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Therapeutic uses of somatostatin and its analogues: Current view and potential applications
Abstract
Somatostatin is an endogeneous cyclic tetradecapeptide hormone that exerts multiple biological activities via five ubiquitously distributed receptor subtypes. Classified as a broad inhibitory neuropeptide, somatostatin has anti-secretory, anti-proliferative and anti-angiogenic effects. The clinical use of native somatostatin is limited by a very short half-life (1 to 3minutes) and the broad spectrum of biological responses. Thus stable, receptor-selective agonists have been developed. The majority of these somatostatin therapeutic agonists bind strongly to two of the five receptor subtypes, although recently an agonist of wider affinity has been introduced. Somatostatin agonists are established in the treatment of acromegaly with recently approved indications in the therapy of neuroendocrine tumors. Potential therapeutic uses for somatostatin analogues include diabetic complications like retinopathy, nephropathy and obesity, due to inhibition of IGF-1, VEGF together with insulin secretion and effects upon the renin-angiotensin-aldosterone system. Wider uses in anti-neoplastic therapy may also be considered and recent studies have further revealed anti-inflammatory and anti-nociceptive effects. This review provides a comprehensive, current view of the biological functions of somatostatin and potential therapeutic uses, informed by the wide range of pharmacological advances reported since the last published review in 2004 by P. Dasgupta. The pharmacology of somatostatin receptors is explained, the current uses of somatostatin agonists are discussed, and the potential future of therapeutic applications is explored.
Copyright © 2015. Published by Elsevier Inc.
... Somatostatin (SST) is a polypeptide hormone existing in two forms (14 and 28 amino acids). The properties of SST consist of antisecretory, antiproliferative and antiangiogenic effects [7]. SST has a short half-life and binds with high affinity to five different subtypes of receptor ubiquitously distributed. ...
... SST has a short half-life and binds with high affinity to five different subtypes of receptor ubiquitously distributed. The binding of SST with its receptor determines several biological functions [7]. The expression levels of SST receptors (SSTRs) have been determined in multiple human tissues across the human body, including the brain, gastrointestinal tract, pancreas, lung and genitourinary tract. ...
... SSAs are very effective drugs for hormonal syndrome control in functioning tumors and exert an antiproliferative effect by inducing cell cycle arrest and apoptosis, and through immunomodulatory effects and angiogenesis inhibition. Considering these data, they have been approved for the treatment of acromegaly and NET [7,8]. SSAs allow the control of cell proliferation through two different mechanisms: a direct one, consisting of the binding to specific surface receptors, and an indirect one, consisting of the inhibition of growth factors and modulation of immune response [7]. ...
Neuroendocrine neoplasms (NEN) are characterized by a wide clinical heterogeneity and biological variability, with slow progression and long survival in most cases. Although these tumors can affect young adults, there are few studies that focus on the sexual and reproductive system. The aim of this review was to evaluate the effect of NEN treatment, including somatostatin analogues (SSA), targeted therapy (Everolimus and Sunitinib), radiolabeled-SSA and chemotherapy, on male and female reproductive systems and sexual function. This narrative review was performed for all available prospective and retrospective studies, case reports and review articles published up to March 2022 in PubMed. To date, few data are available on the impact of SSA on human fertility and most of studies come from acromegalic patients. However, SSAs seem to cross the blood–placental barrier; therefore, pregnancy planning is strongly recommended. Furthermore, the effect of targeted therapy on reproductive function is still undefined. Conversely, chemotherapy has a well-known negative impact on male and female fertility. The effect of temozolomide on reproductive function is still undefined, even if changes in semen parameters after the treatment have been described. Finally, very few data are available on the sexual function of NEN treatment.
... Detailed analysis of the anatomical expression pattern and pharmacological actions of ArSS2 in A. rubens revealed that it acts as a muscle relaxant and triggers stomach eversion in this species (21). This myoinhibitory effect of ArSS2 in starfish is noteworthy because it is consistent with the effects of SS/ASTC-type neuropeptides as inhibitory regulators of a variety of physiological processes in chordates and protostomes (13,14,(23)(24)(25)(26). Thus, an ancient role of SS/ASTC-type neuropeptides as inhibitory regulators can be traced back to the common ancestor of the Bilateria, with this role being retained in the action of the SS2-type neuropeptide ArSS2 as a myoinhibitor in an echinoderm-the starfish A. rubens (21). ...
... A detailed analysis of the expression of the SS-type neuropeptide ArSS2 in the starfish A. rubens was reported previously (21), which revealed a widespread pattern of expression in the central nervous system, digestive system, and body wall-associated tissues/ organs. Furthermore, analysis of the pharmacological actions of ArSS2 revealed that it acts as a muscle relaxant, an action that is consistent with the actions of SS-type neuropeptides in vertebrates and ASTC-type neuropeptides in protostomes as inhibitory regulators of physiological processes (13,14,(23)(24)(25)(26). Here, the expression and actions of the ASTC-type neuropeptide ArSS1 in A. rubens were investigated. ...
... Interestingly, ArSS1 had a myoexcitatory effect on all three preparations, causing concentration-dependent contraction at physiologically relevant concentrations ranging from 10 À9 M to 10 À6 M. ArSS1 joins a growing list of neuropeptides that have been found to act as myoexcitatory neuropeptides in starfish, as summarized in SI Appendix, Table S3. However, the myoexcitatory effect of ArSS1 in A. rubens is interesting because hitherto it has been discovered that SS-type and ASTC-type neuropeptides in other taxa typically act as inhibitory regulators of physiological processes at the cellular level (13,14,(23)(24)(25)(26). There are reports of SS causing muscle contraction of guinea pig gastric smooth muscle cells, but investigation of the mechanisms of action indicate that this is a consequence of SS causing inhibition of the release of a muscle relaxant (e.g., vasoactive intestinal peptide) [i.e., SS is causing disinhibition (41,42)]. ...
Significance
Somatostatin (SS) and allatostatin-C (ASTC) are related neuropeptide hormones that act as inhibitory regulators of physiological processes in chordates (e.g., humans) and protostome invertebrates (e.g., insects), respectively. We have discovered that echinoderms (e.g., starfish) uniquely have both SS-type and ASTC-type neuropeptides, which act as inhibitory and excitatory regulators of muscle activity, respectively. Our findings suggest that SS-type and ASTC-type neuropeptides evolved by duplication of a common ancestral encoding gene. Then, one of the neuropeptides was lost in protostomes and chordates, probably because of their functional redundancy as inhibitory regulators. Conversely, the unique retention of both neuropeptide types in echinoderms may be explained by evolution of an excitatory role for ASTC-type neuropeptides mediated by yet-to-be-determined signaling mechanisms.
... SST is a small peptide that is also released from the central nervous system besides the sensory nerves (Helyes et al., 2009), from inflammatory and immune cells, pancreas, retinal neurons, and epithelial cells (Rai et al., 2015). SST exerts antiinflammatory, antinociceptive (Helyes et al., 2009;Markovics et al., 2012), antisecretory, and antiproliferative effects (Rai et al., 2015). ...
... SST is a small peptide that is also released from the central nervous system besides the sensory nerves (Helyes et al., 2009), from inflammatory and immune cells, pancreas, retinal neurons, and epithelial cells (Rai et al., 2015). SST exerts antiinflammatory, antinociceptive (Helyes et al., 2009;Markovics et al., 2012), antisecretory, and antiproliferative effects (Rai et al., 2015). There are five G i -protein-coupled transmembrane receptor subtypes of SST (SSTR1-5) (Rai et al., 2015). ...
... SST exerts antiinflammatory, antinociceptive (Helyes et al., 2009;Markovics et al., 2012), antisecretory, and antiproliferative effects (Rai et al., 2015). There are five G i -protein-coupled transmembrane receptor subtypes of SST (SSTR1-5) (Rai et al., 2015). It is known that endogenous SST released from capsaicin-sensitive nerves prevented retinal ischemia/reperfusion injury in a mouse model (Wang et al., 2017). ...
Little is known about the role of the neuropeptide somatostatin (SST) in myocardial ischemia/reperfusion injury and cardioprotection. Here, we investigated the direct cardiocytoprotective effect of SST on ischemia/reperfusion injury in cardiomyocyte cultures, as well as the expression of SST and its receptors in pig and human heart tissues. SST induced a bell-shaped, concentration-dependent cardiocytoprotection in both adult rat primary cardiomyocytes and H9C2 cells subjected to simulated ischemia/reperfusion injury. Furthermore, in a translational porcine closed-chest acute myocardial infarction model, ischemic preconditioning increased plasma SST-like immunoreactivity. Interestingly, SST expression was detectable at the protein, but not at the mRNA level in the pig left ventricles. SSTR1 and SSTR2, but not the other SST receptors, were detectable at the mRNA level by PCR and sequencing in the pig left ventricle. Moreover, remote ischemic conditioning upregulated SSTR1 mRNA. Similarly, SST expression was also detectable in healthy human interventricular septum samples at the protein level. Furthermore, SST-like immunoreactivity decreased in interventricular septum samples of patients with ischemic cardiomyopathy. SSTR1, SSTR2, and SSTR5 but not SST and the other SST receptors were detectable at the mRNA level by sequencing in healthy human left ventricles. In addition, in healthy human left ventricle samples, SSTR1 and SSTR2 mRNAs were expressed especially in vascular endothelial and some other cell types as detected by RNA Scope® in situ hybridization. This is the first demonstration that SST exerts a direct cardiocytoprotective effect against simulated ischemia/reperfusion injury. Moreover, SST is expressed in the heart tissue at the peptide level; however, it is likely to be of sensory neural origin since its mRNA is not detectable. SSTR1 and SSTR2 might be involved in the cardioprotective action of SST, but other mechanisms cannot be excluded.
... Additionally, 68 Ga has a positron energy of 1.9 MeV and a higher positron range than 18 F (635 keV), which results in a lower resolution of the final image. This fact promoted the development of 18 [155][156][157]. Somatostatin (SST) is the endogenous SSTR ligand which is a neuropeptide that is produced and excreted by cells such as neuroendocrine, immune and inflammatory cells [158].It has many downstream biological effects yet it is mainly a broad inhibitor of the secretion of hormones, proliferation and cell growth [159]. ...
... Somatostatin (SST) is the endogenous SSTR ligand which is a neuropeptide that is produced and excreted by cells such as neuroendocrine, immune and inflammatory cells [158].It has many downstream biological effects yet it is mainly a broad inhibitor of the secretion of hormones, proliferation and cell growth [159]. SST itself is suboptimal as a pharmaceutical due to its short biological half-life (<3 min) [154,156,160]. Therefore, somatostatin analogs that have been generated are more 96 stable receptor selective agonists in vivo. ...
... Internalization of the radiolabelled SSA receptor complex allows for accumulation of the radiotracer in the NET cells. Visualization of the tumour localization can then be done via PET or single photon emission computed tomography (SPECT); as well, treatment is available using peptide receptor radionuclide therapy (PRRT) [156,165]. The receptor subtype SSTR2 is a good target for nuclear imaging as well as PRRT not only because it is commonly found overexpressed at a high density on certain tumour cells, but it also has low expression on normal cells allowing for preferential image contrast and minimal off-target effects [166]. ...
Fluorine-18 fluorodeoxyglucose ([18F]FDG), the first radiopharmaceutical used in clinical
applications of positron emission tomography (PET), was a revolutionary development in nuclear medicine that combined biochemistry, medicinal chemistry and radiochemistry. In the 1970s, it was used in brain imaging to aid clinical diagnosis; soon, the detection of malignancies and cardiac diseases also became possible. In the decades that followed, [18F]FDG became widely available owing to the worldwide cyclotron network and automated synthesizers in clinics in many Member States. This paved the way for the development of additional 18F-labelled radiopharmaceuticals adapted for other biological pathways and molecular and cellular mechanisms applicable to human diseases. The production and quality control of 18F radiopharmaceuticals have been revolutionized
from the industrial point of view, with the introduction of national and international safety, legislative and legal requirements. In response to numerous requests from Member States, in 2020 the IAEA organized a number of consultancy meetings aimed at planning and preparing a publication on the production and quality control of 18F radiopharmaceuticals. The present publication is a result of those meetings and provides
information on practical production routes and on quality control and radiopharmaceutical aspects of 18F tracers. It is expected to be of interest to radiopharmacists and radiochemists, as well as graduate students in the field of 18F radiochemistry and radiopharmacy. The IAEA wishes to thank the participating experts for their valuable work and scientific contributions, especially P.H. Elsinga (Netherlands) for compiling and carrying out the technical editing of this publication and J. Vera Araujo (Bolivarian Republic of Venezuela) for her editorial support. The IAEA technical officer responsible for this publication was A.R. Jalilian of the Division of Physical and Chemical Sciences.
... Moreover, the simultaneous stimulation of SSTR 2 and 5 achieves significant inhibition of Ras and extracellular signal-regulated kinase (ERK)-1/2. [20][21][22][23] Similarly, cabozantinib inhibits the activity of VEGFR2, c-MET and AXL at the level of both cancer cells and peritumoral vessels, thus leading to the downstream inhibition of PI3K/Akt/mTOR and Ras/MAPK, with antiproliferative and antiangiogenic effects. [24] Also SSAs exert antiangiogenic effects by engaging SSTRs on the vascular endothelium and by downregulating the secretion of proangiogenic factors, such as VEGF and PDGF [25]. ...
... In our opinion, the combination of cabozantinib with other agents such as SSAs may result in synergistic antiproliferative effects, potentially enhancing antitumor activity and clinical outcomes. The biological rationale of the synergistic effects of cabozantinib in combination with SSAs resides in the concomitant inhibition of intracellular signaling pathways associated with tumor cell proliferation, angiogenesis and immune modulation [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. ...
Background
Well-differentiated (WD) neuroendocrine tumors (NETs) are a group of rare neoplasms with limited therapeutic options. Cabozantinib is an inhibitor of multiple tyrosine kinases with a pivotal role in NET pathogenesis, including c-MET and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2). LOLA is the first prospective phase II trial aiming to assess the safety and activity of cabozantinib combined with lanreotide in WD NETs of gastroenteropancreatic (GEP), thoracic and of unknown origin.
