黄芩苷及其含药血清在大鼠体内的药动学、药效学相关性研究

目的：以黄芩苷含药血清对PC12细胞氧化损伤的保护作用为药效指标，研究黄芩苷的体内药动学及药效学过程的相关性。方法：大鼠灌胃后，测定不同取血点血清样本中的黄芩苷含量，运用血清药理学方法，观察血清样本对H2O2诱导PC12细胞氧化损伤模型的保护作用，对浓度．时间、效应．时间曲线进行相关分析，建立药动．药效结合模型；观察不同浓度黄芩苷溶液的保护作用，获得黄芩苷体外抗氧化作用的量效关系。结果：黄芩苷含药血清对PC12细胞氧化损伤有明显保护作用，且具有时间依赖性。效应-时间曲线的Emax为98％，fmax为15min；浓度-时间曲线的Cmax为9．39μg·ml^-1，fmax亦为15min，以Log（AUC）-AUE作图，图形近似呈“S”形。体外实验中，黄芩苷浓度在0．16～10μg·ml^-1范围内有抑制作用，且作用随剂量增加而增大。结论：黄芩苷体内、外均具有抗氧化作用，且效应的时效关系与血清中黄芩苷的时量关系呈正相关。

中药复方配伍规律的现代研究进展

近年来随着中药研究的不断深入,已有积累了大量单味中药的药效物质基础以及药理效应研究基础,关于中药复方的研究的突破与创新也是日新月异,层出不穷。传统的复方配伍理论有七情配伍和君臣佐使等,是古代医家的智慧凝练与经验汇总。而现代复方配伍规律研究工作主要围绕复方的有效组分配伍、给药后的入血成分和仿生学筛选得到的潜在活性成分研究,药效与配伍量或是指纹图谱的关系,活性成分的药代学-药动学特征以及复方的代谢组学等层次,结合化学,药理,数据分析,代谢多角度多交叉学科,证明其内在蕴含的科学性与协同性规律。

Determination of Plasma Concentration of Cinnamic Acid by High-Performance Liquid Chromatography and Its Pharmacokinetics in Rats after Oral Administration of Zi-Shen Pill

Aim To develop a simple and sensitive high-performance liquid chromatographicmethod for determination of plasma concentration of cinnamic acid and pharmacokinetic study in ratsafter a single oral dose of traditional Chinese medicinal preparation Zi-Shen pill. Method Plasmasamples were acidified with hydrochloric acid and extracted with ethyl acetate . Cinnamic acid wasdetermined by HPLC using a G_(18) column. A mobile phase ofmethanbl-acetonitrile-water-triethyl-amine (7:22:73 = 0.2, V/V), with the pH adjusted to 4.0 withphosphoric acid, and with a UV detector set at 340 nm. Results The standard curve was linear overthe range of 1.92- 192.0 μg·mL^(-1). The LLOQ was 1.92 μg·mL^(-1) . The RSDs of within-day andbetween-day precision were < 8%. The mean recovery was 82.0% . Conclusion After validation, themethpd has been used to investigate the pharmacokinetic profiles of the traditional Chinesemedicinal preparation Zi-Shen pill.

Preparation and characterization of 9-nitrocamptothecin self-emulsifying microemulsion injection

Aim To prepare a self-emulsifying microemulsion of 9-nitrocamptothecin （9-NC ME） for intravenous injection and investi- gation of its pharmacokinetic profiles in normal SD rats. Methods 9-NC ME was optimized in terms of droplet size and lack of drug precipitation following aqueous dilution using a pseudo-ternary phase diagram. Physicochemical properties of 9-NC ME were evaluated. 9-NC ME was intravenously administered via tail vein in healthy rats. Results A stable microemulsion was formulated consisted of soybean oil as oil phase, EPC/Tween-80 as emulsifier, and anhydrous ethanol as co-emulsifier. The droplets of the microemulsion were spherical shape with mean diameter of 38.3 ± 4.0 nm after 1：20 dilution with 5% glucose injection. The pharmacokinetic parameters of 9-NC ME after intravenous administration in rats were t1/2 of 0.97 ± 0.14 h, A UC0-8 of 372.77 ±49.62 ng·h·mL^-1 and MRT of 1.40 ± 0.21 h which were 1.4-fold, 1.65-fold, and 1.4-fold more than those of 9-NC solution （P〈0.01）. Conclusion The results suggested that 9-NC ME was a promising drug delivery system and it was expected to provide a novel 9-NC injection for cancer patients.

