Pharmaceutical Biotechnology 西安电子科技大学夏玉琼 Insulin and human growth hormone By Yuqiong Xia 5/19/2017
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1 Pharmaceutical Biotechnology Insulin and human growth hormone By Yuqiong Xia 5/19/2017
2 生物技术制药 2 技术基础 生物技术药物 生物技术制药概念药物的开发药物的生产细胞因子生长因子激素类药物血液制品和治疗性酶抗体 疫苗和佐剂核酸药物 药物的发现 专利的申请临床前试验临床试验生物药物的来源生物药物的生产和纯化生物药物的分析干扰素白介素造血生长因子
3 True endocrine hormone Definition A substance synthesized and released from a specific gland in the body, which can affect distant target cells Gland Blood circulation Hormone 3 Target cells
4 Hormones VS Cytokines Generation Hormone: by gland (cells producing a secretion) Cytokine: by immune cells or non-immune cells Types Hormone: protein, steroid, amino acid derivatives, fatty acid derivative Cytokine: small proteins Function Hormone: change the homeostasis, reproduction, development, and/or behavior Cytokine: regulate cell growth, cell differentiation and modulate immune response 4
5 Outline Insulin Introduction Chemical description Pharmacology and formulations Human growth hormone 5
6 胰脏的位置 6
7 Source of insulin inside the body Common bile duct Duodenum Stomach Pancreatic duct pancreas islet β-cell 7
8 Source of commercial insulin First-line therapy Human insulin and insulin analog Others and not produced by major manufacturer Bovine and porcine insulin 8
9 The function of insulin Regulate carbohydrate and fat metabolism Cause cells in the skeletal muscles, and fat tissue to absorb glucose from the blood Inhibit the release of glucagon( 胰高血糖素 ) and stop the use of fat as an energy source Provided within the body in a constant proportion to remove excess glucose from the blood 9
10 Types of Diabetes Type I Diabetes Younger people Depend on external insulin Insulin is no longer produced in the patients Type II Diabetes Older people Insulin resistant or have relatively low insulin production or both; Some patients require insulin 10
11 History of insulin 1921 Banting and Best discovered insulin Enhance purity Optimize formulation: acidic to neutral, zinc, protamine After 1980 Recombinant DNA technology >98% purity Insulin analog 11
12 Outline Insulin Introduction Chemical description Pharmacology and formulations Human growth hormone 12
13 Chemical structure of Insulin Preproinsulin 前胰岛素原 Proinsulin 胰岛素原 Insulin 13
14 Amino acid sequence A6-A11 21 AA A7-B7 A20-B19 30 AA 14
15 Charge properties pi = 5.3 ph = pi positive charge = negative charge ph < pi -NH 2 become NH 3 + ph > pi COOH become COO - 15
16 Association properties 16
17 T6 and R6 T-state monomer T-state dimer T-state hexamer R-state hexamer 17
18 Outline Insulin Introduction Chemical description Pharmacology and formulations Human growth hormone 18
19 Insulin secretion In response to a meal, μu/ml Background insulin secreted continually, 5-15 μu/ml 19
20 Formulations 1 Regular and rapid-acting soluble formulations 2 Intermediate-acting insulin formulations 3 Long-acting insulin formulations gEvBohg00mysY*elFKwirdD8x0vI0aDOj7WctXHNv5PmnArF-5N-FY0Vq/figure7.png
21 1 西安电子科技大学 夏玉琼 Regular and rapid-acting soluble formulations Zinc ~0.4%; Phenolic ( 酚的 ) preservatives Peak insulin 2-4 hr; Maximum duration 5-8 hr Delay: hexamer to monomer takes time Takes time 21
22 夏玉琼 Insulin dissociation after SC administration 西安电子科技大学 R-state hexamer T-state hexamer 22
23 To minimize delay (Insulin Lispro) Peak insulin ~1h Hexamer formed by insulin analog rapid Much quicker Insulin analog 23
24 24 Insulin lispro disassociation after SC administration
25 2 Intermediate-acting insulin formulation NPH Neutral Protamine Hagedorn Lente 25
26 NPH Neutral crystalline suspension Co-crystallization with protamine Protamine 30 AA, 65-70% Arg Onset 1-2 hr, Peak 2-8 hr, Duration hr 26
27 NPH/regular 27
28 Lente zinc Single daily injection Onset 1-2 hr, Peak 3-10 hr, Duration hr Mix with regular, only for temporary use 28
