Biomedical subjects
Publications and source records attributed to D J Nichols.
The effect of dofetilide on the steady-state pharmacokinetics of digoxin was evaluated in a randomized, double-blind study. Five days of dofetilide treatment did not significantly affect steady-state pharmacokinetic variables of digoxin compared with placebo; therefore, the use of dofetilide does not necessitate an adjustment in digoxin dose to maintain therapeutic digoxin levels.
The objective of the research was to establish the capability of the Intelisite capsule to deliver the probe drugs, theophylline and frusemide, in the form of split immediate release (IR) tablets, to the small intestine and colon. The two probe drugs were administered together in an open, random, three-way crossover study in eight healthy volunteers, comparing absorption following Intelisite delivery in the small bowel and colon to conventional IR dosing. Gamma scintigraphy was employed to monitor the gastrointestinal transit and activation of the Intelisite capsule. Standard pharmacokinetic parameters, and the percentage remaining in the capsules post defecation were determined. The Intelisite capsule was well tolerated in human volunteers and successfully activated on 15/16 occasions. Pharmacoscintigraphy showed internal marker release from the Intelisite capsule to be approximately 10-fold faster in the small intestine than in the colon. Theophylline and frusemide were both well absorbed following Intelisite activation in the small intestine, whereas complete colonic absorption was only observed in 1/7 subjects for theophylline, and 0/7 subjects for frusemide. The probe drugs were successfully delivered in particulate form from the Intelisite capsule in the small intestine and produced expected pharmacokinetic profiles. However drug release in the colon was incomplete and variable possibly due to: low water content, poor mixing, and a high loading dose.
Chemical modification of maize starch synthase IIb-2 (SSIIb-2) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), which modifies acidic amino acid residues, resulted in a time- and concentration-dependent inactivation of SSIIb-2. ADPGlc was found to completely protect SSIIb-2 from inactivation by EDAC. These results suggest that glutamate or aspartate is important for SS activity. On the basis of the sequence identity of SS, conserved acidic amino acids were mutagenized to identify the specific amino acid residues important for SS activity. Three amino acids (D21, D139, and E391) were found to be important for SS activity. D21N showed 4% of the wild-type enzyme activity and a 10-fold decrease in the affinity for ADPGlc, while the conservative change from D21 to E resulted in a decrease in V(max) and no change in affinity for ADPGlc, suggesting that the negative charge is important for ADPGlc binding. When sites D139 and E391 were changed to their respective amide form, no SS activity was detected. With the conservative change, D139E showed a decrease in V(max) and no changes in apparent K(m) for substrates. E391D showed a 9-fold increase in K(m) for ADPGlc, a 12-fold increase in apparent K(m) for glycogen, and a 4-fold increase in apparent K(m) for amylopectin. The circular dichroism analysis indicates that these kinetic changes may not be due to a major conformation change in the protein. These results provide the first evidence that the conserved aspartate and glutamate residues could be involved in the catalysis or substrate binding of SS.
AIMS: The aim of this open-label, placebo-controlled, randomized, four-period crossover study was to determine the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide. METHODS: Twenty healthy male subjects received 100 or 400 mg twice daily of cimetidine, 150 mg twice daily of ranitidine, or placebo for 4 days. On the second day, a single oral 500 microg dose of dofetilide was administered immediately after the morning doses of cimetidine, ranitidine, or placebo. Treatment periods were separated by 1-2 weeks. Pharmacokinetic parameters were determined from plasma and urinary dofetilide concentrations; prolongation of the QTc interval was determined from three-lead electrocardiograms. RESULTS: Ranitidine did not significantly affect the pharmacokinetics or pharmacodynamics of dofetilide; however, a dose-dependent increase in exposure to dofetilide was observed with cimetidine. When dofetilide was administered with 100 and 400 mg of cimetidine, the area under the plasma concentration-time curve of dofetilide increased by 11% and 48% and the maximum plasma dofetilide concentration increased by 11% and 29%, respectively. The respective cimetidine doses reduced renal clearance of dofetilide by 13% and 33% and nonrenal clearance by 5% and 21%. Dofetilide-induced prolongation of the QTc interval was enhanced by cimetidine; the mean maximum change in QTc interval from baseline was increased by 22% and 33% with 100 and 400 mg of cimetidine, respectively. However, the relationship between the prolongation of the QTc interval and plasma dofetilide concentrations was unaffected by cimetidine or ranitidine; a 1 ng ml-1 increase in plasma dofetilide concentration produced a 17-19 ms prolongation of the QTc interval. Dofetilide was well tolerated, with no treatment-related adverse events or laboratory abnormalities. CONCLUSIONS: These results suggest that cimetidine increased dofetilide exposure by inhibiting renal tubular dofetilide secretion, whereas ranitidine did not. This effect is not an H2-receptor antagonist class effect but is specific to cimetidine. If therapy with an H2-receptor antagonist is required, it is recommended that cimetidine at all doses be avoided; since ranitidine has no effect on dofetilide pharmacokinetics or prolongation of the QTc interval, it can be seen as a suitable alternative.
