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Biomedical subjects

D Perrier

Publications and source records attributed to D Perrier.

At least 37 records · Page 2Linked to original sources
PubMed1984

Kinetics of digitoxin and the bis- and monodigitoxosides of digitoxigenin in normal subjects.

The kinetics of digitoxin and two of its metabolites, the bis- and monodigitoxosides of digitoxigenin, were determined in six normal subjects. Mean t 1/2s and total body clearances were 134.4, 15.4, and 0.59 hr and 2.66, 27.3, and 1071 ml/min. Mean renal clearance of the monodigitoxoside was more rapid (7.24 ml/min) than those of digitoxin (0.81 ml/min) or the bisdigitoxoside (0.94 ml/min). The volumes of distribution were of the same order, 0.45 l/kg for digitoxin, 0.57 l/kg for the bisdigitoxoside, and 0.83 l/kg for the monodigitoxoside. The short t 1/2 of monodigitoxoside would make it unsuitable for clinical use, but the bisdigitoxoside of digitoxigenin has a t 1/2 of an intermediate length and may have significant therapeutic advantages.

Adult↗
PubMed1984

Kinetics of digitoxin and the bis- and monodigitoxosides of digitoxigenin in renal insufficiency.

The kinetics of digitoxin and two of its major metabolites, the bis- and monodigitoxosides of digitoxigenin, were determined in six subjects with renal insufficiency and compared to those in six age- and sex-matched normal control subjects. No significant differences between the two groups were found in elimination t 1/2, total body clearance, or volume of distribution. Average renal clearances of all three drugs were reduced in subjects with renal failure, but the differences were significant only in the case of digitoxin. The bis-digitoxoside of digitoxigenin has kinetic properties that offer clinical advantages.

Acute Kidney Injury↗
PubMed1984

Pharmacokinetics and bioavailability of digitoxin by a specific assay.

The pharmacokinetics and bioavailability of digitoxin were examined in six normal human subjects using an assay that separates digitoxin from its metabolites. After intravenous administration, the mean systemic clearance was 2.44 ml/min; the volume of distribution was 0.47 l/kg; and the elimination half-life was 6.5 days. After oral administration, the elimination half-life was 5.8 days. The bioavailability was 81.5% using the specific assay. Using a non-specific, direct serum digitoxin radioimmunoassay the bioavailability was 98.0%. Assay of aqueous fractions from extracted serum samples indicated higher levels of water-soluble metabolites following oral compared to intravenous digitoxin administration. These findings suggest that previously reported values for digitoxin bioavailability using non-specific methods may be falsely elevated due to the presence of digitoxin metabolites in serum.

Adult↗
PubMed1983

Quantitation of digitoxin and the bis- and monodigitoxosides of digitoxigenin in serum.

A specific assay is described for measuring the concentration of digitoxin and the bis- and monoglycosides of digitoxigenin in serum. The procedure includes: (1) addition of a tracer amount of tritium labeled parent compound to the serum in order to measure percentage recovery; (2) solvent extraction to separate polar and non-polar metabolites; (3) reversed-phase thin-layer chromatography of the non-polar fraction to separate digoxigenins from digitoxigenins; (4) thin-layer chromatography to isolate digitoxin, and the bis- and monoglycosides of digitoxigenin; and (5) use of an 125I-radioimmunoassay to determine the concentration of the glycosides. Each of these three glycosides was administered intravenously to a normal subject, and the concentration of parent compound was measured in the serum at various times.

Adult↗
PubMed1983

Effect of the ouabain-quinidine interaction on left ventricular and left atrial function in conscious dogs.

