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At least 1,081 records · Page 60Linked to original sources
PubMed1997

Picogram determination of a novel dopamine D4 receptor antagonist in human plasma and urine by liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry.

A sensitive and specific assay for the determination of 3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]p yri dine (I, L-745,870), a potential antipsychotic agent, has been developed, utilizing high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS-MS) detection. The analyte and the internal standard (II, 3-[[4-(4-trifluoromethyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b] pyridine) were isolated from a basified biological matrix using liquid-liquid extraction with methyl-tert.-butyl ether. The organic extract was evaporated to dryness, the residue was reconstituted in a mobile phase and injected into the HPLC system. The chromatographic conditions used for the analysis were a Keystone Scientific C18 BDS 150 x 4.6 mm, 5 microns column with a mobile phase consisting of a 40:60 (v/v) mixture of acetonitrile and water containing 10 mM ammonium acetate and 0.1% formic acid pumped at a flow-rate of 1.2 ml/min, yielding retention times of 3.4 and 5.0 min for I and II, respectively. The MS-MS detection was performed on a PE Sciex API III Plus tandem mass spectrometer using a heated nebulizer interface. Multiple reaction monitoring using the parent-->product ion combinations of m/z 327-->131 and 361-->131 were utilized to quantitate I and II, respectively. The assays were validated in the concentration range of 0.1 to 100 and 0.5 to 500 ng/ml for plasma and urine, respectively. The precision of the assays, expressed as coefficients of variation were less than 10% over the entire concentration range, with adequate assay accuracy, sensitivity and specificity to determine the pharmacokinetics in human subjects following a single 1-mg dose.

Antipsychotic Agents↗
PubMed1997

Determination of a novel growth hormone secretagogue (MK-677) in human plasma at picogram levels by liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry.

A sensitive and specific method for the determination of N-[1(R)¿[1,2-dihydro-1-methylsulfonylspiro(3H-indole-3,4'-piper idin)-1'-yl]carbonyl¿-2-(phenylmethoxy)ethyl]-2-amino-2-meth ylpropanamide (MK-677, I), a growth hormone secretagogue, has been developed. The method is based on high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS-MS) detection. The analyte and internal standard (II) were isolated from the basified plasma using a liquid-liquid extraction with methyl-tert.-butyl ether (MTBE). The organic extract was evaporated to dryness, the residue was reconstituted in mobile phase and injected into the HPLC system. The MS-MS detection was performed on a PE Sciex API III Plus tandem mass spectrometer using a heated nebulizer interface. Multiple reaction monitoring of parent-->product ion combinations at m/z 529-->267 and 527-->267 was used to quantify I and II, respectively. The assay was validated in human plasma in the concentration range of 0.1 to 100 ng/ml, and the limit of quantification (LOQ) was 0.1 ng/ml. The precision of the assay, as expressed as coefficients of variation (C.V.,%) was less than 7% at all concentrations within the standard curve range, with adequate assay specificity and accuracy. The HPLC-MS-MS method provided sufficient sensitivity to completely map the pharmacokinetic time-course following a single 5-mg oral dose of I.

Chromatography, Liquid↗
PubMed1997

Low level determination of a novel 4-azasteroid and its carboxylic acid metabolite in human plasma and semen using high-performance liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry.

