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Urinary Metabolites (urinary + metabolite)
Selected AbstractsSynthesis and Characterization of Hydroxylated Mesocarb Metabolites for Doping ControlARCHIV DER PHARMAZIE, Issue 4 2009Mikko Vahermo Abstract The synthesis and method of analysis of hydroxylated mesocarb metabolites are described. Six potential hydroxylated mesocarb metabolites were prepared, characterized, and compared with the mesocarb metabolites synthesized enzymatically in vitro using human liver proteins and also compared with metabolites extracted from human urine after oral administration of mesocarb. p -Hydroxymesocarb was the most prevalent metabolite (conjugated and non-conjugated) observed. With respect to doping analysis, synthesis of p -hydroxymesocarb, the main urinary metabolite of mesocarb, and its availability as a reference material is important. [source] Aldosterone synthase gene variation and adrenocortical response to sodium status, angiotensin II and ACTH in normal male subjectsCLINICAL ENDOCRINOLOGY, Issue 2 2004Brian Kennon Summary objective, Aldosterone synthase, a key enzyme in the terminal steps of aldosterone synthesis, is encoded by the CYP11B2 gene. A polymorphism in the 5, coding region of this gene (,344 C/T) is associated with hypertension, particularly with elevation of the aldosterone to renin ratio. A second polymorphism (a conversion in intron 2 to resemble that of the neighbouring 11,-hydroxylase (CYP11B1) gene) is found in close linkage dysequilibrium with the variant at ,344 C/T. The mechanism by which these variants predispose to cardiovascular disease and the precise intermediate phenotype associated with them remains speculative. design, We performed a focused physiological study in normal volunteers stratified by CYP11B2 genotype. patients, Twenty-three subjects homozygous for the T allele and 21 homozygous for the C allele of the ,344 C/T polymorphism of CYP11B2 were studied. measurements, Basal and angiotensin II stimulated plasma and 24-h urinary steroid excretion during low (60 mmol/day) and high (160 mmol/day) sodium intake and plasma steroids after ACTH stimulation were measured. results, No influence of polymorphic variation on basal or stimulated plasma cortisol or aldosterone or other plasma steroid concentrations during either dietary phase was seen. However, excretion of tetrahydro-11-deoxycortisol (the urinary metabolite of 11-deoxycortisol), which is the precursor of cortisol) was increased in TT subjects during sodium restriction, consistent with impairment of zona fasciculata 11,-hydroxylation. conclusions, We conclude that this polymorphism has no major influence on normal zona glomerulosa function but is associated with a change in 11,-hydroxylation in the zona fasciculata. The mechanism remains uncertain, but alteration of 11-deoxycortisol levels without change in cortisol suggests altered efficiency of 11,-hydroxylation. In the long term, this may lead to a minor but chronic increase in ACTH drive to the gland, which may have consequences for steroid synthesis and predispose to the risk of cardiovascular disease. [source] Evaluation of CE methods for global metabolic profiling of urineELECTROPHORESIS, Issue 14 2010Rawi Ramautar Abstract In this study, the usefulness of noncovalently coated capillaries with layers of charged polymers is investigated to obtain global electrophoretic profiles of urinary metabolites covering a broad range of different compound classes in a highly repeatable way. Capillaries were coated with a bilayer of polybrene (PB) and poly(vinyl sulfonate) (PVS), or with a triple layer of PB, dextran sulfate (DS) and PB. The bilayer and triple layer coatings were evaluated at acidic (pH 2.0) and alkaline (pH 9.0) separation conditions, thereby providing separation conditions for basic and acidic compounds. A representative metabolite mixture and spiked urine samples were used for the evaluation of the four CE methods. Migration time repeatability (RSD<2%) and plate numbers (N, 100,000,400,000) were similar for the test compounds in all CE methods, except for some multivalent ions that may exhibit adsorption to oppositely charged coatings. The analysis of cationic compounds with the PB-DS-PB CE method at low pH (i.e. after the EOF time) provided a larger separation window and number of separated peaks in urine compared to the analysis with the PB-PVS CE method at low pH (i.e. before the EOF time). Approximately, 600 molecular features were detected in rat urine by the PB-DS-PB CE-MS method whereas about 300 features were found with the PB-PVS CE-MS method. This difference can be attributed to reduced comigration of compounds with the PB-DS-PB CE-MS method and a related decrease of ion suppression. With regard to the analysis of anionic compounds by CE-MS, in general analyte responses were significantly lower than that for