (jejunum). GLP-1 administered intravenously raised plasma GLP-1, but not GLP-2. GLP-1 0.7 pmol/kg·min significantly suppressed MI to 4.6±0.2, 4.7±0.4 and 5.0±0.2, respectively, while 1.2 pmol/kg·min suppressed corresponding MI to 5.4±0.2, 4.4±0.3 and 5.4±0.3 (p<0.0001-0.005). GLP-1 and ROSE-010 prevented bethanechol- or EFS-induced muscle contractions (p <0.005-0.05). Inhibitory responses to GLP-1 and ROSE-10 were blocked by exendin(9-39)amide, L-NMMA, DDA or TTX (all p <0.005-0.05). GLP-1 and GLP-2 were localized to epithelial cells; GLP-1 also in myenteric neurons. GLP-1R and GLP-2R were localized at myenteric neurons but not muscle, GLP-1R also in epithelial cells.

    Conclusions: GLP-1 inhibits postprandial motility through GLP-1R at myenteric neurons, involving nitrergic and cAMP-dependent mechanisms.

  • 33.
    Halim, M. Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Boghus, Sandy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellstrom, Per. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nitric oxide regulation of migrating motor complex: randomized trial of N-G-monomethyl-L-arginine effects in relation to muscarinic and serotonergic receptor blockade2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, p. 105-118Article in journal (Refereed)
    Abstract [en]

    Aim: The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using N-G-monomethyl-L-arginine (L-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron. Methods: Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor L-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using L-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry. Results: L-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. L-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated by L-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells. Conclusion: Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.

  • 34.
    Halim, Md Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Boghus, Sandy
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Dominic-Luc, Webb
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    M. Hellström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nitric oxide regulation of migrating motor complex: randomised trial of L-NMMA effects in relation to muscarinic and serotonergic receptor blockade2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, p. 105-118Article in journal (Refereed)
    Abstract [en]

    Aim

    The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using NG-monomethyl-l-arginine (l-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron.

    Methods

    Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor l-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using l-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry.

    Results

    l-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. l-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. l-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated byl-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells.

    Conclusion

    Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.

  • 35.
    Hansdotter, Ida
    et al.
    Umea Univ Hosp, Dept Surg & Perioperat Sci, Surg, S-90185 Umea, Sweden..
    Björ, Ove
    Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden..
    Andreasson, Anna
    Karolinska Inst, Div Family Med, Huddinge, Sweden.;Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden..
    Agreus, Lars
    Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden..
    Hellström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Forsberg, Anna
    Karolinska Inst, Mol Med & Surg, Stockholm, Sweden..
    Talley, Nicholas J.
    Univ Newcastle, Fac Med, Newcastle, NSW 2300, Australia..
    Vieth, Michael
    Klinikum Bayreuth, Inst Pathol, Bayreuth, Germany..
    Wallner, Bengt
    Umea Univ Hosp, Dept Surg & Perioperat Sci, Surg, S-90185 Umea, Sweden..
    Hill classification is superior to the axial length of a hiatal hernia for assessment of the mechanical anti-reflux barrier at the gastroesophageal junction2016In: ENDOSCOPY INTERNATIONAL OPEN, ISSN 2364-3722, Vol. 4, no 3, p. E311-E317Article in journal (Refereed)
    Abstract [en]

    Background and study aims: The pathogenesis of gastroesophageal reflux disease (GERD) is multifactorial, including the mechanical anti-reflux barrier of the gastroesophageal junction. This barrier can be evaluated endoscopically in two ways: by measuring the axial length of any hiatal hernia present or by assessing the gastroesophageal flap valve. The endoscopic measurement of axial length is troublesome because of the physiological dynamics in the area. Grading the gastroesophageal flap valve is easier and has proven reproducible. The aim of the present study was to compare the two endoscopic grading methods with regard to associations with GERD. Patients and methods: Population-based subjects underwent endoscopic examination assessing the axial length of hiatus hernia, the gastroesophageal flap valve using the Hill classification, esophagitis using the Los Angeles (LA) classification, and columnar metaplasia using the Z-line appearance (ZAP) classification. Biopsies were taken from the squamocolumnar junction to assess the presence of intestinal metaplasia. Symptoms were recorded with the validated Abdominal Symptom Questionnaire. GERD was defined according to the Montreal definition. Results: In total, 334 subjects were included in the study and underwent endoscopy; 86 subjects suffered from GERD and 211 presented no symptoms or signs of GERD. Based on logistic regression, the estimated area under the curve statistic (AUC) for Hill (0.65 [95 % CI 0.59-0.72]) was higher than the corresponding estimate for the axial length of a hiatal hernia (0.61 [95 % CI 0.54-0.68]), although the difference was not statistically significant (P=0.225). Conclusion: From our data, and in terms of association with GERD, the Hill classification was slightly stronger compared to the axial length of a hiatal hernia, but we could not verify that the Hill classification was superior as a predictor. The Hill classification may replace the axial length of a hiatal hernia in the endoscopic assessment of the mechanical anti-reflux barrier of the gastroesophageal junction.

