Mechanisms of risk for sulfoniamide hypersensitivity

磺酰胺过敏的风险机制

基本信息

  • 批准号:
    8321113
  • 负责人:
  • 金额:
    $ 28.6万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-04-15 至 2016-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): "Mechanisms of risk for sulfonamide hypersensitivity" Hypersensitivity (HS) to potentiated sulfonamide antibiotics is one of the most common idiosyncratic adverse drug reactions, affecting about 3% of the general population, and up to 50-60% of HIV-infected patients. Sulfamethoxazole (SMX), in combination with trimethoprim (TMP), can lead to fever, skin rash and multi-organ toxicity, and is the leading cause of life-threatening bullous skin eruptions in human patients. A better understanding of the mechanisms of risk in both immunocompetent and HIV-infected patients is needed to better predict and prevent these reactions. This is particularly important in light of the widespread use of these antimicrobials fo infection prophylaxis in immunocompromised patients, as well as their renewed use for methicillin-resistant Staph. aureus infections. Specific aim 1a will focus on genetic risk of sulfonamide HS in immunocompetent patients, which appears to be familial, using a two-stage GWAS design with tolerant patients as controls. Specific aim 1b will focus on the observation that peripheral blood mononuclear leukocytes (PBMCs) from HS patients are more susceptible to toxicity from sulfonamide metabolites compared to drug tolerant patients. Understanding the mechanism(s) for this surrogate marker may provide insight into the mechanisms of risk for systemic drug hypersensitivity. This subaim will identify differentially expressed transcripts in PBMCs from carefully phenotyped sulfonamide HS versus tolerant patients, and confirm the mechanistic significance of candidate transcripts by determining the effects of knock-down or over-expression on the cytotoxicity from sulfonamide metabolites in lymphoid cells. Together, these studies will characterize genetic risk for sulfonamide HS patients on both the genomic and transcriptional levels. In Aim 2, we will explore acquired risk factors for sulfonamide HS in HIV infection, using an SIV infection model in rhesus macaques. Baseline data, to include antioxidant and cytokine profiles, in vitro cytotoxicity assays, and liver and leukocyte expression profiles, will be obtained, followed by oral administration of a therapeutic dosage of TMP-SMX. Primary outcomes will include development of serum drug adducts, drug specific T cells, and toxicologic signs consistent with sulfonamide HS, along with baseline predictors for these outcomes. The goal of these aims is to better understand the genetic and acquired risk factors for sulfonamide drug hypersensitivity, so that better predictive and preventative measures can be developed. The ultimate goal is to improve the safety of this inexpensive antimicrobial for both the general population and for HIV-infected patients. PUBLIC HEALTH RELEVANCE: The potentiated sulfonamide antimicrobial, sulfamethoxazole with trimethoprim, is one of the most common causes of drug hypersensitivity reactions, to include fever and pruritic skin rash. Idiosyncratic sulfonamide drug hypersensitivity reactions are difficult to predict, but appear to have a genetic predisposition in the general population, with a acquired risk that is much higher in HIV-infected patients. The overall goals of the proposed studies are to identify genetic risk factors for sulfonamide hypersensitivity in the general population, and to characterize the reasons for the high incidence of these reactions in HIV-infected patients, so that we can develop better ways to predict and prevent these adverse drug reactions. !
描述(由申请人提供):“磺酰胺过敏的风险机制” 对强化磺酰胺抗生素的过敏 (HS) 是最常见的特殊药物不良反应之一,影响约 3% 的普通人群,以及高达 50-60% 的 HIV 感染患者。磺胺甲恶唑 (SMX) 与甲氧苄啶 (TMP) 合用可导致发烧、皮疹和多器官毒性,是危及生命的主要原因 人类患者的大疱性皮疹。需要更好地了解免疫功能正常的患者和艾滋病毒感染者的风险机制,以更好地预测和预防这些反应。鉴于这些抗菌药物在免疫功能低下患者中广泛用于预防感染,以及它们重新用于耐甲氧西林葡萄球菌,这一点尤其重要。金黄色葡萄球菌感染。 具体目标 1a 将重点关注免疫功能正常的患者中磺胺类 HS 的遗传风险,这似乎是家族性的,使用两阶段 GWAS 设计,以耐受患者作为对照。具体目标 1b 将重点观察与耐药患者相比,HS 患者的外周血单核白细胞 (PBMC) 更容易受到磺酰胺代谢物毒性的影响。了解该替代标记的机制可以深入了解全身药物过敏的风险机制。该子目标将鉴定来自仔细表型磺酰胺 HS 与耐受患者的 PBMC 中差异表达的转录本,并通过确定敲低或过度表达对淋巴细胞中磺酰胺代谢物的细胞毒性的影响来确认候选转录本的机制意义。总之,这些研究将在基因组和转录水平上描述磺胺类热射病患者的遗传风险。 在目标 2 中,我们将使用恒河猴 SIV 感染模型,探讨 HIV 感染中磺酰胺 HS 的获得性危险因素。基线数据,包括抗氧化剂和细胞因子谱、体外细胞毒性测定以及肝脏和白细胞表达 获得谱图,然后口服治疗剂量的 TMP-SMX。主要结果将包括血清药物加合物、药物特异性 T 细胞和与磺胺 HS 一致的毒理学体征的发展,以及这些结果的基线预测因子。 这些目的的目的是更好地了解磺酰胺药物过敏的遗传和获得性危险因素,以便制定更好的预测和预防措施。最终目标是提高这种廉价抗菌药物对普通人群和艾滋病毒感染者的安全性。 公共卫生相关性:强效磺酰胺类抗菌剂磺胺甲恶唑与甲氧苄啶联用是药物过敏反应的最常见原因之一,包括发烧和瘙痒性皮疹。特异质磺胺类药物过敏反应是 很难预测,但似乎在普通人群中具有遗传倾向,艾滋病毒感染者的获得性风险要高得多。拟议研究的总体目标是确定一般人群中磺胺类药物过敏的遗传危险因素,并描述HIV感染者中这些反应高发的原因,以便我们能够开发出更好的方法来预测和预防这些药物不良反应。 !

