Effect of mercury and gold on growth,nutrient uptake,and anatomical changes in Chilopsis linearis

Plants of Chilopsis linearis were grown with 0, 50, 100, and 200 μM Hg [as Hg(CH₃COO)₂] and 0 and 50 μM Au (as KAuCl₄) in hydroponics. The results showed that seedling grown with 50 μM Au + 50 μM Hg and 50 μM Au + 100 μM Hg had roots 25 and 55% shorter than control roots, respectively. The element uptake determination using ICP/OES demonstrated that Hg at 50 and 100 μM (with and without Au) significantly increased (p < 0.05) the S concentration in leaves. On the other hand, the concentration of Fe significantly increased in roots of plants treated with Au–Hg. In addition, the stems of plants treated with Hg at 100 μM, with and without Au, had 239 and 876 mg Hg/kg dry biomass (d wt), respectively. Also, at 50 μM Hg, with and without Au, stems accumulated 375 and 475 mg Hg/kg d wt. The Hg concentration in leaves (287 mg Hg/kg d wt) was higher (p < 0.05) for the treatment containing 50 μM Au + 100 μM Hg. Without Au, the Hg concentration in leaves decreased to 75 mg Hg/kg d wt. Toxicity symptoms induced by Hg in cortex cells and the vascular system were lower in plants exposed to 50 μM Au + 50 μM Hg compared to plants exposed to 50 μM Hg only. Further, the SEM micrographs revealed deposition of Au–Hg particles inside the root. Although the concentrations of Hg used in this study showed different degree of toxicity, the plants displayed good agronomic value.     

Insecticide susceptibility of Ephemera orientalis (Ephemeroptera: Ephemeridae) and two mosquito species,Anopheles sinensis and Culex pipiens in the Republic of Korea

Field-collected populations of mayflies, Ephemera orientalis were tested for susceptibility to 10 different insecticides using a direct-contact mortality bioassay. Ephemera orientalis subimagoes were susceptible to the insecticides chlorpyrifos, fenitrothion and chlorfenapyr with LD₅₀ values of 69.7, 78.8 and 81.9 μg/♀, and adults had LD₅₀ values of 71.9, 78.8 and 85.4 μg/♀, respectively. Susceptibility ratios (SRs) of subimagoes and adults of E. orientalis to the 10 insecticides were 1.0 to1.2 folds. The mayflies showed higher susceptibility to organophosphates than to pyrethroids. The SRs of Anopheles sinensis to E. orientalis were 514 to 1438 folds higher for organophosphates (LD₅₀ values of 0.05 to 0.23 μg/♀) and 62 to 1155 folds higher for pyrethroids (LD₅₀ values of 0.13 to 2.41 μg/♀). The SRs of Culex pipiens to E. orientalis were 606 to 3595 folds higher for organophosphates with LD₅₀ values of 0.02–0.17 μg/♀ and 81 to 1365 folds higher for pyrethroids with LD₅₀ values of 0.11–1.83 μg/♀. These results indicate that the use of ineffective insecticides will result in unsatisfactory control against field populations of the subimagoes and adults of E. orientalis.     

