งานนำเสนอกำลังจะดาวน์โหลด โปรดรอ

งานนำเสนอกำลังจะดาวน์โหลด โปรดรอ

Miacalcic differentiation value by relieve bone pain & high safety profile Dr. Suppasin Soontrapa Department of Orthopedics Khon Kaen University, Khon.

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งานนำเสนอเรื่อง: "Miacalcic differentiation value by relieve bone pain & high safety profile Dr. Suppasin Soontrapa Department of Orthopedics Khon Kaen University, Khon."— ใบสำเนางานนำเสนอ:

1 Miacalcic differentiation value by relieve bone pain & high safety profile Dr. Suppasin Soontrapa Department of Orthopedics Khon Kaen University, Khon Kaen, Thailand 31 July 2010

2  consisting of 32 amino acids  which is the most potent of all calcitonins Synthetic Salmon Calcitonin

3 P.R.O.O.F. Prevent Recurrence of Osteoporotic Fractures A Multicentered, Double-Blind, Randomized, 5-Year Study to Investigate the Efficacy of Salmon Calcitonin Nasal Spray in the Prevention of Osteoporotic Vertebral Fractures Final Analysis Chesnut CH 3 rd, Silverman S, Andriano K, Genant H, Gimona A, Harris S, Kiel D, LeBoff M, Maricic M, Miller P, Moniz C, Peacock M, Richardson P, Watts N, Baylink D. Am J Med Sep; 109(4):

4 conclusion 200 IU of salmon calcitonin nasal spray per day significantly reduces the risk of new vertebral fracture by 33% to 36% in postmenopausal women with low bone mass or prevalent vertebral fractures. 200 IU of salmon calcitonin nasal spray per day significantly reduces the risk of new vertebral fracture by 33% to 36% in postmenopausal women with low bone mass or prevalent vertebral fractures.

5 1. Riggs BL et al. N Engl J Med. 1990;322: Chesnut CH III et al. Am J Med. 2000;109: Ettinger B et al. JAMA. 1999;282: Harris ST et al. JAMA. 1999;282: Black DM et al. Lancet. 1996;348: – – 3 3– 5 6– 8 Positive Bone Former/ Antiresorptive Agent % Increase in Vertebral BMD % Decrease in Vertebral Fracture Risk Fluoride 1 Calcitonin-salmon 2 Raloxifene 3 Risedronate 4 Alendronate เปรียบเทียบผลการรักษาของยาชนิดต่างๆโดย พิจารณาการเพิ่มขึ้นของค่า BMD และ ความสามารถในการลดอุบัติการณ์ของกระดูก สันหลังหัก Per protocol

6 ข้อน่าสังเกตจากการเปรียบเทียบ ข้างต้น น่าจะมีสิ่งอื่นนอกจาก ความหนาแน่นของ กระดูกที่ช่วยให้กระดูก แข็งแรงขึ้น Bone Quality

7 The QUEST study (QUalitative Effects of Salmon Calcitonin Therapy)

8 Conclusion CT-NS 200 IU พ่นจมูก ทุกวันเป็นเวลา 2 ปีในสตรี หลังหมดประจำเดือนที่ เป็นโรคกระดูกพรุน สามารถเพิ่มหรือคงสภาพ ของ trabecular microarchitecture ของ กระดูก distal radius เมื่อ เทียบกับก่อนรักษา ในขณะที่ยาลวงมีแนวโน้ม ลดลง

9 Calcitonin & Pain 21 Jan 09

10

11 Objective To assess the effects of calcitonin vs. placebo for the treatment of acute pain in patients sustaining stable, recent, osteoporotic vertebral compression fractures

12 IU IM IU IN

13 IU suppo IU BID of IN

14 results The combined results from five randomized controlled trials, involving 246 patients Calcitonin significantly reduced the severity of pain using a visual analogue scale following diagnosis Pain at rest was reduced as early as 1 week into treatment (weighted mean difference [WMD] =3.08; 95% confidence interval [CI]: 2.64, 3.52)

15 results The effect on pain continued weekly to 4 weeks (WMD =4.03; 95% CI: 3.70, 4.35). A similar pattern was seen for pain scores associated with sitting, standing, and walking.

