Octreotide Research Articles

7145 Enhanced Ability of the Small Peptide GH Receptor Antagonist, AZP-3813, to Decrease IGF1 When Combined with the Somatostatin Analog, Octreotide

Abstract Disclosure: G. Ravel: None. C. Berardet: Employee; Self; Amolyt Pharma. C. Chalmey: Employee; Self; Amolyt Pharma. H. Kurasaki: Employee; Self; Peptidream Inc. T. Tomiyama: Employee; Self; Peptidream Inc. P. Reid: Employee; Self; Peptidream Inc. D. Duracher: Employee; Self; Amolyt Pharma. R. Datta: Consulting Fee; Self; Amolyt Pharma. M. Aouadi: Employee; Self; Amolyt Pharma. M.D. Culler: Employee; Self; Amolyt Pharma. There is a strong rationale for combining a growth hormone (GH) receptor antagonist (GHRA) with somatostatin analog (SSA) therapy for acromegalic patients. While SSAs are the primary medical therapy for treatment of acromegaly, insulin-like growth factor 1 (IGF1) levels fail to normalize with SSA monotherapy in most patients. Even in patients with controlled IGF1, GH levels can remain elevated and induce symptoms by interacting with GH receptors throughout the body. In addition, while GHRAs have no significant effect on the causative pituitary tumor, SSAs can often induce tumor stabilization or shrinkage. AZP-3813 is a 16-amino acid, bicyclic peptide GHRA which has been demonstrated to potently decrease IGF1 in both rats and dogs. In order to examine the effect of combining AZP-3813 with a SSA in decreasing IGF1, 8-week old, male, Sprague Dawley rats were implanted subcutaneously with Alzet model 2002 minipumps containing either vehicle or the SSA, octreotide (OCT), at concentrations required to deliver either 20 or 40μg OCT/kg/day. Blood samples for IGF1 measurement were collected before, and 48 and 72 hours after pump implantation. Immediately following the 72-hour blood collection, rats from each infusion group were injected subcutaneously with either vehicle or AZP-3813 at 0.3, 1, 3, 10 or 30mg/kg (n=7/group). A subsequent blood sample was collected 24 hours after the injection of vehicle or AZP-3813, which also corresponded to 96 hours after pump implantation. Plasma levels of IGF1 were assessed by radioimmunoassay. In rats infused with vehicle, the 0.3mg/kg dose of AZP-3813 had no effect on IGF1 as compared with baseline; however, with higher doses a clear, dose-related decrease in IGF1 was observed ranging from -7 ± 3.0% with 1mg/kg AZP-3813 to -29 ± 2.0% with 30mg/kg. OCT infusion alone at 20μg/kg/day produced a -10 ± 3.6% decrease in IGF1, while injection of AZP-3813 into rats infused with 20μg/kg/day OCT, produced an enhanced, dose-related decrease, ranging from -7 ± 3.8% with 0.3mg/kg AZP-3813 to -38 ± 3.4% with 30mg/kg. A clear additive relationship was observed by focusing on the 3mg/kg dose of AZP-3813, which, alone, decreased IGF1 by -13 ± 2.8% in vehicle-infused rats. When injected into rats infused with OCT, which alone decreased IGF1 by -10 ± 3.6%, a combined decrease of -23 ± 3.3% was observed. The magnitude of the combined decrease was not statistically different from the decrease obtained with 30mg/kg AZP-3813 alone in vehicle-infused rats; thus, demonstrating a 10-fold increase in the effectiveness of AZP-3813 when combined with OCT. Similar results were observed with 40μg/kg/day OCT infusion. These results demonstrate the enhanced efficacy of AZP-3813 in decreasing IGF1 when combined with the SSA, OCT, and support the development of AZP-3813 as an add-on therapy in patients inadequately controlled with SSA treatment. Presentation: 6/3/2024

