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Current Vascular Pharmacology Mar 2014Compared to such native vitamin D agents as cholecalciferol (D3), egocalciferol (D2), and calcifediol (25- hydroxy vitamin D3, which need 1-alpha hydroxylase to be... (Review)
Review
Compared to such native vitamin D agents as cholecalciferol (D3), egocalciferol (D2), and calcifediol (25- hydroxy vitamin D3, which need 1-alpha hydroxylase to be activated, 1-alpha-ergocalciferol, also known as doxercalciferol, is a synthetically manufactured vitamin D analog used for treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). Doxercalciferol exhibits more structural similarities to plant-based vitamin D2, ergocalciferol, than with animal-based vitamin D3, cholecalciferol. Because doxercalciferol does not have a 25-hydroxy group, it requires 25-hydroxylation by the liver to be activated, a process independent of kidneys. Doxercalciferol shares these features with its D3 equivalent, 1-alpha-hydroxy-cholecalciferol (alphacalcidol), both of which are activated hepatically and independent of renal or extra-renal 1-alpha hydroxylase. In experimental and clinical studies of CKD and SHPT, doxercalciferol effectively reduces parathyroid hormone levels and restores abnormal bone pathology. The efficacy of doxercalciferol is similar to other vitamin D analogs including calcitriol, alphacalcidol, paricalcitol (19-nor-1,25-dihydroxyvitamin D2 ) and maxacalcitol (1,25-dihydroxy-22-oxa-vitamin D3). The frequency and magnitude of hypercalcemia or hyperphosphatemia observed with doxercalciferol treatment may be less than calcitriol or alphacalcidol therapy but not less than such vitamin D-mimetics as paricalcitol or maxacalcitol. Doxercalciferol can be used for the treatment of SHPT across all ranges of CKD, particularly if hypercalcemia is of concern. There are limited data as to whether doxercalciferol confers greater efficacy or better outcome and survival than other vitamin D analogs and D-mimetics. Whereas further studies are warranted, doxercalciferol can safely be used for correction of SHPT in the entire spectrum of CKD.
Topics: Animals; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Molecular Structure; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 23713877
DOI: 10.2174/15701611113119990025 -
Current Vascular Pharmacology Mar 2014Numerous drugs with vitamin D activity are available for clinical use and it may not be easy for the nonspecialist to select the most suitable for the individual... (Review)
Review
Numerous drugs with vitamin D activity are available for clinical use and it may not be easy for the nonspecialist to select the most suitable for the individual patient. In this paper we review the main characteristics of the available drugs and provide evidence about any potential specific clinical indications, with special emphasis on renal patients, in order to facilitate the optimal choice. Natural vitamin D products (i.e. those identical to natural metabolites) are first examined, followed by the most frequently used synthetic molecules (i.e. bioengineered molecules not-existing in nature), which are generally indicated as " analogs". Either cholecalciferol, ergocalciferol or calcifediol can be employed in subjects with normal renal function and in CKD stage 3-5 patients to correct vitamin D deficiency and improve, respectively, age- or growth-related bone disease and secondary hyperparathyroidism. Calcifediol can be considered more rapid and effective. In all cases, especially with increasing doses, the risk of hypercalcemia must be taken into account. Calcitriol, which can be regarded as the active hormonal form of vitamin D, has the most potent hypercalcemic effect in both normal and renal failure patients. In renal patients calcitriol is a potent inhibitor of parathyroid activity, but the risk of hypercalcemia, now regarded as harmful, is evident whenever pharmacologic doses are used. Alfacalcidol, requiring 25-hydroxylation to become the active hormonal form of vitamin D3, is prescribed in normal subjects to treat osteoporosis and in renal patients to cure hyperparathyroidism and renal bone disease. Doxercalciferol, transformed into the active hormonal form of vitamin D2 following 25-hydroxylation, is mostly studied in renal patients in whom it cures secondary hyperparathyroidism, possibly with a lower calcemic effect than calcitriol. Paricalcitol, a vitamin D2 analog not requiring activation, has been specifically developed to suppress PTH in renal patients with a limited calcemic effect. As such it is now regarded as a powerful drug useful to treat even severe cases of secondary hyperparathyroidism. Importantly, reno-protective and cardio-protective effects of this analog have been recently evaluated by means of randomized clinical trials in renal patients with partially positive renal effects and negative cardiac results, thus additional studies are needed for confirmation. 22-oxacalcitriol, a vitamin D3 analog with a limited calcemic effect available in Japan, is mostly used in renal patients affected by secondary hyperparathyroidism. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. In summary, available drugs with vitamin D like activity are not all the same either in terms of pharmacological actions, and side-effects. They have specific characteristics that may be useful to know in order to operate the best choice in the individual patient.
