Reversible inhibitors of monoamine oxidase-A (RIMAs): robust, reversible inhibition of human brain MAO-A by CX157.
Reversible inhibitors of monoamine oxidase-A (RIMAs): robust, reversible inhibition of human brain MAO-A by CX157.
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DOI：
10.1038/npp.2009.167
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发表时间：
2010-02
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影响因子：
--
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中科院分区：
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可逆性单胺氧化酶-A抑制剂（RIMA）抑制三种主要神经递质，5-羟色胺，去甲肾上腺素和多巴胺的分解，为抑郁症的治疗提供了一种多神经递质策略。CX 157（3-氟-7-（2，2，2-三氟乙氧基）吩恶噻-10，10-二氧化物）是一种RIMA，目前正在开发用于治疗重度抑郁症。我们检查了口服给药后不同时间脑单胺氧化酶-A（MAO-A）和血浆CX 157水平抑制的程度和可逆性，以建立未来临床疗效研究的给药模式，并确定血浆CX 157水平是否反映脑MAO-A抑制的程度。15名正常男性口服CX 157（20-80 mg）后，用正电子发射断层扫描（PET）和[11 C]氯吉林测定脑MAO-A水平。在24小时的时间过程中，在单次和重复剂量的CX 157后进行PET成像。我们发现，60和80 mg剂量的CX 157在给药后2 h对[11 C]氯吉林与脑MAO-A的结合产生了强烈的剂量相关抑制（47-72%），并且脑MAO-A在给药后24 h完全恢复。血浆CX 157浓度与脑MAO-A的抑制高度相关（EC 50：19.3 ng/ml）。因此，CX 157是RIMA类中第一种对人脑MAO-A具有记录的可逆抑制的药物，支持其被分类为RIMA，并且是第一种具有可用作脑MAO-A抑制程度的生物标志物的观察到的血浆水平的RIMA。这些数据用于确定当前CX 157临床疗效试验的给药方案。
Reversible inhibitors of monoamine oxidase-A (RIMA) inhibit the breakdown of three major neurotransmitters, serotonin, norepinephrine and dopamine, offering a multi-neurotransmitter strategy for the treatment of depression. CX157 (3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin-10,10-dioxide) is a RIMA, which is currently in development for the treatment of major depressive disorder. We examined the degree and reversibility of the inhibition of brain monoamine oxidase-A (MAO-A) and plasma CX157 levels at different times after oral dosing to establish a dosing paradigm for future clinical efficacy studies, and to determine whether plasma CX157 levels reflect the degree of brain MAO-A inhibition. Brain MAO-A levels were measured with positron emission tomography (PET) imaging and [11C]clorgyline in 15 normal men after oral dosing of CX157 (20–80 mg). PET imaging was conducted after single and repeated doses of CX157 over a 24-h time course. We found that 60 and 80 mg doses of CX157 produced a robust dose-related inhibition (47–72%) of [11C]clorgyline binding to brain MAO-A at 2 h after administration and that brain MAO-A recovered completely by 24 h post drug. Plasma CX157 concentration was highly correlated with the inhibition of brain MAO-A (EC50: 19.3 ng/ml). Thus, CX157 is the first agent in the RIMA class with documented reversible inhibition of human brain MAO-A, supporting its classification as a RIMA, and the first RIMA with observed plasma levels that can serve as a biomarker for the degree of brain MAO-A inhibition. These data were used to establish the dosing regimen for a current clinical efficacy trial with CX157.
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影响因子：
56.9
作者：
FOWLER, JS;MACGREGOR, RR;LANGSTROM, B
通讯作者：
LANGSTROM, B
影响因子：
3.1
作者：
ALEXOFF, DL;SHEA, C;WOLF, AP
通讯作者：
WOLF, AP
影响因子：
16.1
作者：
Bortolato, Marco;Chen, Kevin;Shih, Jean C.
通讯作者：
Shih, Jean C.
DOI：
10.1111/j.1365-2125.1990.tb05445.x
发表时间：
1990-12-01
影响因子：
3.4
作者：
BERLIN, I;ZIMMER, R;PUECH, AJ
通讯作者：
PUECH, AJ
影响因子：
10.5
作者：
BLACKWELL, B;MARLEY, E;TAYLOR, D
通讯作者：
TAYLOR, D