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Stewart A Turner - One of the best experts on this subject based on the ideXlab platform.

  • cinacalcet hydrochloride maintains long term normocalcemia in patients with primary hyperparathyroidism
    The Journal of Clinical Endocrinology and Metabolism, 2005
    Co-Authors: Munro Peacock, Preston S. Klassen, Matthew Guo, Stewart A Turner, John P Bilezikian, Dolores M Shoback
    Abstract:

    Calcimimetics increase the sensitivity of parathyroid calcium-sensing receptors to extracellular calcium, thereby reducing PTH secretion. This multicenter, randomized, double-blind, placebo-controlled study assessed the ability of the oral Calcimimetic cinacalcet HCl to achieve long-term reductions in serum calcium and PTH concentrations in patients with primary hyperparathyroidism (HPT). Patients (n = 78) were randomized to cinacalcet or placebo. Cinacalcet was titrated from 30-50 mg twice daily during a 12-wk dose-titration phase. Efficacy was assessed during 12-wk maintenance and 28-wk follow-up phases. The primary endpoint was the achievement of normocalcemia [serum calcium urine biochemistry, biochemical measures of bone turnover, bone mineral density, and safety were also assessed. Seventy-three percent of cinacalcet-treated patients vs. only 5% of placebo-treated patients achieved the primary endpoint (P < 0.001). Fasting predose plasma PTH decreased 7.6% in cinacalcet patients but increased 7.7% in placebo patients (P < 0.01). Bone mineral density was unchanged by cinacalcet, but bone resorption and formation markers increased (P < 0.05). Adverse events were mild and similar between treatment groups. Cinacalcet rapidly normalizes serum calcium and reduces PTH in patients with primary HPT, and these effects are maintained with long-term treatment. Cinacalcet may be an effective, nonsurgical approach for management of primary HPT.

  • cinacalcet hydrochloride maintains long term normocalcemia in patients with primary hyperparathyroidism
    The Journal of Clinical Endocrinology and Metabolism, 2005
    Co-Authors: Munro Peacock, Preston S. Klassen, Stewart A Turner, John P Bilezikian, Dolores M Shoback
    Abstract:

    Calcimimetics increase the sensitivity of parathyroid calcium-sensing receptors to extracellular calcium, thereby reducing PTH secretion. This multicenter, randomized, double-blind, placebo-controlled study assessed the ability of the oral Calcimimetic cinacalcet HCl to achieve long-term reductions in serum calcium and PTH concentrations in patients with primary hyperparathyroidism (HPT). Patients (n = 78) were randomized to cinacalcet or placebo. Cinacalcet was titrated from 30–50 mg twice daily during a 12-wk dose-titration phase. Efficacy was assessed during 12-wk maintenance and 28-wk follow-up phases. The primary endpoint was the achievement of normocalcemia [serum calcium ≤ 10.3 mg/dl (2.57 mmol/liter)] with at least 0.5 mg/dl (0.12-mmol/liter) reduction from baseline. Plasma PTH, serum and urine biochemistry, biochemical measures of bone turnover, bone mineral density, and safety were also assessed. Seventy-three percent of cinacalcet-treated patients vs. only 5% of placebo-treated patients achieve...

  • cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis
    The New England Journal of Medicine, 2004
    Co-Authors: Geoffrey A Block, Stewart A Turner, Kevin J Martin, Angel L M De Francisco, Morrell M Avram, Michael Suranyi, Gavril Hercz, John Cunningham, Ali K Abualfa, Piergiorgio Messa
    Abstract:

    BACKGROUND: Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the Calcimimetic agent cinacalcet hydrochloride. METHODS: Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. RESULTS: Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. CONCLUSIONS: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.

  • the Calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism
    The Journal of Clinical Endocrinology and Metabolism, 2003
    Co-Authors: Dolores M Shoback, Matthew Guo, Stewart A Turner, John P Bilezikian, Laura C Mccary, Munro Peacock
    Abstract:

