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Biomedical subjects

T M Ludden

Publications and source records attributed to T M Ludden.

At least 73 records · Page 4Linked to original sources
PubMed1985

Population pharmacokinetics of racemic warfarin in adult patients.

The population pharmacokinetics of racemic warfarin was evaluated using 613 measured warfarin plasma concentrations from 32 adult hospitalized patients and 131 adult outpatients. Warfarin concentrations were measured in duplicate using a high-performance liquid chromatographic procedure. The pharmacokinetic model used was a one-compartment open model with first-order absorption (absorption rate constant set equal to 47 day-1) and first-order elimination. The extent of availability was assumed to be one. A linear regression model was used to evaluate the influence of various demographic factors on warfarin oral clearance. Age appeared to be an important determinant of warfarin clearance in this adult population. There was about a 1%/year decrease in oral clearance over the age range of 20-70 years. Smoking appeared to result in a 10% increase in warfarin clearance, while coadministration of the inducers phenytoin or phenobarbital yielded about a 30% increase in clearance. This study has yielded a predictive model that, when combined with appropriate pharmacological response data, may be useful in the design and adjustment of warfarin regimens.

Adolescent↗
PubMed1985

Determinants of systemic availability of oral hydralazine in heart failure.

Short-term therapy with oral hydralazine can favorably affect abnormal hemodynamics in patients with congestive heart failure, but the range of dosage is large. To investigate whether this variability in effective dose is a result of altered systemic availability, we studied 10 patients with congestive heart failure. Bioavailability (F) was calculated as the ratio of the blood AUC for a single 75 mg oral dose to the AUC of a 0.3 mg/kg iv dose. Acetylation capability was determined by sulfamethazine metabolic clearance (CLsmz). The F value in six subjects with CLsmz greater than 100 ml/min was 9.9% +/- 6.0% (means +/- SD) and was lower than the value of 26.2% +/- 13.0% (P less than 0.05) in the four patients with CLsmz less than 60 ml/min. Thus acetylation ability is an important consideration during low-dose hydralazine therapy (less than or equal to 225 mg/day). The clearance of the single intravenous dose of hydralazine averaged 29.5 +/- 8.0 ml/min/kg, which is not different than that reported in populations without heart failure. After oral dosage titration to induce maximum hemodynamic changes, the dose-normalized hydralazine AUC rose from 53.5 +/- 50.5 to 247.2 +/- 213.4 min/L X 10(3). Thus large oral doses of hydralazine result in disproportionate increases in systemic availability compatible with saturation of the first-pass effect or systemic clearance. In the doses required for maximum hemodynamic effects in our patients (225 to 3000 mg/day), this saturation phenomenon was a prominent determinant of systemic availability.

Aged↗
PubMed1985

Bayesian pharmacokinetic/pharmacodynamic forecasting of prothrombin response to warfarin therapy: preliminary evaluation.

The ability of a pharmacokinetic/pharmacodynamic Bayesian forecasting computer program to predict prothrombin response to warfarin therapy was investigated. The performance of the program was evaluated retrospectively in an inpatient study population of 45 subjects. Predictions of prothrombin response at discharge, based on zero to five serially measured prothrombin ratios, were compared. Precision of prediction was measured by root mean squared error (rmse), bias was measured by average prediction error, and significance (p less than 0.05) was determined by 95% confidence intervals and correlation coefficients. Eleven (3.8%) predictions exceeded established limitations of the pharmacokinetic/pharmacodynamic model and were excluded from data analysis. Correlations between measured and predicted prothrombin ratios for all methods were significant. The five prothrombin ratio feedbacks provided the most accurate predictions (rmse 0.219). These predictions were significantly better than the population parameter (rmse 0.418), one (rmse 0.401), and two (rmse 0.459) prothrombin ratio feedback predictions. The predictions based on population parameters and one prothrombin ratio feedback were significantly biased. When provided with sufficient feedback, the bias was not apparent and the predictive performance improved with each additional prothrombin ratio. The predictive performance of the four and five prothrombin ratio feedbacks is sufficient to provide clinically useful dosage guidelines early in the course of warfarin therapy. The population parameter estimates require further delineation in order to improve the performance of limited prothrombin ratio feedback predictions.

Bayes Theorem↗
PubMed1984

Plasma protein binding of warfarin: methodological considerations.

