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Biomedical subjects

C L Shaffer

Publications and source records attributed to C L Shaffer.

16 recordsLinked to original sources
PubMed2001

N-dealkylation of an N-cyclopropylamine by horseradish peroxidase. Fate of the cyclopropyl group.

Cyclopropylamines inactivate cytochrome P450 enzymes which catalyze their oxidative N-dealkylation. A key intermediate in both processes is postulated to be a highly reactive aminium cation radical formed by single electron transfer (SET) oxidation of the nitrogen center, but direct evidence for this has remained elusive. To address this deficiency and identify the fate of the cyclopropyl group lost upon N-dealkylation, we have investigated the oxidation of N-cyclopropyl-N-methylaniline (3) by horseradish peroxidase, a well-known SET enzyme. For comparison, similar studies were carried out in parallel with N-isopropyl-N-methylaniline (9) and N,N-dimethylaniline (8). Under standard peroxidatic conditions (HRP, H(2)O(2), air), HRP oxidizes 8 completely to N-methylaniline (4) plus formaldehyde within 15-30 min, whereas 9 is oxidized more slowly (<10% in 60 min) to produce only N-isopropylaniline (10) and formaldehyde (acetone and 4 are not formed). In contrast to results with 9, oxidation of 3 is complete in <60 min and affords 4 (20% yield) plus traces of aniline. By using [1'-(14)C]-3, [1'-(13)C]-3, and [2',3'-(13)C]-3 as substrates, radiochemical and NMR analyses of incubation mixtures revealed that the complete oxidation of 3 by HRP yields 4 (0.2 mol), beta-hydroxypropionic acid (17, 0.2 mol), and N-methylquinolinium (16, 0.8 mol). In buffer purged with pure O(2), the complete oxidation of 3 yields 4 (0.7 mol), 17 (0.7 mol), and 16 (0.3 mol), while under anaerobic conditions, 16 is formed quantitatively from 3. These results indicate that the aminium ion formed by SET oxidation of 3 undergoes cyclopropyl ring fragmentation exclusively to generate a distonic cation radical (14+*) which then partitions between unimolecular cyclization (leading, after further oxidation, to 16) and bimolecular reaction with dissolved oxygen (leading to 4 and 17 in a 1:1 ratio). Neither beta-hydroxypropionaldehyde, acrolein, nor cyclopropanone hydrate are formed as SET metabolites of 3. The synthetic and analytical methods developed in the course of these studies should facilitate the application of cyclopropylamine-containing probes to reactions catalyzed by cytochrome P450 enzymes.

Alkylation↗
PubMed2001

Effect of aerosolized uridine 5'-triphosphate on mucociliary clearance in mild chronic bronchitis.

Previous studies show that uridine 5'-triphosphate (UTP), a P2Y(2) receptor agonist, is effective at acutely enhancing mucociliary clearance in healthy, nonsmoking adults. UTP solution for inhalation is being developed by Inspire Pharmaceuticals under the compound number INS316. In a double-blind, randomized, crossover, placebo-controlled study we tested the single-dose effect of UTP in chronic smokers with mild chronic bronchitis (n = 15) by measuring the clearance of (99m)Tc-Fe(2)O(3) particles (4.0 microm mass median aerodynamic diameter [MMAD]) after inhalation of nebulized placebo (0.9% saline) and two doses of UTP (20 and 100 mg in the nebulizer). On each study day, gamma camera scanning was performed over a 2-h period. After an initial deposition scan, subjects inhaled placebo or UTP during the first 20 min of scanning. Analysis of whole lung clearance showed that the retention-time curves for each day were biphasic and that the earliest break point in the average curves occurred at 50 min. Mean particle clearance rate (Clr in %/min) through 50 min for placebo treatment was Clr = 0.65 +/- 0.27 whereas treatment with UTP showed Clr significantly increased to 0.95 +/- 0.48 and 0.93 +/- 0.44 for the 20-mg and 100-mg dose respectively, p < 0.005 for both as compared with placebo. These data show that mucociliary clearance associated with mild chronic bronchitis is acutely improved with minimal doses of aerosolized UTP, presumably because of its stimulation of ciliary beating and hydration of airway secretions.

