A vitamin D-based strategy overcomes chemoresistance in prostate cancer.

BACKGROUND AND PURPOSE: Castration-resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first-line treatment, docetaxel. The benefits of vitamin D on prostate cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC. EXPERIMENTAL APPROACH: Structure function relationships of potent vitamin D analogues were determined. The combination of the most potent analogue and docetaxel was explored in chemoresistant primary PCa spheroids and in a xenograft mouse model derived from a patient with a chemoresistant CRPC. KEY RESULTS: Here, we show that Xe4MeCF3 is more potent than the natural ligand to induce vitamin D receptor (VDR) transcriptional activities and that it has a larger therapeutic window. Moreover, we demonstrate that VDR agonists restore docetaxel sensitivity in PCa spheroids. Importantly, Xe4MeCF3 reduces tumour growth in a chemoresistant CRPC patient-derived xenograft. In addition, this treatment targets signalling pathways associated with cancer progression in the remaining cells. CONCLUSION AND IMPLICATIONS: Taken together, these results unravel the potency of VDR agonists to overcome chemoresistance in CRPC and open new avenues for the clinical management of PCa.

A narrative review of fixed combination calcipotriol/betamethasone aerosol foam (Enstilar®) in the management of psoriasis with scalp involvement.

The scalp is the most common site affected in patients with psoriasis with up to 80% of these patients having some degree of scalp involvement. In this narrative review, we evaluate available data on the use of an innovative aerosol foam formulation of calcipotriol plus betamethasone dipropionate (Cal/BD) to treat patients with psoriasis and scalp involvement. The full PubMed database was searched using the terms "calcipotriol", "betamethasone dipropionate" and "aerosol foam", and all articles relating to "psoriasis with scalp involvement" were retrieved and used in the preparation of this review. The evidence supporting the clinical effectiveness, tolerability and impact on health outcomes of Cal/BD aerosol foam in patients with scalp psoriasis was obtained from a phase II clinical trial and real-world evidence data from a non-interventional study as well as from two case series. The findings from these studies show that Cal/BD aerosol foam is rapidly effective, improves skin condition, alleviates symptoms such as itch, and has a positive impact on patient quality of life. These attributes address several unmet needs for patients with psoriasis with scalp involvement and have the potential to improve individual adherence to treatment.

Effects of active vitamin D analogues on muscle strength and falls in elderly people: an updated meta-analysis.

Background: Elderly people are at high risk of falls due to decreased muscle strength. So far, there is currently no officially approved medication for treating muscle strength loss. The active vitamin D analogues are promising but inconsistent results have been reported in previous studies. The present study was to meta-analyze the effect of active vitamin D analogues on muscle strength and falls in elderly people. Methods: The protocol was registered with PROSPERO (record number: CRD42021266978). We searched two databases including PubMed and Cochrane Library up until August 2023. Risk ratio (RR) and standardized mean difference (SMD) with 95% confidence intervals (95% CI) were used to assess the effects of active vitamin D analogues on muscle strength or falls. Results: Regarding the effects of calcitriol (n= 1), alfacalcidol (n= 1) and eldecalcitol (n= 1) on falls, all included randomized controlled trials (RCT) recruited 771 participants. Regarding the effects of the effects of calcitriol (n= 4), alfacalcidol (n= 3) and eldecalcitol (n= 3) on muscle strength, all included RCTs recruited 2431 participants. The results showed that in the pooled analysis of three active vitamin D analogues, active vitamin D analogues reduced the risk of fall by 19%. Due to a lack of sufficient data, no separate subgroup analysis was conducted on the effect of each active vitamin D analogue on falls. In the pooled and separate analysis of active vitamin D analogues, no significant effects were found on global muscle, hand grip, and back extensor strength. However, a significant enhancement of quadriceps strength was observed in the pooled analysis and separate analysis of alfacalcidol and eldecalcitol. The separate subgroup analysis on the impact of calcitriol on the quadriceps strength was not performed due to the lack to sufficient data. The results of pooled and separate subgroup analysis of active vitamin D analogues with or without calcium supplementation showed that calcium supplementation did not affect the effect of vitamin D on muscle strength. Conclusions: The use of active vitamin D analogues does not improve global muscle, hand grip, and back extensor strength but improves quadriceps strength and reduces risk of falls in elderly population.

