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1.
Quinidine kinetics after a single oral dose in relation to the sparteine oxidation polymorphism in man. 总被引:6,自引:5,他引:1
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The kinetics at a single oral dose (400 mg) of quinidine were studied in four extensive metabolizers (EM) and four poor metabolizers (PM) of sparteine. The clearance of quinidine by 3-hydroxylation was significantly lower in PM than in EM, but the difference was small (25-30%). This finding suggests that 3-hydroxylation, in part, is catalyzed by the same isoenzyme of cytochrome P450, P450db1 which oxidizes sparteine. Otherwise, no significant phenotypic differences in total or metabolic clearance were found and it is concluded that the metabolism of quinidine is largely carried out by P450 isoenzymes different from P450db1. A biexponential decline in the log plasma quinidine concentration vs time curves was observed in all subjects, and the mean elimination half-life was 11-12 h. This is about twice as long as generally reported in the literature. 相似文献
2.
Drug related hospital admissions 总被引:13,自引:0,他引:13
J. Hallas B. Harvald J. Worm J. Beck-Nielsen L. F. Gram E. Grodum N. Damsbo J. Schou H. Kromann-Andersen F. Frølund 《European journal of clinical pharmacology》1993,45(3):199-203
Summary As part of a high-intensity monitoring study of drug events as the cause of admission to departments of internal medicine, the effect of an educational intervention programme was studied. Two departments were included, one specialising in geriatrics and one that received patients by non-selected referral. The series consisted of 607 consecutive admissions studied before and 703 after the intervention. The drug events considered were adverse drug reactions and dose-related therapeutic failures, mainly due to non-compliance.A modest, statistically non-significant decrease in drug related hospital admissions (DRH) was seen, from 14% before to 13% after the intervention period. However, DRHs classified as definitely avoidable showed the significant decrease of 83%.There was no apparent relationship between the topics selected for the intervention programme and changes in the pattern of DRHs. No relationship between alterations in sales data and hospital admissions caused by a given drug could be demonstrated. A blinded external evaluation of case abstracts did not disclose any significant shift in the investigators' assessments.The intervention may have had an non-specific effect on avoidable DRHs. 相似文献
3.
K. Brøsen L. F. Gram P. N. Nielsen K. Brusgaard K. Skjødt 《European journal of clinical pharmacology》1994,47(3):221-225
CYP2D6 genotyping was carried out by XbaI restriction fragment length polymorphism analysis and polymerase chain reaction in 168 healthy Danish volunteers, 77 extensive metabolizers (EM) and 91 poor metabolizers (PM) of sparteine. All EM were genotyped correctly as heterozygous or homozygous for the functional (wild type) gene, D6-wt. However, the D6-wt gene was apparently also present in 11 (12%) of the PM who accordingly were incorrectly genotyped as EM. The specificity of genotyping PM thus was 100% but the sensitivity was only 88%. The most common allele was the D6-wt with an apparent frequency of 0.741 (0.026) in the Danish population and the second most common allele was the D6-B with an apparent frequency of 0.194 (0.024). The median (range) of the sparteine metabolic ratio (MR) in 47 homozygous D6-wt EM was 0.28 (0.11–4.10) and the corresponding value in heterozygous EM was 0.36 (0.11–9.10). The median difference was 0.09 (95% confidence interval: 0.02–0.16). CYP2D6 phenotyping is a promising tool in tailoring the individual dose of tricyclic antidepressants, some neuroleplics and some antiarrhythmics. However if the genotype test could be improved with regard to both sensitivity in PM and the ability to predict CYP2D6 activity in EM then it would be of even greater clinical value in therapeutic drug monitoring. 相似文献
4.
