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PubMed2006

Treatment of severe hypercalcemia due to refractory hyperparathyroidism in renal transplant patients with the calcimimetic agent cinacalcet.

Calcimimetic agents increase the sensitivity of calcium sensing receptors of parathyroid glands and suppress both serum calcium levels and parathyroid hormone. There are still limited data on the treatment of renal transplant patients with severe hypercalcemia and hyperparathyroidism with calcimimetics (cinacalcet). We describe two such renal transplant patients with chronic kidney disease Stage 3 who presented with persistent hypercalcemia (serum calcium 11.5-12 mg/dl) and refractory hyperparathyroidism (iPTH 194-547 pg/ml). Control of hypercalcemia with cinacalcet (serum calcium <10 mg/dl) resulted also in an improvement of hyperparathyroidism, but with a slower rate than that of the lowering of serum calcium. Addition of a vitamin D analog together with the calcimimetic agent resulted in faster control of the resistant hyperparathyroidism in both patients (iPTH <145 pg/ml) with clinical improvement and without any side effect. It seems that this new agent will improve our clinical approach of renal bone disease permitting a more integrated and successful treatment of hyperparathyroidism and its consequences on patients with chronic kidney disease.

Aged↗
PubMed2006

Hypercalcemia due to resistant hyperparathyroidism in renal transplant patients treated with the calcimimetic agent cinacalcet.

INTRODUCTION AND AIMS: Calcimimetic agents increase the sensitivity of calcium-sensing receptors of parathyroid glands and suppress both serum calcium levels and parathyroid hormone (PTH). The use of these drugs in patients with a functioning graft suffering from resistant hyperparathyroidism and hypercalcemia is still under investigation. We report seven patients who were treated with the calcimimetic agent cinacalcet. METHODS: The four male and three female patients of 38 to 72 years of age received a renal transplant from 4 to 35 months before cinacalcet treatment. Serum creatinine was 1.2 to 1.8 mg/dL (estimated glomerular filtration rate between 40 and 75 mL/min). Immunosuppressive treatment consisted of interleukin-2 antibody induction therapy, calcineurin inhibitors (cyclosporine or tacrolimus), prednisolone, and mycophenolate mofetil. Mild to severe hyperparathyroidism resistant to vitamin D analog treatment (intact parathyroid hormone molecule [iPTH] 174 to 519 pg/mL) was accompanied by severe hypercalcemia (Ca >11 mg%). To date the patients have completed 3 to 18 months of therapy. Cinacalcet 30 mg/d was initially administered. RESULTS: This treatment resulted in a rapid decrease in total serum calcium (8.6 to 9.2 mg/dL) while PTH showed a milder, progressive decrease. Having controlled calcium levels, 1alpha OH vitamin D (0.25 microg/d per os) was added to the treatment, which resulted in a further decline of iPTH without producing an increase in serum calcium concentrations (median initial iPTH value 401 pg/mL, median value after treatment 176 pg/mL). Therapy was well tolerated without hypocalcemic events. CONCLUSION: Cinacalcet offered a better holistic treatment approach to such patients.

Adult↗
PubMed2003

Calcimimetic agents and secondary hyperparathyroidism: rationale for use and results from clinical trials.

Calcimimetic agents are small organic molecules that act as allosteric activators of the calcium sensing receptor (CaSR). In parathyroid cells, they lower the threshold for receptor activation by extracellular calcium ions and diminish parathyroid hormone (PTH) secretion. Calcimimetic compounds thus represent a novel way of controlling excess PTH secretion in clinical disorders such as secondary hyperparathyroidism (SHPT) due to chronic renal failure. Clinical trials have documented that the calcimimetic agent cinacalcet hydrochloride effectively lowers plasma PTH levels without increasing serum calcium or phosphorus concentrations in adult hemodialysis patients with SHPT. Serum phosphorus levels and values for the calcium-phosphorus ion product in serum often decline as plasma PTH levels fall during treatment. Experimental evidence suggests that calcimimetic agents may also impede the development of parathyroid gland hyperplasia, an integral component of SHPT due to chronic renal failure. Calcimimetic agents have considerable potential, therefore, as part of new therapeutic strategies for SHPT.

