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Biomedical subjects

C T Ueda

Publications and source records attributed to C T Ueda.

At least 19 recordsLinked to original sources

Factors affecting pharmacists' selection of rural or urban practice sites in Nebraska.

A questionnaire was used to determine why pharmacists in Nebraska chose urban or rural practice sites and to help the University of Nebraska College of Pharmacy encourage students to consider rural practice. Questionnaires were mailed to 1427 Nebraska pharmacists to gather data about their practice, job satisfaction, location of rearing, location of spouse's rearing, and prepharmacy and clerkship training. Usable responses were sorted into those from urban pharmacists (residing in Omaha and Lincoln and their suburban areas) and those from rural pharmacists (all others). Of the 689 usable responses, 315 (45.7%) were from urban pharmacists and 374 (54.3%) were from rural pharmacists. Of the rural pharmacists, 93% [corrected] grew up in communities of fewer than 100,000 people and 60% grew up in communities of fewer than 5,000 people. Respondents cited income potential, desirability of practice site, influence of spouse and family, and quality of children's schools as factors that most influenced their choice of practice site. Based on the survey results, the University of Nebraska College of Pharmacy took actions to recruit students from rural communities and increase students' exposure to rural practice settings. Pharmacists who were reared or trained in rural areas were more likely to practice in rural Nebraska than pharmacists who had only urban experience.

Career Choice

Radiolabeled 9- or 10-monoiodostearic acid and 9- or 10-monoiodostearyl carnitine--I. Synthesis and purification.

The purpose of this investigation was to synthesize and purify radiolabeled 9- or 10-monoiodostearyl carnitine for potential use as a perfusion and metabolic imaging agent for the heart. Oleic acid was iodinated via a free radical addition reaction of HI across the double bond to give 9- or 10-monoiodostearic acid which in turn was esterified with carnitine. The identity of 9- or 10-monoiodostearic acid and 9- or 10-monoiodostearyl carnitine was determined using nuclear magnetic resonance (NMR), infrared (i.r.), ultraviolet (u.v.), and mass spectroscopy. The purity of the fatty acid and carnitine ester was established by thin layer chromatography. 9- or 10-Monoiodo[125I]stearic acid and 9- or 10-monoiodo[125I]stearyl carnitine were synthesized via the isotopic exchange of 125I for cold iodine bonded to 9- or 10-monoiodostearic acid and 9- or 10-monoiodostearyl carnitine.

Carnitine

Amiodarone pharmacokinetics. III. Influence of thyroid dysfunction on amiodarone absorption and disposition.

Hypothyroid, hyperthyroid and euthyroid rats were given 45 or 80 mg/kg i.v. or 100 mg/kg p.o. of amiodarone hydrochloride to determine the effects of thyroid dysfunction on the absorption and disposition characteristics of amiodarone. Serial blood samples were obtained for 48 hr and assayed for amiodarone and desethylamiodarone by high-performance liquid chromatography. In the hypothyroid rats, reductions in amiodarone clearance (CL) of 73% (26.9-7.3 ml/min/kg) and 61% (18.7-7.3 ml/min/kg) were observed with the 45- and 80-mg/kg i.v. bolus doses, respectively. Accompanying the decreases in CL were increases in the terminal disposition half-life (T1/2 gamma), 89% (18-34 hr) with the 45-mg/kg dose and 185% (20-57 hr) after the 80-mg/kg dose. The steady state (Vss) and apparent (Vd) volumes of distribution were smaller at the lower dose but were invariant after administration of the larger dose. Furthermore, the central compartment volume was not altered. In the hyperthyroid rats, a 67% increase in CL (12.8-21.4 ml/min/kg) and 75 to 80% increases in Vss (15.5-27.1 liters/kg) and Vd (25.0-44.8 liters/kg) were observed with the 45-mg/kg of amiodarone dose. However, no changes in CL, Vd and Vss were seen with the 80-mg/kg dose. Furthermore, gamma, T1/2 gamma and central compartment volume were not altered in the hyperthyroid rats. The effects of thyroid dysfunction on the p.o. bioavailability characteristics of amiodarone were minor. These studies demonstrated that the disposition kinetics of amiodarone are altered in hypo- and hyperthyroidism.

