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The Journal of Clinical Endocrinology... Oct 2023Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD) affecting mineral and bone metabolism and characterized by excessive parathyroid... (Meta-Analysis)
Meta-Analysis
CONTEXT
Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD) affecting mineral and bone metabolism and characterized by excessive parathyroid hormone (PTH) production and parathyroid hyperplasia.
OBJECTIVE
The objective of this analysis was to compare the efficacy and adverse effects of extended-release calcifediol (ERC) and paricalcitol (PCT) by assessing their effect on the biomarkers PTH, calcium, and phosphate in patients with non-dialysis CKD (ND-CKD).
METHODS
A systematic literature research was performed in PubMed to identify randomized control trials (RCTs). Quality assessment was done with the GRADE method. The effects of ERC vs PCT were compared using random effects in a frequentist setting.
RESULTS
Nine RCTs comprising 1426 patients were included in the analyses. The analyses were performed on 2 overlapping networks, due to nonreporting of outcomes in some of the included studies. No head-to-head trials were identified. No statistically significant differences in PTH reduction were found between PCT and ERC. Treatment with PCT showed statistically significant increases in calcium compared with ERC (0.2 mg/dL increase; 95% CI, -0.37 to -0.05 mg/dL). No differences in effects on phosphate were observed.
CONCLUSION
This network meta-analysis showed that ERC is comparable in lowering PTH levels vs PCT. ERC displayed avoidance of potentially clinically relevant increases in serum calcium, offering an effective and well-tolerated treatment option for the management of SHPT in patients with ND-CKD.
Topics: Humans; Calcifediol; Calcium; Ergocalciferols; Hyperparathyroidism, Secondary; Network Meta-Analysis; Parathyroid Hormone; Phosphates; Renal Insufficiency, Chronic; Randomized Controlled Trials as Topic
PubMed: 37235771
DOI: 10.1210/clinem/dgad289 -
International Journal of Molecular... Dec 2023Herein, we measured the antidiabetic and nephroprotective effects of the sodium-glucose cotransporter-2 inhibitor (empagliflozin; SGLT2i) and synthetic active vitamin D...
Herein, we measured the antidiabetic and nephroprotective effects of the sodium-glucose cotransporter-2 inhibitor (empagliflozin; SGLT2i) and synthetic active vitamin D (paricalcitol; Pcal) mono- and co-therapy against diabetic nephropathy (DN). Fifty mice were assigned into negative (NC) and positive (PC) control, SGLT2i, Pcal, and SGLT2i+Pcal groups. Following establishment of DN, SGLT2i (5.1 mg/kg/day) and/or Pcal (0.5 µg/kg/day) were used in the designated groups (5 times/week/day). DN was affirmed in the PC group by hyperglycaemia, dyslipidaemia, polyuria, proteinuria, elevated urine protein/creatinine ratio, and abnormal renal biochemical parameters. Renal SREBP-1 lipogenic molecule, adipokines (leptin/resistin), pro-oxidant (MDA/HO), pro-inflammatory (IL1β/IL6/TNF-α), tissue damage (iNOS/TGF-β1/NGAL/KIM-1), and apoptosis (TUNEL/Caspase-3) markers also increased in the PC group. In contrast, renal lipolytic (PPARα/PPARγ), adiponectin, antioxidant (GSH/GPx1/SOD1/CAT), and anti-inflammatory (IL10) molecules decreased in the PC group. Both monotherapies increased insulin levels and mitigated hyperglycaemia, dyslipidaemia, renal and urine biochemical profiles alongside renal lipid regulatory molecules, inflammation, and oxidative stress. While SGLT2i monotherapy showed superior effects to Pcal, their combination demonstrated enhanced remedial actions related to metabolic control alongside renal oxidative stress, inflammation, and apoptosis. In conclusion, SGLT2i was better than Pcal monotherapy against DN, and their combination revealed better nephroprotection, plausibly by enhanced glycaemic control with boosted renal antioxidative and anti-inflammatory mechanisms.
