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

Hannan, Fadil; Olesen, Mie K; Thakker, Rajesh V.

doi:10.1111/bph.14086

Cited by 31 publications

(34 citation statements)

References 69 publications

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“…CaSR antagonists (i.e. calcilytics), allosteric modulators of the CaSR, have been indicated as the therapy of choice of ADH, for their effect of increasing serum calcium and at the same time limiting urinary calcium excretion [44].…”

Section: Disordermentioning

confidence: 99%

Causes and pathophysiology of hypoparathyroidism

Cianferotti

Marcucci

Brandi

2018

Best Practice & Research Clinical Endocrinology & Metab

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Section: Disordermentioning

confidence: 99%

Causes and pathophysiology of hypoparathyroidism

Cianferotti

Marcucci

Brandi

2018

Best Practice & Research Clinical Endocrinology & Metab

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“…Its activation causes the G α11 -dependent activation of PLC-β and the production of diacylglycerol (DAG) and IP 3 from membrane-bound phosphatidylinositol 4,5-bisphosphate ( figure 1). The increase in intracellular IP 3 levels facilitates the release of Ca 2+ from intracellular stores, whereas DAG activates protein kinase C and the p38 mitogen-activated protein kinase (MAPK) pathway [73].…”

Section: Calcilyticsmentioning

confidence: 99%

The future of bronchodilation: looking for new classes of bronchodilators

2019

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@ERSpublicationsThere is a real interest among researchers and the pharmaceutical industry in developing novel bronchodilators. There are several new opportunities; however, they are mostly in a preclinical phase. They could better optimise bronchodilation. http://bit.ly/2lW1q39Cite this article as: Cazzola M, Rogliani P, Matera MG. The future of bronchodilation: looking for new classes of bronchodilators.ABSTRACT Available bronchodilators can satisfy many of the needs of patients suffering from airway disorders, but they often do not relieve symptoms and their long-term use raises safety concerns. Therefore, there is interest in developing new classes that could help to overcome the limits that characterise the existing classes. At least nine potential new classes of bronchodilators have been identified: 1) selective phosphodiesterase inhibitors; 2) bitter-taste receptor agonists; 3) E-prostanoid receptor 4 agonists; 4) Rho kinase inhibitors; 5) calcilytics; 6) agonists of peroxisome proliferator-activated receptor-γ; 7) agonists of relaxin receptor 1; 8) soluble guanylyl cyclase activators; and 9) pepducins. They are under consideration, but they are mostly in a preclinical phase and, consequently, we still do not know which classes will actually be developed for clinical use and whether it will be proven that a possible clinical benefit outweighs the impact of any adverse effect.It is likely that if developed, these new classes may be a useful addition to, rather than a substitution of, the bronchodilator therapy currently used, in order to achieve further optimisation of bronchodilation.

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“…(14) However, use of this treatment is expensive and limited, as it is administered by s.c. bolus injections or continuous pump infusion, and may not prevent patients with ADH1 from developing hypercalciuric renal complications. (14) Thus, better treatments are required, and antagonists of the CaSR, which are referred to as calcilytics, (15,16) have the potential to act as a targeted therapy for ADH1. To date, all calcilytics are negative allosteric modulators (NAMs) of the CaSR and comprise two main classes of orally active compounds: the amino-alcohols and the quinazolinones.…”

Section: Introductionmentioning

confidence: 99%

Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal Dominant Hypocalcemia Type 1 Mouse Model

et al. 2020

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Calcilytics are calcium-sensing receptor (CaSR) antagonists that reduce the sensitivity of the CaSR to extracellular calcium. Calcilytics have the potential to treat autosomal dominant hypocalcemia type 1 (ADH1), which is caused by germline gain-of-function CaSR mutations and leads to symptomatic hypocalcemia, inappropriately low PTH concentrations, and hypercalciuria. To date, only one calcilytic compound, NPSP795, has been evaluated in patients with ADH1: Doses of up to 30 mg per patient have been shown to increase PTH concentrations, but did not significantly alter ionized blood calcium concentrations. The aim of this study was to further investigate NPSP795 for the treatment of ADH1 by undertaking in vitro and in vivo studies involving Nuf mice, which have hypocalcemia in association with a gain-of-function CaSR mutation, Leu723Gln. Treatment of HEK293 cells stably expressing the mutant Nuf (Gln723) CaSR with 20nM NPSP795 decreased extracellular Ca 2+-mediated intracellular calcium and phosphorylated ERK responses. An in vivo doseranging study was undertaken by administering a s.c. bolus of NPSP795 at doses ranging from 0 to 30 mg/kg to heterozygous (Casr +/ Nuf) and to homozygous (Casr Nuf/Nuf) mice, and measuring plasma PTH responses at 30 min postdose. NPSP795 significantly increased plasma PTH concentrations in a dose-dependent manner with the 30 mg/kg dose causing a maximal (≥10-fold) rise in PTH. To determine whether NPSP795 can rectify the hypocalcemia of Casr +/Nuf and Casr Nuf/Nuf mice, a submaximal dose (25 mg/kg) was administered, and plasma adjusted-calcium concentrations measured over a 6-hour period. NPSP795 significantly increased plasma adjusted-calcium in Casr +/Nuf mice from 1.87 AE 0.03 mmol/L to 2.16 AE 0.06 mmol/L, and in Casr Nuf/Nuf mice from 1.70 AE 0.03 mmol/L to 1.89 AE 0.05 mmol/L. Our findings show that NPSP795 elicits dose-dependent increases in PTH and ameliorates the hypocalcemia in an ADH1 mouse model. Thus, calcilytics such as NPSP795 represent a potential targeted therapy for ADH1.

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

Abstract: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.

Cited by 31 publications

References 69 publications

Causes and pathophysiology of hypoparathyroidism

Causes and pathophysiology of hypoparathyroidism

The future of bronchodilation: looking for new classes of bronchodilators

Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal Dominant Hypocalcemia Type 1 Mouse Model

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