目的:我们的目的是检验假设,在双盲中,安慰剂对照研究表明,vipoglanstat,微粒体前列腺素E合酶-1(mPGES-1)的抑制剂,可降低前列腺素E2(PGE2)并增加前列环素的生物合成,提高RP。
方法:在基线访视前最后一周的筛查中,患有系统性硬化症(SSc)和≥7次RP发作的患者被随机分配到120mgvipoglanstat或安慰剂治疗4周。每日电子日记记录RP攻击(持续时间和疼痛)和雷诺的状况评分,以RP发作/周的变化为主要终点。在基线和治疗结束时进行冷攻击评估。探索性终点包括患者和医生对变化的全球印象,硬皮病相关雷诺现象问卷的评估,mPGES-1活性,和花生四烯酸代谢产物的尿排泄。
结果:69名受试者接受了vipoglanstat(n=33)或安慰剂(n=36)。平均每周RP发作次数(基线;vipoglanstat14.4[SD6.7],安慰剂18.2[12.6])每周发作次数分别减少3.4[95%CI-5.8;-1.0]和4.2[-6.5;-2.0]次(p=0.628)。所有患者报告的结果都有所改善,两组之间没有差异。冷激发后外周血流量恢复的平均变化在研究组之间没有差异。Vipoglanstat完全抑制mPGES-1,导致尿中PGE2减少57%,前列环素代谢物增加50%。Vipoglanstat是安全的,耐受性良好。
结论:尽管vipoglanstat是安全的,并且在完全抑制mPGES-1的剂量下耐受性良好,在SSc相关RP中无效。因此,维泊格兰他的进一步开发和评估将在mPGES-1发挥致病作用的其他疾病中进行。
OBJECTIVE: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP.
METHODS: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud\'s Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients\' and physicians\' global impression of change, Assessment of Scleroderma-associated Raynaud\'s Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites.
RESULTS: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated.
CONCLUSIONS: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.