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At least 343 records · Page 19Linked to original sources
PubMed2006

Proteomic analysis by multidimensional protein identification technology.

Multidimensional chromatography coupled to mass spectrometry is an emerging technique for the analysis of complex protein mixtures. One approach in this general category, multidimensional protein identification technology (MudPIT), couples biphasic or triphasic microcapillary columns to high-performance liquid chromatography, tandem mass spectrometry, and database searching. The integration of each of these components is critical to the implementation of MudPIT in a laboratory. MudPIT can be used for the analysis of complex peptide mixtures generated from biofluids, tissues, cells, organelles, or protein complexes. The information described in this chapter will provide researchers with details for sample preparation, column assembly, and chromatography parameters for complex peptide mixture analysis.

Animals↗
PubMed2001

Anatomical-physiological approaches in pharmacokinetics and pharmacodynamics.

Use of an anatomical-physiological approach allows an investigator an alternative to regarding the whole body as a 'black box' producing biofluid specimens for drug assay, and then blindly applying a formula-driven mathematical approach to determine the pharmacokinetics and pharmacodynamics of the drug of interest. Instead, it means the investigator can consider that the body is the sum of interacting parts or regions connected anatomically by blood flow carrying the drug of interest, that the regions as well as the carrier blood are not homogeneous because each has a physiological role, and that the parts or regions are connected neurally and humorally so that the response in any region or part of the system may be modified by and/or modulate effects at another region or part. Such an approach is difficult to institute experimentally because a complicated (and often expensive) preparation is usually required in animal studies, and is rarely possible in research with humans because of ethical constraints. Despite these restrictions, there are many examples of the use of an anatomical-physiological approach allowing greater insight into pharmacological problems than would have been possible with a conventional 'whole body' approach alone. This paper takes a number of examples from the discipline of anaesthesia and pain management and groups them to illustrate the principles of the approach regarding drug arterio-venous equality and tissue distribution, multiple sites of clearance and multiple sites of action.

Analgesics, Opioid↗
PubMed2006

Important contributions of a new quantitative preparative native continuous polyacrylamide gel electrophoresis (QPNC-PAGE) procedure for elucidating metal cofactor metabolisms in protein-misfolding diseases--a theory.

The quantitative analysis of metallochaperone proteins in biofluids (e.g. blood, liquor) may be a major prerequisite for clinical investigations concerning the structure-function relationships of biologically-active metal cofactor-containing chaperones in protein-misfolding diseases (e.g. Alzheimer's or related diseases). For these purposes, a new state-of-the-art gel electrophoresis [quantitative preparative native continuous polyacrylamide gel electrophoresis procedure (QPNC-PAGE)] combined with biological mass and NMR spectrometries might essentially contribute to provide fundamental insights into the metabolisms of important metal cofactors in biological systems and the proper folding of metallochaperones in conformational diseases.

Alzheimer Disease↗
PubMed2002

In vivo toxicity screening programs using metabonomics.

Metabonomics is an emerging technology that enables rapid in vivo screening for toxicity, disease state, or drug efficacy. The technology combines the power of high-resolution nuclear magnetic resonance (NMR) techniques with statistical data analysis methods to rapidly evaluate the metabolic "status" of an animal. Complimentary to other profiling technologies like proteomics and genomics, metabonomics provides a fingerprint of the small-molecules contained in a given biofluid through the time course of a study. This article reviews the steps in implementing a metabonomics-based screening program from study design through data analysis. While metabonomics is still a relatively new technology in comparison to the other "omics", published results from metabonomics studies demonstrate its potential impact in the drug discovery process by enabling the incorporation of safety endpoints much earlier in the drug discovery process, reducing the likelihood (and cost) of later stage attrition.

Algorithms↗
PubMed2000

Fluorine nuclear magnetic resonance, a privileged tool for metabolic studies of fluoropyrimidine drugs.

