Therapies with CCL25 require controlled release via microparticles to avoid strong inflammatory reactions.

BACKGROUND: Chemokine therapy with C-C motif chemokine ligand 25 (CCL25) is currently under investigation as a promising approach to treat articular cartilage degeneration. We developed a delayed release mechanism based on Poly (lactic-co-glycolic acid) (PLGA) microparticle encapsulation for intraarticular injections to ensure prolonged release of therapeutic dosages. However, CCL25 plays an important role in immune cell regulation and inflammatory processes like T-cell homing and chronic tissue inflammation. Therefore, the potential of CCL25 to activate immune cells must be assessed more thoroughly before further translation into clinical practice. The aim of this study was to evaluate the reaction of different immune cell subsets upon stimulation with different dosages of CCL25 in comparison to CCL25 released from PLGA particles. RESULTS: Immune cell subsets were treated for up to 5 days with CCL25 and subsequently analyzed regarding their cytokine secretion, surface marker expression, polarization, and migratory behavior. The CCL25 receptor C-C chemokine receptor type 9 (CCR9) was expressed to a different extent on all immune cell subsets. Direct stimulation of peripheral blood mononuclear cells (PBMCs) with high dosages of CCL25 resulted in strong increases in the secretion of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-1ß (IL-1ß), tumor-necrosis-factor-α (TNF-α) and interferon-γ (IFN-γ), upregulation of human leukocyte antigen-DR (HLA-DR) on monocytes and CD4+ T-cells, as well as immune cell migration along a CCL25 gradient. Immune cell stimulation with the supernatants from CCL25 loaded PLGA microparticles caused moderate increases in MCP-1, IL-8, and IL-1ß levels, but no changes in surface marker expression or migration. Both CCL25-loaded and unloaded PLGA microparticles induced an increase in IL-8 and MCP-1 release in PBMCs and macrophages, and a slight shift of the surface marker profile towards the direction of M2-macrophage polarization. CONCLUSIONS: While supernatants of CCL25 loaded PLGA microparticles did not provoke strong inflammatory reactions, direct stimulation with CCL25 shows the critical potential to induce global inflammatory activation of human leukocytes at certain concentrations. These findings underline the importance of a safe and reliable release system in a therapeutic setup. Failure of the delivery system could result in strong local and systemic inflammatory reactions that could potentially negate the benefits of chemokine therapy.

Isogeneic MSC application in a rat model of acute renal allograft rejection modulates immune response but does not prolong allograft survival.

Application of mesenchymal stromal cells (MSCs) has been proposed for solid organ transplantation based on their potent immuno-modulatory effects in vitro and in vivo. We investigated the potential of MSCs to improve acceptance of kidney transplants in an MHC-incompatible rat model including isogeneic kidney transplantation (RTx) as control. MSCs were administered i.v. or i.a. at time of transplantation. No immunosuppression was applied. Renal function was monitored by serum-creatinine, histopathology, immunochemistry for graft infiltrating cells and expressions of inflammatory genes. We demonstrated the short-term beneficial effects of MSC injection. In the long term, however, MSC-related life-threatening/shortening events (thrombotic microangiopathy, infarctions, infections) were evident despite decreased T- and B-cell infiltration, lower interstitial inflammation and downregulated inflammatory genes particularly after i.a. MSC injection. We conclude that i.a. MSC administration provides efficient immunomodulation after allogeneic RTx, although timing and co-treatment strategies need further fine-tuning to develop the full potential of powerful cell therapy in solid organ transplantation.

Optimal resource allocation in colonoscopy: timing of follow-up colonoscopies in relation to adenoma detection rates.

