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      Pasireotide for the Medical Management of Feline Hypersomatotropism

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          Abstract

          Background

          Feline hypersomatotropism ( HST) is a cause of diabetes mellitus in cats. Pasireotide is a novel multireceptor ligand somatostatin analog that improves biochemical control of humans with HST.

          Hypothesis/Objectives

          Pasireotide improves biochemical control of HST and diabetes mellitus in cats.

          Animals

          Hypersomatotropism was diagnosed in diabetic cats with serum insulin‐like growth factor‐1 ( IGF‐1) concentration >1,000 ng/mL by radioimmunoassay and pituitary enlargement.

          Methods

          Insulin‐like growth factor 1 was measured and glycemic control assessed using a 12‐hour blood glucose curve on days 1 and 5. On days 2, 3, and 4, cats received 0.03 mg/kg pasireotide SC q12h. IGF‐1, insulin dose, and estimated insulin sensitivity (product of the area under the blood glucose curve [ BGC] and insulin dose) were compared pre‐ and post treatment. Paired t‐tests or Wilcoxon signed rank tests were employed for comparison where appropriate; a linear mixed model was created to compare BGC results.

          Results

          Insulin‐like growth factor 1 decreased in all 12 cats that completed the study (median [range] day 1: 2,000 ng/mL [1,051–2,000] and day 5: 1,105 ng/mL [380–1,727], P = .002, Wilcoxon signed rank test). Insulin dose was lower on day 5 than on day 1 (mean reduction 1.3 [0–2.7] units/kg/injection, P = .003, paired t‐test). The product of insulin dose and area under the BGC was lower on day 5 than day 1 (difference of means: 1,912; SD, 1523; u × mg/dL × hours, P = .001; paired t‐test). No clinically relevant adverse effects were encountered.

          Conclusions

          Short‐acting pasireotide rapidly decreased IGF‐1 in cats with HST and insulin‐dependent diabetes. The decrease in IGF‐1 was associated with increased insulin sensitivity.

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          Most cited references38

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          Acromegaly: an endocrine society clinical practice guideline.

          The aim was to formulate clinical practice guidelines for acromegaly.
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            SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile.

            The aim of the present study was to identify a small, metabolically stable somatotropin release inhibiting factor (SRIF) analog with a more universal binding profile similar to that of natural somatostatin, resulting in improved pharmacological properties and hence new therapeutic uses. A rational drug design approach was followed by synthesizing alanine-substituted SRIF-14 analogs to determine the importance of single amino acids in SRIF-14 for SRIF receptor subtype binding. The incorporation of structural elements of SRIF-14 in a stable cyclohexapeptide template in the form of modified unnatural amino acids resulted in the identification of the novel cyclohexapeptide SOM230. SOM230 binds with high affinity to SRIF receptor subtypes sst1, sst2, sst3 and sst5 and displays a 30- to 40-fold higher affinity for sst1 and sst5 than Sandostatin (octreotide; SMS 201-995) or Somatuline (BIM 23014). In vitro, SOM230 effectively inhibited the growth hormone releasing hormone (GHRH)-induced growth hormone (GH) release in primary cultures of rat pituitary cells with an IC(50) of 0.4+/-0.1 nmol/l (n=5). In vivo, SOM230 also potently suppressed GH secretion in rats. The ED(50) values determined at 1 h and 6 h post injection of SOM230 indicated its very long duration of action in vivo. This property was also reflected in pharmacokinetic studies comparing plasma levels of SMS 201-995 and SOM230 after subcutaneous application. Whereas SMS 201-995 had a terminal elimination half life of 2 h, this was markedly prolonged in SOM230-treated animals (t(1/2)=23 h). Furthermore, in rats SOM230 demonstrated a much higher efficacy in lowering plasma insulin-like growth factor-I (IGF-I) levels compared with SMS 201-995. The infusion of 10 microg/kg/h of SOM230 using subcutaneously implanted minipumps decreased plasma IGF-I levels far more effectively than SMS 201-995. After 126 days of continuous infusion of SOM230 plasma IGF-I levels were decreased by 75% of placebo-treated control animals. For comparison SMS 201-995, when used under the same experimental conditions, resulted in only a 28% reduction of plasma IGF-I levels, indicating a much higher efficacy for SOM230 in this animal model. It is important to note that the inhibitory effect of SOM230 was relatively selective for GH and IGF-I in that insulin and glucagon secretion was inhibited only at higher doses of SOM230. This lack of potent inhibition of insulin and glucagon release was also reflected in the lack of effect on plasma glucose levels. Even after high dose treatment over 126 days no obvious adverse side effects were noticed, including changes in plasma glucose levels. We have identified a novel short synthetic SRIF peptidomimetic, which exhibits high affinity binding to four of the five human SRIF receptor subtypes and has potent, long lasting inhibitory effects on GH and IGF-I release. Therefore SOM230 is a promising development candidate for effective GH and IGF-I inhibition and is currently under evaluation in phase 1 clinical trials.
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              Octreotide.

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                Author and article information

                Journal
                J Vet Intern Med
                J. Vet. Intern. Med
                10.1111/(ISSN)1939-1676
                JVIM
                Journal of Veterinary Internal Medicine
                John Wiley and Sons Inc. (Hoboken )
                0891-6640
                1939-1676
                06 May 2015
                Jul-Aug 2015
                : 29
                : 4 ( doiID: 10.1111/jvim.2015.29.issue-4 )
                : 1074-1080
                Affiliations
                [ 1 ] Department of Clinical Sciences and ServicesRoyal Veterinary College North MymmsUK
                [ 2 ]Novartis Institutes for BioMedical Research Oncology Research Novartis Pharma AG BaselSwitzerland
                [ 3 ]Newcastle Medical School Newcastle Tyne and WearUK
                Author notes
                [*] [* ]Corresponding author: C.J. Scudder, Department of Clinical Sciences and Services, Royal Veterinary College, North Mymms, UK; e‐mail cscudder@ 123456rvc.ac.uk .
                Article
                JVIM12608
                10.1111/jvim.12608
                4895359
                25945588
                a76fa6ec-98b7-4bfb-a0b1-c25a1f5a38f9
                Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 29 December 2014
                : 23 March 2015
                : 07 April 2015
                Page count
                Pages: 7
                Categories
                Standard Article
                SMALL ANIMAL
                Standard Articles
                Endocrinology
                Custom metadata
                2.0
                jvim12608
                July/August 2015
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.8.9 mode:remove_FC converted:06.05.2016

                Veterinary medicine
                diabetes mellitus,growth hormone,inhibition,pituitary
                Veterinary medicine
                diabetes mellitus, growth hormone, inhibition, pituitary

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