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Journal of Musculoskeletal & Neuronal... Dec 2020Calcitonin regulates blood calcium levels and possesses certain clinically useful anti-fracture properties. Specifically, it reduces vertebral fractures in... (Review)
Review
Calcitonin regulates blood calcium levels and possesses certain clinically useful anti-fracture properties. Specifically, it reduces vertebral fractures in postmenopausal osteoporotic women significantly compared to a placebo. Nevertheless, the use of calcitonin has declined over the years and salmon calcitonin is no longer the first-line treatment for many of its indications. Commercial calcitonin only exists in intranasal or injectable preparations, which are less preferable for patients. Efficacy of a potential oral formulation has been under investigation but achieving adequate bioavailability remains a conundrum and the latest phase III trials have not shown promising evidence justifying its use. Associations with cancer have also derailed this treatment option. Furthermore, the rise of bisphosphonates and, more recently, monoclonal antibodies (such as denosumab), has revolutionised the treatment of osteoporotic fractures. Therefore, we are posed with an interesting question: is calcitonin a treatment of the past? This review aims to explore the reasons behind this paradigm shift and outline the potential role of calcitonin in the management of fractures and other conditions in the years to come.
Topics: Animals; Calcitonin; Humans; Osteoporotic Fractures
PubMed: 33265089
DOI: No ID Found -
MMW Fortschritte Der Medizin Jun 2021
Review
Topics: Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Humans; Procalcitonin
PubMed: 34086237
DOI: 10.1007/s15006-021-9959-7 -
Clinical Chemistry and Laboratory... Aug 2019Background Procalcitonin (PCT)-guided antibiotic stewardship (ABS) has been shown to reduce antibiotics (ABxs), with lower side-effects and an improvement in clinical...
Background Procalcitonin (PCT)-guided antibiotic stewardship (ABS) has been shown to reduce antibiotics (ABxs), with lower side-effects and an improvement in clinical outcomes. The aim of this experts workshop was to derive a PCT algorithm ABS for easier implementation into clinical routine across different clinical settings. Methods Clinical evidence and practical experience with PCT-guided ABS was analyzed and discussed, with a focus on optimal PCT use in the clinical context and increased adherence to PCT protocols. Using a Delphi process, the experts group reached consensus on different PCT algorithms based on clinical severity of the patient and probability of bacterial infection. Results The group agreed that there is strong evidence that PCT-guided ABS supports individual decisions on initiation and duration of ABx treatment in patients with acute respiratory infections and sepsis from any source, thereby reducing overall ABx exposure and associated side effects, and improving clinical outcomes. To simplify practical application, the expert group refined the established PCT algorithms by incorporating severity of illness and probability of bacterial infection and reducing the fixed cut-offs to only one for mild to moderate and one for severe disease (0.25 μg/L and 0.5 μg/L, respectively). Further, guidance on interpretation of PCT results to initiate, withhold or discontinue ABx treatment was included. Conclusions A combination of clinical patient assessment with PCT levels in well-defined ABS algorithms, in context with continuous education and regular feedback to all ABS stakeholders, has the potential to improve the diagnostic and therapeutic management of patients suspected of bacterial infection, thereby improving ABS effectiveness.
Topics: Adult; Algorithms; Anti-Bacterial Agents; Antimicrobial Stewardship; Bacterial Infections; Biomarkers; Calcitonin; Consensus; Female; Humans; Male; Middle Aged; Procalcitonin; Sepsis
PubMed: 30721141
DOI: 10.1515/cclm-2018-1181 -
Clinical Chemistry and Laboratory... Apr 2023Procalcitonin (PCT) is a host-response biomarker that has shown clinical value for assessing the likelihood of bacterial infections and guiding antibiotic treatment.... (Review)
Review
OBJECTIVES
Procalcitonin (PCT) is a host-response biomarker that has shown clinical value for assessing the likelihood of bacterial infections and guiding antibiotic treatment. Identifying situations where PCT can improve clinical care is therefore highly important.
METHODS
The aim of this narrative review is to discuss strategies for the usage and integration of PCT into clinical routine, based on the most recent clinical evidence.
