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1.
《Drug metabolism and pharmacokinetics》2019,34(1):87-94
The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with Ki values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with Km values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CLR) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CLR (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CLR of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates. 相似文献
2.
大鼠肢体缺血再灌注后内皮素-1含量的变化及BQ-123的干预作用 总被引:2,自引:0,他引:2
①目的 探讨肢体缺血再灌注 (LIR)后内皮素 - 1 (ET - 1 )含量的变化及BQ - 1 2 3的干预作用。②方法 采用大鼠肢体缺血再灌注损伤模型 ,将Wistar大鼠随机分 8组 ,即 :对照组、单纯缺血组、再灌注 0 .5、2、4、6、1 0小时组与BQ - 1 2 3组 ,分别测定血浆LDH、CK活性、ET - 1水平及骨骼肌中MDA含量、ET - 1放免活性和组织湿 /干重比值。③结果 IR各组与对照组比较 ,血浆和骨骼肌的各项生化指标显著增高 (P <0 .0 1orP <0 .0 5) ;BQ - 1 2 3组与再灌注 4小时组比较 ,各项指标明显降低 (P <0 .0 1orP <0 .0 5)。④结论 ET - 1可能参与了肢体缺血再灌注损伤。BQ - 1 2 3可减轻肢体缺血再灌注损伤 ,对骨骼肌有保护作用。 相似文献
3.
Cerebralvasospasm(CVS)remainsoneofthemajorcausesofseriousoutcomeinpatientswithsubarachnoidhemorrhage(SAH);however,themechanismofwhichisstillnotwellunderstood.Sofaralargenumberofputativespasmogenshavebeenproposedandoneofwhichisendothelins(ETs).ETs,akindofverypotentendogenousvasoconstrictorsubstancesknown[1],hasthreeiso-forms:ET-1,2and3,andET-1isthemostpo-tentvasoconstrictorofthem.lnrecentstudies,ET-lhasbeenproposedasamediatorofCVSfol-lowingSAH[2-4j.TheavailabilityofETantagonistprovided… 相似文献
4.
Gérald Vanzetto Marc Janier Daniel Fagret Luc Cinotti Xavier André-Fouet Michel Comet Jacques Machecourt 《European journal of nuclear medicine and molecular imaging》1997,24(2):170-178
The best test presently available to ascertain residual viability within an infarct-related area involves the use of fluorine-18
fluorodeoxyglucose (FDG) to detect the persistence of some cellular metabolism. Rest reinjection of thallium-201 is a less
accurate alternative but is easy to perform. Iodinated fatty acids, which are used with standard gamma cameras, are proposed
as markers of cellular metabolism. This study was performed to assess the value of 16-iodo-3-methyl-hexadecanoic acid (MIHA)
as a marker of the residual cellular metabolism by comparison with FDG in patients with a recent myocardial infarction, and
to evaluate its contribution compared with the201Tl stress-redistribution-reinjection technique. Stress-redistribution-reinjection201T1 imaging, rest MIHA imaging and glucoseloaded FDG imaging were performed in 22 patients with recent myocardial infarction.
Out of the 628 myocardial segments obtained from the left ventricular analysis, 400 were hypoperfused (relative uptake <0.75
of maximum uptake on stress201T1 imaging), 177 of which were severely hypoperfused (relative uptake <0.50). Receiver operating characteristic (ROC) curves
for predicting metabolic myocardial viability with FDG were derived from the results in respect of (a)201T1 activity during exercise, redistribution and reinjection and (b) MIHA up-take, using the two FDG thresholds most commonly
considered to define metabolic viability (0.50 and 0.60). Analysis of the 400 hypoperfused segments demonstrated that201T1 reinjection was the most accurate test in predicting the presence of myocardial viability (area under the ROI curves=0.85
and 0.86 at the 0.50 and 0.60 FDG thresholds, respectively;P<0.05 vs other tests). The global predictive values of MIHA and201T1 reinjection were, respectively, 0.87 and 0.89 at the 0.50 FDG threshold (NS), and 0.82 and 0.87 at the 0.60 FDG threshold
(NS). When only the 177 severely hypoperfused segments were considered,201T1 reinjection remained the most accurate test (accuracy 0.84 at the 0.50 FDG threshold and 0.82 at the 0.60 FDG threshold),
while the accuracy of MIHA decreased significantly (0.78 at the 0.50 FDG threshold and 0.73 at the 0.60 FDG threshold,P<0.05 vs201T1 reinjection). In all circumstances, MIHA was less specific than201T1 reinjection for the detection of metabolic viability. In conclusion, in patients with recent myocardial infarction, MIHA
accurately detects the persistence of metabolic viability, but is not superior to201T1. 相似文献
5.