Administration, Inhalation↗
PubMed2001

A multicenter evaluation of gentamicin therapy in the neonatal intensive care unit.

STUDY OBJECTIVE: To evaluate traditional nomogram (TN) versus individualized pharmacokinetic gentamicin dosing practices in neonatal intensive care units, focusing on achieving target therapeutic concentrations (peak > 8 microg/ml, trough < 2 microg/ml), number of dosing changes, number of concentrations obtained, and evidence of nephrotoxicity. DESIGN: Retrospective chart review. SETTING: Three neonatal intensive care units. PATIENTS: Three hundred nine infants prescribed gentamicin. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Sixty-seven percent of patients receiving pharmacokinetic dosing had initial peak concentrations of 8 microg/ml or greater compared with 7% of patients receiving TN dosing (p<0.001). Trough concentrations exceeding 2 microg/ml were reported in 23% of patients receiving TN dosing compared with 2% of pharmacokinetic-dosed patients (p<0.001). Forty-two percent and 6%, respectively, required dosage adjustments (p<0.01). The mean number of concentrations obtained per patient was 2.8 and 2.1, respectively (p<0.01). Neither group had evidence of gentamicin-related nephrotoxicity. CONCLUSION: Compared with TN dosing, administering gentamicin loading doses and performing initial pharmacokinetic analysis resulted in rapid attainment of desired concentrations and fewer dosage adjustments, and allowed for a decrease in the number of gentamicin concentrations.

Anti-Bacterial Agents↗
PubMed1995

Acute hemodynamic effects of the prostacyclin analog 15AU81 in severe congestive heart failure.

This multicenter, open-label study provides the first assessment of the safety and acute hemodynamic effects of a short-term infusion of 15AU81, a chemically stable analog of prostacyclin, in patients with New York Heart Association class III or IV heart failure. Twelve patients underwent sequential dose escalation by increasing the rate of the infusion at 15-minute intervals until the drug was no longer tolerated. Patients then received a 90-minute infusion at their maximum tolerated dose. The infusion was then discontinued and the subjects were observed during a 90-minute washout segment. Serial hemodynamic measurements were made throughout the dose-ranging, maintenance, and washout segments. A significant decrease in systemic vascular resistance (1,935 +/- 774 vs 1,243 +/- 351 dynes.s.cm-5; p < 0.001) and pulmonary vascular resistance (395 +/- 335 vs 223 +/- 198 dynes.s.cm-5; p = 0.008) occurred from the infusion of vehicle to the maximum tolerated dose. During dose titration, there was a a significant increase in cardiac index (1.9 +/- 0.7 vs 2.6 +/- 0.6 liters/min/m2; p < 0.001) and a tendency for a mild reduction in pulmonary artery wedge pressure (18 +/- 7 vs 17 +/- 6; p = 0.055) for the 8 patients with values on vehicle and maximum tolerated dose. These hemodynamic changes persisted during the maintenance infusion and disappeared rapidly during the washout segment. The most common adverse event to limit dose-ranging was headache, which occurred at a mean maximum tolerated dose of 36 +/- 15 ng/kg/min. Administration of 15AU81 was associated with significant acute hemodynamic improvement in patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Interexaminer agreement for readings of dip slide tests for salivary mutans streptococci and lactobacilli.