  • 36.
    Hellstrom, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Satiety signals and obesity2013In: Current Opinion in Gastroenterology, ISSN 0267-1379, E-ISSN 1531-7056, Vol. 29, no 2, p. 222-227Article, review/survey (Refereed)
    Abstract [en]

    Purpose of review The obesity epidemic over the world has called to attention different ways to manage this development. As bariatric surgery today is the only manner by which rapid and sustained weight control can be achieved, new ways of treating obesity are under investigation. This review focuses on today's knowledge on satiety signaling as a means to combat obesity. Recent findings The combined knowledge achieved from obesity surgery with gastric bypass and duodenal switch together with the pharmacological treatment of type 2 diabetes have given us some clues of how to manage obesity. The basis for our understanding is the present research focusing on the gut peptide hormones that are released in response to food intake, and the paucity of satiety signaling seems to prevail in obesity. This means that obese patients experience less activation of higher brain centers in association with a meal and therefore compensate with increased meal size or frequent food intake. Summary Altered satiety signaling primarily emanating from the gastrointestinal tract seems to lead to the development of obesity and type 2 diabetes. Pharmacological tools that enhance the gut hormone signaling are in focus for the upcoming venues of treatment.

  • 37.
    Hellström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    ULIMORELIN Ghrelin (GHS) Receptor Agonist Treatment of Postoperative Ileus Treatment of Gastroparesis2011In: Drugs of the future, ISSN 0377-8282, E-ISSN 2013-0368, Vol. 36, no 12, p. 899-907Article in journal (Refereed)
    Abstract [en]

    Hunger contractions consist of a series of strong contractions of the stomach that evolve to phase Ill of the migrating motor complex and move down the small intestine. Ghrelin is considered to be important for the initiation of hunger contractions and promotes gastric emptying. Other gastrointestinal endocrine and neuronal systems play powerful supplementary roles in the development of hunger. Macrocyclic template chemistry (MATCH (TM)) has produced the macrocyclic peptidomimetic ulimorelin (TZP-101). By an action selectively directed to the ghrelin receptor, this peptide analogue has been shown to be able to stimulate gastric emptying in diabetic gastroparesis and relieve the associated symptom burden in gastroparesis, predominantly nausea and vomiting. Ulimorelin has also been shown to be effective in reducing postoperative ileus in colectomy. These effects are not associated with any serious adverse events. As ulimorelin opens up new indications for treatment, this will strengthen the possibility of relieving patients of symptoms related to stasis of contents in the upper gastrointestinal tract. Thus, ulimorelin is a promising pharmaceutical that should activate gastrointestinal regulatory systems in disorders associated with gastric hypomotility.

  • 38.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Chapter Twelve – Glucagon-like peptide-1: gastrointestinal regulatory role in metabolism and motility2010In: Vitamines and Hormones, ISSN 0083-6729, Vol. 84, p. 319-329Article, review/survey (Refereed)
    Abstract [en]

