咖啡酸苯乙酯对缺血-再灌注氧化应激损伤保护作用的研究进展

目的:为咖啡酸苯乙酯(CAPE)用于缺血-再灌注氧化应激损伤的预防与治疗提供依据。方法:查阅近年来国内、外相关文献,总结CAPE在心肌、大脑、骨骼肌以及皮瓣、肾、肠、卵巢、睾丸及视网膜等器官的缺血-再灌注方面的研究结果,概述其在缺血-再灌注氧化应激损伤中的保护作用及其机制。结果:CAPE作为抗氧化剂,通过影响抗氧化酶、氧自由基、NO水平等发挥保护组织器官缺血-再灌注损伤的作用。结论:CAPE已被证实具有较强的保护缺血-再灌注损伤作用,它确切的作用机制以及在人体内的药动学及药物效应动力学需要更进一步的研究。     

缺血后处理结合经皮冠状动脉介入疗法对急性心肌梗死患者心率震荡的影响

<正>随着经皮冠脉介入疗法(PCI)、溶栓治疗及冠状动脉搭桥术在临床上广泛应用,急性心肌梗死(AMI)的治疗进入缺血再灌注时代。然而缺血再灌注在治疗AMI的同时,会进一步加重心肌损伤。研究表明氧自由基生成、钙超载及白细胞激活导致局部炎症等是缺血再灌注损伤的作用机制~([1]),针对这些机制进行处理如抗氧化治疗、腺苷受体激动剂等对心肌缺血再灌注损伤起重要防治作用。近年来,缺血后处理在心     

抗氧自由基药物对心肌再灌注损伤的作用

近年来大量研究结果表明,心肌缺血/再灌注损伤(再灌注损伤)与自由基主要是氧自由基有密切关系。因此,应用抗氧自由基药物保护心肌再灌注损伤的研究十分活跃。本文简要介绍这类药物的作用。一、缺血/再灌注心肌组织氧自由基的生成及其对心肌的损伤凡是外层轨道上有不配对电子的原子、原子团、分子或离子,均称为自由基。与人类关系最密切的自由基为氧自由基系统。心肌缺血后,特别是再灌     

丹参酮ⅡA对不同器官缺血再灌注损伤保护作用的研究进展

丹参酮ⅡA是从中药材丹参根茎中提取的脂溶性有效活性成分,具有清除氧自由基、稳定血管内皮功能、保护细胞和肌体免受脂质过氧化损伤等作用,可通过多种机制减轻缺血再灌注器官的损伤,从而对心、脑、肝、肺、肾等器官起到保护作用.本文综合近几年国内外的实验研究成果,对丹参酮ⅡA在缺血再灌注损伤的器官保护作用进行综述,为临床治疗局部缺血再灌注损伤提供依据.     

二乙基二硫代氨基甲酸钠对沙土鼠脑缺血再灌注损伤的影响

沙土鼠脑缺血60min后,脑组织氧自由基和MDA含量无明显升高,而Mn-SOD的活性下降。缺血60min再灌注5min时,氧自由基显著升高。再灌注30min时,MDA的生成显著增多,Mn-SOD和Cu,Zn-SOD活性显著降低。缺血前15 min,iv DTC对缺血再灌注脑组织中氧自由基和MDA升高有显著抑制作用,对Mn-SOD活性有显著保护作用,且呈剂量依赖关系。     

肝移植患者术中氧自由基相关指标的变化

目的：研究在肝移植术中氧自由基对肝脏缺血再灌注损伤的作用。方法：测定比较18例肝移植患者术前、无肝期、再灌注后1h血浆中脂质过氧化物(LPO)、超氧化物歧化酶(SOD)、总抗氧化能力(TAC)、一氧化氮水平(NO)，分析其变化。结果：再灌注后LPO和TAC下降，SOD和NO升高。结论：氧自由基在肝移植缺血再灌注损伤中有重要作用，再灌注后，激活了保护机制，手术中输血及某些药物的使用也可以减轻自由基损害，对机体具有保护作用。     