Aniline Compounds↗
PubMed2001

Calcimimetic agents for the treatment of hyperparathyroidism.

Calcimimetic agents are small organic molecules that act as allosteric activators of the calcium sensing receptor. They lower the threshold for receptor activation by extracellular calcium ions and, in parathyroid cells, diminish parathyroid hormone secretion. Calcimimetic compounds represent a novel class of therapeutic agents that may provide a way of controlling excess parathyroid hormone secretion in several clinical disorders. Although experience from clinical trials in humans is limited, available data suggest that calcimimetic agents effectively lower plasma parathyroid hormone levels in patients with primary hyperparathyroidism and those with secondary hyperparathyroidism caused by end-stage renal disease. Calcimimetic compounds thus have considerable potential as a new approach to the medical management of several important clinical disorders of bone and mineral metabolism.

Animals↗
PubMed2004

Calcimimetic agents for the treatment of secondary hyperparathyroidism.

Calcimimetic agents function as allosteric activators of the calcium-sensing receptor (CaSR). In parathyroid tissue, they decrease the threshold for CaSR activation by extracellular calcium ions and diminish parathyroid hormone (PTH) secretion directly. Results from small clinical studies in hemodialysis patients with secondary hyperparathyroidism have shown that single oral doses of calcimimetic compounds abruptly decrease plasma PTH levels within 1 to 2 hours in a dose-dependent manner. Sustained decreases in plasma PTH levels can be achieved when daily oral doses are given for as long as 18 weeks. Decreases in plasma PTH levels often are associated with modest decreases in serum calcium and phosphorus levels, but symptomatic hypocalcemia is uncommon. Data gathered during larger more recent clinical trials lasting 12 to 24 months again indicate that plasma PTH levels can be decreased effectively with persistent and favorable decreases in serum phosphorus levels and in values for the calcium-phosphorus ion product in serum. Calcimimetic agents thus offer a novel treatment for secondary hyperparathyroidism in patients with chronic kidney disease stage 5, who are managed with dialysis. Unlike the vitamin D sterols, calcimimetic compounds effectively decrease plasma PTH levels without aggravating disturbances in mineral metabolism that have been associated with adverse clinical outcomes.

Aniline Compounds↗
PubMed1998

A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure. Rapid communication.

The control of hyperparathyroidism in patients with chronic renal failure continues to be a problem, particularly when parathyroid hormone (PTH) suppression becomes refractory to calcitriol activation of parathyroid cell 1,25-dihydroxyvitamin D receptors. To evaluate whether parathyroid cell calcium receptor activation may be useful in suppressing PTH levels, we tested the safety and effectiveness of a novel calcimimetic agent in dialysis patients with hyperparathyroidism. In a prospective, dose finding study, the calcimimetic agent, NPS R-568, was administered orally to seven patients at the start of a hemodialysis session and again 24 hours later. Plasma PTH, calcitonin and ionized calcium levels were measured over a 48 hour period and patients were observed for adverse events. Plasma PTH levels fell abruptly in all patients after a single dose of the compound, with the maximum suppression occurring within one to two hours after its administration. Following the administration of low doses (40 or 80 mg), the suppressed PTH levels rose to baseline values over 48 hours, whereas in patients who received high doses (120 or 200 mg) the mean PTH level remained 51% below baseline. Plasma calcitonin increased after the administration of both low and high doses (peak effect within 4 to 6 hr), with levels always returning to baseline by 48 hours. There were no episodes of hypocalcemia and no adverse effects were reported. We conclude that the activation of parathyroid cell calcium receptors by a novel calcimimetic compound is safe and effective in acutely suppressing PTH secretion in dialysis patients with hyperparathyroidism. Whether concomitant stimulation of calcitonin secretion will provide added beneficial effects on bone remodeling remains to be determined in long-term studies.

