在腹膜透析（PD）的发展历史中，1976年标志着一个重要的进步，当时Popovich和Moncrief通过引入平衡PD的概念并将留腹时间延长至4-10小时。尽管PD的实践发生了根本性的变化，但用于在腹膜上产生渗透力的基本原理仍未改变。该原理依赖于传统的通过“理想”的半透膜进行渗透的概念，需要使透析液渗透压高于血浆，并添加葡萄糖作为渗透剂。不幸的是，腹膜不是“理想”的半透膜，而部分溶质也会透过腹膜，腹膜会快速吸收葡萄糖，导致渗透梯度逐渐丧失和超滤持续时间短。虽然对于短时间留腹（间歇性PD留腹30-60分钟）影响不大，但对于长留腹来讲，情况并非如此，例如在持续性非卧床腹膜透析（CAPD）和自动化腹膜透析（APD）中，会导致起初超滤出来的液体被重吸收。此外，每日持续的葡萄糖吸收会加重长期的代谢并发症，包括高脂血症和肥胖。
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In the history of peritoneal dialysis (PD), 1976 marked a significant step forward when Popovich and Moncrief revolutionized the practice by introducing the concept of equilibration PD and extending the duration of dwell time to 4 – 10 hours (1). Despite this fundamental change in the practice of PD, the basic principle used to generate osmotic forces across the peritoneum remained unaltered. This principle relied on the traditional concept of osmotic flow across an “ideal” semipermeable membrane, necessitating making dialysis solution hypertonic to plasma with the addition of glucose as osmotic agent. Unfortunately, not being an “ideal” semipermeable membrane but being partially permeable to solutes, the peritoneum allows rapid absorption of glucose with progressive dissipation of the osmotic gradient and ultrafiltration of short duration. While this is of little significance during short dwell exchanges (30 – 60 minutes’ dwell in intermittent PD), it is not the case for long exchanges, such as in continuous ambulatory PD (CAPD) and automated PD, where reabsorption of initially ultrafiltered peritoneal fluid occurs. In addition, the continuous daily absorption of glucose aggravates long-term metabolic complications, including hyperlipidemia and obesity (2,3).
早在 20 世纪 80 年代，人们就已经清楚地认识到有一种替代渗透剂，它可以最大限度地减少代谢紊乱，并具备可长留腹的超滤属性。基于一个简单的概念，即大分子量（MW）的溶质不易通过腹膜被吸收，并且可能产生持续的超滤，同时减少代谢并发症，人们评估了一系列不同的大分子物质。早期研究清楚地认识到使用非生理性高黏性的大分子物质带来的相关问题，并确定了对可溶性，非过敏性和易代谢的中性物质的需求。
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Even as early as the 1980s there was clear recognition for an alternative osmotic agent that would minimize metabolic derangements and provide the ultrafiltration profile to suit long dwell exchanges. A range of different macromolecules was evaluated based on thesimplistic concept that large molecular weight (MW) agents are less readily absorbed through the peritoneum and are likely to produce sustained ultrafiltration while reducing metabolic complications. Early investigations clearly identified the problems associated with use of nonphysiological hyperviscous macromolecules and defined the need for a neutral substance thatis soluble, nonallergenic, and readily metabolized (3).
从水解的玉米淀粉中提取的葡萄糖聚合物（GP）似乎是一个天然的竞争者，几个集团已经拥有不同分子量片段的专利。其中，Abbott集团通过研究动物和人类中的狭窄的分子量片段（MW 1000 Da）而处于领先地位。在曼彻斯特，探索这种新型药物的潜力我们有一定优势，因为在研究葡萄糖聚合物（Caloreen）作为肝肾功能衰竭患者管理中的静脉注射高能营养源时，已经积累了丰富的经验。我们与来自Fisons制药公司的Caloreen专利持有人Jerry Milner，以及来自伯明翰大学生物化学系的J. Fox密切合作，Jerry Milner在葡萄糖聚合物分离技术方面非常专业，J. Fox在碳水化合物分析方法方面拥有丰富的经验。
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Glucose polymer (GP), derived from hydrolyzed cornstarch, seemed a natural contender and several groupsalready held patents of diverse MW fractions. Among them, the Abbott group ledthe way by studying a narrow MW fraction (MW 1000 Da) in both animals (4) andhumans (5). In Manchester, we were well placed to explore the potential of this novel agent as considerable experience had been developed while investigating GP (Caloreen) as an intravenous high-energy nutrient source in the management of patients with renal (6) and hepatic failure (7). We worked closely in collaboration with Jerry Milner, the holder of the patent for Caloreen, Fisons Pharmaceutical, who had established expertise in fractionating GP technology, and J. Fox, Department of Biochemistry, University of Birmingham, who had extensive experience in methods of carbohydrate analysis.
