• 【在II型糖尿病中aPDT对强力霉素非手术牙周治疗的其他影响:一项随机对照临床试验。】 复制标题 收藏 收藏
    DOI:10.1007/s10103-013-1285-6 复制DOI
    作者列表:Macedo Gde O,Novaes AB Jr,Souza SL,Taba M Jr,Palioto DB,Grisi MF
    BACKGROUND & AIMS: :The association of doxycycline and periodontal treatment in non-controlled diabetes mellitus (DM) has shown positive results on clinical and metabolic parameters. Antimicrobial photodynamic therapy (aPDT) is a local and painless antimicrobial treatment that can be applied in periodontal treatment without systemic risks. The aim of this study was to evaluate the potential improvement of aPDT on clinical and metabolic effects in patients with type 2 diabetes mellitus in conjunction with nonsurgical periodontal treatment plus doxycycline. Thirty patients with type 2 diabetes and diagnosis of chronic periodontitis were treated with scaling and root planning (SRP; N = 15) or SRP plus phenothiazine chloride photosensitizer-induced aPDT (SRP + aPDT, N = 15). Patients of both groups took doxycycline (100 mg/day) for 2 weeks and plaque index, bleeding on probe (BOP), probing pocket depth (PPD), suppuration, clinical attachment level (CAL), and glycated hemoglobin levels (HbA1c) were measured at baseline and 3 months after therapy. An improvement in clinical parameters such as PPD, CAL, S, and BOP between groups was observed but without statistical significance (p > 0.05). Intragroup analysis showed a significant reduction of HbA1c (8.5 ± 0.9 to 7.5 ± 0.1, p < 0.01) in the SRP + aPDT group. The differences of HbA1c between baseline and 3 months were greater for the SRP + aPDT (11.4 %) than SRP (10 %) (0.87 ± 0.9 and 0.4 ± 0.84 respectively; p < 0.05). A single application of the aPDT as an adjunct to periodontal treatment did not show additional benefits in the clinical parameters but resulted in a slight greater decrease in HbA1c.
    背景与目标: :在非控制性糖尿病(DM)中,强力霉素与牙周治疗的关联在临床和代谢参数方面显示出积极的结果。抗菌素光动力疗法(aPDT)是一种局部且无痛的抗菌素疗法,可用于牙周治疗而无系统性风险。这项研究的目的是评估aPDT对2型糖尿病患者结合非手术牙周治疗加强力霉素的临床和代谢作用的潜在改善作用。 30例2型糖尿病并诊断为慢性牙周炎的患者接受了结垢和牙根计划(SRP; N = 15)或SRP加上吩噻嗪氯化物光敏剂诱导的aPDT(SRP aPDT,N = 15)。两组患者均接受强力霉素(100 mg /天)治疗2周,其斑块指数,探针出血(BOP),探查袋深度(PPD),化脓,临床依从水平(CAL)和糖化血红蛋白水平(HbA1c)均为在基线和治疗后3个月进行测量。两组之间的临床参数如PPD,CAL,S和BOP均有改善,但无统计学意义(p> 0.05)。组内分析显示,SRP aPDT组的HbA1c显着降低(8.5±0.9至7.5±0.1,p <0.01)。对于SRP aPDT,基线和3个月之间HbA1c的差异(11.4%)大于SRP(10%)(分别为0.87±0.9和0.4±±0.84; p <0.05)。单独应用aPDT作为牙周治疗的辅助手段并未在临床指标上显示出其他益处,但导致HbA1c的下降幅度更大。
  • 【米诺环素和强力霉素在亨廷顿舞蹈病模型中无益。】 复制标题 收藏 收藏
    DOI:10.1002/ana.10614 复制DOI
    作者列表:Smith DL,Woodman B,Mahal A,Sathasivam K,Ghazi-Noori S,Lowden PA,Bates GP,Hockly E
    BACKGROUND & AIMS: :Huntington's Disease (HD) is an inherited neurological disorder causing movement impairment, personality changes, dementia, and premature death, for which there is currently no effective therapy. The modified tetracycline antibiotic, minocycline, has been reported to ameliorate the disease phenotype in the R6/2 mouse model of HD. Because the tetracyclines have also been reported to inhibit aggregation in other amyloid disorders, we have investigated their ability to inhibit huntingtin aggregation and further explored their efficacy in preclinical mouse trials. We show that tetracyclines are potent inhibitors of huntingtin aggregation in a hippocampal slice culture model of HD at an effective concentration of 30 microM. However, despite achieving tissue levels approaching this concentration by oral treatment of R6/2 mice with minocycline, we observed no clear difference in their behavioral abnormalities, or in aggregate load postmortem. In the light of these new data, we would advise that caution be exercised in proceeding into human clinical trials of minocycline.