AIMS: The pharmacokinetics and pharmacodynamics of oral dofetilide, a novel, class III antiarrhythmic drug, were assessed during administration either twice or three times daily. METHODS: Dofetilide was administered orally to three groups of healthy subjects in daily doses of 1000 microg (n = 8), 1500 microg (n = 8), or 2500 microg (n = 9) as twice daily and three times daily treatment regimens, with the two regimens assigned randomly as a two-way crossover for each subject and separated by at least a 6 day washout period. RESULTS: Pharmacokinetic analysis indicated a rise in plasma dofetilide concentrations until steady state was attained on day 3. Ctrough had a linear dependence on dose for both the twice daily and three times daily dosing regimens. The maximum concentration attained (Cmax) and the area under the concentration vs time curve (AUC(0,tau) increased linearly with dose for each dosing regimen on both days 1 and 5 of dosing. Cmax occurred at 2 h. Pharmacodynamic measurements showed that the QTc interval increased in a dose-dependent manner and that the time to maximum QTc was 2 h after dosing. A linear relationship was determined between plasma dofetilide concentration and the prolongation of the QTc interval. The slope of this line was significantly greater on day 1 (ranging from 12.9 to 14.2 ms/ng ml-1) than on day 5 (ranging from 9.9 to 12. 8 ms/ng ml(-1). CONCLUSIONS: The pharmacokinetics and pharmacodynamics of dofetilide are predictable and based on a linear relationship for both twice daily and three times daily dosing regimens. The QT responsiveness to dofetilide is greater on day 1 than on day 5.
Since starch synthases IIa (SSIIa) and SSIIb have not been purified from plant tissue, their structure-function relationships have not been well characterized. Therefore, we have expressed these SS genes in Escherichia coli, purified them to apparent homogeneity, and studied their kinetic properties. In addition, the N-terminally truncated forms of these enzymes were studied in an attempt to understand the function of the diverse N-terminal sequences in SS. Our results show that, like SSI, the N-terminal extensions of SSIIa and SSIIb are not essential for catalytic activity and no extensive changes in their kinetic properties are observed upon their N-terminal truncation. Each isoform of SS can be distinguished based on its kinetic properties. Maize SSI and maize SSIIb exhibit higher Vmax with glycogen as a primer, while the converse is true for SSIIa. However, the specific activity of SSIIb is at least two- to threefold higher than that for either SSI or SSIIa. Although SSIIb exhibits the highest maximal velocity of the isoforms compared, its apparent affinity for primer is twofold lower than the affinity of SSI and SSIIa for primer. Perhaps these differences in primer affinity, primer preference, and maximal velocities all contribute in some way to the different structure(s) of starch during its synthesis. Expression and purification of maize SS has now provided us a useful tool to address the role(s) of SS in starch synthesis and starch structure.
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1. Following intravenous administration to animals at 2.5 mg/kg, darifenacin exhibited terminal plasma half-lifes < 2 h due to high plasma clearance (with respect to blood flow) and volumes of distribution greater than total body water. 2. Following oral administration to animals at doses > 4 mg/kg there was evidence of saturation of clearance since oral AUCs exceeded those expected from the high plasma clearances. In addition, terminal plasma half-lifes were greater than those estimated from intravenous administration. 3. In man, oral clearance was high with respect to liver blood flow. 4. Following oral administration of the radiolabelled drug to animals and man, unchanged darifenacin was only a minor component of the faecal radioactivity indicating that darifenacin was well absorbed from the gut. 5. Darifenacin was metabolized by three main routes in all species: monohydroxylation, oxidative dihydrobenzfuran ring opening and N-dealkylation. There were no marked species differences in the metabolism of darifenacin.
