A Single-center, Open-label, Parallel Control Study Comparing the Pharmacokinetics and Safety of a Single Oral Dose of Roflumilast and Its Active Metabolite Roflumilast N-oxide in Healthy Chinese and Caucasian Volunteers.

Roflumilast is a phosphodiesterase-4 inhibitor which treats chronic obstructive pulmonary disease (COPD). Roflumilast N-oxide is the major metabolite of roflumilast with a similar mechanism of action to roflumilast. Although racial differences in roflumilast drug disposition have been observed, the necessity of dose adjustment is subject to debate. This study compares the pharmacokinetics of a single 500 µg dose of roflumilast in healthy Chinese and Caucasian subjects under uniform conditions. Chinese subjects were found to have longer t1/2 and higher AUC0-t and Cmax than Caucasian subjects. The point estimates on the geometric mean of AUC0-t in Chinese subjects were 22% higher for roflumilast and 46% higher for roflumilast N-oxide. Point estimates on the geometric mean of Cmax were 9% and 24% higher for roflumilast and roflumilast N-oxide, respectively. Total phosphodiesterase-4 (PDE4) inhibitory (tPDE4i) activity, a theoretical parameter that describes the combined contribution to PDE4 inhibitory activity of roflumilast and roflumilast N-oxide, was 44% higher in Chinese subjects than in Caucasian subjects. With about a 10-fold higher plasma AUC compared to the parent roflumilast and a much longer observed half-life, roflumilast N-oxide has been estimated to contribute about 90% of tPDE4i, with 10% attributed to the parent compound roflumilast. Following body weight normalization, these figures were lower but remained significant. Safety analysis showed signs of reduced tolerance or different pharmacodynamic response to roflumilast in Chinese recipients than in Caucasians. Our results suggest that Chinese patients should receive a dose of roflumilast lower than 500 µg daily during future clinical trials.

Antibacterial Activity Prediction Model of Traditional Chinese Medicine Based on Combined Data-Driven Approach and Machine Learning Algorithm: Constructed and Validated.

Traditional Chinese medicines (TCMs), as a unique natural medicine resource, were used to prevent and treat bacterial diseases in China with a long history. To provide a prediction model of screening antibacterial TCMs for the design and discovery of novel antibacterial agents, the literature about antibacterial TCMs in the China National Knowledge Infrastructure (CNKI) and Web of Science database was retrieved. The data were extracted and standardized. A total of 28,786 pieces of data from 904 antibacterial TCMs were collected. The data of plant medicine were the most numerous. The result of association rules mining showed a high correlation between antibacterial activity with cold nature, bitter and sour tastes, hemostatic, and purging fire efficacies. Moreover, TCMs with antibacterial activity showed a specific aggregation in the phylogenetic tree; 92% of them came from Tracheophyta, of which 74% were mainly concentrated in rosids, asterids, Liliopsida, and Ranunculales. The prediction models of anti-Escherichia coli and anti-Staphylococcus aureus activity, with AUC values (the area under the ROC curve) of 77.5 and 80.0%, respectively, were constructed by the Neural Networks (NN) algorithm after Bagged Classification and Regression Tree (Bagged CART) and Linear Discriminant Analysis (LDA) selection. The in vitro experimental results showed the prediction accuracy of these two models was 75 and 60%, respectively. Four TCMs (Cirsii Japonici Herba Carbonisata, Changii Radix, Swertiae Herba, Callicarpae Formosanae Folium) were proposed for the first time to show antibacterial activity against E. coli and/or S. aureus. The results implied that the prediction model of antibacterial activity of TCMs based on properties and families showed certain prediction ability, which was of great significance to the screening of antibacterial TCMs and can be used to discover novel antibacterial agents.

[Spectrometric determination of trace elements in anticancer new medicine Fagopyrum dibotrys].