Compound I (4.7beta-dimethyl-4-azacholestan-3-one, MK-0386) is a potent 5alpha-reductase type 1 (5alphaR1) inhibitor. Sensitive (0.2 ng/ml), specific and separate assays have been developed and validated for the analysis of I and its carboxylic acid metabolite (II) in human semen and plasma based on high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS-MS) detection. After liquid-liquid extraction of the analytes from biological matrix, the extracts were chromatographed on a short (50 mm) analytical column during analysis of I, and on a longer (150 mm) column with a weaker mobile phase during the analysis of II. This additional chromatographic separation was required to separate II from a secondary metabolite present in post-dose plasma samples interfering with the quantification of II. The MS-MS detection was performed on a Sciex API III Plus tandem mass spectrometer using the heated nebulizer probe. Monitoring the parent-->product ion combinations of m/z 416-->114 and 404-->114, in the multiple reaction monitoring (MRM) mode, after chromatographic separation, allowed quantification of both analytes. The standard curve in plasma was linear in the concentration range of 0.2 to 200 ng/ml for both I and II with correlation coefficients greater than 0.99 and coefficients of variation of less than 15% for replicate (n=5) analysis at all concentrations within the standard curve range. For the semen assay the linear range for determination of I was from 0.2 to 50 ng/ml. These assays were applied to support a number of clinical studies with I and their validity and long-term performance was confirmed during analyses of clinical samples from these studies. The need for careful assessment of the specificity of MS-MS assays in post-dose biological fluid samples in the presence of metabolites was emphasized.

5-alpha Reductase Inhibitors↗
PubMed1997

Rapid and automated determination of the beta2-agonist reproterol in human plasma by atmospheric pressure chemical ionisation high-performance liquid chromatography-tandem mass spectrometry.

An on-line HPLC assay with tandem mass spectrometric detection for the fast and sensitive determination of reproterol in human plasma was developed, utilising a methylated structural analogue as the internal standard. Automated solid-phase extraction of diluted plasma samples, based on 250 microl plasma aliquots, at pH 6.5, allowed a reliable quantification of reproterol down to 400 pg/ml. Injection of 100 microl of plasma extracts onto a 30 mm x 4.6 mm reversed-phase guard column provided retention times ranging from 20 to 30 s for reproterol and the internal standard. The standard curves were linear from 0.2 to 200 ng/ml using weighted linear regression analysis (1/y2). The inter-assay and intra-assay accuracies were -0.9% and +3.2%, exhibiting a precision (C.V.) of +/- 11% and +/- 9.3%, respectively. Up to 100 unknowns may be analysed each 24 h per analyst.

Administration, Inhalation↗
PubMed1998

Determination of a novel selective inhibitor of type 1 5alpha-reductase in human plasma by liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry.

A sensitive and specific assay of human plasma for the determination of (5alpha,7beta,16beta)-16[(4-chlorophenyl)oxy]-4,7- dimethyl-4-aza-androstan-3-one (I), a selective inhibitor of human type 1 5alpha-reductase, has been developed. The method is based on high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS-MS) detection. The analyte (I) and internal standard, Proscar (II), were isolated from the basified biological matrix using a liquid-liquid extraction with methyl-tert.-butyl ether (MTBE). The organic extract was evaporated to dryness, the residue was reconstituted in mobile phase and injected into the HPLC system. The MS-MS detection was performed on a PE Sciex API III Plus tandem mass spectrometer using a heated nebulizer interface. Multiple reaction monitoring using the precursor-->product ion combinations of m/z 430-->114 and 373-->305 was used to quantify I and internal standard (II), respectively. The assay was validated in the concentration range of 0.5 to 500 ng/ml in human plasma. The precision of the assay, expressed as coefficient of variation (C.V.), was less than 7% over the entire concentration range, with adequate assay specificity and accuracy. The HPLC-MS-MS method provided sufficient sensitivity to completely map the 24 h pharmacokinetic time-course following a single 0.5 mg dose of I.

Azasteroids↗
PubMed1999

Determination of the enantiomers of omeprazole in blood plasma by normal-phase liquid chromatography and detection by atmospheric pressure ionization tandem mass spectrometry.

An enantioselective assay of omeprazole in blood plasma using normal-phase liquid chromatography on a Chiralpak AD column and detection by mass spectrometry is described. Omeprazole is extracted by a mixture of dichloromethane and hexane and, after evaporation, redissolution and injection, separated into its enantiomers on the chiral stationary phase. Detection is made by a triple quadrupole mass spectrometer, using deuterated analogues as internal standards. The method enables determination in plasma down to 10 nmol/l (LOQ) and shows excellent consistency suited for pharmacokinetic studies in man.

