Showing papers by "Flinders University published in 1983"
TL;DR: There is considerable scope to improve pain management in children after surgery and this improvement must be based on improved education of medical and nursing staff in contemporary clinical pharmacology and on improved communication between staff, parents and patients.
Abstract: The incidence of pain in 170 children recovering from surgery was surveyed in two major teaching hospitals along with an analysis of analgesic medication prescribed and administered. Analgesic medication was not ordered for 16% of the patients and narcotic analgesic medication ordered was no
395 citations
TL;DR: Fentanyl is rightly regarded as having a redistribution-limited duration of action after single or infrequent doses (analogous to thiopentone), but the magnitude of the pharmacokinetic constants reported for fentanyl are remarkably inconsistent even in healthy volunteers.
Abstract: Fentanyl, a synthetic opiate with a (clinical) potency of 50 to 100 times that of morphine, was introduced into clinical practice in the early 1960s. Usually administered by single intravenous doses, it developed a reputation for having a short duration of action and it was assumed that this was a consequence of rapid removal from the body. However, as clinical experience increased, it was realised that administration of multiple doses or large doses during narcotic-based anaesthesia sometimes led to delayed recovery and prolonged respiratory depression, suggesting that the duration of action was limited by redistribution within the body rather than removal from the body. Recent developments in analytical techniques have allowed pharmacokinetic studies and these have confirmed this opinion; fentanyl is rightly regarded as having a redistribution-limited duration of action after single or infrequent doses (analogous to thiopentone). However, the magnitude of the pharmacokinetic constants reported for fentanyl are remarkably inconsistent even in healthy volunteers, for reasons apparently only explainable by assay differences. Hence, estimates of apparent volume of distribution (area) range from around 60L to over 300L, estimates of terminal half-life range from about 1.5 to 6 hours (15 hours in geriatric patients) and total body clearance ranges from 0.4 to over 1.5 L/min. Renal excretion accounts for up to 10% of the dose; the remainder of the clearance would appear to be predominantly hepatic, but with contributions from other tissues. Continued clinical developments of narcotic-based anaesthetic techniques have resulted in high doses of narcotic being used, with oxygen, as the sole anaesthetic agents. At present these techniques are usually based on fentanyl, and the technique is frequently called ’stressfree anaesthesia’ because of the effects in obtunding the ’stress response’ caused by surgery (elevation of plasma concentrations of cortisol, glucose, ADH, etc. in the intra- and postoperative period) and the lack of deleterious effects on the cardiovascular system. With the hypothesis that increased potency is associated with increased specific opiate effects and decreased nonspecific cardiovascular depressant effects, chemical congeners of fentanyl were developed. Alfentanil has about one-third the (clinical) potency of fentanyl, while sufentanil has about 5 to 10 times the (clinical) potency of fentanyl. Lofentanil and carfentanil have about 20 to 30 times the potency of fentanyl and have yet to find clinical roles. Alfentanil is characterised by a rather small apparent volume of distribution for a base (Varea = 40-70L), short terminal half-life (100 minutes), intermediate total body clearance (0.3–0.5 L/min) and negligible renal clearance. Sufentanil would appear to have pharmacokinetic properties intermediate to those of alfentanil and fentanyl. At physiological pH, approximately 15 to 20% of fentanyl is unbound in plasma compared with 5 to 10% of alfentanil, sufentanil and lofentanil. Except for alfentanil, there is a marked plasma binding dependence on pH. Also except for alfentanil, there is a predominance of ionised drug species and a high octanol: water partition coefficient in the physiological pH range. These factors act to influence the tissue binding of the agents and reflect back on other important factors such as uptake by blood cells. Whole blood: plasma concentration ratios of 0.97, 0.63, 0.74 and 0.71 have been reported for fentanyl, alfentanil, sufentanil and lofentanil, respectively. The range of opiate duration of action has been extended by the appearance of these newer compounds, where alfentanil may be regarded as having an ultrashort duration of action, fentanyl and sufentanil as short acting, while lofentanil has a long duration of action. Knowledge of the pharmacokinetic properties of these agents has provided more information than could be obtained from clinical studies alone, and has added a basis on which to rationalise and enhance their usefulness.
372 citations
TL;DR: PPLI is located in periarterial noradrenergic nerves of the guinea-pig stomach and intestine with the use of antibodies raised against avian, bovine and human pancreatic polypeptide (PP), the C-terminal hexapeptide of mammalian PP, and against the related peptide, NPY.
