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American Journal of Physiology. Renal... Mar 2011Despite an only minor reduction in the glomerular filtration rate, uninephrectomy (UNX) markedly accelerates the rate of growth of atherosclerotic plaques in ApoE-/-...
Despite an only minor reduction in the glomerular filtration rate, uninephrectomy (UNX) markedly accelerates the rate of growth of atherosclerotic plaques in ApoE-/- mice. It has been suggested that vitamin D receptor (VDR) activation exerts an antiproliferative effect on vascular smooth muscle cells, but the side effects may limit its use. To assess a potentially different spectrum of actions, we compared the effects of paricalcitol and calcitriol on remodeling and calcification of the aortic wall in sham-operated and UNX ApoE-/- mice on a diet with normal cholesterol content. Sham-operated and UNX mice were randomly allotted to treatment with solvent, calcitriol (0.03 μg/kg) or paricalcitol (0.1 μg/kg) 5 times/wk intraperitoneally for 10 wk. Semithin (0.6 μm) sections of the aorta were analyzed by 1) morphometry, 2) immunohistochemistry, and 3) Western blotting of key proteins involved in vascular calcification and growth. Compared with sham-operated animals (5.6 ± 0.24), the wall-to-lumen ratio (x100) of the aorta was significantly higher in solvent- and calcitriol-treated UNX animals (6.64 ± 0.27 and 7.17 ± 0.81, respectively, P < 0.05), but not in paricalcitol-treated UNX (6.1 5 ± 0.32). Similar differences were seen with respect to maximal plaque height. Expression of transforming growth factor (TGF)-β1 in aortic intima/plaque was also significantly higher in UNX solvent and UNX calcitriol compared with sham-operated and UNX paricalcitol animals. Treatment with both paricalcitol and calcitriol caused significant elevation of VDR expression in the aorta. While at the dose employed paricalcitol significantly reduced TGF-β expression in plaques, calcitriol in contrast caused significant vascular calcification and elevated expression of related proteins (BMP2, RANKL, and Runx2).
Topics: Animals; Aorta; Apolipoproteins E; Bone Density Conservation Agents; Bone Morphogenetic Protein 2; Calcinosis; Calcitriol; Cholesterol; Core Binding Factor Alpha 1 Subunit; Disease Models, Animal; Ergocalciferols; Kidney; Male; Mice; Mice, Knockout; Nephrectomy; Plaque, Atherosclerotic; RANK Ligand; Receptors, Calcitriol; Transforming Growth Factor beta1
PubMed: 21159735
DOI: 10.1152/ajprenal.00042.2010 -
World Journal of Gastroenterology Jul 2009Pancreatic cancer is ranked fifth among cancer-related deaths worldwide with a 5-year survival rate of less than 5%. Currently, surgery is the only effective therapy.... (Review)
Review
Pancreatic cancer is ranked fifth among cancer-related deaths worldwide with a 5-year survival rate of less than 5%. Currently, surgery is the only effective therapy. However, most patients are diagnosed in the late stage and are not suitable for receiving curative surgery. Moreover, pancreatic cancer doesn't respond well to traditional chemotherapy and radiotherapy, leaving little effective treatment for advanced pancreatic cancer cases. 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the biologically active form of vitamin D(3), was originally identified during studies of calcium and bone metabolism, though it is now recognized that it exerts biological effects in almost every tissue in the body. Abundant evidence has shown that 1alpha,25(OH)(2)D(3) has antiproliferative, apoptotic, pro-differentiation and antiangiogensis effects in many types of cancer cells in vivo and in vitro, including breast, prostate, and colon. Similarly, the antitumor growth effect of 1alpha,25(OH)(2)D(3) on pancreatic cells has been demonstrated. The clinical use of 1alpha,25(OH)(2)D(3) is impeded by the lethal side effects of hypercalcemia and hypercalciuria. Therefore, 1alpha,25(OH)(2)D(3) analogs, which are either equipotent or more potent than 1alpha,25(OH)(2)D(3) in inhibiting tumor cell growth but with fewer hypercalcemic and hypercalciuric side effects, have been developed for the treatment of different cancers. Recently, a pre-clinical study demonstrated that a less calcemic analog of 1alpha,25(OH)(2)D(3), 19-nor-1alpha,25(OH)(2)D(2) (Paricalcitol), is effective in inhibiting tumor growth in vitro and in vivo, via upregulation of p21 and p27 tumor suppressor genes. Studies on the anti-tumor effects of a more potent analog of Paricalcitol are underway. 1alpha,25(OH)(2)D(3) and its analogs are potentially attractive novel therapies for pancreatic cancer.
