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Biomedical subjects

R L Smith

Publications and source records attributed to R L Smith.

At least 433 records · Page 24Linked to original sources
PubMed1984

Impaired oxidation of debrisoquine in patients with perhexiline liver injury.

Perhexiline maleate is an antianginal agent which depends on hepatic oxidation for its elimination. Its use may be complicated by the development of peripheral neuropathy and liver damage. The majority of patients with perhexiline neuropathy have an impaired ability to effect metabolic drug oxidation which is genetically determined. Information has not been available on drug oxidation capacity in patients with perhexiline liver injury. Drug oxidation was measured using an oxidation phenotyping procedure in four patients with perhexiline liver injury and in 70 patients with chronic liver disease serving as a control group. All four patients with perhexiline liver damage showed a substantial metabolic defect; three of the four patients (75%) showed a genetically determined impairment of oxidation capacity. The incidence of severely impaired oxidation capacity in the perhexiline group was significantly greater than in the patients with chronic liver disease (6/70; 8.6%) and in the healthy population (9%) (F = 0.0048). A clear association exists between perhexiline liver injury and diminished drug metabolic activity, suggesting that the propensity to develop perhexiline liver injury is, at least in part, genetically determined.

Adolescent↗
PubMed1984

Architecture of the corneal stroma of the hen.

The corneal stroma architecture was studied in the adult chicken. Utilizing gross preparations, light and electron microscopic observations, the authors described the stromal lamellar arrangement. The stroma consists of two systems of lamellae: (1) a superficial or subepithelial system, formed by fan like spreading lamellae disposed in a spiral fashion localized at the superficial one fourth of the stroma and through the whole cornea, and (2) a deep system formed by an orthogonal gridwork of lamellae. Both systems are continuous.

Animals↗
PubMed1984

Review of glycol ether and glycol ether ester solvents used in the coating industry.

Ethylene oxide-based glycol ether and glycol ether ester solvents have been used in the coatings industry for the past fifty years. Because of their excellent performance properties (evaporation rate, blush resistance, flow-out and leveling properties, solubility for coating resins, solvent activity, mild odor, good coupling ability, good solvent release) a complete line of ethylene oxide-based solvents of various molecular weights has been developed. These glycol ether and glycol ether ester solvents have better solvent activity for coating resin than ester or ketone solvents in their evaporation rate range. The gloss, flow and leveling, and general performance properties of many coating systems are dependent on the use of these products in the coating formula. Because of the concern about the toxicity of certain ethylene oxide-based solvents, other products are being evaluated as replacements in coating formulas.

Chemical Phenomena↗
PubMed1984

The metabolism of S-methyl-L-cysteine in man.

The excretion and metabolism of radiolabelled S-methyl-L-cysteine (150 mg orally) was studied in three male volunteers. The major route of excretion was the urine with 55.9% of the administered radioactivity being voided over three days (33.3% during the first 24 h). Faecal excretion was relatively unimportant (c. 1.4%). The remaining radioactivity was either slowly excreted in the urine over the next 21 d (35S-labelled compound) or exhaled (14C-labelled compounds). Metabolism occurred via the pathways of S-oxidation, N-acetylation and deamination. Extensive degradation of the molecule was observed with the production of large amounts of inorganic sulphate and CO2. The options for the sequence of metabolic degradation of the amino acid derivative are discussed.

Acetylation↗
PubMed1984

D-Penicillamine induced toxicity in rheumatoid arthritis: the role of sulphoxidation status and HLA-DR3.

Sulphoxidation of carbocysteine, a drug structurally similar to D-penicillamine, displays a skewed distribution within a population. In 66 patients with rheumatoid arthritis (RA) a significant association between impaired sulphoxidation and toxicity (p less than 0.001) was found; HLA-DR3, although associated with toxicity (p less than 0.05), appeared to be an independent risk factor of most importance in the group with extensive sulphoxidation. The relative risk of toxicity in a patient possessing either DR3 or impaired sulphoxidation was 25. The prevalence of poor sulphoxidizers within this group of RA patients was increased compared to that in a previous population study and requires further investigation. Our findings explain a number of the toxic phenomena associated with D-penicillamine administration in RA.

Adult↗
PubMed1984

The effect of juvenile inflammatory synovial fluid on in vitro cartilage.

Inflammatory and noninflammatory juvenile synovial fluid (SF) samples were examined in vitro for their effect on cartilage. SF from 3 of 6 patients with pauciarticular juvenile arthritis (JA), 7 of 7 patients with polyarticular JA and 2 of 2 patients with ankylosing spondylitis had significantly increased proteoglycan (PG) releasing activity in 4 day cultures of living but not of freeze-killed cartilage. Noninflammatory SF did not cause increased PG release. Cartilage collagen content was not significantly altered by either inflammatory or noninflammatory SF. Our in vitro results showed PG releasing activity was present in inflammatory but not in normal juvenile SF.

Animals↗
PubMed1983

Nuclear magnetic resonance studies of amino acids and proteins. Side-chain mobility of methionine in the crystalline amino acid and in crystalline sperm whale (Physeter catodon) myoglobin.

