Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1 alpha, 25-dihydroxyvitamin D3 [1 alpha, 25(OH)2D3] and its analogs have been shown to repress the production of parathyroid hormone-related peptide (PTHrP) in tumors, which is a major factor causing humoral hypercalcemia associated with various cancers. Since vitamin D analogs may be applicable to the treatment of cancer patients, the present study was undertaken to examine whether OCT, an analog with little calcemic activity, is incorporated into tumor tissues, and to identify cellular and subcellular sites of its specific uptake and retention. [26-3H]OCT was injected i.v. into nude mice inoculated with a human pancreatic carcinoma cell line (FA-6). At 1 hour after the injection, intracellular concentration of radioactivity was visualized by receptor (thaw-mount) autoradiography. The results indicate a heterogeneous distribution of radioactivity in nuclei of certain large cancer cells as well as in single or clustered small and elongated cells within the tumor, while connective tissue cells outside of the tumor remained free of nuclear labeling. The data suggest that OCT acts selectively at the genome of cancer cells during a certain maturational stage and also of a second population of small fibroblast-like cells that may have been transplanted with the tumor or are host-derived.
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PMID:In vivo nuclear uptake of a vitamin D analog (OCT) in different tumor cell populations of FA-6 cancer xenograft in nude mice by receptor autoradiography. 1069 95

OCT (22-oxa-calcitriol), a vitamin D analog, has been reported to show strong inhibitory effects on mesangial cell proliferation in vitro. In the present study, we report a study of the effect of OCT on anti-thy-1 glomerulonephritis. Both OCT and 1,25(OH)(2)D(3) significantly inhibited mesangial cell proliferation, the degree of glomerulosclerosis, and albuminuria at day 8 compared to the disease control group. The OCT-treated group showed normal calcium levels but the 1,25(OH)(2)D(3)-treated group showed higher levels. The disease control group showed a marked increase of type I and type IV collagens, and alpha-smooth muscle actin (alpha-SMA) compared to the normal group. The treatment of OCT or 1,25(OH)(2)D(3) significantly reduced the expression of these proteins. The mRNA of the glomeruli of anti-thy-1 model expressed significantly higher levels of type I and type IV collagens, and alpha-SMA at day 8 compared to normal rats. Treatment with OCT or 1,25(OH)(2)D(3) inhibited the mRNA expressions of type I and type IV collagens, as well as that of alpha-SMA. These data demonstrate that OCT inhibits mesangial cell proliferation and extracellular matrix expansion with a low calcemic activity. Disease control rats showed significantly increased levels of transforming growth factor-beta1 protein in the glomeruli, but treatment with OCT or 1,25(OH)(2)D(3) markedly reduced this expression. The levels of mRNA in glomeruli were also consistent with these protein levels. Therefore, the suppressive effect of OCT may be mediated by inhibition of transforming growth factor-beta1. The present results suggest that OCT has potential for use in therapeutic strategy for the treatment of glomerulonephritis without inducing hypercalcemia.
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PMID:A vitamin D analog ameliorates glomerular injury on rat glomerulonephritis. 1133 71

Maxacalcitol (22-oxacalcitriol [OCT]) is a newly developed vitamin D analogue in Japan. OCT has shown less calcemic action and a strong suppressive effect on parathyroid hormone (PTH) in uremic rats and dogs. In uremic patients with secondary hyperparathyroidism, OCT dose-dependently suppressed PTH secretion and increased serum calcium levels. However, more than 60% of patients achieved a greater than 30% decrease in intact PTH level from baseline with long-term OCT treatment up to 1 year without an unphysiological increase in mean serum calcium levels. Long-term treatment also brought about a reduction in bone metabolic markers, including bone alkaline phosphatase, tartrate-resistant acid phosphatase, and bone gra-protein. These results suggest that although careful attention should be paid to the onset of hypercalcemia and oversuppression of PTH, OCT is one of the effective tools for the treatment of secondary hyperparathyroidism.
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PMID:Clinical effects of maxacalcitol on secondary hyperparathyroidism of uremic patients. 1157 42