Topics: Humans; Pancreatic Neoplasms; Vitamin D
PubMed: 19610135
DOI: 10.3748/wjg.15.3349 -
Danish Medical Journal Feb 2012Vitamin D analogs are used for treatment of secondary hyperparathyroidism in patients with chronic kidney disease in order to prevent renal osteodystrophy, bone fracture... (Comparative Study)
Comparative Study Randomized Controlled Trial
Vitamin D analogs are used for treatment of secondary hyperparathyroidism in patients with chronic kidney disease in order to prevent renal osteodystrophy, bone fracture and pain. Calcium and phosphate levels increase with increasing doses of vitamin D analogs and are associated with increased risk of vascular calcification and cardiovascular morbidity and mortality. Therefore, in everyday clinical practice, hypercalcemia and hyperphosphatemia often limits the ability to suppress secondary hyperparathyroidism in patients with chronic kidney disease. In Denmark, alfacalcidol and paricalcitol are the most frequently used vitamin D analogs. The present thesis describes the first comparative study of alfacalcidol and paricalcitol and their ability to control the disturbances in the mineral metabolism in hemodialysis patients. In a multicenter randomised 2 × 16-week cross-over study (n = 86), with a 6-week wash out period preceding and between treatment periods, intravenous alfacalcidol and paricalcitol were given by forced titration (50% dose increase) every second week, until parathyroid hormone were sufficiently suppressed or ionised calcium and/or phosphate levels were elevated. Due to the presence of a period effect, only data from the initial 16-week intervention period (n = 80) were available for statistical tests of effect on parathyroid hormone. The proportion of patients achieving a 30% decrease in parathyroid hormone over the last four weeks was similar in the two groups (alfacalcidol 82%, paricalcitol 93% (p = 0.180)). A significant interaction effect between baseline parathyroid hormone and treatment was found (p = 0.012), suggesting the effects of alfacalcidol to be independent of baseline parathyroid hormone level, whereas paricalcitol to be more efficient at low than at high baseline levels. There were no differences in incidence of hypercalcemia and hyperphosphatemia. FGF23 increases renal phosphate excretion and decreases levels of 1,25-dihydroxyvitamin D. FGF23 is elevated in hemodialysis patients by mechanisms not fully understood. We explored the influence of alfacalcidol and paricalcitol on FGF23 in stored blood samples from the beginning and the end of each treatment period. FGF23 increased significantly and equally during treatment with alfacalcidol and paricalcitol. Furthermore, we found baseline FGF23 to predict PTH levels after 16 weeks of vitamin D analog treatment. Overall, alfacalcidol and paricalcitol are equal candidates for treatment of disturbances in mineral metabolism in hemodialysis patients.
Topics: Aged; Animals; Bone Density Conservation Agents; Cross-Over Studies; Ergocalciferols; Fibroblast Growth Factor-23; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Middle Aged; Parathyroid Hormone; Renal Dialysis
PubMed: 22293059
DOI: No ID Found -
The British Journal of Radiology Aug 2012The aim of the study was to assess the effect of paricalcitol on the experimental contrast-induced nephropathy (CIN) model. We hypothesised that paricalcitol may prevent...
OBJECTIVES
The aim of the study was to assess the effect of paricalcitol on the experimental contrast-induced nephropathy (CIN) model. We hypothesised that paricalcitol may prevent CIN.