The golden buckwheat Fagopyrum dibotrys produced in Yunnan has a unique anti-cancer effects. It is a main raw material of "Wei Mai ning" capsules which is the national second-class anti-cancer drug. The present paper used (5 : 1) mixed acid as digestive juice to process the sample, and determine the twelve elements including K, Ca, Cu, Na, Mg, Mn, Fe, Zn, Pb, Cr, Cd and Co in the Fagopyrum dibotrys by inductively coupled plasma atomic emission spectrometry(ICP-AES). The detection limits of this method were 0.017-0.084 microg x mL(-1), the RSDs (n = 8) were all 0.09%-1.87%, and the addition standard recoveries(ASR) (n = 8) were 98.2%-107.4% for all elements. The research results showed that there is rich K(1 477.3 microg x g(-1)) in the Fagopyrum dibotrys, there are not harmful elements Cd and Pb, and this result is mainly related to the geochemistry background where the sample lived. The contents of seven remaining kinds of elements ranked as Na (826.1) > Ca (765.2 > Mg (493.4) > Zn (112.7) > Fe (56.5) > Cu (11.4) > Mn (4.49 microg x g(-1)). This result provides some theoretical basis for the study of internal relations between trace elements in Fagopyrum dibotrys and efficacy. It' s also useful for better development and utilization of the resource.

[Distributional difference of fat-soluble compounds in the roots, stems and leaves of four Salvia plants].

To illustrate distribution of fat-soluble compounds in the roots, stems and leaves of four Salvia plants, the methods of Histochemistry and HPLC were adopted to analyze different parts of the four Salvia plants in this paper. The results showed that distribution was differential, and following as this: the roots, stems and leaves of four Salvia plants contained fat-soluble compounds, moreover, the fat-soluble compounds of the roots located in periderm and the stems and leaves in epidermis. The main components of the fat-soluble compounds were Tanshinone IIA, Tanshinone I and Dihydrotanshinone I in the toots of Salvia miltiorrhiza Bunge and Salvia miltiorrhiza bge. f. alba, yet there were only Tanshinone IIA in the roots of Salvia japonica and Salvia officinalis. And fat-soluble compounds were not Tanshinone IIA, Tanshinone I and Dihydrotanshinone I in the stems and leaves of four Salvia plants. The type and content of fat-soluble compounds related to the species and introduction regions, they changed with the species and introduction regions. The conclusion clarified the accurate distribution of fat-soluble compounds in the different parts of four Salvia plants, and provided some theoretical basis for the application of Chinese herbs.

Three new flavonoid glycosides isolated from Elsholtzia bodinieri.

Three new flavonoid glycosides, eriodictyol 7-O-(6''-feruloyl)-beta-D-glucopyranoside (1), eriodictyol 7-O-[6''-(3'''-hydroxy-4'''-methoxy cinnamoyl)]-beta-D-glucopyranoside (2), and luteolin 7-O-[6''-(3'''-hydroxy-4'''-methoxy cinnamoyl)]-beta-D-glucopyranoside (3), and eight known flavonoids were isolated from the whole plants of Elsholtzia bodinieri. The structures of the 3 new compounds were elucidated on the basis of extensive spectroscopic analysis.

A simplified model to predict P-glycoprotein interacting drugs from 3D molecular interaction field.

A new two components partial least squares discriminant analysis (PLS) model for the prediction of P-glycoprotein-associated ATPase activity of drugs by using VolSurf compute theoretical molecular descriptors derived from 3D molecular interaction field was reported in the present study. By using 27 diverse drugs from literature, two models were constructed (R(2)=0.9003, 0.8150; Q(2)=0.7165, 0.7630) in this paper, which were similar to models that utilized MolSurf parametrization (R(2)=0.7760, 0.7180; Q(2)=0.7420, 0.6950) by using 22 drugs reported in the same literature. The results investigated VolSurf software was superior to MolSurf in its simplicity. Properties associated with the volume, polarizability, and hydrogen bond could have important impact on the P-glycoprotein-associated ATPase activity.

Effects of pretreatment with 8018 on the toxicokinetics of soman in rabbits and distribution in mice.

The effects of 8018 [3-(2'-phenyl-2'-cyclopentyl-2'-hydroxyl-ethoxy)quinuclidine] on the elimination of soman in rabbits blood and distribution in mice brain and diaphragm were investigated using the chirasil capillary gas chromatographic analysis method. In all experiments, the concentration of P(+)soman was below the detection limit (<0.1 ng x mL(-1)). 8018 (1 mg x kg(-1), im, 10 min pre-treated) could significantly reduce the concentration of P(-)soman in rabbit blood from 53.6 +/- 13.3 to 26.2 +/- 9.70 ng x mL(-1) blood as compared to soman-treated control animal at 15 s following soman injection (43.2 microg x kg(-1), iv). Toxicokinetic parameters showed 8018 could increase clearance (CL((S))) from 20.8 +/- 1.54 to 38.2 +/- 15.3 mLx kg(-1) x s(-1) and reduce AUC of P(-)soman from 2.08 +/- 0.151 to 1.30 +/- 0.564 mg x s x L(-1). 8018 could reduce the concentration P(-)soman in diaphragm from 74.7, 70.5, 88.7 ng x g(-1) to 54.5 45.6, 50.0 ng x g(-1) at the time of 30, 90, 120 s after intoxication of soman subcutaneously vs. soman control respectively, but it had no influence on the concentration of free P(-)soman in brain. Isotope trace experiments showed that it could significantly increase the distribution amount of bound [3H]soman in mice plasma and small intestine during 0-120 min after mice received [3H]soman (0.544 GBq.119 microg x kg(-1), sc) compared to soman control group.

