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PubMed2003

Octreotide acts as an antitumor angiogenesis compound and suppresses tumor growth in nude mice bearing human hepatocellular carcinoma xenografts.

PURPOSE: To investigate the effect of octreotide on angiogenesis induced by human hepatocellular carcinoma (HCC) and to evaluate whether octreotide can suppress tumor growth in nude mice bearing human HCC xenografts through inhibition of angiogenesis. METHODS: Using MTT assay, invasion assay, migration assay, and Matrigel assay, the effects of octreotide on endothelial cells stimulated by vascular endothelial growth factor (VEGF) were evaluated in vitro. MTT assay was also used to investigate the effects of octreotide on human HCC cells with high (MHCC97-H) and low (MHCC97-L) metastatic potential that were established from the animal model of human HCC LCI-D20 in nude mice. The expression of somatostatin receptor (SSTR) subtypes in human umbilical vein endothelial cells (HUVECs), MHCC97-H, and MHCC97-L cells was detected by RT-PCR analysis. An LCI-D20 corneal micropocket model in nude mice was used to evaluate the effect of octreotide on angiogenesis induced by human HCC in vivo. Male nude mice were subcutaneously implanted with LCI-D20 tumor tissues for the tumor xenograft studies. Microvessel density was analyzed in CD34-stained tumor sections by the immunohistochemical SP method. RESULTS: In vitro, octreotide inhibited the proliferation, invasion, and differentiation of HUVECs elicited by VEGF. RT-PCR analysis demonstrated that HUVECs expressed the somatostatin receptor subtype SSTR3. In vivo, octreotide was sufficiently potent to suppress nude mice corneal neovascularization induced by tumor tissues from LCI-D20. Systemic administrations of octreotide produced a significant suppression of the growth of LCI-D20. In cell culture, MHCC97-H and MHCC97-L cells were insensitive to octreotide at concentrations that significantly inhibited endothelial cells proliferation. The HCC cells used did not express any known SSTRs. Immunohistochemical studies of tumor tissues revealed decreased microvessel density in octreotide-treated animals as compared with controls. CONCLUSIONS: The present study demonstrates that the somatostatin analogue octreotide is a potent antitumor angiogenesis compound and the antiproliferative effect of octreotide on tumor growth in nude mice bearing HCC xenografts may be mediated, at least in part, by its suppressive effect on blood vessel supply. The somatostatin analogue octreotide might provide a useful and relatively nontoxic adjuvant therapy in the treatment of HCC.

Animals↗
PubMed1998

Hemodynamic effects of terlipressin and octreotide administration alone or in combination in portal hypertensive rats.

BACKGROUND/AIMS: The action sites and kinetic effects of octreotide and terlipressin may be different. Therefore, we studied the hemodynamic effects of acute administration of these drugs alone or in combination in rats with portal hypertension due to portal vein ligation. METHODS: In a first study performed in anesthetized rats, hemodynamics were measured before and after drug administration (placebo, octreotide: 8 microg x kg(-1) x h(-1) for 30 min, terlipressin: 50 microg/kg bolus, terlipressin + octreotide at the same doses). The second study, performed in conscious rats, included the same groups and drug doses; hemodynamics were measured every 10 min for 1 h. The third study tested the effect of preinfusion of octreotide on responsiveness to terlipressin. RESULTS: Terlipressin produced more marked systemic effects than octreotide by decreasing heart rate and cardiac output and increasing mean arterial pressure. Terlipressin produced a greater decrease in portal pressure than octreotide: placebo: -3+/-5%, terlipressin: -42+/-8%, octreotide: -16+/-10%, combination: -44+/-8% (conscious rats at 20 min, p<10(-4)). The decrease in portal pressure was immediate and lasted at least 60 min with both drugs. Octreotide significantly decreased spleno-renal shunt blood flow (% variation): placebo: -6+/-8, terlipressin: -15.5+/-20, octreotide: -22.5+/-20, combination: -27+/-10 (p<10(-2)). Octreotide preinfusion significantly increased the responsiveness of arterial pressure and heart rate to terlipressin. CONCLUSIONS: Terlipressin decreases portal pressure significantly more than octreotide, while only octreotide significantly decreases collateral blood flow. Simultaneous administration of these drugs does not have significant additive effects but has complementary effects. The preadministration of octreotide alters systemic response to terlipressin.

Animals↗
PubMed2000

Octreotide: an antidote for sulfonylurea-induced hypoglycemia.

