Search PubMed⌕ Search

Biomedical subjects

L J Lesko

Publications and source records attributed to L J Lesko.

At least 73 records · Page 4Linked to original sources
PubMed1983

Clinical pharmacokinetics and efficacy of amiodarone for refractory tachyarrhythmias.

Using a high-pressure liquid chromatographic assay, we measured serum amiodarone concentrations serially in 122 patients treated with amiodarone for 1.5-53 months (mean 9.3 months) for control of refractory symptomatic atrial or symptomatic and life-threatening ventricular tachyarrhythmias. The atrial tachyarrhythmias were successfully controlled in 45 of 54 patients (83%) during a mean follow-up of 10.0 months. In the ventricular tachyarrhythmia group, which included 22 survivors of sudden cardiac death, 38 of 50 patients (76%) responded to amiodarone during a mean follow-up of 10.9 months. Although the mean serum amiodarone concentration did not differ between responders and nonresponders, eight responders relapsed when their serum concentration fell below 1.0 mg/l. Side effects resulted in withdrawal of amiodarone in only 10 of 122 patients (9%) despite a 30% overall incidence of side effects. Central nervous system and gastrointestinal side effects became more frequent with serum concentrations greater than 2.5 mg/l, although only central nervous system side effects achieved statistical significance. Absorption and disposition kinetics of a single oral 800-mg dose of amiodarone were studied in eight patients. Serum values were measured for 24 hours in five patients during maintenance therapy, and elimination kinetics after long-term therapy were evaluated in three patients. The tissue concentration of amiodarone was determined in two patients who died during long-term amiodarone therapy and an attempt was made in 14 patients to correlate serum concentrations with daily dosages during maintenance therapy. The pharmacokinetics of oral amiodarone support the practice of using high loading dosages until arrhythmia suppression or apparent steady state is achieved (usually 2-4 weeks), followed by low-dose maintenance therapy (200-600 mg once a day) for treatment of symptomatic atrial and ventricular tachyarrhythmias.

Adult↗
PubMed1983

Amiodarone for tachyarrhythmias: pharmacology, kinetics, and efficacy.

Amiodarone, although widely studied in Europe, is a recent addition to the investigational antiarrhythmics being used in the U.S. Pharmacologically, its primary cardiac effects are to increase coronary artery blood flow, increase the effective refractory period, and produce an atropine-resistant bradycardia. Amiodarone is incompletely (approximately 50 percent) and slowly (peak serum concentration approximately 6 h) absorbed. With chronic administration, it deposits both in adipose tissue and in organs with high blood perfusion. It has an apparent elimination half-life of 15-45 days, which presents unique dosing problems. The apparent therapeutic range is 0.6-3 microgram/ml. Amiodarone is 85-95 percent effective in the treatment of atrial tachyarrhythmias and 70-80 percent effective in ventricular tachyarrhythmias. It appears to be of particular value in chronic atrial fibrillation/flutter because it may be able to maintain sinus rhythm after cardioversion. Side effects, although uncommon, may prevent the drug from becoming a standard of therapy. Drug interactions, particularly with warfarin and digoxin, as well as pulmonary fibrosis are of concern.

Amiodarone↗
PubMed1983

Lithium test-dose methodology using flame photometry: problems and alternatives.

Two published methods of assessing test-dose 24-hour serum lithium concentrations as measured by flame emission spectrophotometry were compared in 17 patients. The first method was unsuccessful in predicting required maintenance dosage in 53% of patients studied. By applying the second methodology, a strong positive correlation (r = 0.69) was obtained between the reciprocal of the maintenance dose required to achieve a steady-state serum lithium concentration of 1.0 mEq/L and the test-dose 24-hour serum lithium level. Problems relating to the use of flame photometry to measure serum lithium concentrations less than 0.05 mEq/L are discussed.

Adult↗
PubMed1982

Acute pharmacodynamics and pharmacokinetics of oral amrinone.