We originally reported that vitamin K(2) (VK2) effectively induces apoptosis in various types of primary cultured leukemia cells and leukemia cell lines in vitro. In addition, VK2 was shown to induce differentiation of leukemia cells when the cells were resistant against VK2-inducing apoptosis. A novel synthetic vitamin D(3)derivative, 22-oxa-1,25-dihydroxyvitamin D(3) (OCT: oxacarcitriol) shows a more potent differentiation-inducing ability among myeloid leukemia cells in vitro with much lesser extent of the induction of hypercalcemia in vivo as compared to the effects of 1alpha,25(OH)(2)D(3). In the present study, we focused on the effects of a combination of OCT plus VK2 on leukemia cells. Treatment of HL-60 cells with OCT for 72 h induces monocytic differentiation. A combination of OCT plus VK2 dramatically enhances monocytic differentiation as assessed by morphologic features, positivity for non-specific esterase staining, and cell surface antigen expressions. This combined effect far exceeds the maximum differentiation induction ability at the optimal concentrations of either OCT or VK2 alone. In addition, pronounced accumulation of the cells in the G0/G1 phase is observed by combined treatment with OCT plus VK2 as compared with each vitamin alone. In contrast to cell differentiation, caspase-3 activation and apoptosis induction in response to VK2 are significantly suppressed in the presence of OCT in HL-60 cells. These data suggest that monocytic differentiation and apoptosis induction of HL-60 cells are inversely regulated. Furthermore, pronounced induction of differentiation by combined treatment with VK2 plus OCT was also observed in four out of six cases of primary cultured acute myeloid leukemia cells in vitro, suggesting that VK2 plus OCT might be a potent combination for the differentiation-based therapy for acute myeloid leukemias.
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PMID:Combination of 22-oxa-1,25-dihydroxyvitamin D(3), a vitamin D(3) derivative, with vitamin K(2) (VK2) synergistically enhances cell differentiation but suppresses VK2-inducing apoptosis in HL-60 cells. 1214 93

Renal osteodystrophy is the term used to describe the spectrum of bone diseases associated with chronic renal failure. Deficiency of 1,25-dihydroxycholecalciferol (calcitriol) plays a major role in the development of renal osteodystrophy, in particular the evolution of secondary hyperparathyroidism. In recent decades, our understanding of the complex interactions between calcium, phosphorus, vitamin D, and parathyroid hormone (PTH) has increased, resulting in a rational approach to therapy in which vitamin D analogs have become an essential component. The initial vitamin D analogs that have been in widespread clinical use include calcitriol (1,25-[OH](2)D(3)) and alfacalcidol (1alpha-[OH]D(3)). These agents have been extensively studied to optimize their effects on secondary hyperparathyroidism. The occurrence of significant hypercalcemia and hyperphosphatemia limiting their use has led to the development of alternative vitamin D analogs that effectively reduce PTH secretion without causing these complications. Recently, 3 such analogs, 22-oxa-1,25-(OH)(2)D(3) (OCT), 1alpha-(OH)D(2) (doxercalciferol), and 19-nor-1,25-(OH)(2)D(2) (paricalcitol), have been released for clinical use. Only paricalcitol has been studied in comparative human clinical trials with calcitriol in dialysis patients. Preliminary findings suggest a clinical advantage over calcitriol, however, analysis of the larger comparative studies are forthcoming.
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PMID:Use of vitamin D analogs in chronic renal failure. 1220 99

