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At least 19 recordsLinked to original sources
PubMed1993

A case of antibody formation against octreotide visualized with 111In-octreotide scintigraphy.

A case of antibody formation in a patient with carcinoid syndrome is described. The patient was treated with octreotide in dosages up to 1.5 mg/day. Serum samples were analysed for the presence of octreotide antibodies before and after 20 months of octreotide treatment. In-vivo 111In-octreotide scintigraphy was performed before and during therapy, and after antibodies had developed. Before treatment, no serum antibodies against octreotide were detected. After 20 months of treatment, they were detectable up to a 1:115 serum dilution. The serum binding of 125I-Tyr3-octreotide was blocked by adding excess unlabelled Tyr3-octreotide, indicating the presence of specific octreotide antibodies. Before treatment, a normal distribution of radioactivity in the spleen and kidneys, irregular uptake in the liver due to metastases, and a hot spot in the lower abdomen were found during 111In-octreotide scintigraphy. After antibodies had developed, increased radioactivity over the heart and high background radioactivity in the abdomen with only faint visualization of the spleen, liver, and kidneys were found, indicating a prolonged presence of 111In-octreotide in the blood resulting from its being bound to antibodies. Increased radioactivity was also seen at the injection sites of the drug in the upper legs. In-vitro incubation of biopsy tissue from this site with 125I-Tyr3-octreotide revealed diffuse guanosine triphosphate (GTP) independent specific binding, indicating non-G-protein linked binding of labelled octreotide. This report describes the characteristic abnormalities during in-vivo 111In-octreotide scintigraphy in a patient with octreotide antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Internalization of the radioiodinated somatostatin analog [125I-Tyr3]octreotide by mouse and human pituitary tumor cells: increase by unlabeled octreotide.

Recently, we developed a technique that allows the in vivo visualization in man of somatostatin receptor-positive neuroendocrine tumors after i.v. injection of [125I-Tyr3]octreotide or [111In-DTPA-D-Phe1]octreotide. Radiotherapy of such tumors using somatostatin analogs coupled to alpha- or beta-emitting radionuclides has been proposed as an application for radiolabeled somatostatin analogs. To develop this concept further, it is of importance to know whether the above-mentioned radiolabeled somatostatin analogs are internalized by the tumor cells, and whether it might be possible to manipulate the degree of internalization. In the present study we investigated the internalization of a stable somatostatin analog, [125I-Tyr3]octreotide, by mouse AtT20/D16V pituitary tumor cells and primary cultures of human GH-secreting pituitary tumor cells. Treatment of the cells with low pH was used to distinguish between membrane-bound (acid-releasable) and internalize (acid-resistant) radioligand. [125I-Tyr3]octreotide showed a time-dependent increasing accumulation in AtT20 cells; after 4 h of incubation, values up to 6-8% of the dose of radioligand added were obtained. Binding and internalization of [125I-Tyr3]octreotide were temperature dependent and inhibited by pertussis toxin. Inhibitors of lysosomal degradation did not increase the amount of internalized radioligand. After 4 h of incubation, 88% of the radioactivity present in the cells was still peptide bound, suggesting a low intracellular breakdown of this radioligand. Six of seven human GH-secreting adenoma cell cultures also internalized [125I-Tyr3]octreotide (variation between 0.24-4.98% of the dose radioligand added). Displacement of binding and internalization of [125I-Tyr3]octreotide by unlabeled octreotide showed a bell-shaped curve in AtT20 cells. At low concentrations (0.1 and 1 nM), binding and internalization were increased, whereas at higher concentrations, saturation occurred. In contrast to this, binding of [125I-Tyr3]octreotide to a broken cell preparation of AtT20 cells was displaced in a dose-dependent manner by unlabeled octreotide, with an IC50 of 0.1 nM. Similar observations were made in the human GH-secreting adenoma cell cultures. In conclusion, a high amount of [125I-Tyr3]octreotide is internalized in a specific-, time-, temperature-, and pertussis toxin-sensitive GTP-binding protein-dependent manner by mouse AtT20 and human GH-secreting pituitary tumor cells. In the presence of a low concentration of unlabeled octreotide, a rapid increase in the amount of [125I-Tyr3]octreotide internalized by AtT20 cells and by the majority of the human GH-secreting adenoma cell cultures was found.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenoma↗
PubMed1992

Somatostatin receptor scintigraphy with indium-111-DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide.

