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The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期292卷 584-596页

作者： Bartolomeo, AC Morris, H Buccafusco, JJ Kille, N Rosenzweig-Lipson, S Husbands, MG Sabb, AL Abou-Gharbia, M Moyer, JA Boast, CA Wyeth Ayerst Res CNS Disorders Div Cent Nervous Syst Med Chem Cent Nervous Syst Res Princeton NJ 08543 USA Med Coll Georgia Dept Pharmacol & Toxicol Alzheimers Res Ctr Augusta GA 30912 USA Vet Adm Med Ctr Augusta GA 30904 USA

Muscarinic M1 preferring agonists may improve cognitive deficits associated with Alzheimer's disease. Side effect assessment of the M1 preferring agonist WAY-132983 showed significant salivation (10 mg/kg i.p. or p.o.) and produced dose-dependent hypothermia after i.p. or p.o. administration. WAY-132983 significantly reduced scopolamine (0.3 mg/kg i.p.) induced hyperswimming in mice. Cognitive assessment in rats used pretrained animals in a forced choice, 1-h delayed non-match-to-sample radial arm maze task. WAY-132983 (0.3 mg/kg i.p) significantly reduced scopolamine (0.3 mg/kg s.c.)-induced errors. Oral WAY-132983 attenuated scopolamine-induced errors;that is, errors produced after combining scopolamine and WAY-132983 (to 3 mg/kg p.o.) were not significantly increased compared with those of vehicle-treated control animals, whereas errors after scopolamine were significantly higher than those of control animals. With the use of miniosmotic pumps, 0.03 mg/kg/day (s.c.) WAY-132983 significantly reduced AF64A (3 nmol/3ml/lateral ventricle)-induced errors. Verification of AF64A cholinotoxicity showed significantly lower choline acetyltransferase activity in the hippocampi of AF64A-treated animals, with no significant changes in the striatal or frontal cortex. Cognitive assessment in primates involved the use of pretrained aged animals in a visual delayed match-to-sample procedure. Oral WAY-132983 significantly increased the number of correct responses during short and long delay interval testing. These effects were also apparent 24 h after administration. WAY-132983 exhibited cognitive benefit at doses lower than those producing undesirable effects;therefore, WAY-132983 is a potential candidate for improving the cognitive status of patients with Alzheimer's disease.

关键词：氮丙啶类/药理学行为动物/药物作用脑/代谢桥基化合物/投药和剂量桥基化合物/药理学桥基化合物/毒性胆碱/类似物和衍生物胆碱/药理学胆碱O-乙酰转移酶/代谢认知/药物作用剂量效应关系药物药物相互作用额叶/药物作用额叶/代谢海马/代谢低温/化学诱导恒河猴毒蕈碱激动剂/投药和剂量毒蕈碱激动剂/药理学毒蕈碱激动剂/毒性神经肌肉阻滞药/药理学吡嗪类/投药和剂量吡嗪类/药理学吡嗪类/毒性吡啶类/药理学大鼠 Sprague-Dawley 唾液分泌/药物作用东莨菪碱/药理学噻二唑类/药理学时间因素视皮质/药物作用视皮质/代谢动物女(雌)性男(雄)性小鼠大鼠

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Two mechanisms for the meperidine block of action potential production in frog's skeletal muscle;non‐specific and opiate drug receptor mediated blockade.

引用

The Journal of Physiology 1975年第3期252卷 585-601页

作者： Frank, G.B.

The effects of meperidine and naloxone, and their interaction effects on action potential production in frog's sartorius muscle fibres, were studied with intracellular micro‐electrode techniques. 1. Meperidine, a narcotic analgesic drug, depressed the rate of rise, the rate of fall and the amplitude of the action potentials. 2. At a meperidine concentration of 0‐35 mM, the depression in the action potential maximum rate of rise followed a diphasic time course. At first there was a rapid reduction in the maximum rate of rise which was levelling off at about 60% of control 60‐90 min after drug application. This was followed by the second phase during which there was an initial rapid decrease in the maximum rate of rise and all surface fibres were inexcitable by 180 min. 3. The addition of naloxone, a narcotic antagonist, in low concentrations (3 X 10(‐5) to 3 X 10(‐4) mM) at 70‐90 min blocked the second phase of the meperidine‐induced depression. 4. With lower concentrations of meperidine (0‐18 and 0‐07 mM) the depression usually developed more slowly (up to 6 hr with the latter dose) and the addition of low naloxone concentrations partially antagonized the effects of meperidine. However, under no conditions was it possible to completely antagonize the effects of meperidine by the addition of naloxone. 5. A linear relation was found between action potential amplitude and the action potential maximum rate of fall. 6. Meperidine caused a shift in the relation of rate of fall against amplitude to higher action potential amplitudes, indicating that the drug inhibited the increase in potassium conductivity (gK) associated with the falling phase of the action potential. 7. When low naloxone concentrations antagonized the effects of meperidine on the rate of rise and restored action potential amplitudes to control levels, the effect of meperidine on the maximum rate of fall was not antagonized. 8. Larger naloxone concentrations (1‐5 X 10(‐2) mM or more) depressed the action

关键词：动作电位/药物作用无尾目动力学哌替啶/拮抗剂和抑制剂哌替啶/药理学肌/药物作用肌/生理学纳洛酮/药理学神经肌肉阻滞药/药理学豹纹蛙受体药物钠/生理学时间因素动物

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Practical pediatric regional anesthesia

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Anesthesiology Clinics of North America 2002年第1期20卷 83-113页

作者： Suresh, Santhanam Wheeler, Melissa Department of Anesthesiology Children's Memorial Hospital Northwestern Univ. Medical School Chicago IL 60614 United States

In children, regional anesthetic techniques are safe and effective adjuncts to general anesthesia and for postoperative pain relief. Application of the techniques described in this article will contribute to improved care for pediatric patients undergoing surgical procedures. The judicious choice of local anesthetics, along with the blockades of targeted nerves, decrease the need for supplemental analgesics in the recovery phase.

关键词：腹部麻醉传导麻醉硬膜外麻醉脊椎麻醉药局部/药理学麻醉药局部/毒性四肢神经传导阻滞神经肌肉阻滞药/药理学神经肌肉阻滞药/毒性儿童儿童学龄前人类婴儿婴儿新生

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Botulinum toxin A (Allergan). AGN 191622, Botox.

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Drugs in R&D 1999年第6期2卷 381-382页

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