scholarly journals A novel approach to rapid induction of remission in primary membranous nephropathy

2021 ◽  
Vol 93 (6) ◽  
pp. 706-712
Author(s):  
Vladimir A. Dobronravov ◽  
Olga B. Bystrova ◽  
Zinaida Sh. Kochoyan ◽  
Evgeniya N. Fomicheva
Keyword(s):  
Membranous Nephropathy ◽  
Cumulative Incidence ◽  
Therapy Group ◽  
High Serum ◽  
High Dose ◽  
Control Groups ◽  
Open Label ◽  
Serious Adverse Events ◽  
Rapid Induction ◽  
Phospholipase A2 Receptor

Aim. То evaluate the effectiveness of a novel multi-targeted treatment approach including rituximab (RTX), cyclophosphamide (CPH) and steroids (S) to the induction of remission in patients with primary membranous nephropathy (PMN) compared to standard immunosuppression (IST). Materials and methods. An open-label prospective comparative study included 56 PMN patients (pts) with nephrotic syndrome (NS) and high serum level of antibodies to the phospholipase A2 receptor anti-PLA2R (mean age 5112 years, men 70%). We recorded demographic and clinical parameters at the time of kidney biopsy, data from light-optical and immunomorphological studies. All pts were on stable doses of the renin-angiotensin systems blockers. We compared the effectiveness of different treatments in the inductions of clinical and immunological remissions in pts who received experimental treatment with RTX, CPH and S (RTX+CPH+S group, n=14) and two control groups: high-dose RTX therapy (group RTX, n=12), cyclosporine and steroids (group CsA+S, n=30). Results. In the RTX+CPH+S group, remission was achieved in 100% of cases (of which complete remissions CR in 21.4%). The median time-to-remission (2.5 [1.0; 3.5] months) was significantly lower compared to both control groups: RTX (8.7 [6.6; 14.0] months, p=0.005) and CsA+S (12.4 [6.5; 19.9] months, p0.001). The cumulative incidence of clinical and immunological remissions was also significantly higher in the RTX+CPH+S group than in the control groups. These results were confirmed in comparative analyzes in the same treatment groups after propensity score matching. The cumulative incidence of clinical and immunological remissions in the RTX+CPH+S group was higher than in the combined group of patients who received other therapies (p0.001). The incidence of serious adverse events was low and did not differ between groups. Conclusion. The use of multi-targeted therapy with rituximab, cyclophosphamide, and steroids seems to be an effective approach for the rapid induction of PMN remission and prevention of NS complications.

scholarly journals Open-Label Clinical Trials of Oral Pulse Dexamethasone for Adults with Idiopathic Nephrotic Syndrome

2019 ◽  
Vol 49 (5) ◽  
pp. 377-385 ◽  
Author(s):  
Monique E. Cho ◽  
Mary H. Branton ◽  
David A. Smith ◽  
Linda Bartlett ◽  
Lilian Howard ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Adverse Events ◽  
Idiopathic Nephrotic Syndrome ◽  
High Dose ◽  
Open Label ◽  
Serious Adverse Events ◽  
Oral Dexamethasone ◽  
Dose Oral ◽  
Pulse Dexamethasone ◽  
Daily Prednisone

Background: In adults with primary focal segmental glomerulosclerosis (FSGS), daily prednisone may induce complete remissions (CR) and partial remissions (PR), but relapses are frequent and adverse events are common. Methods: We carried out 2 open-label, uncontrolled trials to explore the efficacy and tolerability of pulse oral dexamethasone as an alternative to daily prednisone. We enrolled adult patients with proteinuria > 3.5 g/day despite the use of renin-angiotensin-aldosterone blockade. In the first trial, we enrolled 14 subjects with FSGS and administered 4 dexamethasone doses (25 mg/m2) daily for 4 days, repeated every 28 days over 32 weeks. The second trial involved a more intensive regimen. Eight subjects received 4 dexamethasone doses of 50 mg/m2 every 4 weeks for 12 weeks, followed by 4 doses of 25 mg/m2 every 4 weeks for 36 weeks; subjects were randomized to 2 doses every 2 weeks or 4 doses every 4 weeks. Results: In the first trial, we enrolled 13 subjects with FSGS and 1 with minimal change disease and found a combined CR and PR rate of 36%. In the second trial, we enrolled 8 subjects. The combined CR and PR rate was 29%. Analysis combining both trials showed a combined CR and PR rate of 33%. Adverse events were observed in 32% of subjects, with mood symptoms being most common. There were no serious adverse events related to the study. Conclusion: We conclude that high dose oral dexamethasone is well tolerated by adults with idiopathic nephrotic syndrome and may have some efficacy.

