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Purpose: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST 2 and SST 5 . Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST 2 . However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST 3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST 3 -agonists and characterize their effects on experimental NFPT models.Experimental Design: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST 3agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST 3 -agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST 3 -agonist.Results: We successfully identified the first SST 3 -agonist peptides. SST 3 -agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro, and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST 3 -agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST 3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST 3 -agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs.Conclusions: This study demonstrates that SST 3 -agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST 3 , suggesting that targeting this receptor could be an efficacious treatment for NFPTs.

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Abstract. The present work focuses on the preparation and evaluation of lecithin organogel system of thermoreversible polymer pluronic F127, which would enhance the stability and absorption of sumatriptan succinate across the skin. Formulations were developed with and without co-surfactant (pluronic F127). The prepared organogels were evaluated for its appearance, organoleptic characteristics, and feel upon application, homogeneity, occlusivenes, washability, pH, viscosity, spreadability, gel transition temperature of formulations. The formulations were also evaluated for drug content, in vitro drug diffusion properties and skin irritation testing. In vivo evaluation of formulations was carried out by hot plate and writhing test method, and finally the optimized formulation was subjected to stability studies. The developed formulations were easily washable, smooth in feel, and showed no clogging which indicate superior texture of system. Formulation, containing pluronic showed greater spreadability and higher drug diffusion rate as compared to pluronic free organogel. Drug content of organogel formulations was in the range of 94-97%. The pH of the formulations was 6.48±0.5 and 6.98±0.1, reflecting no risk of skin irritation. Pluronic not only enhances the stability of organogel by increasing the viscosity (from 6,541±234.76 to 7,826±155.65 poise) but also increases the release of drug from 67.39± 1.53% to 74.21±1.7%. The sumatriptan exhibits higher and long lasting antinociceptive effect as indicated by the persistent increase in reaction time in hot plate and inhibited abdominal contraction in acetic acid-induced writhing test (p<0.05). The prepared optimized formulation was found to be stable without any significant changes at room temperature.

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