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PubMed1995

Hepatic uptake of octreotide, a long-acting somatostatin analogue, via a bile acid transport system.

The hepatic transport mechanism of octreotide (Sandostatin), a somatostatin analogue, was studied using freshly prepared rat hepatocytes. The initial uptake rate of octreotide represented exclusively a saturable transport process. The half-saturation constant, Kt, and the maximum uptake-rate, Jmax, for the uptake of octreotide were 91.1 +/- 28.4 microM and 104.6 +/- 19.7 pmol/mg protein/min, respectively. An energy requirement was demonstrated for [14C]octreotide uptake since metabolic inhibitors (DNP, rotenone, antimycin and NaCN) significantly reduced the initial uptake rate. [14C]octreotide uptake was also significantly inhibited by ouabain. [14C]octreotide uptake was reduced in the absence of Na+ in the uptake medium. [14C]octreotide uptake was significantly inhibited by bile acids, iodipamide, d-tubocurarine, whereas it was not inhibited by bilirubin, TEMA and insulin. Competitive inhibition of taurocholic acid was observed for octreotide uptake with the inhibition constant, Ki, of 82 +/- 17 microM. Moreover, a significant inhibitory effect of octreotide was observed for the Na+ dependent uptake of [14C]taurocholic acid. These results suggest that octreotide is transported into hepatocytes via a bile acid carrier-mediated system.

Amino Acid Sequence↗

PubMed2003

Indium-111-labelled octreotide scintigraphy in the diagnosis and management of non-iodine avid metastatic carcinoma of the thyroid.

Treatment of differentiated thyroid cancer is a success of modern medicine with the use of radioiodine ((131)I). However, a significant proportion of thyroid cancers may be non-iodine avid. Thyroid tumours are known to express somatostatin receptors. Octreotide, an analogue of somatostatin, can be combined with a radioactive isotope, such as (111)In-DTPA(0) to visualise tumours with high concentrations of somatostatin receptors. We assessed 18 patients with histologically proven metastatic or locally recurrent non-iodine avid thyroid carcinoma to determine the usefulness of (111)In-DTPA(0) octreotide scintigraphy compared to conventional radiology in diagnosing sites of metastasis. The diagnosis of metastatic disease was made using conventional radiology and all had prospective scintigraphy using (111)In-DTPA(0)octreotide. Of the 18 patients, 14 had octreotide-positive scans. In eight, the octreotide scans identified the same sites of metastases as conventional radiology, that is, were concordant. In nine patients, conventional radiology showed more extensive disease than revealed on the octreotide scans. In one patient with widespread bone metastases, octreotide gave a more detailed assessment of metastatic disease than conventional radiology. These data indicate that (111)In-DTPA(0)octreotide imaging for patients with non-iodine avid carcinoma of the thyroid may be a useful diagnostic and staging tool. One patient with Hurthle cell carcinoma metastatic to bone and a positive octreotide scan has been treated with (90)yttrium-labelled octreotide.

Antineoplastic Agents, Hormonal↗

PubMed1999

Comparison of monthly intramuscular injections of Sandostatin LAR with multiple subcutaneous injections of octreotide in the treatment of acromegaly; effects on growth hormone and other markers of growth hormone secretion.

