Therapeutic hormones

Therapeutic hormones

1. Therapeutic Hormones

2. Introduction Harmones Most Important group among regulatory molecules produce by the body. Synthesized and released from a specific glands. Interacting with a receptor present in/on a distant sensitive cell brought about a change in that target cell. Hormones travel to the target cell via the circulatory system.

3. Hormone to be any regulatory substance that carries a signal to generate some alteration at a cellular level. Under such a broad definition all cytokines for example could be considered hormones.

4. Examples Insulin Glucagon Somatotrophins Gonadotrophins Adrenaline

5. Insulin Insulin is a polypeptide hormone Produced by the beta cells of the pancreatic islets of Langerhans. It plays a central role in regulating blood glucose levels. .

6. Other examples Glucagon maintain blood glucose level. Somatotrophin stimulates growth. Gonadotrophins control secondary sexual characters

7. Therapeutic Hormones Hormones administered as drug. Synthesize in lab /industries. Nowaday genetic manipulation techniques are used to generate therapeutic hormones. E.g. rHGH , rInsulin

8. Insulin Insulin is a polypeptide hormone Produced by the beta cells of the pancreatic islets of Langerhans . Islets of Langerhans : Known as the insulin-producing tissue

9. It stimulates glucose transport It stimulates intracellular biosynthetic pathways It inhibits catabolic pathways, such as glycogenolysis

10. Diabetes mellitus Failure of the body to synthesize sufficient insulin results in the development of insulin-dependent diabetes mellitus (IDDM ). Also known as type-1 diabetes. IDDM is caused by T-cell-mediated autoimmune destruction of the insulin-producing β-pancreatic islet cells in genetically predisposed individuals.

11. genetic predisposition   sometimes also called  genetic   susceptibility. Dosage of insulin: Rapid-acting insulin Short-acting insulin Intermediate-acting insulin Long-acting insulin

12. The insulin molecule First identified as an anti-diabetic factor in 1921 Its complete amino acid sequence was determined in 1951 . The insulin receptor is a tetrameric integral membrane glycoprotein consisting of two 735 amino acid α-chains and two 620 amino acid β-chains. These are held together by disulfide linkages.

13. Insulin Production

14. Traditionally insulin preparations Animal insulin was the first type of insulin to control diabetes. Until the 1980s, animal insulin was the only treatment for insulin dependent diabetes. Animal insulin is derived from cows and pigs. D irect extraction from pancreatic tissue of slaughterhouse pigs and cattle.

15. Disadvantages Slight structural difference of 1-3 amino acids between the animal insulin and human insulin. Diabetic patient developed antibodies against the animal insulin thereby causing allergic reactions. large number of animals were to be sacrificed for extracting the insulin from their pancreas. For example: To obtain 5 kgs . Of pancreatic juice about 75 pigs have to be killed to get insulin for treating only a single diabetic patient just for one year.

16. By recombinant DNA technology First approved for general medical use in 1982. First product approved for therapeutic use in humans. Insulin consist of two polypeptide chains A and B. inserting the A and B chains into two different E. coli cells. Chain A and B separately synthesized.

17. The A- and B-chains are then incubated under required parameters. Bond formation.

18. Formulation of insulin

19. Insulin are formulating in number of way to alert the order of pharmacokinetic profile There are two types pharmacokinetic profiling Fast (short)-acting insulins Slow-acting insulins

20. In healthy individuals In healthy individuals, insulin is typically secreted continuously into the bloodstream at low basal level With rapid increases evident in response to elevated blood sugar levels low-acting insulin preparation, however, accurately reproduces normal serum insulin baseline level fast-acting insulin will not produce a plasma hormone peak for 1.5–2 h post injection, and levels then remain elevated for up to 5 h.

21. Prolong the duration of insulin action This is generally achieved in one of two ways: Addition of zinc in order to promote Zn–insulin crystal growth Addition of a protein to which the insulin will complex The proteins normally used are protamine's

22. Engineered insulins Recombinant DNA technology facilitates not only production of human insulin in microbial systems, but also facilitates generation of insulins of modified amino acid sequences The major aims of generating such engineered insulin analogues include: Identification of insulins with altered pharmacokinetic properties Identification of super-potent insulin forms The insulin amino acid residues that interact with the insulin receptor have been identifi ed (A1, A5, A19, A21, B10, B16, B23-25), and a number of analogues containing amino acid substitutions at several of these points have been manufactured.

