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The calcimimetic agents: Perspectives for treatment
Kidney International, Vol. 61, Supplement 80 (2002), pp. S149–S154
The calcimimetic agents: Perspectives for treatment JOA˜O M. FRAZA˜O, PATRI´CIA MARTINS, and JACK W. COBURN Department of Nephrology, Hospital Sa˜o Joa˜o, Porto, Porto School of Medicine, University of Porto, Porto, Portugal; and Medical and Research Services, Veterans Affairs, West Los Angeles Healthcare Center Department of Medicine, UCLA School of Medicine, Los Angeles, California, USA
The calcimimetic agents: Perspectives for treatment. Recognition of the role of the extracellular calcium sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca⫹⫹), and control of urinary calcium excretion with small changes in blood Ca⫹⫹. The CaR also affects the renal handling of sodium, magnesium, and water. Mutations affecting the CaR that make it either less or more sensitive to Ca⫹⫹ cause various clinical disorders. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca⫹⫹, can suppress PTH levels with a resultant fall in blood Ca⫹⫹. Experiences with R-568 in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In humans with hyperparathyroidism, these agents produce a dose-dependent fall in PTH and blood Ca⫹⫹, with larger doses causing more sustained effects. The second generation calcimimetic, AMG 073, with a better pharmacokinetic profile appears to be an effective and safe treatment for secondary hyperparathyroidism, producing suppression of PTH levels with a simultaneous reduction in serum phosphorus levels and the calcium X phosphorus product. The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium X phosphorus product is very promising. Treatment trials have been relatively shortterm except for one patient treated with R-568 for more than 600 days for parathyroid carcinoma; nonetheless the drug had no major side effects and appeared to be safe. Further longterm controlled studies are underway to further confirm the effectiveness and safety of these compounds.
The discovery and cloning of the extracellular calcium sensing receptor (CaR) and its molecular role in mineral metabolism represents a major scientific advance during the last decade [1, 2]. This low affinity, G-protein-coupled receptor is found in high concentrations on the surKey words: calcium-sensing receptor, calcimimetics, secondary hyperparathyroidism, primary hyperparathyroidism, parathyroid carcinoma, blood ionized calcium, phosphorus levels, calcium X phosphorus product, review.
2002 by the International Society of Nephrology
face of parathyroid cells, on calcitonin-secreting C-cells of the thyroid, at various sites along the nephron, in certain areas of the brain, on bone cells, and in other tissues. The activation of this receptor by small changes in extracellular ionized Ca (Ca⫹⫹) accounts for both the steep inverse relationship between parathyroid hormone (PTH) levels and small changes of blood Ca⫹⫹ [1], and the sharp rise in urinary Ca that occurs as serum Ca rises slightly above a “threshold” value. This provides the mechanism whereby the body controls calcium homeostasis and tightly regulates the blood Ca⫹⫹. Alterations of this receptor are responsible for certain disease states, including familial hypocalciuric hypercalcemia [3], severe infantile hyperparathyroidism [4, 5], and hereditary forms of hypoparathyroidism [6, 7]. Acquired alterations in the CaR may play a role in the pathogenesis of secondary and primary hyperparathyroidism. This receptor became an ideal target for the development of compounds that enhances the affinity of the CaR for Ca⫹⫹ and reduces PTH secretion [8]. These compounds, the calcimimetic agents, have been explored as potential therapy for primary and secondary hyperparathyroidism. This review describes the data on the clinical use of the calcimimetic agents. CHARACTERISTICS OF THE CALCIUM-RECEPTOR The features of the CaR, a member of the superfamily of G-protein-coupled receptors, are reviewed in detail elsewhere [9–11]. It has a large extracellular domain comprised of approximately 700 amino acids, seven membrane-spanning segments, and a cytoplasmic carboxyl terminal segment consisting of approximately 200 amino acids. Unique in comparison to many hormone receptors, which are activated by nanomolar quantities of agonist, the CaR is sensitive to relatively small changes in Ca⫹⫹ in extracellular fluid having a very high concentration of extracellular Ca⫹⫹ (over one millimole/liter). The CaR is a G-protein coupled receptor which on activation stimulates phospholipase C that results in increased levels of inositol 1,3,5-triphosphate, which in turn elevates the cytosolic Ca⫹⫹ activity by mobilizing Ca
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from various intracellular sites. Activation of the CaR also inhibits the accumulation of hormone-stimulated intracellular cAMP [1]. Another feature of the CaR is its lack of specificity; thus, it is stimulated by other divalent cations, such as magnesium (Mg), by the trivalent elements gadolinium and lanthanum, and by polycationic compounds such as neomycin and spermine. It is likely that the affinity of magnesium for the CaR is responsible for the effects of acute hypermagnesemia to suppress PTH secretion [12]. Also, many effects of an elevated serum magnesium levels on the renal handling of calcium, sodium, and chloride [13, 14] probably arise because of the activation of the renal tubular CaR by Mg⫹⫹. The activation of the CaR by the polyvalent cations, neomycin and gentamicin, may account for certain effects of these agents on the kidney, including the development of nonoliguric renal failure, perhaps due to impairment of the vasopressin-sensitive renal concentrating mechanism via activation of the CaR of the collecting duct. ROLE OF CaR IN PARATHYROID CELLS The secretory response of the parathyroid cell to changes in blood Ca⫹⫹ occurs within seconds, an observation that suggested that Ca⫹⫹ acts directly on the plasma membrane [1]. The presence of CaR in very high concentrations on the parathyroid cell membrane provides the extracellular Ca⫹⫹-sensing mechanism for these cells. The extracellular domain of the CaR contains several clusters of acidic amino acids that are involved in Ca⫹⫹ binding. This provides a mechanism whereby the CaR regulates the secretion of PTH in response to small changes in extracellular Ca⫹⫹ concentration [11, 15]. ROLE OF CaR IN THE KIDNEY Within the kidney, transcripts of the CaR have been found in the juxtaglomerular apparatus, along the luminal proximal convoluted tubule, the basolateral surface of the cortical thick ascending limb (CTAL), and the apical as well as luminal membrane of the inner medullary collecting duct (IMCD) [10, 16]. The CaR localization in the CTAL may account for the effects of increased extracellular concentrations of Ca⫹⫹ and Mg⫹⫹ to inhibit the reabsorption of calcium, magnesium, sodium, and chloride at this tubular site. Normally, Ca and Mg reabsorption occurs through the intercellular space and is driven by the high transtubular voltage gradient that is generated by the luminal Na⫹K⫹2Cl⫺ transporter. Activation of the apical CaR stimulates phospholipase C which releases arachidonic acid that is, in turn, metabolized by cytochrome P450; the active metabolites inhibit the apical K⫹ channel and may also directly inhibit the Na⫹K⫹2Cl⫺ cotransporter. These effects result in a marked
