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Biomedical subjects

W A Kradjan

Publications and source records attributed to W A Kradjan.

At least 19 recordsLinked to original sources
PubMed1994

Lack of interaction between glipizide and co-trimoxazole.

To identify the effects of co-trimoxazole on the elimination and disposition kinetics of glipizide, eight healthy male volunteers were studied in an unblinded, randomized, cross-over trial with two phases (no treatment or co-trimoxazole 160/800 mg twice a day). During each phase, subjects were treated at home for 7 days with one of the treatment regimens, followed by a 24-hour hospitalization for a single-dose challenge with 10-mg oral glipizide and detailed blood studies. A 7-day washout period was interspersed between the phases. Pharmacokinetic and pharmacodynamic parameters were determined and compared using the Student's t-test for paired observations. Glipizide area under the curve (AUC), clearance, and half life for treatment and control phases were 5758 +/- 1874 versus 5176 +/- 1505 micrograms/L/hour (P = .21), 0.41 +/- 0.15 versus 0.45 +/- 0.14 mL/min/kg (P = .27), and 5.13 +/- 2.10 versus 3.95 +/- 1.37 hours (P = .04), respectively. Twenty-four-hour glucose AUCs for treatment and control phases were 112.24 +/- 8.76 versus 114.86 +/- 11.98 mmol/L/hour (P = .55), respectively. The only parameter reaching statistical significance was glipizide half life, but the difference is of doubtful clinical significance because of difficulty in identifying a clear elimination phase in several subjects. It is concluded that co-trimoxazole administration did not significantly alter glipizide disposition and elimination kinetics in this study population.

Adult↗
PubMed1993

Salmeterol: a novel, long-acting beta 2-agonist.

OBJECTIVE: The clinical pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of the long-acting beta 2-agonist salmeterol are reviewed. DATA SOURCES: A MEDLINE search was performed to identify English-language publications pertaining to salmeterol. STUDY SELECTION: Open and controlled trials were reviewed in assessing clinical efficacy. Only the results of controlled, randomized trials were considered in the effectiveness evaluation. DATA EXTRACTION: The primary measures of effectiveness in the clinical trials were bronchodilator activity and reduction of hyperresponsiveness that may reflect antiinflammatory activity. Bronchodilator activity was measured as changes in pulmonary function; reduction of hyperresponsiveness was evaluated using respiratory challenge with methacholine, histamine, allergen, or cold air. Secondary measures included symptom scores, need for rescue doses, and patient preference. DATA SYNTHESIS: Salmeterol is a selective, beta 2-agonist that has been studied in the treatment of exercise-induced, nocturnal, and allergen-induced asthma. Salmeterol interacts with the traditional beta-receptor in a similar manner as other beta-agonists, and it exhibits potent in vitro antiinflammatory effects as an inhibitor of inflammatory mediator release. Less evidence exists for its in vivo antiinflammatory activity. Salmeterol demonstrates prolonged receptor occupancy, which is thought to contribute to its long duration of action. The recommended dose is 50 micrograms via metered-dose inhaler or dry-powdered inhalation. In the published clinical trials, salmeterol was more effective than albuterol in treating asthma, including exercise and allergen-induced asthma. Salmeterol's major advantage over other inhaled beta-agonists is its long duration of action (12 hours), making it an excellent choice for treatment of nocturnal asthma. A potential disadvantage is delayed onset of action. Tachyphylaxis to salmeterol's bronchodilator effects has not been shown, but tolerance to its protective effects against methacholine-induced bronchoconstriction has occurred. Adverse effects reported have been mild and have included headache, tremor, and palpitations. CONCLUSIONS: Salmeterol is an effective beta 2-agonist in the treatment of asthma. However, several issues require further investigation regarding its long-term effects on disease control, significance of antiinflammatory activity, and role as a rescue medication.

Adrenergic beta-Agonists↗
PubMed1992

Effect of age on bronchodilator response.