Amiodarone

Amiodarone pharmacokinetics. I. Acute dose-dependent disposition studies in rats.

Single intravenous bolus doses of amiodarone hydrochloride of 30, 60, 90 and 120 mg/kg were administered to male Sprague-Dawley rats to determine the effects of dose on amiodarone pharmacokinetics. Serial blood samples and total urine were collected over 48 hr and assayed for amiodarone and desethylamiodarone by HPLC. The blood amiodarone concentration-time curves for the four doses were best described by a triexponential equation with terminal half-lives (t1/2 gamma) ranging from 17 to 20 hr. Over the dose range studied, no changes in gamma, t1/2 gamma, or central compartment volume (Vc = 1.2-1.4 L/kg) were observed. On the other hand, reductions in amiodarone clearance (CL) and steady-state volume of distribution (Vss) of 44% (17.7 to 10.0 ml/min per kg) and 50% (16.4 to 8.2 L/kg), respectively, were noted as the dose of amiodarone increased. The conversion of amiodarone to desethylamiodarone (fm) was dose-independent and amounted to approximately 10% of each amiodarone dose. No amiodarone or desethylamiodarone was detected in the urine of any of the treated animals. The blood-to-plasma concentration ratio of amiodarone was concentration-independent and therefore did not account for the dose-dependent changes in Vss and CL observed. The data suggested that the dose-dependent changes noted were due to an alteration in the volume (s) of the peripheral tissue compartment(s).

Amiodarone

Quinidine and dihydroquinidine interactions in human plasma.

The protein-binding characteristics of dihydroquinidine, a known impurity in drug grade quinidine, in human plasma and the effects of dihydroquinidine on quinidine interactions with these plasma constituents were studied by equilibrium dialysis. In the plasma concentration range of 1.75-23.0 mg/liter, dihydroquinidine binding was similar to the binding observed with quinidine. The data suggested the presence of a single class of binding sites for both compounds in the plasma drug concentration range and samples studied. The mean values for the association constant, K, and the total concentration of binding sites, nPt, for dihydroquinidine were 4.75 +/- 0.67 X 10(4) M-1 and 5.78 +/- 0.17 x 10(-5) M, respectively. The corresponding values for quinidine were 4.78 +/- 1.00 x 10(4) M-1 and 5.65 +/- 0.48 x 10(-5) M. In the presence of 5 and 10% (of total alkaloid content) dihydroquinidine, the plasma concentration of unbound quinidine did not change significantly. At a 20% level of dihydroquinidine, however, an increase in unbound quinidine was observed (p less than 0.05). The elevations in free quinidine concentrations were directly related to the level of dihydroquinidine present. The results of this study indicate that the interactions between dihydroquinidine and quinidine for binding sites on human plasma proteins are competitive.

Binding, Competitive

Pharmacokinetics of dihydroquinidine in congestive heart failure patients after intravenous quinidine administration.

The pharmacokinetics of dihydroquinidine were studied in 8 patients with congestive heart failure following a 22 min intravenous infusion of a quinidine preparation that contained 5.9% dihydroquinidine as an impurity. Using a thin layer chromatography-fluorometric assay procedure for dihydroquinidine, the post-infusion plasma dihydroquinidine concentrations declined biexponentially. The half-life of the fast and slow dispositional processes was 4.42 +/- 1.81 min and 6.52 +/- 2.40 h, respectively. The central compartment volume for dihydroquinidine in these patients was 0.44 +/- 0.11 l/kg with an overall apparent volume of distribution of 1.14 +/- 0.38 l/kg. The computed values of total body plasma clearance of dihydroquinidine ranged from 1.29 to 2.69 ml/min/kg with a mean value of 1.94 +/- 0.60 ml/min/kg. In these patients, approximately 16% of the administered dihydroquinidine dose was excreted intact into the urine in 48 h. The estimated value of renal clearance was 0.314 +/- 0.129 ml/min/kg. When compared to control cardiac patients, the data showed that the apparent volume of distribution for dihydroquinidine is smaller in patients with congestive heart failure and as a result of this diminished volume, the clearance rate of dihydroquinidine was slower. The net effect of these differences was the production of higher plasma concentrations of dihydroquinidine in the heart failure group.