reduction in transluminal voltage, leading to reduced paracellular transport of Ca and Mg. Activation of the CaR also inhibits the PTH stimulated adenylate cyclase, reducing the cAMP-mediated transport of Ca and Mg. In the IMCD, increased Ca⫹⫹ inhibits the generation of cAMP by vasopressin through its effect on the CaR at the basolateral surface, causing less concentrated urine and polyuria. Also, increased tubular fluid Ca⫹⫹ activates the luminal CaR which specifically reduces ADHstimulated osmotic H2O permeability via the aquaporin channels, and lowers the urinary concentrating ability [17]. The action of increased extracellular fluid Ca⫹⫹ to inhibit the Na⫹K⫹2Cl⫺ cotransporter located in the thick ascending limb reduces the medullary hypertonicity and the effectiveness of the countercurrent mechanism and, therefore, further reduces the maximum urinary concentrating ability. Thus, the effect of hypercalcemia to lower GFR, to reduce the renal cortical synthesis of calcitriol [18], to cause increased urinary excretion of both Ca and Mg, and to lead to increased volumes of dilute urine may arise, in whole or in part, through activation of the CaR within various parts of the nephron. CaR IN OTHER TISSUES The role of the CaR that are found in the intestine [19], parts of the brain [20], the lungs, and bone remains to be clarified. It is probable that Ca⫹⫹ activation of a Ca⫹⫹-sensitive receptor acts to stimulate bone formation and to inhibit bone resorption; moreover, the G-protein coupled CaR has been identified in bone cell precursors [21]. Alternatively, Ca⫹⫹-sensing proteins of other types may play a role in regulating bone metabolism [22, 23]. It seems apparent that the very tight regulation of blood Ca⫹⫹, which is affected in a major way by PTH, calcitriol, and, to a lesser extent, by calcitonin, occurs due to the tight “fine tuning” that arises from activation of the CaR to modulate PTH secretion and to regulate the renal excretion of calcium. CALCIUM RECEPTOR IN SECONDARY HYPERPARATHYROIDISM There may be acquired disorders involving the CaR. Various data indicate that parathyroid glands obtained surgically from uremic patients with secondary hyperparathyroidism may exhibit reduced expression of the CaR on the surface of parathyroid cells [24, 25]. In patients with parathyroid adenomas or parathyroid carcinoma the data are somewhat inconsistent, although reduced staining is observed in some glands. It is possible that changes in the density of CaR in parathyroid cells may account, in part, for the shift in “set point” of parathyroid cells (i.e., the calcium concentration required to
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suppress maximal PTH secretion by 50%) observed in patients with secondary hyperparathyroidism. In experimental animals, data suggesting that there is regulation of the CaR are either negative or controversial. Two studies done in vitamin D-deficient rats have demonstrated no regulation of the mRNA for CaR by Ca⫹⫹ [26, 27]. One study reported no effect of calcitriol on the mRNA for the CaR, while another study found a 40% reduction of mRNA for CaR in vitamin D-deficient rats that was restored by calcitriol replacement [27]. Thus, some uncertainty exists about the role of altered regulation of the CaR being a major factor predisposing to the development of secondary hyperparathyroidism in patients with progressive renal failure. Experimental data indicate a reduction in the density of the CaR on the parathyroid cells of rats of increasing age; in the kidney, no alterations in the CaR were observed [28]. If a similar process exists in man, it could account for the changes in PTH levels with age and the propensity for the development of hyperparathyroidism with advancing years. There is evidence that the CaR expression in renal tissue is modestly reduced in experimentally induced renal failure in rats; this might contribute to hypocalciuria noted with renal insufficiency [29]. CLINICAL USE OF CALCIMIMETIC AGENTS For the clinician, the development of calcimimetic compounds that modulate the CaR, making it more sensitive to Ca⫹⫹ suppressive effect on PTH secretion, may provide a means for the medical treatment for both primary and secondary hyperparathyroidism. The first generation calcimimetic agent, R-568, was developed by scientists at NPS Pharmaceuticals [30, 31], and has undergone extensive testing. Because of a poor pharmacokinetic profile its development has been discontinued and a second generation calcimimetic agent, the AMG 073, has been developed and undergone clinical evaluation. The calcimimetic agent R-568 was given to a patient with inoperable parathyroid carcinoma, who presented with hypercalcemia (blood Ca⫹⫹ 1.96 mmol/L), high PTH levels (1,128 pg/mL) and altered mental status; the hypercalcemia failed to respond to intravenous saline and furosemide, several doses of intravenous pamidronate, and salmon calcitonin over 18 days [32]. The calcimimetic was initiated at 200 mg/day and subsequently increased to 400 mg/day. The patient’s symptoms improved after three days of R-568 treatment, and he was discharged home after 28 days of treatment with a blood Ca⫹⫹ of 1.53 mmol/L and PTH level of 357 pg/mL. Treatment with the calcimimetic was continued and the dose was titrated up to 600 mg/day; this treatment maintained the total serum calcium between 2.75–3.0 mmol/L despite the progressive increase in PTH levels to 2000–3500
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pg/mL; this PTH increase was believed to occur due to progression of the parathyroid carcinoma. The patient remained very active, travelling extensively, and had no side effects over a follow up longer than 600 days. In addition, all measures of cardiac, renal, hepatic, hematological, and pancreatic function remained stable throughout the period of treatment. Although such observations were made only in one patient, the data showed that R-568 could be given safely over a prolonged period. Several reports have documented the effectiveness of single doses or two daily doses of R-568 to reduce PTH levels in patients with primary and secondary hyperparathyroidism (abstract; Silverberg et al, J Am Soc Nephrol 9:516A, 1998) [33, 34]. In primary and secondary hyperparathyroidism, a single initial oral dose of R-568 produced a maximum suppression of PTH levels, that was dose-dependent, at 1 to 2 hours after administration. The decrease in blood Ca⫹⫹ was significant only with the largest dose and occurred only after PTH levels fell. The percentage reductions of PTH from pretreatment values were remarkably similar following 100 to 200 mg doses of R-568, with the average PTH reductions between 63% and 73% in three reported studies (abstract; Silverberg et al, J Am Soc Nephrol 9:516A, 1998) [33, 34] and one preliminary report (abstract; Akizawa et al, J Am Soc Nephrol 9:516A, 1998); this suppression was independent from pretreatment