Neuroprotective effects of macamide from maca (Lepidium meyenii Walp.) on corticosterone-induced hippocampal impairments through its anti-inflammatory, neurotrophic, and synaptic protection properties.

The present study aims to investigate the protective effects of N-(3-methoxybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (M 18:3) on corticosterone-induced neurotoxicity. A neurotoxic model was established by subcutaneous injection of corticosterone (40 mg per kg bw) for 21 days. Depressive behaviors (the percentage of sucrose consumption, the immobility time in the forced swimming test, and the total distance in the open field test) were observed. The levels of the brain-derived neurotrophic factor, the contents of tumor necrosis factor-α and interleukin-6, and the numbers of positive cells of doublecortin and bromodeoxyuridine in the hippocampus were measured. The density of hippocampal neurons was calculated. The morphological changes of hippocampal neurons (the density of dendritic spines, the dendritic length, and the area and volume of dendritic cell bodies) were observed. The expression levels of synaptophysin, synapsin I, and postsynaptic density protein 95 were measured. Behavioral experiments showed that M 18:3 (5 and 25 mg per kg bw) could remarkably improve the depressive behaviors. The enzyme-linked immunosorbent assay showed that M 18:3 could considerably reduce hippocampal neuroinflammation and increase hippocampal neurotrophy. Nissl staining showed that M 18:3 could remarkably improve the corticosterone-induced decrease in the hippocampal neuron density. Immunofluorescence analysis showed that M 18:3 could considerably promote hippocampal neurogenesis. Golgi staining showed that M 18:3 could remarkably improve the corticosterone-induced changes in the hippocampal dendritic structure. Western blotting showed that M 18:3 could considerably increase the expression levels of synaptic-structure-related proteins in the hippocampus. In conclusion, the protective effects of M 18:3 may be attributed to the anti-inflammatory, neurotrophic, and synaptic protection properties.

Acetyl-CoA carboxylase 2 inhibition reduces skeletal muscle bioactive lipid content and attenuates progression of type 2 diabetes in Zucker diabetic fatty rats.

Intramyocellular lipid (IMCL) accumulation in skeletal muscle is closely associated with development of insulin resistance. In particular, diacylglycerol and ceramide are currently considered as causal bioactive lipids for impaired insulin action. Recently, inhibition of acetyl-CoA carboxylase 2 (ACC2), which negatively modulates mitochondrial fatty acid oxidation, has been shown to reduce total IMCL content and improve whole-body insulin resistance. This study aimed to investigate whether ACC2 inhibition-induced compositional changes in bioactive lipids, especially diacylglycerol and ceramide, within skeletal muscle contribute to the improved insulin resistance. In skeletal muscle of normal rats, treatment of the ACC2 inhibitor compound 2e significantly decreased both diacylglycerol and ceramide levels while having no significant impact on other lipid metabolite levels. In skeletal muscle of Zucker diabetic fatty (ZDF) rats, which exhibited greater lipid accumulation than that of normal rats, compound 2e significantly decreased diacylglycerol and ceramide levels corresponding to reduced long chain acyl-CoA pools. Additionally, in the lipid metabolomics study, ZDF rats treated with compound 2e also showed improved diabetes-related metabolic disturbance, as reflected by delayed hyperinsulinemia as well as upregulated gene expression associated with diabetic conditions in skeletal muscle. These metabolic improvements were strongly correlated with the bioactive lipid reductions. Furthermore, long-term treatment of compound 2e markedly improved whole-body insulin resistance, attenuated hyperglycemia and delayed insulin secretion defect even at severe diabetic conditions. These findings suggest that ACC2 inhibition decreases diacylglycerol and ceramide accumulation within skeletal muscle by enhancing acyl-CoA breakdown, leading to attenuation of lipid-induced insulin resistance and subsequent diabetes progression.

