Silveira Pedro, Vaz-da-Silva Manuel, Almeida Luis, Maia Joana, Falcão Amilcar, Loureiro Ana, Torrão Leonel, Machado Rita, Wright Lyndon, Soares-da-Silva Patrício
Department of Research and Development, BIAL, A Av. da Siderurgia Nacional, 4745-457 S. Mamede do Coronado, Portugal.
Eur J Clin Pharmacol. 2003 Nov;59(8-9):603-9. doi: 10.1007/s00228-003-0680-5. Epub 2003 Sep 27.
BIA 3-202 is a novel catechol-O-methyltransferase (COMT) inhibitor being developed for use as a levodopa-sparing agent in Parkinson's disease. This study investigated the effect of four single oral doses of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg) compared with placebo on plasma concentrations of levodopa and its metabolite 3- O-methyl-levodopa (3-OMD) and on inhibition of erythrocyte COMT in healthy subjects receiving 100 mg of levodopa and 25 mg of benserazide (Madopar 125). This was a single-centre, double-blind, placebo-controlled, randomised, crossover study with five single-dose treatment periods. The washout period between doses was 2 weeks. On each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Madopar 125. Tolerability was assessed by recording adverse events, vital signs, continuous electrocardiogram and clinical laboratory parameters. In the study, 18 subjects (12 male and 6 female) participated. The drug combination was well tolerated. All doses of BIA 3-202 significantly increased the area under the concentration-time curve (AUC) versus placebo, ranging from 39% (95% confidence intervals, 1.06-1.69) with 50 mg to 80% (95% confidence intervals, 1.42-2.22) with 400 mg. No significant change in mean maximum plasma concentrations (C(max)) of levodopa was found. Mean C(max) and AUC of 3-OMD significantly decreased for all doses tested. BIA 3-202 caused a rapid and reversible inhibition of S-COMT activity, ranging from 57% (50 mg) to 84% (400 mg). In conclusion, the novel COMT inhibitor BIA 3-202 was well tolerated and significantly increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard release levodopa/benserazide.
BIA 3-202是一种新型儿茶酚-O-甲基转移酶（COMT）抑制剂，正被开发用作帕金森病中左旋多巴的辅助用药。本研究调查了与安慰剂相比，单次口服四剂BIA 3-202（50毫克、100毫克、200毫克和400毫克）对接受100毫克左旋多巴和25毫克苄丝肼（美多芭125）的健康受试者血浆中左旋多巴及其代谢物3-O-甲基左旋多巴（3-OMD）浓度以及对红细胞COMT抑制作用的影响。这是一项单中心、双盲、安慰剂对照、随机交叉研究，有五个单剂量治疗期。各剂量间的洗脱期为2周。在每个治疗期，将不同剂量的BIA 3-202或安慰剂与美多芭125同时给药。通过记录不良事件、生命体征、连续心电图和临床实验室参数来评估耐受性。本研究中有18名受试者（12名男性和6名女性）参与。该药物组合耐受性良好。与安慰剂相比，所有剂量的BIA 3-202均显著增加了浓度-时间曲线下面积（AUC），50毫克剂量时增加39%（95%置信区间，1.06 - 1.69），400毫克剂量时增加80%（95%置信区间，1.42 - 2.22）。未发现左旋多巴的平均最大血浆浓度（C(max)）有显著变化。所有测试剂量的3-OMD的平均C(max)和AUC均显著降低。BIA 3-202对S-COMT活性产生快速且可逆的抑制作用，抑制率范围为57%（50毫克）至84%（400毫克）。总之，新型COMT抑制剂BIA 3-202耐受性良好，与标准释放的左旋多巴/苄丝肼合用时，显著提高了左旋多巴的生物利用度并减少了3-OMD的形成。
