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R L Smith

Publications and source records attributed to R L Smith.

At least 451 records · Page 25Linked to original sources
PubMed1983

The contribution of genetically determined oxidation status to inter-individual variation in phenacetin disposition.

The oxidative O-de-ethylation and aromatic 2-hydroxylation of phenacetin have been investigated in panels of extensive (EM, n = 13) and poor (PM, n = 10) metabolizers of debrisoquine. The EM group excreted in the urine significantly more paracetamol (EM: 40.8 +/- 14.9% dose/0-8 h; PM: 29.2 +/- 8.7% dose/0-8 h, 2P less than 0.05) and significantly less 2-hydroxylated metabolites (EM: 4.7 +/- 2.3% dose/0-8 h; PM: 9.7 +/- 3.5% dose/0-8 h, 2P less than 0.005) than the PM group. Apparent first-order rate constants, calculated from pooled phenotype data, for overall elimination of phenacetin (k) and formation of paracetamol (kml) were higher in the EM group (EM: k = 0.191 +/- 0.151 h-1; kml = 0.091 +/- 0.025 h-1; PM: k = 0.098 +/- 0.035 h-1, 2P less than 0.05, kml = 0.052 +/- 0.019 h-1, 2P less than 0.05) than the PM group. The apparent first-order rate constant for 2-hydroxylation displayed no significant inter-phenotype differences. Correlation analysis demonstrated that genetically determined oxidation status accounted for approximately 50% of the inter-individual variability in phenacetin disposition encountered in this study.

Acetaminophen↗
PubMed1983

Anaerobic oxalate degradation: widespread natural occurrence in aquatic sediments.

Significant concentrations of oxalate (dissolved plus particulate) were present in sediments taken from a diversity of aquatic environments, ranging from 0.1 to 0.7 mmol/liter of sediment. These included pelagic and littoral sediments from two freshwater lakes (Searsville Lake, Calif., and Lake Tahoe, Calif.), a hypersaline, meromictic, alkaline lake (Big Soda Lake, Nev.), and a South San Francisco Bay mud flat and salt marsh. The oxalate concentration of several plant species which are potential detrital inputs to these aquatic sediments ranged from 0.1 to 5.0% (wt/wt). In experiments with litter bags, the oxalate content of Myriophyllum sp. samples buried in freshwater littoral sediments decreased to 7% of the original value in 175 days. This suggests that plant detritus is a potential source of the oxalate within these sediments. [C]oxalic acid was anaerobically degraded to CO(2) in all sediment types tested, with higher rates evident in littoral sediments than in the pelagic sediments of the lakes studied. The turnover time of the added [C]oxalate was less than 1 day in Searsville Lake littoral sediments. The total sediment oxalate concentration did not vary significantly between littoral and pelagic sediments and therefore did not appear to be controlling the rate of oxalate degradation. However, depth profiles of [C]oxalate mineralization and dissolved oxalate concentration were closely correlated in freshwater littoral sediments; both were greatest in the surface sediments (0 to 5 cm) and decreased with depth. The dissolved oxalate concentration (9.1 mumol/liter of sediment) was only 3% of the total extractable oxalate (277 mumol/liter of sediment) at the sediment surface. These results suggest that anaerobic oxalate degradation is a widespread phenomenon in aquatic sediments and may be limited by the dissolved oxalate concentration within these sediments.

Journal Article↗
PubMed1983

The genetic control of sparteine and debrisoquine metabolism in man with new methods of analysing bimodal distributions.

Debrisoquine and sparteine tests were carried out in 215 random white British subjects. There is a high degree of correlation between the urinary 'metabolic ratios' of the two drugs. New mathematical techniques have been developed (1) to define phenotypes and (2) to identify the genotypes within the dominant phenotype. The members of 15 families were tested with both debrisoquine and sparteine. The results indicate that persons who are 'poor metabolisers' of sparteine are also 'poor metabolisers' of debrisoquine and are autosomal Mendelian recessives.

Adult↗
PubMed1983

Physician knowledge in the use of canister nebulizers.

