Disease relevance of Zemplar

• Paricalcitol, when combined with As2O3, showed a markedly enhanced antiproliferative effect against acute myeloid leukemia (AML) cells [1].
• Importantly, hypercalcemia did not occur before achieving target serum iPTH levels in any of the paricalcitol-treated patients [2].
• Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy [3].
• Paricalcitol [19-nor-1,25-(OH)2D2] in the treatment of experimental renal bone disease [4].
• After a 15-week postoperative disease progression period, the NTX rats were further allocated to uremic control (NTX) and treatment (NTX + paricalcitol) groups, the latter of which received paricalcitol for the subsequent 12 weeks [4].

High impact information on Zemplar

• In summary, the combination of paricalcitol and As2O3 potently decreased growth and induced differentiation and apoptosis of AML cells [1].
• Paricalcitol induced monocytic differentiation of U937 AML cells, which was partially blocked by inducing expression of APL-related PML-retinoic acid receptor alpha (RARalpha) chimeric protein in the U937 cells containing a Zn2+-inducible expression vector coding for this fusion protein (PR9 cells) [1].
• In addition, paricalcitol suppressed renal TGF-beta1 and its type I receptor expression, restored vitamin D receptor abundance, and inhibited cell proliferation and apoptosis after obstructive injury [3].
• In vitro, paricalcitol abolished TGF-beta1-mediated E-cadherin suppression and alpha-smooth muscle actin and fibronectin induction in tubular epithelial cells, underscoring its ability to block directly the epithelial to mesenchymal transition (EMT) [3].
• 19-Nor-1-alpha-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis [2].

Chemical compound and disease context of Zemplar

• Phase I/II study of 19-nor-1alpha-25-dihydroxyvitamin D2 (paricalcitol) in advanced, androgen-insensitive prostate cancer [5].
• The in vitro evaluation of 25-hydroxyvitamin D3 and 19-nor-1alpha,25-dihydroxyvitamin D2 as therapeutic agents for prostate cancer [6].
• The vitamin D2 analogue 19-nor-1alpha,25-dihydroxyvitamin D2 (paricalcitol) has been tested for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease [7].
• Clinical studies have shown that paricalcitol reduces serum parathyroid hormone (PTH) levels with minimal potential to cause hypercalcemia, a common side effect of vitamin D3 therapy [7].
• Vitamin D analogs such as paricalcitol and calcitriol that activate the vitamin D receptor (VDR) provide survival benefit for Stage 5 chronic kidney disease (CKD) patients, possibly associated with a decrease in cardiovascular (CV)-related incidents [8].

Biological context of Zemplar

• Effect of hemodialysis on the pharmacokinetics of 19-nor-1alpha,25-dihydroxyvitamin D2 [7].
• Real-time RT-PCR analysis demonstrated that paricalcitol dose- and time-dependently regulated the expression of IGF1, WT1 and TGFbeta3, three genes known to modulate cell proliferation [9].
• CONCLUSIONS: Paricalcitol inhibits colony formation, induces maturation and causes cell cycle arrest in HL-60 and U937 cells [10].
• Paricalcitol inhibited colony formation of HL-60 cells in a soft agar semisolid media after 10-day incubation (estimated IC50 of 5 x 10(-9) M [11].
• Exposure to 10(-8)M paricalcitol for 72 h increased the number of cells in G0/G1 phase, and decreased the number of cells in S phase, and significantly increased the number of HL-60 cells undergoing apoptosis [11].

Anatomical context of Zemplar

• After exposure to paricalcitol at 10(-8) M for 72 h, the ability of HL-60 cells to reduce NBT was markedly increased [10].
• In order to explore paricalcitol as a potential agent against leukemia, we tested its effects on HL-60 and U937 leukemia cell lines [10].
• Thus, although both compounds have similar effects on calcium efflux from bone, at therapeutic concentrations, paricalcitol does not seem to inhibit osteoblast activity [12].
• We hypothesized that paricalcitol, a new vitamin D derivative, will have a positive effect on the immune system with minimal adverse effects on calcium homeostasis [13].
• In vitro experiments showed that paricalcitol led to greater dose-dependent thymidine uptake than calcitriol in lymphocytes isolated from either dialysis patients or control subjects [13].

Associations of Zemplar with other chemical compounds

• In well designed clinical trials, paricalcitol was as effective as calcitriol and as well tolerated in terms of the incidence of prolonged hypercalcaemia and/or elevated calcium-phosphorus product (Ca x P) [14].
• Although there was a statistically significant difference between the change from baseline to final-visit Ca levels in the paricalcitol group and the placebo group (P < 0.001), the final-visit mean Ca level in the paricalcitol group was within the normal range (9.44 mg/dL) [15].
• The ability of HL-60 cells to reduce nitroblue tetrazolium (NBT) was markedly increased after exposure to paricalcitol at 10(-8)M for 72 h [11].
• Differential effects of very high doses of doxercalciferol and paricalcitol on serum phosphorus in hemodialysis patients [16].
• 13 hemodialysis patients received 160 mcg of paricalcitol and 120 mcg of doxercalciferol on 2 separate occasions in a research center while on a low calcium, low phosphorus diet, and sevelamer alone as a phosphorus binder [16].

Gene context of Zemplar

• Recent studies in dialysis patients suggest that paricalcitol, a selective activator of the vitamin D receptor (VDR), is associated with a more favorable efficacy to side effect profile than calcitriol, with less morbidity and better survival [17].
• In vitro studies have shown that paricalcitol inhibits PTH secretion from bovine parathyroid cells in a dose-dependent manner [18].
• Production of plasminogen activator inhibitor-1 (PAI-1) by endothelial cells: differential responses to calcitriol and paricalcitol [19].
• These results show that paricalcitol safely and effectively reduces iPTH levels in hemodialysis patients with secondary HPT [15].
• RESULTS: Paricalcitol induced the maturation of HL-60 and U937 cells, as shown by increased expression of CD11b differentiation surface antigen [10].

Analytical, diagnostic and therapeutic context of Zemplar

• These studies demonstrate that paricalcitol safely and effectively suppresses iPTH levels in hemodialysis patients [2].
• Paricalcitol (19-nor-1alpha-25-dihydroxyvitamin D2), a new vitamin D analog developed for the treatment of secondary hyperparathyroidism, was evaluated in three double-blind, placebo-controlled, dose-escalating, randomized multicenter trials [2].
• Plasma concentrations of paricalcitol in the samples were determined by a specific high-performance liquid chromatography (HPLC)/radioreceptor assay (RRA) with a lower limit of quantification of 40 pg/mL [7].
• Six patients requiring HD received a single dose of paricalcitol, 0.08 microg/kg, intravenously approximately 2 hours before HD, and blood samples were collected by venipuncture immediately before and 15 minutes after HD [7].
• For those patients who started and remained on the same vitamin D product, paricalcitol-treated patients experienced 0.846 fewer hospitalizations per year and 9.17 fewer hospital days per year, P<0.001 for both [20].

References