cationic compounds, most probably due to less efficient ionization and to ion suppression effects caused by the background electrolyte. Hence, further optimization is required for the sensitive CE-MS analysis of anionic compounds in body fluids. It is concluded that the selection of a CE method for profiling of cationic metabolites in urine depends on the purpose of the study. For high-throughput analyses, the PB-PVS CE-MS method is favored whereas the PB-DS-PB CE-MS method provides a more information-rich metabolic profile, but at the cost of prolonged analysis time. [source] Analysis of urinary metabolites for metabolomic study by pressurized CECELECTROPHORESIS, Issue 23 2007Guoxiang Xie Abstract A new approach for the metabolomic study of urinary samples using pressurized CEC (pCEC) with gradient elution is proposed as an alternative chromatographic separation tool with higher degree of resolution, selectivity, sensitivity, and efficiency. The pCEC separation of urinary samples was performed on a RP column packed with C18, 5,,m particles with an ACN/water mobile phase containing TFA. The effects of the acid modifiers, applied voltage, mobile phase, and detection wavelength were systematically evaluated using eight spiked standards, as well as urine samples. A typical analytical trial of urine samples from Sprague Dawley (S.D.) rats exposed to high-energy diet was carried out following sample pretreatment. Significant differences in urinary metabolic profiles were observed between the high energy diet-induced obesity rats and the healthy control rats at the 6th,wk postdose. Multivariate statistical analysis revealed the differential metabolites in response to the diet, which were partially validated with the putative standards. This work suggests that such a pCEC-based separation and analysis method may provide a new and cost-effective platform for metabolomic study uniquely positioned between the conventional chromatographic tools such as HPLC, and hyphenated analytical techniques such as LC-MS. [source] Pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western subjectsEPILEPSIA, Issue 8 2009Peter Zannikos Summary Purpose:, To compare the pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western adults, and to comparatively assess carisbamate safety and tolerability between the two populations. Methods:, An open-label study was conducted in 24 Japanese and 24 Caucasian healthy subjects. Subjects received a single oral dose of 250 mg carisbamate on day 1 followed by a 3-day washout period; twice-daily dosing of 250 mg carisbamate on days 5,8; subsequently, 500 mg on days 9,12 and a single dose of 500 mg on day 13. Plasma samples were collected for a pharmacokinetic analysis on days 1, 8, and 13. Plasma and urine samples were analyzed for carisbamate and its urinary metabolites by liquid-chromatography-mass-spectrometry. Results:, Following a single dose, carisbamate Cmax and area under the curve (AUC) geometric mean ratios were 16.4% and 28.8% higher in Japanese than in Caucasians, respectively; these differences were statistically significant and their 90% confidence intervals (CIs) fell outside of the 80,125% limits, which are considered not to be of clinical significance. With dose,body weight normalization, Cmax and AUC were similar in Japanese and Caucasian subjects and the 90% CIs were within the 80,125% boundaries. Carisbamate was well tolerated, and its mean oral clearance and half-life were similar in both groups, ranging from 35.1,41.4 ml/h/kg and 11.5,12.8 h. Discussion:, Carisbamate plasma exposure (AUC) and Cmax in Japanese subjects is ,20,25% higher than in Caucasians due to a higher mg/kg dose. After body weight normalization, carisbamate pharmacokinetics was similar between Japanese and Caucasian subjects following single and multiple dosing, and showed the same dose proportionality. [source] Inhibitory effects of urinary metabolites on platelet aggregation after orally administering Shimotsu-To, a traditional Chinese medicine, to ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2003Takaaki Yasuda ABSTRACT Shimotsu-To, which consists of four herbal extracts, has been used clinically for improving abnormal blood coagulation, fibrinolysis, atherosclerosis and chronic inflammation in Japan and China. We have investigated the pharmacological relationship between the effects and chemical components of Shimotsu-To after oral administration to rats. The urinary constituents were separated and identified by three dimensional (3D-) HPLC equipped with a photodiode array detector as a new tool and the chemical structures were determined by spectroscopic methods to be trans -ferulic acid-3- O -sulfate (1), vanillic acid (2), m -hydroxyphenylpropionic acid (3), trans -ferulic acid (4) and cis -ferulic acid (5). Of these compounds, 2,5 strongly inhibited platelet aggregation induced by ADP and arachidonic