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The Journal of Clinical Endocrinology... Jul 2012Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed... (Comparative Study)
Comparative Study Randomized Controlled Trial
CONTEXT
Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed with injected octreotide and maintaining its biological activity.
OBJECTIVES
The aim of the study was to determine oral octreotide absorption and effects on pituitary GH secretion compared to sc octreotide injection.
DESIGN
Four single-dose studies were conducted in 75 healthy volunteers.
INTERVENTION
Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100 μg octreotide were administered.
MAIN OUTCOME MEASURE
We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion.
RESULTS
Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc octreotide resulted in equivalent pharmacokinetic parameters [mean peak plasma concentration, 3.77 ± 0.25 vs. 3.97 ± 0.19 ng/ml; mean area under the curve, 16.2 ± 1.25 vs. 12.1 ± 0.45 h × ng/ml); and median time ≥ 0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide resulted in basal (P < 0.05) and GHRH-stimulated (P < 0.001) mean GH levels suppressed by 49 and 80%, respectively.
CONCLUSIONS
The results support an oral octreotide alternative to parenteral octreotide treatment for patients with acromegaly.
Topics: Absorption; Administration, Oral; Adolescent; Adult; Antineoplastic Agents, Hormonal; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Human Growth Hormone; Humans; Infusions, Parenteral; Infusions, Subcutaneous; Male; Middle Aged; Octreotide; Research Subjects; Treatment Outcome; Young Adult
PubMed: 22539587
DOI: 10.1210/jc.2012-1179 -
The American Journal of Gastroenterology Sep 1993Three patients with a history of bleeding due to small bowel angiodysplasia (repeated melena or occult fecal blood with serious anemia) were treated for 10-40 months...
Three patients with a history of bleeding due to small bowel angiodysplasia (repeated melena or occult fecal blood with serious anemia) were treated for 10-40 months with octreotide, a somatostatin analog that reduces the splanchnic flow. A dose of 0.1 mg subcutaneously twice a day was followed by an increase in hemoglobin, and reduction or elimination of the need for transfusions. There were no further melena episodes, and stool hemoglobin became stably negative in two cases. Suspension of the drug after 6 months in one case was followed by renewed bleeding, and resumption led to a further response. Lower doses tried in another case were ineffective. Although these uncontrolled clinical cases do not prove its efficacy, octreotide appears to be beneficial in the control and prevention of bleeding due to diffuse small bowel angiodysplasia. There is no evidence that it results in regression of angiodysplasias, as they persisted in the patient subjected to control jejunoileoscopy.
Topics: Adolescent; Aged; Angiodysplasia; Female; Gastrointestinal Hemorrhage; Humans; Intestinal Diseases; Intestine, Small; Middle Aged; Octreotide
PubMed: 8362842
DOI: No ID Found -
The Journal of Endocrinology Oct 1997
Review
Topics: Acromegaly; Drug Administration Schedule; Evaluation Studies as Topic; Hormones; Humans; Injections, Subcutaneous; Octreotide; Somatostatin
PubMed: 9389999
DOI: No ID Found -
Bioconjugate Chemistry 1998The persistent localization of radioactivity in the kidney after administration of 111In-DTPA-D-Phe1-octreotide impairs the diagnostic accuracy of this...
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.