Methods
This is a multicenter, open-label, double-cohort, non comparative, non-randomized, three-stage phase II trial. Eligible patients have to meet the following inclusion criteria: diagnosis of advanced or metastatic, progressive, non-functioning WD thoracic NETs, GEP-NETs or NETs of unknown origin with Ki67 ≥ 10%; positive 68 Ga-PET uptake or somatostatin receptor 2 immunohistochemical (IHC) stain; maximum 1 prior systemic regimen for metastatic disease. Two cohorts will be considered: pNETs and carcinoids (typical or atypical lung and thymus NETs, gastro-intestinal NETs or NETs of unknown origin). In stage I, the primary objective is to find the optimal dose of cabozantinib in combination with lanreotide and to evaluate the safety of the combination (percentage of patients experiencing grade 3–5 toxicities according to NCI-CTCAE version 5.0). Starting dose of cabozantinib is 60 mg/day continuously, plus lanreotide 120 mg every 28 days. In stage II and III, co-primary endpoints are safety and overall response rate (ORR) according to RECIST version 1.1. The uninteresting antitumor activity is fixed in ORR ≤ 5%. Secondary endpoints are progression-free survival and overall survival. Exploratory objectives include the assessment of c-MET, AXL and VEGFR2 IHC expression, to identify predictive or prognostic tissue biomarkers. Enrolment started in July 2020, with an expected trial duration of 42 months comprehensive of accrual, treatment and follow-up. Considering a drop-out rate of 5%, the maximum number of enrolled patients will be 69.
Discussion
Supported by a solid rationale, the trial has the potential to generate milestone data about the synergistic effects of cabozantinib plus lanreotide in a group of NET patients with relatively aggressive disease and limited therapeutic options.
Trial registration
LOLA is registered at ClinicalTrials.gov (NCT04427787) and EudraCT (2019–004506-10).
... Their natural peptide ligand, somatost is found in humans under two different forms: one of 14 amino acids (SS-14) and on 28 amino acids (SS-28) (Figure 1) [17,18]. Natural somatostatin has been shown to be suitable for in vivo use due to its short plasma half-life (about 3 min) [19]. Analogu this hormone, more resistant to enzymatic degradation, have therefore been develope making various modifications to the natural molecule [20,21]. ...
... Retreatment with 177 Lu-PRRT resulted in 24.2% objective radiological responses (ORRs) and 42.4% SDs. The median PFS was 13 (9-18) months from the start of the salvage therapy and 22 (19)(20)(21)(22)(23)(24)(25) months after the initial 177 Lu-PRRT. Remarkably, these results are slightly lower than those obtained in the pretreated subgroups of the Ballal et al. study involving [ 225 Ac]Ac-DOTATATE [212]. ...
The widespread use of peptide receptor radionuclide therapy (PRRT) represents a major therapeutic breakthrough in nuclear medicine, particularly since the introduction of 177 Lu-radiolabeled somatostatin analogs. These radiopharmaceuticals have especially improved progression-free survival and quality of life in patients with inoperable metastatic gastroenteropancreatic neuroen-docrine tumors expressing somatostatin receptors. In the case of aggressive or resistant disease, the use of somatostatin derivatives radiolabeled with an alpha-emitter could provide a promising alternative. Among the currently available alpha-emitting radioelements, actinium-225 has emerged as the most suitable candidate, especially regarding its physical and radiochemical properties. Nevertheless, preclinical and clinical studies on these radiopharmaceuticals are still few and heterogeneous, despite the growing momentum for their future use on a larger scale. In this context, this report provides a comprehensive and extensive overview of the development of 225 Ac-labeled somatostatin analogs; particular emphasis is placed on the challenges associated with the production of 225 Ac, its physical and radiochemical properties, as well as the place of 225 Ac-DOTATOC and 225 Ac-DOTATATE in the management of patients with advanced metastatic neuroendocrine tumors.
... when the curative operation is no longer feasible, drug treatment options for unoperated patients are divided into four main categories, for example, somatostatin analogs (SSA), targeted therapy, peptide receptor radionuclide therapy (PRRT), and chemotherapy [10]. It has been validated that SSAs performed a critical role in retarding cell proliferation and tumorigenesis by targeting the SST, especially SST2, somatostatin receptor subtype-5 (SST5) [11,12]. Octreotide is the first discovered longlasting SSA [13]. ...
... Glu2-Tag mice underwent α cell hyperplasia, abnormal dysplastic islets, hyperglycemia, and endocrine tumors of different grades. In Glu2-Tag, Tag was expressed in the pancreas and brain in 12 week, but only developed glucagonoma at 18 months [65]. Because of striking similarities between human sporadic glucagonomas and Glu2-Tag mouse tumor spectrums, this model is considered to be an appropriate preclinical tool to study human glucagonoma. ...
The neuroendocrine neoplasm, in general, refers to a heterogeneous group of all tumors originating from peptidergic neurons and neuroendocrine cells. Neuroendocrine neoplasms are divided into two histopathological subtypes: well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Pancreatic neuroendocrine tumors account for more than 80% of pancreatic neuroendocrine neoplasms. Due to the greater proportion of pancreatic neuroendocrine tumors compared to pancreatic neuroendocrine carcinoma, this review will only focus on them. The worldwide incidence of pancreatic neuroendocrine tumors is rising year by year due to sensitive detection with an emphasis on medical examinations and the improvement of testing technology. Although the biological behavior of pancreatic neuroendocrine tumors tends to be inert, distant metastasis is common, often occurring very early. Because of the paucity of basic research on pancreatic neuroendocrine tumors, the mechanism of tumor development, metastasis, and recurrence are still unclear. In this context, the representative preclinical models simulating the tumor development process are becoming ever more widely appreciated to address the clinical problems of pancreatic neuroendocrine tumors. So far, there is no comprehensive report on the experimental model of pancreatic neuroendocrine tumors. This article systematically summarizes the characteristics of preclinical models, such as patient-derived cell lines, patient-derived xenografts, genetically engineered mouse models, and patient-derived organoids, and their advantages and disadvantages, to provide a reference for further studies of neuroendocrine tumors. We also highlight the method of establishment of liver metastasis mouse models.
... We assessed eptifibatide (platelet inhibitor), 76 desmopressin (antidiuretic), 77 and vapreotide (vasoconstrictor). 78 For these studies, we used 1,5-diiodopentane as a standard linker. We found that bis-Dha analogs of each peptide could be formed and reacted under our diversification conditions to afford new carbocyclic peptides in conversions of 22−44%, Table 2 compounds 27−29. ...
... Examples include zolantidine (log P eh −1.47), clonidine (log P eh −1.80), and antipyrine (log P eh −2.28). 78 For SMT, we determined log P eh = −1.16, reflective of its good water solubility and mild blood−brain permeability. ...
One way to improve the therapeutic potential of peptides is through cyclization. This is commonly done using a disulfide bond between two cysteine residues in the peptide. However, disulfide bonds are susceptible to reductive cleavage, and this can deactivate the peptide and endanger endogenous proteins through covalent modification. Substituting disulfide bonds with more chemically robust carbon-based linkers has proven to be an effective strategy to better develop cyclic peptides as drugs, but finding the optimal carbon replacement is synthetically laborious. We report a new late-stage platform wherein a single disulfide bond in a cyclic peptide can serve as the progenitor for any number of new carbon-rich groups, derived from organodiiodides, using a Zn:Cu couple and a hydrosilane. We show that this platform can furnish entirely new carbocyclic scaffolds with enhanced permeability and structural integrity and that the stereochemistry of the new cycles can be biased by a judicious choice in silane.
... The therapeutic effects of SST were found in patients with acute or chronic pancreatitis [5][6][7][8]. However, with its peptide nature, SST can be easily degraded by the peptidase in plasma/tissue and suffers from a very short half-life (<1~3 min), which limits its clinical translation [9]. To improve the bioavailability, SST analogues such as octreotide acetate, lanreotide and pasireotide have been developed to obtain t 1/2 ranging from 2 h to 600 h [10][11][12]. ...
... It was, therefore, important to develop strategies to prolong the bioactivity of SST in its native form in vivo. Given the wide distribution of SST receptors throughout the central nervous system and periphery [9], new formulations of SST capable of tissue targeting may be necessary to avoid or alleviate potential side effects. ...
The clinical translation of therapeutic peptides is generally challenged by multiple issues involving absorption, distribution, metabolism and excretion. In this study, a macrophage membrane-coated poly(lactic-co-glycolic acid) (PLGA) nanodelivery system was developed to enhance the bioavailability of the somatostatin (SST) peptide, which faces the hurdles of short half-life and potential side effects in the treatment of chronic pancreatitis. Using a facile nanoprecipitation strategy, SST was loaded in the nanoparticles with an encapsulation efficiency (EE) and a loading efficiency (LE) of 73.68 ± 3.56% and 1.47 ± 0.07%, respectively. The final formulation of SST-loaded nanoparticles with the camouflage of macrophage membrane (MP-SST) showed a mean diameter of 151 ± 4 nm and an average zeta potential of −29.6 ± 0.3 mV, which were stable long term during storage. With an above 90% cell viability, a hemolysis level of about 2% (
... SST inhibits the release of several endocrine hormones such as growth hormone, prolactin, thyrotropin, gastrin, insulin, secretin, and glucagon [3,[5][6][7], and the local inflammatory reaction at the periphery [8,9]. As a neurotransmitter, SST plays role in many mechanisms centrally, such as pain transmission, mood coordination, and learning and behavioral responses to stress [3,[10][11][12][13]. ...
... As a neurotransmitter, SST plays role in many mechanisms centrally, such as pain transmission, mood coordination, and learning and behavioral responses to stress [3,[10][11][12][13]. It has emerging therapeutic relevance for the diagnosis and/or the treatment of numerous diseases, such as type 2 diabetes mellitus, Cushing disease, Alzheimer's disease, acromegaly, several neuroendocrine tumors, pain-associated SST inhibits the release of several endocrine hormones such as growth hormone, prolactin, thyrotropin, gastrin, insulin, secretin, and glucagon [3,[5][6][7], and the local inflammatory reaction at the periphery [8,9]. As a neurotransmitter, SST plays role in many SST exerts its diverse biological effects via modulating somatostatin receptors (SSTRs). ...
Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of the endocrine system, local inflammatory reactions, mood and motor coordination, and behavioral responses to stress. Somatostatin exerts its effects via binding to G-protein-coupled somatostatin receptors of which the fourth subtype (SSTR4) is a particularly important receptor mediating analgesic, anti-inflammatory, and anti-depressant effects without endocrine actions. Thus, SSTR4 agonists are promising drug candidates. Although the knowledge of the atomic resolution-binding modes of SST would be essential for drug development, experimental elucidation of the structures of SSTR4 and its complexes is still awaiting. In the present study, structures of the somatostatin-SSTR4 complex were produced using an unbiased, blind docking approach. Beyond the static structures, the binding mechanism of SST was also elucidated in the explicit water molecular dynamics (MD) calculations, and key binding modes (external, intermediate, and internal) were distinguished. The most important residues on both receptor and SST sides were identified. An energetic comparison of SST binding to SSTR4 and 2 offered a residue-level explanation of receptor subtype selectivity. The calculated structures show good agreement with available experimental results and indicate that somatostatin binding is realized via prerequisite binding modes and an induced fit mechanism. The identified binding modes and the corresponding key residues provide useful information for future drug design targeting SSTR4.
... Somatostatin inhibits the secretion of insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal polypeptide, the insulin-like growth factor-1, and other compounds. Somatostatin is used for therapy of hormonal disorders that are associated with hyperproduction of the somatotropin growth hormone and various diseases of the gastrointestinal tract and pancreas [65]. The modustatin and stilamin drugs that have the natural structure of somatostatin were developed and introduced into medicinal practice at the end of 1980s. ...
... The structure-functional studies of somatostatin resulted in the creation of its highly active agonistic analogs, octreotide and lanreotide [65][66][67][68]. Octreotide is a cyclic octapeptide of the following primary structure: D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-Ol(S-S 2-7 ). ...
This review is devoted to the 100-year history of the investigation of peptide hormones and the creation of drugs on their basis, starting from the insulin discovery and its introduction into a medical practice in 1921. The basic groups of the peptide hormones are discussed: neurohypophyseal hormones, hypothalamic releasing hormones, incretins, insulin, adrenocorticotropic hormone (ACTH), and calcitonin. The first therapeutic agents based on the peptide hormones were created by a traditional approach that involved the isolation of peptides from animal tissues, their purification to individual compounds, determination of their primary structure, their chemical synthesis or their deep purification, and the creation of a pharmaceutical substance. A modern approach to creation of peptide hormone drugs is based on their consideration as ligands of the corresponding cellular receptors and the use of computer modeling, efficient synthesis methods, and high-throughput screening. The combination of these methods enabled the development of analogs which would be more active than the corresponding natural compounds, exhibit other activities in addition to the hormonal regulation, and be resistant to biodegradation. Such therapeutic agents have been designed on the basis of agonistic and antagonistic analogs of somatostatin and luliberin, and have found wide application in hormonal regulation and cancer treatment. Over the past two decades, the glucagon-like peptide (GLP-1) has been intensively investigated as a potential therapeutic agent. In our review, we describe modifications which resulted in the most highly effective long-acting drugs. Now, natural hormones and their analogs are widely present in the pharmaceutical market.
... Specifically, sst5TMD4 has been shown to be overexpressed in several hormone-related tumors compared with non-tumor tissues, where it enhanced aggressiveness features [14][15][16][17][18][19][20][21][22]. Moreover, sst5TMD4 has been shown to reduce the response to somatostatin analogs (SSAs; e.g., octreotide) [14,17,18,22,23], which are used as valuable drugs to treat different tumor pathologies, including pituitary and neuroendocrine tumors [24,25]. Unfortunately, attempts to use SSAs as medical therapy in brain tumors have rendered controversial results since some of the available studies have not reported a clear therapeutic value for SSAs; however, the mechanistic reasons underlying those experimental failures remain unknown [26][27][28][29][30]. ...
... In this context, the development of SSAs as therapeutic opportunities has revolutionized the clinical management of patients with certain endocrine pathologies, and nowadays are considered the mainstay in the medical management of some pituitary and neuroendocrine tumors [24,25,37]. However, SSAs are frequently ineffective in a subset of patients, suggesting that key molecular determinants could be essential for the response to this pharmacological treatment [38]. ...
