Paricalcitol

Paricalcitol is the third generation of vitamin D analog, and is a selective activator of VDR used for the treatment of secondary hyperparathyroidism. The vascular calcification process in chronic kidney disease is also directly influenced by paricalcitol. [1]
Vitamin D has important roles in physiological processes, and is primarily involved in calcium and phosphorus homeostasis and bone metabolism. Vitamin D can prevent or ameliorate inflammatory disease in animal autoimmune disease models and in patients. The mechanism by which vitamin D regulates inflammatory response appears to be dependent on the activation of regulatory CD4+T cells. [2]
The intraperitoneal administration of paricalcitol modulates peritoneal dialysis fluid (PDF)-induced peritoneal fibrosis. The treatment reduced peritoneal IL-17 levels. In vitro studies demonstrate that both CD4+ and CD8+ regulatory T cells appear to impact the regulation of IL-17. Paricalcitol treatment resulted in a significantly increased frequency of CD8+ T cells showing a regulatory phenotype. The frequency of CD4+ Tregs tends to be increased. However, paricalcitol treatment increased the number of CD4+ and CD8+ Treg cells in vivo. In conclusion, the activation of immunological regulatory mechanisms by VDR signaling could prevent or reduce fibrosis, as shown in peritoneal fibrosis induced by PDF exposure in mice. In a rat model of gentamicin-induced renal injury, paricalcitol preventes upregulated inflammatory cytokines, nuclear factor-kappaB and phosphorylated ERK1/2 expression, and adhesion molecules (monocyte chemoat¬tractant protein-1, ICAM-1, VCAM-1), and they reversed the transforming growth factor (TGF)-beta1-induced epithelial-to-mesenchymal transition process and extracel¬lular matrix accumulation. [2]
Paricalcitol has a good effect on proteinuria in non-dialysis CKD patients with secondary hyperparathyroidism treated according to Kidney Disease. After treatment with paricalcitol, statistically significant reduction (paired t-test) in 24hUA (P < 0.011) and 24hUQP (P < 0.0001) are found. The reduction of UACR was not significant (P = 0.074). In the observational period no statistically significant reduction in 24hABP was found. Treatment with 1 mg paricalcitol daily according to clinical practice in non-dialysisCKDpatients with secondary hyperparathyroidism and proteinuria significantly reduces 24hUA and 24hUQP without significant change in 24hABP. [3]
References:
[1]Darko Duplancic, Marijan Cesarik, Nikola Kolja Poljak et al. The influence of selective vitamin D receptor activator paricalcitol on cardiovascular system and cardiorenal protection.  Clinical Interventions in Aging 2013:8 149–156
[2]Guadalupe T. Gonza´lez-Mateo et al. Paricalcitol Reduces Peritoneal Fibrosis in Mice through the Activation of Regulatory T Cells and Reduction in IL-17 Production. PLOS ONE October 2014 | Volume 9 | Issue 10 | e108477
[3]Nina Hojs, Sebastjan Bevc et al. Paricalcitol Reduces Proteinuria in Non-Dialysis Chronic Kidney Disease Patients Therapeutic Apheresis and Dialysis 2013; 17(4):368–372

[Paricalcitol - a selective vitamin D receptor activator for secondary hyperparathyroidism in patients with chronic kidney disease].[Pubmed:28033603]

Wiad Lek. 2016;69(5):756-759.

Secondary hyperparathyroidism is a frequently encountered complication of chronic kidney disease (CKD) attributable to altered phosphate/calcium homeostasis, increased synthesis of phosphaturic hormone (FGF-23) and profound active vitamin D deficiency. The disorder is associated with severe bone disease, progressive cardiovascular calcification and increased mortality. Calctriol and its analogs (alphacalcidol) can suppress parathyroid activity, however at the cost of hypercalcemia and hiperphosphatemia, thus aggravating the vascular disease. During the last decade, selective vitamin D receptor activators (VDRA) have been introduced, that reduce parathyroid activity with minimal changes in calcium and phosphate metabolism. Paricalcitol is the only selective VDRA registered in Europe for the management of patients with different stadia of CKD. For today, with its efficacy and safety confirmed in several clinical trials Paricalcitol increases the vitamin D therapeutic window in this population. Furthermore, the clinical data on its possible positive effect on survival together with its reduced or even lacking experimental procalcifying effects on vessels, call for extensive research, since selective VDRA may provide additional clinical benefits going beyond mineral-bone disorder.

The vitamin D analogue paricalcitol attenuates hepatic ischemia/reperfusion injury through down-regulation of Toll-like receptor 4 signaling in rats.[Pubmed:28261302]

Arch Med Sci. 2017 Mar 1;13(2):459-469.