Abstract: Pancreatic polypeptide-like immunoreactivity (PPLI) has been localized in nerves of the guinea-pig stomach and intestine with the use of antibodies raised against avian, bovine and human pancreatic polypeptide (PP), the C-terminal hexapeptide of mammalian PP, and against the related peptide, NPY. Each of the antibodies revealed the same population of neurones. Reactive cell bodies were found in both myenteric (5% of all neurones) and submucous ganglia (26% of all neurones) of the small intestine, and varicose processes were observed in the myenteric plexus, circular muscle, mucosa and around arterioles. The nerves were unaffected by bilateral subdiaphragmatic truncal vagotomy, but the staining of the periarterial nerves disappeared after treatment of animals with reserpine or 6-hydroxydopamine and was also absent after mesenteric nerves had been cut and allowed to degenerate. Vascular nerves showing immunoreactivity for dopamine it-hydroxylase and PPLI had the same distribution. It is concluded that PPLI is located in periarterial noradrenergic nerves. However, other noradrenergic nerves in the intestine do not show PPLI, and PPLI also occurs in nerves that are not noradrenergic. Analysis of changes in the distribution of terminals after microsurgical lesions of pathways in the small intestine showed that processes of myenteric PP-nerve cells provide terminals in the underlying circular muscle and in myenteric ganglia up to about 2 mm more anal. Submucous PP-cell bodies provide terminals to the mucosa.
264 citations
TL;DR: The in vivo mutation frequency is of the order of that observed for human fibroblast lines cultured in vitro, and cloned peripheral blood lymphocytes (PBL) by a technique which is highly efficient and results in large clones of 103–104 cells that are readily scored using an inverted microscope.
Abstract: A means of measuring in vivo mutations in man would be valuable in assessing the importance of mutation in ageing and human disease and for monitoring individuals exposed to environmental mutagens and carcinogens. The hypoxanthine–guanine phosphoribosyl transferase (HGPRT) locus has been used to study mutagenesis in cultured mammalian (and other) cells1; clones are selected by their ability to grow in the presence of the purine analogue, 6-thioguanine (6-TG). Such clones are almost always HGPRT− and are therefore probably the progeny of a mutant cell. This system has been applied to human lymphocytes by using autoradiography to detect single mutant cells2–6. This approach probably does detect mutant cells, particularly if their number is increased, but the results obtained are variable and rather imprecise4,5. Also, the technique does not allow isolation of clones, thus the mutational origin of thioguanine-resistant (TGr) cells cannot be determined as the gene product, HGPRT, cannot be measured. Previous methods for cloning peripheral blood lymphocytes (PBL) have been so inefficient that detection of TGr lymphocytes has not been practicable. We have cloned PBL by a technique which is highly efficient (20–60% of PBL form a clone) and results in large clones of 103–104 cells that are readily scored using an inverted microscope6,7. We report here that the in vivo mutation frequency is of the order of that observed for human fibroblast lines cultured in vitro1.
225 citations
TL;DR: It is concluded that vasoactive intestinal polypeptide is contained in neurons of a number of intrinsic nerve pathways, influencing motility, blood flow and mucosal transport.
204 citations
TL;DR: In this paper, Backman et al. found that the use of time was positively associated with self-esteem and negatively associated with depressive symptoms in both employed and unemployed male and female university graduates.
Abstract: Employed and unemployed male and female university graduates completed a questionnaire that included the Backman et al. (1978) self-esteem scale, the short form of the Beck Depression Inventory (Beck & Beck, 1972) and items designed to measure employment importance and the extent to which time was used in a structured and purposeful way. It was found that graduates in the unemployed sample were less organized and less purposeful in their use of time and reported more depressive symptoms when compared with the employed sample. In both groups structured and purposeful use of time was positively associated with self-esteem and negatively associated with depressive symptoms. Correlations between employment importance and the use of time measures (total score, engagement, direction, structure and routine) were negative for the unemployed sample and positive for the employed sample, indicating that employment importance functioned as a moderator variable. Female respondents reported higher employment importance and more use of a routine but their self-esteem scores were lower than those of the male respondents. Results were related to Jahoda's analysis of the latent functions of employment and to other recent studies of employment and unemployment but were seen as extending beyond the Jahoda analysis.
