The use of an indwelling Doppler probe to study acute changes in umbilical artery waveforms in the fetal sheep

A chronic sheep model for Doppler umbilical vascular analysis was developed, in which indwelling Doppler probes were used. These were designed with a fixed angle of insonation and implanted directly on the umbilical cord to register umbilical artery velocity waveforms. The fetuses in eight pregnant ewes underwent maternal aortic and umbilical cord constrictions producing serial blood flow reductions. Occlusion of the umbilical cord and maternal aorta caused distinctly different waveforms. Cord occlusion produced an immediate response with an elevated systolic/diastolic ratio and disappearance of diastolic velocity. Maternal aortic occlusion produced a delayed response with drops in both systolic and diastolic velocity; diastolic velocity never reached zero. Although systolic/diastolic ratios are believed to reflect placental resistance, the maintenance of the systolic/diastolic ratio with diminution of systolic velocity suggests declining fetal cardiac output as an additional factor. It is possible to differentiate uteroplacental from umbilicoplacental insufficiency by Doppler methods. With technologic improvements Doppler ultrasonography may allow better analysis of acute stressful conditions during human labor.     

A novel antibacterial iridoid and triterpene from Caiophora coronata

Bioassay-guided fractionation of the antibacterial CH(2)Cl(2)-MeOH extract obtained from the aerial parts of the Argentinean plant Caiophora coronata led to the isolation of a new triterpene, 1beta,3beta-dihydroxyurs-12-en-27-oic acid, 1, and a new iridoid, 1alpha-methoxy-6alpha,10-dihydroxyisoepiiridomyrmecin (caiophoraenin), 2, along with the known iridoid isoboonein 3. Their structures were established by spectroscopic techniques (1D and 2D NMR, HRFABMS, FTIR). The MIC values of isolated compounds were determined against methicillin-sensitive (MSSA) and -resistant (MRSA) strains of Staphylococcus aureus, Bacillus subtilis (BS), vancomycin-resistant Enterococcus faecium (VREF), Escherichia coli (EC), E. coli imp (ECimp), and Candida albicans (CA). Compound 1 was found active against BS, MSSA, MRSA, VREF, and ECimp with MIC values of 2, 4, 4, 4, and 16 microg/mL, respectively.     

N‐acetyl cysteine‐mediated effective attenuation of methoxychlor‐induced granulosa cell apoptosis by counteracting reactive oxygen species generation in caprine ovary

Methoxychlor (MXC), an organochloride insecticide, is a potent toxicant‐targeting female reproductive system and known to cause follicular atresia by inducing apoptosis within granulosa cells. Oxidative stress plays a pivotal role in apoptosis; thus, this study focuses on the ameliorative action of N‐acetyl cysteine (NAC) on MXC‐induced oxidative stress and apoptosis within granulosa cell of caprine ovary. Classic histology, fluorescence assay, and biochemical parameters were employed to evaluate the effect of varied concentration of NAC (1, 5, and 10 mM) on granulosa cell apoptosis after 24, 48, and 72 h exposure duration. Histomorphological studies revealed that NAC diminished the incidence of apoptotic attributes like condensed or marginated chromatin, pyknosis, crescent‐shaped nucleus, empty cell spaces, and degenerated cellular structure along with the presence of cytoplasmic processes within granulosa cells in dose‐ and time‐dependent manner. NAC significantly downregulated the percentage of MXC‐induced granulosa cell apoptosis within healthy ovarian follicle with its increasing dose, maximum at 10 mM concentration. It also significantly (p < 0.05) upregulated the activity of antioxidant enzymes, namely catalase, superoxide dismutase, and glutathione‐s‐transferase, along with ferric reducing antioxidant power further declining lipid peroxidation in the MXC‐treated caprine ovary. The results revealed a negative correlation between apoptosis frequency and antioxidant enzymes’ activity (r _CAT = ?0.67, r _SOD = ?0.56, r _GST = ?0.31; p < 0.05) while a positive correlation was observed with lipid peroxidation (r = 0.63; p < 0.05) after NAC supplementation. Thus, NAC supplementation reduces the MXC‐generated oxidative stress that perhaps declines the ROS generating signal transduction pathway of apoptosis, thereby preventing MXC‐induced granulosa cell apoptosis and follicular atresia. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 156–166, 2017.     

