PDF(Pubmed)
Abstract：
Chronic pancreatitis (CP) is a rare but debilitating condition with an 8-fold increased risk of developing pancreatic cancer. In addition to the symptoms that come from the loss of endocrine and exocrine function in CP, the management of chronic pain is problematic. We previously showed that the CCK-receptor antagonist called proglumide could decrease inflammation, acinar-ductal metaplasia, and fibrosis in murine models of CP. We hypothesized that proglumide would be safe and diminish pain caused by CP. A Phase 1 open-labeled safety study was performed in subjects with clinical and radiographic evidence of CP with moderate to severe pain. After a 4-week observation period, the subjects were treated with proglumide in 400 mg capsules three times daily (1200 mg per day) by mouth for 12 weeks, and then subjects returned for a safety visit 4 weeks after the discontinuation of the study medication. The results of three pain surveys (Numeric Rating Scale, COMPAT-SF, and NIH PROMIS) showed that the patients had significantly less pain after 12 weeks of proglumide compared to the pre-treatment observation phase. Of the eight subjects in this study, two experienced nausea and diarrhea with proglumide. These side effects resolved in one subject with doses reduced to 800 mg per day. No abnormalities were noted in the blood chemistries. A blood microRNA blood biomarker panel that corresponded to pancreatic inflammation and fibrosis showed significant improvement. We conclude that proglumide is safe and well tolerated in most subjects with CP at a dose of 1200 mg per day. Furthermore, proglumide therapy may have a beneficial effect by decreasing pain associated with CP.
摘要：
慢性胰腺炎（CP）是一种罕见但令人衰弱的疾病，患胰腺癌的风险增加了8倍。除了来自CP的内分泌和外分泌功能丧失的症状外，慢性疼痛的管理是有问题的。我们以前表明，CCK受体拮抗剂称为丙谷胺可以减少炎症，腺泡-导管化生,和CP小鼠模型中的纤维化。我们假设丙谷胺是安全的，可以减轻CP引起的疼痛。在具有中度至重度疼痛的CP的临床和放射学证据的受试者中进行了1期开放标记安全性研究。经过4周的观察期，受试者用400毫克胶囊每天三次（1200毫克/天）口服治疗12周，然后受试者在研究药物停药4周后返回进行安全访视。三项疼痛调查的结果(数字评定量表，COMPAT-SF,和NIHPROMIS）显示，与治疗前观察阶段相比，丙谷胺治疗12周后患者的疼痛明显减轻。在这项研究的八个受试者中，两名患者使用丙谷胺出现恶心和腹泻。这些副作用在剂量减少至每天800mg的一名受试者中解决。在血液化学中没有发现异常。对应于胰腺炎症和纤维化的血液microRNA血液生物标志物组显示出显著改善。我们得出结论，丙谷胺在大多数CP患者中每天1200mg的剂量是安全且耐受性良好的。此外，丙谷胺治疗可能通过减少与CP相关的疼痛而产生有益效果。
