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Frontiers in Pharmacology 2021Inflammatory bowel disease is an immune-mediated chronic inflammatory disease of the gastrointestinal tract for which curative drugs are currently not available. This...
Inflammatory bowel disease is an immune-mediated chronic inflammatory disease of the gastrointestinal tract for which curative drugs are currently not available. This study was performed to assess the therapeutic effects of cinacalcet on dextran sulfate sodium (DSS)-induced colitis. Primary macrophages obtained from bone marrow and the macrophage cell line RAW264.7 were used to examine the inhibitory effect of cinacalcet on cytokine production, the PKCδ/ERK/P65 signaling pathway, and NF-κB P65 translocation. Colitis was induced using DSS to assess the treatment effect of cinacalcet. Bioinformatics approaches were adopted to predict potential targets of cinacalcet, and a drug affinity responsive target stability (DARTs) assay was performed to confirm binding between cinacalcet and potential target. analysis showed that cinacalcet reduced the disease activity score, prevented shortening of the colon, diminished inflammatory cell infiltration, and protected the structural integrity of the intestinal wall. Cinacalcet also reduced production of the inflammatory cytokines TNFα, IL-1β, and IL-6 in the colon and sera of mice with DSS-induced colitis. studies revealed that cinacalcet suppressed the translocation of P65 and inhibited production of the inflammatory cytokines IL-1β and IL-6. Mechanistic studies revealed that the target of cinacalcet was neurokinin-1 receptor (NK1R) and their binding was confirmed by a DARTs assay. Furthermore, the inhibition of NK-κB P65 activation was found to occur via the suppression of PKCδ/ERK/P65 signaling mediated by cinacalcet. Cinacalcet inhibits the activation of NF-κB and reduces the production of inflammatory cytokines by suppressing the PKCδ/ERK/P65 signaling pathway via targeting NK1R, suggesting that it can be used to treat inflammatory diseases, particularly colitis.
PubMed: 34880751
DOI: 10.3389/fphar.2021.735194 -
Endocrine Connections Jan 2021Palliation of symptoms related to malignancy-associated hypercalcemia (MAH) is essential and clinically meaningful for patients, given the continued poor prognosis, with... (Review)
Review
Palliation of symptoms related to malignancy-associated hypercalcemia (MAH) is essential and clinically meaningful for patients, given the continued poor prognosis, with high morbidity and mortality associated with this disease process. Historically, agents have been temporizing, having no impact on patient morbidity nor survival. We suggest that cinacalcet can be an efficacious agent to be taken orally, reducing patients' time in the hospital/clinic settings. It is well-tolerated and maintains serum calcium levels in the normal range, while targeted cancer treatments can be employed. This has a direct, major impact on morbidity. Maintaining eucalcemia can increase quality of life, while allowing targeted therapies time to improve survival. Given that our case (and others) showed calcium reduction in MAH, there is promising evidence that cinacalcet can be more widely employed in this setting. Future consideration should be given to studies addressing the efficacy of cinacalcet in calcium normalization, improvement of quality of life, and impact on survival in patients with MAH. Though the exact mechanism of action for cinacalcet's reduction in calcium in this setting is not currently known, we can still afford patients the possible benefit from it.
PubMed: 33289687
DOI: 10.1530/EC-20-0487 -
The Cochrane Database of Systematic... 2014Calcimimetic agents lower abnormal serum parathyroid hormone (PTH) levels in people who have chronic kidney disease (CKD), but the benefits and harms on patient-level... (Review)
Review
BACKGROUND
Calcimimetic agents lower abnormal serum parathyroid hormone (PTH) levels in people who have chronic kidney disease (CKD), but the benefits and harms on patient-level outcomes are uncertain. Since this review was first published in 2006 showing that evidence for calcimimetics was largely restricted to biochemical outcomes, additional studies have been conducted. This is an update of a review first published in 2006.
OBJECTIVES
To evaluate the benefits and harms of cinacalcet on patient-level outcomes in adults with CKD.