STUDY OBJECTIVES: Sulfonylurea agents are widely used as therapy for hyperglycemia in type 2 diabetes mellitus. In overdose, these agents can produce sustained and profound hypoglycemia that is refractory to treatment with dextrose alone. Our objective was to determine whether treatment with octreotide decreases glucose requirements and the number of hypoglycemic episodes in patients with sulfonylurea-induced hypoglycemia. METHODS: We retrospectively reviewed the charts of patients treated with octreotide for sulfonylurea-induced hypoglycemia from 1995 through 1998. The study took place in a large urban teaching hospital in the United States. We measured the number of episodes of hypoglycemia reported and the amount of dextrose used before and after treatment with octreotide. Using a failure time analysis, we compared the risk of hypoglycemia before and after octreotide administration. RESULTS: The age range of the 9 patients was 20 to 65 years. Six patients ingested glyburide and 3 ingested glipizide. The number of hypoglycemic events recorded per patient before octreotide (mean 3.2) was greater than the number of hypoglycemic events recorded per patient after octreotide (mean 0.2, P =.008). Similarly, the number of ampules of 50% dextrose administered per patient before octreotide (mean 2.9) was greater than the number of ampules administered per patient after octreotide (0.2, P =.004). The risk of recurrent hypoglycemia before octreotide treatment was 27 times the risk of the group after octreotide treatment (P <.001). Stabilization of blood glucose concentration and cessation of rebound hypoglycemia occurred immediately after the administration of octreotide in all 9 patients. CONCLUSION: Octreotide appears to be safe and effective in preventing rebound hypoglycemia after sulfonylurea ingestion. Octreotide in combination with dextrose should be considered for first-line therapy in the treatment of sulfonylurea-induced hypoglycemia.

Adult↗
PubMed1994

Treatment with octreotide and bromocriptine in patients with acromegaly: an open pharmacodynamic interaction study.

OBJECTIVE: Several studies suggest that the combination of octreotide and bromocriptine is more effective than octreotide alone in reducing GH levels in patients with acromegaly. However, these studies have evaluated either the acute effects of single doses of octreotide and bromocriptine, or the effects of long-term combination therapy, in which octreotide was given only twice a day. The aim of the study was to evaluate the effects of the combination of octreotide and bromocriptine compared to octreotide alone, using a treatment scheme of three daily injections of octreotide during a period long enough to ensure a pharmacokinetic and pharmacodynamic steady state. PATIENTS: Eleven patients with acromegaly. DESIGN AND MEASUREMENTS: Different treatment regimes were performed during three periods. During the first period there was no administration of octreotide or bromocriptine, during the second period 100 micrograms octreotide was given subcutaneously three times a day, and during the third period 100 micrograms octreotide was given subcutaneously three times a day in combination with bromocriptine, given orally 5 mg twice daily. When the patients were without any treatment a single oral dose of 5 mg bromocriptine was given at 0730 h. Individual GH levels were assessed as the mean value of 11 observations during the day, at hourly intervals from 0730 to 1530 h, and at 1730 and 1930 h, and the GH levels for the whole group were calculated as the mean of the individual mean values. Serum IGF-I and PRL were measured in fasting samples at 0730 h on the same days as GH, GH, IGF-I, and PRL were evaluated at the end of each treatment regime. RESULTS: Basal mean GH value for all 11 patients was 54.2 +/- 17.4 mU/l. During octreotide therapy mean GH value was significantly reduced compared to basal mean GH level; 19.86 +/- 6.82 mU/l (P < 0.05). The reduction of mean GH during combination therapy was also significant compared to basal, 18.70 +/- 6.72 mU/l (P < 0.05). Basal mean IGF-I value for all 11 patients was 716 +/- 96 micrograms/l. During octreotide therapy mean IGF-I value was significantly reduced compared to basal mean IGF-I level; 458 +/- 100 micrograms/l (P < 0.05). The reduction of mean IGF-I during combination therapy was also significant compared to basal, 456 +/- 93 micrograms/l (P < 0.05). There was no difference between the levels of mean IGF-I during the two treatment periods. One patient, the only patient with hyperprolactinaemia, showed an additional reduction of GH levels of > 50% during combination therapy. This was also the patient showing the most pronounced reduction of GH levels after the administration of a single dose of bromocriptine. CONCLUSION: When octreotide is administered three times a day, the additive effect of bromocriptine on GH and IGF-I suppression seems to be negligible in most patients with acromegaly.

Acromegaly↗
PubMed1993

Octreotide long term treatment of acromegaly: effect of drug withdrawal on serum growth hormone/insulin-like growth factor-I concentrations and on serum gastrin/24-hour intragastric pH values.

