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Clinics and Research in Hepatology and... Sep 2016Gastrointestinal vascular malformations are responsible for 2-8% of all cases of bleeding and 30-40% of all obscure hemorrhages, being the most frequent cause of occult... (Review)
Review
Gastrointestinal vascular malformations are responsible for 2-8% of all cases of bleeding and 30-40% of all obscure hemorrhages, being the most frequent cause of occult bleeding in older people. The aim of this review was to provide an up-to-date report about the use of octreotide in bleeding from both hereditary and acquired vascular malformations of the gastrointestinal tract. A systematic literature search was performed, using the keywords "gastrointestinal vascular malformation", "octreotide", "angiodysplasia", "portal hypertensive gastropathy", "gastric antral vascular ectasia", and "hereditary vascular malformations". The first line therapy of acute/chronic bleeding from digestive vascular malformations is endoscopy, followed by angiographic embolization and surgical resection when this is unsuccessful. In the setting of difficult-to-treat patients, octreotide has been proposed as an alternative therapeutic strategy. Studies reported in the literature show a high efficacy and safety of octreotide, but described only a small number of enrolled patients, heterogeneous therapeutic schedules and short-term follow-up, with the exception of acute bleeding from esophageal varices. As a consequence, the use of octreotide is not approved in this setting and it is currently still prescribed as an off-label drug. Studies in larger populations are needed to confirm the promising results observed in the small case series reports, so as to provide physicians with a treatment option for patients without available alternatives. Octreotide could also determine a strong decrease in the management costs of these clinical conditions, and especially, could dramatically reduce hospital admission costs.
Topics: Cost-Benefit Analysis; Gastrointestinal Agents; Gastrointestinal Hemorrhage; Humans; Octreotide; Off-Label Use; Vascular Malformations
PubMed: 27595456
DOI: 10.1016/j.clinre.2016.02.003 -
ASAIO Journal (American Society For... 2018Left ventricular assist devices (LVADs) offer a therapeutic strategy for patients with end-stage heart failure. Increased device utilization has also increased the... (Review)
Review
Left ventricular assist devices (LVADs) offer a therapeutic strategy for patients with end-stage heart failure. Increased device utilization has also increased the incidence of device-related complications including gastrointestinal bleeding (GIB). Multiple mechanisms have been proposed in the pathophysiology of continuous-flow LVAD-associated GIB including physiologic changes associated with high shear and nonpulsatile flow such as gastrointestinal arteriovenous malformations and acquired von Willebrand syndrome. Strategies to minimize the morbidity and mortality of LVAD-associated GIB are needed. Octreotide, a somatostatin analogue, has been described as an adjunct to current therapies and interventions. Factors that contribute to LVAD-associated GIB may be targeted by the pharmacologic effects of octreotide, including improved platelet aggregation, increased vascular resistance, and decreased splanchnic circulation. Octreotide has demonstrated clinical benefit in several case series and clinical trials for the treatment of LVAD-associated GIB. The focus of this article will be to review the pathophysiology of LVAD-associated GIB, discuss pharmacologic and nonpharmacologic treatment modalities, and review available literature on the role of octreotide in the management of LVAD-associated GIB.
Topics: Gastrointestinal Hemorrhage; Heart Failure; Heart-Assist Devices; Humans; Octreotide
PubMed: 29406356
DOI: 10.1097/MAT.0000000000000758 -
Molecular Pharmaceutics Aug 2021Peptide drugs face several barriers to oral delivery, including enzymatic degradation in the gastrointestinal tract and low membrane permeability. Importantly, the...
Peptide drugs face several barriers to oral delivery, including enzymatic degradation in the gastrointestinal tract and low membrane permeability. Importantly, the direct interaction between various biorelevant colloids (i.e., bile salt micelles and bile salt-phospholipid mixed micelles) present in the aqueous gastrointestinal environment and peptide drug molecules has not been studied. In this work, we systematically characterized interactions between a water-soluble model peptide drug, octreotide, and a range of physiologically relevant bile salts in solution. Octreotide membrane flux in pure bile salt solutions and commercially available biorelevant media, i.e., fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF), was evaluated using a side-by-side diffusion cell equipped with a cellulose dialysis membrane. All seven micellar bile salt solutions as well as FaSSIF and FeSSIF decreased octreotide membrane flux, and dihydroxy bile salts were found to have a much larger effect than trihydroxy bile salts. An inverse relationship between octreotide membrane flux and pancreatic enzymatic stability was also observed; bile salt micelles and bile salt-phospholipid mixed micelles provided a protective effect toward enzymatic degradation and prolonged octreotide half-life in vitro. Diffusion ordered nuclear magnetic resonance (DOSY NMR) spectroscopy and dynamic light scattering (DLS) were used as complementary experimental techniques to confirm peptide-micelle interactions in solution. Experiments were also performed using desmopressin as a second model peptide drug; desmopressin interacted with bile salts in solution, albeit to a lower extent relative to octreotide. The findings described herein demonstrate that amphiphilic, water-soluble peptide drugs do interact with bile salts and phospholipids in solution, with an effect on peptide membrane flux and enzymatic stability. Correspondingly, oral peptide drug absorption and bioavailability may be impacted.
