Imperial College London

Emeritus ProfessorJeremyNicholson

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Emeritus Professor of Biological Chemistry
 
 
 
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Contact

 

+44 (0)20 7594 3195j.nicholson Website

 
 
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Assistant

 

Ms Wendy Torto +44 (0)20 7594 3225

 
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Location

 

Office no. 665Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

991 results found

Holmes E, Nicholson JK, Nicholls AW, Lindon JC, Connor SC, Polley S, Connelly Jet al., 1998, The identification of novel biomarkers of renal toxicity using automatic data reduction techniques and PCA of proton NMR spectra of urine, 5th Scandinavian Symposium on Chemometrics (SSC5), Publisher: ELSEVIER SCIENCE BV, Pages: 245-255, ISSN: 0169-7439

Conference paper

Nicholson JK, 1998, NMR and pattern recognition approaches to drug toxicity and metabolic analysis, Journal de Pharmacie de Belgique, Vol: 53, ISSN: 0047-2166

High resolution NMR spectroscopy provides a rapid method of characterising and quantifying a wide range of endogenous and drug-related metabolites in biofluids and provides a powerful means of exploring drug-induced toxicological processes. 1H NMR spectra of biofluids such as urine and plasma are highly complex, containing signals from hundreds of metabolites that represent many key biochemical pathways. The 1H NMR-generated biofluid metabolite profiles are characteristically changed in different toxicological conditions according to the exact site and mechanism of the drug-induced lesion. Thus, interrogation of the biofluid NMR data can give direct diagnostic information and aid the detection of novel biomarkers of toxic effect. Identification of such biomarkers is further aided by the use of multidimensional NMR and directly coupled HPLC-NMR-MS approaches. By use of computer pattern recognition (PR) methods, complex biofluid NMR data can be reduced and analyzed quantitatively to provide PR maps showing the physiological and toxicological effects of test xenobiotics in pre-development drug toxicity studies. Neural network, rule induction and other expert system methods can also be implemented to give direct diagnostic outputs on toxicity type based on NMR input data. NMR-PR based diagnostics can be extremely sensitive for the detection of low level damage in a variety of organ systems and is potentially a powerful new adjunct to conventional toxicological procedures for lead compound selection in drug development programmes. The NMR-PR and expert system approach to rapid in vivo toxicological assessment of drugs will be illustrated for a wide range of drug and toxin-induced lesions in both experimental animals and man.

Journal article

Schewitz J, Gfrorer P, Pusecker K, Tseng LH, Albert K, Bayer E, Wilson ID, Bailey NJ, Scarfe GB, Nicholson JK, Lindon JCet al., 1998, Directly coupled CZE-NMR and CEC-NMR spectroscopy for metabolite analysis: paracetamol metabolites in human urine, ANALYST, Vol: 123, Pages: 2835-2837, ISSN: 0003-2654

Journal article

Foxall PJD, Nicholson JK, 1998, Nuclear magnetic resonance spectroscopy: A non-invasive probe of kidney metabolism and function, EXPERIMENTAL NEPHROLOGY, Vol: 6, Pages: 409-414, ISSN: 1018-7782

Journal article

Wilson ID, Lindon JC, Nicholson JK, 1998, Liquid, chromatography directly Jointly combined with nuclear magnetic resonance spectroscopy and mass spectrometry, LC GC-MAGAZINE OF SEPARATION SCIENCE, Vol: 16, Pages: 842-+, ISSN: 0888-9090

Journal article

Pusecker K, Schewitz J, Gfrorer P, Tseng LH, Albert K, Bayer E, Wilson ID, Bailey NJ, Scarfe GB, Nicholson JK, Lindon JCet al., 1998, On-flow identification of metabolites of paracetamol from human urine using directly coupled CZE-NMR and CEC-NMR spectroscopy, ANALYTICAL COMMUNICATIONS, Vol: 35, Pages: 213-215, ISSN: 1359-7337

Journal article

Holmes E, Nicholls AW, Lindon JC, Ramos S, Spraul M, Neidig P, Connor SC, Connelly J, Damment SJP, Haselden J, Nicholson JKet al., 1998, Development of a model for classification of toxin-induced lesions using H-1 NMR spectroscopy of urine combined with pattern recognition, NMR IN BIOMEDICINE, Vol: 11, Pages: 235-244, ISSN: 0952-3480

Journal article

Moka D, Vorreuther R, Schicha H, Spraul M, Humpfer E, Lipinski M, Foxall PJD, Nicholson JK, Lindon JCet al., 1998, Biochemical classification of kidney carcinoma biopsy samples using magic-angle-spinning H-1 nuclear magnetic resonance spectroscopy, JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 17, Pages: 125-132, ISSN: 0731-7085

Journal article

Liu ML, Mao XA, Ye CH, Huang H, Nicholson JK, Lindon JCet al., 1998, Improved WATERGATE pulse sequences for solvent suppression in NMR spectroscopy, JOURNAL OF MAGNETIC RESONANCE, Vol: 132, Pages: 125-129, ISSN: 1090-7807

