Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Cinacalcet HCl: a calcimimetic agent for the management of primary and secondary hyperparathyroidism. 1288 26

Secondary hyperparathyroidism (SHPT) is associated with parathyroid gland hyperplasia, increased parathyroid hormone (PTH) production and secretion, disturbed bone and mineral metabolism, soft tissue calcification and an increased risk of death. The condition is an almost universal complication of end-stage renal disease (ESRD) and currently is managed by treatment with phosphate binders and vitamin D compounds, both of which are associated with significant side effects, including hypercalcaemia and hyperphosphataemia. Therapy with calcimimetics is a new approach to the treatment of SHPT. These agents act at the calcium-sensing receptor (CaR), where they increase the sensitivity of the receptor to ionized serum calcium. Activation of the CaR results in a rapid reduction in PTH secretion. The calcimimetic drug cinacalcet HCl currently is undergoing clinical trials in dialysis patients who have uncontrolled SHPT, despite treatment with vitamin D compounds and/or phosphate binders. Clinical trials have confirmed that the drug rapidly reduces plasma PTH, phosphorus and calcium-phosphorus product (Ca x P) levels, and that levels of PTH, phosphorus and Ca x P remain suppressed for up to 3 years. In clinical trials, cinacalcet HCl was a well-tolerated drug; only nausea and vomiting occurred more frequently in patients who took cinacalcet HCl than in those who took placebo, and the occurrence of transient hypocalcaemia was limited to the initial phase of the treatment. Cinacalcet HCl is therefore a potentially highly effective and well-tolerated treatment for SHPT in patients with ESRD.
 ...
PMID:Clinical experience with cinacalcet HCl. 1528 57

As suggested by its American brand name (Sensipar), the calcimimetic cinacalcet sensitizes the parathyroid cells to the extracellular calcium signal, suppressing parathyroid hormone (PTH) release and synthesis and preventing parathyroid cell proliferation. This primary PTH suppression decreases the release of calcium and phosphate from bone without increasing intestinal absorption of calcium and phosphate. Therefore cinacalcet decreases the risk of hypercalcemia and hyperphosphatemia in contrast to 1alpha-OH vitamin D derivatives. Compared with calcium-containing oral phosphate binder (OPB), it increases the risk of hypocalcemia and may decrease the PTH-mediated phosphaturia in predialysis patients. This justifies its combined use with calcium-containing OPB in order to prevent hypocalcemia and enhance the hypophosphatemic effect of the latter, while improving PTH suppression. The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) has recommended restriction of supplemental elemental calcium to 1.5 g/day, a recommendation that we believe should be revised. No pathophysiologic or randomized trial data have yet evidenced the absolute necessity for systematically using 1alpha-OH vitamin D derivatives and noncalcium-containing OPB rather than higher doses of calcium-containing OPB alone in uremic patients without vitamin D insufficiency. In patients with hyperparathyroidism as severe as in the "Treat to Goal Study," the Durham study showed that a calcium carbonate dose more than three times the K/DOQI limit could decrease PTH into the recommended range, with the advantage of a lower calcium-phosphate product compared with the combination of calcitriol and noncalcium OPB. Besides the efficient PTH suppression associated with lower calcium-phosphate product and a good gastrointestinal tolerance, long-term data suggest that cinacalcet may decrease the risk of parathyroidectomy and fracture, while high bone turnover lesions are improved. However, no long-term data on bone mineral density and cardiovascular calcification and complications are yet available. Such studies, along with those comparing cinacalcet and 1alpha-OH vitamin D-based approaches to hyperparathyroidism, are needed.
 ...
PMID:How do calcimimetics fit into the management of parathyroid hormone, calcium, and phosphate disturbances in dialysis patients? 1593 70

Secondary hyperparathyroidism (SHPT) remains an inevitable consequence of untreated chronic uremia. It is the result of a combination of phosphate (P) retention, failure of calcitriol synthesis, and hypocalcemia. Therapies used to correct these abnormalities, namely active vitamin D replacement, calcium (Ca) supplementation, and phosphate (P) restriction, have moderate efficacy but are prone to unacceptable side-effects. However, there have been new developments in the control of P, vitamin D replacement and modulation of the Ca sensing receptor (CaSR) using calcimimetics. Sevelamer, and in the near future lanthanum, are offering a reasonable level of P control without the toxicities inherent with either aluminum- or Ca-based phosphate binders, and other phosphate binders are in development. 'Non calcemic' vitamin D metabolites include 22-oxacalcitriol, paricalcitol, and doxercalciferol. In various experimental models 22-oxacalcitriol, in particular, exhibits impressive suppression of parathyroid hormone (PTH) with minimal calcemia, although it has been less impressive when compared with calcitriol in controlled studies in hemodialysis (HD) patients. The advantages of these agents over conventional treatment with calcitriol or alfacalcidol remain uncertain. Cinacalcet, a calcimimetic agent that up-regulates the sensitivity of the CaSR in parathyroid and other cells, is a new type of therapy for SHPT that simultaneously reduces the concentrations of PTH, Ca, and P in HD patients, enabling a significant number to achieve K/DOQI or other national guidelines. The extent to which this new therapy will improve clinical outcomes remains uncertain. In conclusion, with the advent of new therapies the emphasis in the management of SHPT has evolved to incorporate reduction of Ca loading, control of PTH within specific target ranges, and avoidance of hypercalcemia, hyperphosphatemia and elevation of the calcium phosphorus product.
 ...
PMID:Management of secondary hyperparathyroidism. 1610 40

