Indaziflam: Control Effectiveness in Monocotyledonous and Eudicotyledonous Weeds as a Function of Herbicide Dose and Soil Texture.

<b>Background and Objective:</b> The indaziflam herbicide has efficiency in the control of monocotyledons weeds and is recommended for some eudicotyledonous species. However, the efficiency of the control can vary to the detriment of the species, dose and soil texture. Therefore, the objective of the present work was to evaluate the effectiveness of the control of indaziflam herbicide for weeds species <i>Mucuna aterrima</i>, <i>Sorghum halepense</i>, <i>Ipomoea purpurea</i>, <i>Rottboellia exaltata</i>, <i>Urochloa decumbens</i>, <i>Merremia aegyptia</i>, <i>Cenchrus echinatus</i>, <i>Digitaria horizontalis</i>, <i>Panicum maximum</i>, <i>Tridax procumbens</i>, <i>Urochloa plantaginea</i> and <i>Eleusine indica</i>, besides elaborating the calculation of DL₈₀, DL₉₀ and DL₉₅ of the product in two types of soil. Material and Methods: Thus, experiments were carried out in a greenhouse, isolated for each weed species, in a completely randomized experimental design, with four replications and a 10×2 factorial scheme, with ten doses of the herbicide indaziflam (0 D, 1/16 D, 1/8 D, 1/4 D, 1/2 D, D, 2 D, 4 D, 8 D, 16 D, being D = 100 g ha¹), applied in pre-emergence and two contrasting soil textures (clayey and sandy). At 7, 14, 21, 28, 35, 42, 49 and 56 days after weed emergence (DAE), visual control assessments were performed and in the last evaluation, the dry mass of the aerial part was performed. <b>Results:</b> The weeds of the Poaceae family showed greater susceptibility to the indaziflam herbicide, on the other hand, the <i>Mucuna aterrima</i>, <i>Ipomoea purpurea</i> and <i>Merremia aegyptia </i>weeds required a higher dose of active ingredient to be controlled efficiently. <b>Conclusion:</b> In general, the current study concluded that a lesser amount of active ingredient was needed in sandy soil than in clayey soils to promote adequate weed control. Therefore, the difference in the susceptibility of the studied plants as function of dose indaziflam, weeds species and soil texture.

Ecotoxicity thresholds for ametryn, diuron, hexazinone and simazine in fresh and marine waters.

Triazine and urea herbicides are two groups of photosystem II inhibiting herbicides frequently detected in surface, ground and marine waters. Yet, there are few water quality guidelines for herbicides. Ecotoxicity thresholds (ETs) for ametryn, hexazinone and simazine (triazine herbicides) and diuron (a urea herbicide) were calculated using the Australian and New Zealand method for deriving guideline values to protect fresh and marine ecosystems. Four ETs were derived for each chemical and ecosystem that should theoretically protect 99, 95, 90 and 80% of species (i.e. PC99, PC95, PC90 and PC80, respectively). For all four herbicides, the phototrophic species were significantly more sensitive than non-phototrophic species, and therefore, only the former data were used to calculate the ETs. Comparison of the ET values to measured concentrations in 2606 samples from 15 waterways that discharge to the Great Barrier Reef (2011-2015) found three exceedances of the simazine PC99, regular exceedances (up to 30%) of the PC99 in a limited number of rivers for ametryn and hexazinone and frequent (> 40%) exceedances of the PC99 and PC95 ETs in at least four waterways for diuron. There were no exceedances of the marine ETs in inshore reef areas. Further, ecotoxicity data are required for ametryn and hexazinone to fresh and marine phototrophic species, for simazine to marine phototrophic species, for tropical phototrophic species, repeated pulse exposures and long-term (2 to 12 months) exposures to environmentally relevant concentrations.

Sensitive inexpensive HPLC determination of four antiepileptic drugs in human plasma: application to PK studies.