Vitamin D plays a pivotal role in the pathogenesis and treatment of renal bone disease. Vitamin D levels decline in the early phase of renal failure, however, through a compensatory mechanism parathyroid hormone (PTH) stimulates the production of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3), calcitriol) to return it to normal circulating concentrations. Nevertheless, resistance to calcitriol is observed and may be related to the decreased presence of the heterodimeric, DNA-binding partner for the vitamin D receptor protein. In end-stage kidney disease (ESKD) the circulating levels of calcitriol are invariably low. The indications of vitamin D therapy are the replacement of the missing hormone vs suppression of hyperparathyroidism (HPT) requiring daily low-dose oral vs intermittent 'pulse' or oral administration. However, this therapy must be accompanied by careful patient monitoring to avoid hypercalcaemia and low bone turnover. Low bone turnover is not merely a histologic entity, but a clinical condition associated with a high risk of extraosseous calcifications, in particular in the cardiovascular system, leading to increased morbidity. Thus, determination of bone turnover in patients with ESKD is essential. Bone biopsy is the gold standard to assess bone turnover, however, it is not always available and nephrologists rely on PTH levels. The intact PTH assay measures PTH(1-84) and large C-PTH fragments, which may antagonize the PTH(1-84) effects on bone. An assay that measures exclusively PTH(1-84) has recently become available and a calculated PTH(1-84)/C-PTH fragment ratio has been shown to be the best predictor of bone turnover in patients with ESKD not treated with vitamin D or with other medications known to affect bone metabolism. 1,25-dihydroxy-22-oxavitamin D(3) (22-oxacalcitriol, OCT) is a vitamin D analogue that could control serum PTH concentrations without deleterious effects on bone.
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PMID:Use and indication of vitamin D and vitamin D analogues in patients with renal bone disease. 1238 63

Secondary hyperparathyroidism (2HPT), a common disorder in patients with chronic renal failure, develops in response to phosphate retention and low serum 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3), calcitriol). Replacement therapy with calcitriol or its precursor 1alpha-hydroxyvitamin D(3) (1alphaOHD(3), alfacalcidol) often produces hypercalcaemia, especially when combined with calcium-based phosphate binders. In addition, these vitamin D compounds can aggravate the hyperphosphataemia in these patients. Several vitamin D analogues have been developed that retain the direct suppressive action of 1,25(OH)(2)D(3) on the parathyroid glands but have less calcaemic activity, thereby offering a safer and more effective means of controlling 2HPT. 1,25-Dihydroxy-19-norvitamin D(2) (19-norD(2)) and 1alpha-hydroxyvitamin D(2) (1alphaOHD(2)) are available in the US and 1,25-dihydroxy-22-oxavitamin D(3) (22-oxacalcitriol, OCT) and 1,25-dihydroxy-26,26,26,27,27,27-hexafluorovitamin D(3) (1,25(OH)(2)26,27F6 D(3), falecalcitriol) have been approved for use in Japan. Animal studies have demonstrated that OCT and 19-norD(2) have a wider therapeutic window for suppression of parathyroid hormone (PTH) because of their lower calcaemic and phosphataemic activities. The low calcaemic activity of OCT has been attributed to its rapid clearance, which prevents sustained effects on intestinal calcium absorption and bone resorption, but still allows a prolonged suppression of PTH gene expression and parathyroid cell growth. The calcaemic activity of 19-norD(2) diminishes with the duration of treatment by as yet unknown mechanisms. The lower toxicity of 1alphaOHD(2), compared with 1alphaOHD(3), has also been noted with chronic, but not acute administration, perhaps due to differential metabolism. The unique actions of falecalcitriol may also result from an altered metabolism. A clear understanding of the molecular basis for the selectivity of vitamin D analogues on parathyroid function may allow the design of even more effective analogues.
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PMID:Vitamin D analogues for secondary hyperparathyroidism. 1238 64

Secondary hyperparathyroidism (2HPT) is characterized by an abnormal threshold for suppression of parathyroid hormone (PTH) secretion by serum ionized Ca (ICa). It is therefore critical to examine the threshold of PTH secretion in chronic renal failure patients in relation to the physiopathological conditions and the severity of 2HPT. The effect of 1,25-dihidroxy-22-oxavitamin D(3) (22-oxacalcitriol, OCT) on parathyroid gland function was investigated in six haemodialysis patients with 2HPT. OCT was administered three times a week for 26 consecutive weeks. The maximum serum PTH (PTHmax), the minimum serum PTH (PTHmin), and ICa concentration required to inhibit 50% of PTHmax were estimated based on the model formula of the sigmoid curve describing the relationship between ICa and intact-PTH levels. The sigmoid ICa-PTH curves displayed a downward shift at 12 and 26 weeks of OCT treatment. Parathyroid gland function, as reflected by both PTHmax and PTHmin, decreased over time. A steep slope was found at 12 and 26 weeks, compared with that at the start of OCT treatment. There were no marked changes in the set point of calcium. Hypercalcaemia and elevated creatine phosphokinase, probably due to OCT therapy, were observed during the study period. In view of the findings that the sigmoid ICa-PTH curve displayed a downward shift, that both PTHmax and PTHmin decreased, and that functional mass of the parathyroid gland was reduced, OCT appears to be useful in ameliorating parathyroid gland function, contributing to the management of 2HPT.
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PMID:Effects of 1,25-dihydroxy-22-oxavitamin D(3) on parathyroid gland function in haemodialysis patients with secondary hyperparathyroidism. 1238 65

