Synthetic Somatostatin Analogue Research Articles

Somatostatin Peptides Prevent Increased Human Colonic Epithelial Permeability Induced by Hypoxia.

Mesenteric ischemia increases gut permeability and bacterial translocation. In human colon, chemical hypoxia induced by 2,4-dinitrophenol (DNP) activates basolateral intermediate conductance K+ (IK) channels (designated KCa3.1 or KCNN4) and increases paracellular shunt conductance/permeability (GS), but whether this leads to increased macromolecule permeability is unclear. Somatostatin (SOM) inhibits IK channels and prevents hypoxia-induced increases in GS. Thus, we examined whether octreotide (OCT), a synthetic SOM analogue, prevents hypoxia-induced increases GS in human colon and hypoxia-induced increases in total epithelial conductance (GT) and permeability to FITC-dextran 4000 (FITC) in rat colon. The effects of serosal SOM and OCT on increases in GS induced by 100 µM DNP were compared in isolated human colon. The effects of OCT on DNP-induced increases in GT and transepithelial FITC movement were evaluated in isolated rat distal colon. GS in DNP-treated human colon was 52% greater than in controls (P = 0.003). GS was similar when 2 µM SOM was added after or before DNP treatment, in both cases being less (P <0.05) than with DNP alone. 0.2 µM OCT was equally effective preventing hypoxia-induced increases in GS, whether added after or before DNP treatment. In rat distal colon, DNP significantly increased GT by 18% (P = 0.016) and mucosa-to-serosa FITC movement by 43% (P = 0.01), and 0.2 µM OCT pre-treatment completely prevented these changes. We conclude that OCT prevents hypoxia-induced increases in paracellular/macromolecule permeability and speculate it may limit ischemia-induced gut hyperpermeability during abdominal surgery, thereby reducing bacterial/bacterial toxin translocation and sepsis.

Expression of somatostatin receptors in canine and feline meningioma.

The standard treatment for canine and feline meningiomas includes radiotherapy, surgical excision or combined therapy. However, new therapeutic approaches are required due to the possible recurrence or progression of meningiomas despite initial therapy. Adjunctive therapy with synthetic long-acting somatostatin (SST) analogues has been described in humans with SST-expressing tumours. The expression of SST receptors (SSTRs) by feline meningiomas is currently unknown, and there are little data about canine meningiomas. We hypothesized that SSTR is expressed by canine and feline meningiomas (S1). Seven canines and 11 felines with histologically confirmed meningiomas underwent STTR screening. RNA expressions of SSTR1, SSTR2, SSTR3 and SSTR5 (canine) and SSTR1-SSTR 5 (feline) in fresh frozen and formalin-fixed and paraffin-embedded (FFPE) samples were investigated using real-time (RT)-qPCR. The expression of SSTR1 and SSTR2 in FFPE samples was evaluated using immunohistochemistry (IHC). The specificity of applied antibodies for canine and feline species was confirmed by western blotting. In canine meningiomas (n=7), RNA expression of SSTR1, SSTR2 and SSTR5 was detected in all samples; SSTR3 RNA expression was detected in only 33% of samples. In feline meningiomas (n=12), RNA expression of SSTR1, SSTR4, SSTR5 and SSTR2 was detected in 91%, 46%, 46% and 36% of samples, respectively; SSTR3 was not expressed. Overall, the detection rate was lower in FFPE samples. IHC revealed the expression of SSTR1 and SSTR2 in all samples from both species. However, it is important to exercise caution when interpreting IHC results due to the presence of diffuse background staining. SSTRs are widely expressed in canine and feline meningiomas, thereby encouraging further studies investigating SSTR expression to conduct trials about the effect of adjunctive therapy with long-acting SST-analogues.

#2662 Octreotide-LAR in ADPKD patients with very low kidney function: a monocentric real-life experience

