Calcitriol Pulse Research Articles

Safety and efficacy of high dose pulse calcitriol and docetaxel for androgen-independent prostate cancer

Abstract Background: Previous therapy usually included prostatectomy or radiation to remove or destroy the cancerous cells within the prostate capsule. But, many patients eventually fail therapy and die of recurrent androgen-independent prostate cancer (AIPC). To date, there is no effective cure for prostate cancer. This study aims to evaluate the clinical safety and efficacy of high-dose pulse calcitriol and docetaxel for androgen-independent prostate cancer to guide the clinician's drug use. Methods: Seven Eight databases included PubMed, PubMed Central, EMbase, Medline, China National Knowledge Infrastructure, WAN FANG Database, and Web of Science will be systematically retrieved from January 1st, 2010 to May 30th, 2021. We will screen eligible studies to meet the inclusion criteria. Two independent reviewers will extract data, evaluate the risk of bias and analyze data independently. The quality of the included studies will be evaluated by the RevMan 5.4 software. The Cochrane risk of bias tool will be used to assess the quality of the studies. Results: This systematic review will provide high-quality evidence for the safety and efficacy of high-dose pulse calcitriol and docetaxel for AIPC. Conclusions: The findings of the study will provide scientific evidence of the safety and efficacy of high dose pulse calcitriol, and docetaxel for AIPC to guide the clinician's drug use. Ethics and dissemination: Not applicable INPLASY registration number: INPLASY202170028.

Evaluation of the association of Wnt signaling with coronary artery calcification in patients on dialysis with severe secondary hyperparathyroidism

BackgroundPatients with end-stage renal disease have a higher risk of death from cardiovascular events, which can be mainly attributed to coronary artery calcification (CAC). Wnt signaling is involved in vascular development and may play a role in vascular calcification. This study aimed to evaluate CAC prevalence in patients on dialysis with severe secondary hyperparathyroidism (SHPT) and identify CAC risk factors.MethodsThe study is a retrospective analysis of the severe hyperparathyroidism registration study that prospectively recruited patients on dialysis with severe SHPT who were candidates for parathyroidectomy, from October 2013 to May 2015. CAC and bone mineral density (BMD) were measured. Demographic and clinical data including calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone, Dickkopf-related protein 1 (DKK1), and sclerostin levels were analyzed. CAC scores were reported in Agatston units (AU).ResultsA total of 61 patients were included in this study. No CAC, mild CAC (<100 AU), moderate CAC (>100 AU), and severe CAC (>400 AU) were observed in 4.9%, 11.4%, 14.8%, and 68.9% of patients, respectively. DKK1 and sclerostin were not associated with CAC. In univariate analysis, CAC was significantly correlated with age, sex (male), total cholesterol, and intravenous pulse calcitriol (p<0.05). CAC was not inversely correlated with the BMD, T scores, or Z scores of the femoral neck (p>0.05). In multivariate analysis, the stepwise forward multiple linear regression revealed that CAC was associated with age, male sex and intravenous pulse calcitriol (p<0.05). Furthermore, serum sclerostin was positively correlated with the BMD of the femoral neck but negatively associated with intact parathyroid hormone (p<0.05). Serum sclerostin was significantly associated with severely low bone mass with Z-scores<-2.5 of the femoral neck, even when adjusted for serum intact parathyroid hormone, vitamin D status, dialysis pattern, sex, and DKK-1 (p<0.05).ConclusionsThe patients on dialysis with severe SHPT have a high prevalence of vascular calcification. Although the Wnt signaling pathway could play a role in hyperparathyroid bone disease, CAC may be mainly due to the treatment modality rather than the Wnt signaling pathway associated bone metabolism in patients on dialysis with severe SHPT.