PTH, which averaged 77 pg/mL in patients with primary hyperparathyroidism and varied from 218 to 1,287 pg/mL in the groups with secondary hyperparathyroidism. In women with mild primary hyperparathyroidism, the maximal decrease in PTH occurred by 1 h after lower doses of R-568, while it occurred at 2 h after larger doses [35]. The duration of effect increased with the dose; the PTH levels returned to baseline by 4 h after doses of 80 mg or less but returned to baseline only at 8 h after the 160 mg dose. A small but significant reduction of blood Ca⫹⫹ occurred only with the largest dose, 160 mg. After this dose, urinary calcium, expressed as the calcium/creatinine ratio, rose by 4 h but returned close to baseline by 8 h. Two trials in dialysis patients with secondary hyperparathyroidism employed two separate doses of R-568, each given on two successive days [33] (abstract; Akizawa et al, J Am Soc Nephrol 9:516A, 1998). In seven patients with mild hyperparathyroidism [33], doses of 40 or 80 mg caused PTH levels to fall by more than 30% after the first dose in five of seven patients and more than 60% after the second dose in six of seven patients. With doses of 120 and 200 mg, PTH was reduced by more than 60% after the first dose in six of seven patients. After 24 h, the pretreatment PTH level was still 50% lower than the initial basal value; nonetheless, the PTH fell 50% or more after the second dose in six of seven patients. Blood Ca⫹⫹ was not significantly changed after
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the low dose, but fell significantly after the high dose. Preliminary data from hemodialysis patients with severe secondary hyperparathyroidism (abstract; Akizawa et al, J Am Soc Nephrol 9:516A, 1998) revealed significant reductions after 100 mg and even greater reductions after 200 mg of R-568. The PTH levels had not returned to baseline after 24 h, when the second dose caused a similar percent reduction of PTH. Serum total Ca levels fell, with more marked reductions after the larger dose. Calcitonin levels did not change after either dose. The administration of R-568 in doses of 100 mg per day led to the sustained suppression of PTH levels that persisted for the 15 days duration of treatment [34]. This study evaluated the effect of the administration of R568 (N ⫽ 16) or placebo (N ⫽ 5) in hemodialysis patients with secondary hyperparathyroidism. The pretreatment iPTH levels were 599 ⫾ 105 (mean ⫾ SE) and 600 ⫾ 90 pg/mL in subjects given R-568 or placebo, respectively. Values on the first day of treatment did not change in those given placebo. In contrast, PTH levels fell by 66 ⫾ 5%, 78 ⫾ 3%, and 70 ⫾ 3% at 1, 2 and 4 h, respectively, after the initial dose of R568 and then PTH levels remained below the pre-treatment values for 24 h. Despite lower ionized calcium concentrations, predose iPTH levels declined progressively over the first 9 days of treatment with R-568 and remained below pretreatment levels for the duration of the study, in contrast with the placebo treated group. Serum total and blood ionized calcium levels decreased from pretreatment levels in patients given R-568, whereas values were unchanged in those given placebo. Blood ionized calcium levels fell below 1 mmol/L in 7 of 16 patients receiving R-568; five patients withdrew from the study after developing symptoms of hypocalcemia, whereas three completed treatment after the R-568 dose was reduced. Serum phosphorus levels varied considerably from day to day in both groups of subjects, but values did not change from pretreatment levels during the study in either group. The pharmacokinetic and pharmacodynamic data showed a hight variability [34]. Peak serum levels of R-568 were achieved an average of 2.5 to 4.4 h after daily oral doses, but there was considerable heterogeneity among subjects. Maximum drug concentration were observed as early as 1 h and as late as 24 h after individual doses of R-568. Peak drug levels also varied widely among subjects, ranging from 0.42 to 42.2 ng/mL. Due to the pharmacokinetic profile and interactions with other drugs, the development of R-568 has been discontinued and a second generation calcimimetic agent, AMG 073, has been developed. The calcimimetic AMG 073 has shown potential to treat hemodialysis patients with secondary hyperparathyroidism with promising results in the initial clinical trials. A randomized, double blind, placebo controlled, multicenter study was conducted in hemodialysis patients with
secondary hyperparathyroidism and six sequential single doses were administered (5, 10, 25, 50, 75, and 100 mg of AMG 073 or placebo) (abstract; Coburn et al, J Am Soc Nephrol 11:573A, 2000). Doses of 25, 50, 75, and 100 mg caused a dose dependent decrease in plasma iPTH with a maximum suppression observed between 2 and 4 h after administration followed by a slow recovery of the iPTH during the subsequent hours but remaining below the baseline values after 24 h. Single doses of 75 and 100 mg of AMG 073 reduced serum calcium by 8.3% and 9.4%, respectively. Following this result, another study evaluated the use of daily, fixed doses of 10, 25, and 50 mg of AMG 073 for 8 consecutive days in hemodialysis patients with plasma iPTH ⱖ 250 pg/mL and ⱕ 1500 pg/mL (abstract; Goodman et al, J Am Soc Nephrol 11:576A, 2000). Doses of 25 and 50 mg were associated with decreases in iPTH concentrations. The dose of 50 mg was associated with a decrease in the mean serum calcium levels. On day 8 serum phosphorus levels and the calcium X phosphorus product were reduced from baseline levels in all treatment groups receiving AMG 073. The efficacy and safety of AMG 073 was shown in a double-blind, placebo-controlled, dose titration trial with daily doses of 10, 20, 30, 40, and 50 mg per day (abstract; Lindberg et al, J Am Soc Nephrol 11:578A, 2000). Sequential dose increases every 3 weeks for 12 weeks based on plasma iPTH response and safety profile. The final dose of AMG 073 was then maintained for 6 weeks. The 72 patients that enrolled in this study were continued on their concurrent therapy with phosphate binders and vitamin D for secondary hyperparathyroidism. During the maintenance period there was a mean decrease in the iPTH levels by 26% from the baseline value compared to an increase of 22% in the placebo treated group. The calcium X phosphorus product at the end of the maintenance period was decreased by 16.9% from the baseline value compared to an increase of 11.4% in the placebo treated group. The serum phosphorus levels were also reduce by 14.4% in the AMG 073 treated patients and the mean serum calcium levels were reduced by 3.3% from the baseline value. Transient asymptomatic hypocalcemia occurred in 3 of the 38 patients treated with AMG 073. Because of good safety profile the previous study was repeated with doses titrated up to 100 mg per day (abstract; Quarles et al, J Am Soc Nephrol 12:773A, 2001). Seventy one hemodialysis patients were evaluated. The baseline iPTH value was 625 ⫾ 310 pg/mL (mean ⫾ SE) for the 36 patients treated with AMG 073 and 582 ⫾ 421 pg/mL for the placebo treated patients. The iPTH levels decreased by 32.5% from the baseline during the maintenance phase in the AMG 073 group and increased by 3% in the placebo treated patients. In the AMG 073 group the calcium X phosphorus product at the end of
