Non-human primate species as metabolic models for the human situation: comparative studies on meperidine metabolism.
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Biomedical subjects
Publications and source records attributed to R L Smith.
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1 The synthesis of [14C]-debrisoquine hydrochloride and 4-hydroxy-debrisoquine sulphate is described. 2 The metabolic fate and excretion profile in both urine and faeces of 14C-labelled debrisoquine was studied in five healthy human subjects. 3 Investigations showed that the drug is well-absorbed after a single oral dose of 32 mg and quantitatively eliminated from the body within three days. 4 4-Hydroxy-debrisoquine is the major metabolite of debrisoquine, although significant amounts of 5-,6-, 7- and 8-hydroxy-debrisoquine are also formed. 5 Electron-capture gas chromatography is a useful method for measuring debrisoquine and its five hydroxylated metabolites in urine at the pg level.
The continuous fetal heart rate rate pattern, condition of the baby at birth and its subsequent behaviour were compared in three groups of infants whose mothers received during labour either no drugs, intramuscular pethidine or epidural bupivacaine. The blood levels of pethidine and bupivacaine were measured at delivery in a maternal vein, and umbilical artery and vein, and in the newborn during the first 48 hours of life. The only significant changes in the fetal heart rate pattern occurred in association with maternal hypotension or uterine hyperstimulation. The Apgar scores at one minutes were 7 or less in more infants in the intramuscular pethidine and epidural bupivacaine groups as compared with the controls. There were no differences in the Apgar scores at five minutes. Neonatal behaviour during the first six weeks of life was not significantly affected by pethidine or epidural bupivacaine when compared with the control group. Pethidine and bupivacaine were shown to cross the placenta freely. The half-life of these drugs in the newborn was longer than in the adult.
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Results are reviewed concerning some effects, at a units's characteristic frequency, of a short-term conditioning stimulus on the responses to perstimulatory and poststimulatory test tones. A phenomenological equation is developed from the poststimulatory results and shown to be consistent with the perstimulatory results. According to the results and equation, the response to a test tone equals the unconditioned or unadapted response minus the decrement produced by adaptation to the conditioning tone. Furthermore, the decrement is proportional to the driven response to the conditioning tone and does not depend on sound intensity per se. The equation has a simple interpretation in terms of two processes in cascade--a static saturating nonlinearity followed by additive adaptation. Results are presented to show that this functional model is sufficient to account for the "physiological masking" produced by wide-band backgrounds. According to this interpretation, a sufficiently intense background produces saturation. Consequently, a superimposed test tone cause no change in response. In addition, when the onset of the background precedes the onset of the test tone, the total firing rate is reduced by adaptation. Evidence is reviewed concerning the possible correspondence between the variables in the model and intracellular events in the auditory periphery.
We have isolated Azospirillum (Spirullum lipoferum) from roots of grasses of several genera collected from a number of tropical and subtropical-temperate locations. Pure cultures were obtained from a small percentage of samples; no higher percentage was secured from tropical than from other grasses. Acetylene reduction and distinctive growth in N-free soft agar deeps were inadequate to identify this genus, although helpful in initial screening. Fluorescent antibody tests with antiserum against characterized strains were helpful. There is some evidence that this genus of bacteria may be favored in the rhizoplane.
1. Debrisoquine hydroxylation exhibited profound variation in 72 Egyptian volunteers. 2. The frequency distribution histogram of the metabolic ratio (ratio unchanged drug: 4-hydroxy metabolite in 0-8 h urine) was polymodal. 3. From family data it was possible to define more clearly than before the heterozygous characteristics. 4. Egyptians appear in general to be more extensive oxidizers of debrisoquine than do English subjects. 5. Ramadan fasting was found to lower the absorption of debrisoquine.
1. The qualitative and quantitative aspects of the urinary elimination of orally administered 4-methoxy[14C]amphetamine have been examined in the rat and guinea-pig and in three volunteer human subjects, to determine interspecies and interindividual variations in disposition of the drug. 2. Both rat and guinea-pig excreted 70--80% of the administered dose(6 mg/kg) in the urine within 24 h, mainly as metabolites. 3. In the guinea-pig, the drug was metabolized by O-demethylation to give 4-hydroxyamphetamine, which was excreted free (4% dose) and conjugated (73%). No other metabolite was detected. 4. The rat metabolizes the drug both by O-dealkylation and by side-chain oxidation, the products being 4-hydroxyamphetamine (5% of dose free and 60% conjugated) and 1-(4'-methoxyphenyl)propan-2-one oxime (5% dose, free and conjugated). 5. In man the drug (dose 5 mg) is metabolized by O-demethylation and by side-chain oxidation. Marked intersubject variations were observed both in the array and quantitative aspects of metabolite excretion. Two subjects excreted mainly 4-hydroxyamphetamine (free and conjugated) together with smaller amounts of 1-(4'-methoxyphenyl)propan-2-one oxime and 4-hydroxynorephedrine. The third subject, however, who was previously known to exhibit a genetically determined defect in drug oxidation, was defective in O-dealkylation of 4-methoxyamphetamine, and the main excretion products were the unchanged drug together with products of side-chain oxidation, namely, 1-(4'-methoxyphenyl)propan-2-one oxime, 1-(4'-methoxyphenyl)propan-2-one and 4-methoxybenzoic acid. 6. Inter-individual differences in oxidative O-demethylation of the drug are discussed in relation to current theories on the aetiology of schizophrenia and reported fatalities arising from abuse of the drug.
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The influence of percent egg yolk during cooling from 37 to 5 C on ability of sperm to withstand subsequent freezing was studied with semen from each of eight bulls. Treatments were arranged factorially and included .5, 1, 2, 4, 8, 16, and 32% egg yolk, cooling times of .5, 1, 2, and 4 h, and freezing in ampules and straws. Percent egg yolk did not influence motility or percent intact acrosomes when semen was frozen in ampules. For sperm in straws, both post-thaw percentages of motile sperm and intact acrosomes were similar for sperm cooled with .5, 1, 2, 4, or 8% egg yolk and greater than with 16 or 32% egg yolk. Optimal egg yolk during cooling was not dependent upon rate of cooling, regardless of how semen was packaged for freezing. The influence of percent egg yolk during freezing was investigated in a second study. Treatments included eight bulls; 1, 2, 4, 8, 16, and 32% egg yolk; freezing times from +5 to -130 C of 3.5, 20, and 40 min; and freezing in ampules or straws. Optimal egg yolk during freezing in either ampules or straws was independent of the rate of freezing. For sperm frozen in ampules, differences in motility or the percent intact acrosomes due to egg yolk were small. However, the use of only 1 or 2% egg yolk depressed motility whereas 16 or 32% egg yolk decreased the percentage of intact acrosomes. Thus, extremely high or low egg yolk should be avoided. For sperm in straws, survival was optimal when the extended semen contained 4 to 32% egg yolk during freezing.
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