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首页> 外文期刊>Life sciences >PHASE I CLINICAL TRIALS WITH WAL 2014, A NEW MUSCARINIC AGONIST FOR THE TREATMENT OF ALZHEIMERS DISEASE
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PHASE I CLINICAL TRIALS WITH WAL 2014, A NEW MUSCARINIC AGONIST FOR THE TREATMENT OF ALZHEIMERS DISEASE

机译：WAL 2014的I期临床试验，一种治疗老年性痴呆的新型肌理药

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The safety, tolerability and pharmacological activity of WAL, 2014, a new centrally-acting M(1) agonist were examined in two clinical studies (0.5 - 80 mg and 100 - 160 mg). Single increasing p.o. doses were administered to groups of 8 volunteers (6 verum, 2 placebo) each. Both studies were placebo controlled with single-blind observation within the respective dose groups. Vital functions (BP, HR, resp. rate) did not reveal any clinically significant substance-induced changes up to a dose level of 60 mg. A slight, but obvious increase in HR was measured with a dose of 80 mg and higher; a slight increase in systolic BP was registered at the dose levels of 120 and 160 mg. No substance-related alterations were observed in the laboratory tests (exception: a significant, reversible increase of the salivary fraction of alpha-amylase in 3 volunteers at the dose levels 100 mg - 140 mg). The majority of volunteers reported an increased salivary secretion with doses of 40 mg and higher; this was confirmed by the greater volume of measured saliva. Furthermore, with doses of 100 mg upwards there were isolated reports of side effects such as a desire to urinate, a burning sensation on urination, increased lacrimation and nasal secretion, disturbances of accommodation, heartburn, rumbling of the stomach as well as cramps, nausea, diarrhoea, excessive sweating and palpitation. WAL 2014 did not cause any abnormal changes in the EEG. Dose dependent central effects were observed with 40, 60, 80, 100 and 140 mg treatments. Pharmacokinetic data indicate a rapid and good absorption and an absolute bioavailability greater than or equal to 70%. The pharmacodynamic and side effects observed in both studies are regarded as being drug-dependent and might be due to the cholinergic activity of the compound and a weak sympathetic activation via M(1) receptors. In summary, the substance did not produce any effects in the dose range tested to suggest further use in man might be inadvisable. [References: 13]
机译：在两项临床研究（0.5-80 mg和100-160 mg）中研究了WAL，2014年一种新的中枢作用M（1）激动剂的安全性，耐受性和药理活性。单点增加剂量分别由8名志愿者组成（6名verum，2名安慰剂）。两项研究均在各自剂量组内以单盲观察进行安慰剂对照。直至60 mg的剂量水平，其重要功能（血压，心率，缓解率）均未显示任何临床上由物质引起的显着变化。剂量为80 mg或更高时，HR略有升高，但明显升高。在120和160 mg剂量水平时，收缩压略有增加。在实验室测试中未观察到与物质相关的变化（例外：3位志愿者在100 mg-140 mg剂量水平下唾液中α-淀粉酶的唾液分数显着可逆地增加）。大多数志愿者报告唾液分泌增加，剂量为40 mg或更高;大量的唾液被证实了这一点。此外，当剂量超过100 mg时，有单独的副作用报告，例如排尿欲望，排尿时灼热感，流泪和鼻分泌物增多，调节障碍，胃灼热，胃部隆隆，抽筋，恶心，腹泻，过度出汗和心慌。 WAL 2014没有引起脑电图的任何异常变化。用40、60、80、100和140 mg治疗观察到剂量依赖性中枢作用。药代动力学数据表明吸收迅速且良好，绝对生物利用度大于或等于70％。在两项研究中观察到的药效学和副作用被认为是药物依赖性的，可能是由于该化合物的胆碱能活性和通过M（1）受体的弱交感性激活。总之，该物质在所测试的剂量范围内未产生任何影响，建议不建议在人体内进一步使用。 [参考：13]

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