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30.08.2015 | Review

Calcimimetic and Calcilytic Drugs: Feats, Flops, and Futures

verfasst von: E. F. Nemeth, W. G. Goodman

Erschienen in: Calcified Tissue International | Ausgabe 4/2016

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Abstract

The actions of extracellular Ca²⁺ in regulating parathyroid gland and kidney functions are mediated by the extracellular calcium receptor (CaR), a G protein-coupled receptor. The CaR is one of the essential molecules maintaining systemic Ca²⁺ homeostasis and is a molecular target for drugs useful in treating bone and mineral disorders. Ligands that activate the CaR are termed calcimimetics and are classified as either agonists (type I) or positive allosteric modulators (type II); calcimimetics inhibit the secretion of parathyroid hormone (PTH). Cinacalcet is a type II calcimimetic that is used to treat secondary hyperparathyroidism in patients receiving dialysis and to treat hypercalcemia in some forms of primary hyperparathyroidism. The use of cinacalcet among patients with secondary hyperparathyroidism who are managed with dialysis effectively lowers circulating PTH levels, reduces serum phosphorus and FGF23 concentrations, improves bone histopathology, and may diminish skeletal fracture rates and the need for parathyroidectomy. A second generation type II calcimimetic (AMG 416) is currently under regulatory review. Calcilytics are CaR antagonists that stimulate the secretion of PTH. Several calcilytic compounds have been evaluated as orally active anabolic therapies for postmenopausal osteoporosis but clinical development of all of them has been abandoned because they lacked clinical efficacy. Calcilytics might be repurposed for new indications like autosomal dominant hypocalcemia or other disorders beyond those involving systemic Ca²⁺ homeostasis.

Brown EM (2015) Control of parathyroid hormone secretion by its key physiological regulators. In: Bilezikian JP, Marcus R, Levine MA, Marcocci C, Silverberg SJ, Potts JT (eds) The parathyroids, 3rd edn. Elsevier, Amsterdam, pp EP101–EP118

Riccardi D, Brown EM (2010) Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol 298:F485–F499

Goltzman D, Hendy GN (2015) The calcium-sensing receptor in bone—mechanistic and therapeutic insights. Nat Rev Endocrinol Metab 11:298–307CrossRef

Raue F, Scherübl H (1995) Extracellular calcium sensitivity and voltage-dependent calcium channels in C-cells. Endocr Rev 16:752–764PubMed

Brown EM (2007) Clinical lessons from the calcium-sensing receptor. Nat Clin Pract Endocr Metab 3:122–133CrossRef

Hannan FM, Thakker RV (2013) Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte and water metabolism. Best Prac Res Clin Endocr Metab 27:359–371CrossRef

Nemeth EF (2013) Allosteric modulators of the extracellular calcium receptor. Drug Disc Today Technol 10:e273–e284CrossRef

Nemeth EF (2006) Misconceptions about calcimimetics. Ann NY Acad Sci 1068:471–476CrossRefPubMed

Widler L (2011) Calcilytics: antagonists of the calcium-sensing receptor for the treatment of osteoporosis. Future Med Chem 3:535–547CrossRefPubMed

10.

Fox J, Lowe SH, Conklin RL, Petty BA, Nemeth EF (1999) Calcimimetic compound NPS R-568 stimulates calcitonin secretion but selectively targets parathyroid gland Ca²⁺ receptor in rats. J Pharmacol Exp Ther 290:480–486PubMed

11.

Nemeth EF, Heaton WH, Miller M, Fox J, Balandrin MF, Van Wagenen BC, Colloton M, Karbon W, Scherrer J, Shatzen E, Rishton G, Scully S, Qi M, Harris R, Lacey D, Martin D (2004) Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl. J Pharmacol Exp Ther 308:627–635CrossRefPubMed

12.

Ohashi N, Uematsu T, Nagashima S, Kanamaru M, Togawa A, Hishida A, Uchida E, Akizawa T, Koshikawa S (2004) The calcimimetic agent KRN 1493 lowers plasma parathyroid hormone and ionized calcium concentrations in patients with chronic renal failure on haemodialysis both on the day of haemodialysis and on the day without haemodialysis. Br J Clin Pharmacol 57:726–734CrossRefPubMedPubMedCentral

13.