Adult↗
PubMed2004

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.

AIMS: Treatment with vitamin D sterols can lower plasma parathyroid hormone (PTH) in patients with secondary hyperparathyroidism; however, hypercalcaemia, hyperphosphataemia, or both, often develop. Calcimimetic agents, employed in alternative therapeutic approaches, directly inhibit PTH secretion by activating the calcium-sensing receptor in the parathyroid glands. METHODS: In this study, patients were given orally 25, 50, and 100 mg doses of the calcimimetic agent KRN 1493 each on two occasions, on the day of haemodialysis and on the day without haemodialysis. RESULTS: In the pharmacokinetic results, because the clearance of KRN 1493 by haemodialysis was much smaller than the systemic clearance, the influence of haemodialysis was not remarkable. In the pharmacodynamic study, on both the days with or without haemodialysis, plasma PTH concentrations decreased in a dose-dependent manner. Serum calcium concentrations decreased in association with the decrease in plasma PTH concentrations. Mild dose-dependent adverse effects (mainly nausea) were seen after the administration of KRN 1493 on both the day of haemodialysis and the day without haemodialysis. CONCLUSIONS: We conclude that the pharmacokinetics of KRN 1493 after a single administration were similar on the day of haemodialysis and the day without haemodialysis. KRN 1493 is safe and effective in suppressing PTH secretion and serum calcium concentrations on the day of haemodialysis and on the day without haemodialysis in patients with secondary hyperparathyroidism.

Administration, Oral↗
PubMed2002

The Calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism.

Treatment with vitamin D sterols can lower plasma parathyroid hormone (PTH) in many patients with secondary hyperparathyroidism due to end-stage renal disease, but hypercalcemia, hyperphosphatemia, or both often develop during treatment. As such, alternative therapeutic approaches to managing excess PTH secretion are needed. Calcimimetic agents directly inhibit PTH secretion by activating the calcium-sensing receptor in the parathyroid glands, but clinical experience with them is limited. Fifty-two hemodialysis patients with secondary hyperparathyroidism were given single orally administered doses of the calcimimetic agent AMG 073 ranging from 5 to 100 mg, or placebo. Plasma PTH levels decreased 2 h after 25-, 50-, 75-, or 100-mg doses, falling by a maximum of 43 +/- 29%, 40 +/- 36%, 54 +/- 28%, or 55 +/- 39%, respectively. Plasma PTH levels decreased in all patients given doses of > or =25 mg but did not change in those who received placebo. In patients treated with daily doses of 25 or 50 mg of AMG 073 for 8 d, plasma PTH levels declined for the first 3 to 4 d and remained below baseline values after 8 d of treatment. Serum calcium concentrations also decreased by 5 to 10% from pretreatment levels in patients given 50 mg of AMG 073 for 8 d, but values were unchanged in those who received lower doses. Serum phosphorus levels and values for the calcium-phosphorus ion product both decreased after treatment with AMG 073. Thus, 8 d of treatment with AMG 073 effectively lowers plasma PTH levels and improves several disturbances in mineral metabolism that have been associated with soft tissue and vascular calcification and with adverse cardiovascular outcomes in patients with end-stage renal disease.

Administration, Oral↗
PubMed2000

A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism.