196 citations
TL;DR: Investigation of paracetamol metabolism in healthy males, healthy females and healthy females receiving oral contraceptive steroids found sex-related differences are unlikely to be of clinical importance, but induction by OCS may have clinical and toxicological consequences.
Abstract: Paracetamol metabolism was investigated in eight healthy males, eight healthy females and eight healthy females receiving oral contraceptive steroids (OCS). Paracetamol clearance was 22% greater in males compared to the control female group. This difference was entirely due to increased activity of the glucuronidation pathway in males, there being no sex-related differences in the sulphation or oxidative metabolism of paracetamol. Paracetamol clearance in females using OCS was 49% greater than in the control females. Glucuronidation and oxidative metabolism were both induced in OCS users (by 78% and 36% respectively) but sulphation was not altered. Although sex-related differences in paracetamol metabolism are unlikely to be of clinical importance, induction of paracetamol metabolism by OCS may have clinical and toxicological consequences.
179 citations
TL;DR: The enkephalin neurons represent a population of enteric neurons, with a distinct distribution and projections, which does not correspond to any of the other populations of enteringic neurons that have been studied.
164 citations
Journal Article•
TL;DR: The results suggest that site II is a hydrophobic cleft about 16 A deep and about 8 A wide in the albumin molecule with a cationic group located near the surface.
Abstract: Structure-activity relationships for binding at site II on human serum albumin have been investigated using drugs, fatty acids, and aliphatic amines with chain lengths C-3 to C-18. A negative charge is not required for binding provided a strongly electronegative center is present. For example, diazepam, a basic drug that exists mainly in the un-ionized form at neutral pH, also binds with high affinity to site II. However, aliphatic amines (pKa values 10-11) with chain lengths C-3 to C-12 did not displace markers from either site I or II, showing that the presence of a positive charge precludes binding at these sites. Short-chain fatty acids, C-3 to C-5, did not displace marker drugs or fluorescent probes from either site I or II when added at equimolar ratios with albumin. Displacement of site II (but not site I) markers occurred with medium-chain fatty acids, C-7 to C-11, and was maximal at C-10. Fatty acids with chain lengths C-10 to C-18 caused an enhancement of fluorescence of dansylamide bound to site I, the maximal effect occurring with C-12. Both arylpropionic acid nonsteroidal anti-inflammatory drugs and medium-chain fatty acids binding at site II had molecular lengths within the range 11-16 A. The effect of hydrophobicity (and/or molecular length) on binding affinity was much more marked with the arylpropionic acids than with the fatty acids, suggesting that bulkier aromatic molecules form more effective interactions at the binding site. The results suggest that site II is a hydrophobic cleft about 16 A deep and about 8 A wide in the albumin molecule with a cationic group located near the surface.
148 citations
TL;DR: The ability of acetylcholinesterase to hydrolyse naturally occurring compounds of different chemical nature, like esters and peptides, may help explain the long-standing puzzle of why the enzyme is more widely distributed than acetylCholine, once thought to be its sole natural substrate.
135 citations
TL;DR: These experiments suggest the activity of 5-HT nerve cells adjacent to the ventrolateral surface of the medulla oblongata and projecting to the intermediolateral cell column serves to elevate arterial pressure and maintain vasomotor tone.
TL;DR: In this paper, a new method for the solution of the problem of electron scattering by a one-electron atom or ion was proposed, which treated all relevant effects explicitly and treated reaction channels under consideration by the coupled-channels method in momentum space.
Abstract: A complete account is given of a new method for the solution of the problem of electron scattering by a one-electron atom or ion. The method treats all relevant effects explicitly. Reaction channels under consideration are treated by the coupled-channels method in momentum space. Other channels, including the continuum, are treated by adding complex-polarization potentials computed from experimentally tested approximate amplitudes for the relevant reactions. Computational methods are discussed in detail since this is the first successful application of the momentum-space solution to the atomic multichannel problem. The effect of the inclusion of channels outside the coupled space is demonstrated by comparison with three-state close coupling for hydrogen at 54.42 eV.
TL;DR: It is concluded that VIP containing nerves innervating the heart and blood vessels form a population distinct from the substance P-containing and the noradrenergic nerves.
