Hydroxylated hierarchical flower-like COF for solid-phase extraction of adrenergic receptor agonists in milk.

A new detection platform based on a hydroxylated covalent organic framework (COF) integrated with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was constructed and used for detecting adrenergic receptor agonists (ARAs) residues in milk. The hydroxylated COF was prepared by polymerization of tris(4-aminophenyl)amine and 1,3,5-tris(4-formyl-3-hydroxyphenyl)benzene and applied to solid-phase extraction (SPE) of ARAs. This hydroxylated COF was featured with hierarchical flower-like morphology, easy preparation, and copious active adsorption sites. The adsorption model fittings and molecular simulation were applied to explore the potential adsorption mechanism. This detection platform was suitable for detecting four α2- and five ß2-ARAs residues in milk. The linear ranges of the ARAs were from 0.25 to 50 µg·kg-1; the intra-day and the inter-day repeatability were in the range 2.9-7.9% and 2.0-10.1%, respectively. This work demonstrates this hydroxylated COF has great potential as SPE cartridge packing, and provides a new way to determine ARAs residues in milk.

Nine prohibited stimulants found in sports and weight loss supplements: deterenol, phenpromethamine (Vonedrine), oxilofrine, octodrine, beta-methylphenylethylamine (BMPEA), 1,3-dimethylamylamine (1,3-DMAA), 1,4-dimethylamylamine (1,4-DMAA), 1,3-dimethylbutylamine (1,3-DMBA) and higenamine.

BACKGROUND: Weight loss and sports supplements containing deterenol have been associated with serious adverse events including cardiac arrest. OBJECTIVE: To determine the presence and quantity of experimental stimulants in dietary supplements labeled as containing deterenol sold in the United States. METHODS: Dietary supplements available for sale in the US and labeled as containing deterenol or one of its synonyms (e.g., isopropylnorsynephrine and isopropyloctopamine) were purchased online. For each brand, one container or subsample was analyzed by NSF International (Ann Arbor, MI) and one container or subsample by the Netherland's National Institute for Public Health and the Environment (RIVM, Bilthoven, The Netherlands). When differences existed between the two containers or subsamples of the same brand, both products were reanalyzed by Sciensano (Brussels, Belgium). NSF International carried out qualitative and quantitative analyses using ultra-high-performance liquid chromatography (UHPLC) quadrupole-Orbitrap mass spectrometry. RIVM performed qualitative and quantitative analysis using UHPLC quadrupole time-of-flight mass spectrometry. Sciensano carried out qualitative analysis using UHPLC quadrupole-Orbitrap mass spectrometry. RESULTS: Seventeen brands of supplements were analyzed. Many brands included more than one prohibited stimulant in the same product: 4 brands (24%, 4/17) included 2 stimulants, 2 (12%, 2/17) combined 3 stimulants, and 2 (12%, 2/17) combined 4 stimulants. The range of quantities per recommended serving size of the 9 stimulants detected were 2.7 mg to 17 mg of deterenol; 1.3 mg to 20 mg of phenpromethamine (Vonedrine); 5.7 mg to 92 mg of beta-methylphenylethylamine (BMPEA); 18 mg to 73 mg of octodrine; 18 mg to 55 mg of oxilofrine; 48 mg of higenamine; 17 mg of 1,3-dimethylamylamine (1,3-DMAA); 1.8 mg to 6.6 mg of 1,3-dimethylbutylamine (1,3-DMBA); and 5.3 mg of 1,4-dimethylamylamine (1,4-DMAA). CONCLUSION: Weight loss and sports supplements listing deterenol as an ingredient contained 9 prohibited stimulants and 8 different mixtures of stimulants, with as many as 4 experimental stimulants per product. These cocktails of stimulants have never been tested in humans and their safety is unknown.

Ratiometric Fluorescent Probe Based on Diazotization-Coupling Reaction for Determination of Clenbuterol.

