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量不断增加，导致 20% 的美国成年人服用 5 种或更多药物 药物（复方药物）。复方用药中常用的超过 500 种药物（例如抗抑郁药、 泌尿解痉药和精神抑制药）具有抗胆碱能（AC）特性，可阻断毒蕈碱 神经调节信号传导。由于毒蕈碱受体在体内分散分布，AC 药物有多种副作用。除了最严重的认知障碍中枢毒性外， 运动障碍和精神病，可导致谵妄，最常见的外周副作用是口干。干燥 口腔的特点是唾液分泌减少（唾液分泌不足），咀嚼导致生活质量受损 或吞咽问题、口腔干燥（口干症）、说话困难、粘膜变化的主诉， 龋齿率增加，牙齿脱落。口干会增加细菌定植的可能性 以及口腔和上呼吸道感染。然而，没有可用的数据来预测 药物引起的口干严重程度或确定牙科中这些药物的 AC 负担 患者。在识别中年高危口干症患者方面存在显着的研究差距 在达到老年之前，口腔健康的损害是不可逆转的。我们设计了一个前瞻性的 队列研究有两个目的来解决这些问题。在目标 1. 中，我们将评估之间的相关性 AC 负担和口干结果，包括 90 名中小唾液腺 (SG) 的流量 老年患者（45-64 岁）。我们将确定是否存在高 AC 负担，通过 AC 药物评分 (ADS) 进行量化 和血液中的血清AC活性（SAA），与更严重的口干症状相关，测量时间为 基线和随访两年。我们将使用唾液流速（未刺激的整体唾液流量）评估口干。 唾液和轻微的 SG）以及与口干相关的口腔健康措施，包括口干症、龋齿、 和口腔健康影响概况。为此，我们将研究小型 SG 流量筛选的可行性—— 口干的护理测试。在目标 2.中，我们将探讨 CYP450 基因多态性是否预测口干 严重程度。最近的研究报告显示，在基因不活跃的患者中，AC 副作用的发生率增加 负责 AC 药物代谢清除的肝细胞色素 P450 酶的变体。我们将分析 患者血液中的 DNA 检测 CYP2D6 和 CYP2C19 酶的遗传变异并比较口腔健康状况 代谢不良和正常代谢表型之间与口干相关的结果。我们建议学习 口干药物遗传学是否为口腔健康结果的个体间差异提供了证据 识别 AC 药物引起的口干严重程度可预测的患者。我们的总体目标 探索性研究旨在建立 AC 负担与口腔健康结果之间的临床相关关联， 这可以支持未来对口干的潜在因果关系的调查和风险计算 发展。