Recent theoretical work has suggested that radiochemical impurities can significantly alter the binding results for highly protein-bound drugs. We compared protein binding of warfarin by ultrafiltration and equilibrium dialysis with 98% radiochemically pure [14C]warfarin. Ultrafiltration and equilibrium dialysis were performed at 37 degrees C and pH 7.45 on the plasma of patients receiving chronic warfarin therapy. Binding to plasma from seven patients were measured in duplicate by both a nonspecific radioisotopic technique and a specific HPLC technique. The nonspecific technique gave percentage of free warfarin values of 1.84 +/- 0.11 (mean +/- SD) and 1.59 +/- 0.14 for ultrafiltration and equilibrium dialysis, respectively. The HPLC procedure yielded a percentage of free warfarin by ultrafiltration of 0.969 +/- 0.203 and a value of 0.690 +/- 0.095 by equilibrium dialysis (p less than 0.05). The HPLC procedure for protein binding was performed on plasma samples from 12 additional patients and yielded a percentage of free warfarin of 1.01 +/- 0.69 by ultrafiltration and 0.44 +/- 0.34 by equilibrium dialysis (p less than 0.05). It can be concluded that radiochemical impurities may lead to significant overestimation of the percentage of free warfarin. Ultrafiltration yielded a higher percentage of free warfarin than did equilibrium dialysis, but the ability to distinguish binding differences among patients was similar.

Blood Proteins↗
PubMed1984

Effect of food on blood hydralazine levels and response in hypertension.

A study with a nonspecific hydralazine assay reported that food increased hydralazine concentrations in plasma. We used a specific HPLC hydralazine assay to determine the effect of food on hydralazine blood levels and hemodynamic responses after oral hydralazine. Six subjects with uncomplicated essential hypertension were given 1 mg/kg hydralazine solution orally on two occasions at least 3 days apart. On 1 study day subjects fasted and on the other they were given a standard meal 45 min before hydralazine. Mean arterial pressure and heart rate were monitored for 2 hr before and for 4 hr after hydralazine and frequent venous blood samples were drawn for hydralazine assay. Hepatic blood flow was estimated by determination of indocyanine green clearance before food, after food, and 30 min after hydralazine. Peak blood hydralazine concentrations fell in all (46.2% +/- 11.5%; means +/- SE) and areas under the blood hydralazine concentration/time curves fell (45.7% +/- 9.5%) after food. This could not be explained by changes in liver blood flow. Food-related reductions in blood levels of hydralazine were associated with reduced vasodepressor effects (41.5% +/- 5.6%). It is possible that food increases intravascular conversion of hydralazine to hydralazine pyruvic acid hydrazone. The reduction in vasodepressor response suggests that patients with hypertension should take hydralazine at a fixed time in relation to meals.

Administration, Oral↗
PubMed1984

Effect of oral dose size on hydralazine kinetics and vasodepressor response.

Levels of hydralazine in blood are log-linearly related to its vasodepressor effect. We examined the effect of oral dose size on the proportion of hydralazine that reaches systemic circulation. Nine subjects with hypertension were given hydralazine in oral doses in the therapeutic range. Blood hydralazine levels, effective liver blood flow, blood pressure, and heart rate were measured. As the hydralazine dose increased, the ratios of the AUC of hydralazine to hydralazine dose and of peak blood hydralazine concentration to hydralazine dose increased, indicating an increase in the proportion of the dose in blood. Liver blood flow tended to increase (maximum 40%) as dose increased above 0.5 mg/kg. Vasodepressor response and degree of tachycardia increased disproportionately with increasing hydralazine dose. There were strong log-linear relationships between peak hydralazine levels and both vasodepressor response and tachycardia that did not change with increasing hydralazine dose. Thus blood hydralazine and vasodepressor response increase disproportionately with increasing hydralazine doses in hypertension.

Acetylation↗
PubMed1983

Determination of hydralazine in human whole blood.

The time required for the separation of plasma from the cellular components of blood can permit the in vitro loss of hydralazine. Thus, a high-performance liquid chromatographic (HPLC) procedure for the measurement of hydralazine in blood has been developed. 4-Methylhydralazine was used as an internal standard. The addition of p-anisaldehyde led to the formation of the p-anisaldehyde hydrazones of hydralazine and the internal standard. HPLC on a reverse-phase cyano column provided an analytical procedure in which the average relative standard deviation over the concentration range of 1-160 ng/ml was 8.3%. Hydralazine pyruvic acid hydrazone, a known circulating metabolite of hydralazine, yielded only 0.05 mole % hydralazine when submitted to this assay procedure.

Chromatography, High Pressure Liquid↗
PubMed1983

Pharmacokinetics of high dose melphalan.

