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- Vitamin D and Vitamin D Receptor Activators in Treatment of Hypertension and Cardiovascular Disease. [JOURNAL ARTICLE]
- Cardiovasc Hematol Disord Drug Targets 2014 Feb 28.
Vitamin D plays an essential role in calcium homeostasis and bone metabolism, but recent research has exposed a larger spectrum of biological actions that also includes induction of cell proliferation, immunomodulation, and control of other hormonal systems. Many cells that play an important role in the cardiovascular system express the Vitamin D receptor (VDR) and respond to 1,25-(OH)2D (the active product of vitamin D conversion by hydroxylase) with cell-specific function and gene regulation. These cells include cardiomyocytes, vascular endothelial cells, vascular smooth muscle cells, phagocytes, and cells of the nephron, which produce renin. VDR activators (calcitriol and paricalcitol) are available for the treatment of vitamin D deficiency, which can result from inadequate cutaneous production and/or low dietary intake. Vitamin-D deficient patients present a higher risk of cardiovascular disease than the general population. Recent clinical observations have shown that VDR activator therapy provides survival benefit and also has a positive impact on cardiovascular function. Compelling results have arisen from previous studies of mice with disrupted genes of the vitamin D signaling pathways. In mice lacking VDR or CYP27B1 (1α-hydroxylase - an enzyme, which converts vitamin D to its active form), in addition, to the expected phenotype (hypocalcaemia, secondary hyperparathyroidism and osteomalacia), development of hypertension and cardiac hypertrophy were also observed. Moreover, these mice presented with overexpression of renin and atrial natriuretic peptide. VDR may play a role in regulating smooth-muscle-cell (SMC) proliferation, thrombosis, fibrinolysis and vessel relaxation. The influence of VDR activators on the modulation of renin expression and vascular function may reduce mortality, organ damage, and cardiovascular morbidity in VDR-activator-treated patients with hypertension. Since clinical use of calcitriol is largely limited, because of the side effect of hypercalcemia, calcitriol analogues have been synthesized to obtain compounds with better therapeutic profiles. The main purpose of this article is to review the role of vitamin D and vitamin D receptor activators in cardiovascular diseases, especially hypertension and its treatment. Due to the high prevalence of hypovitaminosis D among patients with high cardiovascular risk, vitamin D supplementation therapy may be warranted in this population.
- Neuropsychiatric manifestations and their outcomes in chronic hypocalcaemia. [Journal Article]
- J Indian Med Assoc 2013 Mar; 111(3):174-7.
Hypocalcaemia is an established cause of neurological and psychiatric disease with numerous clinical manifestations. The aim of the study was to determine the outcome of severe neuropsychiatric manifestations of chronic hypocalcaemia after correction of calcium levels. Clinical and laboratory data of 22 patients seen between 1999 and 2009 were retrospectively analysed. Calcium, magnesium, phosphorus, albumin and parathormone values were measured in all cases. All patients except infants under one year of age had computed tomography (CT) scans of the head. Most patients (n = 19; 86%) presented with generalised tonic clonic convulsions while three had seizures with psychiatric manifestations. Movement disorders were present in 4 patients and one had candida meningitis. Nineteen of the 22 patients had primary hypoparathyroidism of which one had associated mucocutaneous candidiasis. One had pseudohypoparathyroidism and two had vitamin D deficiency. All patients improved with calcitriol and calcium treatment. Twelve of the 14 patients with convulsions could be taken off anticonvulsants. Hemiballismus disappeared in one patient and choreiform movements disappeared in one patient and dystonia in two patients. Psychiatric manifestations improved but did not disappear in the three patients who had them. Adult patients with seizures or neuropsychiatric manifestations should have calcium levels checked. Seizure disorders due to chronic hypocalcaemia had excellent prognosis on correction of serum calcium levels. Movement disorders improved markedly. Psychiatric manifestations did not improve substantially on correction of serum calcium levels.
- Early Growth Inhibition Is Followed by Increased Metastatic Disease with Vitamin D (Calcitriol) Treatment in the TRAMP Model of Prostate Cancer. [Journal Article]
- PLoS One 2014; 9(2):e89555.
