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Deutsche Medizinische Wochenschrift... Feb 2020Calcium is pivotal for neuromuscular function, coagulation, and signal transduction. An imbalance of enteral calcium uptake, deposition in and resorption from bones, and...
Calcium is pivotal for neuromuscular function, coagulation, and signal transduction. An imbalance of enteral calcium uptake, deposition in and resorption from bones, and renal calcium elimination causes hypercalcemia. The dissociation between total serum calcium and ionized calcium has important implications in diagnosing hypercalcemia. The calcium sensing receptor (CaSR) regulates parathyroid hormone release and renal calcium reabsorption. Knowing the actions of the CaSR is important for diagnosing and treating patients with hyperparathyroidism. Diuretics can cause hypercalcemia, but also provide a clinical tool to lower serum calcium.
Topics: Calcium; Humans; Hypercalcemia; Parathyroid Hormone; Receptors, Calcium-Sensing
PubMed: 32018291
DOI: 10.1055/a-0851-5200 -
Monographs in Pathology 1993
Review
Topics: Amino Acid Sequence; Animals; Humans; Molecular Sequence Data; Neoplasm Proteins; Neoplasms; Parathyroid Glands; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Protein Biosynthesis
PubMed: 8502246
DOI: No ID Found -
Hormones (Athens, Greece) Mar 2019Hypoparathyroidism is a relatively rare endocrine disease characterised by either null or inappropriately low secretion of parathyroid hormone (PTH) for serum calcium... (Review)
Review
Hypoparathyroidism is a relatively rare endocrine disease characterised by either null or inappropriately low secretion of parathyroid hormone (PTH) for serum calcium levels. The other main laboratory findings include hypocalcaemia, inappropriately normal or high urine calcium excretion and hyperphosphataemia with low urine phosphate excretion. The management of hypoparathyroidism should be tailored to each individual case, which makes it a demanding undertaking in everyday clinical practice. In this review, we sought to focus on the diagnostic approach of hypoparathyroidism and the therapeutic challenges of the disease from a clinical perspective. Conventional treatment with vitamin D analogues and calcium salts is no longer the only available treatment, since replacement treatment with PTH(1-84) has recently been approved for the disease. However, the optimal treatment schedule is yet to be defined.
Topics: Hormone Replacement Therapy; Humans; Hypoparathyroidism; Parathyroid Hormone
PubMed: 29876797
DOI: 10.1007/s42000-018-0032-6 -
British Journal of Pharmacology Jan 2018Human parathyroid hormone (PTH) is critical for maintaining physiological calcium homeostasis and plays an important role in the formation and maintenance of the bone....
BACKGROUND AND PURPOSE
Human parathyroid hormone (PTH) is critical for maintaining physiological calcium homeostasis and plays an important role in the formation and maintenance of the bone. Full-length PTH and a truncated peptide form are approved for treatment of hypoparathyroidism and osteoporosis respectively. Our initial goal was to develop an improved PTH therapy for osteoporosis, but clinical development was halted. The novel compound was then repurposed as an improved therapy for hypoparathyroidism.
EXPERIMENTAL APPROACH
A longer-acting form of PTH was synthesised by altering the peptide to increase cell surface residence time of the bound ligand to its receptor. In vitro screening identified a compound, which was tested in an animal model of osteoporosis before entering human trials. This compound was subsequently tested in two independent animal models of hypoparathyroidism.
KEY RESULTS
The peptide identified, LY627-2K, exhibited delayed internalization kinetics. In an ovariectomy-induced bone loss rat model, LY627-2K demonstrated improved vertebral bone mineral density and biomechanical properties at skeletal sites and a modest increase in serum calcium. In a Phase I clinical study, dose-dependent increases in serum calcium were reproduced. These observations prompted us to explore a second indication, hypoparathyroidism. In animal models of this disease, LY627-2K restored serum calcium, comparing favourably to treatment with wild-type PTH.
CONCLUSIONS AND IMPLICATIONS
We summarize the repositioning of a therapeutic candidate with substantial preclinical and clinical data. Our results support its repurposing and continued development, from a common indication (osteoporosis) to a rare disease (hypoparathyroidism) by exploiting a shared molecular target.
LINKED ARTICLES
This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.
Topics: Animals; Bone Density; Calcium; Drug Repositioning; Female; Humans; Hypoparathyroidism; Parathyroid Hormone; Rats
PubMed: 28898923
DOI: 10.1111/bph.14028 -
Scientific Reports Mar 2016Ligand binding to certain classes of G protein coupled receptors (GPCRs) stimulates the rapid synthesis of cAMP through G protein. Human parathyroid hormone (PTH), a...
