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T M Ludden

Publications and source records attributed to T M Ludden.

At least 19 recordsLinked to original sources
PubMed1992

Comparative bioavailability of a sustained-release ion-exchange hydralazine product with a potassium (cation) challenge.

A sustained-release formulation of hydralazine was manufactured by binding hydralazine to an ion-exchange resin and coating the drug-resin complex with a semipermeable membrane. Because the sustained-release characteristics are due in part to displacement of drug from the drug-resin complex by gastrointestinal ions, the stability of the sustained-release formulation could be compromised if challenged by a high concentration of ions. In this study, 12 healthy male volunteers participated in a two-way crossover trial that was designed to test the bioavailability and release of drug from the sustained-release formulation both with and without concomitant ingestion of a solution of KCl. Blood samples were collected over a 14-h period after administration of either treatment. Analysis of whole blood for hydralazine and comparison of the values of the area under the curve of the concentration of hydralazine versus time, the maximum concentration of hydralazine, and the time to reach the maximum concentration between the two experimental groups showed that KCl had no influence on the bioavailability or release characteristics of hydralazine from the sustained-release formulation.

Adult↗
PubMed1992

Pharmacokinetics of quinidine in male patients. A population analysis.

Quinidine pharmacokinetic behaviour was evaluated in 139 adult hospitalised men receiving oral quinidine therapy. A total of 391 serum quinidine concentrations were measured by enzyme immunoassay for routine clinical purposes. The NONMEM programme was used to examine the relationship between quinidine pharmacokinetics and several potential covariates. A 1-compartment open model with first-order absorption and elimination was assumed. The mean apparent volume of distribution (Vd) was about 230L. When measured, alpha 1-acid glycoprotein (AAG) levels were not included in the analysis. Oral quinidine clearance (CL) decreased with age, severe congestive heart failure and renal disease, and increased in patients with a history of alcohol abuse. The interpatient variability in CL and the intrapatient residual variability expressed as coefficients of variation (CV) were 28 and 31%, respectively. When AAG values were incorporated into the analysis, the only important covariates of CL were the AAG measurements and the presence of renal dysfunction as indicated by a calculated creatinine clearance of less than 50 ml/min (3 L/h). The interpatient variability in CL and the residual intrapatient CVs decreased to approximately 24 and 26%, respectively. Improvement of the CL model by inclusion of measured AAG strongly suggests that quinidine elimination is dependent on the free concentration of drug in plasma and supports the use of free serum quinidine concentrations when evaluating and monitoring quinidine therapy.

Aged↗
PubMed1979

Rapid metabolism of phenytoin: a method of calculating proper dosage.

The optimal dosage of phenytoin can be accurately determined by a pharmacokinetic method. By plotting the rate of administration of phenytoin acid against the apparent plasma clearance rate, we estimated the maximum rate of metabolism and the serum concentration at which the rate of metabolism was one half the maximum rate for phenytoin and then applied the Michaelis-Menten equation to optimize the dosage of phenytoin in a 48-year-old man with uncontrolled idiopathic generalized seizures and increased metabolism of phenytoin. The patient became seizure free on a regimen of 650 mg of phenytoin daily and experienced no side effects of phenytoin over-dosage. The pharmacokinetic technique described is simple to use and can be applied in an outpatient clinic.

Dose-Response Relationship, Drug↗
PubMed1979

Phenytoin cumulation kinetics.

Four male subjects were given phenytoin orally in single or twice-daily doses. Subjects were on 2 or 3 different dosing rates from 260 to 600 mg phenytoin sodium daily. Predose blood samples were obtained almost daily. The resulting serum levels, measured by gas-liquid chromatography, ranged from 1 to 18 micrograms/ml. Serum phenytoin concentration-time data were fit to a 1-compartment open model with zero-order input and Michaelis-Menten elimination. The resulting computer-generated parameter estimates (Vmax, 5.28 to 8.41 mg/kg/day; Km, 0.83 to 4.18 mg/1; Vd, 0.74 to 0.97 1/kg) are in agreement with the ranges of values in the literature. The time course of phenytoin cumulation is compatible with the presence of a major elimination pathway exhibiting Michaelis-Menten kinetic behavior.