BACKGROUND: The calcimimetic agent R-568 lowers plasma parathyroid hormone (PTH) levels in hemodialysis patients with mild secondary hyperparathyroidism, but its efficacy in those with more severe secondary hyperparathyroidism has not been studied. METHODS: Twenty-one patients undergoing hemodialysis three times per week with plasma PTH levels between 300 and 1200 pg/mL were randomly assigned to 15 days of treatment with either 100 mg of R-568 (N = 16) or placebo (N = 5). Plasma PTH and blood ionized calcium levels were measured at intervals of up to 24 hours after oral doses on days 1, 2, 3, 5, 8, 11, 12, and 15. RESULTS: Pretreatment PTH levels were 599 +/- 105 (mean +/- SE) and 600 +/- 90 pg/mL in subjects given R-568 or placebo, respectively, and 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 one, two, and four hours, respectively, after initial doses of R-568, remaining below pretreatment values for 24 hours. Blood ionized calcium levels also decreased after the first dose of R-568 but did not change in patients given placebo. Despite lower ionized calcium concentrations on both the second and third days of treatment, predose PTH levels were 422 +/- 70 and 443 +/- 105 pg/mL, respectively, in patients given R-568, and values fell each day by more than 50% two hours after drug administration. Predose PTH levels declined progressively over the first nine days of treatment with R-568 and remained below pretreatment levels for the duration of study. Serum total and blood ionized calcium concentrations decreased from pretreatment levels in patients given R-568, whereas values were unchanged in those given placebo. Blood ionized calcium levels fell below 1.0 mmol/L in 7 of 16 patients receiving R-568; five patients withdrew from study after developing symptoms of hypocalcemia, whereas three completed treatment after the dose of R-568 was reduced. CONCLUSIONS: The calcimimetic R-568 rapidly and markedly lowers plasma PTH levels in patients with secondary hyperparathyroidism caused by end-stage renal disease.

Adult↗
PubMed2004

Metabolism and disposition of calcimimetic agent cinacalcet HCl in humans and animal models.

The metabolism and disposition of calcimimetic agent cinacalcet HCl was examined after a single oral administration to mice, rats, monkeys, and human volunteers. In all species examined, cinacalcet was well absorbed, with greater than 74% oral bioavailability of cinacalcet-derived radioactivity in monkeys and humans. In rats, cinacalcet-derived radioactivity was widely distributed into most tissues, with no marked gender-related differences. In all animal models examined, radioactivity was excreted rapidly via both hepatobiliary and urinary routes. In humans, radioactivity was cleared primarily via the urinary route (80%), with 17% excreted in the feces. Cinacalcet was not detected in the urine in humans. The primary routes of metabolism of cinacalcet were N-dealkylation leading to carboxylic acid derivatives (excreted in urine as glycine conjugates) and oxidation of naphthalene ring to form dihydrodiols (excreted in urine and bile as glucuronide conjugates). The plasma radioactivity in both animals and humans was primarily composed of carboxylic acid metabolites and dihydrodiol glucuronides, with <1% circulating radioactivity accounting for the unchanged cinacalcet. Overall, the circulating and excreted metabolite profile of cinacalcet in humans was qualitatively similar to that observed in preclinical animal models.

Animals↗
PubMed2004

The impact of calcimimetic agents on the use of different classes of phosphate binders: results of recent clinical trials.

Calcimimetic agents bind to and activate the calcium-sensing receptor in the parathyroid glands, lowering the threshold for its activation by extracellular calcium and diminishing parathyroid hormone release from parathyroid cells. In three large randomized, controlled trials, cinacalcet given at doses of 30 to 180 mg orally each day was associated with effective reduction in parathyroid hormone levels over 26 weeks compared with placebo, and was consistently associated with a decrement in serum calcium, phosphorus levels, as well as a decrement in calcium-phosphorus product. In one study, there was a 5% incidence of hypocalcemia (serum calcium levels < 7.5 mg/dL on at least two consecutive measurements) among patients receiving cinacalcet, and less than 1% of patients receiving standard therapy (P < 0.0001). While there were no demonstrated differences between groups with regard to use of phosphate binders and vitamin D sterols in these randomized controlled trials, arguably, the combination of the effects on serum calcium, phosphorus, and calcium-phosphorus product may bring increased focus on the increased mortality risk associated with hypocalcemia.