Glioblastoma (GBM) is the most malignant and lethal brain tumor. Current standard treatment consists of surgery followed by radiotherapy/chemotherapy; however, this is only a palliative approach with a mean post-operative survival of scarcely ~12–15 months. Thus, the identification of novel therapeutic targets to treat this devastating pathology is urgently needed. In this context, the truncated splicing variant of the somatostatin receptor subtype 5 (sst5TMD4), which is produced by aberrant alternative splicing, has been demonstrated to be overexpressed and associated with increased aggressiveness features in several tumors. However, the presence, functional role, and associated molecular mechanisms of sst5TMD4 in GBM have not been yet explored. Therefore, we performed a comprehensive analysis to characterize the expression and pathophysiological role of sst5TMD4 in human GBM. sst5TMD4 was significantly overexpressed (at mRNA and protein levels) in human GBM tissue compared to non-tumor (control) brain tissue. Remarkably, sst5TMD4 expression was significantly associated with poor overall survival and recurrent tumors in GBM patients. Moreover, in vitro sst5TMD4 overexpression (by specific plasmid) increased, whereas sst5TMD4 silencing (by specific siRNA) decreased, key malignant features (i.e., proliferation and migration capacity) of GBM cells (U-87 MG/U-118 MG models). Furthermore, sst5TMD4 overexpression in GBM cells altered the activity of multiple key signaling pathways associated with tumor aggressiveness/progression (AKT/JAK-STAT/NF-κB/TGF-β), and its silencing sensitized GBM cells to the antitumor effect of pasireotide (a somatostatin analog). Altogether, these results demonstrate that sst5TMD4 is overexpressed and associated with enhanced malignancy features in human GBMs and reveal its potential utility as a novel diagnostic/prognostic biomarker and putative therapeutic target in GBMs.
... Furthermore, the SRIF system is characterized by a strong antiproliferative activity, increasing cell apoptosis and inhibiting angiogenesis in most of the cancerous tissues [12,[16][17][18][19][20]. This property is already used in clinical practice [20][21][22][23][24][25][26]. SST acts through the activation of five membrane receptors (SSTRs/SSTs), belonging to the G protein-coupled receptor (GPCR) family [12,16,19,24,27,28]. ...
... SST is a peptide that assumes two forms (SST-14 and SST-28), secreted mostly in a paracrine/neurocrine fashion, released in a pulse manner as a very short-lived peptide of about 3 min bioactive half-life in circulation, where it is degraded rapidly by ubiquitous peptidases [12,22,24,37]. In CNS, the peripheral nervous system (PNS) and pancreas SST-14 is the dominating form, while SST-28 is secreted by D cells in the GI tract [42]. ...
Somatostatin (SST)/somatotropin release-inhibiting factor (SRIF) is a well-known neuropeptide, widely distributed in the central and peripheral nervous systems, that regulates the endocrine system and affects neurotransmission via interaction with five SST receptors (SST1-5). In the gastrointestinal tract, the main SST-producing cells include intestinal enteroendocrine cells (EECs) restricted to the mucosa, and neurons of the submucosal and myenteric plexuses. The action of the SRIF system is based on the inhibition of endocrine and exocrine secretion, as well as the proliferative responses of target cells. The SST1–5 share common signaling pathways, and are not only widely expressed on normal tissues, but also frequently overexpressed by several tumors, particularly neuroendocrine neoplasms (NENs). Furthermore, the SRIF system represents the only peptide/G protein-coupled receptor (GPCR) system with multiple approved clinical applications for the diagnosis and treatment of several NENs. The role of the SRIF system in the histogenesis of colorectal cancer (CRC) subtypes (e.g., adenocarcinoma and signet ring-cell carcinoma), as well as diagnosis and prognosis of mixed adenoneuroendocrine carcinoma (MANEC) and pure adenocarcinoma, is poorly understood. Moreover, the impact of the SRIF system signaling on CRC cell proliferation and its potential role in the progression of this cancer remains unknown. Therefore, this review summarizes the recent collective knowledge and understanding of the clinical significance of the SRIF system signaling in CRC, aiming to evaluate the potential role of its components in CRC histogenesis, diagnosis, and potential therapy.
... SSAs that are often recommended for patients with advanced neuroendocrine tumours since they exhibit a high affinity for at least two of the five types of somatostatin receptors. (14,15) SSAs also exert their inhibitory actions against hormone secretion and cell proliferation, (16) promoting stabilisation in 30-70% of patients with well-differentiated NENs of different origins and prolonged mPFS, although, without proven survival gain. (14,15,17,20,21) We demonstrated that these results were observed in our patients with NETP, independent of the carcinoid subtype (typical or atypical). ...
... (14,15) SSAs also exert their inhibitory actions against hormone secretion and cell proliferation, (16) promoting stabilisation in 30-70% of patients with well-differentiated NENs of different origins and prolonged mPFS, although, without proven survival gain. (14,15,17,20,21) We demonstrated that these results were observed in our patients with NETP, independent of the carcinoid subtype (typical or atypical). ...
Introduction: Well-differentiated neuroendocrine pulmonary tumours (NETp) are morphologically classified as typical carcinoid (TC) and atypical carcinoid (AC). There are limited data on systemic treatment for metastatic disease. Objective: Our study evaluated the median progression-free survival of patients with metastatic tumours, comparing TC and AC status for different treatments.
Methods: Retrospective series of patients with metastatic NETp treated from 2002 to 2019 in a large cancer centre were analysed. Our primary endpoint was progression-free survival according to morphological classification (TC vs. AC). All patients received at least one treatment modality (e.g., somatostatin analogue [SSA], chemotherapy [ChP], and everolimus [Eve]). Variables were analysed using the chi-square test, median progression-free survival (mPFS) rates (months), with comparisons evaluated by the log-rank test.
Results: Twenty-seven patients were included: 44% with TC and 56% with AC. TC patients were on average 58-years-old, 83.3% were female, and 33.3% received more than one treatment. AC patients were on average 61-years-old, 66.7% were female, and 20% received more than one treatment. All patients were treated more frequently with SSA (TC: 75% vs. AC: 80%, p=0.756). Cisplatin and etoposide were the most frequent ChP regimen (TC: 75% vs. AC: 30%, p=0.248). Patients with TC and AC treated with SSA had higher mPFS in months (TC mPFS SSA: 14.5, Eve: 2.50, ChP: 4.0, SSA + Eve: 4.50; AC mPFS SSA: 7.50, Eve: 4.50, ChP: 7.50, SSA + Eve: 7.00).
Conclusion: Although the statistical analyses did not show a significant difference between treatment, numerically, more patients with TC or AC experienced tumor control with SSAs, where the mPFS pairs showed a possible tendency to differentiate themselves from the other regimes (Eve and ChP).
... Representative examples of paracrine retinoprotective proteins include the pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP, [12]), somatostatin [20], and Vascular Endothelial Growth Factor (VEGF, [11]). VIP is expressed in a population of amacrine cells [13], whereas PACAP and its receptors (PAC1, VPAC1, and VPAC2) occur in all retinal layers except the photoreceptors [14]. ...
... Of note, IGF1, previously mentioned above as possessing an autocrine signaling mechanism of action, can also act in a paracrine manner (Table 1), as it is expressed by the microglia and protects photoreceptors in the rd10 mouse model [6]. The paracrine retinoprotective peptide somatostatin or somatotropin release inhibiting factor (SRIF), is a neuropeptide with a broad inhibitory effect on protein secretion, proliferation, and angiogenesis [20]. The SRIF receptors (SST1-4 in mammals) are distributed in all retinal layers and RPE cells, but the main source of secreted SRIF is the RPE cells [14]. ...
Retinoprotective proteins play important roles for retinal tissue integrity. They can directly affect the function and the survival of photoreceptors, and/or indirectly target the retinal pigment epithelium (RPE) and endothelial cells that support these tissues. Retinoprotective proteins are used in basic, translational and in clinical studies to prevent and treat human retinal degenerative disorders. In this review, we provide an overview of proteins that protect the retina and focus on pigment epithelium-derived factor (PEDF), and its effects on photoreceptors, RPE cells, and endothelial cells. We also discuss delivery systems such as pharmacologic and genetic administration of proteins to achieve photoreceptor survival and retinal tissue integrity.
... One may distinguish between five different SSTR subtypes (1, 2A/B, 3, 4, and 5), which are expressed in varying degrees in diverse neoplastic tumors and tissues [17]. In addition to its well-known anti-secretory, anti-nociceptive, and anti-inflammatory functions, researchers have discovered that somatostatin and its receptors also inhibit cell growth and angiogenesis [18]. Somatostatin receptors have been identified in the metaphysis next to hypertrophic cartilage [19]. ...
Reliable preoperative diagnosis between salivary gland tumor entities is difficult. In this monocentric retrospective study, we examined the somatostatin receptor 2 (SSTR2) status of salivary gland tumors after salivary gland tumor resection via immunohistochemistry (IHC), and stains were compared in analogy to the HER2 mamma scale. A total of 42.3% of all pleomorphic adenoma (PA) tumors (42 of 99, 95% confidence interval 32.5–52.8%) demonstrated ≥20% of cells displaying the SSTR2 as compared to just 1% of all other tumors (1/160, 95% CI 0.02–3.4%). The other tumor was a neuroendocrine carcinoma. PA had a higher intensity of SSTR2 staining, with 90.9% staining ≥ an intensity of 2 (moderate). Tumors with an intensity of SSTR2 expression equal to or greater than 2 had an 89.9% likelihood of being a PA (95% CI: 82.2–95.0%, AUC: 0.928). Only one Warthin tumor demonstrated a ‘strong’ SSTR2 staining intensity. No Warthin tumor showed a percentage of cells staining for SSTR2 above ≥20%. This result demonstrates consistent and strong expression of SSTR2 in PAs as compared to Warthin tumors, which may allow physicians to utilize radioligand-somatostatin analog PET CT/MR imaging to diagnose the PA. SSTR2 positivity, if shown to be clinically relevant, may allow peptide receptor radionuclide therapy in the future.
... 9 The SST was used for treatment of diseases like diabetes mellitus, acromegaly, pancreatic tumors, pancreatic cholera, acute variceal and acute ulcer hemorrhages, dumping syndrome, duodenal ulcer, Alzheimer's, and senile dementia. 10,11 The stomach is the most important organ affected by the foods consumed and can be damaged at varying rates depending on the type of food eaten. 12 Nowadays, studies have focused on substances with protective and therapeutic effects for the gastric mucosa. ...
This study aimed to investigate the effects of a high-fat and cholesterol diet (HFCD) on rats' gastric mucosa. In the study, a total of 16 (40-day-old Sprague Dawley) male rats were used and randomly divided into two groups (each consisted of eight rats). The rats in control group had no implementations other than normal feeding. For 10 weeks, rats in a high-fat with cholesterol diet group had daily energy amounts provided by pellet feed mixed with 65.00% butter and 2.00% cholesterol. Before beginning the study and at the end, rats live weight was recorded and their blood samples were taken for biochemical analyses. Hematoxylin and Eosin and Crossman's triple staining techniques were used to investigate the general structure of gastric tissue. The rats fed with HFCD had statistically significant increases in live weight and total cholesterol values, and were identified to have gastric tissue degeneration. The rats' gastric tissue in control group had more intense somatostatin (SST) immunoreactivity in parietal and chief cells than the HFCD group. It was determined that feeding with the HFCD has a negative effect on SST secretion in rats and hence, this may have important areas of use such as in gastric cancer treatment and preventing complications linked to gastric diseases.
... Somatostatin is produced by the body's enzymes and is found in many foods. [83] According to the FDA, Acromegaly and neuroendocrine tumors that express SSTRs are currently being treated using SSTR analogs. As a result of its strong affinity for the steroid hormone receptors 2 and 5, OCT was the first SST analog to be licensed to treat hormone-producing neuroendocrine tumors in the pituitary, pancreas, and intestine. ...
Neuroendocrine tumors (NET) form in the body's neuroendocrine system and are considered malignant; it takes years for most NETs to evolve, but not all. NETs are predominantly located in the lungs and the gastrointestinal tract; NETs in the lungs are carcinoid tumors. Treating these tumors is challenging, and therapeutic strategies have become priorities for researchers and clinicians. A neuroendocrine lung tumor is one such tumor that is very difficult to treat. To manage hormonal disorders caused by neuroendocrine tumors, somatostatin analogs are the gold standard. New data suggests that somatostatin analogs can be antiproliferative treatments for neuroendocrine tumors. Despite their apparent clinical interchangeability, comparative noninferiority studies between octreotide and lanreotide have not been conducted. Thus, it is where we look at different drug conjugates which act on the tumor. Radioligand, for example, is a promising model for Peptide Somatostatin receptors, typically more expressed on the surface of metastatic lung NETs.Consequently, a radioligand-based drug-peptide delivery is a particular target delivery method. Another type of drug conjugate is the novel technology named Peptide-drug conjugate (PDC) has made slow and steady progress in this treatment. PDC has the advantage of covalently altering a ligand peptide, which can target the specific cell surface receptors or biomarkers at the tumor site, exert a long-lasting function, and extend the effect of time, resulting in an overall desirable pharmacokinetic profile as a means of delivering anticancer drugs. Therefore, this review will summarize the recent technologies and anticancer agents that PDC used for the therapeutic efficiency and the intracellular uptake efficiency of active ingredients and receptors expressed on LU-NETs cells.
... Since the fact that SS has anti-proliferative and anti-angiogenic effects and given that its half-life is very short (1-3 min), as well as the wide spectrum of its biological responses, led to the need to develop selective stable receptor agonists that are bind strongly to selective SS receptor subtypes, therefore, in addition to blocking GH secretion (e.g., treatment of Acromegaly), these SS agonists are being used for the therapy of neuroendocrine tumors, diabetic complications (nephropathy, retinopathy), anti-neoplastic therapies. More recently, it has been shown that these agonists have anti-inflammatory and anti-nociceptive effects [25]. ...
Growth hormone (GH) performs very diverse functions in the organism, and this is the reason by which the regulation of the secretion of this hormone is very complex; although the primary regulators are growth hormone-releasing hormone (GHRH) and somatostatin, it is in turn regulated mainly by adrenergic and cholin-ergic pathways, and other factors can act directly on its secretion, particularly on the somatostatin, thus affecting the pituitary secretion of GH. In this chapter, we will analyze the transcription of GH gene and how GH release is affected by different neurotransmitters, metabolic substrates, feeding and fasting, and other hormones, placing special emphasis on why pituitary secretion of GH is sexually dimorphic.
... Thus, many analogues with better metabolic properties and longer halflives have been developed. [144][145][146] The physiologic actions of SST are mediated by 5 SST receptors (SSTRs; SSTR-1 to SSTR-5), which are widely expressed in the whole body. 145,147 The human retina produces abundant SST and its receptors, and the RPE is the primary source. ...