Adult

In vitro and in vivo characteristics of some commercial phenobarbital tablets.

Using an incompletely randomized crossover study design, the oral bioavailability characteristics of 7 different brands of phenobarbital tablets, USP, 100 mg was investigated in 5 adult, male volunteers. From plasma drug concentration-time data, best estimates for the bioavailability parameters of peak plasma phenobarbital concentration (Cmax) and time to peak concentration (tmax) were obtained by curve fitting and area under the plasma drug concentration-time curve (AUC) computed with the trapezoid rule. No significant difference in Cmax or normalized AUC was seen for the 7 products investigated. Additionally, a difference in tmax was observed between 2 preparations (A and E) only (p less than or equal to 0.05). All drug products met USP requirements for weight variation and tablet disintegration and all but one product (D) exhibited reasonably good and similar dissolution characteristics in simulated gastric fluid. No correlation between various in vitro dissolution parameters and in vivo bioavailability of phenobarbital could be found for the 7 phenobarbital products studied.

Adult

Apparent stability of nitroglycerin in dextrose 5% in water.

The apparent stability profile of nitroglycerin (NTG) in dextrose 5% in water when packaged in glass bottles and plastic bags was studied under the following conditions: room temperature (25 +/- 1 C) and room light, room temperature protected from room light, and refrigeration (4 C). NTG stability was assessed by monitoring drug disappearance from solution over a period of five hours after preparation of the admixtures. A spectrophotometric assay was used. There appeared to be no difference in the apparent rate of NTG disappearance when prepared in either glass bottles or plastic bags. Protection of the drug solutions from room light had no apparent effect on the disappearance pattern of NTG. Furthermore, although refrigeration of the NTG solutions appeared to increase the stability of the admixtures, this effect was not seen until approximately four to five hours after preparation of the solutions. It is possible that sorption onto the walls of the glass bottles and plastic bags may account for the observed disappearance of admixed NTG in dextrose 5% in water.

Colorimetry

Clinical and electrophysiological effects of intravenous quinidine in man.

Quinidine gluconate (total dose 4-4 to 9-1 mg/kg) was infused intravenously over 22 minutes in 20 patients with either frequent premature ventricular contractions or supraventricular arrhythmias, 16 of whom had bundle-branch block. Therapeutic plasma quinidine levels (3 to 7 mg/l) were achieved in 15. Heart rate, atrioventricular nodal, and infranodal conduction times did not change significantly. The QRS duration increased significantly from 128+/-30 to 134+/-29 ms at peak plasma quinidine levels (P less than 0.01). Mild hypotension occurred during infusion in most patients. Two patients had a severe but transient toxic response characterised by hypotension, nausea, vomiting, and diaphoresis. Atrioventricular dissociation with escape His bundle or fascicular rhythm occurred in 1 patient with sinus bradycardia. Bundle-branch block does not contraindicate administration of quinidine. Quinidine gluconate administered intravenously (0-3 to 0-4 mg/kg per min) is frequently associated with hypotenstion and should be used only in an intensive care setting and with careful monitoring of blood pressure.

Arrhythmias, Cardiac

Concentration-time effects of quinidine disposition kinetics in rhesus monkeys.

The effects of dose and duration of drug administration (time) on the disposition kinetics of quinidine were investigated in unanesthetized rhesus monkeys. A specific thin-layer chromatography-fluorometric assay was developed for the determination of quinidine in plasma, blood and urine. After the monkeys receive an i.v. bolus dose of 3 to 7 mg/kg, quinidine distributes rapidly in the body (T 1/2alpha = 2 minutes). The half-life associated with elimination (T 1/2 beta) was 27 to 35 minutes and primarily involved metabolic transformation. The volume of distribution varied between 0.2 and 0.65 liters/kg and total clearance between 4.8 and 13 ml/min/kg. Similar estimates of T 1/2 beta, clearance and volume of distribution were obtained following constant infusions producing steady-state concentrations less than 6 microng/ml. Prolonged infusion of quinidine at rates producing plasma concentrations in the range of 6 to 13 microng/ml resulted in increases in the elimination half-life whereas drug clearance remained constant. This observation suggests an increased volume of distribution. Both concentration and time were demonstrated to be important in producing changes in quinidine disposition kinetics. The precise mechanism underlying this phenomenon remains unanswered.