Amrinone was administered orally as a single 100-mg dose to six male patients with moderate-severe congestive heart failure to determine the acute pharmacodynamic effects and pharmacokinetics of the drug. Following right heart catherization and amrinone administration, measurements of hemodynamic parameters including cardiac index (Cl), right atrial pressure (RA), pulmonary capillary wedge pressure (PCW), and serum amrinone concentrations (SAC) were made at hourly intervals for up to 8 hours. Cl increased (29.0 per cent) significantly (P less than 0.05) at 3 hours after dose. PCW declined quickly after dose and was significantly (P less than 0.05) lower (-31.3 per cent) than control at 3 hours. RA declined gradually, and a significant (P less than 0.05) reduction (-25.2 per cent) was achieved 5 hours after the dose. Amrinone was absorbed quickly (tmax = 1.4 hour), and the disappearance of amrinone from serum was log-linear (t1/2 = 5.1 hours). The time courses of per cent change in Cl and SAC were similar, and the correlation between the average per cent change in Cl and average SAC was linear and significant (r = 0.80; P less than 0.05).

Administration, Oral↗
PubMed1981

Relative bioavailability of aspirin gum.

The bioavailability of aspirin gum relative to unbuffered aspirin tablets was determined in six normal volunteers. Twenty-four hours following the administration of two aspirin tablets, 91.2 +/- 1.7% (SE) of the 648-mg dose was recovered in the urine. The relative bioavailability of aspirin gum was 69.5 +/- 3.4% (SE), based on cumulative 4-hr urinary excretion of total salicylate after the chewing of three gum tablets for 15 min. The chewed gum was analyzed for total salicylate and contained an average of 37.8% of the administered dose. When added to the cumulative amount of total salicylate excreted in the urine at 24 hr after dosing, the salicylate contained in the chewed gum accounted for essentially 100% of the dose administered. Chewing aspirin gum for up to 30 min did not significantly (p greater than 0.05) reduce the amount of salicylate entrapped in the gum base when compared to chewing times of 5, 10, and 15 min. Based on the results of this study, four pieces of aspirin gum would be needed to provide the same amount of salicylate to the general circulation as two 324-mg aspirin tablets.

Adolescent↗
PubMed1981

Theophylline serum protein binding in obstructive airways disease.

The percentage of theophylline bound to protein in sera obtained from patients with obstructive airways disease was determined by ultrafiltration. The bound theophylline fraction in 71 serum specimens collected from 51 patients was 60.7 +/- 10.0% (mean +/- SD) and from 30.8% to 83.2%. The correlation between unbound serum theophylline concentration and total concentration (range 0.8 to 90 mg/l) was linear (r = 0.97, p less than 0.001). Theophylline binding correlated poorly with serum albumin (r = 0.39) and total serum protein (r = 0.35), although the correlations were statistically significant (p less than 0.05), Theophylline binding in women did not differ from that in men. The extent of theophylline binding in younger patients was greater than in patients over 55 yr (64.3 +/- 8.5% and 57.0 +/- 10.4%, p less than 0.005). Variation in theophylline binding in 12 patients from whom two or more serum samples were collected was relatively small. Analysis of variance showed interpatient variation in theophylline binding (p less than 0.01) but not between sampling occasions in the same patient. The demonstrated variability in serum protein binding of theophylline should influence theophylline distribution and elimination kinetics and may be another determinant of clinical response. Patients with lower binding levels should have higher plasma levels of unbound drug after a loading dose and will need more frequent dosing.

Adult↗
PubMed1981

Procainamide interference with liquid chromatography of theophylline in serum.

We described potential interference of procainamide with our high pressure liquid chromatography procedure for assaying theophylline (similar to that given by Orcutt et al.). In participating in the AACC-TDM quality-control program, we discovered procainamide interference on a column dedicated to theophylline and acetaminophen serum analyses. Following attempts at rejuvenation, this 7-month-old column was replaced with a new one, which gave base-line separation of theophylline and procainamide with no difficulty. We recommend close attention to the aging characteristics of columns and participation in a quality-control program.

Chromatography, High Pressure Liquid↗
PubMed1981

Stability of trimethoprim-sulfamethoxazole injection in two infusion fluids.