在1983年7月进行的初步临床研究中，我们使用了一种现成的糊精制剂（Caloreen），其双峰分子量分布由67%的“低”分子量片段（链长<12个葡萄糖单位）和33%的“高”分子量片段（链长>12个葡萄糖单位）组成;它的重均分子量（Mw）为7000道尔顿，数均分子量（Mn）为960道尔顿。与葡萄糖溶液相比，多分散葡萄糖聚合物的腹膜选择渗透性是相对未知的，预测其样本的渗透性能也是困难的。我们的初步研究表明，5%（52 mmol/L）和10%（104 mmol/L）浓度的葡萄糖聚合物溶液的渗透能力可能分别与1.36%（76 mmol/L）和3.86%（214 mmol/L）浓度的葡萄糖溶液相当。
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For the initial clinical studiescarried out in July 1983, we utilized a readily available dextrin formulation(Caloreen) with a bimodal MW distribution consisting of a 67% “low” MW fraction (chain length < 12 glucose units) and a 33% “high” MW fraction (chain length> 12 glucose units); weight average MW (Mw) was 7000 Da and number average MW (Mn) was 960 Da. In contrast to glucose solution, predicting osmotic performance of a polydisperse GP sample with a relatively unknown peritoneal permselectivity proved difficult. Our preliminary studies suggested that 5% (52mmol/L) and 10% (104 mmol/L) GP solutions were probably comparable to 1.36% (76mmol/L) and 3.86% (214 mmol/L) glucose respectively (8).
第一个正式的1期研究中，在6小时留腹期间使用含有5%（52 mmol/L）和10%（104 mmol/L）的这种葡萄糖聚合物溶液，结果显示葡萄糖聚合物溶液所产生的净超滤量是葡萄糖溶液的1.5-2.5倍，并且显著降低了碳水化合物经腹膜的吸收：53%-55% vs 66%-69%，这个结果令人兴奋，超出了我们的预期。然而，葡萄糖聚合物的代谢不完全，会导致麦芽糖蓄积，5%浓度的葡萄糖聚合物溶液中的麦芽糖峰值血清水平达到1148mg/L，在10%浓度的溶液中几乎翻了一番。尽管随后的研究证实了尿毒症和透析患者中进入循环的麦芽糖和异麦芽糖水平较低，但使用葡萄糖聚合物溶液交换后其水平增加32至64倍令人难以接受，特别是在之前没有任何关于尿毒症患者暴露水平相关报告的情况下。Winchester等人在一项涉及88名患者的多中心试验中报告了类似的结论，导致美国放弃了该领域的进一步研究。相比之下，我们对血清和透析液中低聚糖片段的详细分析结果充满信心。似乎很明显，低聚糖经腹膜的吸收率存在差异：链长<G12的那部分被吸收75%-80%，其吸收率与葡萄糖不太相似，而链长>G12的那部分被吸收的不多，约为20%-30%。此外，被快速吸收的<G12的那部分，特别是G5-G9，优先被进入循环的淀粉酶水解，并且成为麦芽糖产生的主要来源。因此，从原始聚合物属性中去除<G12的片段，似乎有可能大大减少麦芽糖的蓄积。然而，尚不确定高分子量片段（>G12）本身是否具有渗透效果。
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The first formal Phase 1 study, using solutions containing 5% (52 mmol/L) and 10% (104 mmol/L) of this GP formulation over a 6-hour dwell, was exciting and exceeded our expectation by producing net ultrafiltration 1.5 – 2.5 times greater than glucose solutions, with substantially reduced transperitoneal absorption of carbohydrate: 53% – 55% versus 66% – 69%. However, the metabolism of GP was incomplete, resultingin accumulation of maltose, with a peak serum level reaching 1148 mg/L with 5%GP solution, and this almost doubled with 10% solution (9). Even though subsequent investigations led to identification of a low level of circulating maltose and isomaltose in uremic and dialysis patients (10), a 32- to 64-fold increase following a GP exchange was considered unacceptable, especially in the absence of any previous report of this level of exposure in uremic patients. Asimilar conclusion reported by Winchester et al. in a multicenter trialinvolving 88 patients (5) led to the apparent abandonment of further researchin this field in the USA. In contrast, we were encouraged by the results of our detailed analysis of