    背景与目标: 亨廷顿舞蹈病(HD)是一种遗传性神经系统疾病,导致运动障碍,人格改变,痴呆症和过早死亡,目前尚无有效的治疗方法。据报道,改良的四环素抗生素米诺环素可改善HD R6 / 2小鼠模型的疾病表型。由于四环素还被报道在其他淀粉样蛋白疾病中具有抑制聚集的作用,因此我们研究了它们抑制亨廷顿蛋白聚集的能力,并进一步探索了它们在临床前小鼠试验中的功效。我们表明四环素是有效的浓度为30 microM的海马切片培养模型中的亨廷顿蛋白聚集的有效抑制剂。但是,尽管通过口服米诺环素治疗R6 / 2小鼠达到了接近该浓度的组织水平,但我们观察到它们的行为异常或死后总负荷没有明显差异。根据这些新数据,我们建议在进行米诺环素的人体临床试验时应谨慎行事。
  • 【延长大环内酯类,皮质类固醇,强力霉素和左氧氟沙星对儿童大环内酯无反应性肺炎支原体肺炎的治疗效果和安全性。】 复制标题 收藏 收藏
    DOI:10.3346/jkms.2018.33.e268 复制DOI
    作者列表:Ha SG,Oh KJ,Ko KP,Sun YH,Ryoo E,Tchah H,Jeon IS,Kim HJ,Ahn JM,Cho HK
    BACKGROUND & AIMS: Background:We aimed to compare the therapeutic efficacy of prolonged macrolide (PMC), corticosteroids (CST), doxycycline (DXC), and levofloxacin (LFX) against macrolide-unresponsive Mycoplasma pneumoniae (MP) pneumonia in children and to evaluate the safety of the secondary treatment agents. Methods:We retrospectively analyzed the data of patients with MP pneumonia hospitalized between January 2015 and April 2017. Macrolide-unresponsiveness was clinically defined with a persistent fever of ≥ 38.0°C at ≥ 72 hours after macrolide treatment. The cases were divided into four groups: PMC, CST, DXC, and LFX. We compared the time to defervescence (TTD) after secondary treatment and the TTD after initial macrolide treatment in each group with adjustment using propensity score-matching analysis. Results:Among 1,165 cases of MP pneumonia, 190 (16.3%) were unresponsive to macrolides. The proportion of patients who achieved defervescence within 48 hours in CST, DXC, and LFX groups were 96.9% (31/33), 85.7% (12/14), and 83.3% (5/6), respectively. The TTD after initial macrolide treatment did not differ between PMC and CST groups (5.1 vs. 4.2 days, P = 0.085), PMC and DXC groups (4.9 vs. 5.7 days, P = 0.453), and PMC and LFX groups (4.4 vs. 5.0 days, P = 0.283). No side effects were observed in the CST, DXC, and LFX groups. Conclusion:The change to secondary treatment did not show better efficacy compared to PMC in children with macrolide-unresponsive MP pneumonia. Further studies are needed to guide appropriate treatment in children with MP pneumonia.
    背景与目标: 背景:我们旨在比较延长的大环内酯(PMC),皮质类固醇(CST),强力霉素(DXC)和左氧氟沙星(LFX)对儿童对大环内酯无反应性肺炎支原体(MP)肺炎的疗效,并评估其安全性二级治疗剂。
    方法:我们回顾性分析2015年1月至2017年4月住院的MP肺炎患者的数据。临床定义大环内酯无反应性,并在大环内酯治疗后≥72小时持续发烧≥38.0°C。病例分为四类:PMC,CST,DXC和LFX。我们使用倾向评分匹配分析,通过调整比较了每组中二次治疗后的去铁时间(TTD)和初始大环内酯类药物治疗后的TTD。
    结果:在1,165例MP肺炎患者中,有190例(16.3%)对大环内酯类药物无反应。 CST,DXC和LFX组在48小时内达到退热的患者比例分别为96.9%(31/33),85.7%(12/14)和83.3%(5/6)。 PMC和CST组(5.1 vs.4.2天,P = 0.085),PMC和DXC组(4.9 vs. 5.7天,P = 0.453),PMC和LFX组(4.4 vs. 5.0天,P = 0.283)。在CST,DXC和LFX组中未观察到副作用。
    结论:对大环内酯无反应的MP肺炎患儿,与PMC相比,二级治疗的改变没有显示出更好的疗效。需要进一步研究以指导MP肺炎患儿的适当治疗。
  • 【评估固体微针辊以增强强力霉素的跨膜递送并抑制MMP活性。】 复制标题 收藏 收藏
    DOI:10.1080/10717544.2017.1337826 复制DOI
    作者列表:Omolu A,Bailly M,Day RM
    BACKGROUND & AIMS: :Many chronic wounds exhibit high matrix metalloproteinase (MMP) activity that impedes the normal wound healing process. Intradermal delivery (IDD) of sub-antimicrobial concentrations of doxycycline, as an MMP inhibitor, could target early stages of chronic wound development and inhibit further wound progression. To deliver doxycycline intradermally, the skin barrier must be disrupted. Microneedle rollers offer a minimally invasive technique to penetrate the skin by creating multiple microchannels that act as temporary conduits for drugs to diffuse through. In this study, an innovative and facile approach for delivery of doxycycline across Strat-MTM membrane was investigated using microneedle rollers. The quantity and rate of doxycycline diffusing through the micropores directly correlated with increasing microneedle lengths (250, 500 and 750 μm). Treatment of Strat-MTM with microneedle rollers resulted in a reduction in fibroblast-mediated collagen gel contraction and MMP activity compared with untreated Strat-MTM. Our results show that treatment of an epidermal mimetic with microneedle rollers provides sufficient permeabilization for doxycycline diffusion and inhibition of MMP activity. We conclude that microneedle rollers are a promising, clinically ready tool suitable for delivery of doxycycline intradermally to treat chronic wounds.