Topics: Animals; Calcifediol; Calcitriol; Cholecalciferol; Ergocalciferols; Humans; Hydroxycholecalciferols; Vitamin D
PubMed: 23713876
DOI: 10.2174/15701611113119990024 -
American Journal of Nephrology 2013Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is characterized by vascular calcification, thrombosis and intense inflammation. Prior research has...
BACKGROUND
Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is characterized by vascular calcification, thrombosis and intense inflammation. Prior research has shown that statins have anticalcification, antithrombotic and antiinflammatory properties; however, the association between statin use and CUA has not been investigated.
METHODS
This matched case-control study included 62 adult maintenance hemodialysis (HD) patients with biopsy-confirmed CUA diagnosed between the years 2002 and 2011 (cases). All cases were hospitalized at the time of diagnosis. Controls (n = 124) were hospitalized maintenance HD patients without CUA (matched to cases by gender and timing of hospitalization). Univariate and multivariable logistic regression models were applied to compute odds ratio (OR) and 95% confidence intervals (CI) for CUA in statin users, and also to examine previously described associations.
RESULTS
The mean age of cases was 58 years. Most were females (68%), and of white race (64%). Statin use was more common in controls than in cases (39 vs. 19%, p < 0.01). Statin use was associated with lower odds of CUA in unadjusted (OR 0.38, 95% CI 0.18-0.79) and adjusted (OR 0.20, 95% CI 0.05-0.88) analyses. Hypercalcemia (OR 2.25, 95% CI 1.14-4.43), hypoalbuminemia (OR 5.73, 95% CI 2.79-11.77), calcitriol use (OR 5.69, 95% CI 1.02-31.77) and warfarin use (OR 4.30, 95% CI 1.57-11.74) were positively associated with CUA in adjusted analyses whereas paricalcitol and doxercalciferol were not (OR 1.33, 95% CI 0.54-3.27).
CONCLUSION
Statin use may be negatively associated with odds of CUA. Further large prospective studies with attention to potential confounders are needed to confirm these findings.
Topics: Case-Control Studies; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Skin Diseases, Vascular; Uremia; Vascular Calcification
PubMed: 23548843
DOI: 10.1159/000348806 -
The Prostate Jun 2013Prostate cancer is the most common malignancy and second leading cause of cancer related deaths in American men supporting the study of prostate cancer chemoprevention.... (Randomized Controlled Trial)
Randomized Controlled Trial
Phase II open label, multi-center clinical trial of modulation of intermediate endpoint biomarkers by 1α-hydroxyvitamin D2 in patients with clinically localized prostate cancer and high grade pin.
BACKGROUND
Prostate cancer is the most common malignancy and second leading cause of cancer related deaths in American men supporting the study of prostate cancer chemoprevention. Major risk factors for this disease have been associated with low serum levels of vitamin D. Here, we evaluate the biologic activity of a less calcemic vitamin D analog 1α-hydroxyvitamin D2 [1α-OH-D2] (Bone Care International, Inc.) in patients with prostate cancer and high grade prostatic intraepithelial neoplasia (HG PIN).
METHODS
Patients with clinically organ-confined prostate cancer and HG PIN were randomized to 1α-OH-D2 versus placebo for 28 days prior to radical prostatectomy. Intermediate endpoint biomarkers included serum vitamin D metabolites, TGFß 1/2, free/total PSA, IGF-1, IGFBP-3, bFGF, and VEGF. Tissue endpoints included histology, MIB-1 and TUNEL staining, microvessel density and factor VIII staining, androgen receptor and PSA, vitamin D receptor expression and nuclear morphometry.
