Efficacy Of Octreotide Research Articles

A randomised, double blind, multicentre trial of octreotide in moderate to severe acute pancreatitis

BACKGROUNDThe pharmacological inhibition of exocrine pancreatic secretion with the somatostatin analogue octreotide has been advocated as a specific treatment of acute pancreatitis.AIMTo investigate the efficacy of octreotide in acute pancreatitis...

Octreotide in the Treatment of Refractory Diarrhea

Refractory chronic diarrhea that does not respond to specific antimicrobial therapy or standard unspecific medication may present a challening and serious clinical problem. Octreotide is a candidate drug for the treatment of these patients as it inhibits gastrointestinal motility, pancreatic secretion and inhibits intestinal absorption. Only few mostly uncontrolled studies in small patient groups were published evaluating the efficacy of octreotide in the treatment of patients with chemotherapy-induced diarrhea, short-bowel syndrome, AIDS-associated diarrhea and other conditions with chronic diarrhea not responding to standard treatment. Most of these studies are not conclusive as they yielded either negative or controversial results. Octreotide may be tried in the treatment of refractory diarrhea, in particular AIDS-associated diarrhea if patients do not respond to conventional treatment strategies. Well-designed controlled trials in large patient groups are needed in order to define the place of octreotide in the treatment of patients with refractory diarrhea.

Immunohistochemical localization of somatostatin receptor sst2A in human pancreatic islets.

Somatostatin and octreotide inhibit endocrine pancreatic functions in man, via specific somatostatin receptors. However, the cellular distribution of the different somatostatin receptor subtype proteins has not been determined in the human pancreas. Here, the immunohistochemical distribution of the sst2A receptor was investigated using the sst2A receptor specific anti-peptide antibody R2-88 in cryostat as well as in formalin-fixed paraffin-embedded sections of human pancreatic tissue, and compared with insulin, glucagon and somatostatin immunostaining of adjacent sections. All pancreatic islets were immunostained with R2-88. Most islet cells were labeled: the sst2A receptors were present in insulin as well as glucagon producing cells, but were not detected in intra-islet vessels nor in adjacent acinar tissue. Absorption of the sst2A antibody with 100 nM of the antigen peptide abolished specific staining in tissue sections. Immunohistochemical staining with R2-88 correlated with the labeling observed after receptor autoradiography using the sst2-preferring radioligand, 125I-Tyr3-octreotide. Therefore, the clinical efficacy of octreotide on glucagon and insulin release can be explained by the presence of sst2A receptors in human A and B pancreatic islet cells. Moreover, absence of sst2A receptors in human acinar tissue suggests that the action of somatostatin on pancreatic exocrine secretion is mediated either indirectly or through a different somatostatin receptor subtype on acinar cells.

Inhibition of Myointimal Proliferation by Octreotide in Canine Vein Interposition Grafts

Purpose: The aim of this study was to evaluate the efficacy of octreotide in modulating the progression of intimal hyperplasia in autogenous vein bypass grafts in a canine model. The effect of the drug on the progression of intimal hyperplasia was measured with the Gilman parameter, a measure used extensively as a wound-healing descriptor. Methods: 12 mongrel dogs were randomly and equally divided into two groups. The first group (octreotide group) was administered octreotide 20 µg/kg/day. The control group (group II) received saline solution by subcutaneous injection. Each dog had 8- to 10-cm segments of autogenous jugular vein bypassed to the femoral arteries. Quantitative data on luminel narrowing over time from intimal hyperplasia were compared from calculated Gilman parameters after image analysis of retrieved, histologically processed graft sections. Each vein graft was analyzed by computerized morphometric analysis. Results: The mean Gilman parameter for distal graft segments was 0.47 ± 0.17 mm in the control group and 0.25 ± 0.07 mm in the octreotide group 6 weeks after operation (p < 0.05). Distal graft segments between the control and octreotide groups were statistically significant. In proximal, medial and distal graft segments, the mean Gilman parameters were 0.51 ± 0.16 mm in the control group and 0.37 ± 0.18 mm in the octreotide group, the difference being statistically significant (p < 0.01). Conclusion: Octreotide significantly inhibits myointimal thickening, and these data support the efficacy of octreotide in reducing intimal hyperplasia in arterialized vein grafts during the short postoperative period. Further investigations are required to as certain whether this beneficial effect of octretide persists in the long term.

