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Companion Animals Models of Human Disease
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
The prevalence of GH (growth hormone)-secreting pituitary tumors in domestic cats (Felis catus) is ten-fold greater than in humans. The predominant inhibitory receptors of GH-secreting pituitary tumors are somatostatin receptors (SSTRs) and D2 dopamine receptors (DRD2). The expression of these receptors is associated with the response to somatostatin analog and dopamine agonist treatment in human patients with acromegaly. A study in cats evaluated pathological features of pituitaries from domestic cats with acromegaly, pituitary receptor expression, and investigated correlates with clinical data, including pituitary volume, time since diagnosis of diabetes, insulin requirement, and serum IGF1 concentration. Loss of reticulin structure was identified in 15 of 21 pituitaries, of which 10 of 15 exhibited acinar hyperplasia. SSTR1, SSTR2, SSTR5, and DRD2 mRNA were identified in the feline pituitary, whereas SSTR3 and SSTR4 were not. Expression of SSTR1, SSTR2, and SSTR5 was greater in acromegalic cats compared with controls. A negative correlation was identified between DRD2 mRNA expression and pituitary volume(24,25).
Radionuclide imaging of carcinoid tumors, neurendocrine tumors of the pancreas and adrenals
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
Technetium-labeled investigational somatostatin analogs have also been investigated with favorable results in GEPNETs, and these included 99mTc-depreotide, which binds with high affinity to SSTR2, SSTR3, and SSTR5; 99mTc-vapreotide, which binds with high affinity to SSTR2 and SSTR5 and, to a lesser extent, SSTR3 and SSTR4; 99mTc-HYNIC-TOC; and 99mTc-HYNIC-[Tyr3,Thr8]-octreotide (TATE) [29, 65, 72]. There are advantages of 99mTc-labeled somatostatin analogs over 111In-DTPA-octreotide imparted by superior imaging capabilities of the extrahepatic metastases and better individual separation of lesions. However, these results should be analyzed with caution since most of these reported comparisons did not use the optimal imaging protocols for 111In-DTPA-octreotide SRS defined by the European and U.S. guidelines [20–23].
Peritoneal surface malignancy from neuroendocrine tumors
Published in Wim P. Ceelen, Edward A. Levine, Intraperitoneal Cancer Therapy, 2015
Mladjan Protić, Itzhak Avital, Alexander Stojadinovic
NET-secreting cells have on their surface various types of somatostatin receptors. Specifically, there are five types of somatostatin receptors (sstr1–5). Binding to these receptors, somatostatin inhibits secretion of various hormones, including serotonin, insulin, gastrin, and glucagon, among others [42]. Each type of NET cell can have more than one subtype of somatostatin receptor. Activation of subtypes sstr2 and sstr5 causes antisecretory effect of somatostatin and somatostatin analogs and thereby inhibits the secretion of hormones in functional NETs. On the other hand, there is evidence that subtypes sstr1, sstr2, sstr4, and sstr5 have an antitumor effect through inhibition of tumor cell growth and induction of apoptosis [43].
The triple function of the capsaicin-sensitive sensory neurons: In memoriam János Szolcsányi
Published in Temperature, 2023
Erika Pintér, Zsuzsanna Helyes, Éva Szőke, Kata Bölcskei, Angéla Kecskés, Gábor Pethő
The selective, high affinity SST4 receptor agonist J-2156 is a non-peptide sulfonamidopeptidomimetic (1ʹS,2S)-4-amino-N-(1’-carbamoyl-2’-phenylethyl)-2-(4”-methyl-1”naphthalenesulfonamino)-butanamide. This compound was synthesized by Juvantia Pharma (Turku, Finland). J-2156 binds to the human SST4 receptor with nanomolar affinity, which exceeds the binding affinity of native SOM, and shows nearly 400-fold selectivity for SST4 compared to the other SST receptors [29]. In a cAMP assay indicating receptor activation, it behaved as a full agonist similar to native SOM-14 or SOM-28. In another G-protein activation functional assay, it produced 2.5-fold stronger responses than native SOM. Based on these properties, this molecule was considered as a “superagonist” [29]. Further in vitro studies showed that J-2156 does not cause desensitization after repeated administration, an important consideration for the potential therapeutic use of this compound [30].
New and emerging pharmacological treatment options for acromegaly
Published in Expert Opinion on Pharmacotherapy, 2021
Ximene Antunes, Leandro Kasuki, Mônica R. Gadelha
Somatropim is a unique SRL with affinity for SST2, SST4 and SST5 receptors that, in hormone-secreting studies with rats, has been shown to be 1000-fold and more than 10,000-fold more potent in inhibiting GH secretion than glucagon and insulin secretion, respectively [43]. In an in vitro study in fetal pituitaries and cultures of GH-cell adenomas, somatropim showed similar inhibitory effects to octreotide on GH secretion [44].
Drug treatment strategies for secondary diabetes in patients with acromegaly
Published in Expert Opinion on Pharmacotherapy, 2020
Sylvère Störmann, Jochen Schopohl
Many treatment options for acromegaly have emerged over the past decades and consensus statements have to be revised frequently. Even though acromegaly is considered a rare disease, many patients cannot be surgically cured, but potentially pharmacologically. In these cases, life-long treatment is necessary. A lucrative market with annual revenues of several billion US dollars has emerged and serves as economic incentive for pharmaceutical companies to invest in research and development of newer drugs for which a medical need exists [161]. Recent reviews provide an excellent overview of the development pipeline [162–166]. For some of these drugs, effects on glucose homeostasis have been published. Veldoreotide (formerly known as somatoprim, COR-005, DG3173, and also PTR-3173) is a somatostatin analogue selectively binding at SSTR2, SSTR4, and SSTR5 that was first described almost 20 years ago [167]. Even then in an animal model application of veldoreotide did not impair insulin secretion and glucagon secretion was reduced to a lesser degree than by octreotide. Phase I studies in healthy volunteers as well as phase II in patients with acromegaly were conducted, but not yet published. According to a recent annual report, data from the unpublished studies support the pre-clinical findings and further clinical trials are planned (but no timeline is given). Another somatostatin analogue called AP102 has high binding affinity for SSTR2 and SSTR5 and despite its first description in 2005 only recently investigated in an animal model with male Sprague Dawley rats [168]. In this study, acute and chronic administration of AP102 was tested and showed no hyperglycemia or impaired glucose tolerance. Another study in Zucker diabetic fed rats showed similar results [169]. Recently, results from a phase 2 clinical trial in 26 patients treated with ATL1103 were reported, an antisense oligomer targeting the human growth hormone (GH) receptor [170]. Effects on glucose metabolism were not reported but given the mode of action, no direct effect on glycemia is to be expected, but indirectly from successful acromegaly treatment. Another recent development is CRN00808, a small molecule nonpeptide SSTR2 agonist, that is currently under clinical investigation [171]. As it has no affinity toward other SSTR, it is supposed to be less deleterious in terms of glucose tolerance.