氟虫腈及其砜化物在兔体内的毒物代谢动力学

目的建立兔血浆中氟虫腈及其砜化物的高效液相色谱(HPLC)检测法,并研究其在兔体内的毒物代谢动力学,为氟虫腈中毒的临床诊断与治疗提供依据。方法氟虫腈3 m.gkg-1兔耳缘静脉注射后不同时间取血,采用高效液相色谱法检测血浆中氟虫腈及其砜化物的浓度,计算毒动学参数。结果氟虫腈的毒动学参数:k10为(2.08±0.83)h-1,k12为(0.34±0.07)h-1,k21为(0.27±0.05)h-1,cmax为(3.48±0.52)m.gL-1;t1/2α为(0.31±0.11)h;t1/2β为(3.25±0.59)h;AUC为(4.96±1.22)mg.h.L-1;C l为(1.49±0.44)L.h-1;V1为(0.67±0.15)L.kg-1;V为(2.62±0.65)L.kg-1;砜化物的毒动学参数:cmax为(1.10±0.10)m.gL-1;tmax为(6.08±1.94)h;t1/2ke为(81.3±4.8)h;AUC为(136±16)mg.h.L-1;C l为(0.05±0.005)L.h-1;Vd为(2.32±0.11)L.kg-1。结论氟虫腈静脉给药的毒物代谢动力学符合二室模型;其砜化物的毒物代谢动力学符合一室模型。氟虫腈砜化物的半衰期明显长于氟虫腈。     

Vesicular prurigo pigmentosa cured by minocycline

We present a case of prurigo pigmentosa associated with vesicles that we call 'vesicular prurigo pigmentosa'. The subject was treated using minocycline with good results and no recurrence of the lesions over a 2-year period.     

新型5-HT2A选择性配体N-取代哌啶-4-苯硫醚和砜类衍生物的合成及其生物活性

目的为寻找新型的5-HT_2A受体选择性配体,设计合成了一系列二芳烷基哌啶类化合物的含硫衍生物。方法以2,3-二甲氧基硫酚为原料,经烃化、氧化和水解等反应合成3个N-取代哌啶-4-苯硫醚和砜类化合物,所有目标化合物结构均经元素分析、¹HNMR谱、质谱和红外光谱确证,并测定其对5-HT_2A,5-HT_2C,5-HT₆和5-HT₇受体及其他一些中枢神经递质受体的体外亲和力。结果3个目标化合物(2a-2c)及5个中间体均为新化合物。体外受体竞争结合试验结果表明2a-2c均有较高的5-HT_2A受体选择性。结论此类化合物对5-HT_2A受体的选择性较高,值得进一步研究。     

聚苯胺／含联苯结构聚芳砜导电复合膜的研究

采用溶液共混法得到了聚苯胺／含联苯结构聚芳砜导电复合膜。该复合膜有良好的力学性能和导电性能，对其导电规律进行了探讨。热分析结果表明复合膜有良好的热稳定性，用扫描电镜观察了复合膜的微观形貌，表明ＰＡｎ与ＬＰＥＳ的共混相容性较好。     

大鼠肝微粒体体外代谢奥美拉唑的研究

建立了大鼠肝微粒体体外孵育代谢奥美拉唑酶促反应及用反相HPLC法测定奥美拉唑两种主要代谢物——羟基奥美拉唑和奥美拉唑砜含量的方法.吉果表明,奥美拉唑主要通过羟化和S原子氧化反应进行代谢。其羟化反应的最大反应速率为2033nmol/(min·mgprotein),米氏常数为46.8umol·L^-1,而S原子氧化反应的最大反应速率为187.9nmol/(min·mgprotein),米氏常数为120.7Umol·L^-1。同时证明,美芬妥英、5种苯二氮类药物及罂粟碱对奥美拉唑的羟化代谢均有显著的抑制作用,其中罂粟碱的作用最强。     

Organochlorines inhibit acetaminophen glucuronidation by redirecting UDP-glucuronic acid towards the D-glucuronate pathway

Industry-derived organochlorines are persistent environmental pollutants that are a continuing health concern. The effects of these compounds on drug metabolism are not well understood. In the current study we present evidence that the inhibition of acetaminophen (APAP) glucuronidation by minute concentrations of organochlorines correlates well with their ability to stimulate the d-glucuronate pathway leading to ascorbate synthesis. A set of 6 arylated organochlorines, including 5 PCB (polychlorinated biphenyl) congeners, were assessed for their effects on APAP glucuronidation in isolated hepatocytes from male Sprague-Dawley rats. The capacity of each organochlorine to inhibit APAP glucuronidation was found to be directly proportional to its capacity to stimulate ascorbate synthesis. PCB153, PCB28 and bis-(4-chlorophenyl sulfone) (BCPS) in increasing order were the most effective organochlorines for inhibiting APAP glucuronidation and stimulating the d-glucuronate pathway. None of the 3 inhibitors of APAP glucuronidation were able to alter the expression of UGT1A6, UGT1A7 and UGT1A8 (the major isoforms responsible for APAP glucuronidation in the rat), however, their efficacy at inhibiting APAP glucuronidation was proportional to their capacity to deplete UDP-glucuronic acid (UDPGA). BCPS-mediated inhibition of APAP glucuronidation in isolated hepatocytes had non-competitive characteristics and was insensitive to the inactivation of cytochrome P450. The effective organochlorines were also able to selectively stimulate the hydrolysis of UDPGA to UDP and glucuronate in isolated microsomes, but could not inhibit APAP glucuronidation in microsomes when UDPGA was in excess. We conclude that organochlorines are able to inhibit APAP glucuronidation in hepatocytes by depleting UDPGA via redirecting UDPGA towards the d-glucuronate pathway. Because the inhibition is non-competitive, low concentrations of these compounds could have long term inhibitory effects on the glucuronidating capacity of hepatocytes.     

Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways

Cathepsin S is a lysosomal cysteine protease that is overexpressed in various cancer models and plays important role in tumorigenesis, however the mechanisms are unclear. In the present study, we found that inhibition of cathepsin S induced autophagy and mitochondrial apoptosis in human glioblastoma cells. Blockade of autophagy by either a chemical inhibitor or RNA interference attenuated cathespin S inhibition-induced apoptosis. Furthermore, autophagy and apoptosis induction was dependent on the suppression of phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin/p70S6 kinase (PI3K/AKT/mTOR/p70S6K) signaling pathway and activation of c-Jun N-terminal kinase (JNK) signaling pathway. In addition, reactive oxygen species (ROS) served as an upstream of PI3K/AKT/mTOR/p70S6K and JNK signaling pathways. In conclusion, the current study revealed that cathepsin S played an important role in the regulation of autophagy and apoptosis in human glioblastoma cells.     

Erythrocytes oxidative damage and hematological effects of 2,4,4′,5-tetrachlorodiphenyl sulfone in rats

The effects of subchronic exposure to tetrachlorodiphenyl sulfone (TCDS) on hematological parameters [white blood cells (WBC), red blood cells (RBC), mean cell volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), hemoglobin (Hb) and hematocrite (Ht) levels] were examined. Oxidative stress in erythrocytes was also assessed by measuring thiobarbituric acid reactive substances (TBARS) and enzyme antioxidant activities [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)]. TCDS was administered orally, dissolved in water, ad libitum to 12 female rats at 28.9 mg/kg/day for 6 or 12 weeks. Results showed that TCDS induced significant decreases in RBC, Hb, and Ht. Whereas MCV, MCH, and MCHC remain unchanged and WBC increased only in the second period of the study. Moreover erythrocyte TBARS level increased, and antioxidant enzyme (SOD, GPx, and CAT) activities decreased. We concluded that TCDS intoxication promotes erythrocyte oxidative damage and disrupt hematological constituents in rats.     

Bismuth heterocycles based on a diphenyl sulfone scaffold: synthesis and substituent effect on the antifungal activity against Saccharomyces cerevisiae

A series of heterocyclic organobismuth(III) compounds 2 [ClBi(5-R-C₆H₃-2-SO₂C₆H₄-1'-): R = Me, Ph, MeO, Cl, H, t-Bu, CF₃, F, Me₂N] was synthesized in order to study the relative importance of structure and specific substitutions in relation to their lipophilicity and antifungal activity against the yeast Saccharomyces cerevisiae. A clear structure-activity relationship between the size of the inhibition zone and the value of ClogP was found for 2. These results suggest that the higher the lipophilicity, the lower the antifungal activity. Thus, 2e (R = H) and 2h (R = F), which had ClogP values of 1.18 and 1.45, respectively, were most active. In contrast, 2b (R = Ph) and 2f (R = t-Bu) had ClogP values of 3.06 and 3.00, respectively, and exhibited no antifungal activity. Compound 6b ClBi[5-(OH)C₆H₃-2-SO₂-5′-(OH)C₆H₃-1'-] had an estimated ClogP value of 0.81 but exhibited only low activity in spite of its low ClogP value, suggesting that such a considerable decrease in lipophilicity lowers inhibition activity. Bismuth carboxylate 7b derived from p-nitrobenzoic acid and 2e exhibited inhibition activity comparable to those of 2e and 2h despite its higher lipophilicity (ClogP = 2.68).     

Dimethyl sulfoxide (DMSO) attenuates the inflammatory response in the in vitro intestinal Caco-2 cell model

This study aimed to investigate dose effects of dimethyl sulfoxide (DMSO) (0.05-1%) on the intestinal inflammatory response in confluent- and differentiated-Caco-2 cells stimulated with interleukin (IL)-1β or a pro-inflammatory cocktail for 24 h. Cyclooxygenase-2 (COX-2) activity was assayed by incubating inflamed cells with arachidonic acid and then measuring prostaglandin-E₂ (PGE₂) produced. Soluble mediators (IL-8, IL-6, macrophage chemoattractant protein-1 (MCP-1), and COX-2-derived PGE₂) were quantified by enzyme immunoassays and mRNA expression of 33 proteins by high throughput TaqMan Low Density Array. Data showed that DMSO decreased induced IL-6 and MCP-1 secretions in a dose-dependent manner (P < 0.05), but not IL-8; these effects were cell development- and stimulus- independent. Moreover, in IL-1β-stimulated confluent-cells, DMSO dose-dependently reduced COX-2-derived PGE₂ (P < 0.05). DMSO at 0.5% decreased significantly mRNA levels of 14 proteins involved in the inflammatory response (including IL-6, IL-1α, IL-1β, and COX-2). Thus, DMSO at low concentrations (0.1-0.5%) exhibits anti-inflammatory properties in the in vitro intestinal Caco-2 cell model. This point is important to be taken into account when assessing anti-inflammatory properties of bioactive compounds requiring DMSO as vehicle, such as phenolic compounds, in order to avoid miss-interpretation of the results.