Scintigraphy with 123I-Tyr-3-octreotide has several major drawbacks as regards its metabolic behavior, its cumbersome preparation and the short physical half-life of the radionuclide. The use of another radiolabeled analog of somatostatin, 111In-DTPA-D-Phe-1-octreotide, has consequently been proposed. DTPA-D-Phe-1-octreotide can be radiolabeled with 111In in an easy single-step procedure. DTPA-D-Phe-1-octreotide is cleared predominantly via the kidneys. Fecal excretion of radioactivity amounts to only a few percent of the administered radioactivity. For the radiation dose to normal tissues, the most important organs are the kidneys, the spleen, the urinary bladder, the liver and the remainder of the body. The calculated effective dose equivalent is 0.08 mSv/MBq. Optimal 111In-DTPA-D-Phe-1-octreotide scintigraphic imaging of various somatostatin receptor-positive tumors was obtained 24 hr after injection. In the six patients studied, tumor localization with 123I-Tyr-3-octreotide and with 111In-DTPA-D-Phe-1-octreotide were found to be similar. However, the normal pituitary is more frequently visualized with the latter radiopharmaceutical. In conclusion, 111In-DTPA-D-Phe-1-octreotide appears to be a sensitive somatostatin receptor-positive tissue-seeking radiopharmaceutical with some remarkable advantages: easy preparation, general availability, appropriate half-life and absence of major interference in the upper abdominal region, because of its renal clearance. Therefore, 111In-DTPA-D-Phe-1-octreotide may be suitable for use in SPECT of the abdomen, which is important in the localization of small endocrine gastroenteropancreatic tumors.

Adult↗
PubMed1992

Invasive mixed growth hormone/prolactin secreting pituitary tumour: complete shrinking by octreotide and bromocriptine, and lack of tumour growth relapse 20 months after octreotide withdrawal.

Octreotide and bromocriptine were used to treat an acromegalic patient harbouring an invasive pituitary tumour secreting growth hormone and prolactin. Octreotide (100 micrograms, subcutaneously, three times daily) and bromocriptine (15 mg orally, daily) rapidly improved clinical signs and symptoms, including diabetes that initially required insulin. Complete control of growth hormone and prolactin secretion was obtained and maintained by this treatment protocol for 12 months without affecting the other pituitary functions. A major tumour shrinkage was apparent by magnetic resonance imaging after six months, and was considered to be complete after 12 months of treatment. Octreotide was then discontinued without any relapse in either growth hormone secretion or tumour growth over a 20-month period following withdrawal. Attempts were made to discontinue bromocriptine, but a maintenance therapy (2.5 mg daily) was required to control rebounds of prolactin hypersecretion. Two months after octreotide withdrawal, acute pancreatitis secondary to cholelithiasis required surgery; this complication was attributed to octreotide (pre-treatment ultrasonography was normal). These findings suggest that combination therapy with octreotide and bromocriptine may be considered in pituitary macroadenomas secreting growth hormone and prolactin. They also emphasize the need for a close monitoring of cholelithiasis, not only during octreotide therapy but also after the drug's withdrawal.

Adenoma↗
PubMed1994

Octreotide in the treatment of acute pancreatitis: results of a unicenter prospective trial with three different octreotide dosages.

