Residue behavior and risk assessment of thifluzamide in the maize field ecosystem.

In the present work, the dissipation kinetics and final residue levels of thifluzamide in the maize field ecosystem were investigated. Using a modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction combined with liquid chromatography-tandem mass spectrometric detection (LC-MS/MS), a rapid, sensitive, efficient, and reliable method for extraction and quantitative analysis of thifluzamide residues in maize grain, maize plant, and soil was developed. Satisfactory recoveries of 78.7-97.0% were achieved with relative standard deviations (RSDs) in the range of 1.6 to 8.2%. The limits of detection (LODs) and the limit of quantification (LOQ) were 0.002-0.005 and 0.010 mg kg-1, respectively. The dissipation kinetics of thifluzamide in maize plant was well fitted by the first-order kinetic model with short half-lives of 0.19-0.22 days, while thifluzamide degraded slowly in soil with half-lives of 4.56-15.85 days. The final residues in maize grain, maize plant, and soil samples collected at the milk stage and the physiological maturity stage were no more than 0.010, 0.807, and 0.278 mg kg-1, respectively. Given that no maximum residue limit (MRL) for thifluzamide in maize has been established, the safety of this fungicide application was estimated by a dietary risk assessment. The hazard quotient was 0.03%, which was substantially less than 1, indicating that the long-term risk induced by the thifluzamide application on maize at the recommended dose is negligible. These results help governments to develop regulations for the safe use of thifluzamide.

Box-Behnken study design for optimization of bicalutamide-loaded nanostructured lipid carrier: stability assessment.

Bicalutamide (BCM) is an anti-androgen drug used to treat prostate cancer. In this study, nanostructured lipid carriers (NLCs) were chosen as a carrier for delivery of BCM using Box-Behnken (BB) design for optimizing various quality attributes such as particle size and entrapment efficiency which is very critical for efficient drug delivery and high therapeutic efficacy. Stability of formulated NLCs was assessed with respect to storage stability, pH stability, hemolysis, protein stability, serum protein stability and accelerated stability. Hot high-pressure homogenizer was utilized for formulation of BCM-loaded NLCs. In BB response surface methodology, total lipid, % liquid lipid and % soya lecithin was selected as independent variable and particle size and %EE as dependent variables. Scanning electron microscopy (SEM) was done for morphological study of NLCs. Differential scanning calorimeter and X-ray diffraction study were used to study crystalline and amorphous behavior. Analysis of design space showed that process was robust with the particle size less than 200 nm and EE up to 78%. Results of stability studies showed stability of carrier in various storage conditions and in different pH condition. From all the above study, it can be concluded that NLCs may be suitable carrier for the delivery of BCM with respect to stability and quality attributes.

Monte Carlo studies of drug nucleation 1: formation of crystalline clusters of bicalutamide in water.

A computational method of predicting the effects of the metastability of drug solutions is sought. A simple extension of our in silicio approach to thermodynamic drug solubility is tested on the drug bicalutamide for which we performed vapor pressure measurements complementing earlier measurements of aqueous solubility and crystal-water interfacial tension. The free energy of formation of an N-cluster of the drug molecule is estimated semiempirically by use of an Einstein model of the crystal in which experiment supplies the crystal structure, enthalpy of sublimation, and Einstein frequency of vibration. The rigid drug clusters with N from 2 to 14 are extracted from the bulk crystal by minimization of either cluster energy or radius of gyration. The free energy of hydration is estimated by Monte Carlo simulation combined with simplified response theory based on the OPLS-AA/COMPASS force field for the drug-water interaction and the TIP4P water model. The results have been interpreted in terms of an apparent crystal-water interfacial tension according to classical nucleation theory. The energy-minimal and radius of gyration-minimal clusters seem to give very similar crystal-water interfacial tensions for both the monoclinic and the triclinic polymorph. The interfacial tension of the monoclinic polymorph is significantly higher (by around 20%) than that of the triclinic polymorph in accordance with experiment. For the triclinic polymorph a substantial overestimation of the interfacial tension compared to estimates from crystal nucleation experiments is found, mitigated somewhat by an empirical scaling of the simulated binding energies and free energies of hydration.