RESULTS
Although PCT should not be viewed as a traditional diagnostic marker, it can help differentiate bacterial from non-bacterial infections and inflammation states - particularly in respiratory illness. Several trials have found that PCT-guided antibiotic stewardship reduces antibiotic exposure and associated side-effects among patients with respiratory infection and sepsis. Studies have demonstrated that patient-specific decisions regarding antibiotic usage is highly complex. Factors to consider include: the clinical situation (with a focus on the pretest probability for bacterial infection), the acuity and severity of presentation, as well as PCT test results. Low PCT levels help rule out bacterial infection in patients with both low pretest probability for bacterial infection and low-risk general condition. In high-risk individuals and/or high pretest probability for infection, empiric antibiotic treatment is mandatory. Subsequent monitoring of PCT helps track the resolution of infection and guide decisions regarding early termination of antibiotic treatment.
CONCLUSIONS
PCT possesses high potential to improve decision-making regarding antibiotic treatment - when combined with careful patient assessment, evidence-based clinical algorithms, and continuous notification and regular feedback from all antibiotic stewardship stakeholders. Medical Journals such as () have played a critical role in reviewing and dissemination the high-quality evidence about assays for PCT measurement, observational research regarding association with outcomes among different populations, and interventional research proofing its effectiveness for patient care.
Topics: Humans; Procalcitonin; Calcitonin; Bacterial Infections; Sepsis; Anti-Bacterial Agents; Biomarkers
PubMed: 36317790
DOI: 10.1515/cclm-2022-1072 -
Frontiers in Endocrinology 2020The hormones amylin and calcitonin interact with receptors within the same family to exert their effects on the human organism. Calcitonin, derived from thyroid C cells,... (Review)
Review
The hormones amylin and calcitonin interact with receptors within the same family to exert their effects on the human organism. Calcitonin, derived from thyroid C cells, is known for its inhibitory effect on osteoclasts. Calcitonin of mammalian origin promotes insulin sensitivity, while the more potent calcitonin extracted from salmon additionally inhibits gastric emptying, promotes gallbladder relaxation, increases energy expenditure and induces satiety as well as weight loss. Amylin, derived from pancreatic beta cells, regulates plasma glucose by delaying gastric emptying after meal ingestion, and modulates glucagon secretion and central satiety signals in the brain. Thus, both hormones seem to have metabolic effects of relevance in the context of non-alcoholic fatty liver disease (NAFLD) and other metabolic diseases. In rats, studies with dual amylin and calcitonin receptor agonists have demonstrated robust body weight loss, improved glucose tolerance and a decreased deposition of fat in liver tissue beyond what is observed after a body weight loss. The translational aspects of these preclinical data currently remain unknown. Here, we describe the physiology, pathophysiology, and pharmacological effects of amylin and calcitonin and review preclinical and clinical findings alluding to the future potential of amylin and calcitonin-based drugs for the treatment of obesity and NAFLD.
Topics: Amylin Receptor Agonists; Animals; Body Weight; Calcitonin; Diet, High-Fat; Fatty Liver; Humans; Islet Amyloid Polypeptide; Obesity
PubMed: 33488526
DOI: 10.3389/fendo.2020.617400 -
International Journal of Molecular... Dec 2021Calciotropic hormones, parathyroid hormone (PTH) and calcitonin are involved in the regulation of bone mineral metabolism and maintenance of calcium and phosphate... (Review)
Review
Calciotropic hormones, parathyroid hormone (PTH) and calcitonin are involved in the regulation of bone mineral metabolism and maintenance of calcium and phosphate homeostasis in the body. Therefore, an understanding of environmental and genetic factors influencing PTH and calcitonin levels is crucial. Genetic factors are estimated to account for 60% of variations in PTH levels, while the genetic background of interindividual calcitonin variations has not yet been studied. In this review, we analyzed the literature discussing the influence of environmental factors (lifestyle factors and pollutants) on PTH and calcitonin levels. Among lifestyle factors, smoking, body mass index (BMI), diet, alcohol, and exercise were analyzed; among pollutants, heavy metals and chemicals were analyzed. Lifestyle factors that showed the clearest association with PTH levels were smoking, BMI, exercise, and micronutrients taken from the diet (vitamin D and calcium). Smoking, vitamin D, and calcium intake led to a decrease in PTH levels, while higher BMI and exercise led to an increase in PTH levels. In terms of pollutants, exposure to cadmium led to a decrease in PTH levels, while exposure to lead increased PTH levels. Several studies have investigated the effect of chemicals on PTH levels in humans. Compared to PTH studies, a smaller number of studies analyzed the influence of environmental factors on calcitonin levels, which gives great variability in results. Only a few studies have analyzed the influence of pollutants on calcitonin levels in humans. The lifestyle factor with the clearest relationship with calcitonin was smoking (smokers had increased calcitonin levels). Given the importance of PTH and calcitonin in maintaining calcium and phosphate homeostasis and bone mineral metabolism, additional studies on the influence of environmental factors that could affect PTH and calcitonin levels are crucial.
