[Effect of multicomponent environment on intestinal permeability of puerarin in biopharmaceutics classification system of Chinese materia medica].

The evaluation of permeability in biopharmaceutics classification system of Chinese materia medica (CMMBCS) requires multicomponent as a whole in order to conduct research, even in the study of a specific component, should also be put in the multicomponent environment. Based on this principle, the high content components in Gegen Qinlian decoction were used as multicomponent environmental impact factors in the experiment, and the relevant parameters of intestinal permeability about puerarin were measured with using in situ single-pass intestinal perfusion model, to investigate and evaluate the intestinal permeability of puerarin with other high content components. The experimental results showed that different proportions of baicalin, glycyrrhizic acid and berberine had certain influence on intestinal permeability of puerarin, and glycyrrhizic acid could significantly inhibit the intestinal absorption of puerarin, moreover, high concentration of berberine could promote the absorption of puerarin. The research results indicated that the important research ideas of permeability evaluation in biopharmaceutics classification system of Chinese materia medica with fully considering the effects of other ingredients in multicomponent environment.

[Study on differences between pharmacokinetics and chromatopharmacodynamics for Chinese materia medica formulae].

OBJECTIVE: To study on the differences between chromatopharmacokinetics (pharmacokinetics with fingerprint chromatography) and chromatopharmacodynamics (pharmacodynamics with fingerprint chromatography) of Chinese materia medica formulae to answer the question whether the pharmacokinetic parameters of multiple composites can be utilized to guide the medication of multiple composites. METHOD: On the base of established four chromatopharmacology (pharmacology with chromatographic fingerprint), the pharmacokinetics, and pharmacodynamics were analyzed comparably on their mathematical model and parameter definition. RESULT: On the basis of quantitative pharmacology, the function expressions and total statistical parameters, such as total zero moment, total first moment, total second moment of the pharmacokinetics, and pharmacodynamics were analyzed to the common expressions and elucidated results for single and multiple components in Chinese materia medica formulae. Total quantitative pharmacokinetic, i.e., chromatopharmacokinetic parameter were decided by each component pharmacokinetic parameters, whereas the total quantitative pharmacodynamic, i.e., chromatopharmacodynamic parameter were decided by both of pharmacokinetic and pharmacodynamic parameters of each components. The pharmacokinetic parameters were corresponded to pharmacodynamic parameters with an existing stable effective coefficient when the constitutive ratio of each composite was a constant. CONCLUSION: The effects of Chinese materia medica were all controlled by pharmacokinetic and pharmacodynamic coefficient. It is a special case that the pharmacokinetic parameter could independently guide the clinical medication for single component whereas the chromatopharmacokinetic parameters are not applied to the multiple drug combination system, and not be used to solve problems of chromatopharmacokinetic of Chinese materia medica formulae.

Deviating from clinical practice: Pharmacokinetics of Chinese materia medica faces a substantial challenge.

The pharmacokinetics of Chinese materia medica (PCMM) has made a great contribution to investigations of the in vivo process of various components in Chinese materia medica (CMM), intending to provide useful information for clinical guidance related to CMM. However, some issues are worthy of further consideration, and current PCMM studies face a substantial challenge. First, high-dosage administration is prevalent in PCMM studies, and the obtained results might be meaningless and inappropriate for guiding the clinical application of CMM, as they deviate from clinical practice. Improvements in instrument sensitivity have not reduced the prevalence of high-dosage administration. In addition, the selection of components for detection in PCMM studies is usually uncertain, lacking sufficient scientific support, especially for components without clarified bioactivities. Therefore, the scientific value of current PCMM studies is limited. We believe that these abnormalities can be attributed to the poor recognition of the characteristics of CMM and the improper application of research approaches from Western medicines. Currently, the more pressing key scientific issues for CMM should be clinical effectiveness, quality control and bioactivity discovery, which are closely related to its own characteristics and are beneficial to its modern developments.

Fast Dissolving/Disintegrating Dosage Forms of Natural Active Compounds and Alternative Medicines.

Fast Dissolving/Disintegrating Dosage Forms (FDDFs) are a group of dosage forms which dissolve or disintegrate quickly, leading to fast distribution of active ingredients at the site of administration; thereby providing ease of oral ingestion of solid unit dosage forms and have the potential to enhance transmucosal absorption. With time, the use of FDDFs in alternative systems has significantly increased. Homeopathic systems and traditional Chinese medicine have embraced FDDFs for the delivery of active compounds. Most of the patents in this area are from China or by the Chinese innovators. In Europe and US, FDDFs have been extensively studied for the delivery of natural active compounds. It was fascinating to know that some new dosage forms and new routes of delivering active compounds are also making their way to the family of FDDFs. The dose of active compound, size of dosage forms, standardization of extracts, polyherbal mixtures, stability of active compounds, safety, efficacy and pharmacokinetics are challenging issues for developing FDDF herbal formulations or phytopharmaceuticals.

