Impact of Anticholinergic Medication on Salivary Function; Exploring Potential Genetic Markers for Dry Mouth

抗胆碱能药物对唾液腺功能的影响；

• 批准号: 10283183
• 负责人: Szilvia Arany
• 金额: $ 12.76万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-13 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10283183
• 关键词: Address; Adult; Adverse effects; Affect; Affinity; Age; Alleles; Anti-Cholinergics; Antidepressive Agents; Appointment; Australia; Biological Assay; Blood; CYP2C19 gene; CYP2D6 gene; Chemosensitization; Cholinergic Receptors; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Cytochrome P450; Cytochromes; DNA; Data; Deglutition; Delirium; Dementia; Dental; Dental caries; Development; Drug Prescriptions; Dryness; Dyskinetic syndrome; Elderly; Enzymes; Equipment and supply inventories; Europe; Feeling; Frequencies; Future; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Goals; Gold; Health; Impaired cognition; Impairment; Individual Differences; Infection; Intake; Investigation; Lead; Liver; Mastication; Measurement; Measures; Memory impairment; Metabolic; Minor salivary gland structure; Monitor; Mucous Membrane; Muscarinic Acetylcholine Receptor; Muscarinics; Neurologic; North America; Oral; Oral Health Impact Profile; Oral cavity; Oral health; Organ; Outcome; Parasympathetic Nervous System; Patients; Peripheral; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Polypharmacy; Population; Predisposition; Prevalence; Prevention; Property; Prophylactic treatment; Prospective cohort study; Psychoses; Quality of life; Questionnaires; Randomized; Reporting; Research; Risk; Role; Saliva; Salivary; Salivary Glands; Serum; Severities; Signal Transduction; Spasmolytics; Surveys; Symptoms; Testing; Tooth Loss; Toxic effect; Upper Respiratory Infections; Upper respiratory tract; Variant; Visit; Xerostomia; age effect; aging population; base; cholinergic; clinically relevant; curative treatments; design; double-blind placebo controlled trial; drug metabolism; early screening; genetic variant; genotyped patients; high risk; inter-individual variation; middle age; neuroregulation; neurotransmission; personalized medicine; point of care; point of care testing; prospective; receptor; recruit; risk prediction; saliva secretion; screening; side effect; soft tissue; treatment strategy; urinary

The growing medication use in all ages led to the fact that 20% of the US adult population take five or more drugs (polypharmacy). Over 500 medications commonly prescribed in polypharmacy (e.g., antidepressants, urinary antispasmodics, and psycholeptics) possess anticholinergic (AC) properties blocking the muscarinic signaling of neural regulation. Due to the scattered distribution of muscarinic receptors in the body, AC medications have a wide range of side effects. Besides the most severe central toxicity of cognitive impairment, dyskinesia, and psychosis, which can lead to delirium, the most frequent peripheral side effect is dry mouth. Dry mouth is characterized by reduced saliva secretion (hyposalivation), impaired quality of life by causing chewing or swallowing problems, complaints of oral dryness (xerostomia), speaking difficulties, mucosal changes, increased rate of dental caries, and tooth loss. Dry mouth causes increased susceptibility to bacterial colonization and infections in the oral cavity and the upper respiratory tract. However, no data are available on predicting medication-induced dry mouth severity or determining the AC burden from these medications among dental patients. There is a significant research gap in identifying high-risk xerostomia patients in the middle-aged population before reaching older ages when damage to oral health is irreversible. We designed a prospective cohort study with two aims for addressing these questions. In Aim 1., we will evaluate the correlation between AC burden and dry mouth outcomes, including the flow rates of the minor salivary glands (SG) in 90 middle- aged patients (45-64 years). We will determine whether high AC burden, quantified by the AC drug score (ADS) and serum AC activity (SAA) in blood, is associated with more severe dry mouth symptoms, measured at baseline and follow-ups for two years. We will assess dry mouth using saliva flow rates (unstimulated whole saliva and minor SGs) and oral health measures associated with dry mouth, including xerostomia, dental caries, and oral health impact profile. In this aim, we will examine the feasibility of minor SG flow screening as a point- of-care test for dry mouth. In Aim 2., we will explore whether CYP450 genetic polymorphisms predict dry mouth severity. Recent studies reported an increased prevalence of AC side effects in patients with inactive genetic variants of liver cytochrome P450 enzymes responsible for the metabolic clearance of AC drugs. We will analyze DNA from patients’ blood for the genetic variations of CYP2D6 and CYP2C19 enzymes and compare oral health outcomes associated with dry mouth between poor and normo-metabolizing phenotypes. We propose to study whether dry-mouth pharmacogenetics provides evidence for inter-individual variability in oral health outcomes to identify patients with predictable severity of AC medication-induced dry mouth. The overarching goal of our explorative study is to establish clinically relevant associations between AC burden and oral health outcomes, which can support future investigations of potential causal relationships and risk calculations for dry mouth development.

所有年龄段的药物使用越来越多，这一事实是，美国20％的成年人居民需要五个或更多 药物（多药）。多种药物中通常规定的500多种药物（例如，抗抑郁药， 尿液杂质剂和心理疗法具有抗胆碱能（AC）的特性，阻塞了毒蕈碱 神经调节的信号传导。由于毒蕈碱受体在体内的分布分布，AC 药物具有广泛的副作用。除了认知障碍最严重的中央毒性外， 可能导致del妄的运动障碍和精神病，最常见的外周副作用是口干。 口腔的特征是唾液分泌减少（脱落），通过引起咀嚼而受损的生活质量 或吞咽问题，口腔干燥的抱怨（切除术），说话困难，粘膜变化， 龋齿的速度增加和牙齿脱落。口干会增加对细菌定植的敏感性 和口腔和上呼吸道的感染。但是，没有可预测的数据 药物引起的口干严重程度或确定牙齿中这些药物的AC燃烧 患者。在中年识别高危静脉病患者方面存在显着的研究差距 当口腔健康损害损害时，人口不可逆。我们设计了一个潜在的 队列研究有两个目的解决这些问题。在AIM 1中，我们将评估 AC烧伤和口干的结果，包括90个中间的唾液网格（SG）的流量 老年患者（45-64岁）。我们将确定是否通过交流药物评分（ADS）量化的高AC燃烧是否 血清中血清AC活性（SAA）与更严重的干口症状有关，以在 基线和随访两年。我们将使用唾液流量（未刺激的整体）评估口干 唾液和小型SG）和与口干相关的口腔健康措施，包括静脉，牙齿携带， 和口腔健康影响概况。在此目标中，我们将研究次要SG流量筛选作为一个点的可行性 - 口干的护理测试。在目标2中，我们将探讨CYP450遗传多态性是否预测口干 严重程度。最近的研究报告说，非活性遗传患者AC副作用的患病率增加 肝细胞色素P450酶的变体负责AC药物的代谢清除率。我们将分析 CYP2D6和CYP2C19酶的遗传变异的患者血液中的DNA并比较口腔健康 与较差和正常代谢表型之间的口干有关的结果。我们建议学习 干性药物遗传学是否为口腔健康结果的个体变异性提供证据 鉴定患有可预测的交流药物诱导口干的患者。我们的总体目标 探索性研究是建立AC Burnen和口腔健康结果之间的临床相关关联， 可以支持对潜在因果关系的未来调查和干口干的风险计算 发展。