Efficacy of vitamin D supplementation in the treatment of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials.

Context: COVID-19 has substantial effects on respiratory health and overall well-being. Recent studies suggest vitamin D as a potential treatment, but the results are inconclusive. Objective: The authors conducted a systematic review of randomized controlled trials (RCTs) to examine the link between vitamin D and patients with COVID-19. Data sources: The authors searched electronic databases PubMed, Cochrane, CINAHL, EMBASE and Google Scholar from their inception till August 2023. Study selection: Inclusion criteria used in our systematic review include: (1) patients who tested positive for COVID-19, (2) intervention was vitamin D supplementation, (3) the comparator was either a placebo, standard care of treatment, or, no treatment, (4) at least one of the clinical outcomes of interest were investigated, (5) study design being RCTs. Data extraction: Two independent reviewers manually extracted information from selected articles, including study characteristics, patient characteristics, and the primary outcomes: all-cause mortality, ICU and hospital stay length and secondary outcomes: mechanical ventilation, supplemental oxygen, ICU admission, and adverse events. Risk ratios or mean differences and 95% CIs were calculated using a random-effects model. Data synthesis: The authors' analysis included 14 RCTs with 2165 patients. Vitamin D significantly reduced ICU admissions and lowered the need for mechanical ventilation compared to placebo. However, it did not significantly affect hospital stay length, ICU stay length, mechanical ventilation duration, mortality, or the need for supplemental oxygen. Conclusion: Vitamin D does not significantly improve certain clinical outcomes, such as hospital and ICU stay length, for patients with COVID-19. However, it still may be significantly beneficial in decreasing the burden on intensive care services.

The effect of active vitamin D supplementation on body weight and composition: A meta-analysis of individual participant data.

BACKGROUND & AIMS: Obesity is associated with vitamin D (VitD) deficiency. However, previous studies showed mixed effects of VitD (25-hydroxyVitD/calcidiol) supplementation on body weight. The biological actions of VitD require the hydroxylation of inactive VitD into active VitD (1.25-dihydroxyVitD/calcitriol). This step is highly regulated; therefore, supplementing with inactive VitD might not be sufficient to overcome the potential adverse health effects of VitD deficiency. The objective of this study was to conduct a systematic review and individual participant data (IPD) meta-analysis of data acquired from randomised placebo-controlled calcitriol trials (RCTs) to determine the effects of calcitriol on body weight and weight-related parameters. METHODS: Studies were identified from MEDLINE, EMBASE, and CENTRAL databases up to January 27, 2024, and excluded those involving dialysis or cancer patients. We obtained IPD from eligible trials and assessed bias using the Cochrane Collaboration risk-of-bias tool and methodological quality using the Heyland Methodological Quality Score. The study was prospectively registered with PROSPERO (CRD42017076202). RESULTS: Although none of the studies reported information regarding our primary objective, we obtained IPD for 411 patients, with 206 randomised to receive calcitriol and 205 to placebo. This dataset enabled us to conduct an IPD meta-analysis with 17,084 person-months of follow-up (median: 11 months). Meta-analysis showed that calcitriol does not alter body weight, BMI, waist circumference, fat mass or lean body mass compared to placebo. Adjusting for age and sex did not alter the outcomes. CONCLUSIONS: In conclusion, this systematic review and IPD meta-analysis indicate that calcitriol does not affect body weight in normal-weight postmenopausal women and lean patients with type 1 diabetes nor in people suffering from obesity, type 2 diabetes and chronic kidney disease. Whether calcitriol lowers body weight in VitD-sufficient people with obesity remains to be elucidated.

Dietary supplementation with calcitriol or quercetin improved eggshell and bone quality by modulating calcium metabolism.