7044 It Is Back, Three Decades Later! When To Stop Glucagonoma surveillance?

Abstract Disclosure: A.T. Wahba: None. J.S. Dillon: Advisory Board Member; Self; Crinetics Pharmaceuticals, CA. A 76-year-old woman presented to the Neuroendocrine Tumor (NET) Clinic for evaluation of sore mouth, perianal area and itchy ankles. She had a medical history notable for glucagonoma, status post distal pancreatectomy and splenectomy in 1988, 32 years prior to her current presentation. She recalled that she had CT imaging post operatively for a few years, but no more recent imaging. She was diagnosed with diabetes mellitus in approximately 2002, with highly variable glucose control. She developed a left leg DVT with pulmonary emboli one year prior to presentation. Shortly after her thromboembolic events, she noted her current presenting complaints. A CT abdomen scan with contrast was reported as normal. Three months later, an abdomen ultrasound for evaluation of right upper quadrant pain and intractable vomiting, showed a liver mass. MRI revealed a contrast enhancing 3.1x2.1x1.8 cm lesion in liver segment 6 and 7. Her plasma Glucagon concentration, which had been undetectable when last checked in 2007, was 382 (N: < 80 pg/ml). CT-guided needle biopsy of the liver lesion confirmed a well differentiated neuroendocrine tumor, immunohistochemically positive for somatostatin receptor 2 (SSTR2A), Islet-1 and PAX6, with low mitotic count and Ki-67 proliferation index of 0.45%. Gallium-68 DOTATATE-PET scan showed a single avid hepatic metastasis, with no other evidence of somatostatin receptor expressing tumor. She was initially started on a combination of short-acting Octreotide 100 mcg TID and monthly 20 mg Sandostatin LAR injections for symptomatic relief. Zinc copper 100 mg capsules were prescribed with significant improvement of skin rash and glossitis within 2-4 months. Repeat MRI abdomen at 3 months and 6 months showed a stable single liver lesion without evidence of additional metastasis. She has continued annual clinic visits and abdomen MRI follow up with stable imaging findings at 3 years. Percutaneous ablation, trans hepatic arterial embolization and surgical resection were discussed, but the patient preferred a more conservative approach of monthly octreotide LAR, which she tolerated well, and which resolved her symptoms. Glucagonoma syndrome presents classically with 5D’s: Dermatitis (Necrolytic Migratory Erythema), DVTs, Diabetes mellitus, Depression, Diarrhea. The National Comprehensive Cancer Network guidelines recommend monitoring glucagonoma patients post-resection for up to 10 years with clinical evaluation, glucagon levels every 6-12 months and imaging studies as clinically indicated. Our case illustrates that recurrence can occur after 30 years from initial resection and that longer surveillance should be considered. Presentation: 6/3/2024

A systematic review and meta-analysis of efficacy of vasopressin as a vasoconstrictive and uterotonic drug in laparoscopic myomectomy

Abstract Introduction: Laparoscopic myomectomy is a commonly performed operation with fast recovery and excellent results. However, haemorrhagic nature of the operation mandates us to use variety of vasoconstrictive and uterotonic agents. Amongst which, one of them is vasopressin. It is a synthetic antidiuretic hormone analogue which has been in common use as a vasoconstrictive agent in various surgical procedures including laparoscopic myomectomy. Methods: A meta-analysis of randomised controlled trials published from 2013 to 2023 (10 years) comparing the use of vasopressin against other drug or placebo or different doses of vasopressin was performed. The outcome measures were intraoperative blood loss, need for blood transfusion, difference in the haemoglobin (Hb) and haematocrit (Hct). Results: We identified 176 articles through the study search, amongst which 12 articles were included for the meta-analysis. There was a significant heterogeneity in the studies with moderate risk of bias in eight studies and low risk of bias in four studies. Compared to placebo, vasopressin showed significantly lower odds need of blood transfusion (odds ratio [OR] 0.28, 95% confidence interval [CI]: 0.13–0.61, P = 0.002) and significantly lower pre–post fall in Hb (OR −3.12, 95% CI: −4.63–−1.60, P < 0.0001). However, there was no statistically significant difference in intraoperative blood loss (OR −0.56 (95% CI: −2.04–0.92, P = 0.46) and pre–post fall in Hct (OR −0.94, 95% CI: −1.96–0.07, P > 0.05). Compared to other drug (epinephrine, misoprostol and octreotide acetate), vasopressin showed no significant superiority in controlling blood loss (P > 0.05). Even the two doses of vasopressin (dilute vs. concentrated) showed no statistically significant difference between surgical blood loss and need for blood transfusion (P > 0.05). Conclusion: Vasopressin is an efficacious drug to be used for controlling blood loss, decreasing blood transfusion requirement and maintaining Hb and Hct during laparoscopic myomectomy.