oligosaccharide fractions in serum and dialysate. It seemed clear that there were differential rates of transperitoneal absorption of oligosaccharides: those with chain length < G12 were absorbed (75% – 80%) at rates not too dissimilar to glucose, whereas the remaining fractions >G12 were poorly absorbed (20% – 30% of the load). Furthermore, the rapidly absorbed fraction < G12, particularly G5–G9, was preferentially hydrolyzed by circulating amylase and was the major source of maltose generation. Thus, it seemed possible that removal of this fraction from the original polymer profile would substantially reduce the accumulation of maltose. However, it was uncertain whether the high MW fraction (>G12) on its own would beosmotically effective.
听取了Colin Ricketts的口头意见，并审阅了Kiil发表的文章之后，我们重新考虑了渗透力在溶质渗透生物膜(如腹膜)上应用的原理。我们认识到，通过溶质渗透膜所产生的渗透力方向受反射系数和溶质摩尔浓度乘积之和大小差异的影响，而不是传统的总渗透梯度，这是研究进一步发展的关键。因此，理论上，“大”分子量的葡萄糖聚合物片段在低浓度下可能通过腹膜产生渗透作用，前提是这些葡萄糖聚合物基本上不被腹膜吸收。这些“大”分子量的葡萄糖聚合物片段在低浓度下也可能降低全身的麦芽糖负荷。
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Following a casual comment by colleague Colin Ricketts, and having reviewed the publication by Kiil (11), were considered the principles of osmotic forces as applied to solute-permeable biological membranes, such as the peritoneum. The recognition that the direction of osmotic force across a solute-permeable membrane is governed by the differences in the size of the sum of the products of the reflection coefficients and molar concentrations of solutes rather than the traditional total osmolality gradient (12) was the key to further development. Therefore, it was theore tically possible that a “large” MW GP fraction at a low concentration could exert an osmotic effect across the peritoneum, provided it was largely impermeable, and might even reduce the systemic load of maltose.
我们很荣幸能与Fisons制药公司合作，他们成功地使用传统的溶剂分馏方法将Caloreen分馏成两个部分。分离得到高分子量片段的葡萄糖聚合物，其中95%含有葡萄糖链长度>12的葡萄糖单元，重均分子量为16823道尔顿，数均分子量为5304道尔顿。一项试点研究，使用含高分子量片段的5%葡萄糖聚合物溶液(9.4 mmol/L)，与尿毒症患者血清近似等渗，通过留腹6小时，结果显示其超滤效果显著优于葡萄糖溶液。不幸的是，2例患者因聚合物溶液被热原污染而发生严重的化学性腹膜炎。有趣的是，即使在这些患者中，葡萄糖聚合物溶液仍能产生净超滤。这是第一次表明葡萄糖聚合物可能通过类似胶体渗透的机制发挥作用，并可以作为一种新型渗透剂应用于持续性非卧床腹膜透析（CAPD）。随着生产工艺的改进，我们的临床研究进展迅速，证明了5%等渗葡萄糖聚合物溶液留腹12小时的超滤效果更好。此外，在交换过程中，只有14%-28%的聚合物被腹腔吸收，而葡萄糖有62%-83%被吸收，这使得每毫升超滤量的潜在热量负荷更低。有趣的是，葡萄糖聚合物在腹膜的吸收模式和量级与那些大分子物质相似，表明葡萄糖聚合物主要通过腹膜淋巴管吸收。与原始配方相比，这种较低的吸收率还导致麦芽糖全身性蓄积减少了80%。虽然在不做透析的情况下，麦芽糖的代谢清除是很低的，但在多次透析交换的情况下，一些麦芽糖会经腹膜清除。这在之后的研究中得到了证实，估计麦芽糖经腹膜清除率为3.5 ml/min。因此，随着葡萄糖聚合物溶液的持续使用，麦芽糖的蓄积有可能达到一个稳态的水平。