Comparative pharmacokinetics of seven bioactive components in normal, sham-operated, and myocardial ischemia-reperfusion injury rats after oral administration of the Salvia Miltiorrhiza-Moutan Cortex herb pair.

Recently the Salvia Miltiorrhiza-Moutan Cortex (SM-MC) herb pair is considered as a promising Chinese medicinal mixture exhibiting a range of pharmacological activities, including treating cardiovascular disease due to its unique composition. In this study, we conducted the comparative pharmacokinetic analysis of seven main bioactive components of SM-MC in a different model rat. A straightforward ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) strategy that could simultaneously evaluate the levels of seven compounds was used to ensure the reliability of these pharmacokinetic analyses in rat plasma. The rat plasma samples were collected from normal, sham-operated, and myocardial ischemia-reperfusion injury (MIRI) groups at predetermined time points after the administration of SM-MC. The main pharmacokinetic parameters were detected and calculated. We successfully assessed the maximum concentration (Cmax ), time to Cmax (Tmax ), the elimination rate constant (λz ), total half-life (t1/2 ), total body clearance (CL), and the area under the concentration-time curve from 0 to last sampling time (AUC0-t ) and extrapolated to infinity (AUC0-∞ ). To sum up, an optimized UPLC-MS/MS approach that could be used to rapidly, simultaneously, and sensitively detect seven bioactive compounds derived from SM-MC extract preparations was successfully developed, which may offer a pharmacokinetic basis for preclinical and clinical studies of SM-MC herb pair for treating MIRI.

A HPLC-DAD-MS/MS Method for Simultaneous Determination of Six Active Ingredients of Salviae Miltiorrhizae and Ligustrazine Hydrochloride Injection in Rat Plasma and its Application to Pharmacokinetic Studies.

AIMS: This is a pharmacokinetic study of Salviae miltiorrhizae and ligustrazine hydrochloride injection. The study aimed to evaluate the mechanism of action, safety and rational clinical use of Salviae miltiorrhizae and ligustrazine hydrochloride injection. BACKGROUND: Salviae miltiorrhizae and ligustrazine hydrochloride injection is a compound preparation consisted of Salvia miltiorrhiza extract and ligustrazine hydrochloride for the treatment of cardiovascular and cerebrovascular diseases in China. OBJECTIVE: The study aimed to develop a rapid and sensitive high-performance liquid chromatography-diode array detector-tandem mass spectrometry (HPLC-DAD-MS/MS) method for simultaneous determination of six major active ingredients of Salviae miltiorrhizae and ligustrazine hydrochloride injection, namely danshensu, protocatechuic aldehyde, rosmarinic acid, lithospermic acid, salvianolic acid A, and ligustrazine hydrochloride, in rat plasma. METHODS: Plasma samples were precipitated with methanol, which was spiked with ascorbic acid and the supernatant was separated on a Waters Cortecs C18 column, by using a gradient mobile phase system of acetonitrile-water containing 0.05% formic acid (v/v). For internal standards, puerarin was selected for the five salvianolic acids, while isofraxidin was used for ligustrazine hydrochloride. Besides, electrospray ionization in negative mode and multiplereaction monitoring were used to identify and quantify the five salvianolic acids, whereas ligustrazine hydrochloride was quantified at 310 nm using the diode array detector. RESULTS: Noticeably, all calibration curves showed good linearity (R2>0.99) over the concentration range, with a lower limit of quantification between 0.00411 and 0.0369 µg/mL for salvianolic acids, and 1.74 µg/mL for ligustrazine hydrochloride. Next, the precision of the developed method was evaluated by intra- and inter-day assays, and the percentage of relative standard deviation was within 10%. Although the extraction efficiency of some salvianolic acids was not very satisfactory, the sensitivity of the analytical method met the analysis requirements of rat plasma samples. Moreover, the validated method was successfully applied to a pharmacokinetic study of Salviae miltiorrhizae and ligustrazine hydrochloride injection in the rat model. CONCLUSION: Linear pharmacokinetic characteristics were observed for the six active ingredients after intravenous infusion administration in rats within the dose range examined here. In summary, our study proposed a HPLC-DADMS/ MS method with the simultaneous determination of multiple ingredients, and demonstrated its applicability in pharmacokinetic studies.