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, characterized by development of fluid-filled renal cysts leading to progressive expansion of kidney volume, with decline in kidney function up to end-stage renal disease (ESRD). Octreotide long-acting release (OCT-LAR) is a synthetic somatostatin analogue, which has been shown to reduce kidney and cysts growth and to slow the progression of kidney function decline in ADPKD patients. Although the evidence of the literature supporting the protective effect of the OCT-LAR against progression of the disease in ADPKD patients with both early and later-stages, to date no data are available in ADPKD patients treated with this somatostatin analogue in a real-world clinical setting. In August 2018 OCT-LAR was approved only in Italy for the treatment of ADPKD adult patients with eGFR ranging from 30 to 15 mL/min/1.73 m2 at elevated risk of progression towards ESRD. The present study is aimed to report for the first time the effects on renal function of OCT-LAR in ADPKD patients with severe renal insufficiency (stage 4 CKD) receiving this somatostatin analogue for therapeutic indication in a real-world clinical setting. Method We conducted a retrospective, ADPKD-population-based cohort study using healthcare data from the medical records of patients with ADPKD referred to the Department of Nephrology of University “Federico II” of Naples from November 2018 to April 2023 aimed to analyse within-patient clinical outcomes, including eGFR decline, before and after treatment with OCT-LAR. We include adult ADPKD patients (≥18 years) with GFR (eGFR) between 30 and 15 mL/min/1.73 m2, stably treated from at least 1 years with the regular dose of OCTR-LAR. The primary endpoint was the assessment of eGFR decline from 1 year before the start of the treatment (T-1) to baseline (T0), and after 1 year of therapy with OCT-LAR (T1) in the overall population and in two subgroups of patients with eGFR ≥ or &amp;lt; 25 ml/min/1.73 m2. Results 31 ADPKD patients were analysed (18 with eGFR ≥ 25 and 13 with eGFR &amp;lt; 25). Compared to pre-treatment period, eGFR decline significantly slowed during therapy with OCT-LAR in both eGFR groups (Table 1), while no difference was found between eGFR groups. After the first year of observation, 7 patients required dialysis (all with eGFR &amp;lt;25). Conclusion This is the first study reporting the effects of OCT-LAR on eGFR of ADPKD patients with advanced chronic kidney disease (CKD) in a real-world clinical setting. Our results suggest that, compared the last year of follow-up pre-treatment, OCT-LAR slows eGFR decline after 1 year.

Nanotechnology-Based Strategy for Enhancing Therapeutic Efficacy in Pancreatic Cancer: Receptor-Targeted Drug Delivery by Somatostatin Analog

A novel nanotechnology-based drug delivery system (DDS) targeted at pancreatic cancer cells was developed, characterized, and tested. The system consisted of liposomes as carriers, an anticancer drug (paclitaxel) as a chemotherapeutic agent, and a modified synthetic somatostatin analog, 5-pentacarbonyl-octreotide, a ligand for somatostatin receptor 2 (SSTR2), as a targeting moiety for pancreatic cancer. The cellular internalization, cytotoxicity, and antitumor activity of the DDS were tested in vitro using human pancreatic ductal adenocarcinoma (PDAC) cells with different expressions of the targeted SSTR2 receptors, and in vivo on immunodeficient mice bearing human PDAC xenografts. The targeted drug delivery system containing paclitaxel exhibited significantly enhanced cytotoxicity compared to non-targeted DDS, and this efficacy was directly related to the levels of SSTR2 expression. It was found that octreotide-targeted DDS proved exceptionally effective in suppressing the growth of PDAC tumors. This study underscores the potential of octreotide-targeted liposomal delivery systems to enhance the therapeutic outcomes for PDAC compared with non-targeted liposomal DDS and Paclitaxel-Cremophor® EL, suggesting a promising avenue for future cancer therapy innovations.

Somatostatin analog (octreotide) and sirolimus immunosuppressive therapy in the treatment of chyloperitoneum and chylothorax in newborns and infants

Background: Chyloperitoneum (CP) and chylothorax (CT) are rare conditions that have a high mortality rate and unclear treatment options. Their incidence in neonates ranges from 1 in 20000 to 1 in 187000 live births. This study aims to evaluate the effectiveness of synthetic somatostatin analog (octreotide) and sirolimus therapy in treating chylous pleural and peritoneal collections in newborns and infants. Methods: We conducted a retrospective analysis of 10 children with either chylothorax or chyloperitoneum, treated in our department between 2018 and 2023. The study was approved by the Local Independent Ethics Committee of The National Medical Research Center of Children's Health, under Protocol №7, dated 11 May 2023. The parents voluntarily signed an informed consent form for the off-label use of the drug. We reviewed the medical records for demographic information, clinical presentation, management, and outcome. Results: Our study looked at patients aged between 0 and 5.5 months, with seven cases of chyloperitoneum and three cases of chylothorax. We initially used octreotide, which was then switched to sirolimus if there was no improvement. Octreotide was effective in five children after 10-18 days of treatment, while the effect of sirolimus was observed 8-14 days after starting treatment. One patient, who had a history of a giant omphalocele with primary closure, experienced complications after 8 weeks of sirolimus therapy, including bilateral knee arthritis, leukopenia, and lymphopenia. Fortunately, there were no fatal outcomes. Conclusion: Sirolimus therapy is effective in treating newborns with chylothorax or chyloperitoneum, with a low risk of complications even in those cases not responding to octreotide therapy. It is recommended that octreotide therapy should not exceed 10 days, after which sirolimus can be prescribed.