The knowledge and skills of physicians were evaluated regarding some practical details of the usage of bronchodilators administered by canister nebulizers to determine the need for specific physician instruction in the correct usage. Fifty-five house officers and nonpulmonary attending staff from the Department of Medicine were interviewed individually. Each physician was handed a placebo canister and asked a series of standard questions regarding the recognition, assembly, and correct inhalation technique of the device. Correct assembly of the device was performed by 68 percent and 36 percent of house officers and attending staff, respectively. Only 40 percent of the participants correctly performed more than four of the seven steps felt to constitute a correct inhalation maneuver. The results reveal inadequacies in physicians' knowledge of the correct technical usage of canister nebulizers and suggest that greater attention be paid to instructing physicians in the correct inhalation technique if their role in patient education is to be effectively realized.

Aerosols↗
PubMed1983

The utilization of exogenous taurine for the conjugation of xenobiotic acids in the ferret.

Although the occurrence of the taurine conjugation mechanism for various xenobiotic acids is well established, nothing is known of the source of the taurine used for this conjugation. [14C]Taurine was administered alone and in combination with 2-naphthylacetic acid or clofibric acid (both of which are known to form taurine conjugates) to to ferrets, and the 0--24 h urine collected. Of the dose of [14C]taurine, 26% was recovered in the urine in 24 h and the only 14C-containing material present was unchanged taurine. When either 2-naphthylacetic acid or clofibric acid was co-administered with [14C]taurine, 21 and 17%, respectively, of the 14C dose was recovered in the 0--24 h urine. In both cases, two 14C compounds were present--unchanged taurine (minor) and the taurine conjugate of the acid in question (major). Comparison of these results with those previously obtained with 14C-labelled 2-naphthylacetic and clofibric acids, shows that the taurine used for their conjugation is derived from a pool freely accessible to exogenous taurine. The results are discussed in terms of the availability for metabolic utilization of taurine in the animal body, and of the use of co-administration of [14C]taurine with a xenobiotic acid for the identification of taurine conjugates.

Acids↗
PubMed1983

The metabolism of fenclofenac in the horse.

14C-Fenclofenac (2-(2'-4'-dichlorophenoxy)-phenylacetic acid) was administered orally to horses, and urinary metabolites investigated by chromatography. Fenclofenac was rapidly absorbed and eliminated, with a plasma half-life (t1/2) of 2.3 h, with 83.2 and 85.8% of the dose being recovered in the urine in 0-24 h. The major urinary metabolite was the ester glucuronide (58.8, 70.0% dose), and evidence is presented that this metabolite undergoes a structural rearrangement to give beta-glucuronidase-resistant isomers. The other 14C-labelled components in horse urine were unchanged fenclofenac (13.1, 11.5% dose), and two minor metabolites, one of which was identified as a monohydroxy fenclofenac. This study is the first to show an ester glucuronide to be the major metabolite of a non-steroidal anti-inflammatory drug in the horse.

Animals↗
PubMed1983

Effects of pulsing electromagnetic fields on bone growth and articular cartilage.

Observations made during treatment of juvenile pseudarthrosis by pulsing electromagnetic fields (PEMF) suggested that bone growth might be altered. PEMF applied to immature rabbits under conditions of continuous stimulation (24 hours/day for 8 weeks) produced no major changes in bone growth. Continuous stimulation by PEMF induced a statistically significant increase (22%) in femoral articular cartilage glycosaminoglycan. Intermittent PEMF stimulation (12 hours with stimulation/12 hours without stimulation) for 18 weeks produced no significant change in bone growth or time of epiphyseal plate closure. No significant changes in the physical characteristics of growing bone were observed with any treatment.

Animals↗
PubMed1983

The structural basis of the blood-aqueous barrier in the chicken eye.

