Simulation Analysis of Occupancy Rates of Baicalein， Quercetin and Galangin on Target Sites of Xanthine Oxidase / 中国实验方剂学杂志

Objective:To simulate the occupancy rates of baicalein， quercetin and galangin on the target sites of xanthine oxidase <italic>in vivo</italic>. Method:In this experiment， the half inhibitory concentration （IC₅₀） of febuxostat， baicalein， quercetin and galangin against xanthine oxidase were determined by <italic>in vitro</italic> enzymatic reaction. Binding free energy was predicted by molecular docking technology and their association rate constant （k_on） and dissociation rate constant （k_off） were determined by surface plasmon resonance technology. Based on measured binding kinetic parameters （k_on and k_off） and extracted pharmacokinetic data， the target occupancy model <italic>in vivo</italic> was established. Result:The IC₅₀values of febuxostat， baicalein， quercetin and galangin were 0.002 7， 1.63， 0.38， 1.59 µmol·L^-1， respectively. The IC₅₀ of febuxostat was very close to that reported in the literature. The predicted curve of target occupancy rate <italic>in vivo</italic> of febuxostat was consistent with its duration of clinical efficacy. When single intragastric administration of long-circulating liposomes of quercetin with dose of 100 mg·kg^-1 in rats， the time of target occupancy rate >70% <italic>in vivo</italic> lasted for about 3.9 h. When rats were orally administered baicalein and galangin with dose of 200 mg·kg^-1， the time of target occupancy rate >50% <italic>in vivo </italic>lasted for about 10 h and 1.7 h， respectively. Conclusion:The prediction model of xanthine oxidase target occupancy constructed by drug target binding kinetics and <italic>in vivo</italic> pharmacokinetic curves can effectively evaluate the <italic>in vivo</italic> inhibitory activity of compounds against the target.

Preparation of glycyrrhizic acid-F127/TPGS mixed nanomicelles and its in vivo intestinal absorption in rats / 中草药

Objective: To prepare glycyrrhizic acid (GL)-Pluronic F127 (F127)/polyethylene glycol 1000 vitamin E succinate (TPGS) mixed nanomicelles (MMs) and improve oral absorption of GL. Methods: GL-F127/TPGS-MMs was prepared by thin film dispersion method. The encapsulation efficiency and drug loading of MMs were used as evaluation indexes. The formulation and process, including the ratio of F127 to TPGS, the concentration of polymer and GL, hydration temperature and time, were optimized by the single factor experiment. The morphology of MMs was investigated by transmission electron microscopy. The single-pass perfusion model was established in rats to investigate the intestinal absorption characteristics of GL-F127/TPGS-MMs with absorption rate constant (Ka) and apparent absorption coefficient (Papp) as evaluation indexes. Results: The optimal formulation and process of GL-F127/TPGS-MMs were as follows: TPGS 180 mg, F127 270 mg, GL 70 mg, hydration temperature 50 ℃ and hydration time 3 h. The prepared GL-F127/TPGS-MMs had good clarity and the particle size, polydispersity index, and Zeta potential were (28.20 ± 5.63) nm, 0.20 ± 0.06, and (-5.24 ± 1.55) mV, respectively. The encapsulation efficiency and drug loading were (97.57 ± 5.29) % and (13.13 ± 0.71) %, respectively. The MMs were spherical with distinct vesicle structure. The absorption of GL in the jejunum segment was significantly higher than that in the ileum segment (P < 0.05). Compared with raw GL, GL-F127/TPGS-MMs had a statistically significant higher absorption rate in the intestinal segment (P < 0.05). Conclusion: The prepared GL-F127/TPGS-MMs could significantly improve the absorption of GL in vivo.

