Eric J. Lien

Quantitative structure-activity relationship analysis of phenolic antioxidants

In this report, the quantitative structure-activity relationship (QSAR) analyses of substituted phenols, vitamin E derivatives and flavonoids are presented. Two models have been derived using calculated parameters such as the heat of formation (Hf), the energy of the lowest unoccupied molecular orbital of radicals (E(lumo-r)) the energy of the highest occupied molecular orbital of the parent compounds (E(homo)) and the number of hydroxyl groups (OH). These models can be used to estimate the redox potentials or antioxidant activities of new substituted phenolic compounds or vitamin E derivatives. The Trolox equivalent antioxidant capacities (TEACs) of 42 different flavonoids are found to be mainly governed by the number and location of hydroxyl groups on the flavonoid ring system.

Structure–activity relationship: analyses of p‐glycoprotein substrates and inhibitors

Objective: A large number of structurally and functionally diverse compounds act as substrates or modulators of p‐glycoprotein (p‐gp). Some of them possess multiple drug resistance (MDR)‐reversing activity, but only a small number of them have entered clinical study. In order to uncover the factors which exert a significant impact on the interaction between substrates/modulators and p‐gp, we have performed structure–activity relationship (SAR) analyses, including molecular modelling, two‐dimensional (2D) and three‐dimensional (3D) parameter‐frame‐setting analysis, quantitative structure activity relationship (QSAR) analysis among substrates/modulators, as well as clinically promising MDR‐reversing agents.

Preclinical and clinical examinations of Salvia miltiorrhiza and its tanshinones in ischemic conditions

Salvia miltiorrhiza (Labiatae, Laminaceae), danshen, is an annual sage mainly found in China and neighboring countries. The crude drug (dried root) and its preparations are currently used in China to treat patients suffering from heart attack, angina pectoris, stroke and some other conditions. The use of S. miltiorrhiza has been increasing in the management of stroke. Pharmacological examinations showed that the plant and its active ingredients, tanshinones and salvianolic acids, have anticoagulant, vasodilatory, increased blood flow, anti-inflammatory, free radical scavenging, mitochondrial protective and other activities. This review discusses the pharmacology, medicinal chemistry and clinical studies published, especially in China, for danshen and tanshinone preparations. Clinical examinations are evaluated in terms of S. miltiorrhiza preparation, dose, double blinding, control, clinical assessments of outcomes and other parameters. Meta-analyses of S. miltiorrhiza are also discussed.

Chemical and pharmacological investigations of Epimedium species: A survey

More than 130 different compounds have been identified from over 16 species of the Epimedium genus of the Berberidaceae family. Eight of these species have been used in the Traditional Chinese Medicines (TCM) over centuries to treate a wide range of diseases. From in vitro and in vivo experimental data, and preliminary structure-activity relationship (SAR) analysis of the androgenic/anti-estrogenic and anti-oxidant activities of the icariin series of flavonoids and glycosides, the results appear to be consistent with those of known anti-estrogenic flavonoids, such as luteolin. Further QSAR analysis of the different active ingredients is now in progress and will be reported elsewhere. Our survey suggests the possibility of multiple targets and multiple mechanisms of action by Epimedium preparations and their purified compounds. These may serve as leads for further new drug development.

