Sleep Breath
DOI 10.1007/s11325-016-1367-3
SLEEP BREATHING PHYSIOLOGY AND DISORDERS • REVIEW
Evaluation of oxidative stress markers in obstructive sleep apnea
syndrome and additional antioxidant therapy: a review article
Amanda Bastos Lira 1 & Célio Fernando de Sousa Rodrigues 2
Received: 8 December 2015 / Revised: 5 March 2016 / Accepted: 25 May 2016
# Springer-Verlag Berlin Heidelberg 2016
Abstract
Purpose The hypoxia and reoxygenation cycles in obstructive
sleep apnea syndrome (OSAS) cause a change in the oxidative
balance, leading to the formation of reactive oxygen species
capable of reacting with other organic molecules impairing
their functions. This study aimed to determine the best
markers of oxidative stress in OSAS and what better antioxi-
dant agent to be used to treat the disease.
Methods Searches were conducted in three different databases
(PubMed, LILACS, SCIELO), using as descriptors the terms
obstructive sleep apnea, oxidative stress, and antioxidant ther-
apy. A total of 120 articles were found but only those consid-
ered of interest to the research were selected. Thus, 10 articles
were included for further analysis regarding the biomarkers of
oxidative stress in OSAS, and 6 articles to evaluate the anti-
oxidant most often used for demonstration of efficacy.
Results The thioredoxin, malondialdehyde, superoxide
dysmutase, and reduced iron were the most commonly used
biomarkers and showed a more consistent relationship be-
tween increased oxidative stress and OSAS. As antioxidant
therapy, vitamin C and N-acetylcysteine (NAC) presented in-
teresting results as a reduction of oxidative stress, which may
become an alternative to the complementary treatment of
OSAS.
Conclusions This review’s findings agree mostly to measure that
the markers of oxidative stress in OSAS may be a contributing
* Amanda Bastos Lira
ablira@hotmail.com
1
Medical Sleep and ENT of Santa Casa Hospital, Professora Hígia
Vasconcelos street, 193, Ponta verde, Maceió, Alagoas 57035-140,
Brazil
2
University of Alagoas/Brazil, Maceió, Alagoas, Brazil
aspect to assessment and monitoring of patient, and the antioxi-
dant therapy appears to be beneficial in the treatment of OSAS.
Keywords Obstructive sleep apnea . Oxidative stress .
Markers . Antioxidant therapy
Introduction
The obstructive sleep apnea syndrome (OSAS) is the most
common form of breathing-related sleep disorder. It is a
chronic disease characterized by recurrent episodes of partial
or total obstruction of the upper airway during sleep (obstruc-
tive respiratory events), and it is considered a major cause of
morbidity and mortality. This decrease in air flow causes an
alveolar hypoventilation with oxyhemoglobin desaturation,
and prolonged cases, the increase of carbon dioxide (PaCO2)
[1]. The intermittent hypoxia stimulates arterial chemorecep-
tors (carotid receptors), which increase sympathetic nervous
system activity that affect vascular reactivity dilation and con-
striction, contributing to the formation of free radicals that are
highly reactive chemical molecules that react with nucleic
acids, proteins, and lipids, altering cellular metabolism and
causing cell damage [2].
The hypoxia and reoxygenation cycles cause a
change in oxidative balance, leading to an increase in
free radicals [2]. This oxidative stress is defined there-
fore as an imbalance between the production of oxygen
free radicals and antioxidant capacity, which can be
measured through the measurement of several bio-
markers [3, 4]. The reactive species of oxygen atoms
are able to react with free amino groups in proteins,
impairing their function and causing changes in their
i m m u n o g e n i c i t y, a n d t h i s i s o n e o f t h e m a i n

mechanisms responsible for the development of cardio-
vascular complications in OSAS [3].
Intermittent hypoxia is also able to predispose the activa-
tion of pro-inflammatory factors with production of cytokines
such as tumor necrosis factor and interleukins 6 and 8, which
are involved in the pathogenesis of atherosclerosis and high
blood pressure. So OSAS is considered an independent risk
factor for the onset or worsening of hypertension [5, 6] and
possibly even hypercholesterolemia [7], with no correlation,
however, between blood pressure and cholesterol levels with
disease severity [8].
There are few studies in the literature showing the ex-
cess of reactive oxygen species in OSAS [4], and antiox-
idant therapy can be implemented as a complementary
treatment of illness [5]. But there is no agreement among
authors about which markers should be measured and
whether there is any relationship between oxidative stress
and disease severity [4], as well as about what antioxi-
dants can be used to reduce the harmful oxidative effects
of OSAS [5].
