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101.
Frølund B Jørgensen AT Tagmose L Stensbøl TB Vestergaard HT Engblom C Kristiansen U Sanchez C Krogsgaard-Larsen P Liljefors T 《Journal of medicinal chemistry》2002,45(12):2454-2468
A number of analogues of the low-efficacy partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 5), in which the 4-position of the 3-isoxazolol ring was substituted by different groups, were synthesized and tested as GABA(A) receptor ligands. Substituents of different size and structural flexibility such as alkyl, phenylalkyl, diphenylalkyl, and naphthylalkyl were explored. Pharmacological characterization of the synthesized compounds was carried out using receptor binding assays and by electrophysiological experiments using whole-cell patch-clamp techniques. Whereas none of these compounds significantly affected GABA(B) receptor sites or GABA uptake, they did show affinity for the GABA(A) receptor site. While alkyl or benzyl substitution, compounds 7a-h, provided receptor affinities comparable with that of 5 (K(i) = 9.1 microM), diphenylalkyl and naphthylalkyl substitution, as in compounds 7m-t, resulted in a dramatic increase in affinity relative to 5. The 3,3-diphenylpropyl and the 2-naphthylmethyl analogues, compounds 7s and 7m, respectively, showed the highest affinities of the series (K(i) = 0.074 microM and K(i) = 0.049 microM). In whole-cell patch-clamp recordings from cultured cerebral cortical neurons, all of the tested compounds were able to inhibit the effect of the specific GABA(A) agonist isoguvacine (1), compounds 7m and 7s showing antagonist potency (IC(50) = 0.37 microM and IC(50) = 0.02 microM) comparable with or markedly higher than that of the standard GABA(A) antagonist 4 (IC(50) = 0.24 microM). Highly potent convulsant activity was demonstrated in mice with compounds 7m (ED(50) = 0.024 micromol/kg) and 7s (ED(50) = 0.21 micromol/kg) after intracerebroventricular administration, whereas no effects were found after subcutaneous administration. According to a previously proposed pharmacophore model for GABA(A) receptor agonists, a receptor cavity in the vicinity of the 4-position of the 3-isoxazolol ring in 4-PIOL exists. A molecular modeling study, based on compounds 7o,m,l,q,s, was performed to explore the dimensions and other properties of the receptor cavity. This study demonstrates the importance of the arylalkyl substituents in 7m and 7s and the considerable dimensions of this proposed receptor cavity. 相似文献
102.
Nizatidine and omeprazole enhance the effect of metronidazole on Helicobacter pylori in vitro 总被引:1,自引:0,他引:1
Chen M Jensen B Zhai L Colding H Kharazmi A Kristiansen JE Andersen LP 《International journal of antimicrobial agents》2002,19(3):195-200
Treatment failures are common in patients infected with metronidazole-resistant Helicobacter pylori in the gastric mucosa when triple therapy including metronidazole is used. In patients with treatment failure and metronidazole-resistant H. pylori, a higher eradication rate for H. pylori was found after secondary treatment with bismuth/ranitidine in combination with antibiotics including metronidazole, compared with the same antibiotics combined with a standard dose of omeprazole. This agrees with our previous finding that bismuth was able to reduce the susceptibility of H. pylori to metronidazole. In this study, we have found that nizatidine, an H(2)-receptor antagonist, is also able to reduce the susceptibility of H. pylori to metronidazole in vitro, despite having no direct inhibitory effect on the growth of H. pylori. This agrees with earlier findings that compounds having the ability to reverse antibiotic resistance do not necessarily have an antibiotic or chemotherapeutic effect in the sense of growth inhibition. Therefore, it was decided to investigate the effect of nizatidine and omeprazole on the oxidative respiratory chain, as it is known that metronidazole is able to inhibit the activity of fumarate reductase of H. pylori. This enzyme is a key enzyme in the alternative respiratory chain under anaerobic conditions. Nizatidine was, in these preliminary experiments, found to inhibit fumarate reductase in a dose-dependent way, like metronidazole, whereas omeprazole had almost no effect on fumarate reductase. No other significant effects on the enzymes of the respiratory chain were found. The synergistic effect of nizatidine on metronidazole resistant H. pylori strains could be explained by the effect on fumarate reductase, whereas the effect of omeprazole is different and could be an inhibition of a proton pump in H. pylori. Reversal of antimicrobial resistance with the help of different non-antibiotics seems to be possible by using quite different compounds, and is therefore to be explained by different molecular mechanisms. 相似文献
103.
5-hydroxytryptamine (5-HT; serotonin) is a neurotransmitter essential for a large number of physiological processes including the regulation of vascular and non-vascular smooth muscle contraction, modulation of platelet aggregation, and the regulation of appetite, mood, anxiety, wakefulness and perception. To mediate this astonishing array of functions, no fewer than 15 separate receptors have evolved, of which all but two (5-HT(3A) and 5-HT(3B)) are G-protein coupled receptors. This review will summarize our current understanding of the structure and function of the G-protein coupled 5-HT receptors. In particular, a systematic review of the available mutagenesis studies of 5-HT receptors will be presented. This information will be synthesized to provide a working model of agonist and antagonist actions at a prototypic 5-HT receptor the 5-HT(2A) receptor. Finally, examples will be given to demonstrate that a detailed knowledge of the predicted structure of one receptor can be useful for structure-based drug design. 相似文献
104.