RESULTS
The 1α-OH-D2 vitamin D analog was well tolerated and could be safely administered with good compliance and no evidence of hypercalcemia over 28 days. While serum vitamin D metabolite levels only slightly increased, evidence of biologic activity was observed with significant reductions in serum PTH levels. TGF-ß2 was the only biomarker significantly altered by vitamin D supplementation. Whether reduced TGF-ß2 levels in our study is an early indicator of response to vitamin D remains unclear.
CONCLUSIONS
While further investigation of vitamin D may be warranted based on preclinical studies, results of the present trial do not appear to justify evaluation of 1α-OH-D2 in larger clinical prostate cancer prevention studies.
Topics: Biomarkers, Tumor; Endpoint Determination; Ergocalciferols; Fibroblast Growth Factor 2; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Kallikreins; Male; Microvessels; Middle Aged; Placebos; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Vascular Endothelial Growth Factor A; Vitamin D
PubMed: 23335089
DOI: 10.1002/pros.22644 -
Journal of the American Society of... Dec 2012Vitamin D and its analogs have antiproteinuric activity and podocytes express the vitamin D receptor, but whether vitamin D signaling in podocytes accounts for this...
Vitamin D and its analogs have antiproteinuric activity and podocytes express the vitamin D receptor, but whether vitamin D signaling in podocytes accounts for this renoprotection is unknown. To investigate this question, we used the 2.5 kb podocin promoter to target Flag-tagged human vitamin D receptor (hVDR) to podocytes in DBA/2J mice. After the induction of diabetes with streptozotocin, transgenic mice had less albuminuria than wild-type controls. In transgenic mice, a low dose of the vitamin D analog doxercalciferol prevented albuminuria, markedly attenuated podocyte loss and apoptosis, and reduced glomerular fibrosis, but it had little effect on the progression of diabetic nephropathy in wild-type mice. Moreover, reconstitution of VDR-null mice with the hVDR transgene in podocytes rescued VDR-null mice from severe diabetes-related renal damage. In culture, 1,25-dihydroxyvitamin D suppressed high-glucose-induced apoptosis of podocytes by blocking p38- and ERK-mediated proapoptotic pathways. Taken together, these data provide strong evidence that vitamin D/VDR signaling in podocytes plays a critical role in the protection of the kidney from diabetic injury.
Topics: Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Female; Humans; Hyperglycemia; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Inbred DBA; Mice, Knockout; Podocytes; Pregnancy; Promoter Regions, Genetic; Receptors, Calcitriol
PubMed: 23123403
DOI: 10.1681/ASN.2012040383 -
Trends and variations in intravenous vitamin D use among hemodialysis patients in the United States.Renal Failure 2013Injectable vitamin D agents are commonly used to manage secondary hyperparathyroidism in dialysis patients. Yet, there are few data documenting the trends and geographic... (Comparative Study)
Comparative Study
Injectable vitamin D agents are commonly used to manage secondary hyperparathyroidism in dialysis patients. Yet, there are few data documenting the trends and geographic variations in the use of these agents in large, representative samples. We sought to describe patterns and variations in the use of vitamin D formulations (calcitriol, paricalcitol, and doxercalciferol) in hemodialysis patients. We studied patients in the United States Renal Data System between January1999 and December 2008 with Medicare as a primary payer. Annual percentages of patients treated with each type of formulation were tabulated by race, sex, and age at dialysis initiation. The geographical distribution of vitamin D dose per patient was mapped at the state level. Intravenous vitamin D use has increased sharply from 1999 to 2008 with 83.9% of patients treated with any vitamin D formulation in 2008. The use of calcitriol has declined since 1999, going from being administered in 58.6% of patients in 1999 to 1.8% in 2008. Paricalcitol was found to be the overwhelmingly preferred formulation during the study years. In 2008, the average dose among black patients was 84% greater than among white patients (136 mcg vs. 73.6 mcg). Higher doses of vitamin D were administered to patients in the southern region of the country. Vitamin D use has increased and parallels the rise in use of paricalcitol and doxercalciferol. Given the variations in use and known pharmacologic differences in vitamin D formulations, future research should focus on whether the formulations differentially affect patient outcomes.