The effect of the ouabain-quinidine interaction was examined in 10 conscious dogs. Left ventricular (LV) pressure, LV dP/dt, LV diameter and left atrial (LA) diameter were measured with high-fidelity micromanometers and sonomicrometer crystals. Ouabain, 0.025 mg/kg, significantly (p less than 0.05) increased LV dP/dt, LV and LA fractional shortening and LV and LA velocity of circumferential fiber shortening (Vcf). In a separate experiment, quinidine was administered as a bolus dose, 3.85 mg/kg, followed by an infusion, 0.28 mg/kg/min. This resulted in steady-state quinidine concentrations that produced no change in wall motion or hemodynamics. When ouabain was given 1 hour into the quinidine infusion, only LV dP/dt increased significantly (p less than 0.05). Ouabain alone increased LV dP/dt 26.4 +/- 3.5%, whereas ouabain during the quinidine infusion increased it by 9.5 +/- 2.3%. Similar differences were seen in the responses to ouabain in the absence and presence of quinidine: LV Vcf, 22.4 +/- 4.9% vs 6.0 +/- 2.1%, LV fractional shortening, 23.1 +/- 4.6% vs 5.8 +/- 2.1%, LA Vcf, 22.7 +/- 5.9 vs 4.6 +/- 2.0% and LA fractional shortening, 21.8 +/- 7% vs 7.8 +/- 3.3%. Thus, in the presence of quinidine the increase in intropy usually seen with ouabain was markedly attenuated. These data suggest that the quinidine-induced increase in digoxin serum concentrations is accompanied by a decrease in the contractile response of the heart to digoxin.

Animals↗
PubMed1982

Allopurinol kinetics and bioavailability. Intravenous, oral and rectal administration.

Six normal, healthy adult males received a single dose of allopurinol intravenously, orally in the form of a commercial tablet, and rectally in the form of an extemperaneously prepared suppository (either in a cocoa butter or in polyethylene glycol base). Plasma allopurinol and oxipurinol concentrations were measured over a period of at least 60 h. The following mean (+/- SD) values were obtained from the intravenous allopurinol experiment: clearance, 9.62 +/- 3.49 ml . kg-1 . min-1; Vd, 1.61 +/- 0.74 l/kg; t1/2, 1.62 h. Oxipurinol had a mean t1/2 of 16.90 h. The absolute systemic bioavailability of the oral tablet was 67% +/- 23%, while the allopurinol rectal suppositories produced no measurable plasma concentrations of allopurinol or oxipurinol in any of the subjects. Current use of rectal dosage forms as an adjunct in cancer chemotherapy should therefore be re-examined.

Administration, Oral↗
PubMed1982

Thiopental disposition as a function of age in female patients undergoing surgery.

The effect of age on the disposition kinetics of thiopental was studied in 22 lean female patients having a body mass index (weight (kg/height(m)2) less than 30 and whose age ranged between 25 to 83 years. Patients underwent primarily abdominal surgery. A strong positive correlation between age and the apparent volumes of distribution, V beta and Vss, was found (P less than 0.001). No significant relationship was found between total body clearance and age. The elimination half-life (t1/2) of thiopental increased with age, and was primarily a function of volume of distribution. The free or unbound fraction of thiopental in serum (alpha) ranged between 0.168 and 0.276 and was significantly correlated with age (P less than 0.005). Multiple regression analysis indicated that age was the independent variable which contributed most the variability in t1/2, V beta, and Vss. No conclusion can be reached concerning the potential differences in anesthetic induction doses required as a function of age; however, these data suggest that care may be required in the use of a balanced anesthetic technique in the elderly as a result of prolonged elimination.

Abdomen↗
PubMed1982

Thiopental disposition in lean and obese patients undergoing surgery.