OBJECTIVE: To compare the effects of monthly intra-muscular injections of a long acting preparation of octreotide, Sandostatin LAR, with multiple daily subcutaneous injections of octreotide and to study the interrelationships between mean 24 h growth hormone profile, serum total and free IGF-1 levels, 24 h urinary growth hormone levels and serum IGFBP-3. DESIGN: Patients were assessed by 24 h GH profile off octreotide or any other GH modifying drug therapy; on subcutaneous octreotide (200-600 micrograms daily in divided doses for six weeks); and 28 days after the second of two injections of Sandostatin LAR (20 mg by intra-muscular injection) administered 28 days apart. Serum total and free IGF-1, serum IGFBP-3 and 24 h urinary GH were also measured on each occasion. RESULTS: Sandostatin LAR was well tolerated. None of the patients reported any adverse effect and all completed the study uneventfully. Mean GH off treatment was 10.1 +/- 3.0 micrograms/l falling equally significantly (P < 0.05) during therapy with subcutaneous octreotide to 3.0 +/- 0.7 micrograms/l and Sandostatin LAR to 2.8 +/- 0.7 micrograms/l. Fasting 0900 h GH was significantly reduced (P < 0.05) on Sandostatin LAR (3.0 +/- 0.7 micrograms/l) compared with subcutaneous octreotide (5.1 +/- 1.2 micrograms/l). Mean total IGF-1 off treatment was 658.6 +/- 56.1 micrograms/l and was reduced to a comparable extent with subcutaneous octreotide and Sandostatin LAR (466.0 +/- 59.7 and 448.6 +/- 59.5 micrograms/l respectively; both P < 0.05). Free IGF-1 off treatment was 3.1 +/- 0.6 micrograms/l and was reduced equally by subcutaneous octreotide and Sandostatin LAR (1.2 +/- 0.2 and 1.2 +/- 0.2 micrograms/l; both P < 0.05). IGFBP-3 was reduced to a greater extent during Sandostatin LAR than during subcutaneous octreotide (4518.2 +/- 247.3 vs 5132.8 +/- 280.7 micrograms/l; P < 0.05). Twenty-four hour urinary GH excretion was reduced to a comparable extent with both therapies. Highly significant positive correlations were found between mean 24 h GH levels and free IGF-1 (r = 0.66, P < 0.0001) and 24 h urinary GH excretion (r = 0.94, P < 0.0001). The relationships between mean 24 h GH levels and total IGF-1 and IGFBP-3 although significant showed less powerful correlations. CONCLUSIONS: These results suggest that Sandostatin LAR is well tolerated and as effective as subcutaneous octreotide. In addition, urinary growth hormone and serum free IGF-1 may prove valuable for outpatient follow-up of acromegalic patients, as both correlate well with mean 24 h serum growth hormone levels.

Acromegaly↗

PubMed2000

Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly.

BACKGROUND AND OBJECTIVE: The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogues. Long-acting depot formulations for intramuscular injection of two somatostatin analogues have recently become available: octreotide acetate LAR (Sandostatin LAR, Novartis Pharma AG) and lanreotide SR (Somatuline, Ipsen Biotech). We wished to compare efficacy of octreotide LAR and lanreotide SR in acromegalic patients. PATIENTS AND METHODS: A group of 125 patients with acromegaly (67 females; mean age, 47 years; 59 patients had previous pituitary irradiation) from 26 medical centres in France, Spain and Germany were studied. Before the study, all patients had been treated with intramuscular injections of lanreotide SR (mean duration, 26 months) at a dose of 30 mg which was injected every 10 days in 64 and every 14 days in 61 patients, respectively. All patients were switched from lanreotide SR to intramuscular injections of 20 mg of octreotide LAR once monthly for three months. In order to obtain efficacy and safety data of lanreotide SR under study conditions, it was decided to randomly assign at day 1, in a 3 : 1 ratio, the time point of the treatment switch; 27 of the patients were randomly assigned to continue the lanreotide SR treatment for the first 3 months of the study (group A); they were on octreotide LAR 20 mg from month 4-6. The other 98 patients were assigned to be switched to treatment with octreotide LAR 20 mg at day 1 (group B). In group B patients, octreotide LAR treatment was continued until month 6, with an adjustment of the dose based on GH levels obtained at month 3. RESULTS: The mean GH concentration decreased from 9.6 +/- 1.3 mU/l at the last evaluation on lanreotide SR to 6.8 +/- 1.0 mU/l after three injections of octreotide LAR (P < 0.001). The percentages of patients with mean GH values < or = 6.5 mU/l (2.5 microg/l) and < or = 2.6 mU/l (1.0 microg/l) at the last evaluation on lanreotide SR were 54% and 14%, and these values increased after 3 months treatment with octreotide LAR to 68% and 35% (P < 0.001), respectively. IGF-I levels were normal in 48% at the last evaluation on lanreotide SR and in 65% after 3 months on octreotide LAR (P < 0.001). Patients with pre-study pituitary irradiation had lower mean GH and IGF-I concentrations. But the effects of the treatment change did not differ between the irradiated and the nonirradiated patients. In general both drugs were well tolerated. CONCLUSION: Octreotide LAR 20 mg administered once monthly was more effective than lanreotide SR 30 mg administered 2 or 3 times monthly in reducing GH and IGF-I in patients with acromegaly.