Calcium↗
PubMed2003

Calcimimetic agents: review and perspectives.

BACKGROUND: Recognition of the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The activation of this receptor by small changes in the extracellular ionized calcium (ec(Ca2+)) regulates PTH, calcitonin secretion, urinary calcium excretion, and, ultimately, bone turnover. METHODS: The cloning of the CaR and the discovery of mutations that make the receptor less or more sensitive to calcium have allowed a better understanding of several hereditary disorders characterized by either hyperparathyroidism or hypoparathyroidism. The CaR, able to amplify the sensitivity of the CaR to Ca++ and suppress PTH levels with a resulting decrease in blood Ca++, became an ideal target for the development of compounds, the calcimimetics. Experience with the calcimimetic R-568 in patients with primary and secondary hyperparathyroidism and parathyroid carcinoma are summarized. RESULTS: The first clinical studies with the first-generation calcimimetic agents have demonstrated their efficacy in lowering plasma intact PTH concentration in uremic patients with secondary hyperparathyroidism. However, the low bioavailability of these first calcimimetics predicts a difficult clinical utilization. The second-generation calcimimetic, AMG 073, having a better pharmacokinetic profile, appears to be effective and safe for the treatment of secondary hyperparathyroidism, suppressing PTH levels while simultaneously reducing serum phosphorus levels and the calcium x phosphorus product. CONCLUSION: The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium x phosphorus product is very promising.

Aniline Compounds↗
PubMed2000

Calcimimetic agents and the calcium-sensing receptor.

Blood ionized extracellular calcium is closely regulated. To accomplish this, a hormone-like receptor that is responsive to extracellular ionized calcium regulates both the secretion of parathyroid hormone and the excretion of urinary calcium (as well as other cellular processes). Several hereditary disorders have mutations that cause either loss or gain of function of the calcium-sensing receptor, and alterations of the calcium-sensing receptor may play a role in both primary and secondary hyperparathyroidism. Calcimimetics are agents that act to make the calcium-sensing receptor more sensitive to extracellular ionized calcium; thereby they suppress the secretion of parathyroid hormone. Early trials in animal models of secondary hyperparathyroidism and in patients with primary hyperparathyroidism or with uremic secondary hyperparathyroidism have shown that the first generation calcimimetic, R-568, effectively lowers parathyroid hormone levels and is well tolerated.

Aniline Compounds↗
PubMed1999

Calcium-sensing receptor and calcimimetic agents.

Recognizing the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism greatly improves 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 (Ca2+) and control of urinary calcium excretion with small changes in blood Ca2+. 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 Ca2+ cause various clinical disorders; heterozygotes of mutations causing the CaR to be less sensitive to extracellular Ca2+ cause familial hypocalciuric hypercalcemia, while the homozygous form results in severe infantile hyperparathyroidism. Mutations causing increased sensitivity of the CaR to extracellular Ca2+ produce hereditary forms of hypoparathyroidism. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca2+, can suppress PTH levels, leading to a fall in blood Ca2+. Experiences with this agent in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In animals and humans with hyperparathyroidism, this agent produces a dose-dependent fall in PTH and blood Ca2+, with larger doses causing more sustained effects. The treatment has been short-term except for one patient followed for more than 600 days for parathyroid carcinoma; nonetheless the drug did not cause major side-effects and appears to be safe. Further long-term controlled studies are needed with calcimimetic agents of this type.

Aniline Compounds↗
PubMed2000

Effect of calcimimetic agent, KRN568, on gastrin secretion in healthy subjects.