Safety of Prunus africana and Warburgia ugandensis in asthma treatment

The aim of the study was to determine the possible cytotoxicity of the aqueous stem bark extracts of Prunus africana and Warburgia ugandensis to Vero E6 cells and acute toxicity in BALB/c mice. Despite being some of the most popular medicinal plants used in Africa, little is known about the safety. In-vitro cytotoxicity tests on Vero E6 cells were investigated using MTT assay to assess the safety of the two plant extracts. Vero E6 cells on growing to confluence were incubated with different drug concentrations for 48 h for the drug to take effect. Viability of the cells was measured by a scanning multiwell spectrophotometer, color intensity being equivalent to viable cells which reduce MTT to soluble formazan crystals. This was done by determining the CC₅₀ of the extracts, CC₅₀ being the concentration of the dose of the compound/extract that kills 50% of the cells. In acute toxicity a total of 55 mice were used. Mice were divided into eleven groups of 5 mice, one group served as negative control and ten groups received oral gavage doses at 500, 889.56, 1581.6, 2812.15 or 5000 mg/kg body weight once. Mortality and other signs of toxicity were recorded within 24 h and the weights of the surviving mice taken for 14 days thereafter. P. africana had CC₅₀ of 104.08 μg/ml while W. ugandensis had CC₅₀ > 250 μg/ml and both were classified as not cytotoxic. There was no mortality observed in groups of mice that received P. africana extracts at 500 and 889.56 mg/kg body weight. There was 20%, 60% and 100% mortality observed within 24 h for mice that received P. africana extracts at 1581.64, 2812.15 and 5000 mg/kg body weight respectively. Lethal dose (LD₅₀) for P. africana was 2201.207 mg/kg body weight. W. ugandensis extracts had no mortality recorded in all dose levels and the LD₅₀ was > 5000 mg/kg body weight. The weights of mice that survived the entire 14 days in all groups increased and were not significantly different from that of controls p > 0.05. From the in vitro and in vivo studies, the two extracts were safe to use. Though with their customary value among many Kenyan communities in management of asthma among other ailments there is a need for further validation of any anti-asthmatic properties and responsible chemical compounds to augment the findings.     

Toxicity and repellency of origanum essential oil and its components against Tribolium castaneum (Coleoptera: Tenebrionidae) adults

The components of Origanum vulgare L. essential oil showing insecticidal activity and repellency against red flour beetle, Tribolium castaneum (Coleoptera: Tenebrionidae), adults were analysed by GC-MS. All constituents were identified, and the main components were carvacrol (67.2%), p-cymene (16.2%), γ-terpinene (5.5%), thymol (4.9%), and linalool (2.1%). In a vapor phase fumigant assay, the origanum oil was more effective in closed conditions (LD₅₀ = 0.055 mg/cm³) than in open conditions (LD₅₀ > 0.353 mg/cm³). This suggests that toxicity is exerted largely in the vapor phase. Based on 24-h LD₅₀ values, the toxicity of caryophyllene oxide (0.00018 mg/cm³) was comparable with that of dichlorvos (0.00007 mg/cm³). In addition, thymol, camphene, α-pinene, p-cymene, and γ-terpinene showed good insecticidal activity (LD₅₀ = 0.012–0.195 mg/cm³). In repellency tests using 9 constituents of origanum oil, caryophyllene oxide showed complete repellency at 0.03 mg/cm². Hydrogenated monoterpenoids, such as thymol, α-pinene, carvacrol, and myrcene, elicited strong repellency at 0.03 and 0.006 mg/cm². Repellency depended on both time and concentration. These results indicate that origanum oil and its components could be potential candidates as a fumigant and repellent for managing T. castaneum adults.     

Histopathological and biological studies of the effect of cadmium on Rhinella arenarum gonads

This study was to determine the lethal dose 50 (LD₅₀) of CdCl₂ in adult Rhinella arenarum and analyzed the effect of two sublethal doses (0.5 and 5 mg/kg) of the xenobiotic in gonads. The 48 h LD₅₀ were 50.0 and 49.8 mg/kg for males and females respectively. Alterations in the ovary were evidenced by nuclear pleomorphism and cytoplasmic vacuolization of the oocytes at the early stages of development with the highest dose and an increase in the population of atretic oocytes. In the interstitial tissue we noticed congestion, edema and fibroblast proliferation. The nuclear maturation of the oocytes was affected by the xenobiotic in a dose- and time-dependent manner. In males, treatment with 5 mg/kg of cadmium (Cd) caused a decrease in the concentration, viability and straight progressive motility of sperm while there was an increase in immotile sperm. Testis histopathology revealed dilated seminiferous tubules, disappearance of cysts, tissue disorganization and leukocyte infiltration. Numerous germ cells showed hydropic tumefaction or signs of focal necrosis. The Cd content in animals intoxicated gonads with the highest sublethal dose was significantly higher than in the control. Results indicate that R. arenarum gonads are target for the xenobiotic, compromising the formation of gametes competent for fertilization, the effective CdCl₂ dose being 5 mg/kg.     

