| 1. |
- Aftab, Obaid, 1984-, et al.
(författare)
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NMR spectroscopy based metabolic profiling of drug induced changes in vitro can discriminate between pharmacological classes
- 2014
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Ingår i: Journal of chemical information and modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 54:11, s. 3251-3258
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Tidskriftsartikel (refereegranskat)abstract
- Drug induced changes in mammalian cell line models have already been extensively profiled at the systemic mRNA level and subsequently used to suggest mechanisms of action for new substances as well as to support drug repurposing, i.e. identifying new potential indications for drugs already licensed for other pharmacotherapy settings. The seminal work in this field, which includes a large database and computational algorithms for pattern matching, is known as the “Connectivity Map” (CMap). The potential of similar exercises at the metabolite level is, however, still largely unexplored. Only recently the first high throughput metabolomic assay pilot study was published, involving screening of metabolic response to a set of 56 kinase inhibitors in a 96-well format. Here we report results from a separately developed metabolic profiling assay, which leverages 1H NMR spectroscopy to the quantification of metabolic changes in the HCT116 colorectal cancer cell line, in response to each of 26 compounds. These agents are distributed across 12 different pharmacological classes covering a broad spectrum of bioactivity. Differential metabolic profiles, inferred from multivariate spectral analysis of 18 spectral bins, allowed clustering of most tested drugs according to their respective pharmacological class. A more advanced supervised analysis, involving one multivariate scattering matrix per pharmacological class and using only 3 spectral bins (three metabolites), showed even more distinct pharmacology-related cluster formations. In conclusion, this kind of relatively fast and inexpensive profiling seems to provide a promising alternative to that afforded by mRNA expression analysis, which is relatively slow and costly. As also indicated by the present pilot study, the resulting metabolic profiles do not seem to provide as information rich signatures as those obtained using systemic mRNA profiling, but the methodology holds strong promise for significant refinement.
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| 2. |
- Arvidsson, Anna K., 1971-, et al.
(författare)
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Nya regler för en effektivare vinterväghållning : En förstudie
- 2013
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Idag kostar vinterväghållningen årligen cirka 2 miljarder, men det saknas bra uppföljningsverktyg för att se hur dessa pengar fördelas. Detta notat summerar hur inrapportering, regelverk för vintervägsåtgärder och ersättningsmodeller fungerar idag samt diskuterar vilken nyutvecklad teknik som skulle kunna användas framöver för att optimera vinterväghållningen. Det svenska VägVäderinformationsSystemet (VViS) introducerades som hjälpmedel för vinterväghållning under slutet av 1970-talet och har under 80- och 90-talet byggts ut och idag finns det cirka 800 stationer på de statliga svenska vägarna. De mäter bland annat temperaturen i luften och vägytan, vindriktning och vindhastighet, de detekterar nederbördstyp och mängd och på många av stationerna finns det även kameror för bedömning av väglag. Information från VViS används idag, tillsammans med väderprognoser, som det huvudsakliga beslutsunderlaget för att bestämma behovet av vinterväghållningsåtgärder. Syftet med denna förstudie har varit att ta fram ett underlag till ett nytt regelverk för när åtgärder behöver utföras för att få en bra vägstandard på vintern och hur ersättningen ska kunna regleras i förhållande till detta, för att få en effektivare vinterväghållning. Den tekniska utvecklingen har gått framåt de senaste åren inom en rad olika områden, till exempel bilindustrin och när det gäller beröringsfria sensorer för mätning av bland annat friktion och vägytetemperatur. De nya teknikerna kan kopplas samman och tillsammans med VViS skulle det kunna ge en mer tydlig bild av när och var åtgärder behövs för att få den mest effektiva vinterväghållningen. Detta skulle även kunna användas för att utforma ett beslutsstödsystem för att underlätta entreprenörernas arbete.
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| 3. |
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| 4. |
- Engskog, Mikael K R, et al.
(författare)
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The cyanobacterial amino acid beta-N-methylamino-L-alanine perturbs the intermediary metabolism in neonatal rats
- 2013
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Ingår i: Amino Acids. - : Elsevier BV. - 0939-4451 .- 1438-2199. ; 49:5, s. 905-919
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Tidskriftsartikel (refereegranskat)abstract
- The neurotoxic amino acid β-N-methylamino-l-alanine (BMAA) is produced by most cyanobacteria. BMAA is considered as a potential health threat because of its putative role in neurodegenerative diseases. We have previously observed cognitive disturbances and morphological brain changes in adult rodents exposed to BMAA during the development. The aim of this study was to characterize changes of major intermediary metabolites in serum following neonatal exposure to BMAA using a non-targeted metabolomic approach. NMR spectroscopy was used to obtain serum metabolic profiles from neonatal rats exposed to BMAA (40, 150, 460mg/kg) or vehicle on postnatal days 9-10. Multivariate data analysis of binned NMR data indicated metabolic pattern differences between the different treatment groups. In particular five metabolites, d-glucose, lactate, 3-hydroxybutyrate, creatine and acetate, were changed in serum of BMAA-treated neonatal rats. These metabolites are associated with changes in energy metabolism and amino acid metabolism. Further statistical analysis disclosed that all the identified serum metabolites in the lowest dose group were significantly (p<0.05) decreased. The neonatal rat model used in this study is so far the only animal model that displays significant biochemical and behavioral effects after a low short-term dose of BMAA. The demonstrated perturbation of intermediary metabolism may contribute to BMAA-induced developmental changes that result in long-term effects on adult brain function.