BACKGROUND AND STUDY AIMS: The assessment of indications for follow-up colonoscopy may help to improve the allocation of available endoscopy resources. The aim of this study was to assess the timing of early follow-up colonoscopy and surveillance utilization in relation to adenoma detection rate (ADR) at follow-up. METHODS: An assessment of the timing and yield of follow-up colonoscopies was performed in patients with non-inflammatory bowel disease (IBD) in a Dutch multicenter study. The primary outcome was the number of patients with a prior (index) colonoscopy. The necessity for follow-up procedures was assessed using the ADR. RESULTS: Of 4800 consecutive patients undergoing a colonoscopy, 1249 non-IBD patients had undergone an index colonoscopy. Of these, follow-up procedures were performed within 1 year in 27 % (331/1249). Excluding incomplete colonoscopy, incomplete polypectomy, or poor bowel preparation on index, the ADR on early follow-up was 4 % for symptomatic and 26 % for asymptomatic patients. Among the asymptomatic patients with a follow-up colonoscopy at > 1 year (n = 463), an ADR of 23 % (108/463) was found. In 27 % of these patients, the observed surveillance intervals were in accordance with American Gastroenterological Association (AGA) surveillance recommendations; 60 % were classified as over-utilization and 13 % as under-utilization according to the AGA. Optimal utilization follow-up colonoscopies had higher ADRs on follow-up compared with over-utilized procedures (31 % vs. 17 %; P < 0.001). CONCLUSIONS: Follow-up colonoscopy in symptomatic patients within a year has limited value in terms of adenoma detection. A considerable proportion of surveillance colonoscopies are performed too early according to current guidelines, resulting in low detection rates. Both aspects can be targeted for optimal usage in endoscopic capacity.

Comparison of magnetic resonance enteroclysis and capsule endoscopy with balloon-assisted enteroscopy in patients with obscure gastrointestinal bleeding.

BACKGROUND AND STUDY AIMS: New modalities are available for visualization of the small bowel in patients with possible obscure gastrointestinal bleeding (OGIB), but their performance requires further comparison. This study compared the diagnostic yield of magnetic resonance enteroclysis (MRE) and capsule endoscopy in patients with OGIB, using balloon-assisted enteroscopy (BAE) as the reference standard. PATIENTS AND METHODS: Consecutive consenting patients who were referred for evaluation of OGIB were prospectively included. Patients underwent MRE followed by capsule endoscopy and BAE. Patients with high grade stenosis at MRE did not undergo capsule endoscopy. The reference standard was BAE findings in visualized small-bowel segments and expert panel consensus for segments not visualized during BAE. RESULTS: Over a period of 26 months, 38 patients were included (20 female [53 %]; mean age 58 years, range 28 - 75 years). Four patients (11 %) did not undergo capsule endoscopy due to high grade small-bowel stenosis at MRE (n = 3; 8 %) or timing issues (n = 1; 3 %). Capsule endoscopy was non-diagnostic in one patient. The reference standard identified abnormal findings in 20 patients (53 %). MRE had sensitivity, specificity, and positive and negative likelihood ratios of 21 %, 100 %, infinity, and 0.79, respectively. The corresponding values for capsule endoscopy were 61 %, 85 %, 4.1, and 0.46. The reference standard and capsule endoscopy did not differ in percent positive findings (P = 0.34), but MRE differed significantly from the reference BAE (P < 0.001). Capsule endoscopy was superior to MRE for detecting abnormalities (P = 0.0015). CONCLUSION: Capsule endoscopy performed better than MRE in the detection of small-bowel abnormality in patients with OGIB. MRE may be considered as an alternative for the initial examination in patients with clinical suspicion of small-bowel stenosis.

Optimal preparation for video capsule endoscopy: a prospective, randomized, single-blind study.

BACKGROUND AND STUDY AIM: Visualization of the small bowel by video capsule endoscopy (VCE) is frequently impaired by intestinal contents. Different bowel preparations have been studied with controversial results. The aim of this study was to determine a satisfactory and tolerable bowel preparation for VCE. METHODS: Ninety patients were randomized to three preparation regimens. Group A underwent VCE after clear liquid diet and overnight fast, while groups B and C received respectively 1 or 2 L of polyethylene glycol (PEG) solution before VCE. For each VCE five segments of 10 minutes were selected, one at the start of each quartile of the small-intestinal transit time, the fifth being the last 10 minutes of the ileum transit. Mucosal visibility was regarded as good if more than 75 % of the mucosa could be evaluated. All patients answered a questionnaire regarding procedure tolerability. RESULTS: The use of PEG solution led to a significant improvement in mucosal visualization. Mucosal visibility was good in the terminal ileum in 25 % of patients in group A, 52 % in group B, and 72 % in group C. The diagnostic yield did not change significantly. The use of 2 L of PEG solution was considered more uncomfortable than no PEG solution or 1 L of the same. CONCLUSION: One liter of PEG solution improves mucosal visualization without causing discomfort for the patient.

[Occult gastrointestinal bleeding due to a Dieulafoy lesion in the terminal ileum]. / Occult gastro-intestinaal bloedverlies door een laesie van Dieulafoy in het terminale ileum.