Anti-Ulcer Agents↗
PubMed2000

Validated method for the therapeutic drug monitoring of flunitrazepam in human serum using liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry with an ion trap detector.

An HPLC-MS-MS method for the quantitative analysis of flunitrazepam in human serum was established. The method features a very simple liquid-liquid extraction, the use of a standard 4-mm HPLC column, isocratic elution using a buffer-free solvent, short retention times in connection with good peak resolution and the sensitivity and selectivity of an ion trap MS-MS detector. The procedure enables unambiguous identification of analytes by their product ion spectra, as well as sensitive quantitation (limit of quantitation for flunitrazepam=0.5 ng/ml). This feature was used for the confirmation of HPLC-UV results for nitrazepam.

Anti-Anxiety Agents↗
PubMed1997

Low level determination of dorzolamide and its de-ethylated metabolite in human plasma by liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry.

A sensitive and specific method for the determination of dorzolamide (I) and its de-ethylated metabolite (II) in human plasma has been developed utilizing high pressure liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) detection. The analytes and internal standard (III) were isolated from the deproteinized pH 8.0 buffered plasma, using a liquid-liquid extraction with a mixture of ethyl acetate, toluene, and isopropanol. The analytes were then back extracted into 0.085% phosphoric acid (200 microliters) and after washing the acidic extract with hexane, the organic layer was discarded and a fraction (50 microliters) of the acid extract was injected into the LC/MS/MS system. The MS/MS detection was performed on a PE Sciex API III tandem mass spectrometer using a heated nebulizer interface. Multiple reaction monitoring of the parent-->product ion combinations of m/z 325-->199, 297-->199, and 397-->306 were used to quantify I, II, and III, respectively. The assay was validated in the concentration ranges of 0.5-100 and 2.5-100 ng ml-1 of plasma for I and II, respectively. The precision of the assays, expressed as coefficients of variation (C.V.%), were less than 10% over the entire concentration range, with adequate assay specificity and accuracy. The LC/MS/MS method provided a 10-fold increase in the sensitivity of I over the previously reported HPLC/UV method [1].

Antihypertensive Agents↗
PubMed1998

Clinical analysis of sampatrilat, a combined renal endopeptidase and angiotensin-converting enzyme inhibitor I: assay in plasma of human volunteers by atmospheric-pressure ionisation mass-spectrometry following derivatisation with BF3-methanol.

Sampatrilat is a dual inhibitor of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) under development for the treatment of hypertension and congestive heart failure. In order to support the early clinical development (with oral administration and an expected low bioavailability), a sensitive and selective assay was required. A method for plasma was developed and validated employing HPLC APCI MS-MS. The plasma samples were extracted on solid-phase extraction cartridges, derivatised with BF3-methanol, diluted, extracted again and then subjected to HPLC APCI-MS-MS. Derivatisation was necessary because the two carboxyl group in the molecule prevented efficient ionisation in the heated nebuliser source. The calibration range was from 0.5 to 20 ng ml(-1) and the lower limit of quantification was 0.5 ng ml(-1). Imprecision and inaccuracy were determined on three separate occasions at three concentrations (0.5, 5 and 20 ng ml[-1]) and shown to be lower than 10% in every case.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Determination of 2-chlorodeoxyadenosine (cladribine, 2-CdA) in human plasma by liquid chromatography-atmospheric pressure chemical ionization mass spectrometry.

