Triglycyl Lysine Vasopressin Research Articles

An evidence-based terlipressin therapy for gastroesophageal variceal hemorrhage

Gastroesophageal variceal bleeding is one of the major complications of cirrhosis and also the leading causes of death in patients with decompensated cirrhosis. Terlipressin is a triglycyl-lysine vasopressin, a synthetic vasopressin analogue that is mainly used for the treatment of acute variceal hemorrhage. This article aims to review the current status of treatment of gastroesophageal variceal bleeding with terlipressin from the perspective of evidence-based medicine.

Terlipressin: An Asset for Hepatologists!

Terlipressin: An Asset for Hepatologists!

Terlipressin: Vasopressin Analog and Novel Drug for Septic Shock

To review and assess available literature on chemistry, pharmacology, pharmacodynamics, pharmacokinetics, clinical studies, adverse events, drug interactions, and dosing and administration of terlipressin in septic shock. A literature search of MEDLINE (1966-September 2006), International Pharmaceutical Abstracts (1970-September 2006), and Cochrane database (third quarter 2006) was conducted, using key terms of terlipressin, lypressin, triglycyl-lysine vasopressin, hemodynamic support, septic shock, vasopressor, and V1 receptor agonist. Bibliographies of relevant articles were reviewed for additional references. Available English-language literature, including abstracts, animal studies, preclinical studies, clinical trials, and review articles, were examined. Because of potentially favorable pharmacokinetics versus vasopressin and limited availability of vasopressin in some countries, the effects of terlipressin, a vasopressin analog, have been studied recently for the treatment of septic shock. When administered as a 1-2 mg intravenous dose in patients with septic shock, terlipressin increases mean arterial pressure, urine output, systemic vascular resistance index, pulmonary vascular resistance index, and left and right ventricular stroke work index while decreasing heart rate, cardiac output, lactate, and oxygen delivery and consumption index. It is unclear whether lower doses of terlipressin would produce a similar vasopressor response with fewer cardiopulmonary effects and whether the effects of the drug on oxygen transport indices are detrimental. Terlipressin is a promising investigational medication for treatment of septic shock. Small trials have shown terlipressin to have favorable effects on hemodynamics in patients with septic shock refractory to conventional vasopressor treatment. It should be used with extreme caution in patients with underlying cardiac or pulmonary dysfunction. Further studies are needed to verify safety, efficacy, and dosing of terlipressin in patients with septic shock, and its use cannot be recommended in lieu of vasopressin at this time.

Terlipressin for acute esophageal variceal hemorrhage.

Terlipressin (triglycyl lysine vasopressin) is a synthetic analogue of vasopressin, which has been used in the treatment of acute variceal hemorrhage. In contrast to vasopressin, terlipressin can be administered as intermittent injections instead of continuous intravenous infusion and it has a safer adverse reactions profile. However, its effectiveness remains uncertain. To determine if treatment with terlipressin improves outcome in acute esophageal variceal hemorrhage and is safe. Randomized clinical trials were identified by searching the following databases: MEDLINE, EMBASE, the Cochrane Controlled Trials Register, the Cochrane Hepato-Biliary Group Controlled Trials Register, Biosis, and Current Contents. The bibliographies of identified publications were checked. Experts in the field and the manufacturers of terlipressin were contacted. All randomized clinical trials which compared terlipressin with: (a) placebo or no treatment, (b) balloon tamponade, (c) endoscopic treatment, (d) octreotide, (e) somatostatin and (f) vasopressin, in the setting of acute variceal hemorrhage. Eligibility, trial quality assessment and data extraction were done independently by two reviewers. The primary outcome measure was mortality. Secondary outcomes were failure of initial hemostasis, rebleeding, procedures required for uncontrolled bleeding or rebleeding, transfusion requirements and length of hospitalization. Twenty studies were identified for all the comparison groups, involving 1609 patients. There were seven studies (with 443 patients) comparing terlipressin to placebo, five of which were considered to be high quality studies based on the Jadad scale. The meta-analysis indicates that terlipressin was associated with a statistically significant reduction in all cause mortality compared to placebo (relative risk 0.66, 95% confidence interval 0.49 to 0.88). Three studies (with 302 patients) were identified comparing terlipressin to somatostatin, two of which were high quality studies; only one high quality study (219 patients) comparing terlipressin to endoscopic treatment was identified. Within the limited power provided by these small numbers of patients, no statistically significant difference was demonstrated between terlipressin and either somatostatin or endoscopic treatment in any of the outcomes. For the remaining comparison groups (terlipressin versus balloon tamponade, terlipressin versus octreotide and terlipressin versus vasopressin) only small, low quality studies were identified and no difference was demonstrated in any of the major outcomes. There was no difference between the terlipressin group and any of the comparison groups in the number of adverse events that caused death or withdrawal of medication. On the basis of a 34% relative risk reduction in mortality, terlipressin should be considered to be effective in the treatment of acute variceal hemorrhage. Further, since no other vasoactive agent has been shown to reduce mortality in single studies or meta-analyses, terlipressin might be the vasoactive agent of choice in acute variceal bleeding.

