-
Bioconjugate Chemistry Jul 2016We developed a long-acting drug-delivery system that supports subcutaneous administration of the peptidic somatostatin agonist octreotide-a blockbuster drug used to...
We developed a long-acting drug-delivery system that supports subcutaneous administration of the peptidic somatostatin agonist octreotide-a blockbuster drug used to treat acromegaly and neuroendocrine tumors. The current once-a-month polymer-encapsulated octreotide, Sandostatin LAR, requires a painful intragluteal injection through a large needle by a health-care professional. To overcome such shortcomings, Tetra-PEG hydrogel microspheres were covalently attached to the α-amine of d-Phe(1) or the ε-amine of Lys(5) of octreotide by a self-cleaving β-eliminative linker; upon subcutaneous injection in the rat using a small-bore needle, octreotide was slowly released. The released drug from the ε-octreotide conjugate showed a remarkably long serum half-life that exceeded two months. The α-octreotide conjugate had a half-life of ∼2 weeks, and showed an excellent correlation of in vitro and in vivo drug release. Pharmacokinetic models indicate these microspheres should support once-weekly to once-monthly self-administered subcutaneous dosing in humans. The hydrogel-octreotide conjugate shows the favorable pharmacokinetics of Sandostatin LAR without its drawbacks.
Topics: Animals; Delayed-Action Preparations; Drug Carriers; Hydrogels; Injections, Subcutaneous; Microspheres; Octreotide; Polyethylene Glycols; Rats
PubMed: 27253622
DOI: 10.1021/acs.bioconjchem.6b00188 -
Palliative Medicine 1993Gastrointestinal obstruction is a common problem in advanced malignant disease, but its management remains controversial. In those patients for whom surgery is not...
Gastrointestinal obstruction is a common problem in advanced malignant disease, but its management remains controversial. In those patients for whom surgery is not appropriate, medical intervention is the only remaining option. We present a series of 14 patients with intestinal obstruction who were managed with subcutaneous injections of octreotide, a somatostatin analogue which reduces the volume of gastrointestinal secretions. Good control of vomiting was achieved in 12 patients, and no major side effects were observed. Octreotide would appear to be a useful drug in this clinical situation.
Topics: Aged; Female; Gastric Juice; Humans; Injections, Subcutaneous; Intestinal Obstruction; Intubation, Gastrointestinal; Male; Middle Aged; Neoplasms; Octreotide; Palliative Care; Vomiting
PubMed: 7505187
DOI: 10.1177/026921639300700406 -
American Journal of Hospital Pharmacy Oct 1991The activity of octreotide acetate in a total nutrient admixture (TNA) and the effect of the drug on the stability of lipid emulsion in the TNA were studied. Octreotide...
The activity of octreotide acetate in a total nutrient admixture (TNA) and the effect of the drug on the stability of lipid emulsion in the TNA were studied. Octreotide acetate injection was added to a standard solution containing 3% lipids, amino acids, dextrose, electrolytes, vitamins, and trace elements to achieve a theoretical concentration of 45 micrograms/dL. Samples were stored at room temperature for 48 hours. Octreotide concentrations were determined in triplicate by radioimmunoassay; physical stability of the solutions was assessed by lipid particle-size determination, pH measurement, and visual observation of emulsion integrity at 0, 12, 24, and 48 hours. The activity of octreotide in two samples of each solution (with and without lipid) was analyzed immediately after preparation and after seven days under refrigeration. There was no evidence of emulsion breakdown or pH change in any solution over the study period. In addition, particle-size distributions at 48 hours and 7 days were comparable to those at time zero, suggesting physical stability. Octreotide acetate activity was not consistently greater than 90% (mean +/- S.D.) after storage for 48 hours. Octreotide acetate at a theoretical concentration of 45 micrograms/dL in a TNA solution containing 3% lipids appeared to be physically compatible for 48 hours at room temperature and for 7 days under refrigeration. However, the chemical activity of octreotide in TNA was not consistent after storage for 48 hours.
Topics: Chemical Phenomena; Chemistry, Physical; Drug Packaging; Drug Stability; Fat Emulsions, Intravenous; Glass; Hydrogen-Ion Concentration; Lipids; Octreotide; Parenteral Nutrition, Total; Particle Size; Plastics; Radioimmunoassay; Temperature
PubMed: 1781474
DOI: No ID Found -
Design, synthesis and biological evaluation of negatively charged ¹¹¹In-DTPA-octreotide derivatives.Bioorganic & Medicinal Chemistry Feb 2014Our previous studies indicated that (111)In-diethylenetriaminepentaacetic acid ((111)In-DTPA)-octreotide derivatives with an additional negative charge by replacing...
