BackgroundModern medicine often clashes with traditional medicine such as Chinese herbal medicine because of the little understanding of the underlying mechanisms of action of the herbs. In an effort to promote integration of both sides and to accelerate the drug discovery from herbal medicines, an efficient systems pharmacology platform that represents ideal information convergence of pharmacochemistry, ADME properties, drug-likeness, drug targets, associated diseases and interaction networks, are urgently needed.DescriptionThe traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) was built based on the framework of systems pharmacology for herbal medicines. It consists of all the 499 Chinese herbs registered in the Chinese pharmacopoeia with 29,384 ingredients, 3,311 targets and 837 associated diseases. Twelve important ADME-related properties like human oral bioavailability, half-life, drug-likeness, Caco-2 permeability, blood-brain barrier and Lipinski’s rule of five are provided for drug screening and evaluation. TCMSP also provides drug targets and diseases of each active compound, which can automatically establish the compound-target and target-disease networks that let users view and analyze the drug action mechanisms. It is designed to fuel the development of herbal medicines and to promote integration of modern medicine and traditional medicine for drug discovery and development.ConclusionsThe particular strengths of TCMSP are the composition of the large number of herbal entries, and the ability to identify drug-target networks and drug-disease networks, which will help revealing the mechanisms of action of Chinese herbs, uncovering the nature of TCM theory and developing new herb-oriented drugs. TCMSP is freely available at http://sm.nwsuaf.edu.cn/lsp/tcmsp.php.
Orally administered drugs must overcome several barriers before reaching their target site. Such barriers depend largely upon specific membrane transport systems and intracellular drug-metabolizing enzymes. For the first time, the P-glycoprotein (P-gp) and cytochrome P450s, the main line of defense by limiting the oral bioavailability (OB) of drugs, were brought into construction of QSAR modeling for human OB based on 805 structurally diverse drug and drug-like molecules. The linear (multiple linear regression: MLR, and partial least squares regression: PLS) and nonlinear (support-vector machine regression: SVR) methods are used to construct the models with their predictivity verified with five-fold cross-validation and independent external tests. The performance of SVR is slightly better than that of MLR and PLS, as indicated by its determination coefficient (R2) of 0.80 and standard error of estimate (SEE) of 0.31 for test sets. For the MLR and PLS, they are relatively weak, showing prediction abilities of 0.60 and 0.64 for the training set with SEE of 0.40 and 0.31, respectively. Our study indicates that the MLR, PLS and SVR-based in silico models have good potential in facilitating the prediction of oral bioavailability and can be applied in future drug design.
BackgroundThis randomized phase III study was to evaluate the efficacy and safety of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis (PC) from gastric cancer.MethodsSixty-eight gastric PC patients were randomized into CRS alone (n = 34) or CRS + HIPEC (n = 34) receiving cisplatin 120 mg and mitomycin C 30 mg each in 6000 ml of normal saline at 43 ± 0.5°C for 60–90 min. The primary end point was overall survival, and the secondary end points were safety profiles.ResultsMajor clinicopathological characteristics were balanced between the 2 groups. The PC index was 2–36 (median 15) in the CRS + HIPEC and 3–23 (median 15) in the CRS groups (P = 0.489). The completeness of CRS score (CC 0–1) was 58.8% (20 of 34) in the CRS and 58.8% (20 of 34) in the CRS + HIPEC groups (P = 1.000). At a median follow-up of 32 months (7.5–83.5 months), death occurred in 33 of 34 (97.1%) cases in the CRS group and 29 of 34 (85.3%) cases of the CRS + HIPEC group. The median survival was 6.5 months (95% confidence interval 4.8–8.2 months) in CRS and 11.0 months (95% confidence interval 10.0–11.9 months) in the CRS + HIPEC groups (P = 0.046). Four patients (11.7%) in the CRS group and 5 (14.7%) patients in the CRS + HIPEC group developed serious adverse events (P = 0.839). Multivariate analysis found CRS + HIPEC, synchronous PC, CC 0–1, systemic chemotherapy ≥ 6 cycles, and no serious adverse events were independent predictors for better survival.ConclusionsFor synchronous gastric PC, CRS + HIPEC with mitomycin C 30 mg and cisplatin 120 mg may improve survival with acceptable morbidity.