    背景与目标: :许多慢性伤口均表现出高基质金属蛋白酶(MMP)活性,阻碍了正常伤口的愈合过程。皮下递送(IDD)的多西环素抗微生物剂浓度(作为MMP抑制剂)可以靶向慢性伤口发展的早期阶段,并抑制伤口的进一步发展。为了在皮肤内递送强力霉素,必须破坏皮肤屏障。微针辊通过创建多个微通道作为药物扩散的临时导管,从而提供了一种微创技术来穿透皮肤。在这项研究中,使用微针辊研究了一种新颖而简便的方法,用于在多股Strat-MTM膜上递送强力霉素。多西环素扩散通过微孔的数量和速率与微针长度(250、500和750μm)的增加直接相关。与未处理的Strat-MTM相比,用微针滚轮治疗Strat-MTM减少了成纤维细胞介导的胶原凝胶收缩和MMP活性。我们的结果表明,用微针辊治疗表皮模拟物为多西环素扩散和抑制MMP活性提供了足够的通透性。我们得出的结论是,微针滚轮是一种有前途的,临床上可立即使用的工具,适合皮内输送强力霉素治疗慢性伤口。
  • 【用多西环素和temephos地面杀幼虫剂进行试验和治疗,作为在小儿麻痹症共同流行地区加快消除盘尾丝虫病的替代策略:COUNTDOWN财团的多学科研究方案。】 复制标题 收藏 收藏
    DOI:10.1186/s13071-019-3826-8 复制DOI
    作者列表:
    BACKGROUND & AIMS: BACKGROUND:Onchocerciasis is a priority neglected tropical disease targeted for elimination by 2025. The standard strategy to combat onchocerciasis is annual Community-Directed Treatment with ivermectin (CDTi). Yet, high prevalence rates and transmission persist following > 12 rounds in South-West Cameroon. Challenges include programme coverage, adherence to, and acceptability of ivermectin in an area of Loa loa co-endemicity. Loiasis patients harbouring heavy infections are at risk of potentially fatal serious adverse events following CDTi. Alternative strategies are therefore needed to achieve onchocerciasis elimination where CDTi effectiveness is suboptimal. METHODS/DESIGN:We designed an implementation study to evaluate integrating World Health Organisation-endorsed alternative strategies for the elimination of onchocerciasis, namely test-and-treat with the macrofilaricide, doxycycline (TTd), and ground larviciding for suppression of blackfly vectors with the organophosphate temephos. A community-based controlled before-after intervention study will be conducted among > 2000 participants in 20 intervention (Meme River Basin) and 10 control (Indian River Basin) communities. The primary outcome measure is O. volvulus prevalence at follow-up 18-months post-treatment. The study involves four inter-disciplinary components: parasitology, entomology, applied social sciences and health economics. Onchocerciasis skin infection will be diagnosed by skin biopsy and Loa loa infection will be diagnosed by parasitological examination of finger-prick blood samples. A simultaneous clinical skin disease assessment will be made. Eligible skin-snip-positive individuals will be offered directly-observed treatment for 5 weeks with 100 mg/day doxycycline. Transmission assessments of onchocerciasis in the communities will be collected post-human landing catch of the local biting blackfly vector prior to ground larviciding with temephos every week (0.3 l/m3) until biting rate falls below 5/person/day. Qualitative research, including in-depth interviews and focus-group discussions will be used to assess acceptability and feasibility of the implemented alternative strategies among intervention recipients and providers. Health economics will assess the cost-effectiveness of the implemented interventions. CONCLUSIONS:Using a multidisciplinary approach, we aim to assess the effectiveness of TTd, alone or in combination with ground larviciding, following a single intervention round and scrutinise the acceptability and feasibility of implementing at scale in similar hotspots of onchocerciasis infection, to accelerate onchocerciasis elimination.
    背景与目标: 背景:盘尾丝虫病是一种优先被忽视的热带病,目标是到2025年消除。盘尾丝虫病的标准策略是每年使用伊维菌素(CDTi)进行社区定向治疗。然而,喀麦隆西南地区进行了12轮以上的攻击后,高流行率和传播率仍然存在。挑战包括在Loa loa共流行地区的伊维菌素的覆盖率,依从性和可接受性。携带重度感染的精神病患者有CDTi后可能致命的严重不良事件的风险。因此,在CDTi效果欠​​佳的情况下,需要采取其他策略来消除盘尾丝虫病。
    方法/设计:我们设计了一项实施研究,以评估世界卫生组织认可的消除盘尾丝虫病的替代策略,即用大杀线虫剂,强力霉素(TTd)进行试验和治疗,以及用杀幼虫剂抑制地蝇的方法。有机磷酸酯。 20> 2000名参与者将在20个干预(Meme河盆地)和10个控制(印度河盆地)社区中进行以社区为基础的前后干预研究。主要结局指标是在治疗后18个月进行随访时,肠弯曲菌的患病率。该研究涉及四个跨学科的组成部分:寄生虫学,昆虫学,应用社会科学和卫生经济学。盘尾丝虫病皮肤感染将通过皮肤活检来诊断,而Loa loa感染将通过手指刺血样品的寄生虫学检查来诊断。同时进行临床皮肤疾病评估。合格的皮肤剪断阳性个体将接受直接观察到的治疗,为期5周,每天100 mg强力霉素。社区中盘尾丝虫病的传播评估将在每周(0.3l / m3)用腾飞蚊进行地面幼虫之前,收集当地叮咬的粉虱媒介的人工着陆捕捞量,直到叮咬率降至5 /人/天以下。定性研究,包括深度访谈和焦点小组讨论,将用于评估干预接受者和提供者之间已实施替代策略的可接受性和可行性。卫生经济学将评估已实施干预措施的成本效益。
    结论:我们采用多学科方法,旨在通过一次干预后评估TTd单独或与地面杀幼虫剂联合使用的有效性,并仔细研究在类似盘尾丝虫病热点地区大规模实施TTd的可接受性和可行性,以加速盘尾丝虫病的消除。
  • 【强力霉素具有多种抗过敏作用,可减轻小鼠过敏性结膜炎和全身过敏反应。】 复制标题 收藏 收藏
    DOI:10.1016/j.bcp.2014.08.001 复制DOI
    作者列表:Su W,Wan Q,Han L,Huang J,Chen X,Chen G,Zheng SG,Liang D
    BACKGROUND & AIMS: :Allergic diseases, which affect up to 20-30% of the world population, are still therapeutic challenge for allergists. Tetracyclines, which belong to an antibiotic drug family that possesses a striking variety of non-antibiotic properties, have been successfully applied to a wide range of diseases. However, their roles in allergic conjunctivitis and anaphylaxis and their underlying anti-allergy mechanisms remain elusive. Here, we reported that treatment with doxycycline significantly reduced IgE release from mouse B cells and the degranulation and inflammatory cytokines production of mouse mast cells (MCs) activated by IgE-dependent way. Furthermore, doxycycline treatment significantly inhibited histamine-induced vascular hyperpermeability in vitro. Mechanistically, the doxycycline-mediated inhibition of B cells, MCs and histamine may occur via modulation of the PI3K/Akt pathway. In vivo, our results demonstrated that treatment with doxycycline significantly attenuated clinical symptoms of mouse models of experimental allergic conjunctivitis (EAC) with a significant decrease in inflammatory cell frequency, IgE production, histamine release, and a decrease in TNF-α and IL-4 production. Using mouse models of MCs-dependent passive systemic anaphylaxis (PSA), we further confirmed anti-allergy effects of doxycycline and doxycycline-mediated inhibitory effects on MCs. Furthermore, our results showed that doxycycline significantly attenuate histamine-induced systemic anaphylaxis-like reaction (HISA) with a significantly downregulation of PI3K/Akt/eNOS/VE-cadherin pathway. The doxycycline-mediated anti-allergy effects during EAC, PSA and HISA were abrogated when an Akt activator, SC79, was administered. These findings suggest that doxycycline inhibits B cell, MC and histamine function and attenuates experimental allergic conjunctivitis and systemic anaphylaxis by possible modulating the PI3K/Akt pathway.
