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See all topos. Crag is missing access information, so remember that climbing is not always permitted. When parking, remember to leave unobstructed way for local habitants and agricultural machinery. Do not litter or make unnecessarily loud noises when at the cliff. Making fire is allowed only with a permit! Read more. York, United Kingdom. Routes No routes have been added to this crag yet. Log in to add routes. Access info missing Crag is missing access information, so remember that climbing is not always permitted. Activities on this crag. Nearby crags Premium. Anston Stones. Rivelin Edge. Wimberry Routes. Stanage North. Stanage High Neb.
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Federal government websites often end in. The site is secure. Mephedrone, a psychoactive compound derived from cathinone, is widely used as a designer drug. The determination of mephedrone and its metabolites is important for understanding its possible use in medicine. In this work, a method of capillary electrophoresis for the chiral separation of mephedrone and its metabolites was developed. Based on the simplex method, the optimal composition of the background electrolyte was determined: at pH 2. For mephedrone and its metabolites, calibration curves were constructed in a calibration range from 0. Mephedrone, a psychostimulant drug first synthesized in the s, is classified as a synthetic cathinone \\\\\\\\\[ 1 \\\\\\\\\]. According to the European Monitoring Centre for Drugs and Drug Addiction \\\\\\\\\[ 2 \\\\\\\\\], synthetic cathinones, together with synthetic cannabinoids, are the most abundant substances in the group of so-called new psychoactive substances. In most cases, these drugs have stimulant entactogenic effects; however, the biological activity of such substances is difficult to predict and some of these artificially prepared substances have been shown to have potential therapeutic uses \\\\\\\\\[ 3 \\\\\\\\\], for example, bupropion is used to treat depression and smoking cessation \\\\\\\\\[ 4 \\\\\\\\\] and diethylpropion is prescribed as an anti-obesity drug \\\\\\\\\[ 5 \\\\\\\\\]. On the other hand, pyrovalerone has been prescribed for the treatment of chronic obesity and lethargy but has been withdrawn for its abuse by patients \\\\\\\\\[ 4 , 6 \\\\\\\\\]. These new psychoactive substances can also mimic prescription therapeutic psychoactive drugs; for example, phenmetrazine, modafinil, and methylphenidate, and hence are more available even for healthy people because they are available on the Internet \\\\\\\\\[ 7 \\\\\\\\\]. So, an intensive study of these compounds is needed. The most commonly used techniques for isolating new psychoactive substances from biological samples are liquid-to-liquid extraction LLE and solid-phase extraction SPE \\\\\\\\\[ 8 \\\\\\\\\]. LLE is a simple method, but its problems are easy contamination and matrix influence. On the contrary, the SPE is very selective but time-consuming \\\\\\\\\[ 9 \\\\\\\\\]. A popular method is the QuEChERS method quick, easy, cheap, effective, rugged, and safe modified in for the extraction of psychoactive substances from biological samples \\\\\\\\\[ 10 \\\\\\\\\]. Simple colorimetric tests are used for rapid orientation detection of drugs. However, the identification is very indicative, detecting only the presence of certain structural motifs \\\\\\\\\[ 11 \\\\\\\\\]. However, immunological methods that are commercially available are more commonly used for rapid drug detection. However, there is no sufficiently effective immunoassay on the market for the detection of cathinones that does not show cross-reactivity between analogs \\\\\\\\\[ 9 , 12 , 13 \\\\\\\\\]. Of the advanced chromatographic techniques, gas and liquid chromatography with a mass spectrometer GC-MS and LC-MS are the most suitable for the analysis of synthetic cathinones. In general, the GC-MS technique is used more for drug analysis, mainly due to shorter elution times \\\\\\\\\[ 14 , 15 , 16 , 17 , 18 , 19 \\\\\\\\\]. Chiral separation is most often performed in an achiral environment after the previous conversion of enantiomers to diastereoisomers \\\\\\\\\[ 20 \\\\\\\\\], which, however, brings complications for the quantification itself \\\\\\\\\[ 21 \\\\\\\\\]. It should be also noted that cathinones are thermodegradable substances and due to the thermal conditions necessary for separation by GC, their partial decomposition occurs \\\\\\\\\[ 5 \\\\\\\\\]. Rapid separation of cathinones is also possible by supercritical fluid chromatography SFC \\\\\\\\\[ 27 , 28 \\\\\\\\\]. Carnes et al. The first enantioseparation of cathinone derivatives by capillary electrophoresis CE was performed by Mohr et al. For example, to study the incorporation of cathinones into hair, a CE method was developed in which extraction from hair at an elevated temperature and pressure into ammonium hydroxide solution was first