    Calcimimetics increase the sensitivity of the calcium-sensing receptor (CaR) to circulating serum calcium, reducing the secretion of PTH and the serum calcium concentration. We evaluated the Calcimimetic cinacalcet, a novel therapy for the management of primary hyperparathyroidism. In this randomized, double-blind, dose-finding study, patients (n = 22) with primary hyperparathyroidism were given cinacalcet (30, 40, or 50 mg) or placebo twice daily for 15 d and observed for an additional 7 d. Serum calcium, plasma PTH, and 24-h and fasting urine calcium were measured. Baseline mean serum calcium was 10.6 mg/dl for the combined cinacalcet-treated patients (normal range, 8.4-10.3 mg/dl), compared with 10.4 mg/dl for the placebo group. Mean PTH at baseline was 102 pg/ml (normal range, 10-65 pg/ml) for the combined cinacalcet-treated patients, compared with 100 pg/ml in the placebo group. Serum calcium normalized after the second dose on d 1 and remained normal through d 15 in all cinacalcet dose groups. Maximum decreases in PTH of over 50% occurred 2-4 h after dosing in all cinacalcet-treated groups. The fasting and 24-h urine calcium to creatinine ratios were similar in the cinacalcet and placebo groups. This study demonstrates that cinacalcet safely normalized serum calcium and lowered PTH concentrations without increasing urinary calcium excretion in the study subjects, indicating the potential benefit of cinacalcet as a medical treatment for primary hyperparathyroidism.

  • the Calcimimetic amg 073 as a potential treatment for secondary hyperparathyroidism of end stage renal disease
    Journal of The American Society of Nephrology, 2003
    Co-Authors: Darryl L Quarles, Stewart A Turner, Laura C Mccary, Donald J Sherrard, Stephen Adler, Steven J Rosansky, David A Bushinsky
    Abstract:

    Current treatment of secondary hyperparathyroidism in chronic kidney failure with calcium and active vitamin D is potentially limited by hypercalcemia and hyperphosphatemia. AMG 073 represents a new class of compounds for the treat- ment of hyperparathyroidism known as Calcimimetics, which reduce parathyroid hormone (PTH) synthesis and secretion by increasing the sensitivity of the parathyroid calcium-sensing receptor (CaR) to extracellular calcium. The current study evaluates the efficacy and safety of AMG 073 when added to conventional treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD). Seventy-one hemodialysis patients with uncontrolled secondary hyperparathyroidism, de- spite standard therapy with calcium, phosphate binders, and active vitamin D sterols, were treated in this 18-wk, dose- titration study with single daily oral doses of AMG 073/ placebo up to 100 mg. Changes in plasma PTH, serum calcium, serum phosphorus, and calcium phosphorus levels were compared between AMG 073 and placebo groups. Mean PTH decreased by 33% in the AMG 073 patients compared with an increase of 3% in placebo patients (P 0.001). A significantly greater proportion of AMG 073 patients (44%) had a mean PTH 250 pg/ml compared with placebo patients (20%; P 0.029). Also, a significantly greater proportion of AMG 073 patients (53%) had a decrease in PTH 30% compared with placebo patients (23%; P 0.009). Calcium phosphorus levels decreased by 7.9% in AMG 073 patients compared with an increase of 11.3% in placebo patients (P 0.013). Adverse event rates were low and mostly mild to moderate in severity; however, the incidence of vomiting was higher in AMG 073 patients. In this study, the Calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and effective means to attain significant reductions in PTH and calcium phosphorus levels in ESRD patients. AMG 073 represents a novel and promising therapy to improve the management of secondary hyperparathyroidism.

Darryl L Quarles - One of the best experts on this subject based on the ideXlab platform.

  • Calcimimetics or vitamin d analogs for suppressing parathyroid hormone in end stage renal disease time for a paradigm shift
    Nature Reviews Nephrology, 2009
    Co-Authors: James B Wetmore, Darryl L Quarles
    Abstract:

    Considerable advances have been made in the understanding of the pathogenesis and treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). These include the discovery that the calcium-sensing receptor has an important role in the regulation of parathyroid gland function, the development of Calcimimetics to target this receptor, the recognition that vitamin D receptor activation has important functions beyond the regulation of mineral metabolism, the identification of the phosphaturic factor fibroblast growth factor 23 and the contribution of this hormone to disordered phosphate and vitamin D metabolism in CKD. However, despite the availability of Calcimimetics, phosphate binders, and vitamin D analogs, control of SHPT remains suboptimal in many patients with advanced kidney disease. In this Review, we explore several unresolved issues regarding the pathogenesis and treatment of SHPT. Specifically, we examine the significance of elevated circulating fibroblast growth factor 23 levels in CKD, question the proposition that calcitriol deficiency is truly a pathological state, explore the relative importance of the vitamin D receptor and the calcium-sensing receptor in parathyroid gland function and evaluate the evidence to support the treatment of SHPT with Calcimimetics and vitamin D analogs. Finally, we propose a novel treatment framework in which Calcimimetics are the primary therapy for suppressing parathyroid hormone production in patients with end-stage renal disease.