The aim of this study was to characterize population pharmacokinetics and the exposure–neutropenia relationship with nanoparticle albumin-bound (nab)-paclitaxel in patients with solid tumors. Plasma and blood concentrations of paclitaxel and neutrophil data were collected from 150 patients with various solid tumors over the nab-paclitaxel dose range of 80–375 mg/m2. Data were analyzed using nonlinear mixed-effect modeling or logistic regression. Pharmacokinetics of nab-paclitaxel were described by a 3-compartment model with saturable distribution and elimination. The rapid disappearance of circulating paclitaxel was driven by its fast distribution to peripheral compartments; maximum rate for saturable distribution (325000 μg/h) was 40-fold greater than that for saturable elimination (8070 μg/h). Albumin was a significant covariate of paclitaxel elimination (P < .001), while total bilirubin, creatinine clearance, body size, age, sex, and tumor type had no significant or clinically relevant effect. The probability of experiencing a ≥50% reduction in neutrophils was best correlated to the duration above the drug concentration of 720 ng/mL. At a given exposure level, neutropenia development was positively correlated with increasing age but not significantly influenced by hepatic function, tumor type, sex, or dosing schedule. Covariate analyses supports exposure-matched dose adjustments in patients with moderate to severe hepatic impairment.
Systems pharmacology is an emerging field that integrates systems biology and pharmacology to advance the process of drug discovery, development and the understanding of therapeutic mechanisms. The aim of the present work is to highlight the role that the systems pharmacology plays across the traditional herbal medicines discipline, which is exemplified by a case study of botanical drugs applied in the treatment of depression. First, based on critically examined pharmacology and clinical knowledge, we propose a large-scale statistical analysis to evaluate the efficiency of herbs used in traditional medicines. Second, we focus on the exploration of the active ingredients and targets by carrying out complex structure-, omics- and network-based systematic investigations. Third, specific informatics methods are developed to infer drug-disease connections, with purpose to understand how drugs work on the specific targets and pathways. Finally, we propose a new systems pharmacology method, which is further applied to an integrated platform (Herbal medicine Systems Pharmacology) of blended herbal medicine and omics data sets, allowing for the systematization of current and traditional knowledge of herbal medicines and, importantly, for the application of this emerging body of knowledge to the development of new drugs for complex human diseases.
Bisphenol A (BPA) is a widespread endocrine-disrupting chemical used as the building block for polycarbonate plastics. Epidemiological evidence has correlated BPA exposure with higher risk of heart disease and type 2 diabetes. However, it remains unknown whether there are critical windows of susceptibility to BPA exposure on the development of dysglycemia. This study was an attempt to investigate the critical windows and the long-term consequences of perinatal exposure to BPA on glucose homeostasis. Pregnant mice were given either vehicle or BPA (100 µg/kg/day) at different time of perinatal stage: 1) on days 1–6 of pregnancy (P1–P6, preimplantation exposure); 2) from day 6 of pregnancy until postnatal day (PND) 0 (P6–PND0, fetal exposure); 3) from lactation until weaning (PND0–PND21, neonatal exposure); and 4) from day 6 of gestation until weaning (P6–PND21, fetal and neonatal exposure). At 3, 6 and 8 months of age, offspring in each group were challenged with glucose and insulin tolerance tests. Then islet morphometry and β-cell function were measured. The glucose homeostasis was impaired in P6-PND0 mice from 3 to 6 months of age, and this continued to 8 months in males, but not females. While in PND0-PND21 and P6-PND21 BPA-treated groups, only the 3-month-old male offspring developed glucose intolerance. Moreover, at the age of 3 months, perinatal exposure to BPA resulted in the increase of β-cell mass mainly due to the coordinate changes in cell replication, neogenesis, and apoptosis. The alterations of insulin secretion and insulin sensitivity, rather than β-cell mass, were consistent with the development of glucose intolerance. Our findings suggest that BPA may contribute to metabolic disorders relevant to glucose homeostasis and the effects of BPA were dose, sex, and time-dependent. Fetal development stage may be the critical window of susceptibility to BPA exposure.
The PreDC database is available at http://sm.nwsuaf.edu.cn/lsp/predc.php.
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