Our previous studies indicated that (111)In-diethylenetriaminepentaacetic acid ((111)In-DTPA)-octreotide derivatives with an additional negative charge by replacing N-terminal d-phenylalanine (d-Phe) with an acidic amino acid such as l-aspartic acid (Asp) or its derivative exhibited low renal radioactivity levels when compared with (111)In-DTPA-D-Phe(1)-octreotide. On the basis of the findings, we designed, synthesized and evaluated two Asp-modified (111)In-DTPA-conjugated octreotide derivatives, (111)In-DTPA-Asp(1)-octreotide and (111)In-DTPA-Asp(0)-D-Phe(1)-octreotide. While (111)In-DTPA-Asp(1)-octreotide showed negligible AR42J cell uptake, (111)In-DTPA-Asp(0)-D-Phe(1)-octreotide exhibited AR42J cell uptake similar to that of (111)In-DTPA-D-Phe(1)-octreotide. When administered to AR42J tumor-bearing mice, (111)In-DTPA-Asp(0)-D-Phe(1)-octreotide exhibited renal radioactivity levels significantly lower than did (111)In-DTPA-D-Phe(1)-octreotide at 1 and 3 h post-injection. No significant differences were observed in tumor accumulation between (111)In-DTPA-Asp(0)-D-Phe(1)-octreotide and (111)In-DTPA-D-Phe(1)-octreotide after 1 and 3h injection. The findings in this study suggested that an interposition of an Asp at an appropriate position in (111)In-DTPA-D-Phe(1)-octreotide would constitute a useful strategy to develop (111)In-DTPA-D-Phe(1)-octreotide derivatives of low renal radioactivity levels while preserving tumor accumulation.
Topics: Amino Acid Sequence; Animals; Cell Line, Tumor; Drug Design; Half-Life; Mice; Mice, Nude; Octreotide; Pentetic Acid; Radiopharmaceuticals; Rats; Tissue Distribution; Transplantation, Heterologous
PubMed: 24457092
DOI: 10.1016/j.bmc.2013.12.063 -
Annals of the Academy of Medicine,... Mar 1994Octreotide is a synthetic analogue of somatostatin with a longer half-life than the native peptide. It has been used extensively in a variety of clinical settings for... (Review)
Review
Octreotide is a synthetic analogue of somatostatin with a longer half-life than the native peptide. It has been used extensively in a variety of clinical settings for some years. More recently, its uses in malignant disease processes have been studied and it is proving to be an excellent addition to the palliative care pharmacy. We look at the current uses of octreotide for the palliation of malignant disease with particular emphasis on inoperable malignant bowel obstruction. Octreotide may palliate nausea and vomiting in this distressing condition when other therapies fail. Octreotide may also control severe diarrhoea and help in the closure of fistulae from benign and malignant conditions. It has unique analgesic properties. Radio-labelled isotopes of octreotide may be used to image some tumours. Recently, it has also shown potential in anti-cancer treatment.
Topics: Humans; Intestinal Obstruction; Neoplasms; Octreotide; Palliative Care; Terminal Care; Treatment Failure
PubMed: 7521613
DOI: No ID Found -
Cephalalgia : An International Journal... Aug 1994We report on headache induced by a somatostatin octapeptide analog (octreotide) used for the treatment of acromegaly. This "rebound" headache has severe tension-type...
We report on headache induced by a somatostatin octapeptide analog (octreotide) used for the treatment of acromegaly. This "rebound" headache has severe tension-type characteristics and occurs every 6-8 h. It resolves dramatically within minutes with octreotide administration. This is the first report of headache developing under treatment with octreotide.
Topics: Acromegaly; Adult; Female; Headache; Humans; Octreotide; Substance Withdrawal Syndrome
PubMed: 7954762
DOI: 10.1046/j.1468-2982.1994.1404303.x -
Acta Medica Portuguesa Jan 1993Nowadays, the digestive system, must be considered as an actual endocrinous gland. The authors, after pointing out the pharmacological and immunomodulating actions of... (Review)
Review
Nowadays, the digestive system, must be considered as an actual endocrinous gland. The authors, after pointing out the pharmacological and immunomodulating actions of endogenous somatostatine, briefly describe a new synthetic octapeptid, somatostatine-analogue, with similar pharmacological effects (octreotide). Finally they stress the therapeutic trials in which the adverse effects, dosage and administration have been studied.