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 analog, 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. OCT (0.2 µM) 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 pretreatment completely prevented these changes. We conclude that OCT prevents hypoxia-induced increases in paracellular/macromolecule permeability and speculate that it may limit ischemia-induced gut hyperpermeability during abdominal surgery, thereby reducing bacterial/bacterial toxin translocation and sepsis.NEW & NOTEWORTHY Somatostatin (SOM, 2 µM) and octreotide (OCT, 0.2 µM, a long-acting synthetic analog of SOM) were equally effective in preventing chemical hypoxia-induced increases in paracellular shunt permeability/conductance in isolated human colon. In rat distal colon, chemical hypoxia significantly increased total epithelial conductance and transepithelial movement of FITC-dextran 4000, changes completely prevented by 0.2 µM OCT. OCT may prevent or limit gut ischemia during abdominal surgery, thereby decreasing the risk of bacterial/bacterial toxin translocation and sepsis.

177Lu-labeled somatostatin receptor targeted radionuclide therapy dosimetry in meningioma: a systematic review.

Few therapeutic options are currently available for refractory meningiomas. Encouraging results have been reported for 177Lu-labeled somatostatin receptor-targeted radiopeptide therapy (SSTR-RT). The current therapeutic scheme is based on the fixed doses that are recommended for neuroendocrine tumor treatment. However, in personalized medicine, tumor dosimetry can be determined from repeat 177Lu scintigraphy. The aim of this review was to report on the methods used for calculating the tumor absorbed dose (AD) in meningioma patients treated with 177Lu-SSTR-RT and their values. The search was performed in Medline, Embase and the Cochrane Library until March 1st, 2024 to retrieve papers related to the topic. The following terms were used for searching: (meningioma) AND ((sstr) OR (receptors somatostatin) OR (somatostatin) OR (octreotide)) AND ((PRRT) OR (radionuclide therapy) OR (dotatate) OR (dotatoc) OR (177Lu-DOTATOC) OR (177Lu-DOTATATE) OR (radiopeptide)). Seven articles (including 46 patients and 108 cycles of treatment) reporting on tumor AD during 177Lu-SSTR-RT were included in the analysis. The methods of acquisition, reconstruction parameters and postimage processing to determine tumor AD were very heterogeneous among the studies. The meningioma AD associated with the agonist 177Lu-SSTR-RT reported in the majority of studies ranged from 0.1-1.5 Gy/GBq, which was lower than that reported for neuroendocrine tumors (1.3-22.9 Gy/GBq). The tumor AD that was reported during treatment with 177Lu-SSTR-RT in refractory meningioma patients is generally low. Harmonization of the methodology for dosimetry calculations is needed to compare the different reported values and optimize treatment at the individual level.

Utilizing erythrosine B absorption spectrum shifts for quantitative determination of octreotide and bromocriptine in their pure forms and pharmaceutical formulations. Evaluation of the method greenness

In the present study, two drugs for treating acromegaly are investigated which are either synthetic growth hormone inhibiting hormone (GHIH) or dopamine receptor agonist. Octreotide (OCT) and bromocriptine (BCT) were quantified with a quick, simple, and sensitive spectrophotometric approach in their authentic forms and commercial dosage forms. This approach was based upon formation of ion pair complex between erythrosine B and investigated drugs in an aqueous buffered solution. For OCT determination the higher sensitivity was obtained using ΔA at 525 nm. On the other hand, BCT was estimated using the absorbance at 556 nm. Under optimal conditions for the reaction, construction of calibration curves were performed within concentration range of 0.4–4 µg ml−1 for OCT and 1–9 µg ml−1 for BCT with with low detection limits (0.094 and 0.235 µg ml−1) and low quantitation limits (0.29 and 0.71 µg ml−1) for OCT and BCT respectively. The developed approach was assessed for linearity, accuracy, precision, limits of detection, and limits of quantitation in compliance with ICH validation recommendations. The suggested approaches demonstrated good linearity, as evidenced by determination coefficients (r2) of 0.999 with a slope 0.14 for OCT and 0.9989 with a slope 0.06 for BCT. Additionally, the environmental friendliness of the investigated method was assessed with some of the recent green analytical chemistry metrics.