Chemical and pharmacological research on the polyphenol acids isolated from Danshen: A review of salvianolic acids.

Danshen, the dried root of Salvia miltiorrhiza Bge, is a common medicinal herb in Traditional Chinese Medicine, which has been used for the treatment of a number of diseases for thousands of years. More than 2000 years ago, the Chinese early pharmacy monograph "Shennong Materia Medica" recorded that Danshen could be used for the treatment of gastrointestinal diseases, cardiovascular diseases, certain gynecological diseases, etc. Since then, Danshen has been widely used clinically in many different prescriptions for many different diseases, especially for the treatment of cardiovascular diseases. Nowadays, many pharmacological studies about the water-soluble components from Danshen have been reported, especially salvianolic acids. It turned out that salvianolic acids showed strong anti-lipid peroxidation and anti-thrombic activities, and among them, SalAA and SalAB were the most potent. This review focused on the achievements in research of salvianolic acids regarding their bioactivities and pharmacological effects. These studies not only shed light on the water-soluble active components of Danshen and their mechanisms at the molecular level, but also provided theoretical information for the development of new medicines from Danshen for the treatment of cardiovascular and cerebrovascular diseases, inflammatory diseases, metabolic diseases, etc.

Impact of Sodium N-[8-(2-Hydroxybenzoyl)amino]-caprylate on Intestinal Permeability for Notoginsenoside R1 and Salvianolic Acids in Caco-2 Cells Transport and Rat Pharmacokinetics.

For drugs with high hydrophilicity and poor membrane permeability, absorption enhancers can promote membrane permeability and improve oral bioavailability. Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) is a new kind of absorption enhancer that has good safety. To investigate the absorption enhancement effect of SNAC on non-polar charged and polar charged drugs and establish the absorption enhancement mechanism of SNAC, SNAC was synthesized and characterized. Two representative hydrophilic drugs-notoginsenoside R1 (R1) and salvianolic acids (SAs)-were selected as model drugs. In vitro Caco-2 cells transport and in vivo rat pharmacokinetics studies were conducted to examine the permeation effect of SNAC on R1 and SAs. R1, rosmarinic acid (RA), salvianolic acid B (SA-B) and salvianolic acid B (SA-A) were determined to compare the permeation enhancement of different drugs. The MTT assay results showed that SNAC had no toxicity to Caco-2 cells. The transepithelial electrical resistance (TEER) of Caco-2 cell monolayer displayed that SNAC facilitated passive transport of polar charged SAs through the membrane of epithelial enterocytes. The pharmacokinetics results demonstrated that area under the curve (AUC) of RA, SA-B and SA-A with administration of SAs containing SNAC was 35.27, 8.72 and 9.23 times than administration of SAs. Tmax of RA, SA-B and SA-A were also prolonged. The AUC of R1 with administration of R1 containing SNAC was 2.24-times than administration of R1. SNAC is more effective in promoting absorption of SAs than R1. The study demonstrated that SNAC significantly improved bioavailability of R1 and SAs. What's more, the effect of SNAC on absorption enhancement of charged drugs was larger than that of non-charged drugs. The current findings not only confirm the usefulness of SNAC for the improved delivery of R1 and SAs but also demonstrate the importance of biopharmaceutics characterization in the dosage form development of drugs.

Design, synthesis and antimicrobial evaluation of propylene-tethered ciprofloxacin-isatin hybrids.