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the maintenance period was decreased by 7.9% from the baseline value compared to an increase of 11% in the placebo treated group. The serum phosphorus was also reduced by 2.6% in the AMG 073 treated patients and the mean serum calcium levels were reduced by 4.6% from baseline, although the absolute serum calcium levels remained within normal range. The potential of the second generation calcimimetic for treatment of secondary hyperparathyroidism in hemodialysis patients has been shown in the combined results of three dose-titration trials (abstract; Drueke et al, J Am Soc Nephrol 12:764A, 2001). Sequential dose increments could occur every 3 weeks for 12 weeks based on the iPTH response and safety profile. The dose range varied from 10 mg to 100 mg per day. Two hundred and fifteen hemodialysis patients (141 AMG 073 treated and 74 placebo treated) with serum iPTH levels ⱖ300 pg/mL, calcium level between 8.8 mg/dL and 11 mg/dL and a calcium X phosphorus product less than 70 were evaluated. They were continued on their current therapy with phosphate binders and/or vitamin D for secondary hyperparathyroidism. The baseline iPTH was 636 ⫾ 285 pg/mL (mean ⫾ SD) in the combined AMG group and 611 ⫾ 438 pg/mL in the placebo group. The treatment with AMG 073 reduced both the iPTH and the calcium X phosphorus product consistently over 12 weeks in these three studies. The mean iPTH was reduced by 20 to 33% in the AMG 073 groups and increased by 16% in the placebo groups. Eighty three percent of the AMG 073 patients had a PTH reduction equal or more than 30% at any time in the first 12 weeks of these studies. The mean calcium X phosphorus product decreased in the AMG group by 7.1% and increased in the placebo group by 14%. All these trials indicate that calcimimetic agents effectively reduce plasma PTH levels in patients with mild primary hyperparathyroidism and in those with secondary hyperparathyroidism of varying severity. In the latter a reduction in serum phosphorus and calcium X phosphorus product was also observed. The duration of action following a dose was substantially longer in the patients with end-stage renal disease than in those with primary hyperparathyroidism and normal renal function. In each study, there was a reduction in blood Ca⫹⫹ or total serum Ca but with the second generation calcimimetic this finding was minor and rarely troublesome. Many patients treated with the second generation calcimimetic agent were already being treated with phosphate binders and vitamin D sterols; this represents a group of patients that had poorly controlled secondary hyperparathyroidism despite such therapy. Furthermore, despite the lower serum calcium levels observed with calcimimetic treatment there was a consistent suppression of PTH levels favoring the impressive potency of this compounds. Thus, calcimimetic agents are powerful tools that may
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be highly useful for the treatment of hyperparathyroidism, parathyroid carcinoma, and probably a few other rare disorders, such as parathyromatosis and calciphylaxis. This may be an alternative to surgery in patients with primary hyperparathyroidism or in those with a high surgical risk. The complex management of end-stage renal disease associated hyperparathyroidism might become much safer with avoidance of treatment-induced hypercalcemia, hyperphosphatemia, and high calcium X phosphorus product. Reprint requests to Joa˜o M. Fraza˜o, Hospital de S. Joa˜o Servic¸o de Nefrologia, Al. Hernani Monteiro, 4200-451 Porto, Portugal. E-mail: [email protected]
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of vitamin D-deficient rats are not regulated by plasma calcium or 1,25-dihydroxyvitamin D3. Endocrinol 136:499–504, 1995 Brown AJ, Zhong M, Finch J, et al: Rat calcium sensing receptor is regulated by vitamin D but not by calcium. Am J Physiol 270: F454–F460, 1996 Autry CP, Kifor O, Brown EM, et al: Ca2⫹ receptor mRNA and protein increase in the rat parathyroid gland with advancing age. J Endocrinol 153:437–444, 1997 Mathias RS, Nguyen HT, Zhang MYH, Portale AA: Reduced expression of the renal calcium-sensing receptor in rats with experimental chronic renal insufficiency. J Am Soc Nephrol 9:2067– 2074, 1998 Nemeth EF, Steffey ME, Hammerland LG, et al: Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Nat Acad Sci 95:4040–4045, 1998 Nemeth EF, Bennett SA: Tricking the parathyroid gland with novel calcimimetic agents. Nephrol Dial Transplant 13:1923–1925, 1999 Collins MT, Skarulis MC, BilezikiaN JP, et al: Treatment of hypercalcemia secondary to parathyroid carcinoma with a novel calcimimetic agent. J Clin Endocrinol Metab 83:1083–1088, 1998 Antonsen JE, Sherrard DJ, Andress DL: A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure. Kidney Int 53:510–511, 1998 Goodman WG, Frazao JM, Goodkin DA, et al: A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney Int 58:436–445, 2000 Silverberg SI, Bone H, Marriot T, et al: Short-term inhibition of parathyroid hormone secretion by a calcium receptor agonist in primary hyperparathyroidism. N Engl J Med 337:1506–1510, 1997
The calcimimetic agents: Perspectives for treatment JOA˜O M. FRAZA˜O, PATRI´CIA MARTINS, and JACK W. COBURN Department of Nephrology, Hospital Sa˜o Joa˜o, Porto, Porto School of Medicine, University of Porto, Porto, Portugal; and Medical and Research Services, Veterans Affairs, West Los Angeles Healthcare Center Department of Medicine, UCLA School of Medicine, Los Angeles, California, USA
The calcimimetic agents: Perspectives for treatment. Recognition of the role of the extracellular calcium sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca⫹⫹), and control of urinary calcium excretion with small changes in blood Ca⫹⫹. The CaR also affects the renal handling of sodium, magnesium, and water. Mutations affecting the CaR that make it either less or more sensitive to Ca⫹⫹ cause various clinical disorders. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca⫹⫹, can suppress PTH levels with a resultant fall in blood Ca⫹⫹. Experiences with R-568 in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In humans with hyperparathyroidism, these agents produce a dose-dependent fall in PTH and blood Ca⫹⫹, with larger doses causing more sustained effects. The second generation calcimimetic, AMG 073, with a better pharmacokinetic profile appears to be an effective and safe treatment for secondary hyperparathyroidism, producing suppression of PTH levels with a simultaneous reduction in serum phosphorus levels and the calcium X phosphorus product. The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium X phosphorus product is very promising. Treatment trials have been relatively shortterm except for one patient treated with R-568 for more than 600 days for parathyroid carcinoma; nonetheless the drug had no major side effects and appeared to be safe. Further longterm controlled studies are underway to further confirm the effectiveness and safety of these compounds.
