MyMedR

Displaying all 3 publications

Abstract:

Sort:

Fulltext Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635)

Roberts MS, Gafni RI, Brillante B, Guthrie LC, Streit J, Gash D, et al.

J. Bone Miner. Res., 2019 09;34(9):1609-1618.
PMID: 31063613 DOI: 10.1002/jbmr.3747

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by heterozygous, gain-of-function mutations of the calcium-sensing receptor gene (CAR). Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria. Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1. Five adults with ADH1 due to four distinct CAR mutations received escalating doses of the calcilytic compound NPSP795 (SHP635) on 3 consecutive days. Pharmacokinetics, pharmacodynamics, efficacy, and safety were assessed. Parallel in vitro testing with subject CaR mutations assessed the effects of NPSP795 on cytoplasmic calcium concentrations (Ca2+i ), and ERK and p38MAPK phosphorylation. These effects were correlated with clinical responses to administration of NPSP795. NPSP795 increased plasma PTH levels in a concentration-dependent manner up to 129% above baseline (p = 0.013) at the highest exposure levels. Fractional excretion of calcium (FECa) trended down but not significantly so. Blood ionized calcium levels remained stable during NPSP795 infusion despite fasting, no calcitriol supplementation, and little calcium supplementation. NPSP795 was generally safe and well-tolerated. There was significant variability in response clinically across genotypes. In vitro, all mutant CaRs were half-maximally activated (EC50 ) at lower concentrations of extracellular calcium (Ca2+o ) compared to wild-type (WT) CaR; NPSP795 exposure increased the EC50 for all CaR activity readouts. However, the in vitro responses to NPSP795 did not correlate with any clinical parameters. NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose-dependent manner, and thus, serves as proof-of-concept that calcilytics could be an effective treatment for ADH1. Albeit all mutations appear to be activating at the CaR, in vitro observations were not predictive of the in vivo phenotype or the response to calcilytics, suggesting that other parameters impact the response to the drug. © 2019 American Society for Bone and Mineral Research.

Matched MeSH terms: Hypocalcemia/drug therapy*
Fulltext Mediastinal parathyroid adenoma: diagnostic and management challenges

Che Kadir S, Mustaffa BE, Ghazali Z, Hasan Z, Imisairi AH, Mustafa S

Singapore Med J, 2011 Apr;52(4):e70-4.
PMID: 21552777

Primary hyperparathyroidism due to ectopic parathyroid adenomas can pose diagnostic and management challenges, especially when imaging studies have localised the lesions to different sites. We report a case of symptomatic hypercalcaemia due to a mediastinal parathyroid adenoma. Ultrasonography identified a nodule posterior to the right thyroid gland. However, computed tomography and technetium-99m sestamibi scintigraphy revealed an ectopic parathyroid adenoma located in the anterior mediastinum. The adenoma was successfully removed through a median sternotomy. However, postoperatively, the patient developed prolonged symptomatic hypocalcaemia, possibly due to suppression of the normal parathyroid gland function, although the presence of concomitant hungry bone syndrome was possible. The histopathology of the mediastinal mass was consistent with a parathyroid adenoma.

Matched MeSH terms: Hypocalcemia/drug therapy
Fulltext Novel calcium infusion regimen after parathyroidectomy for renal hyperparathyroidism

Tan JH, Tan HC, Loke SC, Arulanantham SA

Nephrology (Carlton), 2017 Apr;22(4):308-315.
PMID: 26952689 DOI: 10.1111/nep.12761

AIM: Calcium infusion is used after parathyroid surgery for renal hyperparathyroidism to treat postoperative hypocalcaemia. We compared a new infusion regimen to one commonly used in Malaysia based on 2003 K/DOQI guidelines.
METHODS: Retrospective data on serum calcium and infusion rates was collected from 2011-2015. The relationship between peak calcium efflux (PER) and time was determined using a scatterplot and linear regression. A comparison between regimens was made based on treatment efficacy (hypocalcaemia duration, total infusion amount and time) and calcium excursions (outside target range, peak and trough calcium) using bar charts and an unpaired t-test.
RESULTS: Fifty-one and 34 patients on the original and new regimens respectively were included. Mean PER was lower (2.16 vs 2.56 mmol/h; P = 0.03) and occurred earlier (17.6 vs 23.2 h; P = 0.13) for the new regimen. Both scatterplot and regression showed a large correlation between PER and time (R-square 0.64, SE 1.53, P

Matched MeSH terms: Hypocalcemia/drug therapy*

Filters

Please provide feedback to Administrator ([email protected])

External Links