SEARCH METHODS
MEDLINE, EMBASE, CENTRAL and conference proceedings were searched for randomised controlled trials (RCTs) evaluating any calcimimetic against placebo or another agent in adults with CKD (persistent albuminuria > 30 mg/g with or without reduced glomerular filtration rate (GFR) (below 60 mL/min/1.73 m²)). We updated searches to 7 February 2013 including the Cochrane Renal Group's Specialised Register to complete this update.
SELECTION CRITERIA
We included all RCTs of a calcimimetic administered to patients with CKD for the treatment of elevated serum PTH levels.
DATA COLLECTION AND ANALYSIS
Data were extracted on all relevant patient-centred and surrogate outcomes. We summarised treatment estimates using random effects and expressed treatment effects as a risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).
MAIN RESULTS
Eighteen studies (7446 participants) compared cinacalcet in addition to standard therapy with no treatment or placebo plus standard therapy. In adults with GFR category G5 (GFR below 15 mL/min/1.73 m²) treated with dialysis, routine cinacalcet treatment had little or no effect on all-cause mortality (RR 0.97, 95% CI 0.89 to 1.05), imprecise effects on cardiovascular mortality (RR 0.67, 95% CI 0.16 to 2.87), and prevented surgical parathyroidectomy (RR 0.49, 95% CI 0.40 to 0.59) and hypercalcaemia (RR 0.23, 95% CI 0.05 to 0.97), but increased hypocalcaemia (RR 6.98, 95% CI 5.10 to 9.53), nausea (RR 2.02, 95% CI 1.45 to 2.81) and vomiting (RR 1.97, 95% CI 95% CI 1.73 to 2.24). Cinacalcet decreased serum PTH (MD -281.39 pg/mL, 95% CI -325.84 to -234.94) and calcium (MD -0.87 mg/dL, 95% CI -0.96 to -0.77) levels, but had little or no effect on serum phosphorous levels (MD -0.23 mg/dL, 95% CI -0.58 to 0.12).Data were sparse for adults with GFR categories G3a to G4 (GFR 15 to 60 mL/min/1.73 m²) and kidney transplant recipients.Overall, based on GRADE criteria, evidence for cinacalcet in adults with GFR category G5 treated with dialysis (mortality, parathyroidectomy, hypocalcaemia, and nausea) is of high or moderate quality. High quality evidence suggests "further research is very unlikely to change our confidence in the estimate of treatment effect" and moderate quality evidence is "further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate". Information for adults with less severe CKD GFR category G3a to G4 is of low or very low quality. This means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
AUTHORS' CONCLUSIONS
Routine cinacalcet therapy reduced the need for parathyroidectomy in adults treated with dialysis and elevated PTH levels but does not improve all-cause or cardiovascular mortality. Cinacalcet increases risks of nausea, vomiting and hypocalcaemia, suggesting harms may outweigh benefits in this population.
Topics: Calcimimetic Agents; Calcium; Cardiovascular Diseases; Cause of Death; Cinacalcet; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Naphthalenes; Parathyroid Hormone; Phosphorus; Randomized Controlled Trials as Topic; Renal Dialysis
PubMed: 25490118
DOI: 10.1002/14651858.CD006254.pub2 -
Endocrinology, Diabetes & Metabolism... 2017Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients. It is associated with a poor prognosis, since it reflects an advanced...
UNLABELLED
Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients. It is associated with a poor prognosis, since it reflects an advanced cancer stage. Among all cancer in females, breast cancer is the most common malignancy, and it has the highest prevalence of hypercalcemia. Approximately 70% of patients with breast cancer have bone metastases and 10% of them will have hypercalcemia as a complication at some point in the disease. Herein, we report a 69-year-old female patient with metastatic breast cancer, who developed severe hypercalcemia in the course of her disease and was diagnosed with humoral hypercalcemia of malignancy (HHM). Intense hydration along with corticoisteroids and antiresorptive medication (calcitonin, bisphosphonates and denosumab) were administered to the patient. Despite the above treatment, serum calcium levels remain elevated and calcimimetic cinacalcet was added. Upon discontinuation of cinacalcet, calcium levels were raised and returned back to the normal levels following re-initiation of the calcimimetic. Her calcium level restored to normal, and she was discharged with the following medical treatment: denosumab monthly, and cinacalcet at a titrated dose of 90 mg per day. The patient is followed as an outpatient and 11 months later, her calcium level remained within the normal range.