STUDY OBJECTIVE: Our objective was to compare the differential effects of age and drug type on bronchodilator response. DESIGN: The design was an unblinded, randomized crossover study. SETTING: An ambulatory pulmonary drug study unit was the setting. PATIENTS: Nineteen young (18 to 25 yr) and 17 elderly (greater than 65 yr) stable asthmatic subjects were studied. INTERVENTIONS AND MEASUREMENTS: Albuterol or ipratropium was given on two separate mornings using an MDI with extender. Subjects inhaled two puffs initially and then one puff every 30 min to a total of six puffs. Pulmonary function, blood pressure, and pulse were measured at baseline and every 30 min for 3 h. RESULTS: All subjects had a greater than 15 percent increase in FEV1 with one or both drugs. More patients responded to albuterol than to ipratropium in both age groups. The maximum percentage of change from baseline was greater (p less than 0.05) with albuterol (mean, 40.1 percent in young and 60.5 percent in old) than with ipratropium (21.2 percent in young; 31.2 percent in old) in both groups. These differences remain significant after correction for baseline differences using area-under-the-curve analysis of the percent of maximum improvement; however, the differences between age groups for the same drug were not statistically significant by either index of change. There were also no differences between drugs or between age groups for time (or number of puffs) to reach maximum improvement (mean, 2.0 to 2.2 h for albuterol and 1.6 to 1.7 h for ipratropium). The changes in FVC and FEF25-75% were similar to FEV1. Changes in blood pressure and pulse were not significant. Three subjects stopped therapy with albuterol with side effects. CONCLUSIONS: Both drugs are effective bronchodilators in young and old asthmatic subjects, but albuterol results in a greater magnitude of response in both age groups. Age is not a predictor of response to either drug.

Adolescent↗
PubMed1989

Glipizide pharmacokinetics: effects of age, diabetes, and multiple dosing.

Aging and disease may contribute to alterations in drug pharmacokinetics. The purpose of this study was to determine the effects of aging, the presence of NIDDM, and multiple dosing on the pharmacokinetics of glipizide, an oral hypoglycemic drug. Ten healthy young men (under age 25), ten healthy older men (over age 65) and 15 older diabetic men ingested a single 5 mg tablet of glipizide after an overnight fast. Blood samples for measurement of serum glipizide were obtained over the next 24 hours. The study was repeated in the diabetics after 2 weeks of daily therapy. The mean values for Tmax (range 2.0-2.5 hours), Cmax (385-465 micrograms/l), and t1/2 (4.0-4.2 hours) were not significantly different in the three populations after single doses of glipizide. Several subjects in each population had slow absorption, with peak concentrations delayed for up to 12 hours. Only one elderly diabetic subject had evidence of drug accumulation at steady state. AUC, Cl, Vss and V area were not significantly different in the three populations or at steady state, but there was a trend for AUC to be smaller and each of the other parameters to be increased in the older diabetics. The young subjects had a significantly higher fp (0.83%) than either of the two elderly groups (0.55-0.64%), but Cl int did not differ between groups. Age, diabetes, and multiple dosing appear to have little effect on the pharmacokinetics of glipizide and should have little influence on the clinical response to this drug.

Adult↗
PubMed1988

Single-dose efficacy and safety of zindotrine, a new oral bronchodilator.

Zindotrine, a new bronchodilator, may be an alternative to theophylline in treating reversible airflow obstruction. Efficacy and cardiovascular effects of a single 300 mg oral dose of zindotrine were compared with placebo in a two-period, double-blind, crossover trial. Twelve subjects with airflow obstruction reversible after isoproterenol and theophylline completed the trial. Improvement in pulmonary function (forced vital capacity [FVC], forced expiratory volume in one second, and forced expiratory flow rate from 25 to 75 percent of FVC) was greater after zindotrine than with placebo. Pulmonary function tests increased 15 percent or more over baseline in 30 minutes after active drug, lasting up to 6 hours. Mild decreases in heart rate and mean blood pressure occurred after both treatments, with changes equal in both treatment groups. Six subjects had mild subjective side effects after zindotrine (headache, dizziness, vertigo, flushing, and heartburn) compared with one report of lightheadedness after placebo. A single dose of zindotrine 300 mg provides effective bronchodilator action with a relatively prolonged response and tolerable side effects.

Adult↗
PubMed1988

Glipizide pharmacokinetics in young and elderly volunteers.

The effects of aging on the pharmacokinetics of glipizide were studied. Ten healthy young men (24.9 +/- 1.9 years of age) and 10 healthy older men (74.4 +/- 7.9 years of age) each ingested a single 5-mg tablet of glipizide after an overnight fast. Blood samples were obtained immediately before drug ingestion and at 10, 20, 30, 45, 60, 90, and 120 minutes and at 3, 4, 6, 8, 10, 12, and 24 hours after drug ingestion. Serum samples were assayed for glipizide content by a modified high-pressure liquid chromatographic method. Clearance, volume of distribution at steady state, and half-life were estimated from the serum concentration-time curve data. Area under the concentration-time curve and area under the moments curve were calculated using the trapezoidal rule. The mean values for young and older subjects for time to peak concentration (2.1 versus 2.5 hours), peak concentrations (465 versus 399 micrograms/mL), elimination half-life (4.2 versus 4.0 hours), clearance (38.8 versus 38.1 mL/min), and distribution volume at steady state (12.5 versus 14.3 L) were not significant. However, two older individuals had a markedly prolonged time to peak concentration (six to eight hours). For 8 of the 20 subjects a more prolonged terminal half-life may have existed. Further study is required to determine whether significant pharmacokinetic differences between young and elderly subjects appear with multiple dosing of glipizide.

