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61.
Fuchs P Haefeli WE Ledermann HR Wenk M 《European journal of clinical pharmacology》1999,54(11):869-876
Objectives: To evaluate the in vivo effect of xanthine oxidase (XO) inhibition by allopurinol on the determination of polymorphic N-acetyltransferase 2 (NAT2) and cytochrome P450 1A2 (CYP1A2) with urinary caffeine metabolic ratios.
Methods: In an open, prospective study involving 21 healthy subjects (eight fast, 13 slow NAT2 acetylators) allopurinol (300 mg perday)
was administered orally on trial days 1–8, followed by a wash-out period of 8 days. Urinary caffeine tests (200 mg caffeine
p.o.) were performed repetitively. Urine was collected for 8 h and venous blood samples for the determination of allopurinol,
oxypurinol and uric acid were drawn. The urinary caffeine metabolites 1-methyluric acid (1MU), 1-methylxanthine (1MX), 1,7-dimethyluric
acid (17MU), 1,7-dimethylxanthine (17MX), 5-acetylamino-6-formylamino-3-methyluracil (AFMU), plasma allopurinol and oxypurinol
were analysed using high-performance liquid chromatography (HPLC).
Results: During XO inhibition by allopurinol, the formation of 1MU from 1MX and therefore the XO ratio 1MU/1MX decreased to 15.9
(1.2)% [mean with (SEM)] of baseline values (P < 0.005). The NAT2 ratio AFMU/1MX decreased likewise to 56.7 (6.3)% (P < 0.005). AFMU/(AFMU + 1MX + 1MU), an alternative NAT2 ratio, remained constant, but the CYP1A2 ratio (AFMU + 1MX + 1MU)/17MU,
used to express CYP1A2 activity, transiently increased to 167 (13)% (P < 0.005). The NAT2 phenotype did not influence CYP1A2 and XO ratios or plasma oxypurinol pharmacokinetics.
Conclusions: Several caffeine metabolic ratios are commonly used to express the activities of NAT2, CYP1A2 and XO both in healthy volunteers
and in polymedicated patients, although their reliability has not been evaluated thoroughly during concurrent drug administration.
The findings of this study suggest that NAT2 phenotyping should be performed using the ratio AFMU/(AFMU + 1MX + 1MU) if an
XO inhibitor may be present. It also shows that the determination of CYP1A2 activity with caffeine as a metabolic probe is
considerably altered under these conditions. Thus, concomitant drug administration may impair the robustness of multiple pathways
of the complex caffeine test. This points to the need for alternative probes, designed to assess only the activity of a single
enzyme because, in contrast to healthy volunteers, in patients known or unknown drug interactions may often be present.
Received: 10 August 1998 / Accepted in revised form: 5 October 1998 相似文献
62.
Jakubetz J Schmuck S Poller U Fuchs B Gorf A Radke J Pönicke K Brodde OE 《Journal of cardiovascular pharmacology》1999,33(3):461-472
The aim of this study was to find out whether cardiac responses to the beta-adrenoceptor antagonists with intrinsic sympathomimetic activity (ISA) xamoterol and celiprolol are mediated by cardiac beta1- or beta2-adrenoceptors or both. For this purpose we assessed, in six healthy male volunteers, the effects of xamoterol (100 and 200 mg, p.o.) and celiprolol (200, 600, and 1,200 mg, p.o.) on blood pressure, heart rate, and heart rate-corrected duration of the electromechanical systole (QS2c, as a measure of inotropism). Xamoterol, in both doses, increased systolic blood pressure and heart rate, transiently decreased diastolic blood pressure, and shortened QS2c; all these effects were attenuated after pretreatment of the volunteers with the beta1-adrenoceptor antagonist bisoprolol. Celiprolol, in all three doses, increased heart rate, decreased diastolic blood pressure, and shortened QS2c but only marginally increased systolic blood pressure. Bisoprolol did not attenuate these celiprolol effects but rather enhanced celiprolol effects on systolic blood pressure and heart rate. In a further set of experiments, we studied cardiovascular effects of celiprolol in six healthy volunteers whose beta2-adrenoceptors had been desensitized by a 2-week treatment with 3x5 mg/day terbutaline. Under these conditions, celiprolol failed to increase heart rate or to shorten QS2c. We conclude that, under resting conditions, in healthy volunteers, beta-adrenoceptor antagonists with ISA can exert increases in heart rate and contractility that are mediated by either cardiac beta1-adrenoceptor (xamoterol) or cardiac beta2-adrenoceptor (celiprolol) stimulation. Thus in the human heart, the ISA of beta-adrenoceptor antagonists can be a beta1- or beta2-adrenoceptor agonistic component. 相似文献
63.