performed. Subsequently, the extract was concentrated on a solid phase that was part of the CE capillary inline coupling of SPE-CE , and analysis was performed using various cyclodextrins as chiral selectors \\\\\\\\\[ 34 \\\\\\\\\]. Mephedrone is referred to as a catecholamine reuptake inhibitor \\\\\\\\\[ 35 , 36 , 37 \\\\\\\\\], but it also positively affects the release of catecholamines into the synaptic cleft \\\\\\\\\[ 13 , 38 , 39 , 40 , 41 \\\\\\\\\]. Therefore, it seems to have a mixed effect \\\\\\\\\[ 42 , 43 , 44 \\\\\\\\\]. In both cases, the result is an increase in the concentration of catecholamines in the synaptic cleft, resulting in the typical action of psychostimulants. Acute intoxication with mephedrone, usually in combination with other drugs and alcohol, has already resulted in hundreds of deaths across Europe \\\\\\\\\[ 9 \\\\\\\\\]. Both enantiomers have a similar affinity for dopaminergic transporters, but S -mephedrone is about 50 times more potent as a serotonergic mediator. Nevertheless, the R -enantiomer is primarily responsible for the euphoric effects \\\\\\\\\[ 45 \\\\\\\\\]. The major metabolites of mephedrone 1 ; 4-methyl methcathinone are 4-methylcathinone 2 ; 4-MC and 4-hydroxymethyl methcathinone 3 ; 4-OH-MMC. The aim of this work was to find the optimal conditions for the separation of mephedrone and its metabolites by capillary electrophoresis for details about this method, see, for example, Bernardo-Bermejo et al. The optimization of the background electrolyte BGE was carried out by using the simplex procedure, which was thoroughly described by Catai and Carrilho \\\\\\\\\[ 50 \\\\\\\\\]. Mephedrone and all its available metabolites, selected on the basis of current knowledge on the biotransformation of mephedrone, are chiral substances that may undergo different metabolic pathways and thus have different biological effects for individual enantiomers. The first optimization step was to select a suitable CD. From the measured electropherograms, it was concluded that the separation proceeds better in the phosphate buffer at a lower pH value. From the selected CDs Figure 5 , i. In its presence, 18 diastereomers were separated within 30 min, so it was used in all the other work. Thus, in the search for optimal separation conditions, it is possible to achieve higher concentrations if necessary. The enantioselective separation of ionic analytes with ionic CDs is controlled by at least two mechanisms. The first is the interaction of the hydrophobic cavity of the CD derivative with the analyte; the second is the electrostatic interaction between the ionic groups of the CD derivative and the analyte \\\\\\\\\[ 54 \\\\\\\\\]. Cathinones are basic drugs and have high values of dissociation constants; for example, the p K a of mephedrone is 8. In addition to pH, the separation is also affected by the concentration of cyclodextrin, which affects the amount of complexed analyte and thus affects its overall electrophoretic mobility \\\\\\\\\[ 49 \\\\\\\\\]. The separation efficiency can be increased at higher voltages, but this also increases the temperature difference in the middle and at the edge of the capillary, which leads to a decrease in efficiency. Based on our experience with a similar BGE \\\\\\\\\[ 51 \\\\\\\\\], we have chosen a voltage see Section 3. In addition to voltage, the current also depends on the ionic strength of the BGE. In order to monitor both parameters simultaneously, the simplex method was used to find the optimal conditions \\\\\\\\\[ 60 \\\\\\\\\]. The first step was to construct an initial simplex. The first two points correspond to the conditions: 1 pH 2. The third point was calculated on the basis of the properties of an equilateral triangle, i. Based on the resolution of the peaks of the individual enantiomers, the average criterion R kr was calculated see above , which served as a compared response for the simplex procedure. Simplex followed the rules of the equilateral simplex procedure. After calculating the coordinates of point 8 , the simplex looped. Thus, the chiral separation proceeded best under the initial conditions chosen. The simplex procedure is summarized in Figure 6 A. A half-simplex was designed to more accurately determine the optimal chiral separation conditions Figure 6 B. The first point corresponds to the first determined optimal conditions: 1 pH 2. Furthermore, the simplex proceeded according to the rules of the equilateral simplex procedure. Points 3 and 4 also provide the maximum value of the criterion R kr. Point 3 was chosen as the point meeting the optimal conditions, as in the second case the analysis was extended to more than min. The simplex procedure is summarized in Figure 6 B. The resulting optimum was found at pH 2. At pH 2. Metabolites 5, 6, and 9 carry a carboxyl group on the aromatic nucleus in the para position. Upon approximation with benzoic acid, whose p K a is 4. Thus, it is clear that pH plays an important