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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Physiological principles are presented of calcium receptor (CaR) as well as agents affecting the receptor, defined as calcimimetics. Positive influence of type 1 and type 2 calcimimetics on calcium metabolism is discussed. The clinical indications for calcimimetics, especially type 2, in the future, seem to be hypercalcemia in the course of primary and secondary hyperparathyroidism as well as hypercalcemia in patients with parathyroid carcinoma.
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PMID:[Calcimimetics as a new chance for effective treatment of calcium metabolism disturbances]. 1262 66

The purpose of this study was to evaluate whether the natriuresis and polyuria seen in parathyroid hormone (PTH)-induced hypercalcemia are associated with dysregulation of renal Na transporters. Rats were infused with three different doses of human PTH [PTH (1-34); 7.5, 10, and 15 microg.kg(-1).day(-1) s.c.] or vehicle for 48 h using osmotic minipumps. The rats treated with PTH developed significant hypercalcemia (plasma total calcium levels: 2.71 +/- 0.03, 2.77 +/- 0.02, and 3.42 +/- 0.06 mmol/l, respectively, P < 0.05 compared with corresponding controls). The rats with severe hypercalcemia induced by high-dose PTH developed a decreased glomerular filtration rate (GFR), increased urine output, reduced urinary osmolality, increased urinary Na excretion, and fractional excretion of Na. This was associated with downregulation (calculated as a fraction of control levels) of whole kidney expression of type 2 Na-P(i) cotransporter (NaPi-2; 16 +/- 6%), type 3 Na/H exchanger (NHE3; 42 +/- 7%), Na-K-ATPase (55 +/- 2%), and bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1; 25 +/- 4%). In contrast, an upregulation of the Ca(2+)-sensing receptor (CaR) was observed. Rats treated with moderate-dose PTH exhibited unchanged GFR but decreased urinary concentration. The whole kidney expression of NHE3 (52 +/- 8%) and NaPi-2 (26 +/- 5%) was persistently decreased, whereas BSC-1 and Na-K-ATPase protein levels were not altered. CaR expression was also increased. Moreover, rats treated with low-dose PTH showed very mild hypercalcemia but unchanged GFR, normal urinary concentration, and unchanged expression of Na transporters and CaR. In conclusion, the reduced expression of major renal Na transporters is likely to play a role in the increased urinary Na excretion and decreased urinary concentration in rats with PTH-induced hypercalcemia. Moreover, the increase in the CaR in the thick ascending limb (TAL) may indicate a potential role of the CaR in inhibiting Na transport in the TAL.
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PMID:Reduced expression of renal Na+ transporters in rats with PTH-induced hypercalcemia. 1462 99

To ensure a multitude of essential cellular functions, the extracellular concentration of calcium is maintained within a narrow physiological range. This depends on integrated regulation of calcium fluxes with respect to the intestine, kidneys and bone. The precise regulation of serum calcium is controlled by calcium itself, through a calcium receptor and several hormones, the most important of which are parathyroid hormone and 1,25(OH)(2) vitamin D. This balance can be disturbed by mutations in the calcium-sensing receptor, inappropriately high or low levels of parathyroid hormone, resistance to parathyroid hormone effects, insufficient intake or production of 1,25(OH)(2) vitamin D and inactivation of the vitamin D receptor. Mineral homeostasis is moreover influenced by many other systemic factors (e.g. sex steroid, thyroid and glucocorticoid hormones) or humoral factors (e.g. cytokines and growth factors). A specific example is the major abnormalities of mineral homeostasis in case of malignancy by excessive production of parathyroid hormone-related peptide resulting in hypercalcaemia. Several new drugs have been developed based on factors in this axis, including calcimimetics, calcilytics, vitamin D analogues and parathyroid hormone-related peptide inhibitors.
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PMID:Disorders of calcium homeostasis. 1468 87

Treatment of excessive secretion of parathyroid hormone (PTH) in primary hyperparathyroidism (I degree HPT) as well as in secondary hyperparathyroidism (II degree HPT) in chronic renal insufficiency is symptomatic, short-term acting and far from expectations. Recognition of properties of calcium receptor (CaR) expressed on parathyroid principal cell membranes created possibilities to explore new compounds that could alter directly PTH secretion and provide a novel therapy for direct correction of increased secretion of the hormone in these disorders. Ligands that activate this receptor and inhibit PTH secretion are called calcimimetics. Recently clinical trials with NPS R-568, a calcimimetic of the Ist generation, and AMG 073, a representative of calcimimetics of IInd generation, were completed. Calcimimetics, taken orally, effectively lower increased secretion of PTH and hypercalcemia in I degree HPT, by "pharmacologic parathyroidectomy". Such compounds are also safe and effective in dialysed patients with II degree HPT in chronic renal insufficiency: they decrease PTH plasma level and prevent parathyroid cell hyperplasia. The other compounds, called calcilytics and represented by NPS 2143, inhibit CaR resulting therefore in increase of PTH secretion. Administration of calcilytics would provide a valuable alternative to inhibit progression of osteoporosis. Subcutaneous, pulsative low doses of recombinant PTH (ALX1-11) administration induces increase of bone formation. Such an effect to some extent was obtained by transient increase of endogenous PTH secretion induced by oral administration of calcilytic NPS 2143 to osteopenic ovariectomized rats, especially if it was accompanied by supplementation of estrogens.
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PMID:[Calcimimmetic and calcilytics: new perspectives of correction of abnormal parathormone (PTH) secretion]. 1497 81