Fluorine-19 nuclear magnetic resonance (19F NMR) spectroscopy provides a highly specific tool for identifying fluorine-containing drugs and their metabolites in biological media. This article focuses on the application of 19F NMR to the metabolic studies of fluoropyrimidine drugs in clinical use. The value and difficulties encountered in investigations on drug metabolism are first discussed. The metabolism and disposition studies of the anticancer drug 5-fluorouracil, the mainstay of antimetabolite treatment for solid tumors, and its prodrugs, doxifluridine and capecitabine, are then extensively reviewed. The studies dealing with the antimycotic agent, 5-fluorocytosine, as well as the novel anticancer drug, gemcitabine, are also considered. From in vitro (biofluids or tissue extracts) 19F NMR analysis, seven new metabolites of 5-fluorouracil, doxifluridine, capecitabine and 5-fluorocytosine were identified. Except two, they were only detected using this technique. This emphasizes the high analytical potential of in vitro 19F NMR. In vivo 19F NMR is non-invasive and thus allows the quantitative monitoring of the metabolism of 5-fluorouracil in the target tissue, e.g. the tumor, as well as its biodistribution. Another promising application is its ability to estimate the level of yeast cytosine deaminase gene expression in human tumors from the quantitative monitoring of 5-fluorouracil formation from the non-cytotoxic drug 5-fluorocytosine. Notwithstanding these successes, the limited sensitivity and spectral resolution of 19F NMR precludes its extensive applicability to all the fluorinated drugs.

Animals↗
PubMed2005

The Consortium for Metabonomic Toxicology (COMET): aims, activities and achievements.

The utility of metabonomics in the evaluation of xenobiotic toxicity has been comprehensively assessed by the Consortium for Metabonomic Toxicology (COMET), formed between five major pharmaceutical companies and Imperial College London, UK. The main objectives were to assess methodologies, to generate a metabonomic database using (1)H nuclear magnetic resonance (NMR) spectroscopy of rodent urine and blood serum and to build a predictive expert system for target organ toxicity. The analytic and biologic variation that might arise through the use of metabonomics was evaluated and a high degree of robustness demonstrated. With the completion of 147 studies, the chief deliverables of a curated database of rodent biofluid NMR spectra and computer-based expert systems for the prediction of kidney or liver toxicity in rat and mouse based on the spectral data have been generated, and delivered to the sponsoring companies. The project, with its relatively modest resources, has met and exceeded all of its targets and was judged a resounding success by the sponsoring companies who are, in many cases, already enhancing and making use of the data in their in-house studies.

Animals↗
PubMed1989

The application of nuclear magnetic resonance spectroscopy to drug metabolism studies.

1. The applications of n.m.r. spectroscopy studies to drug metabolism, both in vitro (biofluids, isolated cells, excised tissue samples, isolated organs) and in vivo (animals, humans) are reviewed. 2. N.m.r. is a relatively insensitive technique, but it has the great advantage of being non-invasive and non-destructive, i.e. it allows a direct study of intact biological samples. 3. The majority of studies examined deal with 19F-n.m.r. spectroscopy mainly because of the favourable n.m.r. characteristics of this nucleus, and the low level of endogenous fluorine which gives no detectable 19F signal. However, the potential utility of 1H-31P- and 13C-n.m.r. is also emphasized.

Animals↗
PubMed1992

PVC as a biomedical polymer--plasticizer and stabilizer toxicity.

During the last 40 years PVC has become the most widely studied and understood polymeric biomaterial. The success of PVC compounds is due to their ability to fulfill the complex needs of the medical device industry. The range of properties they possess, which includes flexibility and low toxicity, is achieved by their various formulations. Plasticizers are used to meet many of the requirements and because of their ability to be extracted into biofluids they present the greatest toxicological risk. In his discussion, the author looks at the ingredients of compound formulations and the influence of plasticizers on the toxicity. A detailed report is provided of studies carried out in connection with di(2-ethylhexyl)phthalate (DEHP), the most extensively used plasticizer, and the author questions the validity of using the results of animal tests for the assessment of risk to humans. A description of the commercial production of PVC polymers and a review of the various pharmocopoeia and national standards and requirements are also included.

Equipment Design↗
PubMedDate not supplied

[Speciation of bioactive Al(III) and VO(IV) complexes in biological systems].

The speciation of the toxic Al(III) and the beneficial VO(IV) in various biofluids and tissues is discussed in order to describe the solution state of these metal ions in the organism. The possibility and the importance of ternary complex formation with relevant biomolecules is emphasised. The importance of the biospeciation of Al(III) ion in its transport and involvement in neurological disorders, and of insulin mimetic VO(IV) complexes is discussed.