This study was aimed to investigate the effects of dietary calcitriol or quercetin supplementation on eggshell and bone quality of laying hens. In trial 1, 72 Hy-Line Brown layers (80-week-old) with weak-shelled strength (25 to 30 N) were assigned into 4 dietary treatments with 6 replicates of 3 birds and fed a basal diet (4% calcium level) or basal diets supplemented with 0.5% calcium, 5 µg/kg calcitriol or 500 mg/kg quercetin for 4 weeks. In trial 2, 360 Hy-Line Brown layers (60-week-old) were divided into 3 groups with 8 replicates of 15 birds: control group (basal diet), calcitriol group (basal diet + 5 µg/kg calcitriol), and quercetin group (basal diet + 500 mg/kg quercetin). This trial lasted for 12 weeks. The results showed that dietary calcitriol or quercetin improved eggshell quality in both trials (P < 0.05). In trial 2, compared with the control group, both calcitriol and quercetin supplementations improved femoral bone quality, calcium retention of hens and calcium content in uterine fluid at 18.5 h post-oviposition (PO) (P < 0.05), along with enhancing uterine morphology. Compared to the control group, supplemental calcitriol or quercetin up-regulated the relative mRNA expression levels of uterine transient receptor potential cation channel, subfamily V, member 6 (TRPV6) at 8.5 h PO and plasma membrane calcium-ATPase (PMCA), vitamin D receptor (VDR), estrogen receptor alpha (ERα) at 18.5 h PO (P < 0.05), but down-regulated the uterine caspase 3 (CASP3) relative mRNA expression level at 8.5 h PO (P < 0.05). Meanwhile, the femoral relative mRNA expression levels of tartrate-resistant acid phosphatase (TRAP) (up-regulated at 8.5 and 18.5 h PO) and alkaline phosphatase (ALP) (up-regulated at 8.5 h PO but down-regulated at 18.5 h PO) were also affected by calcitriol or quercetin supplementation (P < 0.05). Compared to the calcitriol, quercetin increased hen-day egg production and femoral medullary bone volume/bone tissue volume but reduced femoral stiffness (P < 0.05), which were accompanied by increased relative mRNA expression levels of uterine TRPV6, estrogen receptor beta (ERß) at 18.5 h PO (P < 0.05). Overall, both dietary calcitriol and quercetin could improve eggshell and bone quality by modulating calcium metabolism of aged layers. Compared to calcitriol, dietary quercetin up-regulated the expression of uterine calcium transporters, without affecting eggshell quality.

A pharmacovigilance study on clinical factors of active vitamin D3 analog-related acute kidney injury using the Japanese Adverse Drug Event Report Database.

Acute kidney injury (AKI) due to vitamin D therapy for osteoporosis is encountered in clinical practice, but epidemiological studies are scarce. We aimed to determine the association between AKI and vitamin D therapy and to identify risk factors for AKI using the Japanese Adverse Drug Event Report database. We used reporting odds ratios (RORs) to detect signals and evaluate risk factors using multiple logistic regression analysis. Among 298,891 reports from April 2004 to September 2023, 1071 implicated active vitamin D3 analogs as suspect drugs for adverse events. There was a significant association between AKI and active vitamin D3 analogs (ROR [95% confidence interval {CI}], eldecalcitol: 16.75 [14.23-19.72], P < 0.001; alfacalcidol: 5.29 [4.07-6.87], P < 0.001; calcitriol: 4.46 [1.88-10.59], P < 0.001). The median duration of administration before AKI onset was 15.4 weeks. Multiple logistic regression analysis showed a significant association between AKI and age ≥ 70 years (odds ratio [95% CI], 1.47 [1.04-2.07]; P = 0.028), weight < 50 kg (1.55 [1.12-2.13]; P = 0.007), hypertension (1.90 [1.42-2.54]; P < 0.001), and concomitant use of nonsteroidal anti-inflammatory drugs (1.58 [1.10-2.25], P = 0.012) and magnesium oxide (1.96 [1.38-2.78]; P < 0.001). Our results suggest that active vitamin D3 analogs are associated with AKI development. Physicians prescribing these medications to patients with risk factors should consider the possibility of AKI, especially during the first 6 months.

Vitamin B1 and calcitriol enhance glibenclamide suppression of diabetic nephropathy: Role of HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA trajectories.