Topics: Animals; Indicators and Reagents; Indium Radioisotopes; Injections, Intravenous; Kidney; Male; Mice; Octreotide; Pentetic Acid; Radiopharmaceuticals; Subcellular Fractions; Tissue Distribution
PubMed: 9815158
DOI: 10.1021/bc9702258 -
Deutsche Medizinische Wochenschrift... Jul 1992
Comparative Study Review
Topics: Gastrinoma; Gastrointestinal Neoplasms; Glucagonoma; Humans; Insulinoma; Malignant Carcinoid Syndrome; Multiple Endocrine Neoplasia; Neoplasm Metastasis; Octreotide; Pancreatic Neoplasms; Time Factors; Vipoma
PubMed: 1352235
DOI: 10.1055/s-2008-1062412 -
Pain Apr 1992Somatostatin-14 has been reported to relieve severe cancer pain when given intraspinally. We have studied a stable analog, octreotide, which is suitable for long-term... (Clinical Trial)
Clinical Trial
Somatostatin-14 has been reported to relieve severe cancer pain when given intraspinally. We have studied a stable analog, octreotide, which is suitable for long-term infusion by a drug pump. In preclinical trials in dogs, chronic intrathecal and intraventricular perfusion at 40 micrograms/h did not produce neurotoxicity. On the basis of these findings cancer patients with pain unrelieved by oral opiates were treated for periods of 13 to 91 days with intrathecal octreotide 5-20 micrograms/h. During octreotide infusion, pain scores were lower while oral opiate usage was reduced. No central or systemic side effects of intrathecal administration were seen. The pain relief occurred in patients who had previously not obtained satisfactory pain control with systemic or intrathecal opiates, which is consistent with a non-opiate spinal pathway. These preliminary findings, if confirmed, suggest that octreotide is a potent non-opiate analgesic appropriate for long-term intrathecal infusion.
Topics: Adult; Aged; Analgesics; Brain; Female; Humans; Infusion Pumps; Injections, Intraventricular; Injections, Spinal; Male; Middle Aged; Morphine; Neoplasms; Octreotide; Pain; Pain Measurement; Spinal Cord
PubMed: 1594275
DOI: 10.1016/0304-3959(92)90182-B -
Best Practice & Research. Clinical... Jan 2016Somatostatin analogues (SSA) are well established antisecretory drugs that have been used as first line treatment for symptomatic control in hormonally active... (Review)
Review
Somatostatin analogues (SSA) are well established antisecretory drugs that have been used as first line treatment for symptomatic control in hormonally active neuroendocrine tumours (NET) for three decades. Both available depot formulations of SSA, long-acting repeatable (LAR) octreotide and lanreotide autogel, seem similarly effective and well tolerated, although comparative trials in NET have not been performed. The importance of SSA as antiproliferative treatment has been increasingly recognized during recent years. Two placebo-controlled trials demonstrated significant prolongation of progression free survival under SSA treatment. However, objective response as assessed by imaging is rare. Interferon-α (IFNα) also has antisecretory and antiproliferative efficacy in NET. Due to the less favourable toxicity profile it mainly has a role as add-on option in the refractory setting, especially in carcinoid syndrome patients. Further studies are needed to evaluate the antiproliferative efficacy of the multiligand SSA pasireotide and the role of pegylated IFNα.
Topics: Animals; Antineoplastic Agents, Hormonal; Cell Proliferation; Clinical Trials as Topic; Humans; Molecular Targeted Therapy; Neuroendocrine Tumors; Octreotide; Receptors, Somatostatin
PubMed: 26971845
DOI: 10.1016/j.beem.2015.09.004 -
Cancer Science Feb 2012Medullary thyroid carcinoma is a rare endocrine tumor, which shows overexpression of somatostatin receptor subtype 2. There is no systemic therapy for medullary thyroid...
Medullary thyroid carcinoma is a rare endocrine tumor, which shows overexpression of somatostatin receptor subtype 2. There is no systemic therapy for medullary thyroid carcinoma. Previously we reported that octreotide-PEG liposomes loaded with irinotecan, which target somatostatin receptor subtype 2, showed high therapeutic efficacy for medullary thyroid carcinoma xenografts compared with free irinotecan or non-targeted non-PEGylated liposomal irinotecan. In this study, we evaluated octreotide-PEG liposomes loaded with irinotecan in terms of the biodistribution of irinotecan and its active metabolite, and its therapeutic efficacy, compared with PEGylated liposomes. Furthermore, to elucidate the effect of octreotide ligand after cellular association, we assessed the cytotoxicity in tumor cells and the inhibition of protein phosphorylation in the tumor cells and xenografts using empty octreotide-PEG liposomes, which were loaded with no drug. In a therapeutic study, octreotide-PEG liposomes loaded with irinotecan significantly improved median survival compared with PEGylated liposomes. In tumor tissue at 6 h after injection, octreotide-PEG liposome-treated mice showed significantly higher concentrations of irinotecan and 7-ethyl-10-hydrocamptothecin compared with PEGylated liposome-treated mice, indicating that octreotide-PEG liposomes accumulated rapidly and to a high level in the tumor. Furthermore, empty octreotide-PEG liposome inhibited the phosphorylation of p70S6K in vitro and in vivo. These findings indicated that octreotide-PEG liposomal irinotecan has dual functions with targeted tumor delivery and assistance of cellular cytotoxicity, which led to higher therapeutic efficacy than PEGylated liposomes for medullary thyroid carcinoma xenografts.
