Safety, Pharmacokinetics and Pharmacodynamics of TNHH, a Novel Targeted Neutrophil-Inhibitory Hirulog Hybrid Glycoprotein, in Healthy Volunteers.

BACKGROUND: Targeted neutrophil inhibitory-hirulog (TNHH) is a novel hybrid glycoprotein that may be a potential drug candidate for acute ischaemic stroke. OBJECTIVE: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TNHH in healthy volunteers and thereby determine the dose range for future clinical studies. METHODS: This randomized, placebo-controlled study was a single ascending dose design with dose levels of 0.05-1.8 mg/kg (n = 4-6 active, 2 placebos per cohort) in 68 participants. In the TNHH 0.2-1.8 mg/kg and control cohorts, pharmacokinetic and pharmacodynamic blood samples were collected over 168 h after intravenous (IV) administration. TNHH occupancy in peripheral blood neutrophils and blood coagulation were evaluated as the markers of target engagement. RESULTS: Two subjects withdrew from the trial before administration of the study treatment, 66 subjects are included in the data analysis. TNHH was well tolerated in all dose regimens. In total, five mild, self-limiting adverse events (AEs) were observed in 4 of the 66 study subjects. Dose-proportional increases in maximum plasma concentration (Cmax) and area under the curve (AUC0-t) of TNHH were observed. Traces of TNHH were excreted in urine. The elimination half-life (t½) ranged from 0.6 to 1.3 h in the eight groups with ascending dose levels. TNHH combined with CD11b/CD18 quickly achieved > 90% receptor occupancy in groups with doses above 0.2 mg/kg. The Cmax and AUC of binding TNHH with CD11b/CD18 increased with the dose. A significant prolongation with dose was observed on thrombin time (TT), and weak influences were observed on prothrombin time (PT) and activated partial thromboplastin time (APTT). CONCLUSION: TNHH was well-tolerated following IV infusion. The pharmacokinetic and pharmacodynamic characteristics of TNHH indicate that it merits clinical trials. It is recommended that the single dose of TNHH should be 1.0 mg/kg in future studies, and the expected effect may be achieved after 5-7 days of continuous administration. TRIAL REGISTRATION: The study is registered at http://www.chictr.org.cn as ChiCTR-TQR-14004752.

Application of data mining methods to improve screening for the risk of early gastric cancer.

BACKGROUND: Although gastric cancer is a malignancy with high morbidity and mortality in China, the survival rate of patients with early gastric cancer (EGC) is high after surgical resection. To strengthen diagnosing and screening is the key to improve the survival and life quality of patients with EGC. This study applied data mining methods to improve screening for the risk of EGC on the basis of noninvasive factors, and displayed important influence factors for the risk of EGC. METHODS: The dataset was derived from a project of the First Hospital Affiliated Guangdong Pharmaceutical University. A series of questionnaire surveys, serological examinations and endoscopy plus pathology biopsy were conducted in 618 patients with gastric diseases. Their risk of EGC was categorized into low and high risk of EGC by the results of endoscopy plus pathology biopsy. The synthetic minority oversampling technique (SMOTE) was used to solve imbalance categories of the risk of EGC. Four classification models of the risk of EGC was established, including logistic regression (LR) and three data mining algorithms. RESULTS: The three data mining models had higher accuracy than the LR model. Gain curves of the three data mining models were convexes more closer to ideal curves by contrast with that of the LR model. AUC of the three data mining models were larger than that of the LR model as well. The three data mining models predicted the risk of EGC more effectively in comparison with the LR model. Moreover, this study found 16 important influence factors for the risk of EGC, such as occupations, helicobacter pylori infection, drinking hot water and so on. CONCLUSIONS: The three data mining models have optimal predictive behaviors over the LR model, therefore can effectively evaluate the risk of EGC and assist clinicians in improving the diagnosis and screening of EGC. Sixteen important influence factors for the risk of EGC were illustrated, which may helpfully assess gastric carcinogenesis, and remind to early prevention and early detection of gastric cancer. This study may also be conducive to clinical researchers in selecting and conducting the optimal predictive models.

A QSAR Study Based on SVM for the Compound of Hydroxyl Benzoic Esters.

Hydroxyl benzoic esters are preservative, being widely used in food, medicine, and cosmetics. To explore the relationship between the molecular structure and antibacterial activity of these compounds and predict the compounds with similar structures, Quantitative Structure-Activity Relationship (QSAR) models of 25 kinds of hydroxyl benzoic esters with the quantum chemical parameters and molecular connectivity indexes are built based on support vector machine (SVM) by using R language. The External Standard Deviation Error of Prediction (SDEPext), fitting correlation coefficient (R2), and leave-one-out cross-validation (Q2LOO) are used to value the reliability, stability, and predictive ability of models. The results show that R2 and Q2LOO of 4 kinds of nonlinear models are more than 0.6 and SDEPext is 0.213, 0.222, 0.189, and 0.218, respectively. Compared with the multiple linear regression (MLR) model (R2 = 0.421, RSD = 0.260), the correlation coefficient and the standard deviation are both better than MLR. The reliability, stability, robustness, and external predictive ability of models are good, particularly of the model of linear kernel function and eps-regression type. This model can predict the antimicrobial activity of the compounds with similar structure in the applicability domain.

A pharmacokinetic and pharmacodynamic comparison of a novel pegylated recombinant consensus interferon-α variant with peginterferon-α-2a in healthy subjects.

