PubMed Health⌕ Search

Biomedical subjects

A L Fisher

Publications and source records attributed to A L Fisher.

At least 19 recordsLinked to original sources
PubMed2003

Long-term SO2 dispersion modeling over a coastal region.

Air dispersion modeling over coastal regions has proven to be a remarkable challenge in the field of air quality. Many conventional plume dispersion models, such as ISC2 and HYSPLIT, are unable to model such dispersion with the precision that is necessary to accurately predict ground-level concentrations in coastal areas. Considering this, the present work was carried out with two primary objectives: i) to evaluate the effectiveness of currently available mathematical models in predicting plume dispersion over a coastal region and ii) to study the impact of sulfur dioxide emissions from a petroleum refinery over a different community located in the adjacent area. This study demonstrates that CALPUFF predictions are more reliable compared to those of the other models studied, however the operation of CALPUFF is highly data intensive and in many instances, it is difficult to obtain all required input data. This is a particular problem for regions outside ofthe United States of America where sufficient data is difficult to obtain. In addition, the study concluded that the predicted annual average SO2 concentrations in the nearby communities are well within regulatory limits.

Air Movements↗
PubMed2002

LC-MS/MS determination of a farnesyl transferase inhibitor in human plasma and urine.

To support clinical pharmacokinetic studies in cancer patients, sensitive and specific methods for measuring 4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-1-(3-chlorophenyl) piperazinone (I), a farnesyl transferase inhibitor (FTI), in human plasma and urine were developed and validated. The methods are based on high-performance liquid chromatography (HPLC) with atmospheric pressure chemical ionization (APCI) and tandem mass spectrometric (MS/MS) detection in the positive ion mode using a heated nebulizer interface. Drug and internal standard were isolated from plasma or basified urine using automated solid-phase extraction on cyano cartridges. The organic extracts were dried, reconstituted in aqueous acetonitrile and injected into the system. Chromatographic separation of I and internal standard (IS) was achieved using a BDS Hypersil C8 analytical column, with a mobile phase consisting of acetonitrile:methanol:water (50:4:46) and trifluoroacetic acid (0.05%) at a flow rate of 0.6 ml/min. MS/MS detection was performed on a PE-Sciex API 300 tandem mass spectrometer operated in selected reaction monitoring mode. The parent-->product ions monitored were m/z 406-->195 for analyte I and m/z 448-->195 for the internal standard. Unusual in this method is that quantitation is accomplished using a secondary product ion, m/z 195, of drug I and IS. The assays were validated over the concentration range of 0.5-1000 ng/ml (1.2 nM to 2.5 microM, respectively) in plasma, and 2.5-500 ng/ml (6.2 nM to 1.23 microM) in urine. Accuracy was within +/-10% of nominal concentration at all levels in urine, and all but the lowest standard in plasma (+/-14% at 0.5 ng/ml). Intraday precision (expressed as coefficients of variation, CVs) for standard replicates and interday precision for quality control (QC) samples were less than 8% at all concentrations in both matrices. Detailed descriptions of the extraction procedure and analytical methodology used in the assay of I in plasma and urine are presented. This procedure may have utility in the quantitation of other imidazole-based FTIs with cyanobenzyl substructures.

Alkyl and Aryl Transferases↗
PubMed2002

A rapid and sensitive liquid chromatography/negative ion tandem mass spectrometry method for the determination of an indolocarbazole in human plasma using 96-well diatomaceous earth plates for solid-liquid extraction [correction of using internal standard (IS) 96-well diatomaceous earth plates for solid-liquid extraction].

A sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the quantitation of a novel topoisomerase I inhibitor (indolocarbazole derivative I) in human plasma was developed to support clinical studies. Drug and internal standard were isolated from plasma by solid-liquid extraction using 96-well diatomaceous earth plates. Various extraction solvents were evaluated for extraction of I and 9% isopropyl alcohol (IPA) in methyl-tert-butyl ether (MtBE) was chosen as the optimal extraction solvent. The sensitivity of this LC/MS/MS method is 10x higher in negative ion mode using alkaline conditions than in positive ion mode using a wide range of pH's. A mobile phase with 2 mM ammonium hydroxide enhanced the sensitivity in negative ion mode over other volatile bases. The calibration curve for compound I is linear over the range 0.05-200 ng/mL in plasma and the lower limit of quantification (LLOQ) of the assay is 0.05 ng/mL, when 0.25 mL of plasma is processed. The method was fully validated and successfully applied to plasma samples from clinical studies. Performing chromatography at high pH, for enhanced negative ion sensitivity, eliminates the need for post-column addition of base. Furthermore, the 96-well diatomaceous earth plate extraction offers the following advantages over liquid-liquid extraction (LLE) or solid-phase extraction (SPE): clean sample extracts with reduced sample preparation time; increased sample throughput; no conditioning or washing steps; and a neutral eluate applicable to acid/base labile compounds.