role in the separation. A lower or higher pH than 2. For a given racemic mixture, there is an optimal concentration at which the individual enantiomers will be separated as best as possible \\\\\\\\\[ 49 , 61 \\\\\\\\\]. This concentration depends on the stability constants of the individual enantiomers and the given chiral selector. In the case of separation of a mixture of racemic substances, as in our case, it is necessary to choose a compromise between these concentrations. Calibration solutions were measured under the optimized BGE composition, namely at 7. Furthermore, the regression parameters of the calibration curves were calculated. In the case of analytes 1, 2, 5, and 7, the size of the intercept is insignificant according to the test. Subsequently, the confidence intervals for the intercept a and the slope b of all calibration equations were calculated. Ignoring the intercept improved the values of the coefficient of determination R 2 and thus allowed us to reduce the confidence intervals Table 1. Psychoactive amines 1—9 Figure 2 in the form of hydrochloride salts were prepared previously \\\\\\\\\[ 46 \\\\\\\\\]. The background electrolyte used for the optimizing of the chiral selector concentration and pH consisted of Between the runs, the capillary was rinsed at The analytes were injected hydrodynamically at a pressure of 1. Detection was carried out at nm during the optimization step and nm for analytes 1, 2, 3, and 6; nm for analyte 5; and nm for analytes 4 and 7 i. For calibration, seven different mixtures of analytes 1—7 Figure 2 at concentration ranges from 0. For optimizing the BGE composition, the two-dimensional simplex method was used \\\\\\\\\[ 60 \\\\\\\\\]. As an evaluation criterion, R cr was introduced and calculated as follows. In this work, the composition of the basic electrolyte for the chiral separation of mephedrone and its selected metabolites was optimized. A total of seven cyclodextrin derivatives were selected as potential chiral selectors. Cyclodextrin concentration and pH were determined based on the simplex method for two parameters. The optimized pH was found to be 2. A total of nine analytes were present in the mixture, and 18 distinguishable peaks were found. Thus, all analytes were separated. Furthermore, the data for the construction of calibration dependences were measured. Based on the test of significance of the parameter, the intercept on the y -axis was neglected in some cases. Conceptualization, P. All authors have read and agreed to the published version of the manuscript. Sample Availability: Samples of the compounds 1 — 9 Figure 2 are available from the authors. As a library, NLM provides access to scientific literature. Published online Jun Received May 25; Accepted Jun Abstract Mephedrone, a psychoactive compound derived from cathinone, is widely used as a designer drug. Keywords: capillary electrophoresis, chiral separation, cyclodextrin, mephedrone, metabolites. Introduction Mephedrone, a psychostimulant drug first synthesized in the s, is classified as a synthetic cathinone \\\\\\\\\[ 1 \\\\\\\\\]. Open in a separate window. Figure 1. Figure 2. Results and Discussion 2. Cyclodextrin Optimization The first optimization step was to select a suitable CD. Figure 3. Figure 4. Figure 5. BGE Optimization The enantioselective separation of ionic analytes with ionic CDs is controlled by at least two mechanisms. Figure 6. Figure 7. Calibration Calibration solutions were measured under the optimized BGE composition, namely at 7. Materials and Methods 3. Simplex Method For optimizing the BGE composition, the two-dimensional simplex method was used \\\\\\\\\[ 60 \\\\\\\\\]. Conclusions In this work, the composition of the basic electrolyte for the chiral separation of mephedrone and its selected metabolites was optimized. Author Contributions Conceptualization, P. Conflicts of Interest The authors declare no conflict of interest. Footnotes Sample Availability: Samples of the compounds 1 — 9 Figure 2 are available from the authors. References 1. Sanchez: S. Busardo F. Is etizolam a safe medication? Effects on psychomotor perfomance at therapeutic dosages of a newly abused psychoactive substance. Forensic Sci. Prosser J. The toxicology of bath salts: A review of synthetic cathinones. Kerrigan S. Thermal degradation of synthetic cathinones: Implications for forensic toxicology. Goldberg J. A controlled evaluation of pyrovalerone in chronically fatigued volunteers. Batisse A. Use of new psychoactive substances to mimic prescription drugs: The trend in France. Alremeithi R. Methods Chem. Majchrzak M. The newest cathinone derivatives as designer drugs: An analytical and toxicological review. Forensic Toxicol. Usui K. Toole K. Color tests for the preliminary identification of methcathinone and analogues of methcathinone. Microgram J. Ellefsen K. Validation of the only commercially available immunoassay for synthetic cathinones in urine: Randox Drugs of Abuse V