Topics: Mice; Animals; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2 Inhibitors; Glycemic Control; Hydrogen Peroxide; Diabetic Nephropathies; Inflammation; Antioxidants; Anti-Inflammatory Agents; Hyperglycemia; Dyslipidemias
PubMed: 38139208
DOI: 10.3390/ijms242417380 -
Clinical Cancer Research : An Official... Dec 2023Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models.
PURPOSE
Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models.
PATIENTS AND METHODS
We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2). The primary endpoint was safety, and secondary endpoints included overall response rate, progression-free survival (PFS), and overall survival (OS). Correlative objectives aimed to identify molecular predictors of response and alterations in the tumor stroma.
RESULTS
Twenty patients (10 each in DL1 and DL2) enrolled between March 2019 and May 2021. No grade 3/4 adverse events related to paricalcitol were observed. The most common toxicities were nausea, diarrhea and fatigue, which were similar in both cohorts. Three patients discontinued study after one cycle and were not radiographically evaluable. Of the remaining 17 evaluable patients, 2 had partial response and 12 had stable disease. The median PFS for response-evaluable patients in DL1 was 4.14 months, for DL2 was 4.83 months. Intent-to-treat median OS was 6.15 and 6.66 months for DL1 and DL2, respectively. Correlative studies showed increased tumor vascularity in posttreatment samples in patients receiving the higher dose of paricalcitol (DL2).
CONCLUSIONS
Paricalcitol at 7 mcg/kg/week in combination with Nal-iri/ 5-FU/LV is safely tolerated, may increase tumor vascularity and warrants further investigation.
Topics: Humans; Irinotecan; Gemcitabine; Pilot Projects; Fluorouracil; Liposomes; Pancreatic Neoplasms; Ergocalciferols; Antineoplastic Combined Chemotherapy Protocols; Leucovorin
PubMed: 37801295
DOI: 10.1158/1078-0432.CCR-23-1405 -
Healthcare (Basel, Switzerland) Dec 2022Introduction: secondary hyperparathyroidism (SHP) is frequent in patients with chronic kidney disease (CKD), particularly in those in dialysis. To treat this...
Introduction: secondary hyperparathyroidism (SHP) is frequent in patients with chronic kidney disease (CKD), particularly in those in dialysis. To treat this complication, the current options available include phosphorus restriction, phosphate binders, the inhibition of parathyroid hormone (PTH) synthesis and secretion by the supplementation of vitamin D or VDR activators, or the use of calcimimetics. Beyond the control of PTH, the effects of the treatment of SHP on other biomarkers of risk may represent an additional benefit for this population. In this study, we explore the benefits of current SHP treatment options, mainly paricalcitol and/or etelcalcetide in the inflammatory state of hemodialysis (HD) patients. Results: the study finally included 142 maintenance HD patients (5 patients were excluded) followed for 6 months (dialysis vintage 26 ± 30 months, mean age 70 years old, 73% women, 81% Spanish white, 47% diabetic). In this case, 52 patients were on regular treatment with paricalcitol for SHP and 25 patients were eligible to initiate etelcalcetide. The baseline serum levels of Ca, P, PTH, Ferritin, albumin, C-reactive protein (CRP), and other variables were measured. We found serum PTH levels showed an improvement after the treatment with etelcalcetide again paricalcitol and no treatment (p < 0.04). Of note, serum levels of CRP were significantly lower in a small group of patients (n = 11) receiving paricalcitol + etelcalcetide compared to paricalcitol or etelcalcetide alone. The proportion of patients with CRP within target ranges (≤1.0 mg/dL) increased significantly after combined treatment (p < 0.001). Conclusions: etelcalcetide proved to safely reduce the PTH levels without significant adverse events and the possibility of a synergic anti-inflammatory effect with the simultaneous use of Paricalcitol in HD patients.
PubMed: 36611532
DOI: 10.3390/healthcare11010072 -
International Journal of Molecular... Sep 2021Recently, the role of kidney pericytes in kidney fibrosis has been investigated. This study aims to evaluate the effect of paricalcitol on hypoxia-induced and...