Quantitative Variation of Time-Activity Curve Derived Parameters with Regional Variation of Background Region of Interest, in Salivary Scintigraphy: A Retrospective Comparative Evaluation

Aim and Objective: Quantitative analysis of time-activity curve (TAC) derived from 99mTc-pertechnetate salivary glandscintigraphy, used in the evaluation of salivary gland function, is almost always corrected for background count. The objectiveof this study was to: (a) Examine the effect of the alteration of anatomical position of the background region of interest (ROI) onthe (1) semi-quantitative parameters, i.e., upslope (Us) and stimulated downslope (Ds), derived from TAC and (2) on minimumand maximum pixel counts of pixel histogram of background ROI. (b) Examine the effect of minimum and the maximum pixelcounts of the background ROI on the values of Us and Ds.Materials and Methods: In this retrospective study, 16 patients were included who had undergone 99mTc-pertechnetatesalivary scintigraphy for various reasons but had normal salivary scintigraphy reports. Three different sets of background indifferent anatomical positions were chosen: (i) A pair of supraclavicular background ROI, (ii) an isolated central rectangularbackground ROI in brain, and (iii) an isolated suprathyroid ROI. We then calculated two important semi quantitative parameters,i.e., Us and Ds from the TAC of the salivary glands. Individual TAC was generated against each set of the above-mentionedbackgrounds. Individual pixel histogram was also generated against each TAC. Minimum and maximum pixel count of thegenerated background pixel histograms was identified. Comparative studies were made among the afore-mentioned variables.Results and Conclusion: The values of Us and Ds derived from respective background corrected TAC matched well amongeach other irrespective of the altered anatomical positions of the background ROI. The minimum pixel counts per second (CPS)of the background pixel histogram varied with the change in anatomical position of the background ROI but it did not affect thevalues of Us and Ds. In contrast, the maximum pixel CPS of the background pixel histogram varied inversely with the valuesof Ds, although the value of Ds, showed no variation with the change in position of the background ROI.

The Analysis of the Accelerated Degradation Test for Protein-type Biological Standard Substances / 中国药学杂志

OBJECTIVE: To establish a weighted least square method for the accelerated degradation analysis of protein-type biological standard substances.METHODS: A mathematical model was proposed to estimate the parameters of degradation rate constants k at the elevated temperatures based on the Arrhenius or Eyring equation and chemical reaction principles under the suitable assumptions. Hence, it is probably to predict the stability of biological standard at the normal condition by solving the model.RESULTS: According to the experimental data of recombinant human granulocyte colony-stimulating factor and interferon α-2a, the preliminary numerical experiments were also performed and the results confirm the reliability of the method in the paper.CONCLUSION: The same methodology may be applied in the pharmaceutical industry where it is necessary to predict the viable shelf-life of biological products.

In vitro release and in situ gastrointestinal absorption of evodiamine butyryl derivative-loaded solid lipid nanoparticles / 中国药理学通报

Aim To prepare evodiamine butyryl deriva-tive (EBD) and evodiamine butyryl derivative-loaded solid lipid nanoparticles (EBDLN), and study its re-lease in vitro,and to investigate its in situ gastrointesti-nal absorption. Methods EBD was prepared by a one-step synthetized method, and then EBDLN was prepared by a film dispersion method. Dynamic dialy-sis was used to evaluate drug release in vitro,and sin-gle-pass gastrointestinal perfusion was employed to study the gastrointestinal absorption of EDM,EBD and EBDLN. Results In identical release media, there were identical drug release tendencies of EBD and EB-DLN, but the release rate of EBDLN was faster than EBD. Compared with EDM and EBD, the Kavalues and Pappvalues of EBDLN in every perfusion segment increased significantly. The Kaof EBDLN in stomach, duodenum, jejunum, ileum and colon was 110.14-fold,56.70-fold,51.23-fold,45.70-fold and 127.23-fold of free EDM respectively. The Pappvalue of EB-DLN was 9.74-fold, 4.48-fold, 3.82-fold and 11.3-fold of that of free EDM. Conclusion EBDLN has sustained effect and can enhance the gastrointestinal absorption of EDM and EBD.

