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971.
Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects 总被引:4,自引:0,他引:4
Hiemke C Peled A Jabarin M Hadjez J Weigmann H Härtter S Modai I Ritsner M Silver H 《Journal of clinical psychopharmacology》2002,22(5):502-506
Olanzapine is a substrate of the cytochrome P450 enzyme (CYP) 1A2. In this study, pharmacokinetic interactions and clinical effects of adding the CYP1A2 inhibitor fluvoxamine to steady-state olanzapine was examined in patients suffering from schizophrenia. Eight patients had been treated for at least 3 months with 10 to 20 mg/day olanzapine. Fluvoxamine (100 mg/day) was added (week 0) to the olanzapine treatment and continued for 8 weeks. Concentrations of olanzapine and its metabolite N-desmethylolanzapine and of fluvoxamine were analyzed at weeks 0, 1, 4, and 8. Addition of fluvoxamine resulted in a 12% to 112% ( < 0.01) increase of olanzapine from 31 +/- SD 15 ng/mL (week 0) to 56 +/- 31 ng/mL (week 8) in all patients. N-desmethylolanzapine concentrations were not significantly changed ( > 0.05). Fluvoxamine concentrations were 48 +/- 26 ng/mL on week 1 and 83 +/- 47 ng/mL on week 8. It is concluded that fluvoxamine affects olanzapine degradation and thus increases olanzapine concentrations. Although the combination was well tolerated in this sample and the negative symptom response appeared to be favorable in at least five patients, the combination therapy of olanzapine and fluvoxamine should be used cautiously and should be controlled by therapeutic drug monitoring to avoid olanzapine-induced side effects or intoxications. 相似文献
972.
Obesity is a general medical condition associated with an increase in morbidity and mortality. Although it would be desirable to use efficacious prevention programs, the success rates reported to date have been rather disappointing. In this observational study, a new drug treatment regimen was evaluated in five obese patients with a mean age of 39.6 +/- 4.2 years and an initial body mass index between 34.5 and 38.3 kg/m for a period of 96 weeks. The patients showed restrained and unrestrained eating patterns according to a German version of the Three-Factor Eating Questionnaire and were treated in an add-on regimen with the combination of three drugs with different anorectic properties that were consecutively introduced in an interval of 16 weeks. First, orlistat (120 mg three times a day) was given as a monotherapy. Sibutramine (15 mg in the morning) and then topiramate (in a dose dependent on appetite suppression and side effects) were added for a total duration of 48 weeks. A 48-week maintenance and relapse prevention treatment period with topiramate monotherapy followed the discontinuation of orlistat and sibutramine. This outpatient treatment procedure was tolerated well, although side effects occurred in all patients depending on the phase of the treatment regimen. After 96 weeks, the mean body mass index was 25.7 +/- 1.2 kg/m. Moreover, a normalization of eating patterns according to the Three-Factor Eating Questionnaire could be noticed. Factor 3, hunger, was significantly reduced. This treatment plan may be highly effective and safe in a subpopulation of obese patients. 相似文献
973.
Dittrich S Lippek F Gratopp A Grosse-Siestrup C Lange PE Bührer C 《Clinical and experimental pharmacology & physiology》2002,29(10):909-914
1. Renal postischaemic reperfusion injury constitutes a significant problem after kidney transplantation. The polysaccharide fucoidin improves postischaemic function in lamb hearts, presumably by blocking selectin-mediated leucocyte adhesion. 2. In the present study, eight pairs of ischaemic pig kidneys were reperfused in an ex vivo model with autologous blood with or without fucoidin (100 mg/L). 3. Fucoidin resulted in a significant decrease in renal blood flow (45 +/- 5 vs 178 +/- 22 mL/min per 100 g; P < 0.001) and increased vascular resistance (3.80 +/- 0.07 vs 0.60 +/- 0.12 mmHg/mL per min per 100 g; P < 0.001). 4. Histological examination revealed granulocyte emboli in afferent glomerular arteries in five of six fucoidin-treated kidneys and in one of six controls (Fisher's exact test; P < 0.001). 5. In vitro experiments with human granulocytes showed that large granulocyte aggregates were induced by fucoidin at concentrations similar to those used in reperfused kidneys, whereas slightly lower doses of fucoidin prevented l-selectin-dependent homotypic granulocyte adhesion. 6. The formation of embolizing granulocyte aggregates defines a narrow therapeutic range for fucoidin and calls into question its experimental use as an inhibitor of selectin-mediated leucocyte adhesion. 相似文献
974.
Plasma concentration response to drinks containing beta-carotene as carrot juice or formulated as a water dispersible powder 总被引:1,自引:0,他引:1
Thürmann PA Steffen J Zwernemann C Aebischer CP Cohn W Wendt G Schalch W 《European journal of nutrition》2002,41(5):228-235
Summary. Background: Bioavailability of β-carotene is highly variable and depends on the source, the formulation and other nutritional factors.
