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Biomedical subjects

T M Ludden

Publications and source records attributed to T M Ludden.

At least 109 records · Page 6Linked to original sources
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↗
PubMed1977

Individualization of phenytoin dosage regimens.

Two methods for arriving at optimum, individual phenytoin dosage regimens have been evaluated in 12 patients. (1) Individual Michaelis-Menten pharmacokinetic parameters for phenytoin were estimated from two reliable steady-state phenytoin serum concentrations resulting from different daily doses: The observed steady-state phenytoin serum levels obtained after 3 to 8 wk of compliance with dosage regimens calculated from the individual pharmacokinetic parameters agreed well with predicted levels (r = 0.824, p less than 0.02). The average deviation between observed and predicted levels was 0.04 mug/ml (range, +/- 3.2 mug/ml). (2) A previously published nomogram for making adjustments in phenytoin dosage regimens: The serum phenytoin concentration actually expected from the dose indicated by the nomogram was calculated using individual pharmacokinetic parameters. The daily dose for one patient would have exceeded his estimated maximal rate of metabolism. The correlation between calculated and predicted phenytoin serum levels in the other 11 patients was weak but significant (r= 0.360, p less than 0.05). The average deviation was --3 mug/ml (range, 3.9 to --11.3 mug/ml). It was concluded that the use of individual pharmacokinetic parameters is practical and is also superior to the nomogram.

Adolescent↗
PubMed1976

Tritiated naltrexone binding in plasma from several species and tissue distribution in mice.

The binding of 15,16,-3H-naltrexone in human, monkey, dog, guinea pig, rat, and mouse plasma was investigated over a range of concentrations, including predicted therapeutic levels. Studies using equilibrium dialysis at 37 degrees indicate that the extent of binding is independent of naltrexone concentration over the concentration range of 1-500 ng/ml for dog plasma and of 0.1-500 ng/ml for human, monkey, guinea pig, rat, and mouse plasma. The extent of naltrexone binding in plasma is similar in the six species studied, the range being from 20% bound in rat plasma to 26% in plasma from beagle and mongrel dogs. This relatively low extent of naltrexone binding in plasma is consistent with previous findings of a large apparent volume of distribution of this drug in the dog. To investigate further the distribution of tritiated naltrexone, the tissue levels of radioactivity in mice at 1, 5, and 15 min after intravenous administration of 8-3H-naltrexone were determined. Naltrexone was rapidly distributed from plasma to tissues, with less than 4% of the dose being present in plasma at 1 min after injection.

Animals↗
PubMed1976

The bioavailability, dispostion kinetics and dosage of sulphadimethoxine in dogs.

The disposition kinetics of sulphadimethoxine were studied in six normal beagle dogs after intravenous injection of a single dose (55 mg/kg). The median (range) distribution and elimination half times of the drug were 2.36 (2.06-3.35) hours and 13.10 (9.71-16.50) hours, respectively. Total body clearance of the drug had a median value of 21.7 ml/kg/h and a mean value of 21.4 ml/kg/h. While the overall tissue to plasma level ratio (k12/k21) of the drug was 0.55 after distribution equilibrium had been attained, analogue computer simulated curves showed that at 24 hours the fractions (percentage) of the dose in the central and tissue compartments were 12 and 11%, respectively. The drug was shown, by equilibrium dialysis method, to be highly bound to plasma proteins (greater than 75%) within the usual therapeutic range (50 to 150 mug/ml) of plasma levels. The systemic availability of sulphadimethoxine from the oral suspension was 32.8% (22.5-80.0). Since the absorption half time, 1.87 (0.86-3.22) hours, was considerably shorter than the half-life, 13.10 (9.71-16.50) hours, of the drug, the rate of absorption would have little influence on the dosage regimen. Based on the experimental data obtained, a satisfactory dosage regimen might consist of a priming dose of 55 mg/kg by the intravenous route and maintenance doses of either 27.5 mg/kg of sulphadimethoxine injection given intravenously or 55 mg/kg of the oral suspension administered at 24 hour intervals. The adequacy and duration of therapy will depend upon the clinical response obtained.

