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PubMed1991

Octreotide stimulates insulin-like growth factor binding protein-1 (IGFBP-1) levels in acromegaly.

Insulin-like growth factors (IGFs) circulate in a complexed state with several binding proteins (BPs). Of these, IGFBP-1 is regulated by hormonal and nutritional factors. The somatostatin analogue, octreotide, has been used to effectively control hypersomaototropism in acromegaly. IGFBP-1 levels were measured by RIA in 17 acromegalic patients receiving octreotide. Serum hormone sampling was conducted hourly for 8 hr periods. Among 13 octreotide responders, mean pre-treatment basal GH, IGF-1, and IGFBP-1 levels were 19 +/- 5 micrograms/L, 1021 +/- 168 micrograms/L, and 36 +/- 8 micrograms/L respectively. One month following octreotide treatment, an acute subcutaneous injection (100 micrograms) maximally attenuated GH to 3 +/- 0.6 microgram/L (18% of control, P less than 0.03) and IGF-1 to 467 +/- 75 micrograms/L (46% of control, P less than 0.008) after 4 hrs. IGFBP-1 levels, however, were stimulated to 95 +/- 16 micrograms/L (297% of control, P less than 0.003) during the same time period. A significant increase in IGFBP-1 levels occurred within 2 hrs (158% of baseline, P less than 0.03), and was sustained until the 7th hr following injection. Insulin, a known suppressor of IGFBP-1, did not change during this time. Among the 4 octreotide non-responders, mean basal IGFBP-1 levels were 42 +/- 4 micrograms/L, and 4 hrs following octreotide administration IGFBP-1 was 40 +/- 7 micrograms/L. Octreotide induced a dynamic inverse relationship between circulating GH and IGFBP-1 levels (r = -0.73, P less than 0.001). The absence of IGFBP-1 changes in octreotide non-responders and the non-suppression of insulin in octreotide responsive patients, suggest a direct GH-mediated mechanism of IGFBP-1 regulation in octreotide treated patients with acromegaly. IGFBP-1 may be another useful marker in evaluating the response of acromegaly to octreotide treatment in patients who experience clinical benefit but equivocal GH and IGF-1 attenuation.

Acromegaly↗
PubMed1992

Octreotide stimulates insulin-like growth factor-binding protein-1: a potential pituitary-independent mechanism for drug action.

As the long-acting somatostatin analog octreotide attenuates polypeptide hormone hypersecretion, it has recently been used to effectively treat acromegaly and gastrointestinal carcinoid tumors. Most growth-promoting actions of GH are mediated by insulin-like growth factor-I (IGF-I), which circulates complexed with multiple binding proteins (IGFBPs). IGFBP-1, a nonglycosylated peptide, competes with the IGF-I receptor for ligand binding and also regulates IGF action. To examine GH-independent mechanisms for octreotide regulation of the GH axis, circulating levels of IGFBP-1 were measured hourly after sc octreotide or saline administration in normal and GH-deficient adults. As IGFBP-1 is inhibited by insulin and GH, the dynamic pattern of alterations in GH and insulin levels was also assessed. After octreotide (100 micrograms) administration to 10 normal subjects, mean IGFBP-1 concentrations were stimulated from 23 +/- 4 to 72 +/- 18 micrograms/L (P < 0.007 vs. saline) after 2 h. Maximal induction of IGFBP-1 levels occurred after 3 h (325 +/- 115 micrograms/L; P < 0.02 vs. saline) and remained elevated (P < 0.005) for 6 h. IGFBP-1 was induced by octreotide in all subjects and was confirmed by Western ligand blotting. Insulin and GH levels preceding the rise in IGFBP-1 were unaltered by octreotide. Octreotide stimulated IGFBP-1 5-fold during a sustained fast in 4 normal subjects, despite equally suppressed insulin levels in both saline- and octreotide-treated groups. In 4 GH-deficient adults, IGFBP-1 levels were stimulated by octreotide from 16 +/- 3 to 146 +/- 36 and 154 +/- 28 micrograms/L after 3 and 4 h, respectively. In conclusion, the somatostatin analog octreotide induces IGFBP-1 independently of GH and insulin. As IGFBP-1 regulates the action of IGF-I, octreotide stimulation of IGFBPs may represent an additional pharmacological mechanism for attenuating the GH-IGF-I axis.

Adolescent↗
PubMed2001

Bim-23244, a somatostatin receptor subtype 2- and 5-selective analog with enhanced efficacy in suppressing growth hormone (GH) from octreotide-resistant human GH-secreting adenomas.

