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1.
Evocalcet with vitamin D receptor activator treatment for secondary hyperparathyroidism.
Shigematsu, T, Asada, S, Endo, Y, Kawata, T, Fukagawa, M, Akizawa, T
PloS one. 2022;(2):e0262829
Abstract
This ad hoc analysis of a previously conducted phase 3 head-to-head comparison study of evocalcet and cinacalcet in secondary hyperparathyroidism patients undergoing maintenance hemodialysis evaluated the efficacy and safety of combined once-daily oral evocalcet and intravenous vitamin D receptor activator treatment stratified by weekly vitamin D receptor activator dose (117, 45, and 91 patients in no, low [< 1.5 μg], and high [≥ 1.5 μg] dose groups, respectively). Effects of vitamin D receptor activator were assessed on the basis of intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels; percent changes from baseline; proportions of patients who achieved target intact parathyroid hormone, corrected calcium, and phosphorus at Weeks 28-30; and adverse drug reactions. Intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels decreased in all groups; phosphorus and fibroblast growth factor-23 levels remained high in the high dose group. In the low and high dose groups, greater proportions of patients achieved the corrected calcium target compared with the no dose group (p = 0.043). Ratios of intact-to-C-terminal fibroblast growth factor-23 decreased in all groups. In low and high dose groups, hypocalcemia was less common than in the no dose group (p = 0.014). Evocalcet with concomitant vitamin D receptor activator demonstrated benefits such that more patients achieved the corrected calcium target and exhibited decreased fibroblast growth factor-23 synthesis; the incidence of hypocalcemia also decreased. Clinical trial registration: ClinicalTrials.gov (NCT02549391) and JAPIC (JapicCTI-153013).
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2.
The efficacy of calcitriol treatment in non-alcoholic fatty liver patients with different genotypes of vitamin D receptor FokI polymorphism.
Yaghooti, H, Ghanavati, F, Seyedian, SS, Cheraghian, B, Mohammadtaghvaei, N
BMC pharmacology & toxicology. 2021;(1):18
Abstract
BACKGROUND Vitamin D deficiency is prevalent in patients with non-alcoholic fatty liver disease (NAFLD), but there are debates on the usefulness of vitamin D treatment. The interindividual variations in response may be due to different genetic backgrounds. The present study evaluated the efficacy of calcitriol treatment in NAFLD patients with regard to the vitamin D receptor (VDR) genotypes of FokI polymorphism. METHODS The study was conducted on 128 NAFLD patients randomly divided into two groups and were subjected to intervention with 0.25 mcg calcitriol/day or placebo for 4 months, while anthropometric parameters, glycemic status, lipid profiles, inflammatory markers, liver enzymes, and fatty liver indices were measured. The ARMS-PCR method was used to genotype the VDR FokI polymorphism. RESULTS Calcitriol treatments along with weight loss and diet recommendations decreased the liver enzymes (AST, ALT, and ALP, p < 0.001 for all) and fatty liver indices (HSI, p < 0.01 and APRI, p < 0.001), compared to the baseline. But when the calcitriol effects were compared to the placebo group, only ALP decrease remained significant (17.5 IU. P = 0.02). The prevalent FokI variants in our population were FF (53.1%) and Ff genotype (45.3%). No significant interaction of FokI variants to the calcitriol effects was found except for ALP. The decrease in the ALP activity was higher in calcitriol-received patients with the Ff genotype (p = 0.05). CONCLUSIONS The FF and Ff variants of VDR FokI polymorphism did not interact with the effects of calcitriol on fatty liver, but the ALP was more responsive in subjects with the Ff variant. IRCT REGISTRATION NUMBER IRCT2017053034222N1 Registration date: 2017-06-28 - Retrospectively registered, https://en.irct.ir/trial/26203.
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3.
Effects of Vitamin D Receptor, Cytochrome P450 3A, and Cytochrome P450 Oxidoreductase Genetic Polymorphisms on the Pharmacokinetics of Remimazolam in Healthy Chinese Volunteers.