Application of "spider-web" mode in discovery and identification of Q-markers from Xuefu Zhuyu capsule.

BACKGROUND: The selection of quality control indicators in a complex system is a key scientific issue for the study of Chinese materia medica (CMM), which is directly related to its safety and efficacy. In order to scientifically understand and control the quality of CMM, quality marker (Q-marker) has been recently raised as a new concept, which provided a novel research idea for the quality control and evaluation of CMM. PURPOSE: By a new and integrated "spider-web" mode, Q-markers of Xuefu Zhuyu capsule (XZC) were comprehensively uncovered, conducing to great improvement of quality control of XZC. METHODS: Mainly established by three dimensions derived from six variables including content, stability and activity, "spider-web" mode was constructed to evaluate Q-marker property of candidate compounds by taking regression area of the tested compounds into account. RESULTS: The candidate compounds with larger regression area were preferentially adopted as Q-markers, which should possess the satisfactorily integrated properties of content, stability and activity. Six compounds, naringin, isoliquiritin, paeoniflorin, protocatechuic acid, neohesperidin and ferulic acid, were identified and preferred as Q-markers of XZC. CONCLUSION: Based on "spider-web" mode, Q-markers from Xuefu Zhuyu capsule were successfully screened, which would substantially perform quality control of XZC and prove the feasibility of "spider-web" mode in solving the selection of quality control indicators from compound formulae.

[Discovery strategy for effective and active constituents of Chinese material medica based on processes of metabolism and disposition in intra-body].

Chinese material medica is the natural therapeutic agent used under the guidance of the theories of traditional Chinese medicine. Its sources are mainly derive from plants, some derive from animals and minerals, and a few derive from chemical drugs and biologic products. It was made up into a colossal complexed system because it's diversity of biological sources, ecological environments, chemical structures, processing methods, processes of metabolism and disposition in intra-body, biological activity and clinical use, and involved a lot of scientific problems. The elucidation of the effective and active constituents is a basic and scientific problem to clarify complexed system of Chinese material medica. Along with research progressing of processes of metabolism and disposition of Chinese material medica in intra-body and metabonomics, a new and rapid-developing technology, the discovery strategy for effective and active constituents of Chinese material medica based on the processes of metabolism and disposition would be made up, which will provide a new methodology and pathway to clarify of complexed system of Chinese material medica.

[The medicinal serum of yi-shen ruan-jian san antagonized the effect of aristolochic acid on human proximal tubular epithelial cells in vitro].

OBJECTIVE: To evaluate whether the medicinal serum of Yi-shen Ruan-jian san can antagonize the fibrogenic effect of human proximal tubular epithelial cell line (HKC) activated by aristolochic acid (AA) in vitro. METHOD: The HKC was incubated in the media containing 40 mg x L(-1) aristolochic acid sodium salt (AA-Na) with or without 10% concentration of Yi-shen Ruan-jian san medicinal serum. Then the cell proliferation and cytotoxicity of HKC were determined by MTF and lactate dehydrogenase (LDH) release assay respectively, the antigen expression of cytokeratin and alpha-smooth muscle actin on HKC was detected by immunocytochemistry, the mRNA expression of transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and type I Collagen (Col I) of HKC was measured by RT-PCR, and their protein expression was measured by ELISA or Western blot. RESULT: No cytotoxic effect was found in HKC after stimulation of AA-Na with or without the medicinal serum of Yi-shen Ruan-jian san (P > 0.05). No epithelial-myofibroblast transdifferentiation was found in HKC after AA-Na stimulation. The mRNA and protein expression of TGF-beta1, CTGF, PAI-1 and TIMP-1 of HKC was significantly upregulated by AA-Na (P < 0.05). The above-mentioned enhanced mRNA and protein expression, except for PAI-1, was significantly downregulated by the medicinal serum of Yi-shen Ruan-jian san, compared with the control (normal rat serum in the same concentration) (P < 0.05). CONCLUSION: The fibrogenic effects of HKC activated by AA are antagonized by Yi-shen Ruan-jian san, through downregulating the expression of promoting excellular matrix (ECM) synthesis factors (TGF-beta1, CTGF) and inhibiting ECM degradation factor (TIMP-1).

[Key foundational science problem in experimental medicine study of Chinese materia medica: ascertainment of active and toxic constituents from Chinese materia medica].