Vitamin D and Its Analogues: From Differences in Molecular Mechanisms to Potential Benefits of Adapted Use in the Treatment of Alzheimer's Disease.

Lifestyle habits and insufficient sunlight exposure lead to a high prevalence of vitamin D hypovitaminosis, especially in the elderly. Recent studies suggest that in central Europe more than 50% of people over 60 years are not sufficiently supplied with vitamin D. Since vitamin D hypovitaminosis is associated with many diseases, such as Alzheimer's disease (AD), vitamin D supplementation seems to be particularly useful for this vulnerable age population. Importantly, in addition to vitamin D, several analogues are known and used for different medical purposes. These vitamin D analogues differ not only in their pharmacokinetics and binding affinity to the vitamin D receptor, but also in their potential side effects. Here, we discuss these aspects, especially those of the commonly used vitamin D analogues alfacalcidol, paricalcitol, doxercalciferol, tacalcitol, calcipotriol, and eldecalcitol. In addition to their pleiotropic effects on mechanisms relevant to AD, potential effects of vitamin D analogues on comorbidities common in the context of geriatric diseases are summarized. AD is defined as a complex neurodegenerative disease of the central nervous system and is commonly represented in the elderly population. It is usually caused by extracellular accumulation of amyloidogenic plaques, consisting of amyloid (Aß) peptides. Furthermore, the formation of intracellular neurofibrillary tangles involving hyperphosphorylated tau proteins contributes to the pathology of AD. In conclusion, this review emphasizes the importance of an adequate vitamin D supply and discusses the specifics of administering various vitamin D analogues compared with vitamin D in geriatric patients, especially those suffering from AD.

Vitamin D Analogues and Fracture Risk in Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Vitamin D receptor agonists (VDRAs) are commonly prescribed in chronic kidney disease (CKD). However, their protective effects on bone remain controversial. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of VDRAs on fracture risk and bone mineral density (BMD) in adult patients with CKD. We searched MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov, and the WHO's International Clinical Trials Registry Platform databases from inception to June 19, 2021. We included RCTs comparing VDRAs, to placebo or another medication, in adults with CKD requiring or not dialysis. Conference abstracts and trials involving kidney transplant recipients and/or comparing VDRAs to antiresorptive or anabolic bone therapy were excluded. Primary outcome was fracture at any anatomical site. Secondary outcomes were BMD at femoral neck, lumbar spine, and/or total hip. Prespecified subgroup analyses were conducted according to baseline demographics, overall risk of bias, and follow-up time. From 6868 references retrieved, eight RCTs were eligible: five reported fracture, two reported BMD, and one reported both outcomes. As comparator, one study used no VDRAs, one used nutritional intervention and no medication, and six used placebo. In meta-analysis, VDRAs were not associated with a significant reduction in total fractures in overall (risk ratio = 0.79, 95% confidence interval 0.38-1.65, I2 = 0%, six trials, 1507 participants, 27 fractures) or in prespecified subgroup analyses. Three trials reported BMD at different sites and with different BMD measurements; thus, a meta-analysis could not be performed. Two RCTs were at high risk of bias, notably because of deviations from the intended interventions. As limitation, we have to mention the low total number of fractures included in our meta-analysis. In conclusion, current evidence from RCTs is insufficient to associate VDRAs with bone protection in CKD. Further large and long-term studies specifically designed to evaluate the efficacy of VDRAs on bone outcomes are thus required. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Drug-Related Hypercalcemia.