A. L. Barry P. C. Fuchs C. Thornsberry J. C. McLaughlin S. G. Jenkins D. J. Hardy S. D. Allen 《European journal of clinical microbiology & infectious diseases》1996,15(8):676-678
Three methods approved by the National Committee for Clinical Laboratory Standards for testing the susceptibility of anaerobic bacteria were used to evaluate the fluoroquinolone, trovafloxacin. The methods gave essentially comparable results with 126 anaerobes and with three quality control strains. A collaborative study defined the quality control range for trovafloxacin MICs. Trovafloxacin had good in vitro activity against the more common anaerobes (MIC 90 <- 2.0 (g/ml).Trovafloxacin (CP-99,219) is a fluoroquinolone with a broad spectrum of antibacterial activity (1–3). Its in vitro spectrum includes many anaerobic bacteria (4).The National Committee for Clinical Laboratory Standards (NCCLS) currently recommends three different methods for testing the susceptibility of anaerobic bacteria (5). The standard reference method is an agar dilution procedure using Wilkins-Chalgren agar. Two alternative methods are an agar dilution technique using Brucella blood agar and a microdilution procedure using a broth version of Wilkins-Chalgren medium. It is important to determine whether these three procedures actually produce identical test results with each antimicrobial agent likely to be tested against anaerobes. 相似文献
64.
Efficacy and tolerance of vinpocetine in ambulant patients suffering from mild to moderate organic psychosyndromes 总被引:2,自引:0,他引:2
The efficacy and tolerance of orally administered vinpocetine was investigated in patients suffering from mild to moderate organic psychosyndromes including primary dementia. Two hundred and three patients were included in a placebo-controlled, randomized double-blind, multicentre trial and received every day for 16 weeks either: 3 x 10 mg doses of vinpocetine, 3 x 20 mg doses of vinpocetine, or 3 x placebo. Patients were assessed on ratings of clinical global impression, cognitive performance and on measures of the quality of life including depressive illness. There were no clinically relevant side-effects reported and the frequencies of adverse events between patients treated with vinpocetine (30 mg or 60 mg) and placebo were comparable. Statistically significant improvements were found in favour of both active treatment groups compared to placebo in both confirmatory evaluations of efficacy of treatment: the "Global Improvement" (on the CGI scale) and cognitive performance (SKT). Vinpocetine was also superior to placebo in ratings of the "severity of illness". This study demonstrates the usefulness and efficacy of vinpocetine in the management of patients with moderate organic psychosyndromes. An apparently greater therapeutic efficacy of 3 x 10 mg vinpocetine compared with the higher vinpocetine dosage is statistically not significant. 相似文献
65.
66.
Fuchs Robert P.P.; Lang Marie-Claude E.; Miller Elizabeth C.; Miller James A. 《Carcinogenesis》1981,2(7):655-659
Earlier studies showed that N-acetyl-2-aminofluorene (AAF) ismuch more carcinogenic than N-acetyl-2-amino-7-iodofluorene(AAIF). Subsequently it was found that substitution of C-8 ofguanine bases in DNA with AAF residues resulted in displacementof the guanine bases outside the DNA helix. This did not occurafter similar substitution with AAIF residues. As one approachto assessing the possible importance of this gross conformationaldifference to the carcinogenicity of AAF, the carcinogenic activitiesof two electrophilic esters, N-myristoyloxy-AAF and its 7-iododerivative, were compared by s.c. injection into male Fischerrats. On injection of a total of 64 µmol, each ester induceda high incidence of sarcomas, and the latent periods were similar.N-Myristoyloxy-AAIF was solvolyzed in aqueous media at aboutone-half the rate of N-myristoyloxy-AAF, and it was less than10% as reactive with native DNA as N-myristoyloxy-AAF. N-Myristoyloxy-AAFand N-myristoyloxy-AAIF were each less reactive than the correspondingacetoxy derivatives. These data suggest that the low carcinogenicityof AAIF as compared to that of AAF may not be associated withthe conformations of their adducts in the DNA. This differencein carcinogenicity may be related to differences in the ratesof metabolic activation and inactivation of these two amides. 相似文献
67.
