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71.
C von Bahr C Birgersson E T Morgan O Eriksson M G?ransson E Spina K Woodhouse 《Xenobiotica; the fate of foreign compounds in biological systems》1986,16(5):391-400
Data obtained from human studies in vivo show that the dispositions of the tricyclic antidepressant drugs desmethylimipramine (DMI) and nortriptyline are related to the debrisoquine hydroxylation phenotype. To obtain insight into the enzymic mechanisms behind this, the metabolism of debrisoquine and antidepressant drugs by human liver preparations have been studied. The 2-hydroxylation of DMI in vitro correlates with the 4-hydroxylation of debrisoquine among various livers (rs = 0.90). Debrisoquine inhibits DMI hydroxylation competitively, and DMI inhibits debrisoquine hydroxylation, suggesting that DMI hydroxylation is catalysed by the debrisoquine hydroxylase in human liver. By monitoring the hydroxylation of DMI in various fractions during separation and purification of cytochrome P-450 from human liver microsomes we have purified a cytochrome P-450 which efficiently hydroxylates this drug. The apparently electrophoretically homogeneous enzyme had a molecular weight of 51,500 and hydroxylated DMI and debrisoquine at rates of up to 0.95 and 0.45 nmol/min . nmol P-450, respectively. This is probably the major debrisoquine hydroxylating cytochrome P-450 in man. Nortriptyline 10-hydroxylation correlates strongly (r = 0.96) with debrisoquine hydroxylation in human liver microsomes. Nortriptyline inhibits DMI-hydroxylation competitively, and the drug also inhibits the 4-hydroxylation of debrisoquine. Thus it is probable that nortriptyline is hydroxylated by debrisoquine hydroxylase. Imipramine N-demethylation did not correlate significantly (P greater than 0.1) with debrisoquine hydroxylation among microsomes from nine livers. However, if a liver from a subject, which was a poor metabolizer of debrisoquine in vivo, was included, a correlation was obtained (r = 0.79, P less than 0.01, N = 10). Imipramine demethylation also correlated with DMI-hydroxylation only if the 'poor metabolizer' liver was included (r = 0.75, P less than 0.05, N = 10). Debrisoquine inhibited imipramine demethylation competitively. The data indicate that imipramine can interact with debrisoquine- and DMI-hydroxylase, but it is uncertain if this enzyme plays an important quantitative role in its demethylation. Ethoxyresorufin O-deethylation correlated with DMI hydroxylation (r = 0.80) in human liver preparations, and DMI inhibited the former reaction in what is probably a mixed competitive-non-competitive inhibition. Liver preparations from a subject who was a poor oxidizer of debrisoquine both in vivo and in vitro had unusually low capacity to metabolize ethoxyresorufin. Thus ethoxyresorufin, at least partly, seems to interact with an enzyme that can metabolize DMI in human liver.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
72.
The 5-lipoxygenase inhibitors, AA861 and phenidone, have been shown to inhibit the formation and release of leukotrienes C4, D4 and B4 from isolated perfused sensitised guinea pigs lungs when challenged through either the pulmonary system or the airways. The same drugs inhibit the thoracic neutrophil, but not platelet, accumulation observed following i.v. antigen challenge of sensitised guinea pigs. Indomethacin, a cyclooxygenase inhibitor, at doses which inhibited an arachidonic acid-induced thoracic platelet accumulation, had no effect on the platelet response following antigen challenge. Indomethacin did affect, however, the neutrophil response to antigen challenge presumably through mechanisms unrelated to cyclooxygenase inhibition. These observations suggest a role for lipoxygenase products, possibly LTB4, but not cyclooxygenase products in the neutrophil response to i.v. antigen challenge. 相似文献
73.
Background
Persistent whiplash associated disorders (WAD) have been associated with alterations in kinesthetic sense and motor control. The evidence is however inconclusive, particularly for differences between WAD patients and patients with chronic non-traumatic neck pain. The aim of this study was to investigate motor control deficits in WAD compared to chronic non-traumatic neck pain and healthy controls in relation to cervical range of motion (ROM), conjunct motion, joint position error and ROM-variability. 相似文献74.
75.
Abstract Hypercholesterolaemia is a known risk factor for coronary artery disease. This study describes a retrospective analysis of 176 patients admitted to the Coronary Care Unit (CCU) in a six month period with an admission fasting serum cholesterol of greater than 5.5 millimoles per litre (mmols/L). The patient records were examined at least six months after hospital discharge to determine what action, if any, was instituted in response to their hypercholesterolaemia. One hundred and thirty-four (76%) patients had a discharge diagnosis of myocardial ischaemia or infarction. Of the 176 patients, 73 were referred to a dietitian, 31 were given dietary advice by a medical officer, 13 were commenced on lipid-lowering drugs with nine continuing lipid-lowering drugs and only 13 patients were referred to this hospital's lipid clinic. Sixty-nine (39%) received no response to their hypercholesterolaemia. It is likely that our experience is not unique and greater attention to CCU measured lipid results and risk factor modification should be instituted by physicians. (Aust NZ J Med 1991; 21: 401–404.) 相似文献
76.
