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Medical research on rocaltrol
Catalytic asymmetric Nozaki-Hiyama reactions with a tridentate bis(oxazolinyl)carbazole ligand.
Chem Rec. 2008 Jun 18; 8(3): 169-181
Inoue M, Suzuki T, Kinoshita A, Nakada M
Nozaki-Hiyama reactions are powerful Cr(II)-mediated C--C bond-forming reactions conducted under mild conditions that show excellent compatibility with various functional groups. Therefore, Nozaki-Hiyama reactions have been utilized for many total syntheses of complex natural products, but at least two equivalents of Cr(II) salt are required to complete the reaction because Cr(II) salt is a one-electron donor. In 1996, however, the quantity of Cr(II) salts required was successfully reduced by a catalytic redox system reported by Fürstner and Shi. Since the report by Fürstner, the catalytic asymmetric Nozaki-Hiyama reactions have attracted attention because they would allow control over enantioselectivity, thereby further enhancing the versatility of Nozaki-Hiyama reactions. In this review, we describe the development of a tridentate bis(oxazolinyl)carbazole ligand for the catalytic asymmetric Nozaki-Hiyama allylation, methallylation, propargylation, and allenylation. Also described are their successful applications to the highly stereoselective construction of the side chain of calcitriol lactone, as well as structure elucidation and the enantioselective first total synthesis of the potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, FR901512 and FR901516. (c) 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 8: 169-181; 2008: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20148.
Nat Clin Pract Nephrol. 2008 Jun 17;
Hamano T
Observational studies have demonstrated that therapy with vitamin D analogs for treatment of secondary hyperparathyroidism is associated with improved survival in patients receiving maintenance hemodialysis. This Practice Point commentary discusses an observational study of male predialysis patients with stage 3-5 chronic kidney disease performed by Kovesdy et al., in which incidence rate ratios for all-cause mortality and combined death or dialysis initiation were found to be significantly lower in patients treated with calcitriol than in non-calcitriol-treated patients. These data are compatible with many experimental data on the beneficial effect of vitamin D analogs on the cardiovascular system, renal structure and renal function. Without data from randomized trials, however, it is still unclear whether calcitriol should be administered to all patients with chronic kidney disease, even those without secondary hyperparathyroidism.
[Unilateral nevoid hyperkeratosis of the nipple and areola treated with topical calcitriol.]
Actas Dermosifiliogr. 2008 Jul; 99(6): 500-1
Guevara-Gutiérrez E, Tarango-Martínez VM, Sandoval-Tress C, Hernández-Torres M
Nephrol Dial Transplant. 2008 Jun 13;
Carrillo-López N, Alvarez-Hernández D, González-Suárez I, Román-García P, Valdivielso JM, Fernández-Martín JL, Cannata-Andía JB
BACKGROUND: The regulatory mechanisms of parathyroid hormone (PTH) synthesis are complex, involving calcium, calcitriol, the calcium-sensing receptor (CaR) and the vitamin D receptor (VDR). In this study, the effects of calcium and calcitriol on the simultaneous expression of CaR and VDR mRNA and protein levels were assessed in parathyroid glands cultured in vitro. METHODS: Parathyroid glands (N = 424) were removed and cultured for 24 h to study the effect of calcium on the CaR, VDR and PTH. In addition, the effect of calcitriol at low calcium concentrations (0.6 mM) on CaR and VDR levels was studied after 48 h of incubation. CaR, VDR and PTH mRNAs were measured by quantitative real-time PCR (qRT-PCR), and CaR and VDR protein levels were measured by immunohistochemistry. RESULTS: PTH gene expression was reduced by high calcium concentration. No differences were found in the CaR mRNA levels among the different calcium concentrations tested (0.6 mM calcium: 100%; 1.2 mM calcium: 120%; 2.0 mM calcium: 112%; median values), but VDR gene expression rose when calcium increased (0.6 mM calcium: 100%; 1.2 mM calcium: 164%; 2.0 mM calcium: 195%; median values). Calcitriol increased both CaR (control: 100%; 10(-8) M calcitriol: 196%; median values) and VDR genes expression (control: 100%; 10(-8) M calcitriol: 176%; median values). The same findings were corroborated at protein levels for both CaR and VDR. CONCLUSIONS: In parathyroid glands cultured in vitro, calcium up-regulates VDR but not CaR. Conversely, calcitriol up-regulates both VDR and CaR mRNAs and protein levels, even at low calcium concentrations.
Advances in bone biology and new treatments for bone loss.