Identification of 1-[4-Benzyloxyphenyl)-but-3-enyl]-1H-azoles as New Class of Antitubercular and Antimicrobial Agents

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Synthesis and characterization of novel conjugates of 4-[3-(aryl/heteroaryl)-3-oxo-propenyl]-benzaldehyde with thiazole and thiazolidinones as possible voltage-gated sodium channel blockers

A series of chalcones of thiazole and thiazolidinone (3a–3j) were synthesized, characterized and evaluated for anticonvulsant activity. The structures of all the new synthesized compounds were established by spectral and elemental analysis. The anticonvulsant activity was performed by maximal electroshock seizure (MES) in mice, and all the derivatives were found to be active. The compounds investigated for their ability to prevent chemically (isoniazid) induced seizures, when compared with phenytoin and diazepam. Results of the anticonvulsant activity revealed that among all the synthesized compounds, naphthalene and halo (4-fluoro-phenyl)-substituted ring serves as the lipophilic aryl portion. Thus, compound 3c (95.61 % inhibition of the convulsions) and 3b (66.07 % inhibition of the convulsions), with log P values of 3.40 and 2.70, respectively, exhibited potential anticonvulsant activity in MES and isoniazid-induced convulsion model at a dose of 50 mg/kg, respectively. Compound 3c was also found to be least hydrolysed (1.92 %) in simulated gastric fluid (SGF). Thus, hydrolysis and most lipophilic character of compound 3c made it a potent member of the series. Results showed that all the derivatives were more effective against MES model than isoniazid (INH) model. It can be promulgated that these compounds may act bind preferentially to the inactive form of the voltage-gated sodium channels (VGSCs) through blocking sustained high-frequency repetitive firing of action potentials, similar to phenytoin. Compound 3-(4-{[4-(4-methoxy-phenyl)-thiazol-2-yl]-hydrazonomethyl}-phenyl)-1-naphthalen-2-yl-propenone (3c) was found to be almost equipotent to phenytoin (97.32 % inhibition of the convulsions) in the MES model.     

4-Thiazolidinone and 1-thia-3,4,9-triaza fluorene conjugates: synthesis, characterization and antimicrobial screening

Some novel 4-thiazolidinone derivatives have been synthesized by the condensation of isatin/5-chloroisatin with thiosemicarbazide to yield thiosemicarbazones, which were then cyclized to form corresponding thia-3,4,9-triaza-fluoren-2-ylamines. These were reacted with substituted aldehydes to give corresponding Schiff bases, which were cyclized using thioglycolic acid in the presence of zinc chloride to obtain the 4-thiazolidinone derivatives. All the synthesized compounds were characterized by spectral (IR, MS and NMR) and elemental analysis. The compounds were screened for their antibacterial activity against Gram-positive bacteria (B. subtilis, S. aureus, B. pumilus and M. luteus), Gram-negative bacteria (P. aeruginosa, E. coli and P. fluorescens) and for antifungal activity against A. niger and P. chrysogenum by agar-diffusion method. The minimum inhibitory concentrations of these compounds were also determined by tube dilution method. The antimicrobial effectiveness of all the compounds was found to be concentration dependent. Two compounds—2-methyl-3-(1-thia-3, 4, 9-triaza-fluoren-2-yl)-thiazolidin-4-one (7aI) and 2-naphthalen-1-yl-3-(1-thia-3, 4, 9-tri aza-fluoren-2-yl)-thiazolidin-4-one (7aII)—exhibited good antibacterial activity. The antibacterial activity of all the compounds was found to be better than the antifungal activity.     