Nemeth EF (1996) Calcium receptors as novel drug targets. In: Bilezikian JP, Raisz LG, Rodan GA (eds) Principles of bone biology. Academic Press, New York, pp 1339–1359

14.

Nemeth EF (1990) Regulation of cytosolic calcium by extracellular divalent cations in C-cells and parathyroid cells. Cell Calcium 11:323–327CrossRefPubMed

15.

Nemeth EF, Shoback D (2013) Calcimimetic and calcilytic drugs for treating bone and mineral-related disorders. Best Prac Res Clin Endocr Metab 27:373–384CrossRef

16.

Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D (2005) Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocr Metab 90:135–141CrossRefPubMed

17.

Peacock M, Bolognese MA, Borofsky M, Scumpia S, Sterling LR, Cheny S, Shoback D (2009) Cinacalcet treatment of primary hyperparathyroidism: biochemical and bone densitomertric outcomes in a five-year study. J Clin Endocr Metab 94:4860–4867CrossRefPubMed

18.

Nemeth EF (2010) Calcimimetics and calcilytics in the treatment of chronic kidney disease-mineral bone disorder. In: Olgaard K, Salusky IB, Silver J (eds) The spectrum of mineral and bone disorders in chronic kidney disease, 2nd edn. Oxford University Press, Oxford, pp 443–461CrossRef

19.

Drüeke TB (2013) Calcimimetics and outcomes in CKD. Kidney Intl Suppl 3:431–435CrossRef

20.

Cooper K, Quarles D, Kubo Y, Tomlin H, Goodman W (2012) Relationship between reductions in parathyroid hormone and serum phosphorus during the management of secondary hyperparathyroidism with calcimimetics in hemodialysis patients. Nephron Clin Pract 121:c124–c130CrossRefPubMed

21.

Block GA, Martin KJ, De Francisco ALM, Turner SA, Avram MM, Suranyi MG, Hercz G, Cunningham J, Abu-Alfa AK, Messa P, Coyne DW, Locatelli F, Cohen RM, Evenepoel P, Moe SM, Fournier A, Braun J, McCary LC, Zani VJ, Olson KA, Drüeke T, Goodman WG (2004) The calcimimetic cinacalcet hydrochloride for the treatment of secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 350:1516–1525CrossRefPubMed

22.

Gutierrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G, Sarwar A, Hoffmann U, Coglianese E, Christenson R, Wang TJ, deFilippi C, Wolf M (2009) Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119:2545–2552CrossRefPubMedPubMedCentral

23.

Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, Wahl P, Gutierrez OM, Steigerwalt S, He J, Schwartz S, Lo J, Ojo A, Sondheimer J, Hsu CY, Lash J, Leonard M, Kusek JW, Feldman HI, Wolf M (2011) Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 305:2432–2439CrossRefPubMedPubMedCentral

24.

Galitzer H, Ben-Dov I, Lavi-Moshayoff V, Naveh-Many T, Silver J (2008) Fibroblast growth factor 23 acts on the parathyroid to decrease parathyroid hormone secretion. Curr Opin Nephrol Hypertens 17:363–367CrossRefPubMed

25.

David V, Dai B, Martin A, Huang J, Han X, Quarles LD (2013) Calcium regulates FGF-23 expression in bone. Endocrinology 154:4469–4482CrossRefPubMedPubMedCentral

26.

Wetmore JB, Gurevich K, Sprague S, DaRoza G, Buerkert J, Reiner M, Goodman W, Cooper K (2015) A randomized trial of cinacalcet versus vitamin D analogs as monotherapy in secondary hyperparathyroidism (PARADIGM). Clin J Am Soc Nephrol. doi:10.2215/CJN.07050714

27.

Wetmore JB, Liu S, Krebill R, Menard R, Quarles LD (2010) Effects of cinacalcet and concurrent low-dose vitamin D on FGF23 levels in ESRD. Clin J Am Soc Nephrol 5:110–116CrossRefPubMedPubMedCentral

28.

Chertow GM, Block GA, Correa-Rotter R, Drüeke TB, Floege J, Goodman WG, Herzog CA, Kubo Y, London GM, Mahaffey KW, Mix TC, Moe SM, Trotman ML, Wheeler DC, Parfrey PS (2012) Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 367:2482–2494CrossRefPubMed

29.