A 50-year-old man awaiting liver transplantation for primary sclerosing cholangitis developed iron-deficiency anaemia. Repeated occult gastrointestinal bleeding led to an increasing need for blood transfusions. After multiple oesophagogastroduodenoscopies and colonoscopies, videocapsule endoscopy finally demonstrated a polyp-like lesion in the terminal ileum. The lesion had not been detected despite two attempts (oral and anal) at double-balloon enteroscopy and even a peroperative enteroscopy. Only during a second laparotomy, again involving peroperative enteroscopy, a small red lesion was detected and resected 80 cm proximal to the ileocecal valve (Bauhin's valve). Histology revealed a Dieulafoy lesion. Four months later, after normalisation and stabilisation of his haemoglobin level, the patient received a successful liver transplant. If the cause of occult gastrointestinal bleeding in a patient remains unclear despite regular endoscopic procedures, new techniques like videocapsule endoscopy and double-balloon enteroscopy may contribute to identifying the cause. This may lead to an exceptional finding such as a Dieulafoy lesion in the distal ileum.

Results of videocapsule endoscopy in 250 patients with suspected small bowel pathology.

We aimed to assess technical feasibility, clinical applicability, and diagnostic yield of videocapsule endoscopy (VCE) in a large group of unselected patients. VCE was performed with the Given Imaging swallowable capsule. Findings were considered diagnostic if the observed finding could explain the symptomatology of the patient. Findings were considered suspicious if an observed finding failed to completely explain the patient's symptoms. We studied 250 patients. A definite diagnosis was made in 95 patients (38%). Suspicious findings were noted in 80 patients (32%). No diagnosis was obtained in 74 patients (30%). The yield of VCE was higher in patients with suspected Crohn's disease. Mean viewing time decreased significantly from 51 +/- 14 to 30 +/- 7 minutes after reviewing 50 procedures. VCE is an important diagnostic tool, but a definite diagnosis is established in only 38% of the patients. The highest diagnostic yield is obtained in patients with suspected Crohn's disease.

Video capsule endoscopy: procedure, indications and diagnostic yield.

Video capsule endoscopy (VCE) is a new noninvasive imaging technique for the complete small bowel. It provides good to excellent visualisation of the mucosa of the small bowel and has a high diagnostic yield in selected patients with gastrointestinal blood loss of suspected small bowel origin and in patients with Crohn's disease. In comparison with small bowel X-ray and push enteroscopy, diagnostic yield appears to be superior. Although VCE is becoming increasingly popular, good studies on its clinical implications and application are only just emerging. In this paper we review the possibilities and limitations of clinical application of VCE.

Clinical application of video capsule endoscopy.

BACKGROUND: Non-invasive imaging of the complete small bowel has become possible with the recently available video capsule endoscopy technique. The aim of this study was to review and assess the possibilities and limitations of the clinical application of video capsule endoscopy. METHODS: Literature review. RESULTS: Video capsule endoscopy is a new promising technique with good to excellent visualization of the mucosa of the small bowel. It has a high diagnostic yield in patients with occult gastrointestinal blood loss (OGIB) and Crohn disease (CD). Several other indications need further study. Compared to small-bowel X-ray and push enteroscopy, diagnostic yield appears to be superior. Video capsule endoscopy is very well tolerated by patients. Its most important limitation is the impossibility of taking biopsies and therapeutic interventions. CONCLUSION: Video capsule endoscopy is a promising new diagnostic tool for small-bowel disease.

Remifentanil-sevoflurane anaesthesia for laparoscopic cholecystectomy: comparison of three dose regimens.

The objective of this study was to determine a dosing regimen for remifentanil-sevoflurane anaesthesia that achieves an optimal balance between quality of anaesthesia and time to recovery. Patients undergoing elective laparoscopic cholecystectomy were randomly allocated to receive 0.4, 0.8 or 1.2 MAC (minimal alveolar concentration) of sevoflurane combined with remifentanil as required to maintain stable anaesthesia. For induction of anaesthesia, the remifentanil dose was 25 microg x kg(-1) x h(-1) and the mean propofol dose which was required to obtain loss of consciousness was 1.59 mg x kg(-1). During the maintenance phase, the mean remifentanil dose was 16.0, 14.1 and 13.0 microg x kg(-1) x h(-1) for the 0.4, 0.8 and 1.2 MAC groups, respectively. The mean sevoflurane maintenance dose was 0.91, 1.24 and 2.1% end-tidal for the 0.4, 0.8 and 1.2 MAC groups, respectively. The incidence of somatic responses was significantly higher in the 0.4 MAC sevoflurane group. Recovery times were significantly faster in the 0.4 compared to the 0.8 and 1.2 MAC groups and in the 0.8 compared to the 1.2 MAC group. The combination of 14 microg x kg(-1) x h(-1) remifentanil and 1.24% end-tidal sevoflurane achieved the optimal balance between the quality, and recovery from anaesthesia.