TL;DR: The microvascular organization of endocrine and digestive system as revealed by this technique as well as various hypotheses are proposed regarding the physiological significance of the microcirculatory patterns observed.
Abstract: This paper reviews firstly the microvascular corrosion casting/scanning electron microscope method and secondly the microvascular organization of endocrine and digestive system as revealed by this technique. Detailed descriptions of the microvascular arrangement of the hypophysis, pineal body, thyroid gland, pancreas, adrenal gland, salivary gland, liver, stomach and small intestine are given. Various hypotheses are also proposed regarding the physiological significance of the microcirculatory patterns observed.
TL;DR: It is suggested that increasing tidal volume may directly distort the alveolar type II cell; each cell reacts to its own threshold distortion by releasing a pool of S in all-or-none fashion.
TL;DR: Differences between the 3 antibodies in their reactivity with leukemic cells and tissue macrophages indicate that they are directed against distinct antigens, which may serve as differentiation markers in the monocyte/macrophage lineage.
TL;DR: In this article, the authors considered the problem of sequential search, where a searcher can choose his sample size and whether or not to stop search at each of a sequence of decision points.
Abstract: This paper considers the wide class of problems in which a searcher can choose his sample size and whether or not to stop search at each of a sequence of decision points. Sequential search problems are the special cases in which the sample size chosen at each decision point is unity. Several properties of the optimal sample size sequence are established, with particular attention being paid to the effects of recall, decision horizons and fallback utilities. These properties yield necessary and sufficient conditions for the optimality of sequential search strategies within the class of problems considered.
TL;DR: The results are interpreted as indicating that addition of fatty acid to liver cells induces various energy-dependent processes, including ATP synthesis, reversed electron transfer and metabolite translocation, all of which contribute to the observed stimulation of O2 uptake.
Abstract: The rates of O2 consumption during fatty acid oxidation to acetyl-CoA and to CO2 were determined for isolated liver cells from starved rats on the basis of measured rates of respiration and ketogenesis. About 60% of the endogenous O2 uptake was associated with acetyl-CoA formation. The remainder was assumed to represent total combustion of fatty acid to CO2 and H2O through the Krebs cycle. In the absence of added fatty acid, 1.90 μmol · min-1· g-1 of acetyl-CoA was generated, of which 1.40 μmol · min-1· g−1 gave rise to ketone bodies. O2 consumption was stimulated about 30% by the addition of 2 mM palmitate or 4 mM hexanoate. This increase was entirely due to stimulation of O2 consumption related to oxidation of fatty acid to acetyl-CoA. The extra acetyl-CoA produced was channelled into ketone body formation.
The gluconeogenic substrate lactate, which increases hepatic demand for ATP, stimulated O2 consumption almost 40%, but in this case the increase was due to an enhancement of Krebs cycle activity, and acetyl-CoA generation was depressed 25%. In the absence of added fatty acid, 83% of the total acetyl-CoA produced by cells incubated with lactate was oxidized in the Krebs cycle. Addition of fatty acid caused a further stimulation of O2 uptake which reflected a promotion of acetyl-CoA production with an associated increase in ketone body formation.
The uncoupling agent, 2,4-dinitrophenol, stimulated total O2 consumption of cells incubated without exogenous substrate or with added fatty acid. In each circumstance this stimulation of O2 uptake was related entirely to enhancement of Krebs cycle activity and depression of ketogeneis. The large increment in O2 consumption induced by the combination of lactate and 2,4-dinitrophenol in the presence of added fatty acid was likewise attributable solely to a marked stimulation of Krebs cycle flux. Added ethanol caused only a small inhibition of total acetyl-CoA production and had little effect on respiration, but considerably depressed Krebs cycle activity. This depression was relieved by 2,4-dinitrophenol.
Oligomycin and antimycin had markedly different effects on fatty acid catabolism although both inhibitors depressed O2 consumption to the same extent. Oligomycin caused only a small diminution of rates of acetyl-CoA formation but induced a strong depression of cellular ATP concentrations and of acetyl-CoA oxidation to CO2. In contrast antimycin had no effect on acetyl-CoA oxidation and brought about only a small decline in cellular ATP levels, but considerably depressed formation of acetyl-CoA.
