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Leukemia & Lymphoma Jan 2008We conducted a phase II trial of doxercalciferol, a vitamin D2 analogue, in 15 patients with MDS. Each received doxercalciferol 12.5 microg orally daily for 12 weeks....
We conducted a phase II trial of doxercalciferol, a vitamin D2 analogue, in 15 patients with MDS. Each received doxercalciferol 12.5 microg orally daily for 12 weeks. Nine of 15 patients completed the prescribed course and of these, six had stable disease. No patient had a response (IWG criteria) and overall eight patients experienced progressive disease while on therapy. Two patients with chronic myelomonocytic leukemia (CMML) had a marked rise in monocytes on study. Overall the treatment was well tolerated. One patient was removed from study due to hypercalcemia. We conclude that short-term treatment with doxercalciferol has limited activity in patients with MDS.
Topics: Aged; Aged, 80 and over; Disease Progression; Ergocalciferols; Humans; Hypercalcemia; Leukemia, Myelomonocytic, Chronic; Middle Aged; Myelodysplastic Syndromes; Treatment Failure
PubMed: 18203012
DOI: 10.1080/10428190701713648 -
Peritoneal Dialysis International :... 2015Limited well-controlled research exists examining the impact of different formulations of oral vitamin D on clinical outcomes in dialysis patients, specifically those on... (Comparative Study)
Comparative Study
BACKGROUND
Limited well-controlled research exists examining the impact of different formulations of oral vitamin D on clinical outcomes in dialysis patients, specifically those on peritoneal dialysis. For this retrospective mortality analysis, we compared mortality rates of patients on 3 of the most commonly prescribed vitamin D agents.
METHODS
We examined 2 years (7/1/2008 to 6/30/2010) of oral medication records of peritoneal dialysis patients from a large US dialysis organization. Patients were identified whose physicians prescribed a single form of vitamin D (calcitriol, paricalcitol, or doxercalciferol) for ≥ 90% of all patient-months. We excluded incident patients (< 90 days on dialysis) and patients whose physicians treated < 5 peritoneal dialysis patients at a dialysis facility, and we assessed mortality.
RESULTS
The analysis inclusion criteria identified 1,707 patients. The subset in this analysis included 12.6% of all prevalent peritoneal dialysis patients and 11.8% of prevalent patient-months. Patients with physicians who predominately prescribed calcitriol had a lower mortality rate: 9.33 (confidence interval (CI) 7.06, 11.60) deaths per 100 patient-years than the doxercalciferol, 12.20 (CI 9.34, 15.06) or paricalcitol, 12.27 (CI 9.27, 15.28) groups. However, these differences were not statistically significant. A Cox proportional hazards model, adjusting for differences in age, vintage, gender, race, body mass index, and comorbidities also showed no significant differences.
CONCLUSIONS
For this peritoneal dialysis population, instrumental variable analyses showed no significant difference in mortality in patients taking the most common oral vitamin D formulations (calcitriol, doxercalciferol, paricalcitol).
Topics: Adult; Aged; Calcitriol; Cause of Death; Cohort Studies; Confidence Intervals; Dietary Supplements; Drug Administration Schedule; Ergocalciferols; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Prognosis; Proportional Hazards Models; Reference Values; Retrospective Studies; Risk Assessment; Survival Analysis; Treatment Outcome; Vitamin D
PubMed: 24584595
DOI: 10.3747/pdi.2012.00324 -
Kidney International Oct 2002Calcitriol, 1,25-(OH)(2)D(3) (1,25D), the most active metabolite of vitamin D, has been used in the treatment of secondary hyperparathyroidism (SH) because it controls...
BACKGROUND
Calcitriol, 1,25-(OH)(2)D(3) (1,25D), the most active metabolite of vitamin D, has been used in the treatment of secondary hyperparathyroidism (SH) because it controls parathyroid gland growth and suppresses parathyroid hormone (PTH) synthesis and secretion. Due to the calcemic and phosphatemic actions of 1,25D, two analogs with potentially less side effects, 19-nor-1,25-(OH)(2)D(2) (19-nor) and 1alpha(OH)D(2) (1alphaD(2)) are currently being used in the treatment of SH.
METHODS
This study compares the effects of these two analogs on calcium (Ca) and phosphorus (P) metabolism in normal, uremic, and parathyroidectomized (PTX) rats. Using doses of 50 to 250 ng of 19-nor or 1alphaD(2), experiments were conducted in normal and uremic rats.