KRN568 is a calcimimetic compound which acts on the calcium sensing receptors (CaR) on the parathyroid gland to suppress secretion of PTH. A recent report has demonstrated that CaRs are expressed on cultured human antral gastrin cells and that gastrin secretion is stimulated by an increase in extracellular calcium level. However, the effect of KRN568 on serum gastrin levels has yet to be clinically assessed. We therefore studied the effect of this calcimimetic on gastrin secretion in healthy subjects enrolled in the phase 1 study for KRN568 currently carried out in Japan. Single doses of KRN568, ranging from 25 mg to 400 mg, were orally administered to 6 healthy male volunteers at fasting and after meal. One subject proved to be a poor metabolizer (PM) for this compound and showed more than 10-fold high concentrations of plasma KRN568 (fasting Cmax 90.8 and non-fasting 83.8 ng/ml) compared to the other 5 individuals (Cmax 6.5 +/- 2.2 and 7.4+/- 1.6 ng/ml, respectively). Plasma gastrin levels showed mild but apparent increase (from 30 to 125 pg/ml) in this particular subject, while there were no significant increases in the other five people (from 34 +/- 6 to 63 +/- 3 pg/ml) after oral administration of 400 mg KRN568 at fasting. In the PM, administration of KRN568 resulted in extraordinarily high serum drug levels associated with transient increase of gastrin levels. This observation suggested that calcium-induced stimulation of gastrin secretion in human was mediated by a mechanism involving CaR. Potential side effects related to the increased gastrin secretion may be warranted in the practical use of this compound.

Administration, Oral↗
PubMed2003

Cinacalcet HCl: a calcimimetic agent for the management of primary and secondary hyperparathyroidism.

Cinacalcet HCl (AMG 073) is an investigational oral calcimimetic drug currently being evaluated for the treatment of primary and secondary hyperparathyroidism (HPT). Calcimimetics bind to the calcium-sensing receptors of the parathyroid glands and lower the sensitivity for receptor activation by extracellular calcium, thereby diminishing parathyroid hormone release. Cinacalcet HCl has demonstrated efficacy in controlling the hypercalcaemia of severe primary HPT and in reducing parathyroid hormone levels in patients with secondary HPT. Asymptomatic dose-dependent hypocalcaemia has occurred in some clinical trials. This drug has a favourable pharmacokinetic profile compared to its precursors and will prove useful as an additional/alternative agent in patients with primary and secondary HPT.

Cinacalcet↗
PubMed2005

Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study.

Management of secondary hyperparathyroidism is challenging with traditional therapy. The calcimimetic cinacalcet HCl acts on the calcium-sensing receptor to increase its sensitivity to calcium, thereby reducing parathyroid hormone (PTH) secretion. This phase 3, multicenter, randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of cinacalcet in hemodialysis (HD) and peritoneal dialysis (PD) patients with PTH > or =300 pg/ml despite traditional therapy. A total of 395 patients received once-daily oral cinacalcet (260 HD, 34 PD) or placebo (89 HD, 12 PD) titrated from 30 to 180 mg to achieve a target intact PTH (iPTH) level of < or =250 pg/ml. During a 10-wk efficacy assessment phase, cinacalcet was more effective than control for PTH reduction outcomes, including proportion of patients with mean iPTH levels < or =300 pg/ml (46 versus 9%), proportion of patients with > or =30% reduction in iPTH from baseline (65 versus 13%), and proportion of patients with > or =20, > or =40, or > or =50% reduction from baseline. Cinacalcet had comparable efficacy in HD and PD patients; 50% of PD patients achieved a mean iPTH < or =300 pg/ml. Cinacalcet also significantly reduced serum calcium, phosphorus, and Ca x P levels compared with control treatment. The most common side effects, nausea and vomiting, were usually mild to moderate in severity and transient. Once-daily oral cinacalcet was effective in rapidly and safely reducing PTH, Ca x P, calcium, and phosphorus levels in patients who received HD or PD. Cinacalcet offers a new therapeutic option for controlling secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.

Administration, Oral↗
PubMed2002

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 short-term 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 long-term controlled studies are underway to further confirm the effectiveness and safety of these compounds.

Calcium-Binding Proteins↗