This study reports the interexaminer agreement of three pairs of evaluators of salivary dip slide tests for mutans streptococci and lactobacilli. 717 Cariescreen SM and Bactotest LB dip slides were available for assessment by 2 dentists and 1 dental hygienist. A single calibration session was held prior to the onset of the study. Each dip slide was read once by each examiner independently. Among the three pairs of examiners, Pearson R values ranged from 0.84 to 0.90 for Cariescreen and from 0.78 to 0.87 for Bactotest. Kappa statistic values ranged from 0.56 to 0.61 for Cariescreen and from 0.70 to 0.74 for Bactotest. The range of agreement was from 72.2 to 76.9% for Cariescreen and from 86.4 to 88.3% for Bactotest. The majority of disagreements were of one category in magnitude, though there were a few disagreements of greater magnitude. This study found moderately strong agreement among the three examiners; it suggests that multiple examiners of dip slide tests carefully calibrated initially and periodically to ensure a high level of agreement.

Child↗
PubMed1993

Caries risk assessment by a cross-sectional discrimination model.

Although the prevalence of dental caries is continuing to decline, it still affects a majority of the US population and can be a serious problem for those afflicted. The objective of this project was to develop and perfect a model for assessment of risk of dental caries onset in children. In the first study, reported herein, a set of clinical, microbiological, biochemical, and socio-demographic variables was identified that distinguished, with an acceptable level of sensitivity and specificity, between children who had no previous caries experience and children who had high caries levels. A total of 313 children--age 12-15 years, 140 from a fluoridated community and 173 from a fluoride-deficient community--was selected on the basis of previous caries experience, either zero DMFS or high DMFS (> or = 6 in the fluoridated or > or = 8 in the fluoride-deficient community). Clinical exams for DMFS, dental fluorosis, and plaque were conducted. Stimulated whole saliva was collected for analysis of mutans streptococci, lactobacilli, total viable flora, and fluoride concentration. A questionnaire was used for collection of demographic data as well as information on prior fluoride exposure, dietary habits, and oral hygiene practices. By means of discriminant analyses, with use of seven key clinical and laboratory variables, it was possible for zero-DMFS subjects to e classified correctly (specificity) in 77.6% of cases in the fluoridated community and in 86.1% of cases in the fluoride-deficient community. High-caries subjects were classified as such (sensitivity) in 79.3% and 88.1% of cases, respectively.

Adolescent↗
PubMed1993

Caries risk assessment in a longitudinal discrimination study.

Our objective was to develop and perfect a model for the assessment of risk of dental caries onset in children. Even though dental caries prevalence in children is continuing to decline, there is still a significant minority for whom it is a problem. In this study, we sought to ascertain whether a set of variables selected in a previous cross-sectional study could be used to differentiate between caries-free six-year-olds who would or would not subsequently present with clinically-detectable caries. A total of 472 caries-free six-year-olds--286 from a fluoridated community and 186 from a fluoride-deficient community--was selected. Clinical examinations for DMFS, dental fluorosis, and plaque were conducted. Stimulated whole saliva was collected for analysis of mutants streptococci, lactobacilli, total viable flora, and fluoride, calcium, and phosphate concentrations. A questionnaire was used for collection of demographic data as well as information on prior fluoride exposure, dietary habits, and oral hygiene practices. By means of linear discriminant analyses, it was possible to predict correctly which children would develop caries within six to 12 months (sensitivity) in 82.8% of cases and which children would not develop caries during that period (specificity) in 82.4% of cases.

Apatites↗
PubMed1990

Use of open-ended essays and computer content analysis to survey college students' knowledge of AIDS.

This study used computer content analysis of written essays to explore university students' knowledge and attitudes about AIDS. Because the essays were long, averaging 650 words each, and were on the very general topics of what individuals and society should do about AIDS, it was possible to study a wide variety of subjects. Computer scoring of the essays showed that education and individual changes in sexual behavior were the two methods of prevention mentioned most often. The majority of students accurately identified the most important methods of transmitting the disease. Only one fourth of the respondents discussed casual contact; a majority of those knew that the disease could not be transmitted in this manner. A minority of the students advocated isolating people infected with HIV or marking these individuals in ways that are accessible to others in society. The new computer methods used to analyze the essays offer flexible and efficient procedures for analyzing text on a variety of topics.

Acquired Immunodeficiency Syndrome↗