An Enzyme-Based Antidote for Acute Nicotine Toxicity
一种基于酶的急性尼古丁中毒解毒剂
基本信息
- 批准号:10790758
- 负责人:
- 金额:$ 27.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-30 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:5 year oldAccident and Emergency departmentAccidentsAcetylcholineActivated CharcoalAcuteAddressAdrenergic AntagonistsAdultAffinityAgonistAnimal ModelAntibodiesAntidotesAttenuatedAutonomic ganglionBenzodiazepinesBindingBiodistributionBiologicalBiological AssayBloodBlood PressureBradycardiaBrainBrain regionBuffersCandyCarbonCessation of lifeChildChildhoodCholinergic ReceptorsChronicClinical ResearchClinical TrialsComaComplexConsumptionDirected Molecular EvolutionDoseDrug KineticsDyspneaElectronic cigaretteEngineeringEnzymesEvolutionExposure toFailureFatal OutcomeFruitGastric LavageGene LibraryGenerationsGenesGenetic RecombinationGoalsHalf-LifeHandHeart RateHourHypotensionImmunologicsIn SituInformation SystemsIngestionInterventionLibrariesMarketingMeasuresMechanical ventilationMentholMetabolismModelingMonoclonal AntibodiesMuscleMutagenesisNeuromuscular JunctionNeuronsNicotineNicotinic ReceptorsNitrogenOral IngestionOverdoseOxidoreductasePatientsPeripheralPharmaceutical PreparationsPharmacodynamicsPlethysmographyPoisonPoisoningPopulationPositioning AttributePseudomonas putidaPublishingReportingRespiratory FailureRiskRodentRodent ModelSalesSeizuresSerumSigns and SymptomsSiteSocietiesSourceStructureSupportive careSystemTherapeuticTobaccoToxic effectTreatment ProtocolsUncertaintyVaccinesVariantVulnerable Populationsaspiratecardiovascular collapsecholinergiccombustible cigaretteefficacy evaluationelectronic cigarette useelectronic liquidexperimental studyimprovedliquid nicotinemouse modelmutantnerve agentneuralnicotine cessationnicotine exposurenicotine oxidasenicotine usenicotine vaccineorganophosphate poisoningpharmacologicplacebo grouppre-clinicalreceptorrespiratoryresponsesmoking abstinencesmoking cessationtherapeutic enzymethermostabilitytobacco products
项目摘要
Project Summary/Abstract. Electronic cigarettes are gaining popularity as alternative to traditional cigarettes,
with sales increasing from $283 million in 2012 to $2.5 billion in 2018 in the US. The global e-cigarette market is
estimated to reach $24.2 billion by 2024. E-cigarette solutions, also known as e-liquids, are highly variable with
enticing flavors, such as tobacco, menthol, fruit, candy, and dessert. Liquid nicotine concentrations vary in these
products from 0 to 100 mg/ml according to an FDA study. Although nicotine toxicity in adults is rare with an
estimated lethal dose between 60 and 500 mg (0.8-6.7 mg/kg), flavored e-liquids are increasingly being ingested
orally, putting children at risk for exposure to high concentrations of nicotine. Indeed, nicotine toxicity in children
under 5 years of age can occur with consumption of as little as a teaspoon of liquid nicotine. The unforeseen
consequences of e-cigarettes, with respect to nicotine poisoning in children, presents an unmet need to
counteract the harmful and potentially fatal outcomes that may occur among this vulnerable population. It is the
pediatric population we plan to address in this proposal, as a high potential of accidental ingestion of liquid
nicotine from e-cigarettes exists. Despite the increase in nicotine-related poisonings reported, there is no
treatment for acute nicotine toxicity. Current treatment regimens for nicotine poisoning range from supportive
care, to activated charcoal, to respiratory support with mechanical ventilation. An alternative means of altering
the toxicity of nicotine poisoning could come via simple sequestering of the drug. Antibodies to nicotine have
been prepared as a means to block the pharmacological effects of this drug. To date, vaccines for smoking
cessation have shown promise in preclinical animal models; however, in clinical studies, these vaccines failed
to measure significant differences in smoking abstinence between the intervention and placebo groups. Thus,
the likelihood of an antibody attenuating an acute dose of nicotine is doubtful. What is needed is a sufficient
pharmacokinetic (PK) biologic with the capacity to not just sequester nicotine but also increase its metabolism.
