Genetically determined impaired drug sulphoxidation.
Explore the source record for details and available documents.
Alleles↗
Biomedical subjects
R L Smith
Publications and source records attributed to R L Smith.
Junction-like structure appearing at apposing membranes in the double cone of chick retina.
No type of junction has yet been recognized between the two entities of the retinal double cone. In the present study, a junction-like structure was observed in serial sections of the double cone of the chick retina. It is recognized from the slightly outer part of the double cone to the outer limiting membrane. The apposing membranes are virtually parallel and separated by 5 to 7 nm of extracellular space. Dense material is associated on the cytoplasmic side of the opposing membranes. The structure resembles a gap junction, but there are no cross striations between the two membranes. Further experiments are required to establish this as a new type of junction.
Animals↗
Clinical pharmacokinetics and pharmacodynamics of fazadinium in renal failure.
The pharmacokinetic behaviour and neuromuscular blockade produced by the administration of fazadinium bromide at a dose of 1 mg/kg have been studied in seven patients with end-stage renal failure. No significant differences were found in the pharmacokinetic or pharmacodynamic properties when compared with patients with normal renal function. It is suggested that fazadinium may be superior to either d-tubocurarine or pancuronium in providing muscle relaxation for patients with renal failure.
Adult↗
Polymorphic 4-hydroxylation of debrisoquine in chronic discoid psoriasis.
Explore the source record for details and available documents.
Administration, Oral↗
Some observations on the oxidation phenotype status of Nigerian patients presenting with cancer.
The hypothesis is being explored that there may be an association between genetically determined oxidation status and propensity to develop carcinoma in response to environmental chemical carcinogens. For this purpose, the genetic structure of a normal, healthy Nigerian population with respect to oxidation status, has been compared with that found for a group of 59 Nigerian patients presenting with carcinoma of the liver and gastrointestinal tract. Genetically determined oxidation status was assessed by measuring the extent of oxidation of a probe drug, debrisoquine, to its major metabolite, 4-hydroxydebrisoquine. The cancer group contained a disproportionately large number of individuals who were extensive oxidizers compared to the controls (2 P = 0.0045). The findings support the view that genetically determined oxidation status may be an important host factor in influencing responsiveness to chemical carcinogens that require oxidative metabolic activation.
Adolescent↗
2-(Aminomethyl)phenols, a new class of saluretic agents. 2. Synthesis and pharmacological properties of the 5-aza isostere of 2-(aminomethyl)-4-(1,1-dimethylethyl)-6-iodophenol.
The synthesis and biological evaluation of 4-(aminomethyl)-6-(1,1-dimethylethyl)-2-iodo-3-pyridinol dihydrochloride (7b) are described. Compound 7b proved to be highly active as a saluretic diuretic in both rats and dogs.
Animals↗
2-(Aminomethyl)phenols, a new class of saluretic agents. 3. Effects of functional group reorientation and modification.
A series of modified 2-(aminomethyl)phenols was synthesized and tested orally in rats for saluretic and diuretic effects. Intravenous dog data are included as supplementary material to show that the diuretic responses, or lack thereof, may be obtained in a second species. Reorientation of the 2-(aminomethyl) group either meta or para to the hydroxyl substituent resulted in loss of diuretic effects. Similarly, replacement of either the phenolic hydroxyl or the aminomethyl group with other functional moieties substantially diminished saluretic effects.
Amines↗
Influence of DH/DL alleles regulating debrisoquine oxidation on phenytoin hydroxylation.
