Table1_Optimization of the dosage regimen of zoledronic acid with a kinetic-pharmacodynamic model and exposure-response analysis.DOCX

Purpose: In order to support the dose optimization of zoledronic acid, the kinetic-pharmacodynamic model and exposure-response analysis were used to describe the changes in bone mineral density in different doses of zoledronic acid and establish the relationship between dose and acute phase reaction.Methods: Data were extracted from literature in accessible public databases. The kinetic-pharmacodynamic model was developed based on the above data using the NONMEM package to estimate parameters describing the relationship between the dose of zoledronic acid and bone mineral density. Exposure-response analysis was developed to establish the relationship between dose and acute phase reaction. Model evaluation was performed using goodness-of-fit, coefficient of variation (CV%). And sensitivity analyses were performed to assess the necessity of related parameters. Then the established model was used to simulate the changes of bone mineral density under different administration regimens, and the literature data was verified.Results: The kinetic-pharmacodynamic model successfully described zoledronic acid dose and change of bone mineral density in osteoporosis patients, with coefficient of variation of most less than 71.5%. The exposure-response analysis showed the incidence of acute phase reaction is dose-dependent. The bone mineral density was simulated based on the developed kinetic-pharmacodynamic model. And the simulated change of bone mineral density and the incidence of acute phase reaction could be helpful to propose a dosage regimen.Conclusion: Overall, the kinetic-pharmacodynamic model described changes of bone mineral density in different doses of zoledronic acid in vivo. And, the model and the exposure-response analysis also showed to provide the assessment of dose-response relationship for zoledronic acid.</p

One-Pot Synthesis and Combined Use of Modified Cotton Adsorbent and Flocculant for Purifying Dyeing Wastewater

A one-pot polymerization system using tetradecyl allyldimethylammonium chloride (TADMAC) and grafting cotton with unsaturated bonds (G-cotton) was designed to synthesize novel long-chain alkylation polycationic cotton (LP-cotton) and the homopolymer of TADMAC (PTADMAC). The LP-cotton had a high cationic degree of substitution of 0.108. The high monomer conversion of 98.8% suggests that almost all the TADMAC monomers participated in the polymerization. It is possible that when only LP-cotton was used as the adsorbent, its long-chain alkylation cationic TADMAC unit played the role of a similar surfactant in enhancing the association between the dye and cotton surface, resulting in a great improvement in adsorption capacity. The adsorption capacities were 57.5, 531.7, 4.4, and 2.9 times higher than those of the widely used activated carbon, untreated cotton, G-cotton, and polycationic film-coated cotton (PF-cotton), respectively, reported in our previous study. Using only PTADMAC as the flocculant led to a wide range of application adaptability, removing more than 97.0% of various anionic dyes in the water by forming flocs. As a result, PTADMAC could also be used as an enhancer at a low dosage for improving the flocculation ability of some conventional flocculants. Moreover, due to the mutual associations of the long-chain tetradecyl groups, the combined use of the LP-cotton adsorbent and PTADMAC flocculant not only reduced the dosage of LP-cotton adsorbent to 30% of that required for adsorption-only treatments but also decreased the dye removal time to 10 s. The dye solution became clear almost instantly, enhancing the removal of water-soluble dyes from water more comprehensively than the use of adsorbent or flocculant alone

<i>Pth1r</i> and <i>Igf-1r</i> mRNA Expression Levels After siRNA Transfection.

<p>The real-time PCR results showed that <i>Pth1r</i> and <i>Igf-1r</i> mRNA expression levels were significantly diminished in the left tibia compared with the right tibia (I-1-1 and P-1-1, one injection for one week; I-1-2 and P-1-2, one injection for two weeks; I-2-2 and P-2-2, two injections over two weeks). *p<0.01, **p<0.05 vs. the right tibia.</p

Animal Treatment Protocol and Images of the Intraosseous Injection Location.

<p>(A) Animal treatment protocol. (B) Anteroposterior and (D) lateral view of the minimally invasive puncture. The entry point was located at the front of the tibial intercondylar eminence, and the needle path penetrated the tibial plateau parallel to the long axis of the tibia. Representative (C) anteroposterior and (E) lateral X-ray radiographs of the tibia.</p

Maximum Force in the Three-point Bending Biomechanical Test.

<p>In the <i>Igf-1r</i> and <i>Pth1r</i> siRNA transfection groups, the mechanical properties of the left tibias, which received <i>Igf-1r</i> or <i>Pth1r</i> siRNA injections, were dramatically diminished compared to the right tibias (I-1-1 and P-1-1, one injection for one week; I-1-2 and P-1-2, one injection for two weeks; I-2-2 and P-2-2, two injections over two weeks). *p<0.05 and **p<0.01.</p

Quantitative μCT Analysis of Tibial Microstructural Parameters.

<p>Quantitative μCT Analysis of Tibial Microstructural Parameters.</p

Representative Images of Double Fluorochrome Labeling.

<p>In the <i>Igf-1r</i> siRNA transfection group, the distance between the two labels in the left tibias treated with <i>Igf-1r</i> siRNA and IGF-1 was significantly shorter than that in the right tibias treated with IGF-1 only. In the <i>Pth1r</i> siRNA transfection group, this distance was also markedly decreased in the left tibias treated with <i>Pth1r</i> siRNA and rhPTH (1–34) compared to the right tibias treated with rhPTH (1–34) only. Scale bar = 20 μm.</p

Representative Three-dimensional Trabecular Architecture of the Tibia After <i>Pth1r</i> or <i>Igf-1r</i> siRNA Injection.

<p>In the <i>Igf-1r</i> siRNA transfection groups, the trabeculae in the left tibias treated with <i>Igf-1r</i> siRNA and IGF-1 were dramatically weakened compared to those in the right tibias treated with IGF-1 only. In the <i>Pth1r</i> siRNA transfection groups, the trabeculae in the left tibias treated with <i>Pth1r</i> siRNA and rhPTH (1–34) were also significantly weakened compared to those in the right tibias treated with rhPTH (1–34) only.</p

Quantification of MARs.

<p>In the <i>Igf-1r</i> and <i>Pth1r</i> siRNA transfection groups, quantification of the MAR revealed that <i>Igf-1r</i> or <i>Pth1r</i> siRNA injection in the left tibias dramatically reduced the bone formation rate compared to the right tibias treated with IGF-1 or rhPTH (1–34) only (I-1-1 and P-1-1, one injection for one week; I-1-2 and P-1-2, one injection for two weeks; I-2-2 and P-2-2, two injections over two weeks). *p<0.05 and **p<0.01.</p

Immunohistochemical Staining for IGF-1R and PTH1R.

<p>The first three rows are representative images of the bone marrow of left tibias treated with <i>Igf-1r</i> siRNA and IGF-1 or <i>Pth1r</i> siRNA and rhPTH (1–34). The bottom row represents the isotype control for the anti-IGF-1R and anti-PTH1R antibodies. Scale bar = 50 μm.</p