The ocular tissue microenvironment is immune-privileged and uses multiple immunosuppressive mechanisms to prevent the induction of inflammation. The retinal pigment epithelium plays an essential role in ocular immune privilege. In addition to serving as a blood barrier separating the fenestrated choriocapillaris from the retina, the retinal pigment epithelium is a source of immunosuppressive cytokines and membrane-bound negative regulators that modulate the activity of immune cells within the retina. This article reviews the current understanding of how retinal pigment epithelium cells mediate immune regulation, focusing on the changes under pathologic conditions.
... The GH is produced in a pulsatile fashion via somatotroph cells of the pituitary gland, where an imbalance of GH level in the body stimulates the hepatic secretion of insulin-like growth factor-1 (IGF-1) . Both of these hormones, GH and IGF-1, are further responsible for extra-somatic growth, which is a prominent characteristic of pituitary adenoma Rai et al., 2015). More than 90 % of pituitary cancer cases show abnormal growth of adenomas on the pituitary somatotroph cells (Leonart et al., 2018) occurring mostly in middle-age population and are also diagnosed with acromegaly (Winters et al., 2015). ...
Octreotide acetate (OA), a potent octapeptide, is used in the treatment of pituitary adenoma. An approach has been made in the present research to formulate an OA-loaded intranasal in situ gel (OA-ISG) to target pituitary adenoma. To achieve the objective of the present work, OA-ISG was fabricated using cold method, and further optimization was done by 3² factorial design. The optimized formulation was evaluated for gelation temperature, mucoadhesive strength, and % drug release (8 h), and the results were found to be 30.01 ± 0.4 °C, 40.12 ± 0.5 g, and 98.54 ± 0.45%, respectively. Brain availability of OA was determined through gamma scintigraphy, wherein Cmax for technetium (99mTC) labeled intranasal OA-ISG (99mTC-OA-ISG) was found to be 1.041% RA/g, and the findings for 99mTC-OA-Solution (intranasal) and 99mTC-OA-Solution (intravenous) were 0.395% and 0.164% RA/g, respectively. Consequently, a 3-10 fold increase in brain OA concentrations was observed upon intranasal administration (OA-ISG) as compared to others. Additionally, drug targeting index (100.13), targeting efficiency (10013%), and direct transport percentage (2564.1%) corroborate brain targeting of OA via intranasal route. Further, the cytotoxic potential of OA-ISG was screened on human pituitary tumor (GH3) cell lines using MTT assay. The IC50 value was found to be 9.5 μg/mL for OA-ISG, whereas it was 20.1 μg/mL for OA-Solution, thereby confirming the superior results of OA-ISG as compared to OA-Solution. Hence, the developed intranasal OA-ISG can be further explored for establishing its potential clinical safety, and as effective platform for targeted drug delivery to the brain in pituitary adenoma.
... Octreotide, a synthetic version of somatostatin with a comparatively longer half-life (approximately 1.7-1.9 hours) was explored as a possible treatment option for AP [76,78]. Overall, neither somatostatin nor octreotide is effective in the treatment of AP [79,80]. ...
Acute pancreatitis (AP), a complex inflammatory disease of the pancreas, is associated with increased morbidity and mortality. Currently, no specific therapies are approved for its treatment, and management is primarily based on supportive care. Despite enhanced understanding of AP pathogenesis, patients remain at significant risk owing to a lack of targeted drug treatments. Therefore, there is an urgent need for effective pharmacological therapeutic measures which may inhibit the early systemic inflammation, thereby preventing subsequent organ failure. This narrative review summarizes the available treatment options for AP and highlights the potential drug classes and pharmacologic therapies including those under clinical development. Although, several therapies targeting different aspects of AP pathogenesis have been investigated, some therapies with promising preclinical activity have been rendered ineffective in clinical trials. Other novel drug classes or molecules including dabigatran (anticoagulant), ulinastatin (protease inhibitor), infliximab (monoclonal antibody), spautin-A41 (autophagy inhibitor), and CM4620-Injectible Emulsion (calcium channel inhibitor) await further clinical assessment. Alternative treatment options using stem cells and nanoparticles are also being explored and may hold promise for AP therapy. However, challenges for exploring targeted treatment approaches include disease complexity, timing of therapeutic intervention, and establishing appropriate clinical endpoints. Understanding the role of specific biomarkers may help in identifying appropriate targets for drug discovery and facilitate determining relevant clinical study endpoints to monitor disease severity and progression, thereby aiding in design of more precise therapies with improved clinical outcomes.
... A total of 20 patients received-on surgical indication -SOMATO, to reduce pancreatic secretions, and protect pancreaticoduodenal anastomosis. Besides reducing pancreatic secretions, SOMATO also induces a mesenterial vasoconstriction [30]. PVF is determined by the outflow of blood from the mesenteric organs and as a result, SOMATO treated patients were shown to have a lower PVF [31,32]. ...
Abstract Background Norepinephrine (NE) is a α1-adrenergic mediated vasopressor and a key player in the treatment of perioperative hypotension. Apart from modulating systemic hemodynamics, NE may also affect regional blood flow, such as the hepatic circulation, which contains a wide variety of adrenergic receptors. It may alter regional vascular tonus and hepatic blood flow (HBF) by reducing portal vein flow (PVF) or hepatic arterial flow (HAF). The aim of this study was to assess the effects of NE on HBF. Methods Patients scheduled for pancreaticoduodenectomy were included. All patients received standardized anesthetic care using propofol and remifentanil and were hemodynamically stabilized using a goal-directed hemodynamic strategy guided by Pulsioflex™. On surgical indication, somatostatin (SOMATO) was given to reduce pancreatic secretion. HBF measurements were performed using transit-time ultrasound (Medistim™). Baseline hemodynamic and HBF measurements were made after pancreatectomy, at T1. Afterwards, NE infusion was initiated to increase mean arterial pressure (MAP) by 10 – 20% of baseline MAP (T2) and by 20 – 30% of baseline MAP (T3). HBF and hemodynamic measurements were performed simultaneously at these three time-points. Results A total of 28 patients were analyzed. Administration of NE significantly increased MAP but had no effect on cardiac index. NE infusion reduced total HBF in all patients (p
... After the administration of JF, the level of gastrin was increased, which could stimulate the secretion of gastric acid, pepsin and trypsin (Zhao et al., 2011), promote the contraction of gastric antrum, increase the flow of gastric mucosa, and nourish the mucosa of gastrointestinal tract. The decrease of somatostatin content indicated that JF could reduce the inhibitory effect on gastric emptying and intestine peristalsis, enhance the secretion of gastric acid and pepsin, as well as the absorption of carbohydrates, amino acids and other nutrients in the small intestine (Rai et al., 2015;Schubert and Rehfeld, 2020). By reducing the white blood cell count and increasing lymphocyte ratio in the blood, JF were found to enhance immunity and relieve inflammation. ...
Jujube (Ziziphus jujuba Mill.) fruit (JF) is widely consumed as food in Asian countries due to its potential effects for human health. As a traditional Chinese medicine, JF is often used to treat anorexia, fatigue and loose stools caused by spleen deficiency syndromes in China, but the mechanism underlying this effect has not been thoroughly elucidated. In this study, a rat model of spleen deficiency syndromes was adopted to investigate the therapeutic effect of JF extract and its possible mechanism by metabolomics analyses of plasma and urine as well as the intestinal flora analysis. The results showed that the changes in plasma and urine metabolites caused by spleen deficiency were reversed after administration of JF, and these changed endogenous metabolites were mainly involved in retinol metabolism, pentose and glucuronate interconversions, nicotinate and niacinamide metabolism pathways. The 16S rDNA sequencing results showed that JF could regulate intestinal flora imbalance caused by spleen deficiency. The covariance analysis of intestinal flora structure and metabolome indicated that Aerococcus may be a candidate strain for predicting and treating the metabolic pathways of spleen deficiency and related disorders. In summary, it can be revealed that spleen deficiency, which alters metabolic profiles and the intestinal flora, could be alleviated effectively by JF extract.
... Other hallmarks of tumourigenesis, such as angiogenesis and cell migration, are also regulated by SST signalling. The VEGF plateletderived growth factor (PDGF), insulin-like growth factor, and basic fibroblast growth factor have been shown to enhance the neovascularization and cell growth of tumours [75][76][77][78]. On a cell signalling and functional level, SST and SSTR significantly inhibit hormonal secretion, cell cycle progression, angiogenesis, and cell migration. ...
Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group of tumours that can develop in various parts of the body, including the digestive system, lungs, and pituitary. NETs are usually slow growing, but they are often diagnosed in advanced stages and can display aggressive behaviour. The mortality rate of NETs is not outstandingly increased compared to other malignant tumours, even in the metastatic setting. One of the intrinsic properties of NETs is the expression of SSTRs that serve as drug targets for SST analogues (SSAs), which can delay tumour progression and downregulate hormone overproduction. Additionally, in many NETs, it has been demonstrated that the SSTR expression level provides a prognostic value in predicting a therapeutic response. Furthermore, higher a SSTR expression correlates with a better survival rate in NET patients. In recent studies, other epigenetic regulators affecting SST signalling or SSA–mTOR inhibitor combination therapy in NETs have been considered as novel strategies for tumour control. In conclusion, SST signalling is a relevant regulator of NET functionality. Alongside classical SSA treatment regimens, future advanced therapies and treatment modalities are expected to improve the disease outcomes and overall health of NET patients.
... More specifically, it may function as a neurotransmitter, a neuromodulator, an endocrine hormone, or a paracrine factor, while its role as a trophic factor has also been proposed [29,30]. Physiologically, its levels are very low due to its prompt deg-radation by ubiquitous peptidases [31]. It exists in two isoforms known as SRIF14 and SRIF28-SRIF standing for somatotropin release inhibitory peptide. ...
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and affects about 8% of cirrhotic patients, with a recurrence rate of over 50%. There are numerous therapies available for the treatment of HCC, depending on cancer staging and condition of the patient. The complexity of the treatment is also justified by the unique pathogenesis of HCC that involves intricate processes such as chronic inflammation, fibrosis, and multiple molecular carcinogenesis events. During the last three decades, multiple in vivo and in vitro experiments have used somatostatin and its analogs (SSAs) to reduce the proliferative and metastatic potential of hepatoma cells by inducing their apoptosis and reducing angiogenesis and the inflammatory component of HCC. Most experiments have proven successful, revealing several different pathways and mechanisms corresponding to the aforementioned functions. Moreover, a correlation between specific effects and expression of somatostatin receptors (SSTRs) was observed in the studied cells. Clinical trials have tested either somatostatin or an analog, alone or in combination with other drugs, to explore the potential effects on HCC patients, in various stages of the disease. While the majority of these clinical trials exhibited minor to moderate success, some other studies were inconclusive or even reported negative outcomes. A complete evaluation of the efficacy of somatostatin and SSAs is still the matter of intense debate, and, if deemed useful, these substances may play a beneficial role in the management of HCC patients.
... S omatostatin is a regulatory peptide that takes widely actions in endocrine, neuroendocrine, neuronal, smooth muscle, and immune cells (Rai et al., 2015;Olias et al., 2004). These actions include modulation of neurotransmission in the central and peripheral nervous system (Epelbaum et al., 1994), inhibition of hormone secretion by the pancreas and the pituitary, inhibition of exocrine secretion in the pancreas and the gastrointestinal tract, and regulation of smooth muscle contraction (De Martino et al., 2010). ...
... The main anti-secretory therapies currently used in clinic on patients with certain NETs and endocrine syndromes are the somatostatin analogues [48,49]. However, the impact of somatostatin analogues on pheochromocytoma-associated catecholamine hypersecretion has been poorly explored in vitro. ...
Increasingly common, neuroendocrine tumors (NETs) are regarded nowadays as neoplasms potentially causing debilitating symptoms and life-threatening medical conditions. Pheochromocytoma is a NET that develops from chromaffin cells of the adrenal medulla, and is responsible for an excessive secretion of catecholamines. Consequently, patients have an increased risk for clinical symptoms such as hypertension, elevated stroke risk and various cardiovascular complications. Somatostatin analogues are among the main anti-secretory medical drugs used in current clinical practice in patient with NETs. However, their impact on pheochromocytoma-associated catecholamine hypersecretion remains incompletely explored. This study investigated the potential efficacy of octreotide and pasireotide (SOM230) on human tumor cells directly cultured from freshly resected pheochromocytomas using an implemented catecholamine secretion measurement by carbon fiber amperometry. SOM230 treatment efficiently inhibited nicotine-induced catecholamine secretion both in bovine chromaffin cells and in human tumor cells whereas octreotide had no effect. Moreover, SOM230 specifically decreased the number of exocytic events by impairing the stimulation-evoked calcium influx as well as the nicotinic receptor-activated inward current in human pheochromocytoma cells. Altogether, our findings indicate that SOM230 acts as an inhibitor of catecholamine secretion through a mechanism involving the nicotinic receptor and might be considered as a potential anti-secretory treatment for patients with pheochromocytoma.
... ; https://doi.org/10.1101/2021.09.10.459853 doi: bioRxiv preprint 11 minutes in plasma (for SST) 34 , and ~20 mins in brain cerebrospinal fluid (CSF, oxytocin and vasopressin) 35 . With these transport parameters, we calculated the time for the released neuropeptide to diffuse and reach the threshold concentration (C t , Equation 2) and peak concentration (Equation 4) at different distances. ...
Neuropeptides are essential signaling molecules in the nervous system involved in modulating neural circuits and behavior. Although hypothesized to signal via volume transmission through G-protein coupled receptors (GPCR), remarkably little is known about their extrasynaptic diffusion. Here, we developed an all-optical approach to probe neuropeptide volume transmission in mouse neocortex. To control neuropeptide release, we engineered photosensitive nanovesicles with somatostatin-14 (SST) that is released with near-infrared light stimulation. To detect SST, we created a new cell-based neurotransmitter fluorescent engineered reporter (CNiFER) using the SST2 GPCR. Under two-photon imaging, we determined the time to activate SST2R at defined distances as well as the maximal distance and loss rate for SST volume transmission in neocortex. Importantly, we determined that SST transmission is significantly faster in neocortex with a chemically degraded extracellular matrix, a diseased condition indicated in neuroinflammation and Parkinson′s disease. These new neurotechnologies can reveal important biological signaling processes previously not possible, and provide new opportunities to investigate volume transmission in the brain.
... Die in grün dargestellten Aminosäuren befinden sich im sog. β-turn des Sst und beschreiben das Pharmakophor des Peptids [modifiziert nach Rai et al. 2015, mit Genehmigung vom 18.05.2021]. ...