Carbazoles↗
PubMed2001

Determination of a beta(3)-agonist in human plasma by LC/MS/MS with semi-automated 48-well diatomaceous earth plate.

Methods for the determination of a beta(3)-agonist (A) in human plasma were developed and compared based on high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) detection using a turbo ion spray (TIS) interface. Drug and internal standard were isolated from plasma by three sample preparation methods, liquid-liquid extraction, Chem Elut cartridges and 48-well diatomaceous earth plates, that successively improved sample throughput for LC/MS/MS. MS/MS detection was performed on a PE Sciex API 365 tandem mass spectrometer operated in positive ion mode and using multiple reaction monitoring (MRM). The precursor/product ion combinations of m/z 625/607 and 653/515 were used to quantify A and internal standard, respectively, after chromatographic separation of the analytes. Using liquid-liquid extraction and Chem Elut cartridges, the assay concentration range was 0.5-100 ng/ml. Using diatomaceous earth plates, the concentration range of the assay was extended to 0.5-200 ng/ml. For all three assays, the statistics for precision and accuracy is comparable. The assay accuracy ranged from 91-107% and intraday precision as measured by the coefficient of variation (CV) ranged 2-10%. The sample throughput was tripled when the diatomaceous earth plate method was compared with the original liquid-liquid extraction method.

Adrenergic beta-3 Receptor Agonists↗
PubMed2001

Liquid chromatographic-tandem mass spectrometric urine assay for a highly metabolized cyclic ureidobenzenesulfonamide: issues concerning assay specificity and quality control preparation.

An LC-MS-MS method was validated for the quantitation of a beta(3) agonist (A) in human urine to support Phase I studies. A was designed to accelerate metabolism for weight reduction. During assay development a significant loss of A was apparent from frozen urine quality control samples. The addition of 0.75% bovine serum albumin (BSA) in urine (v/v) was required to maximize the recovery of A from urine. Urine samples were basified and extracted into methyl t-butyl ether-isopropyl alcohol (90:10, v/v). The organic layer was washed, evaporated, reconstituted, and injected onto a 5 cm, C8 HPLC column prior to MS-MS analysis. The standard curve was linear from 5 to 500 ng/ml. Intraday precision for peak area ratios from BSA urine samples at seven separate concentrations over a range of 5-500 ng/ml (n=5) was <4.0% and calculated concentrations were within 91-115% of nominal concentrations. Interday precision for BSA urine quality control (QC) samples at four separate concentrations (n=10 of each) was <5.0% and individual calculated concentrations were within 90-111% of nominal concentrations. This work emphasizes that potential metabolites and quality control standards should be prepared and assayed as early as possible in method development, especially before the sample collection section of the clinical protocol is prepared. The methods described here have wide utility to other compounds containing basic benzene sulfonamides and to beta3 agonist candidates.

Adrenergic beta-Agonists↗
PubMed2000

Structure-based optimization of peptide inhibitors of mammalian ribonucleotide reductase.

Mammalian ribonucleotide reductase (mRR), a potential target for cancer intervention, is composed of two subunits, mR1 and mR2, whose association is critical for enzyme activity. In this article we describe the structural features of the mRR-inhibitor Ac-F-c[ELAK]-DF (Peptide 3) while bound to the mR1 subunit as determined by transferred NOEs. Peptide 3 is a cyclic analogue of the N-acetylated form of the heptapeptide C-terminus of the mR2 subunit (Ac-FTLDADF), which is the link between the two subunits and previously shown to be the minimal sequence inhibitor mRR by competing with mR2 for binding to mR1. Structural refinement employing an ensemble-based, full-relaxation matrix approach resulted in two structures varying in the conformations of F(1) and the cyclic lactam side chains of E(2) and K(5). The remainder of the molecule, both backbone and side chains, is extremely well-defined, with an RMSD of 0.54 A. The structural features of this conformationally constrained analogue provide unique insight into the requirements for binding to mR1, critical for further inhibitor development.