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We were fortunate in our collaboration with Fisons Pharmaceutical, who successfully fractionated Caloreen into two component parts using the conventional solvent-based fractionation process. The high MW fraction of GP was isolated, with 95% of the profile containing glucose chain length > 12 glucose units with Mw 16823 Da and Mn 5304 Da. A pilot study using a 5% GP solution (9.4 mmol/L) containing high MW fraction, with osmolality similar to uremic serum, produced remarkably good ultrafiltration compared to glucose solutions over a 6-hour dwell (13). Unfortunately, 2 patients developed severe chemical peritonitis with polymersolution contaminated with pyrogens (8). Even in these patients it was interesting to note that the GP fraction resulted in net ultrafiltration. This was the first indication that GP probably exerted its effect by a mechanism resembling colloid osmosis and could be adapted as a novel osmotic agent in CAPD. Following refinement of the manufacturing process, our clinical studies progressed rapidly and demonstrated superior ultrafiltration with 5% iso-osmolar GP solution for dwells up to 12 hours. Furthermore, only 14% – 28% of polymer was absorbed transperitoneally, compared to 62% – 83% of glucose, during the exchanges, resulting in a lower potential calorie load per milliliter ultrafiltration (14). Interestingly, the pattern and magnitude of peritoneal absorption of GP was similar to that described for much larger molecules (15), suggesting GP is absorbed primarily via peritoneal lymphatics (16). This lower rate of absorption also led to an 80% reduction in systemic accumulation ofmaltose compared to the original formulation. Although the metabolic clearance of maltose was minimal in the absence of dialysis, some transperitoneal maltose clearance was expected during multiple-exchange regimes. This was confirmed in subsequent studies, with estimated transperitoneal clearance of maltose 3.5mL/min (8). Therefore, it seemed likely that maltose accumulation would achievea steady state level with continuous use of polymer solution.
随着生产工艺由溶剂分馏向膜分离的转变，我们得到了分子量稍大的(重均分子量为22000道尔顿；数均分子量为7000道尔顿)，且更具再生性的葡萄糖聚合物片段。7.5%葡萄糖聚合物溶液（10.7 mmol/L）的超滤效果与之前的5%葡萄糖聚合物溶液相似，7.5%溶液的渗透压（277 mOsm/kg）低于尿毒症患者血清渗透压。这是临床首次进行低渗透析液与常规渗透梯度透析液的对比，最终强化了葡萄糖聚合物作为胶体渗透剂的作用。此外，这项研究也提供了一个很好的机会来证明这样一个假设：在不同的留腹时间内，可以使用不同比例的胶体和晶体渗透剂组合成等渗透析液来优化超滤。
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With the change in the manufacturing process from solvent-based to membrane-based fractionation, we obtained a slightly larger (Mw 22000 Da; Mn 7000 Da) but more reproducible fraction. A 7.5% solution (10.7 mmol/L) yielded ultrafiltration similar to the previous 5% GP solution but was hypo-osmolar (277 mOsm/kg) to uremic serum. This was the first clinical demonstration of osmotic flow against the conventional osmolality gradient using a hypo-osmolar dialysate that finally consolidated the role of GP as a colloid osmotic agent (17). Furthermore, it provided a wonderful opportunity to prove the hypothesis that ultrafiltration profiles over varying dwell times could be optimized using different proportions of colloid and crystalloid agents combined in an iso-osmolar dialysate (18).