In view of the potential harm caused by illegal feeding of clenbuterol (CLB) in the livestock industry, herein, a novel ratiometric fluorescent probe based on graphene quantum dots (GQDs)@[Ru(bpy)3]2+ was elaborately constructed for CLB detection. In this probe, GQDs acted as response signals, and their fluorescence was remarkably quenched by CLB through the diazotization-coupling reaction. As for [Ru(bpy)3]2+ as a reference signal, its fluorescence was hardly affected. The intensity ratio of two fluorophores showed good linearity with CLB concentration in the range of 0.05-40 µM, accompanied by visualization of fluorescence variation from yellow to red. The detection limit was as low as 0.029 µM. Particularly, the probe was successfully used to detect CLB in pork and beef samples with satisfactory recoveries. To our knowledge, this is the first report on a ratiometric fluorescent probe for the detection of CLB, which possesses broad application prospects in food safety risk monitoring.

Emerging nanosensing technologies for the detection of ß-agonists.

Illegal usage of ß-agonists as the animal growth promoters can lead to multiple harmful impacts to public health, thus detection of ß-agonists at trace level in complex sample matrixes is of great importance. In recent years, emergence of advanced nanomaterials greatly facilitates the advancement of sensors in terms of sensitivity, specificity and robustness. Plenty of nanoparticles-based sensors have been developed for ß-agonists determination. In this review, we comprehensively summarized the construction of emerging nanoparticles-based sensors (including colorimetric sensors, fluorescent sensors, chemiluminescent sensors, electrochemical sensors, electrochemiluminescent sensors, surface enhanced Raman scattering sensors, surface plasmon resonance sensors, quartz crystal microbalance sensors, etc.), and nanomaterial-based enzyme-linked immunosorbent assay (nano-ELISA). Impressively, the applications of nanoparticles-based sensors and nano-ELISAs in the detection of ß-agonists have also been summarized and discussed. In the end, future opportunities and challenges in the design construction of nanoparticles (NPs)-based sensors and their applications in ß-agonist assay are tentatively proposed.

Spectrofluorimetric determination of certain adrenergic agonist drugs in their pure forms and pharmaceutical formulations: Content uniformity test application.

A new, simple, sensitive and rapid spectrofluorimetric method has been developed for determination of certain adrenergic agonists such as isoxsuprine hydrochloride, ritodrine hydrochloride and etilefrine hydrochloride in their pure forms and pharmaceutical dosage forms. The method depends on micellar enhancement of the native fluorescence of investigated drugs by using 2% w/v sodium dodecyl sulfate (SDS) as an anionic surfactant. The enhanced fluorescence intensity of investigated drugs was measured at 305 nm after excitation at 278 nm. The interaction of studied drugs with SDS was studied, and the enhanced fluorescence intensity was exploited to develop an assay method for the determination of investigated drugs. The relative fluorescence intensity-concentration plots were rectilinear over the range 0.15-3.00 µg ml-1 , with low quantification limits of 0.132, 0.123 and 0.118 µg mL-1 for isoxsuprine, ritodrine and etilefrine, respectively. The proposed method was successfully applied for determination of studied drugs in their pharmaceutical formulations. Moreover, the high sensitivity of the proposed method allows performing the content uniformity testing of the studied drugs in their tablets by using the official United States Pharmacopeia (USP) guidelines. Statistical comparisons of the results with those of the reported methods revealed excellent agreement and indicated no significant difference in accuracy and precision.

Fate and transport of the ß-adrenergic agonist ractopamine hydrochloride in soil-water systems.

The feed additive ractopamine hydrochloride was fortified at four concentrations into batch vials containing soils that differed in both biological activity and organic matter (OM). Sampling of the liquid layer for 14days demonstrated that ractopamine rapidly dissipated from the liquid layer. Less than 20% of the fortified dose remained in the liquid layer after 4hr, and recoveries of dosed ractopamine ranged from 8 to 18% in the liquid layer at 336hr. Sorption to soil was the major fate for ractopamine in soil:water systems, i.e., 42%-51% of the dose at 14days. The major portion of the sorbed fraction was comprised of non-extractables; a smaller fraction of the sorbed dose was extracted into water and acetone, portions which would be potentially mobile in the environment. Partitioning coefficients for all soils suggested strong sorption of ractopamine to soil which is governed by hydrophobic interactions and cation exchange complexes within the soil OM. Ractopamine degradation was observed, but to mostly non-polar compounds which had a higher potential than ractopamine to sorb to soil. The formation of volatiles was also suggested. Therefore, despite rapid and extensive soil sorption, these studies indicated a portion of ractopamine, present in manures used to fertilize soils, may be mobile in the environment via water-borne events.