Structure and Function of Somatostatin and its Receptors in Endocrinology.

Somatostatin analogs, such as octreotide (OCT), lanreotide, and pasireotide, which function as somatostatin receptor ligands (SRLs), are the main drugs used for the treatment of acromegaly. These ligands are also used as important molecules for radiation therapy and imaging of neuroendocrine tumors (NETs). Somatostatin receptors (SSTRs) are canonical G protein-coupled proteins (GPCRs) that play a role in metabolism, growth, and pathological conditions such as hormone disorders, neurological diseases, and cancers. Cryogenic electron microscopy (cryo-EM) combined with the protein structure prediction platform AlphaFold has been used to determine the three-dimensional structures of many proteins. Recently, several groups published a series of papers illustrating the three-dimensional structure of SSTR2, including that of the inactive/activated SSTR2-G protein complex bound to different ligands. The results revealed the residues that contribute to the ligand binding pocket and demonstrated that Trp8-Lys9 (the W-K motif) in somatostatin analogs is the key motif in stabilizing the bottom part of the binding pocket. In this review, we discuss the recent findings related to the structural analysis of SSTRs and SRLs, the relationships between the structural data and clinical findings, and the future development of novel structure-based therapies.

Chylous Ascites: A Rare Complication After Donor Right Hepatectomy

Abstract Chylous ascites (CA) is a rare complication after abdominal surgeries, particularly donor hepatectomy and liver transplantation. We present a case of CA developed following donor right hepatectomy. Initially managed with a high-protein, low-fat diet and Sandostatin® (Octreotide Acetate), the patient’s condition improved but did not resolve. Subsequently, the treatment plan was modified to include clear oral fluids, total parenteral nutrition, and Sandostatin®, resulting in a significant improvement and ultimate discontinuation of CA drainage. This case sheds light on the management strategies for CA following donor hepatectomy and emphasizes the need for a multimodal approach.

Selective and Sensitive MIP-Based Electrochemical Sensor for the Analytical Determination of Lanreotide

Lanreotide (LAN) is an analog of somatostatin used to treat acromegaly and neuroendocrine tumors. Considering drug toxicity and the lack of sensitive techniques in drug analysis, the development of sensitive analytical methods is of great importance. During this research, a molecular imprinted polymer (MIP) based film [P(HEMA-MAGA)@MIP/GCE] was prepared by photopolymerization technique for electrochemical determination of LAN for the first time. N-methacryloyl-L-glutamic acid (MAGA) and hydroxyethyl methacrylate (HEMA) were used as functional and basic monomers, respectively. The surface alterations were investigated using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) and the chemical composition of the MIP-based sensor. Theelectrochemical characterization of the modifiedelectrodes was assessed using electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). Using differential pulse voltammetry (DPV) in standard solution and spiked serum sample of LAN, the linear response range for LAN was obtained as 1.0x10 − 14 M – 1.0x10 − 13 M. The limit of detection (LOD) values were 1.76x10 − 15 M and 1.82x10 − 15 M in water and commercial human serum, respectively. The limit of quantitation(LOQ) values for these were 5.85x10 − 15 M and 6.07x10 − 15 M, respectively. The P(HEMA-MAGA)@MIP/GCE sensor also showed excellent recovery in pharmaceutical preparation and commercial human serum form with of 99.37 % and 99.27 %, respectively, with a good RSD value (0.51–0.73), confirming the accuracy and precision of the sensor. As a control, the non-imprinted polymer (NIP) was also prepared to serve in the same way but without the template. The selectivity experiments were conducted using somatostatin (SOM) and octreotide (OC) as potential competitors to demonstrate the selectivity of the proposed sensor against LAN molecules.

