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Alimentary Pharmacology & Therapeutics Apr 2002We hypothesized that part of the non-specific antidiarrhoeal effect of octreotide is mediated by a proabsorptive or antisecretory effect on small intestinal active...
BACKGROUND
We hypothesized that part of the non-specific antidiarrhoeal effect of octreotide is mediated by a proabsorptive or antisecretory effect on small intestinal active electrolyte transport.
METHODS
To measure the effect of octreotide on net absorption, the jejunum and ileum of normal human subjects were perfused with a balanced electrolyte solution; to measure the effect of octreotide on normal active chloride secretion, the jejunum was perfused with a bicarbonate-free solution.
RESULTS
During perfusion of a balanced electrolyte solution, octreotide increased basal net fluid absorption in the jejunum and ileum by about 40 mL/h per 30 cm. In the jejunum, octreotide markedly inhibited basal and sham feeding-stimulated active chloride secretion and inhibited water secretion by 28 and 51 mL/h per 30 cm, respectively.
CONCLUSIONS
Octreotide causes an increase in the net epithelial cell absorption rate of a balanced electrolyte solution in the normal jejunum and ileum. In the jejunum, this proabsorptive effect is mediated mainly by the reduction of normal active electrolyte secretion, rather than by stimulation of normal active electrolyte absorption. These results support the hypothesis that part of the antidiarrhoeal action of octreotide is due to its effects on active electrolyte transport mechanisms by normal epithelial cells of the small intestine.
Topics: Adult; Antidiarrheals; Female; Humans; Ileum; Intestinal Absorption; Jejunum; Male; Middle Aged; Octreotide; Perfusion; Water-Electrolyte Balance
PubMed: 11929395
DOI: 10.1046/j.1365-2036.2002.01228.x -
Annals of Oncology : Official Journal... May 2002Somatostatin (SST) analogues represent a novel approach for the treatment of certain cancers. The objective of this article is to summarise the current knowledge on SST... (Review)
Review
BACKGROUND
Somatostatin (SST) analogues represent a novel approach for the treatment of certain cancers. The objective of this article is to summarise the current knowledge on SST analogues in the treatment of cancer patients.
METHODS
Computerised (Medline) and manual searches were performed to identify publications on clinical trials published in the English-speaking literature between 1966 and 2000. Information abstracted included patients' pre-treatment status, histology, SST receptor (SSTR) evaluation, type of SST analogue, application schedule and dose, duration of treatment, side-effects, response criteria applied (i.e. WHO response criteria, biochemical criteria or symptomatic investigations) and survival.
RESULTS
Our search disclosed 22 case reports, five phase 1 and 47 phase II trials, and eight randomised clinical trials using SST analogues (octreotide, lanreotide and vapreotide) as antineoplastic agents. With regard to the phase II trials, conflicting results have been demonstrated in almost all tumour entities investigated. The few randomised studies published so far have shown an impact on survival in patients with hepatocellular cancer, while the effect attributed to treatment in patients with gastrointestinal adenocarcinomas might well have been due to an exceptionally short survival in the control group. There appears to be evidence that SST analogues are able to enhance the therapeutic effects of hormonal intervention in patients with breast cancer, prostate cancer and probably pancreatic cancer. Interpretation of the findings, however, is complicated by the fact that patients were heavily pre-treated in some studies and response criteria have not been uniformly applied. In addition, most studies have not been designed to distinguish between receptor-mediated (direct) and indirect effects of SST analogues in tumour patients.
CONCLUSIONS
According to the results obtained so far, there can be no doubt about the wide therapeutic index and the high efficacy of SST analogues in the symptomatic management of neuroendocrine tumours. Apart from these indications, the data do not justify recommendation of SST analogues as antineoplastic agents outside of clinical trials, as the optimal dose and schedule of application for antineoplastic activity has not been defined for currently used agents. Carefully designed clinical trials including investigation of SSTR status before treatment, evaluation of an indirect mechanism of SST analogues, and assessment of optimal combination of hormone therapy and chemotherapy with SST analogues are clearly needed in the near future.
Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Neoplasms; Octreotide; Peptides, Cyclic; Randomized Controlled Trials as Topic; Sensitivity and Specificity; Somatostatin; Survival Analysis; Treatment Outcome
PubMed: 12075733
DOI: 10.1093/annonc/mdf142 -
Saudi Journal of Gastroenterology :... 2012We report our experience with the use of octreotide as primary or adjunctive therapy in children with various gastrointestinal disorders.
BACKGROUND/AIM
We report our experience with the use of octreotide as primary or adjunctive therapy in children with various gastrointestinal disorders.
PATIENTS AND METHODS
A pharmacy database identified patients who received octreotide for gastrointestinal diseases. Indications for octreotide use, dosing, effectiveness, and adverse events were evaluated by chart review.
RESULTS
A total of 21 patients (12 males), aged 1 month to 13 years, were evaluated. Eleven received octreotide for massive gastrointestinal bleeding caused by portal hypertension-induced lesions (n=7), typhlitis (1), Meckel's diverticulum (1), and indefinite source (2). Blood transfusion requirements were reduced from 23 ± 9 mL/kg (mean ± SD) to 8 ± 15 mL/kg (P<0.01). Four patients with pancreatic pseudocyst and/or ascites received octreotide over 14.0 ± 5.7 days in 2 patients. In 3 children, pancreatic pseudocyst resolved in 12 ± 2 days and pancreatic ascites resolved in 7 days in 2. Three patients with chylothorax received octreotide for 14 ± 7 days with complete resolution in each. Two infants with chronic diarrhea received octreotide over 11 ± 4.2 months. Stool output decreased from 85 ± 21 mL/kg/day to 28 ± 18 mL/kg/day, 3 months after initiation of octreotide. The child with dumping syndrome responded to octreotide in a week. Adverse events developed in 4 patients: Q-T interval prolongation and ventricular fibrillation, hyperglycemia, growth hormone deficiency, and hypertension.
CONCLUSION
Octreotide provides a valuable addition to the therapeutic armamentum of the pediatric gastroenterologist for a wide variety of disorders. Serious adverse events may occur and patients must be closely monitored.
Topics: Adolescent; Blood Transfusion; Child; Child, Preschool; Diarrhea; Dumping Syndrome; Female; Gastrointestinal Agents; Gastrointestinal Hemorrhage; Humans; Infant; Male; Octreotide; Retrospective Studies
PubMed: 22421712
DOI: 10.4103/1319-3767.93807 -
British Journal of Clinical Pharmacology Dec 2000To develop a population model that can describe the pharmacokinetic profile of microencapsulated octreotide acetate in healthy cholecystectomized subjects. To... (Clinical Trial)
Clinical Trial
AIMS
To develop a population model that can describe the pharmacokinetic profile of microencapsulated octreotide acetate in healthy cholecystectomized subjects. To investigate the correlation between serum IGF-1 and octreotide concentration.
METHODS
A population pharmacokinetic analysis was performed on octreotide data obtained following a single dose of 30 mg microencapsulated octreotide acetate intramuscularly. The relationship between serum IGF-1 concentration and octreotide concentration was effectively described by a population pharmacokinetic/pharmacodynamic model.
RESULTS
The pharmacokinetic profile of octreotide was characterized by an initial peak of octreotide followed by a sustained-release of drug. Plateau concentration were sustained up to day 70, and gradually declined to below the detection limit by day 112. A one-compartment linear model was constructed which consisted of two absorption processes, characterized by KIR and KSR, rate constants for immediate-release and sustained-release, respectively, with first-order elimination (Ke; 1.05 h-1). The surface, unencapsulated drug was immediately absorbed into the central compartment with first-order absorption (KIR; 0.0312 h-1), while the microencapsulated drug was first released in a zero-order fashion into a depot before being absorbed into the central compartment with first-order absorption (KSR; 0.00469 h-1) during a period of tau (1680 h). Body weight and gender were important covariates for the apparent volume of distribution. The type of formulation was an important covariate for KIR but had no effect on KSR. An inhibitory Emax population pharmacokinetic/pharmacodynamic model could adequately describe the relationship between IGF-1 (expressed as percent baseline) and octreotide concentration. Baseline IGF-1 concentration was found to be a significant covariate for the baseline effect (E0). A relationship between GH concentration and octreotide concentration was not established.