THU020 Bilateral Adrenal Hyperplasia (BAH): Undesirable Effect Of Glucocorticoid Receptor Competitive Antagonist (GRCAnt) In Cushing’s Disease

Abstract Disclosure: A. Canturk: None. C. Villabona: None. A. Kargi: None. We present a case of a complicated ACTH (adrenocorticotropic hormone)-dependent tumor and hypercortisolism, we discuss the potential side effects of mifepristone, a GRCAnt potentially causing bilateral adrenal hyperplasia and we discuss potential pathophysiologic mechanisms. This is a 73 years old male who presents to the clinic for a follow-up of Cushing’s Disease (CD). He has a pmh of osteoporosis, hypopituitarism, and secondary DM in the setting of an aggressive and medication-resistant Corticotroph Pituitary Neuroendocrine Tumor (cPNET). He has undergone a total of four transsphenoidal surgeries since 2013 and two treatments with external beam radiations. He still has residual tissue invading his cavernous sinus, thus another surgery was not an option, so Gamma Knife (GK) therapy was given. In the past, he has received a trial of ketoconazole for a period of 2-3 years, temozolomide, and octreotide, and is currently on mifepristone for the past four years. He underwent Bilateral Adrenalectomy in 2016 and had a small adrenal residual. It is demonstrated in a PET scan from 2018 that he had BAH and confirmed in a recent CT abdomen on 12/2022. While on mifepristone his ACTH was 1173pg/mL (nl:10 and 60 pg/mL), and cortisol 92.7 mcg/dL (nl:5 to 25 mcg/dL). Cortisol urine was 1627.2 mcg/24hr (nl:4 to 40 mcg/24hr). For treatment of his cPNET, we discontinued mifepristone and started on ketoconazole, and referred him to surgery for a second adrenalectomy. We reordered IHC on pathology specimens obtained in 2019 for SSTRs 1-5 and might consider starting synthetic somatostatin analog. We illustrate the potential negative effect of the long-term use of mifepristone. This is a GRCAnt that increases ACTH levels (8-10 fold in some cases) and will potentially cause BAH. This is an aggressive cPNET with hypercortisolism, who has been on long-standing medical therapy with mifepristone. He has developed BAH which has been potentially caused or exacerbated by GRCAnt. Reviewing the literature, there is limited data on this topic. This effect appears not to occur in all patients with Cushing’s disease. We propose potential pathophysiologic mechanisms of the indirect or direct effect of mifepristone causing BAH and potential factors explaining why this phenomenon might only occur in selected patients, we also propose management of patients on long therapy with GRCAnts. Presentation: Thursday, June 15, 2023

A somatostatin analogue and immunosuppressive therapy in the treatment of complex forms of chyloperitoneum and chylothorax in newborns and infants

Chyloperitoneum and chylothorax are rare conditions with high mortality rates whose optimal treatment strategy remains unclear. The aim of the study was to evaluate the results of chyloperitoneum and chylothorax treatment with a synthetic somatostatin analogue (octreotide) and immunosuppressive therapy with sirolimus. The study was approved by the Independent Ethics Committee and the Scientific Council of the National Medical Research Center for Children’s Health of Ministry of Healthсare of Russia. The patients' parents gave their consent to the use of their children's data, including photographs, for research purposes and in publications. We conducted a retrospective study of nine children diagnosed with congenital chyloperitoneum and chylothorax who had been treated from 2018 to 2022. All the children received either abdominal or pleural drainage, parenteral nutrition, and conservative therapy with drugs. The first line of therapy was octreotide for 14–20 days that was then switched to sirolimus if there had been no effect. The effectiveness of conservative therapy with octreotide at a dose of 5–10 µg/kg/hour was observed in 5 cases. If there had been no effect by day 14, the patients were started on sirolimus at a dose of 0.05–0.2 mg/day which proved to be effective in all the patients (n = 4). Our study showed that sirolimus is effective in complex cases of chyloperitoneum and chylothorax in newborns and infants. Because of the rarity of these disorders, our conclusions were based on the analysis of a small cohort. To confirm our results and develop uniform diagnostic and treatment guidelines, further, more targeted multicenter research is needed. Until such guidelines are adopted, decisions on the treatment of chyloperitoneum and chylothorax should be made on an individual basis and approved by the medical committee of a treatment center.