Although both somatostatin receptor subtype 2 (SSTR2) and SSTR5 messenger ribonucleic acid (mRNA) are consistently expressed in GH-secreting adenomas, SSTR2 has been believed to be the key modulator of somatostatin-mediated inhibition of GH release. The somatostatin agonists currently in clinical use, octreotide and lanreotide, are directed mainly to SSTR2 (IC(50) 12- to 18-fold higher than for SSTR5). Recently, however, it was demonstrated that an SSTR5 preferential agonist, BIM-23268, not only suppressed PRL release from prolactinomas and mixed GH-PRL adenomas, but also inhibited GH release in about half of GH adenomas. In addition, the SSTR5-preferring analog showed a slight additive effect when used in combination with SSTR2 preferential drugs at submaximal concentrations in octreotide partially sensitive adenomas. In the present study we quantified SSTR2 and SSTR5 mRNA expression and the GH-suppressive effects of somatostatin-14; octreotide; a SSTR2-preferential compound, BIM-23197; a SSTR5-preferential compound, BIM-23268; and a new SSTR2- and SSTR5-bispecific compound, BIM-23244, in GH-secreting tumors classified as either full responders to octreotide (n = 5) or partially sensitive to octreotide (n = 5). The octreotide-sensitive GH secretory adenomas presented with a high level of both SSTR2 and SSTR5 mRNA expression [222 +/- 61 and 327 +/- 136 pg/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH), respectively]. In these tumors the suppression of GH release was similarly achieved at picomolar ranges by octreotide, BIM-23197, and BIM-23244 (EC(50) = 25 +/- 15, 3 +/- 2, and 3 +/- 3 pmol/L, respectively). The compounds preferential for only SSTR5 were unable to inhibit GH release in such tumors. Among the octreotide partially responsive tumors, SSTR2 mRNA expression was 9-fold lower than in the octreotide-sensitive tumors (25 +/- 12 vs. 222 +/- 61 pg/pg GAPDH; P < 0.015), whereas SSTR5 mRNA expression was approximately 7-fold higher than in the octreotide-sensitive tumors (2271 +/- 1197 pg/pg GAPDH). In these octreotide partially responsive tumors, the SSTR5-preferential compound, BIM-23268, and the SSTR2- and SSTR5-bispecific compound, BIM-23244, were quite effective in suppressing GH secretion (EC(50) = 25 +/- 13 and 50 +/- 31 pmol/L, respectively). Similarly, BIM-23244, was able to suppress by 51 +/- 5% PRL release from five mixed GH- and PRL-secreting adenomas. These data indicate that due to heterogeneous expression of SSTR2 and SSTR5 receptor subtypes, in GH-secreting tumors, a bispecific analog, such as BIM-23244, that can activate both receptors could achieve better control of GH hypersecretion in a larger number of acromegalic patients.

Acromegaly↗
PubMed1998

Characterization of the transport of a cationic octapeptide, octreotide, in rat bile canalicular membrane: possible involvement of P-glycoprotein.

The cyclic cationic octapeptide octreotide is known to be taken up by hepatocytes, with more than 70% of an intravenous dose being excreted into bile in unchanged form. We have already reported that a transporter other than the canalicular multispecific organic anion transporter (cMOAT) is responsible for the biliary excretion of octreotide in vivo. The aim of this study is to obtain an insight into the transporter of octreotide in bile canalicular membrane. The effect of various compounds on the ATP-dependent uptake of octreotide by rat bile canalicular membrane vesicles (CMV) was investigated. The ATP-dependent uptake of [14C]octreotide by CMV was inhibited by verapamil, vincristine and PSC833 in a concentration-dependent manner, the maximum inhibitory effects of these compounds being almost equal to that of excess unlabeled octreotide, while taurocholic acid (TCA) caused no inhibition at concentrations much higher than the Km of TCA uptake by CMV. Mutual inhibition between octreotide and dinitrophenylglutathione (DNP-SG), a representative substrate for cMOAT was only minor and could only be observed at concentrations much higher than the Km for each ligand uptake. To examine the contribution of P-glycoprotein to the biliary excretion of octreotide in vivo, biliary excretion of octreotide was compared between P-glycoprotein-induced rats by phenothiazine (PTZ) treatment and normal rats. A significant increase in the biliary excretion rate was observed in PTZ-treated rats. Only a slight decrease in biliary excretion was observed in mdr1a knock-out mice compared with normal mice, which may be explained by the associated induction of mdr1b. These results demonstrate that the transporter for octreotide is different from cMOAT and the bile acid transporter. The involvement of P-glycoprotein in the biliary excretion of octreotide is suggested.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Octreotide exerts different effects in vivo and in vitro in Cushing's disease.