This review was performed to determine the best
markers of oxidative stress in OSAS and what the main
antioxidant agent to be used as adjuvant treatment of
disease.
Methods
Data extraction
The data extraction was done by two independent researchers.
If the results were different, a third researcher would be invited
but it was not necessary because there was always agreement
between the two. Searches were conducted in three different
databases (PubMed, LILACS, SCIELO) during the months of
August and September 2015. It was used as descriptors the
terms Bobstructive sleep apnea^, Boxidative stress^ and
Bantioxidant therapy^, using the following strategies:
Bobstructive sleep apnoea^[All Fields] OR Bsleep apnea,
obstructive^[MeSH Terms] OR (Bsleep^[All Fields] AND
Bapnea^[All Fields] AND Bobstructive^[All Fields]) OR
Bobstructive sleep apnea^[All Fields] OR (Bobstructive^[All
Fields] AND Bsleep^[All Fields] AND Bapnea^[All Fields])
AND (Boxidative stress^[MeSH Terms] OR (Boxidative^[All
Fields] AND Bstress^[All Fields]) OR Boxidative stress^[All
Fields]) AND (Bantioxidants^[Pharmacological Action] OR
Bantioxidants^[MeSH Terms] OR Bantioxidants^[All Fields]
OR Bantioxidant^[All Fields]) AND (Btherapy^[Subheading]
OR Btherapy^[All Fields] OR Btherapeutics^[MeSH Terms]
OR Btherapeutics^[All Fields]). Then, a total of 120 articles
were found wherein readings of titles and abstracts were made
to select the articles for reading the full text.
Sleep Breath
Eligible studies
Searchers were considered eligible for this study if they ful-
filled all of the following criteria: (1) studies in humans over
18 years old with a diagnosis of OSAS according to the
American Academy of Sleep Medicine diagnostic criteria [9]
(Table 1) or in experimental models of OSAS in animals; (2)
they have been made dosages of blood biomarkers of oxida-
tive stress; and (3) agents with proven antioxidant effects have
been administered as a single treatment. Unpublished studies
or/and those not meeting the above criteria were not included.
Thus, 10 articles were selected for detailed analysis with
respect to oxidative stress markers in OSAS, and 6 articles to
assess the antioxidant most often used with demonstration of
its effectiveness for complementary treatment of the disease.
Each reviewer held readings of articles 16 independently,
and then the results were compared. There was agreement
among reviewers with respect to the main results of the arti-
cles, but it was not possible to perform meta-analysis due to
heterogeneity of the variables.
Results and discussion
The pathogenesis of oxidative stress in OSAS is one of the most
challenging hypotheses for sleep researchers. Oxidative stress
has been proposed to represent paradigms to cardiovascular mor-
bidity in these patients, and associate it with organic metabolic
disorders. A relationship between lipid peroxidation, intima, and
Table 1 The diagnosis of OSAS in adults requires the presence of the
criteria described in this table according to the American Academy of
Sleep Medicine, 2005
Criteria: A + B + D or C + D:
A. At least one of the following criteria
- Episodes of unintended sleep during waking, daytime sleepiness
excessive, non-restorative sleep, fatigue or insomnia
- Agree with pauses in breathing, gagging or choking
- Companion (a) reports loud snoring and/or breathing pauses during
sleep
B. Polysomnography featuring
- Five or more detectable respiratory events (apneas and/or hypopneas
and/or awakening related to respiratory effort) per hour sleep
- Evidence of respiratory effort for all or part of each event
C. Polysomnography featuring
- Fifteen or more detectable respiratory events (apneas and/or hypopneas
and/or awakening related to respiratory effort) per hour sleep
- Evidence of respiratory effort for all or part of each event
D. The disorder cannot be better accounted for by another disorder sleep,
medical or neurological diseases, use of medications or use of
substances
Source: The international classification of sleep disorders: Diagnostic and
coding manual. Westchester: American Academy of Sleep Medicine [9]
Sleep Breath

media carotid thickness and intermittent hypoxia in non-obese Table 2 Results of the research on markers of oxidative stress in OSAS
