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91.
Sarah I. Sheikh Ivan Nestorov Heidy Russell John O’Gorman Ron Huang Ginger L. Milne Robert H. Scannevin Mark Novas Katherine T. Dawson 《Clinical therapeutics》2013
Background
Delayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment for relapsing forms of multiple sclerosis. The most common adverse events associated with DR-DMF are flushing and gastrointestinal (GI) events, the incidences of which diminish over time.Objective
The purpose of this study was to evaluate the tolerability and pharmacokinetic (PK) profile of DR-DMF with or without concomitant acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor.Methods
Healthy volunteers (N = 56) were randomized to receive different dosing regimens of DR-DMF or matching placebo with or without pretreatment with 325 mg aspirin for 4 days. Plasma levels of the active metabolite monomethyl fumarate were assessed on days 1 and 4. Flushing and GI events were assessed using patient-reported scales. Potential flushing mediators were explored.Results
DR-DMF showed a safety, tolerability, and PK profile consistent with previous clinical experience, with no evidence of accumulation. Pretreatment with aspirin had no effect on the primary PK parameters, AUC0–10h, or Cmax. Flushing severity, assessed by 2 subject-reported rating scales, was generally mild and was rated highest at the start of treatment. Pretreatment with aspirin reduced flushing incidence and intensity without affecting GI events or the PK profile of DR-DMF. In some DR-DMF–treated individuals, plasma concentrations of a prostaglandin D2 (PGD2) metabolite were increased.Conclusions
In healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD2 in some DR-DMF–treated individuals suggest that flushing may be, at least in part, prostaglandin mediated. ClinicalTrials.gov identifier: ID: NCT01281111. 相似文献92.
Paraskeva MP van Vuuren SF van Zyl RL Davids H Viljoen AM 《Journal of ethnopharmacology》2008,119(3):673-679
Ten South African Commiphora (Burseraceae) species were investigated to validate their use in traditional healing rites. The leaf and stem extracts of each species were analysed for the anti-oxidant (ABTS and DPPH assays), antimicrobial (MIC and death kinetic assays), anti-inflammatory (5-LOX assay), anticancer (SRB assay) properties, as well as the cytotoxic effects (tetrazolium-based assay). The best anti-oxidant activity (ABTS assay) was observed for the stem extracts of Commiphora tenuipetiolata IC(50)=5.10 microg/ml), Commiphora neglecta (IC(50)=7.28 microg/ml) and Commiphora mollis (IC(50)=8.82 microg/ml). Extracts generally exhibited poor anti-oxidant activity in the DPPH assay, with the exception of Commiphora schimperi (stem), Commiphora neglecta (stem), Commiphora tenuipetiolata (stem and leaf), and Commiphora edulis (stem), with IC(50) values ranging between 7.31 and 10.81 microg/ml. The stem extracts exhibited moderate to good 5-LOX inhibitory activity with Commiphora pyracanthoides (stem) displaying the greatest inhibitory effect (IC(50)=27.86+/-4.45 microg/ml). For the antimicrobial (MIC) assay, a greater selectivity was exhibited by the extracts against the Gram-positive bacteria (0.01-8.00 mg/ml) and the yeasts (0.25-8.00 mg/ml) than against the Gram-negative bacteria (1.00-8.00 mg/ml). Using death kinetic studies (time-kill studies), the rate at which Commiphora marlothii (stem) kills Staphylococcus aureus over a 24h period was determined. Mostly, a concentration-dependent antibacterial activity was observed beginning after ca. 30 min. All concentrations exhibited antibacterial activity, with complete bactericidal effect achieved by the 24(th) hour. The most active Commiphora species against the HT-29 cells (SRB anticancer assay) were Commiphora glandulosa (leaf and stem) and Commiphora marlothii (leaf). The MCF-7 cells (SRB anticancer assay) exhibited the highest sensitivity to indigenous Commiphora species, with Commiphora edulis (leaf and stem), Commiphora glandulosa (leaf and stem), Commiphora marlothii (leaf), Commiphora pyracanthoides (leaf and stem), Commiphora schimperi (stem), and Commiphora viminea (stem) all possessing a percentage inhibition greater than 80% at 100 microg/ml. Commiphora glandulosa (leaf and stem) and Commiphora pyracanthoides (leaf and stem) were the two most active species against the SF-268 cells (SRB anticancer assay), with IC(50) values ranging between 68.55+/-2.01 and 71.45+/-1.24 microg/ml. The majority of the Commiphora extracts were largely non-cytotoxic against Graham human kidney epithelial cells when investigated in the MTT assay. 相似文献
93.