Determination of Zolmitriptan in Human Plasma by High-Performance Liquid Chromatography-Electrospray Mass Spectrometry and Study on Its Pharmacokinetics

Aim To establish a new and sensitive HPLC-MS method for the determination ofzolmitriptan in human plasma and study the pharmacokinetics of zolmitriptan in healthy volunteers.Methods A single oral dose of 5 mg of zolmitriptan tablet was given to 20 healthy male volunteers.After dosing, blood samples were collected for a period of 24 h, and zolmitriptan concentration inplasma was analyzed by HPLC-MS. Results The plasma concentration-time course fitted well atwo-compartment open model with a lag time, giving the following pharmacokinetic parameters: T_(max)1.60 ± 0.24 h, C_(max) 9.73 ± 1.43 ng·mL^(-1). T_(1/2α)1.72±0.46 h, T_(1/2β) 4.52 + 0.97 h,and AUC_(0-t) 55.59 ± 5.12 ng·mL^(-1)·h. Conclusion The improved analytical method forzolmitriptan is rapid, sensitive and suitable for application to pharmacokinetic studies and routinedetermination of numerous samples.

Pharmacokinetic-Pharmacodynamic Studies on Propra-nolol and 4-Hydroxypropranolol

The pharmacokinetic-pharmacodynamics of propranolol (PPL) and its activemetabolite 4-hydroxypropranolol (4-OH-P) was studied on Chinese subJects by single or multipleoral administration. The efficiency of beta-blockade was measured as the reduction of heart rates orblood pressure in the supine and upnght positions during rest or exercise period. After a single doseof 40 mg PPL, the plasma concentration of 4-OH-P was quite high, C (m) max and AUC (m) were26. 1±13.2 ng/ml and 180±69 ng.h/ml respectively, which were 50% and 73% of those of PPL.Whileafter multiple dose administration, the plasma PPL concentration increased much greater than that insingle administration and the 4-OH-P/PPL plasma level ratio fell from 0.79±0.64 at single dose toonly 0.48±0.32 at steady-state. The pharmacodynamic half-life of PPL on inbibiting exercising heart-rate was much longer than the halflife of drug concentration (8.78±2.27 vs 4.23±1.33 h. P<0.0 1).The Css 50. plasma concentration at steady-state producing 50% maximal efficacy, was 44.66±35.24ng/ml. The study showed that 4-OH-P is an important active metabolite of PPL and one of thepossible factors causing the considering variations in the response to PPL in Chinese people.

Construction and Evaluation of Merged Pharmacophore Based on Peroxisome Proliferator Receptor-Alpha Agonists

Pharmacophore is a commonly used method for molecular simulation, including ligand-based pharmacophore （LBP） and structure-based pharmacophore （SBP）. LBP can be utilized to identify active compounds usual with lower accuracy, and SBP is able to use for distin- guishing active compounds from inactive compounds with frequently higher missing rates. Merged pharmacophore （MP） is presented to integrate advantages and avoid shortcomings of LBP and SBP. In this work, LBP and SBP models were constructed for the study of per- oxisome proliferator receptor-alpha （PPARα） agonists. According to the comparison of the two types of pharmacophore models, mainly and secondarily pharmacological features were identified. The weight and tolerance values of these pharmacological features were adjusted to construct MP models by single-factor explorations and orthogonal experimental design based on SBP model. Then, the reliability and screening efficiency of the best MP model were validated by three databases. The best MP model was utilized to compute PPARα activity of compounds from traditional Chinese medicine. The screening efficiency of MP model outperformed individual LBP or SBP model for PPARα agonists, and was similar to combinatorial screening of LBP and SBP. However, MP model might have an advantage over the combination of LBP and SBP in evaluating the activity of compounds and avoiding the inconsistent prediction of LBP and SBP, which would be beneficial to guide drug design and optimization.