  • identification of a novel extracellular cation sensing g protein coupled receptor
    Journal of Biological Chemistry, 2005
    Co-Authors: Pieter W Faber, George Mbella Ekema, David P Jackson, Anthony E Ting, Nancy M Wang, Michelle Fontillapoole, Robert W Mays, Kurt R Brunden, John J Harrington, Darryl L Quarles
    Abstract:

    The C family G-protein-coupled receptors contain members that sense amino acid and extracellular cations, of which calcium-sensing receptor (CASR) is the prototypic extracellular calcium-sensing receptor. Some cells, such as osteoblasts in bone, retain responsiveness to extracellular calcium in CASR-deficient mice, consistent with the existence of another calcium-sensing receptor. We examined the calcium-sensing properties of GPRC6A, a newly identified member of this family. Alignment of GPRC6A with CASR revealed conservation of both calcium and Calcimimetic binding sites. In addition, calcium, magnesium, strontium, aluminum, gadolinium, and the Calcimimetic NPS 568 resulted in a dose-dependent stimulation of GPRC6A overexpressed in human embryonic kidney cells 293 cells. Also, osteocalcin, a calcium-binding protein highly expressed in bone, dose-dependently stimulated GPRC6A activity in the presence of calcium but inhibited the calcium-dependent activation of CASR. Coexpression of β-arrestins 1 and 2, regulators of G-protein signaling RGS2 or RGS4, the RhoA inhibitor C3 toxin, the dominant negative Gαq-(305-359) minigene, and pretreatment with pertussis toxin inhibited activation of GPRC6A by extracellular cations. Reverse transcription-PCR analyses showed that mouse GPRC6A is widely expressed in mouse tissues, including bone, calvaria, and the osteoblastic cell line MC3T3-E1. These data suggest that in addition to sensing amino acids, GPRC6A is a cation-, Calcimimetic-, and osteocalcin-sensing receptor and a candidate for mediating extracellular calcium-sensing responses in osteoblasts and possibly other tissues.

  • extracellular calcium sensing receptors in the parathyroid gland kidney and other tissues
    Current Opinion in Nephrology and Hypertension, 2003
    Co-Authors: Darryl L Quarles
    Abstract:

    PURPOSE OF REVIEW The discovery of the extracellular calcium-sensing receptor, CasR has broadened our understanding of calcium homeostasis and led to the development of new pharmacological agents, Calcimimetics, for treating hyperparathyroidism. In the present review, I discuss the function of CasR as well as provide evidence for the presence of additional calcium-sensing mechanisms in the skeleton and possibly other tissues. RECENT FINDINGS Inactivating and activating mutations of the CasR respectively cause hereditary hyperparathyroidism, and demonstrate the predominant role of the CasR in controlling parathyroid gland function. Calcimimetics, which increase the sensitivity of CasR to extracellular calcium have been developed to treat secondary and primary hyperparathyroidism. In recent clinical trials in patients with end stage kidney disease, the Calcimimetic cinacalcet suppressed parathyroid hormone to a greater degree than conventional therapy with vitamin D analogues without causing hypercalcemia or hyperphosphatemia. CasR receptor also has functions in other tissues, including regulation of renal calcium excretion and calcitonin secretion by thyroidal C-cells, but the presence of redundant sensing mechanisms for extracellular calcium in other tissues, including bone, confounds the assessment of the receptor's function at these sites. Mouse genetic approaches have so far failed to identify any essential, non-redundant role for the calcium-sensing receptor in regulating chondrogenesis or osteogenesis, and have failed to establish a function for the protein outside of the parathyroid gland, kidney, and thyroidal C-cells. Rather, there is evidence for other putative calcium sensing receptor-like mechanisms in osteoblasts that remain to be identified. SUMMARY Sensing of extracellular calcium by CasR is important in regulating calcium homeostasis, but CasR may have vestigial function in various tissues where it is expressed in low abundance. The relative importance of CasR and the novel calcium-sensing mechanisms in mediating response to extracellular calcium in many of these tissues remain to be determined.