scholarly journals Efficacy of low or high-dose rituximab treatment in membranous nephropathy: a systematic review and meta-analysis

2021 ◽  
Author(s):  
Naresh Kharbuja ◽  
Min Wu ◽  
Yu-Chen Han ◽  
Dan Liu ◽  
Bin Wang ◽  
...  
Keyword(s):  
Membranous Nephropathy ◽  
Low Dose ◽  
Control Strategies ◽  
Therapeutic Option ◽  
Meta Analysis ◽  
Biological Indicators ◽  
High Dose ◽  
Serious Adverse Events ◽  
Protein Levels ◽  
Significant Difference

Abstract Background: Rituximab (RTX) has emerged as a promising therapeutic option in patients with primary membranous nephropathy (MN). But the optimal dosing of RTX protocol has not been established. Recently, favorable outcomes even with low-dose of RTX has been described in MN patients. Thus, the aim of this meta-analysis is to compare the efficacy and safety between high-dose and low-dose RTX in patients with MN.Methods: After literature search, eligible studies were further classified into high-dose and low-dose groups according to the dosage of one cycle RTX therapy. A meta-analysis was performed to evaluate remission rates and changes in biological indicators in two groups. Results: Eight studies involving 588 patients were included in this meta-analysis. In comparison to the control groups (including cyclosporin, cyclophosphamide, chlorambucil, prednisone, non-immunosuppressive anti-proteinuria treatment), RTX significantly improved the complete remission (CR) rate. Furthermore, there is no significant difference between high-dose and low-dose RTX in inducing total remission (TR) and CR. Also, high-dose RTX did not significantly improve serum albumin, creatine and urinary protein levels when compared with the low-dose RTX group. However, high-dose RTX did reduce the serum PLA2R antibody titers in patients. Even the difference was not significant, there was a tendency for low-dose RTX to have less serious adverse events (SAEs) than high-dose RTX groups. Conclusion: RTX administration indicated a better efficacy than the control strategies for the treatment of primary MN. And a low-dose regimen of RTX was non-inferior to high-dose usage in inducing long-term TR up to 24 months and holds the superior tendency in preventing SAEs in MN patients.

scholarly journals Effect of belimumab on proteinuria and anti-phospholipase A2 receptor autoantibody in primary membranous nephropathy

2019 ◽  
Vol 35 (4) ◽  
pp. 599-606 ◽  
Author(s):  
Christine Barrett ◽  
Lisa C Willcocks ◽  
Rachel B Jones ◽  
Ruth M Tarzi ◽  
Robert B Henderson ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Membranous Nephropathy ◽  
Remission Induction ◽  
Experimental Medicine ◽  
Open Label ◽  
Intention To Treat ◽  
Phospholipase A2 Receptor ◽  
B Cell Subsets ◽  
Treat Population