Acute necrotizing pancreatitis is still associated with high morbidity and mortality. In this prospective clinical trial, we analyzed the effect of octreotide in patients with acute pancreatitis. Eight patients received either 3 x 100, 3 x 200 or 3 x 500 micrograms octreotide subcutaneously per day over a period of 10 days. The complication rate was lower in the group of patients who received 3 x 200 or 3 x 500 micrograms octreotide than in the control group and the group of patients who received the dosis of 3 x 100 micrograms octreotide per day. The results of this study are promising and must be validated in a controlled clinical trial with octreotide in a larger patient population.

Acute Disease↗
PubMed1991

Continuous subcutaneous octreotide infusion: dose-response relationships between metabolic effects and octreotide clearance in patients with insulin-dependent (type 1) diabetes.

Octreotide (Sandostatin), a potent and long-acting octapeptide analogue of somatostatin, exhibits variable metabolic effects in type 1 diabetes. We have postulated that interindividual variability in octreotide metabolism could be responsible in part for the differences in metabolic responses reported in previous clinical studies. To this end, we determined plasma levels and MCR of octreotide during 24-hour continuous SC infusion (low dose, 200 micrograms; high dose, 400 micrograms) in nine female, C peptide-negative patients with type 1 diabetes. The metabolic effects of the analogue were assessed by measuring serum glucose, free insulin, glucagon, GH, and PP levels before and at 1- to 2-hour intervals during each dose of the analogue or control (0.9% saline solution) infusion in a single-blind randomized manner. Mean daytime (0800-0000 hours) and bedtime (0000-0800 hours) serum glucose levels decreased significantly (p less than 0.05 to 0.02) during analogue therapy compared with control. Mean serum free insulin levels were significantly (p less than 0.02) greater during octreotide infusion compared with control, despite the similar daily insulin requirements. Both doses of the analogue effectively suppressed 24-hour GH by 50%, glucagon by 50%, and PP by 80%. Steady-state octreotide levels varied considerably among patients (low, mean +/- SEM), 1000 +/- 101, range 638 to 1375 pg/ml; high, mean 1940 +/- 147, range 1032 to 2462 pg/ml). Although mean MCR values were similar with both doses, we observed greater interindividual variability (low, mean 2.45 +/- 0.30, range 1.31 to 3.78 ml/kg/min; high, mean 2.36 +/- 0.19, range 1.68 to 3.48 ml/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1993

Hepatobiliary handling of iodine-125-Tyr3-octreotide and indium-111-DTPA-D-Phe1-octreotide by isolated perfused rat liver.

Radiolabeled bioactive peptides may show receptor-mediated binding to tumors, making them suitable for scintigraphic imaging. The liver is an important organ for peptide clearance. To gain insight into the uptake and intracellular processing of somatostatin analogs, we compared the hepatobiliary handling of 125I-Tyr3-octreotide and 111In-DTPA-D-Phe1-octreotide, which are successfully used to image somatostatin receptor-positive tumors in vivo in isolated recirculating perfused rat livers. Sixty minutes following administration of the radiolabeled peptides, perfusion medium and biliary radioactivity were analyzed. Radioiodinated Tyr3-octreotide was rapidly cleared by the liver and 60% of the dose was excreted intact into the bile after 60 min. In contrast, 111In-DTPA-D-Phe1-octreotide was not cleared by the liver; medium radioactivity levels remained about constant and only 2% of the dose was found in the bile. These results are in agreement with in vivo findings in rats and humans. We concluded that isolated rat liver perfusion is a good system to rapidly gain insight into the hepatic handling of radiopharmaceuticals.

Animals↗
PubMed1995

Effects of treatment with octreotide in acromegalic patients--a multicenter Italian study. Italian Multicenter Octreotide Study Group.

