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  1. 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: Hypercalciuria/drug therapy*; Hypercalciuria/genetics
  2. Constable PD, Megahed AA, Hiew MWH
    J Dairy Sci, 2019 Dec;102(12):11370-11383.
    PMID: 31548071 DOI: 10.3168/jds.2019-16805
    Urine pH (UpH) and net acid excretion (NAE) are used to monitor the degree of systemic acidification and predict the magnitude of resultant hypercalciuria when feeding an acidogenic ration to control periparturient hypocalcemia in dairy cattle. The objectives of this study were to evaluate the diagnostic performance of urine dipstick and pH paper for measuring UpH, and to characterize the UpH-NAE relationship and the association of urine Ca concentration ([Ca]) with UpH and NAE. Urine samples (n = 1,116) were collected daily from 106 periparturient Holstein-Friesian cows fed an acidogenic ration during late gestation. Net acid excretion was measured by titration, and UpH was measured by a glass-electrode pH meter (reference method), Multistix-SG urine dipsticks (Siemens Medical Solutions Inc., Ann Arbor, MI), and Hydrion pH paper (Micro Essential Laboratory Inc., Brooklyn, NY). Diagnostic performance was evaluated using Spearman correlation coefficient (rs), Bland-Altman plots, and logistic regression. Urine pH measured by urine dipstick (rs = 0.94) and pH paper (rs = 0.96) were strongly associated with UpH. Method-comparison studies indicated that the urine dipstick measured an average of 0.28 pH units higher, and pH paper 0.10 pH units lower, than UpH. Urine [Ca] was more strongly associated with UpH (rs = -0.65) than NAE (rs = 0.52). Goals for controlling periparturient hypocalcemia under the study conditions were UpH <6.22 and <6.11, based on achieving urine [Ca] ≥5 mmol/L and estimated urinary Ca excretion ≥4 g/d, respectively. Urine pH was as accurate at predicting urine [Ca] as NAE when UpH >6.11. We conclude that pH paper is an accurate, practical, and low-cost cow-side test for measuring UpH and provides a clinically useful estimate of urine [Ca].
    Matched MeSH terms: Hypercalciuria
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