The effect of the long-acting somatostatin analog octreotide (SMS 201-995) on adrenocorticotropin (ACTH) secretion was studied in five patients with untreated Cushing's disease in vivo and in six human corticotropic adenoma cell cultures in vitro. For the in vivo study, 100 micrograms of octreotide sc was given 30 and 180 min after cannulation of the cubital vein and 100 micrograms of corticotropin-releasing hormone (CRH) was injected iv at 210 min. Serum ACTH and cortisol levels were measured for 390 min. In vivo, octreotide had no significant effect either on basal or CRH-stimulated ACTH levels and did not influence cortisol levels. The in vitro studies were conducted with corticotropic adenoma cell cultures derived from adenoma tissue obtained from six patients with Cushing's disease. In four of six cell cultures, octreotide (1 nmol/l-1 mumol/l) inhibited basal ACTH secretion in a dose-dependent manner. The inhibition ranged from 70 to 92% for 1 nmol/l octreotide to 14-46% for 1 mumol/l octreotide as compared to controls (100%). In three of three octreotide-responsive adenoma cell cultures investigated. CRH-stimulated ACTH secretion was suppressed by octreotide. Hydrocortisone pretreatment in vitro abolished the inhibitory effect of octreotide on ACTH secretion in one octreotide-responsive corticotropic adenoma cell culture. In conclusion, we showed that octreotide in most cases could inhibit the ACTH release from human corticotropic adenoma cells in vitro but had no suppressive effect on ACTH levels of patients with Cushing's disease in vivo. This discrepancy could be due to a somatostatin receptor down-regulation by cortisol at the hypercortisolemic state in vivo.

Adrenal Cortex Neoplasms↗
PubMed2000

Occurrence and effects of octreotide antibodies during nasal, subcutaneous and slow release intramuscular treatment.

OBJECTIVE: Previous studies have indicated that antibody formation against octreotide is extremely rare. We examined the occurrence of octreotide antibody formation after treatment with three administration forms in large populations of patients with acromegaly or carcinoid syndrome. DESIGN: (i) Nasally administered octreotide: 70 previously untreated patients and 81 previously s.c. octreotide-treated patients participated. (ii) Subcutaneously administered octreotide: 172 acromegalic patients and 59 patients with carcinoid syndrome treated for up to 12 years participated. (iii) Intramuscularly administered depot octreotide (Sandostatin LAR): 62 acromegalic patients participated. METHODS: Presence of antibodies is defined as increased precipitation by polyethylene glycol of (125)I-octreotide after incubation with serum; this was also used for screening of cross-reaction with somatostatin and lanreotide (Somatuline). RESULTS: In patients who received nasal octreotide for at least 9 and up to 12 months (n=42), the occurrence of octreotide antibodies was 77% and 81% for previously untreated and treated patients respectively. In subcutaneously treated patients it was 63/231 (27%) after a mean exposure of 3 years. In patients treated for more than 5 years (n=53) it was 57% and after 8 years (n=18) 72%. In contrast, no patient could with certainty be identified to be antibody-positive after a mean of 2.5 years intramuscular Sandostatin LAR treatment (n=47). In all populations, the antibody-positive patients were as well controlled as the antibody-negative patients. Octreotide antibodies did not cross-react with native somatostatin (n=141), while about 25% of the antibody-positive sera did cross-react with the somatostatin analogue, lanreotide (Somatuline, Ipstyl, Angiopeptin). CONCLUSIONS: Antibody formation against octreotide is much more frequent than previously believed. It depends primarily on drug exposure time and route of administration. It does not alter the GH/IGF-I status in treated acromegalic patients and induces only mild local reactions in some patients.

Acromegaly↗
PubMed1989

Octreotide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in conditions associated with excessive peptide secretion.

