Oxidative stress in asthma and COPD: Antioxidants as a therapeutic strategy


Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory lung diseases that are characterized by systemic and chronic localized inflammation and oxidative stress. Sources of oxidative stress arise from the increased burden of inhaled oxidants, as well as elevated amounts of reactive oxygen species (ROS) released from inflammatory cells. Increased levels of ROS, either directly or via the formation of lipid peroxidation products, may play a role in enhancing the inflammatory response in both asthma and COPD. Moreover, in COPD it is now recognized as the main pathogenic factor for driving disease progression and increasing severity. ROS and lipid peroxidation products can influence the inflammatory response at many levels through its impact on signal transduction mechanisms, activation of redox-sensitive transcriptions factors, and chromatin regulation resulting in pro-inflammatory gene expression. It is this impact of ROS on chromatin regulation by reducing the activity of the transcriptional co-repressor, histone deacetylase-2 (HDAC-2), that leads to the poor efficacy of corticosteroids in COPD, severe asthma, and smoking asthmatics. Thus, the presence of oxidative stress has important consequences for the pathogenesis, severity, and treatment of asthma and COPD. However, for ROS to have such an impact, it must first overcome a variety of antioxidant defenses. It is likely, therefore, that a combination of antioxidants may be effective in the treatment of asthma and COPD. Various approaches to enhance the lung antioxidant screen and clinical trials of antioxidant compounds are discussed.



Antioxidants and coronary artery disease among individuals with type 1 diabetes: Findings from the Pittsburgh Epidemiology of Diabetes Complications Study


Objective: Oxidative stress has been implicated in the development of diabetes and cardiovascular disease. We evaluated the effect of serum antioxidants and total antioxidant reserve (TAR) on coronary artery disease (CAD) incidence in type 1 diabetes.
Methods: Subjects were identified from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) cohort, a 10-year prospective study of childhoodonset type 1 diabetes. Mean age at baseline was 28 and diabetes duration 19 years. Coronary artery disease was defined as physiciandiagnosed angina, confirmed MI, stenosis z50%, ischemic electrocardiogram (ECG), or revascularization. Controls were gender, age, and diabetes duration (F3 years) matched with cases. Samples and risk factors used in analyses were identified from the earliest exam prior to incidence in cases (54 cases, 67 controls).
Results: None of the antioxidant measures (a-tocopherol, g-tocopherol, retinol, TAR) showed protection against incident CAD overall. However, a protective effect of a-tocopherol against CAD was observed among antioxidant supplement users (HR=0.22, 95% CI=0.10–0.49) and in renal disease (HR=0.46, 95% CI=0.23–0.91). Despite similar a-tocopherol concentration, there was no protective effect among nonusers of antioxidant supplements.
Conclusions: High a-tocopherol levels among patients with renal disease and in those using vitamin supplements were associated with lower CAD risk in type 1 diabetes. The specificity of these effects merits further investigation


Dietary antioxidants in preventing atherogenesis


Several naturally occurring constituents have received considerable attention because of their potential antioxidant activity. Consuming a diet rich in natural antioxidants has been associated with prevention from and/or treatment of atherosclerosis. Bioactive components of food, which are of special interest, include the Vitamins E and C, polyphenols, carotenoids—mainly lycopene and -carotene, and coenzyme Q10, featured by antioxidant properties. Antioxidant therapy is supposed to be effective in the early stages of atherosclerosis by preventing LDL oxidation and the oxidative lesion of endothelium. This reviewfocuses on the effect of dietary antioxidants pertained to LDL oxidation and to the vascular endothelial dysfunction. Now that the human genome has been completely sequenced, genetic factors involved in oxidation may open new horizons to identify persons at risk for cardiovascular disease, allowing effective dietary intervention strategies to recover normal homeostasis and to prevent diet-related implications. On this basis, current studies on the action of selected antioxidant nutraceuticals on the activity of transcription factors, such as final targets in the signal transduction cascade and gene regulation, may emerge into new treatment concepts.


A Randomized Controlled Trial of Antioxidant Supplementation for Pain Relief in Patients With Chronic Pancreatitis


Background & Aims: Oxidative stress has been implicated in the pathophysiology of chronic pancreatitis (CP). We evaluated the effects of antioxidant supplementation on pain relief, oxidative stress, and antioxidant status in patients with CP.
Methods: In a placebo-controlled double blind trial, consecutive patients with CP were randomized to groups that were given placebo or antioxidants for 6 months. The primary outcome measure was pain relief, and secondary outcome measures were analgesic requirements, hospitalization, and markers of oxidative stress (thiobarbituric acid-reactive substances [TBARS]) and antioxidant status (ferric-reducing ability of plasma [FRAP]).
Results: Patients (age 30.5  10.5 years, 86 male, 35 alcoholic, and 92 with idiopathic CP) were assigned to the placebo (n  56) or antioxidant groups (n  71). After 6 months, the reduction in the number of painful days per month was significantly higher in the antioxidant group compared with the placebo group (7.4  6.8 vs 3.2  4, respectively; P < .001; 95% CI, 2.07, 6.23). The reduction in the number of analgesic tablets per month was also higher in the antioxidant group (10.5  11.8 vs 4.4  5.8 respectively; P  .001; 95% CI, 2.65, 9.65). Furthermore, 32% and 13% of patients became pain free in the antioxidant and placebo groups, respectively (P  .009). The reduction in the level of TBARS and increase in FRAP were significantly higher in the antioxidant group compared with the placebo group (TBARS: placebo 1.2  2.7 vs antioxidant 3.5  3.4 nmol/mL; P  .001; 95% CI 0.96, 3.55; FRAP: placebo 5.6  154.9 vs antioxidant 97.8  134.9 MFe2 liberated, P  .001, 95% CI 44.98, 161.7). Conclusions: Antioxidant supplementation was effective in relieving pain and reducing levels of oxidative stress in patients with CP.


A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS


Background: The combination of a small pool of patients at any given time with the availability of many potential neuroprotective agents to be tested in ALS requires efficient phase II trial designs.
Objective: To describe the design of the Clinical Trial of High Dose Coenzyme Q10 (CoQ10) in ALS (QALS study)—a phase II, randomized, placebo-controlled, double-blind, multicenter clinical trial.
Methods: The study design features two stages. The first stage (dose selection) identifies which of two doses of CoQ10 (1800 mg or 2700 mg) is preferred using a selection procedure rather than a formal hypothesis test. The second stage (early efficacy test) compares the preferred dose of CoQ10 against placebo using a non-superiority or futility design. Data from patients assigned to the preferred dose of CoQ10 in the first stage are also used in the second stage. The primary outcome measure is the decline in Amyotrophic Lateral Sclerosis Functional Rating Scale–revised (ALSFRSr) score from baseline to 9 months.
Results: The total sample size required is 185 patients, as compared to a much larger sample size estimated to be necessary using a conventional superiority design (total: 852 patients). The authors report a bias correction made necessary by the inclusion of patient data from the first stage in the second stage.
Conclusions: Several features of the Clinical Trial of High Dose Coenzyme Q10 in ALS study design promote efficiency. These features may be beneficial in phase II trials in amyotrophic lateral sclerosis and other fields.