RESULTS
In uremic rats, 19-nor did not increase plasma Ca or P while 1alphaD2 caused a dose-dependent increase in both. In addition, while the Ca x P product remained unchanged in 19-nor-treated rats, it increased progressively with 1alphaD(2)administration. In metabolic studies in normal rats treated with vehicle, 10 ng of 1,25D, 100 ng of 19-nor or 100 ng 1alphaD(2), intestinal calcium absorption and urinary calcium excretion were significantly higher in 1alphaD(2)-treated rats compared to those receiving 19-nor. Similar results were seen for intestinal phosphorus absorption and urinary phosphorus excretion. Finally, the skeletal response to these two analogs was tested in PTX rats fed a calcium-deficient diet and treated daily with 100 ng of 19-nor or 1alphaD(2). The increase in plasma calcium in 1alphaD2-treated rats was markedly higher than in those receiving 19-nor. Similar results were seen in plasma phosphorus when these studies were repeated using a phosphorus-deficient diet.
CONCLUSIONS
These studies demonstrate that when given in large doses to rats 19-nor is less calcemic and phosphatemic than 1alphaD(2). The lower Ca x P product in 19-nor treated rats may be an important consideration in patient therapy. Further studies in patients are necessary to define the clinical applicability of these differences.
Topics: Animals; Calcium; Ergocalciferols; Female; Male; Parathyroidectomy; Phosphorus; Rats; Rats, Sprague-Dawley; Uremia
PubMed: 12234297
DOI: 10.1111/j.1523-1755.2002.kid573.x -
Bone Oct 2019Impaired osteoblast and osteocyte maturation contribute to mineralization defects and excess FGF23 expression in CKD bone. Vitamin D sterols decrease osteoid...
Impaired osteoblast and osteocyte maturation contribute to mineralization defects and excess FGF23 expression in CKD bone. Vitamin D sterols decrease osteoid accumulation and increase FGF23 expression; these agents also increase osteoblast maturation in vitro but a link between changes in bone cell maturation, bone mineralization, and FGF23 expression in response to vitamin D sterols has not been established. We evaluated unmineralized osteoid accumulation, osteocyte maturity markers (FGF23: early osteocytes; sclerostin: late osteocytes), and osteocyte apoptosis in iliac crest of 11 pediatric dialysis patients before and after 8 months of doxercalciferol therapy. We then evaluated the effect of 1,25(OH)vitamin D on in vitro maturation and mineralization of primary osteoblasts from dialysis patients. Unmineralized osteoid accumulation decreased while numbers of early (FGF23-expressing) increased in response to doxercalciferol. Osteocyte apoptosis was low but increased with doxercalciferol. Bone FGF23 expression correlated with numbers of early, FGF23-expressing, osteocytes (r = 0.83, p < 0.001). In vitro, 1,25(OH)vitamin D increased expression of the mature osteoblast marker osteocalcin (BGLAP) but only very high (100 nM) concentrations affected in vitro osteoblast mineralization. High doses (10 and 100 nM) of 1,25(OH)vitamin D also increased the ratio of RANKL/OPG expression in CKD osteoblasts. Vitamin D sterols directly stimulate osteoblast maturation. They also increase osteocyte turnover and increase osteoblast expression of osteoclast differentiation factors, thus likely modulating osteoblast/osteoclast/osteocyte coupling. By increasing numbers of early osteocytes, vitamin D sterols increase FGF23 expression in CKD bone.
Topics: Adolescent; Apoptosis; Bone and Bones; Calcification, Physiologic; Cell Count; Cell Differentiation; Cells, Cultured; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Male; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Renal Insufficiency, Chronic; Sterols; Vitamin D
PubMed: 31377240
DOI: 10.1016/j.bone.2019.07.026 -
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 -
British Journal of Pharmacology Sep 2011Vitamin D receptor (VDR) modulators (VDRMs) such as calcitriol, paricalcitol and doxercalciferol are commonly used to manage hyperparathyroidism secondary to chronic...
BACKGROUND AND PURPOSE
Vitamin D receptor (VDR) modulators (VDRMs) such as calcitriol, paricalcitol and doxercalciferol are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). CKD patients experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRM therapy may be associated with cardio-renal protective and survival benefits for CKD patients. However, hypercalcaemia remains a serious side effect for current VDRMs, which leads to the need for frequent dose titration and serum Ca (calcium) monitoring. Significant clinical benefits can be derived from a VDRM with cardiovascular protective effects without the hypercalcaemic liability.