Glibenclamide is one of the most prescribed insulin secretagogues in diabetes due to its low cost, but its efficacy on suppressing diabetic complications is limited. Here, we examine whether addition of either vitamin B1 or calcitriol to glibenclamide could produce more suppression of diabetic nephropathy. Type 2 diabetes was induced by high fructose (10 % in drinking water), high salt (3 % in diet), and high fat diet (25 % in diet) for 3 weeks, followed by single dose of STZ (40 mg/kg, i.p.). Diabetic rats were treated with either glibenclamide (0.6 mg/kg), vitamin B1 (70 mg/kg), glibenclamide/vitamin B1, calcitriol (0.1 µg/kg), or glibenclamide/calcitriol. Addition of either vitamin B1 or calcitriol to glibenclamide therapy enabled more suppression of diabetic nephropathy development as evidenced by more preserved creatinine clearance and less renal damage scores. Combination therapy resulted in mild enhancement in the effect of glibenclamide on glucose tolerance without affecting the area under the curve. Combination therapy was associated with more suppression of inflammatory cascades as evidenced by reducing the expression of high mobility group box-1 (HMGB1), toll-like receptor-4 (TLR4), nuclear factor-kappa B (NF-κB), and tumor necrosis factor-α (TNF-α). In addition, combination therapy enhanced the antioxidant mechanisms as evidenced by increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione content and reducing malondialdehyde and nitric oxide levels. Furthermore, combination therapy provided more suppression of fibrotic pathways as appear from reducing collagen deposition and the expression of α- smooth muscle actin (α-SMA). In conclusion, addition of vitamin B1 or calcitriol to glibenclamide therapy can enhance the therapeutic efficiency of glibenclamide in suppressing diabetic nephropathy progression to the same extend, the protective effect is mediated through modulating HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA trajectories.

Calcitriol/vitamin D receptor system alleviates PM2.5-induced human bronchial epithelial damage through upregulating mitochondrial bioenergetics in association with regulation of HIF-1α/PGC-1α signaling.

PM2.5 exposure causes lung injury by triggering oxidative stress, mitochondrial dysfunction, and modulating HIF-1α signaling. Calcitriol activates VDR, which regulates cellular homeostasis. This study evaluated the protective role of the calcitriol/VDR system in PM2.5-induced damage to BEAS-2B bronchial epithelial cells by reducing oxidative stress, upregulating mitochondrial bioenergetics, and downregulating HIF-1α. We found that the calcitriol/VDR system decreased ROS formation and restored mitochondrial bioenergetics in PM2.5-treated cells. This improvement correlated with reduced HIF-1α nuclear translocation and increased PGC-1α protein and mitochondrial gene expressions. This study is the first to suggest that targeting the calcitriol/VDR system could be a promising pharmacological strategy for mitigating PM2.5-induced lung epithelial damage by promoting mitochondrial bioenergetics and regulating PGC-1α and HIF-1α signaling.

Vitamin D3 reduces the expression of M1 and M2 macrophage markers in breast cancer patients.

Vitamin D3 (VD) is known for its immunomodulatory and anticancer effects. This study aimed to characterize tumor-associated macrophages (TAMs) in breast cancer (BC) and assess the influence of VD and its active metabolite, calcitriol, on their polarization. TAMs were isolated from BC patients and characterized. Monocytes were differentiated into macrophage classes (M0, M1, M2a, M2c) and treated ex vivo with calcitriol. The expression of VD-related proteins in tumor tissue was correlated with TAMs and monocyte-derived macrophages (MDMs) characteristics. TAM expression of CD200R, CD204, CD80, HLA-DR, and CD44 was negatively correlated with CYP27B1 in selected patient groups. Patients with high CYP27B1 tumor expression showed significantly lower CD200R, CD204, and CD44 expression. In patients with normal VD levels and premenopausal, CD80 expression in M2a and M2c MDMs (control, untreated ex vivo with calcitriol) was negatively correlated with plasma VD. Calcitriol reduced HLA-DR during MDM differentiation in all patients; CD80 decrease significantly except in patients with normal VD levels or metastasis. Calcitriol also decreased CD163 expression. The decrease in both M1 and M2 macrophage markers by calcitriol or their negative correlation with CYP27B1 indicate the modulatory, but rather anticancer activity of VD. The intensity of these effects was the strongest in postmenopausal patients and those without metastases.

Targeting Calcitriol Metabolism in Acute Vitamin D Toxicity-A Comprehensive Review and Clinical Insight.