acid. Compound 1, the sulfate conjugate of 4, did not show any inhibitory effect, which suggested that the inhibitory effect on platelet aggregation was inactivated by sulfate conjugation. These results indicated that compounds 2,5 partly contributed to the anti-Oketsu effect of Shimotsu-To through the inhibition of platelet aggregation. [source] Analysis of urinary biomarkers for exposure to alkyl benzenes by isotope dilution gas chromatography-mass spectrometryJOURNAL OF SEPARATION SCIENCE, JSS, Issue 18 2005Adriaan A. S. Marais Abstract A validated GC-MS method for the analysis of urinary metabolites of alkyl benzenes is reported. Metabolites for exposure to toluene, xylene and ethylbenzene were analyzed simultaneously using stable isotope substituted internal standards. The method entailed acidic deconjugation of urine samples followed by extractive alkylation with pentafluorobenzyl bromide as alkylating agent. The resulting pentafluorobenzyl derivatives of ortho -, meta -, para -cresol, mandelic acid (MA), hippuric acid (HA) and ortho -, meta -, para -methylhippuric acid (MHA) were then quantified by SIM. Optimized reaction conditions for the extractive alkylation step are reported. The derivatives were found to be sufficiently stable for overnight batch analysis. The LODs were below 0.1 ,mol/L for the cresols and below 1 ,mol/L for MA and the HAs. Within-batch precision for o -MHA was 7%, for m -MHA 5%, for p -MHA 5.2% and below 5% for the rest of the analytes. [source] Effect of recombinant porcine somatotropin (rpST) on drug disposition in swineJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2010J. C. KAWALEK Kawalek, J.C., Howard, K.D. Effect of recombinant porcine somatotropin (rpST) on drug disposition in swine. J. vet. Pharmacol. Therap.33, 69,75. Treatment of pigs with recombinant porcine somatotropin (rpST) causes a marked increase in feed utilization with increased weight-gain over untreated controls. Physiological parameters such as creatinine clearance were increased by rpST treatment. Clearance of drugs eliminated by hepatic extraction, like indocyanine green (ICG), were also increased by rpST treatment. However, clearance of intravenous (i.v.)-dosed propranolol (PPL) was not affected by rpST treatment and data from oral (p.o.) - dosing was inconclusive because of the low bioavailability, probably because of a high first-pass effect. The very low oral bioavailability indicates that intestinal metabolism of PPL is probably quite high. Analysis of urinary metabolites indicated production of the two phenolic isomers, but there was no metabolite corresponding to N-dealkylase activity; although the latter metabolite could have been eliminated in the bile with subsequent fecal elimination. PPL was an excellent in vitro substrate for measuring hepatic DME activity in vitro; two phenolic and one N-dealkylated metabolite were formed. The overall conclusions regarding this study must be that the effects of rpST on drug bioavailability and elimination were equivocal. As ICG and creatinine clearances were both increased significantly, one cannot rule out the probability that rpST would increase drug elimination in pigs as a result of increased hepatic uptake and/or renal clearance. One can only speculate that clearance of concurrently administered drugs would be increased. This would reduce residue levels, but it might also reduce efficacy. [source] Characterization of urinary metabolites of testosterone, methyltestosterone, mibolerone and boldenone in greyhound dogsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2000T. M. Williams Androgenic steroids are used in female greyhound dogs to prevent the onset of estrus; moreover, these steroids also have potent anabolic activity. As anabolic steroids increase muscle mass and aggression in animals, the excessive use of these agents in racing greyhounds gives an unfair performance advantage to treated dogs. The biotransformation of most anabolic steroids has not been determined in greyhound dogs. The objective of the present study was to identify the urinary metabolites of testosterone, methyltestosterone, mibolerone, and boldenone in greyhound dogs. These steroids were administered orally (1 mg/kg) to either male or female greyhound dogs and urine samples were collected pre-administration and at 2, 4, 8, 12, 24, 72, and 96 h post-administration. Urine extracts were analyzed by high-performance liquid chromatography/mass spectrometry (HPLC/MS) to identify major metabolites and to determine their urinary excretion profiles. Major urinary metabolites, primarily glucuronide, conjugated and free, were detected for the selected steroids. Sulfate conjugation did not appear to be a major pathway for steroid metabolism and excretion in the greyhound dog. Phase I biotransformation was also evaluated using greyhound dog liver microsomes from untreated dogs. The