Study on intestinal absorption features of berberine hydrochloride phospholipid solid dispersions by rat single-pass perfusion model / 中草药

Objective: To compare intestinal absorption features of berberine hydrochloride phospholipid solid dispersions (BBH-PSD) by rat single-pass perfusion model, and to explore the mechanism of berberine bioavailability increasing mechanism by phospholipid solid dispersion technology. Methods: The single-pass perfusion model was established in rats, the concentration of berberine in intestinal perfusion was determined by HPLC, and phospholipid solid dispersion technology promoting intestinal absorption of berberine was investigated. Results: Compared with berberine, BBH-PSD could promote much more absorption of berberine in various intestinal segments, especially in jejunum, and the mechanism was related to improving permeability and strengthen simple diffusion of berberine. The Ka and Papp values of BBH and BBH-PSD in jejunum were obviously higher than BBH (P < 0.05); When the volumetic flow rate of BBH-PSD was 0.2, 0.4, and 0.8 mL/min, Ka and Papp were both higher than BBH (P < 0.05); The increasing mass concentration was not obvious to intestinal absorption of BBH, while the increasing mass concentration of BBH-PSD obviously increased the intestinal absorption of BBH (P < 0.05). Conclusion: Intestinal absorption characteristics of berberine phospholipid solid dispersion is beneficial to improve berberine oral bioavailability, and it can provide a scientific basis for the development of new dosage forms of berberine hydrochloride.

Key physical parameters of hawthorn leaf granules by stepwise regression analysis method / 中国中药杂志

The purpose of this study was to investigate the effect of key physical properties of hawthorn leaf granule on its dissolution behavior. Hawthorn leaves extract was utilized as a model drug. The extract was mixed with microcrystalline cellulose or starch with the same ratio by using different methods. Appropriate amount of lubricant and disintegrating agent was added into part of the mixed powder, and then the granules were prepared by using extrusion granulation and high shear granulation. The granules dissolution behavior was evaluated by using equilibrium dissolution quantity and dissolution rate constant of the hypericin as the indicators. Then the effect of physical properties on dissolution behavior was analyzed through the stepwise regression analysis method. The equilibrium dissolution quantity of hypericin and adsorption heat constant in hawthorn leaves were positively correlated with the monolayer adsorption capacity and negatively correlated with the moisture absorption rate constant. The dissolution rate constants were decreased with the increase of Hausner rate, monolayer adsorption capacity and adsorption heat constant, and were increased with the increase of Carr index and specific surface area. Adsorption heat constant, monolayer adsorption capacity, moisture absorption rate constant, Carr index and specific surface area were the key physical properties of hawthorn leaf granule to affect its dissolution behavior.

Screening of amount of humectant (glycerin) for eczema cream / 中国药学杂志

OBJECTIVE: To determine the optimum amount of humectant (glycerin) in eczema cream to solve the water loss and cracking problem during storage. METHODS: Eight eczema cream samples with different dosages of glycerol were prepared. The percentage of water loss was determined, and the dynamic equations at different temperatures for different times were established. The constant of water loss rate was calculated, the speed of water loss was compared for the eight samples with the method of test for grade consistency, and the optimal amount of humectant (glycerin) was determined. RESULTS: The mathematical expressions for the samples at different temperatures all complied to power function model, and the constant of water loss rate was the slope of the equation. The rating tended to be consistent, which indicated that there were significant differences in the water loss rate constants of the samples at different temperatures (P < 0.05). The grade summation of Ri and moisturizing effect tended to top when the dosage of moisturizer (glycerin) was 13.6% in eczema cream. CONCLUSION: The optimal amount of glycerol in eczema cream is 13.6% with the lowest water loss in the temparature range of 25-65℃.

