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Biomedical subjects

R L Williams

Publications and source records attributed to R L Williams.

At least 307 records · Page 17Linked to original sources
PubMed1982

Nonlinear theophylline elimination.

Elimination kinetics of theophylline and its major metabolites were investigated in 14 healthy adults in single-dose studies and in a multiple-plateau study. The plasma concentrations of theophylline and the metabolites 3-methylxanthine (3-MX), 1-methyluric acid (1 MU), and 1,3-dimethyluric acid (13-MU) were monitored to about 0.020 mg/l and became convex descending at concentrations below 1 mg/l after single theophylline doses. Renal clearance values of 3-MX, 1-MU, and 13-MU were 12.0 +/- 1.3 l/hr, 22.5 +/-1.5 l/hr, and 22.6 +/- 1.6 l/hr. Metabolite formation of the three metabolites followed Michaelis-Menten kinetics and became capacity limited within the therapeutic range of theophylline. The apparent Michaelis-Menten parameters for each metabolite formation step were obtained by computer fitting. For the formation of 3-MX. 1-MU, and 13-MU, the approximate mean maximal rate of formation of metabolite (Vmax) values were 5 mg/hr, 13 mg/hr, and 34 mg/hr and the apparent concentration of theophylline at which metabolite formation rate is half of Vmax values were 2.7 mg/l, 9.3 mg/l, and 14.2 mg/l. The elimination of each of the metabolites was rate limited by the elimination of theophylline. Concomitant measurement of theophylline urinary excretion rate showed the renal clearance of the drug to be highly dependent on urine flow. The initial renal clearance, elevated due to diuresis, and the distribution phase tended to counterbalance the saturable metabolic formation clearance after a single therapeutic dose. Therefore, plasma theophylline concentration decayed roughly in a log-linear fashion and the convex-descending curve, characterized by capacity-limited elimination kinetics, was observed only at lower concentrations.

Administration, Oral↗
PubMed1982

Effects of probenecid on ketoprofen kinetics.

When six normal men took probenecid with ketoprofen in a two-treatment crossover study, steady-state plasma concentrations of ketoprofen and ketoprofen conjugates rose, but plasma protein binding of ketoprofen and urinary excretion of ketoprofen conjugates decreased. Probenecid decreased protein binding of ketoprofen by 28 +/- 7%, total ketoprofen clearance by 67 +/- 11%, clearance of unbound ketoprofen by 74 +/- 10%, clearance of unbound ketoprofen by conjugation by 91 +/- 5%, and renal clearance of ketoprofen conjugates by 93 +/- 4%. An apparent decrease (22 +/- 29%) in unbound ketoprofen clearance by mechanisms other than conjugation might have been established in a study of more than six subjects. Probenecid, which reaches plasma concentrations that approach 100 times those of ketoprofen or its conjugates, appears to inhibit both the conjugation of ketoprofen and the renal excretion of ketoprofen conjugates. An alternative explanation to inhibition of conjugation involves cumulation and subsequent hydrolysis of ketoprofen conjugates as a result of the renal action of probenecid. In addition to the advantages of obtaining simultaneous uricosuric and anti-inflammatory effects, there may be clinical kinetic advantages of administration of probenecid with ketoprofen, because the large interdose concentration swings of ketoprofen are then substantially reduced.

Adult↗
PubMed1982

Fetal growth and perinatal viability in California.

To produce more appropriate information for evaluating fetal growth and viability, vital records data were used to compute percentile curves and perinatal, neonatal, and fetal mortality rates at specific birth weights and gestational ages. Percentile values were in good agreement with previous studies, and the large number of births (2,288,806) allowed for a more precise determination of fetal viability at various weight-age combinations than has been previously available. Mortality rates were found to be much more sensitive to birth weight than to gestational age, especially for small-for-gestational age fetuses. Optimal weight-age combinations were found to be up to 500 g and 2 weeks greater than the average combination. The results consistently emphasize the importance of rapid and sustained fetal growth at all gestational ages.

Birth Weight↗
PubMed1982

Improved liquid-chromatography of aspirin, salicylate, and salicyluric acid in plasma, with a modification for determining aspirin metabolites in urine.

Detailed performance specifications are given for a specific and sensitive liquid-chromatographic assay for aspirin, salicylic acid, and salicyluric acid in plasma. The sensitivity of this method for aspirin (50 micrograms/L) is 10-fold that of previous methods, so that concentrations of aspirin in plasma can now be followed for about four or five half-lives after the peak plasma concentration arising from a single 650-mg dose. In addition, this assay is as sensitive for salicylic and salicyluric acid in plasma as any hitherto. A modification permits measurement of gentisic acid, salicylic acid, and salicyluric acid in urine; further modifications allow indirect measurement of conjugated gentisate and salicylate in urine.