Octreotide is an analogue of somatostatin. Like endogenous somatostatin, it exerts a potent inhibitory effect on the release of anterior pituitary growth hormone and thyroid-stimulating hormone, and peptides of the gastroenteropancreatic endocrine system, while overcoming some of the shortcomings of exogenously administered somatostatin, namely a short duration of action, a need for intravenous administration and postinfusion rebound hypersecretion of hormone. Clinical studies have shown that octreotide is effective in the treatment of acromegaly and thyrotrophinomas. In comparative trials octreotide was significantly superior to bromocriptine in patients with acromegaly. Octreotide also appears to provide a significant advantage over existing therapies in the management of the carcinoid syndrome and offers considerable therapeutic potential in reversing carcinoid crises which may be life-threatening. Trials in patients with tumours producing vasoactive intestinal peptide demonstrated that octreotide may be an effective first-line choice for this condition, which has usually metastasised and become refractory to traditional symptomatic therapy. In limited studies in patients with high-output secretory diarrhoea, including cryptosporidium-related diarrhoea associated with AIDS and in patients with small bowel fistulas, octreotide has been shown to be effective in reducing stool/fistula output. However, well-designed clinical trials are still required to confirm its long term usefulness in these disorders. Similarly, although the use of octreotide in other conditions such as neonatal hypoglycaemia caused by nesidioblastosis, reactive pancreatitis, insulin-dependent diabetes mellitus, postprandial hypotension and the dumping syndrome has provided encouraging preliminary results, more studies are needed to clarify the place of octreotide in their treatment. Overall, octreotide appears to be well tolerated with the most frequently reported reactions being pain at the site of injection and gastrointestinal symptoms such as abdominal cramps, nausea, bloating, flatulence, diarrhoea and steatorrhoea. These adverse effects usually abate with time. Additionally, octreotide, like endogenous somatostatin, may also result in cholelithiasis, presumably by altering fat absorption and possibly by decreasing motility of the gallbladder. Thus, octreotide represents a new departure from traditional therapies in the treatment of various pathophysiological states associated with excessive peptide production and secretion. It offers a significant advantage over existing therapies in the medical management of patients with acromegaly, thyrotrophinomas, the carcinoid syndrome, tumours producing vasoactive intestinal peptide and severe secretory diarrhoea in whom conventional management options have either become exhausted or have provided suboptimal symptomatic relief.

Animals↗
PubMedDate not supplied

Octreotide inhibits pancreatic exocrine secretion and prevents pancreatoenterostomy leakage.

The effects of octreotide, a synthetic somatostatin analogue, were examined in 43 Japanese patients with pylorus-preserving pancreatoduodenectomy. The 43 patients were divided into two groups: 13 patients to whom a daily dose of 100 microg of octreotide was administered continuously and subcutaneously for the first 10 postoperative days (octreotide group); and 30 patients to whom octreotide was not administered (control group). Within 10 postoperative days, pancreatoenterostomy leakage was evident in one (7.7%) of the 13 patients in the octreotide group, but in five (16.7%) of the 30 patients in the control group. The total amount of the pancreatic juice drained externally during the first 10 postoperative days was 848+/-200 ml in the octreotide group and 1152+/-180 ml in the control group. When limited to 20 patients who underwent pancreatoenterostomy with total tube drainage, the amount of pancreatic juice in 10 patients in the octreotide group examined was 796+/-232 ml, which was significantly lower than the 1690+/-334 ml in 10 patients in the control group examined (P < 0.05). Of the 10 patients in the octreotide group, the amount of pancreatic juice during postoperative days 6-10 when octreotide was given was reduced to 382+/-104 ml compared to 445+/-108 ml during postoperative days 11-15 when octreotide was not administered (P < 0.05). These findings suggest that subcutaneous injection of octreotide, 100 microg per day during the first 10 postoperative days, inhibits pancreatic exocrine secretion and decreases pancreatoenterostomy leakage.

Adult↗
PubMed1989

The use of the long-acting somatostatin analogue, octreotide acetate, in patients with islet cell tumors.

Octreotide lowers plasma concentrations of the marker peptide in the majority of patients with islet cell tumors. However, as described above the effect of octreotide on plasma concentrations of marker peptides is not necessarily related to the effect on symptoms. Nevertheless octreotide is capable of producing symptomatic relief in a large proportion of patients with islet cell tumor syndromes. The data on the effect of octreotide on the symptoms due to VIPoma and due to the carcinoid syndrome (presumably including some who have islet cell tumors) are strong and the drug has been approved for these indications by the Food and Drug Administration. With respect to the other islet cell tumor syndromes, the published data suggest that the utility of octreotide differs in the different syndromes. Insulinomas are usually single, benign, and can and should be removed surgically, resulting in cure. Octreotide therefore has no role to play in such patients, particularly since the response of insulinomas is variable. However in the 10 per cent of insulinomas that are malignant octreotide is certainly effective in at least a portion of cases, although as yet the true response rate and efficacy compared with diazoxide is not clear. Although octreotide is effective at reducing acid output, and thus improving symptoms in patients with Zollinger-Ellison syndrome, because of the effectiveness of histamine H2-receptor antagonists and omeprazole, there is no need for octreotide in this syndrome. For patients with glucagonoma, GHRHoma, Cushing's syndrome, and other rare islet cell tumor syndromes octreotide may well be of benefit and should be considered. The current data do not support the use of octreotide for an antitumor effect.