We have obtained deuterium (2H) nuclear magnetic resonance (NMR) spectra and spin-lattice relaxation times (T1) of L-[epsilon-2H3]methionine, L-[epsilon-2H3]methionine in a D,L lattice, and [S-methyl-2H3]methionine in the crystalline solid state, as a function of temperature, in addition to obtaining 2H T1 and line-width results as a function of temperature on [epsilon-2H3]methionine-labeled sperm whale (Physeter catodon) myoglobins by using the method of magnetic ordering [Rothgeb, T. M., & Oldfield, E. (1981) J. Biol. Chem. 256, 1432-1446]. The results indicate that in the L-amino acid, methyl rotation having an activation energy (delta E) of 8.3 +/- 1 kJ dominates T1 at low temperatures (less than or equal to 10 degrees C), while at higher temperatures an additional large-amplitude side-chain motion occurs which causes changes in the 2H NMR line shape and T1. This motion is inhibited in the D,L lattice, indicating that lattice effects may have a strong effect on the mobility of anhydrous amino acids in the solid state. Further substitution at S delta to form the sulfonium salt [S-methyl-2H3]-methionine causes a large increase in delta E, to 15.9 +/- 2 kJ, a value comparable to the 14-16 kJ found in valine and leucine, which contain the structurally similar isopropyl moiety. These results suggest that the very low barriers to methyl rotation in the methionine side chain are due to long C-S bond lengths and the presence of only two substituents on sulfur, while the anomalous high-temperature behavior is due to a lattice-packing effect. 2H T1 results with methionine-labeled myoglobin are complex, reflecting the presence of fast large-amplitude side-chain motions, in addition to rapid methyl rotation. Our data indicate that Met-55 and Met-131 are motionally inequivalent in crystalline cyanoferrimyoglobin, in contrast to solution NMR results. We have also recorded 13C cross-polarization "magic-angle" sample-spinning NMR spectra of [epsilon-13C]methionine-labeled crystalline cyanoferrimyoglobin (at 37.7 MHz, corresponding to a magnetic field strength of 3.52 T) and of the same protein in aqueous solution. Cross-polarization transfer rates and proton rotating-frame relaxation time results again indicate that Met-55 and Met-131 are motionally inequivalent in the solid state, and the TCH data indicate that Met-55 is more solidlike. However, we find that 13C chemical shifts in solution and those in the crystalline solid state are in very close agreement, suggesting that the average solution and crystal conformations are the same, in the area of Met-55 and Met-131.

Animals↗
PubMed1983

Comparison of cartilage destruction between infectious and adjuvant arthritis.

The timing and molecular profile of cartilage destruction in Escherichia coli and Staphylococcus aureus infectious arthritis and killed Mycobacterium butyricum adjuvant arthritis are presented. Infectious arthritis was studied for 3 weeks; cartilage samples were analyzed at 2, 10, and 21 days. At 48 h postinfection, glycosaminoglycan content was reduced by 20% (p less than 0.05) in E. coli infected knees and by 42% (p less than 0.05) in tibial plateau cartilage of S. aureus infected knees. By the 3rd week of infection, glycosaminoglycan losses amounted to as much as 73% (p less than 0.005). In comparison, collagen losses were not significant prior to the 3rd week of infection, at which time 42% (p less than 0.05) was lost. Adjuvant arthritic tibial plateau cartilage was examined at 1, 3 and 12 weeks. Glycosaminoglycans decreased by 42% the 1st week, plateauing at 62% by the 3rd and 12th weeks. Collagen degradation began at 3 weeks (28% loss, p less than 0.10) and by the 12th week was reduced by 49% (p less than 0.005). Analysis of the individual species of glycosaminoglycan showed a parallel loss of chondroitin sulfate and keratan sulfate. Fractionation of glycosaminoglycans with respect to size produced no evidence of shortened chains in cartilage from infected joints. Hyaluronic acid losses were greatest when collagen was significantly decreased. The pattern by which chondroitin and keratan sulfates are lost demonstrates that a prominent feature of infectious and noninfectious inflammatory arthritis is a rapid loss of proteoglycan subunits that precedes collagen loss.

Animals↗
PubMed1983

The metabolism of p-propylanisole in the rat and mouse and its variation with dose.

We have studied the metabolism of the synthetic flavouring p-propylanisole in rats and mice and investigated the variation in its metabolism with dose. [methoxy-14C]-p-Propylanisole was given to female Wistar albino rats orally and male CD-1 mice ip at doses ranging from 0.05-1500 mg/kg body weight (0.2-20 20 microCi/animal). The urine, faeces and 14CO2 in the expired air were collected. The urinary metabolites were separated by solvent extraction, thin-layer chromatography and high-pressure liquid chromatography, and characterized by mass and nuclear magnetic resonance spectroscopy and comparison with authentic samples. Three major 14C-labelled urinary metabolites were excreted, 1'- and 2'-hydroxy-p-propylanisole and p-methoxyhippuric acid. 14CO2 was eliminated in the expired air, arising from oxidative O-demethylation. The relative quantities of the metabolites varied markedly with dose. The percentage of the dose that was O-demethylated fell as the dose increased and the proportion in the form of urinary metabolites increased. The relative proportions of the major urinary metabolites also changed with dose. In view of the great discrepancy between human exposure to p-propylanisole in foods (about 15 micrograms/day) and the doses used for its toxicological evaluation in animals, these results emphasize the importance of considering dose-dependent metabolism when interpreting the significance for man of animal data obtained at very high doses.