Treatment of acromegaly is effective in reversing the reduced life-span of patients only when serum growth hormone (GH) concentrations are lowered to less than 2.5 micrograms/l. Usual treatments achieve this goal in no more than 50-60% of patients. The effects of octreotide were studied in a prospective, open label study with 68 acromegalic patients enrolled in 10 Italian centers. Octreotide was administered sc at a dose of 100 micrograms t.i.d. for 1 year. After 3 months of therapy, octreotide was effective in decreasing serum GH levels below 2.5 micrograms/l in 16 out of 64 acromegalic patients (25%). Fifteen of them had pretreatment GH levels below 25 micrograms/l. Insulin-like growth factor I (IGF-I) levels normalized in about 40% of patients. No further GH reduction was observed after 1 year of treatment. The presence of abnormal GH responses to thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone was reduced from 54 to 24% and from 16 to 12%, respectively. Tumor shrinkage was observed in 50% of 26 non-irradiated patients after 12 months of treatment. Both basal and TRH-stimulated serum prolactin levels significantly decreased in the 11 hyperprolactinemic patients. Although serum thyrotropin, free triiodothyronine and free thyroxine concentrations were not modified, a significant reduction of thyrotropin response to TRH was observed in the 9th month of therapy. In non-diabetic patients, an increase of mean blood glucose levels without modifications of fasting morning concentrations was found. About one-quarter of the patients with overt diabetes mellitus had an impairment of their metabolic control. Main clinical symptoms of acromegaly improved in 70-80% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗
PubMed1994

Iodine-123-Tyr-3-octreotide uptake in pancreatic endocrine tumors and in carcinoids in relation to hormonal inhibition by octreotide.

UNLABELLED: Uptake of 123I-Tyr-3-octreotide (TOCT) by hormone-secreting abdominal tumors was studied to compare scintigraphic observations with the reduction in hormone levels brought about by a brief therapeutic test. METHODS: A prospective study was conducted on 17 patients, totalizing 46 proven lesions, with endocrine tumors of the pancreas (10 patients, 20 lesions) and/or carcinoid metastases (8 patients, 26 lesions). Tumor hormonal hypersecretion was inhibited by octreotide. RESULTS: There was good agreement between the results of these examinations. CONCLUSIONS: The detection of abdominal tumors using this radiotracer is strongly related to its functional characteristics. Variations in the scintigraphic and test results according to different tumor types were in agreement with published data on the density of somatostatin receptors measured by in vitro studies or scintigraphy and by the therapeutic effects of octreotide.

Adult↗
PubMed1989

Octreotide, a new somatostatin analogue.

The chemistry, pharmacology, pharmacokinetics, clinical uses, adverse effects and drug interactions, dosage, availability and cost, and indications for use of octreotide, a new synthetic analogue of the peptide hormone somatostatin (SS), are reviewed. Like SS, octreotide suppresses secretion of pituitary growth hormone (GH) and thyrotropin and decreases release of a variety of pancreatic islet cell hormones including insulin, glucagon, and vasoactive intestinal peptide (VIP). Octreotide also reduces splanchnic blood flow, gastric acid secretion, GI motility, and pancreatic exocrine function and alters the absorption of water, electrolytes, and nutrients from the GI tract. The elimination half-life of i.v. octreotide is 72-98 minutes, compared with 2-3 minutes for i.v. SS. Usual administration of octreotide is by the i.v. or s.c. route. Octreotide has been studied in the treatment of hormone-secreting pituitary tumors and pancreatic islet cell tumors. Octreotide therapy lowers GH secretion and improves clinical symptoms in patients with acromegaly and may suppress clinical symptoms to a greater degree than bromocriptine. Patients with carcinoid syndrome and VIP-secreting tumors (vipomas) have had substantial improvement in clinical symptoms with administration of octreotide. This agent does not appear to be effective in the treatment of nonvariceal upper GI bleeding and acute pancreatitis; its relative usefulness in the treatment of variceal bleeding is not established. Adverse effects associated with octreotide therapy generally have been mild, including pain or burning at the injection site, abdominal pain, and diarrhea. Octreotide has been shown to interfere with absorption of oral cyclosporine. Standard initial therapy is octreotide acetate 50-100 micrograms s.c. every 8-12 hours, with titration based on clinical and biochemical effects. Up to 3000 micrograms/day of octreotide acetate has been administered to patients with acromegaly without serious adverse effect. Octreotide is marketed under the brand name Sandostatin and is available in 1-mL ampuls containing 50, 100, and 500 micrograms of octreotide acetate. Because the conditions for which octreotide appears to be most effective are uncommon, the drug should be considered for addition to the formulary in tertiary-care institutions only; addition of octreotide to the formulary of a community hospital is probably unnecessary. The synthetic analogue octreotide is longer acting and more specific in pharmacologic action than SS.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Evaluation in vitro and in rats of 161Tb-DTPA-octreotide, a somatostatin analogue with potential for intraoperative scanning and radiotherapy.