一系列研究使用含有该聚合物片段的溶液进行夜间留腹，使用常规的葡萄糖溶液进行日间交换，结果很清楚地表明，超滤效果具有持续性，麦芽糖水平在6天内达到稳定，几乎没有日常的变化且没有明显的组织内蓄积。虽然这个结果令人安心，但根本问题是，体内麦芽糖水平尽管保持在比较稳定的水平，长期来看其水平的升高是否有害？因此，我们进行了一项为期3个月的研究，良好的研究结果为MIDAS研究打下了很好的基础，MIDAS研究是在CAPD患者中进行的首次大型的、长期的、随机对照研究，旨在比较艾考糊精腹透液与传统葡萄糖腹透液的疗效与安全性。
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A series of studies using solutions containing this fraction overnight and conventional glucose exchanges during the daytime clearly demonstrated sustained ultrafiltration with very little day-to-day variation: maltose levels reached steady state within 6 dayswithout apparent tissue accumulation (19). While this was reassuring, the fundamental question remained whether these elevated but steady state levels would be harmful in the long term. Therefore, we undertook a 3-month study (20), the favorable results of which paved the way for the MIDAS study, thefirst large, long term, randomized controlled study undertaken in CAPD to compare the efficacy and safety of icodextrin with conventional glucose solutions (21).
在近十年间里，葡萄糖聚合物的发展主要依赖于一个单中心里的一小群非常专注的临床医生和护士，以及一群忠实的患者。在这段时间里，我们对33名患者进行了超11项单独的临床试验，其中许多患者都是自愿参加的，他们为这项研究工作的快速进展做出了贡献。毫无疑问，这项为期3个月的研究是该项目的关键一步，所有参与者都对麦芽糖蓄积的潜在风险感到担忧。这可能是一个有近十年经验的单中心的优势，而且许多病人已经反复使用过这种产品，这才让我们可以迈出这一步。尽管缺乏长期的药物毒性数据，但因为我们有之前的经验，所以自然而然的感到放心，我们也很幸运地与患者建立了特殊的关系，他们热情地持续参与葡萄糖聚合物的发展。
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For almost a decade, the development of GP was based primarily at a single center with a small highly focused group of clinicians and nurses, and a faithful committed group of patients. Over this period, more than 11 separate clinical trials were conducted with only 33 patients, many of whom volunteered on a number of occasions, contributing to the rapid progress we made. There is no doubt that the criticalstep in the project was the 3-month study, and all those involved were apprehensive regarding the potential risk of maltose accumulation. It was perhaps the advantage of being in a single center with almost a decade of experience and the many patients that had already been repeatedly exposed to the product that allowed us to take this step. We were naturally reassured by our previous experience, despite the lack of long-term toxicity data, and fortunate to have a special relationship with our patients, who were enthusiastic to continue their involvement with the development of GP.
最初，在1983年，该项目（艾考糊精研发）的资金有限，英国曼彻斯特和西北地区肾脏研究所支持该研究中注册人员的工资，Jerry Milner支付糊精测定的费用。在这个阶段，所有的护理援助都是自愿的，主要是在下班后和周末的时间进行。经过2年的快速临床进展，制药行业对于这个充满前景的药物表现出浓厚的兴趣。1987年，一家领先的制药公司在关键一步撤回了支持，几乎结束了葡萄糖聚合物的发展。然而，当Jerry Milner与企业家Kevin Leech合作组建了一家新的生物制药公司：M L Laboratories Plc时，该项目得到了挽救。1988年，Fisons退出了该项目，M L Laboratories Plc在英国利物浦的Wavertree科技园建立了一个小型工厂，能够通过膜分离的新工艺制造该产品。使用这个工艺，最佳的葡萄糖聚合物片段（Mw 22000 Da;Mn 7000 Da）用于超滤，可最大限度地减少麦芽糖蓄积，随后用于所有长期的研究。这个片段，最初被称为“糊精20”，后来更名为“icodextrin”，这个名字来源于希腊语icosa，意思是二十。1991年，M L Laboratories开始了一项随机，对照，多中心试验（MIDAS研究），这个试验涉及11个中心和209名患者，为期6个月，评估艾考糊精用于CAPD治疗的安全性和有效性。在此之后，Icodextrin于1993年1月在英国获得了产品许可证，于1994年3月获得了欧洲上市许可，之后在2002年获得了美国的上市许可。最初，M L Laboratories与费森尤斯公司达成协议，在PD领域进行合作，并计划在欧洲和美国推出该产品，但该协议于1996年3月终止，2个月后，M L Laboratories将全球独家许可授予百特公司。2005年，M L Laboratories被Quadrant Technologies（作为Innovata plc）收购，并于2007年被VecturaGroup plc收购。