AIM: Recently, polytherapy regimen has been introduced for the treatment of epileptic patients for better seizure control with lesser side effects and better control of multiple seizure types. METHODOLOGY: A simple, sensitive and highly specific reversed-phase HPLC method was developed for simultaneous determination of four antiepileptic drugs (AEDs), levetiracetam, lamotrigine, oxcarbazepine and carbamazepine, in real human plasma without interference from endogenous components of plasma. CONCLUSION: The method was proved to be linear in the range of 0.5-50 µg/ml for all drugs. It was successfully applied for clinical PK study of the AEDs in healthy volunteers following single administration. Also, this method was applied for simultaneous determination of the studied drugs in volunteers' plasma receiving synergistic binary combinations from the four AEDs when used as add-on therapy. The good precision and selectivity of the developed method allow it to be used for routine therapeutic drug monitoring of such drugs as a useful tool in epilepsy management.

Integrated Application of Quality-by-Design Principles to Drug Product Development: A Case Study of Brivanib Alaninate Film-Coated Tablets.

Modern drug product development is expected to follow quality-by-design (QbD) paradigm. At the same time, although there are several issue-specific examples in the literature that demonstrate the application of QbD principles, a holistic demonstration of the application of QbD principles to drug product development and control strategy, is lacking. This article provides an integrated case study on the systematic application of QbD to product development and demonstrates the implementation of QbD concepts in the different aspects of product and process design for brivanib alaninate film-coated tablets. Using a risk-based approach, the strategy for development entailed identification of product critical quality attributes (CQAs), assessment of risks to the CQAs, and performing experiments to understand and mitigate identified risks. Quality risk assessments and design of experiments were performed to understand the quality of the input raw materials required for a robust formulation and the impact of manufacturing process parameters on CQAs. In addition to the material property and process parameter controls, the proposed control strategy includes use of process analytical technology and conventional analytical tests to control in-process material attributes and ensure quality of the final product.

Melamine contamination in nutritional supplements--Is it an alarm bell for the general consumer, athletes, and 'Weekend Warriors'?

BACKGROUND: Nutritional supplements are used or experimented with by consumers, notably these are; competitive and recreational athletes of all ages, and 'weekend warriors'. As a consequence the supplement industry has grown to meet the increasing demand. A Global Industry Analysts Inc. report indicates that the herbal supplement market has not declined during the worldwide recession, but in fact exhibited steady growth over the period 2008 to 2009. It is anticipated that the market will reach US$93.15 billion by the year 2015. These supplements may contain adulterated substances that may potentially have harmful short - and long-term health consequences to the consumer. "Scrap Melamine" is such an example, which has been implicated in the kidney failure and death of several cats, dogs and pigs. In China in 2008, reports described very severe health effects in infants and young children. At the time over 294,000 infants were screened and diagnosed with urinary tract stones and sand-like calculi associated with melamine in milk products, of which 50,000 infants were hospitalised, and at least six associated deaths, recorded. The extent that melamine contamination occurs in nutritional supplements is not known. Therefore, the aim of this study was to determine whether commercially available nutritional and traditional supplement products contain melamine, even though they are not declared by the manufacturer on the product label. METHODS: A total of 138 nutritional supplements products were obtained from (i) direct purchases from shops, pharmacies and outlets, (ii) directly from consumers, and (iii) from suppliers, manufacturers and distributors. The products were laboratory analysed for melamine, using Tandem Liquid Chromatography Mass Spectrometry. RESULTS: Forty-seven % of all the products (n = 138) tested positive for melamine. Eight-two % of the South African produced products (n = 27) tested positive and 58 % of the products imported into South Africa (n = 50) tested positive. The median concentration estimate for melamine in the products tested were, 6.0 µg/g for the 138 supplements tested, 8.9 µg/g for South African produced products, and 6.9 µg/g for products imported into South Africa. CONCLUSION: The melamine (undeclared on product label) levels detected in the nutritional supplements products investigated were within the Tolerable Daily intake (TDI) limit guidelines of 200 µg/g as set by WHO and others. Melamine over exposure within the context of the nutritional supplements consumption in the products investigated should not be of concern to the consumer provided the recommended guidelines of daily product use are adhered to. Further investigation is warranted to determine, (i) the link of melamine as (part) substitute for the perceived total declared protein content on the product label, (ii) cyanuric and uric acid presence in the supplement products that could form chemical-complex formation with melamine and/or analogues that could cause adverse health effects.