These results are interpreted as indicating that addition of fatty acid to liver cells induces various energy-dependent processes, including ATP synthesis, reversed electron transfer and metabolite translocation, all of which contribute to the observed stimulation of O2 uptake. It is inferred that oxidation of acetyl-CoA to CO2 is preferentially coupled to ATP synthesis whereas oxidation of fatty acid to acetyl-CoA is obligatorily associated with reversed electron transfer. Thus, ketogenesis is not constrained by the hepatic phosphorylation potential and provides a mechanism for the rapid disposal of fatty acids, independent of the ATP demands of the liver.
TL;DR: The results support the operation of immunological enhancement induced by prior coital antigen exposure in the genesis of PE, but raised the possibility of a mechanism of sensitisation of the female partner to seminal components over a long period of time when the husband was oligozoospermic compared with one whose husband was azoospermic.
TL;DR: The data do not provide empirical support for BW's theory and their key variables (real wages and income) do not aid in forecasting fertility rates, indicating that their key vairable do not help to explain fertility.
TL;DR: In this paper, simple Gauss knots are obtained as eigenvalues of symmetric tridiagonal matrices and a rapidly converging simple iterative process, based on the merging of free and fixed knots, of quadratic convergence is presented for multiple Gaussian knots.
Abstract: Algorithms are derived for the evaluation of Gauss knots in the presence of fixed knots by modification of the Jacobi matrix for the weight function of the integral. Simple Gauss knots are obtained as eigenvalues of symmetric tridiagonal matrices and a rapidly converging simple iterative process, based on the merging of free and fixed knots, of quadratic convergence is presented for multiple Gauss knots. The procedures also allow for the evaluation of the weights of the quadrature corresponding to the simple Gauss knots. A new characterization of simple Gauss knots as a solution of a partial inverse eigenvalue problem is derived.
TL;DR: The evidence, taken in conjunction with numerous examples from the literature showing calcium involvement in the action of all of the plant hormones, support a unifying theory of hormone action.
Abstract: Trifluoperazine, a phenothiazine tranquilizer, and tetracaine, a local anesthetic, have been found to inhibit a variety of plant hormone responses at concentrations compatible with their known inhibition of Ca2+-calmod-ulin-dependent enzyme activities. Among these responses are cytokinin-dependent betacyanin synthesis and increase in fresh weight in Amaranthus tricolor cotyledons, auxin-dependent increase in length of wheat coleoptile segments and gibberellic acid-dependent induction of α-amylase synthesis in barley aleurone layers. The reversibility of some of these inhibitory effects has been demonstrated, indicating that, up to a point, a generalized membrane destruction can be ruled out. The evidence, taken in conjunction with numerous examples from the literature showing calcium involvement in the action of all of the plant hormones, support a unifying theory of hormone action.
TL;DR: This paper presents two methods not requiring the explicit knowledge of the roots of r and obtains various properties of the similarity transformations between Jacobi matrices, which are proved by simple matrix calculus without using the generalized Christoffel theorem.
TL;DR: The results are compatible with the hypothesis that cytokinins may act, at least in part, by changing ion fluxes, with the additional involvement of a calmodulin.
Abstract: Two classes of compounds which bind to calmodulin in a calcium-dependent manner (neuroleptic drugs and local anaesthetics) were used to investigate the possible involvement of a calcium-dependent regulator protein in the action of the plant hormones cytokinins. The cytokinin-induced synthesis of betacyanin in Amaranthus tricolor seedlings was used as one test system. The calmodulin antagonists inhibited betacyanin synthesis with the following order of potency: fluphenazine > trifluoperazine = pimozide > chlorpromazine > dibucaine > penfluridol > haloperidol > tetracaine, over a concentration range (IC 50 ) of 0.1 to 0.6 millimolar. Red light and fusicoccin increase betacyanin accumulation and are synergistic with cytokinins. These red light- and fusicoccin-dependent inductions were inhibited by lower concentrations of the drugs than cytokinin-dependent induction, and the order of potency of the drugs was not precisely the same. The results are compatible with the hypothesis that cytokinins may act, at least in part, by changing ion fluxes, with the additional involvement of a calmodulin. The second cytokinin-regulated response studied was growth in soybean callus culture. In this system, inhibition was observed with lower concentrations of drugs than in cytokinin-dependent betacyanin synthesis with an order of inhibitory potency of pimozide = trifluoperazine > penfluridol > chlorpromazine > haloperidol > tetracaine. The effective concentration range (IC 50 ) was from 0.07 to 0.5 millimolar. Inhibition of betacyanin synthesis by 0.15 millimolar trifluoperazine and of soybean callus growth by 2 millimolar tetracaine were both reversible.