The discovery and cloning of the extracellular calcium sensing receptor (CaR) and its molecular role in mineral metabolism represents a major scientific advance during the last decade [1, 2]. This low affinity, G-protein-coupled receptor is found in high concentrations on the surKey words: calcium-sensing receptor, calcimimetics, secondary hyperparathyroidism, primary hyperparathyroidism, parathyroid carcinoma, blood ionized calcium, phosphorus levels, calcium X phosphorus product, review.
2002 by the International Society of Nephrology
face of parathyroid cells, on calcitonin-secreting C-cells of the thyroid, at various sites along the nephron, in certain areas of the brain, on bone cells, and in other tissues. The activation of this receptor by small changes in extracellular ionized Ca (Ca⫹⫹) accounts for both the steep inverse relationship between parathyroid hormone (PTH) levels and small changes of blood Ca⫹⫹ [1], and the sharp rise in urinary Ca that occurs as serum Ca rises slightly above a “threshold” value. This provides the mechanism whereby the body controls calcium homeostasis and tightly regulates the blood Ca⫹⫹. Alterations of this receptor are responsible for certain disease states, including familial hypocalciuric hypercalcemia [3], severe infantile hyperparathyroidism [4, 5], and hereditary forms of hypoparathyroidism [6, 7]. Acquired alterations in the CaR may play a role in the pathogenesis of secondary and primary hyperparathyroidism. This receptor became an ideal target for the development of compounds that enhances the affinity of the CaR for Ca⫹⫹ and reduces PTH secretion [8]. These compounds, the calcimimetic agents, have been explored as potential therapy for primary and secondary hyperparathyroidism. This review describes the data on the clinical use of the calcimimetic agents. CHARACTERISTICS OF THE CALCIUM-RECEPTOR The features of the CaR, a member of the superfamily of G-protein-coupled receptors, are reviewed in detail elsewhere [9–11]. It has a large extracellular domain comprised of approximately 700 amino acids, seven membrane-spanning segments, and a cytoplasmic carboxyl terminal segment consisting of approximately 200 amino acids. Unique in comparison to many hormone receptors, which are activated by nanomolar quantities of agonist, the CaR is sensitive to relatively small changes in Ca⫹⫹ in extracellular fluid having a very high concentration of extracellular Ca⫹⫹ (over one millimole/liter). The CaR is a G-protein coupled receptor which on activation stimulates phospholipase C that results in increased levels of inositol 1,3,5-triphosphate, which in turn elevates the cytosolic Ca⫹⫹ activity by mobilizing Ca
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from various intracellular sites. Activation of the CaR also inhibits the accumulation of hormone-stimulated intracellular cAMP [1]. Another feature of the CaR is its lack of specificity; thus, it is stimulated by other divalent cations, such as magnesium (Mg), by the trivalent elements gadolinium and lanthanum, and by polycationic compounds such as neomycin and spermine. It is likely that the affinity of magnesium for the CaR is responsible for the effects of acute hypermagnesemia to suppress PTH secretion [12]. Also, many effects of an elevated serum magnesium levels on the renal handling of calcium, sodium, and chloride [13, 14] probably arise because of the activation of the renal tubular CaR by Mg⫹⫹. The activation of the CaR by the polyvalent cations, neomycin and gentamicin, may account for certain effects of these agents on the kidney, including the development of nonoliguric renal failure, perhaps due to impairment of the vasopressin-sensitive renal concentrating mechanism via activation of the CaR of the collecting duct. ROLE OF CaR IN PARATHYROID CELLS The secretory response of the parathyroid cell to changes in blood Ca⫹⫹ occurs within seconds, an observation that suggested that Ca⫹⫹ acts directly on the plasma membrane [1]. The presence of CaR in very high concentrations on the parathyroid cell membrane provides the extracellular Ca⫹⫹-sensing mechanism for these cells. The extracellular domain of the CaR contains several clusters of acidic amino acids that are involved in Ca⫹⫹ binding. This provides a mechanism whereby the CaR regulates the secretion of PTH in response to small changes in extracellular Ca⫹⫹ concentration [11, 15]. ROLE OF CaR IN THE KIDNEY Within the kidney, transcripts of the CaR have been found in the juxtaglomerular apparatus, along the luminal proximal convoluted tubule, the basolateral surface of the cortical thick ascending limb (CTAL), and the apical as well as luminal membrane of the inner medullary collecting duct (IMCD) [10, 16]. The CaR localization in the CTAL may account for the effects of increased extracellular concentrations of Ca⫹⫹ and Mg⫹⫹ to inhibit the reabsorption of calcium, magnesium, sodium, and chloride at this tubular site. Normally, Ca and Mg reabsorption occurs through the intercellular space and is driven by the high transtubular voltage gradient that is generated by the luminal Na⫹K⫹2Cl⫺ transporter. Activation of the apical CaR stimulates phospholipase C which releases arachidonic acid that is, in turn, metabolized by cytochrome P450; the active metabolites inhibit the apical K⫹ channel and may also directly inhibit the Na⫹K⫹2Cl⫺ cotransporter. These effects result in a marked
