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      In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V 1 and V 2

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          Abstract

          Terlipressin, a synthetic, systemic vasoconstrictor with selective activity at vasopressin-1 (V 1) receptors, is a pro-drug for the endogenous/natural porcine hormone [Lys 8]-vasopressin (LVP). We investigated binding and receptor-mediated cellular activities of terlipressin, LVP, and endogenous human hormone [Arg 8]-vasopressin (AVP) at V 1 and vasopressin-2 (V 2) receptors. Cell membrane homogenates of Chinese hamster ovary cells expressing human V 1 and V 2 receptors were used in competitive binding assays to measure receptor-binding activity. These cells were used in functional assays to measure receptor-mediated cellular activity of terlipressin, LVP, and AVP. Binding was measured by [ 3H]AVP counts, and the activity was measured by fluorometric detection of intracellular calcium mobilization (V 1) and cyclic adenosine monophosphate (V 2). Binding potency at V 1 and V 2 was AVP>LVP>>terlipressin. LVP and terlipressin had approximately sixfold higher affinity for V 1 than for V 2. Cellular activity potency was also AVP>LVP>>terlipressin. Terlipressin was a partial agonist at V 1 and a full agonist at V 2; LVP was a full agonist at both V 1 and V 2. The in vivo response to terlipressin is likely due to the partial V 1 agonist activity of terlipressin and full V 1 agonist activity of its metabolite, LVP. These results provide supportive evidence for previous findings and further establish terlipressin pharmacology for vasopressin receptors.

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          Most cited references 12

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          A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome.

           F Regenstein,  Peter Teuber,   (2008)
          Hepatorenal syndrome (HRS) type 1 is a progressive functional renal failure in subjects with advanced liver disease. The aim of this study was to evaluate the efficacy and safety of terlipressin, a systemic arterial vasoconstrictor, for cirrhosis type 1 HRS. A prospective, randomized, double-blind, placebo-controlled clinical trial of terlipressin was performed. Subjects with type 1 HRS were randomized to terlipressin (1 mg intravenously every 6 hours) or placebo plus albumin in both groups. The dose was doubled on day 4 if the serum creatinine (SCr) level did not decrease by 30% of baseline. Treatment was continued to day 14 unless treatment success, death, dialysis, or transplantation occurred. Treatment success was defined by a decrease in SCr level to
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            Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients With Cirrhosis and Hepatorenal Syndrome Type 1.

            Hepatorenal syndrome type 1 (HRS-1) in patients with cirrhosis and ascites is a functional, potentially reversible, form of acute kidney injury characterized by rapid (<2 wk) and progressive deterioration of renal function. Terlipressin is a synthetic vasopressin analogue that acts, via vascular vasopressin V1 receptors, as a systemic vasoconstrictor. We performed a phase 3 study to evaluate the efficacy and safety of intravenous terlipressin plus albumin vs placebo plus albumin in patients with HRS-1.
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              Vasopressin and terlipressin: pharmacology and its clinical relevance.

              Vasopressin and its analogue, terlipressin, are potent vasopressors that may be useful therapeutic agents in the treatment of cardiac arrest, septic and catecholamine-resistant shock and oesophageal variceal haemorrhage. The aim of this article is to review the physiology and pharmacology of vasopressin and summarise its efficacy and safety in clinical trials and its subsequent therapeutic use. Recent studies indicate that the use of vasopressin during cardiopulmonary resuscitation may improve the survival of patients with asystolic cardiac arrest. Vasopressin deficiency can contribute to refractory shock states associated with sepsis, cardiogenic shock and cardiac arrest. Low doses of vasopressin and terlipressin can restore vasomotor tone in conditions that are resistant to catecholamines, with preservation of renal blood flow and urine output. They are also useful in reducing bleeding and mortality associated with oesophageal variceal haemorrhage. The long-term outcome of the use of these drugs is not known.
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                Author and article information

                Journal
                J Exp Pharmacol
                J Exp Pharmacol
                Journal of Experimental Pharmacology
                Journal of Experimental Pharmacology
                Dove Medical Press
                1179-1454
                2018
                20 December 2017
                : 10
                : 1-7
                Affiliations
                [1 ]Clinical Development, Mallinckrodt Pharmaceuticals, Bedminster
                [2 ]Orphan Therapeutics, LLC, Lebanon, NJ, USA
                Author notes
                Correspondence: Khurram Jamil, Clinical Development, Mallinckrodt Pharmaceuticals, 1405 U.S. Route 206, Bedminster, NJ 07921, USA, Tel +1 908 500 4716, Fax +1 866 572 9449, Email Khurram.Jamil@ 123456mallinckrodt.com
                Article
                jep-10-001
                10.2147/JEP.S146034
                5741980
                © 2018 Jamil et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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