Recently, the role of kidney pericytes in kidney fibrosis has been investigated. This study aims to evaluate the effect of paricalcitol on hypoxia-induced and TGF-β1-induced injury in kidney pericytes. The primary cultured pericytes were pretreated with paricalcitol (20 ng/mL) for 90 min before inducing injury, and then they were exposed to TGF-β1 (5 ng/mL) or hypoxia (1% O and 5% CO). TGF-β1 increased α-SMA and other fibrosis markers but reduced PDGFRβ expression in pericytes, whereas paricalcitol reversed the changes. Paricalcitol inhibited the TGF-β1-induced cell migration of pericytes. Hypoxia increased TGF-β1, α-SMA and other fibrosis markers but reduced PDGFRβ expression in pericyte, whereas paricalcitol reversed them. Hypoxia activated the HIF-1α and downstream molecules including prolyl hydroxylase 3 and glucose transporter-1, whereas paricalcitol attenuated the activation of the HIF-1α-dependent molecules and TGF-β1/Smad signaling pathways in hypoxic pericytes. The gene silencing of HIF-1α vanished the hypoxia-induced TGF-β1, α-SMA upregulation, and PDGFRβ downregulation. The effect of paricalcitol on the HIF-1α-dependent changes of fibrosis markers was not significant after the gene silencing of HIF-1α. In addition, hypoxia aggravated the oxidative stress in pericytes, whereas paricalcitol reversed the oxidative stress by increasing the antioxidant enzymes in an HIF-1α-independent manner. In conclusion, paricalcitol improved the phenotype changes of pericyte to myofibroblast in TGF-β1-stimulated pericytes. In addition, paricalcitol improved the expression of fibrosis markers in hypoxia-exposed pericytes both in an HIF-1α-dependent and independent manner.
Topics: Animals; Cells, Cultured; Ergocalciferols; Fibrosis; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Mice; Myofibroblasts; Oxidative Stress; Pericytes; Phosphorylation; Protective Agents; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta1
PubMed: 34575914
DOI: 10.3390/ijms22189751 -
Journal of Advanced Research May 2022Although the synthetic vitamin D analogue, Paricalcitol, and omega-3 Fatty acids (ω-3) alleviated diabetic nephropathy (DN), their combination was not previously...
INTRODUCTION
Although the synthetic vitamin D analogue, Paricalcitol, and omega-3 Fatty acids (ω-3) alleviated diabetic nephropathy (DN), their combination was not previously explored.
OBJECTIVES
This study measured the potential ameliorative effects of single and dual therapies of Paricalcitol and/or ω-3 against DN.
METHODS
Forty rats were assigned as follow: negative (NC) and positive (PC) controls, Paricalcitol, ω-3 and Paricalcitol + ω-3 groups. Diabetes was generated by high-fat/high-fructose diet and a single streptozotocin injection (40 mg/kg). DN was confirmed by raised fasting blood glucose (FBG), polyuria, proteinuria, and decreased urine creatinine levels. Paricalcitol intraperitoneal injections (0.25 µg/Kg/day; 5 times/week) and oral ω-3 (415 mg/kg/day; 5 times/week) started at week-9 and for eight weeks.
RESULTS
The PC group showed hyperglycaemia, dyslipidaemia, abnormal renal biochemical parameters, elevated caspase-3 expression, and increased apoptosis by TUNEL technique. The mRNAs and proteins of the pathogenic molecules (TGF-β1/iNOS) and markers of tissue damage (NGAL/KIM-1) augmented substantially in the PC renal tissues relative to the NC group. The oxidative stress (MDA/HO/protein carbonyl groups) and pro-inflammatory (IL1β/IL6/TNF-α) markers increased, whereas the anti-inflammatory (IL10) and anti-oxidative (GSH/GPx1/GR/SOD1/CAT) declined, in the PC renal tissues. The monotherapy groups were associated with ameliorated FBG, lipid profile and renal functions, and diminished TGF-β1/iNOS/NGAL/KIM-1/Caspase-3 alongside the apoptotic index than the PC group. The oxidative stress and pro-inflammatory markers decreased, whilst the anti-oxidative and anti-inflammatory molecules escalated, in the monotherapy groups than the PC group. Although the Paricalcitol renoprotective actions were better than ω-3, all the biomarkers were abnormal than the NC group. Alternatively, the Paricalcitol + ω-3 protocol exhibited the best improvements in metabolic control, renal functions, oxidative stress, inflammation, and apoptosis. However, FBG and tissue damage were persistently higher in the co-therapy group than controls.