A trial on the long-term administration of 1,25-dihydroxy-22-oxavitamin D(3) (22-oxacalcitoriol, OCT) was conducted among 124 patients with chronic renal failure on maintenance haemodialysis (HD) complicated with secondary hyperparathyroidism (2HPT). In the trial, OCT was administered three times weekly for 26 weeks subsequent to a 26-week pre-trial. As a result, intact-parathyroid hormone (PTH) levels fell significantly after the start of administration and, at the end of the trial, PTH was decreased by over 30% in 51.6% (64/124) of the patients, and the levels of bone metabolism markers such as alkaline phosphatase (ALP), bone ALP, and tartrate-resistant acid phosphatase (TRACP) were significantly decreased compared with those at the start of administration, suggesting a correction of high-turnover bone disease. Serum calcium (Ca) levels rose significantly following OCT administration, but were successfully maintained within a physiological level. Hypercalcaemia, which was diagnosed in 33.1% of patients, was found to resolve or ameliorate immediately after the withdrawal or dose reduction of OCT. OCT can be administered for as long as 1 year without any major problems other than hypercalcaemia. The final doses ranged from 2.5 to 20.0 microg/HD, and the optimal dose varied among patients depending on the intact-PTH and adjusted serum Ca levels. These results suggest that OCT is a highly effective drug for the suppression of PTH levels in 2HPT, and is an overall safe drug if the dosage is adjusted for serum Ca and intact-PTH levels. This study confirmed that the long-term (1-year) administration of OCT is very useful for the treatment of 2HPT.
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PMID:Long-term effect of 1,25-dihydroxy-22-oxavitamin D(3) on secondary hyperparathyroidism in haemodialysis patients. One-year administration study. 1238 66

1alpha, 25-dihydroxyvitamin D3 [1,25 (OH)(2)D(3)], the active metabolite of vitamin D3, is known for the maintenance of normal skeleton architecture and mineral homeostasis. Apart form these traditional calcemic actions, 1,25 (OH)(3)D(1) and its synthetic analogs are increasingly recognized for their potent anti-proliferative, prodifferentiative and immunomodulatory activities. The calcemic and non-calcemic actions of 1,25 (OH)(2)D(3) and its synthetic analogs are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25 (OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential applications of VDR ligands in inflammation, dermatological indications, osteoporosis, cancers and autoimmune diseases. VDR ligands have shown therapeutic potential in limited clinical trials as well as in animal models of these diseases. As a result, a VDR ligand, calcipotriol is in clinic for psoriasis and another, OCT, [2-oxa-1,25 (OH)(2)D(3)] is being developed as a topical agent for the same indication. Further, 1alpha,-hydroxyvitamin D3 (alphacalcidol), a prodrug of 1,25 (OH)(2)D(3) is in clinic and a synthetic VDR ligand, ED-71, is under consideration for approval in Japan for the treatment of osteoporosis. Interestingly, VDR ligands have shown not only preventive but also potent therapeutic anabolic activities in animal models of osteoporosis. However, the wide spread use of VDR ligands in above-mentioned indications is hampered by their major side effect, namely hypercalcemia. In view of this associated toxicity, synthetic VDR ligands with reduced calcemic potential have been synthesized with the ultimate aim of improving their therapeutic efficacy. This review presents recent advances in VDR biology, novel VDR ligands and therapeutic applications of VDR ligands.
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PMID:Vitamin D receptor as a drug discovery target. 1257 Aug 35


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