CONCLUSIONS
The pharmacokinetic profile of microencapsulated octreotide acetate was effectively described by the derived population model. The relationship between IGF-1 and drug concentration could be used to guide optimization of therapeutic octreotide dosage regimens.
Topics: Adult; Capsules; Cholecystectomy; Computer Simulation; Female; Hormones; Humans; Injections, Intramuscular; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Male; Middle Aged; Models, Biological; Octreotide
PubMed: 11136293
DOI: 10.1046/j.1365-2125.2000.00297.x -
European Journal of Nuclear Medicine... Feb 2012Treatment with radiolabelled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumours.... (Review)
Review
Treatment with radiolabelled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumours. Symptomatic improvement may occur with (177)Lu-labelled somatostatin analogues that have been used for peptide receptor radionuclide therapy (PRRT). The results obtained with (177)Lu-[DOTA(0),Tyr(3)]octreotate (DOTATATE) are very encouraging in terms of tumour regression. Dosimetry studies with (177)Lu-DOTATATE as well as the limited side effects with additional cycles of (177)Lu-DOTATATE suggest that more cycles of (177)Lu-DOTATATE can be safely given. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild and less than those from the use of (90)Y-[DOTA(0),Tyr(3)]octreotide (DOTATOC). Besides objective tumour responses, the median progression-free survival is more than 40 months. The patients' self-assessed quality of life increases significantly after treatment with (177)Lu-DOTATATE. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with (177)Lu-DOTATATE. These findings compare favourably with the limited number of alternative therapeutic approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable neuroendocrine tumours.
Topics: Disease-Free Survival; Humans; Lutetium; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Peptides; Radioisotopes; Radiopharmaceuticals; Radiotherapy Dosage; Receptors, Somatostatin; Somatostatin
PubMed: 22388631
DOI: 10.1007/s00259-011-2039-y -
Journal of Nuclear Medicine : Official... Jul 2022Our objective was to evaluate the prognostic value of somatostatin receptor tumor burden on Ga-DOTATOC PET/CT in patients with well-differentiated (WD) neuroendocrine...
Our objective was to evaluate the prognostic value of somatostatin receptor tumor burden on Ga-DOTATOC PET/CT in patients with well-differentiated (WD) neuroendocrine tumors (NETs). We retrospectively analyzed the Ga-DOTATOC PET/CT scans of 84 patients with histologically confirmed WD NETs (51 grade 1, 30 grade 2, and 3 grade 3). For each PET/CT scan, all Ga-DOTATOC-avid lesions were independently segmented by 2 operators using a customized threshold based on the healthy liver SUV (LIFEx, version 5.1). Somatostatin receptor-expressing tumor volume (SRETV) and total lesion somatostatin receptor expression (TLSRE = SRETV × SUV) were extracted for each lesion, and then whole-body SRETV and TLSRE (SRETVwb and TLSREwb, respectively) were defined as the sum of SRETV and TLSRE, respectively, for all segmented lesions in each patient. Time to progression (TTP) was defined as the combination of disease-free survival in patients undergoing curative surgery ( = 10) and progression-free survival for patients with unresectable or metastatic disease ( = 74). TTP and overall survival were calculated by Kaplan-Meier analysis, log-rank testing, and the Cox proportional-hazards regression model. After a median follow-up of 15.5 mo, disease progression was confirmed in 35 patients (41.7%) and 14 patients died. A higher SRETVwb (>39.1 cm) and TLSREwb (>306.8 g) correlated significantly with a shorter median TTP (12 mo vs. not reached; < 0.001). In multivariate analysis, SRETVwb ( = 0.005) was the only independent predictor of TTP regardless of histopathologic grade and TNM staging. According to our results, SRETVwb and TLSREwb extracted from Ga-DOTATOC PET/CT could predict TTP or overall survival and might have important clinical utility in the management of patients with WD NETs.
Topics: Gallium Radioisotopes; Humans; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Positron Emission Tomography Computed Tomography; Prognosis; Receptors, Somatostatin; Retrospective Studies
PubMed: 34740949
DOI: 10.2967/jnumed.121.262652 -
Pharmaceutical Research Sep 2015Polyesters with hydrophilic domains, i.e., poly(D,L-lactic-co-glycolic-co-hydroxymethyl glycolic acid) (PLGHMGA) and a multiblock copolymer of...