INTRODUCTION: Recent studies have revealed that vitamin D and its synthetic analogues have a protective effect on experimental ischemia/reperfusion (I/R) models in several organs, but little is known about its effect on the liver. The aim of this study was to evaluate the beneficial effects of vitamin D in a model of liver I/R in rats, focusing on Toll-like receptor (TLR) 4 signaling, which has been shown to be involved in I/R injury. MATERIAL AND METHODS: Twenty-four male Wistar rats were randomized into four groups: Saline + Sham, Saline + I/R, Paricalcitol + Sham, and Paricalcitol + I/R. A synthetic vitamin D2 analogue, Paricalcitol, was intraperitoneally injected 24 h prior to surgery. The animals were subjected to 60 min of partial warm ischemia (70%), followed by reperfusion for 6 h on the same day. The ischemic lobe of the liver and blood were collected for molecular biochemical analyses. RESULTS: Liver damage following I/R was diminished by pretreatment with Paricalcitol. Pretreatment with Paricalcitol decreased the levels of pro-inflammatory mediators, such as interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and macrophage migration inhibitory factor (MIF), in both plasma and liver tissue. In addition, pretreatment with Paricalcitol markedly down-regulated the expression of TLR4, HMGB1, TNF-alpha and NF-kappaB. CONCLUSIONS: The vitamin D analogue Paricalcitol attenuates hepatic I/R injury through down-regulation of the TLR4 signaling pathway and might be considered to be a potential nutritional therapeutic agent against I/R injury in the liver.

Cholecalciferol Additively Reduces Serum Parathyroid Hormone and Increases Vitamin D and Cathelicidin Levels in Paricalcitol-Treated Secondary Hyperparathyroid Hemodialysis Patients.[Pubmed:27827962]

Nutrients. 2016 Nov 5;8(11). pii: nu8110708.

BACKGROUND: Active Vitamin D analogues are used clinically for prevention and treatment of secondary hyperparathyroidism (SHPT) in hemodialysis (HD) patients. Nutritional vitamin D supplementation is used for additional local parathyroid (PTH) suppression, with lower incidence of hypercalcemia and hyperphosphatemia. This study evaluates the possible beneficial effects of combined vitamin D treatment (Paricalcitol and cholecalciferol). METHODS: Sixty HD patients with serum parathyroid hormone (iPTH) >300 pg/mL were enrolled. All patients administered 2 mcg/day of Paricalcitol and were randomly allocated into control group (placebo) or study group (cholecalciferol) for 16 weeks. Serum 25(OH)D(3), iPTH and human cathelicidin (hCAP-18) were measured at baseline and during follow-up. RESULTS: iPTH levels decreased in the study group appropriately and were more significantly decreased at 16 weeks. Study group had significantly increased 25(OH)D(3) levels. In addition, the study group had significantly increased serum hCAP-18 levels compared with control group. Correlation analysis showed a significant correlation between the percentage increase in serum hCAP-18 and 25(OH)D(3) levels. CONCLUSIONS: Cholecalciferol, in combination with Paricalcitol, additively lowers the iPTH levels in a significant number of patients after 16 weeks of supplementation. A dose of 5000 IU/week of cholecalciferol could maintain serum 25(OH)D(3) levels above 30 ng/dL as early as 8 weeks after beginning supplementation. Doubling of serum cathelicidin levels were noted after 16 weeks of cholecalciferol supplementation in 40% of study patients.

Efficacy and safety of paricalcitol in children with stages 3 to 5 chronic kidney disease.[Pubmed:28332096]

Pediatr Nephrol. 2017 Jul;32(7):1221-1232.

BACKGROUND: Elevated intact parathyroid hormone (iPTH) levels can contribute to morbidity and mortality in children with chronic kidney disease (CKD). We evaluated the pharmacokinetics, efficacy, and safety of oral Paricalcitol in reducing iPTH levels in children with stages 3-5 CKD. METHODS: Children aged 10-16 years with stages 3-5 CKD were enrolled in two phase 3 studies. The stage 3/4 CKD study characterized Paricalcitol pharmacokinetics and compared the efficacy and safety of Paricalcitol with placebo followed by an open-label period. The stage 5 CKD study evaluated the efficacy and safety of Paricalcitol (no comparator) in children with stage 5 CKD undergoing dialysis. RESULTS: In the stage 3/4 CKD study, mean peak plasma concentration and area under the time curve from zero to infinity were 0.13 ng/mL and 2.87 ng*h/((or ngxh/))mL, respectively, for 12 children who received 3 mug Paricalcitol. Thirty-six children were randomized to Paricalcitol or placebo; 27.8% of the Paricalcitol group achieved two consecutive iPTH reductions of >/=30% from baseline versus none of the placebo group (P = 0.045). Adverse events were higher in children who received placebo than in those administered Paricalcitol during the double-blind treatment (88.9 vs. 38.9%; P = 0.005). In the stage 5 CKD study, eight children (61.5%) had two consecutive iPTH reductions of >/=30% from baseline, and five (38.5%) had two consecutive iPTH values of between 150 and 300 pg/mL. Clinically meaningful hypercalcemia occurred in 21% of children. CONCLUSIONS: Oral Paricalcitol in children aged 10-16 years with stages 3-5 CKD reduced iPTH levels and the treatment was well tolerated. Results support an initiating dose of 1 mug Paricalcitol 3 times weekly in children aged 10-16 years.

Paricalcitol is a vitamin D receptor agonist, used for the prevention and treatment of secondary hyperparathyroidism (excessive secretion of parathyroid hormone) associated with chronic renal failure.

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