ACUTE DESTRUCTIVE PANCREATITIS IN CHILDREN

Unlike adults, acute pancreatitis in children is a rare disease. The absence of unified standards for the diagnosis, treatment and rehabilitation of children with acute destructive pancreatitis, as well as high rates of complications and mortality, determined the relevance of our study.Materials and methods. Materials and methods. The results of treatment of 11 children with acute destructive pancreatitis were studied. The age of the patients ranged from 2 to 16 years. Laboratory examination in all patients included general and biochemical analyzes of blood, urine, peritoneal and thoracic exudate. All children underwent an ultrasound examination of the abdomen, chest cavity and mediastinum, and plain radiography of the chest and abdominal cavity. Computed tomography was performed in 6 patients (54.5%). Fibrogastroduodenoscopy (FGDS) was performed in 3 patients (27.3%). All patients underwent surgery. In 8 cases (72.7%), a median laparotomy was performed initially. In 3 observations (27.3%), surgical treatment began with video surgical revision of the abdominal organs, and then switched to conversion. Three patients (27.3%) subsequently underwent cystopancreatic jejunostomy. In one child, transcutaneous drainage of a false pancreatic cyst was performed under video surgical control. Synthetic somatostatin analogs and proteinase inhibitors were used as targeted therapy. All patients received long-term antibacterial therapy. Various methods of extracorporeal detoxification were used in 6 patients (54.5%).Statistical processing of the research results was carried out using standard methods with the calculation of relative values (absolute number of observations, % ratio).The approval of the scientific work was received from the Bioethical Commission of the Donetsk National Medical University (Ukraine).The work is a fragment of proactive research work of the Department of General and Children's Surgery of the Donetsk National Medical University (Ukraine). Results. Complications in the early postoperative period were noted in 8 children (72.7%). The group of the most severe complications included progressive enzymatic bacterial peritonitis, early adhesive intestinal obstruction, failure of cystopancreatic ileal anastomosis, profuse arrosive hemorrhage from the pancreas, cystopancreaticodigestive fistula and eventation. In the early postoperative period, 1 child aged 14 years (9.1%) died, and the rest of the patients were discharged in satisfactory condition. The average hospital stay for children was 23.1 days. In 7 patients (63.6%), complaints characterized by "enteric" discomfort occurred later.Conclusions. The principles of surgical and therapeutic tactics in children with acute destructive pancreatitis are based on a differentiated approach depending on the form of pancreatic necrosis and the development of purulent and destructive complications. Further study requires determination of situational surgical tactics, assessment of the effectiveness of combined therapy with somatostatin and proteinase inhibitors, selection of the optimal regimen of nutritional therapy and rehabilitation.

Octreotide and postoperative pancreatic fistula after pancreaticoduodenectomy: What we know so far? A narrative review.

Postoperative pancreatic fistula (POPF) is the most feared complication following pancreatic resection. Octreotide, a synthetic somatostatin analog, has been widely used by pancreatic surgeons worldwide after pancreatic resections, often as per surgeon's discretion, to prevent POPF especially in cases at high risk of developing POPF. We herein analyze the data available till date of the subject. A PubMed search with keywords "somatostatin OR octreotide OR somatostatin analogues AND postoperative pancreatic fistula" was made. Further filters were applied in the search "Clinical Trial, Meta-Analysis, Randomized Controlled Trial, Systematic Review, from 1990 - 2021," and the 68 results thus obtained were analyzed and included in this narrative review. There is considerable heterogeneity among the studies assessing the role of octreotide in the prevention of POPF making data comparison difficult, and hence results remain inconclusive. Most of the earlier studies used different definitions of POPF and other complications; included patients with varied pancreatic pathologies such as cancer, chronic pancreatitis, and benign lesions; surgical techniques such as pancreaticoduodenectomy, distal pancreatectomy, and other procedures; use of somatostatin and its analogs such as octreotide, lanreotide, pasireotide, and vapreotide; varied surgeon and institutional volume; and so on. Besides, pancreatic surgery is per se a complex surgical procedure and has its own inherent biases related to patient and the pancreas itself affecting the overall outcome. Data indicate favorable role of newer somatostatin analogs, and further studies are urgently needed. The question about the efficacy of prophylactic octreotide to reduce POPF after pancreaticoduodenectomy remains open to debate.

Differential Effects of Somatostatin, Octreotide, and Lanreotide on Neuroendocrine Differentiation and Proliferation in Established and Primary NET Cell Lines: Possible Crosstalk with TGF-β Signaling.