PURPOSE
Polyesters with hydrophilic domains, i.e., poly(D,L-lactic-co-glycolic-co-hydroxymethyl glycolic acid) (PLGHMGA) and a multiblock copolymer of poly(ε-caprolactone)-PEG-poly(ε-caprolactone) and poly(L-lactide) ((PC-PEG-PC)-(PL)) are expected to cause less acylation of encapsulated peptides than fully hydrophobic matrices. Our purpose is to assess the extent and sites of acylation of octreotide loaded in microspheres using tandem mass spectrometry analysis.
METHODS
Octreotide loaded microspheres were prepared by a double emulsion solvent evaporation technique. Release profiles of octreotide from hydrophilic microspheres were compared with that of PLGA microspheres. To scrutinize the structural information and localize the actual modification site(s) of octreotide, liquid chromatography ion-trap mass spectrometry (LC-ITMS) was performed on the acylated adducts.
RESULTS
Hydrophilic microspheres showed less acylated adducts in comparison with PLGA microspheres. LC-MS/MS showed that besides the N-terminus and primary amine of lysine, the primary hydroxyl of the end group of octreotide was also subjected to acylation. Nucleophilic attack of the peptide can also occur to the carbamate bond presented in (PC-PEG-PC)-(PL) since 1,4-butanediisocyanate was used as the chain extender.
CONCLUSIONS
Hydrophilic polyesters are promising systems for controlled release of peptide because substantially less acylation occurs in microspheres based on these polymers. LC-ITMS provided detailed structural information of octreotide modifications via mass analysis of ion fragments.
Topics: Acylation; Chromatography, Liquid; Lactic Acid; Microspheres; Octreotide; Polyesters; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Tandem Mass Spectrometry
PubMed: 25832500
DOI: 10.1007/s11095-015-1685-3 -
Pancreas Oct 2010Octreotide long acting repeatable (LAR) is commonly used to control the symptoms of patients with functional neuroendocrine tumors. Unfortunately, most patients escape...
OBJECTIVES
Octreotide long acting repeatable (LAR) is commonly used to control the symptoms of patients with functional neuroendocrine tumors. Unfortunately, most patients escape control over time and require higher LAR doses or more frequent rescue therapy to remain asymptomatic. Previous work has shown that body weight and monthly LAR dose will significantly affect circulating plasma octreotide levels in patients undergoing therapy.
METHODS
To determine if other parameters change circulating plasma octreotide levels, we prospectively studied 82 patients undergoing long-term LAR therapy.
RESULTS
Multivariate analysis demonstrated that the plasma octreotide levels decrease by approximately 3.4% for each unit of body mass index (BMI) increase (P = 0.03), adjusting for sex and monthly LAR dose. Plasma octreotide levels for females were approximately 47.6% higher than those for males (P = 0.045), adjusting for BMI and monthly LAR dose. Initial and subsequent octreotide LAR doses should take into consideration sex and BMI. Males are estimated to require 14.1-mg (SD, 7.25) higher monthly LAR doses than females with the same BMI.
CONCLUSIONS
We have shown that plasma octreotide levels are affected by not only monthly LAR dose but also BMI and sex. We hope these observations will make choosing initial and subsequent octreotide LAR doses easier for physicians.
Topics: Antineoplastic Agents, Hormonal; Body Mass Index; Female; Humans; Male; Multivariate Analysis; Neuroendocrine Tumors; Octreotide; Prospective Studies; Sex Factors
PubMed: 20467346
DOI: 10.1097/MPA.0b013e3181db01a8 -
AAPS PharmSciTech Dec 2003The purpose of this study was to prepare poly(ethylene glycol) (PEG)ylated octreotide and investigate the stability against acylation by polyester polymers such as...