Administration, Oral↗
PubMed1979

Plasma naltrexone kinetics after intravenous bolus administration in dogs and monkeys.

This investigation generated data characterize a specific electron-capture GLC assay reported previously for naltrexone and applied the method to a determination of naltrexone pharmacokinetics. Extraction efficiencies are reported for the assay, and mass spectral evidence indicates that naltrexone forms a triester when derivatized for electron-capture GLC with pentafluoropropionic anhydride and a base catalyst. Plasma level-time data for intravenous naltrexone at two dose levels in monkeys yielded no evidence of dose-dependent kinetics. A two-compartment open pharmacokinetic model was fitted to plasma level-time data for naltrexone in two dogs and yielded a total body clearance of 51-55 ml/min/kg. Urine collected for 0-24 hr contained 36% of the dose as naltrexone conjugates with less than 1% as unchanged naltrexone. Plasma level-time data for intravenous naltrexone in six monkeys yielded an average terminal half-life of 7.8 hr and a total body clearance of 64 ml/min/kg. The total body clearance for naltrexone was greater than the hepatic plasma or blood flow in both dogs and monkeys. This finding, together with the extremely low renal excretion of naltrexone, suggests the existence of elimination mechanisms besides liver metabolism and renal excretion.

Animals↗
PubMed1979

High-pressure liquid chromatographic assay for hydralazine in human plasma.

A specific high-performance liquid chromatographic assay for hydralazine in human plasma was developed. Plasma hydralazine is reacted with 10 microliter of p-anisaldehyde for 7 min at room temperature to form hydralazine p-anisaldehyde hydrazone. This derivative is extracted into ethyl acetate, and the solvent is removed by evaporation. The residue is reconstituted in 100 microliter of methanol, and 90 microliter is injected onto a reversed-phase column. The mobile phase is 32% acetonitrile in 0.75 M acetate buffer, pH 3.4, at a flow rate of 2 ml/min. The retention time of hydralazine p-anisaldehyde hydrazone is 6.5 min. The average coefficient of variation over 10-200 ng/ml is 5.5%, and the sensitivity limit is 5 ng/ml. Under the assay conditions, hydralazine pyruvic acid hydrazone, a known plasma metabolite of hydralazine, yields less than 0.1% hydralazine. Detectable plasma hydralazine levels of 5-20 ng/ml were found 10-30 min after a 0.5-mg/kg oral dose of hydralazine hydrochloride was given to a male volunteer.

Adult↗
PubMed1979

Excretion pathways of amphotericin B.

The role of the biliary system in excretion of amphotericin B was explored in a dog model that allowed either external diversion of all bile or complete biliary obstruction. In dogs with biliary diversion, which were given a single dose of amphotericin B intravenously, excretion of amphotericin B in the bile lasted for seven to 10 days and accounted for only 3% +/- 2% (mean +/- SD) of the dose, whereas excretion in the urine was prolonged (23--35 days) and greater (21% +/- 5% of the dose); the stool contained no amphotericin B. However, bile salt depletion may have depressed biliary excretion of amphotericin B: in a dog with an intact biliary system, 19% of the dose was excreted in the stool over 11 days. In dogs given amphotericin B daily, serum levels were 19% +/- 3% higher during periods of biliary obstruction than during periods of free bile flow (P less than 0.05). Thus, excretion of amphotericin B in the bile (less than or equal to 19% of the dose) and in the urine (21% of the dose) accounted for a minority of total drug clearance. Nevertheless, prolonged excretion of amphotericin B by these routes after a single dose suggests that infrequent doses of amphotericin B may provide effective treatment for certain forms of fungal infection.

Amphotericin B↗
PubMed1979

Impaired theophylline clearance in patients with cor pulmonale.

1 The relationship between serum theophylline concentration and daily dose was studied in 45 patients receiving aminophylline orally and in 36 patients receiving it by constant intravenous infusion. 2 Patients were categorized as uncomplicated chronic obstructive pulmonary disease (COPD) or COPD with cor pulmonale (CP). 3 Serum theophylline concentration relative to daily theophylline dose was significantly higher in patients with COPD plus CP than in patients with COPD alone. 4 Total body clearance of theophylline estimated from data obtained during constant intravenous infusion was significantly lower in COPD plus CP than in patients with COPD alone. 5 We conclude that reduced maintenance doses of theophylline are indicated in patients with COPD when complicated with CP.