Absence of apolipoprotein E4 genotype, good gallbladder motility and presence of solitary stones delay rather than prevent gallstone recurrence after extracorporeal shock wave lithotripsy.

BACKGROUND/AIMS: Extracorporeal shock wave lithotripsy (ESWL) with adjuvant bile salt dissolution therapy may be successful in selected gallstone patients, but the considerable risk of recurrence is a major drawback. Apolipoprotein E4 genotype and impaired gallbladder motility have been identified as major risk factors for recurrence during short-term follow up. We have now examined their relevance during long-term follow up. METHODS: Eighty-four cholesterol gallstone patients (55 solitary and 29 multiple (two to ten) stones) were followed prospectively up to 10 years after complete stone disappearance. Various potential risk factors for recurrence were evaluated. RESULTS: Gallstone recurrence was found in up to 80% of patients at 10 years follow-up. Absence of the apolipoprotein epsilon4 allele, initial solitary stones, good gallbladder emptying (i.e. minimal postprandial volume < or = 6 ml) and 2-year postdissolution ursodeoxycholic acid prophylaxis (in ten patients) all delayed but did not prevent recurrence. In contrast, regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was identified as an independent protective factor, with greatly decreased recurrence (at 10 years: 58 vs 93% in non-NSAID users, P = 0.03). CONCLUSIONS: Non-apolipoprotein E4 genotype, presence of solitary stones and good gallbladder emptying delay rather than prevent recurrence after initially successful ESWL. Regular use of NSAIDs may prevent recurrence.

Interdigestive gallbladder emptying, antroduodenal motility, and motilin release patterns are altered in cholesterol gallstone patients.

The role of interdigestive gallbladder emptying in gallstone formation is unknown. In fasting healthy subjects, gallbladder emptying is associated with antral phase III of the migrating motor complex (MMC) and high plasma motilin. Therefore, gallbladder volumes and motilin levels were measured during 13 MMC cycles in 10 cholesterol gallstone patients and compared with 20 MMC cycles in 10 healthy subjects. MMC cycle length was longer in gallstone patients than in healthy subjects (158.2 +/- 17.0 vs 105.5 +/- 10.4 min, respectively; P < 0.05), due to longer phase I (39.8 +/- 5.7 vs 17.2 +/- 3.7 min, respectively; P < 0.05). In contrast to healthy subjects, gallstone patients had no significant fluctuations of gallbladder volume during the MMC cycle, and motilin concentrations were not different in MMC cycles with phase III originating in antrum or duodenum. During MMC cycles with phase III originating in the duodenum, motilin levels were twice as high in gallstone patients as in healthy subjects (P < 0.002). In conclusion, cholesterol gallstone patients have an abnormal MMC and motilin release pattern. Their interdigestive gallbladder emptying is reduced and dissociated from the MMC. These disturbances may contribute to gallstone formation.

Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR.

BACKGROUND: Acromegalic patients treated three times daily with subcutaneous injections of the somatostatin analogue octreotide frequently develop gallstones, due to suppressed cholecystokinin release and impaired gall-bladder emptying. AIM: To elucidate the effects of a new long-acting octreotide formulation (Sandostatin LAR) on gall-bladder emptying, cholecystokinin release and gallstone formation. METHODS: Postprandial gall-bladder and gastric emptying were determined by ultrasonography and cholecystokinin release was measured in seven patients on days 0, 14, 28, and 75 (Sandostatin LAR, 20 mg intramuscularly on days 1, 30, and 60). RESULTS: During treatment, fasting gall-bladder volumes increased from 26.5 +/- 3.2 mL to 61.4 +/- 7.5 mL, but postprandial cholecystokinin release and gall-bladder emptying (from 63.9 +/- 3.8% to 12.3 +/- 3.5%) were severely suppressed. Gallstones formed in six out of seven patients within 8 months of treatment. Gastric emptying did not change during the therapy. CONCLUSIONS: The risk of gallstone formation is greatly increased during Sandostatin LAR. This is probably related to profound suppression of cholecystokinin release and gall-bladder emptying.

Hodgkin's disease presenting as a parasternal chest wall mass.