Animals↗
PubMed2000

Electrophysiologic signs of auditory distraction in elderly listeners.

Brain mapping was used to investigate the ability of young and elderly female listeners to attend to /ga/ syllabic events at one ear in the presence of speech babble competition at the opposite ear. An oddball stimulus presentation paradigm was used to record the N1 and P2 components of the late auditory evoked potential (LAEP) from 19 scalp locations. With speech competition, elderly listeners exhibited significantly larger reductions in P2 amplitude than did young listeners. The competition produced no changes in N1 amplitude in either group. These findings contrast with those of an earlier study in which age-related reductions in N1 but not P2 amplitude were found when listeners attended to tones rather than speech stimuli in the presence of speech competition. These studies suggest that amplitude reductions in different LAEP components may provide electrophysiologic indices of age-related breakdowns in processing sounds in the presence of competition. Which LAEP components are affected may depend on experimental variables such as task difficulty or the nature of the stimuli (e.g., speech vs nonspeech).

Adult↗
PubMed1999

The effects of moclobemide on the pharmacokinetics of the 5-HT1B/1D agonist rizatriptan in healthy volunteers.

AIMS: The new 5-HT1B/1D agonist rizatriptan (MK-0462) has recently been registered for the treatment of migraine. Its primary route of metabolism is via monoamine oxidase-A (MAO-A). Antidepressants such as the MAO-A inhibitor moclobemide may be used in patients with chronic headache syndromes. Hence, this study aimed to investigate the interactions between rizatriptan and moclobemide. METHODS: In a double-blind, randomized, placebo-controlled, two-period cross-over study 12 healthy, young volunteers (six males, six females) were treated with moclobemide (150 mg twice daily) or placebo for 4 days. On the fourth day, a single dose of rizatriptan (10 mg) was administered, and subsequently blood and urine samples were collected for assay of rizatripan and N-monodesmethyl rizatriptan. Plasma concentrates of 3,4-dihydroxyphenylglycol (DHPG), a marker of MAO-A inhibition, were also assessed. Supine and standing blood pressure were measured regularly. RESULTS: Both treatments were well tolerated. During moclobemide, the increase in supine diastolic blood pressure following rizatriptan administration was augmented. Inhibition of MAO by moclobemide was inferred from a persistent decrease in DHPG level (43% on average). When rizatriptan was coadministered with moclobemide, the area under the plasma drug concentration-time profiles for rizatriptan and its N-monodesmethyl metabolite increased 2.2-fold (90% CI, 1.93-2.47) and 5.3-fold (90% CI, 4.81-5.91), respectively, when compared with placebo. Peak plasma drug concentrations for rizatriptan and its n-monodesmethyl metabolite increased 1.4-fold (90% CI, 1.11-1.80) and 2.6-fold (90% CI, 2.23-3.14), respectively, and half-lives of both were prolonged. CONCLUSIONS: Moclobemide inhibited the metabolism of rizatriptan and its active N-monodesmethyl metabolite through inhibition of MAO-A. Thus, moclobemide may considerably potentiate rizatriptan action. Concurrent administration of moclobemide and rizatriptan is not recommended.

Adult↗
PubMed1997

Groucho-dependent and -independent repression activities of Runt domain proteins.

Runt domain proteins are transcriptional regulators that specify cell fates for processes extending from pattern formation in insects to leukemogenesis in humans. Runt domain family members are defined based on the presence of the 128-amino-acid Runt domain, which is necessary and sufficient for sequence-specific DNA binding. We demonstrate an evolutionarily conserved protein-protein interaction between Runt domain proteins and the corepressor Groucho. The interaction, however, is independent of the Runt domain and can be mapped to a 5-amino-acid sequence, VWRPY, present at the C terminus of all Runt domain proteins. Drosophila melanogaster Runt and Groucho interact genetically; the in vivo repression of a subset of Runt-regulated genes is dependent on the interaction with Groucho and is sensitive to Groucho dosage. Runt's repression of one gene, engrailed, is independent of VWRPY and Groucho, thus demonstrating alternative mechanisms for repression by Runt domain proteins. Unlike other transcriptional regulatory proteins that interact with Groucho, Runt domain proteins are known to activate transcription. This suggests that the Runt domain protein-Groucho interaction may be regulated.