High-dose vitamin D supplementation is common in the general population, but unsupervised high-dose supplementation in vitamin D-replete individuals poses a risk of severe toxicity. Susceptibility to vitamin D toxicity shows a significant inter-individual variability that may in part be explained by genetic predispositions (i.e., CYP24A1 polymorphism). The classic manifestation of vitamin D toxicity is hypercalcemia, which may be refractory to conventional therapy. Its causes include the endogenous overaction of 1α-hydroxylase, monogenic alterations affecting vitamin D metabolizing enzymes and exogenous vitamin D intoxication. In this manuscript, we include a literature review of potential pharmacological interventions targeting calcitriol metabolism to treat vitamin D intoxication and present a case of severe, exogenous vitamin D intoxication responding to systemic corticosteroids after the failure of conventional therapy. Systemic glucocorticoids alleviate acute hypercalcemia by inhibiting enteric calcium absorption and increasing the degradation of vitamin D metabolites but may cause adverse effects. Inhibitors of 1α-hydroxylase (keto/fluconazole) and inducers of CYP3A4 (rifampicin) may be considered steroid-sparing alternatives for the treatment of vitamin D intoxication.

Effectiveness of 1α-25-dihydroxyvitamin D3 active substance on anastomosis safety in the rat femoral artery end-to-end anastomosis experimental model: Macroscopic and histological analyses.

Under inflammatory conditions, macrophage dominance affects the degree of inflammation. We assessed the effects of the active vitamin D (calcitriol) administration on inflammatory processes and macrophage dominance and aimed to determine the potential positive macroscopic and histological effects in supermicrosurgical arterial anastomosis model of rats. Forty rats were divided into five groups: control surgery (Group 1), surgery with preoperative (Group 2), post-operative (Group 3), perioperative (Group 4) systemic calcitriol and surgery with local calcitriol (Group 5). Eighty femoral artery anastomoses were planned in both legs of rats. Systemic calcitriol was administered intraperitoneally daily to the animals in the relevant groups. Preoperative vessel diameter measurements were taken before anastomosis. Three weeks post-surgery, post-operative vessel diameter measurements were taken, anastomosis patency was assessed and vascular segments were collected for histological examination, which included assessment of M1 and M2 macrophage depolarisation, leucocyte infiltration, intima-media ratio and luminal gap scoring. Systemic calcitriol administration (pre-, post- or perioperative) significantly improved the vessel diameter (p < 0.001); there was no significant difference among Groups 2-4. Histological findings revealed that Groups 3 and 4 had lower intima-media ratios (p < 0.05 and p < 0.01), higher M2-M1 macrophage ratios (p < 0.01 and p < 0.001) and lower leucocyte infiltration (p < 0.05, p < 0.01 and p < 0.001). Local calcitriol administration had no vasodilatory effects or resulted in positive histological outcomes. Although the administration of calcitriol pre- and post-operatively increased the vessel diameter, the latter appeared to have a more favourable impact on the histological analyses.

The effect of an acute bout of exercise on circulating vitamin D metabolite concentrations: a randomised crossover study in healthy adults.

The effect of acute exercise on circulating concentrations of vitamin D metabolites is unclear. To address this knowledge gap, we examined the effect of a bout of treadmill-based exercise versus rest on circulating concentrations of 25(OH)D3, 25(OH)D2, 3-epi-25(OH)D3, 24,25(OH)2D3, 1,25(OH)2D3, and vitamin D2 and D3 in healthy men and women. Thirty-three healthy adults (14 females, 41 (15) years, body mass index 26.2 (3.7) kg/m2, V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ 36.2 (9.2) ml/kg/min; mean (SD)) completed two laboratory visits involving 60 min of moderate-intensity treadmill exercise (60% V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ ) versus 60 min of seated rest, both in an overnight fasted-state, as part of a randomised crossover design. Venous blood samples were drawn at baseline, immediately (0 h), 1 h and 24 h after the exercise or rest-period. There was a significant time × trial interaction effect for total circulating 25(OH)D (P = 0.0148), 25(OH)D3 (P = 0.0127) and 1,25(OH)2D3 (P = 0.0226). Immediately post-exercise, 25(OH)D, 25(OH)D3 and 1,25(OH)2D3 concentrations were significantly elevated compared to the control resting condition, and 1,25(OH) 2D3 remained significantly elevated 1 h later. Circulating albumin, vitamin D binding protein, calcium and parathyroid hormone were elevated immediately post-exercise. Thus, an acute bout of moderate intensity exercise transiently increases concentrations of circulating 25(OH)D and 1,25(OH)2D3 compared to resting conditions. KEY POINTS: Observational studies suggest that acute exercise might change circulating concentrations of vitamin D metabolites, but this has not been investigated using randomised crossover studies and using robust analytical procedures. In this study, we used a randomised crossover design to examine the effect of a bout of treadmill-based exercise (vs. rest) on circulating concentrations of a wide range of vitamin D metabolites in healthy humans. We show that an acute bout of moderate intensity exercise transiently increases concentrations of circulating 25(OH)D and 1,25(OH)2D3 compared to resting conditions. These findings indicate that regular exercise could lead to transient but regular windows of enhanced vitamin D biological action.