Moe SM, Chertow GM, Parfrey PS, Kubo Y, Block GA, Correa-Rotter R, Drüeke TB, Herzog CA, London GM, Mahaffey KW, Wheeler DC, Stolina M, Dehmel B, Goodman WG, Floege J (2015) Cinacalcet, FGF23 and cardiovascular disease in hemodialysis: the EVOLVE trial. Circulation 132(1):27–39CrossRefPubMed

30.

Yajima A, Akizawa T, Tsukamoto Y, Kurihara S, Ito A (2008) Impact of cinacalcet hydrochloride on bone histology in patients with secondary hyperparathyroidism. Ther Apher Dial 12(Suppl 1):S38–S43CrossRefPubMed

31.

Malluche HH, Monier-Faugere MC, Wang G, Fraza OJM, Charytan C, Coburn JW, Coyne DW, Kaplan MR, Baker N, McCary LC, Turner SA, Goodman WG (2008) An assessment of cinacalcet HCl effects on bone histology in dialysis patients with secondary hyperparathyroidism. Clin Nephrol 69:269–278CrossRefPubMed

32.

Behets GJ, Spasovski G, Sterling LR, Goodman WG, Spiegel DM, De Broe ME, D’Haese PC (2015) Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients with secondary hyperparathyroidism. Kidney Int 87:846–856CrossRefPubMedPubMedCentral

33.

Moe SM, Abdalla S, Chertow GM, Parfrey PS, Block GA, Correa-Rotter R, Floege J, Herzog CA, London GM, Mahaffey KW, Wheeler DC, Dehmel B, Goodman WG, Drüeke TB (2015) Effects of cinacalcet on fracture events in patients receiving hemodialysis: the EVOLVE trial. J Am Soc Nephrol 26:1466–1475CrossRefPubMed

34.

Foley RN, Li S, Liu J, Gilbertson DT, Chen SC, Collins AJ (2005) The fall and rise of parathyroidectomy in U.S. hemodialysis patients, 1992 to 2002. J Am Soc Nephrol 16:210–218CrossRefPubMed

35.

Li YC, Amling M, Pirro AE, Priemel M, Meuse J, Baron R, Delling G, Demay MB (1998) Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. Endocr 139:4391–4396

36.

Meir T, Levi R, Lieben L, Libutti S, Carmeliet G, Bouillon R, Silver J, Naveh-Many T (2009) Deletion of the vitamin D receptor specifically in the parathyroid demonstrates a limited role for the receptor in parathyroid physiology. Am J Physiol 297:F1192–F1198

37.

Kruse AE, Eisenberger U, Frey FJ, Mohaupt MG (2005) The calcimimetic cinacalcet normalizes serum calcium in renal transplant patients with persistent hyperparathyroidism. Nephrol Dial Transplant 20:1311–1314CrossRefPubMed

38.

Serra AL, Schwarz AA, Wick FH, Marti HP, Wuthrich RP (2005) Successful treatment of hypercalcemia with cinacalcet in renal transplant recipients with persistent hyperparathyroidism. Nephrol Dial Transplant 20:1315–1319CrossRefPubMed

39.

Bergua C, Torregrosa JV, Fuster D, Gutierrez-Dalmau A, Oppenheimer F, Campistol JM (2008) Effect of cinacalcet on hypercalcemia and bone mineral density in renal transplanted patients with secondary hyperparathyroidism. Transplant 86:413–417CrossRef

40.

Evenepoel P, Cooper K, Holdaas CH, Messa P, Mourad G, Olgaard K, Rutkowski B, Schaefer H, Deng H, Torregrosa JV, Wuthrich RP, Yue S (2014) A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism. Am J Transplant 14:2545–2555CrossRefPubMed

41.

Wolf M, Weir MR, Kopyt N, Mannon RB, Von Visger J, Deng H, Yue S, Vincenti F (2015) A prospective cohort study of mineral Metabolism After Kidney transplantation. Transplantation. doi:10.1097/TP.0000000000000823

42.