Twelve novel propylene-tethered ciprofloxacin-isatin hybrids 3a-f and 4a-f were designed, synthesized and characterized by MS, HRMS, 1H NMR and 13C NMR. All hybrids were evaluated for their in vitro antimicrobial activities against representative Gram-positive, Gram-negative and mycobacterial pathogens, cytotoxicity in VERO cell line as well as metabolic stability and in vivo pharmacokinetic (PK) properties. The preliminary results indicated that all mono-isatin-ciprofloxacin hybrids exhibited excellent antibacterial activities with MIC ranging from ≤0.03 to 0.5 µg/mL against most of the tested strains. In particular, ciprofloxacin-isatin hybrid 3d was highly potent against all tested Gram-positive and Gram-negative strains including clinically important drug-resistant pathogens, which was comparable to or more potent than the parent ciprofloxacin and reference levofloxacin. Whereas, conjugate 3b (MIC: 0.10 and 0.5 µg/mL) was 4- and 8-fold more active than ciprofloxacin (MIC: 0.78 µg/mL) and rifampicin (MIC: 0.39 µg/mL) against MTB H37Rv, and 4->256 times more potent than the three references ciprofloxacin (MIC: 2.0 µg/mL), rifampicin (MIC: 32 µg/mL) and isoniazid (>128 µg/mL) against MDR-TB. Both hybrid 3b and 3d with low cytotoxicity (CC50: 64 and 256 µg/mL) also showed acceptable metabolic stability and in vivo PK properties, could act as leads for further optimization.

Simultaneous determination and tissue distribution studies of four phenolic acids in rat tissue by UFLC-MS/MS after intravenous administration of salvianolic acid for injection.

A rapid, simple and sensitive ultra-fast liquid chromatography tandem mass spectrometric method was developed and validated for simultaneous determination and tissue distribution studies of rosmarinic acid, salvianolic acid D, lithospermic acid and salvianolic acid B in rats after intravenous administration of salvianolic acid for injection. The tissue homogenate samples were pretreated by protein precipitation with pre-cooled acetonitrile. Chromatographic separation was achieved on a Waters Cortecs UPLC C18 column (1.6 µm, 2.1 × 100 mm) with a mobile phase composed of 0.1% formic acid-water and 0.1% formic acid-acetonitrile. Analytes were detected by electrospray ionization mass spectrometry and quantitated using multiple reaction monitoring. The method was fully validated. The calibration curves for the four phenolic acids were linear in the given concentration ranges. The precisions (relative standard deviation) in the measurement of quality control samples were <10% and the accuracies (relative error) were in the range of 0.28-11.22%. The reliable method was successfully applied to the tissue distribution studies of the four phenolic acids. The results showed that rosmarinic acid, salvianolic acid D, lithospermic acid and salvianolic acid B were rapidly distributed in tissues with the major amount found in kidney, and little crossed the blood-brain barrier. The developed method and the results provide a basis for further studies.

The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes.

Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. The formation of tamoxifen bisphenol and metabolite E was studied in human liver microsomes and Supersomes™. Cellular metabolism and impact on CYP enzymes was analyzed in upcyte® hepatocytes. The influence of 5 µM of tamoxifen, anti-estrogenic and estrogen-like metabolites on CYP activity was measured by HPLC MS/MS and on ADME gene expression using RT-PCR analyses. Metabolite E was formed from tamoxifen by CYP2C19, 3A and 1A2 and from desmethyltamoxifen by CYP2D6, 1A2 and 3A. Tamoxifen bisphenol was mainly formed from (E)- and (Z)-metabolite E by CYP2B6 and CYP2C19, respectively. Regarding phase II metabolism, UGT2B7, 1A8 and 1A3 showed highest activity in glucuronidation of tamoxifen bisphenol and metabolite E. Anti-estrogenic metabolites (Z)-4-hydroxytamoxifen, (Z)-endoxifen and (Z)-norendoxifen inhibited the activity of CYP2C enzymes while tamoxifen bisphenol consistently induced CYPs similar to rifampicin and phenobarbital. On the transcript level, highest induction up to 5.6-fold was observed for CYP3A4 by tamoxifen, (Z)-4-hydroxytamoxifen, tamoxifen bisphenol and (E)-metabolite E. Estrogen-like tamoxifen metabolites are formed in CYP-dependent reactions and are further metabolized by glucuronidation. The induction of CYP activity by tamoxifen bisphenol and the inhibition of CYP2C enzymes by anti-estrogenic metabolites may lead to drug-drug-interactions.

