Prolonged large bowel transit increases serum deoxycholic acid: a risk factor for octreotide induced gallstones. (9/953)

BACKGROUND: Treatment of acromegaly with octreotide increases the proportion of deoxycholic acid in, and the cholesterol saturation of, bile and induces the formation of gallstones. Prolongation of intestinal transit has been proposed as the mechanism for the increase in the proportion of deoxycholic acid in bile. AIMS: To study the effects of octreotide on intestinal transit in acromegalic patients during octreotide treatment, and to examine the relation between intestinal transit and bile acid composition in fasting serum. METHODS: Mouth to caecum and large bowel transit times, and the proportion of deoxycholic acid in fasting serum were measured in non-acromegalic controls, acromegalic patients untreated with octreotide, acromegalics on long term octreotide, and patients with simple constipation. Intestinal transit and the proportion of deoxycholic acid were compared in acromegalic patients before and during octreotide. RESULTS: Acromegalics untreated with octreotide had longer mouth to caecum and large bowel transit times than controls. Intestinal transit was further prolonged by chronic octreotide treatment. There were significant linear relations between large bowel transit time and the proportion of deoxycholic acid in the total, conjugated, and unconjugated fractions of fasting serum. CONCLUSIONS: These data support the hypothesis that, by prolonging large bowel transit, octreotide increases the proportion of deoxycholic acid in fasting serum (and, by implication, in bile) and thereby the risk of gallstone formation.  (+info)

Effects of octreotide treatment on early TNF-alpha production and localization in experimental chronic colitis. (10/953)

BACKGROUND: Colitis induced by trinitrobenzene sulphonic acid (TNB) is a model of Th1 disease, mainly explored from the third day of induction. It has recently been shown that octreotide and other somatostatin analogues can modify inflammatory/immune processes by acting on cytokines. AIM: To examine TNFalpha production and the effect of preventive treatment with octreotide, during the early phase of TNB-colitis. METHODS: Thirty milligrams TNB with 50% ethanol was instilled into the colon of male Wistar rats. Treated groups received octreotide (2x10 microg x day/rat) or dexamethasone (1x2 mg x day/kg), subcutaneously, with the first injection before TNB. Eight and 80 h later, the colon was excised and processed for histology, TNFalpha immunohistochemistry, quantification of cytokine release ex vivo and tissue-inducible NO synthase (iNOS) activity. RESULTS: Maximal TNFalpha production was observed at the 8th hour, associated with intense immunostaining of the external muscle layer. Octreotide treatment decreased TNFalpha expression (staining and activity) and iNOS activity. At the 80th hour, submucosal macrophages were positive for TNFalpha and colonic production of IL1beta and interferon gamma was increased; all these effects were reduced by octreotide treatment. CONCLUSIONS: TNFalpha was expressed early by resident muscle cells, before staining of infiltrated immune cells and increased production of interferon gamma. TNFalpha regulation by octreotide suggests that this drug might exert anti-inflammatory properties via smooth muscle cells.  (+info)

Comparison of 111In-DOTA-Tyr3-octreotide and 111In-DTPA-octreotide in the same patients: biodistribution, kinetics, organ and tumor uptake. (11/953)

Scintigraphy with [111In-diethylenetriamine pentaacetic acid0-D-Phe1]-octreotide (DTPAOC) is used to demonstrate neuroendocrine and other somatostatin-receptor-positive tumors. Despite encouraging results, this 111In-labeled compound is not well suited for peptide-receptor-mediated radiotherapy of somatostatin-receptor-positive tumors. Another somatostatin analog, [1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid0, D-Phe1, Tyr3]-octreotide (DOTATOC), can be labeled with the beta-emitter 90Y in a stable manner. METHODS: We compared the distribution, kinetics and dosimetry of 111In-DTPAOC and 111In-DOTATOC in eight patients to predict the outcomes of these parameters in patients who will be treated with 90Y-DOTATOC. RESULTS: Serum radioactivity levels for the radiopharmaceuticals did not differ significantly 2-24 h after injection (P>0.05). Up to 2 h postinjection they were slightly, but significantly, lower after administration of 111In-DOTATOC (P < 0.01 at most time points). The percentage of peptide-bound radioactivity in serum did not differ after administration of either compound. Urinary excretion was significantly lower after administration of 111In-DOTATOC (P < 0.01). The visualization of known somatostatin-receptor-positive organs and tumors was clearer after administration of 111In-DOTATOC than after administration of 111In-DTPAOC. This was confirmed by significantly higher calculated uptakes in the pituitary gland and spleen. The uptake in the tumor sites did not differ significantly (P > 0.05), although in three of the four patients in whom tumor uptake could be calculated, it was higher after administration of 111In-DOTATOC. CONCLUSION: The distribution and excretion pattern of 111In-DOTATOC resembles that of 111In-DTPAOC, and the uptake in somatostatin-receptor-positive organs and most tumors is higher for 111In-DOTATOC. If 90Y-DOTATOC shows an uptake pattern similar to 111In-DOTATOC, it is a promising radiopharmaceutical for peptide-receptor-mediated radiotherapy in patients with somatostatin-receptor-positive tumors.  (+info)