蒙古黄芪总黄酮对大鼠心肌缺血再灌注损伤的保护作用

目的研究蒙古黄芪总黄酮对大鼠心肌缺血再灌注损伤的保护作用及其机制。方法采用结扎大鼠左冠状动脉前降支法,缺血90 min,再灌注24 h,建立心肌缺血再灌注损伤模型。观察大鼠心电图S-T段变化,用氯化三苯基四氮唑(TTC)对心肌染色,观察心肌梗死面积及测定血清乳酸脱氢酶、肌酸激酶、心肌组织超氧化物歧化酶、丙二醛含量,探讨蒙古黄芪总黄酮对心肌缺血再灌注损伤的保护作用。结果蒙古黄芪总黄酮90、270 mg·kg-1可以使心肌缺血再灌注损伤大鼠心电图S-T段降低及降低大鼠血清中乳酸脱氢酶、肌酸激酶的释放;30、90、270 mg·kg-1剂量可减少大鼠心肌梗死面积;270 mg·kg-1剂量减少大鼠心肌组织丙二醛的产生,提高心肌组织超氧化物歧化酶活力。结论蒙古黄芪总黄酮可以使缺血再灌注损伤大鼠心肌缺血程度降低,减少心肌梗死面积,对缺血再灌注损伤具有一定的保护作用,其作用机制可能通过抑制乳酸脱氢酶、肌酸激酶的释放,降低心肌组织氧化产物丙二醛含量、提高内源性氧自由基清除剂超氧化物歧化酶的活力,减轻缺血再灌注损伤后氧自由基对心肌细胞膜脂质过氧化损伤有关。     

依达拉奉的临床研究及进展

依达拉奉是一种自由基清除剂,其良好的脑保护作用已得到国内外临床研究的证实。本品具有独特的清除自由基和减轻缺血再灌注的作用机制,还可进一步扩大用于治疗心肌缺血、肾脏缺血和肝脏缺血等疾病。     

心肌缺血再灌注损伤的主要机制与相关药物治疗的研究进展

缺血性心肌病在治疗后可能发生缺血再灌注损伤,受损心肌的损伤程度加重,梗死面积扩大,这种现象的发生与多种机制有关,包括：钙超载、氧自由基增多、炎症反应等.随着心肌缺血的治疗技术的提高,缺血再灌注时期的治疗已成为缺血性心肌病的治疗重点,因此,针对防治该时期的药物研发也已成为重点.常见药物作用机制包括：减轻钙超载、抗炎症反应、抗氧自由基和改善能量代谢等.本文旨在对MIRI不同病理机制和相关药物的研究进展进行阐述.     

二乙基二硫代氨基甲酸钠对沙土鼠脑缺血再灌注损伤的影响

沙土鼠脑缺血６０ｍｉｎ后，脑组织氧自由基和ＭＤＡ含量无明显升高，而Ｍｎ－ＳＯＤ的活性下降，缺血６０ｍｉｎ再灌注５ｍｉｎ时，氧自由基显著升高。再灌注３０ｍｉｎ时，氧自由基显著升高，Ｍｎ－ＳＯＤ和Ｃｕ，Ｚｎ－ＳＯＤ活性显著降低。缺血前１５ｍｉｎ，ｉｖＤＴＣ对缺血再灌注脑组织中氧自由基和ＭＤＡ升高有显著抑制作用，对Ｍｎ－ＳＯＤ活性有显著保护作用。且呈剂量依赖关系。     

Uric acid increases IL-1β secretion and Caspase-1 activation in PBMCs of Behçet’s disease patients: The in vitro immunomodulatory effect of xanthine oxidase inhibitor Allopurinol

Behçet’s disease (BD) is a multisystem disease, which shares some features with other diseases belonging to the autoinflammatory disorders panel. Recent studies have postulated that IL-1β/Caspase-1 may play a cardinal role in autoinflammatory diseases. In this study, we aimed to (i) elucidate the mechanism underlying the involvement of xanthine oxidase (XO) and Uric Acid (UA) in BD (ii) study the direct effects of UA and XO inhibitor “Allopurinol” on nitric oxide (NO) and caspase-1-mediated IL-1β release in peripheral blood mononuclear cells (PBMCs) of BD patients. In this context, plasma of BD patients and healthy controls (HC) were used to measure XO activity, UA, advanced oxidized proteins products (AOPP) and NO levels. In Addition, PBMCs of BD patients and HC were treated or not with either UA or Allopurinol. Then we quantified NO and IL-1β levels, and Caspase-1 Activity in the supernatants and lysates of PBMCs, respectively. We showed that plasma levels of XO activity, UA, AOPP and NO are significantly increased in BD patients compared to those of HC. Interestingly, a significant positive correlation between XO and UA was observed in BD patients. Additionally, while UA has markedly increased NO, IL-1β, and Caspase-1 activity levels in PBMCs of BD patients, Allopurinol has exerted an immunomodulatory effect resulting in reduced NO, IL-1β and Caspase-1 levels in PBMCs of BD patients particularly during the active stages. Collectively, our results indicate a potential clinical use of XO as a tool for assessing BD activity, and suggest that the in-vitro immunomodulatory effect of Allopurinol may have a promising therapeutic value in BD management.     