Acromegaly↗

PubMed1992

The effect of the somatostatin analogue octreotide on growth hormone secretion in insulin-dependent diabetics without residual insulin secretion.

Growth hormone (GH) hypersecretion is well documented in insulin-dependent diabetes mellitus (IDDM). Somatostatin inhibits GH in acromegalics and healthy subjects although data on its inhibitory effects on high GH levels in IDDM patients are controversial. The effect of treatment with the somatostatin analogue octreotide ("Sandostatin") on GH secretion, IGF1 levels and metabolic control was investigated in insulin-dependent diabetics. Growth hormone and blood glucose were measured at hourly intervals whilst IGF-I was measured every 6 hours during the 24-h period before and after 7 days' treatment with octreotide (200 micrograms subcutaneously three times daily) in 10 C-peptide negative diabetics. Octreotide significantly reduced mean 24 h GH profile (7.2 +/- 0.7 mU/L before; 5.2 +/- 0.5 mU/L on octreotide, p less than 0.01), IGF-I levels (0.62 +/- 0.06 before; 0.47 +/- 0.05 on octreotide, p less than 0.005) mean 24 h blood glucose (14.4 +/- 0.5 mmol/L before; 12.6 +/- 0.4 mmol/L on octreotide, p less than 0.001) and daily insulin requirements (44.8 +/- 3.0 IU before; 37.2 +/- 3.0 IU on octreotide, p less than 0.02). The shape of 24 h GH profile curve changed significantly on octreotide treatment (p less than 0.05) when it consisted of three nadirs and three peaks closely linked with the time of octreotide administration. Moderate (abdominal discomfort) to severe hypoglycaemia) transient side effects have been observed in all treated patients. The results of this study showed that short-term treatment with octreotide given s. c. every eight hours modulates the pattern of GH secretion in C-peptide negative insulin-dependent patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma.

BACKGROUND: Patients with scleroderma may have abnormal motility of the small intestine, with pseudoobstruction and bacterial overgrowth. Standard stimulatory agents are often ineffective in such patients. Because the somatostatin analogue octreotide evokes intestinal motor activity in normal subjects, we hypothesized that it might increase motility in patients with scleroderma. METHODS: We studied the effects of octreotide on intestinal motility and plasma motilin concentrations in five fasting patients with scleroderma who had bacterial overgrowth and in six fasting normal subjects. The motor effects of octreotide were correlated with its effects on abdominal symptoms and bacterial overgrowth as determined by the level of breath hydrogen excretion. RESULTS: In the normal subjects, octreotide (10 micrograms subcutaneously) increased the mean (+/- SD) frequency of intestinal migrating complexes, which reflect intestinal motility, from 1.5 +/- 1.0 to 4.1 +/- 1.1 every three hours. In the patients with scleroderma, who had no spontaneous migrating complexes, octreotide (100 micrograms) induced 3.6 +/- 2.3 complexes every three hours. These complexes propagated at the same velocity and had two-thirds the amplitude of the spontaneous complexes in normal subjects. Plasma motilin concentrations, which were higher in the patients with scleroderma (229 +/- 74 pmol per liter) than in the normal subjects (112 +/- 37 pmol per liter), were inhibited by octreotide, suggesting that intestinal activity evoked by octreotide is independent of motilin. Treatment of the patients with scleroderma with octreotide (50 micrograms every evening) for three weeks reduced breath hydrogen excretion while they were fasting from 25 +/- 5 to 4 +/- 2 ppm (P = 0.001) and breath hydrogen excretion after they ingested 50 g of glucose from 46 +/- 24 to 8 +/- 7 ppm (P = 0.015); these reductions were accompanied by a significant decrease in nausea, bloating, and abdominal pain and by less frequent emesis. CONCLUSIONS: Octreotide stimulates intestinal motility in normal subjects and in patients with scleroderma. In such patients, the short-term administration of octreotide reduces bacterial overgrowth and improves abdominal symptoms. This agent may be useful for the treatment of intestinal dysmotility in patients with scleroderma.

Adult↗

PubMed1990

Octreotide: a long-acting somatostatin analog.