作者用傅利叶交换红外光谱仪对大环醚双内酯和苯并冠醚这两类冠醚系列化合物进行中红外光谱的比较性研究。结果显示:这两类冠醚的醚氧键振动吸收谱带归属存在差异。随着醚环醚氧键的递增,其吸收峰波数呈规律性递增。由于取代基的不同,冠Ⅰ~冠Ⅳ较之冠Ⅴ~冠Ⅸ的酯氧键吸收谱带向低波数位移25cm~(-1)。作者并对以上结果及影响因素进行了探讨。 相似文献
94.
目的 探讨二甲基亚砜(dimethyl sulfoxide,DMSO)对鱼精蛋白(protamine sulfate,PS)诱导的大鼠间质性膀胱炎(interstitial cystitis,IC)治疗作用.方法 SD雌性大鼠48只,按随机数字表法分为正常组、PS灌注组、PS+DMSO组、盐水灌注组(NS组),每组12只大鼠.正常组大鼠未给予任何处理;PS组用0.5 mL,30 mg/mL的PS膀胱内灌注并在膀胱内保留30 min;PS+DMSO组使用50%DMSO溶解PS,按照0.5 mL,30 mg/mL的PS膀胱内灌注并在膀胱内保留30 min;NS组用0.5 mL生理盐水膀胱灌注并保留30 min,各组大鼠每周处理1次,连续处理4周.4周后,HE和甲苯胺蓝染色用于病理学评分和肥大细胞计数;尿动力学和肌条实验被用于评价大鼠膀胱功能和肌肉收缩性改变;Western blot检测SOD2、GSH-Px、IL-6、IL-1B、TNF-α的表达量.结果 与PS组相比,PS+ DMSO组大鼠膀胱病理学评分[(3.00±0.00) vs(0.83±0.40),P<0.05]、肥大细胞计数[(19.66±2.16) vs (6.16±1.16),P<0.05]以及炎症因子IL-6、IL-1B和TNF-α表达(P<0.05)显著降低,而抗氧化应激酶(SOD2和GSH)显著恢复(P<0.05);在膀胱功能学上,与PS组相比,PS+ DMSO组大鼠膀胱排尿频率[(24.83 ±3.06)vs (9.83±1.47),P<0.05]显著降低,排尿间隔[(2.42±0.37)vs (6.40±0.57),P<0.05]显著延长,肌肉收缩频率[(6.93 ±0.97)vs (4.94 ±0.73),P<0.05]显著降低.结论 DMSO可能通过降低炎症和氧化应激改善鱼精蛋白诱导的大鼠膀胱炎. 相似文献
95.
肌醇是自然界中广泛存在的一种六元醇,有广泛的生理、生化作用,特别是能够促进肝和其他组织中的脂肪代谢、降低血中胆固醇,临床用于治疗脂肪肝、肝硬化,动脉硬化及高血脂症。近年来,一些肌醇衍生物已被报道具有其他生物活性,包括降血糖、镇咳,抗炎等作用,其中,松醇、白坚木皮醇、红杉醇等肌醇单甲醚类衍生物的研究较为深入,本文重点对这些肌醇单甲醚类衍生物的生物活性、提取制备和开发应用等方面进行综述。 相似文献
96.
Evaluation of free radical scavenging and antityrosinase activities of standardized longan fruit extract. 总被引:8,自引:0,他引:8
Nuchanart Rangkadilok Somkid Sitthimonchai Luksamee Worasuttayangkurn Chulabhorn Mahidol Mathuros Ruchirawat Jutamaad Satayavivad 《Food and chemical toxicology》2007,45(2):328-336
The protective effects of fruits and vegetables against chronic diseases have been attributed to the antioxidant properties of some secondary metabolites present in these foods. Plant polyphenols have been reported to exhibit bioactive properties, and in particular antioxidant activities. Longan seeds are found to contain high levels of some beneficial polyphenolic compounds such as corilagin, gallic acid and ellagic acid. The present study examined the free radical scavenging activity of longan seed extract by using three different assay methods. Longan extracts contained corilagin ranging from zero to 50.64 mg/g DW, gallic acid from 9.18 to 23.04 mg/g DW, and ellagic acid from 8.13 to 12.65 mg/g DW depending on the cultivars. Dried longan seed extracts of cultivar Edor contained high levels of gallic acid and ellagic acid and also exhibited the highest radical scavenging activities when comparing fresh seed and dried pulp extracts. For scavenging activity of DPPH and superoxide radicals, longan seed extract was found to be as effective as Japanese green tea extract while dried longan pulp and mulberry green tea extracts showed the least scavenging activities. In the ORAC assay, both fresh and dried longan seed also had higher activity than dried pulp and whole fruit. However, the results demonstrate that three polyphenolics may not be the major contributors of the high antioxidant activity of longan water extracts but this high activity may be due to other phenolic/flavonoid glycosides and ellagitannins present in longan fruit. In addition, longan seed also showed tyrosinase inhibitory activity with IC(50) values of 2.9-3.2 mg/ml. Therefore, the preliminary observations suggest that longan seed extract could be another potential source of potent natural dietary antioxidants and also in an application as a new natural skin-whitening agent. 相似文献
97.