Hu, K, Xiang, Q, Wang, Z, Sheng, X, Li, L, Liang, Y, Zhao, X, Ye, X, Cui, Y
Clinical pharmacology in drug development. 2021;(1):22-29
Abstract
Remimazolam is a new ultra-short-acting benzodiazepine used to induce and maintain anesthesia and procedural sedation. Its compound structure is similar to midazolam's. Midazolam metabolism might be affected by vitamin D receptor (VDR), cytochrome P450 3A, and cytochrome P450 oxidoreductase genetic polymorphisms. This study investigated the effects of VDR, cytochrome P450 3A, and cytochrome P450 oxidoreductase genetic polymorphisms on the pharmacokinetics of remimazolam in healthy Chinese volunteers after a single intravenous injection of remimazolam besylate. Blood samples were collected from subjects (n = 62) at scheduled time intervals before and after injection. High-performance liquid chromatography-tandem mass spectrometry was used to quantify plasma remimazolam and RF7054 (its inactive carboxylic acid metabolite) concentrations. The relationship between plasma remimazolam concentration, pharmacokinetic parameters, and polymorphic alleles was assessed for each subject. The rs4516035 allele affected the elimination half-life of RF7054 (P = .043), while the rs1544410 allele affected the dose-normalized maximum observed plasma concentration (Cmax /D) of remimazolam (P = .025) in 46 volunteers. Results showed that VDR genetic polymorphisms might affect the pharmacokinetics of remimazolam in the Chinese population.
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4.
Growth, Dietary Intake, and Vitamin D Receptor (VDR) Promoter Genotype in Indonesian School-Age Children.
Angelin, TC, Bardosono, S, Shinta, D, Fahmida, U
Nutrients. 2021;(9)
Abstract
Nutrition has been known as a predominant factor associated with stunting. However, some studies have discovered a genetic contribution in calcium absorption that will affect growth, known as the VDR gene. The aim of this study was to assess the association between VDR gene polymorphism and dietary intake towards height-for-age z-score (HAZ) of elementary school children in Malang District, East Java. This study analyzed the baseline of a randomized trial in East Java, Indonesia. School children aged 8-10 years old (n = 142) were included in this study. Energy, protein, calcium, and vitamin D intakes were obtained using 4-day 24-h dietary recalls. Two SNPs located in the promoter region of VDR gene were selected (rs11568820 and rs4516035) and analyzed using Real-Time PCR. The result showed a significant correlation between energy and protein intake with HAZ of the children (p = 0.030 and p = 0.016, respectively). The association between VDR gene and HAZ was not found (p > 0.05). Adjusted by other factors, protein intake was significantly correlated with HAZ (β = 0.034, 95% CI 0.015-0.052, p < 0.001, adj. R2 = 0.089). The children in our study had a favorable VDR gene genotype, however the effect of VDR gene promoter activity might not be revealed due to very low vitamin D and calcium intake to stimulate intestinal calcium absorption which in turn affects HAZ.
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5.
FGF23 and the PTH response to paricalcitol in chronic kidney disease.
D'Arrigo, G, Pizzini, P, Cutrupi, S, Tripepi, R, Tripepi, G, Mallamaci, F, Zoccali, C
European journal of clinical investigation. 2020;(2):e13196
Abstract
BACKGROUND The parathyroid glands are endowed both with receptors responsive to FGF23 and to 1,25 vitamin D. Vitamin D receptor (VDR) activation, besides lowering PTH, also raises serum FGF23. FGF23 has been implicated in parathyroid resistance to VDR activation but the issue has never been investigated in predialysis CKD patients. METHODS In the Paricalcitol and Endothelial Functio in Chronic Kidney Disease (PENNY) study (NCT01680198), a 12-week randomized trial in stage G3-4 CKD patients (placebo n = 44 and paricalcitol n = 44), we measured PTH and the active form of FGF23 with no missing value across the trial. RESULTS At baseline, serum FGF23 and PTH were inter-related (r = .54, P < .01). Paricalcitol reduced serum PTH (-75.1 pg/mL, 95% CI: -90.4 to -59.8; P < .001) and increased FGF23 (+107 pg/mL, 95% CI: 44-170 pg/mL, P = .001). Changes in the Ca × P product in response to paricalcitol were closely related to simultaneous FGF23 changes in an analysis adjusted for changes in serum calcium and phosphate (P < .001). Of note, baseline FGF23, appropriately adjusted for baseline PTH, was unrelated with the PTH response to paricalcitol (r = -.06, P = .72). Placebo did not change neither PTH nor FGF23. CONCLUSION Serum FGF23 and PTH are inter-related and changes in the Ca × P product induced by paricalcitol per se correlate with the FGF23 response to this drug. Independently of serum FGF23, the parathyroid glands of patients with moderate to severe CKD maintain an intact ability to respond to VDR activation.
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6.
Genetic Variations in VDR could Modulate the Efficacy of Vitamin D3 Supplementation on Inflammatory Markers and Total Antioxidant Capacity among Breast Cancer Women: A Randomized Double Blind Controlled Trial.