Administration, Oral↗
PubMed1976

Metabolic reduction of naltrexone II. In vitro studies using liver from guinea pig, monkey and rat.

Naltrexone was incubated with the 9000 X g supernatant of guinea pig liver in the presence of an NADPH-generating system to determine the relative amounts of the 6-keto reduction products, alpha- and beta-naltrexol, formed in vitro. After a 0.5-2 hour period both alpha- and beta-naltrexol were formed as detected by electron capture gas chromatography of pentafluoropropionic anhydride-derivatized extracts of the incubation mixture. The identity of alpha-naltrexol was confirmed by nuclear magnetic resonance, infrared and mass spectra, as well as by mixed melting point determination. The percentage of natrexol found as the alpha-epimer ranged from 36-81% and was concentration-dependent at substrate concentrations ranging from 0.0007-0.1 mM. The hepatic enzyme(s) responsible for the reduction of naltrexone were localized in the 105,000 X g supernatant fraction of guinea pig liver. In contrast to results obtained for the reduction of naltrexone using guinea pig liver, the 9000 X g and 105,000 X g supernatant fractions of monkey liver appeared to reduce naltrexone almost exclusively to beta-naltrexol. The 9000 X g supernatant of rat liver was less active than similar preparations from guinea pig or monkey liver; only a small amount of beta-naltrexol and no detectable alpha-naltrexol was formed after two hours of incubation. Incubation of the naltrexone metabolites, alpha- or beta-naltrexol, with the 9000 X g supernatant of guinea pig liver and incubation of alpha-naltrexol with guinea pig kidney slices yielded no evidence of interconversion of these metabolites.

Animals↗
PubMed1975

Metabolic reduction of naltrexone. I. Synthesis, separation and characterization of naloxone and naltrexone reduction products and qualitative assay of urine and bile following administration of naltrexone, alpha-naltrexol, or beta-naltrexol.

Reduction of naltrexone and naloxone with sodium borohydride gave a mixture (85:15) of the 6alpha- and 6beta-hydroxy epimers, alpha- and beta-naltrexol and alpha- and beta-naloxol, respectively. Each pair of epimers was separated by preparative thin-layer chromatography and the physical and spectral properties of each compound were determined. Previous assignments for the configuration of the epimers were verified. A semi-quantitative electron capture gas-liquid chromatographic method was devised for distinguishing either alpha- or beta-naltrexol in the presence of the other and in the presence of large amounts (at least 10-fold greater) of naltrexone. The method was used to determine the approximate weight ratio of beta-naltrexol to naltrexone present in enzymatically hydrolyzed urine samples. It was found that substantially greater quantities of beta-naltrexol and/or its conjugates were excreted in the urine of man, monkey, guinea pig and rabbit after administration of naltrexone, whereas very small quantities were excreted by the mouse, rat and dog. In contrast, just trace amounts of the 6alpha-hydroxy epimer, alpha-naltrexol, were detected in the urine of only 2 of the 7 species that had received naltrexone, i.e., monkey and guinea pig. After administration of 3H-15,16-naltrexone, 1 mg/kg, i.v. to the guinea pig, 25% of the radioactivity found following thin-layer chromatography of the extract of acid-hydrolyzed urine corresponded to beta-naltrexol. In gall bladder bile from the guinea pig, only conjugates of naltrexone and beta-naltrexol were found 2 hours after administration of naltrexone. Following administration of beta-naltrexol, 1 mg/kg, i.v. to guinea pigs only beta-naltrexol and/or its conjugates were detected in urine or bile. However, urine collected after administration of alpha-naltrexol, 1 mg/kg, i.v. to guinea pigs contained alpha-naltrexol and its conjugates, as well as a yet unidentified metabolite.

Animals↗