We studied a possible persistence of low GH concentrations after drug withdrawal in eight acromegalic patients who had been receiving octreotide treatment continuously for 42 months. Since octreotide induces chronic active gastritis, intragastric pH and serum gastrin were also determined before and during drug withdrawal. Results were compared to the respective pretreatment (pre-Tx) values. GH and insulin-like growth factor-I (IGF-I) increased after 4 weeks of octreotide withdrawal to pre-Tx values (GH, 12-h profile, 4.5 +/- 0.6, 2.6 +/- 0.7, and 5.6 +/- 1.1 micrograms/L; IGF-I, three samples, 3.4 +/- 0.4, 0.8 +/- 0.1, and 2.5 +/- 1.0 IU x 10(3)/L; means +/- SE, pre-Tx, on and off octreotide). A reduced insulin and augmented glucose response to oral glucose during therapy normalized after octreotide withdrawal (insulin, 527 +/- 84, 289 +/- 62, and 733 +/- 110 pmol/L; glucose, 6.2 +/- 0.3, 8.5 +/- 0.4, and 6.8 +/- 0.2 mmol/L; pre-Tx, on and off octreotide, means +/- SE). During octreotide treatment, the median 24-h intragastric pH value was 2.8 (pre-Tx pH not determined), and the median serum gastrin concentration (areas under the curve of 12-h profiles) was 1275 +/- 153 ng/L.12 h (n = 7). During octreotide withdrawal, pH decreased to 1.4, while serum gastrin increased to a median of 2937 +/- 472 ng/L.12 h. We conclude that GH and IGF-I suppression by long term octreotide therapy does not persist after drug withdrawal, indicating a need for life-long treatment. Octreotide-induced insulin suppression and glucose elevation are reversible. A high gastric pH during treatment may facilitate the development of octreotide-related gastritis. The gastrin increase during octreotide withdrawal probably reflects a response to chronic active gastritis after release from octreotide-induced gastrin inhibition.

Acromegaly↗
PubMed1999

The pituitary uptake of (111)In-DTPA-D-Phe1-octreotide in the normal pituitary and in pituitary adenomas.

The aim of this study was to compare the pituitary (111)In-DTPA-D-Phe1-octreotide uptake measured in 49 patients subjected to the scintigraphy for SS-R expressing tumors not located in the sellar region with that measured in 38 patients with pituitary adenomas. The 87 subjects enrolled in this study were divided into two groups: the first included SSR-expressing tumors (SS-ET), 10 thymomas, 13 differentiated thyroid carcinomas, 4 carcinoids, 5 neuroendocrine tumors, 5 insulinomas, 6 melanomas, 2 renal carcinomas, 2 pheocromocytomas, and 2 parathyroid tumors, while the second included pituitary adenomas, 25 GH-secreting, 4 GH/PRL-mixed and 9 clinically nonfunctioning adenomas (NFA). Planar and single-photon-emission tomography images of the head were obtained 2-4 and 24 hours after the injection of 77-103 MBq of (111)In-DTPA-D-Phe1-octreotide and pituitary uptake was measured by the region of interest method. A 4 point score was used to grade the pituitary-to-blood (T-to-B) ratios: 0=negative; 1 =faint (T-to-B=<1.5); 2=moderate (T-to-B=1.6-3.5); 3=intense (T-to-B=>3.5). In patients with pituitary adenomas, the percent suppression of GH and alpha-subunit levels after 6-12 months of octreotide treatment (0.3-0.6 mg/day) was correlated to T-to-B ratios. After 2-4 hr from injection, pituitary (111)In-DTPA-D-Phe1-octreotide uptake was moderate/intense in 2 out of 49 SS-ET (4%), 18 out of 29 acromegalics (62%) and 6 NFA (66.6%), while a faint uptake was detected in 4 SS-ET (8%), 8 GH-secreting adenomas (27.5%) and 3 NFA (33.3%). Negative scan was detected in the remaining 43 SS-ET (87.7%) and 3 GH-secreting microadenomas (10.3%). 24 hr after injection, pituitary (111)In-DTPA-D-Phe1-octreotide uptake was moderate/intense in SS-ET (10.2%), 21 GH-secreting adenomas (72.4%), and 9 NFA (100%) while a faint uptake was detectable in 15 SS-ET (30.6%), and 6 GH-secreting adenomas (20.7%). No uptake was visualized in 29 SS-ET, and 2 GH-secreting adenomas. By MRI a pituitary tumor was shown in the 2 SS-ET with early moderate tracer uptake. Normalization of circulating GH/IGF-I levels and suppression of alpha-subunit levels was achieved in 16 of 18 acromegalics (88.9%) and 5 of 6 NFA-bearing patients, respectively, with scan scored 2-3 at early images. Eleven acromegalics (37.9%) and 2 NFA (22.2%) displayed significant tumor shrinkage (> or =30% of baseline size) during long-term octreotide therapy. Both in GH-secreting and in NFA, a significant correlation was found between percent GH or alpha-subunit suppression after 6-12 months of octreotide therapy and T-to-B ratios both in early (r=0.626; p<0.0001 and r=0.738, p=0.003, respectively) and late images (r=0.569; p=0.002 and r=0.8, p=0.01, respectively). In conclusion, the (111)In-DTPA-D-Phe1-octreotide uptake in pituitary adenomas was significantly correlated to octreotide treatment. However, since pituitary (111)In-DTPA-D-Phe1-octreotide uptake was clearly detectable in 40% of patients with SS-ET not located in the pituitary region at 24 hr post-injection, (111)In-DTPA-D-Phe1-octreotide scintigraphy with late pituitary images can not be considered an useful method to predict the chronic responsiveness to octreotide in individual patients. Caution should also be taken in evaluating the results of the scintigraphy with early images in patients with scant uptake before excluding them from treatment.

