Effect of Gamma Tocopherol Enriched Supplementation on Response to Inhaled LPS
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- Comparison of Change in Sputum Percent Neutrophils (PMN)s Following Inhaled Clinical Center Reference Endotoxin (CCRE) Challenge as Affected by Gamma Tocopherol
研究概览
简要总结
To test the hypothesis that gamma tocopherol (vitamin E) supplement inhibits endotoxin induced airways inflammation in allergic asthmatics
详细描述
BACKGROUND:
Allergic asthma (AA) is the most commonly encountered respiratory disease in children and adults in the United States and is a leading cause of morbidity worldwide. Among the most disruptive expressions of disease in AA is acute asthma exacerbation. The Center for Disease Control lists ambient air pollutants and environmental tobacco smoke as among the most common triggers for acute asthma exacerbation. Ozone (O3) is the most commonly encountered ambient air pollutant in the US. Endotoxin (or lipopolysaccharide or LPS) is a component of bioaerosols found in both the indoor and outdoor environment, is a component of tobacco smoke, and is increased in indoor settings where smokers live. LPS is also a component of coarse and fine mode particle matter air pollution.
OXIDATIVE STRESS AND ASTHMA:
Increased oxidative stress and decreased antioxidant capability have been observed in asthmatics. These pollutants are pro-inflammatory and are associated with increased oxidative stress, which would exacerbate reactive oxygen and reactive nitrogen species (ROS and RNS)-induced injury in asthmatics. O3 injures epithelial cells, releasing secondary mediators which activate inflammatory cells, in part by ligation of Toll-Like Receptor 4 (TLR4), the primary receptor for LPS. TLR4 activation of inflammatory cells activates Nuclear Factor-kB (NF-kB) and induces oxidative stress. O3 and LPS has been associated with exacerbation of asthma, and we have reported that O3 and LPS augments allergic airway inflammation in allergic asthmatics (AA). Development of interventions to mitigate these responses will greatly decrease disease morbidity.
Given the role that oxidants play in the pathophysiology of asthma exacerbation, defects in antioxidant levels would increase risk for acute asthma exacerbation. Nutritional deficiencies in vitamin E, ascorbate and selenium have been linked to asthma severity, and asthmatics have decreased antioxidant levels in airway fluid. We and others have shown that vitamins C and E are decreased in airway fluids of asthmatics. Additionally, genetic factors may increase risk for oxidant induced exacerbation of asthma. Many investigators have reported that persons who are homozygous for the null polymorphism of the Glutathione-S-Transferase Mu1 (GSTM1) gene and unable to produce GSTM1 protein (the GSTM1 null genotype) have increased risk of acute pollutant-induced exacerbation of asthma. We have shown in healthy volunteers that the GSTM1 null genotype is associated with increased inflammatory response to O3, with no impact on the nociceptive response to this pollutant. We have also shown that GSTM1 null volunteers have enhanced airway and systemic inflammation following LPS challenge.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-50 of both genders
- •Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy
- •History of episodic wheezing, chest tightness, or shortness of breath consistent with asthma, or physician diagnosed asthma.
- •Positive methacholine test. A positive test is defined as a provocative concentration of methacholine of 10 mg/ml or less producing a 20% fall in Forced Expiratory Volume in 1 second (FEV1) (PC20 methacholine) by the method used in a separate screening protocol.
- •FEV1 of at least 80% of predicted and FEV1/FVC ratio of at least .70 (without use of bronchodilating medications for 12 hours or long acting beta agonists for 24 hours), consistent with lung function of persons with no more than mild episodic or mild persistent asthma.
- •Allergic sensitization to at least one of the following allergen preparations: (House Dust Mite f, House dust mite p, Cockroach, Tree mix, Grass Mix, Weed Mix, Mold Mix 1, Mold Mix 2, Rat, Mouse, Guinea Pig, Rabbit, Cat or Dog) confirmed by positive immediate skin test response.
- •Symptom Score (this will be submitted as an attachment) no greater than 16 (out of a possible 24) for total symptom score with a value no greater than 3 for any one score. No more than one score may be greater or equal than
- •subjects must be willing to avoid caffeine for 12 hours prior to all visits.
排除标准
- •Any chronic medical condition considered by the PI as a contraindication to the exposure study including significant cardiovascular disease, diabetes, chronic renal disease, chronic thyroid disease, history of chronic infections/immunodeficiency, history of tuberculosis
- •Physician directed emergency treatment for an asthma exacerbation within the preceding 12 months
- •Moderate or Severe asthma
- •Exacerbation of asthma more than 2x/week which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma.
- •Daily requirement for albuterol due to asthma symptoms (cough, wheeze, chest tightness) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current National Heart, Lung and Blood Institute (NHLBI) guidelines for diagnosis and management of asthma. (Not to include prophylactic use of albuterol prior to exercise).
- •Viral upper respiratory tract infection within 2 weeks of challenge.
- •Any acute infection requiring antibiotics within 2 weeks of exposure or fever of unknown origin within 2 weeks of challenge.
- •Severe asthma
- •Mental illness or history of drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements.
- •Medications which may impact the results of the Clinical Center Reference Endotoxin (CCRE) exposure, interfere with any other medications potentially used in the study (to include steroids, beta antagonists, non-steroidal anti-inflammatory agents)
- •Any history of smoking in the year prior to study enrollment; lifetime smoking history > 10 pack years
- •Nighttime symptoms of cough or wheeze greater than 1x/week at baseline (not during a clearly recognized viral induced asthma exacerbation) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma
- •Allergy/sensitivity to study drugs, including E coli, or their formulations.
- •Known hypersensitivity to methacholine or to other parasympathomimetic agents
- •History of intubation for asthma
- •Unwillingness to use reliable contraception if sexually active (Intrauterine device, birth control pills/patch, condoms).
- •Abnormal Prothrombin Time (PT) or Partial Thromboplastin Time (PTT) values at screening or during the treatment period. Normal values will be those published by the clinical lab (Labcorp, INC).
- •Any bleeding disorder
- •Radiation exposure history will be collected. Subjects whose exposure history within the past twelve months would cause them to exceed their annual limits will be excluded.
研究组 & 干预措施
700 mg Gamma Tocopherol daily x 14days
Gamma Tocopherol supplement
干预措施: Gamma Tocopherol 700 mg capsules, (Drug)
Placebo
Safflower oil capsules
干预措施: Placebo (Drug)
结局指标
主要结局
Comparison of Change in Sputum Percent Neutrophils (PMN)s Following Inhaled Clinical Center Reference Endotoxin (CCRE) Challenge as Affected by Gamma Tocopherol
时间窗: after 14 days of gamma tocopherol or placebo treatment
In asthmatic individuals, exposure to CCRE is expected to increase PMNs in the sputum. The sputum PMNs were measured at baseline (immediately prior to dosing) and again on day 14 of treatment (approximately 8 hours after the final dose) with placebo or gamma tocopherol. The outcome is to compare the change in PMNs from baseline to post treatment after exposure to CCRE
次要结局
- Chronic Eosinophilic Airway Inflammation as Affected by Gamma Tocopherol(after 14 days of gamma tocopherol or placebo treatment)
- Mucociliary Clearance (MCC) Associated With CCRE Challenge as Affected by Gamma Tocopherol(after 14 days of gamma tocopherol or placebo treatment)
- Mucociliary Clearance as Affected by Gamma Tocopherol(after 11 days of gamma tocopherol or placebo treatment)