Obesity is often associated with vitamin D deficiency and secondary hyperparathyroidism. Vitamin D supplementation typically leads to the reductions in serum parathyroid hormone (PTH) levels, as shown in normal weight individuals. Meanwhile, the dose of vitamin D supplementation for the suppression of PTH may differ in overweight and obese adults. We conducted a systematic review and meta-analysis of randomized controlled trials to determine the dose of vitamin D supplementation required to suppress PTH levels in overweight/obese individuals. We identified 18 studies that examined overweight or obese healthy adults who were supplemented with varying doses of vitamin D3. The primary outcomes examined were changes in PTH and serum 25-hydroxyvitamin D (25OHD) levels from baseline to post-treatment. The results of the meta-analysis showed that there was a significant treatment effect of vitamin D supplementation on PTH, total standardized mean difference (SMD) (random effects) = −0.38 (95% CI = −0.56 to −0.20), t = −4.08, p < 0.001. A significant treatment effect of vitamin D supplementation was also found on 25OHD, total SMD (random effects) = 2.27 (95% CI = 1.48 to 3.06) t = 5.62, p < 0.001. Data from available clinical trials that supplemented adults with D3 ranging from 400 IU to 5714 IU, showed that 1000 IU of vitamin D supplementation best suppressed serum PTH levels, total SMD = −0.58, while vitamin D supplementation with 4000 IU showed the greatest increase in serum 25OH levels. Vitamin D and calcium supplementation of 700 IU and 500 mg, respectively, also showed a significant treatment effect on the suppression of PTH with a total SMD = −5.30 (95% CI = −9.72 to −0.88). In conclusion, the meta analysis of available clinical trials indicates that 1000 IU vitamin D supplementation can suppress serum PTH levels, while 4000 IU of vitamin D was associated with the largest increase in serum 25OHD levels in the overweight and obese population.
Background: No dose-finding trials are available for rituximab that could guide dosing in non-malignant diseases. We hypothesized that currently used doses (≥ 375mg/m 2) exceed several hundred-fold the half-maximal effective dose, which is most sensitive for detecting putative differences between biosimilars and important for dosefinding. Methods: In an exploratory, dose-finding, trial healthy volunteers received single infusions of 0.1 (n= 4), 0.3 (n= 4) and 1 mg/m 2 (n= 8) rituximab. Subsequently, in a randomized, double-blind trial, healthy volunteers received single infusions of 0.1 (n= 24) or 0.3 mg/ m 2 (n= 12) of two rituximab products. CD19/20+ cell counts were measured, pharmacokinetics and, immunogenicity were assessed. Results: Single infusions of 0.1, 0.3 and 1 mg/m 2 rituximab transiently depleted CD20+ cells by a mean 68% (95%CI: 24-100%), 74% (95%CI: 59-84%) and 97% (95%CI: 95-99%), respectively. In the randomized trial infusion of 0.1mg/m 2 or 0.3mg/m 2 proposed biosimilar or reference rituximab decreased CD20+cells by 45% (95%CI: 32-58%)-55% (95%CI: 45-66%) and 81 (95%CI: 73-87%)-87% (95%CI: 74-100%), respectively. In the randomized trial, 26 of 36 patients developed human anti-chimeric antibodies and 9 of 36 patients developed neutralizing anti-drug antibodies. Pharmacokinetic analyses were limited by the assay sensitivity and the very low rituximab doses. However, there was a clear pharmacokinetic signal during the first 24 hours in the 1mg/m 2 group. Conclusions: It is important to understand that < 1% of the authorized rituximab doses depletes all circulating B lymphocytes in healthy volunteers. This will help particularly countries struggling to meet the financial burden of therapy with biologics.
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