Mohseni, H, Amani, R, Hosseini, SA, Ekrami, A, Ahmadzadeh, A, Latifi, SM
Asian Pacific journal of cancer prevention : APJCP. 2019;(7):2065-2072
Abstract
Background: Low levels of vitamin D are found in a great part of breast cancer women. Study subjects using vitamin D3 supplement had lower rates of cancers and fewer markers of inflammation. Additionally, recent studies demonstrate the power of vitamin D supplementation to lower inflammation and oxidative stress biomarkers associate with VDR polymorphism to reduce inflammation. This study was aimed to assess the impact of vitamin D3 supplementation on the serum concentration of inflammatory markers and antioxidant capacity with regard to VDR polymorphism in the VDR gene in breast cancer women. Methods: A randomized, double-blind, placebo-controlled trial was conducted on 56 breast cancer women. Participants were assigned to 2 treatment arms: placebo and vitamin D3 for 2 months intervention. Supplementation group received 50,000 IU of vitamin weekly. Blood samples were collected at baseline and after the intervention to measure the 25(OH) D3, TNF-α, TGF- β and TAC. Genotyping was performed for FokI, BsmI, ApaI, and TaqI polymorphism. Results: After eight weeks supplementation, the intervention group showed a significant increase in the serum concentration of 25(OH) D3 (28±2.6 to 39±3.5; p=0.004 and TAC (48.9±13.3 to 63.5±13.3; p= 0.017). Changes in TNF-α, TGF- β1 were not significant. Serum TAC levels of participants with the TT/Tt, Ff genotypes were more responsive to supplementation. Conclusions: Supplementation with a vitamin D3 increased the TAC in breast cancer women, although it had no effect on inflammatory markers. Serum TAC in the TT/Tt, Ff were more responsive to vitamin D supplement compared with those with the FF/ff and tt genotypes.
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7.
Vitamin D receptor activation raises soluble thrombomodulin levels in chronic kidney disease patients: a double blind, randomized trial.
D'arrigo, G, Pizzini, P, Cutrupi, S, Tripepi, R, Tripepi, G, Mallamaci, F, Zoccali, C
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2019;(5):819-824
Abstract
BACKGROUND Thrombomodulin (TM) is a proteoglycan highly represented in the endothelial glycocalix that regulates the haemostasis and the endothelial response to inflammation. High soluble TM levels underlie a lower risk for coronary heart disease in population studies. Activation of vitamin D receptor (VDR) upregulates TM, but the effect of this intervention on soluble TM has never been tested in chronic kidney disease (CKD) patients. METHODS We performed a post hoc analysis of a 12 weeks double blind, randomized, placebo-controlled trial testing the effect of VDR activation by paricalcitol (PCT) on endothelium-dependent flow-mediated vasodilatation (FMD) in the forearm (ClinicalTrials.gov identifier: NCT01680198). Circulating TM was measured in the whole CKD population [88 patients: PCT n = 44; placebo n = 44] that took part into this trial. RESULTS Soluble TM at baseline was inversely related to the glomerular filtration rate (r = -0.65, P < 0.001) and to FMD (Spearman's ρ = -0.29, P = 0.01). Alongside the expected effects on bone mineral biomarkers, PCT produced a consistent rise (P = 0.005) in TM levels, from a median value of 8446.0 pg/mL [interquartile range (IQR): 6227.8-10 910.8 pg/mL] to 9127.5 pg/mL (6393.0-11 287.3 pg/mL) while placebo had no effect (between-groups difference P = 0.008). TM levels re-approached baseline values 2 weeks after stopping PCT. TM changes across the trial paralleled simultaneous changes in FMD. CONCLUSIONS VDR activation by PCT raises TM levels and FMD and such effects are rapidly reversible after stopping the treatment. The TM rise induced by PCT is a possible mechanism whereby improvement in endothelial function by VDR activation may favourably impact upon vascular health in CKD patients.
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8.
Effect of combined vitamin D receptor activator and lanthanum carbonate on serum fibroblast growth factor 23 level in predialysis patients (CVD-LAF study): design and method.