Topics: Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Incidence; Injections, Intravenous; Male; Middle Aged; Renal Dialysis; Retrospective Studies; Treatment Outcome; United States; Vitamin D; Vitamins
PubMed: 23088380
DOI: 10.3109/0886022X.2012.734260 -
MicroRNA (Shariqah, United Arab... 20121,25-dihydroxyvitamin D3 (1,25D) has been shown to influence differentiation, cell proliferation and cell death in cultured leukemia cells. However, its clinical use is...
Involvement of microRNA181a in differentiation and cell cycle arrest induced by a plant-derived antioxidant carnosic acid and vitamin D analog doxercalciferol in human leukemia cells.
1,25-dihydroxyvitamin D3 (1,25D) has been shown to influence differentiation, cell proliferation and cell death in cultured leukemia cells. However, its clinical use is limited by its hypercalcemic effects. An analog of 1,25D, doxercalciferol (1-D2), has anti-tumor activity, with markedly reduced calcemic effects, which makes it a potential agent for clinical treatment of AML. Previous studies suggested that the combination of 1,25D with other agents, such as plant-derived antioxidants, can have additive or synergistic anti-cancer activities in leukemia cells. Here we report that 1-D2 induced monocytic differentiation of HL60 and U937 cells, and that the antioxidant carnosic acid (CA) enhanced 1-D2 induced differentiation and cell cycle arrest. MicroRNA181a (miR181a) expression was also reduced after exposure to CA/1-D2. Since the cell cycle regulator p27Kip1 has been shown to be a target of miR181a, we modulated miR181a levels to determine if it plays a role in CA/1-D2 induced differentiation and cell cycle arrest in AML cells. We found that transfection of antisense miR181a potentiated CA/1-D2-induced cell differentiation, while the transfection of precursor of miR181a partially inhibited the effect of CA/1-D2 on the differentiation. These findings imply that miR181a has a role in CA/1-D2- induced differentiation and cell cycle arrest of HL60 and U937 cells, and shows a broader participation of miR181a in cell cycle control in leukemia cells.
Topics: Abietanes; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Cell Cycle Checkpoints; Cell Differentiation; Drug Synergism; Ergocalciferols; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Leukemia; MicroRNAs; Plant Extracts; U937 Cells; Vitamins
PubMed: 25048087
DOI: 10.2174/2211536611201010026 -
Journal of Community Hospital Internal... 2012Vitamin D has become an area of intensive scrutiny, both in medical and lay literature. However, there are limited data to suggest proper repletion regimens for those...
INTRODUCTION
Vitamin D has become an area of intensive scrutiny, both in medical and lay literature. However, there are limited data to suggest proper repletion regimens for those patients who have hypovitaminosis D. Consequently, various methods are used in clinical practice. The aim of this study was to assess the efficacy of various treatment strategies for hypovitaminosis D in an ambulatory internal medicine practice.
METHODS
A retrospective chart review between October 2005 and June 2010 of a suburban internal medicine practice was performed via query of the electronic medical record (Centricity, General Electric Healthcare, UK). Patients with a 25-hydroxyvitamin D concentration less than 32 mg/dl were identified and treated. Treatment success was defined as 25-hydroxyvitamin D concentrations greater than 32 mg/dl. Statistical analysis to assess changes in vitamin D level controlling for season, comorbidities, and demographics were used.
RESULTS
A total of 607 treatment episodes were identified, with 395 excluded due to lack of follow-up vitamin D level within 16 weeks, no treatment documented, topical treatment, doxercalciferol treatment, or non-compliance. Of the remaining patients, there were 212 treatment instances on 178 patients. Ergocalciferol 50,000 international units (IU) was used most frequently (71.4% of the time.). A higher initial vitamin D level was positively associated with treatment success (adjusted odds ratio = 1.11, p=0.002). Increased doses of ergocalciferol increased the likelihood of treatment success (p=0.0011). Seasonal variation was related to posttreatment 25-hydroxyvitamin D concentration as was body mass index (BMI) (p=0.003 and p=0.044).
CONCLUSION
Pretreatment levels of 25-hydroxyvitamin D, BMI, season, and vitamin D dose are predictors of successful hypovitaminosis D treatment. Our data suggest that patients with initial 25-hydroxyvitamin D concentrations of <20 should be treated with a higher total dose of ergocalciferol than 50,000 IU for 8 weeks. Further studies, including prospective, randomized trials, are needed to determine an optimal treatment protocol to account for the numerous variables.