The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (calcitriol) has antiproliferative effects in non-aggressive prostate cancer, however, its effects in more aggressive model systems are still unclear. In these studies, effects of calcitriol and a less-calcemic vitamin D analog, QW-1624F2-2 (QW), were tested in vivo, using the aggressive autochthonous transgenic adenocarcinoma of mouse prostate (TRAMP) model. To study prevention of androgen-stimulated prostate cancer, vehicle, calcitriol (20 µg/kg), or QW (50 µg/kg) were administered to 4 week-old TRAMP mice intraperitoneal (i.p.) 3×/week on a MWF schedule for 14 weeks. Calcitriol and QW slowed progression of prostate cancer as indicated by reduced urogenital tract (p = 0.0022, calcitriol; p = 0.0009, QW) and prostate weights (p = 0.0178, calcitriol; p = 0.0086, QW). However, only calcitriol increased expression of the pro-differentiation marker, cadherin 1 (p = 0.0086), and reduced tumor proliferation (p = 0.0467). By contrast, neither vitamin D analog had any effect on castration resistant prostate cancer in mice treated pre- or post-castration. Interestingly, although vitamin D showed inhibitory activity against primary tumors in hormone-intact mice, distant organ metastases seemed to be enhanced following treatment (p = 0.0823). Therefore, TRAMP mice were treated long-term with calcitriol to further examine effects on metastasis. Calcitriol significantly increased the number of distant organ metastases when mice were treated from 4 weeks-of-age until development of palpable tumors (20-25 weeks-of-age)(p = 0.0003). Overall, data suggest that early intervention with vitamin D in TRAMP slowed androgen-stimulated tumor progression, but prolonged treatment resulted in development of a resistant and more aggressive disease associated with increased distant organ metastasis.
- Vitamin D receptor expression is associated with improved overall survival in human glioblastoma multiforme. [JOURNAL ARTICLE]
- J Neurooncol 2014 Mar 1.
Vitamin D and its analogs have been shown to display anti-proliferative effects in a wide variety of cancer types including glioblastoma multiforme (GBM). These anticancer effects are mediated by its active metabolite, 1α, 25-dihydroxyvitamin D3 (calcitriol) acting mainly through vitamin D receptor (VDR) signaling. In addition to its involvement in calcitriol action, VDR has also been demonstrated to be useful as a prognostic factor for some types of cancer. However, to our knowledge, there are no studies evaluating the expression of VDR protein and its association with outcome in gliomas. Therefore, we investigated VDR expression by using immunohistochemical analysis in human glioma tissue microarrays, and analyzed the association between VDR expression and clinico-pathological parameters. We further investigated the effects of genetic and pharmacologic modulation of VDR on survival and migration of glioma cell lines. Our data demonstrate that VDR is increased in tumor tissues when compared with VDR in non-malignant brains, and that VDR expression is associated with an improved outcome in patients with GBM. We also show that both genetic and pharmacologic modulation of VDR modulates GBM cellular migration and survival and that VDR is necessary for calcitriol-mediated effects on migration. Altogether these results provide some limited evidence supporting a role for VDR in glioma progression.
- MORTALITY RATES DO NOT DIFFER AMONG PATIENTS PRESCRIBED VARIOUS VITAMIN D AGENTS. [JOURNAL ARTICLE]
- Perit Dial Int 2014 Mar 1.
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.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.The analysis inclusion criteria identified 1707 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 (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.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).
- Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. [JOURNAL ARTICLE]
- FASEB J 2014 Feb 20.
Serotonin and vitamin D have been proposed to play a role in autism; however, no causal mechanism has been established. Here, we present evidence that vitamin D hormone (calcitriol) activates the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain at a vitamin D response element (VDRE) and represses the transcription of TPH1 in tissues outside the blood-brain barrier at a distinct VDRE. The proposed mechanism explains 4 major characteristics associated with autism: the low concentrations of serotonin in the brain and its elevated concentrations in tissues outside the blood-brain barrier; the low concentrations of the vitamin D hormone precursor 25-hydroxyvitamin D [25(OH)D3]; the high male prevalence of autism; and the presence of maternal antibodies against fetal brain tissue. Two peptide hormones, oxytocin and vasopressin, are also associated with autism and genes encoding the oxytocin-neurophysin I preproprotein, the oxytocin receptor, and the arginine vasopressin receptor contain VDREs for activation. Supplementation with vitamin D and tryptophan is a practical and affordable solution to help prevent autism and possibly ameliorate some symptoms of the disorder.-Patrick, R. P., Ames, B. N. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.
- Renal osteodystrophy in children: pathogenesis, diagnosis and treatment. [JOURNAL ARTICLE]
- Curr Opin Pediatr 2014 Feb 18.
Disturbances in calcium-phosphate homeostasis play an important role in children with chronic kidney disease, and not only cause renal osteodystrophy but also result in increased cardiovascular morbidity and mortality. This review outlines the current aspects in the pathogenesis, diagnostic approach and treatment of renal osteodystrophy.The pathogenesis of renal osteodystrophy is under strong influence of the fibroblast growth factor 23/Klotho system, which is able to enhance phosphate excretion and reduce calcitriol synthesis in the kidney. Fibroblast growth factor 23 increases tissue calcinosis and is cardiotoxic, and is independently associated with mortality. Despite improvement in diagnostic imaging (bone density measurements), determination of biomarkers, mainly parathyroid hormone, still plays a central role. New treatment options resulted in improved bone health and also a reduction in mortality was achieved in adults with calcium-free phosphate binders. Substitution of active and inactive vitamin D is important and also has a beneficial effect on proteinuria.Knowledge about the biochemical and molecular mechanisms of renal osteodystrophy is increasing dramatically and has an impact not only to bone health but also overall morbidity and mortality. This will ultimately translate into further improved diagnostic approaches and novel treatment options.