Animals↗
PubMed1983

Prostaglandin isosteres. 2. Chain-modified thiazolidinone prostaglandin analogues as renal vasodilators.

Chain modification of a thiazolidinone prostaglandin isostere has led to the production of 4-[3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl] benzoic acid (5b) which at 1 mg/kg po in the conscious dog causes a 70% increase in renal blood flow over control values with a duration of action exceeding 5 h. Preliminary testing indicates that 5b has a relatively specific action on the vasculature of the kidney. The enantiomers of 5b have been separated and the renal vasodilatory activity has been found to be entirely a property of the R-(+) enantiomer.

Animals↗
PubMed1983

2-(Aminomethyl)phenols, a new class of saluretic agents. 5. Fused-ring analogues.

A number of bicyclic ring-fused analogues of 2-(aminomethyl)phenol were synthesized and tested orally in rats and intravenously in dogs for saluretic and diuretic effects. Of the 15 alicylic, aromatic, and heterocyclic ring-fused compounds tested, only 2-(aminomethyl)-4-chloro-1-naphthalenol hydrochloride (2) and 7-(aminomethyl)-6-hydroxy-5,8-dimethyl-1,2,3,4-tetrahydronaphthalene hydrochloride (6) displayed a high order of activity.

Amines↗
PubMed1983

2-(Aminomethyl)phenols, a new class of saluretic agents. 6. Effects of N,O-spiroannulation and subsequent quaternization.

The synthesis of a number of 3,4-dihydrospiro-2H-1,3-benzoxazines and their corresponding benzoxazinium salts are reported. The saluretic effects displayed by these N,O-spiroannulated 2-(aminomethyl)phenols appear to be, in part, inversely related to their respective in vivo rates of hydrolysis. Good antihypertensive effects are found only in spirobenzoxazinium 22. Thus, a combination of spiroannulation and quaternization on 2 to produce 22 leads to a loss of saluretic effects with maintenance of antihypertensive effects and, thereby, serves to separate these pharmacological properties.

Amines↗
PubMed1983

Influence of oxidation polymorphism on phenformin kinetics and dynamics.

Plasma and urinary kinetics and responses of blood lactate, pyruvate, and glucose after a single 50-mg phenformin dose were investigated in eight subjects of known debrisoquin oxidation phenotype, four poor metabolizers (PM) and four extensive metabolizers (EM). Higher peak plasma concentrations of phenformin (152.2 +/- 12.7 ng/ml; mean +/- SE) and a greater plasma AUC (779 +/- 99 ng X hr X ml-1) were reached in PM than in EM (99.8 +/- 13.7 ng/ml and 549 +/- 47 ng X hr X ml-1). Although the urinary excretion of unchanged phenformin was greater in PM between 2 and 24 hr after dosing than in EM, excretion of 4-hydroxy-phenformin could not be detected in most samples collected from PM but was present in every sample from EM. Blood lactate concentrations increased dramatically in PM but fell in EM after phenformin. There were no changes in either blood pyruvate or glucose levels. The results may help to explain lactic acidosis in patients given phenformin in the absence of other predisposing factors.

Adult↗
PubMed1983

Genetically determined oxidation capacity and the disposition of debrisoquine.

1 The disposition in urine of debrisoquine and its hydroxylated metabolites has been studied in subjects of the 'extensive metabolizer' (EM; n = 5) and 'poor metabolizer' (PM; n = 5) phenotypes. The 4-hydroxylation of debrisoquine by PM subjects following a 10 mg oral dose was capacity-limited and displayed significant dose-dependency over a range of 1-20 mg. In contrast, the EM subjects' ability to perform this metabolic oxidation did not deviate from first-order kinetics over a dose range of 10-40 mg. 2 The disposition of debrisoquine in plasma following a 10 mg oral dose has been studied in EM (n = 4) and PM (n = 3) subjects. Whilst PM subjects displayed significantly higher plasma levels of debrisoquine at all time points following 1 h post-dosing, and higher values for areas under the plasma concentration-time curve (EM: 105.6 +/- 7.0 ng ml-1 h; PM: 371.4 +/- 22.4 ng ml-1 h, 2P less than 0.0001), neither debrisoquine plasma half-life (EM: 3.0 +/- 0.5 h; PM: 3.3 +/- 0.4 h) nor renal clearance of the drug (EM: 152.8 +/- 30.3 ml min-1; PM: 137 +/- 4.5 ml min-1) displayed significant inter-phenotype differences. 3 The results of these investigations show that the phenotyping of individuals for debrisoquine oxidation status by means of a 'metabolic ratio' derived from a single 0-8 h urine sample has a sound kinetic basis. The kinetic differences between the two phenotypes would strongly suggest that the metabolic defect manifested in PM subjects is one of pre-systemic elimination capacity.

Administration, Oral↗