The concentrations over time of trimethoprim (TMP) and sulfamethoxazole (SMZ) in solution after preparations of admixtures of TMP-SMZ in 5% dextrose injection (D5W) and in 0.9% sodium chloride injection (NS) were measured. Admixtures (50 ml) containing three TMP concentrations (0.64 mg/ml, 1.6 mg/ml, and 3.2 mg/ml) and three SMZ concentrations (3.2 mg/ml, 8.0 mg/ml, and 16 mg/ml) were prepared in D5W or NS, representing 1:25 v/v, 1:10 v/v, and 1:5 v/v dilutions of TMP-SMZ injection, respectively. Aliquots of each admixture were obtained immediately upon dilution and after 0.5, 1, 2, 4, 8, and 24 hours. The aliquots were filtered and assayed for TMP and SMZ by high-pressure liquid chromatography. Each mixture was inspected visually for any changes in clarity or color, and the pH of each admixture was measured over time. The concentration of SMZ in all admixtures remained constant over 24-hour study period. The TMP concentration did not change significantly (less than 10% of initial concentration) after 1:25 v/v dilutions in either D5W or NS for up to four hours. With a dilution of 1:10 v/vv D5W TMP was stable at D5W for up to two hours. TMP precipitated rapidly in dilutions of 1:5 v/v in either D5W or NS. The pH of the admixtures ranged from 9.39 to 10.10. D5W is the preferred diluent for TMP-SMZ injection if a dilution ratio of 1:10 v/v is desired. Either D5W or NS may be used if a dilution ratio of 1:25 v/v is desired.

Drug Combinations↗
PubMed1980

Temporal variations in trough serum theophylline concentrations at steady state.

Temporal variations in serum theophylline concentrations were observed in 14 healthy volunteers receiving multiple doses of theophylline. After repeated oral doses (6.9--18.2 mg/kg/day) of theophylline as either a nonalcoholic aminophylline solution or a controlled-release capsule, trough theophylline levels at steady state were significantly higher (p less than 0.05) in the morning than in the afternoon or evening. With the solution, the mean (+/-SE) trough serum level at 7 am was 11.1 +/- 0.9 micrograms/ml, and at 1 pm it was 9.6 +/- 0.8 micrograms/ml. With the capsule, the mean (+/-SE) trough serum level at 8 am was 13.8 +/- 0.9 micrograms/ml, and at 8 pm it was 10.7 +/- 0.9 micrograms/ml. Temporal variations in serum theophylline concentrations have not been reported previously and may be important in therapeutic monitoring.

Adult↗
PubMed1980

Two reasons for unusual therapeutic drug monitoring results in hospitalized patients.

In programs where therapeutic drug monitoring is accompanied by interpretation of the data, unusual and unanticipated values may mean more than just a laboratory error. Many times such spurious results will be due to unusual circumstances that result in the drug never reaching the bloodstream. In 3 case reports, we show that purposeful inhospital noncompliance and failure to recognize simple drug absorption interactions can be added to the evergrowing list of factors influencing serum concentrations of therapeutic agents.

Adult↗
PubMed1980

Effect of cholesterol content on antitumor activity and toxicity of liposome-encapsulated 1-beta-D-arabinofuranosylcytosine in vivo.

1-beta-D-Arabinofuranosylcytosine (ara-C) was encapsulated in anionic multilamellar liposomes prepared with different lecithin: cholesterol (L:C) ratios. The chemotherapeutic activity of encapsulated ara-C was compared with comparable doses of ara-C in 0.85% saline solution (single- and multiple-dose schedules) in mice bearing L1210 (i.p.) leukemia. Maximum survival was obtained in animals given injections of ara-C (40 mg/kg) encapsulated in liposomes with a L:C ratio of 1:1. The effect of L:C ratio on survival was not pronounced in multiple-dose schedules. Multiple doses (every 4.5 hr for 3 separate injections) of 40 mg/kg with L:C ratios of 1:1 and 1:0.5 were toxic, resulting in 83 and 50% mortality, respectively, of mice by Day 7. This study shows that drug efflux and in vivo antitumor activity and toxicity of encapsulated ara-C is influenced by the cholesterol content of the liposomal lipid bilayer.

Animals↗
PubMed1979

Pharmacokinetics and relative bioavailability of oral theophylline capsules.

The oral bioavailability of liquid-filled theophylline capsules relative to a nonalcoholic aminophylline solution was determined in normal volunteers. In addition, theophylline absorption and elimination kinetics were reexamined. There were no statistically significant differences between the bioavailability of capsules and liquid as measured by the area under the curve (AUC) from time 0 leads to infinity (p greater than 0.05). The bioavailability parameters of Cmax, tmax, and AUC were determined from actual serum theophylline concentration-time data and from a nonlinear least-squares fit of the serum concentration-time data. Theophylline absorption from the capsules was noticeably faster than from the liquid in most subjects, although the differences in absorption rates were not significantly different (p greater than 0.05). The determined apparent volume of distribution, elimination half-life, and plasma clearance of theophylline were similar to values reported by other investigators. Marked inter- and intraindividual variations in the elimination half-life were noted.

Adult↗