patients with OSAS has been reported, suggesting that oxidative Research about the Positive results on stress Negative results on stress
stress might be involved in the atherosclerotic process, contrib- oxidative balance increase oxidative increase oxidative
uting to the progression of cardiovascular disease. Therefore, markers in OSAS
some studies have evaluated the relationship between oxidative
Volná J, Kemlink D, High sensitivity C-
stress and OSAS. Most of them suggest a relationship between Kalousová M reactive protein
the increase in this stress and disease, including its severity. On et al. (2011) (hsCRP) levels, metal-
the other hand, there are conflicting studies and there is no con- loproteinase 9 and
copper (p < 0.001)
sensus among the authors that OSAS increases the organic oxi- Guo Q, Wang Y, Li Thioredoxin (p < 0.05)
dative stress. Another conflicting aspect is there is no agreement QY et al. (2012)
among researchers regarding the markers to be measured to as- Takahashi K, Chin Thioredoxin (p = 0.02)
K, Nakamura H
sess the oxidative balance and antioxidant capacity. et al. (2008)
Ntalapascha M, Glutathione levels, 8-
Biomarkers of oxidative stress in OSAS Makris D, isoprostane, reactive
Kyparos A et al. substances barbiturate
(2012) acid, catalase activity
In the study of Volna et al. [10], the oxidative stress markers and the copper-zinc
that were evaluated in OSAS were high sensitivity C-reactive superoxide dysmutase
(SOD) (p > 0.05)
protein (hsCRP), metalloproteinases 2 and 9, soluble receptors
Alzoghaibi MA, Superoxide dysmutase
of the final advanced glycation end products (sRAGE) in ad- Bahammam SA (SOD) activity and
dition to copper and plasma zinc comparing their concentra- (2005) concentrations of
tions with the apnea-hypopnea index (AHI), desaturation in- products of lipid
peroxidation
dex of oxyhemoglobin and oxygen saturation time below (0.29 ± 0.015 vs
90 %. There was a strong correlation between the rise in 0.31 ± 0.01 U/mL, and
hsCRP levels, metalloproteinase 9 and copper with increasing 4.64 ± 0.57 vs
4.62 ± 0.54 mmol/mL,
both the AHI and with oxyhemoglobin desaturation index and respectively)
decrease in oxygen saturation, suggesting to the authors there Cofta S, Wysocka E, SOD and
is evidence of increased oxidative stress in OSAS, especially Piorunek T et al. malondialdehyde
(2008) (p < 0.05)
in obese patients (Table 2). Jordan W, Cohrs S, Malondialdehyde
Guo Q et al. [11] evaluated the thioredoxin levels (TRX) as Degner D et al. (p < 0.0005)
the severity of OSAS and found that the increase in concen- (2006)
Mancuso M, Reduced iron (FRAP)
trations of this marker was proportional to the increase in AHI Bonanni E, (p < 0.0001)
and the fall of the O2 saturation, suggesting that the TRX is an LoGerfo A et al.
important marker indicator of the severity of OSAS (TRX and (2012)
Simiakakis M, Reduced iron (FRAP)
AHI, r = 0.313, p < 0.05; TRX and O2 saturation, r = 0.266, Kapsimalis F, (p < 0.004)
p < 0.037). These findings were similar to those reported by Chaligiannis E
Takahashi et al. [12] in that assayed plasma levels of et al. (2012)
Katsoulis K, Serum total antioxidant
thioredoxin in patients with severe OSAS before and after
Kontakiotis T, status (TAS) (p < 0.01)
treatment with CPAP, with a significant increase of this marker Spanogiannis D
in patients with severe OSA compared to untreated controls et al. (2011)
(p = 0.02), and that after 1 month of treatment with CPAP,
there was a significant decrease in their concentrations
(p = 0.03). Thus, these authors also concluded that thioredoxin
might be a marker used to assess oxidative stress in OSAS and substance barbiturate acid by SOD activity and concentrations
to monitor the effectiveness of treatment (Table 2). of products of lipid peroxidation, there was no significant
Negative results however have been obtained by difference between patients with OSAS and control
Ntalapascha et al. [13] when evaluated as a marker of oxida- (0.29 ± 0.015 vs 0.31 ± 0.01 U/mL, and 4.64 ± 0.57 vs
tive stress in OSAS glutathione levels, 8-isoprostane, reactive 4.62 ± 0.54 mmol/mL, respectively). Therefore, these authors
substances barbiturate acid, catalase activity, and the copper- did not agree that OSAS is associated with increased oxidative
zinc superoxide dysmutase (SOD), with no significant corre- stress and decreased antioxidant defenses (Table 2).