A sensitive and specific assay based on combined liquid chromatography mass spectrometry (LCMS) has been developed and validated for the quantification of 2-chlorodeoxyadenosine (cladribine, 2-CdA) in human plasma. Sample preparation consisted of an extraction with ethyl acetate under basic conditions. The organic solvent was evaporated and the residue re-dissolved for analysis. The extracts were chromatographed on a base deactivated C-8 column interfaced via the heated nebulizer probe to a corona discharge chemical ionization source. The mass spectrometer was operated in the positive ion tandem mode. Typical retention times were 1.5 and 2.0 min for 2-CdA and a fluorinated analog internal standard (IS), respectively. The standard curve was linear from 0.1 to 20 ng ml-1 using a 1.0 ml sample volume. The resulting chromatograms produced sharp peaks for 2-CdA and the IS and showed no endogenous peaks from blank plasma. Peak area ratios of 2-CdA to IS were used for standard curve regression analysis. This assay procedure gave interday mean accuracy results for the standards and quality controls that were within 4.9% of target concentrations and interday precision results (RSDs) that were less than 5.3%.

Antineoplastic Agents↗
PubMed2003

Analysis of the effect of foreign gases in the production of hyperpolarized 129Xe gas on a simple system working under atmospheric pressure.

Experimental conditions that affect the degree of polarization of 129Xe gas were tested for a higher degree of polarization to facilitate a laboratory use of 129Xe NMR, primarily on the effect of addition of foreign gases. When He, N(2), or D(2) gas was added separately to pure Xe gas with natural isotope abundance, D(2) gas gave better results than the others in enhancing the degree of polarization in 129Xe atom. When these gases were added in mixture, however, N(2) plus He was proved to be more efficient than D(2) or He in enhancing the degree of polarization. As a result, the degree of polarization was found to be increased by more than an order, when diluent gases were properly mixed; polarization as high as 35% was reached at gas composition of 5% Xe, 10% N(2), and 85% He, whereas only a few percent was attainable when Xe gas was polarized without mixing any foreign gases [J. Magn. Reson. 150 (2), 156-160 (2001)]. These results were discussed on a basis of quenching and buffer effects of foreign gases. Polarization was also measured after separating the pure Xe gas from the mixture; value of 22% was obtained for the Xe gas isolated after solidification in liquid nitrogen trap. Build-up time of the polarization was also tested, which did not change remarkably depending on the gas composition.

Journal Article↗
PubMed2000

Improved ion transmission from atmospheric pressure to high vacuum using a multicapillary inlet and electrodynamic ion funnel interface

A heated multicapillary inlet and ion funnel interface was developed to couple an electrospray ionization (ESI) source to a high-vacuum stage for obtaining improved sensitivity in mass spectrometric applications. The inlet was constructed from an array of seven thin-wall stainless steel tubes soldered into a central hole of a cylindrical heating block. An electrodynamic ion funnel was used in the interface region to more effectively capture, focus, and transmit ions from the multicapillary inlet. The interface of seven capillary inlets with the ion funnel showed more than 7 times higher transmission efficiency compared to that of a single capillary inlet with the ion funnel and a 23-fold greater transmission efficiency than could be obtained using the standard orifice-skimmer interface of a triple-quadrupole MS. The multiple-capillary inlet and ion funnel interface showed an overall 10% ion transmission efficiency and approximately 3-4% overall detection efficiency of ions from solution based (i.e., prior to electrospray). The improved performance was achieved under conditions where ESI operation is robust and results in a significant increase in dynamic range.

Journal Article↗
PubMed2001

A multicapillary inlet jet disruption electrodynamic ion funnel interface for improved sensitivity using atmospheric pressure ion sources.

A new multicapillary inlet and ion funnel interface for electrospray ionization-mass spectrometry has been developed and demonstrated to achieve higher ion transmission efficiency compared to a single-capillary inlet and ion funnel interface. Even though the distance between the end of the ESI inlet capillary and the exit of the ion funnel (10 cm) is significantly longer than that of the conventional interface (typically a few millimeters), a significant part of the directed inlet gas flow persists into the first stage of pumping and results in an increased gas load to the second chamber. A jet disrupter made of a circular metal disk placed on axis in the ion funnel enhanced the dispersion of the directed gas flow from a multicapillary inlet and was also found to improve the ion transmission. The ion funnel with the jet disrupter demonstrated a 15% improvement in ion transmission (compared to that without the jet disrupter) and simultaneously reduced the pumping speed required for the first or second stage by a factor of 2-3. Compared to the sensitivity with the standard mass spectrometer interface (an API 3000, Sciex, Concord, ON, Canada) in MS/MS operation using an interface equipped with the jet disrupter and ion funnel, a 5.3-10.7-fold enhancement in signal was observed for samples with concentrations of 100-500 pg/microL and 10.2 to 14.1-fold enhancement for concentrations of 10 to 50 pg/microL. The decreased enhancement at higher concentrations is attributed to space charge effects and detector saturation.