The Pharmacokinetics of Antiarrhythmic Agents in Pregnancy and Lactation

SummaryThe pharmacokinetics of various drugs may be profoundly altered during different stages of pregnancy, parturition, and lactation. Gastrointestinal absorption or bioavailability of drugs may vary due to changes in gastric secretion and motility. Various haemodynamic changes such as an increase in cardiac output, blood volume, and renal plasma flow may affect drug disposition and elimination. The increase in blood volume and total body water which occurs during pregnancy can alter the volume of distribution for various drugs. Although exact quantifications are not easy, these changes in pharmacokinetic parameters should be considered when dosing antiarrhythmic agents in pregnant women.Plasma protein concentrations and drug binding capacity are altered in the mother and fetus as pregnancy advances. With highly protein bound drugs, these changes may be clinically significant, as the pharmacological efficacy and toxicity are presumed to be related to the concentration of free drug in both the mother and fetus. In some instances, the fetus may be susceptible to greater drug toxicity as free drug concentrations may be underestimated by measurement of total drug concentrations.Changes in maternal drug metabolism and metabolism by the fetoplacental unit also contribute to alterations in the pharmacokinetics of drugs. As the placenta contains many metabolising enzymes, biotransformation of drugs at this site could potentially convert a drug into an active metabolite, or prevent fetal exposure to a toxic drug.Placental transfer of drugs, leading to toxicity in the fetus, is a major concern in the pharmacological management of the pregnant patient. The passage of individual drugs will vary depending on their apparent volumes of distribution, degree of protein binding, the rates of metabolic conversion and excretion within the placenta and fetus, the pH difference between the maternal and fetal fluids, and maternal haemodynamic changes. Drug properties such as lipid solubility, protein binding characteristics, and ionisation constant (pKa) also influence the placental passage of drugs. For weakly basic antiarrhythmic agents, the fetal drug concentration may potentially exceed the maternal plasma concentration when the fetal pH is lowered as in the case of fetal acidosis; this is due to ‘ion trapping’. Additionally, higher free drug concentrations of these basic drugs may exist, due to decreased α1acid glycoprotein concentration and binding affinity in the fetus.Lignocaine(lidocaine) has been shown to enter fetal plasma rapidly with fetal-maternal concentration ratios in the range of 0.52 to 0.66. The metabolites, monoethylglycinexylidide and glycinexylidide have been detected in the maternal plasma within 10 minutes and 40 minutes, respectively, after epidural administration. Fetal-maternal concentration ratios for these metabolites range between 0.55 to 1.0. Alterations in protein binding and pH differences between the mother and fetus may thus be clinically important considerations with lignocaine.Increased dose requirements and reduced plasma phenytoin (diphenylhydantoin) concentrations have been reported during the administration of phenytoin. Impaired drug absorption has also been reported, although the data are conflicting. Phenytoin appears to readily cross the placenta, with fetal cord concentrations ranging from 65 to 100% of the maternal concentrations. Decreases in the maternal albumin concentration with advancing pregnancy have been correlated with a progressive increase in the phenytoin free fraction. However, both total and free drug concentrations were found to be lower during late pregnancy than in the non-pregnant state. Increases in phenytoin plasma clearance have also been reported.Quinidine appears to readily cross the placenta with fetal cord-maternal concentration ratios ranging from 0.24 to 1.4. High concentrations of quinidine have also been detected in the amniotic fluid. Procainamide appears to be transferred across the placenta with fetal-maternal concentration ratios reported as high as 1.32. The N-acetyl procainamide metabolite has been detected in the fetal cord with fetal-maternal concentration ratio of 123.Reports of isolated experiences with disopyramide and mexiletine reveal fetal-maternal concentration ratios of 0.39 and 1.0, respectively. Both digitoxin and digoxin appear to be rapidly transferred into the fetus after maternal administration, with fetal-maternal concentration ratios ranging from 0.38 to 1.0.Both amiodarone and desethylamiodarone have been detected in fetal cord blood. Fetal-maternal drug concentration ratios for amiodarone range from 0.095 to 0.145, while one neonatal-maternal concentration ratio was 0.26. The fetal-maternal concentration ratios for desethylamiodarone ranged from 0.17 to 0.285. Both amiodarone and desethylamiodarone were detected in the amniotic fluid, and high concentrations of desethylamiodarone were detected in the amniotic fluid, and high concentrations of desethylamiodarone were found in the placental tissue.Experience with verapamil in pregnancy is quite limited, but the drug appears to cross the placental membrane with fetal-maternal concentration ratios of 0.17 and 0.26 at 49 minutes and 109 minutes, respectively, after a single oral dose.The β-adrenoceptor blockers reviewed, propranolol, metoprolol, atenolol, and acebutolol all appear to transfer across the placenta, showing fetal-maternal concentration ratios in the range of 0.88 to 1.27. The protein binding of propranolol and alprenolol, but not metoprolol, were reduced during pregnancy. Increased plasma clearance, decreased bioavailability, and an increase in total urinary metabolites are reported with metoprolol during pregnancy.Protein binding, lipid solubility, and ionisation characteristics of the antiarrhythmic agents similarly influence partitioning of these drugs into breast milk during lactation. The pH difference between the maternal plasma and milk may also allow for accumulation of weakly basic agents into breast milk. Although data are limited, attempts have been made to estimate breast milk-maternal plasma concentration ratios with equations that include these physiochemical properties. However, better clinical data supporting the use of the equations to predict milk-maternal concentration ratios are still needed. Several of the antiarrhythmic agents reviewed show that many of these agents show wide variation in the milk-plasma concentration ratios.The clinical impact of antiarrhythmic drug partitioning to the fetus and into breast milk remains to be established. More rigorous studies with appropriate body fluid sampling and pharmacokinetic modelling would provide necessary data to help clinicians establish safe and effective antiarrhythmic dosage regimens in the pregnant and lactating patient.