Bioactivity of essential oil of Litsea cubeba from China and its main compounds against two stored product insects

During our screening program for agrochemicals from Chinese medicinal herbs and wild plants, the essential oil of Litsea cubeba fruits was found to possess strong contact toxicity against the cigarette beetle Lasioderma serricorne adults and the booklouse Liposcelis bostrychophila, with LD₅₀ values of 27.33 μg/adult and 71.56 μg/cm², respectively, and also showed strong fumigant toxicity against the two stored product insects with LC₅₀ values of 22.97 and 0.73 mg/L, respectively. The essential oil obtained by hydrodistillation was investigated by GC MS. The main components of the essential oil were identified to be E-citral (geranial) (27.49%), Z-citral (neral) (23.57%) and d-limonene (18.82%) followed by β-thujene (3.34%), β-pinene (2.85%), α-pinene (2.57%), 6-methyl-5-hepten-2-one (2.40%) and linalool (2.36%). Citral (Z/E-citral), d-limonene, β-pinene, α-pinene and linalool were separated and purified by silica gel column chromatography and preparative thin layer chromatography, and further identified by means of physicochemical and spectrometric analysis. Citral and linalool showed strong contact toxicity against L. serricorne and L. bostrychophila (LD₅₀ = 11.76, 12.74 μg/adult and 20.15, 99.97 μg/cm², respectively) and fumigant toxicity against L. serricorne and L. bostrychophila (16.54, 18.04 mg/L air and 0.14, 0.71 mg/L air, respectively). Otherwise, citral, d-limonene and linalool were strongly repellent against the cigarette beetle L. serricorne as the essential oil whereas β-pinene and α-pinene exhibited weaker repellency against the cigarette beetle compared with the positive control, DEET. Moreover, except α-pinene and linalool, the other three compounds as well as the essential oil exhibited comparable repellency against the booklouse relative to DEET.     

Design,synthesis and biological evaluation of aryl pyrimidine derivatives as potential leishmanicidal agents

A series of substituted aryl pyrimidine derivatives was synthesized and evaluated in vitro for their antileishmanial potential against intracellular amastigotes of Leishmania donovani using reporter gene luciferase assay. Among all, 8 compounds showed promising IC₅₀ values ranging from 0.5 to 12.9 μM. Selectivity indices (S.I.) of all these compounds are far better than reference drugs, sodium stibogluconate (SSG) and miltefosine. On the basis of good S.I., compounds were further screened for their in vivo antileishmanial activity against L. donovani/hamster model. Compounds 2d, 4a and 4b have shown significant inhibition of parasitic multiplication that is 88.4%, 78.1% and 78.2%, respectively at a daily dose of 50 mg/kg × 5 days, when administered intraperitoneally. Compound 2d is most promising one, which may provide a new lead that could be exploited as a new antileishmanial agent.     

Insulinotropic effect of cinnamaldehyde on transcriptional regulation of pyruvate kinase,phosphoenolpyruvate carboxykinase,and GLUT4 translocation in experimental diabetic rats

Diabetes mellitus is a chronic metabolic disorder affecting about 6% of population worldwide with its complications and is rapidly reaching epidemic scale. Cinnamomum zeylanicum is widely used in alternative system of medicine for treatment of diabetes. In the present study, we have performed bioassay guided fractionation of chloroform extract of C. zeylaniucm and identified cinnamaldehyde (CND) as an active principle against diabetes. In continuation to it, a detailed study was undertaken to elucidate its mode of antidiabetic action in STZ induced diabetic rats. Oral administration of CND (20 mg/kg bw) to diabetic rats for 2 months showed significant improvement (p < 0.001) in muscle and hepatic glycogen content. In vitro incubation of pancreatic islets with CND enhanced the insulin release compared to glibenclamide. The insulinotropic effect of CND was found to increase the glucose uptake through glucose transporter (GLUT4) translocation in peripheral tissues. The treatment also showed a significant improvement in altered enzyme activities of pyruvate kinase (PK) and phosphoenolpyruvate carboxykinase (PEPCK) and their mRNA expression levels.Furthermore, the median lethal dose (LD₅₀) of CND could not be obtained even at 20 times (0.4 g/kg bw) of its effective dose. With the high margin of safety of CND, it can be developed as a potential therapeutic candidate for the treatment of diabetes.     