Adenoma↗
PubMed1991

[111In-DTPA-D-Phe1]-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation.

Somatostatin receptor-positive human tumors can be detected using radioiodinated analogues of somatostatin, both in vitro and in vivo. [123I-Tyr3]-octreotide has been successfully used in the visualization of somatostatin receptor-positive tumors by gamma camera scintigraphy, but this radiopharmaceutical has some major drawbacks, which can be overcome with other radionuclides such as 111In. As starting material for a potentially convenient radiopharmaceutical, a diethylenetriaminopentaacetic acid (DTPA) conjugated derivative of octreotide (SMS 201-995) was prepared. This peptide, [DTPA-D-Phe1]-octreotide (SDZ 215-811) binds more than 95% of added 111In in an easy, single-step labeling procedure without necessity of further purification. The specific somatostatin-like biologic effect of these analogues was proven by the inhibition of growth hormone secretion by cultured rat pituitary cells in a dose-dependent fashion by octreotide, [DTPA-D-Phe1]-octreotide and non-radioactive [115In-DTPA-D-Phe1]-octreotide. The binding of [111In-DTPA-D-Phe1]-octreotide to rat brain cortex membranes proved to be displaced similarly by natural somatostatin as well as by octreotide, suggesting specific binding of [111In-DTPA-D-Phe1]-octreotide to somatostatin receptors. The binding of the indium-labeled compound showed a somewhat lower affinity when compared with the iodinated [Tyr3]-octreotide, but indium-labeled [DTPA-D-Phe1]-octreotide still binds with nanomolar affinity. In conjunction with in vivo studies, these results suggest that [111In-DTPA-D-Phe1]-octreotide is a promising radiopharmaceutical for scintigraphic imaging of somatostatin receptor-positive tumors.

Amino Acid Sequence↗
PubMedDate not supplied

Renal metabolism of 111In-DTPA-D-Phe1-octreotide in vivo.

The persistent localization of radioactivity in the kidney after administration of 111In-DTPA-D-Phe1-octreotide impairs the diagnostic accuracy of this radiopharmaceutical. To better understand the mechanisms responsible for the renal radioactivity levels of 111In-DTPA-D-Phe1-octreotide, the renal metabolism of this compound was compared with 111In-DTPA-L-Phe1-octreotide, where the N-terminal D-phenylalanine was replaced with L-phenylalanine to facilitate metabolism. DTPA-D-Phe1-octreotide and DTPA-L-Phe1-octreotide were synthesized by solid-phase methods. Both 111In-DTPA-conjugated octreotide analogues were prepared with radiochemical yields of over 96%, and both remained stable after a 3 h incubation in murine serum at 37 degreesC. When injected into mice, the two 111In-DTPA-conjugated octreotide analogues showed similar radioactivity elimination rates from the blood and accumulation in the kidney with about 60% injected radioactivity being excreted in the urine by 24 h postinjection. Over 85% of the radioactivity in the urine existed as intact peptides for both analogues. Despite the similar renal radioactivity levels, significant differences were observed in the radiolabeled species remaining in the kidney between the two; while 111In-DTPA-L-Phe1-octreotide was rapidly metabolized to the final radiometabolite, 111In-DTPA-L-Phe, the metabolic rate of 111In-DTPA-D-Phe1-octreotide was so slow that various intermediate radiolabeled species were observed. However, both 111In-DTPA-D-Phe and 111In-DTPA-L-Phe remained in the lysosomal compartment of the renal cells as the final radiometabolites for long periods. These findings indicated that although the metabolic stability of 111In-DTPA-D-Phe1-octreotide in the renal cells may be partially involved, the slow elimination rate of the radiometabolite derived from 111In-DTPA-D-Phe1-octreotide from the lysosomal compartment of renal cells would be predominantly attributable to the persistent renal radioactivity levels of 111In-DTPA-D-Phe1-octreotide.