GEP-NETs are heterogeneous tumors originating from the pancreas (panNET) or the intestinal tract. Only a few patients with NETs are amenable to curative tumor resection, and for most patients, only palliative treatments to successfully control the disease or manage symptoms remain, such as with synthetic somatostatin (SST) analogs (SSAs), such as octreotide (OCT) or lanreotide (LAN). However, even cells expressing low levels of SST receptors (SSTRs) may exhibit significant responses to OCT, which suggests the possibility that SSAs signal through alternative mechanisms, e.g., transforming growth factor (TGF)-β. This signaling mode has been demonstrated in the established panNET line BON but not yet in other permanent (i.e., QGP) or primary (i.e., NT-3) panNET-derived cells. Here, we performed qPCR, immunoblot analyses, and cell counting assays to assess the effects of SST, OCT, LAN, and TGF-β1 on neuroendocrine marker expression and cell proliferation in NT-3, QGP, and BON cells. SST and SSAs were found to regulate a set of neuroendocrine genes in all three cell lines, with the effects of SST, mainly LAN, often differing from those of OCT. However, unlike NT-3 cells, BON cells failed to respond to OCT with growth arrest but paradoxically exhibited a growth-stimulatory effect after treatment with LAN. As previously shown for BON, NT-3 cells responded to TGF-β1 treatment with induction of expression of SST and SSTR2/5. Of note, the ability of NT-3 cells to respond to TGF-β1 with upregulation of the established TGF-β target gene SERPINE1 depended on cellular adherence to a collagen-coated matrix. Moreover, when applied to NT-3 cells for an extended period, i.e., 14 days, TGF-β1 induced growth suppression as shown earlier for BON cells. Finally, next-generation sequencing-based identification of microRNAs (miRNAs) in BON and NT-3 revealed that SST and OCT impact positively or negatively on the regulation of specific miRNAs. Our results suggest that primary panNET cells, such as NT-3, respond similarly as BON cells to SST, SSA, and TGF-β treatment and thus provide circumstantial evidence that crosstalk of SST and TGF-β signaling is not confined to BON cells but is a general feature of panNETs.

Stability Estimation of Gallium Complexes of DOTA Derivatives for Radiotheranostic Applications.

1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid (DO3A) has been used to prepare 68Ga-labeled probes for the diagnostic counterpart of radiotheranostic applications. While DO3A provides stable complexes with therapeutic radionuclides such as 90Y, 177Lu, and 225Ac, further improvement of the in vivo stability of the Ga-DO3A complex is required. Considering the high stability of an intact Ga-DOTA complex, the stability of Ga complexes of DOTA and DO3A derivatives, including benzyl-DOTA (Bn-DOTA), was evaluated to gain fundamental knowledge for developing the next-generation radiotheranostic probes using 68Ga as a diagnostic counterpart. Following the complexation reaction to prepare 67Ga-labeled DOTA and DO3A derivatives, the stability of the resulting 67Ga-labeled compounds was evaluated in murine plasma and apo-transferrin challenge. [67Ga]Ga-Bn-DOTA produced two isomers, and one of the isomers exhibited the highest stability among the tested complexes. The X-ray crystallography showed that the less stable isomer of Ga-Bn-DOTA suggested an N3O3 coordination geometry, while Ga-DOTA and Ga-Bn-DO3A show N4O2 coordination. To further evaluate the stability, a synthetic somatostatin analogue, [Tyr3]octreotide (TOC), was used as a model peptide, and p-COOH-Bn-DOTA and DO3A were conjugated with TOC to prepare DOTA-Bn-TOC and DOTATOC. [67Ga]Ga-DOTA-Bn-TOC also yielded two isomers with varying stability, and one isomer exhibited significantly higher stability than [67Ga]Ga-DOTATOC both in vitro and in vivo. These findings indicate that para-substituted Bn-DOTA would constitute a suitable chelating agent for developing next-generation radiotheranostic probes, although high-performance liquid chromatography purification is needed. Thus, further chemical modification on the Bn-DOTA molecule is also needed to avoid the formation of a Ga complex with the N3O3 configuration.

Synthesis and evaluation of a para-carboxylated benzyl-DOTA for labeling peptides and polypeptides

IntroductionRadiolabeled peptides and low-molecular-weight (LMW) polypeptides show high and persistent radioactivity levels in the kidney. To develop a DOTA-based bifunctional chelating agent that provides a radiometabolite with a rapid elimination rate from the kidney, a para-carboxyl Bn-DOTA (p-COOH-Bn-DOTA) was designed, synthesized, and evaluated. MethodsA precursor compound, p-COOH-Bn-DOTA(tBu)4, was synthesized in 9 steps using N-Boc-p-iodo-L-phenylalanine as the starting material. A synthetic somatostatin analog (TOC) was used as a representative peptide metabolized in the renal lysosomes. p-COOH-Bn-DOTA-conjugated TOC (DOTA-Bn-TOC) was synthesized by the conventional solid-phase peptide synthesis using p-COOH-Bn-DOTA(tBu)4. DOTA-tris(tBu ester) was also conjugated with TOC to prepare DOTATOC. 111In-labeling of the peptides was conducted under similar conditions. The radiochemical conversions, stability against apo-transferrin (apoTf), and in vivo behaviors were compared. Results[111In]In-DOTA-Bn-TOC was obtained with higher radiochemical conversions than [111In]In-DOTATOC. Both 111In-labeled TOC derivatives remained stable against apoTf. In biodistribution studies, [111In]In-DOTA-Bn-TOC exhibited higher initial uptake in the kidney, followed by a faster elimination rate of radioactivity into the urine than [111In]In-DOTATOC. The metabolic studies showed that the shorter residence time of the radiometabolite from [111In]In-DOTA-Bn-TOC was responsible for the renal radioactivity decline. Conclusionp-COOH-Bn-DOTA provides stable 111In-labeled peptides in high yields at low peptide concentrations. p-COOH-Bn-DOTA also provides a radiometabolite with a short residence time in the kidney. Such characteristics would render p-COOH-Bn-DOTA useful to the future application to radiolabeled LMW polypeptides with low renal radioactivity levels.