METHODS
32 Wistar albino rats were divided into four groups (n=8 each): control group, paricalcitol group, CIN group and paricalcitol plus CIN group. Paricalcitol (0.4 µg kg(-1) day(-1)) was given intraperitoneally for 5 consecutive days prior to induction of CIN. CIN was induced at day 4 by intravenous injection of indometacin (10 mg kg(-1)), Nω-nitro-L-arginine methyl ester (L-NAME, 10 mg kg(-1)) and meglumine amidotrizoate (6 ml kg(-1)). Renal function parameters, oxidative stress biomarkers, histopathological findings and vascular endothelial growth factor (VEGF) immunoexpression were evaluated.
RESULTS
The paricalcitol plus CIN group had lower mean serum creatinine levels (p=0.034) as well as higher creatinine clearance (p=0.042) than the CIN group. Serum malondialdehyde and kidney thiobarbituric acid-reacting substances levels were significantly lower in the paricalcitol plus CIN group than in the CIN group (p=0.024 and p=0.042, respectively). The mean scores of tubular necrosis (p=0.024), proteinaceous casts (p=0.038), medullary congestion (p=0.035) and VEGF immunoexpression (p=0.018) in the paricalcitol plus CIN group were also significantly lower.
CONCLUSION
This study demonstrates the protective effect of paricalcitol in the prevention of CIN in an experimental model.
Topics: Analysis of Variance; Animals; Antioxidants; Biomarkers; Contrast Media; Ergocalciferols; Immunohistochemistry; Kidney Diseases; Male; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Renal Agents; Vascular Endothelial Growth Factor A
PubMed: 22815410
DOI: 10.1259/bjr/16327485 -
Clinical Therapeutics Mar 1999Patients with end-stage renal disease commonly develop secondary hyperparathyroidism. Calcitriol may be administered to such patients to decrease the synthesis and... (Review)
Review
Patients with end-stage renal disease commonly develop secondary hyperparathyroidism. Calcitriol may be administered to such patients to decrease the synthesis and secretion of parathyroid hormone (PTH) and to help maintain calcium and phosphorus homeostasis. However, the doses of calcitriol required to suppress serum PTH concentrations can lead to hypercalcemia or hyperphosphatemia in many patients undergoing hemodialysis. Paricalcitol is a new vitamin D analogue that is safe and effective in suppressing elevated concentrations of PTH in patients with established hyperparathyroidism who are maintained on chronic hemodialysis. As with vitamin D, the biologic action of paricalcitol is mediated through activation of the vitamin D receptor (VDR). The VDR functions as a ligand-induced transcription factor regulating the rate of expression of genes that are involved in controlling not only calcium homeostasis and bone remodeling but also hormone secretion, inhibition of cell growth, and induction of cell differentiation. In vitro studies have shown that paricalcitol inhibits PTH secretion from bovine parathyroid cells in a dose-dependent manner. Studies in renally insufficient rats demonstrated that paricalcitol caused approximately 10 times less elevation of serum calcium concentrations than calcitriol. In clinical studies, paricalcitol effectively decreased PTH by about 60% over a 12-week period. Mean serum concentrations of calcium were significantly increased but remained within the normal range. There were occasional (5/414 determinations) transient elevations in serum calcium above the upper limit of normal in some (5/401) patients. Serum phosphorus values did not change significantly compared with baseline, although they tended to be slightly higher in the paricalcitol-treated group than in the group receiving placebo. Elevations of the calcium-times-phosphorus product were relatively few but occurred more often in the paricalcitol than in the placebo group. The terminal half-life of paricalcitol was 5 to 7 hours in healthy subjects; in patients undergoing hemodialysis, it was 14 hours. Adverse events associated with paricalcitol use included, among others, chills, feeling unwell, fever, sepsis, palpitations, dry mouth, gastrointestinal bleeding, nausea, vomiting, edema, light-headedness, and pneumonia. Paricalcitol should be considered as an alternative to calcitriol in the treatment of patients who are undergoing maintenance hemodialysis for end-stage renal disease, as it has a decreased potential to induce hypercalcemia and hyperphosphatemia. Additional studies are required to determine the long-term effects of therapy.
Topics: Animals; Clinical Trials, Phase III as Topic; Ergocalciferols; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Renal Dialysis
PubMed: 10321413
DOI: 10.1016/S0149-2918(00)88299-5 -
Kidney Research and Clinical Practice Jun 2017Vitamin D is considered to exert a protective effect on various renal diseases but its underlying molecular mechanism remains poorly understood. This study aimed to...
