SUMMARYAim: To investigate the inhibitory effects on gastric acid secretion of three proton pump inhibitors, omeprazole, lansoprazole and rabeprazole, using a three-way crossover design in healthy Helicobacter pylori-negative, S-mephenytoin 4¢-hydroxylase (CYP2C19) 1 homo-and hetero-extensive metabolizers. Methods: Eight healthy Japanese male volunteers were enrolled. After the administration of rabeprazole (10 mg ⁄ day), lansoprazole (30 mg ⁄ day) or omeprazole (20 mg ⁄ day), intragastric pH monitoring was commenced from 24 h before the first proton pump inhibitor dose, and continued for days 1-3 after proton pump inhibitor administration. The pH electrode was used for 48 h and changed just before pH monitoring on day 2. Results: For the administration of 10 mg ⁄ day rabeprazole, the mean ratios of the 24-h pH ‡ 3 holding time were 5.7 ± 1.1%,13.6 ± 2.2%, 35.3 ± 2.7% and 62.8 ± 3.1% for the pre-treatment day and days 1, 2 and 3, respectively. The same ratios for lansoprazole (30 mg ⁄ day) were 5.7 ± 0.7%, 7.4 ± 1.5%, 13.6 ± 3.4% and 26.6 ± 4.9%; the same ratios for 20 mg ⁄ day omeprazole were 5.9 ± 0.9%, 6.1 ± 1.2%, 11.4 ± 2.8% and 16.4 ± 4.6%. The mean ratio of the 24-h pH ‡ 3 holding time of days 1-3 increased significantly compared to the pre-treatment day (P < 0.01) with the administration of rabeprazole and lansoprazole. The magnitude of inhibition of gastric acid secretion after rabeprazole administration was stronger than that after lansoprazole. A significant elevation of the mean ratio of the 24-h pH ‡ 3 holding time was demonstrated on days 2 and 3 with omeprazole (P < 0.01). Conclusions: In H. pylori-negative CYP2C19 extensive metabolizers, rabeprazole (10 mg ⁄ day) shows a faster onset of rising intragastric pH and a stronger inhibition of gastric acid secretion than do lansoprazole (30 mg ⁄ day) or omeprazole (20 mg ⁄ day).
Using radioreceptor assay with [3H]ce-bungarotoxin (a-BGT) and [3H]phencyclidine (PCP) as probes for the nicotinic acetylcholine receptor (nAChR) in membranes obtained from honeybee heads, the effects of various nAChR ligands, nicotinoids and neonicotinoids were studied. The data indicated differences in pharmacological characteristics between Torpedo electric organ and honeybee brain nAChRs.[3H]a-BGT binds to the acetylcholine (ACh) recognition site of the nAChRs of vertebrate skeletal muscle, Torpedo electric organ and honeybee brain. In vertebrates, [3H]PCP binds to an allosteric site on the receptors ion channel and its binding is stimulated by receptor activation with agonists.However, the tested vertebrate cholinergic agonists inhibited [3H]a-BGT binding, but did not activate[3H]PCP binding to the honeybee nAChR. Saturation isotherms of the binding of [3H]a-BGT with or without PCP indicated that PCP interacted with the ACh recognition site on the nAChR.Furthermore, nicotine inhibited not only [3H]a-BGT binding but also [3H]PCP binding.Detailed study of [3H]PCP binding indicated that [3H]PCP bound to the honeybee brain membranes both at high and low affinity sites. The former corresponded to the vertebrate allosteric site on the nAChR and the latter to the ACh recognition site. Nicotine, anabasine and nitenpyram bound to both sites, while imidacloprid, 6-Cl-PMNI and acetamiprid bound selectively to the ACh recognition site. In houseflies, nicotine and imidacloprid produced excitation followed by paralysis, while PCP was anesthetic, even though PCP was as insecticidal as nicotine.
Effect of various ligands which include Imidacloprid related compounds, on the binding of [3H]phencyclidine (PCP) known as a probe for the allosteric site located in the receptors ion channel and [3H]a-bungarotoxin (a-BGT) known as a probe for the acetylcholine (ACh) recognition site of the nicotinic acetylcholine receptor with its ion channel from the Torpedo electric organ, was examined. Nicotine and anabasine showed a strong agonistic action like carbachol and cytisine, whereas imidacloprid, 6-Cl-PMNI, acetamiprid, NMTHT, nitenpyram and MTENI were weakly agonistic. NMTHT, nitenpyram and MTENI were also noncompetitive blockers like coniine, DMPP, nereistoxin and d-tubocurarine which interacted with both the ACh recognition site and the allosteric site. PCP, TCP, ketamine, chlorpromazine and mecamylamine were noncompetitive blockers; also lobeline and trimethaphan were found to be noncompetitive blockers as against text books.
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