EXPERIMENTAL APPROACH
Male Sprague-Dawley rats were 5/6 nephrectomized and 6 weeks later, after they had established uraemia, elevated parathyroid hormone levels, endothelial dysfunction and left ventricular hypertrophy, the rats were treated with VS-105, a novel VDRM. The effects of VS-105 were also tested in cultured HL-60 cells.
KEY RESULTS
VS-105 induced HL-60 cell differentiation with an EC₅₀ value at 11.8 nM. Treatment (i.p., 3× a week over a period of 2 weeks) of the 5/6 nephrectomized rats by VS-105 (0.004-0.64 µg·kg⁻¹) effectively suppressed serum parathyroid hormone without raising serum Ca or phosphate levels. Furthermore, 2 weeks of treatment with VS-105 improved endothelium-dependent aortic relaxation and attenuated left ventricular abnormalities in a dose range that did not affect serum Ca levels. Similar results were obtained when VS-105 was administered i.p. or by oral gavage.
CONCLUSIONS AND IMPLICATIONS
VS-105 exhibits an overall therapeutic product profile that supports expanded use in CKD to realize the cardiovascular protective effects of VDR activation.
Topics: Animals; Aorta; Calcitriol; Calcium; Cardiotonic Agents; Cell Differentiation; Drug Administration Routes; Endothelium; Ergocalciferols; HL-60 Cells; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Kidney Failure, Chronic; Male; Myocytes, Cardiac; Nephrectomy; Parathyroid Hormone; Phosphates; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Tumor Cells, Cultured; Vasodilation; Ventricular Dysfunction, Left
PubMed: 21557735
DOI: 10.1111/j.1476-5381.2011.01473.x -
The Journal of Steroid Biochemistry and... Mar 2019Standard therapy for Acute Myeloid Leukemia (AML) is rarely curative, and several suggested improvements have had little success so far. We have reported that in an in...
Standard therapy for Acute Myeloid Leukemia (AML) is rarely curative, and several suggested improvements have had little success so far. We have reported that in an in vitro model of a potential therapeutic regimen for AML, the activity of cytarabine (AraC) is enhanced by a sequential treatment with a combination of the vitamin D2 analog Doxercalciferol (D2) and the plant-derived antioxidant carnosic acid (CA). Importantly, the enhancement occurred selectively in patient-derived AML blasts, but not in the normal bone marrow cells. We now demonstrate that TXNIP, previously known as Vitamin D up-regulated protein 1 (VDUP1) [PMID 808674] plays a part in signaling cell death (CD) in this regimen. This is shown by the reduced CD when TXNIP protein levels are decreased by the CRISPR/CAS9 or RNAi technology. Further, we show that direct activation of ASK1 kinase by TXNIP is required for the optimal transmission of the CD signal to apoptotic machinery, regulated by JNK and BIM. These studies provide a rationale for a projected clinical trial of this vitamin D-based new therapeutic regimen for AML.
Topics: Abietanes; Antineoplastic Agents; Antioxidants; Carrier Proteins; Cell Line, Tumor; Cell Survival; Cytarabine; Ergocalciferols; Humans; Leukemia, Myeloid, Acute; MAP Kinase Kinase Kinase 5; Mitogen-Activated Protein Kinase 8; Signal Transduction; Vitamins
PubMed: 30508644
DOI: 10.1016/j.jsbmb.2018.11.015 -
The Journal of Steroid Biochemistry and... Mar 2020Hepatocellular carcinoma (HCC) is the most common form of liver cancer and it is the third leading cause of global cancer mortality. Sorafenib (Sf) is the first oral...
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and it is the third leading cause of global cancer mortality. Sorafenib (Sf) is the first oral multi-kinase inhibitor approved for systemic treatment of advanced HCC, and can prolong survival, although only for three months longer than placebo treated patients. Preclinical studies showed that active forms of vitamin D can induce cell differentiation and regulate cell survival in several cell types, and epidemiological data link vitamin D insufficiency to an increased risk of neoplastic diseases, suggesting a potentially important role of vitamin D in cancer therapy. Other studies showed that the effect of vitamin D analogs on human neoplastic cells is potentiated by carnosic acid (CA), a plant polyphenol with anti-oxidant properties. Here we tested if the addition of the vitamin D2 analog Doxercalciferol (D2) together with CA can enhance the cytotoxic effect of Sf on HCC cell lines Huh7 (Sf-sensitive) and HCO2 (Sf-resistant). Indeed, this combination increased HCC cell death in cell lines, enhancing autophagy as well as apoptosis. Autophagy was confirmed by increased cytoplasmic vacuolation, perinuclear aggregation of LC3, and elevated protein levels of autophagy markers Beclin1, Atg3, and LC3. These results suggest that a regimen which combines a vitamin D2 analog/CA mixture with Sf can be a novel and promising therapeutic option for the treatment of HCC.