Animals

Disposition kinetics of quinidine.

The disposition kinetics of quinidine in 12 hospitalized patients in whom oral quinidine therapy was to be initiated is described. Quinidine in doses of 2.6 to 5.2 mg/kg base were infused intravenously over 22 min. Plasma samples were collected during the postinfusion for 24 hr and analyzed by a specific and sensitive assay procedure. In the 12 hr after administration, postinfusion plasma quinidine concentration decay was described by a biexponential equation. Attempts to include the 24-hr data point in the fitting procedures resulted in poorer agreements between the theoretical and experimental curves. A 2-compartment open model is proposed to describe the disposition of quinidine. The volume of the central pool (Vc) and steady-state volume of distribution (Vdss) were 0.91 +/- 0.11 L/kg and 3.03 +/- 0.25 L/kg, respectively, and indicate that quinidine distribution is predominantly extravascular. Quinidine distribution was quite rapid (t1/2alpha = 7.19 +/- 0.70 min), while the apparent elimination half-life (t1/2beta) was considerably longer, 6.333 +/- 0.47 hr. Total body plasma clearance ranged from 1.49 to 7.15 ml/min/kg (mean 4.70) and is primarily associated with nonrenal mechanisms of drug elimination. Urine specimens collected for 48 hr indicated that 17% of the dose is excreted intact and that urinary excretion was essentially complete within 24 hr. Renal clearance (Clr) was 0.80 +/- 0.18 ml/min/kg. The study demonstrated that there is substantial interpatient variability with respect to quinidine disposition.

Adult

Absolute quinidine bioavailability.

The absolute bioavailability of quinidine was studied in 11 hospitalized patients. A 400-mg dose of quinidine gluconate was administered to each patient by intravenous infusion and as an oral solution. Drug treatments were separated by a 72-hr period. In 8 patients, peak plasma quinidine concentrations were reached in 65 min after the oral dose; in the remaining 3 subjects, peak concentrations were reached later. From the ratio of the total area under the plasma concentration-time curves (AUCoral/AUCir), the absolute bioavailability of quinidine ranged from 44% to 89% (mean, 72). In 8 patients, the ratio of the total amount of quinidine excreted in the urine in 48 hr (AUinfinity oral/AUinfinity ir) indicated that the extent of quinidine bioavailability varied form 47% to 96% (mean, 73). The predicted bioavailability of quindine due to first-pass effects was 76+/-11%. It is concluded that absorption after the oral solution was rapid and that the reduction of quinidine bioavailability was due to first-pass hepatic drug removal.

Administration, Oral

Novel method for the determination of pediatric dosages.

A method by which safe and effective pediatric dosages can be estimated is presented. The method is based on the facts that drugs distribute into body water compartments and that these compartments are significantly different between pediatric and adult populations. The method discussed is tested using data reported in the literature.

Age Factors

Disposition kinetics of dihydroquinidine following quinidine administration.

The disposition kinetics of dihydroquinidine, a known impurity in drug grade quinidine, was studied in 7 patients who were hospitalized for control of cardiac arrhythmias. Quinidine gluconate injection containing 5.4 to 6.2 percent dihydroquinidine was used. Following an overnite fast, dihydroquinidine doses of 0.16 to 0.31 mg/kg base were infused intravenously over 22 min. Plasma samples were collected at various times for 12 hr and analyzed for dihydroquinidine by a thin layer chromatography-fluorometric assay procedure. Postinfusion plasma dihydroquinidine concentration decline was described by a biexponential equation which suggested that the impurity distributes within the body in two kinetically distinguishable pools. The volume of the central pool (Vc) and steady-state volume of distribution (Vdss) were 0.67 +/- 0.15 L/kg and 2.76 +/- 0.63 L/kg, respectively. The halflife of the fast (t1/2alpha) and slow (t1/2beta) disposition processes were 4.71 +/- 0.26 min and 5.71 +/- 1.00 hr. Total plasma clearance was 4.17 +/- 0.68 ml/min/kg. Renal excretion of intact dihydroquinidine accounted for 16 percent of the administered dose. The corresponding value for renal dihydroquinidine clearance (Clr) was 0.61 +/- 0.08 ml/min/kg. The results of this study indicated that there were no significant differences in the distribution and elimination characteristics of dihydroquinidine and quinidine.