identification of several in vivo steroid metabolites generated in this study will be useful in detecting these steroids in urine samples submitted for drug screening. [source] In vitro biotransformation of anabolic steroids in caninesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2000Williams Forensic drug testing of anabolic steroids in racing animals is required because of the potential for steroid abuse. Often when the metabolic products of an administered compound have not been identified, the analysis and verification of the administered compound is difficult. The objective of this study was to qualitatively identify the in vitro phase I biotransformation products of anabolic steroids that have a high potential for abuse in canines. The investigated steroids included testosterone, methyltestosterone, mibolerone and boldenone. Steroid biotransformation products were generated using beagle liver microsomes and analysed by high performance liquid chromatography (HPLC)/mass spectrometry (MS) with an electrospray ionization source. Characterization of steroid metabolites was based on HPLC retention, UV and mass spectra. The major testosterone metabolites were identified as androstenedione and 6,- and 16,-hydroxytestosterone. 6,-Hydroxymethyltestosterone was identified as a major metabolite in the methyltestosterone microsomal incubations. Several mibolerone metabolites were identified as monohydroxylated mibolerones as well as an oxidized mibolerone metabolite. Boldenone metabolites were identified as monohydroxylated boldenones, oxidized boldenone, and testosterone. This information should assist in the determination of anabolic steroid use in canines through the correlation of the urinary metabolites to the administered drug. [source] Estimation of the day-specific probabilities of conception: current state of the knowledge and the relevance for epidemiological researchPAEDIATRIC & PERINATAL EPIDEMIOLOGY, Issue 2006Courtney D. Lynch Summary Conception, as defined by the fertilisation of an ovum by a sperm, marks the beginning of human development. Currently, a biomarker of conception is not available; as conception occurs shortly after ovulation, the latter can be used as a proxy for the time of conception. In the absence of serial ultrasound examinations, ovulation cannot be readily visualised leaving researchers to rely on proxy measures of ovulation that are subject to error. The most commonly used proxy measures include: charting basal body temperature, monitoring cervical mucus, and measuring urinary metabolites of oestradiol and luteinising hormone. Establishing the timing of the ovulation and the fertile window has practical utility in that it will assist couples in appropriately timing intercourse to achieve or avoid pregnancy. Identifying the likely day of conception is clinically relevant because it has the potential to facilitate more accurate pregnancy dating, thereby reducing the iatrogenic risks associated with uncertain gestation. Using data from prospective studies of couples attempting to conceive, several researchers have developed models for estimating the day-specific probabilities of conception. Elucidating these will allow researchers to more accurately estimate the day of conception, thus spawning research initiatives that will expand our current limited knowledge about the effect of exposures at critical periconceptional windows. While basal body temperature charting and cervical mucus monitoring have been used with success in field-based studies for many years, recent advances in science and technology have made it possible for women to get instant feedback regarding their daily fertility status by monitoring urinary metabolites of reproductive hormones in the privacy of their own homes. Not only are innovations such as luteinising hormone test kits and digital fertility monitors likely to increase study compliance and participation rates, they provide valuable prospective data that can be used in epidemiological research. Although we have made great strides in estimating the timing and length of the fertile window, more work is needed to elucidate the day-specific probabilities of conception using proxy measures of ovulation that are inherently subject to error. Modelling approaches that incorporate the use of multiple markers of ovulation offer great promise to fill these important data gaps. [source] Variation across the agricultural season in organophosphorus pesticide urinary metabolite levels for Latino farmworkers in eastern North Carolina: Project design and descriptive resultsAMERICAN JOURNAL OF INDUSTRIAL MEDICINE, Issue 7 2009Thomas A. Arcury PhD Abstract Background Community Participatory Approach to Measuring Farmworker Pesticide Exposure, PACE3, used a longitudinal design to document pesticide biomarkers among farmworkers. This article presents an overview of PACE3 and