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11.
Seoyoung C. Kim Tuhina Neogi Eun Ha Kang Jun Liu Rishi J. Desai MaryAnn Zhang Daniel H. Solomon 《Journal of the American College of Cardiology》2018,71(9):994-1004
Background
Patients with gout are at an increased risk of cardiovascular (CV) disease including myocardial infarction (MI), stroke, and heart failure (HF).Objectives
The authors conducted a cohort study to examine comparative CV safety of the 2 gout treatments—probenecid and allopurinol—in patients with gout.Methods
Among gout patients ≥65 years of age and enrolled in Medicare (2008 to 2013), those who initiated probenecid or allopurinol were identified. The primary outcome was a composite CV endpoint of hospitalization for MI or stroke. MI, stroke, coronary revascularization, HF, and mortality were assessed separately as secondary outcomes. The authors estimated the incidence rate and hazard ratio of the primary and secondary outcomes in the 1:3 propensity score–matched cohort of probenecid and allopurinol initiators.Results
A total of 9,722 probenecid initiators propensity score–matched to 29,166 allopurinol initiators with mean age of 76 ± 7 years, and 54% males were included. The incidence rate of the primary composite endpoint of MI or stroke per 100 person-years was 2.36 in probenecid and 2.83 in allopurinol initiators with a hazard ratio of 0.80 (95% confidence interval: 0.69 to 0.93). In the secondary analyses, probenecid was associated with a decreased risk of MI, stroke, HF exacerbation, and mortality versus allopurinol. These results were consistent in the subgroup analyses of patients without baseline CV disease or those without baseline chronic kidney disease.Conclusions
In this large cohort of 38,888 elderly gout patients, treatment with probenecid appears to be associated with a modestly decreased risk of CV events including MI, stroke, and HF exacerbation compared with allopurinol. 相似文献12.
13.
Gran Wahlstrm 《Basic & clinical pharmacology & toxicology》1978,43(4):260-265
Abstract Some weak organic acids are eliminated from the brain by an acid transport system. The question arose is this system also used to transport drugs out of the brain? In that case probenecid pretreatment (100 mg/kg subcutaneously) should influence the induction time of a slightly lipid soluble barbiturate (barbital) which penetrates into the brain slowly, more than the induction time of a very lipid soluble barbiturate (hexobarbital). In the first experiment barbital (200 mg/kg) was given intraperitoneally and in the second experiment barbital (150 mg/kg) was infused intravenously during 10 min. In both experiments loss of righting reflex occurred more rapidly after pretreatment with probenecid compared with pretreatment with saline. Only in the second experiment did probenecid significantly increase the time during which the righting reflex was lost. In the next experiment hexobarbital was infused intravenously at a rate of 0.25 mg/kg/sec. until a burst suppression which lasted 1 sec. or more was seen in a concomitant EEG-record. When this »silent second« occurred the infusion was stopped and the ensuing anaesthesia times recorded. Probenecid had no effect on the induction when studied with this method, but the ensuing anaesthesia times were increased. The hypothesis of an acid transport system out of the brain was thus not refuted by these experimental results. Studies of brain concentrations of barbital also supported this finding. After 200 mg/kg intraperitoneally the concentration of barbital in the brain was higher after pretreatment with probenecid as compared to saline pretreated controls i.e. at times corresponding to the induction times in the in vivo experiments. No difference was found in the serum levels of barbital. 相似文献
14.
B. -E. Roos G. Wickström P. Hartvig J. L. G. Nilsson 《European journal of clinical pharmacology》1980,17(3):223-226
Summary The concentrations of probenecid and four of its metabolites have been examined in plasma and CSF by electron capture gas chromatography after extractive methylation. The plasma concentration of each of the metabolites was in the range 1,5–15 µg/ml and constituted less than 10% of the parent compound. The penetration into CSF of the metabolites was lower than that of probenecid. The concentration of each of the metabolites was below 0,2 µg/ml and the total concentration never exceeded 10% of the probenecid concentration. The inhibitory effect of the metabolites on uptake was tested in rabbit renal cortex using3H-p-amino-hippuric acid. The inhibitory effect was low. From the low activity and relatively low concentrations of the metabolites in CSF it is concluded that probenecid metabolites do not contribute to the probenecid-induced blocking effect of acid transport from the CSF. 相似文献
15.
The effect of pretreatment with probenecid (200 mg/kg, i.p.) on the sensitivity of the central nervous system (CNS) to thiopental and hexobarbital was investigated with an EEG-threshold method. The threshold dose was significantly decreased by pretreatment with probenecid for thiopental but not for hexobarbital. This was due to an increased penetration of thiopental into the CNS, but for hexobarbital an increase in penetration could also be demonstrated by analysis of brain and serum concentrations after infusion of an equal dose of barbiturate. The concentrations in brain at the EEG-threshold were not influenced by pretreatment with probenecid for either of these barbiturates, which shows that there was no synergism between these barbiturates and probenecid due to the depressant effect of probenecid on the CNS. 相似文献
16.