A Study on the Multi-Compartment Linear Circulation Pharmacokinetic Model for the Targeting Drug Delivery System

By analyzing the observed phenomena and the data collected in the study, a multi-compartment linear circulation model for targeting drug delivery system was developed and the function formulas of the drug concentration-time in blood and target organ by computing were figured out. The drug concentration-time curve for target organ can be plotted with reference to the data of drug concentration in blood according to the model. The pharmacokinetic parameters of the drug in target organ could also be obtained. The practicability of the model was further checked by the curves of drug concentration-time in blood and target organ(liver) of liver-targeting nanoparticles in animal tests. Based on the liver drug concentration-time curves calculated by the function formula of the drug in target organ, the pharmacokinetic behavior of the drug in target organ(liver) was analyzed by statistical moment, and its pharmacokinetic parameters in liver were obtained. It is suggested that the (relative targeting index( can be used for quantitative evaluation of the targeting drug delivery systems.

In vitro Dissolution and Pharmacokinetics in Beagle Dogs of a Self-Emulsifying Formulation of Tretinoin

Aim In vitro dissolution test and pharmacokinetics in beagle dogs wereconducted to assess the formulation of tretinoin in self-emulsifying systems. Methods Theconcentrations of tretinoin were determined by HPLC. A crossover study was performed in four fastingbeagle dogs with the formulation of self-emulsifying systems and commercial capsules. Results Theresults showed that the dissolution rate in 15 min of tretinoin in self-emulsifying systems washigher than 80% while that of the commercial capsules was lower than 5% . The area under the plasmaconcentration-time curve (AUC) of the self-emulsifying formulation was significantly higher andC_(max) was approximately two times greater than those of commercial capsule, respectively, Inaddition, the time taken to reach peak was shorter (2 h to 1.25 h) for self-emulsifying formulationof tretinoin. Conclusion The self-emulsifying drug delivery systems.can significantly increasetretinoin in vitro dissolution and in vivo absorption.

Is the required therapeutic effect always achieved by racemic switch of proton-pump inhibitors?

Many of the drugs currently used in medical practice are racemates. The enantiomers of a racemic drug differ in pharmacodynamics and/or pharmacokinetics, thus in some cases it is preferable to develop pure enantiomers by racemic switch. In a recent study by Pai et al, dexrabeprazole [R(+)-rabeprazole] (10 mg) was found to be more effective than rabeprazole (20 mg) in the treatment of gastroesophageal reflux disease. We read with great interest in this study and discussed whether such racemic switch would be applicable to other proton-pump inhibitors (PPIs). A literature review indicates that stereoselective pharmacokinetics, rather than stereoselective pharmacological activity, is the main cause of differences in clinical efficacy between pure enantiomer and racemic PPI. Racemic switches of PPI provide the therapeutic advantages such as reducing metabolic load on the body, simplifying pharmacokinetics, providing benefit to the non-responders to standard dose of racemate, more homogenous response to treatment and better efficacy with equal safety. Further studies in quantitative structure-activity relationships (QSARs) are needed to address the fact that the preferred enantiomer of PPI is not always in the same absolute configuration, i.e., S-form is for omeprazole, pantoprazole and tenatoprazole whereas R-form is for lansoprazole and rabeprazole.