BACKGROUND
Vitamin D is considered to exert a protective effect on various renal diseases but its underlying molecular mechanism remains poorly understood. This study aimed to determine whether paricalcitol attenuates inflammation and apoptosis during lipopolysaccharide (LPS)-induced renal proximal tubular cell injury through the prostaglandin E (PGE) receptor EP4.
METHODS
Human renal tubular epithelial (HK-2) cells were pretreated with paricalcitol (2 ng/mL) for 1 hour and exposed to LPS (1 μg/mL). The effects of paricalcitol pretreatment in relation to an EP4 blockade using AH-23848 or EP4 small interfering RNA (siRNA) were investigated.
RESULTS
The expression of cyclooxygenase-2, PGE, and EP4 were significantly increased in LPS-exposed HK-2 cells treated with paricalcitol compared with cells exposed to LPS only. Paricalcitol prevented cell death induced by LPS exposure, and the cotreatment of AH-23848 or EP4 siRNA offset these cell-protective effects. The phosphorylation and nuclear translocation of p65 nuclear factor-kappaB (NF-κB) were decreased and the phosphorylation of Akt was increased in LPS-exposed cells with paricalcitol treatment. AH-23848 or EP4 siRNA inhibited the suppressive effects of paricalcitol on p65 NF-κB nuclear translocation and the activation of Akt. The production of proinflammatory cytokines and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were attenuated by paricalcitol in LPS exposed HK-2 cells. The cotreatment with an EP4 antagonist abolished these anti-inflammatory and antiapoptotic effects.
CONCLUSION
EP4 plays a pivotal role in anti-inflammatory and antiapoptotic effects through Akt and NF-κB signaling after paricalcitol pretreatment in LPS-induced renal proximal tubule cell injury.
PubMed: 28680822
DOI: 10.23876/j.krcp.2017.36.2.145 -
Polish Archives of Internal Medicine Dec 2017INTRODUCTION Secondary hyperparathyroidism (SHPT) is a common hormonal disorder associated with chronic kidney disease (CKD). The treatment of SHPT should lead to...
INTRODUCTION Secondary hyperparathyroidism (SHPT) is a common hormonal disorder associated with chronic kidney disease (CKD). The treatment of SHPT should lead to a reduction in parathormone concentrations by calcimimetics or active vitamin D administration and stabilization of calciumand phosphate metabolism. In the event of failure of conservative treatment, complete or partial parathyroid resection should be considered. OBJECTIVES The aim of the study was to assess the beneficial effects of a combination treatment with paricalcitol and cinacalcet in comparison with paricalcitol alone. PATIENTS AND METHODS A total of 64 hemodialyzed patients (mean [SD] age, 58 [16] years) with inadequate control of serum parathyroid hormone levels were treated with intravenous paricalcitol, while 16 patients simultaneously received oral cinacalcet. Laboratory tests (intact parathormone [iPTH], calcium, phosphorus) were performed on a monthly basis. In the study, iPTH, calium, phosphorus, and alkaline phosphatase levels were assessed at baseline and after 24 weeks of treatment with paricalcitol alone or in combination with cinacalcet. RESULTS In both groups, a significant decrease in the iPTH level was observed. Although paricalcitol affects calcium levels, no hypercalcemia was observed. The combination treatment did not result in a significant lowering of iPTH levels in comparison with paricalcitol alone. CONCLUSIONS Treatment of SHPT with intravenous paricalcitol in patients on hemodialysis is effective and has a good safety profile. The combination of paricalcitol and cinacalcet does not improve the outcomes. Moreover, the combined treatment does not affect calcium and phosphorus concentrations. The cost‑effectiveness of therapy should also be considered.