One of the exciting recent developments in endocrinology research has been the introduction of the somatostatin analog, octreotide into clinical practice. Octreotide provides a new therapeutic tool for diseases in which somatostatin or somatostatin-like products are secreted abnormally. Unfortunately, early experience was obtained largely with uncontrolled, compassionate drug use. When clinical information regarding octreotide is critically reviewed, evaluation is hampered by the lack of long-term studies with adequate numbers of patients and controls. Nevertheless, the information available does indicate that octreotide is promising in the acute treatment of some of the manifestations of the carcinoid syndrome, including carcinoid crisis. Similarly, octreotide ameliorates symptoms of other gut neuroendocrine tumors, particularly vasoactive intestinal peptide (VIP)-secreting tumors. Octreotide also has potential in the management of growth-hormone-secreting tumors. Long-term treatment with octreotide for these diseases requires more information regarding alterations in disease progression and development of adverse effects including variable effects on blood sugar regulation and steatorrhoea. Octreotide also has been used in nonmalignant gastrointestinal disorders, but larger studies are necessary before recommendations regarding these applications can be made. The cost of octreotide, as may be expected, is high but is justified for patients with the specific indications outlined in this review. These indications may change as understanding of the drug increases. Octreotide offers promise, particularly as acute treatment for the troublesome symptoms of several neuroendocrine disorders.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Interactions↗

PubMed2002

Tissue distribution of octreotide binding receptors in normal mice and strains prone to autoimmunity.

Somatostatin has diverse functions, including immunomodulatory functions. In humans, sites of active inflammation can be visualized by the administration of 111In-DTPA(0)-octreotide, a radiolabelled somatostatin analogue. We wished to establish an animal model for preclinical evaluation of the effects of somatostatin analogues on the immune system. However, most animal models for immunological diseases are murine. This report is a preliminary study of the distribution of somatostatin receptors in mouse tissues, with emphasis on the immune system. Tissue distribution of octreotide binding receptors in normal (BALB/c) mice was determined in vivo by receptor binding of 111In-DTPA(0)-octreotide and in vitro and ex vivo by receptor autoradiography. Additionally, we investigated the tissue distribution of octreotide binding receptors in inflammatory lesions in a murine model of immune mediated disease, i.e. pre-diabetic pancreatic infiltration in the non-obese diabetic mouse strain. High specific uptake of radioactivity was seen in the thymus (range 1-1.7% ID/g) and the pituitary (1-1.6% ID/g) in all mouse strains. Specific uptake was also found in the stomach (0.1-0.7% ID/g), in the adrenal glands (0.1-0.3% ID/g) and in the pancreas (0.1-0.3% ID/g). However, we did not detect increased uptake of radiolabelled octreotide in the pancreas of pre-diabetic NOD mice. Autoradiography on tissue sections confirmed the presence of octreotide binding sites in the tissues that showed specific uptake. Moreover, by using autoradiography we could localize the cortex of the thymus and the anterior part of the pituitary as the localization of specific and high affinity, octreotide binding sites. A high, but not a receptor mediated, uptake of radioactivity was seen in the kidneys and was significantly higher in females than in males (12-19% vs 4% ID/g, respectively). Our results point to profound species differences in the tissue distribution of octreotide binding receptors. Of particular interest is the high uptake of 111In-DTPA(0)-octreotide in the cortex of the mouse thymus. This offers perspectives for the use of this animal in studies concerning the effect of somatostatin analogues on the immune system. To our knowledge, this is the first report on the tissue distribution of octreotide binding receptors in mice.

Animals↗

PubMed1998

Effect of octreotide on stimulated insulin release from pancreatic tissue slices.

This study was designed to investigate a possible mechanism of action by which octreotide acetate causes insulin suppression in the denervated pancreas. Canine tissue slices were placed in a pH-adjusted medium with varying concentrations of glucose and octreotide acetate: Experiment 1, 30 min in basal medium with 0.6 mg/ml glucose; Experiment 2, addition of 6.0 mg/ml glucose; Experiment 3, addition of 4 microg octreotide acetate/70 ml (comparable to 100 microg/25 kg body weight); Experiment 4, addition of 16 microg octreotide acetate/70 ml; Experiment 5, incubation with 6.0 mg glucose/ml and 4 microg octreotide acetate/70 ml; Experiment 6, incubation with 6.0 mg glucose/ml and 16 microg octreotide acetate/70 ml; Experiment 7, preincubation with 4 microg octreotide acetate/70 ml, then with 6.0 mg glucose/ml; and Experiment 8, preincubation with 16 microg octreotide acetate/70 ml, then with 6.0 mg glucose/ml. Medium levels of insulin, glucagon, and amylase were collected at intervals during the incubation periods. There was an appropriate increase in the rate of insulin release to glucose stimulation in the high-glucose (6.0 mg/ml) group. There was no significant inhibition of basal or glucose-stimulated insulin release with either simultaneous or pretreatment of the canine pancreatic tissue slices with either concentration of octreotide acetate. These studies support an indirect mechanism by which octreotide acetate exerts its inhibitory effect on endocrine and exocrine function in the canine pancreas transplant model.