Journal article

Liu ML, Mao XA, Ye CH, Nicholson JK, Lindon JCet al., 1998, Enhanced effect of magnetic field gradients using multiple quantum NMR spectroscopy applied to self-diffusion coefficient measurement, MOLECULAR PHYSICS, Vol: 93, Pages: 913-920, ISSN: 0026-8976

Journal article

Scarfe GB, Wright B, Clayton E, Taylor S, Wilson ID, Lindon JC, Nicholson JKet al., 1998, F-19-NMR and directly coupled HPLC-NMR-MS investigations into the metabolism of 2-bromo-4-trifluoromethylaniline in rat: a urinary excretion balance study without the use of radiolabelling, XENOBIOTICA, Vol: 28, Pages: 373-388, ISSN: 0049-8254

Journal article

Beckwith-Hall BM, Nicholson JK, Nicholls AW, Foxall PJD, Lindon JC, Connor SC, Abdi M, Connelly J, Holmes Eet al., 1998, Nuclear magnetic resonance spectroscopic and principal components analysis investigations into biochemical effects of three model hepatotoxins, CHEMICAL RESEARCH IN TOXICOLOGY, Vol: 11, Pages: 260-272, ISSN: 0893-228X

Journal article

Scarfe GB, Wright B, Clayton E, Taylor S, Wilson ID, Lindon JC, Nicholson JKet al., 1998, 19F-NMR and directly coupled HPLC-NMR-MS investigations into the metabolism of 2-bromo-4-trifluoromethylaniline in rat: a urinary excretion balance study without the use of radiolabelling., Xenobiotica, Vol: 28, Pages: 373-388, ISSN: 0049-8254

1. The metabolic fate and urinary excretion of 2-bromo-4-trifluoromethylaniline has been studied in rat using 19F-NMR spectroscopic and directly coupled HPLC-NMR-MS methods. The compound was dosed to Sprague-Dawley rats (50 mg kg-1, i.p.) and urine collected over 0-8, 8-24 and 24-48 h post-dosing. 2. A total urinary recovery of 53.5 +/- 7.0% of the dose was achieved up to 48 h after dosing. The major metabolite in the urine was identified as 2-amino-3-bromo-5-trifluoromethylphenylsulphate accounting for a total of 35.7 +/- 6.2% of the dose. 3. Further metabolites detected were 2-bromo-4-trifluoromethylphenylhydroxylamine-1V-glucuronide (9.7 +/- 0.2% of the dose), 2-bromo-4-trifluoromethylaniline-N-glucuronide (3.0 +/- 0.3%) and 2-amino-3-bromo-5-trifluoromethylphenylglucuronide (2-St 0-4). Minor metabolites, including 2-bromo-4-trifluoromethylphenylhydroxylamine-O-glucuronide, 2-amino-3-bromo-5-trifluoromethylphenol and 2-bromo-4-trifluoromethylphenylsulphamate, in total accounted for 2.3 +/- 0.9% of the dose. 4. Directly coupled HPLC-NMR-MS and 19F-NMR spectroscopy proved to be efficient techniques for the unequivocal and rapid determination of the urinary metabolic fate and excretion balance of fluorinated xenobiotics without the need for radiolabelling.

Journal article

Tomlins AM, Foxall PJD, Lynch MJ, Parkinson J, Everett JR, Nicholson JKet al., 1998, High resolution (1)H NMR spectroscopic studies on dynamic biochemical processes in incubated human seminal fluid samples, BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, Vol: 1379, Pages: 367-380, ISSN: 0304-4165

Journal article

Tomlins AM, Foxall PJD, Lindon JC, Lynch MJ, Spraul M, Everett JR, Nicholson JKet al., 1998, High resolution magic angle spinning H-1 nuclear magnetic resonance analysis of intact prostatic hyperplastic and tumour tissues, ANALYTICAL COMMUNICATIONS, Vol: 35, Pages: 113-115, ISSN: 1359-7337

Journal article

Salman SR, Farrant RD, Glen RC, Lindon JCet al., 1998, Molecular flexibility of N-acyl heterocycles studied using C-13 NMR spectroscopy and computational chemistry, SPECTROSCOPY LETTERS, Vol: 31, Pages: 269-274, ISSN: 0038-7010

Journal article

Belton PS, Colquhoun IJ, Kemsley EK, Delgadillo I, Roma P, Dennis MJ, Sharman M, Holmes E, Nicholson JK, Spraul Met al., 1998, Application of chemometrics to the H-1 NMR spectra of apple juices: discrimination between apple varieties, FOOD CHEMISTRY, Vol: 61, Pages: 207-213, ISSN: 0308-8146

Journal article

Mistry N, Ismail IM, Smith MS, Nicholson JK, Lindon JCet al., 1997, Characterisation of impurities in bulk drug batches of fluticasone propionate using directly coupled HPLC-NMR spectroscopy and HPLC-MS, JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 16, Pages: 697-705, ISSN: 0731-7085

Journal article

Liu ML, Mao XA, Ye CH, Nicholson JK, Lindon JCet al., 1997, Three-dimensional maximum-quantum correlation HMQC NMR spectroscopy (3D MAXY-HMQC), JOURNAL OF MAGNETIC RESONANCE, Vol: 129, Pages: 67-73, ISSN: 1090-7807