Adult↗
PubMed1985

Atropine serum concentrations after multiple inhaled doses of atropine sulfate.

Atropine may be given by inhalation for bronchodilation. Intravenous atropine at doses of 0.32 to 1 mg yields serum levels of 2 to 6 ng/ml, with an elimination t1/2 of about 4 hours. Efficient inhalation of large single doses leads to similar concentrations in some individuals, but under clinical conditions drug delivery may be less efficient. Of concern is accumulation of the drug in the body with multiple-dose therapy. We measured serum levels of atropine after single inhaled doses and again after 48 to 72 hours of inhalation every 4 to 6 hours in 11 subjects. The drug was administered by therapists at doses and techniques commonly used in the clinical setting. Serum concentrations of atropine were negligible after the first dose in all subjects but were detectable in six of nine subjects who received the drug for more than 48 hours. Three of the subjects had levels greater than 2 ng/ml.

Absorption↗
PubMed1985

Efficiency of air compressor-driven nebulizers.

Five different volumes of test solutions (1 to 3 ml) containing 15 mg of metaproterenol were placed in each of five different nebulizers. The time to complete nebulization and the amount of drug delivered varied considerably, depending upon the initial volume of solution placed in the nebulizer. Small volumes (1 ml) were almost totally retained in the nebulizer, whereas larger volumes (3 ml) took an unacceptably long time for nebulization. With vigorous agitation, a maximum of 53 to 72 percent of the dose left the nebulizer, but even less (34 to 59 percent) was delivered under simulated clinical conditions. When nebulization was synchronized with breathing, only 0.33 to 0.54 ml of solution (2 to 3.2 mg of metaproterenol) was delivered with 90 deep inhalations. If nebulization was continuous instead of intermittent during the time to take 90 breaths, the majority of the drug was nebulized to the atmosphere.

Aerosols↗
PubMed1982

Effect of hemodialysis on the pharmacokinetics of theophylline in chronic renal failure.

We studied theophylline elimination in 8 patients with chronic renal failure to determine the effect of hemodialysis on the pharmacokinetics of theophylline. Each subject was studied twice, once on a nondialysis day and again during dialysis. Total body theophylline clearance on the nondialysis day was similar to that reported for patients with normal renal function (57.4 +/- 27.2 ml/kg/h). Hemodialysis accelerated theophylline elimination and shortened serum theophylline half-life in all patients (nondialysis t 1/2 = 7.3 h +/- 2.3 vs. dialysis t 1/2 = 2.7 +/- 0.9 h, p less than 0.01). Dialysis clearance averaged 59.7 +/- 16.4 ml/kg/h with a fraction of drug removed of 0.4 liters in 4 h. Guidelines for theophylline management during hemodialysis are suggested.

Adult↗
PubMed1982

Inhaled atropine sulfate: dose-response characteristics in adult patients with chronic airflow obstruction.

Dose-response characteristics of inhaled atropine sulfate were examined in ten patients with chronic airflow obstruction using spirometric and plethysmographic measurements. Inhaled atropine in doses of 0.005, 0.01, 0.25, and 0.05 mg2kg of body weight and placebo were delivered by means of a precision metering device. All pulmonary function tests (FEV1, V50, and SGaw) improved progressively with increasing dose. There was a high degree of linear correlation between the peak response of each test and the logarithm of dose (r greater than or equal to 0.98). The highest dose studied (0.05 mg/kg) was found to have marginal benefit over 0.025 mg/kg, and had the highest incidence of adverse reactions. Duration of effect was dependent on dose. These results suggest that for adult patients with chronic airflow obstruction, 0.025 mg/kg delivered by a dosimeter approximates the optimally effective dose of inhaled atropine sulfate that can be given without unacceptable side effects.

Aerosols↗
PubMed1981

Serum atropine concentrations after inhalation of atropine sulfate.