Urinastatin combined with octreotide versus sole octreotide in severe acute pancreatitis: a meta-analysis

Background: For severe acute pancreatitis (SAP), the combination of urinastatin and octreotide (OCT) is increasingly used. This meta-analysis assesses whether the combination therapy of urinastatin and OCT is more effective than using sole OCT in treating SAP. Methods: After searching 12 databases in English and Chinese as well as two clinical trial centers up to October 7, 2023, we compared the combination of urinastatin and OCT with sole OCT in treating SAP. Statistical measures utilized include risk ratios (RR), weighted mean difference (WMD), and 95% confidence intervals (95% CI). Results: We summarized 145 studies from 145 hospitals in 26 provinces, municipalities, and autonomous regions of China, including 13,605 patients. It was found that for SAP, using urinastatin combined with OCT compared to using sole OCT can improve the total effective rate (I 2 = 0%; RR: 1.22; 95% CI: 1.19-1.24; P &lt; 0.01), reduce mortality rate (I 2 = 0%; RR: 0.21; 95% CI: 0.09-0.46; P &lt; 0.01), and reduce the overall incidence rate of complications (I 2 = 0%; RR: 0.28; 95% CI: 0.23-0.34; P &lt; 0.01). In addition, combination therapy reduced in-hospital length of stay, abdominal pain relief time, time for blood and urine amylase to return to normal, inflammatory markers, and improved oxidative stress indicators, immune function indicators, and hemorheology indicators. Conclusions: Low-quality evidence suggests that for SAP, the combined use of urinastatin and OCT may be associated with better improvement in patients' symptoms, signs, CT imaging manifestations, and laboratory indicators such as inflammatory markers, oxidative stress markers, immune function indicators, and hemorheological indicators compared to using OCT alone. Additionally, the combination therapy compared to monotherapy may also be associated with lower mortality, a reduced incidence rate of complications, and a shorter in-hospital length of stay. Future research calls for multicenter, high-quality, well-designed studies to validate our findings.

Octreotide attenuates intestinal barrier damage by maintaining basal autophagy in Caco2 cells.

The intestinal mucosal barrier is of great importance for maintaining the stability of the internal environment, which is closely related to the occurrence and development of intestinal inflammation. Octreotide (OCT) has potential applicable clinical value for treating intestinal injury according to previous studies, but the underlying molecular mechanisms have remained elusive. This article is based on a cell model of inflammation induced by lipopolysaccharide (LPS), aiming to explore the effects of OCT in protecting intestinal mucosal barrier function. A Cell Counting Kit‑8 assay was used to determine cell viability and evaluate the effectiveness of OCT. Gene silencing technology was used to reveal the mediated effect of somatostatin receptor 2 (SSTR2). The changes in intestinal permeability were detected through trans‑epithelial electrical resistance and fluorescein isothiocyanate‑dextran 4 experiments, and the alterations in tight junction proteins were detected using immunoblotting and reverse transcription fluorescence‑quantitative PCR technology. Autophagosomes were observed by electron microscopy and the dynamic changes of the autophagy process were characterized by light chain (LC)3‑II/LC3‑I conversion and autophagic flow. The results indicated that SSTR2‑dependent OCT can prevent the decrease in cell activity. After LPS treatment, the permeability of monolayer cells decreased and intercellular tight junctions were disrupted, resulting in a decrease in tight junction protein zona occludens 1 in cells. The level of autophagy‑related protein LC3 was altered to varying degrees at different times. These abnormal changes gradually returned to normal levels after the combined application of LPS and SSTR2‑dependent OCT, confirming the role of OCT in protecting intestinal barrier function. These experimental results suggest that OCT maintains basal autophagy and cell activity mediated by SSTR2 in intestinal epithelial cells, thereby preventing the intestinal barrier dysfunction in inflammation injury.

Effect of octreotide on oxidative stress in the erythrocyte and kidney tissue in adriamycin-induced experimental nephrotic syndrome model.