    背景与目标: 过敏性疾病影响着全球20%至30%的人口,仍然是过敏症患者的治疗挑战。四环素属于一种抗生素药物家族,具有惊人的多种非抗生素特性,已成功应用于多种疾病。然而,它们在过敏性结膜炎和过敏反应中的作用及其潜在的抗过敏机制仍然难以捉摸。在这里,我们报道用强力霉素进行治疗可显着降低小鼠B细胞释放的IgE以及通过IgE依赖性方式激活的小鼠肥大细胞(MC)的脱颗粒和炎性细胞因子的产生。此外,强力霉素在体外可显着抑制组胺诱导的血管通透性过高。从机理上讲,强力霉素介导的对B细胞,MC和组胺的抑制作用可能是通过PI3K / Akt途径的调节而发生的。在体内,我们的结果表明,用强力霉素进行治疗可显着减轻实验性变应性结膜炎(EAC)小鼠模型的临床症状,炎症细胞频率,IgE产生,组胺释放以及TNF-α和IL-4的降低均显着降低生产。使用小鼠模型的MCs依赖的被动系统性过敏反应(PSA),我们进一步证实了强力霉素的抗过敏作用和强力霉素对MCs介导的抑制作用。此外,我们的结果表明,强力霉素显着减弱了PI3K / Akt / eNOS / VE-钙粘蛋白途径的组织胺诱导的全身过敏样反应(HISA)。当使用Akt激活剂SC79时,EAC,PSA和HISA中强力霉素介导的抗过敏作用被取消。这些发现表明强力霉素可通过调节PI3K / Akt途径来抑制B细胞,MC和组胺功能,并减轻实验性过敏性结膜炎和全身性过敏反应。
  • 【口服强力霉素是否会到达泪膜?】 复制标题 收藏 收藏
    DOI:10.1136/bjo.2007.125989 复制DOI
    作者列表:Smith VA,Khan-Lim D,Anderson L,Cook SD,Dick AD
    BACKGROUND & AIMS: BACKGROUND/AIMS:Orally administered doxycycline, a broad-spectrum antibiotic, is an established treatment for ocular surface diseases, particularly rosacea, meibomian gland dysfunction and recurrent epithelial cell erosion. In recent times, its efficacy in treating these diseases has been ascribed to an ability to inhibit matrix metalloproteinase (MMP) activity and both MMP and interleukin-1 (IL-1) synthesis. Since these functions are concentration-dependent, the aim of this project was to determine whether sufficient doxycycline reached the tear film to fulfil these roles in vivo. METHODS:Doxycycline was extracted with 1-butanol from tear and blood plasma samples obtained from patients with ocular surface disease and healthy individuals and quantified spectrophotometrically. The MMPs present in the patients tear films before and during doxycycline treatment were analysed zymographically. RESULTS:The quantity of doxycycline detected in the blood plasma samples of patients undergoing treatment ranged from 1.83 to 13.18 microM. Although doxycycline was not detected in their tear samples, the treatment caused the disappearance of the MMPs symptomatic of disease progression. CONCLUSION:The inability to detect doxycycline in the tear film of patients undergoing treatment indicates that doxycycline does not directly inhibit MMP activity or the synthesis/secretion of these proteases and IL-1 from corneal epithelial cells.
    背景与目标: 背景/目的:口服强力霉素,一种广谱抗生素,是一种针对眼表疾病,尤其是酒渣鼻,睑板腺功能障碍和复发性上皮细胞侵蚀的治疗方法。近年来,其治疗这些疾病的功效归因于抑制基质金属蛋白酶(MMP)活性以及MMP和白介素1(IL-1)合成的能力。由于这些功能是浓度依赖性的,因此本项目的目的是确定是否有足够的强力霉素到达泪液膜以在体内发挥这些作用。
    方法:用1-丁醇从眼表疾病患者和健康个体的眼泪和血浆样品中提取强力霉素,并用分光光度法定量。用酶法分析了强力霉素治疗前后患者泪膜中存在的MMP。
    结果:在接受治疗的患者的血浆样本中检测到的强力霉素的含量范围为1.83至13.18 microM。尽管在他们的眼泪样品中未检测到强力霉素,但这种治疗导致疾病进展的MMP消失。
    结论:无法检测接受治疗的患者泪膜中的强力霉素表明,强力霉素不能直接抑制角膜上皮细胞的MMP活性或这些蛋白酶和IL-1的合成/分泌。
  • 【强力霉素的免疫调节作用可改善小鼠多菌性脓毒症模型的全身和肺部炎症。】 复制标题 收藏 收藏
    DOI:10.1007/s10753-020-01188-y 复制DOI
    作者列表:Patel A,Khande H,Periasamy H,Mokale S
    BACKGROUND & AIMS: :Acute lung injury is an inflammatory condition developed after severe sepsis in response to excessive secretion of pro-inflammatory cytokines. Doxycycline is widely reported to possess immunomodulatory activity through inhibition of various inflammatory pathways. Considering the broad spectrum of anti-inflammatory activity, protective effect of doxycycline was evaluated in clinically relevant murine polymicrobial sepsis model induced by caecal ligation and puncture (CLP). In this model, sepsis is accompanied with infection and therefore ceftriaxone at sub-protective dose was combined to retard the bacterial growth. Three hours after CLP challenge, mice were administered vehicle, ceftriaxone (100 mg/kg subcutaneously) alone and in combination with immunomodulatory dose of doxycycline (50 mg/kg, intraperitoneal) and survival were monitored for 5 days. Bacterial count in blood and peritoneal fluid along with cytokines [interleukin (IL)-6, IL-1β, tumour necrosis factor (TNF)-α] and myeloperoxidase (MPO) in plasma and lung homogenate were measured at 18 h post-CLP. Plasma glutathione (GSH) was also determined. Doxycycline in presence of ceftriaxone improved survival of septic mice by significantly reducing the plasma and lung pro-inflammatory cytokines and MPO levels. It also increased plasma GSH levels. Doxycycline did not improve antibacterial effect of ceftriaxone in combination, suggesting that the protective effect of doxycycline was due to its immunomodulatory activity. Doxycycline in the presence of ceftriaxone demonstrated improved survival of septic mice by modulating the immune response.