Aspirin↗
PubMed1981

Ketoprofen pharmacokinetics and bioavailability based on an improved sensitive and specific assay.

A commercial capsule containing 50 mg of ketoprofen (Orudis), a simple capsule containing 50 mg of ketoprofen alone and 50 mg of ketoprofen in an aqueous solution were given as separate doses in a randomized sequence to 12 normal adult males. The areas under the resulting plasma concentration-time curves (AUC) were remarkably consistent for each volunteer. The bioavailability from the commercial capsule relative to that from the solution was 99.7% +/- 10.5% and that from the simple capsule was 102% +/- 10%. After 6 of the volunteers had taken the commercial capsule 6 hourly for thirteen doses, their AUC extrapolated to infinity was significantly higher (by 22%) than that after the single dose indicating, contrary to previous reports, accumulation upon multiple dosing. The interdose AUC after the thirteenth dose was, however, statistically indistinguishable from the AUC-to-infinity after the single dose as might be expected from linear kinetics. The ketoprofen solution generated peak plasma concentrations in only one-third the time (21 +/- 7 min) required for the capsules (commercial, 72 +/- 45; simple, 61 +/- 39 min). Despite plasma concentrations being tracked over a 200-fold range, log linearity was not established within 12 h in any of the 42 profiles obtained. A two-compartment open model was fitted to the solution data giving excellent prediction of the time-to-peak and clearance (Cl/F = 5.2 +/- 1.1l/h) as determined by eye and by log-trapezoidal rule, respectively.

Biological Availability↗
PubMed1981

Hemodynamic effects of prazosin in chronic heart failure.

Three series of investigations were carried out with prazosin (PZN) hydrochloride. In the first, hemodynamic effects of PZN were compared with those of hydralazine (HDZ) in 11 patients with chronic congestive heart failure (CHF). In doses up to 5 mg, PZN increased cardiac output (CO) 20% accompanied by a 20% decrease in pulmonary capillary wedge pressure (LVFP). HDZ increased CO by 50% with little or no effect on LVFP. An additional 12 patients were given multiple 5 mg doses of PZN at 6-hour intervals with measurements of hemodynamic and plasma blood levels. Results suggested an attenuation of the effects of PZN on increasing CO but not on decreasing LVFP. This attenuation of CO was not due to inadequate plasma levels. Acute exercise studies (supine bicycle) were performed in 10 patients with severe CHF before and after the administration of several doses of PZN. There appeared to be a greater effect of PZN during exercise than at rest, with a beneficial increase in CO and reduction in LVFP. These data suggest that, despite hemodynamic attenuation of its effects on CO at rest, PZN may still be beneficial to active patients with CHF. In vitro studies with various vasodilators were performed to evaluate potential intropic effects. Isometric force (cat papillary muscle) increased 2% with 10-4M and 31% with 10-3M HDZ. PZN increased force 4% at 10-6M and 18% at 10-4M. Captopril did not increase force development at any dose level. The doses of HDZ and PZN that increased force development were higher than usual clinical doses.

Adult↗
PubMed1981

Ketoprofen-aspirin interactions.

To assess an interaction between ketoprofen and aspirin we gave both drugs orally, to steady state, to healthy men. Although ketoprofen did not alter salicylate absorption and disposition, we observed that concurrent administration of aspirin decreased ketoprofen protein binding and increased its plasma clearance. Salicylate also appeared to reduce metabolic ketoprofen conversion to conjugates and their renal elimination. The data suggested that salicylate also enhanced the metabolic conversion of ketoprofen to nonconjugate metabolites (p = 0.091). Our findings indicate that the drug-drug interaction between aspirin and ketoprofen is complex.

Adult↗
PubMed1981

Effect of naproxen on glucose metabolism and tolbutamide kinetics and dynamics in maturity onset diabetics.

1 The influence of the nonsteroidal anti-inflammatory drug naproxen on glucose metabolism and on tolbutamide pharmacokinetics and pharmacodynamics has been studied in ten maturity-onset diabetics. 2 Comparison of both plasma glucose decay curves and insulin responses during an intravenous glucose tolerance test before and after eight 12 hourly doses of naproxen revealed that naproxen had no significant influence on fasting glucose levels or on rates of glucose elimination. 3 When the subjects were given a combination of naproxen and tolbutamide for 3 days naproxen had no influence on tolbutamide absorption, protein binding, disposition or pharmacological effect. 4 Treatment with tolbutamide in maturity-onset diabetics need not be modified if concurrent administration of naproxen is contemplated.