Topics: Abietanes; Antineoplastic Agents; Antioxidants; Apoptosis; Autophagy; Bone Density Conservation Agents; Carcinoma, Hepatocellular; Cell Proliferation; Drug Synergism; Drug Therapy, Combination; Ergocalciferols; Humans; Liver Neoplasms; Signal Transduction; Sorafenib; Tumor Cells, Cultured
PubMed: 31704246
DOI: 10.1016/j.jsbmb.2019.105524 -
The Journal of Steroid Biochemistry and... Mar 2018Numerous clinical studies of vitamin D, its derivatives or analogs, have failed to clearly demonstrate sustained benefits when used for the treatment of human malignant...
Numerous clinical studies of vitamin D, its derivatives or analogs, have failed to clearly demonstrate sustained benefits when used for the treatment of human malignant diseases. However, given the strong preclinical evidence of anti-neoplastic activity and the epidemiological associations suggesting that vitamin D compounds may have a place in cancer therapy, attempts are continuing to devise new approaches to their therapeutic use. This laboratory has developed a strategy to enhance the effectiveness of the currently standard therapy of Acute Myeloid Leukemia (AML) by the immediate addition of the vitamin D2 analog Doxercalciferol combined with the plant polyphenol-derived Carnosic acid to AML cells previously treated with Cytarabine (AraC). Enhancement of AML cell death was noted to be dependent on VDR and BRAF kinase. Here we document that the stress-related kinase JNK is an important additional component of cell death enhancement in this protocol. Either the Knock-down or the inhibition of JNK activity reduced the enhancement of AraC-induced cell death, and we show that JNK signaling to the apoptosis regulator BIM and Caspase executioners of cell death are downstream of VDR and BRAF. A clear understanding of the molecular basis for the increased efficacy of AraC in the therapy of AML is expected to bring this regimen to a clinical trial.
Topics: Antimetabolites, Antineoplastic; Cell Death; Cytarabine; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 9; Proto-Oncogene Proteins B-raf; RNA, Messenger; RNA, Small Interfering; Receptors, Calcitriol; Signal Transduction
PubMed: 28765039
DOI: 10.1016/j.jsbmb.2017.07.005 -
Kidney International. Supplement Aug 2010Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease. The management of SHPT commonly involves vitamin D, either calcitriol or newer... (Clinical Trial)
Clinical Trial
Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease. The management of SHPT commonly involves vitamin D, either calcitriol or newer analogs (paricalcitol or doxercalciferol), along with dietary phosphorus restriction and phosphate binding agents. Published reports have suggested that treatment with paricalcitol in hemodialyzed (HD) patients offers a morbidity or mortality advantage in comparison with treatment with calcitriol. We have recently reported that switching from calcitriol to paricalcitol resulted in a lower serum calcium and calcium-phosphorus product (Ca x P product), as well as lower parathyroid hormone (PTH) and alkaline phosphatase during 6 months of serial treatment. We converted all HD patients in our large urban dialysis center from calcitriol to paricalcitol using a 1:3 conversion ratio, on the basis of published data. Comparisons of individual patient mean biochemical values, as well as episodes of hypercalcemia and elevated Ca x P product, were made after adjusting for equivalent doses. In addition, we recorded the number of missed doses during two years of therapy. No patient in this study had received a calcimimetic before or during the study period. Fifty-nine patients were treated with calcitriol for at least 12 months and then completed 12 months of paricalcitol. Conversion from calcitriol to paricalcitol resulted in lower serum calcium (P=0.0003), lower serum phosphorus (P=0.027), lower Ca x P product (P=0.003), reduced PTH (P=0.001) and reduced serum alkaline phosphatase (P=0.0005). Most dramatically, there was a highly significant difference in the number of missed doses (P<0.0001) during the treatments. This 2-year single-center study, comparing long-term calcitriol with paricalcitol treatment in the same HD patients, extends our previous findings, offers new information regarding single episodes of potentially adverse biochemical effects related to vitamin D therapy, and provides several clues that may explain the outcome advantages suggested by previously published retrospective analyses of large dialysis provider-pooled databases.
Topics: Aged; Calcinosis; Calcitriol; Calcium; Cross-Over Studies; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Retrospective Studies
PubMed: 20671742
DOI: 10.1038/ki.2010.191