PURPOSE: To illuminate the history of nurses' participation in institution-building in the early 1900s, using the Baby Hospital in Oakland, California (now called Children's Hospital Oakland) as a case. DESIGN: Historical research using a framework of women's history theory focused on the women who founded Oakland's Baby Hospital, 1910-1930. METHOD: Data collection included studying original sources, archival material, and interviews. Data evaluation included external criticism for authenticity and genuineness, and internal criticism for accuracy and bias. FINDINGS: In 1912, nurse Bertha Wright and social worker Mabel Weed, with a circle of community women, including Jessica Peixotto and Jean Howard McDuffie, established the Baby Hospital. Their activism included home visits, education, research, publications, political lobbying, and state policy and program development. At the center of this activity, was the lifelong commitment of Wright and Weed, who created new definitions of family. With social changes in the late 1920s, the male Board of Directors seized control of the hospital, and relegated women to auxiliary roles. CONCLUSIONS: Health and social issues of the United States at the turn of the century are still problematic as a new century approaches and pertain to maternal-child health, foster care, and immigration. Feminists, including nurses, have played a central role in creating solutions. Knowledge of some of their incredible effort has been lost, particularly nursing's history in the western United States.
BACKGROUND: The objective of this study was to assess the influence of heart rate on QT-interval duration and dispersion during administration of the new selective potassium-channel blocker dofetilide in normal subjects. METHODS AND RESULTS: Dofetilide 0.25 and 0.75 mg was administered for 4 days to 12 subjects in a randomized-sequence, double-blind, three-period, placebo-controlled, crossover study. QT-RR pairs were measured on study day 4 over a wide range of RR intervals obtained at rest and during an exercise test. QT-interval durations were calculated at seven predetermined RR intervals ranging from 400 ms (150 bpm) to 1000 ms (60 bpm) by use of monoexponential nonlinear curve fitting. QTmax and QTmin were calculated similarly, and QT-interval dispersion was measured as QTmax-QTmin at each predetermined RR interval. Minimal effects were found with 0.25 mg dofetilide. Two hours after administration of 0.75 mg dofetilide, QT interval was prolonged by 16.7 +/- 8.7% at a heart rate of 60 bpm (P < .01) and by 7.4 +/- 8.2% at a heart rate of 150 bpm (P < .05). QT prolongation at a heart rate of 150 bpm was less pronounced than at lower heart rates. Neither placebo nor dofetilide at either dose significantly increased QT-interval dispersion at any heart rate. CONCLUSIONS: Dofetilide increases QT-interval duration but does not increase QT-interval dispersion in healthy subjects. QT-interval prolongation remains significant at high heart rates, although some degree of reverse rate dependence is observed at high concentrations.
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A cross-sectional study was done, focusing on the prevalence of exercise-induced asthma in Jamaica and variables that may account for this rate. No previous study of this nature had been undertaken, and the investigators contend that there is a need to identify children who suffer from this condition but are unaware of it. A sample of 214 students from primary and secondary schools in the Corporate Area were chosen and given questionnaires to complete. Eighty-four of the children reported a history consistent with that of exercise-induced asthma and were further subjected to stress testing for a definitive diagnosis of this condition. A prevalence of 20.8% [C.I. +/- 5.35] was identified which reflected a rate comparable to that recorded in North America. There was a significantly higher prevalence in children of primary school ages, but all other variables considered for significance testing to determine associations between these and the prevalence of EIA proved not significant. A recommendation has been made for opportunity screening by medical practitioners.
The pharmacokinetics of trospectomycin (75-1000 mg free base equivalents) were studied in 128 healthy males (eight per dose group), after a 20 min intravenous (i.v.) infusion and intramuscular (i.m.) injection of trospectomycin sulphate. The concentrations of trospectomycin in serum were described by bi- or tri-exponential disposition functions indicating an initial half-life of 1.1-1.4 h for the i.v. dose and 1.6-2.1 h for the i.m. dose and terminal half-lives of over 15 h. Most of the drug was eliminated rapidly (mean residence time 5-12 h). The distribution volume was 59-112% of body weight and clearance was 112-152 ml min-1. The absorption into blood after i.m. dosing was rapid. The area under the concentration-time curve and maximum concentration values were linearly related to dose. Serum drug concentrations fell below the minimum inhibitory concentration values for a variety of organisms by 8-12 h, which indicates that two or three times daily dosing would be appropriate. However, the long terminal half-life suggests that significant accumulation is likely in some tissues with an 8 h dose interval and this may prolong the action of trospectomycin.