Locoregional regulatory peptide receptor targeting with the diffusible somatostatin analogue 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC): a pilot study in human gliomas. (12/953)

Human gliomas, especially of low-grade type, have been shown to express high-affinity somatostatin receptor type 2 (J-C. Reubi et al., Am. J. Pathol, 134: 337-344, 1989). We enrolled seven low-grade and four anaplastic glioma patients in a pilot study using the diffusible peptidic vector 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC) for receptor targeting. The radiopharmakon was locoregionally injected into a stereotactically inserted Port-a-cath. DOTATOC competes specifically with somatostatin binding to somatostatin receptor type 2 in the low nanomolar range as shown by a displacement curve of 125I-[Tyr3]-octreotide in tumor tissue sections. Diagnostic (111)In-labeled DOTATOC-scintigraphy following local injection displayed homogeneous to nodular intratumoral vector distribution. The cumulative activity of regionally injected peptide-bound 90Y amounted to 370-3300 MBq, which is equivalent to an effective dose range between 60 +/- 15 and 550 +/- 110 Gy. Activity was injected in one to four fractions according to tumor volumes; 1110 MBq of 90Y-labeled DOTATOC was the maximum activity per single injection. We obtained six disease stabilizations and shrinking of a cystic low-grade astrocytoma component. The only toxicity observed was secondary perifocal edema. The activity:dose ratio (MBq:Gy) represents a measure for the stability of peptide retention in receptor-positive tissue and might predict the clinical course. We conclude that SR-positive human gliomas, especially of low-grade type, can be successfully targeted by intratumoral injection of the metabolically stable small regulatory peptide DOTATOC.  (+info)

Clinical and morphological features of undifferentiated monomorphous GH/TSH-secreting pituitary adenoma. (13/953)

A 41-year-old male presented with progressive visual defects, acromegaly and hyperthyroidism. After clinical evaluation a giant GH/TSH-secreting pituitary adenoma was diagnosed. Administration of the somatostatin analog octreotide at doses of 150 microg s.c. per day inhibited the secretion of both GH and TSH. A three-week treatment with octreotide prior to surgery led to slight visual improvement and CT scan showed some new necrotic areas within the tumor mass. Transcranial surgery was performed. By immunohistochemical analyses of the adenoma tissue GH, prolactin and beta-chorionic gonadotropin were detected; TSH was negative. Electron microscopy revealed an undifferentiated, monomorphous adenoma with morphological features of an acidophil stem cell adenoma such as the presence of misplaced exocytoses, fibrous bodies and mitochondrial gigantism. However, the tumor cells contained small secretory granules (up to 250 nm) accumulated along the cell membrane characteristic of thyrotrope cells. Furthermore, some adenoma cells were fusiform with long cytoplasmic processes resembling thyrotropes. Two months after the operation CT scan revealed a large residual tumor. Serum GH and TSH levels had increased again and the TSH level was even higher than before the treatment. The patient died suddenly, most probably of lethal arrhythmia. Specimens of the adenoma tissue obtained at autopsy confirmed the previous findings with the exception of positive immunostaining for TSH which was found in less than 1% of the adenoma cells. This undifferentiated, monomorphous GH/TSH-secreting pituitary adenoma represents an entity that is unusual both in its ultrastructural features and clinical manifestations suggesting a cytogenesis from an early, undifferentiated stem cell.  (+info)

IGF-I production by adult rat hepatocytes is stimulated by transforming growth factor-alpha and transforming growth factor-beta1. (14/953)

Previously, we have observed that epidermal growth factor (EGF), a potent mitogen for cultured hepatocytes, stimulates the production of IGF-I and IGF-binding proteins (IGFBPs) by cultured hepatocytes from adult rats. This study was undertaken to investigate the possibility that other growth factors of hepatic origin could specifically be involved in the regulation of IGF-I and IGFBP expression. The effects of transforming growth factor-alpha (TGF-alpha), through EGF receptors to induce a mitogenic response, and transforming growth factor-beta1 (TGF-beta1), produced by non-parenchymal liver cells and able to inhibit hepatocyte proliferation in vivo and in culture, have been studied in cultured adult rat hepatocytes. Our results demonstrate that TGF-alpha and TGF-beta1 significantly stimulate IGF-I and IGFBP secretion by cultured hepatocytes but no change in the abundance of IGF-I and IGFBP mRNAs was observed with respect to controls. Cycloheximide is able to inhibit both basal and TGF-stimulated release of IGF-I and a similar effect was elicited by octreotide, the somatostatin analog, known to directly affect hepatic IGF-I gene expression. Our findings show the role of the liver in the secretion of IGF-I and IGFBPs, not only under endocrine and nutritional control but also under autocrine and paracrine control.  (+info)

A randomised, double blind, multicentre trial of octreotide in moderate to severe acute pancreatitis. (15/953)