Somatostatin receptors: localization and imagining methods (review)

Neuroendocrine tumors (NET) is a rare pathology characterized by dysfunction of the pituitary gland and endocrine glands. The survival prognosis depends on the stage of the disease at which the malignant growth was detected.The study objective was to summarize information on the methods of early diagnosis of NETs and antitumor therapy using peptide hypothalamic hormone somatostatin analogues.The review provides a chronological analysis of studies of the expression of somatostatin receptors (SSTRs) in different tissues and organs, methods of their visualization and quantitative determination over 50 years. The expression of SSTRs was revealed on NET cell membranes. The history of SSTRs study dates back to 1972, when somatostatin was first isolated and its structure established. Later, the peptide therapeutic activity in the treatment of NET, realized through somatostatin receptors, was discovered, and a number of somatostatin analogues were synthesized. Five main types of SSTRs are known, including subtypes which are expressed in characteristic volumes in the corresponding pathologies. Determining the expression of SSTRs provides diagnosis and staging of malignant neoplasms. Now the regulation of tumor growth is carried out by synthetic somatostatin analogues. SSTRs imaging is an important stage in planning NET therapy with drugs of this pharmacological group. Clinical studies of the therapy of tumors of various organs and tissues, in vitro and in vivo imaging are being carried out, methods for detecting SSTRs are being studied and compared.A retrospective analysis of the methods used to visualize SSTRs and diagnose and treat NETs is presented. It has been shown that positron emission tomography combined with computed tomography, using SSTRs-binding radioligands is the safest and most accurate method for visualizing SSTRs and diagnosing NETs.

Аналоги соматостатина, меченные радионуклидами, для терапии онкологических заболеваний. Обзор

Currently, a specific action on tumor cells with minimal toxicity to healthy tissues is the main re-quirement for radionuclide therapy of cancer. The molecular target of selective antitumor therapy is determined by somatostatin receptors (SSTR) overexpression in various tumors and its metas-tases. Natural somatostatin cannot be used as a vector molecule for radionuclide delivery due to its short half-life in blood (1-3 min). Synthetic peptide somatostatin analogs labeled with thera-peutic radionuclides (radiopeptides) also have high affinity to SSTR and better pharmacokinetics compared to somatostatin and therefore they are of great interest for targeted cancer therapy, al-so called peptide-receptor radionuclide therapy (PRRT). The data about the most important to date somatostatin analogs labeled with In-111, Y-90, Lu-177 radionuclides for therapy of tumors over-expressing SSTR is presented. The results of treatment efficacy and toxicity profile of PRRT, which is administered with various generations of targeting SSTR radiopharmaceuticals, includ-ing the randomized controlled trial NETTER-1, is reviewed. In addition, some strategies for opti-mization of PRRT such as tandem therapy, intra-arterial administration of radiopharmaceuticals, their modification for better pharmacokinetic properties, and the development of new compounds containing alfa-emitting radionuclides or SSTR antagonist analogs are discussed.

Role of Octreotide in Sulfonylurea-Induced Hypoglycemia

Introduction: The most common adverse effect associated with sulfonylurea ingestion is hypoglycemia. Sulfonylureas have very narrow therapeutic indices with a prolonged half-life in End-Stage renal Disease (ESRD). As per literature review, insulin and oral sulfonylureas are responsible for 13.9% and 10.7% of emergency hospitalizations respectively. It is, however, not surprising that intentional or unintentional overdose with these agents can lead to prolonged hypoglycemia which can prove to be fatal. Case Report:76-year-old female presented to the Emergency Department (ED) with complaints of generalized weakness since the past three days. Her past medical history was significant for ESRD, Hypertension and Non-Insulin Dependent Diabetes Mellitus type II (home regimen of glipizide 10 mg daily). On physical exam, she was tachypneic and appeared lethargic. Her neurological exam was intact, and she was oriented to time, place and person. Her labs were significant for BUN of 77 mg/dL (5–20 mg/dL), Creatinine of 9.94 mg/dL (<1.3mg/dL) and blood glucose of 89 mg/dL (70-140mg/dL). Liver and thyroid function tests were normal. Computed Tomography scan of the head was unremarkable. In the ED, she received 5 mg of glipizide after which she became more confused and lethargic. Her blood glucose level was 21mg/dL thus she received seven pushes of intravenous (IV) dextrose (25g each), two doses of intramuscular glucagon (1mg each) and was started on a continuous infusion of dextrose (D10) at 75cc/hour. Her blood glucose levels continued to remain low with a repeat value of 34 mg/dL and her mental status continued to worsen. Labs checked at that time were significant for a C-Peptide level of 22.13ng/ml (1.00–4.00ng/ml) and an insulin level of 43.7uU/ml (<20uU/ml) suggesting it to be sulfonylurea toxicity. Sulfonylurea level could not be checked due to laboratory limitations. She was started on subcutaneous octreotide 30 mcgs every 6 hours as per endocrinology recommendations. Her blood glucose started to improve, and her mental status returned to baseline. Per oral food intake was resumed, she remained euglycemic and octreotide was discontinued. Conclusion: Octreotide is a synthetic octapeptide analogue of somatostatin which can effectively suppress insulin secretion. Glucose, on the other hand, would stimulate insulin release and cause rebound hypoglycemia. Boyle et al, showed that octreotide was superior to diazoxide and glucose in preventing sulfonylurea-induced hypoglycemia. Therefore, we as clinicians should be able to quickly recognize sulfonylurea toxicity as the cause of hypoglycemia and attempt to administer octreotide as soon as possible. This in turn would help decrease length of hospital stay and avoid the detrimental effects of hypoglycemia like seizures, coma and death especially in older individuals.

