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Hu J.,China Pharmaceutical University | Yu Q.,China Pharmaceutical University | Zhao F.,China Pharmaceutical University | Ji J.,China Pharmaceutical University | And 8 more authors.
Chemico-Biological Interactions | Year: 2015

Triptolide (TP) is a diterpene triepoxide with variety biological activities, such as anti-inflammatory, anti-cancerogenic, immunomodulatory and pro-apoptotic activities. However, its clinical application was limited by potential toxicity. Quercetin (Que) is a member of flavonoids with anti-oxidant effects. In this study, we aimed to demonstrate the protective effect of Que in TP-induced oxidative stress and decrease of testosterone generation in reproductive damage. Leydig cells were treated with TP (20, 40 and 60 nM), which caused obvious oxidative stress increasing intracellular ROS, decreasing activities and expressions of GPx and SOD. Apoptosis was resulted from depolarization of mitochondrial membrane potential (ΔΨm) and release of cytochrome C (Cyt-C) showing increase of BAX/Bcl-2 ratio, caspase-3 and caspase-9. Treatment of Que (5 μM) prior to triptolide could restore all the TP-induced alteration in a certain dose range indicating that the oxidative stress might be one reason of TP-induced reproductive toxic effect. These results suggest that the compatibility with Que might reduce the TP-induced reproductive toxicity, which provide a probability to extend the usage of TP. © 2015 Elsevier Ireland Ltd. Source

Lin T.-Y.,Tri Service General Hospital | Yang M.-H.,General Clinical Research Center | Chang F.-Y.,Tri Service General Hospital
Therapeutic Drug Monitoring | Year: 2013

PURPOSE:: The pharmacokinetic parameters of a single 400-mg oral dose of posaconazole suspension, administered under fasting and fed conditions, were compared in healthy male Taiwanese volunteers. METHODS:: After an overnight fast, 16 subjects received a single oral dose of posaconazole suspension (400 mg) under fasting conditions or immediately after a normal-fat (700-800 calories, 30% fat) or high-fat breakfast meal (800-1000 calories, 50% fat). The treatments were administered as per the 3 × 6 Williams square design, with a 1-week washout phase between treatments. Blood samples were drawn at predetermined time points (0, 1, 2, 3, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 48, 72, 96, and 120 hours). All plasma concentrations of posaconazole were measured by high-performance liquid chromatography. The observed maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC0-t and AUC0-â ̂ẑ), time to reach Cmax (tmax), and plasma half-life (t1/2) were assessed. RESULTS:: Fourteen subjects completed the study; 2 subjects withdrew because of adverse events. Thirteen subjects were included in the pharmacokinetic analysis. Sixteen subjects were included in the safety analysis. The mean posaconazole Cmax, AUC0-t, and AUC0-â ̂ẑ values were significantly lower under fasting conditions than after a normal-or a high-fat meal. The mean Cmax values under fasting, normal-fat, and high-fat conditions were 279.00 ± 123.32 ng/mL, 662.46 ± 251.02 ng/mL, and 608.38 ± 183.22 ng/mL, respectively (P < 0.0001); the mean AUC0-t values under each condition were 6828.56 ± 3349.12 ng·mL·h, 20,629.84 ± 8346.45 ng·mL·h, and 20,741.09 ± 7681.02 ng·mL·h, respectively (P < 0.0001); and the mean AUC0-â ̂ẑ values under each condition were 7304.72 ± 3444.54 ng·mL·h, 21,326.65 ± 8495.01 ng·mL·h, and 21,626.08 ± 8193.31 ng·mL·h, respectively (P < 0.0001). The mean tmax value was significantly shorter at 3.15 hours under fasting conditions than at 4.88 hours after normal-or high-fat meals (P = 0.0176). The mean t1/2 values were 22.0, 20.8, and 22.0 hours, respectively. CONCLUSIONS:: The posaconazole AUC increased by approximately 3-fold, Cmax by 2.2-fold, and tmax by 1.5-fold when healthy Taiwanese subjects were administered the drug with food compared with under fasting conditions. These parameters were similar when the drug was administered with either a normal-or high-fat meal. Copyright © 2013 by Lippincott Williams & Wilkins. Source

Mi S.,Clinical Immunobiology Correlative Studies Laboratory | Stinson S.,General Clinical Research Center | Kalos M.,University of Pennsylvania | Lacey S.F.,Clinical Immunobiology Correlative Studies Laboratory | And 3 more authors.
Science Translational Medicine | Year: 2010