Amylases↗

PubMed2001

Haemodynamic effects of propranolol, octreotide and their combination during fasting and post-prandial splanchnic hyperaemia in patients with cirrhosis.

BACKGROUND/AIMS: This double-blind study was designed to evaluate the haemodynamic effect of two drugs, propranolol and octreotide, and their combination in patients with cirrhosis. METHODS: Fifteen patients with cirrhosis were randomly assigned to two groups receiving either octreotide subcutaneously at 100 microg ('octreotide' group, n = 9) or propranolol orally at 40 mg followed by a subcutaneous dose of octreotide (100 microg) after 1 h ('propranolol + octreotide' group, n = 6); then, after 30 min, a standard meal was administered to both groups. The hepatic vein pressure gradient by hepatic vein catheterization, portal and superior mesenteric artery blood flow velocity, superior mesenteric artery pulsatility index by the echo-Doppler duplex system were recorded at baseline, 1 h after propranolol in the 'propranolol + octreotide' group, and in both groups 30 min after octreotide and 30 min after meal. RESULTS: At fast, propranolol was more active in decreasing portal pressure (from 16 +/- 2.2 to 12.7 +/- 3.8 mmHg, -20%, P < 0.05) as compared to octreotide (from 18.6 +/- 4.8 to 16.6 +/- 4.3 mmHg, -11%, P < 0.05). Conversely, octreotide was more active on the mean blood flow velocity of superior mesenteric artery (from 22.8 +/- 5 to 19 +/- 4.5 cm/ s, -17%; P< 0.05). Octreotide administration in patients receiving beta-blockers showed, also, a trend to increase the mesenteric vascular resistances (pulsatility index from 3.14 +/- 0.69 to 3.68 +/- 1.29, +17%, not significant (NS)) which had not been affected by previous treatment with propranolol. After the meal, a reduction of the expected hyperaemic response occurred in both groups. CONCLUSIONS: The combined acute haemodynamic effect of this association suggests the possible combination of these two drugs in critical situations, such as variceal bleeding in patients receiving beta-blockers. The simultaneous use of echo-Doppler and hepatic vein catheterization permitted us a more complete analysis of the acute haemodynamic events.

Adrenergic beta-Antagonists↗

PubMed2006

The effects of treatment with octreotide, diuretics, or both on portal hemodynamics in nonazotemic cirrhotic patients with ascites.

GOALS: To evaluate the effects of diuretic treatment, octreotide, or both on portal hemodynamics in nonazotemic cirrhotic patients with ascites. BACKGROUND: Diuretics and octreotide have been associated with a decrease in portal pressure in cirrhotic patients, suggested to be mediated by plasma volume depletion and splanchnic vasoconstriction, respectively. However, liver cirrhosis is characterized by activation of the renin-angiotensin-aldosterone axis, which increases hepatic vascular resistance and is augmented or suppressed by diuretics or octreotide, respectively. STUDY: Twenty nonazotemic cirrhotic patients with ascites were treated with furosemide and spironolactone. Of them, 10 (group 1) discontinued diuretic treatment for 7 days. Thereafter for 5 days, each patient received subcutaneous octreotide, 300 microg twice per day; ten of them (group 2) received the octreotide in addition to their usual diuretic treatment. Portal and systemic hemodynamics with Doppler ultrasound and endogenous vasoactive systems were evaluated while the patients received diuretics (both groups), after discontinuation of diuretics (group 1), and after octreotide administration (both groups). RESULTS: The withdrawal of diuretics did not alter portal hemodynamics, but it impaired systemic hemodynamics and suppressed the renin-aldosterone axis. The addition of octreotide to diuretic treatment but not octreotide alone improved portal and systemic hemodynamics. In both groups the initiation of octreotide administration suppressed the renin-aldosterone axis and plasma glucagon levels. CONCLUSIONS: In nonazotemic cirrhotic patients with ascites, the combination of diuretics and octreotide improves systemic hemodynamics and inhibits the diuretic-related component of the activated renin-aldosterone axis, which in turn augments the portal hypotensive effect of diuretic-induced plasma volume depletion.