Quercetin in vesicular delivery systems: Evaluation in combating arsenic-induced acute liver toxicity associated gene expression in rat model

Arsenic, the environmental toxicant causes oxidative damage to liver and produces hepatic fibrosis. The theme of our study was to evaluate the therapeutic efficacy of liposomal and nanocapsulated herbal polyphenolic antioxidant Quercetin (QC) in combating arsenic induced hepatic oxidative stress, fibrosis associated upregulation of its gene expression and plasma TGF ß (transforming growth factor ß) in rat model.A single dose of Arsenic (sodium arsenite-NaAsO₂, 13 mg/kg b.wt) in oral route causes the generation of reactive oxygen species (ROS), arsenic accumulation in liver, hepatotoxicity and decrease in hepatic plasma membrane microviscosity and antioxidant enzyme levels in liver. Arsenic causes fibrosis associated elevation of its gene expression in liver, plasma TGF ß (from normal value 75.2 ± 8.67 ng/ml to 196.2 ± 12.07 ng/ml) and release of cytochrome c in cytoplasm. Among the two vesicular delivery systems formulated with QC, polylactide nanocapsules showed a promising result compared to liposomal delivery system in controlling arsenic induced alteration of those parameters. A single dose of 0.5 ml of nanocapsulated QC suspension (QC 2.71 mg/kg b.wt) when injected to rats 1 h after arsenic administration orally protects liver from arsenic induced deterioration of antioxidant levels as well as oxidative stress associated gene expression of liver. Histopathological examination also confirmed the pathological improvement in liver. Nanocapsulated plant origin flavonoidal compound may be a potent formulation in combating arsenic induced upregulation of gene expression of liver fibrosis through a complete protection against oxidative attack in hepatic cells of rat liver.     

The influence of cytokinins on proliferation and polyphenol accumulation in shoot cultures of Scutellaria altissima L.

S. altissima shoots were cultivated on MS (Murashige and Skoog) solid medium supplemented with IAA (indole-3-acetic acid, 0.57 μM) and various concentrations of cytokinin: zeatin, kinetin, BAP (6-benzylaminopurine) (1, 2, 4, 8 μM) or TDZ (thidiazuron) (0.2, 0.5, 1 μM). The effects on shoot proliferation and their accumulation of pharmacologically valuable phenolic compounds (baicalin, wogonoside, luteolin, luteolin-7-O-glucoside, verbascoside) were evaluated. Ultra-high performance liquid chromatography (UHPLC) was used for quantitative analysis of the compounds accumulated in the plant biomass. The metabolites were identified by comparing their retention time, UV spectra and mass spectra with those of the standard compounds and published data. The highest metabolite contents were recorded in shoots treated with TDZ at a concentration of 1 μM; under these conditions, the total level of all evaluated flavones expressed as the sum of baicalin, wogonoside, luteolin and luteolin-7-O-glucoside (17.35 mg/g dry wt) was more than twice that of those grown on MS cytokinin-free medium (7.55 mg/g dry wt). Verbascoside accumulation was also stimulated by 1 μM TDZ; its level was about six times higher than that found on the control medium (6.2 mg/g dry wt vs. 1.03 mg/g dry wt). The highest number of shoots (5.5–6.4 per explant within five weeks) was achieved with 2–8 μM BAP.     