Carcinogenicity, mutagenicity and cancer preventing activities of flavonoids: A structure-system-activity relationship (SSAR) analysis

Flavonoids and related phenolic compounds are widely distributed among vascular plants and are found in numerous fruits, grains vegetables and other parts of higher plants [1–3]. Isolation and structural determination of flavonoids have been employed in plant taxonomy [1, 2]. Because of the wide range of chemical structures of flavonoids, coupled with a variety of test systems and different dose levels used, sometimes conflicting reports have been published in the literature regarding their numerous pharmacological and toxicological activities. This prompted us to conduct a literature survey and a structure-system-activity-relationship (SSAR) analysis of existing data, with particular emphasis on the carcinogenicity/mutagenicity and cancer preventive aspects of the flavonoids.

Immunostimulating polysaccharides from Panax notoginseng.

AbstractPurpose. The main purpose of this study is to prepare and characterize polysaccharides from Panax notoginseng, investigate their effects on immune system in vitro in order to find new immunostimulants for the prevention and supporting treatment of infection and immunodeficiency related diseases. Methods. Polysaccharides were extracted with aqueous solution, separated with column chromatography. Their anticomplementary activities were investigated by using human serum and antibody-sensitized sheep red blood cells. Interferon-γ and tumor necrosis factor inductive activities were studied by using isolated mouse spleen lymphocytes and peritoneal macrophages, respectively. Results. Four polysaccharides, homogeneous in gel-filtration chromatography, were prepared and designated PF3111, PF3112, PBGA11, and PBGA12. Component sugar analysis revealed that they are heteroglycans with MWs ranging from 37 kD to 760 kD, composed of glucose, galactose, arabinose, mannose, and xylose in different molar ratios. Fraction PBGA12 has the most anticomplementary activity which is mediated through both alternative and classical pathways. All the polysaccharides except PBGA11 induced the production of interferon-γ in the presence of concanavalin A. They induced the production of significant amount of TNF-α in cell cultures. Conclusions. The polysaccharides from P. notoginseng have immunostimulating activities invitro.

A survey of Chinese herbal ingredients with liver protection activities

A literature survey was conducted on herbs, their preparations and ingredients with reported liver protection activities, in which a total of 274 different species and hundreds of active ingredients have been examined. These ingredients can be roughly classified into two categories according to their activities: (1) the main ingredients, such as silybin, osthole, coumarin, glycyrrhizin, saikosaponin A, schisandrin A, flavonoids; and (2) supporting substances, such as sugars, amino acids, resins, tannins and volatile oil. Among them, some active ingredients have hepatoprotective activities (e.g. anti-inflammatory, anticancer, antioxidant, immunomodulating and liver cirrhosis-regulating effects). Calculation of physicochemical parameters indicates that the main ingredients with negative and positive Elumo values possibly display their hepatoprotective effects through different mechanisms, such as antioxidative, anti-inflammatory and immunomodulating effects. As the combination of herbs may achieve some treatment effects synergistically and/or additively, it is common in Chinese medicine to use mixtures of various medicinal herbs with pharmacologically active compounds to have synergistic and/or additive effects, or to reduce harmful effects of some pharmacologically active compounds. In particular, the active compounds with Clog P around 2 are suitable for passive transport across membranes and accessible to the target sites. Thus, Elumo and Clog P values are good indicators among the calculated parameters.Seven different physicochemical parameters (MW, Clog P, CMR, μ, Ehomo, Elumo and Hf) and four major biological activities (antioxidant, anti-inflammatory, antiviral/antitumor and immunomodulating) are discussed in this review. It is hoped that the discussion may provide some leads in the development of new hepatoprotective drugs.