项目成果

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LAUREN A TREPANIER其他文献

LAUREN A TREPANIER的其他文献

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{{ truncateString('LAUREN A TREPANIER', 18)}}的其他基金

Translational Research Workforce Training: Leveraging the Veterinary Specialist
转化研究人员培训:利用兽医专家
  • 批准号:
    10475602
  • 财政年份:
    2019
  • 资助金额:
    $ 28.6万
  • 项目类别:
Translational Research Workforce Training: Leveraging the Veterinary Specialist
转化研究人员培训:利用兽医专家
  • 批准号:
    10221789
  • 财政年份:
    2019
  • 资助金额:
    $ 28.6万
  • 项目类别:
Translational Research Workforce Training: Leveraging the Veterinary Specialist
转化研究人员培训:利用兽医专家
  • 批准号:
    9813826
  • 财政年份:
    2019
  • 资助金额:
    $ 28.6万
  • 项目类别:
Mechanisms of risk for sulfoniamide hypersensitivity
磺酰胺过敏的风险机制
  • 批准号:
    8912831
  • 财政年份:
    2012
  • 资助金额:
    $ 28.6万
  • 项目类别:
Mechanisms of risk for sulfoniamide hypersensitivity
磺酰胺过敏的风险机制
  • 批准号:
    8794443
  • 财政年份:
    2012
  • 资助金额:
    $ 28.6万
  • 项目类别:
Mechanisms of risk for sulfoniamide hypersensitivity
磺酰胺过敏的风险机制
  • 批准号:
    8458509
  • 财政年份:
    2012
  • 资助金额:
    $ 28.6万
  • 项目类别:
Mechanisms of risk for sulfoniamide hypersensitivity
磺酰胺过敏的风险机制
  • 批准号:
    8604164
  • 财政年份:
    2012
  • 资助金额:
    $ 28.6万
  • 项目类别:
Nitogen reduction and xenobiotic response
氮减少和外源性反应
  • 批准号:
    8052011
  • 财政年份:
    2010
  • 资助金额:
    $ 28.6万
  • 项目类别:
ROLE OF HYDROXYLAMINE REDUCTION IN DRUG HYPERSENSITIVITY
羟胺减少在药物过敏中的作用
  • 批准号:
    6387221
  • 财政年份:
    2000
  • 资助金额:
    $ 28.6万
  • 项目类别:
ROLE OF HYDROXYLAMINE REDUCTION IN DRUG HYPERSENSITIVITY
羟胺减少在药物过敏中的作用
  • 批准号:
    6636498
  • 财政年份:
    2000
  • 资助金额:
    $ 28.6万
  • 项目类别:

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