Finn Larsen

Effect of food on the pharmacokinetics and pharmacodynamics of an oral ghrelin agonist (ARD-07) in healthy subjects.

ARD‐07 (also known as EP01572) is a peptidomimetic growth hormone secretagogue that can be administered orally. The primary objective of this study is to determine the effects of a meal on the oral bioavailability of ARD‐07 after a single oral dose (0.5 mg/kg). In addition, the pharmacodynamic effects (growth hormone release, insulin‐like growth factor‐1 concentrations) and the tolerability of ARD‐07 are investigated in this open‐label, randomized, crossover study. Sixteen healthy subjects (8 males, 8 females) receive ARD‐07 on 2 different days; the treatment consists of a single oral dose of ARD‐07 (0.5 mg/kg body weight), once with and the second day without a test meal. Plasma kinetics of ARD‐07 and pharmacodynamic effects are quantified by specific assays. Results are given as mean ± SEM: The area under the curve for 0 to 24 hours is approximately twice as high without food (27.8 ± 4.1) than with food (13.7 ± 1.2; P = .002). The maximum observed ARD‐07 concentration relative to dose administration (Cmax) is more than twice as high without food (10.6 ± 1.6 ng/mL) than with food (4.4 ± 0.5 ng/mL; P = .001). Cmax of growth hormone occurs at a significantly (P = .001) later stage with food (Cmax = 13.0 ± 3.5 ng/mL) than without food (37.1 ± 5.3 ng/mL). Food has a marked effect on the absorption of ARD‐07: there is a significant difference in bioavailability between administration of oral ARD‐07 with and without food.

Lanreotide Effect on Splanchnic Blood Flow in Healthy Subjects: Effect of the Rate of Infusion

Somatostatin is a naturally occurring peptide advocated for the management of hemodynamic complications of chronic liver diseases. The route of administration (bolus application or constant infusion) has been a question of debate.

Dose-dependent gastrointestinal effects of the somatostatin analog lanreotide in healthy volunteers.

To investigate the gastrointestinal effects of intravenous lanreotide.

EFFECT OF THE SOMATOSTATIN ANALOGUE LANREOTIDE ON MEAL-STIMULATED PORTAL BLOOD FLOW IN PATIENTS WITH LIVER CIRRHOSIS

Background: Lanreotide, a new long-acting somatostatin analogue, has been shown to inhibit the meal-stimulated increase of splanchnic blood flow in healthy volunteers. To date, similar data in patients with liver cirrhosis have not been available. We have examined the effect of lanreotide compared with placebo on meal-stimulated portal blood flow in patients with liver cirrhosis using Doppler ultrasound. Methods: 20 cirrhotic patients (placebo n = 12, lanreotide n = 8) with proven portal hypertension were studied after an overnight fast. Lanreotide, at a dose of 100 µg/h, was infused intravenously over 7 h after a 1-hour basal period. In parallel to the intravenous infusion, a liquid test meal (Ensure plusTM, 1.5 kcal/min) was perfused for 7 h through an intraduodenal tube at a rate of 3 ml/min. Blood pressure, heart rate and portal vein blood flow (PVF, ml/min, Doppler technique) were determined at regular intervals. Results: Baseline PVF amounted to 725 ± 182 ml/min in the placebo and to 917 ± 252 ml/min in the lanreotide group (n.s.). The meal-stimulated increase in PVF was blunted by lanreotide (AUC, %·min): 62,709.6 ± 6,817 (placebo) vs. 45,237 ± 2,507 (lanreotide), p < 0.05. Lanreotide also blunted the postprandial increase in heart rate for the first 2 h of meal perfusion. Conclusions: Because of potent inhibition of postprandial splanchnic hyperemia in patients with liver cirrhosis, lanreotide may be useful in the treatment of complications of portal hypertension.

Blockade of GRP receptors inhibits gastric emptying and gallbladder contraction but accelerates small intestinal transit in humans

BACKGROUND & AIMSnThis study was designed to characterize [D-F(5)Phe(6)D-Ala(11)]Bn(6-13)OMe (BIM26226) as a gastrin-releasing peptide (GRP)-preferring bombesin receptor antagonist and to determine whether GRP physiologically regulates gastrointestinal motility. Intravenous BIM26226 (5-500 microg. kg(-1). h(-1)) inhibits GRP-induced gallbladder contraction and plasma cholecystokinin (CCK) release in a dose-dependent fashion.nnnMETHODSnGastric emptying and small bowel transit of a solid meal were quantified using scintigraphy. Meal-stimulated gallbladder contraction was measured by sonography in a 2-period crossover design.nnnRESULTSnIntravenous BIM26226 potently inhibited gastric lag time (114 +/- 7 vs. 41 +/- 6 minutes [control]) and gastric emptying rate (0.11 +/- 0.02%/min vs. 0.26 +/- 0.04%/min [control]), whereas concomitant infusion of BIM26226 accelerated small bowel transit time (153 +/- 41 vs. 262 +/- 20 minutes [control]). A continuous liquid meal perfusion into the duodenum induced complete gallbladder contraction (t(50%), 35 +/- 4 minutes), which BIM26226 inhibited significantly (t(50%), 64 +/- 8 minutes). BIM26226 did not alter plasma CCK response, indicating that circulating CCK did not mediate these effects.nnnCONCLUSIONSnThese data show that BIM26226 is a potent antagonist of exogenous and endogenous GRP and suggest that GRP is a major physiologic regulator of gastric emptying, small bowel transit, and gallbladder contraction.