Correction of hypercalcaemia by cinacalcet in familial hypocalciuric hypercalcaemia

Festen-Spanjer, Barbara; Haring, C.; Köster, Johannes; Mudde, Aart N.

doi:10.1111/j.1365-2265.2007.03027.x

Cited by 34 publications

(29 citation statements)

References 4 publications

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“…However, the rapid effect of cinacalcet on PTH levels can be used to readily test the efficacy of cinacalcet in individual patients. The peak serum concentration of cinacalcet and the trough PTH levels seem to coincide between 4 and 6 h after administration of cinacalcet (15,59,76,78,79). Thus, a cinacalcet-test with measurement of PTH before and 6 h after a single dose of 2 mg/kg cinacalcet may be a good predictor of its effectiveness on serum calcium in an individual patient.…”

Section: Casr As a Drug Target For Allosteric Modulatorsmentioning

confidence: 99%

“…Two reports studied the dynamics of calcium and PTH after a single oral dose of cinacalcet in FHH type 1 patients. A significant decrease of PTH was detected as early as 2 h and effects on serum calcium were seen 8-48 h after the administration of cinacalcet (59,62,63). If clinically relevant the rapid effect of cinacalcet on PTH may be used to quickly assess the effectiveness of cinacalcet in individual patients (see below).…”

Section: Casr As a Drug Target For Allosteric Modulatorsmentioning

confidence: 99%

“…Some FHH patients are symptomatic and may suffer, for example, from recurrent episodes of pancreatitis that improve upon treatment (59). Soon after the calcimimetic cinacalcet was available, it was speculated that symptomatic FHH patients could benefit from cinacalcet therapy (Table 1).…”

Section: Casr As a Drug Target For Allosteric Modulatorsmentioning

confidence: 99%

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GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

Mayr¹,

Schnabel²,

Dörr³

et al. 2016

European Journal of Endocrinology

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The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper-or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper-and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.

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Section: Casr As a Drug Target For Allosteric Modulatorsmentioning

confidence: 99%

Section: Casr As a Drug Target For Allosteric Modulatorsmentioning

confidence: 99%

See 1 more Smart Citation

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

Mayr¹,

Schnabel²,

Dörr³

et al. 2016

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…However, evidence from a few case reports suggests that cinacalcet might be effective. 60,61 treatMent of other hypercalcaeMIas…”

Section: Familial Benign Hypocalciuric Hypercalcaemia (Fbhh)mentioning

confidence: 99%

Medical treatment of hypercalcaemia

Makras¹,

Papapoulos²

2009

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Hypercalcaemia results from the failure of renal calcium excretion to compensate increased influx of calcium into the circulation from the intestine, the kidneys and the skeleton. Hypercalcaemia is a common metabolic abnormality of varying severity that can be adequately diagnosed and treated. Primary hyperparathyroidism and malignant neoplasms are responsible for >90% of all cases. The management of hypercalcaemia depends on the underlying cause and involves approaches aiming at reducing serum calcium concentrations and correcting associated metabolic disturbances. A number of pharmacological interventions are currently available for the treatment of hypercalcaemia related to malignancy as well as other forms of hypercalcaemia. Knowledge of the pathophysiology of hypercalcaemia and of the properties of these interventions is essential for the successful management of affected individuals. We herein review available therapeutic interventions for hypercalcaemia of varying aetiology.

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“…In addition, cinacalcet is indicated for the treatment of hypocalcemia in patients with parathyroid carcinoma and in some countries for the treatment of primary hyperparathyroidism. Furthermore, three reports demonstrate the effectiveness of cinacalcet in treating familial hypocalciuric hypercalcemia (Timmers et al, 2006;Festen-Spanjer et al, 2008;Alon and Vandervoorde, 2010).…”

Section: Disorders Of Camentioning

confidence: 99%

Discovery of a Calcimimetic with Differential Effects on Parathyroid Hormone and Calcitonin Secretion

Henley¹,

Yang²,

Davis³

et al. 2011

J Pharmacol Exp Ther

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Calcimimetics are positive allosteric modulators to the calcium-sensing receptor (CaSR). Activation of the CaSR inhibits the secretion of parathyroid hormone (PTH), stimulates the secretion of calcitonin, and decreases serum calcium (Ca 2ϩ ). Cinacalcet, a second-generation calcimimetic, is used therapeutically to control PTH in patients with chronic kidney disease who are on dialysis with secondary hyperparathyroidism. A calcimimetic that displays increased separation of PTH versus Ca 2ϩ lowering in patients would potentially allow the use of calcimimetics to treat patients in earlier stages of renal disease because hypocalcemia can develop in this population. Toward this end, we developed a third-generation calcimimetic, determined the molecular pharmacological properties of it using an operation model of allosteric modulation/agonism, and measured the compound effects on PTH, serum ionized Ca 2ϩ , and calcitonin levels in 5/6 nephrectomized rats. We found the new molecule effectively reduced PTH levels without promoting calcitonin secretion or hypocalcemia. Furthermore, our third-generation molecule was less efficacious at promoting calcitonin secretion from human thyroid carcinoma cells compared with 3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine (R-568), a first-generation calcimimetic. These data provide evidence that calcimimetics with increased potency can be used to lower PTH without production of significant hypocalcemia because the threshold for inhibition of PTH secretion is much lower than the threshold for calcitonin secretion.

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Correction of hypercalcaemia by cinacalcet in familial hypocalciuric hypercalcaemia

Cited by 34 publications

References 4 publications

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

Medical treatment of hypercalcaemia

Discovery of a Calcimimetic with Differential Effects on Parathyroid Hormone and Calcitonin Secretion

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