In vivo and in vitro efficacy of octreotide for treatment of enteric cryptosporidiosis.

Previous evidence suggested a role of enterotoxin in the pathophysiology of cryptosporidiosis. If so, antisecretory drugs should be effective in reducing diarrhea. We evaluated the in vivo and in vitro efficacy of octreotide, which possesses antisecretory effects, for cryptosporidial diarrhea. Two children with severe cryptosporidial diarrhea were treated with octreotide. The volume modifications and chemical composition of stools were determined. Fecal supernatant was added to Caco-2 cell monolayers mounted in Ussing chambers with or without serosal octreotide and electrical parameters were monitored. Octreotide was effective in reducing the stool volume and fecal Na+ concentration. Fecal supernatant induced an enterotoxin-like increase in transepithelial potential difference. Octreotide induced a dose-dependent decrease in basal potential difference, consistent with an absorptive effect. In cells pretreated with octreotide, fecal supernatant induced an increase in the potential difference, whose magnitude and duration were significantly reduced compared to untreated cells. These results provide in vivo and in vitro evidence for the secretory nature of cryptosporidial diarrhea and for the efficacy of octreotide through a direct interaction with the enterocyte.

Antiproliferative Effect of the Somatostatin Analogue Octreotide on Growth Hormone-Producing Pituitary Tumors: Results of a Multicenter Randomized Trial

To determine and quantify the in vivo effects of octreotide on the cell cycle kinetics of growth hormone-producing pituitary adenomas.A multicenter randomized trial had been conducted to assess the clinical efficacy of octreotide, and we studied tissue specimens from pituitary macroadenomas in 32 patients with acromegaly from that trial-16 of whom had received 4 months of octreotide therapy before surgical resection and 16 of whom had undergone surgical resection only.All tumors had been fully characterized on the basis of their immunophenotypic profile and their ultrastructural morphologic features. Included were 16 densely and 16 sparsely granulated somatotroph adenomas. In each case, immunostaining for the cell cycle-specific nuclear antigen Ki-67 was performed with use of the MIB-1 antibody. The staining reaction was manually quantified, and a tumor growth fraction was derived in each case.The mean growth fraction of tumors exposed to octreotide was suppressed by 83% in comparison with untreated surgical controls (0.011+/-0.004% versus 0.065+/-0.016%, respectively; P = 0.0068). The association between octreotide treatment and lower tumor growth fractions was statistically independent of tumor subtype, being evident among both sparsely and densely granulated somatotroph adenomas.Octreotide exerts a significant antineoplastic effect on somatotroph adenomas, one readily reflected at the level of the cell cycle. This antiproliferative response provides insight into several clinicopathologic issues surrounding octreotide therapy for these neoplasms.

Somatostatin receptor expression in clinical immunology

Specific somatostatin receptors (ssts) have been described in normal and tumor tissues and identified on more than 95% of normal mitogen-activated human peripheral lymphocytes. Somatostatin may modulate the immune response by a variety of mechanisms, most of which are inhibitory, sst scintigraphy in patients with immune-mediated diseases revealed sst expression in 97% of patients with sarcoidosis, 100% of patients with tuberculosis or Wegener's granulomatosis, 75% of patients with Sjögren's syndrome, and 50% of patients with systemic lupus erythematosus or uveitis. sst expression appeared to be related to progression or remission of disease. Patients who responded poorly to therapy remained positive at scintigraphy. Investigation of 10 human B-cell lines and eight human T-cell lines, using a polymerase chain reaction, revealed the presence of sst 2-mRNA in two of the B-cell and two of the T-cell lines. Visualization of ssts on activated mononuclear leukocytes by sst scintigraphy may prove useful in evaluating the spread of immune-mediated diseases and their responses to therapy. The efficacy of octreotide should be studied in patients with these diseases.