Efficient and economical access to substituted benzothiazoles: copper-catalyzed coupling of 2-haloanilides with metal sulfides and subsequent condensation.

Don't tell azole: The first metal-catalyzed direct coupling of metal sulfides with aryl halides and subsequent intramolecular condensation provided substituted benzothiazoles (see scheme). A wide range of functional groups are tolerated under the reaction conditions.

In vitro comparative assessment of the scavenging activity against three reactive oxygen species of non-steroidal anti-inflammatory drugs from the oxicam and sulfoanilide families.

The study of the interaction of non-steroidal anti-inflammatory drugs (NSAIDs) with several reactive oxygen species is of great interest in inflammatory conditions where an uncontrolled release of these potentially damaging intermediates has been documented. This study focused on the scavenging of three species (hydroxyl radical, hydrogen peroxide and hypochlorous acid) with several members of the oxicam family and with the sulfoanilide nimesulide. Reaction with hydroxyl radical was assessed by the modified deoxyribose assay, and rate constants were calculated showing values between 0.8 and 1.1 x 10(10) M(-1) s(-1) for oxicams and of about 0.9 x 10(10) M(-1) s(-1) for nimesulide and ibuprofen. These were consistent with those of the literature but in the same range as those for other NSAIDs and for several thiol-containing molecules. The study of hydrogen peroxide scavenging by the horseradish peroxidase (HRP) assay lacked specificity but no interaction could be evidenced by the glutathione peroxidase assay. The scavenging of hypochlorous acid was finally investigated by the recently developed para-aminobenzoic acid assay which demonstrated better performances for meloxicam (1.7 x 10(4) M(-1) s(-1)) as compared to the other oxicams (tenoxicam: 4.0 x 10(4) M(-1) s(-1), piroxicam: 3.6 x 10(4) M(-1) s(-1), lornoxicam: 4.3 x 10(4) M(-1) s(-1)) and nimesulide (2.3 x 10(3) M(-1) s(-1)). These rate constants were, however, lower than those for thiol-containing molecules and ascorbate. These results suggest that the antioxidant properties of NSAIDs could be influenced by a proper pharmacomodulation as far as the scavenging of hypochlorous acid is concerned while the interest is quite limited for the scavenging of hydroxyl radical.

Prediction of activity for nonnucleoside inhibitors with HIV-1 reverse transcriptase based on Monte Carlo simulations.

Results of Monte Carlo (MC) simulations for more than 200 nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) representing eight diverse chemotypes have been correlated with their anti-HIV activities in an effort to establish simulation protocols and methods that can be used in the development of more effective drugs. Each inhibitor was modeled in a complex with the protein and by itself in water, and potentially useful descriptors of binding affinity were collected during the MC simulations. A viable regression equation was obtained for each data set using an extended linear response approach, which yielded r(2) values between 0.54 and 0.85 and an average unsigned error of only 0.50 kcal/mol. The most common descriptors confirm that a good geometrical match between the inhibitor and the protein is important and that the net loss of hydrogen bonds with the inhibitor upon binding is unfavorable. Other physically reasonable descriptors of binding are needed on a chemotype case-by-case basis. By including descriptors in common from the individual fits, combination regressions that include multiple data sets were also developed. This procedure led to a refined "master" regression for 210 NNRTIs with an r(2) of 0.60 and a cross-validated q(2) of 0.55. The computed activities show an rms error of 0.86 kcal/mol in comparison with experiment and an average unsigned error of 0.69 kcal/mol. Encouraging results were obtained for the predictions of 27 NNRTIs, representing a new chemotype not included in the development of the regression model. Predictions for this test set using the master regression yielded a q(2) value of 0.51 and an average unsigned error of 0.67 kcal/mol. Finally, additional regression analysis reveals that use of ligand-only descriptors leads to models with much diminished predictive ability.