S. H. Sindrup L. Arendt-Nielsen K. Brøsen P. Bjerring H. R. Angelo B. Eriksen L. F. Gram 《European journal of clinical pharmacology》1992,42(6):587-591
Summary We have studied the hypoalgesic effect of codeine (100 mg) after blocking the hepatic O-demethylation of codeine to morphine via the sparteine oxygenase (CYP2D6) by quinidine (200 mg). The study was performed in 16 extensive metabolizers of sparteine, using a double-blind, randomized, four-way, cross-over design. The treatments given at 3 h intervals during the four sessions were placebo/placebo, quinidine/placebo, placebo/codeine, and quinidine/codeine. We measured pin-prick pain and pain tolerance thresholds to high energy argon laser stimuli before and 1, 2, and 3 h after codeine or placebo.After codeine and placebo, the peak plasma concentration of morphine was 6–62 (median 18) nmol·.l–1. When quinidine pre-treatment was given, no morphine could be detected (<4 nmol·l–1) after codeine. The pin-prick pain thresholds were significantly increased after placebo/codeine, but not after quinidine/codeine compared with placebo/placebo. Both placebo/codeine and quinidine/codeine increased pain tolerance thresholds significantly. Quinidine/codeine and quinidine/placebo did not differ significantly for either pin-prick or tolerance pain thresholds.These results are compatible with local CYP2D6 mediated formation of morphine in the brain, not being blocked by quinidine. Alternatively, a hypoalgesic effect of quinidine might have confounded the results. 相似文献
5.
Steady state plasma concentrations of imipramine and desipramine were studied at three to nine different imipramine dose levels in 17 extensive metabolizers of sparteine and at two dose levels in two poor metabolizers of sparteine, all treated for diabetic neuropathy symptoms. The imipramine doses were changed stepwise from doses yielding plasma concentrations of imipramine plus desipramine below 150 nM, up to doses yielding therapeutic drug levels of at least 300-500 nM. The imipramine doses required to achieve therapeutic drug levels was 20 or 25 mg/day in the two poor metabolizers and 50-350 mg/day in the extensive metabolizers. In the extensive metabolizers, the concentration/dose ratio increased for imipramine and desipramine with increasing dose. Dose adjustments based on a simple linear prediction from drug levels at initial dose (50 or 75 mg imipramine/day) thus would result in 0-130% (median, 20%) overestimates, most pronounced in patients with initial low steady state levels. The nonlinear kinetics of imipramine thus may be a significant clinical problem in patients treated for diabetic neuropathy symptoms. 相似文献
6.
L B Jensen P Vestergaard A P Hermann J Gram P Eiken B Abrahamsen C Brot N Kolthoff O H S?rensen H Beck-Nielsen S Pors Nielsen P Charles L Mosekilde 《Journal of bone and mineral research》2003,18(2):333-342
The aim of this study was to study the influence of hormone replacement therapy (HRT) on weight changes, body composition, and bone mass in early postmenopausal women in a partly randomized comprehensive cohort study design. A total of 2016 women ages 45-58 years from 3 months to 2 years past last menstrual bleeding were included. One thousand were randomly assigned to HRT or no HRT in an open trial, whereas the others were allocated according to their preferences. All were followed for 5 years for body weight, bone mass, and body composition measurements. Body weight increased less over the 5 years in women randomized to HRT (1.94 +/- 4.86 kg) than in women randomized to no HRT (2.57 +/- 4.63, p = 0.046). A similar pattern was seen in the group receiving HRT or not by their own choice. The smaller weight gain in women on HRT was almost entirely caused by a lesser gain in fat. The main determinant of the weight gain was a decline in physical fitness. Women opting for HRT had a significantly lower body weight at inclusion than the other participants, but the results in the self-selected part of the study followed the pattern found in the randomized part. The change in fat mass was the strongest predictor of bone changes in untreated women, whereas the change in lean body mass was the strongest predictor when HRT was given. Body weight increases after the menopause. The gain in weight is related to a decrease in working capacity. HRT is associated with a smaller increase in fat mass after menopause. Fat gain protects against bone loss in untreated women but not in HRT-treated women. The data suggest that women's attitudes to HRT are more positive if they have low body weight, but there is no evidence that the conclusions in this study are skewed by selection bias. 相似文献
7.
8.
Telfer JF; Thomson AJ; Cameron IT; Greer IA; Norman JE 《Human reproduction (Oxford, England)》1997,12(10):2306-2312
Superoxide, an agent which attenuates the half-life of nitric oxide, is
metabolized and synthesized by superoxide dismutase (SOD) and xanthine
oxidase, respectively. Over the last few years much work has focused on the
role of nitric oxide in human parturition. The aim of this study was to
determine whether the onset of human parturition is associated with a
change in the expression of copper/zinc superoxide dismutase (Cu/Zn SOD),
manganese superoxide dismutase (Mn SOD) or xanthine oxidase within the
uterus. Samples of myometrium, placenta, decidua and fetal membranes were
obtained from women before and after the onset of labour at term.