lation between these markers, AHI, and oxyhemoglobin Cofta et al. [4] studied some markers of oxidative stress in
desaturation index compared to controls (p > 0.05). Also in different stages of the severity of OSAS, including SOD and
the study of Alzoghaibi and Bahammam [14], where oxidative the products of plasma lipid peroxidation, by measuring the
stress was observed from the quantification of a reactive concentration of substances reactive to barbituric acid

(TBARS), the malondialdehyde, one of these leading prod-
ucts. A significant decrease in SOD occurred in patients with
the disease, especially those of mild to moderate severity,
when purchased to control (p < 0.05 for all groups), while
there was a significant increase in TBARS levels, mainly
malondialdehyde, with increasing severity of OSAS
(p < 0.05 for all groups) including correlating it with the du-
ration of O2 desaturation below 85 %. The authors concluded
that oxidative stress increases in accordance with increasing
severity of OSAS, and the blood doses of SOD and
malondialdehyde can contribute to monitor the oxidative bal-
ance in these patients. There was an agreement of these find-
ings with those of Jordan W et al. [15] in which the related
increased malondialdehyde levels of O2 desaturation time
were below 85 % (p < 0.0005). Mancuso et al. [16] were also
favorable to dosing oxidative stress markers, as what is found
in his research that the more severe is the OSAS, the greater
the loss of antioxidant capacity of the patient, mainly through
a significant lowering of the antioxidant power of reduced iron
(FRAP) in OSAS patients than in control
(0.548 ± 0.097 mmol/l vs 0.794 ± 0.182 mmol/l,
p < 0.0001). There was also a significant correlation between
AHI and FRAP (r = −0.410, p < 0.01), suggesting that patients
have high AHI, have severe OSA and thus have a further
decreased antioxidant capacity. Smiakakis et al. [17] also
found a significant decrease in antioxidant capacity, through
the fall of the concentration of reduced iron, in OSAS patients
compared to controls (p < 0.004), the most important predic-
tors of variation of oxidative stress, obesity, gender, and
smoking. Oxidative balance was also observed by Katsoulis
K et al. [18] by measuring the serum total antioxidant status
(TAS) in 32 OSAS patients without comorbidities, before and
after the use of CPAP, with a significant improvement of ox-
idative stress after treatment (p < 0.01) (Table 2).
Antioxidant treatment in OSAS
There are few studies on the use of an antioxidant agent as a
treatment of OSAS in an attempt to minimize the effects of
oxidative stress. One of them, with very interesting results,
was the Sadasivam et al. [19] study, who used N-
acetylcysteine (NAC) 600 mg administered orally three times
a day for 30 days. The NAC is a substance necessary for the
synthesis of glutathione and seems to have better antioxidant
effects compared to other agents, not only fight free radical O2
but also contribute to the formation of glutathione, a powerful
antioxidant organic. In addition, NAC is often prescribed for
the treatment of diseases associated with a systemic inflam-
mation. Oxidative stress and antioxidant capacity were
assessed using measures of lipid peroxidation, which de-
creased significantly in patients treated compared to control
(p < 0.001), and glutathione, whose levels also increased with
significance in patients but not in control (p < 0.001). The
Sleep Breath
authors also observed that in patients treated with NAC, there
was an improvement as the sleep parameters (architecture and
sleep efficiency, respiratory behavior, and snoring), and that
the use of NAC as an antioxidant agent for a period of 1 month,
produce good effects in individuals with OSAS and its use
may reduce the pressure used in the CPAP gradually (Table 3).
Grebe M et al. [20] used as antioxidant vitamin C admin-
istered intravenously because of the improvements that it pro-
vides the endothelial function of various diseases associated
with increased oxidative stress including diabetes mellitus,
hypercholesterolemia, essential hypertension and heart fail-
ure, reducing the circulating quantity of the species reactive
O2, restoring the levels of nitric oxide and thus restoring vas-
cular balance. Researchers assessed, by ultrasound means, the
extent of brachial artery flow before and after administration
of vitamin C. The brachial artery flow is a well-established
marker of endothelial function, and it can be evaluated by
measuring the artery diameter in response to increased flow
for 3 min, observed an increase in this flow in patients treated
OSAS and not in controls (p < 0.01). The authors concluded
then that vitamin C also enhances vascular function in OSAS
and therefore could be included as an antioxidant therapy in
the treatment of disease (Table 3).