The effect of obesity on the disposition kinetics of thiopental was studied in seven morbidly obese (age 25 to 46 years) and eight age-matched lean patients (age 25 to 43 years), undergoing primarily abdominal surgery. Based upon total (bound + free) thiopental concentrations, the average (+/-SD) volumes of distribution in the terminal disposition phase and at steady-state (V beta and V ss) were significantly larger in the obese (7.94 +/- 4.55 1/kg and 4.72 +/- 2.73 1/kg, respectively) than in the age-matched lean patients (1.95 +/- 0.63 1/kg and 1.40 +/- 0.46 1/kg, respectively). Clearance of total thiopental, normalized for total body weight was not significantly different between the obese (0.18 +/- 0.081 . h-1 . kg-1) and lean patients (0.21 +/- 0.06 1 . h-1 . kg-1). However, total body clearance not normalized for total body weight was significantly larger in the obese (24.98+/- 14.87 1/h) than in the lean patients (11.86 +/- 3.66 1/h). The elimination half-life of thiopental was significantly longer in the obese (27.85 h) than in the lean patients (6.33 h) and this difference was primarily a function of a larger apparent volume of distribution for thiopental. The unbound fraction of thiopental in serum (range, 17.8 per cent to 27.6 per cent) was not correlated with the degree of obesity. The most appropriate means of comparing intrinsic metabolizing capacity (i.e., normalized vs. non-normalized for weight) between lean and obese subjects remains unresolved.

Abdomen↗
PubMed1982

Digoxin-quinidine interaction in patients with chronic renal failure.

We evaluated the effect of quinidine on digoxin pharmacokinetic in six patients with severe renal failure. Quinidine reduced the total body clearance of digoxin from 1.87 to 1.06 l/hour (p less than 0.001), and prolonged the digoxin half-life of elimination from 5.20 to 9.61 days (p less than 0.01). The digoxin volume of distribution was unchanged. Renal clearance of digoxin was negligible; thus, the decrease in total body clearance was due to a decrease in the nonrenal clearance of digoxin. The mean trough serum concentrations of quinidine ranged from 1.0 to 3.0 micrograms/ml. We conclude that in patients with chronic renal failure, the dose of digoxin should be decreased by 50% if quinidine therapy is initiated.

Adult↗
PubMed1981

Assessment of beta blockade with propranolol.

Each of seven subjects received on a weekly basis placebo or 10, 20, 40, 80, or 160 mg propranolol orally four times daily. The effect of propranolol on the resting heart rate and the heart rate responses to the Valsalva maneuver, tilt, isoproterenol, and maximal exercise were measured. Coefficients of determination were calculated from the individual dose-response curves. The results indicate that the resting heart rate and the tachycardiac response to the Valsalva maneuver and tilt cannot be used to estimate beta blockade. Propranolol concentrations correlated well (mean r2 = 0.80) with the isoproterenol dose ration minus one, but isoproterenon challenges appear clinically inapplicable. Reduction in maximal exercise tachycardia correlated best with propranolol concentrations (mean r2 = 0.89) but, to the extent that exercise could not be performed, there was no reliable way of clinically documenting beta blockade and only the serum concentration of propranolol was available as an indicator of appropriate therapy.

Administration, Oral↗
PubMed1981

Beta adrenergic blockade with propranolol in conscious euthyroid and thyrotoxic calves: dosage requirements and effects on heart rate and left ventricular performance.

The effects of acute beta adrenergic blockade were studied in nine calves which had been instrumented with sonomicrometer crystals and pressure transducers before and after treatment with thyroxine (200 micrograms/kg) for 14 days. The adequacy of beta adrenergic blockade was determined using graded doses of isoproterenol. The results indicated that beta adrenergic blockade had no significant effect on heart rate, left ventricular dimensions or contractile performance in either thyroid state. However, the average dose of propranolol required to achieve beta adrenergic blockade was increased two to three times by thyroxine treatment. Consequently, the kinetics of propranolol disposition were determined in nine animals after a single i.v. dose of the drug. Also, propranolol was administered to four animals by continuous i.v. infusions at graded dosages to produce a range of serum concentrations in each animal. The amount of isoproterenol required to increase the heart rate by 25 beats/min was determined at each dosage level. It was found that in thyrotoxic animals two to three times higher serum propranolol concentrations were required to block challenge doses of isoproterenol. This could not be explained by changes in the disposition of propranolol. The possibility that there are larger numbers of functionally inactive (uncoupled) beta adrenergic receptors in thyrotoxic myocardium is discussed.