    Gastrointestinal (GI) motility, primarily gastric emptying, balances the hormonal output that takes place after food intake in order to maintain stable blood sugar. The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), work together to reduce postprandial hyperglycemia by glucose-dependent insulin secretion and inhibition of glucagon release, as well as inhibition of GI motility and gastric emptying. GLP-1 is considered the more effective of the two incretins due to its additional inhibitory effects on GI motility. It is observed that patients on treatment with GLP-1 analogues or exenatide achieve a considerable weight loss during treatment. This is of benefit to improve insulin resistance in type 2 diabetes. Furthermore, weight loss per se is of considerable benefit in an even longer health perspective. The weight loss is considered to be due to the inhibition of GI motility. This effect has been studied in animal experimentation, and from there taken to involve studies on GI motility in healthy volunteers and patients with irritable bowel syndrome (IBS). Evolving to a phase II study in IBS, the GLP-1 analogue (ROSE-010) was recently shown to be effective for treatment of acute pain attacks in IBS. Taken together, data speak in favor of GI motility as a central component not only in metabolic disorders but also in IBS, be it due to a direct relaxing effect on GI smooth muscle or a slow emptying of gastric contents resulting in a less outspoken nutritional demand on hormonal regulatory functions in the GI tract.

  • 39. Hellström, Per M.
    Faces of ghrelin--research for the 21st century.2009In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 21, no 1, p. 2-5Article in journal (Refereed)
    Abstract [en]

    In this issue of Neurogastroenterology and Motility we find three new articles on different aspects of ghrelin, dealing with physiological and pathophysiological actions of the peptide. For the reader this is food for thoughts: Does this peptide do everything? Ghrelin is a gut peptide hormone well established to stimulate motility throughout most parts of the gastrointestinal (GI) tract and appetite. Ghrelin has been linked to various GI regulatory mechanisms, the most evident being hunger, over-eating and obesity. In this setting ghrelin has been studied under physiological conditions converging on obesity as a pathophysiological process where the peptide has been employed as an interesting tool for studying the development of obesity. With a widespread distribution of ghrelin receptors on various immune cells, it has been assumed that ghrelin also possesses immunoregulatory properties, thus also being of interest in intestinal inflammation research. Anti-inflammatory effects of exogenous ghrelin have been claimed in experimental colitis in mice. Further studies on this concept using ghrelin gene knock-out mice, however, show an increased inflammatory activity in experimental colitis in wild-type mice pointing to ghrelin as an enhancer of the inflammatory course of the disease. Taken together, recent studies on ghrelin indicate that the peptide is not only a regulatory agent in pathophysiological processes, but also participates in pathological disease conditions with actions that seem to even involve genetic mechanisms.

  • 40. Hellström, Per M.
    GLP-1: broadening the incretin concept to involve gut motility2009In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 156, no 1-3, p. 9-12Article in journal (Refereed)
    Abstract [en]

    The incretin effect of the gut peptide hormone glucagon-like peptide-1 (GLP-1) is a combined result of inhibition of gastric emptying and stimulation of insulin secretion via an incretin mechanism. The temporal pattern of these events implicate that gastric emptying is primarily delayed, while later in the digestive process insulin is released for nutrient disposal. Since the inhibitory effect of GLP-1 on gastric motility is very outspoken, we considered it of value to study its effects on gut motility. Animal experimentation in the rat clearly showed that not only gastric emptying, but also small bowel motility with the migrating myoelectric complex was profoundly inhibited by GLP-1 at low doses. Similar effects were seen with analogues of the peptide. Extending the studies to man supported our earliest data indicating that the migrating motor complex of the small intestine was affected, and even more noticeable, the summarized motility index inhibited. Further extension of our studies to patients with irritable bowel syndrome (IBS) displayed similar results. This encouraged us to embark on a clinical pain-relief multi-centre study in IBS patients using a GLP-1 analogue, ROSE-010, with longer half-life than the native peptide. The outcome of the IBS study proved ROSE-010 to be superior to placebo with a pain-relief response rate of 24% for ROSE-010 compared to 12% for placebo. Taken together, the GLP-1 analogue ROSE-010 is believed to cause relaxation of the gut and can thereby relieve an acute pain attack of IBS, even though its precise mechanism is yet to be defined.