Adult↗

PubMed1995

Review article: the relative effectiveness of somatostatin and octreotide therapy in pancreatic disease.

Somatostatin and octreotide inhibit basal and stimulated pancreatic secretion, stimulate reticuloendothelial system activity, modulate the cytokine cascade and are cytoprotective with respect to the pancreas. These effects of somatostatin and octreotide suggest that both drugs may be useful either in the treatment of pancreatic disorders, or in preventing acute pancreatitis following procedures on the pancreas. In recent years it has become clear that somatostatin is a useful and effective therapy for severe acute pancreatitis and in preventing complications following endoscopic retrograde cholangiopancreatography (ERCP), whereas octreotide has no beneficial effect and may be deleterious in both these indications. The differences in the therapeutic efficacy of somatostatin and octreotide in acute pancreatitis and ERCP appears to be related to their differential effects on sphincter of Oddi motility--the native hormone relaxing, and the analogue increasing, its contractility. Consequently, any beneficial effects of octreotide in both acute pancreatitis and ERCP are offset by the increased contractility of the sphincter of Oddi, which results in retention of activated enzymes within the pancreas and further autodigestion of the gland. Somatostatin and octreotide are equally effective in promoting the closure of pancreatic fistulae. However, the time to closure after commencement of therapy is much more variable and longer in patients treated with subcutaneous octreotide than those receiving intravenous somatostatin, possibly as a result of fluctuations in pancreatic enzyme secretion between consecutive administrations of the hormone. Furthermore, the initial potent inhibitory effect of octreotide on pancreatic secretion is lost after 7 days of continuous subcutaneous administration. Therefore, in terms of cost-effectiveness, somatostatin would appear to be the treatment of choice for pancreatic fistulae. Octreotide markedly reduces the complication rates after elective pancreatic surgery. It remains to be established whether somatostatin is as effective as octreotide in this indication.

Humans↗

PubMed2005

Octreotide in liver cirrhosis: a salvage for variceal bleeding can be a gunshot for kidneys.

BACKGROUND: The renal effects of octreotide, used for bleeding esophageal varices in cirrhosis, are controversial. METHODS: Fourteen cirrhotic patients (Child-Pugh; A/B/C: 1/12/1) were enrolled. Plasma nitrite and endothelin (ET) levels, urinary nitrite output, free water clearance (FWC) and fractional excretion of filtered sodium (FENa) were measured and renal Doppler ultrasound was carried out. Octreotide was infused at a rate of 0.75 microg/kg/h for 3 h after a bolus of 0.75 microg/kg body weight. All the parameters were reevaluated during octreotide administration while the patients acted as their own controls. RESULTS: Octreotide induced significant reductions in urinary nitrite, FENa and FWC. Plasma ET levels increased (baseline: 6.7 pg/ml, octreotide: 8.4 pg/ml), whereas the plasma nitrite level did not change significantly after octreotide infusion. Overall, no significant change in renal resistive index (RRI) could be demonstrated on Doppler after octreotide administration. However, patients with elevated baseline RRI values had significantly more deterioration in FWC and FENa compared with patients with normal RRI in response to octreotide. CONCLUSION: A marked decrease in FENa, FWC and urinary nitrite output, together with a significant increase in plasma ET level in response to octreotide, may indicate renal dysfunction in cirrhotic patients. This deleterious renal effect of octreotide may be more enhanced in patients with elevated baseline RRI.

Adult↗

PubMed2005

Endocytosis of the somatostatin analogue, octreotide, by the proximal tubule-derived opossum kidney (OK) cell line.