16 Subgroup analysis The VAS (sitting) IN calcitonin, WMD 2.55 (95% CI: 2.16, 2.84) calcitonin rectal suppositories, WMD 2.00 (95% CI: 1.46, 2.54) IM calcitonin, WMD 4.00 (95% CI: 3.0, 5.0) IM calcitonin (n =28) better pain control and were able to mobilize more quickly than intra-nasally (IN) or rectal suppository

17

18 Side effects All in mild and were not significant difference

19 Conclusion Calcitonin appears to be effective in the management of acute pain associated with acute osteoporotic vertebral compression fractures by shortening time to mobilization

20 pain after a vertebral fracture The location of the pain is dependent on the location of the vertebral fractures – can be confirmed radiographically. Pain is exacerbated by – weight-bearing activities – Valsalva maneuvers, – lifting and bending, Tenderness to percussion.

21 Goals of Pain Treatment Improvement in pain symptoms Restoration of function

22 Multidisciplinary Pain Management Approach Goal-oriented exercise regimen Appropriate lifestyle modifications Pain relief modalities Psychosocial support Various assistive devices

23 Mechanism of Pain & Pain Pathway

24 presynaptic neurone postsynaptic neurone interneurone lateral STT

25 The Somatosensory System Somatosensory cortex Thalamus Hypothalamus Ascending tracts Midbrain Medulla Spinal cord Frontal cortex Descending pathway Periaqueductal gray matter Dorsal horn area Noxious stimuli activate receptors in periphery interneurone

26 Effect of Calcitonin in the CNS Periaqueductal gray ถือเป็นศูนย์ ควบคุมความรู้สึกปวดที่สำคัญ Periaqueductal gray ถือเป็นศูนย์ ควบคุมความรู้สึกปวดที่สำคัญ พบมี calcitonin receptor ที่บริเวณนี้ มาก เมื่อจับกับ calcitonin จึงมีผล ระงับอาการปวดได้ พบมี calcitonin receptor ที่บริเวณนี้ มาก เมื่อจับกับ calcitonin จึงมีผล ระงับอาการปวดได้

27 The Antinociceptive Effects of calcitonin Opioidergic transmission Serotonergic transmission Guidobono F, et al., Role of catecholamines in calcitonin-induced analgesia. Pharmacology 31:342-8 (1985) Maeda Y, et al., Neuronal mechanism of the inhibitory effect of calcitonin on N-methyl-D-asparatate induced aversive behavior. Eur J Pharmacol 275: (1995)

28 serotonin

29 The Antinociceptive Effects of calcitonin Opioidergic transmission Serotonergic transmission Guidobono F, et al., Role of catecholamines in calcitonin-induced analgesia. Pharmacology 31:342-8 (1985) Maeda Y, et al., Neuronal mechanism of the inhibitory effect of calcitonin on N-methyl-D-asparatate induced aversive behavior. Eur J Pharmacol 275: (1995)

30

31 Mechanism of Action in Animal Models Most evidence indicates that calcitonin has a direct effect on the central nervous system (CNS) for acute pain that is independent of opioid action. In the rabbit dental pulp model, the analgesia subsequent to salmon 1 or porcine 2 calcitonin administration was not reversed by the opioid antagonist naloxone. 1 Braga P, et al. Lack of opiate receptor involvement in centrally induced calcitonin analgesia. Life Sci 1978;22: Yamamoto M, et al. Effect of porcine calcitonin on behavioural and electrophysiological responses elicited by electrical stimulation of the tooth pulp in rabbits. Pharmacology 1982;24:

32 Mechanism of Action in Animal Models SCT and morphine (which acts on  - opioid receptors) acted in an additive manner. In vitro assays suggested that calcitonin potentiates the action of ligands acting on  - and  -opioid receptors, but not on  -opioid receptors. 1 1 Martin MI, et al. Analgesic effect of two calcitonins and in vitro interaction with opioids. Gen Pharmacol 1995;26:641-7.

