BACKGROUND AND PURPOSEAMG 181 is a human anti-a4b7 antibody currently in phase 1 and 2 trials in subjects with inflammatory bowel diseases. AMG 181 specifically targets the a4b7 integrin heterodimer, blocking its interaction with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), the principal ligand that mediates a4b7 T cell gut-homing. EXPERIMENTAL APPROACHWe studied the in vitro pharmacology of AMG 181, and the pharmacokinetics and pharmacodynamics of AMG 181 after single or weekly i.v. or s.c. administration in cynomolgus monkeys for up to 13 weeks. KEY RESULTSAMG 181 bound to a4b7, but not a4b1 or aEb7, and potently inhibited a4b7 binding to MAdCAM-1 (but not vascular cell adhesion molecule-1) and thus inhibited T cell adhesion. Following single i.v. administration, AMG 181 Cmax was dose proportional from 0.01 to 80 mg·kg -1 , while AUC increased more than dose proportionally. Following s.c. administration, dose-proportional exposure was observed with single dose ranging from 5 to 80 mg·kg -1 and after 13 weekly doses at levels between 20 and 80 mg·kg -1 . AMG 181 accumulated two-to threefold after 13 weekly 80 mg·kg -1 i.v. or s.c. doses. AMG 181 had an s.c. bioavailability of 80%. The linear elimination half-life was 12 days, with a volume of distribution close to the intravascular plasma space. The mean trend for the magnitude and duration of AMG 181 exposure, immunogenicity, a4b7 receptor occupancy and elevation in gut-homing CD4+ central memory T cell count displayed apparent correlations. CONCLUSIONS AND IMPLICATIONSAMG 181 has in vitro pharmacology, and pharmacokinetic/pharmacodynamic and safety characteristics in cynomolgus monkeys that are suitable for further investigation in humans.
The possibility that adenosine modulates voltage-dependent conductances in locus coeruleus neurons was investigated in current-clamp and voltage-clamp experiments in a totally submerged rat brain slice preparation. Adenosine (100 PM) reduced the duration of control action potentials and action potentials prolonged by 1 mM barium. Adenosine (100 @I) also reduced the amplitude and slightly reduced the duration of TTX-resistant "calcium" action potentials. Action potential duration was also reduced by the adenosine receptor agonist 2-chloroadenosine in a concentration-dependent manner and the adenosine-induced reduction of action potential duration was blocked by the adenosine receptor antagonist 8-(psulfophenyl)theophylline, indicating that this action of adenosine is mediated by an adenosine receptor. The adenosine-induced reduction of action potential duration persisted in the presence of externally applied tetraethylammonium ion (6 mM) and cesium (3 mM). By contrast, adenosine did not reduce the duration of the action potential in the presence of 500 I.~M 4-aminopyridine (4-AP). Furthermore, 4-AP (30 PM) blocked the adenosine-induced reduction of action potential duration recorded in the presence of 1 mM barium. These data suggested that adenosine may be acting on the voltage-dependent, 4-AP-sensitive potassium current, /,. Single-electrode voltage clamp was used to study IA directly. 1, was activated by depolarizing voltage pulses from a hyperpolarized holding potential and was blocked by 1 mM 4-AP. Adenosine (300 NM) enhanced I,, by shifting the steady-state inactivation curve in the depolarizing direction. The mean shift of the curve at 80% inactivation was 4.6 mV, which increases the amount of IA available for activation at the threshold potential by 2.5-fold. The same concentration of 4-AP (30 PM) that blocked the adenosine-induced reduction in spike duration, completely blocked /, evoked from threshold potential. These data suggest that adenosine reduces action potential duration of locus coeruleus neurons through enhancement of IA.
The aim of this research was to study the influence of a high-carbohydrate diet on the growth and lipid metabolism of Megalobrama amblycephala. Wheat starch (carbohydrate source) and soybean oil (lipid source) were used to prepare a semipurified diet (control) and a high-carbohydrate diet (experimental). A series of measurements were conducted, which included growth performance, blood biochemical indices, muscle components, fatty acid composition, liver lipid deposition, and tissue structure. Results indicated that high levels of carbohydrate significantly reduce weight gain, specific growth rate, protein efficiency, and muscle protein content and increase lipids in fish. Composition of the muscle fatty acids was also altered and the activity of the hepatopancreatic lipid-metabolism enzymes decreased. A large quantity of lipid droplets, and vacuole degeneration, were observed in fish liver sections of the experimental group, indirectly suggesting a negative effect of a high-carbohydrate diet on the liver of M. amblycephala.
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