Intratumorale Heterogenität (ITH) kommt bei allen Tumorentitäten vor und resultiert aus der für Tumoren charakteristischen genomischen Instabilität. Diese genomische Instabilität ist einer der Hauptgründe für den krebsassoziierten Tod von Patienten und ist zudem generelles Charakteristikum für malignes (bösartiges) Wachstum von Tumoren. Die ITH kann sowohl bei „low stage“ Primärtumoren als auch bei hoch differenzierten metastasierenden „high stage“ Tumoren beobachtet werden.
Aus dieser intratumoralen Heterogenität resultieren ferner massive Schwierigkeiten bei der Behandlung von Tumorerkrankungen durch die Entstehung von Therapieresistenzen. Im Falle der neuroendokrinen Tumoren konnte festgestellt werden, dass diese ITH im Zusammenhang mit der spezifischen Expression unterschiedlicher Rezeptoren steht und dabei abhängig vom Tumorstadium die Rezeptorexpression stark variiert. In diesem Fall handelt es sich um den humanen Somatostatinrezeptor (Subtyp-2) (hSst2-R) und den humanen glukoseabhängigen insulinotropen Peptidrezeptor (engl. gastric inhibitory polypetide receptor, kurz, hGIP-R). In der Literatur wird beschrieben, dass in 88 % der Fälle eines Somatostatinrezeptor-negativen (hSst2-R-negativen) Tumors hingegen der hGIP-Rezeptor in überexprimierter Form vorliegt.
Ziel dieser Dissertation war es daher, im Rahmen der Tumorentität der neuroendokrinen Tumoren ein Radiopharmakon zu entwickeln, mit welchem sich der hSst2- und zugleich der hGIP-Rezeptor adressieren lässt. Hierfür wurden zunächst zwei stabil transfizierte Zelllinien etabliert, welche zum einen den Somatostatin- und zum anderen den hGIP-Rezeptor überexprimieren. Für die Herstellung der peptidbasierten Radiopharmaka wurde ein vollautomatischer Peptidsynthesizer qualifiziert, mit welchem die unterschiedlichen Somatostatin- und hGIP-R-Analoga synthetisiert wurden. Dadurch, dass im heterobivalenten Konstrukt sowohl das hSst2-R- als auch das hGIP-R-Bindemotiv enthalten sein sollen, wurden im ersten Schritt unterschiedliche hSst2-R-Analoga synthetisiert. Durch deren spezifischen Modifikationen sollten die pharmakologischen Eigenschaften sowohl des Monomers (im Vergleich zu [68Ga]Ga-DOTA-TATE(Tyr3)), als auch als Bestandteil des heterobivalenten Endprodukts verbessert werden. Im zweiten Schritt wurden anhand eines Alanine Walk die für die Rezeptorbindung kritischen Aminosäuren des GIP(1-30)-NH2-Analogon ausfindig gemacht. Die daraus gewonnenen Erkenntnisse sollten dafür verwendet werden, die pharmakologischen Eigenschaften des GIP(1-30)-NH2 in weiterführenden Versuchen, sowohl für das Monomer, als auch als Bestandteil des heterobivalenten Konstrukts zu verbessern. Im letzten Schritt der Arbeit sollten beide Rezeptorbindemotive (für hSst2-R und hGIP-R) miteinander verbunden werden, mit dem Ziel beide Rezeptoren spezifisch zu binden.
... Such radiopharmaceuticals have been used for imaging neuroendocrine tumors (NETs) by targeting somatostatin receptors (SSTRs), which are characteristically over-expressed on the cell surfaces of these tumor types [52]. Since the endogenous ligand somatostatin has a very short biological t1/2, unsuitable for clinical applications (<3 min), analogues have been produced that have better pharmacological characteristics [53][54][55]. These targeting vectors are often derivatives of the somatostatin analogue octreotide, which has a considerably high affinity for the highly expressed subtype SSTR2 and a more applicable t1/2 of ~72-98 min. ...
The incorporation of silicon fluoride acceptor (SiFA) moieties into a variety of molecules, such as peptides, proteins and biologically relevant small molecules, has improved the generation of 18 F-radiopharmaceuticals for medical imaging. The efficient isotopic exchange radiofluorination process, in combination with the enhanced [ 18 F]SiFA in vivo stability, make it a suitable strategy for fluorine-18 incorporation. This review will highlight the clinical applicability of [ 18 F]SiFA-labeled compounds and discuss the significant radiotracers currently in clinical use.
Objectives:
To explore the effects of somatostatin on the levels of gastrointestinal hormones and clinical outcomes in critically ill infants after gastrointestinal surgery.
Methods:
Using a random number table method, critically ill infants after gastrointestinal surgery who were admitted to the Intensive Care Unit of Xuzhou Children's Hospital from June 2019 to June 2021 were randomly divided into an observation group (29 cases) and a control group (30 cases). The control group received routine treatment such as anti-infection and hemostasis after surgery, while the observation group received somatostatin in addition to the routine treatment [3.5 μg/(kg·h) infusion for 7 days]. The levels of serum gastrin (GAS), motilin (MTL), insulin, and glucagon-like peptide-1 (GLP-1) before surgery, on the 3rd day after surgery, and on the 7th day after surgery were compared between the two groups. The recovery progress and incidence of complications after surgery were also compared between the two groups.
Results:
There was no significant difference in the levels of serum GAS, MTL, insulin, and GLP-1 between the two groups before surgery (P>0.05). On the 3rd and 7th day after surgery, the levels of serum GAS, MTL, insulin, and GLP-1 in the observation group were higher than those in the control group (P<0.05). In the observation group, the levels of GAS, MTL, insulin, and GLP-1 on the 7th day after surgery were higher than those before surgery and on the 3rd day after surgery (P<0.05), and the levels on the 3rd day after surgery were higher than those before surgery (P<0.05). There was no significant difference in the levels of serum GAS, MTL, and insulin before surgery, on the 3rd day after surgery, and on the 7th day after surgery in the control group (P>0.05). The level of GLP-1 on the 7th day after surgery was higher than that before surgery and on the 3rd day after surgery (P<0.05), and the level on the 3rd day after surgery was higher than that before surgery (P<0.05) in the control group. The observation group had shorter first time of anal exhaust, recovery time of bowel sounds, and first time of defecation after surgery compared to the control group (P<0.05). The incidence of complications after surgery in the observation group was lower than that in the control group (10% vs 33%, P<0.05).
Conclusions:
Somatostatin can increase the levels of serum GAS, MTL, insulin, and GLP-1 in critically ill infants after gastrointestinal surgery, promote the recovery of gastrointestinal function, and reduce the incidence of postoperative complications.
Recent studies suggest that disruptions in intestinal homeostasis, such as changes in gut microbiota composition, infection, and inflammatory-related gut diseases, can be associated with kidney diseases. For instance, genomic investigations highlight how susceptibility genes linked to IgA nephropathy are also correlated with the risk of inflammatory bowel disease. Conversely, investigations demonstrate that the use of short-chain fatty acids, produced through fermentation by intestinal bacteria, protects kidney function in models of acute and chronic kidney diseases. Thus, the dialogue between the gut and kidney seems to be crucial in maintaining their proper function, although the factors governing this crosstalk are still emerging as the field evolves. In recent years, a series of studies have highlighted the significance of enteroendocrine cells (EECs) which are part of the secretory lineage of the gut epithelial cells, as important components in gut-kidney crosstalk. EECs are distributed throughout the epithelial layer and release more than 20 hormones in response to microenvironment stimuli. Interestingly, some of these hormones and/or their pathways such as Glucagon-Like Peptide 1 (GLP-1), GLP-2, gastrin, and somatostatin have been shown to exert renoprotective effects. Therefore, the present review explores the role of EECs and their hormones as regulators of gut-kidney crosstalk and their potential impact on kidney diseases. This comprehensive exploration underscores the substantial contribution of EEC hormones in mediating gut-kidney communication and their promising potential for the treatment of kidney diseases.
Decades of published research supports a role for growth hormone (GH) in cancer. Accordingly, there is increasing interest in targeting GH in oncology, with GH antagonists exhibiting efficacy in xenograft studies as single agents and in combination with anticancer therapy or radiation. Here we discuss challenges associated with using growth hormone receptor (GHR) antagonists in preclinical models and considerations for translation, such as the identification of predictive biomarkers for selecting patients and for monitoring drug efficacy. Ongoing research will determine whether suppressing GH signalling pharmacologically will also reduce the risk of developing cancer. An increase in GH-targeted drugs in preclinical development will ultimately provide researchers with new tools to test anti-cancer efficacy of blocking the GH signalling pathway in preclinical models.
Neuropeptides are a highly diverse group of signaling molecules found in the central nervous system (CNS) and peripheral organs, including the enteric nervous system (ENS). Increasing efforts have been focused on dissecting the role of neuropeptides in both neural- and non-neural-related diseases, as well as their potential therapeutic value. In parallel, accurate knowledge on their source of production and pleiotropic functions is still needed to fully understand their implications in biological processes. This review will focus on the analytical challenges involved in studying neuropeptides, particularly in the ENS, a tissue where their abundance is low, together with opportunities for further technical development.
Protein-protein interactions (PPIs) play vital roles in normal cellular processes. Dysregulated PPIs are involved in the process of various diseases, including cancer. Thus, these PPIs may serve as potential therapeutic targets in cancer treatment. However, despite rapid advances in small-molecule drugs and biologics, it is still hard to target PPIs, especially for those intracellular PPIs. Macrocyclic peptides have gained growing attention for their therapeutic properties in targeting dysregulated PPIs. Macrocyclic peptides have some unique features, such as moderate sizes, high selectivity, and high binding affinities, which make them good drug candidates. In addition, some oncology macrocyclic peptide drugs have been approved by the US Food and Drug Administration (FDA) for clinical use. Here, we reviewed the recent development of macrocyclic peptides in cancer treatment. The opportunities and challenges were also discussed to inspire new perspectives.
Peptides are emerging as a promising candidate for therapeutic as well as diagnostic applications within the domain of clinical and scientific research. They are recognized for being highly selective, sensitive and efficacious with minimal or no toxicity. Small size, non-immunogenicity, ease of synthesis and huge scope of modification are some of the well-established properties of peptides, which make them an excellent alternative to not only small drug molecules but also to protein-based biopharmaceuticals such as antibodies and enzymes. The attractive pharmacological profile and intrinsic properties of peptides also make them an interesting diagnostic tool for imaging at the molecular and cellular levels. Molecular imaging coupled with targeted therapy using peptides as theranostics is a two-edged sword. Besides, traditional peptide formats, multifunctional newer peptide designs with improved pharmacokinetics and targetability are also being explored presently. In this review, we come up with a comprehensive summary of the latest progress on peptides and their potential applications in therapeutics and diagnosis for infectious and non-infectious diseases. The last part of the review discusses suitable carrier systems for the delivery of peptides along with highlighting the future challenges.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by loss of neurons and synapses. The aim of this study was to investigate the effect of somatostatin analogue Vapreotide in an in vitro Alzheimer’s model and its effects based on the relationship between somatostatinergic transmission and neurodegenerative functions. In this study, tau transfection was performed using the MAPT gene cloned into the pcDNA3.1 vector and transfection reagent into the SH-SY5Y cell line. In viability experiments using 10 µM Memantine as a positive control, it was observed that Vapreotide at 50 µM (p < 0.0001) and 100 µM (p < 0.05) had a protective effect on cell viability, 100 µM CYN154806 was found to decrease (p < 0.05) cell viability. It was determined that Vapreotide, decreased the expression levels (50 µM-p < 0.001; 100 µM-p < 0.001; 200 µM-p < 0.0001) and phosphorylation of Tau and p-Tau proteins by western blots. With the qRT-PCR method, it was found that Vapreotide, decreased the BAX/BCL2 (50 µM-p < 0.001; 100 µM-p < 0.01; 200 µM-p < 0.001) expression level and decreased the expression level (50 µM-p < 0.01; 100 µM-p < 0.01; 200 µM-p < 0.001) of the APOE4 gene, which constitutes a genetic risk for AD. This study demonstrates a potential therapeutic role for a somatostatin analogue Vapreotide in Alzheimer’s disease.
Targeting protein–protein interactions for modulation of key disease targets requires a fine balance between selectivity for large interaction surfaces, stability and cell permeability. Traditional small molecule therapeutics are frequently limited by their toxicity due to either unintended interactions (e.g., low selectivity) or production of toxic metabolites and are also not well-suited for targeting PPIs since the corresponding interacting surfaces are relatively large and flat without pockets suitable to bind small molecules with high affinity. On the other hand, protein and antibody therapeutics have been limited by poor cell permeability as well as complex and expensive production. Peptides and especially peptidomimetics (modified peptides, such as cyclic peptides) can be used to overcome many of these limitations and hold great promise for pharmaceutical research and development, with successful drugs already approved. Peptides can be identified from naturally occurring molecules, library screening, and/or rational design. Cyclization can be used to overcome selectivity and stability challenges and enhance pharmacokinetic and pharmacodynamic properties. Several approaches to cyclization have been developed, including backbone cyclization, which we focus on in this chapter. Backbone cyclization preserves side chains that are often critical for biological functionality in a feasible solid-phase peptide synthesis approach via reaction with peptide backbone atoms. Diversity of backbone building blocks and bridge chemistries combined with the cycloscan focused library screening technique allows identification of potent, selective, stable, and cell-permeable cyclic peptidomimetic molecules. Herein, we review and critique applications of backbone cyclic peptidomimetics to neuropeptide, peptide hormone, and protein mimetic drug discovery.
In this chapter we discuss oral peptide delivery from a biopharmaceutics perspective to help understand how peptides and formulations can be designed to induce flux across the intestinal barrier in order to achieve systemic exposure. Considerable efforts have gone into understanding developability of small molecule compounds for oral delivery. We aim to extend these considerations to peptide candidates to help guide selection of chemical matter and formulations.
Les cellules neuroendocrines sécrètent des hormones et des neuropeptides par un processus d'exocytose régulé par le calcium. Malheureusement, toutes les cellules neuroendocrines de l'organisme peuvent se transformer en cellules tumorales et potentiellement engendrer un cancer. Bien que constituant un groupe très hétérogène, les tumeurs neuroendocrines possèdent une caractéristique commune intéressante qui est un dysfonctionnement de leur activité sécrétrice entraînant, dans la majorité des cas, une hypersécrétion des hormones et peptides qu'elles stockent. Cette sécrétion anarchique pose problème car elle peut engendrer des conséquences cliniques graves chez les patients. À ce jour, les mécanismes moléculaires qui induisent et maintiennent l’hypersécrétion de ces tumeurs ne sont pas connus et il n’existe aucune thérapie ciblée permettant de l’empêcher. Mes travaux de thèse montrent que l’hypersécrétion du phéochromocytome est la conséquence directe d’un dérèglement des phases tardives de l’exocytose et qu’un traitement par le pasiréotide, un analogue de la somatostatine inhibe efficacement l’hypersécrétion.