Aluminum↗
PubMed2002

Metabonomic assessment of toxicity of 4-fluoroaniline, 3,5-difluoroaniline and 2-fluoro-4-methylaniline to the earthworm Eisenia veneta (Rosa): identification of new endogenous biomarkers.

High-resolution 1H nuclear magnetic resonance (NMR) spectroscopy can be used to produce a biochemical fingerprint of low-molecular-weight metabolites from complex biological mixtures such as tissue extracts and biofluids. Changes in such fingerprint profiles can be used to characterize the effects of toxic insult in in vivo systems. The technique is nonselective and requires little sample preparation or derivatization. In the present study, earthworms (Eisenia veneta) were exposed to three different model xenobiotics by a standard filter paper contact test, and toxicant-induced biochemical changes were then investigated by characterizing the changes in endogenous metabolites visible in 600-MHz 1H NMR spectra of tissue extracts. The NMR spectral intensities were converted to discrete numerical values and tabulated in order to provide data matrices suitable for multivariate analysis. Principal component analysis showed that changes had occurred in the biochemical profiles relative to the undosed controls. The 2-fluoro-4-methylaniline-treated worms showed a decrease in a resonance from a compound identified as 2-hexyl-5-ethyl-3-furansulfonate using a combination of high-performance liquid chromatography (HPLC)-Fourier transform mass spectrometry (IonSpec, Lake Forest, CA, USA) and 1H and 13C NMR spectroscopy. An increase in inosine monophosphate was also observed. The 4-fluoroaniline-treated worms showed a decrease in maltose concentrations, and 3,5-difluoroaniline exerted the same effect as 2-fluoro-4-methylaniline but to a lesser extent. These changes could potentially be used as novel biomarkers of xenobiotic toxicity and could be used to determine the mechanism of action of other toxic chemicals.

Aniline Compounds↗
PubMed2002

Effect of dexamethasone on the metabonomics profile associated with phosphodiesterase inhibitor-induced vascular lesions in rats.

Metabonomics is the evaluation of the multiparametric metabolic response of biological systems to pathophysiological stimuli. High-resolution nuclear magnetic resonance (NMR) spectroscopy of biofluids coupled with pattern recognition-based chemometric analysis is an emerging approach to the study of metabonomics and may be used for the prediction of toxicity in vivo and for identification of surrogate markers of toxicity. Previously, we established that metabonomic analysis of urine samples has significant potential for identification of phosphodiesterase type 4 (PDE-4) inhibitor-induced vascular lesions in rats. It was not clear, however, whether the observed changes in metabonomics profile were related mechanistically to the pathogenesis of these vascular lesions or whether these changes were reflective primarily of the ensuing inflammatory response. In the present study, dexamethasone was used to suppress inflammation associated with vascular lesions induced in rats by the PDE-4 inhibitor CI-1018 and urine samples were evaluated for resultant changes in metabonomic profile. Female Wistar rats were given CI-1018 by gavage at 750 mg/kg with or without concurrent intraperitoneal administration of dexamethasone at 1 mg/kg for 4 days. Dexamethasone induced a characteristic lymphoid depletion and lymphocytolysis but no evidence of vascular lesions. Rats dosed with CI-1018 had mild vascular changes in liver and/or marked vascular lesions in mesentery characterized by medial necrosis, hemorrhage, and/or edema accompanied by perivascular mixed inflammatory cell infiltrates. Inflammatory infiltrates associated with these lesions were eliminated in rats given dexamethasone, yet minimal medial smooth muscle necrosis and degeneration still occurred, suggestive of etiologic changes rather than effects secondary to the inflammatory response. Principle component analysis of urine NMR spectra produced a clear pattern separation within 48 to 72 h between CI-1018-treated rats with vascular lesions and vehicle controls or rats given dexamethasone alone. There was no pattern separation, however, between rats given CI-1018 alone and rats given CI-1018 and dexamethasone concurrently, suggesting that CI-1018-induced urine spectral changes were associated with the vascular lesions, yet were independent of the inflammatory response. These findings provide new insight into the mechanism(s) of PDE inhibitor-induced vasculitis and support the potential use of metabonomics for developing reliable noninvasive methods for detecting vascular changes in rats.

Animals↗
PubMed1991

[Study of biological fluids by nuclear magnetic resonance spectroscopy].