Adult

Amiodarone pharmacokinetics. II. Disposition kinetics following subchronic administration in rats.

A 30 mg kg-1 intravenous bolus of 14C-amiodarone (19 microCi kg-1) was given to male Sprague-Dawley rats pretreated with 0 (vehicle), 25 or 100 mg kg-1 day-1 of amiodarone HCl orally for 37-42 days to determine the effects of dose and duration of administration on the disposition kinetics of amiodarone. Serial blood samples and total urine were collected over 48 hours and assayed for 14C-amiodarone by liquid scintillation counting following separation by HPLC. In all three groups, the blood 14C-amiodarone concentration-time curves declined bioexponentially with terminal half-lives (t1/2 beta) ranging from 14-22 hours. No differences in beta, t1/2 beta, or central compartment volume (Vc) were observed between the three groups of rats. In the rats pretreated with 100 mg kg-1 day-1 of amiodarone HCl for 5-6 weeks, amiodarone clearance (CL) and steady state volume of distribution (Vss) were reduced 52 per cent (12.2 to 5.9 ml min-1 kg-1) and 41 per cent (11.73 to 6.97 l kg-1), respectively. At the lower amiodarone daily dose, no changes in CL or Vss were observed. Negligible levels of radioactivity were detected in the urine. Amiodarone accounted for approximately 30-40 per cent of the total radioactivity in each blood specimen. This study demonstrated that CL and Vss were dose-dependent, and that beta, t1/2 beta and Vc were dose-independent. The results further suggested that the disposition kinetics of amiodarone were independent of the duration of drug administration.

Amiodarone

Further observations on the disposition characteristics of salicylic acid in analbuminemic rats.

The disposition characteristics of salicylic acid (SA) were investigated in analbuminemic rats after intravenous bolus injection of 10 and 173 mg kg-1 of SA to study the effects of plasma protein binding on drug disposition. Following the administration of 10 mg kg-1 of SA, total body SA clearance (CL) was markedly faster and its apparent volume of distribution (Vd) significantly greater in the analbuminemic rats in comparison to the controls. Further, the apparent elimination rate constant (kj) was two-fold greater and the corresponding elimination half-life (t 1/2) shorter in the rats with low plasma albumin. Whole body autoradiograms obtained following the administration of 14C-salicylic acid demonstrated that the tissue distribution of SA was greater in the analbuminemic rats which was in agreement with the larger Vd observed in this group of rats. After the administration of 173 mg kg-1 of SA, no differences in CL, Vd, kk or t 1/2 were noted between the analbuminemic and control rats. Dose-dependent SA disposition was observed in both the analbuminemic and control rats with the effects being more pronounced in the rats with low plasma albumin. The results suggested that the disposition characteristics of SA were markedly altered in the presence of low plasma albumin concentrations due to reduced plasma SA protein binding.

Animals

Comparative bioavailability characteristics of commercial quinidine polygalacturonate and sulfate tablets.

This study compared the relative bioavailability characteristics of quinidine polygalacturonate (QP) and quinidine sulfate (QS) after oral administration of commercial tablets and a liquid form prepared from crushed tablets in 13 healthy adult male volunteers. Each subject received the following four single-dose treatments in a randomized, crossover manner with a one-week washout period between treatments: 400 mg QS liquid, two 200-mg QS tablets, 550 mg QP liquid, and two 275-mg QP tablets. All four treatments were equivalent in terms of the dose of quinidine base. Multiple serum samples and two 24-hour urine specimens were collected over 24 and 48 hours, respectively, and assayed for quinidine with a specific HPLC assay method. For the absorption and disposition parameters measured (maximum serum concentration, time to reach maximum concentration, area under the concentration-time curve [0-48 hours], absorption and elimination rate constants, absorption and elimination half-lives, apparent total body clearance, apparent volume of distribution, and dose fraction excreted in the urine) no significant differences were observed for any of the parameters among the four treatments (p greater than 0.05). The results of the present investigation demonstrated that QP and QS produced identical serum quinidine concentration-time curves when given in the form of a tablet or liquid. The clinical implications of these observations with respect to the dosing of QP are discussed.

Adult