ROLE OF OCTREOTIDE IN MANAGEMENT OF SULPHONYLUREA - INDUCED REFRACTORY HYPOGLYCEMIA : A CASE REPORT

Hypoglycemia in diabetes is generally the result of interplay of relative or absolute therapeutic exogenous or endogenous insulin excess and compromised physiological and behavioral defenses against falling blood glucose concentrations. Thus, it is fundamentally iatrogenic, the result of treatments that include insulin or an insulin secretagogue such as glimepiride. The long-acting, synthetic somatostatin analog, octreotide, can be used to correct refractory hypoglycemia caused by sulfonylurea. There have been few records of it being used in a clinical environment. We present a case in which a subcutaneous injection of octreotide was successful in treating sulfonylurea-induced refractory hypoglycemia. The patient was referred to our hospital for recurrent hypoglycemia caused by sulfonylurea. His medications included tablet glimepiride 4 mg once daily along with tablet metformin 1000mg once daily. His plasma glucose level on arrival was 45 mg/dl. He was treated with 50 ml of 25% glucose solution and administered continuous drip of 5% glucose solution through a peripheral vein, but his hypoglycemia recurred several times. Finally, 100 mcg of octreotide was subcutaneously injected. Thereafter, hypoglycemia did not recur, and additional injections of glucose were not required. The subcutaneous injection of octreotide can be an effective and safe method of treating prolonged, and refractory hypoglycemia caused by sulfonylureas and alleviate impending complications, morbidity, and/ or mortality. The octreotide subcutaneous injection can be used as outpatient department treatment and can greatly reduce the cost of hospitalization.

Prospective Within-Patient Assessment of the Impact of an Unlabeled Octreotide Pre-dose on the Biodistribution and Tumor Uptake of 68Ga DOTATOC as Assessed by Dynamic Whole-body PET in Patients with Neuroendocrine Tumors: Implications for Diagnosis and Therapy.

Gastroenteropancreatic neuroendocrine tumors (GEP NETs) are often associated with high expression of somatostatin receptors (SSTRs) which allows for PET/CT imaging with radiolabeled somatostatin analogs such as 68Ga-DOTATOC. The interplay between 68Ga-DOTATOC and the synthetic somatostatin analogs commonly used to manage patient symptoms may lead to competition between the labelled and unlabeled peptides for receptor binding sites and current product labelling recommends patients be taken off somatostatin analogs before imaging. In this study, we prospectively investigated in human patients the effect of a pre-dose of octreotide, a short-acting somatostatin analog, on the distribution of 68Ga-DOTATOC in GEP NETs and normal organs. Research participants with GEP NETs were studied on two occasions using dynamic whole-body 68Ga-DOTATOC PET/CT. The two imaging studies were performed within 21 days of each other, using an identical acquisition protocol except for the administration of 50 μg of short-acting octreotide (pre-dose) immediately before the second PET/CT. Paired t-tests were used to compare tracer uptake with and without octreotide, for tumor and various normal organs. Seven participants with a mean age of 53 ± 10 years were studied. Octreotide pre-dosing decreased radiotracer uptake in the normal liver and spleen by 25 % (p = 0.04) and 47 % (p = 0.05) respectively but did not significantly change uptake in tumor (p = 0.53), red marrow (p = 0.12), kidneys (p =0.57), or pituitary gland (p = 0.27). Our data indicate SSTR imaging can be improved with a pre-dose of unlabeled octreotide given just prior to injection of the radiotracer. These data suggest there may be no need to discontinue somatostatin analog therapy prior to PET/CT with 68Ga-DOTATOC, allowing for a simpler, less disruptive patient protocol. This approach warrants further study in a variety of settings.