Randomized trial comparing pulse calcitriol and alfacalcidol for the treatment of secondary hyperparathyroidism in haemodialysis patients

Calcitriol and alfacalcidol are used extensively for the treatment of secondary hyperparathyroidism. Unfortunately, there is limited published data comparing the efficacy and tolerability of both active vitamin D sterols. This study was undertaken to determine whether calcitriol provides a therapeutic advantage to alfacalcidol. This was a randomized, active controlled study. Patients with intact parathyroid hormone (iPTH) >32 pmol/L were randomized to receive orally calcitriol or alfacalcidol after each haemodialysis for up to 24 weeks. Reduction of PTH, changes of plasma albumin-corrected calcium and phosphorus were analysed. The initial dose of alfacalcidol was twice that of calcitriol. Sixteen patients were randomized into each group. At baseline, plasma albumin-corrected calcium, phosphorus and PTH were no different between groups. At 24 weeks, PTH changes were -50.8 ± 31.8% and -49.4 ± 32.5% from the baseline in the calcitriol and alfacalcidol groups, respectively (P = 0.91). The patients who achieved target PTH of 16-32 pmol/L were 82% in the calcitriol and 67% in the alfacalcidol group (P = 0.44). Plasma albumin-corrected calcium and phosphorus were not significantly different but showed trends toward gradually increasing from baseline in both groups (calcium, 6.0 ± 7.2% vs 10.9 ± 6.5% (P = 0.10); phosphorus, 13.0 ± 29.4% vs 16.7 ± 57.2% (P = 0.83) in calcitriol and alfacalcidol, respectively). The mean dose of calcitriol and alfacalcidol were 4.1 and 6.9 µg/week, respectively (P < 0.0001). Alfacalcidol can be used to control secondary hyperparathyroidism at doses of 1.5-2.0 times that of calcitriol. The two drugs are equally efficacious and lead to similar changes in calcium and phosphorus.

HIGH DOSE PULSE CALCITRIOL, DOCETAXEL AND ESTRAMUSTINE FOR ANDROGEN INDEPENDENT PROSTATE CANCER: A PHASE I/II STUDY

We determined the safety and preliminary efficacy of the combination of high dose pulse calcitriol (1,25-dihydroxycholecalciferol) with a standard regimen of docetaxel plus estramustine in patients with metastatic androgen independent prostate cancer. Patients were treated with 60 microg calcitriol orally on day 1, 280 mg estramustine orally 3 times daily on days 1 to 5 and 60 mg/m docetaxel on day 2 (70 mg/m after cycle 1) every 21 days for up to 12 cycles. Patients also received 325 mg aspirin and 1 or 2 mg warfarin orally daily. Regimen safety was assessed in the first 6 patients and a dose de-escalation scheme for calcitriol was planned if dose limiting toxicities were noted during treatment cycle 1 in greater than a third of patients. A total of 24 patients, including 11 who were chemotherapy naïve and 13 who had previously been treated with docetaxel, were evaluable for toxicity and 22 for prostate specific antigen decrease data. The regimen was generally well tolerated. Treatment related grades 3 or greater toxicity seen in more than 1 patient included hypophosphatemia in 16.7% and neutropenia in 12.5%. Four patients had thromboembolic complications. Asymptomatic hypercalcemia was seen in 4 patients, including grades 2 and 1 in 1 and 3, respectively. Six of 11 evaluable, chemotherapy naïve patients (55%) met prostate specific antigen response criteria. One of 11 patients (9%) treated with prior docetaxel met these criteria. High dose calcitriol may be safely added to docetaxel and estramustine administered on a 21-day schedule.