Cinacalcet HCl, an allosteric modulator of the calcium-sensing receptor (CaR), has recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, due to its suppressive effect on parathyroid hormone (PTH) secretion. Although cinacalcet's effects in patients with primary and secondary hyperparathyroidism have been reported, the crucial relationship between the effect of calcimimetics and CaR expression on the parathyroid glands requires better understanding. To investigate its suppressive effect on PTH secretion in primary hyperparathyroidism, in which hypercalcemia may already have stimulated considerable CaR activity, we investigated the effect of cinacalcet HCl on PTH-cyclin D1 transgenic mice (PC2 mice), a model of primary hyperparathyroidism with hypo-expression of CaR on their parathyroid glands. A single administration of 30 mg/kg body weight (BW) of cinacalcet HCl significantly suppressed serum calcium (Ca) levels 2 h after administration in 65- to 85-week-old PC2 mice with chronic biochemical hyperparathyroidism. The percentage reduction in serum PTH was significantly correlated with CaR hypo-expression in the parathyroid glands. In older PC2 mice (93-99 weeks old) with advanced hyperparathyroidism, serum Ca and PTH levels were not suppressed by 30 mg cinacalcet HCl/kg. However, serum Ca and PTH levels were significantly suppressed by 100 mg/kg of cinacalcet HCl, suggesting that higher doses of this compound could overcome severe hyperparathyroidism. To conclude, cinacalcet HCl demonstrated potency in a murine model of primary hyperparathyroidism in spite of any presumed endogenous CaR activation by hypercalcemia and hypo-expression of CaR in the parathyroid glands.
 ...
PMID:Relationship between parathyroid calcium-sensing receptor expression and potency of the calcimimetic, cinacalcet, in suppressing parathyroid hormone secretion in an in vivo murine model of primary hyperparathyroidism. 1618 80

Currently, >300,000 patients with end-stage renal disease require dialysis. Secondary hyperparathyroidism is a serious complication of end-stage renal disease and can lead to renal osteodystrophy and other organ failure. Vitamin D sterols and phosphate binders are used to treat hyperparathyroidism, but they can cause hypercalcemia, which contributes to vascular and soft-tissue calcification. Cinacalcet (Sensipar) is the first agent in its class that treats secondary hyperparathyroidism by increasing the sensitivity of calcium sensing receptors. It is also indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma. All clinical trials concluded that cinacalcet is effective for the reduction of parathyroid hormone, serum calcium, phosphorus, and calcium-phosphate product levels. Cinacalcet is available as a once-daily oral therapy. Adverse effects are generally mild.
 ...
PMID:Cinacalcet hydrochloride (Sensipar). 1620 Jan 70

(1) Patients who require dialysis for chronic renal failure develop phosphocalcium metabolic disorders that often lead to secondary hyperparathyroidism. Standard treatment consists of a phosphate chelator and vitamin D, along with the use of an appropriate calcium concentration in the dialysis bath, but is difficult to manage. (2) Parathyroid cancer is a rare malignancy frequently associated with hypercalcaemia. (3) Cinacalcet is a calcimimetic agent that reduces the parathormone level. Clinical evaluation includes more than a dozen dose-finding studies and clinical trials. The optimal dose seems to range from 30 to 180 mg/day and varies widely from one patient to another. (4) 3 double-blind placebo-controlled trials, lasting for a maximum of one year and involving a total of 1136 dialysis patients with chronic renal failure, showed no improvement in quality of life with cinacalcet. The target parathormone level was reached by 40% of patients on cinacalcet versus 5% of patients on placebo, while the effects of cinacalcet on calcium levels (-7%) and phosphate levels (-8%) were modest. No impact on bone complications is mentioned in available reports. (5) The assessment of treatment of parathyroid cancer is limited to one ongoing non comparative trial involving 21 patients. (6) During clinical trials, 11% of dialysis patients had low parathormone levels, creating a risk of adynamic bone disease and fractures, but available data are sparse. (7) Two-thirds of patients receiving cinacalcet have episodes of hypocalcaemia, which may in part account for reports of seizures (1.4% of patients), nausea (31%) and vomiting (27%). Many adverse effects seen in animal studies have not been adequately investigated in the clinical setting, such as an increase in the QT interval, thyroid disorders, and sexual dysfunction. Cinacalcet is a powerful CYP 2D6 inhibitor and is also metabolised by isoenzymes CYP 3A4 and CYP 1A2, creating an increased risk of drug interactions. (8) In practice, treatment with cinacalcet seems difficult to manage and to provide only limited benefits. Available assessment reports leave many questions unanswered, and this is a further reason not to use this product outside of clinical trials, either after failure of phosphate chelator and vitamin D therapy (especially as an alternative to surgery) or in parathyroid cancer.
 ...
PMID:Cinacalcet: new drug. Secondary hyperparathyroidism: where are the clinical data? 1676 95