BACKGROUND: Nephrotoxicity of cancer therapy using radiolabeled somatostatin analogues such as octreotide is due to ultrafiltration and reuptake by proximal tubular cells (PTCs). The mechanism of uptake is unknown. It could occur either by receptor-mediated endocytosis via a somatostatin receptor or, alternatively, the multiligand megalin/cubilin tandem receptor, or by fluid-phase endocytosis. To define the mechanisms of internalization and to identify potential receptors, we have studied the uptake and processing of octreotide by the PTC-derived opossum kidney (OK) cell line. METHODS: We compared the kinetics of uptake and fate of (111)In-diethylenetriamine pentaacetic acid (DTPA)-D-Phe(1)-octreotide and (125)I-human serum albumin ((125)I-HSA). To determine the contribution of receptor-mediated endocytosis, we tested competition for uptake by octreotide and somatostatin and by various megalin/cubilin ligands [receptor-associated protein (RAP), albumin, transferrin, insulin, polymixin B] or basic amino acids. The subcellular localization of fluorescein isothiocyanate (FITC)-D-Phe(1)-octreotide was studied by confocal microscopy. RESULTS: Kinetics of uptake of (111)In-DTPA-D-Phe(1)-octreotide and (125)I-HSA by OK cells were comparable, but only the somatostatin analogue was significantly retained intact. All megalin/cubilin ligands and basic amino acids strongly inhibited (125)I-HSA uptake, but these could not compete for >50% of (111)In-DTPA-D-Phe(1)-octreotide uptake. The same was found for somatostatin and octreotide. The noncompetable uptake of (111)In-DTPA-D-Phe(1)-octreotide was comparable to the clearance of Lucifer Yellow, a marker of fluid-phase endocytosis. By confocal microscopy, FITC-D-Phe(1)-octreotide colocalized with transferrin in endosomes, then accumulated in lysosomes. CONCLUSION: Receptor-mediated endocytosis via megalin/cubilin and fluid-phase endocytosis contribute about equally to the uptake of radiolabeled somatostatin analogues by OK cells.

Animals↗

PubMed1999

Effects of octreotide on central hemodynamics and systemic oxygen use in patients with viral cirrhosis.

OBJECTIVE: Octreotide has potentially beneficial effects in patients with cirrhosis. However, the effects of octreotide on central hemodynamics and oxygen use have not been established. The present study was undertaken to evaluate the effect of octreotide on central hemodynamics and oxygen use in patients with viral cirrhosis. METHODS: Twenty-five patients with cirrhosis were enrolled in the study. They were randomly assigned to receive either placebo (n = 10) or a continuous infusion of 100 microg/h of octreotide after an initial 100-microg bolus (n = 15). Hemodynamic measurements and oxygenation values were obtained before and 60 min after octreotide or placebo administration. RESULTS: Placebo administration did not have any effect on hemodynamic and oxygenation values. In patients who received octreotide, systemic hemodynamic values including cardiac index, mean arterial pressure, and systemic vascular resistance were not affected. The mean pulmonary arterial pressure tended to increase after octreotide administration but was statistically insignificant. There was a significant increase in pulmonary arterial vascular resistance, whereas the pulmonary capillary wedge pressure and right atrial pressure were significantly decreased. Arterial oxygen tension, systemic oxygen uptake, and oxygen extraction ratio were significantly decreased after octreotide administration, whereas oxygen transport as well as arterial and mixed venous oxygen contents remained unchanged. CONCLUSIONS: In patients with viral cirrhosis, octreotide administration exerted a significant effect on pulmonary circulation. It also resulted in a decrease in systemic oxygen uptake and oxygen extraction ratio. These results suggested that octreotide may impair tissue oxygenation in patients with viral cirrhosis.

Aged↗

PubMed1994

Effect of octreotide on gastrointestinal pressure profiles in health and in functional and organic gastrointestinal disorders.

The somatostatin analogue, octreotide, restores normal pressure profiles in disorders of upper gut motility. This study aimed to evaluate the acute effects of octreotide in five healthy subjects and in 50 consecutive patients with functional (n = 22) or organic (n = 28) dysmotility. Antroduodenojejunal manometry was performed during three hours' fasting, for two hours after a standard meal, and 30 minutes after subcutaneous injection of 50 micrograms octreotide. Antral motility, before and after octreotide, and characteristics of spontaneous migrating motor complexes and octreotide induced activity fronts were compared. Octreotide inhibited antral motility and induced a small intestinal activity front followed by motor quiescence in all healthy subjects and patients. The duration and propagation velocity of activity fronts were greater than those of spontaneous migrating motor complexes. Thirty per cent of activity fronts began simultaneously at different levels of small bowel, and in 20%, a second, normally propagated activity front developed within 30 minutes of octreotide injection. Octreotide induces rapidly propagated, long activity fronts, even in patients with neuropathology, and this may initially facilitate the intestinal propulsion of chyme. Propulsion may not occur, however, if octreotide induces simultaneous activity fronts or if the activity front is followed by prolonged quiescence. Inhibition of antral motility suggests that octreotide may not be effective in gastroparesis.