Impact of Sevelamer Hydrochloride and the K/DOQI Guidelines

Sevelamer hydrochloride (SH) was registered as a new drug under the Japanese national health insurance scheme in 2003, and the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for the treatment of renal osteodystrophy were released the same year. At that time, treatment objectives for hemodialysis outpatients at the Kojinkai Ishimaki Clinic were settled established and the outcomes reviewed 18 months later. The relationship between the type and dosage of phosphate binder (PB), and the concentrations of adjusted calcium (Ca), phosphorus (P), intact parathyroid hormone (PTH), and bone alkaline phosphatase (BAP) was examined. Patients receiving calcitriol or maxacalcitol intravenous pulse therapy, or who had undergone simultaneous pancreas-kidney transplant, were excluded from this analysis. The PB was CaCO3 in 60% of cases, SH in 33.3%, and a combination of both in 21.9%; no PB was used in 6.7% of cases. The dosage of CaCO3 was 2.8+/-1.0 g/day, and 1alpha-hydroxy activated vitamin D3 (VD) was 0.46+/-0.24 microg/day; the respective concentrations of adjusted Ca, P, intact PTH, and BAP were 9.4+/-0.7 mg/dL, 5.6+/-1.7 mg/dL, 104+/-83.9 pg/mL, and 22.7+/-10.9 IU/L. In the SH monotherapy group, the dosage of SH was 3.9+/-0.725 g/day, and VD 0.62+/-0.21 microg/day, and the concentrations for adjusted Ca, P, intact PTH, and BAP were 9.6+/-0.4 mg/dL, 6.2+/-1.5 mg/dL, 150+/-42.9 pg/mL, and 38.5+/-14.2 IU/L, respectively. In the combined therapy group, the dosage of CaCO3 was 2.9+/-0.9 g/day, SH was 3.3+/-1.1 g/day, VD was 0.53+/-0.27 microg/day, and the respective concentrations were 9.2+/-1.0 mg/dL, 5.7+/-1.4 mg/dL, 160+/-107.8 pg/mL, and 31.3+/-42.0 IU/L. One-third of all subjects were administered SH, either as monotherapy or in combination with CaCO3, and in these patients the dosage of VD was able to increase.

Comparative Effect of Oral Pulse and Intravenous Calcitriol Treatment in Hemodialysis Patients: The Effect on Serum IL-1 and IL-6 Levels and Bone Mineral Density

Introduction: Increased serum levels of bone-resorptive cytokines such as interleukin-1β (IL-1β) and interleukin-6 (IL-6) have been implicated for changes in bone remodeling in hemodialysis patients. In this prospective randomized study, we aimed to compare the effect of oral and intravenous (IV) pulse calcitriol on serum levels of IL-1β and IL-6. Patients and Methods: Twenty-eight hemodialysis patients were included and consecutively randomized to receive either oral (n = 14, M/F = 7/7, mean age 42 ± 15 years) or IV pulse (n = 14, M/F = 6/8, mean age 38 ± 14 years) calcitriol treatment. No difference was found between groups for age, sex distribution, primary renal disease, mean time on hemodialysis and baseline biochemical parameters including serum levels of IL-1β and IL-6. Results: The percent fall of intact parathyroid hormone (iPTH) was significantly less with oral compared to IV calcitriol between 0 and the 3rd month (32 ± 21 vs. 56 ± 28%, p = 0.03). However, the percent fall in iPTH at the 6th month of the therapy was not different in the oral group compared to the IV group (57 ± 22 vs. 73 ± 24%, p = 0.12). The increase in bone mineral densities was higher in the IV group than the oral group. Oral and IV calcitriol caused a significant fall in IL-1β (p = 0.02 and p = 0.03, respectively) and IL-6 levels (p = 0.02 and p < 0.001, respectively) at the 6th month of treatment. The percent fall in serum IL-6 levels at the 6th month was significantly greater in the IV compared to the oral group (61 ± 18 vs. 36 ± 33%, p = 0.04), while the percent changes in serum IL-1β levels were similar. Conclusion: IV calcitriol therapy has a greater suppression of PTH at the 3rd month of the therapy. Despite no difference in serum PTH levels at the 6th month, IV therapy has a greater increase in bone mineral densities and a greater decrease in serum IL-6 levels. These findings suggest IV calcitriol treatment has a superior effect on bone remodeling by influencing the levels of bone-resorptive cytokines as compared to the oral therapy group, beyond its suppressive effect on iPTH.

