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Prokinetic Activity (prokinetic + activity)
Selected AbstractsDifferences between the abilities of tegaserod and motilin receptor agonists to stimulate gastric motility in vitroBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2007E M Jarvie Background and purpose: Motilin or 5-HT4 receptor agonists stimulate gastrointestinal motility. Differences in activity are suggested but direct comparisons are few. A method was devised to directly compare the gastric prokinetic activities of motilin, the motilin receptor agonist, erythromycin, and the 5-HT4 receptor agonist, tegaserod. Experimental approach: Gastric prokinetic-like activity was assessed by measuring the ability to facilitate cholinergically-mediated contractions evoked by electrical field stimulation (EFS) in rabbit isolated stomach. Comparisons were made between potency, maximal activity and duration of responses. Key results: Rabbit motilin (r.motilin) 0.003,0.3,M, [Nle13]motilin 0.003,0.3,M, erythromycin 0.3,10,M and tegaserod 0.1,10,M caused concentration , dependent potentiation of EFS-evoked contractions. The potency ranking was r.motilin = [Nle13]motilin > tegaserod > erythromycin. The Emax ranking was r.motilin = [Nle13]motilin = erythromycin > tegaserod. Responses to r.motilin and [Nle13]motilin faded rapidly (t1/2 9 and 11 min, respectively) whereas those to erythromycin and tegaserod were maintained longer (t1/2 24 and 28 min). The difference did not appear to be due to peptide degradation. A second application of [Nle13]motilin was excitatory after 60 min contact and fade of the initial response (responses to 0.03 and 0.1,M [Nle13]motilin were not different from those caused by the first application). Conclusions and implications: Prokinetic-like activities of the 5-HT4 agonist tegaserod and the motilin receptor agonists were compared by measuring changes in cholinergically-mediated contractions. This novel approach highlighted important differences between classes (greater Emax of motilin, compared with tegaserod) and for the first time, within each class (short t1/2 for motilin, compared with erythromycin). British Journal of Pharmacology (2007) 150, 455,462. doi:10.1038/sj.bjp.0707118 [source] Effect of oral clarithromycin on gall-bladder motility in normal subjects and those with gall-stonesALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2006S. SENGUPTA Summary Background Motilin receptor stimulation with erythromycin has been shown to have a prokinetic effect on gall-bladder motility in human beings. Aim To find out whether oral clarithromycin has similar prokinetic activity to erythromycin on fasting and postprandial gall-bladder emptying in normal humans and those with gall-stone disease. Methods In a blinded two-way crossover study clarithromycin 500 mg and a placebo were administered to 10 normal subjects and 10 subjects with gall-stone disease. Gall-bladder volumes were assessed in the fasting and postprandial state. Results Fasting volumes were significantly less following clarithromycin administration in both normal subjects and subjects with gall-stones compared with placebo (12.1 ± 1.8 mL vs. 17.8 ± 2.0 mL, P < 0.05 and 16.7 ± 2 mL vs. 26.8 ± 7.2 mL, P < 0.02, mean ± S.E.M). Postprandial volumes were also significantly less following clarithromycin administration. Ejection fraction significantly increased following clarithromycin in both normal subjects (66 ± 5.8% vs. 37 ± 5.9%, P = 0.02) and subjects with gall-stones (45 ± 3.2 vs. 20 ± 1.6%, P < 0.02). Conclusion Clarithromycin enhances both fasting and postprandial gall-bladder contraction in normal humans and also in those with gall-stone disease. [source] Translating 5-HT4 receptor pharmacologyNEUROGASTROENTEROLOGY & MOTILITY, Issue 12 2009G. J. Sanger Abstract, Since metoclopramide was first described (in 1964) there have been several attempts to develop compounds which retained gastrointestinal prokinetic activity (via 5-HT4 receptor activation) but without the limiting side effects associated with dopamine D2 receptor antagonism. Early compounds (mosapride, cisapride, renzapride, tegaserod) were identified before several of the 5-HT receptors were even described (including 5-HT4 and 5-HT2B), whereas prucalopride came later. Several compounds were hampered by non-selectivity, introducing cardiac liability (cisapride: activity at human Ether-a-go-go Related Gene) or potentially, a reduced intestinal prokinetic activity caused by activity at a second 5-HT receptor (renzapride: antagonism at the 5-HT3 receptor; tegaserod: antagonism at the 5-HT2B receptor). Poor intrinsic activity at gastrointestinal 5-HT4 receptors has also been an issue (mosapride, tegaserod). Perhaps prucalopride has now achieved the profile of good selectivity of action and high intrinsic activity at intestinal 5-HT4 receptors, without clinically-meaningful actions on 5-HT4 receptors in the heart. The progress of this compound for treatment of chronic constipation, as well as competitor molecules such as ATI-7505 and TD-5108, will now be followed with interest as each attempts to differentiate themselves from each other. Perhaps at last, 5-HT4 receptor agonists are being given the chance to show what they can do. [source] Increased colonic transit in rats produced by a combination of a cholinesterase inhibitor with a 5-HT4 receptor agonistNEUROGASTROENTEROLOGY & MOTILITY, Issue 11 2009K. Campbell-dittmeyer Abstract, Increased cholinergic stimulation and accelerated gastrointestinal (GI) transit may be produced by direct stimulation of the acetylcholine (ACh) receptor with an appropriate agonist by increased release of ACh from cholinergic nerve terminals or by a decreased removal or breakdown of ACh within cholinergic synapses. The acetylcholinesterase inhibitor, neostigmine, and the 5-HT4 receptor partial agonist tegaserod, are two agents with known prokinetic activity which work by different mechanisms that result in increased levels of ACh at cholinergic synapses innervating intestinal smooth muscle. Here, we aimed to investigate the potential synergistic effect on colonic transit that may occur with concomitant use of these two agents. Colonic transit was indirectly assessed in rats via measurements of fecal pellet output every 30 min for 2.5 h following administration of neostigmine (0.003,0.1 mg kg,1, i.p.), tegaserod (0.01,1.0 mg kg,1, i.p.), or a combination of both compounds. When administered alone, neostigmine or tegaserod caused a dose-dependent increase in fecal pellet output. In combination, low doses of the two agents which did not produce statistically significant effects alone, compared to the vehicle, caused a significant increase in fecal pellet output. Combinations of higher doses of neostigmine and tegaserod did not display synergy. In summary, when combined at low doses, neostigmine and tegaserod produce synergistic effects manifested by a statistically significant increase in the expulsion of fecal pellets. A combination of an anticholinesterase agent with a 5-HT4 receptor agonist may prove to be a useful therapeutic approach to treat conditions associated with slow GI transit. 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