In order to identify the structural basis of the blood aqueous barrier in the chicken eye, the morphology of the blood vessels and epithelium of the ciliary body were examined with light microscopy, conventional electron microscopy, and the freeze-fracturing technique; the permeability properties of the vessels and epithelium were tested with intravascular injection of horseradish peroxidase (HRP). The ciliary body and iris of the adult chicken are supplied principally by a single temporal long posterior ciliary artery that, by dividing into two branches, gives rise to the great circle of the iris. From this circle multiple branches reach the iris, while a few run posteriorly to the ciliary body stroma. Most of the blood supply to the ciliary body stroma is derived from vessels that return from the iris, run in the valleys between ciliary processes, and are continuous, at the ora serrata, with the veins of the vortex system. Electron microscopy shows that the vessels of the ciliary body stroma differ from their counterpart in mammals in two respects: (1) the endothelial cells are joined by simple but continuous zonulae occludentes; (2) the openings in the endothelial lining (plasmalemmal vesicles, fenestrae, and transendothelial channels) are less numerous. The walls of these vessels retard, but do not prevent the diffusion of intravenously injected HRP into the surrounding connective tissue spaces. From the ciliary body stroma, HRP diffuses into the intercellular clefts of the ciliary epithelium, but its progression toward the posterior chamber is blocked by very complex zonulae occludentes between the nonpigmented cells. Thus, in chickens as in mammals tight junctions between the nonpigmented cells of the ciliary epithelium represent the structural equivalent of the blood-aqueous barrier.

Animals↗
PubMed1982

Spectral binding studies of the polymorphically metabolized drugs debrisoquine, sparteine and phenformin by cytochrome P-450 of normal and hydroxylation deficient rat strains.

The mechanisms of polymorphic drug hydroxylation of debrisoquine, sparteine and related drugs in vivo have been investigated using Cyt P-450 preparations of inbred rat strains as an in vitro model of the poor and extensive metabolizer phenotypes found in various rat strains and in man. Optical difference spectroscopy with debrisoquine, sparteine, phenformin and three other drugs (selected test compounds with proven or suspected hydroxylation polymorphisms in man) exhibited Type 1 binding in normal Sprague-Dawley, Fischer and Lewis Cyt P-450, whereas no Type I drug binding was found in the hydroxylation deficient DA rat liver Cyt P-450. Cyt P-450 content and Type II drug binding of metiamide was the same in normal and hydroxylation deficient rat liver microsomes. The pronounced Type I drug binding in extensive hydroxylation Cyt P-450 and the defective Type I binding in DA Cyt P-450 in vitro, therefore, closely parallels the polymorphic hydroxylation pattern of these test drugs found in the four rat strains studied in vivo. Consequently, missing binding properties of Cyt P-450 or of its micro-environment might represent the enzymatic defect underlying the genetically determined hydroxylation deficiency of polymorphically metabolized drugs in the poor metabolizer phenotype in the DA rat and, by inference, in man.

Animals↗
PubMed1982

3-Hydroxy- and 3-keto-3-phenylpropionic acids: novel metabolites of benzoic acid in horse urine.

The metabolism of benzoic acid has been examined in the horse, using 14C- and deuterium-labelled compounds. Chromatographic analysis of the urine showed the presence of hippuric acid, benzoyl glucuronide and benzoic acid and a discrete band which accounted for 2% of the dose administered. This material was isolated by solvent extraction and HPLC and, following treatment with diazomethane, examined by GC/MS. The major component of this fraction was 3-hydroxy-3-phenylpropionic acid methyl ester, which was accompanied by very much smaller amounts of cinnamic acid methyl ester and acetophenone. The two latter minor components have been shown to be artefacts produced during workup and analysis. Cinnamic acid methyl ester arises by the thermal decomposition of 3-hydroxy-3-phenylpropionic acid methyl ester on the GC column. It is proposed that acetophenone has formed, during workup, by decarboxylation of 3-keto-3-phenylpropionic acid. It is suggested that 3-hydroxy and 3-keto-3-phenylpropionic acids, which are also endogenous in horse urine, have arisen by an addition of a 2 carbon fragment to benzoyl CoA, in a sequence analogous to the reactions of fatty acid biosynthesis. Some implications of the metabolic interrelationships between xenobiotic acids and fatty acids are discussed.

Animals↗
PubMed1982

Estradiol suppresses then enhances intracaudate dopamine-induced contralateral deviation.