CONCLUSIONS
Both monotherapies showed modest efficacy against DN, whereas their combination displayed boosted renoprotection, possibly by enhancing renal anti-oxidant and anti-inflammatory pathways.
Topics: Animals; Anti-Inflammatory Agents; Caspase 3; Diabetes Mellitus; Diabetic Nephropathies; Ergocalciferols; Fatty Acids, Omega-3; Female; Humans; Hydrogen Peroxide; Lipocalin-2; Male; Rats; Transforming Growth Factor beta1
PubMed: 35572411
DOI: 10.1016/j.jare.2021.08.010 -
International Journal of Molecular... Apr 2024Neointimal hyperplasia is the main cause of vascular graft failure in the medium term. Vitamin D receptor activation modulates the biology of vascular smooth muscle...
Neointimal hyperplasia is the main cause of vascular graft failure in the medium term. Vitamin D receptor activation modulates the biology of vascular smooth muscle cells and has been reported to protect from neointimal hyperplasia following endothelial injury. However, the molecular mechanisms are poorly understood. We have now explored the impact of the selective vitamin D receptor activator, paricalcitol, on neointimal hyperplasia, following guidewire-induced endothelial cell injury in rats, and we have assessed the impact of paricalcitol or vehicle on the expression of key cell stress factors. Guidewire-induced endothelial cell injury caused neointimal hyperplasia and luminal stenosis and upregulated the expression of the growth factor growth/differentiation factor-15 (GDF-15), the cytokine receptor CD74, NFκB-inducing kinase (NIK, an upstream regulator of the proinflammatory transcription factor NFκB) and the chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). Immunohistochemistry confirmed the increased expression of the cellular proteins CD74 and NIK. Paricalcitol (administered in doses of 750 ng/kg of body weight, every other day) had a non-significant impact on neointimal hyperplasia and luminal stenosis. However, it significantly decreased GDF-15, CD74, NIK and MCP-1/CCL2 mRNA expression, which in paricalcitol-injured arteries remained within the levels found in control vehicle sham arteries. In conclusion, paricalcitol had a dramatic effect, suppressing the stress response to guidewire-induced endothelial cell injury, despite a limited impact on neointimal hyperplasia and luminal stenosis. This observation identifies novel molecular targets of paricalcitol in the vascular system, whose differential expression cannot be justified as a consequence of improved tissue injury.
Topics: Animals; Hyperplasia; Rats; Ergocalciferols; Male; Chemokine CCL2; Anti-Inflammatory Agents; Neointima; Growth Differentiation Factor 15; Tunica Intima; Antigens, Differentiation, B-Lymphocyte; Endothelial Cells; Histocompatibility Antigens Class II
PubMed: 38732029
DOI: 10.3390/ijms25094814 -
Cancers Feb 2023Numerous clinical studies have been conducted to improve the outcomes of patients suffering from pancreatic cancer. Different approaches using targeted therapeutic... (Review)
Review
Numerous clinical studies have been conducted to improve the outcomes of patients suffering from pancreatic cancer. Different approaches using targeted therapeutic strategies and precision medicine methods have been investigated, and synergies and further therapeutic advances may be achieved through combinations with integrative methods. For pancreatic tumors, a particular challenge is the presence of a microenvironment and a dense stroma, which is both a physical barrier to drug penetration and a complex entity being controlled by the immune system. Therefore, the state of immunological tolerance in the tumor microenvironment must be overcome, which is a considerable challenge. Integrative approaches, such as hyperthermia, percutaneous irreversible electroporation, intra-tumoral injections, phytotherapeutics, or vitamins, in combination with standard-oncological therapies, may potentially contribute to the control of pancreatic cancer. The combined application of standard-oncological and integrative methods is currently being studied in ongoing clinical trials. An actual overview is given here.