provides a descriptive analysis of participant characteristics and one set of pesticide biomarkers, the dialkylphosphate (DAP) urinary metabolites of organophosphorus (OP) pesticides. Methods Two hundred eighty seven farmworkers were recruited during 2007 from 44 farmworker camps in 11 eastern North Carolina counties. Participants provided interviews, urine samples, blood samples, and saliva samples up to four times at monthly intervals beginning in May. A total of 939 data points were collected. Results Farmworkers were largely men (91.3%) from Mexico (94.8%) with a mean age of 33.7 years (SE 0.82); 23.3% spoke an indigenous language. Across all data points, frequencies of detection and median urinary concentrations were 41.3% and 0.96,µg/L for dimethylphosphate (DMP), 78.3% and 3.61,µg/L for dimethylthiophosphate (DMTP), 33.3% and 0.04,µg/L for dimethyldithiophosphate (DMDTP), 40.5% and 0.87,µg/L for diethylphosphate (DEP), 32.3% and 0.17,µg/L for diethylthiophosphate (DETP), and 8.09% and 0.00,µg/L for diethyldithiophosphate (DEDTP). The frequencies of detection and urinary concentrations of the DAP metabolites increased during the season. Conclusions More PACE3 participants were from Mexico, male, migrant workers, and spoke an indigenous language compared to national data. PACE3 participants had comparable frequencies of detection and urinary metabolite concentrations with participants in other studies. Variability in the frequencies of detection and urinary concentrations of the DAP metabolites indicates the importance of longitudinal studies of biomarkers of currently used pesticides in farmworker populations. Am. J. Ind. Med. 52:539,550, 2009. © 2009 Wiley-Liss, Inc. [source] A gas chromatography/mass spectrometry method for the determination of sildenafil, vardenafil and tadalafil and their metabolites in human urineRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 11 2010Sabina Strano-Rossi Sildenafil (SDF), vardenafil (VDF) and tadalafil (TDF) are phosphodiesterase type 5 enzyme inhibitors (PDE5Is), used in the treatment of erectile disorders and to improve breathing efficiency in pulmonary hypertension. The increasing incidence of their use among young athletes has drawn the attention of the anti-doping authorities to the possible abuse of PDE5Is by athletes due to their pharmacological activities. This paper describes a method for the determination in urine of PDE5Is and their metabolites by gas chromatography/mass spectrometry (GC/MS) after liquid/liquid extraction of the analytes from urine and derivatisation to obtain trimethylsilyl derivatives. The metabolic profile was studied on real samples collected from subjects taking PDE5Is (Viagra®, Levitra® or Cialis®); the main urinary metabolites were identified and their MS fragmentation characterized. The sample pre-treatment and GC/MS conditions for the detection of the metabolites have been optimised. A method for their preliminary screening and subsequent confirmation is described that takes into account the general requirements of a routine doping analysis to be used for the screening of large numbers of samples. The main metabolites identified can be included in a general purpose screening method and all the metabolites in a more specific confirmation method. The method developed has been applied for the screening of PDE5Is in 5000 urine samples. Based on the obtained results, the proposed method appears to be of practical use in analytical and forensic toxicology, including doping analysis. Copyright © 2010 John Wiley & Sons, Ltd. [source] Development and validation of a gas chromatography/mass spectrometry metabonomic platform for the global profiling of urinary metabolitesRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 19 2008Kishore K. Pasikanti This paper presents a simple and reliable gas chromatography/mass spectrometry (GC/MS) method for the metabonomic analysis of human urine samples. The sample preparation involved the depletion of excess urea via treatment with urease and subsequent protein precipitation using ice-cold ethanol. An aliquot of the mixture was separated, dried, trimethylsilyl (TMS)-derivatized and 1.0,µL of the derivatized extract was injected into the GC/MS system via split injection (1:10). Approximately 150 putative metabolites belonging to different chemical classes were identified from the pooled human urine samples. All the identified metabolites were selected to evaluate precision and stability of the GC/MS assay. More than 95% of the metabolites demonstrated good reproducibility, with intra-day and inter-day precision values below 15%. Metabolic profiling of 53 healthy male and female urine samples in combination with pattern recognition techniques was performed to further validate the GC/MS metabolite profiling assay. Principal component analysis (PCA) followed by orthogonal partial least squares analysis (OPLS) revealed differences between urinary metabolite profiles of healthy male and female subjects. This validated GC/MS metabolic profiling method may be further applied to the metabonomic screening of urinary biomarkers in clinical studies. Copyright © 2008 John Wiley & Sons, Ltd. [source] Human urinary metabolite profile of tea polyphenols analyzed by liquid chromatography/electrospray ionization tandem mass spectrometry with data-dependent acquisitionRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 10 2008Shengmin Sang Tea is rich in polyphenols and has a variety of biological activities. In order to better understand the biological effects of tea constituents on human health, markers for their exposure and their metabolic fates are needed. Previously, we have characterized several catechin metabolites in the blood and urine, but more information on the metabolite profile of tea polyphenols is needed. In the present study, the human urinary metabolite profile of tea polyphenols was investigated using liquid chromatography/electrospray ionization tandem mass spectrometry with data-dependent acquisition. With data-dependent MS/MS analysis by collecting the MS2 and MS3 spectra of the most intense ions in the sample, we identified more than twenty metabolites of tea polyphenols from human urine samples. (,)-Epigallocatechin (EGC) glucuronide, methylated EGC glucuronide, methylated EGC sulfate, (,)-epicatechin (EC) glucruronide, EC sulfate, methylated EC sulfate, as well as the glucuronide and sulfate metabolites of the ring-fission metabolites of tea catechins, 5-(3,,4,,5,-trihydroxyphenyl)- , -valerolactone (M4), 5-(3,,4,-dihydroxyphenyl)- , -valerolactone (M6) and 5-(3,,5,-dihydroxyphenyl)- , -valerolactone (M6,), were the major human urinary metabolites of tea polyphenols. To our knowledge, this is the first report of the direct simultaneous analysis of the human urinary metabolite profile of tea polyphenols using single sample analysis. This method can also be used for thorough investigations of the metabolite profiles of many other dietary constituents. Copyright © 2008 John Wiley & Sons, Ltd. [source] Simultaneous determination of t,t -muconic, S -phenylmercapturic and S -benzylmercapturic acids in urine by a rapid and sensitive liquid chromatography/electrospray tandem mass spectrometry methodRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 17 2004Anna Barbieri We describe a rapid and sensitive high-performance liquid chromatography/electrospray tandem mass spectrometry (HPLC/ESI-MS/MS) method for simultaneous determination of the most relevant metabolites of benzene and toluene, t,t- muconic acid (t,t -MA), S -phenylmercapturic acid (S-PMA), and S -benzylmercapturic acid (S-BMA). Urine samples were purified before analysis by solid-phase microextraction (SPE) on SAX cartridges with 50,mg sorbent mass. The developed method fulfils all the standard requirements of precision and accuracy. Calibration curves were linear within the concentration range of the standards (0,80,,g/Lurine for t,t -MA, and 0,25,,g/Lurine for S-PMA and S-BMA), and had correlation coefficients ,0.997. Limits of detection were 6.0,,g/L for t,t -MA, 0.3,,g/L for S-PMA, and 0.4,,g/L for S-BMA. The method was used to determine t,t -MA, S-PMA and S-BMA levels in urine of 31 gasoline-station workers, with personal monitoring data obtained from radial symmetry passive diffusive samplers. In the context of mean work-shift exposures of 75.9,,g/m3 (range 9.4,220.2) for benzene and 331.9,,g/m3 (78.2,932.1) for toluene, metabolite concentrations in end-of-shift urine samples ranged from 23.5,275.3,,g/gcreatinine for t,t -MA, non-detectable to 0.9,,g/gcreatinine for S-PMA, and 3.8,74.8,,g/gcreatinine for S-BMA. No significant correlation was found between the environmental concentrations and urinary metabolites (p,>,0.05 for all cases); the ratios of benzene metabolites could be influenced by exposure levels and co-exposure to xylenes and toluene. The high throughput of this procedure should facilitate exploration of the metabolic effects of benzene-related co-exposure to toluene and alkylbenzenes in large populations of subjects exposed to gasoline. Copyright © 2004 John Wiley & Sons, Ltd. [source] Pharmacokinetics and safety of oral almotriptan in healthy male volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2004J. McEwen Abstract Almotriptan (LAS 31416) is a new, oral, specific 5-hydroxytryptamine1B/1D receptor agonist for the treatment of migraine. The pharmacokinetics and safety of a range of oral doses were assessed in 23 healthy male volunteers. Peak plasma concentrations were reached between 1.5 and 4 h after dosing. The maximum plasma concentration and area under the curve showed dose proportionality over the dose range 5,200 mg. The elimination half-life was constant at approximately 3 h across all dose levels. A substantial