Adenoma, Islet Cell↗
PubMed1995

Octreotide-associated biliary tract dysfunction and gallstone formation: pathophysiology and management.

Octreotide exerts a wide range of biological actions, many of which have important clinical applications, notably in treatment of acromegaly, gastroenteropancreatic endocrine tumors, and secretory diarrhea. In most patients, octreotide is well tolerated. Side effects are primarily gastrointestinal and are usually transient. Short term (< or = 1 month) octreotide therapy appears to pose minimal risk of gallstone formation, but the risk may increase with longer treatment periods. Chronic octreotide administration may increase the incidence of small, cholesterol gallstones that are typically asymptomatic. The mechanism of octreotide-associated gallstone formation is not delineated but may involve inhibition of gallbladder emptying, hepatic bile secretion, and sphincter of Oddi motility, as well as modification of bile composition. Gallbladder stasis may sequentially lead to increased bile concentration, precipitation of cholesterol and calcium salts, retention of biliary precipitates, and maturation of gallstones. Octreotide-associated gallstones are usually asymptomatic and do not require surgical or medical therapy. Some physicians advocate periodic gallbladder ultrasound evaluations, but, in most cases, the results would not influence management of asymptomatic patients. Symptomatic gallstones may require surgery or nonsurgical treatments after an appropriate work-up. Gallstone prevention strategies (e.g., bile acid or nonsteroidal anti-inflammatory drug therapy) during long term octreotide therapy are under investigation. Currently, clinicians may want to consider noninvasive strategies to reduce gallstone incidence, such as timing octreotide injections in relation to meals or periodic cessation of octreotide treatment. Octreotide is a valuable therapeutic option in managing a variety of hypersecretory states associated with high morbidity and mortality (e.g., acromegaly, carcinoid syndrome, and VIP-secreting tumors), so the benefits of long term octreotide therapy (such as increased quality of life) outweigh the risk of asymptomatic gallstone formation in many patients.

Bile↗
PubMed1995

Fluctuations in the secretion of pancreatic enzymes between consecutive doses of octreotide: implications for the management of fistulae.

OBJECTIVE: To determine whether variations in pancreatic enzyme secretion between consecutive subcutaneous administrations of octreotide explain why octreotide takes longer than somatostatin to facilitate the closure of gastrointestinal fistulae. METHODS: Pancreatic enzyme secretion was studied over a 3-day period in a patient with a catheter left in the pancreatic duct postoperatively. On days 1 and 3 the patient did not receive octreotide (control days) but on day 2 he received subcutaneous octreotide 100 micrograms every 8 h. Pancreatic juice was collected at 2-h intervals over the 3-day period. RESULTS: On the day of octreotide treatment, the patient's pancreatic secretory volume and protein output were significantly reduced (P < 0.001, Mann-Whitney U-test) compared with the 2 control days. The pancreatic secretory volume decreased markedly after the first injection of octreotide and remained low for the duration of the treatment period. The enzyme concentration of the pancreatic juice was also markedly reduced after the first injection of octreotide. However, approximately 4h after each octreotide injection the protein concentration of the pancreatic juice began to rise progressively, peaking approximately 6h after each administration of the analogue. CONCLUSION: Subcutaneous administration of octreotide produces a sustained decrease in the volume of pancreatic juice secreted, but enzyme secretion rises progressively between consecutive administrations of the analogue. The net effect is therefore the production of low volumes of pancreatic juice with a high enzyme concentration between consecutive injections of octreotide, which may delay the healing of the fistula tract. This may explain why longer treatment periods are required to achieve fistula closure with octreotide than with somatostatin, particularly in the case of pancreatic fistulae.

Humans↗
PubMed2000

Treatment of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance.