P-glycoprotein mediated interactions between Chinese materia medica and pharmaceutical drugs

P-glycoprotein(P-gp)is an important transmembrane ATP-binding cassette(ABC)drug efflux transporter expressed in various human tissues such as the intestines,liver,kidneys,and bloodbrain barrier.It limits the intracellular concentration of xenobiotics by pumping them out of the cells,affecting drug pharmacokinetics and therapeutic effects.With its broad substrate specificity,it has the potential to remove a wide range of drugs from Chinese materia medica(CMM),including conventional medicines and active compounds.Increasing evidence has confirmed the superior therapeutic effectiveness of CMM in treating a wide range of diseases worldwide,as well as in conjunction with western drugs.As a result,herbal medicine-drug compounds have prompted widespread concern,with the majority of these interactions involving transporters such as P-gp.This review systematically summarizes the inhibition or induction of P-gp expression/function by active CMM compounds and the underlying regulatory mechanisms.It will aid in improving understanding of the synergistic or inhibiting effects associated with transporter P-gp as well as rational safety concerns for using CMM,particularly in combination with drugs.

Effect of Buyang Huanwu Decoction on Platelet Activating Factor Content in Arterial Blood Preand Post-Arterial Thrombosis in Rats

To explore the effect of Buyang Huanwu Decoction (BHD) on platelet activating factor (PAF) content in arterial blood pre- and post-arterial thrombosis in rats, male Wistar rats were randomly divided into 3 groups, the medicine group treated with BHD, the control group with dexamethasone liquid, and the blank group with distilled water. Oral administration was given for 14 consecutive days, once daily. Model of arterial thrombosis was established in the animals 2 hours after final medication, the blood content of PAF, dry weight (DW) and occlusion time (OT) of thrombus, and dry weight of thrombus/body weight (TW/BW) ratio were observed. Results indicated that BHD could markedly lower the arterial blood content of PAF after thrombosis, increase the OT of thrombus, reduce the dry weight of thrombus and the TW/BW ratio (P

Pharmacokinetic Study of a Novel Recombinant Human Granulocyte Colony-stimulating Factor in Rats

Objective To study the pharmacokinetics of a novel recombinant human granulocyte colonystimulating factor (rhG-CSFa) in rats and to determine the proteolytic rates of rhG-CSFa in the whole blood and serum of rats in vitro. Methods The pharmacokinetics of rhG-CSFa and conventional (wild type,WT) granulocyte colonystimulating factor (G-CSF) were investigated in Sprague-Dawley rats which received either intravenous or subcutaneous injection of rhG-CSFa or WT G-CSF at three different doses (20,50,or 100 μg/kg). The blood samples of rats were collected at multiple time points (from 0.08 to 12 h) and the concentrations of rhG-CSFa and WT G-CSF in serum were determined with a sandwich enzyme-linked immunosorbent assay (ELISA). For the study of proteolytic rates in vitro,the concentrations of rhG-CSFa or WT G-CSF were determined at 3-minute intervals after addition of the respective drug to rat’s whole blood or serum. Results Pharmacokinetic analysis of serum rhG-CSFa or WT G-CSF levels indicated that,at each dose tested,for either route of drug administration,the area under concentration-time curve values and the maximum serum concentration of rhG-CSFa were higher than those of WT G-CSF,and the serum half life of rhG-CSFa was longer than that of WT G-CSF. Subsequent in vitro whole blood and serum stability study showed that the rates of drug degradation in WT G-CSF were 1.8 folds and 1.5 folds higher than those in rhG-CSFa,respectively. Conclusion rhG-CSFa has better serum and whole blood stability in vitro and higher bioavailability in vivo as compared to WT G-CSF.

Pharmacokinetics and Pharmacodynamics of Subcutaneous Single Doses of Pegylated Human G-CSF Mutant(PEG30-rhG-CSF) in Beagle Dogs