Topics: Humans; Octreotide; Somatostatin
PubMed: 8097350
DOI: No ID Found -
Digestion 1990A comparison of octreotide infusion (25 micrograms/h) and placebo in 16 stable cirrhotic patients revealed a 30% reduction in transhepatic venous gradient between 0 and... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
A comparison of octreotide infusion (25 micrograms/h) and placebo in 16 stable cirrhotic patients revealed a 30% reduction in transhepatic venous gradient between 0 and 60 min in the octreotide group without an effect on systemic haemodynamics. In a separate trial, 40 patients with active variceal bleeding were randomized to octreotide infusion (25 micrograms/h for 48 h) or oesophageal tamponade. The 2 treatments gave comparable control of variceal bleeding. Tolerance of treatment was significantly better in the octreotide group. In summary, octreotide infusion is simple to administer, has few side effects, and may be of use in the immediate control of oesophageal bleeding.
Topics: Esophageal and Gastric Varices; Hemodynamics; Hemorrhage; Humans; Infusions, Intravenous; Middle Aged; Octreotide; Randomized Controlled Trials as Topic
PubMed: 2185967
DOI: 10.1159/000200264 -
AAPS PharmSciTech Dec 2011The study reports on the drug release behavior of a potent synthetic somatostatin analogue, octreotide acetate, from biocompatible and biodegradable microspheres...
The study reports on the drug release behavior of a potent synthetic somatostatin analogue, octreotide acetate, from biocompatible and biodegradable microspheres composed of poly-lactic-co-glycolic acid (PLGA) following a single intramuscular depot injection. The serum octreotide levels of three Oakwood Laboratories formulations and one Sandostatin LAR(®) formulation were compared. Three formulations of octreotide acetate-loaded PLGA microspheres were prepared by a solvent extraction and evaporation procedure using PLGA polymers with different molecular weights. The in vivo drug release study was conducted in male Sprague-Dawley rats. Blood samples were taken at predetermined time points for up to 70 days. Drug serum concentrations were quantified using a radioimmunoassay procedure consisting of radiolabeled octreotide. The three octreotide PLGA microsphere formulations and Sandostatin LAR(®) all showed a two-phase drug release profile (i.e., bimodal). The peak serum drug concentration of octreotide was reached in 30 min for all formulations followed by a decline after 6 h. Following this initial burst and decline, a second-release phase occurred after 3 days. This second-release phase exhibited sustained-release behavior, as the drug serum levels were discernible between days 7 and 42. Using pharmacokinetic computer simulations, it was estimated that the steady-state octreotide serum drug levels would be predicted to fall in the range of 40-130 pg/10 μL and 20-100 pg/10 μL following repeat dosing of the Oakwood formulations and Sandostatin LAR(®) every 28 days and every 42 days at a dose of 3 mg/rat, respectively.
Topics: Animals; Chemistry, Pharmaceutical; Computer Simulation; Drug Carriers; Drug Compounding; Drug Implants; Injections, Intramuscular; Lactic Acid; Male; Microspheres; Models, Biological; Octreotide; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Solubility; Technology, Pharmaceutical
PubMed: 21948321
DOI: 10.1208/s12249-011-9693-z -
Journal of Pediatric Gastroenterology... Nov 1998The somatostatin analogue octreotide has been proposed as a possible therapeutic agent in patients with abnormal gastrointestinal motility. This study was conducted to... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
The somatostatin analogue octreotide has been proposed as a possible therapeutic agent in patients with abnormal gastrointestinal motility. This study was conducted to study the effects of 0.5 microg/kg and 1.0 microg/kg subcutaneous octreotide on antroduodenal motility in children with chronic gastrointestinal disorders.
METHODS
Twenty-three children were studied, eight with intestinal pseudo-obstruction, six with nonulcer dyspepsia, six with gastroesophageal reflux disease, and three with intractable constipation. After recording fasting motility for more than 4 hours, the children were randomized to receive 0.5 microg/kg or 1 microg/kg of subcutaneous octreotide. Motility was recorded for another hour after feeding in 12 children.
RESULTS
Phase III of the motor migrating complex was present in 13 of 23 children before and in 21 after octreotide (p < 0.02). All phase III episodes after administration of octreotide except one originated in the small intestine. Phase IIIs after octreotide were longer and were propagated faster than the spontaneous phase IIIs. There were no antral contractions during fasting after octreotide. There was a significant decrease in phase II intestinal motor activity in the hour after administration of octreotide (p < 0.001). There was no difference in effect between the two doses. After feeding, antral contractions were present in all children, and intestinal phase IIIs were not abolished.
CONCLUSIONS
In children with chronic bowel disorders, subcutaneous octreotide induced phase IIIs that differed from spontaneous phase IIIs and were not inhibited by meals. Octreotide decreased antral motility during fasting and inhibited intestinal phase II. Feeding abolished the inhibitory effect of octreotide on antral motility.
Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Octreotide
PubMed: 9822313
DOI: 10.1097/00005176-199811000-00002