AIDS patients who develop lymphoma are often treated with transplanted hematopoietic progenitor cells. As a first step in developing a hematopoietic cell-based gene therapy treatment, four patients undergoing treatment with these transplanted cells were also given gene-modified peripheral blood-derived (CD34+) hematopoietic progenitor cells expressing three RNA-based anti-HIV moieties (tat/rev short hairpin RNA, TAR decoy, and CCR5 ribozyme). In vitro analysis of these gene-modified cells showed no differences in their hematopoietic potential compared with nontransduced cells. In vitro estimates of successful expression of the anti-HIV moieties were initially as high as 22% but declined to ∼1% over 4 weeks of culture. Ethical study design required that patients be transplanted with both gene-modified and unmanipulated hematopoietic progenitor cells obtained from the patient by apheresis. Transfected cells were successfully engrafted in all four infused patients by day 11, and there were no unexpected infusion-related toxicities. Persistent vector expression in multiple cell lineages was observed at low levels for up to 24 months, as was expression of the introduced small interfering RNA and ribozyme. Therefore, we have demonstrated stable vector expression in human blood cells after transplantation of autologous gene-modified hematopoietic progenitor cells. These results support the development of an RNA-based cell therapy platform for HIV. Source

Ouyang W.-C.,Jianan Mental Hospital | Ouyang W.-C.,General Clinical Research Center | Ouyang W.-C.,Chung Hwa University of Medical Technology | Hsu M.-C.,I - Shou University | And 2 more authors.
International Journal of Psychiatry in Clinical Practice | Year: 2012

Objective. The current study evaluated the efficacy and safety of risperidone and haloperidol as an adjunctive agent in combination with divalproate in patients with an episode of acute mania. Methods. This 6-week randomized, single-blind study was conducted in psychiatric wards of a mental hospital. A total of 41 patients were randomly assigned to the risperidone (risperidone plus divalproate) or haloperidol groups (haloperidol plus divalproate). Efficacy was assessed by changes in symptom rating scales [Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI) scores]. Safety and tolerability were assessed by monitoring the Extrapyramidal Symptom Rating Scale (ESRS) and Hamilton Rating Scale for depression. Results. Mean doses at baseline, and at weeks 4 and 6 were 3.77, 4.95 and 5.00 mg/day of risperidone and 5.89, 9.95 and 8.58 mg/day of haloperidol, respectively. Risperidone was shown to have significant anti-manic effects which was observed as early as week 1, following start of treatment. The BPRS scores were in favor of risperidone at week 2. Patients receiving risperidone exhibited significant greater global improvement on the CGI, as early as week 2 and over the entire treatment period, than haloperidol after 4 weeks of treatment. The ESRS at endpoint were significantly higher in the haloperidol patients. Conclusions. Risperidone plus divalproate was more efficacious than haloperidol plus divalproate for treatment of acute mania, and was well tolerated due to its evidence showing rapid anti-manic action, effective and sustained control of manic and psychotic symptoms and a favorable safety and tolerability profile in acute mania. © 2012 Informa Healthcare. Source

Horvath P.,University of California at Irvine | Horvath P.,Clinical Translational Science Institute | Oliver S.R.,University of California at Irvine | Oliver S.R.,Clinical Translational Science Institute | And 7 more authors.
Journal of Investigative Medicine | Year: 2013

Introduction: Cardiovascular complications are the leading cause of mortality in type 2 diabetes (T2DM), in which onset and progression of atherosclerosis is linked to chronic inflammation. Activation status of innate immune cells (granulocytes [Gc], monocytes [Mc]), as reflected by increased CD11b, CD66b, and other surface markers, increases their endothelial and cytokines/chemokines release. Whereas this inflammatory activation seems inversely related to poor glycemic control, the effect of acute spontaneous hyperglycemia on innate immune cell activation remains unclear. Methods: Expression of key markers (CD11b, CD14, CD16, CD62L, and CD66b) was therefore determined by flow cytometry on whole blood of healthy subjects and patients with T2DM with spontaneous fasting euglycemia or hyperglycemia both at baseline and after 30, 90, and 240 minutes of incubation at room temperature. Results: Hyperglycemic patients with T2DM had significantly higher Gc and Mc CD11b and Gc CD66b surface mean fluorescence intensity compared with the euglycemic patients with T2DM whose values were similar to those of the healthy controls. CD16 expression in CD14+CD16+ Mc was elevated in all patients with T2DM, regardless of glycemic levels. Conclusion: Our data suggest that whereas the presence of diabetes per se may have a proinflammatory effect, hyperglycemia seems to further acutely exacerbate innate cell inflammatory status and their consequent endothelial adhesion and vascular damage potential. Copyright © 2013 by The American Federation for Medical Research. Source

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