Nephrotic syndrome (NS) is one of the reasons of end-stage kidney disease, and elucidating the pathogenesis and offer new treatment options is important. Oxidative stress might trigger pathogenesis systemically or isolated in the kidneys. Octreotide (OCT) has beneficial antioxidant effects. We aimed to investigate the source of oxidative stress and the effect of OCT on experimental NS model. Twenty-four non-uremic Wistar albino rats were divided into 3 groups. Control group, 2 mL saline intramuscular (im); NS group, adriamycin 5 mg/kg intravenous (iv); NS treatment group, adriamycin 5 mg/kg (iv) and OCT 200 mcg/kg (im) were administered at baseline (Day 0). At the end of 21 days, creatinine and protein levels were measured in 24-hour urine samples. Erythrocyte and renal catalase (CAT) and thiobarbituric acid reactive substance (TBARS) were measured. Renal histology was also evaluated. There was no significant difference among the 3 groups in terms of CAT and TBARS in erythrocytes. Renal CAT level was lowest in NS group, and significantly lower than the control group. In treatment group, CAT level significantly increased compared with NS group. In terms of renal histology, tubular and interstitial evaluations were similar in all groups. Glomerular score was significantly higher in NS group compared with control group and it was significantly decreased in treatment group compared to NS group. Oxidative stress in NS might be due to the decrease in antioxidant protection mechanism in kidney. Octreotide improves antioxidant levels and histology in renal tissue and might be a treatment option.

Proton-pump inhibitor-induced bone loss is preventable by concomitant use of a long-acting somatostatin analogue.

Long-term consumption of pump inhibitors causes osteoporosis. Some possible mechanisms are gastrin over-secretion and hypochlorhydria. Octreotide is a somatostatin analog that inhibits the secretion of many hormones such as gastrin. This study aimed to assess the effects of pantoprazole on the bone when used with octreotide in an animal model. Forty-eight male Wistar rats were randomly assigned into 4 groups: A) pantoprazole 3 mg/Kg/day orally; B) Sandostatin LAR 1 mg/month intramuscular injection; C) Pantoprazole and Sandostatin LAR; and D) Control group. After 90 days of the experiment, bone densitometry was done and serum and urine samples were collected for analysis. The results indicated a significant decrease in the global, spine, femur, and tibia bone mineral density (BMD) and bone mineral content (BMC) in the pantoprazole group compared to the control group (P<0.05). There was a significant increase in the levels of PTH, gastrin, and alkaline phosphatase (ALP) in the pantoprazole group compared to the control group (P<0.05). There was no significant difference in the serum levels of gastrin, PTH, ALP, and also BMD in the rats that received sandostatin+ pantoprazole or sandostatin alone, compared to the control group. This study showed that the pantoprazole-induced bone loss, through elevation of serum gastrin and PTH, was preventable by concomitant use of a long-acting somatostatin analog.

A case of lung adenocarcinoma with markedly elevated amylase in airway secretions

A 45-year-old male patient was admitted to the hospital because of intermittent cough and expectoration for more than 1 year, worsened by dyspnea for 2 months, and was finally diagnosed with lung adenocarcinoma. The CT scan of the chest revealed lesions of diversity with fibrosis, mass and effusion, but his severe cough limited biopsy of the lesions. The difficult process of diagnosis was aided by the further analysis of the sputum, which showed significantly elevated amylase without any evidence of pancreatic disease. The cough was relieved by intravenous pumping octreotide acetate, and both CT-guided lung biopsy and transbronchial biopsy revealed the lung adenocarcinoma. The diagnostic process of this case provided a helpful diagnostic thinking and demonstrated the rare clinical features of lung adenocarcinoma.

Quantitative spectrofluorimetric method for determination of octreotide acetate synthetic peptide derivative in pure and its Sandostatin ampules forms

A unique spectrofluorimetric protocol has been conceived for octreotide (a synthetic peptide drug) quantitation in both its authentic form and its application to dosage form. The protocol has been established simply upon condensation of octreotide by ninhydrin / phenyl acetaldehyde reagent in buffered media (pH 6.2). An intense fluorescence product has been formed and quantified at 463 nm (390 nm for excitation). After optimization for various experimental conditions, a wide linear interval (0.2–4.0 µg/ml) has been used to construct the calibration curve with a determination coefficient (r2) of 0.9994, a slope ± SD of 81.147 ± 0.7985, and a highly sensitive detection and quantitation limits nearly equal to 0.066 and 0.2 µg/ml, respectively. A proposed protocol has been checked in accordance with ICH validation guidelines, which indicate good accuracy and high precision of the proposed method. Furthermore, this protocol could be perfectly applied for the quantitative estimation of octreotide in its ampoules with a high degree of accuracy and precision. As a result, a developed protocol is ideally appropriate for fast and simple octreotide quantitative estimation in quality control laboratories.

