Octreotide s.c. depot provides sustained octreotide bioavailability and similar IGF-1 suppression to octreotide LAR in healthy volunteers.
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ABSTRACT:
SUBMITTER: Tiberg F
PROVIDER: S-EPMC4574831 | biostudies-other | 2015 Sep
REPOSITORIES: biostudies-other
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Project description:Previous studies have shown that treatment with the somatostatin analogue octreotide LAR causes regression of gastric ECL-cell carcinoids in patients with hypergastrinaemia due to chronic atrophic gastritis, reducing both the number and size of tumours. The main objective of the present study was to examine the molecular mechanisms behind the antiproliferative effect of octreotide in the oxyntic mucosa on a genome wide scale. Female Sprague-Dawley rats were dosed with octreotide LAR and control group were given the LAR vehicle for 21 days. Serum gastrin levels were measured and tissue samples for histology and RNA extraction collected from the oxyntic mucosa. Histomorphological examination showed a significant decrease in the number of gastric glands, cells per gland and length of glands, indicating a negative effect of octreotide on growth of the oxyntic mucosa. Further immunohistochemical studies showed a tendency towards increased apoptosis and decreased proliferation in the group receiving octreotide. Affymetrix GeneChip microarrays were used to detect differentially expressed genes. Many regulated genes could be related to regulation of apoptosis, fewer to proliferation, and the largest group of regulated genes was transcriptional factors several of which may be involved in regulation of growth. Control studies using quantitative real-time RT-PCR showed a high degree of consistency of the microarray results. In conclusion, octreotide exerts a negative effect on growth of the oxyntic mucosa, and extensive gene expression changes relevant to growth regulation can be detected. Keywords: regulation, proliferation, Affymetrix GeneChip, qRT-PCR, immunohistochemistry.
2006-09-27 | GSE5910 | GEO
Project description:Purpose Treatment options for neuroendocrine tumors (NETs) remain limited. This trial assessed the progression-free survival (PFS) of bevacizumab or interferon alfa-2b (IFN-α-2b) added to octreotide among patients with advanced NETs. Patients and Methods Southwest Oncology Group (SWOG) S0518, a phase III study conducted in a US cooperative group system, enrolled patients with advanced grades 1 and 2 NETs with progressive disease or other poor prognostic features. Patients were randomly assigned to treatment with octreotide LAR 20 mg every 21 days with either bevacizumab 15 mg/kg every 21 days or 5 million units of IFN-α-2b three times per week. The primary end point was centrally assessed PFS. This trial is registered with ClinicalTrials.gov as NCT00569127. Results A total of 427 patients was enrolled, of whom 214 were allocated to bevacizumab and 213 to IFN-α-2b. The median PFS by central review was 16.6 months (95% CI, 12.9 to 19.6 months) in the bevacizumab arm and was 15.4 months (95% CI, 9.6 to 18.6 months) in the IFN arm (hazard ratio [HR], 0.93; 95% CI, 0.73 to 1.18; P = .55). By site review, the median PFS times were 15.4 months (95% CI, 12.6 to 17.2 months) for bevacizumab and 10.6 months (95% CI, 8.5 to 14.4 months) for interferon (HR, 0.90; 95% CI, 0.72 to 1.12; P = .33). Time to treatment failure was longer with bevacizumab than with IFN (HR, 0.72; 95% CI, 0.58 to 0.89; P = .003). Confirmed radiologic response rates were 12% (95% CI, 8% to 18%) for bevacizumab and 4% (95% CI, 2% to 8%) for IFN. Common adverse events with bevacizumab and octreotide included hypertension (32%), proteinuria (9%), and fatigue (7%); with IFN and octreotide, they included fatigue (27%), neutropenia (12%), and nausea (6%). Conclusion No significant differences in PFS were observed between the bevacizumab and IFN arms, which suggests that these agents have similar antitumor activity among patients with advanced NETs.