Octreotide in the control of post-sclerotherapy bleeding from oesophageal varices, ulcers and oesophagitis.

Bleeding from oesophageal varices, oesophageal ulcers or oesophagitis is occasionally massive and difficult to control. Octreotide, a synthetic analogue of somatostin lowers portal pressure and collateral blood flow including that through varices, increases lower oesophageal sphincter pressure, and inhibits the gastric secretion of acid as well as pepsin. Our current experience suggests it is effective in controlling acute variceal haemorrhage. Therefore we have examined the efficacy of octreotide in the control of postsclerotherapy bleeding from oesophageal varices, oesophageal ulcers and oesophagitis. During the study period 77 patients experienced a significant gastrointestinal bleed (blood pressure < 100 mm Hg, pulse > 100 beats per min or the need to transfuse 2 or more units of blood to restore the haemoglobin level) following injection sclerotherapy of oesophageal varices. The source of bleeding was varices in 42 patients, oesophageal ulcers in 31 and oesophagitis in 4. All patients received a continuous intravenous infusion of octreotide (50 μg/h) for between 40–140h. If bleeding was not controlled in the first 12h after commencing octreotide hourly bolus doses (50 μg) for 24h were superimposed on the continuous infusion. Haemorrhage was successfully controlled by an infusion of octreotide in 38 of the 42 patients with bleeding from varices, in 30 of 31 patients with oesophageal ulceration, and all patients with oesophagitis. In the 1 patient with persistent bleeding from oesophageal ulceration and in 2 of the 4 with continued haemorrhage from varices, haemostasis was achieved by hourly boluses of 50 μg octreotide for 24h in addition to the continuous infusion. No major complications were associated with octreotide administration. The results of this study clearly indicate that octreotide is a safe and effective treatment for the control of severe haemorrhage after technically successful injection sclerotherapy.

The place of octreotide in the medical management of the dumping syndrome.

Following gastric surgery, 25-50% of patients experience dumping symptoms. Early dumping usually involves both gastro-intestinal and vasomotor complaints, while late dumping involves mainly the latter. Management is mainly achieved by dietary modification. Drug therapy has been investigated, without consistent success. However, the somatostatin analogue octreotide alleviates dumping by slowing gastric emptying, inhibiting insulin release, decreasing enteric peptide secretion and intestinal absorption of water and sodium, slowing monosaccharide absorption, increasing gut transit time and preventing haemodynamic changes. The short-term efficacy of octreotide has been confirmed in five randomised, controlled trials. Promising results are also available from long-term studies on a limited number of patients.

Efficacy of octreotide in controlling refractory diarrhea following bone marrow transplantation

We report the use of octreotide in 10 patients with severe diarrhea, refractory to loperamide, following bone marrow transplantation (BMT). Five patients had regime‐related toxicity (RRT) and 5 were suffering from acute intestinal graft versus host disease (GVHD). Complete responses were observed for all patients with RRT, with optimal response being observed with dose escalation to 250 ug tds. Only partial responses were observed in the patients with intestinal GvHD. Increased doses of systemically administered cyclosporin‐A (CSA) were necessary to maintain therapeutic levels for 2 patients. Octreotide is very effective in controlling RRT diarrhea. It is less effective in the control of GvHD‐related diarrhea. CSA levels require close monitoring, whether the drug is administered systemically or orally.