A Phase I trial of pulse calcitriol in patients with refractory malignancies

BACKGROUND Calcitriol is the principal biologically active metabolite of vitamin D. Calcitriol's activity against many neoplasms is well documented, but calcitriol's therapeutic application has been hampered by predictable hypercalcemia when it is given daily. Because laboratory data has suggested that intermittent exposure to high levels of calcitriol may be sufficient to produce antiproliferative effects, the authors developed a Phase I trial to determine the maximal tolerated dose, dose-limiting toxicity, and the pharmacokinetic profile of calcitriol given weekly by mouth. METHODS Patients with refractory malignancies were enrolled for 4 weeks of treatment followed by 4 weeks of observation. Reenrollment at a higher dose level was permitted for patients who had evidence of response or stable disease and no Grade 3 or greater toxicity. The starting dose was 0.06 μg/kg. RESULTS Fifteen patients received 20 cycles of therapy. Doses up to 2.8 μg/kg of calcitriol weekly produced no dose-limiting toxicity. While peak levels and the area under the serum concentration-time curve of calcitriol increased in a linear fashion at lower doses, saturable absorption was observed at doses above 0.48 μg/kg. Doses of 0.48 μg/kg and above produced mean peak calcitriol levels of 1625 pg/mL, approximately 25-fold greater than top normal levels and well within the therapeutic range suggested by in vitro experiments. Eight patients experienced self-limiting Grade 1 hypercalcemia. CONCLUSIONS Weekly dosing of oral calcitriol permitted substantial dose escalation with minimal toxicity. Peak serum calcitriol levels were in the predicted therapeutic range. A dose of 0.5 μg/kg was selected for evaluation in Phase II studies. Cancer 2001;91:2431–9. © 2001 American Cancer Society.

A Phase I trial of pulse calcitriol in patients with refractory malignancies

Calcitriol is the principal biologically active metabolite of vitamin D. Calcitriol's activity against many neoplasms is well documented, but calcitriol's therapeutic application has been hampered by predictable hypercalcemia when it is given daily. Because laboratory data has suggested that intermittent exposure to high levels of calcitriol may be sufficient to produce antiproliferative effects, the authors developed a Phase I trial to determine the maximal tolerated dose, dose-limiting toxicity, and the pharmacokinetic profile of calcitriol given weekly by mouth. Patients with refractory malignancies were enrolled for 4 weeks of treatment followed by 4 weeks of observation. Reenrollment at a higher dose level was permitted for patients who had evidence of response or stable disease and no Grade 3 or greater toxicity. The starting dose was 0.06 microg/kg. Fifteen patients received 20 cycles of therapy. Doses up to 2.8 microg/kg of calcitriol weekly produced no dose-limiting toxicity. While peak levels and the area under the serum concentration-time curve of calcitriol increased in a linear fashion at lower doses, saturable absorption was observed at doses above 0.48 microg/kg. Doses of 0.48 microg/kg and above produced mean peak calcitriol levels of 1625 pg/mL, approximately 25-fold greater than top normal levels and well within the therapeutic range suggested by in vitro experiments. Eight patients experienced self-limiting Grade 1 hypercalcemia. Weekly dosing of oral calcitriol permitted substantial dose escalation with minimal toxicity. Peak serum calcitriol levels were in the predicted therapeutic range. A dose of 0.5 microg/kg was selected for evaluation in Phase II studies.