The characteristics of terbium-161 diethylene triamine penta-acetic acid (DTPA) labelled octreotide with respect to specific binding to somatostatin (octreotide) receptors on rat brain cortex membranes, biological activity, uptake and excretion by isolated perfused rat livers and metabolism in vivo in normal and tumour-bearing rats were determined and compared to those of indium-111 DTPA-octreotide. The results of the binding studies demonstrate that 161Tb-DTPA-octreotide is a high-affinity radioligand for somatostatin receptors, with an affinity comparable to that of 111In-DTPA-octreotide. Rat growth hormone secretion inhibition experiments showed that 161Tb-DTPA-octreotide has a similar potency to 111In-DTPA-octreotide. 161Tb-DTPA-octreotide appeared to be taken up even less by the isolated perfused rat liver than 111In-DTPA-octreotide, as almost no tracer disappeared from the perfusion medium. Furthermore, hardly any radioactivity was found in the liver, and excretion into the bile was negligible. The biodistribution studies showed that for octreotide receptor-positive organs, such as pancreas and adrenals, uptake of 161Tb-DTPA-octreotide is lower then that of 111In-DTPA-octreotide. However, as the clearance from the blood of the former compound is faster than that of the latter, the tissue/blood ratio is higher in the case of 161Tb-DTPA-octreotide than with 111In-DTPA-octreotide. Furthermore, these studies demonstrated that the uptake of 161Tb-DTPA-octreotide by the renal tubular cells after glomerular filtration can be reduced by administration of lysine or sodium maleate. Increase in urine production before and during the experiment had no effect on the kidney uptake of 161Tb-DTPA-octreotide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Generally applicable, convenient solid-phase synthesis and receptor affinities of octreotide analogs.

Octreotide, an analogue of the hormone somatostatin, has applications as a therapeutic and imaging agent for somatostatin-positive tumors. We have developed a generally applicable, convenient stepwise solid-phase synthetic protocol for octreotide (D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-threoninol). [Cys(Acm)2,D-Trp(Boc)4,Lys(Boc)5,Thr(tBu)6,Cys(Acm)7, des(threoninol)]-octreotide was assembled by Fmoc solid-phase synthesis and the intramolecular disulfide bond formed by treatment of the resin-bound peptide with thallium trifluoroacetate [Tl(Tfa)3]. Side-chain protection of Trp by the Boc group was found to preserve Trp integrity during Tl(Tfa)3 treatment. The protected peptide was cleaved from the resin by aminolysis with threoninol and purified by semipreparative RP-HPLC. Isolated [D-Trp(Boc)4,Lys(Boc)5,Thr(tBu)6]octreotide had the correct molecular mass ([M+H]+ = 1275 Da) and sequence and was obtained in 14% yield at > 98% purity. [D-Trp(Boc)4,Lys(Boc)5,Thr(tBu)6]octreotide was utilized for the solution-phase synthesis of CPTA-D-Phe1-octreotide, where CPTA is 4-[(1,4,8,11-tetraazacyclotetradec-1-yl)methyl]benzoic acid. Cyclic dianhydride of diethylenetriaminepentaacetic acid (DTPA) was coupled to a portion of the protected peptide-resin following disulfide bond formation. The DTPA-conjugated, side-chain-protected peptide was cleaved from the resin by aminolysis with threoninol, side-chain deprotected with trifluoroacetic acid, and purified by semipreparative RP-HPLC. The isolated DTPA-D-Phe1-octreotide had the correct molecular mass ([M+H]+ = 1395 Da) and was obtained in 5% yield at > 90% purity. The efficiency of aminolysis was partially dependent upon the linkage between 4-(hydroxymethyl)phenoxy (HMP) handles and the resin and/or resin particle size. The somatostatin receptor binding affinities of synthetic DTPA-D-Phe1-octreotide and CPTA-D-Phe1-octreotide to AtT-20 mouse pituitary carcinoma cell membranes were examined by labeling with 111In and 64Cu, respectively, and performing Scatchard analyses. The dissociation constant (Kd) for our synthetic [111In]DTPA-D-Phe1-octreotide was 4.31 nM, which is comparable to a Kd = 5.57 nM obtained with commercially available DTPA-D-Phe1-octreotide. The Kd for [64Cu]CPTA-D-Phe1-octreotide was 78.5 pM. On the basis of the criteria of molecular mass, RP-HPLC elution time, sequence analysis, and somatostatin receptor binding affinity, our synthetic octreotide is identical to commercially available octreotide. The aminolysis protocol used here has distinct advantages over either reductive cleavage or preformed linker methods described previously for the preparation of octreotide.