There is some research linking antioxidant therapy in ani-
mal models subjected to intermittent hypoxia to simulate the
effects of OSAS. Thus, Inamoto S et al. [21] studied the ef-
fects of pitavastatin as an antioxidant agent in preventing the
damages induced by hypoxia on the left cardiac ventricle of
nude mice hypercholesterolemia by assessing myocardial pa-
rameters. The animals subjected to intermittent hypoxia of 8 h
per day for 10 consecutive days showed hypertrophy of
cardiomyocytes, perivascular fibrosis and histological degen-
eration, as well as increased levels of inflammatory cytokines
such as TNF-α and TNF-β. After treatment with pitavastatin,
there was a significant decrease in these cytokines (p < 0.01),
the diameter of cardiomyocytes and perivascular fibrosis
(p < 0.01), illustrating a significant improvement in cardiac
function and may therefore be used for the removal, at least
partially, of both the oxidative stress and inflammation.
Another antioxidant also tested on rats in the same year by
Williams AL et al. [22] was allopurinol, being an inhibitor of
xanthine oxidase, an enzyme that reacts with free radicals. The
group of rats treated with allopurinol showed decreased lipid
peroxidation (p < 0.05) and improved cardiac function
(p < 0.05) when compared to control (Table 3).
Celec P et al. [3] evaluated the effects of vitamins C and E
in an experimental model of OSAS in rats through intermittent
hypoxia by obstruction of the trachea, being anesthetized an-
imals. To evaluate the oxidative balance, levels of
malondialdehyde and advanced products of protein oxidation
were measured. No significant differences were found be-
tween the groups with and without treatment compared to
malondialdehyde. In the protein products of the oxidation,
Sleep Breath
Table 3 Research with favorable
results with the use of an Research about an antioxidant agent for use in OSAS’ treatment
antioxidant in the treatment of
OSAS Sadasivam K, Patial K, Vijayan VK et al. (2011)
Grebe M, Eisele HJ, Weissmann N et al. (2006)
Inamoto S, Yoshioka T, Yamashita C et al. (2010)
Williams AL, Chen L, Scharf SM (2010)
Celec P, Jurkovicová I, Buchta R et al. (2013)
Macrea M, Martin T, Zagrean L et al. (2013)
there was a statistically significant difference between the
groups (p < 0.05). Those treated with vitamins C and E
showed a lower concentration of these products, indicating
that the use of these antioxidant vitamins can be beneficial,
contributing to the reduction of oxidative stress in OSAS, and
consequently about its effects in the pathogenesis of cardio-
vascular complications. Also in 2012, Macrea M et al. [23]
investigated the role of leptin as an antioxidant in OSAS
through an in vitro study using paramagnetic resonance. The
levels of leptin are altered in OSAS patients as an attempt to
fight free radicals O 2, through the activation of SOD.
Solutions containing leptin administered nasally or by periph-
eral puncture are safe and efficient. This study demonstrated
that leptin was associated with a significant decrease in the
activity of these free radicals (p < 0.0003), and a potential
antioxidant and can also be used as marker of oxidative stress
and atherosclerosis risk in OSAS (Table 3).
Conclusions
This review’s findings agree mostly to measure that the
markers of oxidative stress in OSAS may be a contributing
aspect to assessment and monitoring of patients, both with
respect to severity of the disease and the effectiveness of ther-
apy. Among the most commonly used markers and showed
that a more consistent relationship between increased oxida-
tive stress and OSAS were thioredoxin, malondialdehyde, su-
peroxide dysmutase, and reduced iron. The first two markers
present in OSAS higher levels than in unaffected individuals,
whereas for the last two, there is a decrease in their concen-
trations, revealing a reduction of antioxidant capacity in pa-
tients with OSAS.
The antioxidant therapy appears to be beneficial in
the treatment of OSAS. However, there are few both
experimental and human studies demonstrating its posi-
tive effect and they used different antioxidants, making
it difficult to establish which the best antioxidant agent
is. Vitamin C and NAC, however, showed interesting
results as a reduction of oxidative stress and have very
low risk of any complications, can become an alterna-
tive to the complementary treatment of OSAS,
Antioxidants with favorable results
N-Acetylcysteine (NAC) (p < 0.001)
Vitamin C (p < 0.01)
Pitavastatin (p < 0.01)
Allopurinol (p < 0.05)
Vitamins C and E (p < 0.05)
Leptin (p < 0.0003)
especially in patients with low adherence to CPAP or
who need high pressure in the unit.
Acknowledgments The authors would like to thank the University of
Alagoas/Brazil.
Compliance with ethical standards
Ethical approval For this type of study, formal consent is not required.
Conflicts of interest The authors declare that they have no competing
interests.
Funding No founding was received for this research.
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