Michael?BretthauerEmail author Anita?J?rgensen Bj?rn?Erik?Kristiansen Bj?rn?Hofstad Geir?Hoff 《BMC gastroenterology》2003,3(1):15
Background
Endoscopic colorectal cancer (CRC) screening is currently implemented in many countries. Since endoscopes cannot be sterilised, the transmission of infectious agents through endoscopes has been a matter of concern. We report on a continuous quality control programme in a large-scale randomised controlled trial on flexible sigmoidoscopy screening of an average-risk population. Continuously, throughout a two-year screening period, series of microbiological samples were taken from cleaned ready-to-use endoscopes and cultured for bacterial growth. 相似文献105.
Kristiansen IS Nexøe J Gyrd-Hansen D Nielsen JB 《Family practice》2002,19(5):566; author reply 566-566; author reply 567
In a recent editorial, Misselbrook and Armstrong comment uponthe concept of risk in relation to John Everyman1 and claimthat the number needed to treat (NNT) for Mr Everyman is 11.It is 相似文献
106.
Kristiansen IS Gyrd-Hansen D Nexøe J Nielsen JB 《Journal of clinical epidemiology》2002,55(9):888-892
Graphic representation was used to explore to what extent the number needed to treat (NNT) conveys the appropriate notion of benefit for the individual patient in interventions aimed at delaying adverse events. A sample of the Danish population (n = 675) was interviewed face to face, and asked whether they would consent to a hypothetical drug that reduces the risk of heart attack. The benefit of the drug was expressed in terms of NNT and was randomly set at 10, 25, 50, 100, 200, and 400. NNT does not convey information on the proportion of patients being helped by an intervention or the size of the delay of the adverse event intended to be prevented. The proportion of people consenting to the hypothetical drug was about 80%, irrespective of NNT, and some of those who rejected the drug misinterpreted the meaning of NNT. Lay people may have difficulties in understanding the meaning of NNT, and clinicians may do well to use the NNT with caution until more is known about how patients comprehend it. 相似文献
107.
108.
Kristiansen C Lassen JF Dahler-Eriksen BS Dahler-Eriksen K Larsen TB Brandslund I 《Thrombosis research》2000,98(2):157-163
Phenprocoumon, whose elimination half-time is 144 hours, has been the traditional oral anticoagulant of choice in Europe. However, today's most widely used drug is warfarin, whose elimination half-time is 40 hours. This study aims to evaluate a method for safe transition from phenprocoumon to warfarin, which is sometimes required. Hence, the large difference in their elimination rates may on occasion lead to serious overdosage upon transition from one drug to the other. According to average equipotent doses, a stepwise increase in warfarin dose was calculated based on the elimination half-times of the two drugs. The dosage scheme was subsequently tested in a pilot study including 35 patients. The conversion scheme was then adjusted based on the results from the pilot study. The new scheme was tested in 69 patients. The transition factor was 2.3, which implies that equipotency was achieved when the warfarin dose was 2.3 times larger than the phenprocoumon dose (in mg). This scheme proved optimal for 75% of the patients. However, the dose had to be adjusted individually in the remaining 25% of the patients to a level corresponding to the measured international normalised ratios. No patients experienced haemorrhages or thromboembolic complications during the period of changeover. In conclusion, the proposed scheme for changing medication from phenprocoumon to warfarin is safe and convenient. 相似文献
109.
Mette Rasmussen Rikke Krølner Knut-Inge Klepp Leslie Lytle Johannes Brug Elling Bere Pernille Due 《The international journal of behavioral nutrition and physical activity》2006,3(1):22-19
Background
In order to more effectively promote fruit and vegetable intake among children and adolescents, insight into determinants of intake is necessary. We conducted a review of the literature for potential determinants of fruit and vegetable intake in children and adolescents. 相似文献110.
Pernille Tine Jensen Marianne Carol Klee Mogens Groenvold 《Radiotherapy and oncology》2002,65(1):29-38
BACKGROUND AND PURPOSE: Patient self-assessment of symptom severity provides clinicians and researchers with important information. It is crucial to evaluate the validity of a self-assessment questionnaire in the context of its intended use. The objective of this study was to evaluate the validity of the uro-gynaecological questionnaire (UGQ), a new instrument for patient self-assessment of urological-, genital-, menopausal-, and pain symptomatology in gynaecological cancer patients. MATERIAL AND METHODS: The UGQ was developed after literature review, patient- and expert interviews and pilot testing. From February 1992 to October 1992, 88 gynaecological cancer patients were invited to participate in a validation study after the initiation of their primary radiotherapy or chemotherapy. The method of validation investigated whether patients and researchers interpreted the items of the questionnaire in the same way. The patient's written response before interview was compared with an observer rating of the patient's open-ended audio-taped responses to the same questionnaire, administered as an interview. Qualitative recordings by the observer were made to describe potential misinterpretations. RESULTS: The agreement between the patient's and the observer's ratings was high: the median overall agreement was 0.91 (range 0.71-1.00) and the median kappa was 0.88 (range 0.45-1.00). The quantitative and the qualitative results identified a few minor validity problems; especially, the issue of selective reporting, i.e. some patients only reporting those symptoms they considered relevant for the study, which may lead to systematic errors. CONCLUSIONS: The results strongly suggest that patients interpret the UGQ items as intended, i.e. they are valid. The UGQ is recommended for patient self-assessment of uro-gynaecological morbidity in gynaecological cancer patients. 相似文献