  • the Calcimimetic amg 073 as a potential treatment for secondary hyperparathyroidism of end stage renal disease
    Journal of The American Society of Nephrology, 2003
    Co-Authors: Darryl L Quarles, Stewart A Turner, Laura C Mccary, Donald J Sherrard, Stephen Adler, Steven J Rosansky, David A Bushinsky
    Abstract:

    Current treatment of secondary hyperparathyroidism in chronic kidney failure with calcium and active vitamin D is potentially limited by hypercalcemia and hyperphosphatemia. AMG 073 represents a new class of compounds for the treat- ment of hyperparathyroidism known as Calcimimetics, which reduce parathyroid hormone (PTH) synthesis and secretion by increasing the sensitivity of the parathyroid calcium-sensing receptor (CaR) to extracellular calcium. The current study evaluates the efficacy and safety of AMG 073 when added to conventional treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD). Seventy-one hemodialysis patients with uncontrolled secondary hyperparathyroidism, de- spite standard therapy with calcium, phosphate binders, and active vitamin D sterols, were treated in this 18-wk, dose- titration study with single daily oral doses of AMG 073/ placebo up to 100 mg. Changes in plasma PTH, serum calcium, serum phosphorus, and calcium phosphorus levels were compared between AMG 073 and placebo groups. Mean PTH decreased by 33% in the AMG 073 patients compared with an increase of 3% in placebo patients (P 0.001). A significantly greater proportion of AMG 073 patients (44%) had a mean PTH 250 pg/ml compared with placebo patients (20%; P 0.029). Also, a significantly greater proportion of AMG 073 patients (53%) had a decrease in PTH 30% compared with placebo patients (23%; P 0.009). Calcium phosphorus levels decreased by 7.9% in AMG 073 patients compared with an increase of 11.3% in placebo patients (P 0.013). Adverse event rates were low and mostly mild to moderate in severity; however, the incidence of vomiting was higher in AMG 073 patients. In this study, the Calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and effective means to attain significant reductions in PTH and calcium phosphorus levels in ESRD patients. AMG 073 represents a novel and promising therapy to improve the management of secondary hyperparathyroidism.

  • the Calcimimetic amg 073 as a potential treatment for secondary hyperparathyroidism of end stage renal disease
    Journal of The American Society of Nephrology, 2003
    Co-Authors: Darryl L Quarles, Wei Liu, Stewart A Turner, Laura C Mccary, Donald J Sherrard, Stephen Adler, Steven J Rosansky, David A Bushinsky
    Abstract:

    Current treatment of secondary hyperparathyroidism in chronic kidney failure with calcium and active vitamin D is potentially limited by hypercalcemia and hyperphosphatemia. AMG 073 represents a new class of compounds for the treatment of hyperparathyroidism known as Calcimimetics, which reduce parathyroid hormone (PTH) synthesis and secretion by increasing the sensitivity of the parathyroid calcium-sensing receptor (CaR) to extracellular calcium. The current study evaluates the efficacy and safety of AMG 073 when added to conventional treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD). Seventy-one hemodialysis patients with uncontrolled secondary hyperparathyroidism, despite standard therapy with calcium, phosphate binders, and active vitamin D sterols, were treated in this 18-wk, dose-titration study with single daily oral doses of AMG 073/placebo up to 100 mg. Changes in plasma PTH, serum calcium, serum phosphorus, and calcium x phosphorus levels were compared between AMG 073 and placebo groups. Mean PTH decreased by 33% in the AMG 073 patients compared with an increase of 3% in placebo patients (P = 0.001). A significantly greater proportion of AMG 073 patients (44%) had a mean PTH or =30% compared with placebo patients (23%; P = 0.009). Calcium x phosphorus levels decreased by 7.9% in AMG 073 patients compared with an increase of 11.3% in placebo patients (P = 0.013). Adverse event rates were low and mostly mild to moderate in severity; however, the incidence of vomiting was higher in AMG 073 patients. In this study, the Calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and effective means to attain significant reductions in PTH and calcium x phosphorus levels in ESRD patients. AMG 073 represents a novel and promising therapy to improve the management of secondary hyperparathyroidism.

Dolores M Shoback - One of the best experts on this subject based on the ideXlab platform.