Role of key physical parameters of andrographis paniculata (Burm. f.) Nees granules in their dissolution behavior / 中国药学杂志

OBJECTIVE: To establish the relationship between the physical parameters of granules and their dissolution behavior. METHODS: Andrographis paniculata (Burm. f.) Nees extract was utilized as a model drug. The extract was mixed with different excipients (MCC/soluble starch) at the ratio of 1:1 by weight using different methods. The granules were prepared by using high shear granulation and extrusion granulation methods. Then the dissolution behavior of the granules was evaluated by monitoring equilibrium dissolution quantity and dissolution rate constant. The effect of physical properties on the dissolution behavior was analyzed through stepwise regression. RESULTS: Particle size, critical relative humidity (CRH), moisture content, pore volume, and tapped density were the main factors related to the dissolution behavior of granules. CONCLUSION: A higher equilibrium dissolution quantity could be obtained with higher moisture content, smaller particle size, and lower CRH. There is a positive correlation between dissolution rate constant and tapped density of granules, and a negative correlation with particle size (D[4, 3]) and pore volume (PV).

In vitro percutaneous permeability and skin irritation of gastrodigenin / 中草药

Objective: To investigate percutaneous permeability and skin irritation of gastrodigenin so as to provide the basis on the development of transdermal drug delivery formulations. Methods: The modified Franz diffusion cell method and the excised rat skin were used to evaluate the percutaneous permeability of gastrodigenin. The effects of various common-used solvents, transdermal enhancers, and particle carriers on the permeability of gastrodigenin were studied. The rabbit skin irritation test was used to evaluate the safety of gastrodigenin solutions and their gels. Results: Gastrodigenin was easy to permeate rat abdominal skin. The penetration rate constant (Js) was 134.1 μg/(cm2·h), and transit dose accumulated in 24 h was 3 mg/cm2. The solubility and permeability of gastrodigenin could be enhanced by 30% EtOH, so it was an ideal solvent for gastrodigenin. Improvement effects of the transdermal enhancers (Azone, turpentine, and borneol) and the transdermal particle carriers (microemulsion and ethosomes) were not significant. The skin irritation test results indicated that neither gastrodigenin soultions nor their gels exerted irritative effects to the rabbit skin. Conclusion Gastrodigenin has good percutaneous permeability without skin irritation, so it is suitable for the transdermal drug delivery in the treatment of central nervous system diseases.

Nasal absorption of ligustrazine and promotion action of synthetic borneol / 中国临床药理学与治疗学

AIM: To investigate the nasal absorption of ligustrazine and promotion action of synthetic borneol. METHODS: In situ nasal recirculation method was used to study the dose effect relationship of nasal absorption of ligustrazine and the effect of synthetic borneol on nasal absorption of ligustrazine in rats. RESULTS: When the concentrations of ligustrazine were 0.25 , 0.75 ,and 1.25 g?L -1 in circulation liquid, respectively, the corresponding values of the absorption rate constant k were 0.0195 , 0.0227 , and 0.0241 min -1 . However, when the concentrations were 2.5 and 5.0 g?L -1 in circulation liquid, the absorption rate constant k lowered with the concentration being added. CONCLUSION: Ligustrazine can be absorbed through the nasal mucous and synthetic borneol can promote the absorption.

The biological characterization of Pseudomonas aeruginosa phage PaP3 / 解放军医学杂志

Objective To identify some basic biological properties,optimal multiplicity of infection(MOI),one-step growth kinetics,serum neutralization rate constant of Pseudomonas aeruginosa phage PaP3 were determined, respectively. Methods The host bacteria were infected with PaP3 at six different MOI(0.0001,0.001,0.01,0.1,1 and 10,then lysated adequately, the phage titer of supernatant was determined.For one-step growth experiments,the host bacteria were infected with PaP3 at MOI=10, following centrifugation after 15 min adsorption,the pellet containing (partially) infected cells was resuspended in 3 ml of pre-warmed LB broth and incubated with 160rpm at 37℃.Samples(50?l) were taken at 10 min-intervals and immediately tittered by the double-layer agar plate method. A rabbit was immunized with purified PaP3 to prepare anti-PaP3 serum, reaction constants between antiserum and PaP1, PaP2, PaP3 were determined using cross neutralization test. Results 0.001 MOI-infected host bacteria gave the highest phage offsprings. One-step growth curve was determined according to the results of one-step growth experiments.Reaction constant was determined using neutralization test. Conclusion The optimal MOI of PaP3 was determined to be 0.001. One-step growth curve for PaP3 shows that the latent period is about 20 min, the rise period is 60 min, and the average burst size is about 31pfu/cell. Rate constant of reaction between antiserum and PaP3 is 262.