Refractory Hypotension After Induction of Anesthesia in a Patient Chronically Treated with Angiotensin Receptor Antagonists

Refractory Hypotension After Induction of Anesthesia in a Patient Chronically Treated with Angiotensin Receptor Antagonists

The action of vasoconstrictive agents on human tubal arteries.

The aim of this investigation was to compare the response of small arteries of the human tubo-ovarian vasculature to certain vasoactive agents. Ring preparations of the arteries were isolated and mounted in tissue chambers for isometric recording of wall tension. The arteries were exposed to the vasoactive agents adrenalin, prostaglandin F2 alpha and two vasopressin analogues. Adrenalin, prostaglandin F2 alpha, lysin-vasopressin and triglycyl-lysine-vasopressin all produced powerful vasoconstriction, the greatest efficacy being shown by and lysine-vasopressin. The maximum response occurred after addition of a third compound to a combination of two, irrespective of which combination was used. Adrenalin showed faster contraction velocity than the other agents. The results indicate that the human tubo-ovarian arteries may be constricted by a variety of physiological and pharmacological stimuli, at least partly acting via different effector mechanisms. It is proposed that these vasoconstrictive agents--alone or in combination--may be useful in conjunction with gynaecological endoscopic surgery, e.g. in tubal pregnancy or ovarian cysts.

A discussion of how terlipressin limits mortality in cases of bleeding oesophageal varices.

Bleeding oesophageal varices (BOV) are a potentially life-threatening complication of portal hypertension. While endoscopic sclerotherapy and banding ligation are often employed in an attempt to arrest bleeding, the use of vasoactive pharmacological agents to control haemorrhage has a number of advantages. While many of the available vasoactive agents control acute bleeding and may exert a beneficial influence over hepatic haemodynamics, terlipressin (triglycyl lysine-vasopressin) is the only agent that has been shown actually to decrease mortality in cases of BOV. It is hypothesized that this increase in survival rate is due to the apparently unique multifactorial influence of terlipressin over variceal haemostasis and blood flow, hepatic and gastric haemodynamics and renal function, combined with the likelihood of only minimal adverse events.

Hyperuricemia as a Clue for Central Diabetes Insipidus (Lack of V 1 Effect) in the Differential Diagnosis of Polydipsia

PURPOSE: In the differential diagnosis of patients with polyuria-polydipsia one must distinguish usually between primary polydipsia (PP) and central diabetes insipidus (CDI). The first situation is a state of volume expansion and the second of volume contraction. We evaluate whether serum uric acid determination could help to differentiate between the two conditions. PATIENTS AND METHODS: We analyzed the score of 13 consecutive patients with CDI, 7 patients with PP, and 7 patients with nephrogenic diabetes insipidus (NDI). Serum uric acid concentration was available during normonatremia without treatment with 1-desamino-8-D-arginine vasopressin (dDAVP), during mild dehydration and during treatment with dDAVP. In 8 of these patients plasma renin activity (PRA), urate, urea and creatinine clearances were also available. These data were also obtained in the patients with NDI. In 1 patient with CDI, we studied the effect on urate clearance of dDAVP, which stimulates exclusively the V 2 receptors, and of triglycyl-lysine-vasopressin (TGLV), a potent V 1-receptor agonist. RESULTS: Normonatremic polydypsic patients with CDI presented an increase in uric acid concentration (7.1 ± 2.2 mg/dL), whereas in the PP group the value was decreased (3 ± 0.75 mg/dL; P <0.001). All the normonatremic PP presented a serum uric acid concentration lower than 5 mg/dL, whereas all the normonatremic CDI patients, exept 1, presented a value higher than 5 mg/dL. In both groups blood urea concentration was decreased as a consequence of high renal clearances. The hyperuricemia of CDI was related to low uric acid clearances. Patients with hypernatremia and NDI presented a lower increase in serum uric acid concentration than those with similar levels of hypernatremia and CDI (NDI: 5.7 ± 0.8 mg/dL and CDI: 7.9 ± 2.3 mg/dL; P <0.05) and the NDI patients presented an urate clearance corrected for creatinine clearance which was significantly higher than in CDI (9% ± 3% and 4% ± 1.1%; P <0.01). When the patients with CDI were treated with dDAVP and normalyzed their PRA (0.9 ± 0.4 ng/mL/h) we observed still mild hyperuricemia compared to controls (5.5 ± 1.4 mg/dL and 4.3 ± 0.9 mg/dL; P <0.01) and a low fractional excretion of filtered uric acid (6.5% ± 1.7% compared to 8.2% ± 2% in controls; P <0.05). Acute administration of dDAVP, stimulating the V 2 receptors, in one patient with CDI, had no effect on urate clerance, while TGLV, which stimulates the V 1 receptor, increased urate clearance. CONCLUSION: The presence of an serum uric acid concentration higher than 5 mg/dL in polyuric polydipsic patients is highly suggestive of CDI. Even when these patients are treated with dDAVP many of them remain hyperuricemic, and this seems to be the consequence of a lack of V 1 receptor stimulation.