A 53 year-old Moroccan woman presented with a tender parasternal mass. Computerized tomography showed a mediastinal mass protruding through the sternum. Cytologic examination of fluid collected from the mass repeatedly showed acute inflammation. Tuberculostatics were started. Since patient did not improve on tuberculostatics, a small supraclavicular lymph node was removed. Histologic examination showed Morbus Hodgkin of the nodular sclerosing type. Ultimately, cytologic examination of fluid from the parasternal mass showed atypical cells. Response on chemotherapy was excellent with complete disappearance of the parasternal mass. This is a very unusual extranodal presentation of Hodgkin's disease.

Motilin induces gall bladder emptying and antral contractions in the fasted state in humans.

BACKGROUND: Animal studies have shown that motilin affects gall bladder motility. In humans, no effect has been shown, but erythromycin, a motilin receptor agonist, induces gall bladder emptying. AIMS: To explore the effect of increasing doses of exogenous motilin on gall bladder volume and antral contractility in the fasted state in humans. METHODS: After an overnight fast, eight healthy men received increasing intravenous doses of Leu13-motilin (KW-5139) or 0.9% NaCl in a double blind, randomised fashion. Gall bladder volume and antral contraction frequency were determined by ultrasonography. RESULTS: Infusion of motilin increased plasma motilin levels. Motilin induced a reduction in gall bladder volume of 8.0 (5.0)%, 17.1 (5.0)%, 18.5 (4.7)%, and 16.1 (4.9)% of baseline volume at the end of infusion of 2, 4, 8, and 16 pmol/kg/min respectively, compared with mean stable gall bladder volumes during placebo infusion (p < 0.05). Antral contraction frequency increased during motilin infusion, but not during placebo infusion (p < 0.05). CONCLUSIONS: Exogenous motilin reducted fasting gall bladder volume and increased antral contractions. After reaching maximal reduction, the gall bladder volume did not decrease further during continuous motilin infusion at higher doses and stayed at the same reduced volume. The degree of gall bladder volume reduction during motilin infusion mimicked gall bladder emptying preceding antral phase III activity of the migrating motor complex in humans. This study indicates that motilin may play a physiological role in the regulation of gall bladder emptying in the fasted state.

Effect of bile salts on in vitro gallbladder motility: preliminary study.

Impaired postprandial gallbladder emptying may be an important factor in cholesterol crystals precipitation and subsequent gallstone formation. We previously found strongly increased bile salt concentrations in gallbladder bile of gallstone patients with weak (< 50% fasting volume) postprandial gallbladder contraction compared to patients with strong (> 50%) postprandial contraction. Therefore, we studied potential effects of various conjugated and unconjugated bile salts with different relative hydrophobicity on in vitro contractility of gallbladder muscle strips obtained at cholecystectomy. Strips were incubated 5 min with bile salt at concentrations of 10(-8)-10(-4)M. The effect of 10(-3)M acetylcholine was measured and related to preincubation control value. Bile salts used were, in order of increasing hydrophobicity: tauroursodeoxy-, ursodeoxy-, tauro-, taurodeoxy- and deoxycholate. Ursodeoxy- and tauroursodeoxycholate did not significantly reduce gallbladder contractility. Taurocholate significantly reduced contractility at concentrations of 10(-6) M and higher, taurodeoxycholate at 10(-7) M and higher and deoxycholate at 10(-5) M and higher. Contractility induced by acetylcholine 10(-3) M at a bile salt concentration of 10(-4) M was 66.0 +/- 11.7% (taurocholate), 50.2 +/- 6.2% (deoxycholate) and 44.8 +/- 11.5% (taurodeoxycholate) of control. The effect of bile salts correlated with their relative hydrophobicity (r = -0.97; p < 0.01). Suppressing effects on gallbladder muscle strip contractility were long lasting and remained after rinsing. Results show that bile salts in the physiological dose range inhibit in vitro gallbladder contraction. If this mechanism exists in vivo, it may have important implications for gallbladder motility regulation.

Gallbladder emptying in vivo, bile composition, and nucleation of cholesterol crystals in patients with cholesterol gallstones.