29 3 Long-acting insulin formulation Ultralente: solid particles, subcutaneous Lantus : solid particles, subcutaneous Levemir : solution 29
30 Ultralente Similar to NPH, except Larger, no protamine crystallized at acidic conditions Use methylparaben( 对羟基苯甲酸甲酯 ) as preservative Onset hr, Peak 4-20 hr, Duration hr It will not be used soon 30
31 Lantus Prepared in ph =4.0 Insulin analog A21 to glycine Precipitates in the body when ph becomes neutral 31
32 Levemir Insulin analog Acylation with a fatty acid moiety Zinc hexamer Neutral ph Bind to albumin makes it have long circulation time 32
33 Outline Insulin Human growth hormone Introduction hgh structure and isohormones Pharmacology 33
34 夏玉琼 Introduction to human growth hormone (hgh) Protein hormone Normal growth and development in humans Late 1950s, pit-hgh: isolated and identified from Pituitary glands ( 脑垂体 ) of cadaver( 尸体 ) Patients undergoing hypophysectomy ( 垂体切除术 ) 1979 first cloned hgh 1982 rhgh Bacteria, yeast, mammalian cells 西安电子科技大学 34
35 Outline Insulin Human growth hormone Introduction hgh structure and isohormones Pharmacology 35
36 Structure 191 AA
37 Four anti-parallel alpha-helix 37
38 Two types of hgh gene hgh-n (normal) Express normal hgh in pituitary hgh-v (variant) Express several forms of hgh in placenta ( 胎盘 ) of pregnant women 38
39 Outline Insulin Human growth hormone Introduction hgh structure and isohormones Pharmacology 39
40 hgh Secretion From somatotroph ( 促生长激素细胞 )in the anterior pituitary ( 垂体前叶 ) hypothalamus Brain pituitary 40
41 GH secretion with time Highest during night Highest during puberty and gestation 青春期怀孕期
42 Biological activity of IGF1 Primary mediator of the effects of growth hormone (GH) 42
43 Biological actions 43
44 hgh regulation Ultrashort loop By GH receptor (GHR) on somatotroph ( 促生长激素细胞 ) 2. Short loop By GHRH (GH releasing hormone) and GHIH (GH inhibiting hormone) secreted by hypothalamus ( 下丘脑 ) 3. Long loop By insulin-like growth factor ( 类胰岛素生长因子 ) and other modulators
45 神经调节素胃饥饿素 2 生长激素抑素生长激素释放激素 神经调节素胃饥饿素 1 Somatotroph( 促生长激素细胞 ) 3 45 合成代谢
46 hgh Receptor and Binding Proteins hgh of 22 kda and 20 kda forms are secreted by the pituitary. 2. Pituitary hgh is stored bound to zinc 3. Secreted hgh is free or bound to either the low or high affinity GHBP in plasma. 4. Receptor activation involves dimerization of two receptor molecules with one molecule of hgh.
47 The effects of GHBP Decrease clearance of hgh Make hgh more stable Decrease the effects of hgh Compete with GHR 47
48 hgh regulation Ultrashort loop By GH receptor (GHR) on somatotroph ( 促生长激素细胞 ) 2. Short loop By GHRH (GH releasing hormone) and GHIH (GH inhibiting hormone) secreted by hypothalamus ( 下丘脑 ) 3. Long loop By insulin-like growth factor ( 类胰岛素生长因子 ) and other modulators
49 神经调节素胃饥饿素 2 生长激素抑素生长激素释放激素 神经调节素胃饥饿素 1 Somatotroph( 促生长激素细胞 ) 3 49 合成代谢
50 hgh regulation Ultrashort loop By GH receptor (GHR) on somatotroph ( 促生长激素细胞 ) 2. Short loop By GHRH (GH releasing hormone) and GHIH (GH inhibiting hormone) secreted by hypothalamus ( 下丘脑 ) 3. Long loop By insulin-like growth factor ( 类胰岛素生长因子 ) and other modulators
51 神经调节素胃饥饿素 2 生长激素抑素生长激素释放激素 神经调节素胃饥饿素 1 Somatotroph( 促生长激素细胞 ) 3 51 合成代谢
52 Summary Hormone Insulin Structure: A-chain, B-chain, S-S bond Three kind of formulations: regular, intermediate, long Diabete 1 and 2 hgh Structure: single chain, S-S bond hgh regulation GHR and GHBP 52
Insulin and human growth hormone
Pharmaceutical Biotechnology Insulin and human growth hormone By Yuqiong Xia Keywords Insulin, pancreatic, glucagon, diabetes, zinc, protamine peak, maximum, crystallization, acid Human growth factor,
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姓名 : 姚火春性别 : 男毕业院校 : 南京农业大学最高学位 : 博士办公地址 : 逸夫楼 4053 办公电话 :025-84395328 电子邮箱 :yaohch@njau.edu.cn 研究方向 : 动物及人兽共患疫病病原学 细菌及病毒致病机理 病原与宿主互作关系 动物疾病防控 个人简介 : 姚火春 : 男,1963 年 2 月出生, 籍贯浙江湖州 研究工作经历 : 2009/12- 至今,
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