| S-EPMC5455764 | biostudies-literature
Project description:Coenzyme Q10 (CoQ10) is a natural compound with potent antioxidant properties. Its provision through diet does not always allow adequate levels in the human body, and supplementation is often necessary. This bioavailability study intended to explore the plasma concentration levels of a novel CoQ10 oral preparation (COQUN®, Coenzyme Q10 Miniactives Retard 100 mg capsules) mimicking assumption on a regular basis. Twenty-four healthy adults tested a single dose of CoQ10 100 mg in one day to assess bioavailability. After a one week wash-out period, they were randomly assigned (1:1) to continuous administration for four weeks: Group A (n = 12) 100 mg once a day (OD); and Group B (n = 12) 100 mg twice a day (BID). During the single dose phase, Cmax was observed at 4 h, and the mean values of AUCt and Tmax were 8754 ?g/mL·h and 4.29 h, respectively. The multiple dose phase showed increasing plasma levels up to 7 days after the start of administration, and sustained high concentrations during the all administration period. No relevant adverse events were reported. These results show that Miniactives® technology can release CoQ10 to allow high constant blood concentrations without a sharp decrease. This may be the first step of evidence for a potential new antioxidative treatment in human chronic diseases deserving high CoQ10 levels.
| S-EPMC6471387 | biostudies-literature
Project description:The antiproliferative activity of octreotide LAR in neuroendocrine tumours (NETs) has been demonstrated by small retrospective studies and confirmed by a prospective phase III trial (PROMID). However, there are limited data about the duration and predictors of response. The aim of our retrospective study was to determine the time to radiological progression (TTRP) of disease and the factors that were associated with better response.A total of 254 treatment naïve patients with advanced NETs and positive somatostatin receptor scintigraphy were included. Mean follow-up period was 42 months.The location of primary was in the small bowel in 204, pancreas in 22, lungs in 14, rectum in 7 and unknown in 7 patients. Most tumours were well-differentiated, G1 (58%) and G2 (23%). The majority of patients commenced octreotide LAR due to functional symptoms (57%), radiological progression (10%) or in the presence of asymptomatic and stable disease on the basis of data from the PROMID trial (18.5%). Partial response occurred in 5%. For all patients, the median TTRP was 37 months (95% confidence interval, CI: 32-52 months). There was a statistically significant shorter TTRP in patients with pancreatic tumours, liver metastases and intermediate grade tumours. Extremely raised (>10 times the upper limit of normal) baseline chromogranin A levels were associated with an unfavourable outcome. In contrast, male sex, carcinoid heart disease and initiation of treatment in the presence of stable disease were predictive of a better response. Age, extra-hepatic metastases, presence of mesenteric desmoplasia, previous resection and functional status of the primary tumour did not affect response.The duration of the antiproliferative effect of octreotide LAR seems to be longer than previously reported. This study has identified several predictors of response in a large cohort of patients with NETs on somatostatin analogue therapy.
| S-EPMC5129835 | biostudies-literature
Project description:Insulin-like growth factor 1 (IGF-1) is a potent cytoprotective growth factor that has attracted considerable attention as a promising therapeutic agent. Transgenic over-expression of IGF-1 propeptides facilitates protection and repair in a broad range of tissues, although transgenic mice over-expressing IGF-1 propeptides display little or no increase in IGF-1 serum levels, even with high levels of transgene expression. IGF-1 propeptides are encoded by multiple alternatively spliced transcripts including C-terminal extension (E) peptides, which are highly positively charged. In the present study, we use decellularized mouse tissue to show that the E-peptides facilitate in vitro binding of murine IGF-1 to the extracellular matrix (ECM) with varying affinities. This property is independent of IGF-1, since proteins consisting of the E-peptides fused to relaxin, a related member of the insulin superfamily, bound equally avidly to decellularized ECM. Thus, the E-peptides control IGF-1 bioavailability by preventing systemic circulation, offering a potentially powerful way to tether IGF-1 and other therapeutic proteins to the site of synthesis and/or administration.