Activation of human brown adipose tissue by a ß3-adrenergic receptor agonist.

Increasing energy expenditure through activation of endogenous brown adipose tissue (BAT) is a potential approach to treat obesity and diabetes. The class of ß3-adrenergic receptor (AR) agonists stimulates rodent BAT, but this activity has never been demonstrated in humans. Here we determined the ability of 200 mg oral mirabegron (Myrbetriq, Astellas Pharma, Inc.), a ß3-AR agonist currently approved to treat overactive bladder, to stimulate BAT as compared to placebo. Mirabegron led to higher BAT metabolic activity as measured via (18)F-fluorodeoxyglucose ((18)F-FDG) using positron emission tomography (PET) combined with computed tomography (CT) in all twelve healthy male subjects (p = 0.001), and it increased resting metabolic rate (RMR) by 203 ± 40 kcal/day (+13%; p = 0.001). BAT metabolic activity was also a significant predictor of the changes in RMR (p = 0.006). Therefore, a ß3-AR agonist can stimulate human BAT thermogenesis and may be a promising treatment for metabolic disease.

Evaluation of certain veterinary drug residues in food. Seventy-eighth report of the Joint FAO/WHO Expert Committee on Food Additives.

This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of residues of certain veterinary drugs in food and to recommend maximum levels for such residues of food. The first part of the report considers general principles regarding the evaluation of residues of veterinary drugs within the terms of reference of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), including extrapolation of maximum residue limits (MRLs) to minor species, MRLs for veterinary drug residues in honey, MRLs relating to fish and fish species, dietary exposure assessment methodologies, the decision-tree approach to the evaluation of residues of veterinary drugs and guidance for JECFA experts. Summaries follow of the Committee's evaluations of toxicology and residue data on a variety of veterinary drugs: two anthelminthic agents (derquantel, monepantel), three antiparasitic agents (emanectin benzoate, ivermectin, lasalocid sodium), one antibacterial, antifungal and anthelminthic agent (gentian violet), a production aid (recombinant bovine somatotropins) and an adrenoceptor agonist and growth promoter (zilpaterol hydorchloride). Annexed to the report is a summary of the Committee's recommendations on these drugs, including acceptable daily intakes (ADIs)) and proposed MRLs.

[Determination of three adrenergic drugs using capillary electrophoresis with amperometric detection].

A method for the determination of three adrenergic drugs, including phenylephrine hydrochloride (PHE), metaraminol bitartrate (MR) and isoprenaline hydrochloride (IP), was developed using capillary electrophoresis with amperometric detection. The detection potential of working electrode was 0.950 V versus the reference electrode of Ag/AgCl. At the applied voltage of 18 kV, the three analytes were completely separated within 18 min in 50 mmol/L borate buffer (pH 10.00) with the injection time of 10 s. Good linear relationships were obtained for all the three analytes in the range of 2-100 micromol/L. The detection limits for PHE, MR and IP were 0.8, 0.8 and 1.0 micromol/L, respectively. The proposed method was applied to the analysis of some injection drugs, and the results were satisfactory.

Modeling of retention of adrenoreceptor agonists and antagonists on polar stationary phases in hydrophilic interaction chromatography: a review.

Retention prediction models for reversed-phase liquid chromatography (RPLC) have been extensively studied owing to the fact that RPLC remains the most widely used chromatographic technique especially in the field of pharmaceutical and biomedical analyses. However, RPLC is not always the method of choice for the analysis of some compounds that have high polarity. Hydrophilic interaction chromatography (HILIC) has been gaining interest in the last few years as an alternative option to RPLC for the analysis of polar and hydrophilic analytes. HILIC is a variant of normal-phase liquid chromatography, but utilizes water in a water-miscible organic solvent as the eluent in conjunction with a hydrophilic stationary phase. The present review aims to summarize recent contributions on the development of retention prediction models for a group of basic analytes, namely, the adrenoreceptor agonists and antagonists, on different polar stationary phases. The use of multiple linear regression and artificial neural networks in model building is highlighted.

Retention prediction of adrenoreceptor agonists and antagonists on a diol column in hydrophilic interaction chromatography.