reduction in transluminal voltage, leading to reduced paracellular transport of Ca and Mg. Activation of the CaR also inhibits the PTH stimulated adenylate cyclase, reducing the cAMP-mediated transport of Ca and Mg. In the IMCD, increased Ca⫹⫹ inhibits the generation of cAMP by vasopressin through its effect on the CaR at the basolateral surface, causing less concentrated urine and polyuria. Also, increased tubular fluid Ca⫹⫹ activates the luminal CaR which specifically reduces ADHstimulated osmotic H2O permeability via the aquaporin channels, and lowers the urinary concentrating ability [17]. The action of increased extracellular fluid Ca⫹⫹ to inhibit the Na⫹K⫹2Cl⫺ cotransporter located in the thick ascending limb reduces the medullary hypertonicity and the effectiveness of the countercurrent mechanism and, therefore, further reduces the maximum urinary concentrating ability. Thus, the effect of hypercalcemia to lower GFR, to reduce the renal cortical synthesis of calcitriol [18], to cause increased urinary excretion of both Ca and Mg, and to lead to increased volumes of dilute urine may arise, in whole or in part, through activation of the CaR within various parts of the nephron. CaR IN OTHER TISSUES The role of the CaR that are found in the intestine [19], parts of the brain [20], the lungs, and bone remains to be clarified. It is probable that Ca⫹⫹ activation of a Ca⫹⫹-sensitive receptor acts to stimulate bone formation and to inhibit bone resorption; moreover, the G-protein coupled CaR has been identified in bone cell precursors [21]. Alternatively, Ca⫹⫹-sensing proteins of other types may play a role in regulating bone metabolism [22, 23]. It seems apparent that the very tight regulation of blood Ca⫹⫹, which is affected in a major way by PTH, calcitriol, and, to a lesser extent, by calcitonin, occurs due to the tight “fine tuning” that arises from activation of the CaR to modulate PTH secretion and to regulate the renal excretion of calcium. CALCIUM RECEPTOR IN SECONDARY HYPERPARATHYROIDISM There may be acquired disorders involving the CaR. Various data indicate that parathyroid glands obtained surgically from uremic patients with secondary hyperparathyroidism may exhibit reduced expression of the CaR on the surface of parathyroid cells [24, 25]. In patients with parathyroid adenomas or parathyroid carcinoma the data are somewhat inconsistent, although reduced staining is observed in some glands. It is possible that changes in the density of CaR in parathyroid cells may account, in part, for the shift in “set point” of parathyroid cells (i.e., the calcium concentration required to
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suppress maximal PTH secretion by 50%) observed in patients with secondary hyperparathyroidism. In experimental animals, data suggesting that there is regulation of the CaR are either negative or controversial. Two studies done in vitamin D-deficient rats have demonstrated no regulation of the mRNA for CaR by Ca⫹⫹ [26, 27]. One study reported no effect of calcitriol on the mRNA for the CaR, while another study found a 40% reduction of mRNA for CaR in vitamin D-deficient rats that was restored by calcitriol replacement [27]. Thus, some uncertainty exists about the role of altered regulation of the CaR being a major factor predisposing to the development of secondary hyperparathyroidism in patients with progressive renal failure. Experimental data indicate a reduction in the density of the CaR on the parathyroid cells of rats of increasing age; in the kidney, no alterations in the CaR were observed [28]. If a similar process exists in man, it could account for the changes in PTH levels with age and the propensity for the development of hyperparathyroidism with advancing years. There is evidence that the CaR expression in renal tissue is modestly reduced in experimentally induced renal failure in rats; this might contribute to hypocalciuria noted with renal insufficiency [29]. CLINICAL USE OF CALCIMIMETIC AGENTS For the clinician, the development of calcimimetic compounds that modulate the CaR, making it more sensitive to Ca⫹⫹ suppressive effect on PTH secretion, may provide a means for the medical treatment for both primary and secondary hyperparathyroidism. The first generation calcimimetic agent, R-568, was developed by scientists at NPS Pharmaceuticals [30, 31], and has undergone extensive testing. Because of a poor pharmacokinetic profile its development has been discontinued and a second generation calcimimetic agent, the AMG 073, has been developed and undergone clinical evaluation. The calcimimetic agent R-568 was given to a patient with inoperable parathyroid carcinoma, who presented with hypercalcemia (blood Ca⫹⫹ 1.96 mmol/L), high PTH levels (1,128 pg/mL) and altered mental status; the hypercalcemia failed to respond to intravenous saline and furosemide, several doses of intravenous pamidronate, and salmon calcitonin over 18 days [32]. The calcimimetic was initiated at 200 mg/day and subsequently increased to 400 mg/day. The patient’s symptoms improved after three days of R-568 treatment, and he was discharged home after 28 days of treatment with a blood Ca⫹⫹ of 1.53 mmol/L and PTH level of 357 pg/mL. Treatment with the calcimimetic was continued and the dose was titrated up to 600 mg/day; this treatment maintained the total serum calcium between 2.75–3.0 mmol/L despite the progressive increase in PTH levels to 2000–3500
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pg/mL; this PTH increase was believed to occur due to progression of the parathyroid carcinoma. The patient remained very active, travelling extensively, and had no side effects over a follow up longer than 600 days. In addition, all measures of cardiac, renal, hepatic, hematological, and pancreatic function remained stable throughout the period of treatment. Although such observations were made only in one patient, the data showed that R-568 could be given safely over a prolonged period. Several reports have documented the effectiveness of single doses or two daily doses of R-568 to reduce PTH levels in patients with primary and secondary hyperparathyroidism (abstract; Silverberg et al, J Am Soc Nephrol 9:516A, 1998) [33, 34]. In primary and secondary hyperparathyroidism, a single initial oral dose of R-568 produced a maximum suppression of PTH levels, that was dose-dependent, at 1 to 2 hours after administration. The decrease in blood Ca⫹⫹ was significant only with the largest dose and occurred only after PTH levels fell. The percentage reductions of PTH from pretreatment values were remarkably similar following 100 to 200 mg doses of R-568, with the average PTH reductions between 63% and 73% in three reported studies (abstract; Silverberg et al, J Am Soc Nephrol 9:516A, 1998) [33, 34] and one preliminary report (abstract; Akizawa et al, J Am Soc Nephrol 9:516A, 1998); this suppression was independent from pretreatment PTH, which averaged 77 pg/mL in patients with primary hyperparathyroidism and varied from 