Nitric oxide interacts with mitochondrial complex III producing antimycin-like effects

The effect of NO between cytochromes b and c of the mitochondrial respiratory chain were studied using submitochondrial particles (SMP) from bovine heart and GSNO and SPER-NO as NO sources. Succinate-cytochrome c reductase (complex II-III) activity (222±4 nmol/min. mg protein) was inhibited by 51% in the presence of 500 μM GSNO and by 48% in the presence of 30 μM SPER-NO, in both cases at ~1.25 μM NO. Neither GSNO nor SPER-NO were able to inhibit succinate-Q reductase activity (complex II; 220±9 nmol/min. mg protein), showing that NO affects complex III. Complex II-III activity was decreased (36%) when SMP were incubated with l-arginine and mtNOS cofactors, indicating that this effect is also produced by endogenous NO. GSNO (500 μM) reduced cytochrome b₅₆₂ by 71%, in an [O₂] independent manner. Hyperbolic increases in O₂^•- (up to 1.3±0.1 nmol/min. mg protein) and H₂O₂ (up to 0.64±0.05 nmol/min. mg protein) productions were observed with a maximal effect at 500 μM GSNO. The O₂^•-/H₂O₂ ratio was 1.98 in accordance with the stoichiometry of the O₂^•- disproportionation. Moreover, H₂O₂ production was increased by 72–74% when heart coupled mitochondria were exposed to 500 μM GSNO or 30 μM SPER-NO. SMP incubated in the presence of succinate showed an EPR signal (g=1.99) compatible with a stable semiquinone. This EPR signal was increased not only by antimycin but also by GSNO and SPER-NO. These signals were not modified under N₂ atmosphere, indicating that they are not a consequence to the effect of NOx species on complex III area. These results show that NO interacts with ubiquinone-cytochrome b area producing antimycin-like effects. This behaviour comprises the inhibition of electron transfer, the interruption of the oxidation of cytochromes b, and the enhancement of [UQH^•]_ss which, in turn, leads to an increase in O₂^•- and H₂O₂ mitochondrial production rates.     

ACE inhibitory,hypotensive and antioxidant peptide fractions from Mucuna pruriens proteins

Hydrolysates and peptide fractions obtained from Mucuna pruriens protein concentrate were studied for their angiotensin converting enzyme (ACE) inhibitory, hypotensive and antioxidant activities. The hydrolysate obtained by pepsin–pancreatin (HPP) was the most active with an ACE IC₅₀ value of 19.5 μg/mL, a Trolox equivalent antioxidant capacity (TEAC) value of 102.8 mM/mg and a ferric reducing power (FRP) IC₅₀ of 67.2 μg/mL. At a dose of 5 mg/kg HPP decrease systolic (32.2%) and diastolic (37%) blood pressure in rats more pronounced than Captopril. The peptide fraction <1 kDa from HPP was the most active with an ACE inhibitory of 10.2 μg/mL (IC₅₀), a TEAC value of 709.8 mM/mg and a FRP IC₅₀ of 54.9 μg/mL. These results indicate that the hydrolysates and peptide fractions of M. pruriens would be used as nutraceuticals ingredients for preventing and providing therapy against hypertension and diseases related to oxidative damage.     

Quantitative determination of oxytocin receptor antagonist atosiban in rat plasma by liquid chromatography–tandem mass spectrometry

A kinetic study of atosiban was conducted following repeated intravenous administration in Wistar rats. Sample analysis was performed using liquid chromatography–tandem mass spectrometry (LC–MS/MS) following full validation of an in-house method. Eptifibatide, a cyclic peptide, was used as an internal standard (IS). The analyte and internal standard were extracted using solid phase extraction (SPE) method. Chromatographic separation was carried out using an ACE C18 5 μm 50 mm × 4.6 mm column with gradient elution. Mass spectrometric detection was performed using TSQ Quantum ultra AM. The lower limit of quantification was 0.01 μg/ml when 100 μl rat plasma was used. Plasma concentrations of atosiban were measured at 0 (pre-dose), 2, 15, 30, 45, 60, 120 min at the dosage levels of 0.125 mg/kg (low dose), 0.250 mg/kg (mid dose), and 0.500 mg/kg (high dose), respectively. Atosiban plasma concentration measured at Day 1 showed mean peak atosiban concentration (C_max) 0.40, 0.57, 1.95 μg/ml for low, mid and high dose treated animals and mean peak concentration on Day 28 was 0.41, 0.88, 1.31 μg/ml on Day 28 for low, mid and high dose treated animals.     