The hemodynamic effects of triglycyl-lysine-vasopressin (glypressin) in patients with parkinsonism and orthostatic hypotension

The hemodynamic effects of triglycyl-lysine-vasopressin (TGLVP) were investigated in a single-blind study in seven patients with chronic orthostatic hypotension and parkinsonism. Blood pressure, heart rate, and stroke volume were measured in the supine position before and after bolus injection of either placebo or TGLVP (5.0, 7.5, or 10.0 micrograms/kg of body weight). After 40 min in the supine position, the patients were head-up tilted to 45 degrees for 20 min. All patients underwent four tilt studies with different medication. The TGLVP increased supine blood pressure by approximately 25% and total peripheral resistance by approximately 46%, and reduced heart rate by approximately 13%. No changes in supine stroke volume or cardiac output were seen. The TGLVP slightly reduced the relative fall in blood pressure and increased heart rate during the tilt. After TGLVP, blood pressure levels during tilt were similar to supine levels prior to medication. The TGLVP did not change the effects of tilt on stroke volume or cardiac output. Only few and mild side effects were experienced and no cardiotoxic effects were observed. In conclusion, TGLVP showed marked blood pressure effects of very small doses in this category of patients. The clinical effects of TGLVP and other vasopressor-specific analogs of vasopressin should be tested in these patients.

Systemic and portal haemodynamic changes following triglycyllysine vasopressin plus nitroglycerin administration in patients with hepatitis B-related cirrhosis

We measured the haemodynamic changes following triglycyllysine vasopressin administration and after addition of nitroglycerin in twelve patients with portal hypertension due to hepatitis B-related cirrhosis. A bolus i.v. injection of triglycyllysine vasopressin at a dose of 2 mg reduced the hepatic venous pressure gradient from 18.5 +/- 3.7 (mean +/- S.D.) to 15.6 +/- 4.0 mmHg, p less than 0.001. However, the cardiac index decreased from 4.8 +/- 1.0 to 3.7 +/- 0.8 l/min m2, p less than 0.001; the heart rate decreased from 79 +/- 15 to 71 +/- 13, p less than 0.01; the right atrial pressure increased from 3.2 +/- 1.9 to 5.3 +/- 2.3 mmHg, p less than 0.001; the mean arterial pressure increased from 92 +/- 13 to 103 +/- 13 mmHg, p less than 0.05; and the systemic vascular resistance rose from 939 +/- 182 to 1367 +/- 310 dyn/s cm-5, p less than 0.001. Furthermore, both mean pulmonary arterial pressure and pulmonary capillary wedge pressure showed a significant increase following triglycyllysine vasopressin administration as compared with baseline values (p less than 0.005). The addition of sublingual nitroglycerin at a dose of 0.6 mg returned all the systemic haemodynamic parameters to baseline levels. On the other hand, nitroglycerin administration caused no further change in the hepatic venous pressure gradient. We concluded that although triglycyllysine vasopressin significantly reduced portal pressure in patients with hepatitis B-related cirrhosis, it produced untoward systemic haemodynamic changes similar to those seen with vasopressin. The addition of nitroglycerin improved the detrimental systemic haemodynamic effects produced by triglycyllysine vasopressin without further reducing the hepatic venous pressure gradient.

