Utility of cinacalcet in familial hypocalciuric hypercalcemia

Bk, Sethi; Vs, Nagesh; Kelwade, Jayant; Parekh, Harsh; Dukle,

doi:10.4103/2230-8210.202034

Cited by 7 publications

(3 citation statements)

References 9 publications

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“…CaSR PAMs represent a targeted therapy for symptomatic forms of FHH (Hannan et al, 2018b) and potentiate the signaling responses of cells expressing FHH-associated CaSR, Ga 11 , or AP2s mutant proteins in vitro (Table 3) (Rus et al, 2008;Leach et al, 2013;Babinsky et al, 2016;Howles et al, 2016;Gorvin et al, 2018b). Furthermore, cinacalcet treatment is effective Calcium-Sensing Receptor Pharmacology and Function at decreasing serum calcium concentrations in patients with FHH1 and has been reported to improve hypercalcemic symptoms occasionally associated with FHH1, such as anorexia, polydipsia, and constipation (Table 3) (Alon and VandeVoorde, 2010; Rasmussen et al, 2011;Sethi et al, 2017). However, the response of NSHPT to cinacalcet is variable and appears to depend on the underlying CASR mutation.…”

Section: E Therapeutic Interventions-successes and Failuresmentioning

confidence: 99%

“…In Vitro Studies In Vivo Studies Hypercalcemic disorders FHH1/NSHPT NPS R-568 and cinacalcet enhance the signaling responses and cell surface expression of loss-of-function FHH1/ NSHPT-causing CaSR mutants (Rus et al, 2008;Leach et al, 2013) Cinacalcet lowers serum calcium and PTH concentrations and improves hypercalcemic symptoms in patients with FHH1 (Alon and VandeVoorde, 2010; Rasmussen et al, 2011;Sethi et al, 2017) Cinacalcet lowers serum calcium and PTH concentrations in patients with NSHPT harboring a heterozygous Arg185Gln CASR mutation (Reh et al, 2011;Gannon et al, 2014;Fisher et al, 2015) but is less effective for NSHPT caused by biallelic truncating CASR mutations (García Soblechero et al, 2013;Atay et al,…”

Section: Disordermentioning

confidence: 99%

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International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

et al. 2020

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The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, g-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca 2+ o) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca 2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca 2+ o homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca 2+ o , an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via G q/11 , G i/o , potentially G 12/13 , and even G s in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. Significance Statement-The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.

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Section: E Therapeutic Interventions-successes and Failuresmentioning

confidence: 99%

Section: Disordermentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

et al. 2020

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“…Moreover, repetitive daily dosing with 30 mg cinacalcet administered once or twice daily has been shown to result in a sustained lowering of serum calcium concentrations in FHH1 patients and also to increases in urinary calcium excretion (Festen‐Spanjer et al ., ; Rasmussen et al ., ). In addition, long‐term cinacalcet treatment has been reported to improve hypercalcaemic symptoms such as muscle aches, anorexia, polydipsia and constipation (Alon and VandeVoorde, ; Rasmussen et al ., ; Sethi et al ., ). In one patient with FHH1 and recurrent pancreatitis, cinacalcet had a dose‐dependent effect on the frequency of hospital admissions due to pancreatitis with 90 mg·day −1 cinacalcet (administered as 30 mg three times daily) leading to a cessation of acute pancreatitis episodes for >2 years (Gunganah et al ., ).…”

Section: Calcimimetic Treatment For Hypercalcaemic Disorders Of the Cmentioning

confidence: 97%

Calcimimetic and calcilytic therapies for inherited disorders of the calcium‐sensing receptor signalling pathway

Hannan

Olesen

Thakker

2017

British J Pharmacology

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Genotype–Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism

et al. 2022

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Utility of cinacalcet in familial hypocalciuric hypercalcemia

Cited by 7 publications

References 9 publications

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

Calcimimetic and calcilytic therapies for inherited disorders of the calcium‐sensing receptor signalling pathway

Genotype–Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism

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