Intranasal Delivery of Chitosan Nanoparticles for Migraine Therapy

Objective

The objective of the research was to formulate and evaluate sumatriptan succinate-loaded chitosan nanoparticles for migraine therapy in order to improve its therapeutic effect and reduce dosing frequency.

Material and Methods

The Taguchi method design of experiments (L9 orthogonal array) was applied to obtain the optimized formulation. The sumatriptan succinate-loaded chitosan nanoparticles (CNPs) were prepared by ionic gelation of chitosan with tripolyphosphate anions (TPP) and Tween 80 as surfactant.

Results

The CNPs had a mean size of 306.8 ± 3.9 nm, a zeta potential of +28.79 mV, and entrapment efficiency of 75.4 ± 1.1%. The in vitro drug release of chitosan nanoparticles was evaluated in phosphate buffer saline pH 5.5 using goat nasal mucosa and found to be 76.7 ± 1.3% within 28 hours.

Discussion

The release of the drug from the nanoparticles was anomalous, showing non-Fickian diffusion indicating that drug release is controlled by more than one process i.e. the superposition of both phenomena, a diffusion-controlled as well as a swelling-controlled release. This is clearly due to the characteristics of chitosan which easily dissolves at low pH, thus a nasal pH range of 5.5 ± 0.5 supports it very well. The mechanism of pH-sensitive swelling involves protonation of the amine groups of chitosan at low pH. This protonation leads to chain repulsion, diffusion of protons and counter ions together with water inside the gel, and the dissociation of secondary interactions.

Conclusion

The results suggest that sumatriptan succinate-loaded chitosan nanoparticles are the most suitable mode of drug delivery for promising therapeutic action.     

AMPA receptor potentiation can prevent ethanol-induced intoxication.

We present a substantial series of behavioral and imaging experiments, which demonstrate, for the first time, that increasing AMPA receptor-mediated neurotransmission via administration of potent and selective biarylsulfonamide AMPA potentiators LY404187 and LY451395 reverses the central effects of an acutely intoxicating dose of ethanol in the rat. Using pharmacological magnetic resonance imaging (phMRI), we observed that LY404187 attenuated ethanol-induced reductions in blood oxygenation level dependent (BOLD) in the anesthetized rat brain. A similar attenuation was apparent when measuring local cerebral glucose utilization (LCGU) via C14-2-deoxyglucose autoradiography in freely moving conscious rats. Both LY404187 and LY451395 significantly and dose-dependently reversed ethanol-induced deficits in both motor coordination and disruptions in an operant task where animals were trained to press a lever for food reward. Both prophylactic and acute intervention treatment with LY404187 reversed ethanol-induced deficits in motor coordination. Given that LY451395 and related AMPA receptor potentiators/ampakines are tolerated in both healthy volunteers and elderly patients, these data suggest that such compounds may form a potential management strategy for acute alcohol intoxication.     

Cyclodextrin complexes of valdecoxib: properties and anti-inflammatory activity in rat.

The influence of natural beta-cyclodextrin and its hydrophilic derivatives (HPbetaCd and SBE7betaCd) on the in vitro dissolution rate, in vivo absorption and oral bioavailability of a poorly water soluble anti-inflammatory agent, valdecoxib (VALD) was studied. Equimolar drug-cyclodextrin solid complexes were prepared by kneading and coevaporation methods and characterized by infrared spectroscopy, differential scanning calorimetry, X-ray diffraction. In the liquid state, the cyclodextrin complexes were studied using phase solubility analysis, (1)H nuclear magnetic resonance and circular dichroism spectroscopy. Drug solubility and dissolution rate in distilled water were notably improved by employing the betaCds. The DP(15) (i.e. percent of dissolved VALD at 15 min) was 10.5% for the pure drug and 50, 91 and 93% for VALD-betaCd, VALD-HPbetaCd and VALD-SBE7betaCd complexes, respectively. Moreover, it was found that in the, the cyclodextrin complexes of drug showed significant improvement in the anti-inflammatory activity.