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.

各个年龄段的药物使用量都在增长，导致20%的美国成年人服用五种或更多的药物