33 The Antinociceptive Effects of calcitonin Opioidergic transmission Serotonergic transmission Guidobono F, et al., Role of catecholamines in calcitonin-induced analgesia. Pharmacology 31:342-8 (1985) Maeda Y, et al., Neuronal mechanism of the inhibitory effect of calcitonin on N-methyl-D-asparatate induced aversive behavior. Eur J Pharmacol 275: (1995)

34

35

36 12 sham 12: 20 U/kg/d 12: 5 U/kg/d 12: placebo Operation date OVX N= st experiment

37

38 12 sham 12: 20 U/kg/d 12: 5 U/kg/d 12: placebo Operation date OVX N= st experiment

39 Inhibitor of serotonin biosynthesis No serotonin production

40 24: 20 U/kg/d 4 12 sham 12: placebo N=48 2 nd experiment 12: 20 U/kg/d + PCPA 12: 20 U/kg/d + saline

41

42 (inhibitory neurone)

43 presynaptic neurone postsynaptic neurone interneurone lateral STT A , C

44 (fast fiber) (slow fiber)

45 (inhibitory neurone)

46 EPSC = excitatory postsynaptic current

47

48

49

50 Unresponsive to serotonin

51 Some problem on C-fiber

52

53 Calcitonin has some effects on C-fiber

54

55

56

57 Conclusion การที่ calcitonin สามารถลด อาการปวดในผู้ป่วยโรคกระดูก พรุน โดยกระทำผ่าน การที่ calcitonin สามารถลด อาการปวดในผู้ป่วยโรคกระดูก พรุน โดยกระทำผ่าน serotonin pathway โดยการเพิ่ม receptor ต่อ serotonin ที่ C- fiber ให้กลับมาเป็นปกติ serotonin pathway โดยการเพิ่ม receptor ต่อ serotonin ที่ C- fiber ให้กลับมาเป็นปกติ calcitonin จับกับ calcitonin receptor ที่บริเวณ Periaqueductal gray ซึ่งเป็นศูนย์ ควบคุมความรู้สึกปวดที่สำคัญใน CNS และกระตุ้นให้มีการหลั่ง serotonin เพิ่มขึ้น calcitonin จับกับ calcitonin receptor ที่บริเวณ Periaqueductal gray ซึ่งเป็นศูนย์ ควบคุมความรู้สึกปวดที่สำคัญใน CNS และกระตุ้นให้มีการหลั่ง serotonin เพิ่มขึ้น เพิ่มฤทธิ์ของสารที่จับกับ ,  opioid receptor เพิ่มฤทธิ์ของสารที่จับกับ ,  opioid receptor

58 Safety of Calcitonin

59 Therapeutic options for osteoporosis Stimulators of bone formation Parathyroid hormone Inhibitors of bone resorption  Bisphosphonates Alendronate Risedronate Ibandronate Zoledronate Calcitonin Estrogen ± progestin Selective estrogen receptor modulators (SERMs) Raloxifene Mixed mechanism of action Vitamin D and metabolites Vitamin K Strontium ranelate Recommended for all women at risk for osteoporosis Calcium and vitamin D

60 Therapeutic options for osteoporosis Stimulators of bone formation Parathyroid hormone Inhibitors of bone resorption  Bisphosphonates Alendronate Risedronate Ibandronate Zoledronate Selective estrogen receptor modulators (SERMs) Raloxifene Mixed mechanism of action Strontium ranelate Recommended for all women at risk for osteoporosis Calcium and vitamin D ใช้ได้เฉพาะในกรณีค่า crcl > 30 cc/min

61 Renal Problem in Thai Elderly Women Community survey of the KK elderly women age > 60 yrs. 1,732 cases (S. Soontrpa, 2003: unpublished data) –Mean (SD) = (5.51) CrCl < 30 cc/min = 23% One forth of community elderly women with the age > 60 yrs. had severe renal insufficiency