BACKGROUND: The somatostatin analogues lanreotide and octreotide have previously been shown to be effective in controlling flushing and diarrhea in patients with carcinoid syndrome. As lanreotide requires injection only every 10 days, compared with twice-daily injections of octreotide, a direct comparison between these two treatments in terms of patient acceptability, patient preference, and efficacy in controlling symptoms was performed in patients with carcinoid syndrome. METHODS: Thirty-three patients with carcinoid syndrome were included in an open, multicenter, crossover study. Half of the patients received octreotide 200 microg subcutaneously twice or thrice daily for 1 month followed by lanreotide 30 mg intramuscularly every 10 days for 1 month, while the other half commenced with lanreotide followed by octreotide in a similar fashion. Quality-of-life assessments were performed at each visit and patient preference for one of the two treatments evaluated. The number and intensity of flushing episodes and bowel movements, urinary 5-hydroxyindoleacetic acid (5HIAA) levels, and plasma serotonin levels were recorded. RESULTS: No significant differences were found between lanreotide and octreotide in terms of quality of life. The majority of patients (68%) preferred lanreotide (P = 0.03), largely due to its simplified mode of administration. Disappearance or improvement in flushes occurred in 53.8% of patients (14 of 26) while on lanreotide and in 68% (17 of 25) on octreotide. A disappearance or improvement of diarrhea in 45.4% (10 of 22) on lanreotide, compared with 50% (11 of 22) on octreotide, was also observed. Lanreotide and octreotide were equally effective in reducing urinary 5HIAA levels and plasma serotonin levels. Both treatments were well tolerated, with mild symptoms of abdominal pain and nausea observed in 29% and 14% receiving octreotide and lanreotide, respectively. CONCLUSIONS: Lanreotide and octreotide are equally efficacious in terms of symptom control and reduction in tumor cell markers for patients with carcinoid syndrome. Due to its simplified mode of administration, most patients prefer treatment with lanreotide.

Antineoplastic Agents↗
PubMed1996

Effects of long-term administration of octreotide in portal vein-stenosed rats.

The hemodynamic effects of long-term administration of octreotide in portal hypertension has not been established. In addition, whether long-term octreotide treatment prevents the development of portosystemic shunts has not yet been evaluated. Hence, the current study was undertaken to evaluate the effects of long-term administration of octreotide in rats with portal vein stenosis. Immediately after portal vein stenosis or sham operation, rats were given either a long-term octreotide administration of 100 micrograms/kg or a placebo every 12 hours by subcutaneous injection for 14 consecutive days. Systemic hemodynamics and regional blood flows, degree of mesenteric-systemic shunts, and plasma glucagon concentrations were measured after the final dose of octreotide or placebo. A fifth group of portal vein-stenosed rats received hemodynamic and plasma glucagon measurements after 1-day octreotide treatment given at 14 days after surgery. Long-term octreotide treatment modified the hyperdynamic circulation without affecting the degree of mesenteric-systemic shunts, and 1-day octreotide treatment decreased portal tributary blood flow without affecting the portal pressure, systemic hemodynamics, and degree of mesenteric-systemic shunts. Plasma glucagon levels were decreased in portal vein-stenosed rats receiving either long-term or 1-day octreodtide compared with rats receiving placebo. In contrast, chronic octreotide treatment did not affect any of the hemodynamic values or plasma glucagon levels in sham-operated rats. In conclusion, long-term administration of octreotide modified in part the development of portal hypertension and hyperdynamic circulation in portal vein-stenosed rats without affecting the degree of mesenteric-systemic shunts.

Analysis of Variance↗
PubMed2000

Local arterial vasoconstriction induced by octreotide in patients with cirrhosis.

Peripheral vasodilation initiates the hyperdynamic circulation in cirrhosis. Somatostatin and its analogues, such as octreotide, have a vasoconstrictive effect in cirrhotic patients and experimental animals with portal hypertension. The exact mechanism of octreotide-induced vasoconstriction remains unknown. To investigate whether octreotide produces vasoconstriction through suppression of vasodilatory peptides, such as glucagon, or through a local effect, we evaluated the effect of an intra-arterial dose on forearm blood flow (FBF), while measuring systemic glucagon levels. FBF was measured in 10 cirrhotic patients by venous occlusion plethysmography. The brachial artery of the nondominant arm was catheterized, and vasoactive drugs were administered: methacholine 4 microg/min; octreotide 20 microg/h, and octreotide 20 microg/h + methacholine 4 microg/min. Each infusion, lasting 5 minutes, was followed by saline for washout. FBF was measured in both arms during the last minute of each infusion and at the end of washout, with the uninfused arm acting as the control. Nitrates and nitrites, octreotide, and glucagon blood levels were determined at baseline and after each infusion. Percent change in flow (%triangle up) was obtained by comparing the flow during drug administration to that during the preceding saline infusion. Saline infusion did not alter FBF, but octreotide infusion resulted in a 34% +/- 7.7 (P <.005) reduction in FBF in the infused arm. FBF in the control arm was unchanged despite a significant decrease in systemic glucagon levels. Methacholine infusion increased FBF around 300%, which was not altered by the concomitant infusion of octreotide. Octreotide has a local vasoconstrictive effect that seems nitric oxide (NO)-independent. Octreotide probably has a facilitating effect over vasoconstrictors increased in chronic liver diseases.