Animals↗
PubMed1998

Octreotide ameliorates glucose intolerance following acute experimental pancreatitis.

The long-term effects of octreotide, the synthetic analog of the hormone somatostatin, on acute experimental pancreatitis were studied. Acute pancreatitis was induced in rats by intraparenchymal injections of 0.5 ml 5% or 10% sodium taurocholate. Octreotide (10 mg/kg/day, subcutaneously), or saline injections as controls, were started four hours later, and their effects were assessed 30, 60, and 90 days after the induction of pancreatitis. Neither intrapancreatic saline injections nor octreotide administration without the induction of pancreatitis caused any biochemical or histological abnormalities. Taurocholate-induced pancreatitis was followed by remarkable hyperglycemia, which was ameliorated by octreotide. Thirty days after induction of pancreatitis, glucose levels were 269+/-21 mg/100 ml and 153+/-17 mg/100 ml in the control and octreotide treated animals, respectively (P < 0.02). Octreotide administration was associated with increased pH values after 60 and 90 days (P < 0.05 for the 90 days group). The levels of hematocrit, calcium, and amylase were already within the normal ranges after 30 days and were unaffected by octreotide. There were no signs of chronic exocrine insufficiency and all the surviving rats gained weight during the follow-up. However, the relative weights of the pancreases of the octreotide-treated animals were higher than those of the controls 30 days after IOP. Histopathological evaluation demonstrated regeneration of the pancreatic tissue, and increased number and hypertrophy of the islets of Langherhans. There were no significant differences whether the octreotide treatment was given for only 48 or 96 hr. Survival was significantly improved by octreotide; only one octreotide-treated rat (2.5%) with 10% taurocholate-induced pancreatitis died, while six (15%) of the control animals succumbed (P < 0.05). These studies provided data on the sequelae of acute pancreatitis and showed that octreotide may have long-term beneficial effects in this disease.

Acute Disease↗
PubMed1997

Haemodynamic responses to a combination of terlipressin and octreotide in portal hypertensive rats.

BACKGROUND: An enhancement of the haemodynamic effects of terlipressin by octreotide (and vice versa) may be useful in the treatment of portal hypertension. The aim of this study was to investigate the short-term effects of terlipressin, octreotide or a combination of these substances on splanchnic and systemic haemodynamics in rats with portal vein stenosis. METHODS: Eight rats received an intravenous (i.v.) infusion of isotonic saline (10 microL/min for 15 min). Eight rats received terlipressin first (0.05 mg/kg) and then an i.v. infusion of octreotide (8 micrograms.h/kg for 15 min) 15 min later. Eight other rats first received an i.v. infusion of octreotide and then terlipressin 15 min later. Splanchnic and systemic haemodynamics (radioactive microsphere method) were measured after saline, after terlipressin or octreotide alone, and after the combined treatments. RESULTS: Terlipressin and octreotide alone significantly decreased portal pressure, portal tributary blood flow and cardiac index. Terlipressin, but not octreotide, significantly increased heptocollateral vascular resistance and arterial pressure. Octreotide administration in rats pre-treated with terlipressin did not change portal pressure, caused portal tributary blood flow to increase and decreased hepatocollateral vascular resistance; it also decreased arterial pressure but not cardiac index. Terlipressin administration in rats pre-treated with octreotide further decreased portal pressure, portal tributary blood flow and increased hepatocollateral vascular resistance; terlipressin increased arterial pressure and further decreased cardiac index. CONCLUSIONS: In rats with portal vein stenosis, octreotide decreased short-term splanchnic and systemic vasoconstriction due to terlipressin. In contrast, terlipressin enhanced the splanchnic and systemic vasoconstriction due to octreotide. Thus, the haemodynamic responses to the combination of octreotide and terlipressin depend on the order of administration of these substances.

Animals↗
PubMed1998

Haemodynamic effects of 8-day octreotide and prazosin administration in portal hypertensive rats.