Despite the obvious differences in the pathophysiology of distinct neuropsychiatric diseases or neurodegenerative disorders, some of them share some general but pivotal mechanisms, one of which is the disruption of excitation/inhibition balance. Such an imbalance can be generated by changes in the inhibitory system, very often mediated by somatostatin-containing interneurons (SOM-INs). In physiology, this group of inhibitory interneurons, as well as somatostatin itself, profoundly shapes the brain activity, thus influencing the behavior and plasticity; however, the changes in the number, density and activity of SOM-INs or levels of somatostatin are found throughout many neuropsychiatric and neurological conditions, both in patients and animal models. Here, we (1) briefly describe the brain somatostatinergic system, characterizing the neuropeptide somatostatin itself, its receptors and functions, as well the physiology and circuitry of SOM-INs; and (2) summarize the effects of the activity of somatostatin and SOM-INs in both physiological brain processes and pathological brain conditions, focusing primarily on learning-induced plasticity and encompassing selected neuropsychological and neurodegenerative disorders, respectively. The presented data indicate the somatostatinergic-system-mediated inhibition as a substantial factor in the mechanisms of neuroplasticity, often disrupted in a plethora of brain pathologies.
Objective
Subcutaneous injections of octreotide acetate require chronic administration by healthcare providers (HCPs). We aimed to validate the safe and effective use of the octreotide acetate pen injector, its labelling, and instructions for use (IFU) by patients, caregivers, and HCPs and mitigation of use-related risks.
Methods
This summative human factors validation study enrolled adults with neuroendocrine tumors and related diarrhea or flushing, adult caregivers, and HCPs. Prior to simulated use, participants self-familiarized as they desired. Each participant was assigned 1 injection site for administration into an injection pad. The first of 2 unaided injections assessed first use and required priming; the second assessed routine use and dose change. Participants gave subjective feedback after each injection and completed knowledge probes and reading comprehension questions after the second injection.
Results
The study enrolled 45 participants (15/group). Forty-two participants completed the first injection successfully by administering the dose correctly. Three participants did not successfully dose; 3 failed to prime the pen and 1 also failed to dial the correct dose. Unrelated to dosing, 2 participants failed to remove the needle after injection. Forty-four participants completed the second injection–1 participant failed to dial the correct dose. No other errors were observed. Overall success rates on knowledge probes and reading comprehension questions were 99.1% and 99.6%, respectively. All participants found the IFU easy to follow and understand.
Conclusion
The octreotide acetate pen injector, labelling, and IFU enabled intended users to administer subcutaneous octreotide safely and effectively. The residual risks of use are low and acceptable.
Hormonal drugs are essential treatment options for some hormone-dependent or hormone-sensitive tumors. The common dosage forms of hormonal drugs have a short half-life. Hence, frequent administration is needed, which results in poor patient compliance. Nevertheless, using drug delivery technology, somatostatin analogues (SSAs) and gonadotropin-releasing hormone (GnRH) analogues are prepared into long-acting formulations that can significantly prolong the action time of these drugs, reducing medication frequency and increasing patient compliance. Such drugs are advantageous when treating acromegaly, gastroenteropancreatic neuroendocrine tumors (GEP-NETs), breast cancer, prostate cancer, and other diseases having a relatively long course. SSAs and GnRH analogues are two typical hormonal drugs, the long-acting formulations of which are essential in clinical practice. This review summarized the preparation methods and clinical application of long-acting formulations in cancer. Further, the action mechanism and new research of SSAs and GnRH analogues were discussed, and suggestions related to the development of long-acting SSAs and GnRH analogues were provided.
Objective:
Liver cirrhosis is a common, often progressive, and usually fatal disorder. Upper gastrointestinal bleeding is a leading cause of death in patients with liver cirrhosis. The purpose of this study was to evaluate the effectiveness of somatostatin combined with restricted fluid resuscitation in the treatment of upper gastrointestinal bleeding in the patients with liver cirrhosis.
Methods:
From January 2018 to December 2020, 84 patients with liver cirrhosis complicated by upper gastrointestinal bleeding admitted to the Department of Gastroenterology of Ningbo Yinzhou No. 2 Hospital were selected as study participants. They were randomly assigned into the study group (n = 42) and control group (n = 42). All patients were given intravenous drip of somatostatin. The study group was supplemented with restricted fluid resuscitation therapy. The hemoglobin (Hb), platelet, fibrinogen, hematocrit, transfusion volume of red blood cells, hemostatic time, hemostatic rates in 0 h-24 h, 24 h-48 h, and >48 h, rebleeding rates, resuscitation rate, and incidence rates of complications were compared between the two groups 48 h after treatment.
Results:
It was found that the Hb, platelet, fibrinogen, and hematocrit were notably increased in the study group compared to the control group 48 h after treatment (P < 0.01). The proportion of patients with excellent response was notably higher in the study group than in the control group (P < 0.05). The overall response rate of the study group was 90.48%, which was significantly higher than 71.43% in the control group (P < 0.05). The study group had lower transfusion volume of red blood cells, shorter hemostatic time, and lower rebleeding rates than the control group (P < 0.01). The hemostatic rate of 0 h-24 h in the study group was remarkably higher than that in the control group (P < 0.05). The hemostatic rate of >48 h in the study group was lower than that in the control group (P < 0.05). The overall incidence rate of complications in the study group was 9.52%, which was significantly lower than 30.95% in the control group (P < 0.05).
Conclusion:
These data suggest that intravenous drip of somatostatin followed by restricted fluid resuscitation leads to a better clinical efficacy in treating upper gastrointestinal bleeding in patients with liver cirrhosis considering higher resuscitation rate and hemostatic rate and reduced incidence of complications, which is conducive to the recovery of patients and worthy of further clinical promotion.
Blood glucose homeostasis requires proper function of pancreatic islets, which secrete insulin, glucagon, and somatostatin from the β-, α-, and δ-cells, respectively. Each islet cell type is equipped with intrinsic mechanisms for glucose sensing and secretory actions, but these intrinsic mechanisms alone cannot explain the observed secretory profiles from intact islets. Regulation of secretion involves interconnected mechanisms among and between islet cell types. Islet cells lose their normal functional signatures and secretory behaviors upon dispersal as compared to intact islets and in vivo. In dispersed islet cells, the glucose response of insulin secretion is attenuated from that seen from whole islets, coordinated oscillations in membrane potential and intracellular Ca2+ activity, as well as the two-phase insulin secretion profile, are missing, and glucagon secretion displays higher basal secretion profile and a reverse glucose-dependent response from that of intact islets. These observations highlight the critical roles of intercellular communication within the pancreatic islet, and how these communication pathways are crucial for proper hormonal and nonhormonal secretion and glucose homeostasis. Further, misregulated secretions of islet secretory products that arise from defective intercellular islet communication are implicated in diabetes. Intercellular communication within the islet environment comprises multiple mechanisms, including electrical synapses from gap junctional coupling, paracrine interactions among neighboring cells, and direct cell-to-cell contacts in the form of juxtacrine signaling. In this article, we describe the various mechanisms that contribute to proper islet function for each islet cell type and how intercellular islet communications are coordinated among the same and different islet cell types. © 2021 American Physiological Society. Compr Physiol 11:2191-2225, 2021.
The growth hormone–insulin-like growth factor–insulin-like growth factor binding protein (GH–IGF–IGFBP) axis plays a critical role in the maintenance of normal renal function and the pathogenesis and progression of chronic kidney disease (CKD). Serum IGF-I and IGFBPs are altered with different stages of CKD, the speed of onset, the amount of proteinuria, and the potential of remission. Recent studies demonstrate that growth failure in children with CKD is due to a relative GH insensitivity and functional IGF deficiency. The functional IGF deficiency in CKD results from either IGF resistance due to increased circulating levels of IGFBPs or IGF deficiency due to increased urinary excretion of serum IGF–IGFBP complexes. In addition, not only GH and IGFs in circulation, but locally produced IGFs, the high-affinity IGFBPs, and low-affinity insulin-like growth factor binding protein-related proteins (IGFBP-rPs) may also affect the kidney. With respect to diabetic kidney disease, there is growing evidence suggesting that GH, IGF-I, and IGFBPs are involved in the pathogenesis of diabetic nephropathy (DN). Thus, prevention of GH action by blockade either at the receptor level or along its signal transduction pathway offers the potential for effective therapeutic opportunities. Similarly, interrupting IGF-I and IGFBP actions also may offer a way to inhibit the development or progression of DN. Furthermore, it is well accepted that the systemic inflammatory response is a key player for progression of CKD, and how to prevent and treat this response is currently of great interest. Recent studies demonstrate existence of IGF-independent actions of high-affinity and low-affinity-IGFBPs, in particular, antiinflammatory action of IGFBP-3 and profibrotic action of IGFBP-rP2/CTGF. These findings reinforce the concept in support of the clinical significance of the IGF-independent action of IGFBPs in the assessment of pathophysiology of kidney disease and its therapeutic potential for CKD. Further understanding of GH–IGF–IGFBP etiopathophysiology in CKD may lead to the development of therapeutic strategies for this devastating disease. It would hold promise to use of GH, somatostatin analogs, IGFs, IGF agonists, GHR and insulin-like growth factor-I receptor (IGF-IR) antagonists, IGFBP displacer, and IGFBP antagonists as well as a combination treatment as therapeutic agents for CKD.
The present study examined nociceptive behaviors and the expression of phosphorylated cAMP response element-binding protein (pCREB) in the dorsal horn of the lumbar spinal cord and the dorsal root ganglion (DRG) evoked by bee venom (BV). The effect of intraplantar preapplication of the somatostatin analog octreotide on nociceptive behaviors and pCREB expression was also examined. Subcutaneous injection of BV into the rat unilateral hindpaw pad induced significant spontaneous nociceptive behaviors, primary mechanical allodynia, primary thermal hyperalgesia, and mirror-thermal hyperalgesia, as well as an increase in pCREB expression in the lumbar spinal dorsal horn and DRG. Octreotide pretreatment significantly attenuated the BV-induced lifting/licking response and mechanical allodynia. Local injection of octreotide also significantly reduced pCREB expression in the lumbar spinal dorsal horn and DRG. Furthermore, pretreatment with cyclosomatostatin, a somatostatin receptor antagonist, reversed the octreotide-induced inhibition of the lifting/licking response, mechanical allodynia, and the expression of pCREB. These results suggest that BV can induce nociceptive responses and somatostatin receptors are involved in mediating the antinociception, which provides new evidence for peripheral analgesic action of somatostatin in an inflammatory pain state.
Context:
Biochemical control reduces morbidity and increases life expectancy in patients with acromegaly. With current medical therapies, including the gold standard octreotide long-acting-release (LAR), many patients do not achieve biochemical control.
Objective:
Our objective was to demonstrate the superiority of pasireotide LAR over octreotide LAR in medically naive patients with acromegaly.
Design and setting:
We conducted a prospective, randomized, double-blind study at 84 sites in 27 countries.
Patients:
A total of 358 patients with medically naive acromegaly (GH >5 μg/L or GH nadir ≥1 μg/L after an oral glucose tolerance test (OGTT) and IGF-1 above the upper limit of normal) were enrolled. Patients either had previous pituitary surgery but no medical treatment or were de novo with a visible pituitary adenoma on magnetic resonance imaging.
Interventions:
Patients received pasireotide LAR 40 mg/28 days (n = 176) or octreotide LAR 20 mg/28 days (n = 182) for 12 months. At months 3 and 7, titration to pasireotide LAR 60 mg or octreotide LAR 30 mg was permitted, but not mandatory, if GH ≥2.5μg/L and/or IGF-1 was above the upper limit of normal.
Main outcome measure:
The main outcome measure was the proportion of patients in each treatment arm with biochemical control (GH <2.5 μg/L and normal IGF-1) at month 12.
Results:
Biochemical control was achieved by significantly more pasireotide LAR patients than octreotide LAR patients (31.3% vs 19.2%; P = .007; 35.8% vs 20.9% when including patients with IGF-1 below the lower normal limit). In pasireotide LAR and octreotide LAR patients, respectively, 38.6% and 23.6% (P = .002) achieved normal IGF-1, and 48.3% and 51.6% achieved GH <2.5 μg/L. 31.0% of pasireotide LAR and 22.2% of octreotide LAR patients who did not achieve biochemical control did not receive the recommended dose increase. Hyperglycemia-related adverse events were more common with pasireotide LAR (57.3% vs 21.7%).
Conclusions:
Pasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option for acromegaly.
Somatostatin (SST) and some of its receptor subtypes have been implicated in pain signaling at the spinal level. In this study we have investigated the role of SST and its sst2A receptor (sst2A) in dorsal root ganglia (DRGs) and spinal cord.
SST and sst2A protein and sst2 transcript were found in both mouse and human DRGs, sst2A-immunoreactive (IR) cell bodies and processes in lamina II in mouse and human spinal dorsal horn, and sst2A-IR nerve terminals in mouse skin. The receptor protein was associated with the cell membrane. Following peripheral nerve injury sst2A-like immunoreactivity (LI) was decreased, and SST-LI increased in DRGs. sst2A-LI accumulated on the proximal and, more strongly, on the distal side of a sciatic nerve ligation. Fluorescence-labeled SST administered to a hind paw was internalized and retrogradely transported, indicating that a SST-sst2A complex may represent a retrograde signal. Internalization of sst2A was seen in DRG neurons after systemic treatment with the sst2 agonist octreotide (Oct), and in dorsal horn and DRG neurons after intrathecal administration. Some DRG neurons co-expressed sst2A and the neuropeptide Y Y1 receptor on the cell membrane, and systemic Oct caused co-internalization, hypothetically a sign of receptor heterodimerization. Oct treatment attenuated the reduction of pain threshold in a neuropathic pain model, in parallel suppressing the activation of p38 MAPK in the DRGs CONCLUSIONS: The findings highlight a significant and complex role of the SST system in pain signaling. The fact that the sst2A system is found also in human DRGs and spinal cord, suggests that sst2A may represent a potential pharmacologic target for treatment of neuropathic pain.