A pharmacokinetic study of high dose intravenous melphalan, 180 mg/m2, was performed in eight patients. Plasma levels of melphalan declined in a biexponential fashion with a mean terminal half-life (t 1/2 beta) of 61 min (range 40.3-132.8 min). Estimated peak concentrations ranged from 5.45 to 16.57 mcg/ml. The average volume of distribution at steady state (Vdss) and clearance were 0.479 +/- 0.164 l/kg and 6.73 +/- 1.60 ml/min/kg, respectively. These kinetic parameters are similar to those reported from studies using lower doses of melphalan.

Adult↗
PubMed1983

Characterization of the pharmacokinetics of bisantrene (NSC-337766).

The pharmacokinetics of bisantrene, 9,10-anthracenedicarboxaldehyde bis [4,5-dihydro-1 H-imidazol-2-yl) hydrazone) dihydrochloride were evaluated during a Phase I clinical investigation. Bisantrene at doses of 20 to 280 mg/m2 was administered by variable infusion rates to nine patients with advanced metastatic cancer. Bisantrene's plasma clearance followed a triexponential pattern with a harmonic mean terminal half-life (t1/2 gamma) of 26 h. The steady state volume of distribution (Vdss) was large, averaging 627 l/m2. Plasma clearance averaged 42.6 +/- 6.7 l/h/m2. The cumulative urinary excretion of bisantrene was 3.6 +/- 1.6% at 48 h.

Aged↗
PubMed1983

Effect of intravenous dose on hydralazine kinetics after administration.

Six male hypertensive patients, three rapid and three slow acetylators, each received four different intravenous hydralazine doses by constant infusion over 100 sec. Two to four days elapsed between doses. Plasma or whole-blood hydralazine concentrations were measured by HPLC after each dose. There was no influence of acetylator phenotype on hydralazine kinetics after intravenous dosing. There also was no consistent effect of dose size on hydralazine clearance or volume of distribution at doses up to 0.45 mg (2.3 mumol/kg). One subject, who received doses up to 0.6 mg/kg (3.05 mumol), had an apparent decrease in clearance at the higher doses. These findings are consistent with the fact that hydralazine is converted intravascularly to hydralazine pyruvic acid hydrazone and the fact that potentially saturable hepatic metabolic pathways play only a modest role in systemic clearance.

Dose-Response Relationship, Drug↗
PubMed1983

Effect of erythromycin on carbamazepine kinetics.

Two recent reports of carbamazepine-induced intoxication during concurrent therapy with macrolide antibiotics prompted us to perform a carefully controlled two-way cross-over study in eight healthy male nonsmokers. Treatment A was 250 mg erythromycin every 6 hr for 5 days before and 3 days after 400 mg carbamazepine. Treatment B was 400 mg of carbamazepine alone. One half of the subjects received treatment A, then B, while the other half received treatment B, then A. There was a 4-wk washout period between treatments. Plasma samples obtained at various times up to 72 hr after the carbamazepine dose were assayed in duplicate by HPLC. The data were fit to a one-compartment open model with first-order absorption and elimination. Clearance of oral carbamazepine was lower in the presence of erythromycin (mean +/- SD, 0.290 +/- 0.074 and 0.360 +/- 0.072 1 X kg-1 X day-1). There were no differences in apparent volume of distribution (1.01 +/- 0.20 and 1.04 +/- 0.12 1 X kg-1), elimination rate constant (0.302 +/- 0.113 and 0.348 +/- 0.079 day-1), or absorption rate constant (14.5 +/- 8.7 and 15.5 +/- 16.6 day-1) between the two treatment groups. The decrease in clearance of oral carbamazepine secondary to erythromycin indicates that further clinical studies are warranted.

Adult↗
PubMed1983

Latamoxef (moxalactam) kinetics in volunteers studied by a specific HPLC assay technique.

Pharmacokinetic parameters were calculated from plasma and urine latamoxef ('Moxalactam') levels determined by HPLC assay after single and multiple intramuscular (im) and single intravenous (iv) doses of 500 mg given to eight healthy volunteers. After im administration, systemic bio-availability was 92% after both the first and sixth doses. Peak plasma concentration was 18 mg/l (first dose) and 22 mg/l (sixth dose), reached at 1.2 h and 1.3 h respectively. The terminal phase half-lives were 2.5 h and 2.7 h respectively. After iv administration, the initial phase plasma half-life was 0.23 h and the terminal phase half-life, 2.4 h. Plasma clearance was 87.0 ml/min. The steady state distribution volume was 210 ml/kg. After iv administration, 72% of the dose was found in the urine in the first 24 h. Urinary clearance was 66 ml/min (iv dose) and 63 ml/min (sixth im dose). Most systemic infections will permit eight hourly dosing with 500 mg im or iv. Many urinary infections will be best treated with im administration, rather than iv administration.