proportion of the initial dose was excreted in urine (27%,39%) during 12 h post-dose and the main excretory product was unchanged drug. Three major urinary metabolites were detected, all of which were pharmacologically inactive. The most common events following almotriptan administration were headache, tiredness and mild nausea. Nine events (18%) were classed as probably related to almotriptan and these were all at the highest dose level of 200 mg. The maximum tolerated dose of almotriptan was, therefore, determined as 150 mg. In conclusion, almotriptan is well tolerated following single, oral doses up to 150 mg and has predictable pharmacokinetics. Copyright © 2004 John Wiley & Sons, Ltd. [source] Chronological aspects of ultrasonic, hormonal, and other indirect indices of ovulationBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 8 2001René Ecochard Objective To improve prediction of ovulation in normal cycles. Design Collection of women's characteristics and their menstrual cycles. Monitoring and analysis of time relationships between several indicators of ovulation: transvaginal ultrasonography, cervical mucus, basal body temperature, urinary luteinising hormone, and ratio of urinary oestrogen to progesterone metabolites. Setting Each of eight natural family planning clinics was to study 12 women for at least three cycles. Population One hundred and seven normally fertile and cycling women aged 18 to 45. Methods Daily measurements of urinary luteinising hormone, follicle stimulating hormone, oestrone-3-glucuronide and pregnanediol-3, -glucuronide. Basal body temperature recording and cervical mucus checking. Transvaginal ultrasound examination of the ovaries. Main outcome measures Delays between the expected day of ovulation according to the luteinising hormone peak or to ultrasound evidence and the expected days according to the other indices of ovulation. Results Ultrasonography was able to show evidence of ovulation in 283 out of 326 cycles. The average time lag between luteinising hormone peak and ultrasound evidence was less than one day (+0.46) but premature and late luteinising hormone-expected date of ovulation were observed in nearly 10% and 23% of cycles, respectively. Basal body temperature rise was observed in 98% of cycles. Cervical mucus peak symptom, rapid drop in the ratio of urinary metabolites, and luteinising hormone initial rise were all close to ultrasonographic evidence in more than 72% of cycles. Conclusions For accuracy and practical reasons, the cervical mucus peak symptom, the ratio of urinary metabolites and luteinising hormone initial rise might be better indices of ovulation than the luteinising hormone peak. [source] Urinary leukotriene E4 and 9,, 11,-prostaglandin F2 concentrations in mild, moderate and severe asthma, and in healthy subjectsCLINICAL & EXPERIMENTAL ALLERGY, Issue 4 2004N. L. A. Misso Summary Background Airway inflammation in asthma is associated with cysteinyl leukotriene and prostaglandin D2 production. Measurement of urinary metabolites of these eicosanoids may be useful for monitoring asthma patients. However, the influence of asthma phenotype and severity on basal urinary excretion of these metabolites is unknown. Objective To compare urinary leukotriene (LT)E4 and 9,, 11,-prostaglandin (PG)F2 concentrations in large groups of mild, moderate and severe asthmatic patients and healthy control subjects. Methods Asthma severity, treatment and aspirin sensitivity were assessed by questionnaire in 168 asthmatic patients. Basal LTE4 and 9,, 11,-PGF2 concentrations were measured in urine samples from these patients and from 175 control subjects using enzyme immunoassays. Results Urinary LTE4 was correlated with 9,, 11,-PGF2 in both control subjects and asthmatic patients (P<0.002). Median LTE4 and 9,, 11,-PGF2 concentrations in patients with severe asthma were significantly reduced compared with mild asthmatic patients (P<0.05 and <0.001, respectively). Urinary 9,, 11,-PGF2, but not LTE4 was lower in asthmatic patients using inhaled corticosteroids (P<0.02). Multiple regression analysis indicated that urinary 9,, 11,-PGF2 concentration was negatively correlated with asthma severity (P=0.003) and also with % predicted FEV1 (forced expiratory volume in 1 s) (P=0.005). Conclusions Baseline urinary LTE4 and 9,, 11,-PGF2 concentrations are of limited value in discriminating between patients with different severities of asthma. Reduced urinary LTE4 and 9,, 11,-PGF2 in patients with severe asthma suggest that direct or indirect effects of high-dose corticosteroid therapy combined with other factors associated with severe asthma may influence eicosanoid production. However, the negative association of urinary 9,, 11,-PGF2 with lung function suggests an adverse effect of chronic PGD2 production on lung function in asthma, irrespective of severity. [source] | |||||||||||||