  • 41.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    GLP-1 playing the role of a gut regulatory compound2011In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 201, no 1, p. 151-156Article, review/survey (Refereed)
    Abstract [en]

    Gastric emptying is the first step in the metabolic endocrine cascade that takes place after food intake. The incretin hormones originating in the gut, particularly GLP-1, exert multiple antihyperglycaemic actions such as enhancement of glucose-dependent insulin secretion, suppression of glucagon secretion, slowing of gastric emptying with an ensuing decrease in food intake and weight loss. From extensive studies in experimental animals and humans we have found that GLP-1 also exerts a motility-inhibiting and antispasmodic effect in the gut that was verified in healthy volunteers and patients with irritable bowel syndrome (IBS). In order to further investigate the effect of GLP-1 in humans, we used the dipeptidyl peptidase-IV resistant GLP-1 analogue ROSE-010, thereby extending its biological activity. A randomized, double-blinded, prospective clinical trial was carried out in order to investigate the effect of two doses of ROSE-010 in 166 patients suffering from pain attacks of IBS. We found that injections of ROSE-010 were twice as effective as placebo in terms of total pain relief response in those affected by pain attacks due to IBS. Our results show that basal physiological research studies can be translated into clinical use. The current pharmaceutical incentive with incretin mimetics, such as GLP-1 analogues and exenatide, is an interesting development that apart from its obvious use in diabetes type 2, may also be useful in terms of gut motility-regulating effects with effects on appetite, food intake and motility disorders that may provide an opportunity to bring about new improvements in medical care.

  • 42.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Obesity research in adolescence: moving object-hard to target2013In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 98, no 5, p. 1147-1148Article in journal (Other academic)
  • 43.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Diaz, Hetzel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Lönnkvist, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Befrits, R.
    Fecal calprotectin and serum C-reactive protein predict outcome of infliximab induction therapy in inflammatory bowel disease2015In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 9, no S1, p. S287-S288Article in journal (Other academic)
  • 44.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Halim, Md Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Tryggve, Ljung
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University.
    Holst, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Karolinska Institutet.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Luminal Nitric Oxide and Plasma Nitrite/Nitrate As Predictors of Colectomy in Corticosteroid-Treated Acute Colitis2015In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 148, no 4, suppl. 1, article id Sul 231Article in journal (Refereed)
    Abstract [en]

    Background: Nitric oxide (NO) is known to be up-regulated by the induction of induciblenitric oxide synthase (iNOS) in inflammatory conditions. NO gas can be used as a markerof inflammatory activity in hollow organs. In parallel, plasma nitrite + nitrate (NOx) canreflect the ongoing inflammatory activity. We analyzed rectal NO before and after threedays, as well as plasma NOx in patients on glucocorticosteroid (GC) therapy in hospitalizedpatients. The aim of the study was to evaluate the relationship of rectal luminal NO andcirculating plasma NOx in acute fulminant colitis to the outcome as therapeutic responseor colectomy.

    Methods: 50 patients with median age 41 (range 20-78) years were hospitalizeddue to acute fulminant colitis and received treatment with high-dose GCs. Luminal nitricoxide was analyzed with chemiluminescence before therapy onset of therapy with GC andon day 3 of treatment. NOx was measured by nitrite/nitrate colorimetric assay. NO levelsand plasma NOx were compared to clinical disease activity index and C-reactive protein(CRP).

    Results: 32 responded to GC treatment and 18 did not, resulting in colectomy.The responders had higher luminal NO than non-responders (day 1: 12525±2600, day 3:15590±4157 ppb) vs non-responders (day 1: 2874±1283, day 3: 1137±297 ppb) (p<0.0114).Using an optimal cut-off NO level of 2250 ppb, sensitivity and specificity was 86% and81% for colectomy (p<0.0001). The area under the curve was 0.88 and likelihood ratio4.8. Similarly, plasma NOx was higher in responders vs non-responders (day 1: 6.2±0.3 vs3.9±0.4 umol/L) (p<0.0001). Using plasma NOx, we found a corresponding cut-off at 5umol/L with sensitivity 87% and specificity 87%. The area under the curve was 0.88 andlikelihood ratio 6.7. Luminal NO was also correlated to plasma NOx (r=0.33, p=0.0205).In the responder group, CRP levels decreased (day 1: 22.31±2.95, day 3: 15.69±3.57mg/L), whereas among non-responders CRP levels increased (day 1: 45.83±11.10, day 3:76.35±16.96 mg/L) (p<0.0167). Kaplan-Meier analysis showed that patients with baselineNO levels lower than 2250 ppb were at a significantly higher risk of colectomy within onemonth from onset of GCS treatment (p<0.0001). Twelve out of 18 (67%) in patients withday 1 NO <2250 ppb were colectomized, the corresponding number of patients with NO>2250 ppb was 3 out of 32 (9%). In a similar manner, using plasma NOx <5 uml/L foranalysis, we found 13 (72%) to be colectomized, and with >5 umol/L only two (6%).

