Triglycyl-lysine vasopressin (tGLVP) is activated in the circulation when theN-triglycyl residue of the molecule is cleaved by endothelial peptidases, releasing lysine vasopressin. We compared the effect of an intravenous bolus dose of tGLVP (20 μg/kg) with a constant infusion (2.75 mU/kg/min) of arginine and lysine vasopressin (PitressinR) in normal mongrel dogs. Portal pressure was artifactually increased by a constricting flow probe. Baseline values were similar in both groups; at the time of near-maximal reduction in portal pressure, both drugs equally reduced portal venous pressure (38±4 vs 39±4%), superior mesenteric arterial blood flow (40±8 vs 39±9%), portal venous flow (35±4 vs 40±5%), and heart rate (9±2 vs 11±7%. Cardiac output obtained 10–30 min after tGLVP administration was similar to that of VP, and each drug reduced cardiac output significantly when compared with its own baseline (18±4 vs 21±7%). Mean arterial pressure increased similarly with both drugs (11±3 vs 11±3%). The only difference observed was the hepatic arterial flow response. While tGLVP increased HAF 34±11%, the physiologic autoregulatory response to a decrease in portal venous flow and pressure; vasopressin was associated with no such compensatory response (1±6%). Whether this advantage of tGLVP and its more prolonged reduction of portal venous pressure (mean 103 min) are beneficial in the clinical setting requires additional studies.

Comparison of vasopressin and triglycyl-lysine vasopressin on splanchnic and systemic hemodynamics in dogs.

Action of the triglycyl hormonogen of vasopressin (glypressin) in patients with liver cirrhosis and bleeding esophageal varices.

Triglycyl-lysin-vasopressin is a long-acting vasopressin derivative which is under consideration for the treatment of acute variceal bleeding in cirrhosis. However, its splanchnic hemodynamic effects have not been investigated thoroughly. In 11 patients with alcoholic cirrhosis, systemic and splanchnic hemodynamics were evaluated before and 20–40 min after intravenous administration of 2 mg triglycyl-lysin-vasopressin. Following the drug administration, heart rate decreased by 10% and cardiac index by 22% on the average, respectively; mean arterial pressure increased by 14% and systemic vascular resistence index by 48%. Hepatic venous pressure gradient showed a marked and persistent fall, averaging 31%. Hepatic and splenic blood flow decreased by 31% and 56%, respectively. A significant correlation was found between the decrease in hepatic venous pressure gradient and in splenic blood flow. By contrast, the decrease in the hepatic venous pressure gradient was not significantly correlated to the decrease in hepatic blood flow or in cardiac index. We conclude that in patients with alcoholic cirrhosis, triglycyl-lysin-vasopressin decreases portal pressure as well as hepatic and splenic blood flows. The decrease in portal pressure was due to the decrease in splanchnic blood inflow and not to the decrease in cardiac index.

Hemodynamic changes of systemic, hepatic, and splenic circulation following triglycyl-lysin-vasopressin administration in alcoholic cirrhosis.

Peptides are rapidly being developed as potential new therapeutic agents and the nasal route is being evaluated as a means of achieving systemic absorption. Current research in man is being directed at a number of polypeptides, including calcitonin, growth hormone releasing hormones (GHRH), insulin, gonadotropin hormone releasing hormones (GnRH) and vasopressin analogues. The underlying protective functions of the nose provide anatomical, temporal and enzymatic barriers to absorption of peptides. The nasal route is relatively unsuccessful when used for high molecular weight polypeptides. Penetration enhancers improve bioavailability but are poorly tolerated. Reproducibility of effect is highly variable, major contributing factors including the site of deposition and type of delivery system as well as changes in the mucous secretion and mucociliary clearance, compounded by the presence of allergy, hay fever and the common cold in treated subjects. The future potential for this route lies in development of effective and well tolerated formulations in highly accurate delivery systems for the chronic administration of peptides, enabling the replacement of impractical and invasive intravenous injections in patients on lifelong substitution treatment for various deficiency states.

Review: Clinical Opportunities Provided by the Nasal Administration of Peptides

In eight patients with cirrhosis of the liver and portal hypertension an intravenous infusion of lysine vasopressin induced a rapid increase in the plasma level of the fibrinolytic proenzyme plasminogen activator. In contrast, triglycyl lysine vasopressin (glypressin; GVP), in a dose known to lower portal venous pressure, produced no fibrinolytic response. This lack of fibrinolytic response represents an advantage of GVP over lysine vasopressin in addition to its longer in vivo half-life and lower cardiotoxicity. Clinical trials of GVP in the treatment of bleeding oesophageal varices are needed.

https://gut.bmj.com/content/gutjnl/20/7/565.full.pdf

Effects of lysine vasopressin and glypressin on the fibrinolytic system in cirrhosis.

Nα-glycyl-glycyl-glycyl-(8-Lysin)-Vasopressin ist ein Hormonanalog mit prolongierter pharmakologischer Wirkung aufgrund der Tatsache, das in vivo das aktive Nonapeptid nur langsam durch enzymatische Spaltung freigesetzt wird. Es wurde bei 5 Kontrollpersonen und 14 im oberen Gastrointestinaltrakt blutenden Patienten angewandt. Die Kontrollpersonen zeigten bei einer Dosierung von 100 µg/kg Korpergewicht fur langere Zeit einen erhohten Blutdruck, begleitet von einem vergroserten Herzminutenvolumen, ohne EKG-Hinweis auf Myocardtoxizitat. 13 der 14 blutenden Patienten zeigten nicht nur eine pressorische Wirkung sowie eine hamodynamische und klinische Besserung nach 20–100 µg/kg, sondern auch deutliche Zeichen von Blutstillung sowohl bei peptischen Ulcera als auch Oesophagusvaricen.

S. Wetterlin

Papers

Die Wirkung von Triglycyl-Lysin-Vasopressin auf Kontrollpersonen und Patienten mit Blutungen des oberen Gastrointestinaltraktes