  • cinacalcet hydrochloride maintains long term normocalcemia in patients with primary hyperparathyroidism
    The Journal of Clinical Endocrinology and Metabolism, 2005
    Co-Authors: Munro Peacock, Preston S. Klassen, Stewart A Turner, John P Bilezikian, Dolores M Shoback
    Abstract:

    Calcimimetics increase the sensitivity of parathyroid calcium-sensing receptors to extracellular calcium, thereby reducing PTH secretion. This multicenter, randomized, double-blind, placebo-controlled study assessed the ability of the oral Calcimimetic cinacalcet HCl to achieve long-term reductions in serum calcium and PTH concentrations in patients with primary hyperparathyroidism (HPT). Patients (n = 78) were randomized to cinacalcet or placebo. Cinacalcet was titrated from 30–50 mg twice daily during a 12-wk dose-titration phase. Efficacy was assessed during 12-wk maintenance and 28-wk follow-up phases. The primary endpoint was the achievement of normocalcemia [serum calcium ≤ 10.3 mg/dl (2.57 mmol/liter)] with at least 0.5 mg/dl (0.12-mmol/liter) reduction from baseline. Plasma PTH, serum and urine biochemistry, biochemical measures of bone turnover, bone mineral density, and safety were also assessed. Seventy-three percent of cinacalcet-treated patients vs. only 5% of placebo-treated patients achieve...

  • cinacalcet hydrochloride maintains long term normocalcemia in patients with primary hyperparathyroidism
    The Journal of Clinical Endocrinology and Metabolism, 2005
    Co-Authors: Munro Peacock, Preston S. Klassen, Matthew Guo, Stewart A Turner, John P Bilezikian, Dolores M Shoback
    Abstract:

    Calcimimetics increase the sensitivity of parathyroid calcium-sensing receptors to extracellular calcium, thereby reducing PTH secretion. This multicenter, randomized, double-blind, placebo-controlled study assessed the ability of the oral Calcimimetic cinacalcet HCl to achieve long-term reductions in serum calcium and PTH concentrations in patients with primary hyperparathyroidism (HPT). Patients (n = 78) were randomized to cinacalcet or placebo. Cinacalcet was titrated from 30-50 mg twice daily during a 12-wk dose-titration phase. Efficacy was assessed during 12-wk maintenance and 28-wk follow-up phases. The primary endpoint was the achievement of normocalcemia [serum calcium urine biochemistry, biochemical measures of bone turnover, bone mineral density, and safety were also assessed. Seventy-three percent of cinacalcet-treated patients vs. only 5% of placebo-treated patients achieved the primary endpoint (P < 0.001). Fasting predose plasma PTH decreased 7.6% in cinacalcet patients but increased 7.7% in placebo patients (P < 0.01). Bone mineral density was unchanged by cinacalcet, but bone resorption and formation markers increased (P < 0.05). Adverse events were mild and similar between treatment groups. Cinacalcet rapidly normalizes serum calcium and reduces PTH in patients with primary HPT, and these effects are maintained with long-term treatment. Cinacalcet may be an effective, nonsurgical approach for management of primary HPT.

  • the Calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism
    The Journal of Clinical Endocrinology and Metabolism, 2003
    Co-Authors: Dolores M Shoback, Matthew Guo, Stewart A Turner, John P Bilezikian, Laura C Mccary, Munro Peacock
    Abstract:

    Calcimimetics increase the sensitivity of the calcium-sensing receptor (CaR) to circulating serum calcium, reducing the secretion of PTH and the serum calcium concentration. We evaluated the Calcimimetic cinacalcet, a novel therapy for the management of primary hyperparathyroidism. In this randomized, double-blind, dose-finding study, patients (n = 22) with primary hyperparathyroidism were given cinacalcet (30, 40, or 50 mg) or placebo twice daily for 15 d and observed for an additional 7 d. Serum calcium, plasma PTH, and 24-h and fasting urine calcium were measured. Baseline mean serum calcium was 10.6 mg/dl for the combined cinacalcet-treated patients (normal range, 8.4-10.3 mg/dl), compared with 10.4 mg/dl for the placebo group. Mean PTH at baseline was 102 pg/ml (normal range, 10-65 pg/ml) for the combined cinacalcet-treated patients, compared with 100 pg/ml in the placebo group. Serum calcium normalized after the second dose on d 1 and remained normal through d 15 in all cinacalcet dose groups. Maximum decreases in PTH of over 50% occurred 2-4 h after dosing in all cinacalcet-treated groups. The fasting and 24-h urine calcium to creatinine ratios were similar in the cinacalcet and placebo groups. This study demonstrates that cinacalcet safely normalized serum calcium and lowered PTH concentrations without increasing urinary calcium excretion in the study subjects, indicating the potential benefit of cinacalcet as a medical treatment for primary hyperparathyroidism.