Abstract Background Immunosuppressant drugs reduce proteinuria and anti-phospholipase A2 receptor autoantibodies (PLA2R-Ab) in primary membranous nephropathy (PMN) with varying success and associated toxicities. This study aimed to evaluate the effect of belimumab on proteinuria and PLA2R-Ab in participants with PMN. Methods In this prospective, open-label, experimental medicine study, 14 participants with PMN and persistent nephrotic-range proteinuria received up to 2 years belimumab monotherapy (10 mg/kg, every 4 weeks). Changes in proteinuria (urinary protein:creatinine ratio), PLA2R-Ab, albumin, cholesterol, B-cell subsets and pharmacokinetics were analysed during treatment and up to 6 months after treatment. Results Eleven participants completed to the primary endpoint (Week 28) and nine participants completed the study. In the intention-to-treat population population, baseline proteinuria of 724 mg/mmol [95% confidence interval (CI) 579–906] decreased to 498 mg/mmol (95% CI 383–649) and 130 mg/mmol (95% CI 54–312) at Weeks 28 and 104, respectively, with changes statistically significant from Week 36 (n = 11, P = 0.047). PLA2R-Ab decreased from 174 RU/mL (95% CI 79–384) at baseline to 46 RU/mL (95% CI 16–132) and 4 RU/mL (95% CI 2–6) at Weeks 28 and 104, respectively, becoming statistically significant by Week 12 (n = 13, P = 0.02). Nine participants achieved partial (n = 8) or complete (n = 1) remission. Participants with abnormal albumin and/or cholesterol at baseline gained normal/near normal levels by the last follow-up. Adverse events were consistent with those expected in this population. Conclusions Belimumab treatment in participants with PMN can reduce PLA2R-Ab and subsequently proteinuria, important preludes to remission induction.

Safety and efficacy of letetresgene autoleucel (lete-cel; GSK3377794) in advanced myxoid/round cell liposarcoma (MRCLS) following high lymphodepletion (Cohort 2): Interim analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11521-11521
Author(s):  
Sandra P. D'Angelo ◽  
Mihaela Druta ◽  
Brian Andrew Van Tine ◽  
David A. Liebner ◽  
Scott Schuetze ◽  
...  
Keyword(s):  
T Cell ◽  
Interim Analysis ◽  
Tumor Regression ◽  
Cell Receptor ◽  
High Dose ◽  
Open Label ◽  
Serious Adverse Events ◽  
T Cell Therapy ◽  
Dose Cohort ◽  
Multiple Tumor

11521 Background: Cancer testis antigen NY-ESO-1 is expressed in multiple tumor types, including 80‒90% of MRCLS [1,2]. Overall response rates (ORRs) to MRCLS treatment are low (1L, <20%; 2L, <10%) [2]. Lete-cel, an autologous T-cell therapy, targets NY-ESO-1/LAGE-1a+ tumors using a genetically modified, high-affinity T-cell receptor. High-dose lymphodepletion (LD) was linked with better responses in synovial sarcoma [3]; the current study tested this hypothesis in MRCLS. Methods: This open label, pilot study evaluates lete-cel efficacy and safety in advanced MRCLS following low-dose (Cohort 1 [C1]; 30 mg/m2 fludarabine [flu] x 3d + 600 mg/m2 cyclophosphamide [cy] x 3d) or high-dose (Cohort 2 [C2]; 30 mg/m2 flu x 4d + 900 mg/m2 cy x 3d; initiated based on C1 data) LD. Key eligibility: age ≥18 y; HLA-A*02:01; A*02:05, or A*02:06; advanced high-grade NY-ESO-1+ MRCLS (≥30% of cells 2+/3+ by IHC); prior anthracycline; measurable disease; specified washouts; and active/chronic/intercurrent illness restrictions. Stages include screening, leukapheresis, lete-cel manufacture, LD, lete-cel infusion (1– 8 × 109 transduced T cells), follow-up. Response is assessed at wk 4, 8, 12, and 24, then every 3 mo to disease progression/death/withdrawal. The primary efficacy endpoint is investigator-assessed ORR by RECIST v1.1. In C1 (n=10 patients [pts]), lete-cel was well tolerated and linked with 2 confirmed partial responses (PR; ORR, 20%) and stable disease (SD) in 8 pts. Planned interim analysis for C2, shown here, was done once all 10 treated pts had ≥3 post-baseline disease assessments or progressed/died/withdrew. Efficacy data will be correlated with transduced cell kinetics and pharmacodynamics marker profiles. Results: Durable (1.0–7.8 mo) PR (4/10 pts [ORR, 40%]; 2 ongoing) and prolonged (2.7–10.6 mo) SD (5/10 pts; 3 ongoing) with tumor regression were observed. Treatment-emergent cytopenias occurred in all pts. All experienced T-cell related cytokine release syndrome (5 serious adverse events; 30% Grade 3), with onset ≤5d of infusion and median duration 7.5d. Graft-vs-host disease, immune effector cell–associated neurotoxicity syndrome, pancytopenia, or aplastic anemia were not reported. Conclusions: A single lete-cel infusion after high LD showed antitumor activity in advanced MRCLS and a manageable safety profile consistent with other lete-cel studies. The trial is active but no longer recruiting (NCT02992743). MRCLS is included in a separate, ongoing lete-cel study (NCT03967223). References: 1. D’Angelo SP, et al. J Clin Oncol 2018;36:15_suppl, 3005. 2. Pollack SM, et al. Cancer Med 2020;9(13):4593–602. 3. D’Angelo SP, et al. J Immunother Cancer 2020;8:P298. Funding: GSK (208469; NCT02992743). Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health, and funded by GSK. Clinical trial information: NCT02992743.