Angiotensin II (AII) stimulation of steroidogenesis is known to be associated with depolarization of the adrenocortical cell membrane. In these cells, membrane permeability to potassium ions governs electrical potential. The effects of AII on the rate of efflux of K+ in relation to the control of aldosterone synthesis has been investigated in bovine adrenocortical cells preloaded with 43K. In static incubations, the pattern of 43K efflux fitted a model with two exponential components with t1/2 values of 47.7 +/- 1.7 and 14.2 +/- 0.6 (S.E.M.) min. AII increased the efflux rate of the slow-exchange component (t1/2 37.1 +/- 0.6 min) and retarded efflux from the fast-exchange component. With ouabain present to prevent reuptake of the isotope, the rate of efflux for both components was increased in unstimulated cells (t1/2 28.4 +/- 1.1 and 12.0 +/- 0.7 min). AII again increased the rate of efflux from the slow component (t1/2 = 24.2 +/- 1.7 min, P less than 0.01) and retarded efflux from the fast component. These biphasic effects were apparent in cells treated with a range of AII concentrations (0.1 nmol/l-1 mumol/l) but the point in time at which increased efflux from the slower component predominated over retardation of the slow component was earlier for cells treated with 1 mumol AII/l than for cells treated with lower concentrations. We suggest that decreases and increases in K+ efflux caused by AII are associated with depolarization and repolarization respectively. Changes in intracellular concentrations of Ca2+ may link these events.
1. The pharmacokinetics and fate of 3H-trospectomycin sulphate, a novel aminocyclitol antibiotic, were examined in male and female rats after intramuscular (i.m.), intravenous (i.v.) and subcutaneous (s.c.) dosing. 2. Total radioactivity levels in plasma were associated with unchanged trospectomycin. Two radioactive components were found in urine, one was indistinguishable from trospectomycin and the other was probably a degradation product formed after excretion or during storage rather than a metabolite. 3. The disappearance of drug from plasma followed a biphasic pattern with half lives of 0.3-0.4 h and 45-80 h and a large distribution volume, which indicated some retention of drug by tissues. Clearance rates were within the normal range for glomerular filtration rate, which indicated that the primary process of elimination is filtration of unchanged drug. 4. Excretion was initially rapid (greater than 40% by 4 h) and mainly into urine (faecal excretion greater than 20%). Urinary excretion was significantly larger in males than females but faecal excretion was significantly smaller, so that there was no significant difference in total excretion. 5. The bioavailability following s.c. dosing was only approximately 75% but there were few other biologically significant differences between the routes of administration. Absorption following i.m. and s.c. dosing was rapid. 6. Clearance rate and volume of distribution were higher in males than females. Over the dose range 50-200 mg/kg the pharmacokinetics appeared to be mostly linear.
Trospectomycin sulfate is a novel aminocyclitol antibiotic. This study evaluated the tolerance and the pharmacokinetics of multiple, intravenous doses of trospectomycin (TRO) in healthy male volunteers. Three groups of 10 volunteers were studied. Eight volunteers in each group were studied in a parallel design to receive trospectomycin (Group 1 = 250 mg, Group 2 = 500 mg, Group 3 = 750 mg) while 2 volunteers received placebo (normal saline). Drug doses were administered in 30 ml volumes over 30 min every 8 h for 7 days (i.e. 21 total doses). Evaluations of vital signs, side effects, and safety laboratory tests were made at regular intervals during the study. The most frequent medical events observed in the volunteers receiving trospectomycin were perioral/facial paresthesias (54%), pain at the i.v. infusion site (46%), dizziness/lightheadedness (58%), and GI symptoms (38%). A statistically significant dose response relationship was observed for the incidence of perioral/facial paresthesias and pain at the i.v. infusion site (i.e., increased incidence with increased dose). All the medical events were mild or moderate in severity and reversible following drug discontinuation. In the 500 and 750 mg trospectomycin groups, standing systolic blood pressure decreased significantly with the first dose of study drug. Elevated levels of SGPT were observed in 9 volunteers (1 in placebo, 3 in 250 mg, 1 in 500 mg, and 4 in 750 mg dose groups). This study demonstrates that multiple intravenous trospectomycin doses up to 750 mg are reasonably well tolerated in healthy male volunteers. The concentration of trospectomycin in serum, measured with a sensitive HPLC assay, was less than 3 mcg/ml at 8 h postinfusion for all dose levels.(ABSTRACT TRUNCATED AT 250 WORDS)
1. The measurement of fluid volumes by the indicator dilution technique and compartmental analysis was re-evaluated in free-swimming, undisturbed rainbow trout. 2. Plasma (33.5 ml/kg body wt) and blood (41.3 ml/kg body wt) volumes estimated by compartmental analysis from blood samples taken early (less than 5 min) after dye injection were 40% lower than volumes calculated by sampling late (greater than or equal to 80 min). 3. The rate of exchange of dye between plasma and interstitial fluid was high (48%/hr) compared to mammals (5%/hr) which supports the hypothesis that teleost capillaries have high protein permeability. 4. Total extracellular volume estimated using a single pool model (210.5 ml/kg body wt) of inulin kinetics was 20% higher than that calculated by a three pool model (172.8 ml/kg body wt).