Biochip Array Technology. Drug Test. Paillet-Loilier M. Emerging drugs of abuse: Current perspectives on substituted cathinones. Abuse Rehabil. Daeid N. Camilleri A. Chemical analysis of four capsules containing the controlled substance analogues 4-methylmethcathinone, 2-fluoromethamphetamine, alpha-phthalimidopropiophenone and N-ethylcathinone. Fujii H. High throughput chiral analysis of urinary amphetamines by GC-MS using a short narrow-bore capillary column. Meyer M. Beta-keto amphetamines: Studies on the metabolism of the designer drug mephedrone and toxicological detection of mephedrone, butylone, and methylone in urine using gas chromatography-mass spectrometry. Olesti E. GC—MS quantification method for mephedrone in plasma and urine: Application to human pharmacokinetics. Rasmussen L. Ribeiro C. Mohr S. Chiral separation of new cathinone-and amphetamine-related designer drugs by gas chromatography—mass spectrometry using trifluoroacetyl-l-prolyl chloride as chiral derivatization reagent. Pedersen A. Screening for illicit and medicinal drugs in whole blood using fully automated SPE and ultra-high-performance liquid chromatography with TOF-MS with data-independent acquisition. Paul M. Concheiro M. Simultaneous determination of 40 novel psychoactive stimulants in urine by liquid chromatography—high resolution mass spectrometry and library matching. Taschwer M. Pauk V. Fast separation of selected cathinones and phenylethylamines by supercritical fluid chromatography. Geryk R. Enantioselective separation of biologically active basic compounds in ultra-performance supercritical fluid chromatography. Carnes S. Comparison of ultra high performance supercritical fluid chromatography, ultra high performance liquid chromatography, and gas chromatography for the separation of synthetic cathinones. Chiral separation of cathinone derivatives used as recreational drugs by cyclodextrin-modified capillary electrophoresis. Merola G. Chiral separation of 12 cathinone analogs by cyclodextrin-assisted capillary electrophoresis with UV and mass spectrometry detection. Analysis and characterization of the novel psychoactive drug 4-chloromethcathinone clephedrone Forensic Sci. Nowak P. Baciu T. Enantioselective determination of cathinone derivatives in human hair by capillary electrophoresis combined in-line with solid-phase extraction. Simmler L. Pharmacological characterization of designer cathinones in vitro. Martinez-Clemente J. Interaction of mephedrone with dopamine and serotonin targets in rats. Lopez-Arnau R. Comparative neuropharmacology of three psychostimulant cathinone derivatives: Butylone, mephedrone and methylone. Chavant F. New synthetic drugs in addictovigilance. Philogene-Khalid H. Synthetic cathinones and stereochemistry: S enantiomer of mephedrone reduces anxiety- and depressant-like effects in cocaine- or MDPV-abstinent rats. Drug Alcohol Depend. Schifano F. Psychopharmacology Heidelb. Ciechomska M. Activity and biotransformation of three synthetic legal highs: Mephedrone, methylone and 3,4-methylenodioxypyrovalerone. Z Zagadnien Nauk Sadowych. Karila L. Papaseit E. Human pharmacology of mephedrone in comparison with MDMA. Sichova K. Gregg R. Stereochemistry of mephedrone neuropharmacology: Enantiomer-specific behavioural and neurochemical effects in rats. Linhart I. Metabolic profile of mephedrone: Identification of nor-mephedrone conjugates with dicarboxylic acids as a new type of xenobiotic phase II metabolites. Pozo O. Mass spectrometric evaluation of mephedrone in vivo human metabolism: Identification of phase I and phase II metabolites, including a novel succinyl conjugate. Drug Metab. Bernardo-Bermejo S. Chiral capillary electrophoresis. TrAC Trends Anal. Rezanka P. Application of cyclodextrins in chiral capillary electrophoresis. Catai J. Simplex optimization of electrokinetic injection of DNA in capillary electrophoresis using dilute polymer solution. Enantioseparation of novel psychoactive chiral amines and their mixture by capillary electrophoresis using cyclodextrins as chiral selectors. Jurasek B. Synthesis of methoxetamine, its metabolites and deuterium labelled analog as analytical standards and their HPLC and chiral capillary electrophoresis separation. RSC Adv. Szeman J. Effect of the degree of substitution of cyclodextrin derivatives on chiral separations by high-performance liquid chromatography and capillary electrophoresis. Sabbah S. Cyclodextrin-induced acidity modification of substituted cathinones studied by capillary electrophoresis supported by density functional theory calculations. Gibbons S. Wan H. Rapid screening of pKa values of pharmaceuticals by pressure-assisted capillary electrophoresis combined with short-end injection. Glicksberg L. Postmortem distribution and redistribution of synthetic cathinones. Spendley W. Sequential application of simplex designs in optimisation and evolutionary operation. Copy Download.
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