Ito, E, Inaguma, D, Koide, S, Takahashi, K, Hayashi, H, Hasegawa, M, Yuzawa, Y
Clinical and experimental nephrology. 2018;(6):1309-1314
Abstract
BACKGROUND Whether vitamin D receptor activator (VDRA) use is beneficial in chronic kidney disease (CKD) is unclear, because it is possible that VDRA increases serum fibroblast growth factor 23 (FGF23) levels. We will conduct a randomized controlled trial in predialysis patients to determine the effect of VDRA alone or in combination with lanthanum carbonate (LC) on serum FGF23 levels. METHODS This is a single-center, open-label, randomized controlled trial. Enrollment will commence February 1, 2018, using the following inclusion criteria: (1) age ≥ 20 years, (2) CKD with an estimated glomerular filtration rate of 10-45 mL/min/1.73 m2, (3) serum adjusted calcium level < 9.5 mg/dL, (4) serum phosphate level 4.0-6.0 mg/dL, and (5) serum intact parathyroid hormone (PTH) level ≥ 60 pg/mL. Study patients will be randomized 1:1 to receive alfacalcidol alone or in combination with LC. The initial dose of alfacalcidol will be 0.25-0.5 µg once a day according to serum adjusted calcium level. The initial dose of LC will be 250 mg once a day. We will measure serum intact and C-terminal FGF23 at 0, 4, 8, 12, 24, and 52 weeks. The primary outcome will be serum FGF23 level at 24 weeks compared with baseline. DISCUSSION This study aims to determine whether low-dose oral VDRA increases serum FGF23 level and whether the combination of VDRA and LC inhibits this increase. The results will be useful in the management of CKD-mineral and bone disorder in predialysis patients. TRIAL REGISTRATION UMIN000030503. Registered 20 January 2018.
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9.
Etiologic risk factors and vitamin D receptor gene polymorphisms in under one-year-old infants with urolithiasis.
Ergon, EY, Akil, İO, Taneli, F, Oran, A, Ozyurt, BC
Urolithiasis. 2018;(4):349-356
Abstract
The incidence of urinary tract stones in infancy has been increasing in Turkey. Risk factors and vitamin D receptor (VDR) gene polymorphisms were investigated in infants aged < 1 year who had stones. Forty infants with urinary tract stones and 80 infants without stones, aged < 1 year were enrolled in this study. Detailed surveys were taken of all infants, metabolic parameters and ApaI and FokI VDR gene polymorphisms were investigated. Infants with stones tended to be more commonly fed formula and multivitamins (vitamins A, C, D) (p < 0.05). Positive family history came into prominence in the stony group (p < 0.05). There were no significant differences in ApaI and FokI VDR gene polymorphisms between the groups with stones and the control groups. However, CA genotype of ApaI polymorphism was associated with family history and C allele of ApaI was related with family history and hypercalciuria (p < 0.05). Hypercalciuria emerged as an underlying metabolic abnormality in the etiology of stones, and was observed at a rate of 38%. Infants who are given formula and multivitamins for vitamin D supplementation are at increased risk for the formation of urinary tract stones. VDR gene polymorphisms cause the formation of urinary tract stones and affect calcium (Ca) metabolism.
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10.
Associations of Vitamin D Levels and Vitamin D Receptor Genotypes with Patient-Reported Outcome/Disease Activity in Patients with Rheumatoid Arthritis.
Khoja, SO, El-Miedany, Y, Iyer, AP, Bahlas, SM, Balamash, KS, Elshal, MF
Clinical laboratory. 2018;(1):51-58
Abstract
BACKGROUND The aim of this study is to evaluate the prevalence of vitamin-D insufficiency and vitamin-D receptor (VDR) polymorphisms in rheumatoid arthritis (RA) patients and its association with disease activity and patient reported outcomes (PROs). METHODS Eighty-two individuals were included in a cross-sectional study (41 RA patients, 41 controls). Prior to assessment, each patient completed a PRO questionnaire. Serum vitamin-D levels and genotyping for VDR were assessed. Vitamin-D deficient patients received vitamin-D supplementation. Re-assessment of disease activity (DAS28) was performed after 9-months. RESULTS Low vitamin-D levels were more frequent in RA patients (p < 0.01). A negative, but insignificant, association with DAS-28 score was identified; whereas, there was a significant negative association with the PROs (p < 0.01). Vitamin-D supplementation was associated with significant improvement in the patients' scores for pain, fatigue, global assessment, physical disability, and quality of life. In contrast to the control group, the frequency of the recessive TaqI and FokI genotypes was higher in RA patients. CONCLUSIONS In RA patients, serum vitamin-D level was significantly and inversely associated with both PROs and disease activity. The TaqI and FokI fragment length polymorphisms of VDR significantly contributed to the risk of RA. Having a significant positive impact on patient reported outcomes, vitamin-D supplementation may have a role in RA management.