    Conclusion: NO and its oxidation product NOx are markers of inflammatory activity in thegut. However, with more intense inflammation and mucosal damage, the less NO is produced.Luminal NO as well as plasma NOx can be used as a sensitive biomarker to predict colectomyin the outcome of acute fulminant colitis

  • 45. Hellström, Per M.
    et al.
    Hein, J
    Bytzer, P
    Björnsson, E
    Kristensen, J
    Schambye, H
    Clinical trial:  The glucagon-like peptide-1 analogue ROSE-010 for management of acute pain in patients with irritable bowel syndrome2009In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 29, no 2, p. 198-206Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    There is currently no treatment available to manage acute pain attacks in IBS patients regardless of subtype.

    AIMS:

    To evaluate efficacy and safety of the GLP-1 analogue ROSE-010 in patients with irritable bowel syndrome (IBS) through a randomized, double-blind, placebo-controlled study.

    METHODS:

    Eligible patients (n = 166) meeting Rome II criteria were randomly assigned to receive single subcutaneous injections of ROSE-010 100 microg, 300 microg and placebo in a cross-over design. Safety was assessed from spontaneously reported adverse events and measurement of vital signs. Patient-rated pain relief and intensity were measured on a 100-mm visual analogue scale. The primary efficacy variable was proportion of patients with >50% maximum total pain relief response from 10 to 60 min after treatment. Secondary endpoints included the maximum summed pain intensity difference, time to meaningful pain relief and patient ratings of satisfaction with treatment.

    RESULTS:

    Twice as many patients were responders in the primary efficacy endpoint after both ROSE-010 injections compared to placebo (24%P = 0.011, 23%P = 0.005, and 12% after 300 microg, 100 microg and placebo injections, respectively). Similar results were obtained for the proportion of patients with total pain intensity response. Times to meaningful and total pain relief were shorter for both doses of ROSE-010 compared with placebo. Compared with placebo, more patients (P < 0.05) were satisfied with ROSE-010 and considered ROSE-010 better than previous IBS medications used.

    CONCLUSION:

    ROSE-010 was well tolerated and provided fast and effective relief of acute pain attacks on demand in IBS patients.

  • 46.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hendolin, Panu
    Biohit Oyj, Clin Sci, Helsinki, Finland..
    Kaihovaara, Pertti
    Biohit Oyj, Clin Sci, Helsinki, Finland.;Univ Helsinki, Res Unit Acetaldehyde & Canc, Helsinki, Finland..
    Kronberg, Leif
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Organ Chem, Turku, Finland..
    Meierjohann, Axel
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Organ Chem, Turku, Finland..
    Millerhovf, Anders
    Univ Uppsala Hosp, Clin Trial Consultants, Uppsala, Sweden..
    Paloheimo, Lea
    Biohit Oyj, Clin Sci, Helsinki, Finland..
    Sundelin, Heidi
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Organ Chem, Turku, Finland..
    Syrjanen, Kari
    Biohit Oyj, Clin Sci, Helsinki, Finland..
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Salaspuro, Mikko
    Univ Helsinki, Res Unit Acetaldehyde & Canc, Helsinki, Finland..
    Slow-release L-cysteine capsule prevents gastric mucosa exposure to carcinogenic acetaldehyde: results of a randomised single-blinded, cross-over study of Helicobacter-associated atrophic gastritis2017In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 2, p. 230-237Article in journal (Refereed)
    Abstract [en]