Michihito Wada - One of the best experts on this subject based on the ideXlab platform.

  • A novel Calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro.
    PloS one, 2018
    Co-Authors: Takehisa Kawata, Shin Tokunaga, Miki Murai, Nami Masuda, Waka Haruyama, Youji Shoukei, Yutaka Hisada, Tetsuya Yanagida, Hiroshi Miyazaki, Michihito Wada
    Abstract:

    Cinacalcet hydrochloride (cinacalcet), an oral Calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized Calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral Calcimimetic agent, with a wider safety margin.

  • a novel Calcimimetic agent evocalcet mt 4580 khk7580 suppresses the parathyroid cell function with little effect on the gastrointestinal tract or cyp isozymes in vivo and in vitro
    PLOS ONE, 2018
    Co-Authors: Takehisa Kawata, Shin Tokunaga, Miki Murai, Nami Masuda, Waka Haruyama, Youji Shoukei, Yutaka Hisada, Tetsuya Yanagida, Hiroshi Miyazaki, Michihito Wada
    Abstract:

    Cinacalcet hydrochloride (cinacalcet), an oral Calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized Calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral Calcimimetic agent, with a wider safety margin.

  • Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism
    Kidney international, 2005
    Co-Authors: Matthew Colloton, Michihito Wada, Gerald Miller, Edward Shatzen, Catherine Stehman-breen, David L. Lacey, David Martin
    Abstract:

    Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism . Background Secondary hyperparathyroidism (HPT) in chronic kidney disease (CKD) is a physiologic response to kidney failure characterized by elevated serum parathyroid hormone (PTH) levels and parathyroid gland enlargement. Calcimimetic agents acting through allosteric modification of the calcium-sensing receptor (CaR) can attenuate parathyroid hyperplasia in rats with secondary HPT. The present study explores the effects of the Calcimimetic cinacalcet HCl on parathyroid hyperplasia, apoptosis, and PTH secretion in a rat model of secondary HPT. Methods Cinacalcet HCl was gavaged daily (1, 5, or 10 mg/kg) for 4 weeks starting 6 weeks post-5/6 nephrectomy. After dosing, hyperplasia was determined using parathyroid weight and proliferating cell nuclear antigen (PCNA) immunochemistry. Apoptosis was determined using in situ techniques. Serum PTH (1–34) and blood chemistries were determined throughout the course of the study. Results Administration of cinacalcet HCl (5 or 10 mg/kg) significantly reduced the number of PCNA-positive cells and decreased parathyroid weight compared with vehicle-treated 5/6 nephrectomized rats. There was no difference in apoptosis from cinacalcet HCl–treated or vehicle-treated animals. Serum PTH and blood ionized calcium levels decreased in cinacalcet HCl–treated animals compared with vehicle-treated controls. Conclusion The results confirm previous work demonstrating that Calcimimetic agents attenuate the progression of parathyroid hyperplasia in subtotally nephrectomized rats, extending earlier observations to now include cinacalcet HCl. These results support a role for the CaR in regulating parathyroid cell proliferation. Therefore, cinacalcet HCl may represent a novel therapy for improving the management of secondary HPT.

  • Control of parathyroid cell growth by Calcimimetics
    Nephrology Dialysis Transplantation, 2003
    Co-Authors: Michihito Wada, Nobuo Nagano
    Abstract:

    Parathyroid cell hyperplasia is commonly observed in patients with chronic renal insufficiency and largely accounts for refractory secondary hyperparathyroidism. Calcimimetics are newly synthesized compounds that activate a calcium receptor on the parathyroid cell and can suppress parathyroid hormone secretion. The Calcimimetic compound AMG 073 has been examined in clinical trials, and the data obtained so far demonstrate that the compound can lower the circulating levels of parathyroid hormone and calcium-phosphorus product in patients with secondary hyperparathyroidism. Furthermore, experimental evidence indicates that Calcimimetics have the potential to inhibit parathyroid cell proliferation and block the progression of parathyroid hyperplasia. These beneficial effects, especially the potential to control parathyroid cell proliferation, would place Calcimimetics among the essential therapeutic agents for treating secondary hyperparathyroidism.

