第六章治疗用激素概要课件

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1、Charpter 6 Incretion applied to treatment Fangzhen Zhou 2011.4What We Will CoverDiabetes and insulin1Insulin and insulinR2Character of insulin3Production of insulin4Diabetes and treatment5Diabetes and insulinBefore Insulin Before insulin was discovered in 1921,everyone with type 1 diabetes died with

2、in weeks to years of its onsetJL on 12/15/22 and 2 mos later1922 Leonard ThompsonIn Jan,1922,Banting and Best injected a 14-year-old charity”patient who weighed 64 lb with 7.5 ml of a thick brown muck in each buttockAbscesses developed and he became more acutely illHowever,his blood glucose had drop

3、ped enough to continue refining what was called iletin”insulin 6 weeks later,a refined extract caused his blood glucose to fall from 520 to 120 mg/dL in 24 hoursLeonard lived a relatively healthy life for 13 years before dying of pneumonia(no Rx then)at 27Insulin Production BeginsFirst produced as “

4、Connaught”by the Univ of TorontoOn May 30,1922,Eli Lilly signed an agreement to pay royalties to the University to increase productionFirst bottles contained U-10 insulin 3 to 5 cc were injected at a timePain and abscesses were common until purer U-40 insulin became availableImpact Of Insulin OnLife

5、 Expectancy By The 1940sAge at start of diabetes503010Avg.age of death in 189758.034.111.3Avg.age of death in 194565.960.545.0Years Gained82634返回返回胰岛素的化学性质本品为白色或类白色结晶粉末，是从猪或牛胰中提取制得的。据精制方法不同，有两种形态：不规则细粉颗粒(无定形)和扁斜形六面体。可溶于稀醇、稀丙酮、酸、碱中，不溶于90%以上乙醇及其他有机溶剂，在pH 2-4时更稳定，在碱性介质中易破坏，加热易变性。遇蛋白酶、强酸、强碱均能破坏。等电点pH 5.

6、3-5.4，易与锌、镉、钴等2价金属结合。药用常制成锌胰岛素，与鱼精蛋白能形成复合体，且作用时间较长。返回传统生产工艺：常规胰岛素传统生产工艺：常规胰岛素浓缩液去脂溶液盐析物滤 液减压30以下速热速冷NaClpH22.5水、丙酮、氨水pH4.24.3沉淀结晶柠檬酸，Zn(Ac)2，丙酮，氨水pH8.0，5以下，调pH6.0 除碱性蛋白，结晶除碱性蛋白，结晶 水、丙酮、乙醚胰岛素精品 洗涤，干燥洗涤，干燥 猪胰脏提取液碱化液乙酸，草酸1015氨水pH88.4 提取提取 碱化碱化 硫酸pH3.63.8，5酸化液 酸化酸化 浓浓缩缩 除酸性蛋白除酸性蛋白 盐析盐析 去脂去脂 氨水，Zn(Ac)2pH

7、 6.0猪胰岛素生产的工艺路线猪胰岛素生产的工艺路线浓缩液去脂溶液盐析物滤 液减压30以下速热速冷NaClpH22.5水、丙酮、氨水pH4.24.3沉淀结晶柠檬酸，Zn(Ac)2，丙酮，氨水pH8.0，5以下，调pH6.0 除碱性蛋白，结晶除碱性蛋白，结晶 水、丙酮、乙醚胰岛素精品 洗涤，干燥洗涤，干燥 猪胰脏提取液碱化液乙醇，草酸1015氨水pH88.4 提取提取 碱化碱化 硫酸pH3.63.8，5酸化液 酸化酸化 浓浓缩缩 除酸性蛋白除酸性蛋白 盐析盐析 去脂去脂 氨水，Zn(Ac)2pH 6.0猪胰岛素生产的工艺路线猪胰岛素生产的工艺路线常规胰岛素制剂：常规胰岛素制剂：保存在较低的pH

8、2.5-3.5现代动物来源的胰岛素制剂现代动物来源的胰岛素制剂单峰胰岛素：并非均一的制剂单峰胰岛素：并非均一的制剂中性中性pH保持，保持，“速效速效”胰岛胰岛素素纯胰岛素（美国）纯胰岛素（美国）高纯胰岛素（英国）高纯胰岛素（英国）：经过凝胶过滤及离子交换层析纯化的：经过凝胶过滤及离子交换层析纯化的胰岛素。胰岛素。进一步去除了：分子质量相近的胰岛蛋白水解酶；去除了修饰的胰岛素；去除前胰岛素，将制剂中的前胰岛素含量降至10 g/g以下，即十万分之一以下。猪胰岛素的酶转化：人胰岛素人胰岛素 1982年，在美国、德国、英国与荷兰，通过重组DNA技术生产的人胰岛素首次获得许可应用于临床，它是第一个准许用

9、于人体治疗的重组DNA技术产品。优点：供应充分；消除病原体导致疾病意外传播的危险；经济实用；重组重组DNA技术制备胰岛素产品：人技术制备胰岛素产品：人胰岛素胰岛素crb/prb/pry 在酵母中，首先表达出一个类似与人胰岛素原的中间产物，然后在酶的作用下，切去连接肽，产生人胰岛素Pry1。(Precursor,recombinant,yeast)1 Markussen,et al.In peptides,1986:189-194.胰岛素的各种制备途径胰岛素的各种制备途径 基因工程胰岛素类似物基因工程胰岛素类似物 胰岛素泵 Little Change In A1c8.6%in 396 Canad

10、ian Type 1s in 199229.7%in 1,120 German children in 199639.7%in in U.S.in NHANES III,1988 to 19948.6%in 2,873 European children and adolescents in 199719.2%in 62 Canadian Type 1s in 20041.HB Mortensen et al:Diabetes Care.1997 May;20(5):714-202.Diabetes Care.1997 May;20(5):714-203.Horm Res 1998;50:10

11、7140GOAL:A1c 6.5%Not A CureSome early users died of hypoglycemia,but insulin seemed a remarkable cure.By the 1940s,however,diabetic complications began to appearIt became clear that injecting insulin was not the full answerWhen a system is not working for patients,trying harder will not work.Only changing the care system or our approach to care will work.Convergence Toward AutomationInsulinMonitoringHCPSelf ManagementAutomationInsulin&syringesPumpsPensConnectivityClinic MonitoringHome MonitorsData ManagementAdvice/FeedbackOpen LoopDeliveryClosed LoopYou are here胰岛素合成细胞治疗糖尿病胰岛素合成细胞治疗糖尿病