Octreotide long-acting release (LAR) in combination with other therapies for treatment of neuroendocrine neoplasia: a systematic review.

In the last decades, the incidence of neuroendocrine neoplasia (NEN) increased from 1 to 5 new diagnoses/100,000 persons/year. The synthetic somatostatin analogues (SSAs) represent the first-choice treatment for both functionally active and inactive gastro-enteric-pancreatic NEN. This systematic review examines the role of octreotide long-acting release (LAR) in combination with other therapies for NEN management. Primary outcomes were the disease control rate and the progression free survival (PFS), defined as the time between treatment initiation and progression of disease. Secondary outcomes were overall survival (OS) and safety. This systematic review identified 13 studies, concerning the use of octreotide LAR in association with other therapies in advanced NENs and included 1,206 patients. Patients were treated with octreotide LAR in combination with other drugs, mainly with everolimus (404 patients, 35%), but even with Peptide Receptor Radionuclide Therapy, bevacizumab, interferon or fluoride-derivatives. Disease control was observed in 85% cases with SSAs in combination with other therapies; PFS ranged from 15 to 16.4 months and OS from 25 to 61.9 months. SSAs are very well tolerated drugs, with few side effects which are usually mild, not requiring drug withdrawn. The review summarizes the effectiveness and available safety data on octreotide LAR in combination with other therapies in patients with NEN and may provide suggestions to address the therapeutic strategy. Further comparative head-to-head studies are needed to understand which is the best combination treatment for patients with progressive NEN after failure of first-line therapy.

Imaging Somatostatin Positive Tumors with Tyr3-Octreotate/Octreotide Conjugated to Desferrioxamine B Squaramide Radiolabeled with either Zirconium-89 or Gallium-68.

Radiolabeled derivatives of Tyr3-octreotide and Tyr3-octreotate, synthetic analogues of the peptide hormone somatostatin, can be used for positron emission tomography (PET) imaging of somatostatin receptor expression in neuroendocrine tumors. In this work, a squaramide ester derivative of desferrioxamine B (H3DFOSq) was used attach either Tyr3-octreotide or Tyr3-octreotate to the metal binding ligand to give H3DFOSq-TIDE and H3DFOSq-TATE. These new peptide-H3DFOSq conjugates form stable complexes with either of the positron-emitting radionuclides gallium-68 (t1/2 = 68 min) or zirconium-89 (t1/2 = 3.3 days). The new complexes were evaluated in an AR42J xenograft model that has endogenous expression of SSTR2. All four agents displayed good tumor uptake and produced high-quality PET images. For both radionuclides, the complexes formed with H3DFOSq-TATE performed better, with higher tumor uptake and retention than the complexes formed with H3DFOSq-TIDE. The versatile ligands presented here can be radiolabeled with either gallium-68 or zirconium-89 at room temperature. The long radioactive half-life of zirconium-89 makes distribution of pre-synthesized tracers produced to certified standards feasible and could increase the number of clinical centers that can perform diagnostic PET imaging of neuroendocrine tumors.

Carcinoid Syndrome in a Patient with Duodenal Carcinoid Tumor

Duodenal carcinoid tumors accounts for 5% of all Gastrointestinal Neuroendocrine Tumors (GI-NETs). Only 4% of all duodenal carcinoid tumors present with a full-blown carcinoid syndrome. We report a case of duodenal carcinoid tumor presenting as carcinoid syndrome in a 58 year old man, who presented with upper abdominal discomfort, diarrhoea, hot flushes and occasional wheezing. Histopathology following endoscopic resection of the tumor and 24 hour urinary 5-Hydroxyindolacetic acid (5-HIAA) confirmed the diagnosis. Duodenal carcinoid tumors are one of the rarest tumors of gastrointestinal tract and their association with a typical carcinoid syndrome is not that common. A high level of suspicion is required for an early diagnosis. With proper resection (endoscopic or surgical) of a localized tumor, recurrence and progression of the disease can be halted. Symptoms of carcinoid syndrome should be controlled by antidiarrheal agents, inhaled β-adrenergic agonist bronchodilators and somatostatin analogs (octreotide, lanreotide). Patients should be advised to avoid stress and conditions or substances that precipitate these symptoms. Dietary supplementation with nicotinamide can help in this regard. Patients with hepatic metastases are treated with synthetic analogues of somatostatin (octreotide, lanreotide). Systemic chemotherapy is not recommended in metastatic disease by the current guidelines. Patients should be followed up by monitoring serum chromogranin and urinary 5-HIAA. EUS, CT, MRI & somatostatin receptor scintigraphy can also be used for following up the patients.