Bone disease is a common clinical problem following renal transplantation. In renal transplant recipients, multiple underlying factors determine the extent of bone loss and the subsequent risk of fractures. In addition to the well-recognized risk to bone disease posed by steroids, calcineurin inhibitors and pre-existing bone disease, persistent hyperparathyroidism (HPT) contributes to post-transplant bone loss. HPT is usually treated with vitamin D supplements combined with calcium. Patients whose HPT is associated with hypercalcemia pose a difficult therapeutic dilemma which often requires parathyroidectomy. Cinacalcet, a calcium mimetic agent, offers a unique pharmacologic approach to the treatment of patients with post-transplant hypercalcemia and HPT. In this paper, we describe the clinical course and biochemical changes in 10 renal transplant recipients with hypercalcemia and severe HPT early after renal transplantation treated with cinacalcet. Cinacalcet therapy corrected hypercalcemia and decreased parathyroid hormone (PTH) levels in all cases. A transient rise in the level of alkaline phosphatase was noted following initiation of cinacalcet therapy. In this patient population, correction of HPT was not permanent as discontinuing cinacalcet therapy led to a rapid rise in PTH level.
 ...
PMID:Early and severe hyperparathyroidism associated with hypercalcemia after renal transplant treated with cinacalcet. 1686 7

Secondary hyperparathyroidism (SHPT) leads not only to bone disorders, but also to cardiovascular complications in long-term dialysis patients. Conventional treatment with calcium (Ca) supplement, phosphate (P) binders and active vitamin D analogs lead in part to amelioration of SHPT, but are simultaneously associated with unacceptable side-effects, including hypercalcemia, hyperphosphatemia, and increased Ca x P products, which are the risk factors for cardiovascular disease in dialysis patients. Conventional treatment has been unable to facilitate the attainment of optimal management of SHPT proposed in the K/DOQI guidelines. Cinacalcet HCl (cinacalcet), a novel calcimimetic compound, restores the sensitivity of the Ca-sensing receptor in parathyroid cells, and decreases serum parathyroid hormone (PTH) without introducing hypercalcemia or hyperphosphatemia. Cinacalcet treatment enables a significant number of patients to achieve the K/DOQI guideline. Based on experimental data, calcimimetics could ameliorate cardiovascular calcification and remodeling in uremic rats with SHPT. Clinical trials have shown that cinacalcet significantly reduced the risks of parathyroidectomy, fracture and cardiovascular hospitalization among long-term dialysis patients with SHPT. Parathyroid intervention therapy (parathyroidectomy and percutaneous direct injection) is also a useful alternative. In the present article, we review novel therapeutic strategies for SHPT.
 ...
PMID:Therapeutic strategies for secondary hyperparathyroidism in dialysis patients. 1691 Nov 89

Calcimimetics suppress the secretion of parathyroid hormone by sensitizing the parathyroid calcium receptor to serum calcium. Cinacalcet (Sensipar/Mimpara), Amgen Inc., Thousand Oaks, CA), the first-in-class calcimimetic agent approved for treatment of secondary hyperparathyroidism in dialysis patients, is, in association with higher dose of a calcium-based oral phosphate binder, a well-tolerated and effective alternative to standard treatments such as vitamin D derivatives in association with a non-calcium-based oral phosphate binder. Here, we present an overview of evidence in support of this assertion. We extend our discussion to encompass other indications for calcimimetics -- secondary hyperparathyroidism in predialysis chronic kidney disease patients, hypercalcemic hyperparathyroidism in renal transplant recipients, primary hyperparathyroidism, and hypercalcemia associated with parathyroid carcinoma -- as well as providing guidance on optimal usage of this drug.
 ...
PMID:Drug Insight: renal indications of calcimimetics. 1693 53


1 2 3 4 5 6 7 Next >>