Walter S, Baruch A, Dong J, Tomilnson Alexander ST, Janes J, Hunter T, Yin Q, Maclean D, Bell G, Mendel DB, Johnson RM, Karim F (2013) Pharmacology of AMG 416 (velcalcetide), a novel peptide agonist of the calcium-sensing receptor, for the treatment of secondary hyperparathyroidism in hemodialysis patients. J Pharmacol Exp Ther 346:229–240CrossRefPubMed

43.

Walter S, Baruch A, Alexander ST, Janes J, Sho E, Dong J, Yin Q, Maclean D, Mendel DB, Karim F, Johnson RM (2014) Comparison of AMG 416 and cinacalcet in rodent models of uremia. BMC Nephrol 15:81–86CrossRefPubMedPubMedCentral

44.

Martin KJ, Pickthorn K, Huang S, Block GA, Vick A, Mount PF, Power DA, Bell G (2013) AMG 416 (velcalcetide) is a novel peptide for the treatment of secondary hyperparathyroidism in a single-dose study in hemodialysis patients. Kidney Intl 85:191–197CrossRef

45.

Bell G, Huang S, Martin KJ, Block GA (2015) A randomized, double-blind, phase 2 study evaluating the safety and efficacy of AMG 416 for thre treatment of secondary hyperparathyroidism in hemodialysis patients. Curr Med Res Opin 31:943–952CrossRefPubMed

46.

Chen P, Melhem M, Xiao J, Kuchimanchi M, Perez Ruixo JJ (2015) Population pharmacokinetics analysis of AMG 416, an allosteric activator of the calcium-sensing receptor, in subjects with secondary hyperparathyroidism receiving hemodialysis. J Clin Pharmacol 55:620–628CrossRefPubMed

47.

Amgen press release http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2014&releaseID=1948573

48.

Amgen press release http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2014&releaseID=1959215

49.

Amgen press release http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2015&releaseID=2020209

50.

Silve BC, Bilezikian JP (2015) Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol 22:41–50CrossRef

51.

Gardella TJ (2015) Interations of PTH with receptors and signaling. In: Bilezikian JP, Marcus R, Levine MA, Marcocci C, Silverberg SJ, Potts JT (eds) The parathyroids, 3rd edn. Elsevier, Amsterdam, pp 65–80

52.

Leder BZ, O’Dea LSTL, Zanchetta JR, Kumar P, Banks K, McKay K, Lyttle CR, Hattersley G (2014) Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. doi:10.1210/jc.2014-3718

53.

Nemeth EF (2008) Anabolic therapy for osteoporosis: calcilytics. IBMS BoneKEy 5:196–208CrossRef

54.

Gowen M, Stroup GB, Dodds RA, James IE, Votta BJ, Smith BR, Bhatnagar PK, Lago AM, Callahan JF, DelMar EG, Miller MA, Nemeth EF, Fox J (2000) Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J Clin Invest 105:1595–1604CrossRefPubMedPubMedCentral

55.

John MR, Widler L, Gamse R, Buhl T, Seuwen K, Breitenstein W, Bruin GJM, Belleli R, Klickstein LR, Kneissel M (2011) ATF936, a novel oral calcilytic, increases bone mineral density in rats and transiently releases parathyroid hormone in humans. Bone 49:233–241CrossRefPubMed

56.

Kimura S, Nakagawa T, Matsuo Y, Ishida Y, Okamoto Y, Hayashi M (2011) JTT-305, an orally active calcium-sensing receptor antagonist, stimulates transient parathyroid hormone release and bone formation in ovariectomized rats. Eur J Pharmacol 668:331–336CrossRefPubMed

57.

Fisher JE, Scott K, Wei N, Zhao JZ, Cusick T, Tijerina M, Karanam B, Duong L, Glantschnig H (2012) Pharmacodynamic responses to combined treatment regimens with the calcium sensing receptor antagonist JTT-305/MK-5442 and alendronate in osteopenic ovariectomized rats. Bone 50:1332–1342CrossRefPubMed

58.

Kumar S, Matheny CJ, Hoffman SJ, Marquis RW, Schultz Liang X, Vasko J, Stroup GB, Vaden VR, Haley H, Fox J, DelMar EJ, Nemeth EF et al (2010) An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation. Bone 46:534–542CrossRefPubMed

59.