AIMS: The aims of the study were to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of a novel, pegylated recombinant human consensus interferon-α variant (PEG-IFN-SA) in healthy volunteers. A pharmacokinetic and pharmacodynamic comparison of PEG-IFN-SA and peginterferon-α-2a in healthy subjects was evaluated. METHODS: A randomized, dose-escalating, single administration dose phase I clinical study was conducted. Thirty healthy subjects received PEG-IFN-SA as a single dose of 0.5-2.0 µg kg(-1) by subcutaneous (s.c.) injection in four parallel groups. Eight subjects received peginterferon-α-2a as a single dose of 180 µg s.c. RESULTS: The incidence rates of adverse events for PEG-IFN-SA and peginterferon-α-2a were 29 of 30 and 7 of 8, respectively. The adverse events for PEG-IFN-SA were mild to moderate and similar to those of peginterferon-α-2a. Within 168 h after injection, the mean values of maximal concentration and area under the plasma concentration-time curve from time of dosing to 168 h [AUC(0-168h) ] for 2',5'-oligoadenylate, neopterin and ß2 -microglobulin for PEG-IFN-SA at 1.5 µg kg(-1 ) s.c. were similar to or higher than those for peginterferon-α-2a at a dose of 180 µg s.c. After s.c. injection of PEG-IFN-SA at 1.5 µg kg(-1) , the mean geometric mean values of plasma half-life, time to maximal concentration, maximal concentration and AUC(0-168h) were 55.3 h, 26.9 h, 0.53 µg l(-1) and 44.0 µg l(-1) h, respectively. CONCLUSIONS: The tolerance, pharmacokinetic and pharmacodynamic characteristics of PEG-IFN-SA support its administration by s.c. injection as a single dose of 1.5 µg kg(-1) or at 2.0 µg kg(-1) per week.

[Pharmacokinetics of rhGH decorated by polyethylene glycol in rat in vivo].

To study the pharmacokinetics of rhGH decorated by polyethylene glycol (PEG-rhGH) after sc administration in rat, serum PEG-rhGH concentrations were measured by 125I labeled method after sc in rat, the pharmacokinetic model and parameters were fitted and calculated by the 3P97 program. After sc injection at doses of 150, 300, and 600 microg x kg(-1) in rat, the serum PEG-rhGH concentration-time curves were fitted to a one-compartment model. The rhGH decorated by polyethylene glycol could prolong the action duration of rhGH in vivo, and reach the goal of long-action.

[Application and expectation of data mining in traditional Chinese medical research of syndrome and treatment].

The data mining technology was introduced, and the law and peculiarity of TCM syndrome and treatment were analyzed in this paper. Concurrently, the application of the data mining in TCM researches on rule of syndrome and treatment was roughly summarized and its advantages and existing problems were pointed out. In order to enhance the efficiency and the appliance value of the mining technology and to accelerate the development of TCM research, the method for integrating multi-algorithms to make the mining was proposed.

[Efficacy of once-per-cycle administration pegylated recombinant human granulocyte colony-stimulating factor in chemotherapy-induced neutropenia in a phase I trial].

OBJECTIVE: To explore the efficacy of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in the prophylaxis of chemotherapy-induced neutropenia. METHODS: Patients with previously untreated non-small cell lung cancer or breast cancer and with normal bone marrow function were eligible for the trial. In the phase I trial, patients were to treated with two cycles of paclitaxel/carboplatin chemotherapy every 21 days. In cycle 1, if absolute neutrophil count (ANC) dropped below 1.0 x 10(9)/ L with fever and/or ANC dropped below 0.5 x 10(9)/L, rhG-CSF 150 microg/d was administrated until WBC > or = 10 x 10(9)/L or ANC > or = 5.0 x 10(9)/L. In cycle 2, patients were to receive a single injection of PEG-rhG-CSF (30, 60, 100, or 200 microg/kg) 48 hours after chemotherapy. Pharmacodynamic analyses were performed. RESULTS: All the 16 patients enrolled (4 in each group) were eligible for efficacy evaluation. In cycle 1, 7 patients received rhG-CSF administration because of grade 4 neutropenia, while in cycle 2, there was only 1 episode of grade 4 neutropenia, which were in the 30 microg/kg group. In cycle 1, the mean ANC nadir of 1.37 x 10(9)/L occurred on day 13 in the 9 patients who received no rhG-CSF administration. In cycle 2, the mean ANC nadirs were 0.77 x 10(9)/L, 4.54 x 10(9)/L, 3.00 x 10(9)/L, and 5.56 x 10(9)/L, respectively, in 30, 60, 100, or 200 microg/kg group. The nadirs of the first two groups occurred on day 8 of cycle 2, while those of the other two groups appeared on day 7. After PEG-rhG-CSF administration, two mean ANC peaks were observed. The first one ranging from 20.87 x 10(9)/L to 33.61 x 10(9)/L in the 4 groups appeared on day 3 to day 4. In the 30 microg/ kg group, the mean ANC reached the second peak at 5.03 x 10(9)/L on day 14. The second peaks on day 10 in the other groups were 12.42 x 10(9)/L, 11.59 x 10(9)/L, and 18.92 x 10(9)/L, respectively. Pharmacodynamic analyses showed sustained serum concentrations of PEG-rhG-CSF during the period of neutropenia. CONCLUSIONS: PEG-rhG-CSF administration may decrease the incidence of grade 4 neutopenia and result in earlier and higher nadir ANCs. PEG-rhG-CSF has a potential of once-per-cycle administration. The ANC and serum concentration of PEG-rhG-CSF are consistent with neutrophil receptor-mediated clearance.