    背景与目标: :急性肺损伤是严重的脓毒症后,由于促炎性细胞因子的过度分泌而引起的炎性疾病。据报道,强力霉素通过抑制各种炎症途径而具有免疫调节活性。考虑到广谱的抗炎活性,在盲肠结扎和穿刺(CLP)诱导的临床相关鼠类微生物败血症模型中评估了强力霉素的保护作用。在该模型中,败血症伴有感染,因此联合使用次保护剂量的头孢曲松以延缓细菌的生长。 CLP攻击后三小时,对小鼠单独给予媒介物,头孢曲松(皮下注射100 mg / kg),并与强力霉素的免疫调节剂量(50 mg / kg,腹膜内)结合使用,并监测存活5天。在CLP后18小时,测定血浆和肺匀浆中血液和腹膜液中的细菌计数以及细胞因子[白介素(IL)-6,IL-1β,肿瘤坏死因子(TNF)-α]和髓过氧化物酶(MPO)。还测定了血浆谷胱甘肽(GSH)。在存在头孢曲松钠的情况下,强力霉素可通过显着降低血浆和肺部促炎性细胞因子及MPO水平来提高败血症小鼠的存活率。它还增加了血浆谷胱甘肽水平。多西环素并不能改善头孢曲松的抗菌作用,表明多西环素的保护作用是由于其免疫调节活性。在头孢曲松存在的情况下,强力霉素可通过调节免疫应答来提高败血性小鼠的存活率。
  • 【基于TetR阻遏物的生物报告基因,用于使用大肠杆菌和油不动杆菌检测强力霉素。】 复制标题 收藏 收藏
    DOI:10.1007/s00253-014-5566-1 复制DOI
    作者列表:Hong H,Park W
    BACKGROUND & AIMS: :Tetracycline (TC)-sensing bioreporters using green fluorescent protein (GFP) were generated in Escherichia coli and solvent-tolerant Acinetobacter oleivorans. A TC-inducible promoter, tetH promoter, and a TetR repressor of the pAST2 plasmid recovered from sludge were used to construct plasmid-based and chromosome-based bioreporters. Two host plasmids with a broad range, pRK415 and pBBR1MCS2, and three randomly chosen chromosomal sites were used to create the reporter strains. Although the copy numbers of the two plasmids in A. oleivorans were greater than those in E. coli, GFP expression from the tetH promoter and growth under TC were significantly higher in E. coli. Thus, the E. coli bioreporter had higher GFP expression driven by TC, and the two plasmids differed in terms of their sensitivity. Our data reflected mosaic evolution of the constructed plasmids, suggesting that the plasmid replication efficiency and the tetH promoter strength differed in the two different hosts. Among the tested TC compounds, doxycycline (DC) was the most effective in promoting GFP expression. qRT-PCR data confirmed that the expression of the tetH promoter in the original pAST2 plasmid produced the most rapid response to DC. E. coli- and A. oleivorans-based plasmid reporters could detect 5 and 30 nM DC, respectively. Insertion of the GFP reporter into different positions of the A. oleivorans chromosome resulted in variations of GFP expression. Our stable A. oleivorans chromosomal bioreporter was functional in the presence of toxic organic solvents. Furthermore, the field test showed that strain A. oleivorans DR1-Tet1 could act as a sensitive bioreporter in activated sludge for DC detection.
    背景与目标: :使用绿色荧光蛋白(GFP)的四环素(TC)感应生物报告在大肠杆菌和耐溶剂不动油杆菌中产生。从污泥中回收的pAST2质粒的TC诱导型启动子,tetH启动子和TetR阻遏物用于构建基于质粒和基于染色体的生物报告基因。使用两个具有广泛范围的宿主质粒pRK415和pBBR1MCS2,以及三个随机选择的染色体位点来创建报告株。尽管在油曲霉中两个质粒的拷贝数大于在大肠杆菌中的拷贝数,但是在大肠杆菌中,来自tetH启动子的GFP表达和TC下的生长明显更高。因此,大肠杆菌生物报道基因具有较高的由TC驱动的GFP表达,并且两种质粒的敏感性不同。我们的数据反映了构建质粒的镶嵌进化,表明在两个不同宿主中质粒复制效率和tetH启动子强度不同。在测试的TC化合物中,强力霉素(DC)在促进GFP表达方面最有效。 qRT-PCR数据证实,原始pAST2质粒中tetH启动子的表达产生了对DC的最快速反应。基于大肠杆菌和油曲霉的质粒报告子分别可以检测5和30 nM DC。 GFP报告基因插入到油曲霉染色体的不同位置会导致GFP表达的变化。在有毒有机溶剂的存在下,我们稳定的油橄榄曲霉染色体生物报告剂可发挥功能。此外,现场测试表明,油曲霉DR1-Tet1菌株可作为活性污泥中的敏感生物报告物用于DC检测。
  • 【头孢曲松和强力霉素联合或不联合甲硝唑治疗急性盆腔炎的随机对照试验。】 复制标题 收藏 收藏
    DOI:10.1093/cid/ciaa101 复制DOI
    作者列表:Wiesenfeld HC,Meyn LA,Darville T,Macio IS,Hillier SL
    BACKGROUND & AIMS: BACKGROUND:Anaerobic organisms are important pathogens in acute pelvic inflammatory disease (PID). The currently recommended PID regimen of a single dose of ceftriaxone and doxycycline for 14 days has limited anaerobic activity. The need for broader anaerobic coverage is unknown and concerns have been raised about metronidazole tolerability. METHODS:We conducted a randomized, double-blind placebo-controlled trial comparing ceftriaxone 250 mg IM single dose and doxycycline for 14 days, with or without 14 days of metronidazole in women with acute PID. The primary outcome was clinical improvement at 3 days following enrollment. Additional outcomes at 30 days following treatment were the presence of anaerobic organisms in the endometrium, clinical cure (absence of fever and reduction in tenderness), adherence and tolerability. RESULTS:We enrolled 233 women (116 to metronidazole and 117 to placebo). Clinical improvement at 3 days was similar between the two groups. At 30 days following treatment, anaerobic organisms were less frequently recovered from the endometrium in women treated with metronidazole than placebo (8% vs 21%, p<0.05) and cervical Mycoplasma genitalium was reduced (4% vs. 14%, p<0.05). Pelvic tenderness was also less common among women receiving metronidazole (9% vs 20%, p<0.01). Adverse events and adherence were similar in each treatment group. CONCLUSIONS:In women treated for acute PID, the addition of metronidazole to ceftriaxone and doxycycline was well tolerated and resulted in reduced endometrial anaerobes, decreased M. genitalium and reduced pelvic tenderness compared to ceftriaxone and doxycycline. Metronidazole should be routinely added to ceftriaxone and doxycycline for the treatment of women with acute PID.
