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Biomedical subjects

D S Wright

Publications and source records attributed to D S Wright.

At least 37 records · Page 2Linked to original sources
PubMed1996

Disposition kinetics of human epidermal growth factor (hEGF1-53) and its truncated fragment (hEGF1-48) in rats.

Clearance of human epidermal growth factor (hEGF1-53) has been proposed to be mediated by a receptor pathway involving a typical cascade of ligand-receptor endocytosis and lysosomal degradation. Deletion of the C-terminal pentapeptide from hEGF1-53, which yields hEGF1-48, is known to be associated with a marked reduction in receptor binding. We defined the intravenous (iv)-bolus (acute exposure) and the iv-infusion (prolonged exposure) pharmacokinetics of hEGF1-53 and hEGF1-48 in rats to investigate the impact of the deletion of C-terminal pentapeptide on the EGF clearance using a validated, sensitive ELISA method for quantitation of the peptides in plasma. Both peptides at the low iv bolus dose of 10 micrograms/kg were cleared from plasma with unusually high clearances (CLtot: 128 +/- 31 ml/min/kg for hEGF1-53 and 168 +/- 47 ml/min/kg for hEGF1-48), which are virtually complete within 4-min postdose, and the difference in the overall pharmacokinetics is of minor significance. A 10-fold increase in bolus dose to 100 micrograms/kg decreased clearances 3- to 6-fold, indicating a nonlinear kinetics for both peptides; however, hEGF1-48 was cleared (52 +/- 11 ml/min/kg) 2.5-fold faster than hEGF1-53. A similar nonlinear kinetics was also noticed for both peptides when they were administered by a 2-hr iv infusion at 30 and 300 micrograms/kg doses. hEGF1-48 at the low and high infusion doses was cleared at 126 +/- 16 and 33.7 +/- 14.5 ml/min/kg, respectively, which are 4-fold greater than the corresponding clearance rates of hEGF1-53. These observations suggest that a) deletion of C-terminal pentapeptide is associated with a faster clearance of the growth factor and b) the receptor clearance pathway may be more sensitive to saturation with hEGF1-53 than with hEGF1-48 at low microgram dose levels. hEGF1-53 at the low infusion dose of 30 micrograms/kg was cleared (32.1 +/- 6.2 ml/min/kg) 4-fold slower in comparison with the low bolus dose of 10 micrograms/kg, indicating a remarkable injection mode-dependent disposition kinetics for hEGF1-53, which does not exist for hEGF1-48. The overall results suggest that deletion of C-terminal pentapeptide leads to faster clearance of the growth factor, and the degree of the impact of deletion of C-terminal pentapeptide on the global pharmacokinetics is also dependent on the length of exposure of the receptor to the ligand. The negative relationship between receptor binding and plasma clearance for the two peptides remains to be elucidated at the molecular and receptor levels.

Amino Acid Sequence↗
PubMed1995

Sensitive high-performance liquid chromatographic method for a dopamine receptor agonist, CI-1007, and its metabolite PD 147693 in monkey plasma.

A sensitive gradient high-performance liquid chromatographic (HPLC) method for the simultaneous quantitation of a dopamine autoreceptor agonist CI-1007 (I) and its metabolite PD 147693 (II) is described. Monkey plasma samples were purified by liquid-liquid extraction using hexane. Liquid chromatographic separation was achieved on two C18 analytical columns (installed in series) using gradient elution. Column effluent was monitored using a fluorescence detector programmed to change wavelengths at specified times. Minimum quantitation limits of I and II were 3.0 and 5.0 ng/ml, respectively, for a plasma sample volume of 0.100 ml. Linearity was demonstrated up to 300 ng/ml. The assay has been applied to the analysis of I and II in plasma from monkeys following intravenous and oral doses of I.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Trace quantitation of the novel cholinesterase inhibitor in human plasma by capillary gas chromatography/ion trap mass spectrometry.

This paper demonstrates the utility of an ion trap mass spectrometer as a detector for trace quantitative determinations of pharmaceuticals in human plasma by capillary gas chromatography/mass spectrometry. A novel acetylcholinesterase inhibitor (CI-1002) was selected as an illustrative example for the technique. When coupled with a selective solid-phase extraction, this approach was capable of quantifying as little as 34 pg (0.50 ng ml-1, RSD = 12.7%) of compound on the column, and the inter-run precision was typically 3-4% RSD over a 0.5-25 ng ml-1 linear range. The advantages and requirements of the technique, in addition to the prospects for improvements in the detection limit, are discussed.

Calibration↗
PubMed1995

Considerations in the development of a sensitive HPLC assay for human epidermal growth factors in human plasma.

A sensitive assay was developed for human epidermal growth factors (hEGF) 1-48 (dosed), hEGF 1-53 (endogenous), without interference from potential metabolites hEGFs 1-47 or 1-46. Spiked human plasma samples were injected directly, utilizing on-line immunoaffinity HPLC (anti-hEGF) clean-up. No change in capacity was noted after 81 cycles. After release from the immunoaffinity column, the fragments were further resolved by strong cation-exchange (SCX) via a column switching valve. Method development also required interfacing immunoaffinity, ion-exchange, and detection components. Immunoassays on collected fractions yielded a detection limit of 1 microgram ml-1, although a detection limit of 75 pg ml-1 appears feasible.

Amino Acid Sequence↗
PubMed1994

Diuretic effects, pharmacokinetics, and safety of a new centrally acting kappa-opioid agonist (CI-977) in humans.