BACKGROUND: Octreotide and prazosin are both effective portal hypotensive drugs in the control or prevention of variceal bleeding. The present study was undertaken to investigate the haemodynamic effects of octreotide and prazosin, alone or in combination, in portal hypertensive rats. METHODS: Portal hypertension was induced by partial portal vein ligation. Portal hypertensive rats were allocated into one of the four groups-vehicle group (saline, 0.5 mL 12 h-1), octreotide group (30 micrograms kg-1 12 h-1), prazosin group (0.4 mg kg-1 12 h-1), and octreotide (30 micrograms kg-1 12 h-1) plus prazosin (0.4 mg kg-1 12 h-1) group-with eight rats in each group. Prazosin or saline was administered by gavage, whereas octreotide was administered by subcutaneous injection. The drug was given on the day of ligation and continued for 8 consecutive days. Systemic as well as splanchnic haemodynamic parameters were measured thereafter. RESULTS: Portal vein-ligated rats exhibited typical hyperdynamic state compared with sham-operated rats. The portal venous pressure, portal tributary blood flow and cardiac index were significantly reduced by treatment of octreotide, prazosin or octreotide plus prazosin in portal hypertensive rats. Hyperdynamic parameters of systemic, renal and portal territory vascular resistances, and renal as well as hepatic arterial blood flow were ameliorated by treatment of octreotide or octreotide plus prazosin in portal hypertensive rats. Overall, octreotide treatment exerted more beneficial haemodynamic effects than prazosin treatment. The combination of octreotide and prazosin exerted better haemodynamic effects in cardiac index but worse effects in systemic as well as portal territory vascular resistance than octreotide treatment alone.

Animals↗
PubMed1995

Prevalence of Helicobacter pylori in acromegalic patients during treatment with octreotide.

BACKGROUND: Octreotide, a synthetic long-acting analogue of somatostatin, now has an established role in the treatment of acromegaly. In acromegalic patients treated with octreotide there is an increased incidence of gallstones and possibly gastritis. OBJECTIVES: (1) To compare the seroprevalence of Helicobacter pylori (H. pylori) infection, in acromegalic patients treated with octreotide to that in patients given other treatment modalities. (2) To study retrospectively the temporal relation between H. pylori acquisition and octreotide treatment. PATIENTS: Three groups of acromegalic patients were studied; 35 (20 M) had been treated with octreotide, 17 (10 M) with bromocriptine and 19 (12 M) had received no pharmacological intervention (untreated, surgically treated or treated with radiotherapy). DESIGN/MEASUREMENTS: The presence of H. pylori infection was assessed serologically (Bio-Rad GAP test for IgG), using stored serum, on the most recent sample from each patient and on serial samples from patients treated with octreotide. RESULTS: The prevalence of H. pylori seropositivity was similar in each treatment group, 34, 35 and 37%, respectively. Mean age and duration of acromegaly were similar in the first two groups. Patients who had never received medical treatment were slightly younger. GH levels were similar in all three groups. Patients on octreotide who were seropositive for H. pylori did not differ from those with negative serology with respect to age, duration of acromegaly, duration of octreotide treatment or serum GH level. Serial samples in octreotide treated patients showed a change in status in only one patient; 18 patients continued with negative serology during a mean period of 30 (range 4-62) months. In each of the 6 patients with persistently positive serology during octreotide treatment, stored samples predating octreotide therapy were shown to have already been positive. CONCLUSIONS: The seroprevalence of H. pylori infection in acromegalic patients does not appear to be increased in a manner dependent on the type or duration of medical treatment. In particular, octreotide therapy, while causing the development of histological gastritis in some patients, does not appear to induce the development of H. pylori infection.

Acromegaly↗
PubMed1998

Haemodynamic effects of chronic octreotide and tetrandrine administration in portal hypertensive rats.

Octreotide is an effective portal hypotensive drug in the control of variceal bleeding. Tetrandrine is a type of calcium channel blocker recently reported to reduce portal hypertension. The present study was undertaken to investigate the haemodynamic effects of octreotide and tetrandrine, alone and in combination, in portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation. Portal hypertensive rats were allocated into one of the four groups: vehicle group (saline, 0.5 mL/day), octreotide group (100 microg/kg per 12 h), tetrandrine group (20 mg/kg per 12 h), and octreotide (100 microg/kg per 12 h) plus tetrandrine (20mg/kg per 12 h) group. Tetrandrine or saline was administered by gavage, and octreotide by subcutaneous injection. The drug was given for 8 consecutive days, starting 1 day before ligation and continuing onwards. Haemodynamic parameters were measured thereafter, using the radioactive microsphere method. The portal venous pressure and portal tributary blood flow were significantly reduced, while portal territory and renal vascular resistances were significantly enhanced, by octreotide, tetrandrine, or octreotide plus tetrandrine in portal hypertensive rats, compared with the vehicle group. Our results showed that long-term administration of octreotide, tetrandrine, or octreotide plus tetrandrine led to portal hypotensive effects in portal hypertensive rats, but octreotide alone exerted better anti-hyperdynamic effects compared with tetrandrine alone. A combination of octreotide and tetrandrine offered no major beneficial anti-hyperdynamic effects compared with octreotide alone.

Alkaloids↗
PubMed1994

Inhibition of pancreatic secretion under long-term octreotide treatment in humans.