    Introduction: Helicobacter-induced atrophic gastritis with a hypochlorhydric milieu is a risk factor for gastric cancer. Microbes colonising acid-free stomach oxidise ethanol to acetaldehyde, a recognised group 1 carcinogen. Objective: To assess gastric production of acetaldehyde and its inert condensation product, non-toxic 2-methyl-1,3-thiazolidine-4-carboxylic acid (MTCA), after alcohol intake under treatment with slow-release L-cysteine or placebo. Methods: Seven patients with biopsy-confirmed atrophic gastritis, low serum pepsinogen and high gastrin-17 were studied in a cross-over single-blinded design. On separate days, patients randomly received 200 mg slow-release L-cysteine or placebo with intragastric instillation of 15% (0.3 g/kg) ethanol. After intake, gastric concentrations of ethanol, acetaldehyde, L-cysteine and MTCA were analysed. Results: Administration of L-cysteine increased MTCA (p < .0004) and decreased gastric acetaldehyde concentrations by 68% (p < .0001). The peak L-cysteine level was 7552 +/- 2687 mu mol/L at 40 min and peak MTCA level 196 +/- 98 mu mol/L at 80 min after intake. Gastric L-cysteine and MTCA concentrations were maintained for 3 h. The AUC for MTCA was 11-fold higher than acetaldehyde, indicating gastric first-pass metabolism of ethanol. With placebo, acetaldehyde remained elevated also at low ethanol concentrations representing 'non-alcoholic' beverages and food items. Conclusions: After gastric ethanol instillation, slow-release L-cysteine eliminates acetaldehyde to form inactive MTCA, which remains in gastric juice for up to 3 h. High acetaldehyde levels indicate a marked gastric first-pass metabolism of ethanol resulting in gastric accumulation of carcinogenic acetaldehyde. Local exposure of the gastric mucosa to acetaldehyde can be mitigated by slow-release L-cysteine capsules.

  • 47.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Saito, Yuri A.
    Bytzer, Peter
    Tack, Jan
    Mueller-Lissner, Stefan
    Chang, Lin
    Characteristics of Acute Pain Attacks in Patients With Irritable Bowel Syndrome Meeting Rome III Criteria2011In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 106, no 7, p. 1299-1307Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    An international multicenter, prospective, non-interventional, 2-month study characterized acute pain attacks in patients with irritable bowel syndrome (IBS).

    METHODS:

    Adult patients meeting the Rome III IBS diagnostic criteria with a history of >= 3 pain attacks per month participated in a survey that captured daily and episodic information regarding IBS symptoms and pain attacks for 2 months. Acute pain attacks were defined as a sudden onset or increase in the intensity of IBS abdominal pain with a minimum intensity of 4 (0-10 scale).

    RESULTS:

    The majority (84%) of the 158 patients taking the survey were women with a mean age of 41 years and time since IBS diagnosis of 5 years. The median pain attack frequency was 5.4 attacks per month and was significantly higher in the IBS with diarrhea (IBS-D, 6.4 per month) group vs. the IBS with constipation (4.4 per month) and the IBS with mixed pattern (5.5 per month) groups (P = 0.019). The median pain attack duration was 2.8 h and the median intensity score was 7. The majority of pain attacks resulted in defecation (78%), and occurred more often in IBS-D patients than in other subgroups. The majority of pain attacks (63%) interfered with work and/or daily activities. Medication to manage pain attacks was used by 44% of patients during 29% of attacks. Although used by less than half of all patients, medication helped 66% of attacks treated.

    CONCLUSIONS:

    The frequency of severe pain attacks was 1.4 per week and the majority affected daily activities. However, most of the pain attacks were untreated in IBS patients. Pain attack management is an unmet need of IBS treatment.

  • 48.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Samuelsson, Bodil
    Danderyd Hosp, Div Orthoped, Karolinska Inst, Dept Clin Sci, Stockholm, Sweden.;Sophiahemmet Univ Coll, Stockholm, Sweden..
    Al-Ani, Amer N.
    Karolinska Univ Hosp, Dept Clin Sci & Technol Clintec, Div Orthoped, Karolinska Inst, Huddinge, Sweden..
    Hedström, Margareta
    Karolinska Univ Hosp, Dept Clin Sci & Technol Clintec, Div Orthoped, Karolinska Inst, Huddinge, Sweden..
    Normal gastric emptying time of a carbohydrate-rich drink in elderly patients with acute hip fracture: a pilot study2017In: BMC Anesthesiology, ISSN 1471-2253, E-ISSN 1471-2253, Vol. 17, article id 23Article in journal (Refereed)
    Abstract [en]

