Priming the (proton) pump.
Priming the (proton) pump.
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启动（质子）泵。
DOI：
10.1007/s10620-014-3105-7
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发表时间：
2014
影响因子：
3.1
通讯作者：
Kaunitz,JonathanD
中科院分区：
文献类型：
--
作者：
Kaunitz,JonathanD
说到这里，我想介绍一下《范式转换视角》系列的第四部分，其中包括乔治·萨克斯的个人回顾，他是最著名的临床医生和研究人员之一，致力于寻找有效的胃抗分泌药物。在今天的抗分泌疗法出现之前，每年回忆起消化性溃疡疾病的医生越来越少。1979年，作为一名GI研究员，我们的大部分培训都是为了认识和治疗消化性溃疡手术的病态影响，以及使用抗酸剂和饮食治疗溃疡。“抗分泌时代”始于1973年由诺贝尔奖得主詹姆斯·布莱克[1]首次报道H2受体拮抗剂甲硫胺，1976年西咪替丁在英国获得临床批准，1981年首次发表关于质子泵抑制剂(PPI)奥美拉唑抗分泌特性的报告[2]，1989年奥美拉唑获得批准。抗分泌性药物使胃酸消化性疾病的治疗发生了革命性变化，几乎废除了外科消化性溃疡的治疗方法[3]，并有效地治疗了与反流相关的粘膜损伤和症状。尽管PPI的不良影响在非专业媒体和医学文献中得到了很大的关注，但相对于数亿次的剂量，这些影响的频率和程度都相当低[4，5]。事实上，PPI是二十世纪下半叶我们胃肠学领域最伟大的进步之一，也可以说是那个时期所有医学领域最重要的发展之一。在随附的文章中，乔治·萨克斯(图1)以个人的、引人入胜的、引人入胜的和有洞察力的方式一瞥了抗分泌性药物出现的世界。萨克斯博士首先描述了胃H+，K+ATPase分泌H+的正确机制[6]，随后其他科学家描述了它的水解性[7，8]。当时，乔治显然处于科学界和制药界的交叉点，他发表的学术和创新文章，以及他与开发西咪替丁的SmithKline和开发奥美拉唑的Astra AB的科学家和管理层自由互动。乔治相当敏锐的科学洞察力、敏锐的洞察力和敏捷的思维使他说服阿斯特拉公司在临床上开发奥美拉唑，声称其销售额将超过10亿美元。他大错特错了，因为过去10年，PPI在全球的年销售额已超过200亿美元，自1989年获得批准以来，累计销售额可能超过4000亿美元。在科学影响方面，自从最初的描述以来，已经发表了30,000多篇关于质子泵的文章和10,000多篇关于胃质子泵的文章。
With these quotations, I would like to introduce the fourth installment of the ‘‘Paradigm Shifts in Perspective’’series, which features a personal retrospective by George Sachs, one of the most prominent clinician-investigators in the quest to discover effective gastric antisecretory drugs. Fewer physicians each year recall the scourge that was peptic ulcer disease prior to the advent of today’s antisecretory therapy. As a GI fellow in 1979, much of our training was geared toward recognizing and treating the morbid effects of peptic ulcer surgery and the use of antacids and diets to treat ulcers. The ‘‘antisecretory era’’started with the original report of the H2 receptor antagonist metiamide in 1973 by Nobel Laureate James Black [1], clinical approval of cimetidine in the UK in 1976, the initial report of the antisecretory properties of the original proton pump inhibitor (PPI) omeprazole published in 1981 [2], culminated by the approval of omeprazole in 1989. Antisecretory drugs have revolutionized the treatment of acid-peptic disease, with the near abolition of surgical peptic ulcer treatments [3] and the effective treatment of reflux-related mucosal injury and symptoms. Although adverse effects of PPIs have received much attention in the lay press and in the medical literature, the frequency of and magnitude of these effects are quite low relative to the hundreds of millions of doses taken [4, 5]. Indeed, PPIs are one of the greatest advances to our field of gastroenterology in the second half of the twentieth century and arguably one of the paramount developments in all of medicine during that period.In the accompanying article, George Sachs (Fig. 1) spins a personal, compelling, fascinating, and insightful glimpse into the world from which antisecretory drugs emerged. Dr. Sachs first described the correct mechanism of H+ secretion by the gastric H+, K+ ATPase [6], following descriptions by other scientists of its hydrolytic activity [7, 8]. At that time, George was clearly positioned at the intersection of scientific world with his scholarly and innovative articles and the pharmaceutical world in which he interacted freely with the scientists and management of SmithKline, which developed cimetidine, and Astra AB, which developed omeprazole. George’s considerable scientific acumen, keen perspective, and quick mind enabled him to convince Astra to develop omeprazole clinically, claiming that its sales would exceed $ US 1 bn. How wrong he was, since the annual worldwide sale of PPIs has exceed $ US 20 bn in the last 10 years, with cumulative sales since approval in 1989 likely exceeding $ US 400 bn.[9]. In terms of scientific impact, over 30,000 articles have been published about PPIs and over 10,000 about the gastric proton pump since their original descriptions, a paradigm