John MR, Harfst E, Löeffler J, Belleli R, Mason J, Bruin GJM, Seuwen K, Klickstein LB, Mindelholm Widler L, Kneissel M (2014) AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. Bone 64:204–210CrossRefPubMed

60.

Halse J, Greenspan S, Cosman F, Ellis G, Santora A, Leung A, Heyden N, Samanta S, Doleckyj S, Rosenberg E, Denker AE (2014) A Phase 2, randomized, placebo-controlled, dose-ranging study of the calcium-sensing receptor antagonist MK-5442 in the treatment of postmenopausal women with osteoporosis. J Clin Endocrinol Metab 99:E2207–E2215CrossRefPubMed

61.

Fitzpatrick LA, Dabrowski CE, Cicconetti G, Gordon DN, Papapoulos S, Bone HG III, Bilezikian JP (2011) The effects of ronacaleret, a calcium-sensing receptor antagonist, on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mineral density. J Clin Endocrinol Metab 96:2441–2449CrossRefPubMed

62.

Fitzpatrick LA, Dabrowski CE, Cicconetti G, Gordon DN, Fuerst T, Engelke K, Genant HK (2012) Ronacaleret, a calcium-sensing receptor antagonist, increases trabecular but not cortical bone in postmenopausal women. J Bone Min Res 27:255–262CrossRef

63.

Fitzpatrick LA, Smith PL, McBride TA, Fries MA, Hossain M, Dabrowski CE, Gordon DN (2011) Ronacaleret, a calcium-sensing receptor antagonist, has no significant effect on radial fracture healing time: results of a randomized, double-blinded, placebo-controlled Phase II clinical trial. Bone 49:845–852CrossRefPubMed

64.

Caltabiano S, Dollery CT, Hossain M, Kurtinecz MF, Desjardins JP, Favus MJ, Kumar R, Fitzpatrick LA (2013) Characterization of the effect of chronic administration of a calcium-sensing receptor antagonist, ronacaleret, on renal calcium excretion and serum calcium in postmenopausal women. Bone 56:154–162CrossRefPubMed

65.

Xue Y, Xiao Y, Liu J, Karaplis AC, Pollak MR, Brown EM, Mino D, Goltzman D (2012) The calcium-sensing receptor supplements parathyroid hormone-induced bone turnover in discrete skeletal compartments in mice. Am J Physiol 302:E841–E851

66.

Dvorak MM, Siddiqua A, Ward DT, Carter DH, Dallas SL, Nemeth EF, Riccardi D (2004) Physiological changes in extracellular calcium concentration directly control osteoblast function in the absence of calciotropic hormones. Proc Natl Acad Sci 101:5140–5145CrossRefPubMedPubMedCentral

67.

Hannan FM, Nesbit MA, Zhang C, Cranston T, Curley AJ, Harding B, Fratter C, Rust N, Christie PT, Turner JJO, Lemos MC, Bowl MR, Bouillon R, Brain C, Bridges N, Burren C, Connell JM, Jung H, Marks E, McCredie D, Mughal Z, Rodda C, Tollefsen S, Brown EM, Yang JJ, Thakker RV (2012) Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites. Hum Mol Gen 21:2768–2778CrossRefPubMed

68.

Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, Rust N, Hobbs MR, Heath H III, Thakker RV (2013) Mutations affecting G-protein subunit α₁₁ in hypercalcemia and hypocalcemia. N Engl J Med 368:2476–2486CrossRefPubMedPubMedCentral

69.

Mannstadt M, Harris M, Bravenboer B, Chitturi S, Dreijerink KMA, Lambright DG, Lim ET, Daly MJ, Gabriel S, Jüppner H (2013) Germline mutations affecting Gα₁₁ in hypoparathyroidism. N Engl J Med 368:2532–2534CrossRefPubMedPubMedCentral

70.

Letz S, Rus R, Haag C, Dörr H-G, Schnabel D, Möhlig M, Schulze E, Frank-Raue K, Raue F, Mayr B, Schöfl C (2010) Novel activating mutations of the calcium-sensing receptor: the calcilytic NPS 2143 mitigates excessive signal transduction of mutant receptors. J Clin Endocr Metab 95:E229–E233CrossRefPubMed

71.