Quality by design development of brivanib alaninate tablets: degradant and moisture control strategy.

A quality by design approach was applied to the development of brivanib alaninate tablets. Brivanib alaninate, an ester pro-drug, undergoes hydrolysis to its parent compound, BMS-540215. The shelf-life of the tablets is determined by the rate of the hydrolysis reaction. Hydrolysis kinetics in the tablets was studied to understand its dependence on temperature and humidity. The BMS-540215 amount versus time profile was simulated using a kinetic model for the formation of BMS-540215 as function of relative humidity in the environment and a sorption-desorptiom moisture transfer model for the relative humidity inside the package. The combined model was used to study the effect of initial tablet water content on the rate of degradation and to identify a limit for initial tablet water content that results in acceptable level of the degradant at the end of shelf-life. A strategy was established for the moisture and degradant control in the tablet based on the understanding of its stability behavior and mathematical models. The control strategy includes a specification limit on the tablet water content and manufacturing process controls that achieve this limit at the time of tablet release testing.

Detection and structure elucidation of hydroxythiovardenafil as an adulterant in a herbal dietary supplement.

A new derivative of vardenafil was detected in an alleged herbal dietary supplement and identified as 2-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)phenyl)-5-methyl-7-propyl-imidazo[1,5-f][1,2,4]triazin-4(3H)-thione. Structure elucidation was carried out by LC-UV-MS/MS and NMR. Results obtained with high resolution MS and IR spectroscopy confirmed the proposed chemical structure. The compound was distinguished from hydroxyvardenafil, a second active substance identified in the same product, by the conversion of the oxo group to a thio group on the imidazo-triazin moiety. Hydroxythiovardenafil was therefore suggested as a proprietary name for the new molecule. This is the first paper to describe a thio-analog of vardenafil in a commercially available product.

Quantitative analysis of triazine herbicides in environmental samples by using high performance liquid chromatography and diode array detection combined with second-order calibration based on an alternating penalty trilinear decomposition algorithm.

A novel application of second-order calibration method based on an alternating penalty trilinear decomposition (APTLD) algorithm is presented to treat the data from high performance liquid chromatography-diode array detection (HPLC-DAD). The method makes it possible to accurately and reliably analyze atrazine (ATR), ametryn (AME) and prometryne (PRO) contents in soil, river sediment and wastewater samples. Satisfactory results are obtained although the elution and spectral profiles of the analytes are heavily overlapped with the background in environmental samples. The obtained average recoveries for ATR, AME and PRO are 99.7±1.5, 98.4±4.7 and 97.0±4.4% in soil samples, 100.1±3.2, 100.7±3.4 and 96.4±3.8% in river sediment samples, and 100.1±3.5, 101.8±4.2 and 101.4±3.6% in wastewater samples, respectively. Furthermore, the accuracy and precision of the proposed method are evaluated with the elliptical joint confidence region (EJCR) test. It lights a new avenue to determine quantitatively herbicides in environmental samples with a simple pretreatment procedure and provides the scientific basis for an improved environment management through a better understanding of the wastewater-soil-river sediment system as a whole.

Detection, quantifications and pharmacokinetics of toltrazuril sulfone (Ponazuril) in cattle.

Toltrazuril sulfone (Ponazuril) is a triazine-based anti-protozoal agent with highly specific actions against apicomplexan group of organisms, which are undergoing intensive investigation. Toltrazuril sulfone may have clinical application in the treatment of Neospora. caninum and other protozoal infections in cattle. To evaluate absorption, distribution, and elimination characteristics of toltrazuril sulfone in cattle, a sensitive validated quantitative high-pressure liquid chromatography method for toltrazuril sulfone in bovine biological fluids was developed. After a single oral dose of toltrazuril sulfone at 5 mg/kg (as 150 mg/g of Marquis; Bayer HealthCare, Shawnee Mission, KS, USA), samples from six cows showed good plasma concentrations of toltrazuril sulfone, which peaked at 4821 ng/mL +/- 916 (SD) at 48 h postadministration. Thereafter, plasma concentration declined to 1950 ng/mL +/- 184 (SD) at 192 h after administration with an average plasma elimination half-life of approximately 58 h. Following oral dose of toltrazuril sulfone, the observed peak plasma concentrations were in relatively close agreement ranging from the lowest 3925 ng/mL to the highest of 6285 ng/mL with the mean peak plasma concentration being 4821 ng/mL. This study shows that toltrazuril sulfone is relatively well absorbed after oral dose in cattle. These results are therefore entirely consistent with and support the reported clinical efficacy of toltrazuril sulfone in the treatment of experimentally induced clinical cases of N. caninum and other protozoal-mediated bovine diseases.