| S-EPMC3519493 | biostudies-literature
Project description:Previous studies have shown that treatment with the somatostatin analogue octreotide LAR causes regression of gastric ECL-cell carcinoids in patients with hypergastrinaemia due to chronic atrophic gastritis, reducing both the number and size of tumours. The main objective of the present study was to examine the molecular mechanisms behind the antiproliferative effect of octreotide in the oxyntic mucosa on a genome wide scale. Female Sprague-Dawley rats were dosed with octreotide LAR and control group were given the LAR vehicle for 21 days. Serum gastrin levels were measured and tissue samples for histology and RNA extraction collected from the oxyntic mucosa. Histomorphological examination showed a significant decrease in the number of gastric glands, cells per gland and length of glands, indicating a negative effect of octreotide on growth of the oxyntic mucosa. Further immunohistochemical studies showed a tendency towards increased apoptosis and decreased proliferation in the group receiving octreotide. Affymetrix GeneChip microarrays were used to detect differentially expressed genes. Many regulated genes could be related to regulation of apoptosis, fewer to proliferation, and the largest group of regulated genes was transcriptional factors several of which may be involved in regulation of growth. Control studies using quantitative real-time RT-PCR showed a high degree of consistency of the microarray results. In conclusion, octreotide exerts a negative effect on growth of the oxyntic mucosa, and extensive gene expression changes relevant to growth regulation can be detected. Experiment Overall Design: RNA from eigth animals (controls that received the LAR-vehicle) were pooled to produce a control affymetrix chip. Six animals (treatmentgroup) were given octreotide LAR and RNA from two and two animals were pooled to produce three affymetrix chips for comparison to the controlchip.
2008-06-14 | E-GEOD-5910 | biostudies-arrayexpress
Project description:BackgroundLanreotide and octreotide acetate suspension for injectable (LAR) are both recommended for clinical use in patients with locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors. However, each agent possesses unique attributes in terms of their drug-delivery characteristics. The study objective was to compare overall drug-delivery efficiency between lanreotide and octreotide LAR in gastroenteropancreatic neuroendocrine tumor patients.MethodsThis study employed an observational time and motion design among patients treated with lanreotide or octreotide LAR across five US cancer centers. Baseline patient data collection included age, disease grade and duration, prior therapies and performance status. Drug-delivery time (drug preparation and administration), total patient time and resource use data were collected for gastroenteropancreatic neuroendocrine tumors receiving lanreotide (n = 22) or octreotide LAR (n = 22). Following each administration, qualitative data on the drug-delivery experience was collected from patients and nurses.ResultsLanreotide was associated with a significant reduction in mean delivery time (2.5 min; 95% CI:2.0 to 3.1) compared to octreotide LAR (6.2 min; 95%CI: 4.4 to 7.9; p = 0.004). The mean total patient time for lanreotide and octreotide LAR was comparable between groups (32.1 vs. 36.6 minutes; p = 0.97). Nurses reported increased concerns with octreotide LAR related to needle clogging (p = 0.034) and device failures (p = 0.057). Overall, lanreotide had a median satisfaction score of 5.0 compared to a score of 4.0 with octreotide LAR (p = 0.03).ConclusionsLanreotide was associated with significant reductions in drug-delivery time compared to octreotide LAR, which contributed to an improvement in overall healthcare efficiency.Trial registrationclinicaltrials.gov Identifier: NCT03017690.
| S-EPMC6643159 | biostudies-literature
Project description:The aim of the study is to develop a population pharmacokinetic (PPK) model, of Octreotide long acting repeatable (LAR) formulation in healthy volunteers, which describes the highly variable, multiple peak absorption pattern of the pharmacokinetics of the drug, in individual and population levels. An empirical absorption model, coupled with a one-compartment distribution model with linear elimination was found to describe the data well. Absorption was modelled as a weighted sum of a first order and three transit compartment absorption processes, with delays and appropriately constrained model parameters. Identifiability analysis verified that all twelve parameters of the structural model are identifiable. A machine learning method, i.e., cluster analysis, was performed as pre-processing of the PK profiles, to define subpopulations, before PPK modelling. It revealed that 13% of the patients deviated considerably from the typical absorption pattern and allowed better characterization of the observed heterogeneity and variability of the study, while the approach may have wider applicability in building PPK models. The final model was evaluated by goodness of fit plots, Visual Predictive Check plots and bootstrap. The present model is the first to describe the multiple-peak absorption pattern observed after octreotide LAR administration and may be useful to provide insights and validate hypotheses regarding release from PLGA-based formulations.