The somatostatin analogue octreotide (SMS 201-995) is a potent inhibitor of human exocrine pancreatic secretion. In the present study we analyzed the effect of octreotide (3 x 100 micrograms, daily) given over a time period of 7 days on hormone-stimulated exocrine pancreatic secretion in 6 healthy volunteers using a secretin-ceruletide test. The secretin-ceruletide test was carried out before, following the first injection of octreotide (day 1) and after a 7-day treatment with 3 x 100 micrograms octreotide daily. Duodenal fluid was collected over 30 min without stimulation, over 60 min following a bolus injection of 1 U/kg body weight secretin, and over 60 min during a continuous infusion of secretin and ceruletide. Following the first injection of octreotide and following 7 days of octreotide treatment secretin/ceruletide-stimulated amylase secretion was significantly reduced. Trypsin and chymotrypsin secretion was significantly reduced after the first injection of octreotide when pancreatic secretion was stimulated by secretin and ceruletide simultaneously. However, secretin and ceruletide-induced trypsin and chymotrypsin secretion was not inhibited after 7 days of octreotide treatment. Baseline, secretin and secretin/ceruletide-stimulated bicarbonate output were not influenced by octreotide either following the first injection of octreotide or the 7 days' treatment. Octreotide is a potent inhibitor of secretin/ceruletide-stimulated pancreatic amylase, trypsin and chymotrypsin secretion. However, following a 7-day treatment with octreotide this inhibition is only persistent for pancreatic amylase secretion.

Adult↗
PubMed1992

Octreotide inhibits insulin-like growth factor-I hepatic gene expression in the hypophysectomized rat: evidence for a direct and indirect mechanism of action.

Somatostatin and somatostatin analogs are known to interact with the GH-insulin-like growth factor (IGF)-I axis by inhibiting GH secretion and consequently hepatic IGF-I production. Indirect evidence suggests that octreotide, a somatostatin analog, reduces serum IGF-I levels relatively more than expected from GH reduction, implying a GH-independent pathway of action. To study the role of octreotide in the regulation of IGF-I production, independently of endogenous GH, we used the hypophysectomized (hypox) rat to measure hepatic IGF-I expression and also employed cultured rat hepatocytes to examine whether octreotide has any direct effect on the production of IGF-I. Forty male hypox Sprague-Dawley rats were randomized into 4 groups to receive daily injections for 3 days of either saline, human GH (hGH) (100 g), octreotide (100 g twice), or both hGH (100 g) and octreotide (100 g twice). GH stimulated serum IGF-I levels to 104 +/- 10 micrograms/liter as compared to saline (26 +/- 2 micrograms/liter). Octreotide alone had no effect, but combining octreotide and hGH significantly reduced the hGH-induced rise in the IGF-I levels (52 +/- 6 micrograms/liter). The relative expression of hepatic IGF-I in the rats treated with hGH increased by 4-fold compared to that in the saline-treated rats. Octreotide administered simultaneously with hGH potently blocked the hGH-induced IGF-I expression to control levels. In cultured hepatocytes, IGF-I mRNA levels maximally stimulated by combining bGH and glucagon were significantly inhibited in the presence of octreotide at low concentrations (0.3 and 3 ng/ml) by 25% and 45%, respectively. In contrast, high concentrations of octreotide (30 and 300 ng/ml) had no significant effect on IGF-I mRNA abundance. We conclude that: 1) octreotide inhibits IGF-I serum levels and hepatic gene expression in the hypox rat; and 2) octreotide can inhibit partially the direct effects of GH and glucagon on hepatic IGF-I production.

Animals↗
PubMed1999

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

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.

Acromegaly↗
PubMed1993

Clinical pharmacokinetics of octreotide. Therapeutic applications in patients with pituitary tumours.