23. Modified insulins modified insulins have now been approved for medical injected at mealtimes rather than1 h before Several Engineered insulins are inliste Insulin lispro ’ (tradename ‘Humalog’) was the first such engineered short-acting insulin to come to market ‘ Insulin Aspart ’ is a second fast-acting engineered human insulin It differs from native human insulin in that the proline B28 residue has been replaced by aspartic acid This single amino acid substitution

24. Optisulin or Lantus are the tradenames given to one such analogue that gained general marketing approval in 2000 It differs from native human insulin in that the C-terminal aspargine residue of the A-chain has been replaced by a glycine residue and the β -chain has been elongated(again from its C-terminus) by two arginine residues Levemir (tradename) is an alternative engineered long-acting insulin product that gained approval for general medical use in 2004 This differs from native insulin in that it is devoid of the threonine B30 residue and (more importantly from a pharmacokinetic perspective)contains a 14-carbon fatty acid residue covalently attached to the side chain of lysine residue B29

25. Glucagon

26. Glucagon Polypeptide Single chain (29 amino acids) Its function is contradictory to insulin. Secretes in response to hypoglycemia. Promotes catabolic activity. i.e. Break down of stored energy stimulates gluconeogenesis .

27. Glucagon Source: Pancreas Extract from bovine & porcine pancreatic tissues. Used as freeze dried hormone. Dosage routes : Subcutaneous & Intramuscular Now Recombinant products are available. E.g . Glucagen

28. Human Growth Hormone Somatotrophin . Hormone : Stimulates growth 191 amino acid Released by pituitary glands. Traditionally extracted from bovine /porcine source.

29. Therapeutic Uses Wide range of applications Treatment of dwarfism (1958). Stimulation of lactation. rhGH was produce in 1980 . rhGH was first purified (on a laboratory scale) by Genentech

30. Gonadotrophins Group Produced Proteins Hormones Gonadotropes cell Pituitary glands

31. They directly and indirectly regulate ; R eproductive function secondary sexual characteristics

32. Hypothalamus Pituitary glands GnRH FSH LH

33. Types FSH LH HCG

34. Follicle stimulating Hormone Females Helps ovarian follicle to develop. Promotes estrogen secretion. Males Promotes sperm development

35. luteinizing hormone Females Stimulation ovulation Promotes secretion of estrogen and progesterone Males Stimulates production of testosterone

36. Human Chorionic Hormones It is a hormones produced naturally by the pregnant women to ensure the correct nourishment of the baby

37. Medical Applications of Gonadotrophin Hormones

38. T he therapeutic potential of gonadotrophins in treating subfertility /some forms of infertility. Gonadotrophins are also used to induce a superovulatory response in various animal specie. T he human pituitary is the obvious source of human gonadotrophins . T he urine of post-menopausal women does contain both FSH and LH activity.

39. Menotrophin (human menopausal gonadotrophin ) is the name given to FSH-enriched extracts from human urine. Such preparations contain variable levels of LH activity, as well as various other proteins normally present in urine. hCG exhibits similar biological activities to hLH and is excreted in the urine of pregnant women

40. Applications: Treatment of anovulatory infertility. Treatment of females with blocked fallopian tube. Treatment of male subfertility or related conditions. F uture additional clinical applications.

41. 1. Treatment of anovulatory infertility. In females, menotrophins and hCG are used for the treatment of infertility. Menotrophin is administered to stimulate follicular maturation, along with hCG to promote ovulation and corpus luteum formation.

42. Dosage: G onadotrophin , often given for 12 days or more, followed by a single dose of hCG . T hree equal larger doses of menotrophin are given on alternate days. Followed by hCG administration 1–2 days.

43. Dosage Level: Dosage of both hormones is given same as the amount of them produced normally during the reproductive cycle of fertile females. Depending upon the basal hormonal status of the female, calculation of the optimal dosage levels can be tricky. Overdosage can result in risk of multiple pregnancy.

44. 2. Treatment of Female Infertility: FSH given in more quantity than normal to allow the female to stimulate multiple follicular growth. O ften employed when a woman has a blocked fallopian tube. After treatment, the resultant eggs are collected, incubated in vitro with partner’s sperm. Cultured and incubated untill blastocyts formed and implanted back.

45. 3. Treatment of Male Subfertility : FSH and hCG are also involved in treatment of male infertility. Given to males having hypogonadotrophic hypogonadism (HH) to stimulate sperm synthesis. hCG has also application in the treatment of cryptorchidism condition.

