An open-label, multiple-dose study to assess the preliminary pharmacokinetics, pharmacodynamics, clinical activity, and safety of human mouse chimeric anti-CD22 monoclonal antibody (SM03) in patients with rheumatoid arthritis.

BACKGROUND: The pharmacokinetics, safety, and clinical activity of antibodies targeting CD22 have been evaluated in systemic lupus erythematosus (SLE) and non-Hodgkin lymphoma (NHL) patients, however, there have been no reports for the rheumatoid arthritis (RA) population. SM03 is a novel chimeric IgG1 monoclonal antibody which targets the B-cell-restricted antigen CD22. This is the first study of the anti-CD22 antibody in RA patients. OBJECTIVES: This study was designed to preliminarily evaluate the pharmacokinetics, pharmacodynamics, safety, and clinical activity profiles of the anti-CD22 monoclonal antibody SM03 in Chinese patients with active RA. MATERIALS AND METHODS: This study was an open phase I study in 8 RA patients. Eligible patients received two 600 mg doses of SM03 administered through intravenous infusions given 2 weeks apart and were monitored over an 84-day observation period for pharmacokinetics, pharmacodynamics, immunogenicity, safety, and clinical responses. RESULTS: After multiple doses of SM03, the maximum serum concentration of SM03 was reached within 2 - 4 hours. Mean elimination half-life was 16 days (range: 13 - 22 days). Half of the patients responded according to ACR and DAS28 assessments, and CD19+ B lymphocyte counts decreased. Upper respiratory tract infections and headaches were the most common adverse events (AEs). No drug-related serious AEs were reported. CONCLUSION: This study is the first to report on the preliminary pharmacokinetics, pharmacodynamics, clinical activity, and safety of SM03 in RA patients. All AEs were mild or moderate in severity. SM03 showed potential efficacy in RA patients.

Toward Greater Insights on Applications of Modeling and Simulation in Pregnancy.

Pregnant women are often excluded from routine clinical trials. Consequently, appropriate dosing regimens for majority of drugs are unknown in this population, which may lead to unexpected safety issue or insufficient efficacy in this un-studied population. Establishing evidence through the conduct of clinical studies in pregnancy is still a challenge. In recent decades, physiologically-based pharmacokinetic (PBPK) modeling has proven to be useful to support dose selection under various clinical scenarios, such as renal and/or liver impairment, drug-drug interactions, and extrapolation from adult to children. By integrating gestational-dependent physiological characteristics and drug-specific information, PBPK models can be used to predict PK during pregnancy. Population pharmacokinetic (PopPK) modeling approach also could complement pregnancy clinical studies by its ability to analyze sparse sampling data. In the past five years, PBPK and PopPK approaches for pregnancy have made significant progress. We reviewed recent progress, challenges and potential solutions for the application of PBPK, PopPK, and exposure-response analysis in clinical drug development for pregnancy.

A novel therapeutic regimen for hepatic fibrosis using the combination of mesenchymal stem cells and baicalin.

Baicalin, isolated from the root of Scutellaria baicalensis Georgi, has shown anti-inflammatory and antioxidant activities, while mesenchymal stem cells (MSCs) have the capability of self-renewal and multilineage differentiation. In the present study, we found that baicalin could promote differentiation of bone marrow-derived MSCs into hepatocytes in vitro. We then compared the therapeutic effects of five therapeutic regimens for hepatic fibrosis induced by carbon tetrachloride in vivo by analysis of serum enzymes, morphological characteristics, cytokines and cell engraftment. Transplantation of MSCs alone was able to promote partial recovery of liver function and suppression of liver inflammation, but showed little effect on reducing the fibrotic area; transplantation with baicalin-treated MSCs gave an improved therapeutic effect; MSC transplantation and baicalin administration showed a synergistic effect; transplantation with baicalin-treated MSCs in combination with baicalin administration had the best therapeutic effect for hepatic fibrosis. Therefore, we conclude that transplantation of pre-differentiated MSC together with baicalin administration may serve as an effective therapeutic regimen for severe liver diseases.

Tanshinone IIA increases recruitment of bone marrow mesenchymal stem cells to infarct region via up-regulating stromal cell-derived factor-1/CXC chemokine receptor 4 axis in a myocardial ischemia model.

Systemic administration with bone marrow mesenchymal stem cells (BMSCs) is a promising approach to cure myocardial ischemia (MI), while the efficacy of cell transplantation is limited by the low engraftment of BMSCs. Tanshinone IIA (Tan IIA) has been reported many times for the treatment of MI. Therefore, the present study was performed to investigate whether Tan IIA could increase the migration of BMSCs to ischemic region and its potential mechanisms. In our study, we found that combination treatment with Tan IIA and BMSCs significantly alleviated the infarct size when compared with control group (31.46 ± 3.00% vs. 46.95 ± 6.51%, p<0.05). Results of real-time PCR showed that Tanshinone IIA (Tan IIA) did increase the migration of BMSCs to ischemic region in vivo, which was correlated with cardiac function recovery after MI. Furthermore, 2 µM Tan IIA could enhance the migration capability of BMSCs in vitro (3.69-fold of control), and this enhancement could be blocked by AMD3100 (a CXC chemokine receptor 4 blocker). CXCR4, together with its specific receptor, stromal cell-derived factor-1 (SDF-1) plays a critical role in the stem cell recruitment. Our experiment indicated that Tan IIA could promote SDF-1α expression in the infarct area and enhance the CXCR4 expression of BMSCs in vitro. Therefore, we postulated that Tan IIA could increase the BMSCs migration via up-regulating SDF1/CXCR4 axis.

Protective effects of baicalin on carbon tetrachloride induced liver injury by activating PPARγ and inhibiting TGFß1.

CONTEXT: Traditional Chinese herbal medicines have attracted considerable attention in many countries with treatment of several end-stage liver diseases. OBJECTIVE: The present study investigated the protective effects of baicalin on hepatotoxicity and hepatic fibrosis and explored the role of transforming growth factor ß1 (TGFß1) and peroxisome proliferator activated receptors γ (PPARγ) on the rat liver injury model. MATERIALS AND METHODS: The rat liver injury model was introduced by subcutaneous injection of carbon tetrachloride (CCl(4)) for 8 weeks. At week 5, rats were treated with baicalin of different doses or silymarin. Detection of biochemical indicators, histological analysis, and enzyme-linked immunosorbent assays were employed to evaluate severity of liver inflammation, and western blotting and RT-PCR assay were performed to evaluate TGFß1 and PPARγ pathway related proteins and gene expression. RESULTS: The administration of baicalin could significantly improve histological changes of CCl(4) treated rat livers and return biochemical indicators for liver injury to nearly baseline level. In addition, the increased expression of TGFß1 was markedly suppressed by baicalin, and decreased expression of PPARγ was also dramatically elevated by baicalin as well. The hepatoprotective effects of baicalin may be conferred by elevating the level of PPARγ contributing to down-regulation of TGFß1 signaling pathway and suppression of hepatic stellate cell activation. CONCLUSIONS: The studies demonstrated that baicalin is a potent and promising antifibrotic drug in the treatment of hepatic fibrosis.