Adult↗
PubMed1983

Predicting phenytoin dosages using Bayesian feedback: a comparison with other methods.

A Bayesian feedback technique for predicting phenytoin dosage was compared to other dosing methods. Sixty-nine cases were selected on the basis of apparent reliability from 103 medical charts of epileptic patients with multiple phenytoin levels on different dosage regimens. Two published nomograms and a graphical, or computational, technique were compared to the Bayesian technique. Each method was assessed for absolute predictability using measures of bias and precision, i.e., mean percent error and root mean squared percent error, respectively. For a single previous data pair, the Bayesian method was similar to a published nomogram with regard to bias and precision. For multiple data pairs, the graphical or simultaneous equation technique tended to be less biased, but the Bayesian method had better precision. However, none of these differences was statistically significant (p greater than 0.05). The Bayesian method yielded the lowest percentage of predicted doses that exceeded 110% of the actual dose. The Bayesian method conveniently provides a single method applicable to the use of either single or multiple concentration-dosage data pairs and results in fewer extreme dosing errors.

Adult↗
PubMed1983

Phenytoin cumulation profiles.

his study was performed to determine the potential utility of the cumulation profile of phenytoin during multiple oral dosing and to examine, under ideal conditions, the variability in apparent steady state concentrations. Six male subjects were administered oral phenytoin sodium 5-6 mg/kg/d in divided doses every 12h for six days. Predose serum phenytoin concentrations were measured every 12 hours by gas liquid chromatography. The resulting data were analyzed in order to estimate maintenance doses. Subjects were then placed on the estimated daily dose and pre-dose concentrations measured daily for at least two weeks. At the end of the study, all data were fit using non-linear regression analysis to obtain the best estimates of individual kinetic parameters. Parameter values, particularly the Km value, were dependent upon the input function used, either first- or zero-order. In two subjects there was evidence of modest auto-induction. At steady-state the average coefficient of variation of predose concentrations was 10.6% (Range: 5.2-16.2%).

Administration, Oral↗
PubMed1983

Pentane clearance from inspired air by the rat: dependence on the liver.

Pentane, a volatile hydrocarbon, is cleared from inspired air by the rat. We have studied this clearance to learn whether or not it is a function of the liver. Rats were put individually into airtight chambers which contained CO2 absorbent and were connected to an O2 reservoir. Pentane was injected into each chamber and chamber atmosphere was assayed frequently for pentane over 6 h by gas chromatography. Semilog plots of pentane concentration had a rapid distribution phase and a log-linear terminal elimination phase. A chamber clearance value in milliliters at atmosphere cleared per minute per kilogram rat weight was calculated. Nephrectomy had no effect on pentane clearance. Liver injury by thioacetamide (5 mmol/kg) or by CCl4 (75 or 125 microliters/100 g) was associated with a marked decrease in pentane clearance, indicating a major role for the liver in pentane elimination. Treatment of rats with inducers or inhibitors of the hepatic microsomal cytochrome P450 system did not affect their ability to clear pentane. However, administration of ethanol or 4-methyl-pyrazole diminished pentane clearance, suggesting that alcohol dehydrogenase may be involved in pentane metabolism. These findings demonstrate that pentane clearance is a liver function.

Animals↗
PubMed1982

Urine and plasma free phenytoin concentration correlation.

In an attempt to find a simple, noninvasive method for estimating the plasma free concentration (CPf) of phenytoin (PHT), the relationship between urine PHT concentration (Cu) and CPf was studied in 40 epileptic patients who were 6 to 50 yr old. Cu was determined by gas-liquid chromatography and CPf by equilibrium dialysis at 37 degrees. Cu was generally greater than CPf, but correlation between the two was strong (r2 = 0.876) and in the same range as previously published results for saliva and CPf. Correlation of Cu with CPf was not influenced by patient age, urine pH, or urine flow rate. In 24 patients timed urine collections were obtained and calculated renal clearances of PHT were shown to increase in proportion to urine flow rates. Although it is not known if renal impairment and albuminuria will alter the relationship between Cu and CPf it appears that Cu may be useful in estimating the concentration of pharmacologically active PHT in plasma.

Adolescent↗