The use of nuclear magnetic resonance (NMR) spectroscopy in the study of biofluids is rapidly developing and might soon constitute a new major medical application of this technique which benefits from technological and methodological progress such as higher magnetic fields, new probe design, solvent suppression sequences and advanced data processing routines. In this overview, the clinical and pharmacological impact of this new approach is examined, with emphasis on the NMR spectroscopy of plasma, cerebrospinal fluid and urine. Applications to pharmacokinetics and toxicology are illustrated. Interestingly, a number of biochemical components of fluids which are not usually assayed by conventional biochemical methods are readily detected by NMR spectroscopy which is clearly a new competitive entrant among the techniques used in clinical biology. Its ease-of-use, cost effectiveness and high informational content might turn it into a major diagnostic tool in the years to come.

Acute Kidney Injury↗
PubMed1990

[Fluorine-19 nuclear magnetic resonance spectroscopy: a privileged tool for the study of the metabolism and pharmacokinetics of fluoropyrimidines].

This review reports on the various studies using fluorine-19 nuclear magnetic resonance spectroscopy (19F NMR) to study the metabolism of antineoplastic or antifungal fluoropyrimidines. It is divided into 2 parts: the first examines ex vivo studies, ie, of biofluids or excised tissue samples from patients. In vivo studies, ie where the biotransformation of the drug is followed by non-invasively both in animals and in humans, are described in the second part. For ex vivo studies, 19F NMR can already be considered as complementary to the classical analytical methodologies used for drug metabolism studies. In vivo 19F NMR spectroscopic studies, especially in humans, are still at an early stage of development. Several improvements, both methodological (development of volume-selective localization techniques and quantification methods) and clinical (more rigorous definition of pathologies under study and administered treatments), are a prerequisite for useful clinical application.

Antifungal Agents↗
PubMedDate not supplied

Toxic environmental chemicals in human semen: analytical method and case studies.

In 1982, 89 men from all over the FRG participated in an investigation of sperm density and the presence of selected persistent environmental chemicals in their semen. Semen concentrations for the following chemicals were measured: lead, cadmium, hexachlorobenzene (HCBC), a-hexachlorocyclohexane (a-BHC), DDT and metabolites, dieldrin and polychlorobiphenyls (PBC). Heavy metal analyses were performed by Zeeman-AAS with direct sample measurement. A method for the quantitative determination of chlorinated hydrocarbons in semen by liquid-liquid extraction, clean-up and quantitation by gas chromatography with an electron capture detector. Recovery rates ranged from 72 to 120%. Compound identification in samples was confirmed by negative chemical ionization mass spectrometry. Heavy metals and organochlorine compounds in semen were present in the same concentration range as in blood or other biofluids. Occupational exposure as well as extraordinary environmental exposure appeared to influence semen concentrations. Students in chemistry showed elevated levels of organochlorine compounds. Men who lived in the vicinity of an atmospheric source of heavy metals showed strikingly the vicinity of an atmospheric source of heavy metals showed strikingly elevated levels of semen lead and cadmium. We were unable to find a statistically significant correlation between sperm density and any of the variables examined in this study including: orgonochlorine compounds summed or individually; lead and/or cadmium; and tobacco consumption. Significant correlations were found between the simultaneous occurrence of lead and cadmium and between the simultaneous occurrence of HCB, DDT and DDE.

Adult↗
PubMed1986

Evidence for the importance of 5'-deoxy-5-fluorouridine catabolism in humans from 19F nuclear magnetic resonance spectrometry.

The use of a new methodology, 19F nuclear magnetic resonance, has allowed detection of all the fluorinated metabolites in the biofluids of patients treated with 5'-deoxy-5-fluorouridine (5'-dFUrd) injected i.v. at a dose of 10 g/m2 over 6 h. This technique, which requires no labeled drug, allows a direct study of the biological sample with no need for extraction or derivatization and a simultaneous identification and quantitation of all the different fluorinated metabolites. As well as the already known metabolites, unmetabolized 5'-dFUrd, 5-fluorouracil, and 5,6-dihydro-5-fluorouracil, the presence of alpha-fluoro-beta-ureidopropionic acid, alpha-fluoro-beta-alanine (FBAL), N-carboxy-alpha-fluoro-beta-alanine, and the fluoride anion F- is reported. The catabolic pathway proposed for 5'-dFUrd is analogous to that of 5-fluorouracil, completed with FBAL----F- step, and the plasmatic equilibrium of FBAL with N-carboxy-alpha-fluoro-beta-alanine, its N-carboxy derivative. The quantitative analysis of the different metabolites found in plasma and urine emphasizes the significance of the catabolic pathway. High concentrations of alpha-fluoro-beta ureidopropionic acid and FBAL are recovered in plasma from 3 h after the beginning of the perfusion to 1 h after its end. The global urinary excretion results show that there is a high excretion of 5'-dFUrd and metabolites. Unchanged 5'-dFUrd and FBAL are by far the major excretory products and are at nearly equal rates. The protocol followed in this study produces relatively low but persistent plasmatic concentrations of 5-fluorouracil throughout the perfusion.