The diuretic effects, pharmacokinetics, and safety of CI-977, a new centrally acting selective kappa-opioid agonist, were determined in 16 healthy subjects. Subjects received single intramuscular doses of CI-977 (5, 15, or 25 micrograms) or placebo 1 week apart according to a randomized, double-blind, placebo-controlled, four-period, crossover design. Serial blood and urine specimens were collected after each dose. Significant dose-related decreases in negative free water clearance and urine osmolality and increases in urine volume were observed after administration of 15- and 25-micrograms doses of CI-977. CI-977 had no effect on urine electrolyte excretion or serum antidiuretic hormone. Absorption of CI-977 was rapid with individual tmax values ranging from 0.17 to 1.5 hours. Cmax and AUC(0-infinity) increased proportionally with dose. Individual elimination half-life values ranged from 0.6 to 3.3 hours and were independent of dose. Changes in free water clearance were related to CI-977 Cmax (r2 = 0.29, P = 0.0001) and AUC(0-4 hr) (r2 = 0.32, P = 0.0001) values. The most frequently reported adverse events after CI-977 administration were dizziness, fatigue, paresthesia, headache, vasodilatation (facial flushing), emotional lability, high feeling, and abnormal thinking. The frequency and intensity of adverse events increased with increasing CI-977 dose. In conclusion, CI-977 Cmax and AUC(0-infinity) increased in proportion to dose over the range of 5 to 25 micrograms; decreases in negative free water clearance were related to CI-977 dose and Cmax and AUC(0-4 hr) values; and the frequency and intensity of adverse events increased with increasing CI-977 dose.

Adult↗
PubMed1993

The relationship between nasalance and nasality in children with cleft palate.

This study correlated measures of nasalance computed by the Nasometer with listener judgments of nasality. The subjects were 25 children with craniofacial disorders who spoke three passages, each containing a different proportion of nasal consonants. The results showed a significant but modest correlation between nasalance and nasality when nasal consonants (/m, n, eta/) were not included in the speech passage. When nasal consonants were included in the passage nasalance was unrelated to judgments of hypernasality.

Adolescent↗
PubMed1988

Sequestration electrochemistry: the interaction of chlorpromazine and human orosomucoid.

A simple and rapid method is presented for determination of the association constants and stoichiometries describing ligand macromolecule interactions. Based on flow injection analysis and electrochemical detection by amperometry, the only requirements for direct measurements are that the ligand have redox properties and that these properties change upon binding to the macromolecule. Bound ligand may then be measured in the presence of free ligand. Detection limits are of the order of 2 pmol of ligand or less, a level that should provide access to previously unmeasurable systems. For the exemplary system, chlorpromazine and human orosomucoid, K0ass was determined as 0.39 X 10(6) M-1 with 0.76 chlorpromazine binding sites of this affinity per orosomucoid molecule.

Binding Sites↗
PubMed1988

Biological sample preparation and data reduction concepts in pharmaceutical analysis.

This paper describes strategies to rapidly develop sensitive and selective preparations using manual and robotic liquid-solid isolation (LSI) methods. LSI procedures offer selective isolation of drug or metabolites from complex matrices and are applicable to many pharmaceutical compounds. The beneficial effect of weighted linear regression is described, and several data reduction techniques are contrasted.

Chemical Phenomena↗
PubMed1987

Recent analytical methods for cephalosporins in biological fluids.

Since 1980, RP chromatography has been the principal analytical technique used for cephalosporins. This technology offers selectivity, accuracy, and ease of use. Most of the methods rely on protein precipitation and, to a lesser extent, solid-phase isolation or extraction procedures. The proper selection of a method depends on the analytical constraints imposed by the overall objective of the study. For example, pharmacokinetic datum interpretation mandates that the method be validated and provide specific and accurate results. LC is the preferred technique, since it not only meets these specifications but may also distinguish between the drug and metabolites. Those chromatographic methods which quantify several different cephalosporins are not desirable for pharmacokinetic datum interpretation, since accuracy and precision are usually compromised in order that many different drugs may be quantified in a single analysis. The proper selection of sample preparation method is dependent on the presence of potential interferences and the acceptable lower limit of quantitation. Protein precipitation methods offer ease of sample preparation but may suffer from nonselectivity. Solid-phase isolation and extraction procedures may increase selectivity and improve the limit of quantitation. Although LC provides specific and accurate results, clinical laboratories may prefer to use the less specific methods for therapeutic drug monitoring. In this case, microbiological, enzymatic, and fluorimetric methods offer improved sample throughput but less specificity. However, these methods should not be used for drugs that may have a low margin of safety or if the patient is on multiple-antibiotic therapy. Future methods may involve incorporating solid-phase isolation columns to enhance the specificity of chromatographic, microbiological, enzymatic, and fluorescence methods. Advancements in microbore column technology may allow improvements in the selectivity and sensitivity of LC methods. Many investigators prefer to use simple protein precipitation procedures for sample preparation because of sample throughput constraints. However, advances in robotic sample preparation may allow the more cumbersome solid-phase isolation or extraction techniques to be used to improved sample throughput and specificity.

Body Fluids↗
PubMed1981

Peripheral nerve function in patients with bronchial carcinoma. Comparison with matched controls and effects of treatment.

Clinical examination of 80 patients with bronchial carcinoma showed minor neurological abnormalities but in only a few cases were these considered to be due to neuromyopathy. Spontaneous activity in the EMG was shown in 35%, consistent with a mild degree of partial denervation; when 50 of the patients were matched with 50 controls the patients showed a small but significant impairment of nerve conduction velocity in comparison with the controls. These findings accord with subclinical neuropathy in a high proportion of patients with bronchial carcinoma consistent with primary axonal change. Thirty patients participated in a prospective study of the effects of treatment. Of these nine were reassessed following surgery or radiotherapy. Although there was a trend towards improvement in sensory conduction there was no consistent change in the electromyographic findings.

Bronchial Neoplasms↗