Efficacy of octreotide in the prevention of pancreatic fistula after elective pancreatic resections: A prospective, controlled, randomized clinical trial

A prospective, randomized controlled clinical trial was conducted in 33 Italian surgical departments with the aim of evaluating the efficacy of octreotide in the prevention of pancreatic fistula after elective pancreatic resections. Between July 1990 and May 1992, 278 patients were enrolled in the study. Fifty-four dropped out because of unresectable disease and six were excluded because of protocol violation; the remaining 218 were randomly assigned to the octreotide group (n = 111) or to the placebo group (n = 107). There were 131 men and 87 women with a mean age of 58.2 +/- 11.7 yrs. Pancreaticoduodenectomy was the most common operation performed (n = 143), sixty-four percent of patients had a pancreatic or periampullary cancer; chronic pancreatitis accounted for 8.2% of cases. Mortality rate was 6.9%. A pancreatic fistula occurred in 31 patients (14.2%), 9% in the octreotide group and 19.6% in the placebo group (p < 0.05). Morbidity rate was significantly lower in the octreotide (21.6%) than in the placebo group (36.4%) (p < 0.05). When specific pancreatic complications were grouped together and evaluated, they occurred less frequently in the treated (15.3%) than in the placebo group (29.9%) (p < 0.05). Octreotide was able to reduce significantly the incidence of pancreatic fistula after elective pancreatic resections.

Gastroenteropancreatic Endocrine Tumours: Effects of Octreotide Treatment

Octreotide is particularly useful in patients with resistant acromegaly and some gastroenteropancreatic (GEP) tumours, e.g. VIPomas, carcinoids and glucagonomas. The efficacy of octreotide can be attributed to its action regarding somatostatin receptors on GEP tumour cells. The symptoms of these tumours are due to a greater extent to the peptides they secrete than to their actual size. In most patients these symptoms improve or disappear completely with octreotide treatment. Side effects of treatment are mainly mild and do not necessitate withdrawal of the treatment. Octreotide is currently the drug of choice for controlling the symptoms of inoperable GEP tumours.

Intérêt de l'octréotide dans le traitement des fistules entérocutanées postopératoires

Two patients with enterocutaneous fistulas (ileal and duodenal) were successfully treated with bowel rest, total parenteral nutrition and the somatostatine analogue octreotide (150 μg · day −1 and 300 μg · day −1 respectively). At the time octreotide was started the first patient had a high output fistula (1 000 mL · day −1), the second had a low output fistula (120 mL · day −1). Within 24 hours of treatment, a reduction of at least 40 % of the output was observed. The time intervals to fistula closure were respectively 6 days and 10 days after initiation of octreotide therapy. Glucose intolerance was not observed. The efficacy of octreotide combined with total parenteral nutrition supports its routine use instead of somatostatine, more expensive, less tolerated and presenting the risk of rebound effect.

Prophylaxis of Complications after Pancreatic Surgery: Results of a Multicenter Trial in Italy

An Italian prospective multicentre study evaluated the efficacy of octreotide, a synthetic somatostatin analogue, in preventing the complications of elective pancreatic surgery. 303 patients with tumours of the pancreas or the ampullary region, in whom ultrasonography and computed tomography scan had shown a resectable lesion, or with chronic pancreatitis, were randomized in a double-blind fashion to treatment with octreotide 100 micrograms t.i.d. s.c. starting at least 1 h before surgery and continued till the 7th postsurgical day, or with matching placebo. Unresectable lesions were found at laparatomy in 31 patients (15% of those with tumours). In 14 others, procedures not anticipated in the study protocol had to be performed, and in 6 additional cases there were other protocol violations so that these 20 patients were excluded from the study analysis. Considering the 252 evaluable patients, the complication rate was significantly higher in the 130 placebo-treated patients than in the 122 who received octreotide (29.2 vs. 15.6%; p = 0.01). We therefore suggest that octreotide may substantially reduce the risk of complications after elective pancreatic surgery.