Topics: Bile Acids and Salts; Biological Availability; Cellulose; Colloids; Deamino Arginine Vasopressin; Half-Life; Intestinal Absorption; Intestinal Mucosa; Intestinal Secretions; Membranes, Artificial; Micelles; Octreotide; Pancreatin; Phospholipids; Solubility; Solutions; Water
PubMed: 34255531
DOI: 10.1021/acs.molpharmaceut.1c00309 -
Journal of Nuclear Medicine : Official... Jun 2016Neuroendocrine tumors (NETs) are uncommon tumors with increasing incidence and prevalence. Current reports suggest that (68)Ga-DOTATATE PET/CT imaging improves diagnosis... (Comparative Study)
Comparative Study Meta-Analysis Review
68Ga-DOTATATE Compared with 111In-DTPA-Octreotide and Conventional Imaging for Pulmonary and Gastroenteropancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis.
UNLABELLED
Neuroendocrine tumors (NETs) are uncommon tumors with increasing incidence and prevalence. Current reports suggest that (68)Ga-DOTATATE PET/CT imaging improves diagnosis and staging of NETs compared with (111)In-DTPA-octreotide and conventional imaging. We performed a systematic review of (68)Ga-DOTATATE for safety and efficacy compared with octreotide and conventional imaging to determine whether available evidence supports U.S. Food and Drug Administration approval.
METHODS
Medline, EMBASE, Web of Science, and Cochrane Reviews electronic databases were searched from January 1999 to September 2015. Results were restricted to human studies comparing diagnostic accuracy of (68)Ga-DOTATATE with octreotide or conventional imaging for pulmonary or gastroenteropancreatic NET and for human studies reporting safety/toxicity for (68)Ga-DOTATATE with 10 subjects or more thought to have NETs. Direct communication with corresponding authors was attempted to obtain missing information. Abstracts meeting eligibility criteria were collected by a research librarian and assembled for reviewers; 2 reviewers independently determined whether or not to include each abstract. If either reviewer chose inclusion, the abstract was accepted for review.
RESULTS
Database and bibliography searches yielded 2,479 articles, of which 42 were eligible. Three studies compared the 2 radiopharmaceuticals in the same patient, finding (68)Ga-DOTATATE to be more sensitive than octreotide. Nine studies compared (68)Ga-DOTATATE with conventional imaging. (68)Ga-DOTATATE estimated sensitivity, 90.9% (95% confidence interval, 81.4%-96.4%), and specificity, 90.6% (95% confidence interval, 77.8%-96.1%), were high. Five studies were retained for safety reporting only. Report of harm possibly related to (68)Ga-DOTATATE was rare (6 of 974), and no study reported major toxicity or safety issues.
CONCLUSION
No direct comparison of octreotide and (68)Ga-DOTATATE imaging for diagnosis and staging in an unbiased population of NETs has been published. Available information in the peer-reviewed literature regarding diagnostic efficacy and safety supports the use of (68)Ga-DOTATATE for imaging of NETs where it is available.
Topics: Humans; Intestinal Neoplasms; Lung Neoplasms; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Pentetic Acid; Positron Emission Tomography Computed Tomography; Stomach Neoplasms
PubMed: 26769864
DOI: 10.2967/jnumed.115.165803 -
Current Radiopharmaceuticals 2016Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogs has become an established procedure for the treatment of patients suffering from... (Review)
Review
Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogs has become an established procedure for the treatment of patients suffering from inoperable neuroendocrine cancers over-expressing somatostatin receptors. Success of PRRT depends on the availability of the radiolabeled peptide with adequately high specific activity, so that required therapeutic efficacy can be achieved without saturating the limited number of receptors available on the target lesions. Specific activity of the radionuclide and the radiolabeled somatostatin analog are therefore an important parameters. Although these analogs have been investigated and improved, and successfully applied for PRRT for more than 15 years, there are still many possibilities for further improvements that fully exploit PRRT with 177Lu-DOTA-TATE. The here summarized data presented herein on increased knowledge of the components of 177Lu-DOTA-TATE (especially the purity of 177Lu and specific activity of 177Lu) and the reaction kinetics during labeling 177Lu-DOTA-TATE clearly show that the peptide dose and dose in GBq can be varied. Here we present an overview of the development, formulation and optimisation of 177Lu-DOTA-TATE, mainly addressing radiochemical parameters.