Daily but not pulse calcitriol therapy improves growth in experimental uremia

Calcitriol (C) pulse therapy is widely used to suppress secondary renal hyperparathyroidism. However, high C serum concentrations may have an antiproliferative effect on growth cartilage cells and may suppress growth rate. The study was designed to evaluate whether daily C and pulse C therapy have differential effects on growth in uremic rats. Female Sprague-Dawley rats (150 g, n=5-10 per group) underwent two-stage subtotal nephrectomy (U). The duration of uremia was 14-18 days. The animals were fed a standard diet or a diet with a low-calcium content. Rats on a low-calcium diet were randomized for recombinant human growth hormone (rhGH) treatment (2.5 IU/kg per day) or solvent. C was injected subcutaneous twice daily (15 pmol/day) or intraperitoneal (105 pmol) twice per week. Weight gain and length gain was determined weekly. After sacrifice, total body calcium was determined by total body neutron activation analysis. Bone micromorphometric analysis of third lumbar vertebra and double staining with tetracycline for determination of mineralization rate were performed. Whereas daily C significantly increased total body length gain within 2 weeks, pulse C did not (U solvent 4.0+/-0.3 cm, UC bolus 4.3+/-0.4 cm, UC daily 5.3+/-0.3 cm, P<0.05). A low-calcium diet reduced and rhGH increased basal length gain and weight gain; regardless of these preconditions, daily but not bolus C increased length gain significantly. C both daily and in bolus form reduced bone osteoid content, but daily C improved mineral apposition rate more than C bolus. Total body calcium corrected for body weight decreased with a low-calcium diet, was lowest with concomitant rhGH treatment, and was not improved by C. In conclusion, daily but not bolus C treatment improves growth in uremic rats.

Randomized Study on the Effect of Daily and Pulse Calcitriol on Serum iPTH: First Eight Weeks' Results

Randomized Study on the Effect of Daily and Pulse Calcitriol on Serum iPTH: First Eight Weeks' Results

Intraperitoneal Pulse Calcitriol in the Treatment of Secondary Hyperparathyroidism in Patients on Continuous Ambulatory Peritoneal Dialysis

To determine whether it is practicable to use intraperitoneal calcitriol to treat continuous ambulatory peritoneal dialysis (CAPD) patients with secondary hyperparathyroidism and whether this form of therapy is effective and safe. A prospective, nonrandomized study. Division of Nephrology, Tertiary Hospital. Eight patients from our CAPD population were recruited (5 F, 3 M), aged 24 to 63 years (mean 38.9 +/- 7.6 yr). They had been on CAPD for 8 to 84 months (mean 47.6 +/- 24.6 months). All the patients had bone biopsy-proven secondary hyperparathyroidism with 2 patients showing mixed lesions. The CAPD system was changed to the twin-bag system (Ultrabag, Baxter Healthcare, McGaw Park, IL, U.S.A.) in all 8 patients, who were taught to inject the calcitriol directly through the short transfer set and the Tenckhoff catheter into the peritoneal cavity, twice per week before bedtime. Calcium carbonate or calcium acetate was used as the main phosphate binder. Intact parathyroid hormone level (iPTH), serum ionized calcium (iCa), serum phosphate, and serum total alkaline phosphatase (alk. phos.) levels were measured at baseline and then every 4 weeks. The mean duration of follow-up was 10.5 months +/- 1.9 months. There was a significant drop of iPTH level from the pretreatment level of 100.6 +/- 35.8 pmol/L to a level of 63.8 +/- 48.7 pmol/L at 24 weeks (p = 0.036). The lowest level of iPTH attained was 43.4 +/- 27.0 pmol/L at 48 weeks. Serum total alk. phos. also dropped from 232.4 +/- 83.3 IU/L pretreatment to 147.9 +/- 52.0 IU/L at 24 weeks (p = 0.017). The decrease in alk. phos. level paralleled the decrease in iPTH level. The mean serum iCa level did not show any significant rise throughout the study period. The maximum dose of calcitriol used was 6.6 +/- 1.5 microg/week and the average dose of calcitriol was 5.4 +/- 1.2 microg/week. One patient did not respond satisfactorily and she subsequently had a parathyroidectomy. Two episodes of peritonitis occurred during the study period, giving a peritonitis rate of one episode per 42 patient-months. There was no significant change in the urea clearance tests or the peritoneal equilibration tests before and after the study. Intraperitoneal calcitriol is practicable, effective, and safe in the treatment of secondary hyperparathyroidism in CAPD patients.