LEARNING POINTS
Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients.Breast cancer has the highest prevalence of hypercalcemia.The cornerstone of therapy remains the intense hydration and intravenous bisphosphonates (preferably zoledronic acid).In case of persistent hypercalcemia of malignancy, the administration of calcimimetic cinacalcet could be an additional effective therapeutic option.
PubMed: 29399364
DOI: 10.1530/EDM-17-0118 -
The Journal of Clinical Endocrinology... Jul 2022
Topics: Calcimimetic Agents; Cinacalcet; Humans; Parathyroidectomy; Renal Dialysis
PubMed: 35427422
DOI: 10.1210/clinem/dgac211 -
Endocrinology Feb 2022Parathyroid hormone (PTH) replacement is a promising approach in the management of hypoparathyroidism but long-acting analogues need to be developed. To date, animal...
CONTEXT
Parathyroid hormone (PTH) replacement is a promising approach in the management of hypoparathyroidism but long-acting analogues need to be developed. To date, animal models for testing PTH required parathyroidectomy by surgery. We have developed a nonsurgical rodent hypoparathyroid model and tested a delayed-clearance PTH molecule (DC-PTH).
OBJECTIVE
The aim of this study was to use cinacalcet to suppress calcium levels in normal rats and to reverse these effects with the administration of PTH or PTH analogues.
METHODS
Male Wistar rats were gavaged with either 30 mg/kg cinacalcet-HCl (cinacalcet) or vehicle only. Animals were then dosed with either single or repeated subcutaneous doses of PTH 1-34 or a DC-PTH at 20 nmol/kg. Control animals received vehicle only. Serum samples were analyzed for ionized calcium (iCa), phosphate, PTH, and DC-PTH. A pharmacokinetic-pharmacodynamic (PK-PD) model was built for cinacalcet, PTH 1-34, and DC-PTH using Phoenix64.
RESULTS
Cinacalcet reduced iCa levels between 2 and 24 hours, returning to baseline by 72 hours post dose with nadir at 8 hours (analysis of variance P < .001), associated with a fall in rat PTH. For phosphate there was a variable biphasic response. Single-dose PTH abrogated the cinacalcet-induced fall in iCa for up to 2 hours. DC-PTH prevented the fall in iCa from 4 hours post dose and gave a prolonged response, with iCa levels quicker to return to baseline than controls. DC-PTH has a half-life of 11.5 hours, approximately 44 times longer than human PTH 1-34. The PK-PD models defined the reproducible effect of cinacalcet on iCa and that DC-PTH had prolonged biological activity.
CONCLUSION
The administration of cinacalcet provides a robust and reproducible nonsurgical animal model of hypoparathyroidism. DC-PTH holds promise for the treatment of hypoparathyroidism in the future.
Topics: Animals; CHO Cells; Calcium; Cinacalcet; Cricetulus; Disease Models, Animal; Hypoparathyroidism; Male; Parathyroid Glands; Parathyroid Hormone; Parathyroidectomy; Phosphates; Rats; Rats, Wistar; Treatment Outcome
PubMed: 34940833
DOI: 10.1210/endocr/bqab239 -
Nuclear Medicine and Biology 2021Parathyroid hyperplasia is a disease characterized by overactive parathyroid glands secreting increased levels of parathyroid hormone. Surgical removal of the...
