Does perfluorocarbon attenuate the severity of SAH by limiting vasospasm and improving tissue oxygenation?
全氟化碳是否可以通过限制血管痉挛和改善组织氧合来减轻 SAH 的严重程度?
基本信息
- 批准号:10604708
- 负责人:
- 金额:$ 22.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-15 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcuteAffectAftercareAirAir EmbolismAnatomyAreaAttenuatedBloodBlood VesselsBlood capillariesBlood flowBrainBrain InjuriesBrain PathologyBrain hemorrhageBrain regionCaliberCerebral IschemiaCerebrovascular CirculationCerebrovascular SpasmCerebrumClinicalCoagulation ProcessComplexCritical CareDataDevelopmentDiffuseDoseDrug KineticsDrug usageEarly InterventionElementsEmulsionsEndotheliumErythrocytesFemaleFluorocarbonsFunctional disorderFutureGasesGoalsHalf-LifeHemoglobinHourHumanHuman ResourcesHyperbaric OxygenImpairmentIschemic StrokeLeadLipidsLiquid substanceMethodsMitochondriaModelingMolecularMonitorMusNutrientOutcomeOxidative StressOxygenOxygentPartial PressureParticle SizePathologicPathologyPatient CarePatientsPercussionPerforationPharmacodynamicsPlasmaPlayReportingResearchResearch PersonnelResidual stateResolutionRiskRodent ModelRoleSafetySeveritiesSolubilityStriated MusclesSubarachnoid HemorrhageSupportive careTestingTherapeuticTherapeutic InterventionTimeTissue SampleTissuesTrainingTranslatingVasospasmarteriolebasecare providerscell motilitycerebral oxygenationdrug candidatedrug repurposingefficacy testingflexibilityfunctional outcomeshuman dataimprovedmalemitochondrial dysfunctionmortalityneuropathologynoveloptimal treatmentsparticlepre-clinicalpreclinical trialpressurepreventprimary outcometherapeutically effectivetissue oxygenationtreatment strategy
项目摘要
Subarachnoid hemorrhage (SAH) is one of the deadliest of hemorrhagic stroke types; however, no effective
therapeutic intervention is yet available, other than supportive care. Vasospasm is reported to trigger within the
first three days after the onset of SAH and sustain for 1-2 weeks. The vasospasm results in delayed cerebral
ischemia (DCI) which is considered as the main cause of mortality after SAH. Since vasospasm leads to a
decrease in O2 level in the affected regions of the brain, novel methods to supply O2 to the compromised brain
region could play a critical role in salvaging the area at risk.
Hyperbaric oxygen/air therapy may have a beneficial effect in decreasing the pathophysiology of SAH by
increasing dissolved tissue O2. However, such treatment is complex, time-limited (a few hours at a time),
extensive monitoring, and trained personnel. Therefore, here we propose perfluorocarbon (PFC)-based
emulsion Oxygent (referred to as PFC-Oxygent onwards), which increases dissolved O2 in blood and tissue.
PFC-Oxygent is reported to have an extended half-life of about 3d. PFCs are emulsified compounds that can
carry and release O2 fundamentally differently than does the hemoglobin. The particle size of these emulsions
allows for PFCs to get to places where red blood cells are blocked such as capillaries affected in SAH.
In a model of striated muscle and cerebral air embolism, we have shown that PFC-Oxygent increased cerebral
blood flow and delivered O2 to the affected area even with little or no red cell movement. Moreover, in preclinical
TBI, we showed that PFC-Oxygent augments cerebral O2 level. These data indicate the therapeutic potential of
PFC-Oxygent in an acute cerebral pathology and its potential efficacy in SAH where cerebral vasospasm plays
a vital role in the progression of pathological and functional outcomes. Since PFC is well tolerated in humans
and the safety profile of this compound has already been tested, it is a prime candidate for drug repurposing.
Here, we are testing the hypothesis that PFC-Oxygent treatment after SAH can increase O2 delivery to the
compromised area after the SAH, attenuate oxidative stress, and improve pathological/functional outcomes.
Aim 1: To test whether PFC rescues functional outcomes and neuropathology after SAH. This aim will test the
effect of PFC-Oxygent on functional and anatomical outcomes after SAH in young and old male and female
mice.