Hyperpolarized (129) Xe MRI using isobutene as a new quenching gas.

The use of a quenching gas, isobutene, with a low vapor pressure was investigated to enhance the utility of hyperpolarized (129) Xe (HP Xe) MRI. Xenon mixed with isobutene was hyperpolarized using a home-built apparatus for continuously producing HP Xe. The isobutene was then readily liquefied and separated almost totally by continuous condensation at about 173 K, because the vapor pressure of isobutene (0.247 kPa) is much lower than that of Xe (157 kPa). Finally, the neat Xe gas was continuously delivered to mice by spontaneous inhalation. The HP Xe MRI was enhanced twofold in polarization level and threefold in signal intensity when isobutene was adopted as the quenching gas instead of N2 . The usefulness of the HP Xe MRI was verified by application to pulmonary functional imaging of spontaneously breathing mice, where the parameters of fractional ventilation (ra ) and gas exchange (fD ) were evaluated, aiming at future extension to preclinical studies. This is the first application of isobutene as a quenching gas for HP Xe MRI.

Quantitatively metabolic profiles of salvianolic acids in rats after gastric-administration of Salvia miltiorrhiza extract.

Salvianolic acids, the well-known active components in Salvia miltiorrhiza, have been shown to possess markedly pharmacological activities. However, due to the complex in vivo course after administration, the pharmacologically active forms are still poorly understood. In present study, we evaluated the stability of eight major salvianolic acids from Danshen extract under different chemical and physiological conditions. We also quantitatively explained the absorption, metabolism and excretion of these salvianolic acids in rats after gastric-administration, which was carried out by simultaneously determining the amounts of salvianolic acids and their metabolites in the rat gastrointestinal contents, gastrointestinal mucosa, plasma, bile and urine. We found that: 1) protocatechuic aldehyde (PAL) was much stable whether in acidic environment (pH4.0) or in alkaline environment (pH8.0), while other salvianolic acids were stable in acidic environment and instable in alkaline environment; 2) PAL, salvianoli acid A (SAA) and salvianolic acid B (SAB) were instable whether in rat stomach or in small intestine, while other salvianolic acids were stable in rat stomach and instable in small intestine; 3) after gastric-administration, except PAL and Danshensu (DSS), other phenolic acids would be metabolized into DSS and caffeic acid (CA) in the rat gastrointestinal tract before absorption, and only free and glucuronidated PAL, CA and DSS were detected in rat plasma, bile and urine. In conclusion, it was the free and glucuronidated PAL, CA and DSS rather than the prototypes of other salvianolic acids that were present in plasma with considerable concentrations after gastric-administration.

Development and validation of a UFLC-MS/MS method for determination of 7'(Z)-(8″S, 8‴S)-epi-salvianolic acid E, (7'R, 8'R, 8″S, 8‴S)-epi-salvianolic acid B and salvianolic acid B in rat plasma and its application to pharmacokinetic studies.