Amines↗
PubMed1992

Dissociation of antiproliferative and antihormonal effects of the somatostatin analog octreotide on 7315b pituitary tumor cells.

The somatostatin (SS) analog octreotide has been successfully used in the treatment of (neuro)endocrine tumors. The mechanism of action of the tumor (growth) inhibitory action by octreotide is not fully understood. We have investigated the effect of octreotide on 7315b rat pituitary tumor cell growth, PRL release, and intracellular PRL concentrations in vitro. When cultured in medium with 10% fetal calf serum, the number of high affinity SS receptors increased with increasing culture time. On days 7, 14, and 21 of culture, the number of SS receptors amounted to 978 +/- 217, 3588 +/- 705, and 5865 +/- 3332 fmol/mg protein, respectively, whereas they were not measurable on day 0. From days 0-7, 7-14, and 14-21 of culture, octreotide (1 pM to 1 microM) inhibited PRL release and the intracellular PRL concentration, with IC50 values in the nanomolar range. However, no inhibition of cell growth was observed by these octreotide concentrations from day 0-7 of culture, while octreotide inhibited cell growth in a dose-dependent fashion from days 7-14 and 14-21 of culture (maximal inhibition by 25% and 26%, respectively). In a series of nine consecutive experiments we found a significant positive correlation between the percent inhibition of cell growth induced by 1 microM octreotide and the number of SS receptors on 7315b cells (r = 0.7865; P = 0.012). Inhibition of PRL release did not correlate with SS receptor numbers. Octreotide (1 microM) inhibited forskolin (0.5 microM)-stimulated cell growth and intracellular PRL concentrations, while in the presence of a high concentration of forskolin (10 microM), octreotide had no effect on forskolin-stimulated cell growth and intracellular PRL concentrations. In addition, its PRL release inhibitory effect was significantly lower in forskolin-stimulated cultures. Pretreatment of the cells with pertussis toxin (10 micrograms/liter) completely prevented the inhibition of cell growth by octreotide and diminished the inhibitory effect of octreotide on PRL release. Finally, 1 microM octreotide significantly inhibited forskolin-stimulated cAMP production (by 29% and 53% on days 7 and 14 of culture, respectively). We conclude that 1) octreotide inhibits 7315b rat pituitary tumor cell proliferation via a pertussis toxin-sensitive GTP-binding protein- and adenylate cyclase-dependent mechanism; and 2) the number of SS receptors on 7315b pituitary tumor cells may determine whether octreotide exerts a direct antiproliferative effect, whereas its antihormonal effect occurs in the presence of relatively low numbers of SS receptors. This suggests a dissociation of the antiproliferative and antihormonal effects induced by octreotide.

Adenylate Cyclase Toxin↗
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↗
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↗
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.

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