218 to 1,287 pg/mL in the groups with secondary hyperparathyroidism. In women with mild primary hyperparathyroidism, the maximal decrease in PTH occurred by 1 h after lower doses of R-568, while it occurred at 2 h after larger doses [35]. The duration of effect increased with the dose; the PTH levels returned to baseline by 4 h after doses of 80 mg or less but returned to baseline only at 8 h after the 160 mg dose. A small but significant reduction of blood Ca⫹⫹ occurred only with the largest dose, 160 mg. After this dose, urinary calcium, expressed as the calcium/creatinine ratio, rose by 4 h but returned close to baseline by 8 h. Two trials in dialysis patients with secondary hyperparathyroidism employed two separate doses of R-568, each given on two successive days [33] (abstract; Akizawa et al, J Am Soc Nephrol 9:516A, 1998). In seven patients with mild hyperparathyroidism [33], doses of 40 or 80 mg caused PTH levels to fall by more than 30% after the first dose in five of seven patients and more than 60% after the second dose in six of seven patients. With doses of 120 and 200 mg, PTH was reduced by more than 60% after the first dose in six of seven patients. After 24 h, the pretreatment PTH level was still 50% lower than the initial basal value; nonetheless, the PTH fell 50% or more after the second dose in six of seven patients. Blood Ca⫹⫹ was not significantly changed after
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the low dose, but fell significantly after the high dose. Preliminary data from hemodialysis patients with severe secondary hyperparathyroidism (abstract; Akizawa et al, J Am Soc Nephrol 9:516A, 1998) revealed significant reductions after 100 mg and even greater reductions after 200 mg of R-568. The PTH levels had not returned to baseline after 24 h, when the second dose caused a similar percent reduction of PTH. Serum total Ca levels fell, with more marked reductions after the larger dose. Calcitonin levels did not change after either dose. The administration of R-568 in doses of 100 mg per day led to the sustained suppression of PTH levels that persisted for the 15 days duration of treatment [34]. This study evaluated the effect of the administration of R568 (N ⫽ 16) or placebo (N ⫽ 5) in hemodialysis patients with secondary hyperparathyroidism. The pretreatment iPTH levels were 599 ⫾ 105 (mean ⫾ SE) and 600 ⫾ 90 pg/mL in subjects given R-568 or placebo, respectively. Values on the first day of treatment did not change in those given placebo. In contrast, PTH levels fell by 66 ⫾ 5%, 78 ⫾ 3%, and 70 ⫾ 3% at 1, 2 and 4 h, respectively, after the initial dose of R568 and then PTH levels remained below the pre-treatment values for 24 h. Despite lower ionized calcium concentrations, predose iPTH levels declined progressively over the first 9 days of treatment with R-568 and remained below pretreatment levels for the duration of the study, in contrast with the placebo treated group. Serum total and blood ionized calcium levels decreased from pretreatment levels in patients given R-568, whereas values were unchanged in those given placebo. Blood ionized calcium levels fell below 1 mmol/L in 7 of 16 patients receiving R-568; five patients withdrew from the study after developing symptoms of hypocalcemia, whereas three completed treatment after the R-568 dose was reduced. Serum phosphorus levels varied considerably from day to day in both groups of subjects, but values did not change from pretreatment levels during the study in either group. The pharmacokinetic and pharmacodynamic data showed a hight variability [34]. Peak serum levels of R-568 were achieved an average of 2.5 to 4.4 h after daily oral doses, but there was considerable heterogeneity among subjects. Maximum drug concentration were observed as early as 1 h and as late as 24 h after individual doses of R-568. Peak drug levels also varied widely among subjects, ranging from 0.42 to 42.2 ng/mL. Due to the pharmacokinetic profile and interactions with other drugs, the development of R-568 has been discontinued and a second generation calcimimetic agent, AMG 073, has been developed. The calcimimetic AMG 073 has shown potential to treat hemodialysis patients with secondary hyperparathyroidism with promising results in the initial clinical trials. A randomized, double blind, placebo controlled, multicenter study was conducted in hemodialysis patients with
secondary hyperparathyroidism and six sequential single doses were administered (5, 10, 25, 50, 75, and 100 mg of AMG 073 or placebo) (abstract; Coburn et al, J Am Soc Nephrol 11:573A, 2000). Doses of 25, 50, 75, and 100 mg caused a dose dependent decrease in plasma iPTH with a maximum suppression observed between 2 and 4 h after administration followed by a slow recovery of the iPTH during the subsequent hours but remaining below the baseline values after 24 h. Single doses of 75 and 100 mg of AMG 073 reduced serum calcium by 8.3% and 9.4%, respectively. Following this result, another study evaluated the use of daily, fixed doses of 10, 25, and 50 mg of AMG 073 for 8 consecutive days in hemodialysis patients with plasma iPTH ⱖ 250 pg/mL and ⱕ 1500 pg/mL (abstract; Goodman et al, J Am Soc Nephrol 11:576A, 2000). Doses of 25 and 50 mg were associated with decreases in iPTH concentrations. The dose of 50 mg was associated with a decrease in the mean serum calcium levels. On day 8 serum phosphorus levels and the calcium X phosphorus product were reduced from baseline levels in all treatment groups receiving AMG 073. The efficacy and safety of AMG 073 was shown in a double-blind, placebo-controlled, dose titration trial with daily doses of 10, 20, 30, 40, and 50 mg per day (abstract; Lindberg et al, J Am Soc Nephrol 11:578A, 2000). Sequential dose increases every 3 weeks for 12 weeks based on plasma iPTH response and safety profile. The final dose of AMG 073 was then maintained for 6 weeks. The 72 patients that enrolled in this study were continued on their concurrent therapy with phosphate binders and vitamin D for secondary hyperparathyroidism. During the maintenance period there was a mean decrease in the iPTH levels by 26% from the baseline value compared to an increase of 22% in the placebo