John P Bilezikian - One of the best experts on this subject based on the ideXlab platform.

  • an n terminal molecular form of parathyroid hormone pth distinct from hpth 1 84 is overproduced in parathyroid carcinoma
    Clinical Chemistry, 2007
    Co-Authors: Mishaela R Rubin, Shonni J Silverberg, P Damour, Jeanhugues Brossard, Louise Rousseau, James Sliney, Tom Cantor, John P Bilezikian
    Abstract:

    Background: A new parathyroid hormone (PTH) species, the N-terminal PTH form (N-PTH), is distinct from intact human PTH of 84 amino acid residues [hPTH(1–84)] and is recognized in a 3rd-generation assay of “whole” PTH (wPTH; the 1–2 epitope) but not in a 2nd-generation assay of “total” PTH (tPTH; the 12–18 epitope). N-PTH usually represents <15% of wPTH but can be overproduced in severe primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism. We investigated whether N-PTH is also overproduced in parathyroid cancer and whether N-PTH concentration is influenced by Calcimimetic therapy. Methods: We studied 8 patients with parathyroid carcinoma before and at week 16 of cinacalcet therapy, 6 patients with PHPT, and 6 control individuals. We fractionated sera with HPLC and analyzed fractions with the 2 assays to quantify hPTH(1–84), N-PTH, and non-(1–84) PTH fragments. Results: Half of parathyroid carcinoma patients had an increased wPTH:tPTH ratio [mean (SD), 1.35 (0.29)]; the others had a typical ratio [0.72 (0.12)]. HPLC fractionation of sera from 2 high-ratio patients confirmed N-PTH overproduction [65% (12%) of wPTH]. The N-PTH fraction was <15% of wPTH in PHPT and healthy individuals. Calcimimetic therapy appreciably reduced calcium concentrations in parathyroid carcinoma patients but had little influence on PTH concentration, the wPTH:tPTH ratio, or the PTH HPLC profile. Conclusion: N-PTH is overproduced in some parathyroid cancer patients, but Calcimimetic therapy does not influence its production. The clinical implications of this finding in parathyroid carcinoma await additional studies with an emphasis on N-PTH’s biological activity and with larger numbers of patients.

  • cinacalcet hydrochloride maintains long term normocalcemia in patients with primary hyperparathyroidism
    The Journal of Clinical Endocrinology and Metabolism, 2005
    Co-Authors: Munro Peacock, Preston S. Klassen, Stewart A Turner, John P Bilezikian, Dolores M Shoback
    Abstract:

    Calcimimetics increase the sensitivity of parathyroid calcium-sensing receptors to extracellular calcium, thereby reducing PTH secretion. This multicenter, randomized, double-blind, placebo-controlled study assessed the ability of the oral Calcimimetic cinacalcet HCl to achieve long-term reductions in serum calcium and PTH concentrations in patients with primary hyperparathyroidism (HPT). Patients (n = 78) were randomized to cinacalcet or placebo. Cinacalcet was titrated from 30–50 mg twice daily during a 12-wk dose-titration phase. Efficacy was assessed during 12-wk maintenance and 28-wk follow-up phases. The primary endpoint was the achievement of normocalcemia [serum calcium ≤ 10.3 mg/dl (2.57 mmol/liter)] with at least 0.5 mg/dl (0.12-mmol/liter) reduction from baseline. Plasma PTH, serum and urine biochemistry, biochemical measures of bone turnover, bone mineral density, and safety were also assessed. Seventy-three percent of cinacalcet-treated patients vs. only 5% of placebo-treated patients achieve...