PubMed: 23882348
DOI: 10.3402/jchimp.v2i1.10494 -
Nephrology (Carlton, Vic.) Mar 2012Vitamin D deficiency is highly prevalent in end-stage renal disease and has been associated with atherosclerosis, endothelial dysfunction and left ventricular...
AIM
Vitamin D deficiency is highly prevalent in end-stage renal disease and has been associated with atherosclerosis, endothelial dysfunction and left ventricular hypertrophy. Although activated vitamin D has shown to be cardioprotective, the cardiovascular benefits of nutritional vitamin D (i.e. ergocalciferol or cholecalciferol) have not been explored in the dialysis population. The aim of this investigation was to evaluate the effect of ergocalciferol therapy on vascular adhesion molecules, markers of inflammation and atherosclerosis among haemodialysis patients.
METHODS
This was a pilot study of matched haemodialysis patients. For every patient enrolled taking ergocalciferol, an age and race matched control was recruited. Predialysis blood samples were collected and assayed for adhesion molecules (soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), E-selectin and P-selectin), inflammatory cytokines (interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α)), oxLDL-β(2) GPI and IgG anticardiolipin.
RESULTS
A total of 40 haemodialysis patients were studied (20 on ergocalciferol therapy, 20 not receiving ergocalciferol therapy). Patients taking ergocalciferol had higher 25-hydroxyvitamin D levels compared with those not taking ergocalciferol. Even though doxercalciferol usage and dosing was similar between groups, plasma sVCAM-1, sICAM-1 and P-selectin concentrations were lower among ergocalciferol treated patients. No significant differences in E-selectin, IL-6, TNF-α, oxLDL-β(2) GPI or anticardiolipin antibody levels were observed.
CONCLUSION
Patients receiving ergocalciferol had lower plasma levels of vascular adhesion molecules despite equivalent use of activated vitamin D therapy. Future investigations should confirm the role of nutritional vitamin D therapy, in addition to activated D therapy, in haemodialysis patients and the potential vascular benefits of these agents.
Topics: Adult; Aged; Dietary Supplements; Ergocalciferols; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Lipoproteins, LDL; Male; Middle Aged; P-Selectin; Pilot Projects; Renal Dialysis; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vitamins; beta 2-Glycoprotein I
PubMed: 22181351
DOI: 10.1111/j.1440-1797.2011.01555.x -
Journal of Cardiac Failure Dec 2011Activated vitamin D analog, paricalcitol, has been shown to attenuate the development of cardiac hypertrophy in Dahl salt sensitive (DSS) rats. To determine whether an...
BACKGROUND
Activated vitamin D analog, paricalcitol, has been shown to attenuate the development of cardiac hypertrophy in Dahl salt sensitive (DSS) rats. To determine whether an antihypertrophic effect is class specific, we tested if doxercalciferol (a pro-hormone vitamin D2 analog) could also attenuate the development of cardiac hypertrophy in DSS rats.
METHODS AND RESULTS
Male DSS rats were fed a high salt (HS) diet for 6 weeks beginning at 6 weeks of age. Doxercalciferol was administered intraperitoneally at 150 ng, 3 times per week (Monday, Wednesday, Friday) for 6 weeks. Pathological and echocardiographic findings demonstrated that rats on HS diet with doxercalciferol administration had significant decrease in cardiac hypertrophy and improved cardiac function compared to the HS + vehicle. In addition, there was a significant decrease in plasma brain natriuretic peptide (BNP) level and tissue atrial natriuretic factor (ANF) mRNA level with doxercalciferol treatment. Doxercalciferol also significantly reduced the level of protein kinase C-α (PKCα) suggesting that PKC-mediated cardiac hypertrophy may be associated with vitamin D deficiency.
CONCLUSIONS
Administration of doxercalciferol attenuated the development of HS diet induced cardiac hypertrophy and cardiac dysfunction in DSS rats.
Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; Ergocalciferols; Heart Failure; Hypertrophy, Left Ventricular; Male; Natriuretic Peptide, Brain; RNA, Messenger; Rats; Rats, Inbred Dahl; Signal Transduction; Ultrasonography; Vitamins
PubMed: 22123370
DOI: 10.1016/j.cardfail.2011.08.006