    Background: Guidelines for fasting in elderly patients with acute hip fracture are the same as for other trauma patients, and longer than for elective patients. The reason is assumed stress-induced delayed gastric emptying with possible risk of pulmonary aspiration. Prolonged fasting in elderly patients may have serious negative metabolic consequences. The aim of our study was to investigate whether the preoperative gastric emptying was delayed in elderly women scheduled for surgery due to acute hip fracture. Methods: In a prospective study gastric emptying of 400 ml 12.6% carbohydrate rich drink was investigated in nine elderly women, age 77-97, with acute hip fracture. The emptying time was assessed by the paracetamol absorption technique, and lag phase and gastric half-emptying time was compared with two gender-matched reference groups: ten elective hip replacement patients, age 45-71 and ten healthy volunteers, age 28-55. Results: The mean gastric half-emptying time in the elderly study group was 53 +/- 5 (39-82) minutes with an expected gastric emptying profile. The reference groups had a mean half-emptying time of 58 +/- 4 (41-106) and 59 +/- 5 (33-72) minutes, indicating normal gastric emptying time in elderly with hip fracture. Conclusion: This pilot study in women with an acute hip fracture shows no evidence of delayed gastric emptying after an orally taken carbohydrate-rich beverage during the pre-operative fasting period. This implies no increased risk of pulmonary aspiration in these patients. Therefore, we advocate oral pre-operative management with carbohydrate-rich beverage in order to mitigate fasting-induced additive stress in the elderly with hip fracture.

  • 49.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Smithson, A.
    Stowell, G.
    Greene, S.
    Kenny, E.
    Damico, C.
    Leone-Bay, A.
    Baughman, R.
    Grant, M.
    Richardson, P.
    Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat2012In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 179, no 1-3, p. 71-76Article in journal (Refereed)
    Abstract [en]

    Background: ROSE-010, a Glucagon-Like Peptide-1 (GLP-1) analog, reduces gastrointestinal motility and relieves acute pain in patients with irritable bowel syndrome (IBS). The rat small bowel migrating myoelectric complex (MMC) is a reliable model of pharmacological effects on gastrointestinal motility. Accordingly, we investigated whether ROSE-010 works through GLP-1 receptors in gut musculature and its effectiveness when administered by pulmonary inhalation. Materials and methods: Rats were implanted with bipolar electrodes at 5, 15 and 25 cm distal to pylorus and myoelectric activity was recorded. First, intravenous or subcutaneous injections of ROSE-010 or GLP-1 (1, 10, 100 mu g/kg) with or without the GLP-1 receptor blocker exendin(9-39)amide (300 mu g/kg.h), were studied. Second, ROSE-010 (100, 200 mu g/kg) Technosphere (R) powder was studied by inhalation. Results: The baseline MMC cycle length was 17.5 +/- 0.8 min. GLP-1 and ROSE-010. administered intravenously or subcutaneously, significantly inhibited myoelectric activity and prolonged MMC cycling; 100 mu g/kg completely inhibited spiking activity for 49.1 +/- 4.2 and 73.3 +/- 7.7 min, while the MMC cycle length increased to 131.1 +/- 11.4 and 149.3 +/- 15.5 min, respectively. Effects of both drugs were inhibited by exendin(9-39) amide. Insufflation of ROSE-010 (100, 200 mu g/kg) powder formulation totally inhibited myoelectric spiking for 52.6 +/- 5.8 and 70.1 +/- 5.4 min, and increased MMC cycle length to 102.6 +/- 18.3 and 105.9 +/- 9.5 min, respectively. Conclusions: Pulmonary delivery of ROSE-010 inhibits gut motility through the GLP-1R similar to natural GLP-1. ROSE-010 causes receptor-mediated inhibition of MMC comparable to that of intravenous or subcutaneous administration. This suggests that ROSE-010 administered as a Technosphere (R) inhalation powder has potential in IBS pain management and treatment.

  • 50.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Stålhammar, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Beydogan, H.
    QuintilesIMS, Real World Evidence Solut & HEOR, Solna, Sweden..
    Huetson, P.
    QuintilesIMS, Real World Evidence Solut & HEOR, Solna, Sweden..
    Skup, M.
    AbbVie Inc, N Chicago, IL USA..
    Agreus, L.
    Karolinska Institute.
    Indirect burden of patients with moderate inflammatory bowel disease in Uppsala County Council, Sweden: a retrospective study using real-world data2017In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 11, p. S457-S457Article in journal (Other academic)
12 1 - 50 of 91
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