Terlipressin (Triglycyl-Lysine Vasopressin) Controls Acute Bleeding Oesophageal Varices: A Double-Blind, Randomized, Placebo-Controlled Trial

The haemostatic effect of terlipressin (triglycyl-lysine vasopressin; Glypressin) on bleeding from oesophageal varices was evaluated in a placebo-controlled, double-blind, randomized clinical trial. Patients with clinically suspected liver cirrhosis were included in the study if they had been admitted to hospital with an extensive haemorrhage within the last 24h before diagnostic endoscopy. The patients randomized after stratification for severity of liver disease. Terlipressin or placebo was administered as intravenous bolus injections every 4th h during a period of 24 to 36 h or until the clinical course necessitated active intervention (failure or withdrawal). Sixty patients entered the study; 31 patients were allocated to receive terlipressin, and 29 patients to receive placebo. Bleeding from varices was arrested in 28 of the 31 receiving terlipressin, as compared with 17 of the 29 receiving placebo (p less than 0.01). Patients receiving active drug required significantly fewer blood transfusions (p less than 0.05). Most of the side effects were classified as mild and were registered in the terlipressin group.

The effect of triglycyl-lysine-vasopressin (terlipressin INN, Glypressin) on skin blood flow, measured with laser Doppler flowmetry, thermography and plethysmography. A dose-response study.

Triglycyl-lysine-vasopressin (TGLVP) has been shown to reduce blood loss in connection with early excision of experimentally induced burns in pigs. In order to determine an appropriate dosage of TGLVP in patients with burns, a dose-response study was undertaken. TGLVP was administered intravenously in various doses to healthy volunteers, and skin blood flow was measured with laser Doppler flowmetry, thermography and plethysmography. Blood pressure, heart rate and electrocardiac activity were monitored as well as serum and urine changes. The doses of 5, 10 and 20 micrograms TGLVP/kg b.wt. caused statistically significant reduction of skin blood flow; minimal values were 35, 26 and 25% of predrug values for the three doses, respectively. Thermography and plethysmography were less sensitive for detecting effects of TGLVP than laser Doppler flowmetry. Minor effects on blood pressure and heart rate were recorded after TGLVP, but no disturbances in electrocardiac activity. Urinalyses revealed an antidiuretic action of TGLVP. The study supports earlier findings and suggests a dose level of TGLVP for the use in excision of burns.

Circulatory and renal effects of triglycyl-lysine-vasopressin and excision in experimental burns.

The circulatory and renal effects of a deep dermal burn, covering one third of the total body surface area were studied in 12 thiopentone/N2O anesthetized piglets. Central circulation and renal function was monitored during 24 h and regional blood flows were determined before burn, 5 and 24 h after burn using radioactively labeled microspheres. One group was treated conservatively with fluid infusion only (control group) and the other with fluids, intermittent injections of a long-acting hormonogen, triglycyl-lysine-vasopressin (TGLVP), and excision 5 h after burn. There was earlier circulatory recovery in the TGLVP excision group with significantly higher arterial blood pressure and cardiac output than in the controls. TGLVP induced a major redistribution of blood flows, favoring the liver at the expense of the gastrointestinal tract, carcass and skin, while the blood flows were unchanged to the brain, heart and kidneys. There were also increased excretions of sodium and potassium and a temporarily increased diuresis. The earlier circulatory stabilization and blood flow redistribution might have clinical implications in burn care.

Reduction of blood loss by triglycyl-lysine-vasopressin during early excision of burns in pigs.

In a burn model using anesthetized piglets, the circulatory and renal effects and the blood loss during and after excision were compared in two groups, one treated by triglycyl-lysine-vasopressin (TGLVP) given as intermittent bolus injections and the other serving as control. The third degree burn covered approximately 33% of the body surface area, and a solution containing 100 mmol NaCl/l in 2.5% glucose was infused at a rate of 2.4 ml/kg/% burn. Regional blood flows were determined before burn, 5 and 24 h after burn with the aid of radioactively labeled microspheres. Cardiac output (CO) decreased about 30% after burn and there was a slight further decrease of CO after the first TGLVP dose. After the excision there were similar restitutions of CO in the two groups. TGLVP induced an increase of blood flow to the hepatic artery, did not change flows to the brain, heart and kidneys and decreased flows to the preportal organs, carcass and skin 5 h after burn. After 24 h the perfusion of the skin and pancreas remained low but there were no differences in other organs. There was a significant decrease of blood loss associated with burn excision performed 5 h after burn in the TGLVP treated group, mean blood loss 39 g/25 kg versus 145 g/25 kg in the control group. There was a temporary increase in diuresis following TGLVP and also increased excretions of sodium and potassium. The results obtained in this study and possible clinical applications are discussed.