Journal article

Nicholls AW, Lindon JC, Caddick S, Farrant RD, Wilson ID, Nicholson JKet al., 1997, NMR spectroscopic studies on the metabolism and futile deacetylation of phenacetin in the rat, XENOBIOTICA, Vol: 27, Pages: 1175-1186, ISSN: 0049-8254

Journal article

Gibb JOT, Holmes E, Nicholson JK, Weeks JMet al., 1997, Proton NMR spectroscopic studies on tissue extracts of invertebrate species with pollution indicator potential, COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY, Vol: 118, Pages: 587-598, ISSN: 0305-0491

Journal article

Corcoran O, Spraul M, Hofmann M, Ismail IM, Lindon JC, Nicholson JKet al., 1997, 750 MHz HPLC-NMR spectroscopic identification of rat microsomal metabolites of phenoxypyridines, JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 16, Pages: 481-489, ISSN: 0731-7085

Journal article

Spraul M, Hofmann M, Ackermann R, Nicholls AW, Damment JP, Haselden JN, Shockcor JP, Nicholson JK, Lindon JCet al., 1997, Flow injection proton nuclear magnetic resonance spectroscopy combined with pattern recognition methods: Implications for rapid structural studies and high throughput biochemical screening, ANALYTICAL COMMUNICATIONS, Vol: 34, Pages: 339-341, ISSN: 1359-7337

Journal article

Foxall PJD, Singer JM, Hartley JM, Neild GH, Lapsley M, Nicholson JK, Souhami RLet al., 1997, Urinary proton magnetic resonance studies of early ifosfamide-induced nephrotoxicity and encephalopathy, CLINICAL CANCER RESEARCH, Vol: 3, Pages: 1507-1518, ISSN: 1078-0432

Journal article

Farrant RD, Cupid BC, Nicholson JK, Lindon JCet al., 1997, Investigation of the feasibility of directly-coupled HPLC-NMR with H-2 detection with application to the metabolism of N-dimethylformamide-d(7), JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 16, Pages: 1-5, ISSN: 0731-7085

Journal article

Humpfer E, Spraul M, Nicholls AW, Nicholson JK, Lindon JCet al., 1997, Direct observation of resolved intracellular and extracellular water signals in intact human red blood cells using H-1 MAS NMR spectroscopy, MAGNETIC RESONANCE IN MEDICINE, Vol: 38, Pages: 334-336, ISSN: 0740-3194

Journal article

Liu ML, Nicholson JK, Lindon JC, 1997, Analysis of drug-protein binding using nuclear magnetic resonance based molecular diffusion measurements, ANALYTICAL COMMUNICATIONS, Vol: 34, Pages: 225-228, ISSN: 1359-7337

Journal article

Moloney GP, Robertson AD, Martin GR, MacLennan S, Mathews N, Dodsworth S, Sang PY, Knight C, Glen Ret al., 1997, A novel series of 2,5-substituted tryptamine derivatives as vascular 5HT1B/1D receptor antagonists., J Med Chem, Vol: 40, Pages: 2347-2362, ISSN: 0022-2623

The design, synthesis, and activity of a novel series of 2,5-substituted tryptamine derivatives at vascular 5HT1B-like receptors is described. Several important auxiliary binding sites of the 5HT1B-like receptor have been proposed following various modifications to the 2-substituent and especially to the methylene- or ethylene-linked 5-side chain. Careful design of new molecules based on a proposed pharmacophoric model of the 5HT1B-like receptor has resulted in the discovery of ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(2, 5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylate (40), a highly potent, silent, competitive, and selective antagonist which shows affinity at the vascular 5HT1B-like receptors only. Changes to the size of the 2-ester substituent have a significant effect on affinity at the 5HT1B-like receptor and other receptors. Prudent placement of the carbonyl substituent in the heterocycle of the 5-side chain is crucial for good affinity and selectivity over the 5HT2A and other receptors. Several key structural and electronic features were identified which are crucial for producing antagonism within a tryptamine-based series. An electron deficient indole ring system appears essential in order to achieve antagonism, and this is achieved by the inclusion of electron-withdrawing groups at the 2-position of the indole ring. The molecule displacement within the receptor resulting from the inclusion of the bulky 2-substituents also enhances antagonism as this results in the removal of the pi electron density of the indole ring from the region of the receptor normally occupied by the indole ring of 5HT. There also appears to be a structural requirement on the side chain incorporating the protonatable nitrogen, and this is achieved by the inclusion of the bulky 2-ester group which neighbors the 3-ethylamine side chain.

Journal article

Holmes E, Foxall PJD, Spraul M, Farrant RD, Nicholson JK, Lindon JCet al., 1997, 750 MHz H-1 NMR spectroscopy characterisation of the complex metabolic pattern of urine from patients with inborn errors of metabolism: 2-hydroxyglutaric aciduria and maple syrup urine disease, JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 15, Pages: 1647-1659, ISSN: 0731-7085

Journal article

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