Avner Ramu Daniel Glaubiger Nill P. Ramu Noreen Eldridge Terrence F. Blaschke 《Journal of pharmacokinetics and pharmacodynamics》1978,6(5):389-397
Probenecid is known to inhibit the renal excretion of methotrexate (MTX) and the transport of organic anions by the choroid plexus of the brain. The effect of probenecid on the CSF clearance of MTX given by the intrathecal route was examined in anesthetized dogs. Plasma and CSF MTX levels were measured following intrathecal injection of 0.4 mg/kg MTX, with and without pretreatment with probenecid. In the absence of probenecid, the peak plasma MTX concentration of 3.18×10–7±1.09×10–7 M (mean±SD) was reached 5 hr after intrathecal injection. With probenecid pretreatment, the mean peak plasma MTX concentration was lower (2.09×10–7+-0.98×10–7 M) and plasma disappearance was prolonged. A biexponential decay of CSF MTX levels was observed over the duration of sampling. The half-life of the second exponential phase was 21 hr without probenecid pretreatment and was longer after probenecid pretreatment. These results provide strong evidence that probenecid inhibits transfer of MTX from CSF to plasma following intrathecal injection.This work was supported by NIGMS Grant GM22209 and the Oncology Research Donation Fund of the Children's Hospital at Stanford. Terrence Blaschke was the recipient of a Faculty Development Award in Clinical Pharmacology from the Pharmaceutical Manufacturers Association Foundation. 相似文献
17.
1. One isotopic and three non-isotopic methods were used to determine the effect of an acute intravenous dose of Δ9-tetrahydrocannabinol (Δ9-THC, 2 mg/kg) on the rat brain turnover rate of serotonin. 2. In control animals the turnover rate of serotonin was about 2 nmol/g per h. This rate was not altered by Δ9-THC when it was calculated from the rise of 5-hydroxyindoleacetic acid following probenecid or from the rise of serotonin following pargyline. 3. Δ9-THC did not alter the serotonin turnover rate when it was calculated from the conversion of 3H-tryptophan to 3H-serotonin. 4. The serotonin turnover rate was significantly increased by Δ9-THC when the rate was calculated from the decline of 5-hydroxyindoleacetic acid following pargyline. 5. These results suggest that Δ9-THC does not alter the turnover of rat brain serotonin. The previously reported Δ9-THC-induced changes in body temperature and increased brain levels of 5-hydroxyindoleacetic acid may be mediated by some other mechanism such as interference by Δ9-THC of the vesicular binding of serotonin. 相似文献
18.
R. M. J. Ings D. S. Reeves L. O. White R. P. Bax M. J. Bywater H. A. Holt 《Journal of pharmacokinetics and pharmacodynamics》1985,13(2):121-142
The pharmacokinetics of cefotaxime were investigated in human volunteers given constant intravenous infusions, intravenous bolus, and intramuscular doses of the drug. After intravenous dosing, the plasma levels of cefotaxime declined in a biphasic manner with a terminal half-life varying between 0.92 and 1.65 hr. Moreover, the pharmacokinetics were linear up to at least a 2.0 g dose for volume of distribution based on area (23.3–31.31), plasma clearance (249–288 ml/min), and renal clearance (151–177 ml/min). Renal tubular secretion of intact cefotaxime and each of its metabolites was demonstrated by its interaction with probenecid, although the ratio of drug to metabolites ultimately excreted in urine after probenecid was similar to that seen normally (54±6, 19±4, 6.5±0.7 and 5.5±0.7% for cefotaxime, DACM, M2, and M3, respectively, when calculated as a percentage of the dose). The observed half-lives of DACM, M2, and M3 were 2.3±0.4, 2.2 ±0.1 and 2.2 hr, respectively. However, when the true half-life of DACM was calculated (0.83±0.23 hr) it was not only significantly shorter than that observed but also shorter than that for intact cefotaxime. The plasma clearance of DACM (744 ±226 ml/min) was much higher than that of cefotaxime while the volume of distribution was of a similar order (56 ±241). When administered intramuscularly, there was good absorption of cefotaxime from the site of injection (92–94%) giving maximum plasma levels of the drug of between 30 and 35 mg/l at approximately 40 min after dosing. Thereafter, the plasma levels of cefotaxime declined in a monophasic manner with a half-life (1.0–1.2 hr) similar to that of the terminal half-life seen after intravenous administration. Lidocaine had no significant effect on either its absorption or elimination kinetics. 相似文献
19.
MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid 总被引:3,自引:0,他引:3
Huisman MT Chhatta AA van Tellingen O Beijnen JH Schinkel AH 《International journal of cancer. Journal international du cancer》2005,116(5):824-829
ATP binding cassette (ABC) multidrug transporters such as P-glycoprotein (P-gp, ABCB1) and BCRP (ABCG2) confer resistance against anticancer drugs and can limit their oral availability, thus contributing to failure of chemotherapy. Like P-gp and BCRP, another ABC transporter, MRP2 (ABCC2), is found in apical membranes of pharmacologically important epithelial barriers and in a variety of tumors. MRP2 transports several anticancer drugs and might thus have a similar impact on chemotherapy as P-gp and BCRP. We here show that human MRP2 transduced into epithelial MDCKII cells efficiently transported the taxane anticancer drugs paclitaxel and docetaxel and that this transport could be substantially stimulated with the drug probenecid, a representative of a range of MRP2-stimulating drugs. Transport of 2 previously identified MRP2 substrates, etoposide and vinblastine, was likewise stimulated by probenecid. MRP2 further conferred substantial resistance against paclitaxel toxicity, and this resistance was 2.7-fold stimulated by probenecid. Our data indicate that MRP2 function might affect chemotherapy with taxanes, potentially influencing both tumor resistance and taxane pharmacokinetics. Moreover, coadministration of probenecid and other MRP2-stimulating drugs might lead to unforeseen drug-drug interactions by stimulating MRP2 function, potentially leading to suboptimal levels of taxanes and other anticancer drugs in plasma and tumor. 相似文献
20.
Cornelia B Landersdorfer Carl M J Kirkpatrick Martina Kinzig Jürgen B Bulitta Ulrike Holzgrabe Ulrich Jaehde Andreas Reiter Kurt G Naber Michael Rodamer Fritz S?rgel 《British journal of clinical pharmacology》2010,69(2):167-178