Peptide Receptor Analysis in Neuroendocrine Gastroenteropancreatic Tumors

Peptide and growth factor receptors are frequently expressed in high density in human tumors. A particularly high abundance of receptors for the peptide somatostatin (SS) is found in neuroendocrine tumors of the pancreas and gastrointestinal tract. 90% of the carcinoids and a majority of islet cell carcinomas, including their metastases, have usually a high density of SS receptors. The number of receptors correlates with the degree of differentiation of the tumor. Several different SS receptor subtypes can be expressed by these tumors, the SSTR2 subtype being the most frequently and abundantly expressed. The somatostatin receptors in tumors are identified with in vitro binding methods, molecular biology techniques or in vivo imaging techniques; the latter allow the precise localization of the tumors and their metastases in the patients. Since SS receptors in human hormone-producing gastroenteropancreatic tumors are functional, their identification can be used to predict the therapeutic efficacy of octreotide to inhibit excessive hormone release. Undifferentiated tumors, such as atypical carcinoids, exocrine pancreatic carcinomas and most of the colorectal carcinomas, usually do not express SS receptors in the tumor itself, but, interestingly, may trigger the expression of SS receptors in the peritumoral veins, where SS may play a role in hemodynamic tumor-host interactions.

Octreotide Therapy for Thyroid-Stimulating Hormone-Secreting Pituitary Adenomas: A Follow-up of 52 Patients

To evaluate the efficacy of octreotide in the treatment of pituitary thyroid-stimulating hormone (TSH)-secreting adenomas. Combination of review and original data. Review data included information supplied by Sandoz Pharmaceuticals from patient case report forms and information from abstracts and articles published in the French or English language between 1987 and 1991. Original data included follow-up data on 15 of 37 previously reported cases and data on 15 new cases provided by 11 investigators. Fifty-two cases from 24 medical centers in nine countries reported between 1987 and 1991. Chief clinical characteristics of the patients; dose and duration of octreotide treatment; serum TSH, thyroid hormone, and free alpha-subunit levels before and during treatment; serial anatomic evaluation of the pituitary gland by either computed tomographic scanning or magnetic resonance imaging; and side effects. After the first octreotide dose (50 to 100 micrograms), TSH levels decreased in all but 2 patients (mean decrease for the whole group, 55.8% +/- 27%). Levels of alpha-subunit decreased in 15 of the 19 patients who had alpha-subunit assessments (mean decrease, 37.5% +/- 24%). Reduction of TSH levels after short-term treatment (50 or 100 micrograms two or three times daily) was observed in 30 to 33 patients (mean decrease, 74.1%). Thyroid hormone levels were reduced in all patients and returned to normal in 73%. Despite an initial response to therapy, thyroid hormone levels continued to rise ("true escape") in 2 patients receiving short-term therapy and in 3 patients receiving long-term therapy. Partial shrinkage of the adenoma occurred in 11 patients. Octreotide is an effective treatment for TSH-secreting adenomas. Thyroid-stimulating hormone levels almost always decreased, and thyroid hormone levels reverted to normal in about three quarters of patients. Partial tumor shrinkage was observed in one third of patients receiving long-term octreotide treatment.

Somatostatin analog sandostatin and inhibition of tumor growth in patients with metastatic endocrine gastroenteropancreatic tumors.

A prospective study was performed to determine the efficacy of octreotide (Sandostatin; SMS 201-995) 200 micrograms tid in controlling tumor growth. The study included 21 patients with metastasized endocrine GEP tumors: 6 gastrinomas, 8 carcinoid syndromes, 7 nonfunctioning tumors. Treatment was performed for 3 to 59 months (median 15 months). Evaluation of the response to octreotide was facilitated in 12 patients by a pretreatment observation period of 3 to 47 months (median 17 months) during which the natural growth behavior was determined. Based on the presence or absence of a control period prior to treatment, 5 patients were considered to be responders, 7 as questionable responders (no pretreatment phase available), and 9 as nonresponders. None of the 21 patients had documented shrinkage of the tumor mass. The most favorable response was tumor standstill. In all but one responder an escape to an initially favorable response occurred after 6 to 28 months (median 14 months). Proved inhibition of growth was paralleled by a reduction of serum and urine hormone parameters, whereas unaltered progression of tumor growth was observed also in the presence of hormone suppression. Tumor growth and hormone release was inhibited in the absence and presence of somatostatin receptors on the tumor. It is concluded that octreotide exerts a limited effect on metastatic GEP tumor growth. The evaluation of a response to octreotide is facilitated by an observation period prior to the drug that provides information on growth characteristics of the tumor. The presence of octreotide receptors does not predict the success of therapy.