Study on In-vivo Nasal Mucosa Absorption of Tetramethylpyrazine Phosphate Liposome in Rats / 中药新药与临床药理

Objective To study the characteristic of in-vivo nasal mucosa absorption of tetramethylpyrazine phosphate(TMPP) liposome in rats. Methods Nasal circulatory perfusion method in rats was used to study the effects of different circulatory rates and TMPP concentrations on nasal mucosa absorption of TMPP liposome. Nasal mucosa absorption rate constants of TMPP liposomes and TMPP solutions at the same concentration were also compared. Results The absorption rate constant of TMPP liposomes was increased with the increase of circulatory rates at the range of 1.2～2.4 mL/min and with the increase of TMPP concentrations at the range of 0.245～0.98 mg/mL. Both the absorption rate constant and absorbed amount of TMPP for TMPP liposomes were higher than those for TMPP solutions at the same concentration. Conclusion The nasal mucosa absorption of TMPP liposome was complete as compared with that of TMPP solution.

Comparison of the Clinical Effects of the Different Ventilatory Care Strategies in the Neonates with Acute Respiratory Failure: High Flow Rate - Constant Flow Rate

PURPOSE: High flow rate (FR) and pressure limit (PL) strategy with time-cycled pressure-limited (TCPL) ventilator is employed routinely in the neonates. Theoretical basis of this strategy is the two-compartment theory that the lung with acute respiratory failure consists of units with different compliance and resistance. But such constant pressure strategy has the risk of ventilator induced lung injury. We compared the ventilatory indices and clinical outcomes of two different strategies, high FR-constant pressure and low FR-constant FR in the ventilator care of the neonates with acute respiratory failure. METHODS: For the neonates born in our hospital and treated with mechanical ventilation from March to August in 1997, two different ventilator strategies were employed randomly with flow control ventilator. In the high-FR group, the FR was fixed at 10 L/ min and the PL was adjusted according to the arterial blood gas analysis (ABGA) results. In the low-FR group, the FR was adjusted to 10 mL/kg of tidal volume. Sixty neonates were enrolled, 32 in high-FR and 28 in low-FR group. Ventilatory indices and clinical outcomes were statistically cornpared in the two groups. RESULTS: Perinatal factors were not different in the two groups. Initial ventilator settings, ABGA results and ventilatory indices were not different. The tidal volume, fraction of inspired oxygen, peak inspired pressure and oxygenation index were higher and dynamic compliance was lower in the high-FR group compared to the low-FR group after 3 to 72 hours of ventilator care. In clinical outcomes, incidences of pulmonary interstitial emphysema, pneumothorax and chronic lung disease were significantly lower in the low-FR group. CONCLUSION: Low-FR with constant FR strategy resulted in better clinical outcomes in the ventilator care of neonates. We conclude that constant FR strategy prevents damage of the better compliant lung units and decreases the incidence of acute and chronic complications of ventilator care.

Scavenging of superoxide radical by ascorbic acid.

Using acetaldehyde and xanthine oxidase as the source of superoxide radical, the second order rate constant for the reaction between ascorbic acid and superoxide radical was estimated to be 8·2 × 107 M-1 s–1. In rats, the average tissue concentration of ascorbic acid was of the order of 10–3 Μ and that of superoxide dismutase was of the order of 10–6 M. So, taking together both the rate constants and the tissue concentrations, the efficacy of ascorbic acid for scavenging superoxide radical in animal tissues appears to be better than that of superoxide dismutase. The significance of ascorbic acid as a scavenger of superoxide radical has been discussed from the point of view of the evolution of ascorbic acid synthesizing capacity of terrestrial vertebrates.