Lithium treatment, which is still extensively used in bipolar affective disorders, may give rise to hypercalcaemia induced by hyperparathyroidism. We present a patient of 50-year-old treated with lithium for 19 years for bipolar illness and who developed an important hypercalcaemia. After symptomatic treatment of the hypercalcaemia and extrarenal dialysis the clinical evolution was favorable but measurements of serum calcium and parathormon showed that he had developed hyperparathyroidism. Neck exploration was performed and parathyroid adenomas, which had been detected by scintigraphy was removed. The lithium treatment expose to many side effects. Among other biologically and clinically important effects of lithium the possible induction of hyperparathyroidism was first suggested in 1973. Since, 1973, since about forty case reports have been described. Few cross-sectional studies show a relationship of lithium to hyperparathyroidism. Unusual metabolic features are associated with hyperparathyroidism and long-term lithium treatment: low urinary calcium excretion, normal urinary cyclic AMP excretion. The mechanism probably results from lithium linking with the calcium receptor on the parathyroid and then stimulating PTH secretion. The cessation of lithium therapy does not lead to normocalocaemia and a parathyroidectomy is usually indicated.
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PMID:[Important hypercalcaemia due to hyperparathyroidism induced by lithium]. 1579 60

The Ca(2+)-sensing receptor (CaSR) belongs to the class III G-protein-coupled receptors (GPCRs), which include receptors for pheromones, amino acids, sweeteners, and the neurotransmitters glutamate and gamma-aminobutyric acid (GABA). These receptors are characterized by a long extracellular amino-terminal domain called a Venus flytrap module (VFTM) containing the ligand binding pocket. To elucidate the molecular determinants implicated in Ca(2+) recognition by the CaSR VFTM, we developed a homology model of the human CaSR VFTM from the x-ray structure of the metabotropic glutamate receptor type 1 (mGluR1), and a phylogenetic analysis of 14 class III GPCR VFTMs. We identified critical amino acids delineating a Ca(2+) binding pocket predicted to be adjacent to, but distinct from, a cavity reminiscent of the binding site described for amino acids in mGluRs, GABA-B receptor, and GPRC6a. Most interestingly, these Ca(2+)-contacting residues are well conserved within class III GPCR VFTMs. Our model was validated by mutational and functional analysis, including the characterization of activating and inactivating mutations affecting a single amino acid, Glu-297, located within the proposed Ca(2+) binding pocket of the CaSR and associated with autosomal dominant hypocalcemia and familial hypocalciuric hypercalcemia, respectively, genetic diseases characterized by perturbations in Ca(2+) homeostasis. Altogether, these data define a Ca(2+) binding pocket within the CaSR VFTM that may be conserved in several other class III GPCRs, thereby providing a molecular basis for extracellular Ca(2+) sensing by these receptors.
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PMID:Delineating a Ca2+ binding pocket within the venus flytrap module of the human calcium-sensing receptor. 1614 94

Calcium is a major ion in human metabolism and its level is highly controlled. This regulation is performed via the Calcium Sensing Receptor, a discovery which ten years ago led to the explanation of a number of clinical disorders. The syndromes caused by CaSR abnormalities are characterized by hypercalcemia or hypocalcemia, associated with inappropriate calciuria. An underlying genetic or auto-immune cause may be demonstrated. High blood calcium levels linked to mutations of the CaSR gene lead to familial hypocalciuric hypercalcemia and the neonatal and non neonatal forms with severe hypercalcemic. Hypocalcemia determined by mutations in the CaSR gene include autosomal dominant hypocalcemia and its sporadic form. Another clinical presentation similar to Bartter syndrome has been reported. Auto-antibodies directed against CaSRs, seen in auto-immune diseases, can lead to similar clinical presentations. Finally, CaSR polymorphisms modulate the range of blood calcium levels. With diagnosis of these diseases deleterious therapeutics can be avoided. The discovery of this receptor has led to new therapeutic prospects such as calcimimetics for hyperthyroidism.
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PMID:[Calcium sensing receptor: physiology and pathology]. 1659 58

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.
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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.
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PMID:Drug Insight: renal indications of calcimimetics. 1693 53

Secondary hyperparathyroidism (2 degrees HPT) commonly develops in patients with chronic kidney disease (CKD) in response to high phosphate, low calcium and low 1,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)]. High PTH levels increase the rate of bone turnover, with a net efflux of calcium and phosphate leading to vascular calcification and coronary artery disease. Treatment of 2 degrees HPT with 1alpha,25(OH)(2)D(3) and calcium-based phosphate binders often produces hypercalcemia and over-suppression of PTH, resulting in adynamic bone that cannot buffer excess calcium and phosphate, which increases the risk of vascular calcification. It is essential, then, to reduce PTH levels to a range that supports normal bone turnover and minimizes ectopic calcification. Vitamin D analogs that inhibit PTH gene transcription and parathyroid hyperplasia, and that have less calcemic activity than 1alpha,25(OH)(2)D(3,) have provided a greater safety margin for the treatment of 2 degrees HPT, as well as enhancing the survival of CKD patients. Although several analogs with less calcemic activity are now used in patients (paricalcitol and doxercalciferol in the USA, and OCT and falecalcitriol in Japan), efforts to develop even more selective analogs continue. Parathyroid glands express both 25-hydroxylase and 1alpha-hydroxylase and may be capable of activating prohormones or prodrugs to suppress PTH and parathyroid growth by an autocrine mechanism. Moreover, the introduction of non-calcium-based phosphate binders (sevelamer and lanthanum carbonate) and cinacalcet (an allosteric activator of the calcium receptor that reduces PTH and the serum calciumxphosphate product) may reduce the risk of hypercalcemia with vitamin D therapy. Combining these agents with higher doses of vitamin D compounds may achieve greater suppression of PTH and possibly enhance survival in patients with chronic kidney disease.
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PMID:Vitamin D analogs for secondary hyperparathyroidism: what does the future hold? 1736 85


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