Molecularly imprinted electrochemical sensor for the selective and sensitive determination of octreotide in cancer patient plasma sample

In this study, a molecularly imprinted polymer film (P (ANI)@MIP) on the electrode surface was fabricated using aniline as a functional monomer and octreotide (OC) as a template molecule. The developed P (ANI)@MIP was electrochemically electropolymerized on a glassy carbon electrode (GCE) surface. Each step of MIP production was evaluated by viewing the [Fe (CN)6]3-/4- signal obtained using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The P (ANI)@MIP film layer was studied with a scanning electron microscope (SEM), Raman, and contact angle measurements. The parameters consisting of monomer, template ratio, cycle number, removal solution, removal time, and rebinding time were optimized to obtain the best electrochemical sensor. The developed method was validated in line with ICH guidelines. The linear range, LOD, and LOQ were found as 10–80 fM, 0.801 fM, and 2.670 fM, respectively. The selectivity of the method was tested with the response of somatostatin and lanreotide from the same growth hormone family by comparing the OC response. The developed P (ANI)@MIP/GCE sensor is the first reported method for electrochemical analysis of OC. The P (ANI)@MIP/GCE sensor exhibited high sensitivity and selectivity for OC. The novel MIP sensor was used to determine OC in cancer patient plasma samples. The concentration of OC in cancer patients varied between 8.98 ng/mL and 10.10 ng/mL.

The Structure of Cyclic Neuropeptide Somatostatin and Octapeptide Octreotide in the Presence of Copper Ions: Insights from Transition Metal Ion FRET and Native Ion Mobility-Mass Spectrometry.

The conformation and function of somatostatin (SST), a cyclic neuropeptide, was recently found to be altered in the presence of Cu(II) ions, which leads to self-aggregation and loss of biological function as a neurotransmitter. However, the impact of Cu(II) ions on the structure and function of SST is not fully understood. In this work, transition metal ion Förster resonance energy transfer (tmFRET) and native ion mobility-mass spectrometry (IM-MS) were utilized to study the structures of well-defined gas-phase ions of SST and of a smaller analogue, octreotide (OCT). The tmFRET results suggest two binding sites of Cu(II) ions in both native-like SST and OCT ions, either in close proximity to the disulfide bond or complexed by two aromatic residues, consistent with results obtained from collision-induced dissociation (CID). The former binding site was reported to initiate aggregation of SST, while the latter binding site could directly affect the essential motif for receptor binding and therefore impair the biological function of SST and OCT when bound to SST receptors. Our results demonstrate that tmFRET is capable of locating transition metal ion binding sites in neuropeptides. Furthermore, multiple distance constraints (tmFRET) and global shape (IM-MS) provide additional structural insights of SST and OCT ions upon metal binding, which is related to the self-aggregation mechanisms and overall biological functions.

Influence of octreotide on apoptosis and metabolome expression in lipopolysaccharide-induced A549 cells

Abstract Lung cancer shows a high rate of incidence and mortality. This study aimed to investigate the influence of octreotide (OCT) on lipopolysaccharide (LPS)-induced apoptosis and metabolome expression in A549 cells. After A549 cells were treated by LPS or co-cultured with LPS and OCT, cell apoptosis was tested by flow cytometry, and gas chromatography-mass spectrometer (GC/MS) and high-performance liquid chromatography-mass spectrometer (LC/MS) were subjected to determine the differently expressed metabolites, and the interaction network was constructed. Results found that OCT promoted the apoptosis of A549 cells and significantly affected LPS-regulated cell apoptosis. Following the further investigation by orthogonal partial least squares discriminant analysis (OPLS-DA), the metabolites with different expression levels were obtained, and most of which belong to amino acids, phospholipids, organic acid, and saccharides. Fourteen components with the role of the marker metabolites included serotonin, indole, threonine, serine, glucose, phenylalanine, lactose, fumarate, 4-hydroxyphenyllactate, aspartate, asparagine, putrescine, proline, and succinate. It is indicated that OCT promotes apoptosis through five metabolism pathways and 14 key metabolism elements in A549 cells.