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Initially, in 1983 the funding for the project was limited, with the Manchester & North West Region Kidney Research supporting the research registrar’s salary and Jerry Milner meeting the expenses for dextrin assays. During this phase, all nursing assistance was voluntary, mostly out of hours and on weekends. After 2 years of rapid clinical progress, and with potentially a promising product, a high level of interest was shown by the pharmaceutical industry. In 1987, the withdrawal of support by a leading pharmaceutical company at a crucial step almost ended the development of GP. However, the project was salvaged when Jerry Milner, in partnership with Kevin Leech, an entrepreneur, formed a new biopharmaceutical company: M L Laboratories Plc. In 1988, Fisons withdrew from the project and M L Laboratories Plc set up a small manufacturing unit at Wavertree Technology Parkin Liverpool, UK, with the capacity to manufacture the product by a new process involving membrane fractionation. Using this process, the optimal GP fraction (Mw 22000 Da; Mn 7000 Da) for ultrafiltration that minimized maltose accumulation was subsequently used in all long-term studies. This fraction, originally referred to as “dextrin 20,” was later renamed “icodextrin,” from the Greek icosa, meaning twenty. In 1991, M L Laboratories embarked on a randomized, controlled, multicenter trial oficodextrin in CAPD involving 11 centers and 209 patients to evaluate safety and efficacy over a 6-month period (21). Following this, Icodextrin received aproduct license in the UK in January 1993, European Marketing approval in March1994, and, finally, USA Marketing approval in 2002. Initially, M L Laboratories reached an agreement with Fresenius AG to collaborate in the field of PD and tolaunch the product in Europe and the USA, but that agreement was terminated in March1996, and 2 months later M L Laboratories granted an exclusive worldwide license to Baxter Healthcare. In 2005, M L Laboratories was acquired by Quadrant Technologies (as Innovata plc), and in 2007 this was taken over by Vectura Group plc.
（截至文章发表时间2009年）艾考糊精现已在临床上使用超过15年，是PD历史上向前迈出的重要一步。它不仅是葡萄糖很好的替代渗透剂，而且是第一种利用胶体渗透作用的新型渗透剂，从而能够产生持续超滤，并具有多种代谢优势，特别适合长时间留腹的PD治疗使用。它的成功无疑归功于其在英国曼彻斯特的谦逊开始，在那里，高度积极的临床工作人员和33名忠诚勇敢的患者的独特融合创造了这个成功产品的前途，并激发了一家新的制药公司M L Laboratories Plc的成立，该公司通过专业知识、资源的积累和投入，最终完成了艾考糊精的开发。据估计，全球有超过55个国家的3万多名患者使用艾考糊精腹透液，在较发达的国家，使用率可能超过50%。这是对所有项目参与者的极大致敬，15年后，特别令人欣喜的是，艾考糊精越来越成功。
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Icodextrin has now been inclinical use for more than 15 years and has been an important step forward in the history of PD. It is not only a successful alternative osmotic agent to glucose but the first novel agent developed to exploit the physiological process of colloid osmosis, thereby providing sustained ultrafiltration with manymetabolic advantages (22,23) particularly suited to long-dwell PD regimens. Its success is undoubtedly attributable to its humble beginning in Manchester, UK, wherea unique blend of highly motivated clinical staff and 33 loyal and courageous patients created a promise of a successful product and inspired the formation of a new pharmaceutical company, M L Laboratories Plc, which secured the necessary expertise and resources to complete the development of icodextrin. It is estimated that icodextrin is used by more than 30 000 patients worldwide in more than 55 countries, and in richer countries penetration probably exceeds 50% (24). It is a great tribute to all those involved and, after 15 years, it is particularly satisfying to see that the use of icodextrin goes from strength to strength.
DISCLOSURES
The author does not have any conflict of interests to declare
ACKNOWLEDGMENT
A special thanks to Stephen Actonfor his review of this manuscript and helpful suggestions.
参考文献：
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