nps-r-467 and Hyperparathyroidism--Secondary

Topics: Aniline Compounds; Animals; Humans; Hyperparathyroidism, Secondary; Parathyroid Hormone; Rats; Receptors, Calcium-Sensing

The discovery, characterization, and cloning of the calcium-sensing receptor (CaR) in 1993 was soon followed by the creation of a new type of drug, the calcimimetics-NPS R-568 and NPS R-467-which are small phenylalkylamine derivative compounds that act as CaR agonists and increase the sensitivity of the CaR to activation by extracellular calcium (Ca2+). As expected, these compounds turned out to have a significant effect on the Ca2+/parathyroid hormone (PTH) relationship, resulting in a dramatically greater suppression of the PTH level than would otherwise occur at the actual extracellular Ca2+ levels. Renal osteodystrophy (RO) due to secondary hyperparathyroidism (HPT) in chronic renal failure was an obvious target for studying the effects of NPS R-568. 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. A similar effect was found in patients with chronic renal failure and secondary HPT. At the same time, the calcimimetics induced a slight degree of hypocalcemia. Such a significant suppressive effect on PTH secretion would be expected to result in therapeutic potential for a preventive or therapeutic effect on the RO accompanying chronic uremia. Administration would probably be in close concert with present strategies, phosphate binders and vitamin D analogs. A wide distribution of CaRs have now been demonstrated in the body, and an important question is how calcimimetics will affect the function of different tissues and organs when used for long-term treatment or prevention of secondary HPT and RO. Although relatively few experimental and clinical investigations have been completed, they clearly confirm the suppressive effect of calcimimetics on PTH secretion. In rats with experimental chronic renal failure, a significant and beneficial effect on the prevention of RO has been demonstrated. The effect of calcimimetic compounds is presently being evaluated in humans. Besides induction of hypocalcemia, the adverse effects in these mainly short-term studies have been few. Future studies with calcimimetics will further define the physiology and pathophysiology of the CaR and the long-term benefit of calcimimetic compounds in patients with chronic renal failure.

Topics: Aniline Compounds; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Phenethylamines; Propylamines; Receptors, Calcium-Sensing; Receptors, Cell Surface; Treatment Outcome; Uremia

Furosemide induces nephrocalcinosis in both humans and animals. We showed previously that parathyroidectomy protected against the development of furosemide-induced nephrocalcinosis in young rats, indicating a possible role for parathyroid hormone (PTH) in its pathogenesis. Calcimimetic agents such as NPS R-467 are potent and selective agonists at the calcium-sensing receptor in parathyroid glands and inhibit PTH secretion.. To determine whether NPS R-467 could, like parathyroidectomy, prevent furosemide-induced nephrocalcinosis, we studied 35 6-week-old male Sprague-Dawley rats, divided into five groups. Group A served as control, group B received intraperitoneally furosemide (40 mg/kg), groups C, D, and E received furosemide and NPS R-467 intraperitoneally at doses of 10, 20, and 40 micromol/kg, respectively, daily for 8 days. During the last 3 days, animals were placed in metabolic cages for measurement of urine output, food, and water intake. Blood and kidneys were collected on day 8, 60 to 90 minutes after the last doses. Kidney calcium content was measured and nephrocalcinosis scoring (0 to 5) was assessed histologically.. Furosemide increased urine output and fluid intake, and decreased body weight gain similarly in all groups. Serum PTH levels (mean +/- SD) were significantly higher in furosemide-treated control animals (276 +/- 226 pg/mL vs. 64 +/- 21 pg/mL); NPS R-467 induced a dose-dependent decrease in PTH levels (52 +/- 51 pg/mL, 18 +/- 7 pg/mL, and 13 +/- 3 pg/mL in groups C, D, and E, respectively). Plasma Ca(2+) was slightly, but significantly lower in all three NPS R-467 treated groups (5.1 +/- 0.4 mg/dL, 4.8 +/- 0.3 mg/dL, and 4.5 +/- 0.3 mg/dL in groups C, D, and E, respectively) compared to 5.7 +/- 0.1 mg/dL and 5.5 +/- 0.2 mg/dL in groups A and B, respectively. Furosemide treatment induced a substantial increase in kidney calcium content (1819 +/- 664 microg/g dry weight vs. 126 +/- 26 microg/g dry weight) and nephrocalcinosis scoring (5.0 +/- 0.0 vs. 0.0 +/- 0.0). Treatment with NPS R-467 ameliorated the furosemide-induced increase in kidney calcium content (673 +/- 312 microg/g, 361 +/- 188 microg/g, and 563 +/- 291 microg/g) and nephrocalcinosis scoring (2.2 +/- 1.2, 0.7 +/- 0.8, and 1.0 +/- 1.2) in groups C, D, and E, respectively.. The calcimimetic agent NPS R-467 prevents the development of hyperparathyroidism and attenuates nephrocalcinosis in the furosemide-treated young rat.

Topics: Aniline Compounds; Animals; Calcium; Furosemide; Hyperparathyroidism, Secondary; Kidney; Male; Nephrocalcinosis; Parathyroid Hormone; Rats; Rats, Sprague-Dawley

To observe the effect of NPS R-467, a calcimimetic, on PTH secretion of cultured parathyroid cells from severe secondary hyperparathyroidism (SHPT) patient.. The parathyroid tissue from a severe SHPT patient (iPTH: 2000 pg/ml) who had underwent parathyroidectomy was cultured in medium containing 1.05 mmol/L Ca and 0.8 mmo/L Mg. After 90 minutes' culture, NPS R-467 or NPS S-467, as negative control, with the final concentrations of 25, 50, and 100 nmol/L was added. The supernatant of medium was aspirated after 15, 30, and 60 minutes and iPTH therein was measured by radioimmunoassay.. There was no difference between the PTH concentrations in NPS R-467 group and NPS S-467 15 minutes after the reagents were added (1.8 ng/10(5) cells). In the NPS S-467 group, the PTH secretion was elevated along with the culture time, at 60 minutes up to 2.3 ng/10(5) cells. The PTH concentration of NPS R-467 was 80% of that of control group 30 minutes later and 60% of that in control group 60 minutes later. No difference was found among the effects of NPS R-467 at different concentrations.. The calcimimetic NPS R-467 significantly suppresses the PTH secretion, even in severe uremic hyperparathyroidism patient. It is an effective medicine for hyperparathyroidism.

Topics: Aniline Compounds; Calcium; Cells, Cultured; Humans; Hyperparathyroidism, Secondary; Parathyroid Glands; Parathyroid Hormone