Kaempferol induces apoptosis in human lung non-small carcinoma cells accompanied by an induction of antioxidant enzymes. 总被引:3,自引:1,他引:3
Henry W-C Leung C-J Lin M-J Hour W-H Yang M-Y Wang H-Z Lee 《Food and chemical toxicology》2007,45(10):2005-2013
Kaempferol (3, 4',5,7-tetrahydroxyflavone) is one of the most commonly found dietary flavonols. The biological and pharmacological effects of kaempferol may depend upon its behavior as either an antioxidant or a prooxidant. However, the clear biological effects of prooxidant or antioxidant character of kaempferol has not been clarified yet. The overall objective of the present study is to explore the role of prooxidant or antioxidant in kaempferol-induced cell toxicity. In this paper, we have proved that antioxidant pathway may be involved in kaempferol induces H460 cell apoptosis. Kaempferol-induced H460 cell apoptosis is a typical apoptosis that was accompanied by a significant DNA condensation and increasing intracellular ATP levels. Kaempferol-induced apoptosis is related to its ability to change the expression of apoptotic markers, such as caspase-3 (caspase-dependent) and AIF (caspase-independent). The overexpression of antioxidant enzyme Mn SOD protein levels, which was promoted to a new type tumor suppressor gene in several human cancer cells recently, may be an important role in kaempferol-induced H460 cell apoptosis. 相似文献
98.
Guang Ri Dong Qing Ri Li Seol Hee Woo In Su Kim Young Hoon Jung 《Archives of pharmacal research》2008,31(11):1393-1398
This paper reports a novel synthetic method for the preparation of various urethanes and the application to the synthesis
of carisbamate. The reaction of primary (2a, 2e and 2f) or secondary (2g–2i) trimethylsilyl ethers with chlorosulfonyl isocyanate afforded the corresponding urethanes in good yields without affecting
the olefin moiety. However, in the case of secondary benzylic trimethylsilyl ether 2j, the corresponding urethane 3j was obtained in low yield. From the difference in reactivity between the primary and secondary benzylic trimethylsilyl ethers,
the one-pot synthesis of carisbamate 1 from bis-trimethylsilyl ether 2l was achieved. 相似文献
99.
Quash G Fournet G Chantepie J Gore J Ardiet C Ardail D Michal Y Reichert U 《Biochemical pharmacology》2002,64(8):1279-1292
4-Amino-4-methyl-pent-2-ynthioc acid S-methyl ester (ampal thiolester: ATE) was used as a lead compound to synthesise new amino-substituted derivatives of alpha, beta acetylenic thiolester compounds as inhibitors of aldehyde dehydrogenase 1, (ALDH1). Of these compounds, the dimethyl derivative (DIMATE) was a competitive irreversible inhibitor (K(i) approximately 280 microM) of baker's yeast ALDH1 in vitro showing 80% inhibition at 400 microM when preincubated with the enzyme for 30min, whereas the trimethyl ammonium and the morpholine derivatives showed only 15% inhibition at 600 microM even after 60min preincubation. ATE inhibited ALDH1 activity in ALDH1-transfected L1210 T cells resistant to hydroperoxycyclophosphamide (HCPA) and inhibited growth synergistically in the presence of HCPA. In non-transfected L1210 counterparts ATE did not potentiate growth inhibition by HCPA. DIMATE was a 30-100-fold more effective growth inhibitor than ATE. Endogenous ALDH1 activities of BAF(3) cells over-expressing different levels of bcl(2) (0-100%) were similar (16-20mU/mg protein) and were all inhibited by DIMATE, reaching 20-30% at 4 microM. Up to 4 microM no apoptosis, as measured by DNA-fragmentation was observed, but at 8 and 10 microM DIMATE, DNA-fragmentation increased concomitantly with ALDH1 inhibition. No DNA-fragmentation was observed with ALDH1 irreversible inhibitors devoid of a thiolester group or with thiolesters which were not inhibitors of ALDH1. It was seen only with competitive irreversible inhibitors having the methanethiol and enzyme-inhibitory moieties. The methanethiol putatively released from DIMATE by ALDH1 esterase activity plays a role, albeit undefined, in lowering intramitochondrial glutathione levels which decreased by 47% as DNA-fragmentation increased. 相似文献
100.