Vitamin D Binding Protein (DBP), Free Calcidiol, and Total Calcitriol in Adults from Northern Greece.

Background: An ongoing debate has been raised on whether is better to use total or free calcidiol as a screening test in the population. Methods: In winter and summer, free calcidiol, total calcitriol, and vitamin D binding protein (DBP) concentrations were determined by immunoenzymatic assays in 326 adults (161 males, 165 females). These included 99 osteoporotic patients, 53 type 1 and 51 type 2 diabetics, and 123 athletic healthy persons, all from northern Greece. Results: In the whole sample, free calcidiol mean concentrations differed significantly (p < 0.001) between males (5.53 pg/ml) and females (4.68 pg/ml). Free calcidiol was significantly greater in the athletic healthy group (6.02 pg/ml) than in the three patient groups, and lowest in the osteoporosis group (3.69 pg/ml). Total calcitriol mean concentration did not differ significantly between genders in the whole sample (p = 0.896) or in the study groups, except for type 2 diabetics (males 38.33 pg/ml, females 54.52 pg/ml, p = 0.001). It was significantly less in the osteoporotics (34.61 pg/ml) than in the athletic healthy group (41.65 pg/ml, p = 0.037) and type 1 diabetics (43.73 pg/ml, p = 0.030), whereas it did not differ significantly between the other study groups. The DBP mean concentrations were not significantly different between genders in the whole sample and the study groups nor among the study groups (p = 0.467). Conclusion: Comparisons with our previously reported results of total calcidiol suggest the measurement of free calcidiol offers nothing more than that, and total calcitriol is not a sensitive measure for assessing vitamin D status.

Severe Hypocalcemia Occurring During the Hospitalization of a Patient Affected by Permanent Post-Surgical Hypoparathyroidism with Multimorbidity: A Case Report.

BACKGROUND: Patients with permanent hypoparathyroidism experience an impaired quality of life, due to acute and chronic complications that may affect several organs, with an increased risk of hospitalisation and death. Adequate and continuous replacement therapy with calcium and calcitriol is necessary to avoid symptoms and long-term complications related to hypocalcemia. CASE PRESENTATION: A 63 years old male, affected by permanent post-surgical hypoparathyroidism, was hospitalized in the cardiology department because of a dehiscence of the subcutaneous housing of the double-chambered implantable cardioverter-defibrillator. Chronic replacement therapy for hypoparathyroidism was poorly controlled and, during hospitalization, severe hypocalcemia occurred together with electrocardiographic and echocardiogram life-threatening alterations. CONCLUSION: Constant and targeted long-term replacement therapy with calcium and particularly calcitriol is necessary to avoid major consequences on patients' health, especially during acute events and in the presence of other comorbidities.

Calcitriol alleviates noise-induced hearing loss by regulating the ATF3/DUSP1 signalling pathway.