7'(Z)-(8″S, 8‴S)-epi-Salvianolic acid E (compound 1) and (7'R, 8'R, 8″S, 8‴S)-epi-salvianolic acid B (compound 2), two novel analogs of salvianolic acid B (Sal B), have been recently isolated from Salvianolic acid for injection. They both show powerful antioxidant effects, including inducing NQO1 activity and scavenging DPPH free radical, and potential protecting effects for cerebral ischemia. However, no reports have been described the pharmacokinetic study of them. In this study, an ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) method was developed and validated for the determination of compound 1, compound 2 and Sal B in rat plasma, respectively. Plasma samples were pretreated by liquid-liquid extraction with ethyl acetate. Chromatographic separation was achieved on a Waters Acquity UPLC(®) HSS T3 column (1.7µm particles, 2.1mm i.d.×100mm) with the mobile phase of 0.1% aqueous formic acid (A)-acetonitrile (B) (65:35, v/v). Quantification was performed on a triple quadruple tandem mass spectrometry with electrospray ionization (ESI) by multiple reaction monitoring (MRM) in the negative ion mode. Monitored transitions were set at m/z 717.0→519.0, 717.1→519.1, 717.2→518.9 and 320.9→152.1 for compound 1, compound 2, Sal B and chloramphenicol (internal standard, IS), respectively. Linear calibration curves were acquired over the concentration range of 2.0-1000ng/mL for the three analytes in rat plasma. The extraction recoveries, matrix effects, intra- and inter-day precisions and accuracies of the three analytes were all within acceptable limits. The validated method was successfully applied to the pharmacokinetic study of compound 1, compound 2 and Sal B after intravenous administration of 6.0mg/kg in rats, respectively. The results indicated that compound 1 and compound 2 were both eliminated more slowly than Sal B. Exposure levels of both compound 1 and Sal B were higher than compound 2 in the same dosage range. This study provided critical reference for the pharmacokinetic study of compound 1 and compound 2.

Differential Effects of Structural Modifications on the Competition of Chalcones for the PIB Amyloid Imaging Ligand-Binding Site in Alzheimer's Disease Brain and Synthetic Aß Fibrils.

Alzheimer's disease (AD) is a complex brain disorder that still remains ill defined. In order to understand the significance of binding of different clinical in vivo imaging ligands to the polymorphic pathological features of AD brain, the molecular characteristics of the ligand interacting with its specific binding site need to be defined. Herein, we observed that tritiated Pittsburgh Compound B ((3)H-PIB) can be displaced from synthetic Aß(1-40) and Aß(1-42) fibrils and from the PIB binding complex purified from human AD brain (ADPBC) by molecules containing a chalcone structural scaffold. We evaluated how substitution on the chalcone scaffold alters its ability to displace (3)H-PIB from the synthetic fibrils and ADPBC. By comparing unsubstituted core chalcone scaffolds along with the effects of bromine and methyl substitution at various positions, we found that attaching a hydroxyl group on the ring adjacent to the carbonyl group (ring I) of the parent member of the chalcone family generally improved the binding affinity of chalcones toward ADPBC and synthetic fibrils F40 and F42. Furthermore, any substitution on ring I at the ortho-position of the carbonyl group greatly decreases the binding affinity of the chalcones, potentially as a result of steric hindrance. Together with the finding that neither our chalcones nor PIB interact with the Congo Red/X-34 binding site, these molecules provide new tools to selectively probe the PIB binding site that is found in human AD brain, but not in brains of AD pathology animal models. Our chalcone derivatives also provide important information on the effects of fibril polymorphism on ligand binding.

Determination of salvianolic acid C in rat plasma using liquid chromatography-mass spectrometry and its application to pharmacokinetic study.

A sensitive and reliable LC-ESI-MS method for the determination of salvianolic acid C in rat plasma has been developed and validated. Plasma samples were prepared by liquid-liquid extraction with ethyl acetate and separated on a Zorbax SB-C18 column (3.5 µm, 2.1 × 100 mm) at a flow rate of 0.3 mL/min using acetonitrile-water as mobile phase. The detection was carried out by a single quadrupole mass spectrometer with electrospray ionization source and selected ion monitoring mode. Linearity was obtained for salvianolic acid C ranging from 5 to 1000 ng/mL. The intra- and inter-day precisions (RSD, %) didn't exceed 9.96%, and the accuracy (RE, %) were all within ±3.64%. The average recoveries of the analyte and internal standard were >89.13%. Salvianolic acid C was proved to be stable during all sample storage, preparation and analytic procedures. The validated method was successfully applied to pharmacokinetic study after oral and intravenous administration of salvianolic acid C to rats. The absolute oral bioavailability of salvianolic acid C was 0.29 ± 0.05%. This method was further applied to simultaneous determination of salvianolic acid A, salvianolic acid B and salvianolic acid C in rat plasma and showed good practicability.