Determination of analogs of sildenafil and vardenafil in foods by column liquid chromatography with a photodiode array detector, mass spectrometry, and nuclear magnetic resonance spectrometry.

Two analogs of sildenafil and vardenafil in food were detected by column liquid chromatography (LC) with a photodiode array detector. They were isolated by preparative LC; their structures were established by mass spectrometry and nuclear magnetic resonance spectrometry. One analog was found to be methisosildenafil (compound A), 5-(5-(3,5-dimethylpiperazin-1-ylsulfonyl)-2-ethoxy-phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-7(6H)-one. It is a sildenafil analog with a dimethylpiperazine ring substituted for the methylpiperazine group. The second analog, hydroxyvardenafil (compound B) is reported for the first time in this study. Hydroxyvardenafil's International Union of Pure and Applied Chemistry name is 2-(2-ethoxy-5-(4-(2-hydroxyethyl)-piperazin-1-ylsulfonyl)phenyl)-5-methyl-7-propyl-imidazo[1,5-f][1,2,4]triazin-4(3H)-one. The novel vardenafil analog has a hydroxyl group added to the ethylpiperazine group.

Modifying sorbents in controlled release formulations to prevent herbicides pollution.

The herbicides chloridazon and metribuzin, identified as groundwater pollutants, were incorporated in alginate-based granules to obtain controlled release properties. In this research the effect of incorporation of sorbents such as bentonite, anthracite and activated carbon in alginate basic formulation were not only studied on encapsulation efficiency but also on the release rate of herbicides which was studied using water release kinetic tests. In addition, sorption studies of herbicides with bentonite, anthracite and activated carbon were made. The kinetic experiments of chloridazon and metribuzin release in water have shown that the release rate is higher in metribuzin systems than in those prepared with chloridazon, which has lower water solubility. Besides, it can be deduced that the use of sorbents reduces the release rate of the chloridazon and metribuzin in comparison to the technical product and to the alginate formulation without sorbents. The highest decrease in release rate corresponds to the formulations prepared with activated carbon as a sorbent. The water uptake, permeability, and time taken for 50% of the active ingredient to be released into water, T(50), were calculated to compare the formulations. On the basis of a parameter of an empirical equation used to fit the herbicide release data, the release of chloridazon and metribuzin from the various formulations into water is controlled by a diffusion mechanism. Sorption capacity of the sorbents for chloridazon and metribuzin, ranging from 0.53mgkg(-1) for the metribuzin sorption on bentonite to 2.03x10(5)mgkg(-1) for the sorption of chloridazon on the activated carbon, was the most important factor modulating the herbicide release.

Species-specific sensitivity of aquatic macrophytes towards two herbicides.

The s-triazine herbicide terbutylazine, an inhibitor of photosystem II, is often found in surface waters in concentrations < 1 microg L(-1), but concentrations up to 13 microg L(-1) have been measured. To study the effect on the aquatic flora, we tested the sensitivity of 10 aquatic macrophyte species and a natural epiphyte community in a 2-week laboratory multispecies test at constant terbutylazine concentrations and two irradiance regimes. The data were described by a log-logistic concentration-response model and species sensitivity distributions (SSDs) were created from the EC50 and EC10 values. The 5% hazard concentration (HC5) of the EC10-based SSD for terbutylazine was 1 and 3 microg L(-1); hence the low chronic terbutylazine concentrations measured in the environment are not likely to affect the macrophyte community. To compare the species sensitivity between different groups of herbicides, SSDs were constructed from a published study on the sulfonylurea metsulfuron-methyl, an inhibitor of acetolactate synthase. There was no correlation between species-specific sensitivity to the two herbicides; hence, the combined exposure of different herbicides might affect the macrophyte community more broadly rather than seriously affecting a few susceptible species. Evaluating the standard procedure of leaving at least a factor of 100 between the EC50 of standard tests on Lemna sp. and the predicted environmental concentration seems to be protective for at least 95% of the macrophyte species for both terbutylazine and metsulfuron-methyl.

