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P L Stetson

Publications and source records attributed to P L Stetson.

50 records · Page 3Linked to original sources
PubMed1986

Steady-state nonlinear pharmacokinetics of 5-fluorouracil during hepatic arterial and intravenous infusions in cancer patients.

Hepatic arterial catheters were placed for therapy in 8 patients with primary or metastatic liver cancer. Temporary hepatic venous catheters allowed direct sampling of blood for hepatic venous drug concentrations. Patients were administered from three to six infusions at rates of 10, 30, 90, 135, 180, 210, and 270 mg/kg/day (0.053 to 1.43 microM/kg/min), given over 2 h, of 5-fluorouracil (FUra). In Method 1, FUra was infused i.v., and FUra was measured in plasma from hepatic arterial and hepatic venous blood. In Method 2, FUra was given i.v. at one time and infused into hepatic arterial blood at another time, and FUra was measured in plasma from peripheral blood at the same site in both cases. Steady-state FUra plasma concentrations were measured by a sensitive and specific high-performance liquid chromatography method. Data were computer fitted to the equations appropriate for a physiological two-compartment flow model with Michaelis-Menten elimination from the peripheral compartment and blood flow rate, Q, between the central and peripheral compartment. Methods 1 and 2 gave mean Vmax and Km values which did not differ significantly; the overall mean Vmax was 2.02 microM/kg/min, and the overall mean Km was 10.9 microM. For Method 1 the mean Q1 value was 0.0803 liters/(kg X min) or 5.26 liters/min, which is the same as cardiac output, but for Method 2 the mean Q2 value was higher, namely 0.189 liters/(kg X min) or 13.0 liters/min. Steady-state systemic and intrinsic clearances and extraction ratios decreased progressively as the dose rate increased. Intra- and inter-subject variation of both Vmax and Km were of the same order of magnitude. As a result, dose rate escalation should be conservative for dose rates above 135 mg/kg/day. The results support hepatic arterial infusion as a means of improving the therapeutic index of FUra in the treatment of cancer of the liver.

Adult↗
PubMed1984

Sensitive gas-liquid chromatographic-electron-capture detection method for determination of sobrerol in biological fluids.

A sensitive gas-liquid chromatographic assay for sobrerol in biological fluids has been developed. The assay procedure involves esterification of both hydroxyl groups of sobrerol with pentafluoropropionic anhydride to form the diester which can be quantitated using gas-liquid chromatography-electron-capture detection. The detection limit of plasma sobrerol under the conditions described is 5 ng/ml. The assay procedure permits the measurement of unchanged drug in plasma, whole blood or urine in the presence of its metabolites.

Chromatography, Gas↗
PubMed1984

BCNU solubility and toxicity in the treatment of malignant astrocytomas.

Administration of BCNU into the carotid artery as treatment for malignant astrocytomas has produced retinal and brain toxicity. It is unclear whether the BCNU diluent, ethanol, is the cause of the toxicity, but the elimination of the ethanol is an attractive possibility. Clinically, decreasing the ethanol from 2.0 ml/100 mg BCNU to 0.75 ml/100 mg BCNU resulted in a marked decrease in eye toxicity. To simulate this clinical situation, three 500-mg solutions of BCNU, ethanol, and saline were prepared, decreasing the ethanol concentration from 3.0 ml to 2.0 ml to 0.75 ml/100 mg BCNU. The amount of BCNU recovered in vitro after simulated clinical administration of the three solutions decreased from 84.9% to 38.3% as the diluent decreased. Therefore, drug delivery at a fixed BCNU dose will decrease with the amount of ethanol diluent used. The clinical decrease in eye toxicity must be partly attributed to a decrease in the amount of BCNU delivered to the retina. Simulated administration of a solution of 500 mg BCNU/150 ml of 5% dextrose in water (D5W) gave 83.7% BCNU recovery. The D5W gives solubility comparable to that provided by 3.0 ml ethanol to each 100 mg BCNU, and its use eliminates ethanol as a potential retinal and brain toxin.

Astrocytoma↗
PubMed1981

Specific and sensitive assays for digoxin in plasma, urine and heart tissue.

