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Clinical utility of calcimimetics targeting the extracellular calcium-sensing receptor (CaSR)

西那卡塞特 拟钙质 钙敏感受体 医学 继发性甲状旁腺功能亢进 甲状旁腺激素 甲状旁腺功能亢进 甲状旁腺癌 肾脏疾病 内科学 内分泌学 药理学
作者
Edward M. Brown
出处
期刊:Biochemical Pharmacology [Elsevier]
卷期号:80 (3): 297-307 被引量:67
标识
DOI:10.1016/j.bcp.2010.04.002
摘要

Calcimimetics, which activate the extracellular calcium (Ca(o)(2+))-sensing receptor in the parathyroid and other tissues participating in Ca(o)(2+) homeostasis, were the first described allosteric activators of a G-protein-coupled receptor. Cinacalcet, the only calcimimetic currently approved for human use, is used clinically for treating secondary hyperparathyroidism (e.g., overactivity of parathyroid glands) in patients being dialyzed for chronic kidney disease. By sensitizing the parathyroids to Ca(o)(2+), cinacalcet lowers the circulating parathyroid hormone (PTH) level. It also reduces serum calcium and phosphate, changes increasing the percentage of patients achieving the guidelines recommended by the National Kidney Foundation (NKF) for these minerals. Studies are underway addressing whether better adherence to these guidelines in patients receiving cinacalcet reduces cardiovascular disease and related mortality, which are both common is the dialysis population. The second approved use of cinacalcet is for treating hypercalcemia in patients with inoperable parathyroid carcinoma. In this setting, it provides the first medical therapy chronically lowering serum calcium concentration in this condition, albeit not to normal in most patients. Its effect on the long-term prognosis of these patients, if any, is presently unclear. "Off-label" administration of cinacalcet [i.e., not yet approved by the US Food and Drug Administration (FDA)] effectively lowers serum calcium and/or PTH in various other forms of hyperparathyroidism and increases serum phosphate in renal phosphate-wasting syndromes by reducing PTH-induced phosphaturia. In the future, the drug could conceivably be utilized to modulate the activity of the CaSR in other tissues (i.e., kidney, colon) in therapeutically desirable ways.
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