Arm↗
PubMed2000

[Effect of octreotide combined with growth factors on proliferation of RPE cells in vitro].

BACKGROUND: The long-acting somatostatin analogue octreotide is used as a therapeutic option for patients with diabetic retinopathy and age-related macular degeneration. Growth factors, such as EGF, bFGF, VEGF, and PDGF, have been implicated in the pathogenesis of these diseases. The aim of this study was to investigate the effect of octreotide on the growth-factor-induced proliferation of bovine retinal pigment epithelial (RPE) cells in vitro. METHODS: RPE cells were assayed for proliferation as measured by (3H)-thymidine uptake (ccpm). Bovine RPE cells at passage 3-8 were seeded in a 96-well plate and incubated for a 24-h period with a minimum medium followed by a 24-h incubation with the different growth factors at a concentration of 10 ng/ml with and without 5 x 10(-5) M octreotide. In a different assay the cells were incubated with octreotide at 5 x 10(-10)-5 x 10(-4) M. Afterwards the cells were pulsed with 5 microCi/ml (3H)-thymidine for 12 h, and the incorporated radioactivity was measured on glass fiber filters in a beta-counter (mean +/- SEM ccpm). The Wilcoxon Signed Rank test and the student's t-test were used for statistical analyses. RESULTS: There was a biphasic effect of octreotide on RPE cell proliferation. Exposure of RPE cells to PDGF (20,225 +/- 3304 ccpm) and bFGF (3441 +/- 539 ccpm) resulted in a significantly higher proliferation compared to control medium (1543 +/- 352 ccpm) (p < 0.05). No difference was found for EGF (2385 +/- 383 ccpm). For VEGF (776 +/- 83 ccpm) a significant reduction in RPE cell proliferation was found (P < 0.05). There was a significant reduction in proliferation of RPE cells with PDGF, bFGF, and EGF in combination with octreotide versus growth factors alone (octreotide in combination with PDGF 308 +/- 82 ccpm, with bFGF 229 +/- 88 ccpm, with EGF 2362 +/- 91 ccpm) (p < 0.005). VEGF in combination with octreotide resulted in a significant inhibition of RPE cell proliferation compared to VEGF alone (p < 0.0005). CONCLUSION: The data suggest that there is an inhibitory effect of octreotide on RPE cell proliferation of bovine RPE cells and on the increased proliferation of bovine RPE cells induced by PDGF and bFGF. An enhanced inhibitory effect is found for the combination of octreotide and VEGF.

Animals↗
PubMed1994

The somatostatin analogue octreotide protects against ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa.

Somatostatin 14 and various derivatives protect rat gastric mucosa against ethanol-induced lesions. Their mechanism of action is unknown. We investigated the effect of two somatostatin derivatives, octreotide and 5-(L)-citrullin-octreotide, on ethanol-induced hemorrhagic lesions, microcirculatory stasis and elevated vascular permeability in the rat stomach, with the goal to elucitate the pharmacological and microcirculatory mechanisms behind the gastroprotective effect. Radioligand studies revealed a high affinity of octreotide for the somatostatin receptor (IC50 = 5 x 10(-10) mol/l), in contrast to 5-(L)-citrullin-octreotide (IC50 = 3 x 10(-6) mol/l). This was in good agreement with the inhibition of growth hormone release from rat anterior pituitary cells (octreotide: IC50 = 1.2 x 10(-10) mol/l; 5-(L)-citrullin-octreotide: IC50 = 3 x 10(-6) mol/l). Intragastric administration of ethanol to rats resulted in lesions of the gastric mucosa affecting 18.9 +/- 3.1% of the area of the glandular stomach. Octreotide reduced the area to 6.4 +/- 1.7% (P < 0.05). The dose-response curve was bell-shaped. 5-(L)-citrullin-octreotide was totally devoid of any protective activity (dose range: 0.1 ng/kg to 0.1 mg/kg). We further investigated the effect of the two peptides on ethanol-induced microcirculatory stasis and elevated vascular permeability. Ethanol in a concentration of 50% induced an increase in microvascular permeability, measured by the extravasation of the tracer fluorescein-isothiocyanate-dextran (molecular weight 150,000). Pretreatment with octreotide (0.1 ng/kg s.c.) prevented stasis and reduced capillary permeability significantly. 5-(L)-citrullin-octreotide had no effect on ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The role of bile composition and physical chemistry in the pathogenesis of octreotide-associated gallbladder stones.