D Aharony C A Catanese D P Woodhouse 《The Journal of pharmacology and experimental therapeutics》1991,259(1):146-155
A novel ligand, [4,5-3H-Leu10]substance P ([3H]SP), with high specific activity (137 Ci/mmole) was utilized to investigate the properties of NK (neurokinin)-1 receptors on guinea pig lung membranes (GPLM) and compared them to NK-1 receptors on rat submaxillary glands (RSGM). In the presence of a neutral endopeptidase inhibitor, thiorphan (100 microM), [3H]SP bound with high specificity (greater than 95%), rapidly (k1 = 0.116 nM-1 x min-1) and in a reversible (k-1 = 0.012 min-1) manner to a single class of high-affinity (Kd = 0.16 nM) and saturable (Bmax = 256 fmol/mg protein) receptors. High specific binding with higher density (5-fold) was also detected in RSGM, albeit with a lower affinity (Kd = 1.36 nM). Guanyl-5'-yl-imidodiphosphate and guanosine-5'-O-3-thiotriphosphate inhibited binding to GPLM (and RSGM) in a concentration-related manner. In GPLM, this effect was mediated by a reduction in affinity, mainly via enhancement of ligand dissociation rates and appearance of a lower affinity state (Kd = 3.4 nM). Preincubation of GPLM with sulfhydryl modifying agents (p-chloromercuriphenyl sulfonic acid and N-ethylmaleimide) reduced receptor density and affinity in a time- and concentration-dependent manner. Competition experiments with tachykinins and analogs illustrated a rank order of potency of: SP greater than or equal to [Sar9,Met(O2)11]SP greater than SP-methyl ester greater than or equal to physalaemin greater than SP(6-11) much greater than kassinin greater than neurokinin A = eledoisin much greater than neurokinin B greater than Nle10-NKA(4-10), clearly demonstrating that these receptors are of NK-1 type. Moreover, analysis of over 30 peptide and non-peptide hormones and antagonists demonstrated exquisite selectivity (greater than 10,000-fold) towards NK-1-selective agonists (vs. other ligands. A highly significant (P less than .005) linear correlation (r = 0.924) exists between agonist affinities in GPLM and RSGM. Combined, the data suggest that [3H]SP labels a nearly homogeneous population of high-affinity, G-protein coupled NK-1 receptors on GPLM and RSGM, with very high degree of selectivity. 相似文献
77.
Female sterilization as an interval, postabortal or postpartum procedure, is one of the most widely employed contraceptive techniques on a global basis. The short-term complications of sterilization, which include intra- and extrauterine pregnancies, are well researched and documented. The figures for long-term complications, including ectopic pregnancy, are much less reliable as the follow-up rates diminish as time passes after sterilization. Three cases of tubal pregnancy that occurred long after interval sterilization are presented as a warning against the assumption that long-term complications cannot occur. 相似文献
78.
Home monitors of blood glucose (HMBGs) are gaining acceptance as part of the standard of care for ambulatory self-monitoring and treatment of diabetic patients. Currently there are several HMBGs marketed in the United States, each claiming reliability, accuracy, and "user friendliness," with most of these claims largely unsubstantiated. The objective of our study was to analyze and statistically compare the accuracy and precision of the HMBGs produced by the major competitors in this ever-expanding medical field. Accuracy of each monitor was studied by comparing the glucose value reported by each HMBG with that determined by a reference method (YSI 23A). Precision or reproducibility of results was performed by testing a single, known whole-blood glucose sample 20 times on each monitor. The precision of each device was tested on known low, normal, and elevated samples. Actual and absolute deviations from the reference standard demonstrate that the Accuchek bG and Glucoscan 2000 monitors provide relatively unbiased estimates of blood glucose, whereas the Glucokey, Glucochek II, Glucometer II, and Trendsmeter generally underestimate the true values. The Diascan and Accuchek II monitors, in a separate evaluation, demonstrated acceptable accuracy and precision. We conclude that the Accuchek bG and Glucoscan 2000 statistically are the most accurate and precise HMBGs. 相似文献
79.
Shah S Lewis A Leopold D Dunstan F Woodhouse K 《QJM : monthly journal of the Association of Physicians》2000,93(3):175-181
Gastric acid prevents bacterial colonization of the stomach and suppression of its secretion might predispose to Clostridium difficile (CD) diarrhoea. We retrospectively studied elderly patients admitted to medical wards of an acute hospital to determine whether the incidence of CD diarrhoea was greater among those previously treated with gastric acid suppressants. From records of stool CD toxin tests undertaken in 1995 and 1996, we found 126 cases with positive results, and selected 126 controls with negative results. Information about pre-morbid illness, predisposing factors for CD and medication received in the preceding 16 weeks was obtained from case-notes. A greater number of CD positive cases had received antibiotics such as Cefuroxime, ciprofloxacin or macrolides with or without metronidazole, were more severely disabled, required assistance for feeding, or had hypoalbuminaemia before the onset of diarrhoea. A greater number of controls had received lactulose, suggesting either that its laxative effect resembled CD infection prompting frequent stool tests, or that it offered protection against CD in this group. Both groups were similar for the use of proton-pump inhibitors or H2-receptor antagonists, suggesting that susceptible elderly patients are not more likely to develop CD diarrhoea after receiving gastric acid suppression therapy. 相似文献
80.
S. P. Woodhouse W. H. F. Sutherland E. R. Nye J. Sargent G. Waite C. Merhtens F. M. Cruickshank M. R. Belcher 《Clinical physiology and functional imaging》1984,4(6):475-482
Summary. The present study examined fasting serum insulin levels in relation to body composition and dietary intake during the initial 4 weeks of a 12-week physical training programme in 26 previously sedentary men. Fasting serum insulin concentrations decreased markedly during the first 4 weeks of training and remained at these reduced levels for the rest of the study. The early fall in serum insulin concentration was significantly correlated with the concomitant decrease in body fat, the increase in lean body weight and the age of the subjects. Body weight and reported dietary intake on the other hand, did not change significantly over this period. These results indicate that the decrease in fasting serum insulin in previously sedentary men with physical training is associated with the concomitant changes in body composition. Increased muscle tissue in particular may contribute to this training-induced decrease in serum insulin. 相似文献