This review focuses on the commonly prescribed medicaments that can be responsible for hypercalcemia, considering the prevalence, the predominant pathophysiological mechanisms, and the optimal medical management of each drug-induced hypercalcemia. Vitamin D supplements and 1α-hydroxylated vitamin D analogues increase intestinal calcium absorption, renal calcium reabsorption as well as bone resorption. In patients with hypoparathyroidism receiving recombinant human PTH, transient hypercalcemia can occur because of overtreatment, usually during acute illness. Thiazide-induced hypercalcemia is mainly explained by enhanced renal proximal calcium reabsorption, changing preexistent asymptomatic normocalcemic or intermittently hypercalcemic hyperparathyroidism into the classic hypercalcemic hyperparathyroidism. Lithium causes hypercalcemia mainly by drug-induced hyperparathyroidism.

Plain vitamin D or active vitamin D in the treatment of osteoporosis: where do we stand today?

Osteoporosis is a major cause of morbidity and mortality worldwide and its prevention in order to avert fractures was considered of great importance in maintaining well-being and independence among the elderly. Strategies for osteoporosis prevention are well delineated, but research shows that the treatment options offered today could still be improved. The role of plain vitamin D (cholecalciferol) in bone health and the prevention of osteoporosis are well documented; however, as a treatment for osteoporosis, either with or without calcium, it has been shown to be ineffective. This is due in part to the strong negative feedback mechanisms in place in vitamin D-replete patients. However, other factors linked directly to ageing such as oestrogen depletion, reduced kidney or liver function may also be involved in reducing the body's capability to activate plain vitamin efficiently. This is why active vitamin D analogues such as alfacalcidol, 1-α-(OH)D3, are of clinical interest. Alfacalcidol requires only one hydroxylation reaction to become active 1,25-(OH)2-vitamin D3, and the 25-hydroxylase catalyzing this reaction is found in the liver and also interestingly in osteoblasts suggesting a local effect. Registered for use in postmenopausal osteoporosis, in most countries worldwide, alfacalcidol has also shown efficacy in glucocorticoid-induced and male osteoporosis. The present review provides compelling evidence for the efficacy of this compound in the treatment of osteoporosis and prevention of fractures both in monotherapy and when combined with other osteoporotic drugs where additive effects are clear. The safety profile of alfacalcidol is shown to be highly acceptable and it is considered less likely to induce hypercalcaemia than another more widely used analogue, calcitriol. Therefore, it remains unclear as to why alfacalcidol is not more widely used in clinical practice.

Topical tacalcitol as neoadjuvant for photodynamic therapy of acral actinic keratoses: An intra-patient randomized study.

BACKGROUND: photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) is a well described and widely practiced treatment for actinic keratoses (AKs) on the head and face. Less is known about its use for AKs on upper extremities, which can be challenging for the dermatologist. The aim of our study was to compare the combination of topical tacalcitol before 5-ALA-PDT vs conventional 5-ALA-PDT for acral AKs in a prospective, randomized, intra-individual clinical study. METHODS: patients with AKs of both upper extremities underwent keratolytic pretreatment with topical tacalcitol on the back of one hand and/or forearm (right vs left), randomly selected, for fifteen consecutive days before PDT. All patients underwent one session of 5-ALA-PDT. Visual analog scale for pain was assessed immediately after PDT session and any side effects were recorded after 3 days. Efficacy was evaluated with lesion count (LC) prior to treatment (V0) and 90 days (V1) after PDT. RESULTS: twenty-one patients with multiple acral AKs were enrolled and completed the study. At V1, neoadjuvant combination of topical tacalcitol plus PDT was significantly more effective than PDT alone (percentage reduction in total lesion count was 44.4 %. There was no significant difference in VAS pain score between the two treatment modalities. Mild erythema was the only local side effect reported for both treatment regimens (52.4 %, tacalcitol plus PDT vs 42.9 %, PDT alone). CONCLUSIONS: neoadjuvant use of topical tacalcitol might be useful to improve PDT efficacy, especially in hard-to-treat AKs on extremities.

Calcitriol Analogues Decrease Lung Metastasis but Impair Bone Metabolism in Aged Ovariectomized Mice Bearing 4T1 Mammary Gland Tumours.