Topics: Animals; Calcitonin; Calcium; Homeostasis; Humans; Life Style; Parathyroid Hormone; Phosphates
PubMed: 35008468
DOI: 10.3390/ijms23010044 -
Osteoporosis International : a Journal... Jan 2016Recently an association between the use of calcitonin and cancer has been postulated. We reviewed the biological rationale and performed an additional analysis of... (Meta-Analysis)
Meta-Analysis Review
Recently an association between the use of calcitonin and cancer has been postulated. We reviewed the biological rationale and performed an additional analysis of historical data with respect to the possibility. An association cannot be excluded, but the relationship is weak and causality is unlikely. The purpose of the present study is to review the strength of association and likelihood of a causal relationship between use of calcitonin and cancer. We reviewed the evidence for this association, including the molecular signaling mechanisms of calcitonin, preclinical data, an "experiment of nature," and the results of a previous meta-analysis which showed a weak association. We performed an additional meta-analysis to incorporate the data from a novel investigational oral formulation of salmon calcitonin. Review of the literature did not identify a cellular signaling mechanism of action which might account for a causal relationship or toxicologic or postmarketing data to support the thesis. Additional clinical results incorporated into previous meta-analyses weakened but did not completely negate the possibility of association. A causal association between calcitonin use and malignancy is unlikely, as there is little biological plausibility. The preponderance of nonclinical and clinical evidence also does not favor a causal relationship.
Topics: Animals; Bone Density Conservation Agents; Calcitonin; Drug Evaluation, Preclinical; Humans; Neoplasms; Product Surveillance, Postmarketing
PubMed: 26438308
DOI: 10.1007/s00198-015-3339-z -
British Journal of Pharmacology Feb 2022The calcitonin (CT) receptor family is complex, comprising two receptors (the CT receptor [CTR] and the CTR-like receptor [CLR]), three accessory proteins (RAMPs) and...
BACKGROUND AND PURPOSE
The calcitonin (CT) receptor family is complex, comprising two receptors (the CT receptor [CTR] and the CTR-like receptor [CLR]), three accessory proteins (RAMPs) and multiple endogenous peptides. This family contains several important drug targets, including CGRP, which is targeted by migraine therapeutics. The pharmacology of this receptor family is poorly characterised in species other than rats and humans. To facilitate understanding of translational and preclinical data, we need to know the receptor pharmacology of this family in mice.
EXPERIMENTAL APPROACH
Plasmids encoding mouse CLR/CTR and RAMPs were transiently transfected into Cos-7 cells. cAMP production was measured in response to agonists in the absence or presence of antagonists.
KEY RESULTS
We report the first synthesis and characterisation of mouse adrenomedullin, adrenomedullin 2 and βCGRP and of mouse CTR without or with mouse RAMPs. Receptors containing m-CTR had subtly different pharmacology than human receptors; they were promiscuous in their pharmacology, both with and without RAMPs. Several peptides, including mouse αCGRP and mouse adrenomedullin 2, were potent agonists of the m-CTR:m-RAMP3 complex. Pharmacological profiles of receptors comprising m-CLR:m-RAMPs were generally similar to those of their human counterparts, albeit with reduced specificity.