Objective: It was the aim of the study to compare β-carotene plasma response to b-carotene dosing with two commercially available drinks,
containing β-carotene from carrot juice or as water dispersible β-carotene powder. Design In a randomized, parallel group
study design, 4 volunteers per group received daily β-carotene doses of 6–7 or 18–22 mg of either drink over 6 weeks. Blood
samples for determination of carotenoid and vitamin A plasma concentrations were collected before supplementation and over
the dosing period. Results: Apparent steady-state β-carotene concentrations were attained after 40 days of supplementation. Consumption of the beverage
containing β-carotene as a water dispersible powder resulted in a higher response of β-carotene plasma concentrations with
increments of 3.84 ± 0.60 μmol/L (p < 0.05, dose: 7.2 mg/d) and 5.04 ± 0.72 μmol/L (p < 0.05, dose: 21.6 mg/d), respectively,
in comparison to the carrot juice-based drink with increments of 0.42 ± 0.33 μmol/L (dose: 6 mg/d) and 1.71 ± 0.55 μmol/L
(dose: 18 mg/d), respectively. β-carotene was cleared from the plasma with an apparent half-life of 6–11 days. Plasma concentrations
of α-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene remained almost unchanged, whereas retinol plasma concentrations
increased slightly. By contrast, with the exception of elevated 13-cis-retinoic acid in one group (21.6 mg/d, water dispersible
powder), the concentrations of all-trans-retinoic acid, and the oxo-derivatives or retinoic acid were not significantly affected
by b-carotene supplementation. Conclusions: The results confirm that the relative bioavailability of β-carotene depends largely on the source of b-carotene and demonstrate
the superior bioavailability of β-carotene powder in comparison to that in carrot juice.
Received: 7 May 2002, Accepted: 22 August 2002
This work was supported by a grant from F. Hoffmann-La Roche Ltd., Vitamins and Nutrition Research, Basle, Switzerland.
Correspondence to: Prof. Dr. med. Petra A. Thürmann 相似文献
975.
Summary
Background & aims Epidemiological studies on the association between lifestyle factors and the risk of colorectal polyps have led to conflicting
results. The aim of the present study was to assess the relationship between alcohol consumption, dietary risk factors, cigarette
smoking and colorectal adenomas or hyperplastic polyps, respectively. Methods Information on alcohol consumption, a detailed dietary history, cigarette smoking and intake of non-steroidal anti-inflammatory
drugs was collected among 502 Caucasian subjects undergoing complete colonoscopy, 207 with colorectal adenomas, 71 with hyperplastic
polyps and 224 controls with no polyps. Results Using univariate analysis significant risk factors for adenomas were age above 55 years, male sex, BMI > 24 (OR 1.91 [1.26–2.88]),
an intake of ham + sausage > 15 g/day (OR 1.87 [1.12–3.11]) and smoking (OR 1.71 [1.17–2.5]). The association with alcohol
intake > 7 g/day was not significant (OR 1.42 [0.97–2.07], p = 0.071). In the multiple logistic regression only age > 55 years
(OR 2.97 [1.94–4.52]), male sex (OR 2.12 [1.54–3.6]) and smoking (OR 1.56 [1.01–2.39]) were significant risk factors for adenomas.
Unexpectedly the mean consumption of alcohol, wine and beer, was significantly lower in subjects in whom adenomas were localized
only in the rectum compared to those having adenomas in the sigmoid or in the proximal colon. Significant risk factors in
subjects with hyperplastic polyps on univariate analysis were intake of > 15 g of ham and sausage/day (OR 3.70 [1.49–9.19]),
smoking (OR 1.79 [1.04–3.06]) and male sex. In the multiple logistic regression only intake of > 15 g/day of ham + sausage
and male sex were significant risk factors (OR 3.24 [1.23–140.8] and 1.83 [1.05–318], respectively). Conclusion When controlling for other potential risk factors, smoking was the only significant lifestyle risk factor for colorectal
adenomas and the intake of ham and sausage > 15 g/day for hyperplastic polyps. The intake of alcohol, wine and beer were markedly
higher in subjects with adenomas of the colon compared to those with adenomas in the rectum.
Received: 16 October 2001, Accepted: 16 January 2002 相似文献
976.