Calcitriol and its analogues are considered drugs supporting the anticancer treatment of breast cancer and preventing the osteoporosis that results from the development of cancer or from chemotherapy or hormone therapy. Following the orthotopic implantation of 4T1 mammary carcinoma cells into aged ovariectomized (OVX) mice, we evaluated the effects of calcitriol and its two analogues, PRI-2191 and PRI-2205, on metastatic spread and bone homeostasis. Calcitriol and its analogues temporarily inhibited the formation of metastases in the lungs. Unexpectedly, only mice treated with calcitriol analogues showed a deterioration of bone-related parameters, such as bone column density, marrow column density and the CaPO4 coefficient. These findings correlated with an increased number of active osteoclasts differentiated from bone marrow-derived macrophages in mice treated with the analogues. Interestingly, in the tumours from mice treated with PRI-2191 and PRI-2205, the expression of Tnfsf11 (RANKL) was increased. On the other hand, osteopontin (OPN) levels in plasma and tumour tissue, as well as TRAC5b levels in tumours, were diminished by calcitriol and its analogues. Despite a similar action of both analogues towards bone metabolism, their impact on vitamin D metabolism differed. In particular, PRI-2191 and calcitriol, not PRI-2205 treatment significantly diminished the levels of both 25(OH)D3 and 24,25(OH)2D3. In conclusion, though there is evident antimetastatic activity in old OVX mice, signs of increased bone metabolism and deterioration of bone mineralization during therapy with calcitriol analogues were observed.

Calcipotriol ointment shows comparable efficacy to topical steroids in chronic hand eczema.

Topical potent corticosteroids are the mainstay of treatment for chronic hand eczema (CHE). However, there are numerous adverse effects associated with the chronic use of topical corticosteroids. Calcipotriol has been widely used in psoriasis and has been reported to achieve beneficial effects in several inflammatory diseases. This study aimed to evaluate the efficacy and safety of calcipotriol ointment compared to desoximetasone ointment in the treatment of CHE. Patch testing was performed in all recruited subjects. Then, each hand of the patient was randomly allocated for the application of either calcipotriol ointment or desoximetasone ointment twice daily for 8 weeks. Recurrence was assessed 4 weeks after discontinuation of the treatment. The Hand eczema severity index (HECSI) scores, quartile grading assessments and digital photographs were evaluated. Adverse reactions were also monitored. A total of 13 participants completed the protocol. Mean HECSI scores revealed up to a 75% reduction in both treatments (p < .001) without significant differences between the groups (p > .05). Approximately 70% of the subjects reported more than 75% improvement with calcipotriol at the end of the treatment. Mild scaling and mild dryness were the most common reactions found with calcipotriol and desoximetasone, respectively. In conclusion, calcipotriol ointment is safe and as effective as desoximetasone ointment. Calcipotriol ointment may be an alternative treatment option for CHE.

Imatinib inhibits the regrowth of human colon cancer cells after treatment with 5-FU and cooperates with vitamin D analogue PRI-2191 in the downregulation of expression of stemness-related genes in 5-FU refractory cells.

Conventional cytotoxic drugs preferentially eliminate differentiated cancer cells but spare relatively more resistant stem-like cancer cells capable to initiate recurrence. Due to cancer cell plasticity, the stem-like phenotype can be also acquired by cancer cells refractory to treatment with cytotoxic drugs. We investigated whether drugs inhibiting receptor tyrosine kinases could be used to target human colon cancer cells initiating cancer regrowth following conventional cytotoxic treatment. The moderately differentiated cell line HT-29 and poorly differentiated cell line HCT-116 were exposed to 5-fluorouracil (5-FU). Cells that resisted the exposure to 5-FU were subsequently treated with imatinib or sunitinib. Both drugs reduced clonogenicity of 5-FU-refractory cells under normoxic and hypoxic culture conditions. The expression of numerous stemness-related genes was upregulated in cancer cells following the exposure to 5-FU, and remained at a high level in 5-FU-refractory cells undergoing renewal under normoxia, but decreased spontaneously under hypoxia. Imatinib downregulated the expression of stemness-related genes in cells undergoing renewal under normoxia. A combination of imatinib with PRI-2191, an analogue of 1,25-dihydroxyvitamin D3, downregulated stemness-related genes in HCT-116/5-FU cells more efficiently than imatinib alone. A synthetic analogue of 1,25-dihydroxyvitamin D2 (PRI-1906) abolished the effect of imatinib on gene expression in HCT-116/5-FU cells undergoing renewal under normoxia. Sunitinib promoted shift of phenotype of HT-29/5-FU cells undergoing renewal toward stem-like one. It suggests that the phenotype shift toward stemness induced by sequential sunitinib treatment following 5-FU treatment could increase a risk of cancer recurrence. In contrast to sunitinib, imatinib could be used both to interfere with cancer regrowth after conventional chemotherapy and to downregulate the expression of stemness-related genes in residual colon cancer cells capable to initiate cancer recurrence. The findings suggest that imatinib could also be combined with vitamin D analogue PRI-2191 to prevent recurrence more efficiently than imatinib alone and to compensate for vitamin D deficiency resulting from imatinib treatment.