BACKGROUND: The pharmacological inhibition of exocrine pancreatic secretion with the somatostatin analogue octreotide has been advocated as a specific treatment of acute pancreatitis. AIM: To investigate the efficacy of octreotide in acute pancreatitis in a randomised, placebo controlled trial. METHODS: 302 patients from 32 hospitals, fulfilling the criteria for moderate to severe acute pancreatitis within 96 hours of the onset of symptoms, were randomly assigned to one of three treatment groups: group P (n=103) received placebo, while groups O1 (n=98) and O2 (n=101) received 100 and 200 microg of octreotide, respectively, by subcutaneous injection three times daily for seven days. The primary outcome variable was a score composed of mortality and 15 typical complications of acute pancreatitis. RESULTS: The three groups were well matched with respect to pretreatment characteristics. An intent to treat analysis of all 302 patients revealed no significant differences among treatment groups with respect to mortality (P: 16%; O1: 15%; O2: 12%), the rate of newly developed complications, the duration of pain, surgical interventions, or the length of the hospital stay. A valid for efficacy analysis (251 patients) also revealed no significant differences. CONCLUSIONS: This trial shows no benefit of octreotide in the treatment of acute pancreatitis.  (+info)

Octreotide suppresses the incretin glucagon-like peptide (7-36) amide in patients with acromegaly or clinically nonfunctioning pituitary tumors and in healthy subjects. (16/953)

OBJECTIVE: To study the effect of octreotide on glucagon-like peptide (7-36) amide (GLP-1) and insulin secretion in patients with pituitary tumors during preoperative treatment and in healthy subjects. DESIGN: Open design prospective clinical study. METHODS: Eighteen patients with pituitary macroadenomas (13 clinically nonfunctioning (NFA; 11/13 had GH insufficiency), 5 GH secreting (GHA)) received preoperative octreotide treatment: 3x100 microg/day s. c. for 3 months, and 3x500 microg/day s.c. for an additional 3 months. Seven healthy subjects received (for ethical reasons) only 3x100 microg/day for 10 days. A standardized meal (St-M) test, oral glucose test (oGTT) and i.v. glucose test (ivGTT) were done before octreotide therapy, on days 1, 2 and 3 (D1,2,3), after 3 months (M3) and 6 months (M6) of octreotide treatment in the patients, and before treatment, on D1,2,3 and on D8,9,10 of octreotide treatment in the healthy subjects. Serum GLP-1, insulin and GH as well as plasma glucose were determined for 180 min (oGTT, St-M) or 120 min (ivGTT). RESULTS: Pretreatment fasting GLP-1 concentrations as well as integrated responses (area under the curve 0-180 min) to oGTT and St-M were not significantly different between NFA, GHA and healthy subjects. During the oGTT, octreotide initially almost abolished the early (0-60 min) and diminished the late (60-180 min) GLP-1 and insulin responses in patients and healthy subjects. At M6 integrated insulin responses had significantly recovered, while the increase in GLP-1 response failed to reach significance (GLP-1: 56.5% of pretreatment at D2 versus 93.5% at M6 and 41.2 versus 63.1% in NFA and GHA respectively; insulin: 50.2 versus 71.2% and 35.5 versus 70. 4%). An escape of GLP-1 and insulin in healthy subjects (D2 versus D9) was not significant. Intestinal glucose absorption was apparently not reduced, since the early glucose rise was similar before and during octreotide treatment. During the St-M the GLP-1 and insulin responses were similarly suppressed by octreotide and recovered during ongoing treatment (GLP-1: 49.6% of pretreatment at D1 versus 79.0% at M6 in NFA and 46.9 versus 52.9% in GHA. Insulin: 27.6 versus 83.9% and 23.5 versus 54.4%). The escape was significant in NFA but not in GHA. In the healthy subjects the escape was already significant on D8 (GLP-1: 39.5% of pretreatment at D1 versus 68.3% at D8; insulin: 36.6 versus 53.8%). During the ivGTT GLP-1 did not increase. The early insulin response (0-30 min) was abolished by octreotide, followed by a reduced peak at 60 min. The reduction of the integrated insulin response during ivGTT was similar to that during oGTT. An insulin escape reached significance only for NFA (52. 6% of pretreatment at D3 versus 66.7% at M6). Glucose tolerance (KG value) deteriorated and did not improve during ongoing treatment. Octreotide suppressed the median GH concentration (8h profile) of the GHA patients from 10.3 microg/l (pretreatment) to 5.8, 6.3 and 3. 7 microg/l at D4, M3 and M6 with no escape. GH was 1.5 microg/l postoperatively. CONCLUSIONS: Octreotide abolishes the early and diminishes the late GLP-1 and insulin responses to oGTT and St-M in NFA and GHA patients and in healthy subjects. In contrast to GH, both hormones partially escape from suppression during ongoing therapy. During treatment with our conventional octreotide doses suppression of insulin secretion is maximal. Under these conditions an effect of the additional loss of GLP-1 is not apparent. Basal GLP-1 concentrations and integrated responses to oGTT and St-M were similar in healthy subjects and in patients with GH excess or GH insufficiency.  (+info)