OBJECTIVE To compare the pharmacokinetics and pharmacodynamics of PEG30-rhG-CSF administered to beagle dogs at three different dosages with PEG20-rhG-CSF administered at one dosage, and to provide an experimental basis for clinical trials.METHODS Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200 μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzymeqinked immunosorbent assay （ELISA）. WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis software.METHODS Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzyme-linked immunosorbent assay （ELISA）. WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis software. RESULTS The pharmacokinetic parameters of PEG30-rhG-CSF calculated from the serum concentration data determined by ELISA were as follows： the mean elimination half-life （t1/2ke） was 40.6 h （33.5-45.4 h）; the mean time to reach peak concentration （Tmax） was 19.2 h （11.7-24.0 h）; the drug clearance from the serum （CL） was decreased with increasing doses; the peak concentration （Cmax） and the area under the serum concentration-time curve （AUC） were increased with increasing doses. For PEG20-rhG- CSF, the half-life was shorter （12 h） and Tmax was achieved much earlier （10 h） relative to PEG30-rhG-CSF. The AUC of PEG30- rhG-CSF was much greater than that of PEG20-rhG-CSF, and the relative bioavailability with a subcutaneous injection was 158.7%. Administration of single doses of PEG30-rhG-CSF resulted in substantial increases in the absolute The time to reach ANC （ANCTmax） neutrophil count （ANC）. was 72 h. The maximum observed absolute neutrophil counts （ANCmax） and the area over the baseline effect curve （AOBEC） was increased with increasing doses. The effect-elimination half-life （t1/2E） ranged from 60 h to 80 h after subcutaneous administration. The PLT count was slightly elevated 8-12 h after s.c. injection, and declined after 24 h. CONCLUSION The mean elimination half-life of PEG30-rhG- CSF was longer than that of PEG20-rhG-CSF at the same dose, and the other main pharmacokinetic and pharmacodynamic parameters of PEG30-rhG-CSF, including C ANCmax, AUC and AOBEC were much greater than those following PEG20-rhG-CSF injection.

Bloodstream Infection with Carbapenem-resistant Klebsiella Pneumoniae and Multidrug-resistant Acinetobacter Baumannii:a Case Report

IN the presence of septic shock, every hour in delaying the administration of effective antibiotics is associated with a measurable increase in mortality. This is especially true for neutropenic patients with septic shock. As there is a higher incidence of involving multi-drug resistant pathogens for neutropenic patients, the decision on antibiotics regime remains a challenge for physicians.2 Immunosuppression and previous antibacterial use are factors that promote the spread of multi-drug resistant pathogens, and the possibility of co-existing multi-drug resistant pathogens should be suspected when treating patients with these risk factors who developed refractory shock. Here we present a case with neutropenic fever and refractory shock whose blood culture yielded multi-drug resistant Acinetobacter baumannii and carbapenem- resistant Klebsiella pneumoniae.

Serious response during tilt-table test in elderly and its prophylactic management

Objective: To evaluate the serious response during tilt-table test (TTT) and its prophylactic management. Method: Seventy-six elderly patients were tested at a tilt angle of 70 degrees for a maximum of 45 min and then subjected to isoprotere- nol-provocative tilt testing. ECG and blood pressure were monitored during the test and patients were kept at normal saline con- dition through a peripheral intravenous duct. Results: Fifty-one of 76 patients were defined as positive including 23 having serious response; 6 of the 23 patients had arteriosclerosis involving internal carotid arteries and 7 cases had bradycardia, two of which were associated with II°-I A-V block and the others with chronic atrial fibrillation. The serious response consisted of cardiac arrest for more than 5 s (6 cases), or serious bradycardia for more than 1 min (7 cases) or serious hypotension for more than 1 min (10 cases). Those with serious response were managed by returning to supine position, thus driving up legs and intravenous atropine, CPR (2 cases with cardiac arrest) and needing oxygen supplementation (11 cases). Only 2 hypotension patients recovered gradually by 10 min after emergency management, while others recovered rapidly with no complications. Conclusion: Although non-invasive, TTT may result in serious response, especially in elderly. Therefore proper patient selection, control of isoproterenol infusion and close observation of vital signs are decisive for a safe consequence.

Protective Effect of Rhubarb on Endotoxin-Induced Acute Lung Injury

To approach the mechanism of lipopolysaccharide (LPS) in causing acute lung injury (ALI) and the protective effect of rhubarb and dexamethasone, lung specimens were examined with macroscopy, microscopy, electron microscopy and the biological markers of ALI including lung wet/dry weight, the rate of neutrophils and protein content in the pulmonary alveolar lavage fluid, pulmonary capillary permeability and pulmonary alveolar permeability index were observed. The mechanism of the ALI is mainly due to direct injury of alveolar epithelium and pulmonary vascular endothelium. Rhubarb and dexamethasone could significantly reduce the edema of the lung tissue, decrease the red blood cell exudation, neutrophil infiltration and plasma protein exudation in the alveoli and all the biological markers in comparison with the ALI model rats, indicating they have protective action on vascular endothelium and alveolar epithelium.