46. 4. Clinical Applications: C ell surface receptor of LH & hGC is found in a number of non- gonadal tissue. These hormones may possess other than reproductive functions. I t is expressed by a number of tissues before birth, hinting at a potential developmental role. Receptor levels in non- gonadal tissues are generally much lower than in gonadal tissue.

47. Recombinant gonadotrophins Recombinant DNA technology rhFSH produced in CHO cells has proven clinically effective When administered to humans , the preparation is well tolerated and yields no unexpected side effects hypogonadotrophic hypogonadism

48. Recombinant gonadotrophins now approved for general medical use in the EU and USA Product Company Indication Gonal F ( rhFSH ) Serono Anovulation and Superovulation Puregon ( rhFSH ) N.V. Organon Anovulation and Superovulation Follistim ( rhFSH ) Organon Some forms of infertility Luveris ( rhLH ) Ares- Serono Some forms of infertility Ovitrelle ( rhCG ) Serono Selected assisted reproductive techn

49. Ovitrelle Ovitrelle ( tradename in EU, sold as Ovidrel in the USA and also known as choriogonadotropin alfa ) is a recombinant hCG Treatment of female infertility due to anovulation It is used to trigger final follicle maturation and luteinization after follicle stimulation.

50. Veterinary uses of gonadotrophins T reat subfertility in animals Horses and cattle FSH is administered to the animal such that multiple follicles develop simultaneously After administration of LH to help promote ovulation , the animal is mated, thus fertilizing the released egg cells Embryos are recovered and maintained in cell culture for a short period of time. Single embryo is then usually reimplanted into the donor female , while the remaining embryos are implanted into the surrogate mothers

51. e.g. prize winning horses , or high milk-yield dairy cattle to boost their effective reproductive capacity

52. P orcine FSH (p-FSH) and Porcine LH (p-LH) p-FSH is extracted from the pituitary glands of slaughterhouse pigs . The crude pituitary extract is usually subject to a precipitation step , using either ethanol or salts . The FSH -containing precipitate is normally subjected to at least one subsequent chromatographic step . p-LH is obtained, again, by its partial purification from the pituitary glands of slaughterhouse pigs. The final product often contains some LH and low levels of additional pituitary derived proteins Target recipients are cattle or horses

53. Additional recombinant hormones now approved Three additional recombinant hormones have recently gained marketing approval: T hyroid-stimulating hormone P arathyroid hormone C alcitonin.

54. Thyroid stimulating harmone Structurally, thyroid-stimulating hormone (TSH or thyrotrophin) is classified as a member of the gonadotrophin family, although functionally it targets the thyroid gland as opposed to the gonads. TSH is synthesized by a distinct pituitary cell type: the thyrotroph. Its synthesis and release are promoted by thyrotrophin-releasing hormone. TSH exerts its characteristic effects by binding specific receptors found primarily, but not exclusively, on the surface of thyroid gland cells.

55. Human parathyroid hormone Human parathyroid hormone ( hPTH ) is an 84 amino acid polypeptide that functions as a primary regulator of calcium and phosphate metabolism in bones. It stimulates bone formation by osteoblasts, which display high-affinity cell surface receptors for the hormone. PTH also increases intestinal absorption of calcium.

56. Calcitonin Calcitonin is a polypeptide hormone that plays a central role in regulating serum ionized calcium (Ca2) and inorganic phosphate (Pi) levels. The adult human body contains up to 2 kg of calcium, of which 98 per cent is present in the skeleton (i.e. bone). Up to 85 percent of the 1 kg of phosphorus present in the body is also found in the skeleton.

57. Calcitonin lowers serum Ca2 and Pi levels, primarily by inhibiting the process of bone resorption , but also by decreasing resorption of Pi and Ca2 in the kidney. Calcitonin receptors are predictably found primarily on bone cells (osteoclasts) and renal cells.

58. Calcitonin is used clinically to treat hypercalcaemia associated with some forms of malignancy and Paget’s disease. The latter condition is a chronic disorder of the skeleton in which bone grows abnormally in some regions.

59. Conclusion Several hormone preparations have a long history of use as therapeutic agents. Usually these are administered when the patients are not producing enough quantities of endogenous hormones. I nsulin has saved or prolonged the lives of millions of diabetic patients. Gonadotrophins have allowed thousands of sub-fertile individuals to conceive. GH has improved the quality of life of thousands of people of short stature. Recombinant hormonal preparations, however, are now gaining greater favour , mainly on safety grounds.

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