PubMed: 36831465
DOI: 10.3390/cancers15041116 -
Scientific Reports Jul 2023To investigate the effects and mechanism of Vitamin D receptor (VDR) signaling on arteriovenous fistula (AVF) endothelial cell injury. Venous tissues of AVF stenosis...
To investigate the effects and mechanism of Vitamin D receptor (VDR) signaling on arteriovenous fistula (AVF) endothelial cell injury. Venous tissues of AVF stenosis patients were collected and analyzed, vascular morphology, reactive oxygen species (ROS), and the expression of VDR, P66Shc, fibronectin (FN), collagen-1 (Col-1) were detected. In addition, human umbilical vein endothelial cells (HUVECs) was used in in vitro studies. HUVECs was incubated with transforming growth factor-beta (TGF-β, 50 ng/ml). Aditionally, paricalcitol, VDR overexpression plasmid and Pin1 inhibitor Juglone were used to investigate the regulatory mechanism of VDR in mitochondrial ROS. The parameters of ROS (e.g. MitoSox) and the expression of FN, Col-1 were tested. Moreover, the mitochondrial translocation of P66Shc was analyzed. The expression of VDR was obviously decreased in the venous tissues of AVF stenosis patients. On the contrary, the expression of P66Shc, P-P66Shc, FN, Col-1 and 8-OHdG were increased significantly in the venous tissues of AVF stenosis patients (P < 0.05). In line with this, the level of mitochondrial ROS and the expression of P66Shc, P-P66Shc, FN, Col-1 increased obviously in HUVECs cells under TGF-β condition. Both VDR over-expression plasmid and Pin1 inhibitor Juglone could alleviate TGF-β induced endothelial injury. Mechanistically, VDR overexpression plasmid and Juglone could inhibit the expression of Pin1, and then restrain P66Shc mitochondrial translocation, eventually reduce the level of mitochondrial ROS. Our research indicated that activation of VDR could alleviate venous endothelial cell dysfunction through inhibiting Pin1-mediated mitochondrial translocation of P66Shc and consequently reducing mitochondrial ROS. It suggested that VDR signaling might be an effective target for AVF stenosis treatment.
Topics: Humans; Reactive Oxygen Species; Src Homology 2 Domain-Containing, Transforming Protein 1; Constriction, Pathologic; Human Umbilical Vein Endothelial Cells; Arteriovenous Fistula; Receptors, Calcitriol
PubMed: 37422508
DOI: 10.1038/s41598-023-37510-5 -
Iranian Journal of Medical Sciences Nov 2021Paricalcitol has been proposed for the treatment of secondary hyperparathyroidism in patients with renal failure and vitamin D deficiency (VDD); however, VDD is related...
BACKGROUND
Paricalcitol has been proposed for the treatment of secondary hyperparathyroidism in patients with renal failure and vitamin D deficiency (VDD); however, VDD is related to a range of clinical complaints. We aimed to investigate the effects of paricalcitol on body composition in VDD rats.
METHODS
Thirty adult male rats aged 10 weeks were randomly divided into three groups of 10, comprising control, VDD, and VDD plus paricalcitol (32 ng/rat intraperitoneal injection) (VDD+P), at the Animal Lab of the Endocrinology and Metabolism Research Center, Shiraz, Iran, in 2020. Body composition was assessed after three weeks via serum biochemical tests and dual-energy X-ray absorptiometry. Finally, the data were analyzed by using the paired-sample test, the one-way ANOVA, and the Tukey test.
RESULTS
Global lean mass and fat mass were lower in the VDD and VDD+P groups than in the controls (P<0.001). Global fat percentage was reduced significantly in the VDD+P group (P=0.029).
CONCLUSION
Paricalcitol reduced global fat mass and fat percentage in a rat model with VDD. Evaluation of insulin and adiponectin levels is suggested to clarify the physiology of paricalcitol in VDD states.
Topics: Animals; Body Composition; Ergocalciferols; Male; Rats; Vitamin D; Vitamin D Deficiency
PubMed: 34840387
DOI: 10.30476/ijms.2020.85368.1503