Adult↗
PubMed1981

Newborn risk factors and costs of neonatal intensive care.

To understand the sources of the high costs of neonatal intensive care, financial and medical information on 1,185 admissions to an intensive care nursery was gathered. Multiple regression analysis showed that a significant portion of the variation in individual costs was explained by three measures of risk: low birth weight, surgical intervention, and assisted ventilation. There was a highly skewed distribution of costs. Nearly half of all admissions had none of the above risk factors, had an average cost of about $2,000, and accounted for only 13% of the total costs for the whole sample. In contrast, less than one quarter of the admissions had two or more of the risk factors, had an average cost of $19,800, and accounted for nearly 60% of the total costs. Models that predict costs and length of stay on a basis of seven risk factors were developed to allow for differences in patient populations.

California↗
PubMed1980

Convenient and sensitive high-performance liquid chromatography assay for ketoprofen, naproxen and other allied drugs in plasma or urine.

A new high-performance liquid chromatography technique enables convenient and rapid assay of ketoprofen and naproxen in biological samples at a sensitivity (10 and 2 ng/ml, respectively in plasma; 20 and 50 ng/ml in urine) far greater than previously available. Superior sensitivity is attributable to the buffered neutral eluent employed, which yields improved separation from material of biological origin. There is no interference from the major ketoprofen and naproxen metabolites tested and excellent reproducibility and accuracy can be maintained. Moreover, the same system can be used to assay probenecid and also shows promise of applicability to ibuprofen, fenoprofen and other members of the aryl-alkanoic acid class of non-steroidal anti-inflammatory agents.

Chromatography, High Pressure Liquid↗
PubMed1980

Monitoring perinatal mortality rates: California, 1970 to 1976.

Recent developments have emphasized the need to monitor perinatal mortality statistics by small geographic areas. A method is presented which separates county-specific perinatal mortality rates into a component reflective of socioeconomic, behavioral, and environmental variables, and a component that relates more directly to hospital-based intra- and postpartum care. Major differences in geographic variations were observed between the crude rate and the two components. An arbitrary index of the need for perinatal health services was created by combining the two components with the number of perinatal deaths in each county. Although there are some obvious limitations, the index serves as a useful guidepost for monitoring perinatal mortality on a statewide basis.

Bayes Theorem↗
PubMed1980

Negligible excretion of unchanged ketoprofen, naproxen, and probenecid in urine.

On the average, 0.6% of a dose of ketoprofen or naproxen or 1.2% of a dose of probenecid was found in the urine of normal male volunteers assayed immediately after its collection. Between approximately 60 and 85% of the dose of these drugs can be excreted in the urine as conjugates, which rapidly hydrolyze at body temperature, at room temperature, and even during frozen storage, thereby regenerating the parent drug. Since urine collections involved sample retention in the bladder at 37 degrees for collection intervals as long as 2--3 hr, the given percentages excreted unchanged probably are overestimates. It is possible that no unchanged ketoprofen, naproxen, or probenecid is excreted in urine. This study contrasts with previous reports of up to 50% of a dose of ketoprofen and 15--17% of doses of naproxen and probenecid being excreted in urine as the parent compound. Those reports probably reflect primarily the duration of frozen sample storage between collection and assay along with the urine collection schedules employed the speed of the clinical procedures, and the analytical procedures used. Attention should be given to potential conjugate hydrolysis whenever the pharmacokinetics of carboxylic acids are studied.

Humans↗
PubMed1980

Altered prazosin pharmacokinetics in congestive heart failure.

The pharmacokinetics of prazosin (Minipress) were studied in nine patients with NYHA Class 3 or 4 congestive heart failure and in five healthy controls. After a single 5 mg oral dose, plasma concentrations of prazosin, as reflected in the area under the plasma concentration-time curve (AUC) and prazosin plasma half-life, were approximately double in the patients in comparison to the control group. Reduction in hepatic blood flow, altered gastrointestinal absorption of the drug or diminished intrinsic hepatic metabolic activity in the patient group may have contributed to the observed changes in prazosin disposition. The finding of higher prazosin plasma concentrations in patients with refractory heart failure demonstrates the need for close monitoring of these individuals following administration of the drug in the treatment of chronic congestive heart failure.

Adult↗