BACKGROUND: Calcitriol (Cal) is the most active metabolite of vitamin D and has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the role of Cal in noise-induced hearing loss (NIHL) to further elucidate the mechanism of noise-induced oxidative stress in the mouse cochlea. METHODS: C57BL/6 J mice were given six intraperitoneal injections of Cal (500 ng/kg/d). After 14 days of noise exposure, auditory brainstem response (ABR) thresholds, and the cochlear outer hair cell loss rate were analysed to evaluate auditory function. Real-time fluorescence quantitative PCR, immunofluorescence and western blotting were performed in vitro after the treatment of cochlear explants with 100 µM tert-butyl hydroperoxide (TBHP) for 2.5 h and HEI-OC1 cells with 250 µM TBHP for 1.5 h. RESULTS: In vivo experiments confirmed that Cal pretreatment mitigated NIHL and outer hair cell death. The in vitro results demonstrated that Cal significantly reduced TBHP-induced cochlear auditory nerve fibre degradation and spiral ganglion neuron damage. Moreover, treatment with Cal inhibited the expression of oxidative stress-related factors (3-NT and 4-HNE) and DNA damage-related factors (γ-H2A.X) and attenuated TBHP-induced apoptosis in cochlear explants and HEI-OC1 cells. A total of 1479 upregulated genes and 1443 downregulated genes were screened in cochlear tissue 1 h after noise exposure. The level of transcription factor 3 (ATF3) was significantly elevated in HEI-OC1 cells after TBHP stimulation. Gene Transcription Regulation Database （GTRD）and Cistrome database analyses revealed that the downstream target gene of ATF3 is dual specificity phosphatase 1 (DUSP1). Cistrome DB Toolkit database results showed that the transcription factor of DUSP1 was ATF3. In addition, the ChIP-PCR results indicated that ATF3 might be a direct transcription factor of DUSP1. CONCLUSION: The results of our study suggest that Cal attenuates NIHL and inhibits noise-induced apoptosis by regulating the ATF3/DUSP1 signalling pathway.

Effect of aluminum hydroxide on serum phosphate and fibroblast growth factor 23 concentrations in young adult cats with surgically induced chronic kidney disease.

OBJECTIVE: To describe serum fibroblast growth factor 23 (FGF-23) concentrations in young adult cats with remnant kidney model-induced chronic kidney disease (CKD) and to evaluate the effects of orally administered aluminum hydroxide (ALOH) on serum phosphate and FGF-23 concentrations in these cats. ANIMALS: 17 adult, purpose-bred cats with induced CKD and 13 healthy, age-matched cats. METHODS: A prospective, randomized study. Cats with induced CKD fed a wet renal diet received treatment with ALOH (90 mg/kg/d, PO) on days 0 to 42 and no treatment on days 43 to 84 (treatment group, n = 9) or no treatment on days 0 to 84 (control group, n = 8). Standard serum and urine biochemical analyses and several parameters reflective of calcium-phosphate balance, including serum parathyroid hormone and FGF-23 concentrations, were evaluated at baseline and various time points, including days 42 and 84. Age-matched, healthy, community-owned cats underwent similar evaluations at a single time point. Baseline data from CKD cats were compared to those of healthy cats. Longitudinal data from CKD cats were compared over time. RESULTS: Serum phosphate, total and ionized calcium, and FGF-23 concentrations were significantly higher in CKD cats at baseline relative to healthy cats (all P ≤ .009). Serum phosphate concentration did not change significantly over time in either CKD group; however, FGF-23 concentrations significantly increased over time in the control group (P < .02) but not the treatment group (P = .059). CLINICAL RELEVANCE: Aluminum hydroxide did not reduce serum phosphate or FGF-23 concentrations in this small study of cats with induced CKD chronically eating a phosphate-restricted diet.

Calcitriol in Sepsis-A Single-Centre Randomised Control Trial.

