Disease relevance of NPS R 568

• To test the hypothesis that the CaR plays a role in PT hyperplasia in CRI, we tested the effect of NPS R-568 on PT cell proliferation in rats with renal insufficiency [1].
• The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor [1].
• Renal osteodystrophy (RO) due to secondary hyperparathyroidism (HPT) in chronic renal failure was an obvious target for studying the effects of NPS R-568 [2].
• This study examined the effects of daily oral gavage or continuous subcutaneous infusion for 8 wk of the calcimimetic NPS R-568 on the progression of established mild or moderate-to-severe secondary hyperparathyroidism in rats with CRI induced by 5/6 nephrectomy [3].
• NPS R-568 also suppresses the elevation of serum PTH levels and PTG hyperplasia and can improve bone mineral density (BMD) and strength in rats with chronic renal insufficiency (CRI) [4].

High impact information on NPS R 568

• Treatment of these same cells with a calcimimetic, NPS-R-568, augments the CaSR response to Ca(2+), increasing phosphatidylinositol turnover and ERK1/2 phosphorylation, and overcoming the autoantibody effects [5].
• NPS R-568 potentiated the effects of extracellular Ca2+ on [Ca2+]i and PTH secretion but was without effect in the absence of extracellular Ca2+ [6].
• Both NPS R-467 and NPS R-568 increased [Ca2+]i in HEK 293 cells expressing the human parathyroid Ca2+ receptor but were without effect in wild-type HEK 293 cells [6].
• In a study on experimental animals, the results clearly showed that this first generation of calcimimetics, NPS R-568, had an acute dose-dependent and short-lived suppressive effect on PTH secretion from the parathyroid glands [2].
• NPS R-568 rescued expression of loss-of-function CaR mutants, increasing plasma membrane expression and ERK1/2 phosphorylation in response to 5 mm Ca(2+) [7].

Chemical compound and disease context of NPS R 568

• NPS R-568 decreased plasma Ca(2+) levels in thyroidectomized parathyroid-intact rats, but the rate of onset of hypocalcemia was slower than in controls [8].

Biological context of NPS R 568

• Finally, NPS R-568 induced sustained (>15 min after drug removal) Ca(2+)(i) oscillations, suggesting slow release of the drug from its binding site [9].
• Both oral and infused NPS R-568 completely prevented further hyperplasia but did not reduce total parathyroid cell number below that present at the initiation of treatment [3].
• Neither the magnitude nor the kinetics of the hypocalcemic response was affected by total nephrectomy, demonstrating that NPS R-568 does not induce hypocalcemia by acting on renal Ca(2+) receptors to increase Ca(2+) excretion [10].
• Recently, it was shown that calcimimetic NPS R-568 induced decreased blood pressure in spontaneously hypertensive rats (SHR) in the presence of parathyroid glands [11].

Anatomical context of NPS R 568

• METHODS: In this study, we investigated the effects of the calcimimetic NPS R-568 on the parathyroid gland in rats with CRI induced by ligation of the renal arteries and severe secondary HPT induced by dietary phosphorus loading [12].
• In confirmation, PCaR could not be detected by reverse transcriptase polymerase chain reaction in GCT23 cells and in mouse osteoclasts, and the calcimimetic compound NPS R-568 failed to produce the left shift of the concentration-response curve characteristic for PCaR [13].
• In contrast, parathyroidectomy (intact thyroid) abolished the hypocalcemic response to NPS R-568, regardless of whether the rats were hypocalcemic or rendered acutely normo- or hypercalcemic by calcium infusion before dosing [10].
• The addition of 10 nM NPS-R-568 increased the cumulative longitudinal growth of the metatarsal explants [14].
• To explore the underlying mechanisms, we then assessed the effects of NPS-R-568 on growth plate chondrocyte hypertrophy/differentiation and chondrocyte proliferation [14].

Associations of NPS R 568 with other chemical compounds

• SELECTION CRITERIA: We included all RCTs of any calcimimetic agent, cinacalcet HCl (AMG-073, Sensipar), NPS R-467 or NPS R-568 administered to patients with CKD for the treatment of SHPT [15].

Gene context of NPS R 568

• The calcimimetic NPS R-568 decreases plasma PTH in rats with mild and severe renal or dietary secondary hyperparathyroidism [16].
• When secondary HPT had developed, NPS R-568 was administered and blood samples were collected for up to 6 h [16].
• CONCLUSION: These results demonstrate that the calcimimetic compound NPS R-568 can prevent both the increase in serum PTH levels and parathyroid hyperplasia in rats with CRI and severe secondary HPT [12].
• NPS R-568 rapidly increased plasma calcitonin levels to a peak at 10 to 20 min after oral dosing (ED(50) 40 mg/kg) [8].
• Fetal rat metatarsal bones (dpc 20) were cultured in serum-free medium for 7 days in the presence or absence of NPS-R-568, a CaR agonist [14].

Analytical, diagnostic and therapeutic context of NPS R 568

• Preclinical studies with NPS R-568, a first generation calcimimetic compound that acts as a positive allosteric modulator of the CaR, have demonstrated that oral administration decreases serum levels of PTH and calcium, with a leftward shift in the set-point for calcium-regulated PTH secretion in normal rats [4].
• 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 [17].
• The first-generation calcimimetic, NPS R-568, has undergone clinical trials in primary hyperparathyroidism and in hyperparathyroidism secondary to chronic renal insufficiency [18].
• The most efficient hypotensive effect vs. control group was induced by the NPS R-568 of a dose of 1.0 mg/kg [19].
• After 7 days in culture, NPS-R-568 increased the height of the growth plate hypertrophic zone and the expression of collagen X, a marker of growth plate chondrocyte differentiation (assessed by immunohistochemistry) [14].

References