Triglycyl-lysine-vasopressin or lysine-vasopressin in early excision of burns. An experimental study comparing the effects on blood loss, hemodynamics and renal function.

Twelve piglets were submitted to a third degree burn covering one third of total body surface area under general anesthesia. Fluid treatment was given in amounts corresponding to 2.4 ml/kg/% burn/24 h, and hemodynamics and renal function were monitored for 24 h. Regional blood flows were determined with the aid of the radioactive microsphere technique before burn, 5 and 24 h after burn respectively. One group was treated with triglycyl-lysine-vasopressin (TGLVP) as bolus injections and the other with lysine-vasopressin (LVP) in infusion. Both groups were submitted to excision of the burned tissues after 5 h. Total blood loss was 39 +/- 9 g in the TGLVP group and 51 +/- 7 g in the LVP group (n.s.). TGLVP changed the distribution of cardiac output (CO) more than LVP did, leading to smaller blood flows to the splanchnic organs, skin and carcass while the perfusion of the brain, heart, liver and kidneys was similar after 5 h. The burn caused a 30% decrease of CO in both groups. After the first TGLVP injection there was a small further decrease in CO but after excision there were similar recoveries of CO in both groups. After 24 h the CO redistribution remained during LVP infusion, but those effects had almost vanished in the TGLVP group. Total diuresis and the glomerular filtration rate tended to be larger during LVP treatment but there was no significant difference in serum creatinine after 24 h. Thus both drugs decrease blood loss during early excision and they seem to have similar effects on circulation and renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

CONTROLLED TRIAL OF TERLIPRESSIN ('GLYPRESSIN') VERSUS VASOPRESSIN IN THE EARLY TREATMENT OF OESOPHAGEAL VARICES

In a randomised controlled trial the effect of intermittent bolus injection of triglycyl lysine vasopressin (terlipressin, 'Glypressin') (2 mg 6-hourly), an analogue of vasopressin, was compared with that of a constant peripheral intravenous infusion of vasopressin (0.4 units/min) in the initial management of bleeding oesophageal varices in nineteen patients. Failure of vasopressin therapy was defined as continued bleeding of sufficient severity to necessitate the passage of a Sengstaken tube. Bleeding was controlled in 70% of patients treated with glypressin but in only 9% of patients given vasopressin. The glypressin group required significantly less blood after randomisation than the vasopressin group. Because of its efficacy, lack of side-effects, and ease of administration, glypressin appears to be valuable in the management of bleeding varices.

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

Triglycyl-lysine vasopressin (tGLVPP) is activated in the circulation when the N-triglycyl residue of the molecule is cleaved by endothelial peptidases, releasing lysine vasopressin. We compared the effect of an intravenous bolus dose of tGLV (20 micrograms/kg) with a constant infusion (2.75 mU/kg/min) of arginine and lysine vasopressin (Pitressin) 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 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.

Haemostatic effects of lysine vasopressin and triglycyl lysine vasopressin infusion in patients with cirrhosis.

Eight patients with cirrhosis were infused with lysine vasopressin (10 microgram LVP) and triglyclylysine vasopressin (750 microgram and 2000 microgram Glypressin, GVP) on separate occasions. LVP infusion resulted in an increase in factor VIII, factor VIII-related antigen and plasminogen activator (PA). The factor VIII antigen: activity ratio decreased following infusion, but factor VIII electrophoretic mobility and in vitro decay rate were unchanged. GVP infusion produced no change in factor VIII or PA. Assay of vasopressin-like antigen and antidiuretic activity showed that GVP is cleaved to LVP in vivo. The low levels of LVP formed by this reaction might explain the prolonged vasometer effects of GVP, as well as its inability to cause release of factor VIII or PA. Compared to LVP, GVP has a longer pressor effect in vivo, has no effect on fibronolysis and exhibits no cardiotoxic effects and may therefore be the treatment of choice in bleeding oesophageal varices.

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

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.