Animals↗
PubMed1981

Gas-chromatographic assay for thiopental in plasma, with use of a nitrogen-specific detector.

An accurate, sensitive, and specific gas-liquid-chromatographic procedure is described for determining concentrations of thiopental in human plasma. After a double extraction of 0.2 or 1.0 mL of plasma containing phenobarbital as an internal standard, thiopental and the internal standard are derivatized in a polar non-aqueous solvent system with iodomethane. The reaction mixture is then evaporated, the residue reconstituted with ethyl acetate, and 20 microL injected into a 3% OV-17 column of a gas chromatograph equipped with a nitrogen-phosphorus detector. Linearity and reproducibility over the concentration range 25 microgram/L to 10 mg/L in plasma are excellent. The sensitivity and wide range of linearity exhibited by this method permit thorough characterization of the disposition of thiopental after the usual induction doses of 3-4 mg/kg of body weight.

Blood Chemical Analysis↗
PubMed1981

The "ultra-free" ultrafiltration technique compared with equilibrium dialysis for determination of unbound thiopental concentrations in serum.

We compare a new ultrafiltration technique, involving a unique Millipore membrane, with the classical method of equilibrium dialysis for determining the fraction of thiopental not bound to serum proteins. This fraction, as determined by equilibrium dialysis at 37 degrees C, ranged between 12 and 16% for total concentrations at 50 microgram/L to 10 mg/L of serum. In contrast, ultrafiltration at 37 degrees C yielded a 49% higher value for unbound thiopental: 26.3 (SD 2.6)%. Determined at room temperature (24 degrees C), there was no statistically significant difference for results by the two methods: 14.2 and 15.9%, respectively. The discrepancy between results at 37 degrees C may partly be explained by serum proteins penetrating the Ultra-Free filter. For the routine clinical measurement of unbound drug concentrations, the ultrafiltration membrane at room temperature appears to be sufficiently accurate and less time-consuming than equilibrium dialysis.

Blood Chemical Analysis↗
PubMed1980

Efficacy, plasma concentrations and adverse effects of a new sustained release procainamide preparation.

To assess the efficacy, plasma drug concentrations and adverse effects of a new sustained release preparation of procainamide, 33 patients with heart disease were studied in an acute dose-ranging protocol and a chronic treatment protocol. Patients initially received a daily dose of 3 g of sustained release procainamide; this dose was increased by 1.5 g daily until ventricular premature depolarizations were suppressed by 75 percent or more, adverse drug effects occurred or a total daily dose of 7.5 g of sustained-release procainamide was reached. Twenty-five patients (76 percent) had at least a 75 percent reduction (range 75 to 100percent [mean +/- standard deviation 91 +/- 8.2]) in ventricular permature depolarization frequency at a dosage of 4.8 +/- 1.46 g/day (range 3.0 to 7.5). Despite the 8 hour dosing interval, the variation between maximal and minimal plasma procainamide and N-acetylprocainamide concentrations under steady state conditions was very small. Mean maximal procainamide and N-acetylprocainamide plasma concentrations were 10.4 +/- 6.02 and 12.0 +/- 7.40 micrograms/ml, respectively. The respective mean minimal concentrations were 6.8 +/- 4.50 and 8.7 +/- 5.99 micrograms/ml. In nine patients (27 percent) treatment with sustained release procainamide resulted in conversion of the antinuclear antibody test from negative to positive. Adverse drug effects occurred in 17 (52 percent) of the subjects. In general, adverse effects were minor and abated within 24 hours after administration of the drug was stopped. One patient had the procainamide-induced systemic lupus erythematosus-like syndrome.

Acecainide↗