A Bayesian network analysis on comparative efficacy of treatment strategies for dialysis patients with secondary hyperparathyroidism.

For dialysis patients with end-stage kidney disease and secondary hyperparathyroidism (SHPT), there are three therapeutic treatment options: Cinacalcet, paricalcitol and cinacalcet plus low-dose vitamin D analogues. However, their comparative efficacy remains unclear at present. Thus, in the current study, a Bayesian network analysis was conducted to evaluate the relative efficacy and safety of these three therapeutic regimens. A comprehensive literature database query was performed. The primary outcome was the treatment effect on serum parathyroid hormone (PTH) levels. Secondary outcomes included the occurrence of nausea and hypocalcaemia. A total of 20 randomized clinical trials, including 5,390 dialysis patients, were entered into the analysis. Paricalcitol, cinacalcet plus vitamin D analogue and cinacalcet were significantly more efficacious in controlling PTH levels compared with conventional therapy (which comprises calcium-based phosphate binders, non-calcium-based phosphate binders and vitamin D analogues) [odds ratio (OR)=3.99, 2.91 and 2.47, respectively] and placebo (OR=20.32, 14.89 and 12.56, respectively). Paricalcitol was identified as the most efficacious of the three treatments. According to a ranking analysis, patients treated with cinacalcet had a higher possibility of frequently developing nausea and hypocalcaemia compared with patients treated with cinacalcet plus low-dose active vitamin D analogues. All three therapeutic treatment options were efficacious for the treatment of dialysis patients with SHPT in controlling PTH levels. Paricalcitol had the highest possibility of being the most optimal one. Thus, paricalcitol therapy may be the most optimal regimen in controlling PTH levels, but this should be confirmed by further study.

Synthesis of 1α,25-dihydroxyvitamin D3 analogues with α,α-difluorocycloketone at the CD-ring side chains and their biological properties in ovariectomized rats.

Two novel 1α,25-dihydroxyvitamin D3 derivatives containing a α,α-difluorocyclopentanone (3) or α,α-difluorocyclohexanone (4) moiety at the CD-ring side chains were designed, synthesized, and evaluated for their biological properties on restoring bone mass in ovariectomized (OVX) rats with established osteopenia. The synthesis of compounds 3 and 4 utilized the Wittig-Horner coupling to build up the vitamin D conjugated triene system, followed by the introduction of the cycloketone fragments at the side chain, and subsequent α,α-difluorination of the ketone by the treatment of the derived silyl enol ether with Selectfluor, as the key synthetic steps. In comparison with the natural 1α,25-dihydroxyvitamin D3 (calcitriol; 200 ng/kg/day), oral administration of compounds 3 and 4 at the dose of 25 ng/kg/day for 6 weeks led to much improved bone mass and bone density related parameters, while maintaining normal serum calcium and serum phosphorus levels. The immunohistochemistry results showed that both compounds remarkably decreased in osteoclast number and moderately decreased in osteoblast number on trabecular bone surface. Therefore, our findings suggested that compounds 3 and 4 successfully rescue bone loss by suppression on bone turnover in OVX rat models.

Vitamins D: Relationship between Structure and Biological Activity.