TL;DR: A novel affinity matrix was synthesised by coupling the reversible cholinesterase inhibitor, edrophonium chloride, to epoxy‐activated Sepharose to produce a matrix which was exceptionally stable and had the novel property of selectively binding only one molecular form of acetylcholinestersterase.
Abstract: A single molecular from of soluble acetylcholinesterase was isolated from a variety of mammalian tissues by use of a novel affinity matrix. This matrix was synthesised by coupling the reversible cholinesterase inhibitor, edrophonium chloride, to epoxy-activated Sepharose. This simple synthesis produced a matrix which was exceptionally stable and had the novel property of selectively binding only one molecular form of acetylcholinesterase. Soluble proteins from a variety of mammalian tissues, including brain, adrenal glands, cerebrospinal fluid, and blood, were separated by centrifugation. These contained combinations of acetylcholinesterase (EC 3.1.1.7) and cholinesterase (EC 3.1.1.8), varying from a single form of acetylcholinesterase to multiple forms of both acetylcholinesterase and cholinesterase. The edrophonium-Sepharose matrix bound only one form of acetylcholinesterase. This form of acetylcholinesterase corresponded in molecular size and electrophoretic mobility to the unique form found in cerebrospinal fluid, i.e. secretory acetylcholinesterase. Cholinesterase was not bound to the matrix.
01 Aug 1983-Graphical Models \/graphical Models and Image Processing \/computer Vision, Graphics, and Image Processing
TL;DR: Numerical algorithms for generating the smoothed regradings, which are simple and efficient to implement, are described, and practical applications to the processing of LANDSAT image data are discussed.
Abstract: The technique of constructing a transformation, or regrading, of a discrete data set such that the histogram of the transformed data matches a given reference histogram is commonly known as histogram modification. The technique is widely used for image enhancement and normalization. A method which has been previously derived for producing such a regrading is shown to be “best” in the sense that it minimizes the error between the cumulative histogram of the transformed data and that of the given reference function, over all single-valued, monotone, discrete transformations of the data. Techniques for smoothed regrading, which provide a means of balancing the error in matching a given reference histogram against the information lost with respect to a linear transformation are also examined. The smoothed regradings are shown to optimize certain cost functionals. Numerical algorithms for generating the smoothed regradings, which are simple and efficient to implement, are described, and practical applications to the processing of LANDSAT image data are discussed.
TL;DR: The relationship between reduced syntactic complexity and early age of onset of schizophrenia suggests a salient role for language functioning in the manifestation, or even the etiology, of schizophrenia, and adds putative support to previous findings indicating left hemispheric dysfunction in schizophrenia.
Abstract: Measures of syntactic complexity, derived from the grammatical analysis of free speech samples from schizophrenic subjects, were significantly correlated with age of onset of schizophrenia. A significant correlation remained after controlling for chronological age. These results were independent of duration of illness. The relationship between reduced syntactic complexity and early age of onset of schizophrenia suggests a salient role for language functioning in the manifestation, or even the etiology, of schizophrenia, and adds putative support to previous findings indicating left hemispheric dysfunction in schizophrenia.
TL;DR: This is the first report of the histochemical localization of peripheral neurones with antibodies raised against choline acetyltransferase in a rat against the enzyme purified from porcine brain.
TL;DR: The results show that 1MU derived from theophylline is formed by an initial 3-demethylation to 1MX and then a rapid xanthine oxidase mediated 8-oxidation.
Abstract: The route of formation of 1-methyluric acid (1MU) from theophylline has been investigated by i.v. administration of 1-methylxanthine (1MX) before and after allopurinol treatment and of 1,3-dimethyluric acid (1,3DMU) to healthy male volunteers. 1,3DMU was recovered unchanged in urine and was not demethylated to 1MU. By contrast after administration of 1MX the major part of the dose was recovered as 1MU. After allopurinol this was reversed with most of the 1MX dose being excreted unchanged and only a minor amount as 1MU. The results show that 1MU derived from theophylline is formed by an initial 3-demethylation to 1MX and then a rapid xanthine oxidase mediated 8-oxidation. No 1MU is formed by 3-demethylation of 1,3DMU.