We envision a biologic able to catabolize nicotine rather than simply sequestering the drug would have the
potential to treat acute nicotine poisoning. The proposal at hand details a bacterial strain, Pseudomonas putida,
which has evolved to use nicotine as its sole source of carbon and nitrogen. From this bacterial strain, we will
examine a first-in-class enzyme, a nicotine oxidoreductase termed NicA2, as a means to treat nicotine poisoning.
Our initial characterization of the enzyme indicates that it could be an excellent candidate for altering nicotine
poisoning. However, the successful demonstration of this enzyme reversing nicotine poisoning will require
several experimental undertakings including: (1) Evaluating the efficacy of NicA2 to attenuate acute nicotine
toxicity in rodent models including plethysmography, blood/brain distribution and lethality. (2) Directed evolution
of NicA2 to increase its catalytic capacity through gene recombination and random mutagenesis.
项目总结/抽象。电子烟作为传统香烟的替代品越来越受欢迎,
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)
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Kim Janda其他文献
Kim Janda的其他文献
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{{ truncateString('Kim Janda', 18)}}的其他基金
Discovering modulators of exonucleases PLD3 and PLD4 for immunoregulation
发现用于免疫调节的核酸外切酶 PLD3 和 PLD4 调节剂
- 批准号:
10620110 - 财政年份:2022
- 资助金额:
$ 27.15万 - 项目类别:
Discovering modulators of exonucleases PLD3 and PLD4 for immunoregulation
发现用于免疫调节的核酸外切酶 PLD3 和 PLD4 调节剂
- 批准号:
10353980 - 财政年份:2022
- 资助金额:
$ 27.15万 - 项目类别:
High-Throughput Screen for the Oncoprotein MYC
癌蛋白 MYC 的高通量筛选
- 批准号:
10276232 - 财政年份:2021
- 资助金额:
$ 27.15万 - 项目类别:
High-Throughput Screen for the Oncoprotein MYC
癌蛋白 MYC 的高通量筛选
- 批准号:
10657663 - 财政年份:2021
- 资助金额:
$ 27.15万 - 项目类别:
High-Throughput Screen for the Oncoprotein MYC
癌蛋白 MYC 的高通量筛选
- 批准号:
10436377 - 财政年份:2021
- 资助金额:
$ 27.15万 - 项目类别:
Covalent Inhibition as a Method to Counteract Botulinum Intoxication
共价抑制作为对抗肉毒杆菌中毒的方法
- 批准号:
10177867 - 财政年份:2020
- 资助金额:
$ 27.15万 - 项目类别:
Covalent Inhibition as a Method to Counteract Botulinum Intoxication
共价抑制作为对抗肉毒杆菌中毒的方法
- 批准号:
10408004 - 财政年份:2020
- 资助金额:
$ 27.15万 - 项目类别:
Covalent Inhibition as a Method to Counteract Botulinum Intoxication
共价抑制作为对抗肉毒杆菌中毒的方法
- 批准号:
10034607 - 财政年份:2020
- 资助金额:
$ 27.15万 - 项目类别:
Covalent Inhibition as a Method to Counteract Botulinum Intoxication
共价抑制作为对抗肉毒杆菌中毒的方法
- 批准号:
10624958 - 财政年份:2020
- 资助金额:
$ 27.15万 - 项目类别:
"PRODUCTION AND DISTRIBUTION OF INVESTIGATIONAL GHRELIN VACCINES-- GHRELIN VACCINES AGAINST RAT HORMONE". TASK ORDER 5. 09/21/2019-12/31/2020.
“研究性生长素释放肽疫苗的生产和分销——针对大鼠激素的生长素释放肽疫苗”。
- 批准号:
10037792 - 财政年份:2019
- 资助金额:
$ 27.15万 - 项目类别:














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