Maturitas. 2008 Jun 12;
Gallagher JC
Recent advances in bone biology have led to a more detailed understanding of bone remodeling which is a process that leads to resorption of old bone and replacement by formation of new bone. The most important discoveries in this process of bone remodeling were those of the RANK Ligand/RANK/OPG system which is now recognized the dominant pathway regulating bone resorption. RANK Ligand (RANKL) is a cytokine belonging to the tumor necrosis factor family and is expressed by osteoblasts; it binds to membrane bound receptor RANK on osteoclasts and promotes differentiation of marrow cells through various stages to multinucleated osteoclasts which resorb bone. Several hormones such as parathyroid hormone, calcitriol and prostaglandins stimulate RANK Ligand expression by osteoblasts. Osteoblasts also secrete osteoprotegerin (OPG) which is a soluble receptor that is a potent antagonist of osteoclast formation by binding and inactivating RANKL and OPG is therefore an important regulator of bone resorption. OPG is stimulated by estrogen. OPG has been genetically engineered and in human subjects is a potent inhibitor of bone resorption. Another method for preventing bone resorption is to develope antibodies against RANKL and this has been shown to be a successful strategy. A single subcutaneous injection of this antibody (Denosumab) every 6 months proved to be a potent inhibitor of bone resorption and clinical fracture trials using this agent are now underway. These are novel developments that have risen from basic research in bone biology and other discoveries in the bone remodeling process can be expected to lead to further treatment options for various bone diseases.
Br J Pharmacol. 2008 Jun 16;
Banerjee A, Damera G, Bhandare R, Gu S, Lopez-Boado YS, Panettieri RA, Tliba O
Background and purpose:Chemokines play a critical role in the pathogenesis of asthma and facilitate the recruitment of inflammatory cells in the airways. Evidence now suggests that airway smooth muscle (ASM) may serve as a source of chemokines in inflamed airways. Although vitamin D has potent anti-inflammatory properties in vitro in some cell types, its effects on ASM cells remain unclear. Here, we investigated whether 1alpha, 25-dihydroxy vitamin D(3) (calcitriol) modulated chemokine production in ASM.Experimental approach:Human ASM cell cultures were derived from tracheal samples taken during surgery. ASM cells were treated with tumour necrosis factor alpha (TNFalpha) and/or interferon gamma (IFNgamma) for 24 h in the presence of calcitriol and/or the glucocorticoid fluticasone added 2 h before. RANTES (regulated upon activation, normal T-cell expressed and secreted), interferon-inducible protein 10 (IP-10) and fractalkine (FKN) levels in cell supernatants were measured by ELISA.Key results:In TNFalpha-treated cells, calcitriol inhibited RANTES and IP-10 secretion in a concentration-dependent manner. FKN levels were negligible. In TNFalpha/IFNgamma-treated cells, whereas fluticasone or calcitriol alone partially inhibited RANTES secretion (by 38 and 20%, respectively), the combination of both drugs additively inhibited RANTES secretion (by 60%). No effect was observed on IP-10 secretion. Whereas fluticasone enhanced FKN secretion (by 50%), calcitriol significantly decreased FKN levels (by 50%). Interestingly, calcitriol blocked the stimulatory effect of fluticasone on FKN secretion, which was inhibited by 60% with the combination of calcitriol and fluticasone.Conclusions and implications:These findings suggest that vitamin D uniquely modulates human ASM expression of chemokines and may exert some beneficial effects in the treatment of steroid-resistant patients with asthma.British Journal of Pharmacology advance online publication, 16 June 2008; doi:10.1038/bjp.2008.232.
Otolaryngol Pol. 2007; 61(5): 661-7
Rostkowska-Nadolska B, Kuśmierz D, Kapral M, Latocha M, Swiatkowska L, Fraczek M
INTRODUCTION: Recurrent polyposis in the same patient resulting in the necessity of repeated surgeries forced to search for new pharmacological therapeutic methods. At present, locally acting glycocorticosteroids have the greatest value in the treatment of nasal polyposis. Polyps grow is connected with inflammation process and proliferation of fibroblasts. OBJECTIVE: An evaluation of calcitriol and tacalcitol influence on proliferation of fibroblasts extracted from nasal polyps. MATERIAL: consisted of 9 tissue samples coming from nasal polyps sampled during polypectomies. The testing was performed on the polyps fibroblasts after the sixth passage after the primary culture was established. Three days after the culture was started the cells were poured with nutrient medium without serum added and after further 24 hours was replaced by nutrient medium with takalcitol and calcitriol in the defined concentrations. The expression of the genes coding histone H3 was evaluated with the use of RT-PCR technique. RESULTS: Tacalcitiol and calcitriol in vitro decrease proliferation of fibroblasts sampled from nasal polyps. Inhibition is most effective for the concentration of 10-4M. Tacalcitiol and calcitriol also inhibit level of histone H3 gene expression. CONCLUSION: Experimental data suggest tacalcitiol to be more effective in the same concentration. Present studies may indicate the direction of further investigation in the potential pharmacological treatment on nasal polyps.