The "rubtest" to induce an immediate reaction with various inhalative and ingestive allergens has proved to be a very reliable, easily demonstrable and extremely simple method for detection of allergy-type I, especially of the "highest-sensitivity-type". Recent examinations confirmed the clinical importance and the high correlation between the "rub-test", the IgE-titre (RAST) and the endpoint-skin test-titration. 相似文献
68.
Richard M Goldberg Daniel J Sargent Roscoe F Morton Charles S Fuchs Ramesh K Ramanathan Stephen K Williamson Brian P Findlay Henry C Pitot Steven R Alberts 《Journal of clinical oncology》2004,22(1):23-30
PURPOSE: Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. PATIENTS AND METHODS: Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. RESULTS: A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. CONCLUSION: The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer. 相似文献
69.
David P Ryan Joseph P Eder Thomas Puchlaski Michael V Seiden Thomas J Lynch Charles S Fuchs Philip C Amrein Darrell Sonnichsen Jeffrey G Supko Jeffrey W Clark 《Clinical cancer research》2004,10(7):2222-2230
PURPOSE: BMS-214662 is a nonsedating benzodiazepine derivative that exhibits broad spectrum cytotoxicity against human solid tumor cell lines and potently inhibits farnesylation of the H-ras and K-ras oncogenic proteins. This report describes the initial Phase I clinical trial of the compound. The main objective of the study was to determine the dose-limiting toxicities and the maximum tolerated dose of BMS-214662 when administered as a single dose i.v. over 1 h every 21 days to patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with advanced solid tumors and adequate organ function were eligible for the study. The dose was escalated according to a modified Fibonacci schedule after evaluating groups of at least three patients for toxicity during the first cycle of therapy at each dose level. Pharmacokinetic and pharmacodynamic studies were performed after administration of the two initial doses. RESULTS: The dose of BMS-214662 was escalated from 36 to 225 mg/m(2) through 5 intermediate dose levels in a total of 44 patients. Dose-limiting toxicities occurred in 3 of the 13 (23%) patients during the first cycle of treatment with 225 mg/m(2), consisting of grade 3 nausea/vomiting in 2 patients and grade 3 diarrhea in another patient. In addition, four of these patients experienced reversible grade 3 transaminitis, which was not considered to be dose-limiting. At the recommended dose for Phase II studies, 200 mg/m(2), the most common side effects were reversible transaminitis, nausea, and vomiting. Although there were no objective responses, one patient with pancreatic cancer continues to receive treatment more than 3.5 years after entering the study. BMS-214662 exhibited linear pharmacokinetics and had a mean biological half-life of 1.55 +/- 0.27 h and a total body clearance of 21.8 +/- 10.8 liters/h/m(2), with a low apparent volume of distribution at steady state (31.5 +/- 12.9 liters/m(2)). In patients treated with the recommended Phase II dose, the mean maximum plasma concentration of the drug was 6.57 +/- 2.94 microg/ml, and farnesyltransferase activity in peripheral blood mononuclear cells decreased to a nadir of 10.5 +/- 6.4% of baseline at the end of the infusion but fully recovered within 24 h. CONCLUSIONS: BMS-214662 can be delivered safely as a single 1-h i.v. infusion at a dose that results in pronounced inhibition of farnesyltransferase activity in peripheral blood mononuclear cells. However, the duration of enzyme inhibition was transient, recovering in parallel with the decline in plasma concentrations of this rapidly eliminated drug. Because indications of anticancer activity were observed in several patients, further optimization of the administration schedule for this promising new compound is warranted. 相似文献
70.