Six male subjects with chronic bronchitis were given a single aerosol dose of atropine sulfate (0.05 mg/kg). Spirometry and venous blood samples were obtained before and at 0.25, 0.5, 1.0, 1.5, 2.0, and 4.0 h after inhalation of drug. All subjects had a satisfactory bronchodilator response and detectable serum concentrations of atropine within 15 min. Measurable serum concentrations persisted for 4 h with apparent continued slow absorption occurring throughout the entire time interval. The maximal concentrations achieved ranged from 1.3 to 5.8 ng/ml in five subjects. A sixth subject achieved much higher concentrations (as high as 21 ng/ml) and experienced systemic side effects. This latter concentration is comparable to those achieved with doses of 1.5 to 2.0 mg of parenteral atropine. Significant systemic absorption may occur after inhalation of atropine sulfate, although the degree of absorption is variable.

Aerosols↗
PubMed1981

Atropine and terbutaline aerosols in chronic bronchitis: efficacy and sites of action.

To examine the additive properties and the sites of action of inhaled atropine sulfate (0.05 mg/kg of body weight) and terbutaline sulfate (0.005 mg/kg) in patients with chronic airflow obstruction, we tested these aerosols separately and together in a double-blind random sequence. Twelve patients with chronic bronchitis and perennial obstruction of airflow were studied by measuring three indices of efficacy (specific airway conductance [Gaw/VL], the forced expiratory volume in one second [FEV1] and the forced vital capacity [FVC]) and three indices of the site of action within the airway (delta [(Gaw/VL)/FEV1], the difference between the change in forced expiratory flow at 75 percent of vital capacity and the change in forced expiratory flow at 25 percent of vital capacity, and the change in density dependence of maximal airflow at 50 percent of vital capacity). Both atropine and the combination of atropine and terbutaline improved all indices of efficacy significantly more than did terbutaline. With individual exceptions, the addition of terbutaline to atropine improved Gaw/VL but not forced airflow. All measures of site of action suggested an advantage for atropine in relatively proximal airways. These results indicate that combined therapy with beta-adrenergic and anticholinergic bronchodilator drugs is marginally more effective than therapy with atropine alone in these patients and suggest that anticholinergic aerosols dilate larger airways more effectively than the beta-agonists.

Aerosols↗
PubMed1981

Allergy to aminophylline: lack of predictability by skin testing.

Problems with determining hypersensitivity to aminophylline, ethylenediamine, and theophylline with intradermal skin tests and patch tests are reported in three patients. Three patients were tested with intradermal injections of 0.9% sodium chloride, 1% aminophylline, 1% ethylenediamine, and 0.5% theophylline following apparent allergic reactions to aminophylline. Patch testing using hydrophilic ointment base, 1% aminophylline, 1% ethylenediamine, and 0.5% theophylline was also done. All three patients had no reaction to intradermal sodium chloride or theophylline; all patch tests were negative. The first patient reacted to ethylenediamine strongly and to aminophylline more weakly; punch biopsy of the ethylenediamine reaction site showed a direct toxic effect with no allergic component. Punch biopsy of the aminophylline site showed a typical hypersensitivity reaction. Two concentrations (0.5% and 1.0%) of ethylenediamine injection were used to test the second patient, and he reacted to both concentrations but not to any other injections. His positive reactions contained blisters rather than the typical wheal-and-flare reaction of hypersensitivity. The third patient had similar responses including reactions to 0.5% and 0.1% ethylenediamine (he was not tested with 1% ethylenediamine). Skin testing may be of value in predicting aminophylline or ethylenediamine allergy, but the nonspecific toxic effect of ethylenediamine makes interpretation difficult.

Aged↗
PubMed1980

In vivo inactivation of gentamicin by carbenicillin and ticarcillin.

Inactivation of aminoglycosides by carbenicillin and ticarcillin is a well-recognized in vitro phenomenon. Isolated case reports of in vivo inactivation of gentamicin by either carbenicillin or ticarcillin exist. We report a case of nearly complete in vivo inactivation of gentamicin by both ticarcillin and carbenicillin in the same patient. In the absence of either of the penicillin derivatives, the patient demonstrated predictable plasma concentrations and elimination characteristics of both gentamicin and tobramycin. As in previous reports, the interaction was intensified by high-dose carbenicillin-ticarcillin therapy in the face of underlying renal impairment. When using ticarcillin or carbenicillin along with gentamicin in renally impaired patients, special attention must be paid to both the gentamicin and carbenicillin-ticarcillin doses used and the plasma concentrations obtained.

Acute Kidney Injury↗