Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models.

The preclinical pharmacological profile of 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]amino]ethyl]-2H-1,4-benzoxazin-3(4H)-one monohydrochloride (olodaterol, previously known as BI 1744 CL), a novel, enantiomeric pure, inhaled human beta(2)-adrenoceptor (hbeta(2)-AR) agonist, was compared with marketed drugs, such as salmeterol and formoterol. In vitro, olodaterol showed a potent, nearly full agonistic response at the hbeta(2)-AR (EC(50) = 0.1 nM; intrinsic activity = 88% compared with isoprenaline) and a significant selectivity profile (241- and 2299-fold [corrected] against the hbeta(1)- and hbeta(3)-ARs, respectively). Likewise, olodaterol was able to potently reverse contraction induced by different stimuli in isolated human bronchi. In vivo, antagonistic effects of single doses of olodaterol and formoterol were measured against acetylcholine challenges in anesthetized guinea pigs and dogs for up to 24 h by using the Respimat Soft Mist inhaler. Heart rate and metabolic parameters (serum potassium, lactate, and glucose) were monitored to evaluate systemic pharmacodynamic effects in the dog model. In both models, olodaterol provided bronchoprotection over 24 h. Formoterol applied at an equally effective dose did not retain efficacy over 24 h. In both models olodaterol showed a rapid onset of action comparable with formoterol. Taken together, the preclinical behavior of olodaterol suggests that this novel beta(2)-AR agonist has the profile for once-daily dosing in humans concomitant with a fast onset of action and a favorable systemic pharmacodynamic profile.

Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-à-gogo K(+) channel.

Agonists of the serotonin 5-hydroxytryptamine 4 (5-HT4) receptor are widely used to activate motility in the gastrointestinal tract. Among these, cisapride was recently withdrawn from the U.S. market because of its proarrhythmic effects. Cisapride is a potent blocker of human ether-à-gogo (HERG) K(+) channels and prolongs the cardiac action potential in a reverse use dependence manner. We compared the effects of four different 5-HT4 receptor agonists (cisapride, prucalopride, renzapride and mosapride) on cloned HERG channels with the objective to evaluate and compare their proarrhythmic potential. K(+) currents from HERG-transfected COS-7 cells were recorded under physiological conditions using the whole cell configuration of the patch-clamp technique. Short (500 ms) depolarizing prepulses were used and following deactivating HERG currents were measured. Cisapride inhibited the HERG channels in a concentration-dependent manner with an IC(50) of 2.4 10(-7) M. The IC(50) value for prucalopride to block HERG (5.7 10(-6) M) was 20-fold higher than that of cisapride. Renzapride was slightly more potent than prucalopride (IC(50) = 1.8 10(-6) M). Mosapride produced no significant effects on the recombinant HERG current. The voltage dependence of HERG block was also investigated. The block mediated by cisapride or renzapride was voltage-dependent whereas that produced by prucalopride was not. We conclude that the rank order of potency of 5-HT4 agonists to block HERG is cisapride > renzapride > prucalopride > mosapride. We also conclude that 5-HT4 agonists devoid of side effects on the HERG current such as mosapride can be found as a safe alternative to cisapride.

Effects of intraluminal nutrients on intestinal myoelectric activity in rabbits.

In the unanesthetized rabbit, intraluminal infusions of D- and L-methionine, L-tryptophan, D-glucose, D-xylose, and lactulose had a biphasic effect on small intestinal myoelectric activity. A phase of enhanced activity was followed by a phase of inhibition. The excitatory phase was mimicked by saline solutions equiosmolar to the test solutions. The subsequent inhibition was does dependent and significantly (P less than 0.01) longer for the passively absorbed D-methionine than for the L-stereoisomer. The inhibitory action of 10 mM D-glucose, 10 mM L-methionine, and 5 mM L-tryptophan was blocked by propranolol on the jejunum and by phenoxybenzamine on the ileum. We conclude that the initial excitatory phase induced by luminal amino acids and sugars may be dependent on an action on osmoreceptors, whereas the subsequent inhibitory phase may involve the sympathetic noradrenergic system.

[Diet type, grinding size and anatomo-functional characteristics of the proximal digestive tract in the rabbit]. / Nature de l'aliment, finesse de mouture et données anatomo-fonctionnelles du tube digestif proximal du lapin.

Two diets containing either dehydrated lucerne (40%) or dehydrated beet pulp (50%) both being coarsely (4 mm) of finely (1 mm) ground before pelleting, were fed to 120 rabbits after weaning. Feed intake and weight gain were estimated. After 79 days, 11 rabbits in each group were slaughtered between 14.00 and 17.00 h. The parameters measured were stomach and ileal weights, dry matter, fibre and nitrogen contents, volatile fatty acid concentrations. Gastric emptying and intestinal transit time were estimated in each group. Rabbits fed the beet pulp diet had a better feed conversion ratio associated with a higher solid matter gastric retention and also a longer jejuno-ileal transit time. Finely ground diet further increased the transit time, particularly in the ileum, which was also associated with a higher concentration of fermentation by-products.

Colonic formation of soft feces in rabbits: a role for endogenous prostaglandins.

Rabbits produce hard and soft feces in a circadian rhythm. The motor activity of the haustrated proximal colon is inhibited during the formation of soft feces, whereas the spiking activity of the distal colon is stimulated. A potential role for endogenous prostaglandins (PG) in the control of the soft-feces elaboration by the rabbit colon was investigated in conscious animals by using PGE2 and PGF2 alpha and by inhibiting them with indomethacin. The infusion of both PGE2 and PGF2 alpha induced typical electromechanical events consisting of inhibition of the proximal and stimulation of the distal colon and was followed by soft-pellet defecation. Rabbits accustomed to be fed twice daily produced soft feces at fixed intervals of 252 +/- 32 min after the evening meal, with a soft-to-hard feces ratio of 1.45. After indomethacin treatment, this ratio was significantly (P less than 0.01) reduced to 0.92. These results are consistent with the concept that endogenous prostaglandins play a major role in the motor function involved in soft-feces formation by the rabbit.

[Physico-chemical stimulation of dietary origin and digestive motility in the rabbit]. / Stimulation physico-chimique d'origine alimentaire et motricité digestive chez le lapin.

The effects on gastrointestinal motility of two different diets, one containing dehydrated lucerne and the other dehydrated beet pulp (both being either coarsely or finely ground before pelleting) were studied in 16 unanesthetized 50-60-day old rabbits fed ad libitum. The rabbits fed with lucerne had better antroduodenal and ileo-caecal coordination, a higher level of electrical activity on the duodenum, and more frequent migrating myoelectric complexes on the jejunum and ileum than those fed with beet pulp. Furthermore, the rabbits fed the finely ground pellets showed weak electrical activity on the ileum and poor ileo-caecal coordination irrespective of fiber source, suggesting a unique effect of size per se on these portions of the digestive tract.