Retention prediction models using multiple linear regression (MLR) and artificial neural networks (ANN) were developed for adrenoreceptor agonists and antagonists chromatographed on a diol column under hydrophilic interaction chromatographic (HILIC) mode at three pH conditions (3.0, 4.0 and 5.0). Using stepwise MLR, the retention behavior of the analytes was satisfactorily described by a five-predictor model; the predictors being the percentage of acetonitrile in the mobile phase (% ACN), the logarithm of partition coefficient (log D), the number of hydrogen bond donor (HBD), the number of hydrogen bond acceptor (HBA), and the total absolute atomic charge of the molecule (TAAC). Among the five descriptors, % ACN had the strongest effect on the retention as indicated by its relatively higher standardized coefficient compared to the other four predictors. The inclusion of the four predictors which are related to the properties of the compounds (log D, HBD, HBA and TAAC), suggested hydrophilic interaction, hydrogen bonding and ionic interaction as possible mechanisms of retention of the analytes on the studied system. The models derived from MLR also showed adequate fit as proven by the high correlation (R2 as high as 0.9667) between observed and predicted log k values for the training set and good predictive power on the test set (R2 greater than 0.97). ANN analyses of the data were also conducted using the five predictors derived from MLR as inputs and log k as output. The trained ANNs showed better predictive abilities as compared to MLR models as indicated by relative higher R2 and lower root mean square error of predictions (RMSEP) for both training and test sets. The derived models can be used as references for method development and optimization of chromatographic conditions for the separation of adrenoreceptor agonists and antagonists.

[Quantitative determination of adrenaline by visible spectrophotometric method]. / Determinarea spectrofotometrica în vizibil a adrenalinei.

UNLABELLED: A sensible and rapid spectrophotometric assay for adrenaline was developed. MATERIAL AND METHOD: The method is based on the reaction with ammonium molybdate and sodium nitrite in acid medium. RESULTS: The obtained compound is stable, soluble in water and has the absorbtion maximum at 405 nm. Beer's law is valid within a concentration range of 20-160 microg/mL. The validity of the method was tested by statistical analysis of the experimental data using the linearity, the scale's calibration factor, the detection limit, the quantification limit and the precision. CONCLUSIONS: A new method for the assay of adrenaline in pharmaceutical products has been developed.

Determination of adrenergic agonists from extracts and herbal products of Citrus aurantium L. var. amara by LC.

The purpose of this study was to set up a HPLC method to separate adrenergic amines (dl-octopamine, dl-synephrine and tyramine) and to determine their content in fruits, extracts and herbal products of Citrus aurantium L. var. amara. A rapid method for the quantitative analysis of these amines is described, based on their separation by RP-HPLC technique with UV detection. The analysis were conducted on a Lichrospher RP-18 column at room temperature, using a mobile phase consisting of 0.02 M citric acid-0.02 M NaH2PO4 (7:3 v/v) and adjusted to a final pH of 3. The detection was at 220 nm. Since some of these amines are chiral compounds and their enantiomers showed different pharmacological activity, the direct separation of synephrine enantiomers was carried out with HPLC on a beta-cyclodextrin stationary phase. The mobile phase consisted of methanol-NaH2PO4 25 mM pH 3.5 (20:80 v/v) and tetrabutylammonium hydrogen sulfate 10 mM in ratio of 30:70 v/v in isocratic condition and the detection was at 220 nm. The two proposed methods were applied to the analysis of fruits, extracts and herbal products of C. aurantium L. var. amara. Taking into account that some authors have reported that l-synephrine may be converted into its d-form by high temperature, this optical isomerization was monitored by the same HPLC method used for the separation of enantiomers.

Evaluation of certain veterinary drug residues in food. Forty-seventh report of the joint FAO/WHO Expert Committee on Food Additives.

This report presents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluated the safety of residues of certain veterinary drugs in food and to recommend maximum levels for such residues in food. The first part of the report considers the assessment of the effects of antimicrobial drug residues in food on the human intestinal microflora as well as well as of analytical methods used to obtain residue-depletion data. A summary follows of the Committee's evaluations of toxicological and residue data on a variety of veterinary drugs: two adrenoceptor agonists (clenbuterol and xylazine), two anthelminthic agents (abamectin and moxidectin), seven antimicrobial agents (chlortetracycline, oxytetracycline, tetracycline, neomycin, spiramycin, thiamphenicol and tilmicosin), and two insecticides (cypermethrin and alpha-cypermethrin). Annexed to the report are a summary of the Committee's recommendations on these drugs, including Acceptable Daily Intakes and Maximum Residue Limits, further toxicological studies and other information required, and a discussion of procedures for assessing the effects of antimicrobial drug residues in food on the human intestinal microflora.