Eleven subjects of previously determined debrisoquine oxidation phenotype status (extensive metabolizer [EM], n = 5; poor metabolizer [PM], n = 6) were studied for their ability to perform the aromatic 4-hydroxylation of phenytoin. The PM subjects studied were found to be slower metabolizers of phenytoin than EM subjects in terms of the metabolite formation rate constant (kfHPPH: EM, 0.030 +/- .007 hr-1; PM, 0.016 +/- 0.003 hr-1, 2p less than 0.001) and cumulative excretion of 4-hydroxyphenytoin (48 hr after dosing: EM, 52.8 +/- 10.7%; PM, 36.9 +/- 7.0%, 2p less than 0.01). It is concluded that the metabolic oxidation of phenytoin is influenced by the same DH and DL alleles, acting at the same locus, that regulate the hydroxylation of debrisoquine and that impaired metabolism of phenytoin may be expected to occur in about 9% of the population, being transmitted as an autosomal-recessive trait. It is suggested that debrisoquine oxidation phenotyping may have predictive value in guiding phenytoin dosage, particularly in those with impaired oxidation.
Adult↗
The influence of maternal analgesia on neonatal behaviour: I. Pethidine.
Neonatal behaviour in a group of infants whose mothers received pethidine during labour was assessed at delivery and during the first six weeks of life by means of the Brazelton Neonatal Behavioural Assessment Scale. The influence of the total maternal dose of pethidine and umbilical cord blood concentration of the drug on such behaviour has been examined with the confounding effects of all other variables controlled. Higher cord blood levels of pethidine were associated with babies who were more prone to respiratory difficulties, drowsy and unresponsive immediately after delivery. Throughout the six weeks in which the assessments were made, depressed attention and social responsiveness were found in infants with high drug levels. At three and six weeks, the infant whose exposure ao pethidine had been high tended to change state more frequently, to cry during the test and to be less capable of quieting himself. These findings suggest that the newborn infant responds to pethidine in the same way as the adult, but the changes observed were relatively subtle, and comparison of these infants with a control groups whose mothers had received no drugs revealed no between-group differences in behaviour.
Anesthesia, Obstetrical↗
The influence of maternal analgesia on neonatal behaviour: II. Epidural bupivacaine.
Four areas of neonatal behaviour have been assessed at delivery and during the following six weeks in a group of infants whose mothers were given epidural bupivacaine during labour. The influence on such a behaviour of the total maternal dose of bupivacaine and umbilical cord blood concentration of the drug has been examined with the confounding effects of other maternal and obstetric variables controlled. Significant and consistent effects of bupivacaine throughout the assessment period can be demonstrated. Immediately after delivery, infants with greater exposure to bupivacaine in utero were more likely to be cyanotic and unresponsive to their surroundings. Visual skills and alertness decreased significantly with increases in the cord blood concentration of bupivacaine, particularly on the first day of life by also throughout the next six weeks. Adverse effects of bupivacaine levels on the infant's motor organisation, his ability to control his own state of consciousness and his physiological response to stress were also observed. Muscle tone alone appeared to improve with increases in the values of the drug variables. These results show that the neonate differs from the adult in respect of both the nature of effects of the drug and sensitivity to it.
Anesthesia, Epidural↗
Heparin binding and protease inhibitor activity of chemically modified antithrombin III.
Explore the source record for details and available documents.
2-Hydroxy-5-nitrobenzyl Bromide↗
A metabolic and pharmacokinetic comparison of theophylline and aminophylline (theophylline ethylenediamine).
The metabolism and pharmacokinetics of intravenously administered theophylline and aminophylline (theophylline ethylenediamine) have been studied in 3 volunteers, using 14C-labelled theophylline. Both compounds were metabolized extensively and 1,3-dimethyluric acid, 1-methyluric acid, 3-methylxanthine and two unknown minor metabolites were excreted in the urine, in addition to theophylline. The elimination of theophylline, 1,3-dimethyluric acid, 1-methyluric acid and the unknown metabolites followed first-order kinetics, but that of 3-methylxanthine followed Michaelis-Menten kinetics. When given as aminophylline, theophylline was metabolized more rapidly and extensively than when given alone. The recovery of 14C in the urine was significantly higher after aminophylline than after theophylline. Abstention from intake of dietary methylxanthines for 7 days resulted in more rapid and extensive metabolism of aminophylline compared with results from the same subjects on their usual diets. The results indicate that, from a metabolic and pharmacokinetic viewpoint, aminophylline and theophylline are not equivalent.