Topics: Drug Design; Humans; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Radioisotopes; Radiopharmaceuticals; Receptors, Peptide; Receptors, Somatostatin
PubMed: 25771369
DOI: 10.2174/1874471008666150313111131 -
Advanced Drug Delivery Reviews Feb 2022Molecular Imaging is entering the most fruitful, exciting period in its history with many new agents under development, and several reaching the clinic in recent years.... (Review)
Review
Molecular Imaging is entering the most fruitful, exciting period in its history with many new agents under development, and several reaching the clinic in recent years. While it is unusual for just one laboratory to take an agent from initial discovery through to full clinical approval the steps along the way are important to understand for all interested participants even if one is not involved in the entire process. Here, we provide an overview of these processes beginning at discovery and preclinical validation of a new molecular imaging agent and using as an exemplar a low molecular weight disease-specific targeted positron emission tomography (PET) agent. Compared to standard drug development requirements, molecular imaging agents may benefit from a regulatory standpoint from their low mass administered doses, they nonetheless still need to go through a series of well-defined steps before they can be considered for Phase 1 human testing. After outlining the discovery and preclinical validation approaches, we will also discuss the nuances of Phase 1, Phase 2 and Phase 3 studies that may culminate in an FDA general use approval. Finally, some post-approval aspects of novel molecular imaging agents are considered.
Topics: Clinical Trials as Topic; Drug Approval; Drug Development; Humans; Molecular Imaging; Molecular Weight; Octreotide; Organometallic Compounds; Positron-Emission Tomography; United States; United States Food and Drug Administration
PubMed: 34942275
DOI: 10.1016/j.addr.2021.114086 -
European Journal of Nuclear Medicine... Apr 2023According to IAEA/EANM/SNMMI guidelines, long-acting somatostatin analogues (LA-SSAs) should be discontinued 4-6 weeks prior to peptide receptor radionuclide therapy...
PURPOSE
According to IAEA/EANM/SNMMI guidelines, long-acting somatostatin analogues (LA-SSAs) should be discontinued 4-6 weeks prior to peptide receptor radionuclide therapy (PRRT) to prevent somatostatin receptor saturation. The aim of this study was to determine the effect of continued use of long-acting SSAs during PRRT on the uptake of [Lu]Lu-HA-DOTATATE on SPECT/CT.
METHODS
Consecutive patients with neuroendocrine tumours who were treated with PRRT receiving 7.4 GBq of [Lu]Lu-HA-DOTATATE were included. Patients were divided into 3 groups: (1) control (LA-SSA stopped > 6 weeks prior to PRRT), or continued treatment with (2) long-acting octreotide < 6 weeks prior to PRRT, or (3) long-acting lanreotide < 6 weeks prior to PRRT. The uptake of [Lu]Lu-HA-DOTATATE was quantified in healthy tissues (spleen, liver, kidneys, bone marrow) and tumour lesions on SPECT/CT performed 24 h after PRRT. A Mann-Whitney U test was used to determine differences in uptake between the long-acting octreotide and long-acting lanreotide groups compared to the control group.
RESULTS
Forty-two patients with 135 cycles of PRRT were included: 28 with lanreotide, 50 with octreotide, and 57 cycles without LA-SSAs. Uptake of [Lu]Lu-HA-DOTATATE was significantly decreased in liver parenchyma in patients with lanreotide (p < 0.001) and in the spleen in patients with either octreotide or lanreotide (both p < 0.001). No differences were observed for uptake in kidneys, bone marrow, and blood pool. Uptake of [Lu]Lu-HA-DOTATATE in tumours was the same in patients with lanreotide compared to the control (p = 0.862) and in patients with octreotide compared to the control (p = 0.201), independent of tumour location.
CONCLUSION
Long-acting octreotide and lanreotide do not interfere with the uptake of [Lu]Lu-HA-DOTATATE in tumour lesions 24 h post-injection. Uptake in healthy liver parenchyma significantly decreases after lanreotide administration prior to PRRT, while uptake in healthy spleen tissue significantly decreases with both octreotide and lanreotide administration.
Topics: Humans; Octreotide; Organometallic Compounds; Somatostatin; Receptors, Somatostatin; Neuroendocrine Tumors
PubMed: 36598536
DOI: 10.1007/s00259-022-06094-z -
Trials Jan 2024The current standard of care (SoC) for the initial treatment of unresectable or metastatic well-differentiated gastroenteropancreatic neuroendocrine tumours (GEP-NET)... (Randomized Controlled Trial)
Randomized Controlled Trial
Methodology of the SORENTO clinical trial: a prospective, randomised, active-controlled phase 3 trial assessing the efficacy and safety of high exposure octreotide subcutaneous depot (CAM2029) in patients with GEP-NET.