    背景与目标: 背景:厌氧菌是急性盆腔炎的重要病原体。目前推荐的单剂量头孢曲松和强力霉素的PID治疗方案持续14天,其厌氧活性有限。尚无更广泛的厌氧覆盖范围的需求,人们对甲硝唑的耐受性提出了关注。
    方法:我们进行了一项随机,双盲,安慰剂对照试验,比较了急性PID患者中头孢曲松250 mg IM单剂量和强力霉素14天,有或无14天甲硝唑的情况。主要结果是入选后3天的临床改善。治疗后30天的其他结局是子宫内膜中存在厌氧菌,临床治愈(无发热和压痛减轻),依从性和耐受性。
    结果:我们招募了233名妇女(116名甲硝唑和117名安慰剂)。两组在3天时的临床改善相似。在治疗后30天,甲硝唑治疗的妇女子宫内膜中厌氧菌的恢复率低于安慰剂(8%对21%,p <0.05),生殖器宫颈支原体减少(4%vs. 14%,p <0.05) )。接受甲硝唑的女性盆腔压痛也较少见(9%vs 20%,p <0.01)。每个治疗组的不良事件和依从性相似。
    结论:与头孢曲松钠和强力霉素相比,在接受急性PID治疗的妇女中,对头孢曲松和多西环素添加甲硝唑的耐受性良好,可导致子宫内膜厌氧菌减少,生殖器支原体减少和盆腔压痛。甲硝唑应常规添加到头孢曲松和强力霉素中,以治疗患有急性PID的女性。
  • 【成年Onchocerca贪食虫的自然死亡和强力霉素的杀丝作用诱导了局部FOXP3 / CD4调节性T细胞和颗粒酶的表达。】 复制标题 收藏 收藏
    DOI:10.1016/j.micinf.2007.12.004 复制DOI
    作者列表:Korten S,Badusche M,Büttner DW,Hoerauf A,Brattig N,Fleischer B
    BACKGROUND & AIMS: :Immunosuppression in human filarial disease involves regulatory T cells. We hypothesized that natural or worm antigen-induced FOXP3 regulatory T cells could be involved locally, suppressing effector cells via granzymes. Natural and treatment-induced death of worms implies enhanced exposure to worm antigens. Therefore, we examined FOXP3+T cells and granzyme expression in onchocercomas harbouring adult Onchocerca volvulus worms, with respect to worm viability, productivity, the patient's immune status and filaricidal treatment. The immunohistological analysis revealed that dead adult worms were strongly associated with FOXP3+T cells in generalized hyporeactive onchocerciasis. FOXP3+ cells hardly expressed granzymes, but cell contacts with granzyme A+ or B+ cells were frequent. While suramin directly kills most adult worms within 6 months, the Wolbachia depleting antibiotic doxycycline indirectly causes adult worm degeneration within 18 months. Contrary to suramin, depletion of Th1-driving endobacteria most strongly promoted FOXP3+T cells and granzyme-expressing cells. In hyperreactive patients, FOXP3+ cells were less frequent. This is the first demonstration of local FOXP3+Treg cells in human filariasis and their induction by natural worm death and anti-parasitic treatment. We newly report granzyme responses to helminths and their association with immunosuppression. FOXP3+Treg and granzyme+ cells might locally suppress defence against newly acquired worms.
    背景与目标: 人丝虫病的免疫抑制涉及调节性T细胞。我们假设天然或蠕虫抗原诱导的FOXP3调节性T细胞可能局部参与,通过颗粒酶抑制效应细胞。自然和由治疗引起的蠕虫死亡意味着增加了对蠕虫抗原的暴露。因此,我们就蠕虫的生存能力,生产力,患者的免疫状况和杀螨治疗方面,研究了携带成年Onchocerca volvulus蠕虫的Onchocercomas中的FOXP3 T细胞和颗粒酶的表达。免疫组织学分析表明,死于成虫的蠕虫在广泛的低反应性盘尾丝虫病中与FOXP3 T细胞密切相关。 FOXP3细胞几乎不表达颗粒酶,但是细胞经常与颗粒酶A或B细胞接触。苏拉明可在6个月内直接杀死大多数成虫,而消耗沃尔多巴氏菌的抗生素多西环素会在18个月内间接导致成虫的退化。与苏拉明相反,驱动Th1的内细菌的耗竭最能促进FOXP3 T细胞和表达颗粒酶的细胞。在高反应性患者中,FOXP3细胞的频率较低。这是人类丝虫病中局部FOXP3 Treg细胞的首次展示,并通过自然蠕虫死亡和抗寄生虫治疗诱导它们。我们新近报道了粒酶对蠕虫的反应以及它们与免疫抑制的关系。 FOXP3 Treg和粒酶细胞可能会局部抑制对新获得的蠕虫的防御。
  • 【表达改进的强力霉素调节的逆转录反式激活因子rtTA2S-M2的细胞的生成。】 复制标题 收藏 收藏
    DOI:10.1038/nprot.2006.117 复制DOI
    作者列表:Welman A,Barraclough J,Dive C
    BACKGROUND & AIMS: :Tet-on cell lines engineered to stably express doxycycline (Dox)-regulated reverse transcriptional transactivator (rtTA) have many applications in biomedical research and biotechnology. Unfortunately, construction and maintenance of such cells often proves to be costly, labor intensive and ineffective. Moreover, the Tet-on clones generated using standard methodology were often unstable and frequently displayed significantly changed physiological properties compared with their parental cells. Here we describe an optimized protocol for generation of Tet-on cells. The protocol is based on the use of a recently developed pN1p beta actin-rtTA2S-M2-IRES-EGFP vector (where IRES is an internal ribosome entry site) and permits relatively inexpensive construction of many Tet-on clones with essentially 100% efficiency. The method is well suited for 'difficult' cell lines displaying genetic instability and high levels of epigenetic silencing. The constructed Tet-on cells remain stable with time in the absence of any selection agents, are easy to monitor and preserve the characteristics of parental cells. The protocol can be completed in 2 months.
