The Role of Acetazolamide in Mitigating Inflammation and Innate Immune Activation at High Altitude: a Randomized Cross-over Controlled Trial
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 19
- 试验地点
- 1
- 主要终点
- Distributions of circulating immune cell subsets.
研究概览
简要总结
High altitude travel can lead to inflammation in the body and activation of innate immune cells. The investigators' prior research demonstrates that 1 to 3 days at 3800 m elevation leads to increased expression of genes in blood cells that code for proteins that signal cell damage (damage associated molecular patterns (DAMPs)), cell receptors involved in innate immune responses, as well as increases in monocyte and neutrophil cells which promote inflammation. This study will investigate the potential mechanisms underlying these effects using the drug Acetazolamide, a carbonic anhydrase inhibitor which is known to reduce symptoms of Acute Mountain Sickness.
详细描述
The primary research goal is to investigate the mechanisms underlying the pro-inflammatory response we observe at high altitude. The investigators believe that hypoxemia is a primary driver of this inflammatory response. High altitude exposure causes both chronic sustained hypoxemia due to reduced atmospheric oxygen availability, as well as concomitant nocturnal intermittent hypoxia on top of reduced baseline arterial oxygen pressures. Each of these hypoxic stressors may be drivers of pro-inflammatory responses. To determine if this is the case, ACZ will be used to improve oxygenation (SpO2) and ameliorate sleep disordered breathing at high altitude, thereby reducing the impacts of these factors on the immune response to high altitude.
As a secondary outcome, the study will determine if the anti-inflammatory properties of ACZ may play a key role in modulating AMS symptoms independent of ventilatory stimulation. This may reveal novel mechanisms of action of ACZ, but it is not the primary goal of this study.
The investigators hypothesize that (1) hypoxemia (both daytime chronic sustained hypoxia and noctournal intermittent hypoxia) is an independent driver of innate immune activation and pro-inflammatory responses at high altitude, and that (2) ACZ improves AMS symptoms, in part, by reducing systemic hypoxia-induced inflammation and reducing the activation of innate immune cells (monocytes and neutrophils). This hypothesis will be tested with the following experimental aims: (Aim 1) Determine if ACZ treatment during high altitude exposure blunts plasma inflammatory cytokine expression and levels of circulating pro-inflammatory innate immune cell subsets; (Aim 2) Determine if ACZ treatment during high altitude exposure modulates immune cell function (innate inflammatory responses to bacterial and viral stimuli, cell migration, and bacterial killing efficacy).
To test these hypotheses, this study utilizes a placebo controlled double-blind study design. Participants are prospectively assigned to either placebo or Acetazolamide treatment groups. Acetazolamide is prescribed at 125 mg per dose, taken twice per day starting 2 days before ascent and continuing for 3 days at high altitude.
Prior to ascent, participants complete baseline testing at low altitude. Testing includes collection of basic physiological parameters including height, weight, blood pressure, ECG, lung function testing by spirometry, and collection of self-reported medical history.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Individuals completing statistical analyses will be blinded to participant treatments. Treatment distributions are developed and maintained by a pharmacy team who prepare treatments for participants. Pharmacy team personnel provide a physician team member with the coded treatment orders for prescription and distribution to participants.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Between ages 18 and 65
- •No history of cardiovascular or pulmonary disease (previously diagnosed or indicated by EKG, spirometry, and other medical history)
- •No history of high altitude pulmonary or cerebral edema (HAPE or HACE)
- •No history of obstructive or central sleep apnea
- •No current use of anti-inflammatory medication, steroids, stimulants, or other agents that may interfere with ventilatory chemosensitivity
- •No current pregnancy
- •No travel above 8,000 feet elevation within 1 month of the first measures
- •Non-smokers (including any type of vape use, marijuana usage)
- •No current or recently treated systemic or serious local infection
- •Must be fluent in the English language
- •Participants must refrain from consuming alcohol for at least 1 week prior to the start of the study, throughout the duration of their participation, and for 2 days prior to their follow-up visits.
- •Caffeine and other stimulants may not be consumed during the course of participation in the high-altitude portion of the study (including 12 hours before sea level baseline measures, then starting 2 days before ascent and ending upon return to sea level).
- •Strenuous physical activity including hiking to higher elevations is not permitted during the high altitude portion of the study.
排除标准
- 未提供
研究组 & 干预措施
Placebo Treatment
This group will not be provided ACZ. Instead, participants will take a placebo compound in pill form resembling ACZ on the same schedule as the ACZ treatment.
干预措施: Placebo Arm (Device)
Acetazolamide treatment
Acetazolamide is administered orally in pill form at a 125 mg dose taken twice per day (morning and evening) starting 2 days before ascent to high altitude and each day while at high altitude.
干预措施: ACETAZOLAMIDE oral capsule (Drug)
结局指标
主要结局
Distributions of circulating immune cell subsets.
时间窗: From enrollment to 30 days following return from high altitude (approximately 1.5 months total).
Distributions of peripheral leukocyte subsets in peripheral blood will be quantified at each timepoint of exposure (sea level before ascent, days 1-3 at high altitude, and days 7 and 30 following return to sea level) and in each treatment condition (placebo and ACZ). Blood samples will be collected in the morning immediately following waking, while fasting. Cell distributions will be determined via flow cytometry.
Functional characteristics of peripheral immune cells.
时间窗: From enrollment to 2 years after completion of sample collection.
Peripheral blood mononuclear cells (PBMCs) will be collected at each timepoint for each participant. Cells will be isolated and cryopreserved immediately following blood collection. Cells will then be transported to the laboratory at UC Riverside if collected in the field. To determine the inflammatory reactivity and sensitivity of PBMCs at each timepoint, we will culture these cells in the presence or absence of bacterial (lipopolysaccharide, LPS) and viral stimuli (R848) and measure the concentration of inflammatory cytokines (TNFa) produced by the cells as a result of this stimuli.
次要结局
- Expression of inflammatory biomarkers in peripheral blood(From enrollment to 2 years after completion of sample collection.)
- Acute Mountain Sickness(From enrollment to 2 years following sample collection.)
- Hypoxic ventilatory response(From enrollment to 2 years after data collection.)
- Hypercapnic ventilatory response(From enrollment to 2 years after data collection)
- Minute ventilation at rest(From enrollment to 2 years after data collection)
研究者
Erica Heinrich, PhD
Assistant Professor, Biomedical Science
University of California, Riverside