Aim 2: To test whether PFC improves tissue oxygenation and cerebral blood flow following SAH. In this aim, we
will test whether PFC improves local/global cerebral oxygenation, tissue sampled mitochondrial activity, and
reduces oxidative stress after SAH.
The proposed study will collectively provide the robustness of the therapeutic potential of this clinically used drug
in SAH. Because most of the pharmacokinetics, pharmacodynamics, and safety of PFC-Oxygent is known,
repurposing of this drug in regulating SAH outcomes would be expedited and of high translational value.
蛛网膜下腔出血(SAH)是最致命的出血性中风类型之一;然而,没有有效的
除了支持性护理外,目前还可以进行治疗性干预。据报道,血管痉挛是在
在SAH发作后的前三天,并持续1-2周。脑血管痉挛导致大脑
脑缺血(DCI)是SAH后死亡的主要原因。由于血管痉挛导致
大脑受影响区域的O2水平下降,为受损大脑提供O2的新方法
该区域可以在拯救处于危险中的地区方面发挥关键作用。
高压氧/空气治疗可能通过以下方式在减少SAH的病理生理学方面具有有益效果:
增加溶解的组织O2。然而,这种治疗是复杂的,有时间限制的(一次几个小时),
广泛的监测和训练有素的人员。因此,在这里,我们提出了基于全氟化碳(PFC)的
乳剂Oxygent(以后称为PFC Oxygent),可增加血液和组织中的溶解O2。
据报告,PFC-Oxygent具有约3天的延长半衰期。PFC是乳化化合物,
携带和释放氧气的方式与血红蛋白完全不同。这些乳剂的颗粒大小
允许PFC到达红细胞被阻塞的地方,如SAH中受影响的毛细血管。
在横纹肌和脑空气栓塞模型中,我们已经证明PFC-Oxygent增加了脑动脉栓塞,
即使红细胞很少或没有移动,血液流动和输送O2到受影响的区域。此外,在临床前
TBI,我们发现PFC-Oxygent增加了大脑O2水平。这些数据表明,
PFC-Oxygent在急性脑病理学中的作用及其在脑血管痉挛起作用的SAH中的潜在疗效
在病理和功能结果的进展中起重要作用。由于PFC在人类中耐受良好
这种化合物的安全性已经过测试,它是药物再利用的主要候选者。
在这里,我们正在测试的假设,即PFC氧合治疗后SAH可以增加O2输送到
SAH后受损区域,减弱氧化应激,并改善病理/功能结果。
目的1:测试PFC是否挽救SAH后的功能结局和神经病理学。这一目标将考验
PFC-氧合剂对青年和老年男女蛛网膜下腔出血后功能和解剖结果影响
小鼠
目的2:检测PFC是否改善SAH后的组织氧合和脑血流量。为此,我们
将测试PFC是否改善局部/整体脑氧合,组织采样线粒体活性,
减少SAH后的氧化应激。
拟定研究将共同提供该临床使用药物治疗潜力的稳健性
在SAH。因为PFC-Oxygent的大部分药代动力学、药效学和安全性是已知的,
这种药物在调节SAH结果中的再利用将被加速并且具有高转化价值。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Abdullah S Ahmad其他文献
Abdullah S Ahmad的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Abdullah S Ahmad', 18)}}的其他基金
Does perfluorocarbon attenuate the severity of SAH by limiting vasospasm and improving tissue oxygenation?
全氟化碳是否可以通过限制血管痉挛和改善组织氧合来减轻 SAH 的严重程度?
- 批准号:
10288921 - 财政年份:2021
- 资助金额:
$ 22.8万 - 项目类别:
相似海外基金
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 22.8万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 22.8万 - 项目类别:
Collaborative R&D
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 22.8万 - 项目类别:
Fellowship
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 22.8万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 22.8万 - 项目类别:
Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 22.8万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 22.8万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 22.8万 - 项目类别:
Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 22.8万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Acute human gingivitis systems biology
人类急性牙龈炎系统生物学
- 批准号:
484000 - 财政年份:2023
- 资助金额:
$ 22.8万 - 项目类别:
Operating Grants














{{item.name}}会员