Effects of pretreatment with verapamil on the toxicokinetics of soman in rabbits and distribution in mouse brain and diaphragm.

The effects of verapamil on the elimination of soman in rabbit blood and distribution in mouse brain and diaphragm by determining the concentration of P(-)soman using the chirasil capillary gas chromatographic analysis method were studied in order to study the effects of verapamil on the metabolic detoxification of soman. Verapamil (10 mg kg(-1), im, 30 min before soman administration) could significantly reduce the concentration of P(-)soman in rabbit blood at 15, 60, 90, 120, 180 and 240 s after soman injection (43.2 microg kg(-1), iv) as compared to soman-treated control animal respectively. Toxicokinetics parameters showed verapamil could increase clearance rate from 20.8+/-1.51 to 44.3+/-7.0 ml kg(-1)s(-1) and reduce AUC of P(-)soman from 2.08+/-0.151 to 0.996+/-0.172 mg s l(-1). For experiments in mice, verapamil could reduce the concentration P(-)soman in diaphragm from 74.7, 70.5, 88.7 to 41.1, 39.0, 49.3 ng g(-1) at the time of 30, 90, 120 s after intoxication of soman subcutaneously vs. soman control respectively, but it had no influence on the concentration of free P(-)soman in brain. Verapamil accelerated the elimination of P(-)soman in the rabbits blood and reduced the distribution of P(-)soman in the mouse diaphragm.

Influence of nimodipine on elimination of soman in rabbit blood and distribution of [3H]soman in mice.

AIM: To investigate the effect of nimodipine on the elimination of soman in rabbit blood and distribution of [3H]soman in mice. METHODS: Chirasil capillary gas chromatographic analysis method with large volume injections was used to determine the concentration of C(+/-)P(-)soman in rabbit blood. [3H]soman trace method was used to study the effect of nimodipine on soman distribution in mice. RESULTS: Nimodipine (10 mg/kg, ip, 1 h pre-treated) could significantly reduce the concentration of C(+/-)P(-)soman in rabbit blood from (54+/-13) to (19+/-12) microg/L blood at 15 s after soman injection (43.2 microg/kg, iv). Nimodipine could increase clearance rate [CL(S)] from (20.8+/-1.5) to (31+/-11) mL/kg/s and reduce AUC of C(+/-)P(-)soman from (2.08+/-0.15) to (1.6+/-0.4) mg/s. Nimodipine (10 mg/kg, ip, 1 h pre-treated) treatment could significantly reduce the distribution amount of bound [3H]soman in plasma, brain, lung, and liver, moreover increased the distribution amount of bound [3H]soman in small intestine during 0-120 min after mice received [3H]soman (0.544 GBq*119 microg/kg, sc) compared to soman control group. CONCLUSION: Nimodipine might alter the distribution of soman and reduce the initial concentration of soman in rabbit blood, then accelerated the metabolic detoxication of soman.

Influence of portal vein and liver artery ligation on the toxicokinetics of soman in rabbits.

The portal vein, liver artery ligation treatment and the portal vein ligation treatment could increase the concentration of P(-) soman in rabbit blood 3.6-19.3 times as compared with soman control group at each time points after soman injection (43.2 microgkg(-1), i.v.). Toxicokinetics parameters showed that portal vein, liver artery ligation treatment and portal vein ligation treatment could reduce the clearance (CL) and distribution volume (V(d)). Meanwhile, they could significantly increase the AUC of soman in rabbits from 2.08+/-0.154 to 18.2+/-2.96 and 22.9+/-3.73 mg s l(-1), respectively. All these data showed that the liver and intestine play a very important role on elimination the free soman in rabbit's blood at high dosing of soman.