    背景与目标: :Tet-on细胞系经过工程设计以稳定地表达强力霉素(Dox)调节的逆转录反式激活因子(rtTA),在生物医学研究和生物技术中具有许多应用。不幸的是,这种电池的构造和维护通常被证明是昂贵的,劳动密集型的并且是无效的。此外,与它们的亲代细胞相比,使用标准方法生成的Tet-on克隆通常不稳定,并且经常显示出显着变化的生理特性。在这里,我们描述了生成Tet-on细胞的优化协议。该协议基于最近开发的pN1pβ肌动蛋白-rtTA2S-M2-IRES-EGFP载体(IRES是内部核糖体进入位点)的使用,并允许相对便宜的构建许多Tet-on克隆,效率达到100%。该方法非常适合于显示遗传不稳定性和高水平的表观遗传沉默的“困难”细胞系。所构建的Tet-on细胞在没有任何选择剂的情况下随时间保持稳定,易于监测和保留亲代细胞的特性。该协议可以在2个月内完成。
  • 【一种新的治疗方案与两种常规处方治疗根除幽门螺杆菌的疗效:伊朗患者中强力霉素,共阿莫西拉夫和奥美拉唑的随机,双盲研究。】 复制标题 收藏 收藏
    DOI:10.1007/s10620-008-0374-z 复制DOI
    作者列表:Taghavi SA,Jafari A,Eshraghian A
    BACKGROUND & AIMS: :This study compared a new regimen (group A: doxycycline, co-amoxiclav, omeprazole) and two routinely prescribed regimens (group B: amoxicillin, omeprazole, furazolidone, bismuth; group C: amoxicillin, clarithromycin, omeprazole) to find an acceptable first-line treatment option for Helicobacter pylori. The study population consisted of 189 patients who referred to our clinic to undergo endoscopy due to ulcer-like dyspepsia. The H. pylori eradication rate was 68% in group A, 56% in group B, and 70% in group C according to per-control analysis. There was no statistically significant difference in H. pylori eradication between groups A and B (P = 0.187), groups A and C (P = 0.857), and groups B and C (P = 0.15). In conclusion, although none of the three eradication regimens can be recommended as a first-line eradication treatment, the new regimen is at least as effective and probably better tolerated than the two routinely applied regimens.
    背景与目标: :本研究比较了新方案(A组:多西环素,阿莫西拉夫,奥美拉唑)和两个常规处方方案(B组:阿莫西林,奥美拉唑,呋喃唑酮,铋; C组:阿莫西林,克拉霉素,奥美拉唑),首先找到了可接受的方案幽门螺杆菌的在线治疗选择。研究人群包括189名因溃疡样消化不良而转诊至我们的诊所接受内镜检查的患者。根据对照分析,A组的幽门螺杆菌根除率为68%,B组为56%,C组为70%。 A组和B组(P = 0.187),A组和C组(P = 0.857),B组和C组(P = 0.15)之间的幽门螺杆菌根除没有统计学差异。总之,尽管三种根除方案均不能推荐作为一线根除方案,但新方案至少与两种常规方案一样有效,并且耐受性更好。
  • 【用强力霉素治疗马来布鲁氏菌感染的人,可降低二乙基卡巴马嗪和阿苯达唑治疗后的微丝蛋白血症和不良反应。】 复制标题 收藏 收藏
    DOI:10.1086/586753 复制DOI
    作者列表:Supali T,Djuardi Y,Pfarr KM,Wibowo H,Taylor MJ,Hoerauf A,Houwing-Duistermaat JJ,Yazdanbakhsh M,Sartono E
    BACKGROUND & AIMS: BACKGROUND:The efficacy of doxycycline for treating the causal agent of human lymphatic filariasis, Brugia malayi, is unknown. Standard treatment with diethylcarbamazine-albendazole is associated with adverse reactions. We assessed whether doxycycline alone or in combination with diethylcarbamazine-albendazole would lead to sustained amicrofilaremia and reduced incidence of adverse reactions. METHODS:A double-blind, randomized, placebo-controlled 6-week field trial of doxycycline treatment (100 mg/day) of 161 persons infected with B. malayi was conducted. Four months after receiving doxycycline (n=119) or placebo (n=42), participants received diethylcarbamazine (6 mg/kg) plus albendazole (400 mg) or a matching placebo. Adverse reactions were assessed 48 and 60 h after administration of diethylcarbamazine-albendazole. Treatment efficacy was evaluated at 2, 4, and 12 months after the initial doxycycline treatment. RESULTS:Four months after beginning doxycycline treatment, Wolbachia loads were reduced by 98%. Doxycycline treatment reduced the prevalence of microfilaremia at 2, 4, and 12 months of follow-up (P<.001 for all time points). At the 1-year follow-up, prevalence was reduced by 77% and 87.5% in patients receiving doxycycline alone or doxycycline plus diethylcarbamazine-albendazole, respectively. In contrast, the reduction of microfilaremia in the group receiving placebo doxycycline plus diethylcarbamazine-albendazole was merely 26.7%. Adverse reactions were lowest in the group receiving doxycycline plus placebo diethylcarbamazine-albendazole and highest in the group receiving placebo doxycycline plus diethylcarbamazine-albendazole. The proportion of persons with high fever and severe adverse reactions was significantly reduced in the group treated with doxycycline plus diethylcarbamazine-albendazole. CONCLUSIONS:A 6-week course of doxycycline, either alone or in combination with diethylcarbamazine-albendazole, leads to a decrease in microfilaremia and reduces adverse reactions to antifilarial treatment in B. malayi-infected persons.
