Cinacalcet in Hyperfunctioning Parathyroid Diseases

The calcium‐sensing receptor (CaR) on the parathyroid cell surface senses ionized calcium concentration in the extracellular fluid and regulates minute‐to‐minute parathyroid hormone (PTH) secretion. Synthetic allosteric modulators of CaR have been developed, and one of the positive modulators (calcimimetics) is cinacalcet HCl or cinacalcet. Cinacalcet increases the sensitivity of CaR to be activated by extracellular calcium, and thus suppresses PTH release. Cinacalcet is an effective treatment for secondary hyperparathyroidism (SHPT) in patients with uremia on hemodialysis. In this review, based on basic experiments using cinacalcet, we postulate the beneficial effects of cinacalcet on hyperfunctioning parathyroid diseases.

[1]  M. Inaba,et al.  Animal models of hyperfunctioning parathyroid diseases for drug development , 2009, Expert opinion on drug discovery.

[2]  N. Nagano,et al.  Cinacalcet suppresses calcification of the aorta and heart in uremic rats. , 2008, Kidney international.

[3]  M. Mohammadi,et al.  The parathyroid is a target organ for FGF23 in rats. , 2007, The Journal of clinical investigation.

[4]  A. Arnold,et al.  Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary hyperparathyroidism. , 2007, Journal of the American Society of Nephrology : JASN.

[5]  G. Eknoyan,et al.  Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). , 2006, Kidney international.

[6]  S. Rosansky,et al.  Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl. , 2005, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[7]  B. Culleton,et al.  Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study. , 2005, Journal of the American Society of Nephrology : JASN.

[8]  D. Lacey,et al.  Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism. , 2005, Kidney international.

[9]  Didier Rognan,et al.  Positive and Negative Allosteric Modulators of the Ca2+-sensing Receptor Interact within Overlapping but Not Identical Binding Sites in the Transmembrane Domain* , 2004, Journal of Biological Chemistry.

[10]  F. Locatelli,et al.  Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. , 2004, The New England journal of medicine.

[11]  D. Lacey,et al.  Pharmacodynamics of the Type II Calcimimetic Compound Cinacalcet HCl , 2004, Journal of Pharmacology and Experimental Therapeutics.

[12]  S. Fukumoto,et al.  Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. , 2003, The New England journal of medicine.

[13]  N. Palanisamy,et al.  Clonal chromosomal defects in the molecular pathogenesis of refractory hyperparathyroidism of uremia. , 2002, Journal of the American Society of Nephrology : JASN.

[14]  S. Ganesh,et al.  Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. , 2001, Journal of the American Society of Nephrology : JASN.

[15]  J. Gleason,et al.  Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. , 2001, The Journal of pharmacology and experimental therapeutics.

[16]  Charles B. Hall,et al.  Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. , 2001, The Journal of clinical investigation.

[17]  E. Brown,et al.  Regulation of MAP kinase by calcium-sensing receptor in bovine parathyroid and CaR-transfected HEK293 cells. , 2001, American journal of physiology. Renal physiology.

[18]  R. Elashoff,et al.  Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. , 2000, The New England journal of medicine.

[19]  J. Rastad,et al.  Reduced parathyroid vitamin D receptor messenger ribonucleic acid levels in primary and secondary hyperparathyroidism. , 2000, The Journal of clinical endocrinology and metabolism.

[20]  H. Koyama,et al.  Increased biological potency of hexafluorinated analogs of 1,25-dihydroxyvitamin D3 on bovine parathyroid cells , 1999, The Journal of Steroid Biochemistry and Molecular Biology.

[21]  N. Palanisamy,et al.  Novel chromosomal abnormalities identified by comparative genomic hybridization in parathyroid adenomas. , 1998, The Journal of clinical endocrinology and metabolism.

[22]  F. Port,et al.  Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. , 1998, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[23]  N. Nagano,et al.  NPS R-568 halts or reverses osteitis fibrosa in uremic rats. , 1998, Kidney international.

[24]  E. Brown,et al.  Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism. , 1996, The Journal of clinical endocrinology and metabolism.

[25]  H. Koyama,et al.  Phosphorus intake regulates intestinal function and polyamine metabolism in uremia. , 1996, Kidney international.

[26]  J. Seidman,et al.  A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism , 1995, Nature Genetics.

[27]  E. Brown,et al.  Mutational analysis of the extracellular Ca(2+)-sensing receptor gene in human parathyroid tumors. , 1995, The Journal of clinical endocrinology and metabolism.

[28]  A. Arnold,et al.  Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. , 1995, The Journal of clinical investigation.

[29]  J. Seidman,et al.  Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism , 1993, Cell.

[30]  M. Hediger,et al.  Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid , 1993, Nature.

[31]  E. Brown,et al.  Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. , 1983, The Journal of clinical endocrinology and metabolism.

[32]  F. Locatelli,et al.  The OPTIMA study: assessing a new cinacalcet (Sensipar/Mimpara) treatment algorithm for secondary hyperparathyroidism. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[33]  M. Inaba,et al.  Direct in vitro evidence of the suppressive effect of cinacalcet HCl on parathyroid hormone secretion in human parathyroid cells with pathologically reduced calcium-sensing receptor levels , 2006, Journal of Bone and Mineral Metabolism.

[34]  S. Otani,et al.  Involvement of polyamines in the proliferation of bovine parathyroid cells. , 1995, Mineral and electrolyte metabolism.