scholarly journals Malignancy-Associated Membranous Nephropathy with Positive Anti-PLA2R Autoantibodies: Coincidence or Connection

2021 ◽  
pp. 334-339
Author(s):  
Lyle W. Baker ◽  
Jaime Jimenez-Lopez ◽  
Xochiquetzal J. Geiger ◽  
Nabeel Aslam
Keyword(s):  
Renal Cell Carcinoma ◽  
Nephrotic Syndrome ◽  
Membranous Nephropathy ◽  
High Serum ◽  
Phospholipase A2 Receptor ◽  
Serum Titer ◽  
Current Classification ◽  
Age Appropriate ◽  
Poorly Differentiated ◽  
Very High

Membranous nephropathy (MN) is currently classified as either primary – often associated with positive anti-phospholipase-A2 receptor (PLA2R) autoantibodies – or as secondary – associated with malignancy, infection, medications, or autoimmune disease. We present a case of biopsy-proven MN with very high serum titer of anti-PLA2R autoantibodies in a patient with a synchronous diagnosis of poorly differentiated esophageal adenocarcinoma and renal cell carcinoma who presented with nephrotic syndrome. Based on the current classification, MN in the presence of active malignancy is diagnosed as secondary and unlikely to have positive anti-PLA2R autoantibodies. This raises several questions: whether this patient has secondary MN associated with malignancy and coincidentally discovered anti-PLA2R autoantibodies, primary MN due to anti-PLA2R autoantibodies with coincidentally discovered malignancy, or whether malignancy can induce the formation of anti-PLA2R autoantibodies that result in MN. This case report highlights the importance of age-appropriate cancer screening, even in patients with presumed primary MN and positive anti-PLA2R autoantibodies.

Randomized, Open-Label Phase III Trial of Docetaxel Plus High-Dose Calcitriol Versus Docetaxel Plus Prednisone for Patients With Castration-Resistant Prostate Cancer

2011 ◽  
Vol 29 (16) ◽  
pp. 2191-2198 ◽  
Author(s):  
Howard I. Scher ◽  
Xiaoyu Jia ◽  
Kim Chi ◽  
Ronald de Wit ◽  
William R. Berry ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Phase Iii ◽  
High Dose ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Serious Adverse Events ◽  
Phase Iii Trial ◽  
Castration Resistant ◽  
Open Label Phase

Purpose To compare the efficacy and safety of docetaxel plus high-dose calcitriol (DN-101) to docetaxel plus prednisone in an open-label phase III trial. Patients and Methods Nine hundred fifty-three men with metastatic castration-resistant prostate cancer (CRPC) were randomly assigned to Androgen-Independent Prostate Cancer Study of Calcitriol Enhancing Taxotere (ASCENT; 45 μg DN-101, 36 mg/m2 docetaxel, and 24 mg dexamethasone weekly for 3 of every 4 weeks) or control (5 mg prednisone twice daily with 75 mg/m2 docetaxel and 24 mg dexamethasone every 3 weeks) arms. The primary end point was overall survival (OS), assessed by the Kaplan-Meier method. Results At an interim analysis, more deaths were noted in the ASCENT arm, and the trial was halted. The median-follow-up for patients alive at last assessment was 11.7 months. Median OS was 17.8 months (95% CI, 16.0 to 19.5) in the ASCENT arm and 20.2 months (95% CI, 18.8 to 23.0) in the control arm (log-rank P = .002). Survival remained inferior after adjusting for baseline variables (hazard ratio, 1.33; P = .019). The two arms were similar in rates of total and serious adverse events. The most frequent adverse events were GI (reported in 75% of patients), and blood and lymphatic disorders (48%). Docetaxel toxicity leading to dose modification was more frequent in the ASCENT (31%) than in the control arm (15%). Conclusion ASCENT treatment was associated with shorter survival than the control. This difference might be due to either weekly docetaxel dosing, which, in a prior study, showed a trend toward inferior survival compared with an every-3-weeks regimen, or DN-101 therapy.