Amino Acid Sequence↗
PubMed1996

The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain.

Hairy-related proteins include the Drosophila Hairy and Enhancer of Split proteins and mammalian Hes proteins. These proteins are basic helix-loop-helix (bHLH) transcriptional repressors that control cell fate decisions such as neurogenesis or myogenesis in both Drosophila melanogaster and mammals. Hairy-related proteins are site-specific DNA-binding proteins defined by the presence of both a repressor-specific bHLH DNA binding domain and a carboxyl-terminal WRPW (Trp-Arg-Pro-Trp) motif. These proteins act as repressors by binding to DNA sites in target gene promoters and not by interfering with activator proteins, indicating that these proteins are active repressors which should therefore have specific repression domains. Here we show the WRPW motif to be a functional transcriptional repression domain sufficient to confer active repression to Hairy-related proteins or a heterologous DNA-binding protein, Ga14. This motif was previously shown to be necessary for interactions with Groucho, a genetically defined corepressor for Drosophila Hairy-related proteins. Here we show that the WRPW motif is sufficient to recruit Groucho or the TLE mammalian homologs to target gene promoters. We also show that Groucho and TLE proteins actively repress transcription when directly bound to a target gene promoter and identify a novel, highly conserved transcriptional repression domain in these proteins. These results directly demonstrate that Groucho family proteins are active transcriptional corepressors for Hairy-related proteins and are recruited by the 4-amino acid protein-protein interaction domain, WRPW.

Amino Acid Sequence↗
PubMed1992

Linitis plastica carcinoma of the colon mimicking Crohn's colitis.

Primary linitis plastica carcinoma of the colon is an uncommon morphological type of colorectal carcinoma. Linitis plastica of the stomach may spread to the colon producing a similar lesion to primary colonic linitis plastica. This case report describes a case of linitis plastica of the colon that had many of the clinical, endoscopic, radiological and operative features of Crohn's colitis. The precise origin of the linitis plastica carcinoma was not clear: it may have been clonic or gastric, although the former is favoured. This case illustrates a number of facets of this unusual colonic carcinoma.

Biopsy↗
PubMed1991

Determination of MK-287, a new platelet-activating factor antagonist, in plasma and serum by gas chromatography chemical ionization mass spectrometry.

MK-287 is a novel platelet-activating factor antagonist. A sensitive and specific gas chromatographic/mass spectrometric assay has been developed for the determination of the drug in serum and plasma. The assay utilizes an extraction with methyl-t-butyl ether and subsequent trimethylsilylation of the hydroxyl function. The gas chromatographic/mass spectrometric determinations are carried out with temperature-programmed capillary gas chromatography and ammonia negative chemical ionization mass spectrometry. The method has sufficient sensitivity, precision, accuracy and selectivity for the analysis of drug concentrations in clinical samples.

Furans↗
PubMed1990

Incidence of pulmonary embolism in elderly patients newly admitted to an acute geriatric unit: a prospective study.

To study the incidence of pulmonary embolism (PE) in elderly patients newly admitted to an acute geriatric unit, the authors carried out ventilation perfusion scans on 33 patients, 25 women and 8 men, mean age 79 years, consecutively admitted to the geriatric wards. The first scan was done within 5 days of admission and repeated between days 10 and 20. Where possible, patients with a positive second scan had a repeat scan at 2-3 months. Six (18%) patients were found to have a high probability of PE, 4 (12%) at the time of admission and two (6%) after admission. Three patients (9%) were considered to suffer from chronic pulmonary artery disease. Mortality was 5 for the whole group (15%) and 1 of 6 (17%) with a high probability of PE; this patient was suffering from carcinomatosis. The only patient who was anticoagulated suffered serious side effects. In no patient was PE clinically suspected. The authors conclude that PE is common in sick elderly patients newly admitted to acute geriatric wards, that rehabilitation with mobilization may precipitate new PE, and that nonanticoagulated PE does not seem to appreciably shorten the prognosis for life. Treatment with anticoagulants may be more dangerous than not treating PE in this older age group.

Aged↗