INTRODUCTION
Parathyroid hyperplasia is a disease characterized by overactive parathyroid glands secreting increased levels of parathyroid hormone. Surgical removal of the parathyroid glands is the standard treatment but requires precise pre-operative localization of the glands. However, currently available imaging modalities show limited sensitivity. Since positron emission tomography (PET) is a molecular imaging technique with high accuracy and sensitivity, our aim was to develop a new PET tracer for overactive parathyroid glands imaging by radiolabelling cinacalcet, a drug binding to the calcium-sensing receptor of the parathyroid glands.
METHODS
[F]Cinacalcet was synthesized by copper-catalysed [F]trifluoromethylation of a boronic acid precursor using high molar activity [F]fluoroform. Ex vivo biodistribution and metabolism were evaluated in 12 healthy male Wistar rats at 5, 15, 45 and 90 min. PET scans were performed at baseline and after blocking with NPS R-568.
RESULTS
[F]Cinacalcet was obtained in an overall radiosynthesis time of 1 h with a radiochemical purity of 98 ± 1%, a radiochemical yield of 8 ± 4% (overall, n = 7, corrected for decay) and a molar activity of 40 ± 11 GBq/μmol (n = 7, at EOS). The ex vivo biodistribution showed uptake in the thyroid and parathyroid glands as well as in other glands such as adrenals, salivary glands and pancreas. The tracer was rapidly cleared from the blood via liver and kidneys and showed fast metabolism. PET images confirmed uptake in the target organ. However, in a blocking study with NPS R-568 specific binding of [F]cinacalcet to the CaSR could not be confirmed.
CONCLUSIONS
[F]Cinacalcet was successfully synthesized. First in vivo experiments in healthy rats showed uptake of the tracer in the target organ and fast metabolism, encouraging further in vivo evaluation of this tracer.
Topics: Cinacalcet
PubMed: 34743064
DOI: 10.1016/j.nucmedbio.2021.10.003 -
Medical Science Monitor : International... Aug 2022BACKGROUND Cinacalcet is a calcium-sensing receptor agonist that is clinically approved for the treatment of secondary hyperparathyroidism in chronic kidney disease and...
Label-Free Mass Spectrometry-Based Quantitative Proteomics to Evaluate the Effects of the Calcium-Sensing Receptor Agonist Cinacalcet on Protein Expression in Rat Brains and Livers.
BACKGROUND Cinacalcet is a calcium-sensing receptor agonist that is clinically approved for the treatment of secondary hyperparathyroidism in chronic kidney disease and hypercalcemia in patients with parathyroid carcinoma. This study aimed to use quantitative mass spectrometry-based label-free proteomics to evaluate the effects of cinacalcet on protein expression in rat brains and livers. MATERIAL AND METHODS We randomly assigned 18 Wistar rats to 2 groups: an untreated control group (n=6) and a group treated with cinacalcet at a dose corresponding to the maximum dose used in humans (2 mg/kg/body weight, 5 days/week) divided into 7-day (n=6) and 21-day (n=6) treatment subgroups. A mass-spectrometry-based label-free quantitative proteomics approach using peptides peak area calculation was used to evaluate the changes in protein expression in examined tissues. Bioinformatics analysis of quantitative proteomics data was done using MaxQuant and Perseus environment. RESULTS No changes in protein expression were revealed in the 7-day treatment subgroup. We detected 10 upregulated and 3 downregulated proteins in the liver and 1 upregulated protein in the brain in the 21-day treatment subgroup compared to the control group. Based on Gene Ontology classification, all identified differentially expressed proteins were indicated as molecular functions involved in the enzyme regulator activity (36%), binding (31%), and catalytic activity (19%). CONCLUSIONS These findings indicate that long-term cinacalcet therapy can impair phase II of enzymatic detoxication and can cause disturbances in blood hemostasis, lipid metabolism, and inflammatory mediators or contribute to the acceleration of cognitive dysfunction; therefore, appropriate patient monitoring should be considered.
