Effect of lintitript, a new CCK-A receptor antagonist, on gastric emptying of a solid-liquid meal in humans.

The role of cholecystokinin (CCK) in the regulation of gastric emptying of physiological meals containing solids and liquids in humans remains controversial. We studied the role of endogenous CCK in the emptying of a solid/liquid meal administering the new, highly specific and potent CCK-A receptor antagonist lintitript. Gastric emptying was assessed in nine healthy male volunteers using a randomized, double blind, two-period crossover design with oral lintitript (15 mg 1 h prior to meal intake) or placebo on two different days. After ingestion of a pancake (570 kcal) labelled with 500 microCi of 99mTc-sulfur colloid and 500 ml 10% dextrose containing 80 microCi. 111In-DTPA, subjects were studied in a sitting position, using a dual-headed gamma camera. Plasma CCK and pancreatic polypeptide (PP) were measured by a specific RIA. Lintitript distinctly accelerated gastric emptying of solids, while gastric emptying of liquids was not significantly altered. The lag period was shortened by 20% (P<0.05), AUC and half emptying time of solid emptying were lowered by 12% and 13%, respectively (P<0.03). Lintitript markedly increased postprandial plasma CCK release (P<0.001) while distinctly reducing postprandial PP levels (P<0.01) as compared to placebo. These data provide further evidence for a significant role of CCK in the regulation of gastric emptying of solids. The study demonstrates for the first time the marked gastrokinetic properties of the new CCK-A receptor antagonist lintitript in humans.

Safety, tolerability, and pharmacokinetics of SR 49059, a V1a vasopressin receptor antagonist, after repeated oral administration in healthy volunteers.

UNLABELLED: The conventional evaluation of safety and tolerability during Phase I may not be sufficient for new exploratory non-peptide receptor antagonists as selective vasopressin (AVP) receptor antagonists. Previous research and validation of surrogate markers considerably enhance the understanding of phase I, and may even contribute with high accuracy to an early approach of dose finding. SR 49059 is a new potent and selective non peptide AVP-antagonist, with high affinity, selectivity and efficacy towards both animal and human AVP-V1a receptors. The aim of this study was to assess its tolerability and to determine both its pharmacokinetic and pharmacodynamic profiles. The safety and tolerability of SR 49059 was assessed in an ascending repeated dose tolerability trial, double-blind for each dose. 50 healthy subjects non smoker males, divided into 5 groups (doses) of 10 were included, (8 treated/2 placebo per group) and received oral doses of either 1, 10, 100, 300 or 600 mg of SR 49059 o.d. for 7 days. Clinical tolerability and biological safety was excellent for all subjects up to the highest dose of 600 mg SR 49059 appeared to have no action on AVP plasma level, hemostasis parameters, nor on blood pressure, heart rate, ECG, diuresis or plasma/urine osmolality. Two previously validated surrogate markers using exogenous vasopressin were sufficient to provide evidence of the V1a antagonistic effects of SR 49059 after the first single oral administration, and during the 7 days of treatment: Ex-vivo AVP induced platelet aggregation inhibition: SR 49059 has shown potent antagonistic properties in inhibiting AVP-induced human platelet aggregation in vitro (IC50 = 3.7 nM). Using this ex vivo qualitative test, a dose and time proportional activity was observed at doses as low as 10 mg, and an almost complete inhibition was demonstrated from 100 mg and above, from Day 1 with a steady state level of inhibition from Day 4 up to Day 7. AVP induced blanching skin area inhibition: Intradermic administration of AVP 0.1 ml (25 ng) produced a measurable vasoconstriction (computer analysis of blanching area), which was also dose dependently antagonised by the oral administration of SR 49059 with the same profile as for platelet-aggregation inhibition. Steady state SR 49059 levels were achieved on days 4-5 with moderate (1.8-2.4 fold) accumulation (t1/2: 32 hrs). Cmax values were in the range 0.8-30 ng/ml. The IC50 of AVP (50 nM) -induced platelet aggregation and cutaneous blanching effect were 2.1 +/- 0.7 nM (1.3 ng/mL) and 4.6 +/- 2.5 nM (2.8 ng/mL), respectively. CONCLUSIONS: During early phase I, in addition to the conventional safety profile, validated surrogate markers may provide evidence of activity for selective vasopressin receptor antagonists. The results confirmed that SR 49059 is in human a specific V1a-antagonist without activity at V2 receptors, with a good safety profile.