Topics: Adult; Aged; Calcium-Regulating Hormones and Agents; Cinacalcet; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome
PubMed: 29067991
DOI: 10.20452/pamw.4124 -
Medicina 2014The apoptosis and renal fibrosis are processes inherent to the chronic kidney disease, and consequently a clear deregulation of the mitochondrial respiratory mechanism... (Review)
Review
The apoptosis and renal fibrosis are processes inherent to the chronic kidney disease, and consequently a clear deregulation of the mitochondrial respiratory mechanism has been described in patients with chronic renal disease associated to an increase of the oxidative stress. The injured tubular cells linked to the interstitial macrophages and myofibroblasts produce cytokines and growth factors that encourage an inflammatory condition, inducing the apoptosis of the tubular cells and enabling the accumulation of the extracellular matrix. The angiotensin II has a central role in the renal fibrogenesis leading to a rapid progression of the chronic kidney disease. The growing levels of the angiotensin II induce pro-inflammatory cytokines, the activation of NF-kB, adhesion molecules,chemokines, growth factors, and oxidative stress. The current evidence suggests that the angiotensin II increases the mitochondrial oxidative stress, regulates the induction of the apoptosis and conditions the inflammatory process. Therefore the mitochondria and the oxidative stress would play a determinant role in the renal inflammatory process. Finally, this review summarizes our present knowledge regarding the possible mechanisms that would contribute to the apoptosis conditioned by inflammation and/or oxidative stress during the chronic renal disease. Additionally, a new concept of the anti-inflammatory tools is proposed to regulate the mitochondrial oxidative stress that would directly affect the inflammatory process and apoptosis. This concept could have positive consequences on the treatment of renal inflammatory pathologies and related diseases.
Topics: Angiotensin II; Animals; Apoptosis; Cytoprotection; Ergocalciferols; Humans; Kidney Cortex; Kidney Tubules; Mitochondria; NF-kappa B; Nephritis; Oxidative Stress; Renal Insufficiency, Chronic; Vitamins
PubMed: 24918679
DOI: No ID Found -
Polish Archives of Internal Medicine Dec 2017
Topics: Cinacalcet; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Renal Dialysis
PubMed: 29272256
DOI: 10.20452/pamw.4170 -
PloS One 2017Vitamin D associates with the plasma concentration of the endogenous inhibitor of the nitric oxide system asymmetric dimethyl arginine (ADMA) and cross-sectional studies... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vitamin D associates with the plasma concentration of the endogenous inhibitor of the nitric oxide system asymmetric dimethyl arginine (ADMA) and cross-sectional studies in CKD patients treated with the vitamin D receptor activator paricalcitol show that plasma ADMA is substantially less than in those not receiving this drug.
METHODS
In the frame of a randomized, double-blind, placebo controlled trial, the Paracalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY), we investigated whether vitamin D receptor activation by paricalcitol (2 μg/day x 12 weeks) affects the plasma concentration of ADMA and symmetric dimethyl arginine (SDMA) in 88 patients with stage 3 to 4 CKD.
RESULTS
Paricalcitol produced the expected small rise in serum calcium and phosphate and a marked PTH suppression. However, ADMA [Paricalcitol: baseline 0.75 μMol/L (95%CI: 0.70-0.81), 12 week 0.72 μMol/L (95%CI: 0.66-0.78); Placebo: baseline 0.75 μMol/L (95%CI: 0.70-0.90) 12 weeks 0.70 μMol/L (95%CI: 0.66-0.74)] and SDMA [Paricalcitol: baseline 0.91 μMol/L (95%CI: 0.82-1.00), 12 week 0.94 μMol/L (95%CI: 0.82-0.1.06); Placebo: baseline 0.91 μMol/L (95%CI: 0.82-1.06) 12 weeks 0.99 μMol/L (95%CI: 0.88-1.10)] remained unchanged during the trial and 2 weeks after stopping these treatments.
CONCLUSIONS
Paricalcitol does not modify plasma ADMA and SDMA in patients with stage 3-4 CKD. The apparent beneficial effects of paricalcitol on ADMA registered in cross-sectional studies is likely attributable to confounding by indication rather than to a true effect of this drug on ADMA metabolism.
Topics: Aged; Arginine; Calcium; Cross-Sectional Studies; Double-Blind Method; Ergocalciferols; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Placebos; Vitamin D
PubMed: 28976989
DOI: 10.1371/journal.pone.0185449