62

63 Therapeutic options for osteoporosis Stimulators of bone formation Parathyroid hormone Inhibitors of bone resorption  Bisphosphonates Alendronate Risedronate Ibandronate Zoledronate Calcitonin Estrogen ± progestin Selective estrogen receptor modulators (SERMs) Raloxifene Mixed mechanism of action Vitamin D and metabolites Vitamin K Strontium ranelate Recommended for all women at risk for osteoporosis Calcium and vitamin D Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcer

64 | Cycle Meeting | NP | | Renal Safety | Confidential Calcitonin Renal Actions  Increases in calcium, phosphorus and sodium excretion Inhibits phosphate reabsorption by the kidney tubules 1 Calcitonin inhibits tubular reabsorption of Ca 2+, leading to increased rates of its loss in urine. 1  Stimulation of 25-(OH)D3-1-α-hydroxylase activity 2  Hormone binding site in renal cortical brush border and basolateral membranes 2  Basolateral membrane binding follows with activation of adenylate cyclase  Brush border membrane binding is related to metabolism of calcitonin 3 | Cycle Meeting | NP | | Renal Safety | Confidential 1.Carney SL. Miner Electrolyte Metab (1997) 23 (1): 43–7. 2.Kurokawa K, in Seldin DW, Giebisch G. The Kidney: Physiology and Pathophysiology. New York: Raven Rabkin R, Kitaji J. Mineral Electrolyte Metab (1983) 9:

65 | Cycle Meeting | NP | | Renal Safety | Confidential Calcitonin Renal Metabolism  Renal metabolism accounts for approximately 2/3 of the total metabolism of calcitonin 1  Removal of calcitonin from renal circulation by Glomerular filtration followed by proximal tubular degradation by hydrolysis after contact with brush-border membrane (40%) Receptor-mediated, filtration-independent removal from the postglomerular peritubular circulation -Basolateral endocytosis with intracellular degradation -Basolateral membrane hydrolysis in more distal nephron segments 2  Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically-inactive fragments of the molecule. 3  The metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. The clinical relevance of this finding is not known. 3 | Cycle Meeting | NP | | Renal Safety | Confidential 1.Ardaillou R., Paillard F., Savier C., Bernier A. Rev Eur Etud Clin Biol (1971) 16: Simmons RE, et. al. Am J Physiol Renal Physiol (1988) 254 (4): Electronic Medicines Compendium". Retrieved Electronic Medicines Compendium"http://emc.medicines.org.uk/

66 | Cycle Meeting | NP | | Renal Safety | Confidential Comparison of Bisphosphonates and Calcitonin Renal Tolerability BisphosphonatesCalcitonin Biologically-active in kidney All biologically-activeRapidly degraded to non-active metabolites Induced renal cell apoptosis YesNo Type of renal pathologyAcute Tubular NecrosisNo | Cycle Meeting | NP | | Renal Safety | Confidential

67 P.R.O.O.F. Prevent Recurrence of Osteoporotic Fractures A Multicentered, Double-Blind, Randomized, 5-Year Study to Investigate the Efficacy of Salmon Calcitonin Nasal Spray in the Prevention of Osteoporotic Vertebral Fractures Final Analysis Chesnut CH 3 rd, Silverman S, Andriano K, Genant H, Gimona A, Harris S, Kiel D, LeBoff M, Maricic M, Miller P, Moniz C, Peacock M, Richardson P, Watts N, Baylink D. Am J Med Sep; 109(4):

68 Adverse Effects Rhinitis (nasal congestion, nasal discharge, or sneezing) occurred in active-treated groups higher than in placebo group (22% vs 15%; p<0.01) Most of them were mild to moderate severity, (calcitonin: 67% mild, 30% moderate; placebo: 64% mild, 27% moderate)

69 Key Advantage of Miacalcic Nasal Spray –Easy to use : a simple dose a day –Convenience : any time…….anywhere –Patients need not to be in standing position –Can be taken with food, milk and other medications –No contraindications for patients with - GI problems - Renal problems - Limited mobility –No risk of reflux esophagitis, esophageal ulcer

70 Thank you


ดาวน์โหลด ppt Miacalcic differentiation value by relieve bone pain & high safety profile Dr. Suppasin Soontrapa Department of Orthopedics Khon Kaen University, Khon.

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