Salmon calcitonin: a review of current and future therapeutic indications

Chesnut, Charles H.; Azria, M.; Silverman, Stuart L.; Engelhardt, Marc; Olson, Mark W.; Mindeholm, Linda

doi:10.1007/s00198-007-0490-1

Cited by 183 publications

(141 citation statements)

References 94 publications

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“…62 A high concentration of CT affected calcium and magnesium excretion and even had a diuretic effect. 18,63,64 However, the concentration of CT used in our study was equivalent to the plasma concentration of endogenous thyrocalcitonin that does not cause phosphaturia and natriuresis.…”

Section: Discussionmentioning

confidence: 99%

Calcitonin Has a Vasopressin-like Effect on Aquaporin-2 Trafficking and Urinary Concentration

Bouley¹,

Lu²,

Nunes³

et al. 2011

Journal of the American Society of Nephrology

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The most common cause of hereditary nephrogenic diabetes insipidus is a nonfunctional vasopressin (VP) receptor type 2 (V2R). Calcitonin, another ligand of G-protein-coupled receptors, has a VP-like effect on electrolytes and water reabsorption, suggesting that it may affect AQP2 trafficking. Here, calcitonin increased intracellular cAMP and stimulated the membrane accumulation of AQP2 in LLC-PK1 cells. Pharmacologic inhibition of protein kinase A (PKA) and deficiency of a critical PKA phosphorylation site on AQP2 both prevented calcitonin-induced membrane accumulation of AQP2. Fluorescence assays showed that calcitonin led to a 70% increase in exocytosis and a 20% decrease in endocytosis of AQP2.Immunostaining of rat kidney slices demonstrated that calcitonin induced a significant redistribution of AQP2 to the apical membrane of principal cells in cortical collecting ducts and connecting segments but not in the inner stripe or inner medulla. Calcitonin-treated VP-deficient Brattleboro rats had a reduced urine flow and two-fold higher urine osmolality during the first 12 hours of treatment compared with control groups. Although this VP-like effect of calcitonin diminished over the following 72 hours, the tachyphylaxis was reversible. Taken together, these data show that calcitonin induces cAMP-dependent AQP2 trafficking in cortical collecting and connecting tubules in parallel with an increase in urine concentration. This suggests that calcitonin has a potential therapeutic use in nephrogenic diabetes insipidus.

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Section: Discussionmentioning

confidence: 99%

Calcitonin Has a Vasopressin-like Effect on Aquaporin-2 Trafficking and Urinary Concentration

Bouley¹,

Lu²,

Nunes³

et al. 2011

Journal of the American Society of Nephrology

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“…sCT (molecular weight (MW) 3432 Da) is a more potent analogue of human CT, a small 32 amino acid peptide [6]. The primary structure is characterised by a disulfide bridge between two cysteine (cys) residues at positions 1 and 7 and a proline amide moiety at the C terminus; it also displays an α-helix and β-sheet, but has no tertiary structure.…”

Section: Introductionmentioning

confidence: 99%

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Ryan

Frías²,

Wang

et al. 2011

Journal of Controlled Release

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Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel combed-shaped endfunctionalised poly(PEG) methyl ether methacrylate) (sCT-P) comb-shaped polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40 kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of E max and an EC 50 of 3.7 nM. In vivo, while free sCT and the conjugates reduced serum [calcium] to a maximum of 15-30 % over 240 min, the half life (T½) was increased and the area under the curve (AUC) was extended in proportion to conjugate MW. Likewise, the polymer conferred protection on sCT against attack by trypsin, chymotrypsin, elastase, rat serum and liver homogenates, with the best protection afforded by sCT-P (40 kDa). Mathematical modelling accurately predicted the MW relationships to in vitro efficacy, potency, in vivo PK and enzymatic stability. With a significant increase in T½ for sCT, the 40 kDa MW comb-shaped PEG conjugate of sCT may have potential as a long-acting injectable formulation.

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“…Calcitonin acts by inhibiting osteoclast action and therefore calcium mobilization from bone [Chesnut et al 2008]. It can be given as a subcutaneous (SC) or intramuscular (IM) injection (100 units every 6 hours [QDS]) or as an IV infusion in emergencies (10 units/kg over 6 hours).…”

Section: Calcium-specific Therapymentioning

confidence: 99%