A combined internal standard and marker was added directly to urine, then after mixing, an aliquot was injected directly onto a C18 mu-Bondapak HPLC column. The 4.5 ml digoxin fraction was collected over 1.5 min starting 1 min after the appearance of the marker peak (UV detection), and the digoxin determined in the fraction by radioimmunoassay using 3H-digoxin. Digoxin was extracted from alkalinized plasma into dichloromethane. After evaporating the extract and addition of internal standard the remainder of the assay was as described above for urine. Multiple samples of urine and plasma collected in a single dose bioavailability trial in normal human volunteers were assayed by one of these specific methods as well as by the usual direct nonspecific RIA method. There were no significant differences in results by the specific and nonspecific methods. Heart tissue was homogenized with internal standard and phosphate buffer than the mixture was centrifuged. The supernatant was extracted with dichloromethane, the solvent evaporated from the extract, the residue redissolved in mobile phase and the remainder of the assay carried out as for urine and plasma.

Animals↗
PubMed1980

An in vivo tritium release assay of human dopamine beta-hydroxylase.

A non-invasive method is described for estimating dopamine beta-hydroxylase (DBH) activity in sympathetic neurons. Our assay is based on the measurement of the in vivo rate of tritiated water (THO) release from dopamine specifically labeled in the beta-position ([beta-3H]DA). In validation of this method, we have establsihed in human subjects that 1) THO release from [beta-3H]DA correlates with [beta-3H]norepinephrine metabolite excretion, and 2) partial inhibition of DBH with disulfiram (5.5 mg/kg for 4 days) causes parallel decreases in these two indices of dopamine beta-hydroxylation. Since there is a strong correlation (r = 0.89; P < 0.05) between the effect of disulfiram on THO release and the effect of the drug on [3H]-norepinephrine metabolite excretion, our data indicate that the rate at which THO is liberated from [beta-3H]DA into the total body water can be used as an in vivo index of DBH activity.

Adult↗
PubMed1980

Disopyramide-induced ventricular tachycardia.

A patient with ischemic cardiomyopathy and congestive heart failure was treated with disopyramide phosphate for ventricular arrhythmias. The development of ventricular tachycardia was associated with elevated plasma disopyramide levels and prolongation of the QRS and QT intervals, suggesting a disopyramide-induced depression of ventricular conduction and a prolongation of recovery. Thus, in patients with congestive heart failure, as well as in patients with renal and/or hepatic dysfunction, special care must be exercised with respect to the use of disopyramide.

Alcoholism↗
PubMedDate not supplied

Mutual kinetic interaction between 5-fluorouracil and bromodeoxyuridine or iododeoxyuridine in dogs.

The pharmacokinetics of 5-fluorouracil (FUra) were studied alone and in the presence of either bromodeoxyuridine (BrdUrd) or iododeoxyuridine (IdUrd) in five mixed breed hounds. FUra was administered intravenously over 1 min as a 5 mg/kg dose in all three treatments. BrdUrd or IdUrd was infused intravenously at 2.5 mg/hr.kg x 6 hr and FUra was given 3 hr into the 6-hr infusion of thymidine analog. Serial blood samples were obtained for 3 hr prior to and after FUra dosing. Plasma concentrations of FUra, BrdUrd and bromouracil (BrUra), and IdUrd and iodouracil (IUra) were measured by reversed-phase HPLC. Concomitant administration of BrdUrd or IdUrd resulted in substantial changes in the kinetics of FUra. In particular, the total plasma clearance of FUra was decreased and area under the plasma concentration-time curve was increased. There were also significant changes in the volume of distribution steady-state, and in the mean residence time and half-life of FUra. The data show that FUra had little or no effect on the disposition of BrdUrd or IdUrd. In contrast, FUra had a significant effect on the disposition of BrUra and IUra going to form catabolic products. The observed pharmacokinetic interaction in dogs is probably due to a competition between BrUra (or IUra) and FUra for the rate-limiting catabolic enzyme, dihydropyrimidine dehydrogenase. This kinetic interaction was mutual and of a smaller magnitude for FUra + BrdUrd than for FUra + IdUrd.

Animals↗