Ligand binding to certain classes of G protein coupled receptors (GPCRs) stimulates the rapid synthesis of cAMP through G protein. Human parathyroid hormone (PTH), a member of class B GPCRs, binds to its receptor via its N-terminal domain, thereby activating the pathway to this secondary messenger inside cells. Presently, GPCRs are the target of many pharmaceuticals however, these drugs target only a small fraction of structurally known GPCRs (about 10%). Coordination complexes are gaining interest due to their wide applications in the medicinal field. In the present studies we explored the potential of a coordination complex of Zn(II) and anthracenyl-terpyridine as a modulator of the parathyroid hormone response. Preferential interactions at the N-terminal domain of the peptide hormone were manifested by suppressed cAMP generation inside the cells. These observations contribute a regulatory component to the current GPCR-cAMP paradigm, where not the receptor itself, but the activating hormone is a target. To our knowledge, this is the first report about a coordination complex modulating GPCR activity at the level of deactivating its agonist. Developing such molecules might help in the control of pathogenic PTH function such as hyperparathyroidism, where control of excess hormonal activity is essentially required.
Topics: Circular Dichroism; Cyclic AMP; Humans; Nuclear Magnetic Resonance, Biomolecular; Parathyroid Hormone; Peptides; Protein Binding; Spectrometry, Fluorescence; Thermodynamics
PubMed: 26932583
DOI: 10.1038/srep22533 -
The Journal of Clinical Investigation Mar 1976The response of normal bovine parathyroid glands to hypercalcemia was assessed in vivo by radioimmunoassay of immunoreactive parathyroid hormone concentrations in...
The response of normal bovine parathyroid glands to hypercalcemia was assessed in vivo by radioimmunoassay of immunoreactive parathyroid hormone concentrations in parathyroid effluent blood obtained by surgical cannulation of both anesthetized and nonanesthetized calves. Hypercalcemia was induced for periods of 0.3-35 h by intravenous infusion of a solution of calcium chloride. Assessment of immunoreactivity in effluent and peripheral blood included measurements of selected samples by use of a radioimmunoassay specific for a site residing in the biologically active portion of the hormone molecule. In all instances, the concentration of immunoreactive parathyroid hormone in hypercalcemic venous effluent from a superior parathyroid gland exceeded that of the peripheral blood. Failure of hypercalcemia to suppress completely secretion by normal parathyroids indicates that a portion of parathyroid hormone secretion occurs independent of blood calcium concentration. Consequently, continued parathyroid hormone secretion despite hypercalcemia can no longer be regarded as a unique feature of parathyroid neoplasia.
Topics: Amino Acid Sequence; Animals; Antigen-Antibody Reactions; Antigens; Calcium; Cattle; Hypercalcemia; Hyperparathyroidism; Parathyroid Hormone; Time Factors
PubMed: 1249204
DOI: 10.1172/JCI108324 -
The Lancet. Diabetes & Endocrinology Dec 2013
Topics: Female; Humans; Hypoparathyroidism; Male; Parathyroid Hormone
PubMed: 24622403
DOI: 10.1016/S2213-8587(13)70145-1 -
South African Medical Journal =... Nov 1967
Topics: Humans; Parathyroid Hormone
PubMed: 6075065
DOI: No ID Found -
Journal of Chemical Information and... Nov 2022Parathyroid hormone (PTH) is an endogenous ligand that activates the PTH type 1 receptor (PTH1R) signaling. Ca, a common second messenger, acts as an allosteric...
Parathyroid hormone (PTH) is an endogenous ligand that activates the PTH type 1 receptor (PTH1R) signaling. Ca, a common second messenger, acts as an allosteric regulator for prolonging the activation of PTH1R. However, a clear picture of the underlying allosteric mechanism is still missing. Herein, extensive molecular dynamics (MD) simulations are performed for PTH1R-PTH complexes with and without Ca ions, allowing us to delineate the molecular details of calcium-induced allostery. Our results indicate that acidic residues in the extracellular loop 1 (ECL1) (D251, E252, E254, and E258-E260) and PTH (E19 and E22) serve as key determinants for local Ca-coupling structures and rigidity of ECL1. Moreover, the binding of Ca induces conformational changes of transmembrane domain 6/7 (TM6/7) that are related to PTH1R activation and strengthens the residue-residue communication within PTH and TMD allosterically. Moreover, our results demonstrate that the presence of Ca ions potentiates the interaction between PTH and PTH1R via steered molecular dynamics (SMD) simulations, while the point mutation in the PTH (PTH) weakens the binding of PTH and PTH1R. These results support that Ca ions might further prolong the residence time of PTH on PTH1R and facilitate the positive allostery of PTH1R. Together, the present work provides new insights into the allosteric regulation mechanism of GPCRs induced by ions and related drug design targeting the PTH1R allosteric pathway.
Topics: Humans; Allosteric Regulation; Calcium; Parathyroid Hormone; Receptor, Parathyroid Hormone, Type 1; Signal Transduction
PubMed: 34464108
DOI: 10.1021/acs.jcim.1c00471 -
Clinical Chemistry Dec 2003
Topics: Antibodies, Monoclonal; Biomarkers; Chromatography, High Pressure Liquid; Diagnosis, Differential; Humans; Immunoassay; Parathyroid Hormone
PubMed: 14633866
DOI: 10.1373/clinchem.2003.026948