BACKGROUND
The current standard of care (SoC) for the initial treatment of unresectable or metastatic well-differentiated gastroenteropancreatic neuroendocrine tumours (GEP-NET) requires initiation of first-generation somatostatin receptor ligand (SRL) therapy, octreotide and lanreotide, which provide safe and efficacious tumour/symptom control in most patients. However, disease progression can occur with SoC SRL treatment and the optimal dose response of SRL remains unknown. Octreotide subcutaneous depot (CAM2029) is a novel, long-acting, high-exposure formulation that has shown greater bioavailability and improved administration than octreotide long-acting release (LAR) with a well-tolerated safety profile. Retrospective data have highlighted a potential benefit of high-exposure SRL for improved disease control in patients who did not adequately respond to the current SoC SRL treatment. This trial will investigate the efficacy and tolerability of CAM2029 compared to the current SoC, including octreotide LAR and lanreotide autogel (ATG).
METHODS
SORENTO is a prospective, multicentre, randomised, active-controlled, open-label phase 3 trial aiming to demonstrate superiority of treatment with 20 mg octreotide subcutaneous depot (CAM2029) every 2 weeks (Q2W) compared to treatment with the Investigator's choice of SRL therapy at standard doses for tumour control (octreotide LAR 30 mg or lanreotide ATG 120 mg every 4 weeks [Q4W]) as assessed by progression-free survival (PFS) in approximately 300 patients with unresectable/metastatic and well-differentiated GEP-NET. Upon confirmation of disease progression (determined by a Blinded Independent Review Committee [BIRC] and defined as per RECIST 1.1), patients may enter an open-label extension treatment period with once weekly dosing, to investigate the effects of higher frequency dosing. Overall survival follow-up will end a maximum of 2 years after primary analysis. The primary endpoint will be analysed after 194 confirmed PFS events.
DISCUSSION
This is the first trial investigating the efficacy of CAM2029 versus SoC SRL therapy using a head-to-head, superiority trial design. It is expected to be the first trial to investigate the efficacy of increased dosing frequency of a high-exposure SRL. A BIRC will limit bias and measurement variability and ensure high-quality efficacy data. Additionally, inclusion of patients with well-differentiated Grade 3 NET may elucidate treatment strategies for this rarely investigated patient population.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05050942. Registered on 21st September 2021.
Topics: Humans; Octreotide; Retrospective Studies; Prospective Studies; Neuroendocrine Tumors; Disease Progression
PubMed: 38229199
DOI: 10.1186/s13063-023-07834-8 -
Endocrine Apr 2018
Topics: Diabetic Retinopathy; Humans; Octreotide; Somatostatin
PubMed: 29464407
DOI: 10.1007/s12020-018-1561-0 -
Early Human Development Jul 2015Octreotide is used off-label in infants for treatment of chylothorax, congenital hyperinsulinism, and gastrointestinal bleeding. The safety profile of octreotide in...
BACKGROUND
Octreotide is used off-label in infants for treatment of chylothorax, congenital hyperinsulinism, and gastrointestinal bleeding. The safety profile of octreotide in hospitalized infants has not been described; we sought to fill this information gap.
METHODS
We identified all infants exposed to at least 1 dose of octreotide from a cohort of 887,855 infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. We collected laboratory and clinical information while infants were exposed to octreotide and described the frequency of baseline diagnoses, laboratory abnormalities, and clinical adverse events (AEs).
RESULTS
A total of 428 infants received 490 courses of octreotide. The diagnoses most commonly associated with octreotide use were chylothorax (50%), pleural effusion (32%), and hypoglycemia (22%). The most common laboratory AEs that occurred during exposure to octreotide were thrombocytopenia (47/1000 infant-days), hyperkalemia (21/1000 infant-days), and leukocytosis (20/1000 infant-days). Hyperglycemia occurred in 1/1000 infant-days and hypoglycemia in 3/1000 infant-days. Hypotension requiring pressors (12%) was the most common clinical AE that occurred during exposure to octreotide. Necrotizing enterocolitis was observed in 9/490 (2%) courses, and death occurred in 11 (3%) infants during octreotide administration.
CONCLUSION
Relatively few AEs occurred during off-label use of octreotide in this cohort of infants. Additional studies are needed to further evaluate the safety, dosing, and efficacy of this medication in infants.
Topics: Antineoplastic Agents, Hormonal; Chylothorax; Female; Hospitalization; Humans; Hypoglycemia; Hypotension; Infant; Infant, Newborn; Intensive Care Units, Neonatal; Male; Octreotide; Off-Label Use; Pleural Effusion; Thrombocytopenia
PubMed: 25968047
DOI: 10.1016/j.earlhumdev.2015.04.008