Background/Objectives: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis is a significant cause of hospital admission and the leading reason for admission to the ICU and is associated with high mortality. Vitamin D has shown promising immunomodulatory effects by upregulating the antimicrobial peptide, cathelicidin. However, previous studies analysing the use of calcitriol in sepsis have shown variable results and did not utilise APACHE II (Acute Physiology and Chronic Health Evaluation II) scores as endpoints. This study evaluates the efficacy of intramuscular calcitriol in patients admitted to the ICU with sepsis, focusing on its impact on APACHE II scores. The primary aim was to determine if intramuscular calcitriol improved APACHE II scores from day 1 to day 7 or discharge from the ICU, whichever was earlier. Secondary outcomes included 28-day mortality, ventilator days, vasopressor days, ICU stay length, adverse events, and hospital-acquired infections in ICU patients. Methods: This was a triple-blinded phase III randomised control trial. A total of 152 patients with suspected sepsis were block-randomised to receive either intramuscular calcitriol (300,000 IU) (n = 76) or a placebo (n = 76). The trial was registered with the Clinical Trials Registry-India (CTRI No: CTRI 2019/01/17066) following ethics committee approval and was not funded. Results: There was no significant difference in APACHE II scores between the calcitriol and placebo groups from day 1 to day 7 (p = 0.382). There were no significant changes in 28-day mortality (14.4% vs. 17%, p = 0.65), number of days on a ventilator (5 vs. 5, p = 0.84), number of days on vasopressors (3 vs. 3, p = 0.98), length of ICU stay (10 days vs. 11 days, p = 0.78), adverse events (27.6% vs. 19.7%, p = 0.25), and hospital-acquired infections (17.1% vs. 15.8%, p = 0.82). Conclusions: There was no effect of intramuscular calcitriol in patients admitted to the ICU with sepsis.

Hypercalcemia Secondary to Calcitriol Production From Dual Combination Immunotherapy in Pulmonary Metastatic Melanoma.

Nivolumab and ipilimumab are immunotherapy agents recommended for the treatment of metastatic melanoma. A rare adverse effect of these agents is hypercalcemia. The mechanism of immunotherapy-mediated hypercalcemia is thought to be due to ectopic calcitriol production from activated macrophages, similar to sarcoidosis. We present a case of a 76-year-old female with metastatic melanoma who developed severe hypercalcemia after completing a cycle of combined nivolumab and ipilimumab therapy. After other common causes of hypercalcemia in malignancy were ruled out, the decision was made to aggressively treat her hypercalcemia while inpatient and hold immunotherapy at discharge. Since holding immunotherapy, she has not had a repeat occurrence of hypercalcemia. This case stresses the importance of including immunotherapy adverse effects in the differential diagnosis for hypercalcemia in malignancy.

Hypercalcemia Associated with Pregnancy and Lactation.

Hypercalcemia during pregnancy is a risk for adverse maternal and fetal consequences. Although primary hyperparathyroidism is by far the most common etiology of hypercalcemia in pregnancy, an array of other etiologies of hypercalcemia associated with pregnancy and lactation have been described. Parathyroidectomy continues to be the preferred treatment for primary hyperparathyroidism. Medical management options are limited.

The therapeutic potential of 1, 25-dihydroxy vitamin D3 on cisplatin-affected neurological functions is associated with the regulation of oxidative stress and inflammatory markers as well as levels of MMP2/9.

Calcitriol as a biologically active form of vitamin D3 has beneficial effects on all body systems. This vitamin has a potent neuroprotective effect via several independent mechanisms against brain insults induced by anticancer drugs. The present study was designed to examine the neuroprotective effects of calcitriol against neurotoxicity induced by cisplatin. Induction of neurotoxicity was done with cisplatin administration (5 mg/kg/week) for 5 successive weeks in male Wistar rats. The neuroprotective influence of calcitriol supplementation (100ng/kg/day for 5 weeks) was assessed through behavioral, electrophysiological, and molecular experiments. Cisplatin administration impaired spatial learning and memory and decreased prefrontal brain-derived neurotrophic factor (BDNF). Peripheral sensory neuropathy was induced through cisplatin administration. Cisplatin also reduced the amplitudes of the compound action potential of sensory nerves in electrophysiological studies. Cisplatin treatment elevated MDA levels and reduced anti-oxidant (SOD and GPx) enzymes. Pro-inflammatory cytokines (IL-1ß and TNF-α) and metalloproteinase-2 and 9 (MMP-2/9) were augmented through treatment with cisplatin. Learning and memory impairments along with BDNF changes caused by cisplatin were amended with calcitriol supplementation. Reduced sensory nerve conduction velocity in the cisplatin-treated group was improved by calcitriol. Calcitriol partially improved redox imbalance and diminished the pro-inflammatory cytokines and MMP-2/9 levels. Our findings showed that calcitriol supplementation can relieve cisplatin-induced peripheral neurotoxicity. Calcitriol can be regarded as a promising new neuroprotective agent.