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| 5. |
- Johansson, Monika, et al.
(författare)
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A general analytical platform and strategy in search for illegal drugs
- 2014
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Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085 .- 1873-264X. ; 100, s. 215-229
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Tidskriftsartikel (refereegranskat)abstract
- An effective screening procedure to identify and quantify active pharmaceutical substances in suspected illegal medicinal products is described. The analytical platform, consisting of accurate mass determination with liquid chromatography time-of-flight mass spectrometry (LC-QTOF-MS) in combination with nuclear magnetic resonance (NMR) spectroscopy provides an excellent analytical tool to screen for unknowns in medicinal products, food supplements and herbal formulations. This analytical approach has been successfully applied to analyze thousands of samples. The general screening method usually starts with a methanol extraction of tablets/capsules followed by liquid chromatographic separation on a Halo Phenyl-Hexyl column (2.7μm; 100mm×2.1mm) using an acetonitrile/0.1% formic acid gradient as eluent. The accurate mass of peaks of interest was recorded and a search made against an in-house database containing approximately 4200 substances, mostly pharmaceutical compounds. The search could be general or tailored against different classes of compounds. Hits were confirmed by analyzing a reference substance and/or by NMR. Quantification was normally performed with quantitative NMR (qNMR) spectroscopy. Applications for weight-loss substances like sibutramine and orlistat, sexual potency enhancement (PDE-5 inhibitors), and analgesic drugs are presented in this study. We have also identified prostaglandin analogues in eyelash growth serum, exemplified by isopropyl cloprostenate and bimatoprost. For creams and ointments, matrix solid-phase dispersion (MSPD) was found to give a clean extracts with high recovery prior to LC-MS analyses. The structural elucidation of cetilistat, a new weight-loss substance recently found in illegal medicines purchased over the Internet, is also presented.
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| 6. |
- Rundlöf, Torgny, et al.
(författare)
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Survey and qualification of internal standards for quantification by 1H NMR spectroscopy
- 2010
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Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085 .- 1873-264X. ; 52:5, s. 645-651
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Tidskriftsartikel (refereegranskat)abstract
- In quantitative NMR (qNMR) selection of an appropriate internal standard proves to be crucial. In this study, 25 candidate compounds considered to be potent internal standards were investigated with respect to the ability of providing unique signal chemical shifts, purity, solubility, and ease of use. The 1H chemical shift (δ) values, assignments, multiplicities and number of protons (for each signal), appropriateness (as to be used as internal standards) in four different deuterated solvents (D2O, DMSO-d6, CD3OD, CDCl3) were studied. Taking into account the properties of these 25 internal standards, the most versatile eight compounds (2,4,6-triiodophenol, 1,3,5-trichloro-2-nitrobenzene, 3,4,5-trichloropyridine, dimethyl terephthalate, 1,4-dinitrobenzene, 2,3,5-triiodobenzoic acid, maleic acid and fumaric acid) were qualified using both differential scanning calorimetry (DSC) and NMR spectroscopy employing highly pure acetanilide as the reference standard. The data from these two methods were compared as well as utilized in the quality assessment of the compounds as internal standards. Finally, the selected internal standards were tested and evaluated in a real case of quantitative NMR analysis of a paracetamol pharmaceutical product.
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| 7. |
- Rundlöf, Torgny, et al.
(författare)
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Use and qualification of primary and secondary standards employed in quantitative H-1 NMR spectroscopy of pharmaceuticals
- 2014
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Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085 .- 1873-264X. ; 93:SI, s. 111-117
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Tidskriftsartikel (refereegranskat)abstract
- Standards are required in quantitative NMR (qNMR) to obtain accurate and precise results. In this study acetanilide was established and used as a primary standard. Six other chemicals were selected as secondary standards: 3,4,5-trichloropyridine, dimethylterephthalate, maleic acid, 3-sulfolene, 1,4-bis(trimethylsilyl)benzene, and 1,3,5-trimethoxybenzene. The secondary standards were quantified using the primary standard acetanilide. A protocol for qualification and periodic checks of these secondary standards was developed, and used for evaluation of the stability of the compounds. Periodic monitoring of purity was performed for several years. The purity was higher than 99% for all secondary standards. All standards maintained the initial purity during the time period of monitoring, with very small variations in purity (0.3-0.4%). The selected secondary standards were shown to be suitable qNMR standards and that periodic requalification of the standards by qNMR ensures reliable analytical results. These standards have been used in our laboratory for compliance testing of pharmaceutical active substances and approved medicinal products as well as for analysis of suspected illegal medicines. In total more than 1000 samples have been tested using both internal and external standardization and examples are given.
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