The most active metabolite of vitamin D is 1α,25-dihydroxyvitamin D3, which is a central regulator of mineral homeostasis: excessive administration leads to hypercalcemia. Additionally, 1α,25-dihydroxyvitamin D3 is important to decision-making by cells, driving many cell types to growth arrest, differentiate and undergo apoptosis. 1α,25-Dihydroxyvitamin D3 regulates gene transcription by binding to a single known receptor, the vitamin D receptor. Rapid intracellular signals are also elicited in vitro by 1α,25-dihydroxyvitamin D3 that are independent of transcription. There are many aspects of the multiple actions of 1α,25-dihydroxyvitamin D3 that we do not fully understand. These include how a single receptor and provoked rapid events relate to the different actions of 1α,25-dihydroxyvitamin D3, its calcemic action per se, and whether a large number of genes are activated directly, via the vitamin D receptor, or indirectly. A strategy to resolving these issues has been to generate synthetic analogues of 1α,25-dihydroxyvitamin D3: Some of these separate the anti-proliferative and calcemic actions of the parent hormone. Crystallography is important to understanding how differences between 1α,25-dihydroxyvitamin D3- and analogue-provoked structural changes to the vitamin D receptor may underlie their different activity profiles. Current crystallographic resolution has not revealed such information. Studies of our new analogues have revealed the importance of the A-ring adopting the chair ß-conformation upon interaction with the vitamin D receptor to receptor-affinity and biological activity. Vitamin D analogues are useful probes to providing a better understanding of the physiology of vitamin D.

Atom-based and Pharmacophore-based 3D - QSAR Studies on Vitamin D Receptor (VDR).

AIM AND OBJECTIVE: Vitamin D3 (1,25(OH)2D3) is a biologically active metabolite and plays a wide variety of regulatory functions in human systems. Currently, several Vitamin D analogues have been synthesized and tested against VDR (Vitamin D Receptor). Electrostatic potential methods are greatly influence the structure-based drug discovery. In this study, ab inito (DFT, HF, LMP2) and semi-empirical (RM1, AM1, PM3, MNDO, MNDO/d) charges were examined on the basis of their concert in predicting the docking pose using Induced Fit Docking (IFD) and binding free energy calculations against the VDR. MATERIALS AND METHODS: Initially, we applied ab initio and semi-empirical charges to the 38 vitamin D analogues. Further, the charged analogues have been docked in the VDR active site. We generated the structure-based 3D-QSAR from the docked conformation of vitamin D analogues. On the other hand, we performed pharmacophore-based 3D-QSAR. RESULTS: The result shows that, AM1 is the good charge model for our study and AM1 charge based QSAR produced more accurate ligand poses. Furthermore, the hydroxyl group in the side chain of vitamin D analogues played an important role in the VDR antagonistic activity. CONCLUSION: Overall, we found that charge-based optimizations of ligands were out performed than the pharmacophore based QSAR model.

Impact of Vitamin D on the Cardiovascular System in Advanced Chronic Kidney Disease (CKD) and Dialysis Patients.

In patients suffering from chronic kidney disease (CKD), the prevalence of cardiovascular disease is much more common than in the general population. The role of vitamin D deficiency had been underestimated until a significant association was found between vitamin D therapy and survival benefit in haemodialysis patients. Vitamin D deficiency is present even in the early stages of chronic kidney disease. The results of experimental studies have revealed the relationship between vitamin D deficiency and impairment of cardiac contractile function, higher cardiac mass and increased myocardial collagen content. Experimental models propose that intermediate end points for the relationship between vitamin D deficiency and higher risk of cardiovascular disease comprise diminished left ventricular hypertrophy (LVH), enhanced left ventricular diastolic function, and decreased frequency of heart failure. Multiple observational studies have demonstrated an association between the use of active vitamin D therapy in patients on dialysis and with CKD and improved survival. However, there are also many studies indicating important adverse effects of such treatment. Therefore, large randomized trials are required to analyze whether supplementation of vitamin D may affect outcomes and whether it is safe to be used in CKD patients.