Among somatostatin analogues, octreotide is the most extensively studied. Its pharmacodynamic properties are similar to those of somatostatin, with a wide spectrum of inhibitory effects on anterior pituitary function, pancreas and gut endocrine secretions, and gastrointestinal functions. Compared with the somatostatin, octreotide is highly resistant to enzymatic degradation and has a prolonged plasma half-life of about 100 minutes in humans, allowing its use in the long term treatment of various pathological conditions. Differential effects of octreotide on endocrine secretions such as growth hormone (GH) and insulin in healthy volunteers, as well as variable efficacy in the treatment of endocrine tumours, may relate to the distribution of somatostatin receptor subtypes. The volume of distribution of octreotide ranges from 18 to 30L. Calculated serum distribution half-life ranges from 72 to 98 minutes. In blood, octreotide is mainly distributed in the plasma, 65% being bound to lipoproteins. After subcutaneous injection, absorption appears rapid and complete and bioavailability is about 100%. Mean peak plasma concentrations are between 2 and 4 micrograms/L in patients receiving 50 to 100 micrograms. Peak concentrations are reached within 20 to 30 minutes and are 20 to 40% of corresponding values after intravenous injection. Peak concentrations and values for areas under the plasma concentration-time curve linearly correlate with the dosage. The elimination half-life is about 90 to 110 minutes. Total clearance in healthy individuals is about 160 ml/min (9.6 L/h). Hepatic metabolism of octreotide is extensive (30 to 40%) and about 11 to 20% of the dose is excreted unchanged in the urine. Among pituitary tumours, GH- and thyrotrophin-secreting adenomas are the most sensitive to octreotide. Octreotide has been widely used in the treatment of acromegaly. 50 to 80% of the patients respond to daily multiple subcutaneous injections with insulin-like growth factor-1 (IGF1) levels being normalised in about 40 to 50% of them. Neither desensitisation with long term therapy nor rebound phenomena after octreotide withdrawal have been noticed in these studies. Even in patients with partial response, clinical symptoms improved. Octreotide daily dosages needed to achieve optimum responses may vary greatly from one patient to another. In a minority of patients complete resistance to octreotide was observed and was not always related to the absence of somatostatin receptors in the tumour. The wide spectrum of effects of octreotide in humans accounts for adverse effects seen during long term treatment, primarily cholelithiasis. Other modes of administration are efficient.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1999

In vivo localization of [(111)In]-DTPA-D-Phe1-octreotide to human ovarian tumor xenografts induced to express the somatostatin receptor subtype 2 using an adenoviral vector.

Adenoviral vectors, encoding genes for cell surface antigens or receptors, have been used to induce their high level expression on tumor cells in vitro and in vivo. These induced antigens and receptors can then be targeted with radiolabeled antibodies or peptides for potential radiotherapeutic applications. The purpose of this study was to determine a dosing schema of an adenoviral vector encoding the human somatostatin receptor subtype 2 (AdCMVhSSTr2) for achieving the highest tumor localization of [(111)In]-DTPA-D-Phe1-octreotide, which binds to this receptor, in a human ovarian cancer model as a prelude to future therapy studies. AdCMVhSSTr2 was produced and used to induce hSSTr2 on A427 human nonsmall cell lung cancer cells and on SKOV3.ipl human ovarian cancer cells in vitro, as demonstrated by competitive binding assays using [125I]-Tyr1-somatostatin and [(111)In]-DTPA-D-Phe1-octreotide. Mice bearing i.p. SKOV3.ip1 tumors administered 1 x 10(9) plaque-forming units of AdCMVhSSTr2 i.p. 5 days after tumor cell inoculation, followed by an i.p. injection of [(111)In]-DTPA-D-Phe1-octreotide 2 days later, showed a range of 15.3-60.4% median injected dose/gram (ID/g) in tumor at 4 h after injection compared with 3.5% ID/g when [125I]-Tyr1-somatostatin was administered and 0.3% ID/g when the negative control peptide [125I]-mIP-bombesin was administered. Mice administered a control adenoviral vector encoding the gastrin-releasing peptide receptor did not have tumor localization of [(111)In]-DTPA-D-Phe1-octreotide (<1.6% ID/g), demonstrating specificity of [(111)In]-DTPA-D-Phe1-octreotide for the AdCMVhSSTr2 induced tumor cells. In another set of experiments, the tumor localization of [(111)In]-DTPA-D-Phe1-octreotide was not different 1, 2, or 4 days after AdCMVhSSTr2 injection (31.8, 37.7, and 40.7% ID/g, respectively; P = 0.88), indicating that multiple injections of radiolabeled peptide can be administered with equivalent uptake over a 4-day period. [(111)In]-DTPA-D-Phe1-octreotide tumor localization in animals administered AdCMVhSSTr2 on consecutive days or 2 days apart was 22.4% ID/g and 53.2% ID/g, respectively (P = 0.009) when [(111)In]-DTPA-D-Phe1-octreotide was given 1 day after the second AdCMVhSSTr2 injection. There was no difference in [(111)In]-DTPA-D-Phe1-octreotide localization after a single AdCMVhSSTr2 injection (40.7% ID/g) or two injections of AdCMVhSSTr2 given 1 (45.9% ID/g) or 2 (53.2% ID/g) days apart, where [(111)In]-DTPA-D-Phe1-octreotide was given in each case 4 days after the first AdCMVhSSTr2 injection (P = 0.65). Therefore, two AdCMVhSSTr2 injections did not increase [(111)In]-DTPA-D-Phe1-octreotide tumor localization compared with one injection, which eliminates concerns about an immune response to a second dose of AdCMVhSSTr2. This will be the basis for a therapeutic protocol with multiple administrations of an octreotide analogue labeled with a therapeutic radioisotope.

Adenoviridae↗