普卢卡必利——慢性便秘治疗的新选择

普卢卡必利治疗严重慢性便秘的一项安慰剂对照的临床研究
Camilleri M;Kerstens R;Rykx A;Vandeplassche L.NEJMoa0800670"> A placebo-controlled trial of prucalopride for severe chronic constipation.N Engl J Med 2008 May 29 358(22) :2344-54 

背景：在这一为期12周的临床试验中，我们旨在测定普卢卡必利，一种高亲和力的5-羟色胺受体激动剂对严重慢性便秘患者的疗效。在我们多中心，随机，安慰剂对照的，平行组，3期临床试验中，严重慢性便秘患者（每周自发性、完全的排便≤2次）接受安慰剂或每日服用2mg或4mg普卢卡必利治疗12周。主要的有效终点是在12周研究期间，平均每周自发性、完全的排便3次或以上的患者所占比例，次要有效终点源自患者的日记和由患者完成、经确证有效的问卷调查。我们对不良事件，临床实验室指标和心血管效应均进行了监测。结果：在620位患者中分析了普卢卡必利的有效性。接受2mg普卢卡必利治疗的患者中每周自发性、完全的排便3次或以上者所占比例为30.9%，接受4mg普卢卡必利治疗的患者中每周自发性、完全的排便3次或以上者所占比例为为28.4%，安慰剂组仅有12.0％的患者每周自发性、完全的排便在3次或以上。在研究的12周期间，2 mg或4 mg普卢卡必利治疗组分别有47.3%和46.6%患者自发性、完全的排便次数平均每周增加1次或以上，而安慰剂组只有25.8%(较之两组，P amp;lt;0.001)。使用2mg或4mg普卢卡必利治疗的患者较之安慰剂组在，第12周时所有其他次要有效终点，包括患者对他们肠功能，治疗的满意度，他们对于自身便秘严重程度的感觉均得到明显改善。发生频率最高的治疗相关的不良事件是头痛和腹痛。治疗并没有带来显著的心血管效应。结论：使用12 周，普卢卡必利显著改善严重慢性便秘患者的肠功能，减轻症状的严重程度。还需要进行更大规模，持续时间更长的临床试验以进一步评价使用普卢卡必利治疗慢性便秘的风险及受益。(ClinicalTrials.gov number, NCT00483886 [ClinicalTrials.gov].).

有关Resolor（普卢卡必利）

    Resolor（普卢卡必利）2009 年 10 月在欧洲获批后，2010 年 1 月在 德国上市，2010 年 3 月在英国上市。

    美国罗切斯特梅奥医院报道，采用普卢卡必利治疗重度慢性便秘短期可显著改善肠道功能，减轻便秘症状。

    普卢卡必利（prucalopride）具有高度选择性及特异性的5-HT4受体激动作用。

    Camilleri等进行了一项多中心、随机对照研究，对620名重度慢性便秘（大便次数≤2次/周）分别每天服用安慰剂、普卢卡必利2mg或4mg，疗程12周。结果三组排便次数增加的比例分别为25.8%、47.3%和46.6%。普卡必利治疗的两组患者对治疗的满意度和症状严重程度认知都有显著改善，并未发现严重的心血管影响。

    虽然短期服用普卢卡必利可显著减轻便秘症状，但研究者认为还有待长期、大规模研究，进一步评估该药的风险和受益。

    普卢卡必利（prucalopride）为苯丙咪唑类药物，是特异性S-HT4受体完全激动剂，具有较高选择性和特异性5- HT4受体作用，增加胆碱能神经递质的释放，刺激肠蠕动反射，增强结肠收缩和近端结肠传输，能够有效地缓解便秘病人的症状，主要用于治疗各种便秘及手术的胃肠道蠕动无力和假性梗阻。

曾用名：4-Amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide

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Resolor® (prucalopride)

New treatment for chronic constipation in women#
In October 2009, our lead product, Resolor (prucalopride), has received  the  marketing approval for the symptomatic treatment of Chronic Constipation (CC) in women in whom laxatives fail to provide adequate relief in the EU27 and Iceland, Liechtenstein and Norway. Since August 2010, Switzerland is the 31st country where Resolor is approved in a first indication – i.e. for the treatment of idiopathic chronic constipation in adults for whom the currently available treatment options involving dietary measures and laxatives do not provide sufficient effect, with the statement that “there are currently no sufficient data available to evaluate the effectiveness and safety of Resolor in men.”

Resolor (prucalopride) is the first of a new class of selective high affinity serotonin (5-HT4) receptor agonists with enterokinetic activity. In clinical studies, the efficacy of prucalopride was established in three multicentre, randomised, double-blind, 12-week placebo controlled studies in subjects with chronic constipation (n=1,279 on prucalopride, 1,124 females, 155 males).

Potential market
Chronic Constipation (CC) is a disorder of the gastrointestinal tract. It is a prevalent and debilitating condition that is not always well understood and, in many cases, is inadequately treated. Approximately 34 million patients in the 27 countries of the EU are affected by CC, and an estimated 14 million patients frequently visit their doctor with complaints of constipation after unsatisfactory results with over-the-counter medication or prescription laxatives. It is estimated that 35-50% of patients remain dissatisfied, the vast majority of whom are women.

The impact on the quality of life from CC has been compared to other long-term chronic conditions such as hypertension, diabetes, heart disease and depression. It is also associated with a significant burden on healthcare resources. Each year in the European Union and the United States, approximately 2 billion US dollars are spent on over-the-counter laxatives, the mainstay of therapy for constipation.

In 2008, the world laxative market was estimated in excess of $3 billion dollars.¹ Women suffering from CC are a sizable initial indication as it estimated that up to 85% of patients who visit the doctors office in Europe with CC being female.

Development program
Resolor’s EU approval was based on a marketing authorisation application that included a comprehensive clinical-development program of three large and identically designed pivotal Phase III studies in the target indication (i.e. for the symptomatic treatment of chronic constipation (CC) in women in whom laxatives fail to provide adequate relief).

Movetis is already working on expanding the potential use of Resolor (prucalopride) to other important indications and the company already has encouraging Phase II data for Resolor (prucalopride) suggesting the potential treatment of chronic constipation in males and children as well as opioid induced constipation and post-operative ileus. The use of prucalopride in these conditions will be further tested in Phase III studies.

Commercial rights
The approval of Resolor (prucalopride) by the European Commission means that Resolor (prucalopride) is now approved in the 27 countries of the EU as well as Iceland, Liechtenstein and Norway.

It is our intention to market Resolor (prucalopride) in certain European markets by itself including Germany, the UK, France and the Benelux. Movetis will also seek where necessary to broker partnerships to maximise the sales of Resolor in certain other European territories.

In the first quarter of 2010, Movetis made Resolor s available on the market in Germany and the UK. The company continues to prepare the market introduction in various other European countries.