Effects of Treatment of Secondary Hyperparathyroidism on the Lipid Profile in Patients on Hemodialysis

Abnormalities in circulating lipoprotein concentrations are a characteristic finding in patients undergoing dialytic therapy. A substantial number of these patients display type IV hyperlipoproteinemia. Certain data suggest that secondary hyperparathyroidism may induce disturbances in lipid metabolism. To evaluate the effects of pulse calcitriol therapy on the lipid profile in these patients, we undertook a prospective study in 12 patients on stable bicarbonate hemodialysis. Lipid parameters comprising cholesterol and the low- as well as the high-density lipoprotein subfractions, triglycerides, apolipoproteins A and B, serum parathyroid hormones (iPTH), alkaline phosphatase, calcium, phosphorus, hematocrit, and blood urea were obtained prior to commencement of pulse calcitriol therapy and again 8–10 weeks later. Calcitriol therapy was associated with a decrease in serum iPTH levels (701 ± 103.9 vs. 220.3 ± 50.5 pmol/l; p < 0.001). Significant increases in high-density lipoprotein cholesterol (32.8 ± 2.7 vs. 38.8 ± 2.3 mmol/l; p < 0.05) and apolipoprotein A-I (107.8 ± 6.1 vs. 121.8 ± 5.8 g/l; p < 0.05) were noted during the course of the study. Moreover, serum iPTH correlated inversely with high-density lipoprotein cholesterol and apolipoprotein A-I. There were no changes in other lipid parameters except for low-density lipoprotein cholesterol which showed a tendency to increase. We conclude that in short-term study, pulse oral calcitriol therapy is associated with an improvement in the lipid profile in patients with secondary hyperparathyroidism. However, it remains to be established whether ameliorating the uremic dyslipidemia results in any long-term clinical benefits.

Calcitriol oral pulse therapy in children with renal osteodystrophy

A 6-month protocol of oral pulse calcitriol was used in nine uraemic children (2-14 years old) on dialysis who presented with renal osteodystrophy. Calcitriol was administered twice a week, 4 micrograms per dose for patients over 30 kg and 3 micrograms for patients less than 30 kg. Plasma levels of parathyroid hormone, calcium, phosphorus and alkaline phosphatase were carefully controlled during the study. Parathyroid hormone levels decreased by 68% and 56% by the 2nd and 6th months of treatment in seven patients, while they remained unchanged in two patients with focal segmental glomerulosclerosis and massive proteinuria. Eight hypercalcaemic episodes from 77 determinations were observed, all of them recovered after 1 week of vitamin D withdrawal. We conclude that oral calcitriol pulse therapy is a good alternative for renal osteodystrophy in uraemic children. Careful monitoring of plasma parathyroid hormone and calcium is needed during follow-up when using this approach in paediatric patients.

Control of Hyperparathyroidism with Once Weekly Oral Pulse Calcitriol Therapy in a CAPD Patient

Control of Hyperparathyroidism with Once Weekly Oral Pulse Calcitriol Therapy in a CAPD Patient

Calcitriol Pulse Therapy for Severe Hyperparathyroidism or Calcium Salts as Phosphate Binders in Renal Dialysis Patients?

The concurrent use of calcitriol (CAL) pulse therapy to reduce parathyroid hormone (PTH) secretion and of calcium (Ca) salts as the most appropriate phosphate binders was evaluated for over 1 year in a group of 14 patients with good divalent ion control on CaCO3 therapy but with increasing levels of serum intact PTH. CAL pulse therapy was effective and safe in only 2 patients; in the remaining subjects it resulted in hypercalcemia and/or hyperphosphatemia, not reversed by adjusting the dialysate Ca concentration and or CaCO3 dose, and had to be stopped. Therefore, CAL pulse therapy does not seem to be compatible with Ca salts which, in our opinion, deserve priority in the therapy of renal dialysis patients.

Intravenous calcitriol (IV) vs oral pulse therapy (OPT) in chronic hemodialysis patients (HD)

Intravenous calcitriol (IV) vs oral pulse therapy (OPT) in chronic hemodialysis patients (HD)