Topics: Animals; Brain; Calcium; Cinacalcet; Humans; Liver; Mass Spectrometry; Naphthalenes; Parathyroid Hormone; Proteomics; Rats; Rats, Wistar; Receptors, Calcium-Sensing
PubMed: 35941808
DOI: 10.12659/MSM.937338 -
Cell Reports May 2018Voltage-gated sodium channels (VGSCs) are strategically positioned to mediate neuronal plasticity because of their influence on action potential waveform. VGSC function...
Voltage-gated sodium channels (VGSCs) are strategically positioned to mediate neuronal plasticity because of their influence on action potential waveform. VGSC function may be strongly inhibited by local anesthetic and antiepileptic drugs and modestly modulated via second messenger pathways. Here, we report that the allosteric modulators of the calcium-sensing receptor (CaSR) cinacalcet, calindol, calhex, and NPS 2143 completely inhibit VGSC current in the vast majority of cultured mouse neocortical neurons. This form of VGSC current block persisted in CaSR-deficient neurons, indicating a CaSR-independent mechanism. Cinacalcet-mediated blockade of VGSCs was prevented by the guanosine diphosphate (GDP) analog GDPβs, indicating that G-proteins mediated this effect. Cinacalcet inhibited VGSCs by increasing channel inactivation, and block was reversed by prolonged hyperpolarization. Strong cinacalcet inhibition of VGSC currents was also present in acutely isolated mouse cortical neurons. These data identify a dynamic signaling pathway by which G-proteins regulate VGSC current to indirectly modulate central neuronal excitability.
Topics: Allosteric Regulation; Animals; Animals, Newborn; Cinacalcet; GTP-Binding Proteins; Guanosine Triphosphate; Ion Channel Gating; Mice; Neocortex; Neurons; Receptors, Calcium-Sensing; Voltage-Gated Sodium Channel Blockers; Voltage-Gated Sodium Channels
PubMed: 29847805
DOI: 10.1016/j.celrep.2018.04.109 -
Journal of Bone and Mineral Research :... Feb 2022The possible mechanisms underlying the quantitative and qualitative effects of cinacalcet on bone were explored in a chronic kidney disease-mineral and bone disorder...
Cinacalcet Improves Bone Parameters Through Regulation of Osteoclast Endoplasmic Reticulum Stress, Autophagy, and Apoptotic Pathways in Chronic Kidney Disease-Mineral and Bone Disorder.
The possible mechanisms underlying the quantitative and qualitative effects of cinacalcet on bone were explored in a chronic kidney disease-mineral and bone disorder (CKD-MBD) mouse model in relation to the influence of the interactions among the osteoclast (OC) endoplasmic reticulum (ER) stress, autophagy and apoptosis pathways on OC differentiation. Body weight and biochemical parameters improved significantly in the CKD + cinacalcet groups compared to the CKD group. Micro-computed tomography (μCT) revealed both cortical and trabecular parameters deteriorated significantly in the CKD group and were reversed by cinacalcet in a dose-dependent manner. Nanoindentation analysis of bone quality proved that both cortical hardness and elastic modulus improved significantly with high dose cinacalcet treatment. In vitro studies revealed that cinacalcet inhibited receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB (RANK)-induced OC differentiation in a concentration-dependent manner through a close interaction between activation of caspase-related apoptosis, reversal of OC autophagy through the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) pathways, and attenuation of the OC ER stress/CREBH/NFATc1 signaling pathway. Cinacalcet improves both bone quantity and bone quality in CKD mouse model and inhibits OC differentiation through regulation of the interactions among the apoptosis, ER stress, and autophagy pathways within OCs. © 2021 American Society for Bone and Mineral Research (ASBMR).
Topics: Animals; Autophagy; Cell Differentiation; Chronic Kidney Disease-Mineral and Bone Disorder; Cinacalcet; Endoplasmic Reticulum Stress; Mice; Osteoclasts; RANK Ligand; X-Ray Microtomography
PubMed: 34633122
DOI: 10.1002/jbmr.4459