- Prescribing pattern of medicines in chronic kidney disease with emphasis on phosphate binders. [Journal Article]
- Indian J Pharmacol 2014 Jan; 46(1):35-9.
Patients with chronic kidney disease (CKD) suffer with multiple comorbidities and complications like secondary hyperparathyroidism and hyperphosphotemia. Altered mineral metabolism contributes to bone disease and cardiovascular disease. In patients of CKD, despite dietary phosphorus restriction, phosphate binders (PBs) are recommended to control phosphorous level. No studies about the utilization pattern of PBs in CKD patients have been reported from India. This study analyses the current prescribing trends in the management of CKD patients undergoing tertiary care with focus on PBs.This cross-sectional, observational study was conducted in nephrology department of a government super speciality hospital over 8-month period from January to August 2011. Demographic, clinical, and medication details were collected in a specially designed proforma.A total 111 prescriptions were included in the study. Average number of drugs per prescription was 9.47. About 41.53% of the prescribed drugs were from the World Health Organization essential medicines list. Out of total prescribed drugs (1052), most commonly prescribed were vitamins and minerals (24.71%), cardiovascular drugs, (22.14%), and hematopoietic agents (20.15%). Considering individual drugs, five most commonly prescribed drugs were multivitamins (14.82%), iron (8.65%), folic acid (8.55%), calcium carbonate (8.17%), and calcitriol (5.60%). A total of 11.02% of prescribed drug were PBs. Among PBs, calcium carbonate was the most frequently prescribed and sevelamer was the least prescribed PB. No patient was prescribed lanthanum carbonate.This study identified a wide variety of drug classes including PBs prescribed in CKD patients. Although sevelamer hydrochloride has less side effects as compared to calcium salts, it was less prescribed since it is costlier.
- Therapeutic management of hypophosphatemic rickets from infancy to adulthood. [JOURNAL ARTICLE]
- Endocr Connect 2014 Feb 18.
In children, hypophosphatemic rickets is revealed by delayed walking, waddling gait, leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses and growth failure. If undiagnosed during childhood, patients with hypophosphatemia present with bone and/or joint pain, fractures, mineralization defects such as osteomalacia, entesopathy, severe dental anomalies, hearing loss and fatigue. Healing rickets is the initial endpoint of treatment in children. Therapy aims at counteracting consequences of FGF23 excess, i.e. oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogues (alfacalcidol or calcitriol) to counter the 1,25-dioH-vitamin D deficiency. Corrective surgeries for residual leg bowing at the end of growth are occasionally performed. In absence of consensus regarding indications of the treatment in adults, it is generally accepted that medical treatment should be reinitiated (or maintained) in symptomatic patients to reduce pain, which may be due to bone microfractures and/or osteomalacia. In addition to the conventional treatment, optimal care of symptomatic patients requires pharmacological and non-pharmacological management of pain and joint stiffness, through appropriated rehabilitation. Much attention should be given to the dental and periodontal manifestations of hypophosphatemic rickets. Besides vitamin D analogues and phosphate supplements that improve tooth mineralization, rigorous oral hygiene, active endodontic treatment of root abscesses and preventive protection of teeth surfaces are recommended. Current outcomes of this therapy are still not optimal, and therapies targeting the pathophysiology of the disease, i.e. FGF23 excess, are desirable. In this review, medical, dental, surgical and contributions of various expertises to the treatment of hypophosphatemic rickets are described, with an effort to highlight the importance of coordinated care.
- Supraerythemogenic excimer laser in combination with clobetasol spray and calcitriol ointment for the treatment of generalized plaque psoriasis: Interim results of an open label pilot study. [JOURNAL ARTICLE]
- J Dermatolog Treat 2014 Feb 19.
Abstract Background: The combination of phototherapy and topical therapy is one of the most widely used treatment modalities for moderate to severe psoriasis. The development of targeted phototherapy with excimer laser and new topical spray formulations has made these therapies both more convenient and more effective. In this open label pilot study, we aim to assess the efficacy of combination therapy using 308-nm excimer laser, clobetasol propionate spray and calcitriol ointment for the treatment of moderate to severe generalized psoriasis. Methods: In this 12-week study, patients with moderate to severe psoriasis received twice weekly treatment with XTRAC® Velocity 308-nm excimer laser combined with clobetasol propionate twice daily followed by calitriol ointment twice daily. Results: To date, 21 patients have completed the protocol. By week 12, 76% of the patients had a reduction in Psoriasis Area and Severity Index by at least 75% (PASI-75) and 52% had a Physicians Global Assessment of "clear" or "almost clear". Conclusions: Excimer laser therapy combined with an optimized topical regimen that includes clobetasol spray followed by calictriol ointment appears to be an effective treatment for moderate to severe generalized psoriasis that avoids the risk of serious internal side effects associated with many systemic agents.