Although it is becoming accepted that neuroretinal cells are also affected in diabetes, vascular lesions continue to be considered as the hallmarks of diabetic retinopathy. Animal models are essential for the understanding and treatment of human diabetic retinopathy, and the mouse is intensively used as a model because of its similarity to human and the possibility to be genetically modified. However, until today not all retinal vascular lesions developed in diabetic patients have been reproduced in diabetic mice, and the reasons for this are not completely understood. In this review, we will summarize retinal vascular lesions found in diabetic and diabetic-like mouse models and its comparison to human lesions. The goal is to provide insights to better understand human and mice differences and thus, to facilitate the development of new mouse models that mimic better human diabetic retinopathy.
Pasireotide has a broader somatostatin receptor binding profile than other somatostatin analogues. A 16-week, Phase II trial showed that pasireotide may be an effective treatment for acromegaly. An extension to this trial assessed the long-term efficacy and safety of pasireotide. This study was an open-label, single-arm, open-ended extension study (primary efficacy and safety evaluated at month 6). Patients could enter the extension if they achieved biochemical control (GH ≤ 2.5 μg/L and normal IGF-1) or showed clinically relevant improvements during the core study. Thirty of the 60 patients who received pasireotide (200–900 μg bid) in the core study entered the extension. At extension month 6, of the 26 evaluable patients, six were biochemically controlled, of whom five had achieved control during the core study. Normal IGF-1 was achieved by 13/26 patients and GH ≤ 2.5 μg/L by 12/26 at month 6. Nine patients received pasireotide for ≥24 months in the extension; three who were biochemically controlled at month 24 had achieved control during the core study. Of 29 patients with MRI data, nine had significant (≥20 %) tumor volume reduction during the core study; an additional eight had significant reduction during the extension. The most common adverse events were transient gastrointestinal disturbances; hyperglycemia-related events occurred in 14 patients. Twenty patients had fasting plasma glucose shifted to a higher category during the extension. However, last available glucose measurements were normal for 17 patients. Pasireotide has the potential to be an effective, long-term medical treatment for acromegaly, providing sustained biochemical control and significant reductions in tumor volume.
Electronic supplementary material
The online version of this article (doi:10.1007/s11102-013-0478-0) contains supplementary material, which is available to authorized users.
Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Somatostatin (SST) is an endogenous neuroprotective peptide which is downregulated in the diabetic eye. The aim of the study was to test the usefulness of topical administration of SST in preventing retinal neurodegeneration. For this purpose, streptozotocin-induced diabetic rats (STZ-DM) were treated with either SST eye-drops or vehicle for 15 days. Non-diabetic rats treated with vehicle served as control group. Functional abnormalities were assessed by electroretinography (ERG) and neurodegeneration was assessed by measuring glial activation and the apoptotic rate. In addition, proapoptotic (FasL, Bid, and activation of caspase-8 and caspase-3) and survival signalling pathways (Bclxl) were examined. Intraretinal concentrations of glutamate and its main transporter GLAST (glutamate/aspartate transporter) were also determined. Treatment with SST eye drops prevented ERG abnormalities, glial activation, apoptosis and the misbalance between proapoptotic and survival signalling detected in STZ-DM rats. In addition, SST eye drops inhibited glutamate accumulation in the retina and GLAST downregulation induced by diabetes. We conclude that topical administration of SST has a potent effect in preventing retinal neurodegeneration induced by diabetes. In addition, our findings open up a new preventive pharmacological strategy targeted to early stages of DR.
The sst2 somatostatin receptor mediates the antiproliferative effects of somatostatin analogs. The present study demonstrates
that stable expression of sst2 in the hamster pancreatic cancer cells PC-1 and PC-1.0 activates an autocrine negative loop
leading to an in vitro inhibition of cell proliferation. In vivo studies conducted in Syrian golden hamsters after orthotopic implantation of PC-1.0 cells showed that both tumor growth and
metastatic progression of allografts containing 100% of sst2-expressing cells were significantly inhibited for up to 20 days
after implantation, as compared with control allografts that did not express sst2. A local antitumor bystander effect was
observed after induction of mixed tumors containing a 1:3 ratio of sst2-expressing cells to control cells. Tumor volume and
incidence of metastases of mixed tumors were significantly reduced at day 13 post implantation. This effect decreased with
time as at day 20, growth of mixed tumors was similar to that of control tumors. After administration of the cytotoxic somatostatin
conjugate AN-238 on day 13, antitumor bystander effect observed in mixed tumors was significantly extended to day 20. We also
observed that in vitro invasiveness of sst2-expressing PC-1.0 cells was significantly reduced. Tyrosine dephosphorylation of E-cadherin may participate
in restoring the E-cadherin function, reducing in turn pancreatic cancer cell motility and invasiveness. This dephosphorylation
depends on the tyrosine phosphatase src homology 2-containing tyrosine phosphatase 1 (SHP-1) positively coupled to sst2 receptor.
The inhibitory effect of sst2 gene expression on pancreatic cancer growth and invasion combined with chemotherapy with targeted
cytotoxic somatostatin analog administration provides a rationale for a therapeutic approach to gene therapy based on in vivo sst2 gene transfer.
Somatostatin is a peptide hormone found in the CNS and the gastrointestinal tract. It has the ability to modify a number of metabolic factors associated with food intake. The purpose of the 7 experiments reported here was to determine the effect of somatostatin on the intake of individual meals of 2 species, the rat (131 female Wistar, 20 male Wistar and Long Evans) and the baboon (4 male
Papio cynocephalus). In one set of experiments, Ss received somatostatin (10 ng–2 μg/kg) or a control solution ip. There was a dose-dependent decrease of food intake relative to vehicle-injected controls. In subsequent experiments, these doses had no effect on water intake and did not cause a conditioned taste aversion. Findings suggest that somatostatin acts relatively selectively on food intake and probably does not induce nausea or illness. The administration of somatostatin into cerebrospinal fluid had no effect on food intake. Therefore, somatostatin apparently works peripherally to reduce food intake in both rats and baboons. (46 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
A membrane-associated form of Raf-1 in v-Ras transformed NIH 3T3 cells can be inactivated by protein phosphatases regulated
by GTP. Herein, a distinct protein-tyrosine phosphatase (PTPase) in membrane preparations from v-Ras transformed NIH 3T3 cells
was found to be activated by guanyl-5′-yl imidodiphosphate (GMPPNP) and was identified as an effector for pertussis toxin
(PTx)-sensitive G-protein α subunits. PTPase activation was blocked by prior treatment of cells with PTx. PTPase activation
by GTP, but not GMPPNP, was transient. A GMPPNP-stimulated PTPase (PTPase-G) co-purified with G subunits during Superose 6 and Mono Q chromatography. PTPase-G activity in Superose 6 fractions from GDP-treated membranes
was reconstituted by activated G, but not G, subunits. PTPase-G may contribute to GMPPNP-stimulated inactivation of Raf-1 in v-Ras cell membranes because Raf-1 inactivation
was PTx-sensitive and PTPase-G inactivated exogenous Raf-1.
Somatostatin (SRIH) receptors were identified in human kidneys by in vitro receptor autoradiography using 125I-[Tyr3]octreotide and 125I-[Leu8,D-Trp22,Tyr25]SRIH-28 as radioligands. Characterization of the binding demonstrated a single class of high affinity binding sites with a dissociation constant (Kd) of 0.5 nmol/L. Binding depended on GTP and magnesium and sodium concentrations. SRIH-14, SRIH-28, and octreotide were able to displace the radioligand in the high affinity range, whereas biologically inactive SRIH analogs or unrelated peptides were not. Microscopic localization of these receptors revealed binding over cortical and medullary areas. In the cortex, the receptors were located in the proximal tubules. No SRIH receptors were found in the glomeruli. In the medulla, the receptors were identified in high density in medullary vasa recta. A diffuse labeling of lesser density observed in the remaining medulla corresponded to collecting tubules. The receptor concentration was 32 fmol/mg protein in the renal cortex and 304 fmol/mg protein in the vasa recta. The receptors were undetectable in the rat kidney and are, thus, species dependent. SRIH receptors in the human kidney may be the molecular basis for the actions of SRIH on renal functions and may indicate a therapeutic potential for SRIH analogs in this tissue.
Lipoprotein lipase (LPL) hydrolyzes lipoprotein triglyceride into nonesterified fatty acids, which are then reesterified and stored in adipose tissue. Previous studies have demonstrated increases in LPL in response to insulin-like growth factor I and GH when added in vitro. This study examined the effects of acromegaly treatment on adipose tissue LPL. Ten patients with clinically active acromegaly were recruited. A fasting adipose tissue biopsy was performed both before and 3 months after treatment with octreotide (8 patients) or surgery plus octreotide (2 patients). With treatment, mean baseline insulin-like growth factor I levels fell from 6.41 to 3.98 U/mL (normal, < 2.2 U/mL; P < 0.05), and serum glycohemoglobin fell from 8.6 to 7.2 (normal, < 6.8). Adipose LPL was measured in the heparin-released fraction as well as the cellular fraction extracted with nonionic detergent (EXT). After treatment of acromegaly, there was no change in heparin-released fraction LPL activity or immunoreactive mass. However, there was an increase in EXT activity from 0.73 +/- 0.33 to 1.83 +/- 0.58 nEq/min.10(6) cells (mean +/- SEM; P < 0.05) and an increase in EXT mass from 4.1 +/- 0.89 to 11.4 +/- 2.0 ng/10(6) cells (P < 0.05). There was no change in LPL messenger ribonucleic acid levels with treatment, determined using both quantitative polymerase chain reaction and Northern blotting. Thus, treatment of acromegaly resulted in an increase in the intracellular level of the LPL protein, with no change in messenger ribonucleic acid levels, suggesting posttranscriptional regulation of LPL. These changes in LPL may be due to improved insulin sensitivity, or to other changes associated with acromegaly treatment.
Purpose. The success of hypophysectomy as a treatment modality for proliferate DR correlates directly with the degree of GH deficiency achieved. The somatostatin analogue, OCT, decreases levels of growth hormone (GH) and the GH-related peptide, insulin-like growth factor-I (IGF-I). IGF-I mediates most of GH's mitogenic activity. We investigated the therapeutic efficacy of OCT in prevention of progression of DR in patients (pts) with either severe nonproliferative DR or non "high risk" proliferative DR. Methods. 16 diabetic pts were randomized to treatment (n=8)(continuous infusion or QID sub q administration of maximally tolerated OCT doses ranging from 600-3000 μg/day) or control (n=8)(conventional DM management) groups for 15 months. Pts received clinical and biochemical assessment at entry and at 3 month intervals. Ophthalmic assessment occurred at entry and at 1 month intervals. Seven fields per eye were assessed for characterization of retinopathy and grading using a modified ETDRS grading system. Results. In pts treated with OCT, GH levels (area under curve) were reduced by 33% (p<0.05), IGF-I levels were decreased by 32% (p<0.05), insulin requirements were decreased by 29% (p<0.05) and proteinuria by 82% (p<0.001). Glycemic control, as assessed by mean HgA1c, over 15 months was improved in the OCT treated group (6.4±0.9%) compared to the control group (8.1±1.2%)(p<0.05). Four pts required laser therapy in each group. No regression of DR occurred in either group. The mean time to requiring laser therapy in the control group was 6.0 months and 8.5 months in the treatment group (p=NS). While reducing GH or IGF-I levels in all pts compared to pretreatment levels, OCT therapy decreased these levels into the hypopituitary range in only one of 8 patients. This pt did not require laser therapy during the study period. Conclusions. OCT resulted in improved glycemic control and renal function. OCT plus insulin can be more effective than insulin alone in controlling diabetic hyperglycemia. Failure of OCT to eliminate the need for photocoagulation therapy in our cohort of pts is probably due to the inability of OCT to suppress GH and IGF-I levels into the hypopituitary range.
The core of this work lies on developing a novel Seesaw-type macromonomer strategy for the preparation of “perfect” hyperbranched model samples with uniform subchains and the investigation on their related solution properties.
Objective: To investigate the effect of somatostatin on the electrophysiological changes of early diabetic rats, and to clarify its therapeutic effects on retinopathy in early diabetic rats. Methods: 20 Wistar male rats. which were induced into diabetic rat models by intraperitoneal injection of streptozotocin (STZ), were randomly divided into somatostatin therapy group and model control group, 10 in each group. The rats in somatostatin therapy group were injected with somatostatin 10 μg · kg-1 · d-1, for 8 weeks; the rats in model control group received the same volume of saline. Another 10 male Wistar rats were used as normal control group. The changes of blood glucose and electroretinogram were measured, and the indicators were used for statistical analysis. Results: Compared with model control group, the blood glucose was declined in somatostatin therapy group at the 8th week (P<0. 05). Compared with normal control group, the latent periods of a-wave, b-wave of rod-response and max-response were significantly extended in somatostatin therapy group and model control group at the 1st. 2nd, 4th, 6th, and 8th week (P<0. 05). The latent periods of a-wave, b-wave of rod-response and max-response in somatostatin therapy group were shorter than those in model control group at the 8th week (P < 0. 05). Compared with model control group, the amplitude had no changes at each observation time point in somatostatin therapy group (P>0. 05). Conclusion: Somatostatin has a therapeutic effect on early diabetic retinopathy in rats.
Five somatostatin receptor (sst) subtype genes, sst1, sst2, sst3, sst4 and sst5, have been cloned and characterised. The five sst subtypes all bind natural somatostatin-14 and somatostatin-28 with high affinity. Endocrine pancreatic and endocrine digestive tract tumours also express multiple sst subtypes, but sst2 predominance is generally found. However, there is considerable variation in sst subtype expression between the different tumour types and among tumours of the same type. The predominant expression of sst2 receptors on pancreatic endocrine or carcinoid tumours is essential for the control of hormonal hypersecretion by the octapeptide somatostatin analogues such as octreotide and lanreotide. Somatostatin and its octapeptide analogues are also able to inhibit proliferation of normal and tumour cells. The high density of sst2 or sst5 on pancreatic endocrine or carcinoid tumours further allows the use of radiolabelled somatostatin analogues for in vivo visualisation. The predominant expression of sst2 receptors in these tumours and the efficiency of sst2 receptors to undergo agonist-induced internalisation is also essential for the application of radiolabelled octapeptide somatostatin analogues. Currently, [ 111 In-DTPA 0 ]octreotide, [ 90 Y-DOTA 0 ,Tyr 3 ]octreotide, [ 177 Lu-DOTA 0 Tyr 3 ]octreotate, [ 111 In-DOTA 0 ]lanreotide and [ 90 Y-DOTA 0 ]lanreotide can be used for this purpose.