BACKGROUND/AIMS: Impaired postprandial gallbladder emptying may provide time for progressive bile concentration with formation of instable cholesterol-rich vesicles and fast nucleation of cholesterol crystals. The aim of this study was to assess postprandial gallbladder emptying, bile composition, and nucleation of cholesterol crystals in the same patient. METHODS: In 30 patients with cholesterol gallstones, postprandial gallbladder emptying was measured ultrasonographically. In each patient, gallbladder bile composition (obtained at cholecystectomy) and nucleation of cholesterol crystals was determined. Patients were divided in 22 strong contractors (> 50% postprandial gallbladder emptying) and 8 weak contractors. RESULTS: In weak contractors, bile salt and phospholipid concentrations were much higher than in strong contractors (234.6 +/- 24.7 vs. 130.3 +/- 10.8 mmol/L [P < 0.001] and 44.5 +/- 3.5 vs. 30.2 +/- 3.1 mmol/L [P < 0.05], respectively). Cholesterol concentrations were comparable in strong and weak contractors. Consequently, total lipid concentration was significantly higher (15.5 +/- 1.4 and 9.2 +/- 0.7 g/dL; P < 0.001) and cholesterol saturation index significantly lower (0.90 +/- 0.08 and 1.61 +/- 0.17; P < 0.001) in weak contractors. Nucleation time, percentage of cholesterol in vesicles, bile salt species, and molecular species of phosphatidylcholine were not significantly different. CONCLUSION: Differences in bile composition can be linked to different patterns of postprandial gallbladder emptying and may point to two different pathways of gallstone formation.

The effects of the 3-hydroxy, 3-methylglutaryl coenzyme A reductase inhibitor pravastatin on bile composition and nucleation of cholesterol crystals in cholesterol gallstone disease.

3-hydroxy,3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce biliary cholesterol saturation index (CSI) in duodenal bile in hypercholesterolemic patients and might be useful for gallstone dissolution. However, preliminary data suggest that these drugs are not effective in this respect. We therefore studied 33 patients with radiolucent gallstones in an opacifying gallbladder who were scheduled for elective cholecystectomy. Patients were treated with 40 mg pravastatin day-1 or placebo during the 3 weeks before surgery. Six patients could not be evaluated. Baseline characteristics (age, sex, body mass index, serum cholesterol, and the solitary/multiple gallstone ratio) were similar in both groups. Serum cholesterol fell by 39% in the pravastatin group (P < .001) and remained unchanged in the placebo group. Biliary cholesterol (9.5 +/- 1.3 vs. 14.3 +/- 1.5 mmol/L, P = .026), and phospholipid concentrations (24.8 +/- 3.9 vs. 36.7 +/- 3.9 mmol/L, P = .043) were lower in the pravastatin group. Although bile salt concentrations were lower in the pravastatin group (114 +/- 21 vs. 152 +/- 15 mmol/L), this difference was not significant. CSI was not different between both groups (142 +/- 27% [pravastatin] vs. 113 +/- 6% [placebo], P = NS). Cholesterol crystals were present in fresh bile in 7 of 13 patients in the pravastatin group and in 11 of 14 controls (P = NS). Nucleation time was comparable between the 2 groups (13 +/- 3 vs. 9 +/- 3 days, P = NS). Bile salt species and molecular species of phospholipids determined with high-performance liquid chromatography did not differ either between both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of octreotide on fasting gall bladder emptying, antroduodenal motility, and motilin release in acromegaly.

Subcutaneous octreotide (Sandostatin) injections lead to gall stone formation in 13-50% of acromegaly patients during one year of therapy. This study explored the effects of octreotide on interdigestive gall bladder emptying, antroduodenal motility, and motilin release. Ambulatory antroduodenal manometry was performed in six acromegaly patients before and after two months of octreotide therapy (100 micrograms thrice daily, subcutaneously). Ultrasonographic gall bladder volume measurements and plasma motilin concentrations were obtained during two migrating motor complex (MMC) cycles. Before octreotide treatment, nine of 26 phase III activities started in the antrum and 17 of 26 in the duodenum whereas during treatment 47 of 48 of phase III activity started in the duodenum (p < 0.05). Before treatment, interdigestive gall bladder emptying (mean (SEM) 39.9 (4.0)% of maximal fasting volume) and plasma motilin peaks preceded antral phase III but not duodenal phase III. During octreotide therapy no significant motilin fluctuation or gall bladder emptying was seen. Fasting gall bladder volume increased from 40.9 (9.1) ml before to 68.0 (14.8) ml (p < 0.05) during octreotide treatment. In conclusion, two months' treatment with octreotide increases the number of duodenal phase III like activity and virtually abolishes antral phase III, plasma motilin peaks, and interdigestive gall bladder emptying. These effects might contribute to the high risk of gall stone formation during longterm octreotide treatment.