Study of Linearization of Hill Dose-Effect Curve with Metabolic Velocity Instead of Drug Concentration

Objective To explore the velocity-effect relationship in order to the establish linearization of effect on an equation with regard to the consistency of the Hill dose-effect expression with the metabolic kinetics of receptors.Methods The linear velocity-effect expression was obtained by solving multivariant differential equation groups,which were established to compare the coincidences and basic relations between the Hill dose-effect and metabolic kinetic Michaelis-Menten equation for receptors.The validation test was conducted with acetylcholine,adrenaline,and their mixture as model drugs.Results The linear velocity-effect modelling was represented in vivo or in vitro,for single and multidrug systems.Pharmacodynamic parameters,especially suitable for multicomponent CMM formulas,could be determined and calculated for single or multicomponent formulas at high saturating or low linear concentration for receptors.The validation test showed that the pharmacodynamic parameters of acetylcholine were:k,2.675×10^-3s^-1;ka,5.786×10^-9s^-1;km,2.500×10^-7s^-1;α,4.619×10^9张s·mg^-1;E0,13张(P<0.01)and those of adrenaline were:k,1.415×10^-3s^-1;ka,5.846×10^-9s^-1;km,2.300×10^-7s^-1;α,-1.627×10^9张s·m g^-1;E0,9.2张(P<0.01).For the mixture of the two components,the values were:α,1.375×1010张s·m g^-1;-6.150×10^9张s m g^-1for acetylcholine and adrenaline,respectively,and E0was7.08张in both,with the other parameters unchanged(P<0.01).Conclusion The velocity-effect equation can linearize the Hill dose-effect relationship,which can be applied to study the pharmacodynamics and availability of CMM formulations in vivo and in vitro.

Solubilities of Cimaterol and Mabuterol in SF-CO_2

The solubilities of two β-agonists, cimaterol and mabuterol, in supercritical carbon dioxide (SF-CO2) were measured by a recirculating method at temperatures of 40℃ and 60℃ and pressures between 9 MPa to 49 MPa.The compounds exhibit very limited solubilities in the range of 10^-5 to 10^-7 (mole fraction). Cimaterol has a higher solubility than that of mabuterol. The experimental data of solubility were correlated by four density-based models.The correlation accuracy highly depends on the system investigated, which is mainly determined by the density ranges and temperature.

Comparison of pharmacokinetics,efficacy and toxicity profile of gemcitabine using two different administration regimens in Chinese patients with non-small-cell lung cancer

Objective： To conduct a randomized comparative trial of pharmacokinetics, efficacy and toxicity profile treatment with 1200 mg/m^2 gemcitabine using standard 30-min infusion or fixed dose rate （FDR） infusion [10 mg/（m^2-min）] on days 1 and 8 plus carboplatin AUC （area under curve） 5 on day 1 in Chinese non-small-cell cancer patients. Twelve patients were enrolled in this study. Methods： Plasma gemcitabine concentrations were measured by ion-pair reversed phase high performance liquid chromatography. Antitumoral activity and toxicity of gemcitabine was assessed according to World Health Organization criteria. Results： The obtained mean parameters, such as T1/2 （elimination half time）, AUC, and CL （clearance）, were consistent with those reported in literature. Qualified response rate in our study was 33.3% for standard arm and 50% for FDR ann. Additional 50% and 33.3% patients contracted stable disease （SD） in standard arm and FDR arm, respectively. The predominant toxicity was hematologic, and patients in the standard infusion ann experienced consistently more hematologic toxicity, Conclusion： Pharmacokinetic and clinical data in this trial support the continued evaluation of the FDR infusion strategy with gemcitabine.