Leach K, Wen A, Cook AE, Sexton PM, Conigrave AD, Christopoulos A (2013) Impact of clinically relevant mutations on the pharmacoregulation and signaling bias of the calcium-sensing receptor by positive and negative allosteric modulators. Endocrinology 154:1105–1116CrossRefPubMed

72.

Nakamura A, Hotsubo T, Kobayashi K, Mochizuki H, Ishizu K, Tajima T (2013) Loss-of-function and gain-of-function mutations of calcium-sensing receptor: functional analysis and the effect of allosteric modulators NPS R-568 and NPS NPS 2143. J Clin Endocr Metab 98:E1692–E1701CrossRefPubMed

73.

Park SY, Mun H-C, Eom YS, Baek HL, Jung TS, Kim CH, Hong S, Lee S (2013) Identification and characterization of D410E, a novel mutation in the loop 3 domain of the CaSR, in autosomal dominant hypocalcemia and a therapeutic approach using a novel calcilytic, AXT914. Clin Endocrinol 78:687–693CrossRef

74.

Letz S, Haag C, Schulze E, Frank-Raue K, Raue F, Hofner H, Mayr B, Schöfl C (2015) Amino alcohol- (NPS 2143) and quinazolinone-derived calcilytics (ATF936 and AXT914) differentially mitigate excessive signalling of calcium-sensing receptor mutants causing Bartter syndrome type 5 and autosomal dominant hypocalcemia. PLoS One 9:e115178CrossRef

75.

Babinsky VN, Hannan FM, Howles S et al. (2015) CaSR allosteric modulators rectify signal transduction abnormalities associated with G-protein alpha-11 (Gα₁₁) mutations causing familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2). In: 2nd International Symposium Calcium-Sensing Receptor, San Diego, CA Abst. P-029

76.

Dong B, Endo I, Ohnishi Y, Kondo T, Hasegawa T, Amizuka N, Kiyonari H, Shioi G, Abe M, Fukumoto S, Matsumoto T (2015) Calcilytic ameliorates abnormalities of mutant calcium-sensing receptor (CaSR) knock-in mice mimicking autosomal dominant hypocalcemia (ADH). J Bone Miner Res. doi:10.1002/jbmr.2551

77.

Loupy A, Ramakrishnan SK, Wootla B, Chambrey R, de la Faille R, Bourgeois S, Bruneval P, Mandet C, Christensen EI, Faure H, Cheval L, Laghmani K, Collet C, Eladari D, Dodd RH, Ruat M, Houillier P (2012) PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor. J Clin Invest 122:3355–3367CrossRefPubMedPubMedCentral

78.

Montani D, Günther S, Dorfmüller P, Perros F, Girerd B, Jaïs X, Savale L, Artaud-Macari E, Price LC, Humbert M, Simmonneau G, Sitbon O (2013) Pulmonary arterial hypertension. Orphanet J Rare Dis 8:97CrossRefPubMedPubMedCentral

79.

Yamamura A, Guo Q, Yamamura H, Zimnicka AM, Pohl NM, Smith KA, Fernandez RA, Zeitman A, Makino A, Dong H, Yuan JX-L (2012) Enhanced Ca²⁺-sensing receptor function in idiopathic pulmonary arterial hypertension. Circ Res 111:469–481CrossRefPubMedPubMedCentral

80.

Busse WW (2010) The relationship of airway hyperresponsiveness and airway inflammation. Chest 138:4S–10SCrossRefPubMedPubMedCentral

81.

Yarova PL, Stewart AL, Venkatachalem S et al (2015) Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Sci Transl Med 7:1–11

82.

Goodman WG, Hladik GA, Turner SA et al (2002) The calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol. 13:1017–1024PubMed

Titel: Calcimimetic and Calcilytic Drugs: Feats, Flops, and Futures
verfasst von: E. F. Nemeth
W. G. Goodman
Publikationsdatum: 30.08.2015
Verlag: Springer US
Erschienen in: Calcified Tissue International / Ausgabe 4/2016
Print ISSN: 0171-967X
Elektronische ISSN: 1432-0827
DOI: https://doi.org/10.1007/s00223-015-0052-z

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