Topics: Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Carcinoma, Neuroendocrine; Cell Line, Tumor; Humans; Irinotecan; Liposomes; Mice; Octreotide; Phosphorylation; Receptors, Somatostatin; Ribosomal Protein S6 Kinases, 70-kDa; Thyroid Neoplasms; Xenograft Model Antitumor Assays
PubMed: 22017398
DOI: 10.1111/j.1349-7006.2011.02128.x -
Bioanalysis 2015To establish a robust methodology for quantitative analysis of therapeutic peptide in biological samples.
AIM
To establish a robust methodology for quantitative analysis of therapeutic peptide in biological samples.
MATERIALS & METHODS
Octreotide was chosen as a model therapeutic peptide, and oxidized-octreotide was synthesized as internal standard. Protein precipitation combining liquid-liquid extraction technique was adopted to enhance the recovery and reduce the endogenous interferences effectively. A LC-MS/MS method for the quantification of octreotide in plasma has been optimized and validated according to FDA guidelines.
RESULTS
Linearity, selectivity, accuracy, precision, stability, matrix effect and recovery were within bioanalytical method validation acceptance criteria as FDA guidelines. The methodology was then successfully applied into the studies for octreotide.
CONCLUSION
This robust methodology would be useful for the PK studies for octreotide and other therapeutic peptides.
Topics: Analytic Sample Preparation Methods; Animals; Chromatography, Liquid; Injections, Intravenous; Liquid-Liquid Extraction; Male; Octreotide; Rats; Rats, Sprague-Dawley; Reference Standards; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 25932522
DOI: 10.4155/bio.15.22 -
Journal of Medicinal Chemistry Aug 2010A limited set of novel octreotide dicarba-analogues with non-native aromatic side chains in positions 7 and/or 10 were synthesized. Their affinity toward the ssts1-5 was...
A limited set of novel octreotide dicarba-analogues with non-native aromatic side chains in positions 7 and/or 10 were synthesized. Their affinity toward the ssts1-5 was determined. Derivative 4 exhibited a pan-somatostatin activity, except sst4, and derivative 8 exhibited high affinity and selectivity toward sst5. Actually, compound 8 has similar sst5 affinity (IC50 4.9 nM) to SRIF-28 and octreotide. Structure-activity relationships suggest that the Z geometry of the double-bond bridge is that preferred by the receptors. The NMR study on the conformations of these compounds in SDS(-d25) micelles solution shows that all these analogues have the pharmacophore beta-turn spanning Xaa7-D-Trp8-Lys9-Yaa10 residues. Notably, the correlation between conformation families and affinity data strongly indicates that the sst5 selectivity is favored by a helical conformation involving the C-terminus triad, while a pan-SRIF mimic activity is based mainly on a conformational equilibrium between extended and folded conformational states.
Topics: Animals; Cell Line; Cricetinae; Cricetulus; Humans; Magnetic Resonance Spectroscopy; Micelles; Models, Molecular; Molecular Conformation; Octreotide; Radioligand Assay; Receptors, Somatostatin; Sodium Dodecyl Sulfate; Structure-Activity Relationship
PubMed: 20666484
DOI: 10.1021/jm1005868