| S-EPMC8537465 | biostudies-literature
Project description:Objective: To examine patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who receive sequential treatment with somatostatin analogs. Materials and Methods: This retrospective chart review examined lanreotide depot/autogel tolerability and efficacy among GEP-NET patients who received lanreotide after octreotide long-acting release (LAR) at Tufts University Medical Center. Information obtained included background patient characteristics, dosing, adverse events (AEs), radiologic response, and biochemical markers. Results: Patients (n = 16; 43-81 years; mean age, 64.25 years; 11 female) with nonfunctional, low-grade GEP-NETs receiving octreotide LAR 30-60 mg were transitioned to lanreotide because of patient decision (n = 6), disease progression (n = 6), AEs (n = 2), poor tolerance (n = 1), and injection discomfort/pain (n = 1). Lanreotide doses started at 120 mg (n = 13), 90 mg (n = 1), or 60 mg (n = 2); 8 patients received concomitant therapies, mostly liver-directed (radiofrequency ablation/radioembolization). AEs associated with lanreotide experienced by ≥2 patients were fatigue, diarrhea, nausea, hypertension, pancreatic enzyme deficiency, and hyperglycemia. Radiologic treatment responses of the combination of lanreotide with other therapeutic modalities included complete response (n = 1), partial response (n = 5), and stable disease (n = 9). One patient had radiologic progression. Serum serotonin and chromogranin levels decreased, but urinary 5-hydroxyindoleacetic acid levels appeared relatively unchanged. Conclusion: Among post-octreotide GEP-NET patients, including those with disease progression or poor octreotide tolerance, lanreotide alone or with concomitant therapies was well tolerated and associated with radiologic responses.
| S-EPMC6371583 | biostudies-literature
Project description:BACKGROUND:Antitumor activity of the combination of somatostatin analogues (SSAs) and the mammalian target of rapamycin (mTOR) inhibitor everolimus in patients with neuroendocrine tumors (NETs) has been reported but not confirmed in prospective trials. MATERIALS AND METHODS:This prospective, multicenter, single-arm phase II EVERLAR study evaluated everolimus 10 mg/day and the SSA octreotide 30 mg every 28 days in patients with advanced nonfunctioning well-differentiated gastrointestinal NETs (GI-NETs) that progressed in the last 12 months (ClinicalTrials.gov NCT01567488). Prior treatment with SSAs and any systemic or locoregional therapy was allowed except for mTOR inhibitors. Patients continued treatment until disease progression or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS) at 12 months; secondary endpoints included early biochemical response, objective response rate (ORR) by RECIST v1.0, overall survival (OS), AEs, activation of mTOR pathway (insulin-like growth factor 1 receptor [IGF1R] and phosphoS6 [pS6] expression). RESULTS:Forty-three patients were included in the intent-to-treat analyses. After 12 months of treatment, 62.3% (95% confidence interval [CI] 48%-77%) of patients had not progressed or died. The 24-month PFS rate was 43.6% (95% CI 29%-58%). The confirmed ORR was 2.3%, and stable disease was 58.1%. Median OS was not reached after 24 months of median follow-up. Dose reductions and temporary interruptions due to AEs were required in 14 (33%) and 33 (77%) patients, respectively. The most frequent AEs were diarrhea, asthenia, mucositis, rash, and hyperglycemia. No correlation was observed between IGFR1 and pS6 expression and PFS/OS. CONCLUSION:The everolimus-octreotide combination provided clinically relevant efficacy in nonfunctioning GI-NETs, similar to the results of RADIANT-2 in functioning setting. IMPLICATIONS FOR PRACTICE:The EVERLAR study reports prospective data of somatostatin analogue in combination with everolimus in nonfunctioning gastrointestinal neuroendocrine tumors suggesting meaningful activity and favorable toxicity profile that supports drug combination in this setting.
| S-EPMC6324631 | biostudies-literature