Changes in renal function after discontinuation of vitamin D analogues in advanced chronic kidney disease. / Cambios de la función renal tras la suspensión de análogos de vitamina D en la enfermedad renal crónica avanzada.

BACKGROUND: In routine clinical practice, the prescription of vitamin D analogues (VDA) in patients with chronic kidney disease (CKD) is often associated with a decline of the estimated renal function. The reason for this is not fully understood. AIMS: To analyse the effects of VDA discontinuation in advanced CKD and to determine the factors associated with changes in renal function. MATERIAL AND METHODS: Retrospective cohort study of adult patients with advanced CKD. The case subgroup was treated with VDA and this medication was discontinued at baseline (the first visit). The control subgroup was not treated with VDA and they were selected according to comparability principles for CKD progression by propensity score matching. The primary outcome measure was a change to both the estimated glomerular filtration rate (MDRD-GFR) and the measured glomerular filtration rate (mGFR by combined creatinine and urea clearances). Baseline parameters related to mineral metabolism and creatinine generation were analysed as potential determinants of renal function changes. RESULTS: The study sample consisted of 67 cases and 67 controls. Renal function improved in 67% of cases and worsened in 72% of controls (p<0.0001). Changes in MDRD-GFR for the case subgroup and the control subgroup were +0.455±0.997 vs. -0.436±1.103ml/min/1.73 m2/month (p<0.0001), respectively. Total creatinine excretion was slightly higher in cases than in controls but the difference was not significant. According to multivariate logistic and linear regression analyses, baseline total serum calcium was one of the best determinants of both renal function recovery (Odds ratio=3.49; p=0.001), and of the extent of renal function recovery (beta=0.276; p=0.001). CONCLUSIONS: Discontinuation of VDA treatment in CKD patients is associated with significant recovery of estimated renal function. The extent of these changes is mainly associated with baseline total serum calcium.

Vitamin D and Its Analogues Decrease Amyloid-ß (Aß) Formation and Increase Aß-Degradation.

Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-ß (Aß), as derived from sequential cleavage of the amyloid precursor protein. Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Aß-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D2 and D3 analogues decreased Aß-production and increased Aß-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Aß-producing enzymes BACE1 and γ-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the γ-secretase. Vitamin D and analogues decreased ß-secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention.

The Use of Vitamin D Metabolites and Analogues in the Treatment of Chronic Kidney Disease.

Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with abnormalities in bone and mineral metabolism, known as CKD-bone mineral disorder. CKD and ESRD cause skeletal abnormalities characterized by hyperparathyroidism, mixed uremic osteodystrophy, osteomalacia, adynamic bone disease, and frequently enhanced vascular and ectopic calcification. Hyperparathyroidism and mixed uremic osteodystrophy are the most common manifestations due to phosphate retention, reduced concentrations of 1,25-dihydroxyvitamin D, intestinal calcium absorption, and negative calcium balance. Treatment with 1-hydroxylated vitamin D analogues is useful.

Design, synthesis and biological properties of seco-d-ring modified 1α,25-dihydroxyvitamin D3 analogues.

As a continuation of our efforts directed to the structure-activity relationship studies of vitamin D compounds, we present in this paper the synthesis of new analogues of 1α,25-(OH)2D3 characterized by numerous structural modifications, especially a cleaved D ring. Total synthesis of the CD fragment required for the construction of the target vitamins was based on the Stork approach. The structure of the key intermediate - bicyclic hydroxy lactone - was established by crystallographic and electronic circular dichroism (ECD) spectral analysis. Following the attachment of the hydroxyalkyl side chain, the formed D-seco Grundmann ketone was subjected to Wittig-Horner coupling with the corresponding A-ring phosphine oxides providing two desired D-seco analogues of 19-nor-1α,25-(OH)2D3, one without a substituent at C-2 and the other possessing a 2-exomethylene group. Both compounds were biologically tested and the latter was found to be more active in in vitro tests. Despite so many structural changes introduced in its structure, the biological activity of the 2-methylene analogue approached that of the natural hormone. The synthesized D-seco vitamins, however, proved to be inactive on bone and intestine in vivo.