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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Pharmacological and clinical properties of calcimimetics: calcium receptor activators that afford an innovative approach to controlling hyperparathyroidism.

Circulating levels of calcium ion (Ca2+) are maintained within a narrow physiological range mainly by the action of parathyroid hormone ( PTH) secreted from parathyroid gland (PTG) cells. PTG cells can sense small fluctuations in plasma Ca2+ levels by virtue of a cell surface Ca2+ receptor (CaR) that belongs to the superfamily of G protein-coupled receptors ( GPCR). Compounds that activate the CaR and inhibit PTH secretion are termed 'calcimimetics' because they mimic or potentiate the effects of extracellular Ca2+ on PTG cell function. Preclinical studies with NPS R-568, a first generation calcimimetic compound that acts as a positive allosteric modulator of the CaR, have demonstrated that oral administration decreases serum levels of PTH and calcium, with a leftward shift in the set-point for calcium-regulated PTH secretion in normal rats. NPS R-568 also suppresses the elevation of serum PTH levels and PTG hyperplasia and can improve bone mineral density (BMD) and strength in rats with chronic renal insufficiency (CRI). Clinical trials with cinacalcet hydrochloride (cinacalcet), a compound with an improved metabolic profile, have shown that long-term treatment continues to suppress the elevation of serum levels of calcium and PTH in patients with primary hyperparathyroidism (1HPT). Furthermore, clinical trials in patients with uncontrolled secondary hyperparathyroidism (2HPT) have demonstrated that cinacalcet not only lowers serum PTH levels, but also the serum phosphorus and calcium x phosphorus product; these are a hallmark of an increased risk of cardiovascular disease and mortality in dialysis patients with end-stage renal disease. Indeed, cinacalcet has already been approved for marketing in several countries. Calcimimetic compounds like cinacalcet have great potential as an innovative medical approach to manage 1HPT and 2HPT.[1]


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