Fragrance material review on 2-heptylidenecyclopentan-1-one.

A toxicologic and dermatologic review of 2-heptylidenecyclopentan-1-one when used as a fragrance ingredient is presented. 2-Heptylidenecyclopentan-1-one is a member of the fragrance structural group ketones cyclopentanones and cyclopentenones. The common characteristic structural element of the group members is a cyclopentanone or cyclopentenone ring with a straight or branched chain alkane or alkene substituent. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2-heptylidenecyclopentan-1-one were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, and repeated dose data. A safety assessment of the entire ketones cyclopentanones and cyclopentenones will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all ketones cyclopentanones and cyclopentenones in fragrances.

Pharmacokinetics prediction and drugability assessment of diphenylheptanoids from turmeric (Curcuma longa L).

Cheminformatics approaches are currently not employed in any of the spices to study the medicinal properties traditionally attributed to them. The aim of this study is to find the most efficacious molecule which do not have toxic effects but at the same time have desired pharmacokinetic profile. In the present study of the class 'diphenylheptanoids' from turmeric, cheminformatics methods were employed to predict properties such as physicochemical properties, Absorption, Distribution, Metabolism, Toxicity (mutagenicity, rodent carcinogenicity and human hepatotoxicity). These studies confirmed that curcumin and its derivatives cause dose-dependent hepatotoxicity. The results of these studies indicate that, in contrast to curcumin, few other compounds in turmeric such as compounds (8) and (9) [refer text], exhibit better activities and are drugable and do not have any side-effects.

Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors.

The synthesis, selectivity, rat pharmacokinetic profile, and drug metabolism profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.

Concentrations of the propylene metabolite propylene oxide in blood of propylene-exposed rats and humans--a basis for risk assessment.

Propylene (PE) was not carcinogenic in long-term studies in rodents. However, its biotransformation to propylene oxide (PO) raises questions about a carcinogenic risk. PO alkylates macromolecules, is a direct mutagen, and caused tumors in rodents at high concentrations. In order to acquire knowledge on the species-specific PO concentrations in blood resulting from PE exposure, we exposed male Fischer 344/N rats in closed exposure chambers to constant PE concentrations, between 20.1 and 3000 ppm (7 h at least), and four male volunteers to mean constant PE concentrations of 9.82 and 23.4 ppm (180 min) in inhaled air. In the animal experiments, PE and PO were measured in the chamber atmosphere, PE by gas chromatography with flame ionization detection (GC/FID), PO by GC/FID or GC with mass-selective detection (GC/MSD). In the human studies, PE was measured in inhaled and exhaled air by GC/FID. PO was quantified by GC/MSD from exhaled breath collected in gasbags. Blood concentrations of PO were calculated based on the measured PO concentrations in air using the blood-to-air partition coefficients of 60 (rat) and 66 (human). In rats, PO blood concentrations ranged from 53 nmol/l at 20.1 ppm PE to 1750 nmol/l at 3000 ppm PE. In humans, mean blood concentrations of PO were 0.44 and 0.92 nmol/l at mean PE concentrations of 9.82 and 23.4 ppm, respectively. These findings should be taken into consideration when estimating the carcinogenic risk of PE to humans based on carcinogenicity studies in PE- or PO-exposed rats.

Fragrance material review on cis-3-hexenyl cinnamate.

A toxicologic and dermatologic review of cis-3-hexenyl cinnamate when used as a fragrance ingredient is presented.

Fragrance material review on cinnamyl tiglate.

A toxicologic and dermatologic review of cinnamyl tiglate when used as a fragrance ingredient is presented.