Gastrointestinal: Pancreatic NETs with GCGR heterozygous mutation: Mahvash disease.

A 61 year old female was found to have a pancreatic tumor in 2013. Preoperative laboratory tests showed fasting and 2-h postprandial glucagon levels were more than 400 pg/mL (upper limit, 150 pg/mL) with normal gastrin, blood glucose, and insulin. Preoperative contrast-enhanced CT (CECT) showed diffusely enlarged and inhomogeneously enhanced pancreas with a 2-cm high-density tumor in the pancreatic body. The tumor was obviously enhanced (Fig. 1a–c). Octreotide imaging showed high somatostatin receptor expression in the tumor. The patient underwent subtotal distal pancreatectomy and splenectomy. On postoperative pathological examination, two gray and white solid tumors were found, measuring 1.2 and 2 cm, respectively. On histology, diffuse hyperplastic islets, dysplasia, and microadenomas were detected in residual pancreatic tissue and the pancreatic resected stump. The two lesions were immune-positive for Ki-67 (index 1%), chromogranin A, synaptophysin, E-cadherin, glucagon, gastrin, and insulin (partial) (Fig. 2). The patient was treated with octreotide acetate 20 mg per injection after surgery. But postoperative fasting glucagon level was still high, fluctuating from 513.16 to 3197.49 during 7-year follow-up. Meanwhile, postoperative CECT showed enlargement of the residual pancreatic head (Fig. 1d). Whole-genome sequencing of peripheral blood demonstrated heterozygous mutation of c.1345C>T, which lead to premature termination of translation, and c.922C>T, which lead to arginine replaced by tryptophan. The case was finally diagnosed as Mahvash disease. Mahvash disease is a rare autosomal recessive hereditary pancreatic neuroendocrine neoplasms caused by defective glucagon receptor gene (GCGR) in the liver and associated reactive pancreatic α-cell hyperplasia. Although whole-genome sequencing demonstrated two heterozygous mutations of GCGR, the clinical and pathological features highly suggested Mahvash diagnosis. Diffusely enlarged and unevenly enhanced pancreas indicated coexistence of hyperplastic α cell, hyperplastic islets, and microadenomas. Significant hyperglucagonemia without glucagonoma syndrome further strengthen diagnostic confidence. Most Mahvash diseases were homozygous mutation, and heterozygous mutation are extremely rare. However, reports of patients with heterozygous mutation often showed sub-centimeter lesions (5.5 mm reported by Miller et al. and 5 mm reported by Henopp et al.). To our knowledge, this is the first time large lesions (>1 cm) has been reported in patient with heterozygous mutation of GCGR. There is possibility that heterozygous mutation of GCGR can also be Mahvash disease.

Fabrication of 3D-printed octreotide acetate-loaded oral solid dosage forms by means of semi-solid extrusion printing

Semi-solid extrusion (SSE) 3D printing technology was utilized for the encapsulation of octreotide acetate (OCT) into 3D-printed oral dosage forms in ambient conditions. The inks and the OCT-loaded 3D-printed oral dosage forms were characterized by means of rheology, Fourier-transform infrared (FTIR) spectroscopy and Nuclear Magnetic Resonance (NMR). In vitro studies demonstrated that the formulations released OCT in a controlled manner. The application of these formulations to Caco-2 cell monolayers revealed their capability to induce the transient opening of tight junctions in a reversible manner as evidenced by Transepithelial Resistance (TEER) measurements. Cellular assays (CCK-8 assay) demonstrated the viability of intestinal cells in the presence of these formulations. The in vitro transport studies across Caco-2 monolayers demonstrated the ability of these formulations to enhance the OCT uptake across the cell monolayer over time due to opening of the tight junctions.