Aged↗
PubMed1986

Transport phenomena in pulsating post-stenotic vortex flow in arteries. An interactive concept of fluid-dynamic, haemorheological and biochemical processes in white thrombus formation.

Blood in its native state is a highly "non-Newtonian" or anomalous fluid; this notwithstanding, in its native state, all cellular and plasmatic components remain in isolation and do not interact with each other or with the endothelial cells. The rheological behaviour of flowing blood, and that of blood components during the formation of thrombi, coagulate and thrombotic deposits, can be using a three-step procedure. The present paper deals with these, by delineating: the flow conditions under which flow occurs in various vessels, in stenoses, bifurcations under the influence of variable haemodynamic and geometric conditions; the so-called "flow properties" of blood components such as apparent viscosity, behaviour in shear, their behaviour in non-laminar flow, i.e. that occurring near and at sites of secondary flow. As a subsequent step, it is necessary to design appropriate test devices to assay the rheological behaviour in vitro of blood components under closely controlled fluid-dynamic, physico-chemical and biochemical conditions. The present review outlines the characteristic details of microflow in secondary flow (short-lived vortices) such as they prevail in pulsatile flow in arterial segments with "non-cylindrical configuration". In honour of the late Alexander Naumann, one of the founders of contemporary biofluid dynamics in Germany, the characteristic and functionally inseparable fluid-mechanical and rheological peculiarities of flow in eddies or vortices are termed Alexander Naumann vortex flow. They consist of a combination of high shear, recirculation and stagnation point flow. The micro-rheological, cytological and biochemical behaviour of blood platelets in such vortices is described, the integral effects of which render to the vortex the characteristics of a short-lived flow reactor for rapid pro-coagulatory processes and deposition of activated blood components onto the vessel wall.

Arterial Occlusive Diseases↗
PubMed1978

Time--concentration studies by high-performance liquid chromatography of metabolites removed during hemodialysis.

Reversed-phase high-performance liquid chromatography was used to study the efficiency of hemodialysis. The method, previously used to study uremic hemodialysate, was also found useful for analyzing other uremic biofluids, such as serum and urine. Samples of blood (centrifuged to obtain cell-free serum) and hemodialysate were simultaneously collected from selected patients at regular intervals during the entire 6-hour hemodialysis treatment. These samples were filtered through membranes to remove particulates and proteins and were then analyzed by use of a 60-cm muBondapak-C18 column, an aqueous sodium acetate/methanol gradient, and detection at 254 nm. The identification of components in the eluate was based on retention times, ultraviolet absorption spectra, and mass spectra. From the amounts of several metabolites in the various physiological fluid pools during hemodialysis, we concluded that they mostly originate from tissue fluids. We also observed that the concentrations of most components in serum and hemodialysate fluctuated regularly with time.

Chromatography, High Pressure Liquid↗
PubMed1983

New techniques for detecting tumor markers: a prospective.

The search continues for biomarkers in body fluids that can identify the presence of otherwise undetectable tumors. Presently tumor biomarkers can be useful in monitoring neoplastic disease during and after therapy, although their role in early diagnosis is less certain. The value of each tumor biomarker in each clinical situation can be estimated by its concentration in biofluids, the sensitivity of the detection techniques, and the specificity of its in vivo and in vitro activities. A wide range of new multidisciplinary biotechnologies applied to tumor biomarkers promises additional and improved assays for highly sensitive and specific detections of human neoplasia. These new assays will have the potential for making accurate estimations of initial tumor burden, micrometastasis, and residual and occult tumor cells remaining after surgery.

Breast Neoplasms↗