[Enantiomeric high performance liquid chromatographic separation of epinephrine and analogous using chiral mobile phase additives].

The enantiomeric resolution of epinephrine, isoproterenol, ephedrine was studied by reversed phase HPLC. beta-CD, DM-beta-CD, TM-beta-CD were used as chiral mobile phase additives. The effects of the concentration of DM-beta-CD and the concentration of methanol on resolution of D,L-epinephrine were investigated. The results showed: D,L-epinephrine and D,L-isoproterenol can be separated by beta-CD, DM-beta-CD, TM-beta-CD, but D,L-ephedrine can't. Hydrogen bonding plays an important role in the chiral recognition mechanism. In the separation of isoproterenol, the enantioselectivity of TM-beta-CD was better than those of beta-CD and DM-beta-CD. As the concentration of DM-beta-CD changed from 0.04 mmol/L to 1.00 mmol/L, the resolution varied slightly. The experiment of the effect of methanol concentration on Rs showed: when the ratio of methanol/water was 40/60, the Rs reached the maximum. The coefficients of variation of retention time of D-epinephrine and L-epinephrine were 1.3% and 1.4% respectively. It is demonstrated that the chromatographic systems with a dynamically-generated stationary phase with methylated-beta-cyclodextrin are versatile tools for enantiomer separation. This technique leads to column with excellent time stability and good reproducibility of the enantio-selectivity.

Synovial fluid as a matrix of selection in the detection of beta-adrenergic agonist drugs in carcases and fresh meat.

Previous papers have supported the hypothesis that beta-agonist drugs could accumulate in those tissues with a high content of mucopolysaccharides. Based on our preliminary findings, between October and December 1993 we randomly sampled 534 samples of synovial fluids drawn from the knee joint of fresh carcasses. After a preliminary extraction able to break down the water domains of mucopolysaccharides and the interactions between the matrix and the drugs, samples were concentrated on diatomaceous earth and then screened on two different ELISA plates. We confirmed the structure of suspected fluids by GC-MS (HFBA derivatization), according to EC criteria. Of the 57 samples screened as positive (10.6% of the total), 51 (9.5%) were fully confirmed, while for six it was not possible to identify the drug. The results suggest that the analysis of synovial fluids is an adequate tool to monitor the misuse of beta-adrenergic drugs in animal production, especially when target organs such as liver and kidney are not available for sampling.

Dopexamine hydrochloride in the human heart: receptor binding and effects on cAMP generation.

Dopexamine hydrochloride is a synthetic catecholamine proposed for the short-term treatment of heart failure and postoperative low cardiac output. The pharmacological profile and anatomical localization of dopexamine binding were investigated in sections of right and left ventricle using [3H]-dopexamine and ligand techniques associated with light microscope autoradiography. Its effects on the 3-5-cyclic adenosine monophosphate (cAMP) generating system in membrane particles of the human right or left ventricle were also studied. [3H]-Dopexamine was specifically bound to sections of human right or left ventricle. The binding was time-, temperature- and concentration-dependent and was dissociable. The apparent equilibrium constant of dissociation was 3.5 nM. A decreased [3H]-dopexamine binding capacity from the base to the apex and ventricles was noticeable. The pharmacological profile of [3H]-dopexamine binding to sections of right or left ventricle was consistent with the labelling of both beta 2-adrenoceptors and dopamine DA-2 receptors. The most potent displacer of [3H]-dopexamine was the beta 2-adrenoceptor antagonist ICI 118,551 followed by dopamine, noradrenaline and domperidone. The beta 1-adrenoceptor antagonist metoprolol or the dopamine DA-1 receptor antagonist SCH 23390 were ineffective as displacers of [3H]-dopexamine binding. Light microscope autoradiography revealed the localization of [3H]-dopexamine binding sites within the wall of the human right and left ventricle. The density of silver grains was slightly higher in the right than in the left ventricle and showed a uniform transmural distribution across the ventricular wall.(ABSTRACT TRUNCATED AT 250 WORDS)