Inhibition of herpes simplex virus type 1 and adenovirus type 5 by heterocyclic Schiff bases of aminohydroxyguanidine tosylate

Abstract Eleven heterocyclic Schiff bases of aminohydroxyguanidine tosylate (SB-AHGs), compounds I–XI, were tested for antiviral activity against herpes simplex virus type 1 (HSV-1) and adenovirus type 5 (Ad 5) via plaque reduction and virus yield reduction assays. This work was undertaken to test the hypothesis that low molecular weight SB-AHGs (MW<235 for the free SB) make better antiviral agents than high MW SB-AHGs (MW>300). The plaque reduction assay method demonstrated that three compounds, I, VII and IX, had moderate activity against HSV-1, with 50% inhibitory concentration (IC50) values of 38.0, 23.5 and 52.1 μM, respectively. Against Ad 5, compounds I, VIII and XI exhibited moderate activity, with IC50 values of 52.7, 19.3 and 5.1 μM, respectively. Among the compounds screened, compound I (1-[(3′-hydroxy-6′-methyl-2′-pyridyl)methylene]amino-3-hydroxyguanidine tosylate) was the most promising antiviral candidate, with selectivity indices (SI) of 10.2 (HSV-1) and 7.6 (Ad 5), respectively. Virus yield reduction assays indicated that compound I had less antiviral potency against HSV-1 than against Ad 5. The antiviral effects of compound I at a high input virus multiplicity of infection (MOI>5) indicated that compound I had effective anti-adenoviral activity at 24 h post infection. This work demonstrated that some of SB-AHGs only have moderate antiviral activities against Ad 5 and HSV-1 viruses. In general, low MW SB-AHGs have low cytotoxicities to the host cells.

Caco-2 cell permeability vs human gastro-intestinal absorption: QSPR analysis

The aim of this study is to elucidate quantitative structure-permeability relationship (QSPR) of various organic molecules through Caco-2 cells, and to ascertain the relationship between gastrointestinal (GI) absorption in humans and Caco-2 cell permeability. Caco-2 cell permeability and human GI absorption data were obtained from the literature. The maximum hydrogen bond-forming capacity corrected for intra-molecular H-bonding (Hbc) and Liens QSAR model were used in this study. The latest CQSAR software was utilized in calculating the logarithm of partition coefficient in octanol/water (Clog P) and in deriving all regression equations. For 51 compounds, a significant correlation was obtained between Caco-2 cell permeability (log Pcaco-2) and Hbc, octanol/PBS (phosphate buffered saline, pH 7.4) distribution coefficient (log Doct), log MW and an indicator variable (I) for the charge, with a correlation coefficient of 0.797. When these compounds were divided into three subgroups, namely neutral, cationic and anionic compounds, much better correlations (r = 0.968, 0.915 and 0.931, respectively) were obtained using different combinations of various physico-chemical parameters. A plot of human GI absorption vs. Caco-2 cell permeability obtained from different laboratories reveals that Caco-2 cell permeability cannot be used to precisely predict human GI absorption for compounds with Pcaco-2 below 5 x 10(-6) cm/s, due to interlaboratory and experimental variabilities, and the lack of a simple correlation between human GI absorption and Caco-2 cell permeability. Caco-2 cell permeability may be estimated from the structures of drug molecules using the above-mentioned physicochemical parameters. In general, for compounds with Pcaco-2 above 5 x 10(-6) cm/s, human GI absorption ranges from 50 to 100%. This is generally acceptable for development into oral dosage form. For the compounds with Pcaco-2 below 5 x 10(-6) cm/s, careful interpretation of caco-2 cell permeability and use of internal standard for comparison are recommended. Otherwise, good drug candidates may be excluded due to incorrectly predicted poor absorption.