scholarly journals Efficacy and Safety of Different Immunosuppressive Therapies in Patients With Membranous Nephropathy and High PLA2R Antibody Titer

2022 ◽  
Vol 12 ◽  
Author(s):  
Le Deng ◽  
Qipeng Huang ◽  
Jiang Wang ◽  
Kaiping Luo ◽  
Jiarong Liu ◽  
...  
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Phospholipase A2 ◽  
Predictive Factor ◽  
Membranous Nephropathy ◽  
High Titer ◽  
Independent Predictive Factor ◽  
Serious Adverse Events ◽  
Phospholipase A2 Receptor ◽  
Remission Rates

Background: This study aimed to evaluate clinical features and prognosis and therapy option of patients with different risk ranks based on antibody against the M-type phospholipase-A2-receptor (PLA2Rab) level in seropositive M-type phospholipase-A2-receptor (PLA2R)-associated membranous nephropathy (MN) in a large sample size, multi-center study.Method: Based on the unvalidated cut-off value of PLA2Rab above 150 RU/ml as one of the clinical criteria for high risk of progressive kidney function loss in MN according to 2020 Kidney Disease: Improving Global Outcomes (KDIGO) draft guidelines recommendation, a total of 447 patients who received cyclophosphamide (CTX) or tacrolimus (TAC) combined with corticosteroids treatment for 12 months were divided into high titer (&gt;150 RU/ml) group and non-high titer (20–150 RU/ml) group, which were subdivided into CTX subgroup and TAC subgroup. The overall cohort was classified into CTX group and TAC group as well. Clinical parameters levels and remission rates were recorded at 3, 6, and 12 months follow-up. PLA2Rab was tested by enzyme-linked immunosorbent assay.Results: Patients with high titer PLA2Rab were associated with more severe proteinuria and hypoalbuminemia compared to those with non-high titer antibody, accompanied by lower complete remission (CR) and total remission (TR) rates at 3, 6, and 12 months, which even took longer to remission. Similar remission rates differences between the two titer groups were observed in the CTX and TAC groups, respectively. PLA2Rab level at baseline was an independent predictive factor for CR and TR. In the high titer group, CR and TR rates in the CTX subgroup were significantly higher than those in the TAC subgroup at 12 months, although serious adverse events were more frequent in the former.Conclusion: High-risk rank patients with PLA2Rab level above 150 RU/ml have higher disease activity and worse prognosis among patients with seropositive PLA2R-associated MN, even under different immunosuppressive therapeutic models; moreover, CTX combined with corticosteroids was preferred compared to TAC plus corticosteroids, although serious adverse events were more frequent in the former. Additionally, baseline PLA2Rab level was an independent predictive factor for clinical remission.

scholarly journals High-Dose Rituximab and Early Remission in PLA2R1-Related Membranous Nephropathy

2019 ◽  
Vol 14 (8) ◽  
pp. 1173-1182 ◽  
Author(s):  
Barbara Seitz-Polski ◽  
Karine Dahan ◽  
Hanna Debiec ◽  
Alexandra Rousseau ◽  
Marine Andreani ◽  
...  
Keyword(s):  
B Cells ◽  
Membranous Nephropathy ◽  
High Dose ◽  
Epitope Spreading ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Treatment Modification ◽  
Factors Associated ◽  
Study Population