Search for new pharmacophores for antimalarial activity. Part II: Synthesis and antimalarial activity of new 6-ureido-4-anilinoquinazolines

Synthesis of new 6-ureido-4-anilinoquinazolines have been accomplished and their in vitro antimalarial activity against chloroquine-sensitive P. falciparum have been examined. Out of 64 compounds evaluated, the IC₅₀ of 16 compounds which have displayed MIC of 0.25 μg/mL were also recorded. One of the compounds (24g) had IC₅₀ value of 2.27 ng/mL which was equipotent to the standard drug chloroquine used in the bioassay. The in vivo evaluation of a few compounds among the series led to discovery of one analog (30g) displaying 40% curative activity (28 days) against mdr P. yoeilli nigeriensis at an oral dose of 100 mg/kg × 4days.     

Novel toxins produced by the dinoflagellate Karenia brevisulcata

Karenia brevisulcata (Chang), a new toxic dinoflagellate of the genus Karenia was isolated from a harmful algal bloom that occurred in Wellington Harbour, New Zealand in 1998. The bloom severely affected most marine biota resulting in long-term ecological damage and causing respiratory distress in harbour bystanders. Cultures of K. brevisulcata produced a range of novel toxins including ten lipid-soluble K. brevisulcata toxins (KBTs) and six water-soluble brevisulcatic acids (BSXs). Brevetoxins were not detected. KBT-F, KBT-G, BSX-1 and BSX-2 were isolated from 1450 L of bulk cultures and purified in mg quantities. Preliminary chemical and toxicological investigations show that KBT-F (M 2054 C₁₀₇H₁₆₀O₃₈) and KBT-G (M 2084 C₁₀₈H₁₆₂O₃₉) are complex polycyclic ethers with UVmax at 227 nm. NMR data gave characteristics of ladder frame polyether structures and a 2-methylbut-2-enal side chain, similar to gymnocins. The mouse i.p. LD₅₀s for KBT-F and -G were 0.032 and 0.040 mg kg⁻¹, respectively. These KBTs were also highly cytotoxic and haemolytic. BSX-1 (M 916 C₄₉H₇₂O₁₆) and BSX-2 (M 872 C₄₇H₆₈O₁₅) are polycyclic ether dicarboxylates with UVmax 196 nm. BSX-4 and BSX-5, the lactone ring-closed analogues and the presumed primary toxins in the algal cells, were isolated in smaller quantities. Preliminary structural information from NMR and MS showed a carboxylated side chain and some similarities to brevetoxin-A. However, the structures have not yet been fully elucidated due to conformers confounding the NMR. The mouse i.p. LD₅₀ for BSX-1 was 3.9 mg kg⁻¹ while no deaths were seen in mice injected with BSX-2 at 6.6 mg kg⁻¹. The LD₅₀s for the lactones BSX-4 and -5 were 1.4 and 1.6 mg kg⁻¹ respectively. BSX-4 and -5 were agonists of voltage-gated sodium channels but only weakly haemolytic. Activities in the Neuro-2a cytotoxicity assay were ca 10% of dihydrobrevetoxin-2 and were fully antagonised by saxitoxin.     

Design,synthesis and biological evaluation of imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole derivatives as Mycobacterium tuberculosis pantothenate synthetase inhibitors

In the present study, we have designed imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole derivatives from earlier reported imidazo[1,2-a]pyridine based Mycobacterium tuberculosis (MTB) pantothenate synthetase (PS) inhibitors. We synthesized thirty compounds and they were evaluated for MTB PS inhibition study, in vitro anti-TB activities against replicative and non-replicative MTB, in vivo activity using Mycobacterium marinum infected Zebra fish and cytotoxicity against RAW 264.7 cell line. Among them compound 2-methyl-N′-(4-phenoxybenzoyl)benzo[d]imidazo[2,1-b]thiazole-3-carbohydrazide (5bc) emerged as potent compound active against MTB PS with IC₅₀ of 0.53 ± 0.13 μM, MIC of 3.53 μM, 2.1 log reduction against nutrient starved MTB, with 33% cytotoxicity at 50 μM. It also showed 1.5 log reduction of M. marinum load in Zebra fish at 10 mg/kg.     

