D-Optimal Design and Development of a Koumine-Loaded Microemulsion for Rheumatoid Arthritis Treatment: In vivo and in vitro Evaluation.

Introduction: Koumine (KME) is the most abundant active ingredient separated from Gelsemium elegans Benth and exhibits a significant therapeutic effect on rheumatoid arthritis (RA). It is a lipophilic compound with poor aqueous solubility, and there is an urgent need to develop novel dosage forms of KME and promote its clinical application for the treatment of RA. The aim of this study was to design and develop KME-loaded microemulsions (KME-MEs) for the effective management of RA. Methods: The composition of the microemulsion was selected by carrying out a solubility study and generating pseudoternary phase diagrams, and further optimized by D-Optimal design. The optimized KME-MEs was evaluated for particle size, viscosity, drug release, storage stability, cytotoxicity, cellular uptake, Caco-2 cell transport and everted gut sac investigations. In vivo fluorescence imaging and the therapeutic effects of KME and KME-MEs on collagen-induced arthritis (CIA) rats were also evaluated. Results: The optimized microemulsion contained 8% oil, 32% Smix (surfactant/cosurfactant) and 60% water and was used for in vivo and in vitro studies. The optimal KME-MEs exhibited a small globule size of 18.5 ± 0.14 nm and good stability over 3 months, and the release kinetics followed a first-order model. These KME-MEs had no toxic effect on Caco-2 cells but were efficiently internalized into the cytoplasm. Compared to KME, the KME-MEs displayed significantly increased permeability and absorption in Caco-2 cell monolayer assay and ex vivo everted gut sac experiment. As expected, the KME-MEs attenuated the progression of RA in CIA rats and were more effective than free KME with a reduced frequency of administration. Conclusion: The KME-MEs improved the solubility and therapeutic efficacy of KME by employing formulation technology. These results provide a promising vehicle for the oral delivery of KME to treat RA and have attractive potential for clinical translation.

The retrospective analysis of surgical outcome of portal hypertension / 中华外科杂志

<p><b>OBJECTIVE</b>To retrospectively analyze the surgical outcome of portal hypertension and explore the risk-factors of long-term survival after operation.</p><p><b>METHODS</b>The data of 149 patients (male 119, female 30, aged from 19 to 73 years old) with portal hypertension treated surgically from January 1996 to October 2007 was collected. Among these patients, there were 110 patients for Child A and 39 patients for Child B according to Child-Pugh classification. According to different surgical modality, all patients were divided into devascularization group (n = 85) and shunting group (n = 64).</p><p><b>RESULTS</b>The follow-up rate was 78.8% and the average follow-up time was (46.3 +/- 30.4) months. The overall survival rates of 1-, 3-, 5- and 10-years were 95.6%, 88.7%, 83.4% and 65.1% respectively. Meanwhile the survival rates of 1-, 3-, 5- and 10-years in devascularization group and in shunting group were 95.4%, 87.7%, 80.6%, 56.3% and 95.8%, 90.1%, 86.8%, 72.6% respectively. There was no significant difference in survival rate between these two groups (P > 0.05). Child-Pugh classification has been the most important risk-factor that could influence long-term survival after operation by analysis of COX regression and it showed that the long-term survival time in Child A was longer than in Child B. The re-hemorrhage rates of 1-, 3- and 5-years in shunting group would be much better than in devascularization group. The rate of postoperative encephalopathy in devascularization group and shunting group was 6.9% and 6.1% respectively and there was no significant difference (P > 0.05). The portal venous pressure and flow of portal vein decreased significantly after shunting operation (P < 0.05).</p><p><b>CONCLUSIONS</b>The mainly sole risk-factor of long-term survival for portal hypertension has been the classification of Child-Pugh, not surgical procedure. The individualized proximal splenorenal shunt is much better than devascularization in controlling variceal hemorrhage.</p>