Effects of a chronic treatment with octreotide in patients with functionless pituitary adenomas.

The effects of a chronic treatment with octreotide were evaluated in 19 patients affected with functionless pituitary adenomas. Octreotide caused a significant decrease of GH and IGF-I levels in all the patients and no significant change in thyroid, adrenal and gonadal function. In contrast, during the therapy, the glucose response to an oral glucose tolerance test considerably increased and was delayed, while the insulin response decreased and was delayed. Serum alpha-subunit (alpha-SU) was above normal in 10 of 16 patients in which this evaluation was performed: octreotide caused a significant decrease (p < 0.01) of alpha-SU levels in 6 of these 10 patients. Octreotide did not induce any significant change in visual fields except in 1 patient, who had a great improvement of visual perimetry and a decrease of alpha-SU levels but unmodified CT scan features. In our series of patients, octreotide was ineffective in reducing tumor mass. The efficacy of octreotide might rely on the presence of somatostatin receptors on adenoma-cell membranes. Therefore patients with functionless adenomas to be treated with octreotide might be identified with pituitary scintiscan using the recently available labeled 111In-octreotide.

Efficacy of octreotide and desmopressin in reducing blood loss in patients with angiodysplasia: [formula omitted], G. Tamponi, A. Borchiellini. Chair of Haematology, University of Turin, Italy

Efficacy of octreotide and desmopressin in reducing blood loss in patients with angiodysplasia: [formula omitted], G. Tamponi, A. Borchiellini. Chair of Haematology, University of Turin, Italy

Gastrin-dependent inhibitory effects of octreotide on the genesis of gastric ECLomas.

The efficacy of octreotide in the regulation of endocrine tumor secretion and symptomatology has been well documented. Its effects on neuroendocrine tumor generation and cell proliferation are less well understood. The purpose of this study was to determine if blockade of somatostatin receptors by octreotide would alter gastrin levels and influence enterochromaffin-like (ECL) cell proliferation. The well-established gastric ECLoma model of the rodent, mastomys, was used. Animals received loxtidine (1 mg/kg/day), an irreversible H2 blocker, and subcutaneous slow release, octreotide pellet implants (150 or 300 micrograms/kg/day) or placebo pellets for a 4-month period. Control parameters for gastric mucosal thickness, plasma gastrin level, ECL cell density, and bromodeoxyuridine-positive cells were 517 +/- 20 microns, 46.1 +/- 11.4 pmol/L, 7.4 +/- 0.9 cells/visual field, and 13.8 +/- 2.6 cells/visual field, respectively. After loxtidine-placebo treatment all values were significantly increased (p < 0.05; 883 +/- 70 microns, 192.8 +/- 10.6 pmol/L, 97 +/- 16.2 cells/visual field, and 51.7 +/- 19.2 cells/visual field, respectively). High dose octreotide significantly inhibited all parameters (668 +/- 3.5 microns, 66.2 +/- 20.5 pmol/L, 37.0 +/- 8.0 cells/visual field, and 10.9 +/- 2.2 cells/visual field; p < 0.05). Low dose octreotide failed to significantly inhibit ECL cell density mucosal thickness, or cell proliferation. Irreversible H2 receptor blockade results in hypergastrinemia and ECL cell tumor generation. Hypergastrinemia, ECL cell hyperplasia, and cell proliferation are significantly inhibited by in vivo blockade of somatostatin receptors by administration of octreotide.