别嘌醇致皮肤严重不良反应的文献综述

摘 要别嘌醇作为一种降尿酸药物,因其经济、有效被广泛应用于临床。在发挥降尿酸作用的同时,别嘌醇也被报道可能导致皮肤严重不良反应(severe cutaneo us adverse reactions,SCAR)。本文整理了别嘌醇诱发严重皮肤不良反应的相关文献,总结了其引起的严重皮肤不良反应的类型、危险因素及预防措施,为临床安全用药提供参考。     

别嘌呤醇对氟脲嘧啶化疗作用的影响

本文研究氟脲嘧啶(5—Fluorouracil,5—Fu)并用别嘌呤醇(Allopurinol,HPP)的抗肿瘤作用。5—Fu 并用 HPP 后,使5—Fu 对小白鼠的 LD_(50)数倍增大,对小白鼠艾氏腹水癌(EAC)和肉瘤_(180)(S_(180))实体型的治疗效果有明显的提高。对狗和大白鼠的亚急性毒性实验表明,5—Fu 并用 HPP 后毒性有所降低。     

Metabolic studies of purine metabolism in the pig during the oral administration of guanine and allopurinol

(1) Allopurinol and guanine, both separately and together, were fed over varying periods to diiferent groups of large white/landrace cross pigs. Although allantoin and not uric acid represented the end point of purine metabolism in this species, total urinary purine excretion approximated that of a man of equivalent weight on a purine-free diet. No abnormality in the handling of guanine was found, up to 50 per cent of an exogenous load being absorbed, metabolized and rapidly excreted in the urine as allantoin.(2) Allopurinol alone, in increasing dosage, was capable of total saturation of the enzyme xanthine oxidase at high dosage levels, but produced only slight reduction in total purine excretion at any dosage. Allopurinol riboside was the principal urinary metabolite, increasing with increasing allopurinol dosage, even at dosages above enzyme saturation levels, when oxipurinol excretion had levelled off. Xanthine replaced allantoin as the principal urinary purine metabolite during allopurinol therapy but, despite saturation of the xanthine oxidase, allantoin excretion did not fall to zero and hypoxanthine excretion was not increased. Allopurinol also had an effect on pyrimidine excretion in the pig as indicated by increased urinary orotic acid and orotidine levels, an effect not eliminated when guanine was given together with allopurinol.(3) Combined therapy with allopurinol and guanine produced three additional effects to those when allopurinol was given alone, (a) Allopurinol reduced substantially the considerable increase in total purine excretion resulting from guanine alone, a finding difficult to explain on the basis of feedback inhibition of de novo purine synthesis. (b) Urinary hypoxanthine excretion increased and at the same time allopurinol riboside excretion decreased substantially, suggesting competitive inhibition of allopurinol riboside formation as mediated by the enzyme purine nucleoside phosphorylase. (c) Xanthine was again the principal urinary metabolite, but at levels in excess of its solubility, so that coprecipitation with oxipurinol occurred in the renal tubules causing a considerable degree of renal dysfunction. Crystals were not found in any other tissue, including muscle, so that no evidence of guanine gout was noted, nor any other abnormality of purine metabolism which could be related to leg weakness in pigs.     

Anti-nociceptive properties of the xanthine oxidase inhibitor allopurinol in mice: role of A1 adenosine receptors

Background and purpose

Allopurinol is a potent inhibitor of the enzyme xanthine oxidase, used primarily in the treatment of hyperuricemia and gout. It is well known that purines exert multiple effects on pain transmission. We hypothesized that the inhibition of xanthine oxidase by allopurinol, thereby reducing purine degradation, could be a valid strategy to enhance purinergic activity. The aim of this study was to investigate the anti-nociceptive profile of allopurinol on chemical and thermal pain models in mice.

Experimental approach

Mice received an intraperitoneal (i.p.) injection of vehicle (Tween 10%) or allopurinol (10–400 mg kg⁻¹). Anti-nociceptive effects were measured with intraplantar capsaicin, intraplantar glutamate, tail-flick or hot-plate tests.

Key results

Allopurinol presented dose-dependent anti-nociceptive effects in all models. The opioid antagonist naloxone did not affect these anti-nociceptive effects. The non-selective adenosine-receptor antagonist caffeine and the selective A₁ adenosine-receptor antagonist, DPCPX, but not the selective A_2A adenosine-receptor antagonist, {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304","term_text":"SCH58261"}}SCH58261, completely prevented allopurinol-induced anti-nociception. No obvious motor deficits were produced by allopurinol, at doses up to 200 mg kg⁻¹. Allopurinol also caused an increase in cerebrospinal fluid levels of purines, including the nucleosides adenosine and guanosine, and decreased cerebrospinal fluid concentration of uric acid.