KL-6, a circulating mucin-like glycoprotein, is a pulmonary adenocarcinoma-associated antigen and is also regarded as an indicator of disease activity of interstitial pneumonitis. KL-6 has extensive heterogeneous antigenic determinants and consists of multiple heterogeneous antigen molecules. We have searched for circulating KL-6-associated glycoproteins with superior diagnostic value to KL-6 as a tumor marker for pulmonary adenocarcinoma. A new murine monoclonal antibody EH-123 reacting with an asialosugar chain on KL-6 was established. A new KL-6-associated molecule detected by a bimonoclonal bideterminant sandwich assay using the EH-123 antibody as a catcher and horseradish peroxidase-labeled KL-6 as a tracer was designated as CAM 123-6. In 59% (22 of 37) of patients with pulmonary adenocarcinoma, serum levels of CAM 123-6 were abnormally elevated and the positive rate increased with the progression of clinical stage. Elevated levels were not detected in normal individuals or in patients with benign lung diseases, other histologic types of lung cancer, gastric cancer, colon cancer or breast cancer. CAM 123-6 was more specific to pulmonary adenocarcinoma than carcinoembryonic antigen (CEA), but the sensitivity of CAM 123-6 for pulmonary adenocarcinoma was similar to that of CEA. CAM 123-6 is a promising candidate as a serum tumor marker for pulmonary adenocarcinoma. 相似文献
6.
Chinori Kurata Sakae Shouda Tadashi Mikami Yasushi Wakabayashi Tomoyasu Nakano Tsuyoshi Sugiyama Kei Tawarahara Kazuyuki Sakata 《Journal of nuclear cardiology》1997,4(6):515-523
Background [123I]Metaiodobenzylguanidine (MIBG) imaging has been used to assess cardiac sympathetic nerve abnormalities. We evaluated the
clinical significance of myocardial MIBG imaging as a measure of cardiac sympathetic nervous system function by comparing
it to heart rate variability and plasma norepinephrine level.
Methods and Results In 211 subjects, we analyzed heart rate variability with 24-hour electrocardiography, performed scintigraphy with MIBG, and
measured plasma norepinephrine levels. Time and frequency domain measures of heart rate variability were calculated with the
Marquette heart rate variability program (Marquette Electronics, Milwaukee, Wis.). Early and late myocardial MIBG uptakes
were measured at 15 and 150 minutes after injection, respectively. MIBG clearance rate from the heart and heart-to-lung and
heart-to-mediastinum ratios of MIBG activities were calculated. On the whole, heart rate variability, including low-frequency
power, correlated positively, but modestly so, with late MIBG uptake and negatively with MIBG clearance rate. The plasma norepinephrine
level correlated negatively with late MIBG uptake and with heart rate variability, including low-frequency power, and positively
with MIBG clearance rate. Similar correlations were also observed in patient subgroups with coronary artery disease, diabetes
mellitus, and renal failure, but these correlations were weak (R
2<0.5).
Conclusions Increased cardiac sympathetic nervous system activity may be associated with increased myocardial MIBG clearance and decreased
heart rate variability, including low-frequency power. Because these associations were not strong, however, the combination
of heart rate variability with MIBG may allow an interactive assessment of the cardiac autonomic nervous system. 相似文献
7.
R. WEISSENBERG S. YOSSEFI Y. OSCHRY I. MADGAR L. M. LEWIN 《International journal of andrology》1994,17(5):256-261
During passage of hamster spermatozoa through the epididymis their maturation is shown to involve changes in the sperm head, midpiece (mitochondria) and tail. The sum of these changes results in a dramatic increase in the fertilizing potential of the spermatozoa. When comparable numbers of spermatozoa from the caput or corpus epididymis were injected into one uterine horn of mature females, following ovulation induction, and spermatozoa from the cauda epididymis were injected into the contralateral horn, no fertilization was observed with caput epididymal spermatozoa, 1.7% of oocytes were fertilized by corpus epiddymal spermatozoa, whereas 79.5% fertilization was obtained with cauda epididymal spermatozoa. Total sperm numbers increased from caput to corpus to cauda [28.3 ± 12.2, 40.6 ±20.8, 1434 ±62 mihon, respectively]. The percentage of progressively motile spermatozoa increased from 27.9 ±6.4 to 33.8 ± 4.8 to 70 ± 10.7 during this passage. Viability, measured by exclusion of the dye, propidium iodide, was significantly less in spermatozoa from the cauda than from the proximal or mid-caput epididymis. The percentage of the live cells that were stained intensely by rhodamine-123 (a measure of mitochondrial membrane potential) increased during epididymal passage from 22.8 ±7.8% in the proximal caput epididymis to 57.2 ± 16.5% in the cauda epididymis. Staining with acridine orange (a measure of DNA packaging in the sperm head) indicated an increase in chromatin condensation in cauda epididymal spermatozoa, when compared to those obtained from the caput or corpus. 相似文献
8.