Background and objectivesDifferent rituximab protocols are used to treat membranous nephropathy. We compared two rituximab protocols in patients with membranous nephropathy.Design, setting, participants, & measurementsTwenty-eight participants from the NICE cohort received two infusions of 1-g rituximab at 2-week intervals, whereas 27 participants from the Prospective Randomized Multicentric Open Label Study to Evaluate Rituximab Treatment for Membranous Nephropathy (GEMRITUX) cohort received two infusions of 375 mg/m2 at 1-week interval. We measured serum rituximab levels and compared remission at month 6 and before any treatment modification and analyzed factors associated with remission and relapses.ResultsRemissions occurred in 18 (64%) versus eight (30%) from the NICE and GEMRITUX cohort (P=0.02) at month 6, respectively, and in 24 (86%) versus 18 (67%) participants (P=0.12) before treatment modification, respectively. Median time to remission was 3 [interquartile range (IQR), 3–9] and 9 [IQR, 6–12] months for NICE and GEMRITUX cohorts respectively (P=0.01). Participants from the NICE cohort had higher circulating level of rituximab and lower CD19 counts (3.3 µg/L [IQR, 0.0–10.8] versus 0.0 [IQR, 0.0–0.0] P<0.001 and 0.0 [IQR, 0.0–2.0] versus 16.5 [IQR, 2.5–31.0] P<0.001) at month 3, lower level of anti-PLA2R1 antibodies at month 6 (0.0 [IQR, 0.0–8.0] versus 8.3 [IQR, 0.0–73.5] P=0.03). In the combined study population, lower epitope spreading at diagnosis and higher rituximab levels at month 3 were associated with remissions at month 6 (13/26 (50%) versus 22/29 (76%) P=0.05 and 2.2 µg/ml [IQR, 0.0–10.9] versus 0.0 µg/ml [IQR, 0.0–0.0] P<0.001 respectively). All non-spreaders entered into remission whatever the protocol. Eight of the 41 participants who reached remission had relapses. Epitope spreading at diagnosis (8/8 (100%) versus 16/33 (48%) P=0.01) and incomplete depletion of anti-PLA2R1 antibodies at month 6 (4/8 (50%) versus 5/33 (9%) P=0.05) were associated with relapses.ConclusionsOur work suggests that higher dose rituximab protocol is more effective on depletion of B-cells and lack of epitope spreading is associated with remission of membranous nephropathy.

scholarly journals Pharmacokinetics of Oral Cholecalciferol in Healthy Subjects with Vitamin D Deficiency: A Randomized Open-Label Study

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1553 ◽  
Author(s):  
Angelo Fassio ◽  
Giovanni Adami ◽  
Maurizio Rossini ◽  
Alessandro Giollo ◽  
Cristian Caimmi ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Healthy Subjects ◽  
High Dose ◽  
Open Label ◽  
Serious Adverse Events ◽  
Open Label Study ◽  
Label Study ◽  
Group A ◽  
Group B

Background: The aim of this study was to investigate the pharmacokinetic (PK) and safety profile of high-dose vitamin D supplementation, comparing different schedules (daily, weekly, or bi-weekly) in an otherwise healthy vitamin D-deficient population. Methods: Single-center, open-label study on healthy subjects deficient in vitamin D (25 (OH)D < 20 ng/mL), randomized to receive cholecalciferol (DIBASE®, Abiogen Pharma, Italy) using three different schedules: Group A: 10,000 IU/day for eight weeks followed by 1000 IU/day for four weeks; Group B: 50,000 IU/week for 12 weeks, Group C: 100,000 IU/every other week for 12 weeks. Total cumulative doses were: 588,000 IU, 600,000 IU, 600,000 IU. The treatment regimens corresponded to the highest doses allowed for cholecalciferol for the correction of vitamin D deficiency in adults in Italy. Results: mean 25 (OH)D plasma levels significantly increased from baseline 13.5 ± 3.7 ng/mL to peak values of 81.0 ± 15.0 ng/mL in Group A, 63.6 ± 7.9 ng/mL in Group B and 59.4 ± 12 ng/mL in Group C. On day 28, all subjects showed 25 (OH)D levels ≥20 ng/mL and 93.1% had 25 (OH)D levels ≥30 ng/mL. On day 56 and 84, all subjects had 25 (OH)D levels ≥30 ng/mL. No serious adverse events occurred during the study. Conclusions: normalization of 25 (OH)D serum levels was quickly attained with all the studied regimens. A more refracted schedule provided a higher systemic 25 (OH)D exposure.

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