The effects of estradiol on the amount of contralateral postural deviation elicited by unilateral intracaudate injection of dopamine (DA) were tested 2 days and 6 days after hormone treatment. DA (25 micrograms/0.25 microliter) or a control vehicle solution (VH, 0.25 microliter) was injected unilaterally into the dorsal anterior caudate-putamen of intact male rats and postural deviation was measured. Then, rats were given estradiol benzoate (EB, 50 micrograms/100 g body wt per 0.05 ml) or the vehicle, peanut oil (OIL, 0.05 ml/100 g body wt) once. At 2 days and 6 days after EB or OIL treatment, the rats were again administered DA or VH intrastriatally and the amount of contralateral postural deviation was measured. At 2 days after EB treatment the response to intrastriatal DA was significantly decreased, but by 6 days it was significantly increased; OIL had no effect. Thus, the behavioral effects of estrogen are time-dependent and may affect the postsynaptic response to DA in the striatum.

Animals↗
PubMed1982

Impaired oxidation of debrisoquine in patients with perhexiline neuropathy.

The use of perhexiline maleate as an antianginal agent is occasionally associated with side effects, particularly neuropathy and liver damage. The reason why some individuals develop these toxic reactions is not clear, though some evidence suggests that they may result from impaired oxidative metabolism, due to genetic or hepatic factors, and consequential accumulation of the drug in toxic concentrations. Drug oxidation was measured with an oxidation phenotyping procedure in 34 patients treated with perhexiline, 20 of whom had developed neuropathy and 14 of whom had not. Most of the 20 patients with neuropathy, but not the unaffected patients, showed an impaired ability to effect metabolic drug oxidation. This impairment was independent of hepatic function, concurrent drug therapy, or tobacco or alcohol consumption. The fact that the ability to oxidise several drugs is genetically controlled points to a genetic susceptibility to developing neuropathy in response to perhexiline. Routine determination of the drug oxidation phenotype might lead to safer use of perhexiline by predicting patients who may be more at risk of developing a neuropathic reaction associated with its long-term use.

Adult↗
PubMed1982

Evidence that a Na+/Ca2+ antiport system regulates murine erythroleukemia cell differentiation.

The Na+ and Ca2+ transport properties of cultured murine erythroleukemia (MEL) cells have been investigated. We have previously shown that amiloride prevents dimethyl sulfoxide-induced MEL cell differentiation via inhibition of an essential Ca2+ influx (levenson, R., Housman, D., and Cantley, L. (1980) Proc. Natl. Acad. Sci. U. S. A. 77, 5948-5952). Here we show that external Na+ inhibits Ca2+ influx and stimulates Ca2+ efflux from uninduced MEL cells. Increasing the internal Na+ concentration by a brief incubation of cells with ouabain stimulates the rate of 45Ca2+ influx. Amiloride (40 microM) completely blocks the external Na+-stimulated 45Ca2+ efflux and external Na+-inhibitable 45Ca2+ influx. The same concentration of amiloride had no significant effect on net Na+ uptake. These results suggest that a significant fraction of Ca2+ flux across the MEL cell plasma membrane occurs via a Na+/Ca2+ antiport system and that amiloride prevents differentiation by blocking Ca2+ influx through this system. The importance of a Na+/Ca2+ antiport system for MEL cell differentiation is supported by the following observation: increasing the cellular Na+ level by a brief treatment with ouabain plus monensin accelerates MEL cell commitment as effectively as adding the Ca2+ ionophore A23187. We suggest that dimethyl sulfoxide induces MEL cell differentiation by inhibiting the Na+ pump and consequently allowing Ca2+ influx through the Na+/Ca2+ antiport.

Amiloride↗
PubMed1982

In vitro cartilage degradation by Escherichia coli and Staphylococcus aureus.

Effects of Escherichia coli and Staphylococcus aureus on cartilage and chondrocytes in culture are reported. Under these conditions, bacterial effects on cartilage degradation and cell viability are measured in the absence of inflammation. E coli causes a 28% loss and S aureus an 83% loss of cartilage glycosaminoglycan within 48 hours. Collagen content is unchanged. Both bacterial species induce chondrocyte death in explants and in monolayers within 48 hours. Bacterial effects on glycosaminoglycans and cell viability do not result from depletion of nutrients from the culture medium. Serum in the culture media inhibits the bacterial effects on cartilage degradation but does not prevent cell death.

Animals↗