Adolescent↗

PubMed1996

Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours.

Antiproliferative treatment of patients with metastatic endocrine gastroenteropancreatic tumours (GEP) is based mainly on chemotherapeutic protocols whereby drug toxicity is a major handicap. Octreotide is the first choice in the control of hormone mediated symptoms. From retrospective and a few prospective studies it has been suggested that octreotide exhibits antiproliferative properties. The prospective German Sandostatin multicentre phase II trial investigated the effects of 200 micrograms octreotide thrice daily for one year on tumour growth and endocrine abnormalities in 103 patients. Octreotide treatment was continued in those patients responding to the drug until tumour progression occurred. In 28 of those with tumour progression during 200 micrograms thrice daily octreotide dose was increased to 500 micrograms thrice daily. The study sample consisted of 52 patients with computed tomography confirmed tumour progression and 13 patients with stable disease before octreotide treatment, whereas no preobservation period was available in 38 patients. Nineteen patients (36.5%) with computed tomography confirmed tumour progression experienced stabilisation of tumour growth lasting for at least three months. Median duration of stable disease was 18 months. At month 12, stable disease continued in 12 patients, declined after 24 months to nine patients, and after 36 months to five patients. Tumour regression has not been seen in this or other subgroups. In the subgroup with stable disease before octreotide, stable disease continued in 53.8% of patients over 12 months. Increase of octreotide dose to 500 micrograms thrice daily did not influence progression seen during the lower dose with the exception of one patient in whom tumour progression changed to stable disease. No association of tumour size response and patients' characteristics could be detected. The results suggest that octreotide inhibits tumour growth in patients with metastasised endocrine GEP tumours. The antiproliferative effect is, at least in some patients, longlasting. Currently, octreotide can only be recommended as an antiproliferative drug if patients with clearly progressive disease show stabilisation after treatment for three to six months.

Adenoma, Islet Cell↗

PubMed1997

Reduction of non-steroidal anti-inflammatory drug induced gastric injury and leucocyte endothelial adhesion by octreotide.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) induce gastric ulcers. AIMS: To assess whether the somatostatin analogue octreotide prevents NSAID induced mucosal gastrointestinal damage in both animals and humans. The effect of octreotide on neutrophil adhesion to the endothelium was also evaluated. METHODS: Male Sprague-Dawley rats were pretreated either with saline (0.3 ml subcutaneously) or octreotide (0.001-1 ng/kg subcutaneously). After 30 minutes gastric ulcers were induced by the intragastric application of NSAIDs (20 mg/kg indomethacin, 200 mg/kg aspirin, 200 mg/kg ibuprofen, or 50 mg/kg diclofenac). Four hours later the rats were killed and gastric mucosal lesions were assessed by computed planimetry. To determine whether octreotide could prevent indomethacin induced injury in humans, 20 healthy volunteers were evaluated in a double blind, placebo controlled study. RESULTS: Octreotide prevented NSAID induced gastric mucosal lesions (p < 0.05). The dose response curve was U shaped and the most effective dose was 0.1 ng/kg. Leucocyte adherence in submucosal venules of the stomach was evaluated by in vivo microscopy. Octreotide (0.1 ng/kg subcutaneously) prevented indomethacin (20 mg/kg intragastric) induced leucocyte adherence in gastric submucosal venules (p < 0.05). Healthy human volunteers received 50 mg indomethacin orally thrice a day concomitantly with either an identical placebo or 0.01 microgram, 0.1 microgram, or 1 microgram octreotide subcutaneously thrice a day for three days. Injury was assessed by endoscopy. There was a negative correlation between the octreotide dose and injury score (p < 0.03 for gastric injury, p < 0.001 for duodenal injury). CONCLUSIONS: Octreotide protects the stomach from NSAID induced gastric injury, probably via its ability to reduce NSAID induced neutrophilic adhesion to the microvasculature. Octreotide also ameliorated indomethacin induced gastric and duodenal injury in humans.

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