Conclusions and implications

Allopurinol-induced anti-nociception may be related to adenosine accumulation. Allopurinol is an old and extensively used compound and seems to be well tolerated with no obvious central nervous system toxic effects at high doses. This drug may be useful to treat pain syndromes in humans.     

Clinical pharmacokinetics of allopurinol. 3. Allopurinol/oxipurinol pharmacokinetics following administration of a controlled release allopurinol preparation

Studies of the Clinical Pharmacokinetics of Allopurinol/3rd Communication: Allopurinol/oxipurinol bioavailability and pharmacokinetics following the administration of a controlled release allopurinol formulation. Regarding the results of our studies on the localization of the absorption of allopurinol and the kinetic behavior of allopurinol/oxipurinol following multiple administration the bioavailability and kinetic properties of the drug delivered from controlled release tablets were studied in healthy volunteers. Allopurinol controlled release tablets (Sigapurol CR), containing 200 mg of the drug characterized by rapid absorption and 100 mg characterized by pH-dependent delivery, were identified as a formulation with advantages pharmacokinetic properties.     

Clinical pharmacokinetics of allopurinol

Allopurinol is a widely used drug in the management of hyperuricaemia. It is rapidly and extensively absorbed following oral administration. The major and active metabolite, oxypurinol, is detected in the circulation within 15 minutes of allopurinol administration. Oxypurinol concentrations are higher than those of the parent drug and accumulation occurs during long term administration. Up to 80% of allopurinol is recovered in the urine within 24 hours, mainly in the form of oxypurinol. Allopurinol is negligibly absorbed after rectal administration. In animals, allopurinol is found in highest concentrations in vascular tissue, blood, liver, intestine and heart. It is negligibly bound to plasma proteins. Oxypurinol is eliminated by the kidney and has a much longer elimination half-life than allopurinol. Oxypurinol accumulates in patients with renal dysfunction; hence allopurinol dosages should be adjusted in such patients. Allopurinol inhibits the metabolism of 6-mercaptopurine and azathioprine, which require dosage modifications. The interaction of allopurinol with oral anticoagulants and phenytoin has not been clearly established in clinical practice.     

The effect of allopurinol on the steady-state pharmacokinetics of indomethacin.

The effect of 5 days treatment with allopurinol (300 mg) on the pharmacokinetics of indomethacin at steady-state was investigated in eight patients. Allopurinol produced no significant effect on the indomethacin serum concentration-time curve. Allopurinol did not alter significantly the amounts of indomethacin excreted in the urine within 8 h. However, the urinary ratio of N-deschlorobenzoylindomethacin to indomethacin was reduced significantly by allopurinol administration (P less than 0.05).     

Allopurinol induced erythroderma

Allopurinol, a widely prescribed urate lowering agent is responsible for various adverse drug reactions, including erythroderma. A 45-year-old male patient was admitted with the complaints of fever, redness and scaling all over the body after 3-4 weeks of allopurinol treatment for asymptomatic hyperuricemia. Elevated liver enzymes were detected in his blood analysis. Skin biopsy was consistent with drug induced erythroderma. Allopurinol was stopped and steroids were started. Patient improved over a period of 2 weeks.KEY WORDS: Allopurinol, erythroderma, hyperuricemia     

Allopurinol increases ear swelling and mortality in a dinitrofluorobenzene-induced contact hypersensitivity mouse model.

The immunomodulatory effects of allopurinol were investigated in a mouse contact hypersensitivity model. Allopurinol caused a time- and dose-dependent lethal effect in dinitrofluorobenzene (DNFB)-sensitized mice. Furthermore, allopurinol markedly increased ear swelling in the remaining mice. In contrast, TMX-67, a newly synthesized xanthine oxidase/xanthine dehydrogenase (XOD/XDH) inhibitor, had almost no effect on DNFB-sensitized mice. Allopurinol reduced both the spleen weight and white blood cell count in DNFB-sensitized mice without affecting the T cell subset of splenocytes. The production of interferon (IFN)-gamma, in the splenocytes of DNFB-sensitized mice was reduced by allopurinol administration. Death due to allopurinol was much lower in the non-sensitized mice than in the DNFB-sensitized mice. These findings indicate that allopurinol may interact with DNFB to enhance its toxicity and allopurinol might also modulate or enhance the inflammatory effect of DNFB. Also, DNFB may cause metabolic alterations via inflammation, leading to enhanced allopurinol toxicity.