Immunocytochemistry was used to localize Cu/Zn SOD, Mn SOD and xanthine
oxidase and measure SOD enzyme activity. Cu/Zn and Mn SOD-like
immunoreactivity was detected in syncytiotrophoblast cells, villous stromal
cells and endothelial cells of blood vessels in the placenta. In the
myometrium Cu/Zn and Mn SOD were localized to myocytes and endothelial
cells and to some vascular smooth muscle cells. In the fetal membranes we
observed staining for Cu/Zn SOD and Mn SOD in the amnion, chorion,
extravillous trophoblast and decidua. There was no difference in SOD enzyme
activity or staining intensity for SOD between different cell types before
and during labour. Xanthine oxidase immunoreactivity was identified in each
of the tissues examined and again there was no difference in immunostaining
in tissues obtained from women delivered before or after the onset of
labour. These results show that the pregnant uterus is capable of both
synthesizing and degrading superoxide and suggest that superoxide dismutase
and xanthine oxidase may play a role in the maintenance of uterine
quiescence during pregnancy, but not in the initiation of parturition.
相似文献
9.
Endothelin receptor expression in human decidua 总被引:3,自引:1,他引:3
Kohnen G; Campbell S; Irvine GA; Church HJ; MacLachlan F; Titterington M; Cameron IT 《Molecular human reproduction》1998,4(2):185-193
The endothelins are signalling peptides that act via two receptors, ET(A)
and ET(B). In the human endometrium, endothelin receptors have been
demonstrated in glands and stroma and have been shown to vary during the
course of the menstrual cycle. The present study was undertaken to
determine whether or not expression of endothelin receptors changes during
pregnancy or after administration of exogenous progestagens. The expression
of the receptors was correlated with the appearance of basement membrane
components during decidualization of the endometrial stroma. Decidual
specimens (n = 15) were obtained during the first trimester of pregnancy
and 10 at term. Sixteen pairs of endometrial biopsies were obtained from
women with menorrhagia before and after exposure to exogenous progestagens.
A total of 15 hysterectomy specimens were used as controls for the
expression of stromal basement membrane proteins in the absence of
decidualization. Autoradiography was carried out with selective ligands for
ET(A) ([125I]-PD 151242) and ET(B) ([125I]-BQ3020). The distribution of
ligand binding was then compared with the distribution of laminin alpha2
light chain and collagen IV. ET(A), ET(B), laminin alpha2 light chain, and
collagen IV were expressed in stromal decidual cells in the first trimester
of pregnancy. ET(B) was also found on endometrial glandular epithelium.
Quantitative macro-autoradiography and multiple regression analysis
demonstrated a highly significant positive correlation (P < 0.001)
between expression of ET(B) and laminin alpha2 light chain. In the third
trimester qualitative examination suggested a reduction of ET(A) in the
stroma. Progestagen-induced decidua exhibited a similar pattern to that
found in first trimester decidua. This study has demonstrated up-regulation
of ET(B) during the progesterone- dependent process of decidualization and
suggests a paracrine or autocrine role for endothelins in the decidua.
相似文献
10.
G. J. Gram A. Hemming A. Bolmstedt B. Jansson S. Olofsson L. Åkerblom J. O. Nielsen J. E. S. Hansen 《Archives of virology》1994,139(3-4):253-261
Summary Glycosylation is necessary for HIV-1 gp120 to attain a functional conformation, and individual N-linked glycans of gp120 are important, but not essential, for replication of HIV-1 in cell culture. We have constructed a mutant HIV-1 infectious clone lacking a signal for N-linked glycosylation in the V1-loop of HIV-1 gp120. Lack of an N-linked glycan was verified by a mobility enhancement of mutant gp120 in SDS-gel electrophoresis. The mutated virus showed no differences in either gp120 content per infectious unit or infectivity, indicating that the N-linked glycan was neither essential nor affecting viral infectivity in cell culture. We found that the mutated virus lacking an N-linked glycan in the V1-loop of gp120 was more resistant to neutralization by monoclonal antibodies to the V3-loop and neutralization by soluble recombinant CD4 (sCD4). Both viruses were equally well neutralized by ConA and a conformation dependent human antibody IAM-2G12. This suggests that the N-linked glycan in the V1-loop modulates the three-dimensional conformation of gp120, without changing the overall functional integrity of the molecule. 相似文献