treated group. The calcium X phosphorus product at the end of the maintenance period was decreased by 16.9% from the baseline value compared to an increase of 11.4% in the placebo treated group. The serum phosphorus levels were also reduce by 14.4% in the AMG 073 treated patients and the mean serum calcium levels were reduced by 3.3% from the baseline value. Transient asymptomatic hypocalcemia occurred in 3 of the 38 patients treated with AMG 073. Because of good safety profile the previous study was repeated with doses titrated up to 100 mg per day (abstract; Quarles et al, J Am Soc Nephrol 12:773A, 2001). Seventy one hemodialysis patients were evaluated. The baseline iPTH value was 625 ⫾ 310 pg/mL (mean ⫾ SE) for the 36 patients treated with AMG 073 and 582 ⫾ 421 pg/mL for the placebo treated patients. The iPTH levels decreased by 32.5% from the baseline during the maintenance phase in the AMG 073 group and increased by 3% in the placebo treated patients. In the AMG 073 group the calcium X phosphorus product at the end of
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the maintenance period was decreased by 7.9% from the baseline value compared to an increase of 11% in the placebo treated group. The serum phosphorus was also reduced by 2.6% in the AMG 073 treated patients and the mean serum calcium levels were reduced by 4.6% from baseline, although the absolute serum calcium levels remained within normal range. The potential of the second generation calcimimetic for treatment of secondary hyperparathyroidism in hemodialysis patients has been shown in the combined results of three dose-titration trials (abstract; Drueke et al, J Am Soc Nephrol 12:764A, 2001). Sequential dose increments could occur every 3 weeks for 12 weeks based on the iPTH response and safety profile. The dose range varied from 10 mg to 100 mg per day. Two hundred and fifteen hemodialysis patients (141 AMG 073 treated and 74 placebo treated) with serum iPTH levels ⱖ300 pg/mL, calcium level between 8.8 mg/dL and 11 mg/dL and a calcium X phosphorus product less than 70 were evaluated. They were continued on their current therapy with phosphate binders and/or vitamin D for secondary hyperparathyroidism. The baseline iPTH was 636 ⫾ 285 pg/mL (mean ⫾ SD) in the combined AMG group and 611 ⫾ 438 pg/mL in the placebo group. The treatment with AMG 073 reduced both the iPTH and the calcium X phosphorus product consistently over 12 weeks in these three studies. The mean iPTH was reduced by 20 to 33% in the AMG 073 groups and increased by 16% in the placebo groups. Eighty three percent of the AMG 073 patients had a PTH reduction equal or more than 30% at any time in the first 12 weeks of these studies. The mean calcium X phosphorus product decreased in the AMG group by 7.1% and increased in the placebo group by 14%. All these trials indicate that calcimimetic agents effectively reduce plasma PTH levels in patients with mild primary hyperparathyroidism and in those with secondary hyperparathyroidism of varying severity. In the latter a reduction in serum phosphorus and calcium X phosphorus product was also observed. The duration of action following a dose was substantially longer in the patients with end-stage renal disease than in those with primary hyperparathyroidism and normal renal function. In each study, there was a reduction in blood Ca⫹⫹ or total serum Ca but with the second generation calcimimetic this finding was minor and rarely troublesome. Many patients treated with the second generation calcimimetic agent were already being treated with phosphate binders and vitamin D sterols; this represents a group of patients that had poorly controlled secondary hyperparathyroidism despite such therapy. Furthermore, despite the lower serum calcium levels observed with calcimimetic treatment there was a consistent suppression of PTH levels favoring the impressive potency of this compounds. Thus, calcimimetic agents are powerful tools that may
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be highly useful for the treatment of hyperparathyroidism, parathyroid carcinoma, and probably a few other rare disorders, such as parathyromatosis and calciphylaxis. This may be an alternative to surgery in patients with primary hyperparathyroidism or in those with a high surgical risk. The complex management of end-stage renal disease associated hyperparathyroidism might become much safer with avoidance of treatment-induced hypercalcemia, hyperphosphatemia, and high calcium X phosphorus product. Reprint requests to Joa˜o M. Fraza˜o, Hospital de S. Joa˜o Servic¸o de Nefrologia, Al. Hernani Monteiro, 4200-451 Porto, Portugal. E-mail: [email protected]
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of vitamin D-deficient rats are not regulated by plasma calcium or 1,25-dihydroxyvitamin D3. Endocrinol 136:499–504, 1995 Brown AJ, Zhong M, Finch J, et al: Rat calcium sensing receptor is regulated by vitamin D but not by calcium. Am J Physiol 270: F454–F460, 1996 Autry CP, Kifor O, Brown EM, et al: Ca2⫹ receptor mRNA and protein increase in the rat parathyroid gland with advancing age. J Endocrinol 153:437–444, 1997 Mathias RS, Nguyen HT, Zhang MYH, Portale AA: Reduced expression of the renal calcium-sensing receptor in rats with experimental chronic renal insufficiency. J Am Soc Nephrol 9:2067– 2074, 1998 Nemeth EF, Steffey ME, Hammerland LG, et al: Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Nat Acad Sci 95:4040–4045, 1998 Nemeth EF, Bennett SA: Tricking the parathyroid gland with novel calcimimetic agents. Nephrol Dial Transplant 13:1923–1925, 1999 Collins MT, Skarulis MC, BilezikiaN JP, et al: Treatment of hypercalcemia secondary to parathyroid carcinoma with a novel calcimimetic agent. J Clin Endocrinol Metab 83:1083–1088, 1998 Antonsen JE, Sherrard DJ, Andress DL: A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure. Kidney Int 53:510–511, 1998 Goodman WG, Frazao JM, Goodkin DA, et al: A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney Int 58:436–445, 2000 Silverberg SI, Bone H, Marriot T, et al: Short-term inhibition of parathyroid hormone secretion by a calcium receptor agonist in primary hyperparathyroidism. N Engl J Med 337:1506–1510, 1997