Interaction between Heliopsis longipes extract and diclofenac on the thermal hyperalgesia test

Heliopsis longipes is an herbaceous plant found in Mexico, used traditionally for its analgesic and anesthetic activities. Plant extracts in combined use with synthetic drugs may represent a therapeutic advantage for the clinical treatment of pain, allowing the use of lower doses, and limiting side-effects. Therefore, the main objective of this study was to determine the possible pharmacological interaction between Heliopsis longipes ethanolic extract (HLEE) and diclofenac in the Hargreaves model of thermal hyperalgesia in the mouse. HLEE, diclofenac or fixed-dose ratio HLEE–diclofenac combinations were administered systemically to mice and the antihyperalgesic effect was evaluated using the thermal hyperalgesia test. All treatments produced a dose-dependent antihyperalgesic effect. ED₃₀ values were estimated for all the treatments and an isobologram was constructed. The derived theoretical ED₃₀ value for the HLEE–diclofenac combination was 54.4±9.4 mg/kg body wt, significantly higher than the actually observed experimental ED₃₀ value, 8.6±4.0 mg/kg body wt. This result corresponds to synergistic interaction between HLEE and diclofenac in the Hargreaves model of thermal hyperalgesia. Data suggest that low doses of the HLEE–diclofenac combination can interact synergistically at the systemic level and that this association may therefore represent a therapeutic advantage for the clinical treatment of inflammatory pain.     

Therapeutic and pharmacokinetic characterizations of an anti-amyloidogenic bis-styrylbenzene derivative for Alzheimer’s disease treatment

Alzheimer’s disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-β. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F = 46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD₅₀ >2000 mg/kg) and hERG channel inhibition (14% at 10 μM) results indicated safety of KMS80013.     

Synthesis,biological evaluation,and docking studies of novel heterocyclic diaryl compounds as selective COX-2 inhibitors

Three novel series of diaryl heterocyclic derivatives bearing the 2-oxo-5H-furan, 2-oxo-3H-1,3-oxazole, and 1H-pyrazole moieties as the central heterocyclic ring were synthesized and their in vitro inhibitory activities on COX-1 and COX-2 isoforms were evaluated using a purified enzyme assay. The 2-oxo-5H-furan derivative 6b was identified as potent COX inhibitor with selectivity toward COX-1 (COX-1 IC₅₀ = 0.061 μM and COX-2 IC₅₀ = 0.325 μM; selectivity index (SI) = 0.19). Among the 1H-pyrazole derivatives, 11b was found to be a potent COX-2 inhibitor, about 38 times more potent than Rofecoxib (COX-2 IC₅₀ = 0.011 μM and 0.398 μM, respectively), but showed no selectivity for COX-2 isoform. Compound 11c demonstrated strong and selective COX-2 inhibitory activity (COX-1 IC₅₀ = 1 μM, COX-2 IC₅₀ = 0.011 μM; SI = ～92). Molecular docking studies of compounds 6b and 11b–d into the binding sites of COX-1 and COX-2 allowed to shed light on the binding mode of these novel COX inhibitors.     

Acute toxicity of Orthosiphon stamineus Benth standardized extract in Sprague Dawley rats

The acute toxicity of standardized extract of Orthosiphon stamineus was studied in Sprague Dawley rats. The rats were administered a single dose of 5000 mg/kg body weight (BW) orally on Day 0 and observed for 14 days. There were no deaths recorded and the animals did not show signs of toxicity during the experimental period. The effect of the extract on general behavior, BW, food and water intake, relative organ weight per 100 g BW, hematology and clinical biochemistry were measured. All the parameters measured were unaffected as compared to the control. The acute toxicity LD₅₀ was estimated to be >5000 mg/kg BW.