BACKGROUND/AIMS: Treatment of acromegaly with octreotide inhibits cholecystokinin release and gallbladder contraction and induces gallbladder stones. However, little is known about the effects of octreotide on bile composition. METHODS: Fresh gallbladder bile was obtained from three groups: (1) 11 nonacromegalic patients with cholesterol gallstones, (2) 6 acromegalic patients with octreotide-associated stones (treatment, 300-600 micrograms/day for 3-66 months), and (3) 8 acromogalic patients with no stones before octreotide treatment, 5 of whom were reexamined after 3-24 months of therapy. RESULTS: Compared with stone-free acromegalic patients untreated with octreotide, bile from patients with cholesterol stones and from acromegalic patients with octreotide-associated stones had greater saturation indices (mean +/- SEM) (1.52 +/- 0.17 and 1.32 +/- 0.14 vs. 0.90 +/- 0.05, respectively; P < 0.01); more cholesterol in vesicles (61.2% +/- 4.5% and 67.7% +/- 7.2% vs. 37.7% +/- 3.5%; P < 0.009); more unstable vesicles (cholesterol/phospholipid ratios, 0.97 +/- 0.12 and 0.81 +/- 0.16 vs. 0.52 +/- 0.05; P < 0.02); more rapid nucleation (< 5 and < 5 days vs. > 18 days; P < 0.003); and more deoxycholic acid (22.8% +/- 2.4% and 23.6% +/- 4.8% vs. 13.9% +/- 1.4%; P < 0.05). In the paired studies, the saturation indices increased from 0.89 +/- 0.07 before octreotide treatment to 1.12 +/- 0.03 during octreotide treatment (P < 0.02), as did the percentage of deoxycholic acid from 13.3% +/- 2.1% to 24.9% +/- 2.7% (P < 0.03). CONCLUSIONS: Acromegalic patients with octreotide-associated gallstones and stone-free acromegalic patients treated with octreotide have similar changes in bile composition to those in patients with "conventional" cholesterol gallstone disease.

Acromegaly↗
PubMed1995

Multicenter trial of octreotide in patients with refractory acquired immunodeficiency syndrome-associated diarrhea.

BACKGROUND/AIMS: Diarrhea is a significant problem in patients with acquired immunodeficiency syndrome (AIDS). The aim of this study was to determine octreotide effectiveness in refractory AIDS-associated diarrhea. METHODS: In a 3-week protocol, 129 patients with a stool weight of > 500 g/day despite standard antidiarrheal therapy were randomized to receive octreotide or placebo (3:2 ratio). Octreotide dose was increased 100 micrograms weekly to a maximum of 300 micrograms three times a day based on weekly 72-hour stool collections. Subsequently, patients received open-label octreotide at doses of up to 500 micrograms three times a day. RESULTS: A 30% decrease in stool weight defined response. After 3 weeks, 48% of octreotide- and 39% of placebo-treated patients had responded (P = 0.43). At 300 micrograms three times a day, 50% of octreotide- and 30.1% of placebo-treated patients responded (P = 0.12). At a baseline stool weight of 1000-2000 g/day, 57% of octreotide- and 25% of placebo-treated patients responded (P = 0.06). Response rates based on CD4 counts, diarrhea duration, body weight, human immunodeficiency virus risk factor, and presence or absence of pathogens showed no benefit of octreotide. Adverse events were more frequent in the octreotide-treated group. CONCLUSION: In the doses studied, octreotide was not more effective than placebo in patients with refractory AIDS-associated diarrhea. This lack of effectiveness may be attributable to inadequate sample size, doses, and duration of study treatment.

Acquired Immunodeficiency Syndrome↗