S. Uhlig Roland Lewis Featherstone 《Naunyn-Schmiedeberg's archives of pharmacology》1997,356(3):392-397
To gain more insight into the complex pulmonary interactions of endothelins (ET), we studied airway and vascular responses
to endothelins in isolated perfused rat lungs in the presence of the novel ETB-receptor antagonist BQ788. In particular we focused on airway responses and on prostacyclin release. The effectiveness of
BQ788 in our system was shown by its ability to concentration-dependently prevent vasoconstriction (IC50 0.1μM), bronchoconstriction (IC50 0.1μM) and prostacyclin production (IC50<0.1μM) induced by the ETB-receptor agonist IRL1620 (1nmol). Airway responses to ET-1: ET-1-induced bronchoconstriction was aggravated by BQ123 (1 or
8μM), while BQ788 pretreatment (1 or 8μM) showed no significant effect. Simultaneous treatment with 8μM BQ123 and BQ788 attenuated
the ET-1-induced bronchoconstriction. Vascular responses to ET-1: ET-1 (1nmol)-induced vasoconstriction was potentiated by
BQ788 (1 or 8μM), but attenuated by the ETA-receptor antagonist BQ123 (1μM). In the presence of BQ788 diminished amounts of the stable prostacyclin metabolite 6-keto-PGF1α were detected in the perfusate. Simultaneous treatment with 8μM BQ123 and BQ788 completely prevented the ET-1-induced vasoconstriction.
Conclusions: Both ETA- and ETB-receptors contribute to ET-1-induced vasoconstriction and bronchoconstriction. The ET-1-induced vasoconstriction is attenuated
by stimulation of ETB-receptors, a response that is partly mediated by prostacyclin. Due to the mutual interactions between ETA- and ETB-receptors, simultaneous inhibition of both receptors is required to prevent the deleterious effects of ET-1 on lung functions.
Received: 17 October 1996 / Accepted: 16 May 1997 相似文献
9.
Vera S. Donnenberg Gilbert J. Burckart Albert D. Donnenberg 《Clinical and Applied Immunology Reviews》2003,4(1):15-30
P-glycoprotein (P-gp), a member of the adenosine triphosphate (ATP)-binding cassette (ABC) family of transporter molecules, is responsible for maintaining low intracellular concentrations of a variety of extracellular compounds and xenobiotics, and for transport of various intracellular molecules. Many drugs are P-gp substrates and intracellular concentrations of these agents may be critical for drug action. Experience in oncology indicates that repeated exposure to P-gp substrate cytotoxic drugs leads to the selection of drug-resistant tumor cells that overexpress P-gp. Since immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus and corticosteroids are substrates for P-gp and since T-cells also express P-gp, it is conceivable that an analogous mechanism exits for therapy-resistant graft rejection. As will be discussed in this article, P-gp may interfere with the response to immunosuppressive therapy through several distinct mechanisms, and as such may represent an attractive therapeutic target. 相似文献
10.
Masaki Shinoda Tsuyoshi Yamaguchi Yoshimi Tanaka Osamu Sato Sin Kobayashi Yutaka Suzuki 《Child's nervous system》1992,8(4):219-221
Single photon emission computerized tomography (SPECT) is now widely used as one of the tools in evaluating cerebral blood flow (CBF). The authors report the CBF changes in childhood hydrocephalus. Five pediatric cases studied by 123I-IM SPECT in children are presented. The authors counted radioactivities both in early and delayed images in each patient, and calculated the reabsorption ratio (RR). Two negative-RR cases and three positive-RR cases were found. All of the negative-RR patients had a poor prognosis, while all of the positive-RR patients had a favorable outcome. 相似文献