Protective and toxic effects of vitamin D on vascular calcification: Clinical implications.
Mol Aspects Med. 2008 May 1;
Zittermann A, Koerfer R
The presence of vascular calcification (VC) is a predictor of poor survival in the general population. The development of VC is an active process that requires a pre-existing injury as an inducer and promoting factors such as hyperphosphatemia and hypercalcemia, as well as a deficiency in calcification repressor factors. Vascular smooth muscle cells possess an endogenous enzyme system for the biosynthesis of the vitamin D hormone calcitriol from its precursor 25-hydroxyvitamin D and also a cytosolic calcitriol receptor, indicating that the vasculature is an important target tissue for vitamin D. The toxic effects of supra-physiological vitamin D dosages on the vasculature have been known for several decades. Recent experimental data also demonstrate important physiological effects of vitamin D on factors that are protective for vascular health. This review article summarises the molecular basis of protective and toxic vitamin D actions on the vasculature. Chronic kidney disease can be considered as a human model of severe VC and poor survival. The disease is associated with calcitriol deficiency, hyperparathyroidism, and hyperphosphatemia. Evidence is increasing that phosphate overload plays a key role in the process of VC in chronic kidney disease. The first clinical studies indicate that vitamin D receptor activation can improve survival in these patients. Although less severe than in chronic kidney disease, vitamin D deficiency and secondary hyperparathyroidism are also frequent in the general population, especially in elderly and obese subjects. Future studies should focus on the impact of vitamin D deficiency on VC and clinical outcome in these groups.
Anticancer Drugs. 2008 Jul; 19(6): 645-53
Azim HA, Mok T
Prostate cancer is a hormonal sensitive disease with a response rate ranging from 80 to 90%; however, the majority of patients develop hormone resistance resulting in poor long term survival. Chemotherapy has demonstrated a benefit over steroids in improving the quality of life in the hormone refractory phase. Furthermore, the introduction of docetaxel succeeded in improving the survival of these patients in first-line therapy. Second-line treatment following docetaxel is challenging with no agent classified as standard in this setting. In the last 5 years, several drugs have shown promising results in initial evaluation. However, randomized phase III trials would be needed to answer this question. The majority of patients develop bone metastasis and the use of bisphosphonates has yielded encouraging results. Our understanding of the biology of hormone refractory prostate cancer has improved dramatically over the past few years and has translated into the developments of new therapeutic targets for this disease. Agents affecting several targets, including calcitriol, endotheline-1, bcl-2, and angiogenesis, are being studied currently and have the potential to change the treatment paradigms of this otherwise fatal disease. This review focuses on current and potential treatment options, including cytotoxic agents, bisphosphonates, and targeted agents, for patients with hormone refractory prostate cancer and the impact of these options on survival and quality of life.
Vitamin D in Health and Disease.
Clin J Am Soc Nephrol. 2008 Jun 4;
Heaney RP
Vitamin D functions in the body through both an endocrine mechanism (regulation of calcium absorption) and an autocrine mechanism (facilitation of gene expression). The former acts through circulating calcitriol, whereas the latter, which accounts for more than 80% of the metabolic utilization of the vitamin each day, produces, uses, and degrades calcitriol exclusively intracellularly. In patients with end-stage kidney disease, the endocrine mechanism is effectively disabled; however, the autocrine mechanism is able to function normally so long as the patient has adequate serum levels of 25(OH)D, on which its function is absolutely dependent. For this reason, calcitriol and its analogs do not constitute adequate replacement in managing vitamin D needs of such patients. Optimal serum 25(OH)D levels are greater than 32 ng/mL (80 nmol/L). The consequences of low 25(OH)D status include increased risk of various chronic diseases, ranging from hypertension to diabetes to cancer. The safest and most economical way to ensure adequate vitamin D status is to use oral dosing of native vitamin D. (Both daily and intermittent regimens work well.) Serum 25(OH)D can be expected to rise by about 1 ng/mL (2.5 nmol/L) for every 100 IU of additional vitamin D each day. Recent data indicate that cholecalciferol (vitamin D3) is substantially more potent than ergocalciferol (vitamin D2) and that the safe upper intake level for vitamin D3 is 10,000 IU/d.