CONCLUSION AND IMPLICATIONS
Mouse receptor pharmacology differed from that in humans, with mouse receptors displaying reduced discrimination between ligands. This creates challenges for interpreting which receptor may underlie an effect in preclinical models and thus translation of findings from mice to humans. It also highlights the need for new ligands to differentiate between these complexes.
LINKED ARTICLES
This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary).. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.
Topics: Adrenomedullin; Animals; Calcitonin; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Humans; Ligands; Mice; Migraine Disorders; Peptide Hormones; Rats; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Calcitonin
PubMed: 34289083
DOI: 10.1111/bph.15628 -
British Journal of Pharmacology May 2012The calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR) are two of the 15 human family B (or Secretin-like) GPCRs. CTR and CLR are of considerable... (Review)
Review
The calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR) are two of the 15 human family B (or Secretin-like) GPCRs. CTR and CLR are of considerable biological interest as their pharmacology is moulded by interactions with receptor activity-modifying proteins. They also have therapeutic relevance for many conditions, such as osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine and cardiovascular disease. In light of recent advances in understanding ligand docking and receptor activation in both the family as a whole and in CLR and CTR specifically, this review reflects how applicable general family B GPCR themes are to these two idiosyncratic receptors. We review the main functional domains of the receptors; the N-terminal extracellular domain, the juxtamembrane domain and ligand interface, the transmembrane domain and the intracellular C-terminal domain. Structural and functional findings from the CLR and CTR along with other family B GPCRs are critically appraised to gain insight into how these domains may function. The ability for CTR and CLR to interact with receptor activity-modifying proteins adds another level of sophistication to these receptor systems but means careful consideration is needed when trying to apply generic GPCR principles. This review encapsulates current thinking in the realm of family B GPCR research by highlighting both conflicting and recurring themes and how such findings relate to two unusual but important receptors, CTR and CLR.
Topics: Animals; Calcitonin; Calcitonin Receptor-Like Protein; Humans; Ligands; Protein Binding; Protein Conformation; Proteins; Receptors, Calcitonin
PubMed: 21649645
DOI: 10.1111/j.1476-5381.2011.01525.x -
The Journal of Biological Chemistry May 2017Calcitonin is a 32-amino acid thyroid hormone that can form amyloid fibrils. The structural basis of the fibril formation and stabilization is still debated and poorly...
Calcitonin is a 32-amino acid thyroid hormone that can form amyloid fibrils. The structural basis of the fibril formation and stabilization is still debated and poorly understood. The reason is that NMR data strongly suggest antiparallel β-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp to Phe of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel β-sheets. In this work, we first predict the structure of human calcitonin through two complementary molecular dynamics (MD) methods, finding that human calcitonin forms an α-helix. We use extensive MD simulations to compare previously proposed calcitonin fibril structures. We find that two conformations, the parallel arrangement and one of the possible antiparallel structures (with Asp and Phe aligned), are highly stable and ordered. Nonetheless, fibrils with parallel molecules show bulky loops formed by residues 1 to 7 located on the same side, which could limit or prevent the formation of larger amyloids. We investigate fibrils formed by the DFNKF peptide by simulating different arrangements of this amyloidogenic core sequence. We show that DFNKF fibrils are highly stable when assembled in parallel β-sheets, whereas they quickly unfold in antiparallel conformation. Our results indicate that the DFNKF peptide represents only partially the full-length calcitonin behavior. Contrary to the full-length polypeptide, in fact, the DFNKF sequence is not stable in antiparallel conformation, suggesting that the residue flanking the amyloidogenic peptide contributes to the stabilization of the experimentally observed antiparallel β-sheet packing.
Topics: Amyloid; Calcitonin; Humans; Molecular Dynamics Simulation; Peptides; Protein Stability; Protein Structure, Quaternary; Protein Structure, Secondary
PubMed: 28283568
DOI: 10.1074/jbc.M116.770271