The problem on study of the active and toxic constituents of Chinese materia medica is the core of the problems in the field of modern research of Chinese materia medica. But approved methods for ascertaining the active and toxic constituents in Chinese materia medica have not been developed yet and are in developing phases. In combination with the characteristics of Chinese materia medica in clinical use and the achievements of modern pharmaceutical research, series model may be a finer approach to make certain of the active and toxic constituents from Chinese materia medica, which includes the parent compound biotransformation by human intestinal bacteria to make biotransformation products, and the absorption and further biotransformation in intestinal wall, the metabolization in the liver, and the secretion by the kidney of the parent compounds and biotransformation products. This method is also an important research assignment in the field of experimental medicine study of Chinese materia medica.

[Studies on heart-protecting musk pH-dependent gradient-release pellets].

AIM: To prepare heart-protecting musk pH-dependent gradient-release pellets and investigate the drug release in vitro and in vivo. METHODS: The pH-dependent gradient-release pellet system was prepared by using HPMC, Eudragit L-30D-55 and Eudragit L100-Eudragit S100 (1:5) combinations as coater. The release of borneol and total ginsenoside from pH-dependent gradient-release pellets were determined according to the method of Pharmacopoeia of the People's Republic of China (2000) in the simulated gastrointestinal pH conditions. The gastrointestinal transit and disintegration of pellets was investigated by using gamma-scintigraphic trace in volunteers. The pharmacokinetics of borneol of heart-protecting musk pH-dependent gradient-release pellets was studied in 6 healthy volunteers by GC methods. RESULTS: The f2 value of release data of borneol and total ginsenoside of the heart-protecting musk pH-dependent gradient-release pellets was 79.6 in the simulated gastrointestinal pH conditions. The gamma-scintigraphic trace evaluation demonstrated that the pellets coated with HPMC, Eudragit L-30D-55 or Eudragit L100-Eudragit S100 (1:5) combinations can disintegrate in stomach, duodenum and jejunum or ileum. The gastrointestinal transit time of pellets was about 5 hours in fasted state and about 6 hours in fed state. The concentration-time curves of borneol of heart-protecting musk pills fit in two-compartment model. The pharmacokinetics data showed that borneol had a short time of absorption and elimination. The mean residence time (MRT) of borneol of heart-protecting musk pills was 2.61 hours. The plasma concentration of borneol of heart-protecting musk sustained-release capsule which consisted of three kinds of pellets coated with HPMC, Eudragit L-30D-55 or Eudragit L100-Eudragit S100 (1:5) combinations was steadier than those of heart-protecting musk pills, its Cmax was lower than and Tmax was near to those of heart-protecting musk pills, its MRT was 4.0 hours, and its relative bioavailability was 96%. CONCLUSION: The lipidsoluble borneol and watersoluble total ginsenoside of heart-protecting musk pH-dependent gradient-release pellets can release simultaneously while sustained-releasing in vitro. The heart-protecting musk pH-dependent gradient-release pellets had the characteristics of pH-dependent gradient-releasing and disintegration while transiting in gastrointestinal tract. A characteristic of gradient sustained-release was shown in the concentration-time curves of borneol of heart-protecting musk sustained-release capsule in volunteers.

[Absorption and distribution of mercury and arsenic from realgar and cinnabar of angong niuhuang pill in normal rats and rats with cerebral ischemia].

OBJECTIVE: To study comparatively the characteristics of absorption and distribution of mercury and arsenic from realgar and cinnabar of Angong Niuhuang Pill in normal rats and the rats with cerebral ischemia after oral administration. METHOD: The blood samples and homogenates of liver, kidney and brain were prepared at various intervals after the animals were treated with Angong Niuhuang pill ig. The levels of total mercury and total arsenic in the blood and the organ homogenates were measured with Microwava Accelerated Reaction System and AAs, respectively. RESULT: The blood concentrations of mercury and arseic reached the highest point in normal rats at one hour following single oral dosing of Angong Niuhuang pill. In normal rats, the mercury distribution was characterized by its higher level in blood and kidneys than in other organs, while a higher distribution of arsenic was found in blood than in organs. No difference in the distribution of mercury or arsenic was found between normal rats and rats with cerebral ischemia after the treatment with the pill. CONCLUSION: The highest level of mercury or arsenic in blood occurs at one hour after oral administration of the pill in normal rats. There is a higher distribution of mercury in blood and kidneys, while a higher distribution of the arsenic only in blood. There is no significant difference in the distribution of mercury or arsenic between the normal rats and the ischemic rats.