  • cinacalcet hydrochloride maintains long term normocalcemia in patients with primary hyperparathyroidism
    The Journal of Clinical Endocrinology and Metabolism, 2005
    Co-Authors: Munro Peacock, Preston S. Klassen, Matthew Guo, Stewart A Turner, John P Bilezikian, Dolores M Shoback
    Abstract:

    Calcimimetics increase the sensitivity of parathyroid calcium-sensing receptors to extracellular calcium, thereby reducing PTH secretion. This multicenter, randomized, double-blind, placebo-controlled study assessed the ability of the oral Calcimimetic cinacalcet HCl to achieve long-term reductions in serum calcium and PTH concentrations in patients with primary hyperparathyroidism (HPT). Patients (n = 78) were randomized to cinacalcet or placebo. Cinacalcet was titrated from 30-50 mg twice daily during a 12-wk dose-titration phase. Efficacy was assessed during 12-wk maintenance and 28-wk follow-up phases. The primary endpoint was the achievement of normocalcemia [serum calcium urine biochemistry, biochemical measures of bone turnover, bone mineral density, and safety were also assessed. Seventy-three percent of cinacalcet-treated patients vs. only 5% of placebo-treated patients achieved the primary endpoint (P < 0.001). Fasting predose plasma PTH decreased 7.6% in cinacalcet patients but increased 7.7% in placebo patients (P < 0.01). Bone mineral density was unchanged by cinacalcet, but bone resorption and formation markers increased (P < 0.05). Adverse events were mild and similar between treatment groups. Cinacalcet rapidly normalizes serum calcium and reduces PTH in patients with primary HPT, and these effects are maintained with long-term treatment. Cinacalcet may be an effective, nonsurgical approach for management of primary HPT.

  • the Calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism
    The Journal of Clinical Endocrinology and Metabolism, 2003
    Co-Authors: Dolores M Shoback, Matthew Guo, Stewart A Turner, John P Bilezikian, Laura C Mccary, Munro Peacock
    Abstract:

    Calcimimetics increase the sensitivity of the calcium-sensing receptor (CaR) to circulating serum calcium, reducing the secretion of PTH and the serum calcium concentration. We evaluated the Calcimimetic cinacalcet, a novel therapy for the management of primary hyperparathyroidism. In this randomized, double-blind, dose-finding study, patients (n = 22) with primary hyperparathyroidism were given cinacalcet (30, 40, or 50 mg) or placebo twice daily for 15 d and observed for an additional 7 d. Serum calcium, plasma PTH, and 24-h and fasting urine calcium were measured. Baseline mean serum calcium was 10.6 mg/dl for the combined cinacalcet-treated patients (normal range, 8.4-10.3 mg/dl), compared with 10.4 mg/dl for the placebo group. Mean PTH at baseline was 102 pg/ml (normal range, 10-65 pg/ml) for the combined cinacalcet-treated patients, compared with 100 pg/ml in the placebo group. Serum calcium normalized after the second dose on d 1 and remained normal through d 15 in all cinacalcet dose groups. Maximum decreases in PTH of over 50% occurred 2-4 h after dosing in all cinacalcet-treated groups. The fasting and 24-h urine calcium to creatinine ratios were similar in the cinacalcet and placebo groups. This study demonstrates that cinacalcet safely normalized serum calcium and lowered PTH concentrations without increasing urinary calcium excretion in the study subjects, indicating the potential benefit of cinacalcet as a medical treatment for primary hyperparathyroidism.

  • treatment of hypercalcemia secondary to parathyroid carcinoma with a novel Calcimimetic agent
    The Journal of Clinical Endocrinology and Metabolism, 1998
    Co-Authors: Michael T Collins, John P Bilezikian, Monica C Skarulis, Shonni J Silverberg, Allen M Spiegel, Stephen J Marx
    Abstract:

    Parathyroid carcinoma is one cause of primary hyperparathyroidism, a condition in which there is hypercalcemia and dysregulated hypersecretion of PTH. In normal, and in some neoplastic parathyroid cells, PTH secretion is mediated by the cell surface calcium-sensing receptor. We describe the first therapeutic use of a novel molecule, a Calcimimetic, that has agonist action at the calcium-sensing receptor. A 78-yr-old man with parathyroid carcinoma was admitted with hypercalcemia, markedly elevated PTH, and a change in mental status. He was treated for 17 days with conventional therapy, which included saline hydration, furosemide, pamidronate, and calcitonin. This was ineffective, and on hospital day 18, Calcimimetic at a dose of 50 mg, orally, every 6 h was added. On hospital day 25, the dose was increased to 100 mg, orally, every 6 h, and on hospital day 30, saline and furosemide were discontinued. He was discharged on hospital day 40. With several dose adjustments, he has been treated with monotherapy ca...