Air Pressure↗
PubMed2003

LC-atmospheric pressure chemical ionization-MS/ MS analysis of multiple illicit drugs, methadone, and their metabolites in oral fluid following protein precipitation.

A quantitative LC-APCI-MS/MS method for simultaneous determination of multiple illicit drugs, methadone, and their metabolites in oral fluid was developed and validated. Sample pretreatment was limited to acetonitrile protein precipitation. LC separation was performed in 25.5 min, with a total analysis time of 35 min. Identification and quantitation were based on selected reaction monitoring. Calibration by linear regression analysis utilized deuterated internal standards and a weighing factor 1/x. Limits of detection and lower limits of quantitation (LOQ) were established between 0.25 and 5 ng/ mL and 0.5-10 ng/mL, respectively. linearity was obtained with an average correlation coefficient (R2) of >0.99, over a dynamic range from the LOQ up to maximum 500 ng/mL The method demonstrated good accuracy, intra- and interbatch precision, recovery, and stability for all compounds. No oral fluid matrix effect was observed throughout the chromatographic run. Protein precipitation provided a fast and simple sample pretreatment, while LC-APCI-MS/MS proved to be a sensitive and rugged quantitative method for multiple illicit and legal drugs in oral fluid. The method proved to be suitable for the evaluation of oral fluid as an alternative matrix to urine for monitoring illicit drug use and for determining oral fluid methadone concentrations in pregnant opiate and/or cocaine addicts.

Humans↗
PubMed2003

Effect of moisture on the field dependence of mobility for gas-phase ions of organophosphorus compounds at atmospheric pressure with field asymmetric ion mobility spectrometry.

The electric field dependence of the mobilities of gas-phase protonated monomers [(MH+(H2O)n] and proton-bound dimers [M2H+(H2O)n] of organophosphorus compounds was determined at E/N values between 0 and 140 Td at ambient pressure in air with moisture between 0.1 and 15 000 ppm. Field dependence was described as alpha (E/N) and was obtained from the measurements of compensation voltage versus field amplitude in a planar high-field asymmetric waveform ion mobility spectrometer. The alpha function for protonated monomers to 140 Td was constant from 0.1 to 10 ppm moisture in air with onset of effect at approximately 50 ppm. The value of alpha increased 2-fold from 100 to 1000 ppm at all E/N values. At moisture values between 1000 and 10 000 ppm, a 2-fold or more increase in alpha (E/N) was observed. In a model proposed here, field dependence for mobility through changes in collision cross sections is governed by the degree of solvation of the protonated molecule by neutral molecules. The process of ion declustering at high E/N values was consistent with the kinetics of ion-neutral collisional periods, and the duty cycle of the waveform applied to the drift tube. Water was the principal neutral above 50 ppm moisture in air, and nitrogen was proposed as the principal neutral below 50 ppm.

Chemical Phenomena↗
PubMed2002

Practical Os/Cu-cocatalyzed air oxidation of allyl and benzyl alcohols at room temperature and atmospheric pressure.

[reaction: see text] A new protocol for the oxidation of primary and secondary allyl and benzyl alcohols at room temperature and using 1 atm of air is described. The procedure uses low loadings of copper salts and osmium tetroxide, which is activated with quinuclidine and prereduced with an alkene. Chemoselectivity for allyl and benzyl alcohols is very high, no overoxidation is observed, and the reaction takes place under neutral conditions.

Journal Article↗