Bock KW Bock-Hennig BS Münzel PA Brandenburg JO Köhle CT Soars MG Riley RJ Burchell B von Richter O Eichelbaum MF Swedmark S Orzechowski A 《Biochemical pharmacology》2002,63(9):1683-1690
UDP-glucuronosyltransferases (UGTs) are regulated in a species- and tissue-dependent manner by endogenous and environmental factors. The present study was undertaken to further our knowledge about regulation of UGTs in dogs, a species widely used in preclinical safety evaluation. beta-Naphthoflavone (BNF) was selected as a known aryl hydrocarbon receptor agonist and antioxidant-type inducer. The latter group of inducers is intensively investigated as dietary chemoprotectants against colon cancer. Dog UGTs were investigated in comparison with related human UGTs by examples, (i) expression of dog UGT1A6, the first sequenced dog phenol UGT, and (ii) morphine UGT activities, responsible for intestinal and hepatic first-pass metabolism of morphine. The following results were obtained: (i) dog UGT1A6 was found to be constitutively expressed in liver and marginally increased by BNF treatment. Expression was low in small intestine but ca. 6-fold higher in colon than for example in jejunum. Conjugation of 4-methylumbelliferone, one of the substrates of dog UGT1A6, was also enhanced 7-fold in colonic compared to jejunal microsomes. (ii) Compared to the corresponding human tissues, canine 3-O- and 6-O-morphine UGT activities were found to be >10-fold higher in dog liver and ca. 10-fold lower in small intestinal microsomes. Small intestinal morphine and 4-hydroxybiphenyl UGT activities appeared to be moderately (2- to 3-fold) induced by oral treatment with BNF. (iii) In contrast to dogs, morphine UGT activities were found to be similar in homogenates from human enterocytes and liver. The results suggest marked differences in tissue-specific regulation of canine vs. human hepatic and intestinal phenol or morphine UGTs. 相似文献
977.
Isobolographic analysis of non-depolarising muscle relaxant interactions at their receptor site 总被引:5,自引:0,他引:5
Administration of certain combinations of non-depolarising muscle relaxants produces greater than expected neuromuscular blockade. Synergistic effects may be explained by drug interactions with the postsynaptic muscle nicotinic acetylcholine receptor. To investigate this hypothesis, the adult mouse muscle nicotinic acetylcholine receptor (alpha(2)beta delta epsilon) was heterologously expressed in Xenopus laevis oocytes and activated by the application of acetylcholine (10 microM). The effects of five individually applied muscle relaxants and six combinations of structurally similar and dissimilar compounds were studied. Drug combinations containing equipotent concentrations of two agents were tested and dose-response curves were determined. All compounds tested alone and in combination produced rapid and readily reversible, concentration-dependent inhibition. Isobolographic and fractional analyses indicated additive interactions for all six tested combinations. These findings suggest that synergistic neuromuscular blocking effects, observed for the administration of certain combinations of muscle relaxants, do not result from purely postsynaptic binding events at the muscle nicotinic acetylcholine receptor, but rather from differential actions on pre- and postsynaptic sites. 相似文献
978.
979.
The 90-kDa heat shock family (HSP90) of protein and two-component histidine kinases, although quite distinct at the primary amino acid sequence level, share a common structural ATP-binding domain known as the Bergerat fold. The Bergerat fold is important for the ATPase activity and associated chaperone function of HSP90. Two-component histidine kinases occur in bacteria, yeast, and plants but have yet to be identified in mammalian cells. The antifungal antibiotic radicicol (Monorden) has been shown to bind to the Bergerat fold of HSP90 and to inhibit its ATPase activity. The structural similarity between the Bergerat fold of HSP90 and bacterial two-component histidine kinases prompted our inquiry into whether radicicol could be a potential inhibitor of histidine kinase-like proteins. Structural homology searches suggest that the ATP-binding domains of the yeast histidine kinase Sln1 and the mammalian, branched-chain alpha-keto acid dehydrogenase kinase are very similar to that of other Bergerat fold family members. On the basis of structural homology, we tested radicicol as a potential inhibitor of Sln1 and branched-chain alpha-keto acid dehydrogenase kinase (BCKDHK) and propose a mechanism of inhibition of these kinases. Although BCKDHK has been shown to have serine autophosphorylation activity, we speculate, based on the results from this study and other supporting evidence, that BCKDHK may also have intrinsic histidine kinase activity. 相似文献
980.
Dietz U Horstick G Manke T Otto M Eick O Kirkpatrick CJ Meyer J Darius H 《Cardiology》2003,99(1):32-38
A previous study in rabbit hearts demonstrated the feasibility of creating transmyocardial channels by application of temperature-regulated high-frequency (HF) energy. Feasibility of creating non-transmural channels using a transvascular approach was tested in 14 pigs which were followed for 1 h, and 3 and 9 weeks (group A, B and C). Myocardial channels were found to be highly reproducible and patent in more than two thirds in group A. Channels were replaced by connective tissue during follow-up which contained newly formed small vessels. A functional communication between the left ventricular cavum and newly formed vessels of the channel remnants could be demonstrated in one heart of group C. Thus, intramyocardial HF ablation can be performed with high reproducibility to induce local angiogenesis. 相似文献