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.

各个年龄段不断增长的用药导致20%的美国成年人服用五次或更多的药物 药品(综合药房)。在综合药房中通常开出的500多种药物(例如，抗抑郁药， 尿解痉挛药和精神分裂症药)具有阻断毒扁豆碱的抗胆碱能(AC)特性 神经调节的信号。由于M受体在体内的分散分布，AC 药物有广泛的副作用。除了认知障碍最严重的中枢毒性外， 运动障碍和精神错乱可导致神志不清，最常见的外周副作用是口干。干的 口腔的特点是唾液分泌减少(唾液分泌减少)，因咀嚼而影响生活质量。 或吞咽困难，口腔干燥(口干)，说话困难，粘膜改变， 龋齿和牙齿脱落的比率增加。口干会增加细菌定植的易感性 以及口腔和上呼吸道的感染。然而，目前还没有关于预测的数据 药物引起的口腔干燥严重程度或决定这些药物在牙科中的AC负荷 病人。在识别中年口干症高危患者方面存在显著的研究空白 在对口腔健康的损害不可逆转的情况下，人口在达到老年之前。我们设计了一个未来的 队列研究有两个目的来解决这些问题。在目标1中，我们将评估两者之间的相关性 AC负荷和口干结局，包括90例中老年人小涎腺(SG)的流率。 老年患者(45岁-)。我们将通过AC药物评分(ADS)来确定高AC负荷 和血液中的AC活性(SAA)，与更严重的口干症状有关，在 基线和两年的随访。我们将使用唾液流率(未刺激的整体)来评估口干 唾液和轻微SGS)和与口干有关的口腔健康措施，包括口干症、龋齿、 和口腔健康影响概况。在这个目标中，我们将研究作为一个点的小SG流量筛选的可行性- 口腔干燥的护理测试。在目标2中，我们将探索细胞色素P450基因多态是否预示口干 严肃性。最近的研究报道，遗传不活跃的患者AC副作用的发生率增加 肝脏细胞色素P450酶的变体负责AC药物的代谢清除。我们将分析 口腔健康患者外周血中细胞色素P450酶D6和C19酶基因变异的研究 低代谢表型和正常代谢表型之间的结果与口干有关。我们建议研究 口干药物遗传学是否提供了口腔健康结果个体间差异的证据 确定AC药物所致口干的严重程度可预测的患者。我们的首要目标是 探索性研究旨在建立AC负荷与口腔健康结局之间的临床相关性。 这可以支持未来对口干的潜在因果关系和风险计算的调查 发展。