The purpose of this study was to prepare poly(ethylene glycol) (PEG)ylated octreotide and investigate the stability against acylation by polyester polymers such as poly(lactic acid) and poly(lactic-co-glycolic acid). Octreotide was modified by reaction with monomethoxy PEG-propionaldehyde (molecular weight 5,000) in the presence of sodium cyanoborohydride. The mono-PEGylated fraction was isolated by reversed-phase high-performance liquid chromatography (HPLC) and characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Circular dichroism demonstrated no significant secondary structural differences between mono-PEGylated octreotide (mono-PEG-octreotide) and intact octreotide. As a test system for the stability study against acylation reaction, lactic acid (LA) solutions with various concentrations and pH values were prepared with water dilution and subsequent accelerated equilibration at 90 degrees C for 24 hours. Native octreotide was found to be acylated in all the diluted LA solutions with different concentrations (42.5%, 21.3%, and 8.5%, wt/wt) and pH values (2.25, 1.47, and 1.85, respectively). The remaining amounts of intact octreotide continuously decreased to 50% through 30 days of incubation at 37 degrees C. MALDI-TOF MS identified the octreotide to be acylated by LA units. However, acylation reaction of mono-PEG-octreotide in LA solutions was negligible, and the remaining amounts of intact one through 30 days of incubation in LA solutions were also comparable to the initial concentration. These data suggest that mono-PEG-octreotide may prevent the acylation reaction in degrading PLA microspheres and possibly serve as a new source for somatostatin microsphere formulation.
Topics: Antineoplastic Agents, Hormonal; Chemistry, Pharmaceutical; Drug Delivery Systems; Drug Stability; Microspheres; Octreotide; Peptides; Polyethylene Glycols
PubMed: 15198567
DOI: 10.1208/pt040472 -
Journal of Nuclear Medicine : Official... Nov 2018Pretherapy PET with Y-DOTATOC is considered the ideal dosimetry protocol for Y-DOTATOC therapy; however, its cost, limited availability, and need for infusion of amino...
Pretherapy PET with Y-DOTATOC is considered the ideal dosimetry protocol for Y-DOTATOC therapy; however, its cost, limited availability, and need for infusion of amino acids to mimic the therapy administration limit its use in the clinical setting. The goal of this study was to develop a dosimetric method for Y-DOTATOC using Y-DOTATOC PET/CT and bremsstrahlung SPECT/CT and to determine whether dosimetry-based administered activities differ significantly from standard administered activities. This was a prospective phase 2 trial of Y-DOTATOC therapy in patients with somatostatin receptor-positive tumors. Y-DOTATOC was given in 3 cycles 6-8 wk apart. In the first cycle of therapy, adults received 4.4 GBq and children received 1.85 GBq/m; the subsequent administered activities were adjusted according to the dosimetry of the preceding cycle so as not to exceed a total kidney dose of 23 Gy and bone marrow dose of 2 Gy. The radiation dose to the kidneys was determined from serial imaging sessions consisting of time-of-flight Y-DOTATOC PET/CT at 5 h after therapy and Y-DOTATOC bremsstrahlung SPECT/CT at 6, 24, 48, and 72 h. The PET/CT data were used to measure the absolute concentration of Y-DOTATOC and to calibrate the bremsstrahlung SPECT kidney clearance data. The radiation dose to the kidneys was determined by multiplying the time-integrated activity (from the fitted biexponential curve of renal clearance of Y-DOTATOC) with the energy emitted per decay, divided by the mass of the kidneys. The radiation dose to the kidneys per cycle of Y-DOTATOC therapy was highly variable among patients, ranging from 0.32 to 3.0 mGy/MBq. In 17 (85%) of the 20 adult patients who received the second and the third treatment cycles of Y-DOTATOC, the administered activity was modified by at least 20% from the starting administered activity. Renal dosimetry of Y-DOTATOC is feasible using Y-DOTATOC time-of-flight PET/CT and bremsstrahlung SPECT/CT and has a significant impact on the administered activity in treatment cycles.
Topics: Adolescent; Adult; Aged; Bone Marrow; Female; Humans; Kidney; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Positron Emission Tomography Computed Tomography; Precision Medicine; Prospective Studies; Radiopharmaceuticals; Radiotherapy Dosage; Receptors, Somatostatin; Single Photon Emission Computed Tomography Computed Tomography; Young Adult; Yttrium Radioisotopes
PubMed: 29523629
DOI: 10.2967/jnumed.117.202903