    背景与目标: 背景:强力霉素对人类淋巴丝虫病的致病因子马来氏丝瓜病的疗效尚不清楚。二乙基卡巴马嗪-阿苯达唑的标准治疗与不良反应有关。我们评估了多西环素单独使用还是与二乙基卡巴马嗪-阿苯达唑合用会导致持续的微丝血症和不良反应的发生率降低。
    方法:进行了一项双盲,随机,安慰剂对照的为期6周的强力霉素治疗(100毫克/天)的六周野外试验,该试验对161名感染了马来芽孢杆菌的人进行了研究。接受强力霉素(n = 119)或安慰剂(n = 42)四个月后,参与者接受了二乙基卡巴嗪(6 mg / kg)加阿苯达唑(400 mg)或匹配的安慰剂。给予二乙基卡巴嗪-阿苯达唑后48和60小时评估不良反应。在初始多西环素治疗后第2、4和12个月评估治疗效果。
    结果:开始使用强力霉素治疗四个月后,Wolbachia负荷降低了98%。多西环素治疗在随访的2、4和12个月时降低了微丝虫病的发生率(所有时间点P均<.001)。在为期1年的随访中,单独接受强力霉素或强力霉素加二乙基卡巴嗪-阿苯达唑治疗的患者的患病率分别降低了77%和87.5%。相比之下,接受安慰剂多西环素加二乙基卡巴马嗪-阿苯达唑的组中的微丝血症减少仅26.7%。接受多西环素加安慰剂二乙基卡巴马嗪-阿苯达唑组的不良反应最低,接受安慰剂多西环素加二乙基卡巴马嗪-阿苯达唑组的不良反应最高。强力霉素加二乙基卡巴马嗪-阿苯达唑治疗组的高烧和严重不良反应患者的比例显着降低。
    结论:强力霉素的6周疗程,单独或与二乙基卡巴马嗪-阿苯达唑合用,可降低微丝血症,并减少感染马来芽孢杆菌的人的抗丝虫治疗不良反应。
  • 【盐酸多西环素热敏体系的结构和形貌分析。】 复制标题 收藏 收藏
    DOI:10.4103/0250-474x.119807 复制DOI
    作者列表:Phaechamud T,Mahadlek J,Charoenteeraboon J
    BACKGROUND & AIMS: :To characterize the thermal behavior and texture analysis of doxycycline hyclate thermosensitive gels developed for periodontitis treatment containing zinc oxide prepared by using poloxamer (Lutrol(®) F127) as polymeric material and N-methyl pyrrolidone was used as cosolvent. The thermosensitive gel comprising doxycycline hyclate, Lutrol(®) F127, and N-methyl pyrrolidone were characterized for the thermal behavior and texture analysis. The topography of the system after the dissolution test was characterized with scanning electron microscope. Differential scanning calorimetric thermogram exhibited the endothermic peaks in the systems containing high amount of N-methyl pyrrolidone in solvent. The sol-gel transition temperature of the systems decreased as the zinc oxide amount was increased. The addition of doxycycline hyclate, zinc oxide, and N-methyl pyrrolidone affected the syringeability of systems. The addition of zinc oxide into the doxycycline hyclate-Lutrol(®) F127 systems decreased the diameter of inhibition zone against Staphylococcus aureus, Escherichia coli, and Candida albicans since zinc oxide decreased the diffusion and prolonged release of doxycycline hyclate. From scanning electron microscope analysis, the porous surface of 20% w/w Lutrol(®) F127 system was notably different from that of gel comprising doxycycline hyclate which had interconnected pores and smooth surfaces. The number of pores was decreased with increasing zinc oxide and the porous structure was smaller and more compact. Therefore, the addition of zinc oxide could increase the syringeability of doxycycline hyclate-Lutrol(®) F127 system with the temperature dependence. Zinc oxide decreased inhibition zone against test microbes because of prolongation of doxycycline hyclate release and reduced size of continuous cells. Furthermore, zinc oxide also increased the compactness of wall surfaces of Lutrol(®) F127.
    背景与目标: :为了表征开发用于牙周炎治疗的多西环素氢氟酸热敏凝胶的热行为和质构分析,该凝胶含有使用泊洛沙姆(F127)作为聚合材料和N-甲基吡咯烷酮制备的氧化锌。表征了包含多西环素盐酸盐,F127和N-甲基吡咯烷酮的热敏凝胶的热行为和质构分析。溶解测试后系统的形貌用扫描电子显微镜表征。差示扫描量热法热分析图在溶剂中含有大量N-甲基吡咯烷酮的系统中显示出吸热峰。随着氧化锌量的增加,体系的溶胶-凝胶转变温度降低。盐酸多西环素,氧化锌和N-甲基吡咯烷酮的加入影响了系统的可注射性。在多西环素氢酸盐-Lutrol®F127系统中添加氧化锌减小了对金黄色葡萄球菌,大肠杆菌和白色念珠菌的抑制区的直径,因为氧化锌减少了多西环素盐酸盐的扩散并延长了释放时间。从扫描电子显微镜分析来看,20%w / wLutrol®F127系统的多孔表面与包含具有相互连接的孔和光滑表面的多西环丁烷透明酸盐的凝胶的凝胶表面显着不同。孔的数量随着氧化锌的增加而减少,并且多孔结构更小且更致密。因此,添加氧化锌可以增加温度依赖性的盐酸多西环素-Lutrol®F127系统的可注射性。氧化锌减少了对测试微生物的抑制区,这是由于强力霉素盐酸盐释放的延长和连续细胞尺寸的减小。此外,氧化锌还增加了Lutrol®F127的壁表面的致密性。

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