Raman and IR studies on adsorption behavior of adhesive monomers in a metal primer for Au, Ag, Cu, and Cr surfaces.

6-[N-(4-vinylbenzyl)propylamino]-1,3,5-triazine-2,4-dithione (VBATDT) and 10-methacryloyloxydecyl dihydrogen phosphate (M10P) are functional monomers used for the surface treatment of dental alloys. The aim of our study was to clarify the role of a commercial metal primer containing both the monomers in adhesion between resin and various dental metals on a molecular level. We used surface-enhanced Raman scattering (SERS) and infrared reflection absorption (IRA) spectroscopy. An SERS measurement was performed with a 647 nm laser line for a mixture of aqueous Au colloid and the primer. IRA spectra were taken for cast films of the primer on Au, Ag, Cu, and Cr surfaces as a function of rinse time, and for self-assembled monolayer (SAM) films from dilute mixed solution of VBATDT and M10P. These spectra indicate that VBATDT in the primer is mainly chemisorbed on Au, Ag, and Cu surfaces with respect to thickness, whereas only M10P is adsorbed on Cr. We also examined the tensile bond strengths between resin and Au, Ag, Cu, and Cr plates treated by VBATDT, with and without M10P, and found that VBATDT effectively promotes the bond strength between resin and the metals except for Cr, whereas M10P is effective only for Cr. These adhesion characteristics are consistent with the chemisorbed species on each metal surface as shown in the spectroscopic evidence.

Lamotrigine analysis in blood and brain by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatography assay was developed and validated to determine plasma and brain lamotrigine concentrations allowing pharmacokinetic-pharmacodynamic studies of this new antiepileptic drug in patients and laboratory animals. Lamotrigine and its internal standard were extracted, under alkaline conditions, from plasma and brain homogenate, into ethyl acetate; brain proteins were previously precipitated with trichloroacetic acid. The method was linear between 0.1 and 15.0 mg/l for plasma, with a detection limit of 0.008 mg/l, and between 0.1 and 5.0 mg/l for brain homogenate, with a detection limit of 0.023 mg/l. The method proved to be simple, useful and appropriate, not only for clinical and experimental research, but also for routine monitoring of lamotrigine concentrations in patients.

Anticoccidial efficacy of toltrazuril and halofuginone against Eimeria tenella infection in broiler chickens in Egypt.

The anticoccidial activities of toltrazuril and halofuginone against Eimeria tenella were tested in broiler chickens. Comparisons were made between ummedicated infected and uninfected control birds in addition to infected groups given either toltrazuril at 37.5, 75 and 150 ppm in the drinking water, or halofuginone at 1.5, 3 and 6 ppm in the feed. Both drugs were highly efficacious against E tenella. Treatment improved the bodyweight gain and survival percentage in comparison with the unmedicated, infected group. Intestinal lesions, faecal and oocyst scores and oocyst shedding in dropping were significantly reduced by both drugs. Toltrazuril gave better protection than halofuginone; 75 and 150 ppm toltrazuril in drinking water gave good protection when administered four and five days after inoculation.

Collaborative study of a gas-liquid chromatographic method for the analysis of propazine.

A gas-liquid chromatographic method for the determination of propazine in wettable powder formulations containing about 80% active ingredient was collaboratively studied, using a matched pair scheme. The propazine was extracted from the powder with chloroform, with dieldrin as an internal standard, and chromatographed on Carbowax 20M, using a flame ionization detector. Two samples were analyzed using peak height measurements with the following results (13 collaborators): 1.2% overall coefficient of variation and 1.2% coefficient of variation for the random error. Statistical evaluation of these factors reveals no evidence of systematic error contribution. The method has been adopted as official first action.