Administration, Oral↗
PubMed1979

Pharmacokinetics of hydralazine, apparent hydralazine and hydralazine pyruvic acid hydrazone in humans.

Hydralazine is an antihypertensive vasodilator agent. Lack of specific assay techniques for its measurement have delayed elucidation of its pharmacokinetic profile. This study compares the plasma profiles of hydralazine, measured both by a specific and by a previously published nonspecific assay and of a major plasma metabolite, hydralazine pyruvic acid hydrazone. After po and iv administration of hydralazine, peak hydralazine levels were lower (7-33%) and plasma half lives were shorter (15-31%) when measured by the specific technique. The mean plasma half life of the pyruvic acid hydrazone was 156 min and mean urinary clearance, 28 ml/min. The plasma profile of hydralazine and of the major metabolite, the pyruvic acid hydrazone, do not appear to correspond to the duration of antihypertensive effect of administered hydralazine.

Acetylation↗
PubMed1978

Microdetermination of procainamide in human serum.

An electron-capture GLC method to measure procainamide (0.1-1 microgram/sample) in human serum was developed. An internal standard, p-amino-N-[2-(dipropylamino)ethyl]benzamide, is added to the serum before the sample is alkalinized with pH 10.5 phosphate buffer and extracted with ethyl acetate. The ethyl acetate phase is evaporated to dryness, and the residue is reacted with pentafluoropropionic anhydride. N-Pentafluoropropionyl derivatives of the drug and the internal standard had retention times of 5 and 8 min, respectively, when chromatographed at 235 degrees on a 1-m (4-mm i.d.) glass column packed with 5% OV-17 (carrier gas flow of 40 ml/min). The coefficient of variation was less than 5% for spiked standards. Furthermore, N-acetylprocainamide added to samples did not interfere. One hundred and eighty-six samples from 16 patients receiving procainamide intravenously were assayed by this GLC procedure and by a standard colorimetric method. Linear regression analysis yielded a correlation coefficient of 0.985 (slope, 1.040; intercept, 0.015).

Chromatography, Gas↗
PubMed1978

Brain and plasma concentrations of amphetamine isomers in mice.

Brain and plasma concentrations of (+)- and (-)-amphetamine were compared as a function of dose and time after administration to mice. Doses of an amphetamine isomer contained 12 muCi of [14C]-(+) or (-)-amphetamine. Thirty minutes after administration of 2.5, 5 or 10 mg/kg i.p., (+)-amphetamine/(-)-amphetamine concentration ratios in the brain were significantly greater than 1; this ratio was less than 1 for the 15 mg/kg dose. Plasma concentration ratios were significantly greater than 1 for all doses. The ratios of +/-isomers were consistently greater than 1 in brain and plasma when determined at various times (7.5--120 min) after 2.5 and 10 mg/kg i.p. By contrast, i.v. administration of these doses resulted in no isomeric differences in brain amphetamine, alhough plasma (+)-amphetamine/(-)-amphetamine ratios remained somewhat elevated. After SKF 525-A pretreatment, the i.p. and i.v. routes resulted in similar (+)-amphetamince/(-)-amphetamine concentration ratios. These results suggest that (-)-amphetamine has a higher apparent volume of distribution (Vd) than (+)-amphetamine [Vd for (+)- and (-)-amphetamine, 2.5 mg/kg i.v. = 3.35 and 4.61 liters/kg, respectively; Vd for (+)- and (-)-amphetamine 10 mg/kg i.v. = 2.36 and 4.61 liters/kg, respectively] and that the (-)-isomer may be extracted more efficiently by the liver [plasma clearance (V) for (+)- and (-)-amphetamine 2.5 mg/kg i.v. = 6.91 and 9.09 liters/hr/kg respectively; V for (+)- and (-)-amphetamine 10 mg/kg i.v. = 2.85 and 4.33 liters/hr/kg, respectively] resulting in lower plasma and brain concentrations after i.p. administration.

Amphetamine↗