Somatostatin is a neuropeptide that is widely distributed throughout the body. It acts as a neurohormone and a neurotransmitter and may also have an immunomodulatory role. The genes for five subtypes of somatostatin receptors (sst) have been cloned, suggesting that the diverse eVects of the peptide might be mediated by diVerent receptors. We are interested in studying the role of sst in inflammation, using an animal model. Because of the up-regulation of sst expression in inflamed joints in human rheumatoid arthritis, we chose rat adjuvant arthritis as an experimental model. In order to determine which of the sst subtypes might be important in immune modulation, subtype expression in leukocytes isolated from diVerent lymphoid tissues of the rat was studied. Also, the expression levels of the most abundantly expressed sst mRNAs in leukocytes from spleen and blood were compared in rats with adjuvant arthritis and controls, using a semi-quantitative approach. Furthermore, the eVect of systemic administration of a long-acting somatostatin analogue, octreotide, which binds selectively to sst subtypes 2 and 5 (sst2 and sst5), on the incidence and the severity of rat adjuvant arthritis, was studied. The main sst expressed in cells of the rat immune system, both resting and activated, were found to be sst 3 and sst 4 . This contrasts with the human and murine situations, in which sst 2 appears to be the main subtype expressed in the immune system. No quantitative diVerences in sst subtype mRNA levels in leukocytes from spleen and blood were found between rats with adjuvant arthritis and controls. Finally, no eVect of systemic administration of octreotide on either the incidence or severity of adjuvant arthritis in Lewis rats was found. As octreotide binds selectively to sst2 and sst5, the absence of an immunomodulatory eVect of this analogue in rat adjuvant arthritis corroborates our finding that these sst subtypes are not expressed in cells of the rat immune system. In conclusion, cells of the rat immune system appear to express a spectrum of sst (sst3 and sst4 )d iVerent from that found in human granulomatous and autoimmune disease (mainly sst2). Therefore, the rat adjuvant arthritis model appears to be suitable only for studying the immunomodulatory eVects of somatostatin analogues which have a high aYnity for sst3 and sst4, but not for studying the immunomodulatory eVects of octreotide, which has a high aYnity only for sst2 and sst5.
Ocular diseases such as proliferative diabetic retinopathy are the major cause of blindness in industrialized countries. The main pathologic features of these diseases are hypoxia and overproduction of growth factors resulting in pathologic proliferation of endothelial cells and new vessel formation. Particularly, hypoxia and growth factors, such as VEGF, IGF-1, bFGF and TGF 2 , show a complex interaction in the onset and progression of the diseases. Therefore, to date, most therapeutic strategies for proliferative retinopathies have targeted proliferation of endothelial cells evoked by growth factors. Recently, a synthetic analog of somatostatin, octreotide, has been shown to inhibit the proliferation of various cells in vitro, including endothelial cells. In this study, we have investigated the proliferative response of bovine retinal endothelial cells (BREC) to growth factors under hypoxic conditions and the modulation by octreotide. We found a dose-dependent increase of cell proliferation with VEGF, IGF-1 and bFGF, and inhibition of hypoxia-induced cell proliferation with TGF 2 . Moreover, growth factorinduced, but not hypoxia-induced, cell proliferation was attenuated in the presence of octreotide. In contrast, TGF 2 abolished hypoxia-induced BREC proliferation. Similar to octreotide BIM23027, a somatastatin receptor subtype 2 (SSTR2) receptor agonist was able to attenuate the growth factor-induced proliferation of BREC expressing mRNA and protein for SSTR2. Therefore, we postulate that octreotide exerts its effects mainly through binding to the SSTR2. Taken together, our findings point to octreotide as a promising candidate for the treatment of eye disorders involving growth factor-dependent proliferation of endothelial cells.
To determine whether treatment with a somatostatin analogue can reduce kidney hyperfiltration and hypertrophy in insulin-dependent diabetes mellitus, we studied 11 patients with insulin-dependent diabetes mellitus and glomerular hyperfiltration. The patients were assigned randomly to receive continuous subcutaneous infusion of either octreotide, 300 μg/24 h (five patients) or placebo (six patients) for 12 weeks. At baseline, mean glomerular filtration rate and mean total kidney volume were not significantly different in the two groups. However, after 12 weeks of treatment, the mean glomerular filtration rate was significantly lower in the octreotide group (136 mL/min per 1.73 m2; range, 91 to 158 mL/min per 1.73 m2) than in the placebo group (157 mL/min per 1.73 m2; range, 138 to 184 mL/min per 1.73 m2). Furthermore, the mean total kidney volume was significantly lower after treatment in the octreotide group (379 mL/1.73 m2; range, 307 to 454 mL/1.73 m2) than in the placebo group (389 mL/1.73 m2; range, 347 to 465 mL/1.73 m2). Glycemic control did not change significantly in either group. We conclude that subcutaneous infusion of octreotide for 12 weeks reduces increased glomerular filtration rate and kidney size in patients with insulin-dependent diabetes mellitus despite the fact that glycemic control remains unchanged.(JAMA. 1991;265:888-892)
Objective:
To examine the relative levels of γ-aminobutyric acid (GABA), glutamate, and vascular endothelial growth factor (VEGF) in the vitreous of nondiabetic and diabetic patients.
Methods:
Undiluted vitreous samples were obtained from 22 patients with proliferative diabetic retinopathy (PDR) and 28 patients without diabetes who underwent pars plana vitrectomy. Simultaneous venous blood samples also were obtained. Amino acid concentrations were determined using sensitive high-performance liquid chromatography, and VEGF levels by quantitative enzyme-linked immunosorbent assay. Hemoglobin concentrations in the blood and vitreous were determined using spectrophotometry.
Results:
The level of GABA in the vitreous of patients with PDR, 29.4±7.8 μmol/L, was significantly higher than in controls (18.4±5.5 μmol/L) (P=.004). The vitreous concentration of glutamate was higher in patients with PDR (24.7±14.0 μmol/L) compared with controls (9.1±5.1 μmol/L) (P<.001). Vitreous VEGF level was significantly higher in patients with PDR (1759±1721 pg/mL) compared with controls (27±65 pg/mL) (P<.001). There were moderately strong correlations between GABA and VEGF levels (r=0.68) and glutamate and VEGF levels (r=0.43). Elevated GABA, glutamate, and VEGF levels also correlated strongly with the presence of PDR. Correcting for possible introduction of these molecules by vitreous hemorrhage did not significantly alter these findings.
Conclusions:
Levels of glutamate potentially toxic to retinal ganglion cells are found in the vitreous of patients with PDR. Elevated vitreous GABA may reflect amacrine cell dysfunction and underlie electroretinographic oscillatory potential abnormalities seen in diabetic retinopathy. The correlations of glutamate and GABA levels with an elevated VEGF level provide biochemical support for ischemia-induced neovascularization in patients with PDR. These findings present opportunities for novel therapeutic modalities in the treatment of PDR.
Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotransmission via interaction with G protein-coupled SST receptors and inhibition of the release of different hormones. The aim of this study was to investigate whether the analgesic properties of the selective SSTR4 agonist J-2156 are mediated via peripheral and/or spinal receptors. Effect on mechanical hyperalgesia in the Complete Freund's Adjuvant (CFA) model was measured after intraperitoneal application of J-2156. Electrophysiological neuronal recordings were conducted 24h after injection of CFA or vehicle into the paw of Wistar rats. Mechanosensitivity of peripheral afferents of the saphenous nerve as well as of spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were measured after systemic or spinal application of J-2156. In CFA animals J-2156 dose dependently reduced hyperalgesia in behavioural studies. The minimal effective dose was 0.1mg/kg. Mechanosensitivity of peripheral afferents and spinal neurons was significantly reduced by J-2156. NS neurons were dose dependently inhibited by J-2156 while in WDR neurons only the highest concentration of 100µM had an effect. In sham controls, J-2156 had no effect on neuronal activity. We demonstrated that J-2156 dose-dependently reduces peripheral and spinal neuronal excitability in the CFA rat model without affecting physiological pain transmission. Given the high concentration of the compound required to inhibit spinal neurons, it is unlikely that the behavioral effect seen in CFA model is mediated centrally. Overall these data demonstrated that the analgesic effect of J-2156 is mediated mainly via peripheral SST4 receptors.
Copyright © 2014. Published by Elsevier B.V.
The aim of the study was to provide knowledge on somatostatin and its action on the body, particularly the pancreas-in physiological and pathological conditions. In order to get to know the properties of somatostatin, a hormone discovered over forty years ago, many studies that define its structure and the mechanisms by which it operates have been conducted. The properties of somatostatin receptors and the effect of somatostatin on the body-both a healthy one and in various disease stages-were determined. It was proven that the somatostatin had an inhibitive effect on the endo- and exocrine secretion of this organ, which allowed a hypothesis that it might play an important role in the pathophysiology of diabetes. In patients with severe acute pancreatitis, both somatostatin and octreotide appear to reduce the mortality rate significantly, without any effect on the incidence of complications. Nevertheless, somatostatin analogues may be the cause of acute pancreatitis. With regard to severe chronic pancreatitis, refractory to other forms of therapy, it was demonstrated that octreotide significantly alleviated pain in many patients. A similar risk of death, and generally a lower risk of complications were found in the group of somatostatin-treated patients with chronic pancreatitis when compared to those receiving placebo or untreated. The occurrence of hyperglycemia after the application of somatostatin analogues, and in particular after pasireotide, is disturbing. Somatostatin analogues have found application in the treatment of cancers. They may improve symptoms in patients with gastroenteropancreatic neuroendocrine tumors (NETs) and stabilize the tumor growth (PROMID study). However, the optimal hormone dose sizes and frequencies necessary to ensure a full therapeutic effect in selected diseases of the pancreas have not been completely determined. (C) 2014 Published by Elsevier Masson SAS.
Background:
Several studies have investigated the biochemical remission rate of presurgical somatostatin analogs treatment on acromegaly, but the remission criteria were diversed and the results were contradicting.
Objective:
Aim of this paper is to provide enhanced evidence for the effectiveness of preoperative SSA treatment to improve on surgical results of macroadenomas in acromegaly.
Data source:
Literature is cited from the PubMed, Embase and Cochrane Library, dating from December, 1985 to August, 2013.
Study eligibility criteria:
Eligibility criteria included patients with acromegaly caused by GH-secreting pituitary macroadenomas, patients pretreated with somatostatin analogs versus direct surgery and a stricter remission criteria defined as the GH nadir<1μg/l during an oral glucose tolerance test (OGTT) and the age- and sex- adjusted IGF-1 concentration was normal. Primary end points included Short term and long term postoperative biochemical remission.
Study appraisal and synthesis methods:
A total of 1421 publications were found by the electronic search. After full-text review, 8 were included in our study. 7 of them focus on the postoperative remission in short term; 3 of them focus on the outcomes in long term. For the analysis of the postoperative biochemical remission, a random effect model was used to account for differences.
Results:
The meta analysis shows that patients in the SSA pretreatment groups have had a more significantly cure rate than those in the direct surgery groups (RR=1.72, 95%CI: 1.14-2.60, P=0.009) with a short term follow-up. Subgroup analysis proves benefit from lanreotide pretreated groups (RR=2.27, 95%CI: 1.34-3.84, P=0.002) but not octreotide pretreated groups (RR=1.51, 95%CI: 0.82-2.75, P=0.183). No significant differences appeared between the two groups (RR=1.03, 95%CI: 0.86-1.24, P=0.751) with a long term follow-up.
Limitations:
2 Retrospective trial was included and most of the trials included was designed as single-center study.
Conclusions:
Based on the analysis of this paper, the preoperative SSA treatment was beneficial in the group with short-term follow-up, while it was not advantageous in the group with long-term follow-up. For the limitations in this study, to drawn more solid conclusions, further large, randomized, multi-center, and long-term follow-up trials were required.
Somatostatin (SST) is abundantly produced by the human retina, and the main source is the retinal pigment epithelium (RPE). SST exerts relevant functions in the retina (neuromodulation, angiostatic, and anti-permeability actions) by interacting with SST receptors (SSTR) that are also expressed in the retina. In the diabetic retina, a downregulation of SST production does exist. In this article, we give an overview of the mechanisms by which this deficit of SST participates in the main pathogenic mechanisms involved in diabetic retinopathy (DR): neurodegeneration, neovascularization, and vascular leakage. In view of the relevant SST functions in the retina and the reduction of SST production in the diabetic eye, SST replacement has been proposed as a new target for treatment of DR. This could be implemented by intravitreous injections of SST analogs or gene therapy, but this is an aggressive route for the early stages of DR. Since topical administration of SST has been effective in preventing retinal neurodegeneration in STZ-induced diabetic rats, it seems reasonable to test this new approach in humans. In this regard, the results of the ongoing clinical trial EUROCONDOR will provide useful information. In conclusion, SST is a natural neuroprotective and antiangiogenic factor synthesized by the retina which is downregulated in the diabetic eye and, therefore, its replacement seems a rational approach for treating DR. However, clinical trials will be needed to establish the exact position of targeting SST in the treatment of this disabling complication of diabetes.
Somatostatin is an endogenous inhibitor of secretion and cell proliferation. These features render somatostatin a logical candidate for the management of neuroendocrine tumors that express somatostatin receptors. Synthetic somatostatin analogs (SSAs) have longer half-lives than somatostatin, but have similar activities, and are used for the treatment of these types of disorders. Interest has focused on novel multireceptor analogs with broader affinity to several of the five somatostatin receptors, thereby presenting putatively higher antitumor activities. Recent evidence indicates that SSAs cannot be considered mimics of native somatostatin in regulating signaling pathways downstream of receptors. Here we review this knowledge, discuss the concept of biased agonism, and highlight what considerations need to be taken into account for the optimal clinical use of SSAs.
We described here the first tetradecapeptide somatostatin-analogue where the disulfide bridge has been replaced by a carbon-carbon double bond. This analogue was prepared using microwave assisted ring closing metathesis (RCM) using the 2nd generation Grubbs as catalyst. Under our optimized conditions the cyclization between allylGly 3 and 14 proceeded in moderate yield, excellent cyclic/linear ratio and very high Z-double bond selectivity. NMR studies also demonstrated that the conformational flexibility of this peptide is increased in comparison to that of the natural hormone. Remarkably, this alkene-bridged somatostatin analog is highly selective against somatostatin receptors 1 and 5, suggesting that conformational rigidity is not required for the efficient interaction of somatostatin analogues with these two receptors.