Adult↗
Animal modelling of human polymorphic drug oxidation--the metabolism of debrisoquine and phenacetin in rat inbred strains.
The metabolism of debrisoquine (5 mg kg-1 orally) was investigated in females of 7 strains of rat. Two major metabolic pathways, those of 4- and 6-hydroxylation were found to be polymorphic. The DA strain eliminated in urine only 7-10% of the dose as 4-hydroxy-debrisoquine together with 31-55% debrisoquine while the corresponding values for the Lewis strain were 44-55% and 11-17% respectively. Accordingly, DA and Lewis rats were proposed as models for the human PM (poor metabolizer) and EM (extensive metabolizer) drug oxidation phenotypes. To further test this model, DA and Lewis rats were given phenacetin (200 mg kg-1 orally). This underwent O-de-ethylation to paracetamol (52-55%) and aromatic 2-hydroxylation (7-8%) in Lewis rats. The corresponding findings in DA rats were 35-40% O-de-ethylation and 12-13% 2-hydroxylation. It is suggested that, with respect to both debrisoquine and phenacetin, Lewis and DA inbred rat strains afford a model of oxidative drug metabolism for the human EM and PM phenotypes respectively.
Animals↗
Reduction of sulfur compounds in the sediments of a eutrophic lake basin.
Concentrations of various sulfur compounds (SO(4), H(2)S, S, acid-volatile sulfide, and total sulfur) were determined in the profundal sediments and overlying water column of a shallow eutrophic lake. Low concentrations of sulfate relative to those of acid-volatile sulfide and total sulfur and a decrease in total sulfur with sediment depth implied that the contribution of dissimilatory sulfur reduction to H(2)S production was relatively minor. Addition of 1.0 mM Na(2)SO(4) to upper sediments in laboratory experiments resulted in the production of H(2)S with no apparent lag. Kinetic experiments with S demonstrated an apparent K(m) of 0.068 mmol of SO(4) reduced per liter of sediment per day, whereas tracer experiments with S indicated an average turnover time of the sediment sulfate pool of 1.5 h. Total sulfate reduction in a sediment depth profile to 15 cm was 15.3 mmol of sulfate reduced per m per day, which corresponds to a mineralization of 30% of the particulate organic matter entering the sediment. Reduction of S occurred at a slower rate. These results demonstrated that high rates of sulfate reduction occur in these sediments despite low concentrations of oxidized inorganic compounds and that this reduction can be important in the anaerobic mineralization of organic carbon.
Journal Article↗
Electron donors utilized by sulfate-reducing bacteria in eutrophic lake sediments.
Mineralization rates of C-labeled substrates were determined in the presence and absence of Na(2)MoO(4), an inhibitor of sulfate reduction, in the profundal sediments of a shallow eutrophic lake. Sulfate reduction was inhibited by Na(2)MoO(4) at all concentrations tested (0.2 to 200 mM), whereas methane production was inhibited at Na(2)MoO(4) concentrations greater than 20 mM. Initial mineralization rates of glucose were unaffected by Na(2)MoO(4); however, Na(2)MoO(4) decreased the mineralization rates of lactate (58%), propionate (52%), an amino acid mixture (85%), and acetate (14%). These decreases in the rates of mineralization were attributed to inhibition of sulfate reduction. Hydrogen stimulated the reduction of SO(4) 2.5- to 2.8-fold, demonstrating potential hydrogen oxidation by sulfate-reducing bacteria. These results indicate that sulfate reducers utilize an array of substrates as electron donors and are of potential significance to the in situ mineralization of lactate, propionate, and free amino acids in these sediments.
Journal Article↗
Influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation.
The influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation was studied by giving 500 mg antipyrine to 14 extensive and 10 poor metabolizers of debrisoquine. The pharmacokinetics of antipyrine were determined on the basis of the saliva concentration time curve and the cumulative urinary excretion of 4-hydroxyantipyrine, norantipyrine, 3-hydroxymethyl-antipyrine, and 3-carboxyantipyrine was measured for 32 h following drug administration. Antipyrine elimination half-life, volume of distribution, and total clearance were almost equal for the two groups. Significant differences in the excretion of antipyrine metabolites were not observed, except for 3-hydroxymethyl-antipyrine which was excreted in poor metabolizers about 30% less than in extensive metabolizers (p less than 0.01). However, this difference only reached borderline significance (p less than 0.1) when clearance values for production of this metabolite were calculated. It is concluded that different species of the drug-oxidizing enzymes (cytochrome P-450 system) are involved in the metabolism of debrisoquine and antipyrine. Possibly the enzyme responsible for hydroxylating debrisoquine is partly involved in the formation of 3-hydroxymethyl-antipyrine.
Aging↗
The psychiatric training of medical students.
Undergraduate psychiatric education should be concerned mostly with those aspects of psychiatry required for the proper practice of medicine. Psychiatric concepts and techniques are applicable to all medical practice and relevant to the daily work of every physician or surgeon. Therefore, in the psychiatric training of medical students the focus should be primarily on teaching "psychiatry of medical practice" and much less on teaching "specialty psychiatry." The teaching of psychiatry for medical practice will be best accomplished by selecting patients who are more like those the student will see later on as a practising physician. A systematic effort should be made to develop joint teaching with other departments, if we are to hope that students will carry over the approach we teach them to other subjects of medicine. Counselling and psychotherapy are essential skills for every physician or surgeon; medical students should be taught these skills by psychiatrists who are not just skilled psychotherapists but are also comfortable in their role as physicians in view of the importance of this role for the development of the identity of the medical student as a physician. The quality of the psychiatric training of medical students is dependent to a large extent on the priority accorded to undergraduate teaching by the department of psychiatry; competing activities, however, can result in undergraduate teaching being given less than top priority. Long-standing difficulties which psychiatry and psychiatrists experience in the medical school may impede undergraduate psychiatric education; these difficulties can be lessened by the closer involvement of psychiatrists with other physicians in the clinical and educational programs.
Canada↗
Metabolic conjugation of some carboxylic acids in the horse.
1. 14C-Labelled benzoic acid, salicylic acid and 2-naphthylacetic acid were administered orally to horses, and urinary metabolites investigated by chromatographic and mass spectral techniques. 2. [14C]Benzoic acid (5 mg/kg) was eliminated rapidly in the urine, and quantitatively recovered in 24 h. The major urinary metabolite was hippuric acid (95% of dose) with much smaller amounts of benzoic acid, benzoyl glucuronide and 3-hydroxy-3-phenylpropionic acid. Administration of [ring-D5]benzoic acid together with [14C]benzoic acid to a pony permitted the mass spectral determination of metabolites of the exogenous benzoic acid metabolites in the presence of the same endogenous compounds. 3. [14C]Salicylic acid (35 mg/kg) was eliminated rapidly in the urine, 98% of the 14C dose being excreted in 24 h. The major excretion product was unchanged salicylate (94% of dose). Gentisic acid, salicyluric acid and the ester and ether glucuronides of salicylic acid were very minor metabolites. 4. 2-Naphthyl[14C]acetic acid (2 mg/kg) was excreted very slowly in the urine, with 53 and 77% of the 14C dose being recovered in six days. 2-Naphthylacetylglycine was the major metabolite (26 and 38% dose) and in addition, the glucuronic acid and taurine conjugates were excreted together with unchanged 2-naphthylacetic acid. 5. The study has shown that the horse can utilize glycine, taurine and glucuronic acid for conjugation of xenobiotic carboxylic acids, and that the relative extents of these pathways are governed by the structure of the carboxylic acid.
Animals↗